FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Pecor, ND Li, N Allard, M Li, C Albano, E Delaney, M Dubois, A Onderdonk, AB Bry, L AF Pecor, Nicole D. Li, Ning Allard, Marc Li, Cong Albano, Esperanza Delaney, Mary Dubois, Andrea Onderdonk, Andrew B. Bry, Lynn TI Genomically Informed Surveillance for Carbapenem-Resistant Enterobacteriaceae in a Health Care System SO MBIO LA English DT Article ID MONITORING ANTIMICROBIAL RESISTANCE; KLEBSIELLA-PNEUMONIAE STRAINS; COMPLETE NUCLEOTIDE-SEQUENCE; BETA-LACTAM RESISTANCE; GENE-MUTATIONS; NEW-JERSEY; PLASMIDS; CLOACAE; HOSPITALS; EPIDEMIOLOGY AB Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent public health concern. Rapid identification of the resistance genes, their mobilization capacity, and strains carrying them is essential to direct hospital resources to prevent spread and improve patient outcomes. Whole-genome sequencing allows refined tracking of both chromosomal traits and associated mobile genetic elements that harbor resistance genes. To enhance surveillance of CREs, clinical isolates with phenotypic resistance to carbapenem antibiotics underwent whole-genome sequencing. Analysis of 41 isolates of Klebsiella pneumoniae and Enterobacter cloacae, collected over a 3-year period, identified K. pneumoniae carbapenemase (KPC) genes encoding KPC-2, -3, and -4 and OXA-48 carbapenemases. All occurred within transposons, including multiple Tn4401 transposon isoforms, embedded within more than 10 distinct plasmids representing incompatibility (Inc) groups IncR, -N, -A/C, -H, and -X. Using short-read sequencing, draft maps were generated of new KPC-carrying vectors, several of which were derivatives of the IncN plasmid pBK31551. Two strains also had Tn4401 chromosomal insertions. Integrated analyses of plasmid profiles and chromosomal single-nucleotide polymorphism (SNP) profiles refined the strain patterns and provided a baseline hospital mobilome to facilitate analysis of new isolates. When incorporated with patient epidemiological data, the findings identified limited outbreaks against a broader 3-year period of sporadic external entry of many different strains and resistance vectors into the hospital. These findings highlight the utility of genomic analyses in internal and external surveillance efforts to stem the transmission of drug-resistant strains within and across health care institutions. IMPORTANCE We demonstrate how detection of resistance genes within mobile elements and resistance-carrying strains furthers active surveillance efforts for drug resistance. Whole-genome sequencing is increasingly available in hospital laboratories and provides a powerful and nuanced means to define the local landscape of drug resistance. In this study, isolates of Klebsiella pneumoniae and Enterobacter cloacae with resistance to carbapenem antibiotics were sequenced. Multiple carbapenemase genes were identified that resided in distinct transposons and plasmids. This mobilome, or population of mobile elements capable of mobilizing drug resistance, further highlighted the degree of strain heterogeneity while providing a detailed timeline of carbapenemase entry into the hospital over a 3-year period. These surveillance efforts support effective targeting of infection control resources and the development of institution-specific repositories of resistance genes and the mobile elements that carry them. C1 [Pecor, Nicole D.; Li, Ning; Albano, Esperanza; Delaney, Mary; Dubois, Andrea; Onderdonk, Andrew B.; Bry, Lynn] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Clin & Translat Metagen,Dept Pathol, Boston, MA 02115 USA. [Allard, Marc; Li, Cong] US FDA, Ctr Food Safety & Nutr, Silver Spring, MD USA. RP Bry, L (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Clin & Translat Metagen,Dept Pathol, Boston, MA 02115 USA. EM LBRY@partners.org FU Brigham and Women's Hospital Clinical Laboratories; Center for Clinical and Translational Metagenomics; NIH [R01 LM010100, P30 DK34854]; U.S. FDA CFSAN FX This work was supported by a grant from Brigham and Women's Hospital Clinical Laboratories, the Center for Clinical and Translational Metagenomics, NIH grants R01 LM010100 (L. Bry) and P30 DK34854 (CCTM), and the U.S. FDA CFSAN (M. Allard). NR 50 TC 6 Z9 6 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2015 VL 6 IS 4 AR e01030-15 DI 10.1128/mBio.01030-15 PG 11 WC Microbiology SC Microbiology GA CQ8EN UT WOS:000360839400041 PM 26220969 ER PT J AU Cantor, SL Khan, MA Gupta, A AF Cantor, Stuart L. Khan, Mansoor A. Gupta, Abhay TI Development and optimization of taste-masked orally disintegrating tablets (ODTs) of clindamycin hydrochloride SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Clindamycin; coating; microcrystalline beads; orally disintegrating tablets; pediatrics; taste masking ID CUSHIONING AGENTS; COATED PELLETS; FORMULATION; COMPRESSION AB The purpose of this research was to develop an orally disintegrating tablet (ODT) dosage form containing taste-masked beads of clindamycin HCl. Several formulation strategies were evaluated and a taste-masked ODT of clindamycin HCl was prepared without the use of a waxy cushioning agent. Clindamycin HCl (ca. 46% w/w) was coated onto microcrystalline cellulose beads (Cellets (R) 200) followed by the addition of a taste-masking layer of amino methacrylate copolymer, NF (Eudragit EPO (R) (EPO)) coating suspension. The efficiency of both the drug coating process and the taste-masking polymer coating process, as well as the taste masking ODTs was determined using potency and drug release analysis. Magnesium stearate was found to be advantageous over talc in improving the efficiency of the EPO coating suspension. A response surface methodology using a Box-Behnken design for the tablets revealed compression force and levels of both disintegrant and talc to be the main factors influencing the ODT properties. Blending of talc to the EPO-coated beads was found to be the most critical factor in ensuring that ODTs disintegrate within 30 s. The optimized ODTs formulation also showed negligible (50.5%) drug release in 1 min using phosphate buffer, pH 6.8 (which is analogous to the residence time and pH in the oral cavity). By carefully adjusting the levels of coating polymers, the amounts of disintegrant and talc, as well as the compression force, robust ODTs can be obtained to improve pediatric and geriatric patient compliance for clindamycin oral dosage forms. C1 [Cantor, Stuart L.; Khan, Mansoor A.; Gupta, Abhay] US FDA, OPS, Div Prod Qual Res, Silver Spring, MD 20993 USA. RP Gupta, A (reprint author), US FDA, OPS, Div Prod Qual Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM abhay.gupta@fda.hhs.gov OI cantor, stuart/0000-0001-6506-1419 FU FDA-NIH inter-agency agreement; Medical Countermeasures Initiative (MCMi) grant; U.S. Department of Energy; CDER FX Part of this research was supported by an FDA-NIH inter-agency agreement and by a Medical Countermeasures Initiative (MCMi) grant. This project was also supported, in part, by an appointment to the ORISE Research Participation Program at CDER administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and CDER. NR 35 TC 6 Z9 6 U1 4 U2 22 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 JUL PY 2015 VL 41 IS 7 BP 1156 EP 1164 DI 10.3109/03639045.2014.935392 PG 9 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CP4OM UT WOS:000359861700014 PM 25000481 ER PT J AU Wu, KM Wu, C Dou, J Ghantous, H Lee, S Yu, L AF Wu, K. M. Wu, C. Dou, J. Ghantous, H. Lee, S. Yu, L. TI A update of botanical drug development in the United States: Status of applications SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy CY JUL 25-29, 2015 CL CO SP Amer Soc Pharmacognosy C1 [Wu, K. M.; Wu, C.; Dou, J.; Ghantous, H.; Lee, S.; Yu, L.] US FDA, Bot Review Team, Res Policy & Implementat, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2015 VL 81 IS 11 MA PG4 BP 886 EP 887 PG 2 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA CP6AP UT WOS:000359967000151 ER PT J AU Li, J Pawar, R Krynitsky, AJ Noonan, GO AF Li, J. Pawar, R. Krynitsky, A. J. Noonan, G. O. TI Development of a sensitive and rapid HPLC method for quantitative measurement of ginkgolic acid in dietary supplementarys SO PLANTA MEDICA LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Pharmacognosy CY JUL 25-29, 2015 CL CO SP Amer Soc Pharmacognosy C1 [Li, J.; Pawar, R.; Krynitsky, A. J.; Noonan, G. O.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2015 VL 81 IS 11 MA PX84 BP 947 EP 947 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA CP6AP UT WOS:000359967000442 ER PT J AU Steinbach, T Gad-McDonald, S Kruhlak, N Powley, M Greene, N AF Steinbach, Thomas Gad-McDonald, Samantha Kruhlak, Naomi Powley, Mark Greene, Nigel TI (Q)SAR: A Tool for the Toxicologist SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE (Q)SAR; computational modeling; risk assessment ID HEPATOTOXICITY; TROGLITAZONE AB A continuing education (CE) course at the 2014 American College of Toxicology annual meeting covered the topic of (Quantitative) Structure-Activity Relationships [(Q)SAR]. The (Q)SAR methodologies use predictive computer modeling based on predefined rules to describe the relationship between chemical structure and a chemical's associated biological activity or statistical tools to find correlations between biologic activity and the molecular structure or properties of a compound. The (Q)SAR has applications in risk assessment, drug discovery, and regulatory decision making. Pressure within industry to reduce the cost of drug development and societal pressure for government regulatory agencies to produce more accurate and timely risk assessment of drugs and chemicals have necessitated the use of (Q)SAR. Producing a high-quality (Q)SAR model depends on many factors including the choice of statistical methods and descriptors, but first and foremost the quality of the data input into the model. Understanding how a (Q)SAR model is developed and applied is critical to the successful use of such a tool. The CE session covered the basic principles of (Q)SAR, practical applications of these computational models in toxicology, how regulatory agencies use and interpret (Q)SAR models, and potential pitfalls of using them. C1 [Steinbach, Thomas] EPL Inc, Res Triangle Pk, NC 27709 USA. [Gad-McDonald, Samantha] Gad Consulting Serv, Raleigh, NC USA. [Kruhlak, Naomi] US FDA, Div Drug Safety Res, Silver Spring, MD USA. [Powley, Mark] Off New Drugs, Div Antiviral Prod, Silver Spring, MD USA. [Greene, Nigel] Pfizer Global R&D, Groton, CT USA. RP Steinbach, T (reprint author), EPL Inc, Res Triangle Pk, NC 27709 USA. EM tsteinbach@epl-inc.com NR 10 TC 0 Z9 2 U1 0 U2 3 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 2015 VL 34 IS 4 BP 352 EP 354 DI 10.1177/1091581815584914 PG 3 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CO8FJ UT WOS:000359401300009 PM 25979517 ER PT J AU Abu Sayeed, M Bufano, MK Xu, P Eckhoff, G Charles, RC Alam, MM Sultana, T Rashu, MR Berger, A Gonzalez-Escobedo, G Mandlik, A Bhuiyan, TR Leung, DT LaRocque, RC Harris, JB Calderwood, SB Qadri, F Vann, WF Kovac, P Ryan, ET AF Abu Sayeed, Md. Bufano, Meagan Kelly Xu, Peng Eckhoff, Grace Charles, Richelle C. Alam, Mohammad Murshid Sultana, Tania Rashu, Md. Rasheduzzaman Berger, Amanda Gonzalez-Escobedo, Geoffrey Mandlik, Anjali Bhuiyan, Taufiqur Rahman Leung, Daniel T. LaRocque, Regina C. Harris, Jason B. Calderwood, Stephen B. Qadri, Firdausi Vann, W. F. Kovac, Pavol Ryan, Edward T. TI A Cholera Conjugate Vaccine Containing O-specific Polysaccharide (OSP) of V. cholerae O1 Inaba and Recombinant Fragment of Tetanus Toxin Heavy Chain (OSP:rTTHc) Induces Serum, Memory and Lamina Proprial Responses against OSP and Is Protective in Mice SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID NEONATAL FC-RECEPTOR; B-CELL RESPONSES; FREE MOUSE MODEL; VIBRIO-CHOLERAE; ORAL IMMUNIZATION; IMMUNE-RESPONSES; TRANSCUTANEOUS IMMUNIZATION; CHEMOENZYMATIC SYNTHESIS; HOUSEHOLD CONTACTS; CONTROLLED-TRIAL AB Background Vibrio cholerae is the cause of cholera, a severe watery diarrhea. Protection against cholera is serogroup specific. Serogroup specificity is defined by the O-specific polysaccharide (OSP) component of lipopolysaccharide (LPS). Methodology Here we describe a conjugate vaccine for cholera prepared via squaric acid chemistry from the OSP of V. cholerae O1 Inaba strain PIC018 and a recombinant heavy chain fragment of tetanus toxin (OSP:rTTHc). We assessed a range of vaccine doses based on the OSP content of the vaccine (10-50 mu g), vaccine compositions varying by molar loading ratio of OSP to rTTHc (3:1, 5:1, 10:1), effect of an adjuvant, and route of immunization. Principle Findings Immunized mice developed prominent anti-OSP and anti-TT serum IgG responses, as well as vibriocidal antibody and memory B cell responses following intramuscular or intradermal vaccination. Mice did not develop anti-squarate responses. Intestinal lamina proprial IgA responses targeting OSP occurred following intradermal vaccination. In general, we found comparable immune responses in mice immunized with these variations, although memory B cell and vibriocidal responses were blunted in mice receiving the highest dose of vaccine (50 mu g). We found no appreciable change in immune responses when the conjugate vaccine was administered in the presence or absence of immunoadjuvant alum. Administration of OSP:rTTHc resulted in 55% protective efficacy in a mouse survival cholera challenge model. Conclusion We report development of an Inaba OSP:rTTHc conjugate vaccine that induces memory responses and protection against cholera in mice. Development of an effective cholera conjugate vaccine that induces high level and long-term immune responses against OSP would be beneficial, especially in young children who respond poorly to polysaccharide antigens. C1 [Abu Sayeed, Md.; Bufano, Meagan Kelly; Alam, Mohammad Murshid; Sultana, Tania; Rashu, Md. Rasheduzzaman; Berger, Amanda; Gonzalez-Escobedo, Geoffrey; Mandlik, Anjali; Bhuiyan, Taufiqur Rahman; Leung, Daniel T.; LaRocque, Regina C.; Harris, Jason B.; Calderwood, Stephen B.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Abu Sayeed, Md.; Alam, Mohammad Murshid; Sultana, Tania; Rashu, Md. Rasheduzzaman; Bhuiyan, Taufiqur Rahman; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Ctr Vaccine Sci, Dhaka, Bangladesh. [Xu, Peng] Natl Inst Diabet Digest & Kidney Dis NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD USA. [Eckhoff, Grace; Charles, Richelle C.; Kovac, Pavol; Ryan, Edward T.] Harvard Univ, Sch Med, Boston, MA USA. [Leung, Daniel T.] Univ Utah, Sch Med, Div Infect Dis, Salt Lake City, UT USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Vann, W. F.] US FDA, Ctr Biol Evaluat & Res, Lab Bacterial Toxins, Bethesda, MD USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Abu Sayeed, M (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM etryan@mgh.harvard.edu RI Kovac, Pavol/B-8813-2008; Xu, Peng/K-7036-2012 OI Kovac, Pavol/0000-0001-5044-3449; FU National Institutes of Health; National Institute of Allergy and Infectious Diseases [UO1 AI106878, U01 AI058935, K08 AI089721]; Fogarty International Center [TW005572]; NIH; NIDDK FX This research was supported by core grants to the icddr,b and through programs funded by the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases (UO1 AI106878 [ETR and FQ], U01 AI058935 [SBC, FQ and ETR], and K08 AI089721 [RCC]), the Fogarty International Center, Training Grant in Vaccine Development and Public Health (TW005572 [MAS, MMA, TS, MRR, TRB and FQ]), and the Intramural Research Program of the NIH and NIDDK (PX and PK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 0 Z9 0 U1 3 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2015 VL 9 IS 7 AR e0003881 DI 10.1371/journal.pntd.0003881 PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CO3SM UT WOS:000359079700013 ER PT J AU Rayavarapu, S Braithwaite, E Dorsam, R Osterhout, J Furlong, LA Shetty, D Peters, JR AF Rayavarapu, Sree Braithwaite, Elena Dorsam, Robert Osterhout, James Furlong, Lesley-Anne Shetty, Daiva Peters, John R. TI Comparative Risk Assessment of Formulation Changes in Generic Drug Products: A Pharmacology/Toxicology Perspective SO TOXICOLOGICAL SCIENCES LA English DT Review DE generics; excipients; impurities; residual solvents; toxicity; reference listed drug ID SODIUM METABISULFITE; POLYETHYLENE-GLYCOL; SULFITE SENSITIVITY; PROPYLENE-GLYCOL; IN-VIVO; EXCIPIENTS; TOXICITY; SAFETY; PARACETAMOL; SOLVENTS AB This review highlights general toxicology concerns caused by formulation differences between generic and innovator drugs. It underscores the importance of a scientific, clinically oriented, evidence-based comparative safety evaluation procedure for generic drugs and discusses representative case studies from a pharmacology-toxicology perspective. For consideration by generic drug industry stakeholders, this article provides an overview of comparative risk assessments for generic drug products. C1 [Rayavarapu, Sree; Braithwaite, Elena; Dorsam, Robert; Osterhout, James; Furlong, Lesley-Anne; Shetty, Daiva; Peters, John R.] US FDA, Div Clin Review, Off Bioequivalence, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rayavarapu, S (reprint author), US FDA, Div Clin Review, Off Gener Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,WO75-2631, Silver Spring, MD 20993 USA. EM sree.rayavarapu@fda.hhs.gov NR 43 TC 0 Z9 0 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2015 VL 146 IS 1 BP 2 EP 10 DI 10.1093/toxsci/kfv074 PG 9 WC Toxicology SC Toxicology GA CP1IH UT WOS:000359629000001 PM 26101235 ER PT J AU Chen, S Zhang, ZH Wu, YF Shi, Q Yan, H Mei, N Tolleson, WH Guo, L AF Chen, Si Zhang, Zhuhong Wu, Yuanfeng Shi, Qiang Yan, Hua Mei, Nan Tolleson, William H. Guo, Lei TI Endoplasmic Reticulum Stress and Store-Operated Calcium Entry Contribute to Usnic Acid-Induced Toxicity in Hepatic Cells SO TOXICOLOGICAL SCIENCES LA English DT Article DE usnic acid; liver toxicity; ER stress; apoptosis; store operated calcium entry ID INDUCED LIVER TOXICITY; ER STRESS; MITOCHONDRIAL DYSFUNCTION; INDUCED HEPATOTOXICITY; OXIDATIVE STRESS; RAT HEPATOCYTES; CA2+ CHANNELS; WEIGHT-LOSS; AUTOPHAGY; DISEASE AB The use of usnic acid as a weight loss agent is a safety concern due to reports of acute liver failure in humans. Previously we demonstrated that usnic acid induces apoptosis and cytotoxicity in hepatic HepG2 cells. We also demonstrated that usnic acid induces autophagy as a survival mechanism against its cytotoxicity. In this study, we investigated and characterized further molecular mechanisms underlying the toxicity of usnic acid in HepG2 cells. We found that usnic acid causes endoplasmic reticulum (ER) stress demonstrated by the increased expression of typical ER stress markers, including CHOP, ATF-4, p-eIF2 alpha, and spliced XBP1. Usnic acid inhibited the secretion of Gaussia luciferase measured by an ER stress reporter assay. An ER stress inhibitor 4-phenylbutyrate attenuated usnic acid-induced apoptosis. Moreover, usnic acid significantly increased the cytosolic free Ca2+ concentration. Usnic acid increased the expression of calcium release-activated calcium channel protein 1 (CRAM1 or ORAI1) and stromal interaction molecule 1, two key components of store-operated calcium entry (SOCE), which is the major Ca2+ influx pathway in non-excitable cells, this finding was also confirmed in primary rat hepatocytes. Furthermore, knockdown of ORAI1 prevented ER stress and ATP depletion in response to usnic acid. In contrast, overexpression of ORAI1 increased ER stress and ATP depletion caused by usnic acid. Taken together, our results suggest that usnic acid disturbs calcium homeostasis, induces ER stress, and that usnic acid-induced cellular damage occurs at least partially via activation of the Ca2+ channel of SOCE. C1 [Chen, Si; Wu, Yuanfeng; Tolleson, William H.; Guo, Lei] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhang, Zhuhong; Mei, Nan] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhang, Zhuhong; Yan, Hua] Tianjin Med Univ Gen Hosp, Tianjin 300052, Peoples R China. [Shi, Qiang] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Guo, L (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, HFT-110,3900 NCTR Rd, Jefferson, AR 72079 USA. EM lei.guo@fda.hhs.gov OI MEI, NAN/0000-0002-3501-9014 FU U.S. Department of Energy; U.S. FDA FX S.C., Y.W., and Z.H.Z. were supported by appointments to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. We thank Drs James Fuscoe and Baitang Ning for their critical review of this manuscript. This work was supported by U.S. FDA's intramural grant. NR 50 TC 5 Z9 5 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2015 VL 146 IS 1 BP 116 EP 126 DI 10.1093/toxsci/kfv075 PG 11 WC Toxicology SC Toxicology GA CP1IH UT WOS:000359629000010 PM 25870318 ER PT J AU Liachenko, S Ramu, J Konak, T Paule, MG Hanig, J AF Liachenko, Serguei Ramu, Jaivijay Konak, Tetyana Paule, Merle G. Hanig, Joseph TI Quantitative Assessment of MRI T-2 Response to Kainic Acid Neurotoxicity in Rats in vivo SO TOXICOLOGICAL SCIENCES LA English DT Article DE MRI; rat; brain; registration; toxicity; kainic acid; quantification; T-2 map ID INDUCED STATUS EPILEPTICUS; APPARENT DIFFUSION-COEFFICIENT; FIELD POTENTIAL MEASUREMENTS; MAGNETIC-RESONANCE; RISK-ASSESSMENT; NEURONAL DAMAGE; SEIZURES; BRAIN; KAINATE; HIPPOCAMPUS AB The aim of this study was to assess quantitative changes in T-2 relaxation using magnetic resonance imaging approaches in rats exposed to kainic acid to assess the utility of such endpoints as biomarkers of neurotoxicity. Quantitative T-2 mapping was performed in 21 rats before and 2, 24, and 48h after a single ip injection of 10 mg/kg of kainic acid. Three methods of quantifying T-2 changes were explored: (1) Thresholding: all voxels exhibiting T-2 <= 72ms were designated normal tissue, whereas voxels exhibiting T-2> 72ms were designated as lesioned tissue; (2) Statistical mapping: T-2 maps obtained after treatment were statistically compared with averaged "baseline" maps, voxel-by-voxel; (3) Within-subject difference from baseline: for each individual the baseline T-2 map was subtracted from the T-2 map obtained after treatment. Based on the follow-up histopathological response there were 9 responders, 7 nonresponders, and 5 animals were not classified due to early sacrifice at 2 h which was too soon after treatment to detect any morphological evidence. The "thresholding" method (1) detected differences between groups only at the later time point of 48 h, the "statistical mapping" approach (2) detected differences 24 and 48h after treatment, and the "within-subject difference from baseline" method (3) detected statistically significant differences between groups at each time point (2, 24, and 48 h). T-2 mapping provides an easily quantifiable biomarker and the quantification method employing the use of the same animal as its own control provides the most sensitive metrics. C1 [Liachenko, Serguei; Ramu, Jaivijay; Konak, Tetyana; Paule, Merle G.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Hanig, Joseph] US FDA, Off Testing & Res, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Liachenko, S (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Serguei.liachenko@fda.hhs.gov FU National Center for Toxicological Research (NCTR); Center for Drug Evaluation and Research (CDER); U.S. FDA [E07418] FX This work was supported by the National Center for Toxicological Research (NCTR) and Center for Drug Evaluation and Research (CDER), U.S. FDA [protocol number E07418]. NR 51 TC 2 Z9 2 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2015 VL 146 IS 1 BP 183 EP 191 DI 10.1093/toxsci/kfv083 PG 9 WC Toxicology SC Toxicology GA CP1IH UT WOS:000359629000016 PM 25904105 ER PT J AU Yakes, BJ Handy, SM Kanyuck, KM DeGrasse, SL AF Yakes, Betsy Jean Handy, Sara M. Kanyuck, Kelsey M. DeGrasse, Stacey L. TI Improved screening of microcystin genes and toxins in blue-green algal dietary supplements with PCR and a surface plasmon resonance biosensor SO HARMFUL ALGAE LA English DT Article DE Biosensor; Blue-green algae; Dietary supplements; Microcystins; PCR; Surface plasmon resonance ID CYCLIC HEPTAPEPTIDE MICROCYSTIN; FOOD SUPPLEMENTS; CYANOBACTERIAL TOXINS; LIQUID-CHROMATOGRAPHY; SYNTHETASE GENES; LAKE-ERIE; HEALTH; BIOSYNTHESIS; WATER; OPTIMIZATION AB Microcystins (MCs) comprise a group of cyclic heptapeptide toxins that share a common backbone and have two variable L-amino acids that yield at least 21 known analogs of varying potency. These hepatotoxins and potential tumor promoters are produced by certain cyanobacteria, including Microcystis aeruginosa. The cyanobacterium M. aeruginosa blooms in freshwater lakes and can potentially co-occur with other species such as Aphanizomenon flos-aquae, which is targeted and harvested for the production of dietary supplements known as blue-green algae (BGA). BGA supplements are currently marketed in the U.S. and internationally as a product that may elevate mood, increase energy, and alleviate attention deficit hyperactivity disorder. However, the potential for BGA dietary supplements to be contaminated with MCs is of concern, and there are currently no validated methods for detection of MCs in these products. This research focused on establishing screening methods for toxic Microcystis and MCs in BGA supplements. A DNA-based method employing polymerase chain reaction (PCR) was used as a prescreening tool to evaluate the dietary supplements and to detect the presence of toxin genes (i.e., presence of toxic Microcystis). A rapid, sensitive surface plasmon resonance (SPR) biosensor, directed towards recognition of all MC forms, was also developed and validated. This improved SPR biosensor incorporates a commercial Adda-group antibody (Ab) that has the capacity for broader recognition of MCs than previously developed sensors for BGA supplements that rely solely on an arginine-reactive Ab and can quantitate MC levels down to 0.24 ng/mL (equivalent to 0.24 mu g per gram of BGA supplement) in less than 10 min. Such a rapid, quantitative screening method may allow for further surveillance of BGA products to assist risk assessment efforts, establishment of regulatory guidance levels, and response to potential consumer complaints related to BGA products. The PCR technique and SPR biosensor may be used in concert as prescreening and screening tools, respectively or individually, thereby limiting the number of samples that must be evaluated with confirmatory methods. Published by Elsevier B.V. C1 [Yakes, Betsy Jean; Handy, Sara M.; DeGrasse, Stacey L.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Kanyuck, Kelsey M.] Univ Maryland, Joint Inst Food Safety & Appl Nutr JIFSAN, College Pk, MD 20742 USA. RP Yakes, BJ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM betsy.yakes@fda.hhs.gov; sara.handy@fda.hhs.gov; kkanyuck@terpmail.umd.edu; stacey.degrasse@fda.hhs.gov RI Handy, Sara/C-6195-2008 NR 44 TC 2 Z9 2 U1 4 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9883 EI 1878-1470 J9 HARMFUL ALGAE JI Harmful Algae PD JUL PY 2015 VL 47 BP 9 EP 16 DI 10.1016/j.hal.2015.05.001 PG 8 WC Marine & Freshwater Biology SC Marine & Freshwater Biology GA CO3AA UT WOS:000359027400002 ER PT J AU Crowe, JB Lanzarotta, A Witkowski, MR Andria, SE AF Crowe, John B. Lanzarotta, Adam Witkowski, Mark R. Andria, Sara E. TI Analysis of Hypodermic Needles and Syringes for the Presence of Blood and Polydimethylsiloxane (Silicone) Utilizing Microchemical Tests and Infrared Spectroscopy SO JOURNAL OF FORENSIC SCIENCES LA English DT Article DE forensic science; ATR-FT-IR; polydimethylsiloxane; blood; microchemical; syringes; needles AB Suspect hypodermic needles and syringes were seized from an unlicensed individual who was allegedly injecting patients with silicone (polydimethylsiloxane [PDMS]) for cosmetic enhancement. Since control syringe barrels and needles often contain an interfering PDMS lubricant, a risk for false positives of foreign PDMS exists. The focus of this report was to minimize this risk and determine a quick and reliable test for the presence of blood in PDMS matrices. Using ATR-FT-IR spectroscopy, the risk for false-positive identification of foreign PDMS was reduced by (i) overfilling the sampling aperture to prevent spectral distortions and (ii) sampling a region of the suspect syringe/needle assembly where manufacturer-applied PDMS is not typically located. Analysis for blood indicated that the Teichman microchemical test was effective for detecting blood in the presence of PDMS. Overall, detecting PDMS established intent and detecting blood established that the needle containing the PDMS had been used for injection. C1 [Crowe, John B.; Lanzarotta, Adam; Witkowski, Mark R.; Andria, Sara E.] US FDA, Forens Chem Ctr, Trace Examinat Sect, Cincinnati, OH 45237 USA. RP Crowe, JB (reprint author), US FDA, Forens Chem Ctr, Trace Examinat Sect, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM john.crowe@fda.hhs.gov NR 16 TC 1 Z9 1 U1 1 U2 2 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 JUL PY 2015 VL 60 IS 4 BP 1078 EP 1084 DI 10.1111/1556-4029.12763 PG 7 WC Medicine, Legal SC Legal Medicine GA CO6JL UT WOS:000359262900034 PM 25782994 ER PT J AU Amur, S LaVange, L Zineh, I Buckman-Garner, S Woodcock, J AF Amur, S. LaVange, L. Zineh, I. Buckman-Garner, S. Woodcock, J. TI Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID SURROGATE END-POINTS; DRUG DEVELOPMENT; CLINICAL-TRIALS; PRINCIPAL STRATIFICATION; DIABETES-MELLITUS; PROGRESSION; VALIDATION; RNA; REPRODUCIBILITY; CONSORTIUM AB The discovery, development, and use of biomarkers for a variety of drug development purposes are areas of tremendous interest and need. Biomarkers can become accepted for use through submission of biomarker data during the drug approval process. Another emerging pathway for acceptance of biomarkers is via the biomarker qualification program developed by the Center for Drug Evaluation and Research (CDER, US Food and Drug Administration). Evidentiary standards are needed to develop and evaluate various types of biomarkers for their intended use and multiple stakeholders, including academia, industry, government, and consortia must work together to help develop this evidence. The article describes various types of biomarkers that can be useful in drug development and evidentiary considerations that are important for qualification. A path forward for coordinating efforts to identify and explore needed biomarkers is proposed for consideration. C1 [Amur, S.; Buckman-Garner, S.] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Silver Spring, MD 20993 USA. [LaVange, L.] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Off Biostat, Silver Spring, MD USA. [Zineh, I.] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol, Silver Spring, MD USA. [Woodcock, J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Amur, S (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Silver Spring, MD 20993 USA. EM Shashi.Amur@fda.hhs.gov NR 40 TC 13 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2015 VL 98 IS 1 BP 34 EP 46 DI 10.1002/cpt.136 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CN5WK UT WOS:000358502900019 PM 25868461 ER PT J AU Martinez, M AF Martinez, M. TI KN Use of in-silico models to support drug and drug product understanding SO JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS LA English DT Meeting Abstract C1 [Martinez, M.] US FDA, Off New Anim Drugs, CVM, Rockville, MD 20857 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 2015 VL 38 SU 1 SI SI MA 15.1 BP 44 EP 44 PG 1 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA CN4FF UT WOS:000358385100071 ER PT J AU Pade, D Martinez, M Mistry, B Jamei, M Rostami-Hodjegan, A AF Pade, D. Martinez, M. Mistry, B. Jamei, M. Rostami-Hodjegan, A. TI Use of physiologically based pharmacokinetic (PBPK) models to support canine drug product development SO JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS LA English DT Meeting Abstract C1 [Pade, D.; Jamei, M.] Simcyp Ltd, Modelling & Simulat, Sheffield, S Yorkshire, England. [Martinez, M.; Mistry, B.] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. [Rostami-Hodjegan, A.] Univ Manchester, Syst Pharmacol, Manchester Pharm Sch, Manchester, Lancs, England. NR 1 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0140-7783 EI 1365-2885 J9 J VET PHARMACOL THER JI J. Vet. Pharmacol. Ther. PD JUL PY 2015 VL 38 SU 1 SI SI MA 2.5 BP 96 EP 96 PG 1 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA CN4FF UT WOS:000358385100154 ER PT J AU Gargis, AS Kalman, L Bick, DP da Silva, C Dimmock, DP Funke, BH Gowrisankar, S Hegde, MR Kulkarni, S Mason, CE Nagarajan, R Voelkerding, KV Worthey, EA Aziz, N Barnes, J Bennett, SF Bisht, H Church, DM Dimitrova, Z Gargis, SR Hafez, N Hambuch, T Hyland, FCL Luna, RA MacCannell, D Mann, T McCluskey, MR McDaniel, TK Ganova-Raeval, LM Rehm, HL Reid, J Campo, DS Resnick, RB Ridge, PG Salit, ML Skums, P Wong, LJC Zehnbauer, BA Zook, JM Lubin, IM AF Gargis, Amy S. Kalman, Lisa Bick, David P. da Silva, Cristina Dimmock, David P. Funke, Birgit H. Gowrisankar, Sivakumar Hegde, Madhuri R. Kulkarni, Shashikant Mason, Christopher E. Nagarajan, Rakesh Voelkerding, Karl V. Worthey, Elizabeth A. Aziz, Nazneen Barnes, John Bennett, Sarah F. Bisht, Himani Church, Deanna M. Dimitrova, Zoya Gargis, Shaw R. Hafez, Nabil Hambuch, Tina Hyland, Fiona C. L. Luna, Ruth Ann MacCannell, Duncan Mann, Tobias McCluskey, Megan R. McDaniel, Timothy K. Ganova-Raeval, Lilia M. Rehm, Heidi L. Reid, Jeffrey Campo, David S. Resnick, Richard B. Ridge, Perry G. Salit, Marc L. Skums, Pavel Wong, Lee-Jun C. Zehnbauer, Barbara A. Zook, Justin M. Lubin, Ira M. TI Good laboratory practice for clinical next-generation sequencing informatics pipelines SO NATURE BIOTECHNOLOGY LA English DT Letter ID ACMG RECOMMENDATIONS; INCIDENTAL FINDINGS; STANDARDS C1 [Gargis, Amy S.; Kalman, Lisa; Zehnbauer, Barbara A.; Lubin, Ira M.] Ctr Dis Control & Prevent, Div Lab Syst, Atlanta, GA USA. [Bick, David P.; Dimmock, David P.; Worthey, Elizabeth A.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [da Silva, Cristina; Hegde, Madhuri R.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Funke, Birgit H.; Gowrisankar, Sivakumar; Rehm, Heidi L.] Partners Healthcare Personalized Med, Lab Mol Med, Cambridge, MA USA. [Funke, Birgit H.; Gowrisankar, Sivakumar; Rehm, Heidi L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. [Kulkarni, Shashikant] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Kulkarni, Shashikant] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Kulkarni, Shashikant; Nagarajan, Rakesh] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Mason, Christopher E.] Cornell Univ, Dept Physiol & Biophys, New York, NY 10021 USA. [Voelkerding, Karl V.; Ridge, Perry G.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Voelkerding, Karl V.] Associated Reg & Univ Pathologists ARUP Labs, Inst Clin & Expt Pathol, Salt Lake City, UT USA. [Aziz, Nazneen] Coll Amer Pathologists, Northfield, IL USA. [Barnes, John] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Bennett, Sarah F.] Ctr Medicare & Medicaid Serv, Div Lab Serv, Baltimore, MD USA. [Bisht, Himani] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Church, Deanna M.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Dimitrova, Zoya; Ganova-Raeval, Lilia M.; Campo, David S.] Ctr Dis Control & Prevent, Div Viral Hepatitis, Atlanta, GA USA. [Gargis, Shaw R.] Ctr Dis Control & Prevent, Div Select Agents & Toxins, Atlanta, GA USA. [Hafez, Nabil; Resnick, Richard B.; Skums, Pavel] GenomeQuest, Westborough, MA USA. [Hambuch, Tina] Illumina, Clin Serv, San Diego, CA USA. [Hyland, Fiona C. L.] Thermo Fisher Sci, San Francisco, CA USA. [Luna, Ruth Ann] Texas Childrens Hosp, Texas Childrens Microbiome Ctr, Houston, TX USA. [Luna, Ruth Ann] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [MacCannell, Duncan] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. [Mann, Tobias] Illumina, San Diego, CA USA. [McCluskey, Megan R.] SoftGenetics, State Coll, State Coll, PA USA. [McDaniel, Timothy K.; Wong, Lee-Jun C.] Illumina, Oncol, San Diego, CA USA. [Reid, Jeffrey] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Salit, Marc L.; Zook, Justin M.] NIST, Mat Measurement Lab, Gaithersburg, MD 20899 USA. RP Gargis, AS (reprint author), Ctr Dis Control & Prevent, Div Preparedness & Emerging Infect, Atlanta, GA 30322 USA. RI Zook, Justin/B-7000-2008 OI Zook, Justin/0000-0003-2309-8402 FU NHGRI NIH HHS [U01HG006500, U41HG006834] NR 11 TC 26 Z9 28 U1 2 U2 12 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 JUL PY 2015 VL 33 IS 7 BP 689 EP 693 DI 10.1038/nbt.3237 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CN4JJ UT WOS:000358396100018 PM 26154004 ER PT J AU Vaithianathan, S Raman, S Jiang, W Ting, TY Kane, MA Polli, JE AF Vaithianathan, Soundarya Raman, Siddarth Jiang, Wenlei Ting, Tricia Y. Kane, Maureen A. Polli, James E. TI Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets SO MOLECULAR PHARMACEUTICS LA English DT Article DE lamotrigine; Biopharmaceutics Classification System (BCS); quality; brand; generic; Caco-2 permeability; bioequivalence ID CLASSIFICATION-SYSTEM; IN-VITRO; ANTIEPILEPTIC DRUGS; IMMEDIATE-RELEASE; EPILEPSY; BIOEQUIVALENCE; DISSOLUTION; PRODUCTS; VIVO; PERMEABILITY AB The therapeutic equivalence of generic and brand name antiepileptic drugs has been questioned by neurologists and the epilepsy community. A potential contributor to such concerns is pharmaceutical quality. The objective was to assess the biopharmaceutic risk of brand name Lamictal 100 mg tablets and generic lamotrigine 100 mg tablets from several manufacturers. Larnotrigine was characterized in terms Of the Biopharmaceutics Classification System (BCS), including aqueous solubility and Caco-2 permeability. A panel of pharmaceutical quality tests was also performed on three batches of Lamictal, three batches of Teva generic, and one batch of each of four other generics: appearance, identity, assay, impurity, uniformity of dosage units, disintegration, dissolution, friability, and loss on drying. These market surveillance results indicate that all brand name and generic lamotrigine 100 mg tablets passed all tests and showed acceptable pharmaceutical quality and low biopharmaceutic risk. Lamotrigine was classified as a BCS class lib drug, exhibiting pH-dependent aqueous solubility and dissolution. At pH 1.2 and 4.5, lamotrigine exhibited high solubility, whereas lamotrigine exhibited low solubility at pH 6.8, including non-sink dissolution. Lamotrigine showed high Caco-2 permeability. The apparent permeability (P-app) of lamotrigine was (73.7 +/- 8.7) x 10(-6) cm/s in the apical-to-basolateral (AP-BL) direction and (41.4 +/- 1.6) x 10(-6) cm/s in the BL-AP direction, which were higher than metoprolol's AP-BL P-app of (21.2 +/- 0.9) x 10(-6) cm/s and BL-AP P-app of (34.6 +/- 4.6) x 10(-6) cm/s. Overall, lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest that multisource lamotrigine tablets exhibit a low biopharrnaceutic risk. C1 [Vaithianathan, Soundarya; Raman, Siddarth; Kane, Maureen A.; Polli, James E.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Jiang, Wenlei] US FDA, Rockville, MD 20852 USA. [Ting, Tricia Y.] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. RP Polli, JE (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, HSF2 Room 623, Baltimore, MD 21201 USA. EM jpolli@rx.umaryland.edu FU Food and Drug Administration [HHSF223201010144A] FX We thank Dr. Paresh Chothe for Caco-2 study support. This work was supported by the Food and Drug Administration (Contract HHSF223201010144A). NR 33 TC 1 Z9 1 U1 2 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD JUL PY 2015 VL 12 IS 7 BP 2436 EP 2443 DI 10.1021/acs.molpharmaceut.5b00154 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA CM5DD UT WOS:000357706100022 PM 26001027 ER PT J AU Liu-Chittenden, Y Jain, M Kumar, P Patel, D Aufforth, R Neychev, V Sadowski, S Gara, SK Joshi, BH Cottle-Delisle, C Merkel, R Yang, L Miettinen, M Puri, RK Kebebew, E AF Liu-Chittenden, Yi Jain, Meenu Kumar, Parag Patel, Dhaval Aufforth, Rachel Neychev, Vladimir Sadowski, Samira Gara, Sudheer K. Joshi, Bharat H. Cottle-Delisle, Candice Merkel, Roxanne Yang, Lily Miettinen, Markku Puri, Raj K. Kebebew, Electron TI Phase I trial of systemic intravenous infusion of interleukin-13-Pseudomonas exotoxin in patients with metastatic adrenocortical carcinoma SO CANCER MEDICINE LA English DT Article DE IL-13-PE; maximum-tolerated dose; metastatic adrenocortical carcinoma; pharmacokinetics; Phase I; systemic administration ID CONVECTION-ENHANCED DELIVERY; CHIMERIC FUSION PROTEINS; RECEPTOR ALPHA-2 CHAIN; PSEUDOMONAS EXOTOXIN; MALIGNANT GLIOMAS; CELL CARCINOMA; CANCER THERAPY; EXPRESSION; TARGET; IL-13 AB Adrenocortical carcinoma (ACC) is a rare but lethal malignancy without effective current therapy for metastatic disease. IL-13-PE is a recombinant cytotoxin consisting of human interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin A (PE). The main objectives of this Phase I dose-escalation trial were to assess the maximum-tolerated dose (MTD), safety, and pharmacokinetics (PK) of IL-13-PE in patients with metastatic ACC. Eligible patients had confirmed IL-13 receptor alpha 2 (IL-13R2) expressions in their tumors. IL-13-PE at dose of 1-2g/kg was administered intravenously (IV) on day 1, 3, and 5 in a 4-week cycle. Six patients received 1g/kg and two patients received 2g/kg of IL-13-PE. Dose-limiting toxicity was observed at 2g/kg, at which patients exhibited thrombocytopenia and renal insufficiency without requiring dialysis. PK analysis demonstrated that at MTD, the mean maximum serum concentration (C-max) of IL-13-PE was 21.0ng/mL, and the terminal half-life of IL-13-PE was 30-39min. Two (25%) of the eight patients had baseline neutralizing antibodies against PE. Three (75%) of the remaining four tested patients developed neutralizing antibodies against IL-13-PE within 14-28days of initial treatment. Of the five patients treated at MTD and assessed for response, one patient had stable disease for 5.5months before disease progression; the others progressed within 1-2months. In conclusion, systemic IV administration of IL-13-PE is safe at 1g/kg. All tested patients developed high levels of neutralizing antibodies during IL-13-PE treatment. Use of strategies for immunodepletion before IL-13-PE treatment should be considered in future trials. C1 [Liu-Chittenden, Yi; Jain, Meenu; Patel, Dhaval; Aufforth, Rachel; Neychev, Vladimir; Sadowski, Samira; Gara, Sudheer K.; Cottle-Delisle, Candice; Merkel, Roxanne; Yang, Lily; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kumar, Parag] NIH, Clin Pharmacokinet Res Lab, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Joshi, Bharat H.; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Miettinen, Markku] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, 10 Ctr Dr,Room 4-5952, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Gara, Sudheer Kumar/E-8084-2016; OI Liu-Chittenden, Yi/0000-0001-6357-5360; Patel, Dhaval/0000-0002-5744-568X FU Center for Cancer Research, National Cancer Institute, National Institutes of Health [1 ZIA BC011286 05] FX This research was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (grant # 1 ZIA BC011286 05). NR 27 TC 4 Z9 5 U1 0 U2 0 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 JUL PY 2015 VL 4 IS 7 BP 1060 EP 1068 DI 10.1002/cam4.449 PG 9 WC Oncology SC Oncology GA CM7TJ UT WOS:000357899100011 PM 25767039 ER PT J AU Bjornsdottir-Butler, K Bowers, JC Benner, RA AF Bjornsdottir-Butler, Kristin Bowers, John C. Benner, Ronald A., Jr. TI Prevalence and Characterization of High Histamine-Producing Bacteria in Gulf of Mexico Fish Species SO JOURNAL OF FOOD PROTECTION LA English DT Article ID DAMSELAE SUBSP DAMSELAE; HISTIDINE-DECARBOXYLASE; PHOTOBACTERIUM-DAMSELAE; MORGANELLA-MORGANII; FORMING BACTERIA; SKIPJACK TUNA; PCR DETECTION; IDENTIFICATION; GROWTH; MACKEREL AB Recent developments in detection and enumeration of histamine-producing bacteria (HPB) have created powerful molecular-based tools to better understand the presence of spoilage bacteria and conditions, resulting in increased risk of scombrotoxin fish poisoning. We examined 235 scombrotoxin-forming fish from the Gulf of Mexico for the presence of high HPB. Photobacterium damselae subsp. damselae was the most prevalent HPB (49%), followed by Morganella morganii (14%), Enterobacter aerogenes (4%), and Raoultella planticola (3%). The growth characteristics and histamine production capabilities of the two most prevalent HPB were further examined. M. morganii and P. damselae had optimum growth at 35 degrees C and 30 to 35 degrees C and 0 to 2% and 1 to 3% NaCl, respectively. P. damselae produced significantly (P < 0.001) higher histamine than M. morganii in inoculated mahimahi and Spanish mackerel incubated at 30 degrees C for 24 h, but histamine production was not significantly different between the two HPB in inoculated tuna, possibly due to differences in muscle composition and salt content. Results in this study showed that P. damselae was the most prevalent high HPB in Gulf of Mexico fish. In addition, previously reported results using the traditional Niven's method may underreport the prevalence of P. damselae. Molecular-based methods should be used in addition to culture-based methods to enhance detection and enumeration of HPB. C1 [Bjornsdottir-Butler, Kristin; Benner, Ronald A., Jr.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. [Bowers, John C.] US FDA, Div Publ Hlth Informat & Analyt, College Pk, MD 20740 USA. RP Bjornsdottir-Butler, K (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM Kristin.Butler@fda.hhs.gov NR 44 TC 2 Z9 2 U1 2 U2 7 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD JUL PY 2015 VL 78 IS 7 BP 1335 EP 1342 DI 10.4315/0362-028X.JFP-15-012 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CM5YS UT WOS:000357765500013 PM 26197285 ER PT J AU McCarthy, S Bjornsdottir-Butler, K Benner, R AF McCarthy, Susan Bjornsdottir-Butler, Kristin Benner, Ronald, Jr. TI Storage Time and Temperature Effects on Histamine Production in Tuna Salad Preparations SO JOURNAL OF FOOD PROTECTION LA English DT Article ID FORMING BACTERIA; BIOGENIC-AMINE; PSYCHROTOLERANT BACTERIA; MORGANELLA-MORGANII; FISH; IDENTIFICATION; ADULTERATION; ALBACORE; SAMPLES; FRESH AB Scombrotoxin fish poisoning (SFP), also known as histamine (Hst) poisoning, has been associated with consumption of scombroid-type fish, including tuna and tuna fish products. Preparation of commercial tuna salad contaminated with Hst-producing bacteria (HPB), combined with time-temperature abuse, can present a food safety hazard. A potential source of HPB is raw ingredients, such as celery and onions. The objectives of this study were to determine whether raw ingredients can be a source of HPB and to ascertain the effects of storage time (up to 4 days or 4 weeks) and temperature (4, 10, 18, 25, 30 degrees C) on growth and Hst production by high-HPB (>1,000 ppm of Hst) in tuna salad preparations. Pantoea-Erwinia, Erwinia persicinus, Erwinia spp., and Enterobacter pyrinus isolated from celery in this study were used to inoculate tuna salad and tuna salad with celery or onion. HPB numbers were 0.7 to 4.3 log most probable number per g higher in the presence of celery or onion versus plain tuna salad (3:1 tuna:mayonnaise). E. pyrinus inoculated plain tuna salad and tuna salad with celery and onion had >500 ppm of Hst after 2 days at 30 degrees C and 4 days at 25 degrees C. E. pyrinus inoculated salad with celery and onion had >500 ppm of Hst after 4 days at 18 degrees C and 2 weeks at 10 degrees C. Raw celery can introduce HPB into tuna salad, which can cause SFP if the product is time-temperature abused. Tuna salad products must be refrigerated at <= 4 degrees C to prevent growth and Hst production by the HPB used in this study, to protect consumers from potential SFP. C1 [McCarthy, Susan; Bjornsdottir-Butler, Kristin; Benner, Ronald, Jr.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP McCarthy, S (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM susan.mccarthy@fda.hhs.gov NR 39 TC 1 Z9 1 U1 7 U2 18 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD JUL PY 2015 VL 78 IS 7 BP 1343 EP 1349 DI 10.4315/0362-028X.JFP-14-523 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CM5YS UT WOS:000357765500014 PM 26197286 ER PT J AU Lydon, KA Farrell-Evans, M Jones, JL AF Lydon, Keri Ann Farrell-Evans, Melissa Jones, Jessica L. TI Evaluation of Ice Slurries as a Control for Postharvest Growth of Vibrio spp. in Oysters and Potential for Filth Contamination SO JOURNAL OF FOOD PROTECTION LA English DT Article ID ACTIVE SURVEILLANCE NETWORK; 10 US SITES; SHELLSTOCK OYSTERS; PREDICTIVE MODEL; UNITED-STATES; VULNIFICUS; PARAHAEMOLYTICUS; INFECTIONS; SURVIVAL; REFRIGERATION AB Raw oyster consumption is the most common route of exposure for Vibrio spp. infections in humans. Vibriosis has been increasing steadily in the United States despite efforts to reduce the incidence of the disease. Research has demonstrated that ice is effective in reducing postharvest Vibrio spp. growth in oysters but has raised concerns of possible contamination of oyster meat by filth (as indicated by the presence of fecal coliform bacteria or Clostridium perfringens). This study examined the use of ice slurries (<4.5 degrees C) to reduce Vibrio growth. Ice slurries showed rapid internal cooling of oysters, from 23.9 degrees C (75 degrees F) to 10 degrees C (50 degrees F) within 12 min The initial bacterial loads in the ice slurry waters were near the limits of detection. Following repeated dipping of oysters into ice slurries, water samples exhibited significant (P < 0.05) increases in median levels of fecal coliforms (9.5 most probable number [MPN]/100 ml), C. perfringens (280 MPN/100 ml), Vibrio vulnificus (11,250 MPN/ml), and total Vibrio parahaemolyticus (3,900 MPN/ml). The microbial load in oyster meat, however, was unchanged after 15 min of submergence, with no significant differences (P < 0.05) in levels of filth indicator (range, 250 to 720 MPN/100 g) or Vibrio spp. (range, 9,000 to 20,000 MPN/g) bacteria. These results support the use of ice slurries as a postharvest application for rapid cooling of oysters to minimize Vibrio growth. C1 [Lydon, Keri Ann; Jones, Jessica L.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. [Farrell-Evans, Melissa] US FDA, Div Seafood Safety, College Pk, MD 20740 USA. RP Jones, JL (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. EM Jessica.Jones@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX We thank George Doup for assistance in collecting and processing oysters. Thank you to Thomas Kinsey for assisting with temperature cooling profiles. We also thank Kevin Calci and Catharina Ludeke for assistance in laboratory methods. This project was supported in part by an appointment to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 27 TC 1 Z9 1 U1 1 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 JUL PY 2015 VL 78 IS 7 BP 1375 EP 1379 DI 10.4315/0362-028X.JFP-14-557 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CM5YS UT WOS:000357765500019 PM 26197291 ER PT J AU Toomer, OT Do, AB Fu, TJ Williams, KM AF Toomer, Ondulla T. Do, Andrew B. Fu, Tong J. Williams, Kristina M. TI Digestibility and Immunoreactivity of Shrimp Extracts Using an In Vitro Digestibility Model with Pepsin and Pancreatin SO JOURNAL OF FOOD SCIENCE LA English DT Article DE allergenicity; digestibility; food allergens; shrimp; tropomyosin ID MAJOR ALLERGEN; LITOPENAEUS-VANNAMEI; FOOD ALLERGY; TROPOMYOSIN; PEN-A-1 AB Shellfish allergy affects 2% of the adult population in the United States. Identification of allergenic shrimp proteins is needed for improved management and assessment of shrimp allergy. We determined the temporal pepsin and pancreatin stability of total shrimp proteins using simulated physiological digestive conditions in vitro. Gel electrophoresis was used to determine protein stability, whereas immunoreactivity of protease stable proteins was determined using rabbit antigen-specific antibodies. Potential allergenicity of protease stable proteins was determined utilizing human sera from shrimp allergic patients. Total shrimp myofibrillar proteins were pepsin- and pancreatin-stable for up to 1 h after initiating digestion, whereas only pancreatin-stable total shrimp proteins were Immunoglobulin G (IgG) immunoreactive. However, shrimp proteins of 32 and 25 kDa were pepsin and/or pancreatin stable and Immunoglobulin E (IgE) reactive, denoting the stability and potential allergenicity. These findings suggest that this in vitro digestibility model may be useful for the identification of shrimp allergenic proteins that are more resistant to physiologic digestive conditions and may elicit an immunologic response in vivo. Practical Application Unlike other food allergies, shellfish allergy is typically life-long and predominantly affects the adult population. A major difficulty in managing shellfish allergy is the lack of reliable diagnostic assays due to limited knowledge of clinically relevant shellfish allergens. Therefore, the identification and characterization of digestive-stable and immunoreactive food proteins is fundamental to the development of new polyclonal antibodies for improved food allergen detection methods within the food industry. C1 [Toomer, Ondulla T.; Do, Andrew B.; Williams, Kristina M.] US FDA, Laurel, MD 20708 USA. [Toomer, Ondulla T.; Fu, Tong J.] US FDA, Natl Ctr Food Safety & Technol, Bedford Pk, SA 60501, Australia. RP Toomer, OT (reprint author), US FDA, Laurel, MD 20708 USA. EM Ondulla.Toomer@fda.hhs.gov NR 19 TC 1 Z9 1 U1 4 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-1147 EI 1750-3841 J9 J FOOD SCI JI J. Food Sci. PD JUL PY 2015 VL 80 IS 7 BP T1633 EP T1639 DI 10.1111/1750-3841.12917 PG 7 WC Food Science & Technology SC Food Science & Technology GA CM8JX UT WOS:000357947600030 PM 26077284 ER PT J AU Iwanowicz, DD Sanders, LR Schill, WB Xayavong, MV da Silva, AJ Qvarnstrom, Y Smith, T AF Iwanowicz, Deborah D. Sanders, Lakyn R. Schill, W. Bane Xayavong, Maniphet V. da Silva, Alexandre J. Qvarnstrom, Yvonne Smith, Trevor TI Spread of the Rat Lungworm (Angiostrongylus cantonensis) in Giant African Land Snails (Lissachatina fulica) in Florida, USA SO JOURNAL OF WILDLIFE DISEASES LA English DT Article DE Angiostrongylus cantonensis; Lissachatina fulica; parasite; quantitative PCR; rat lungworm ID INFECTION AB The rat lungworm (Angiostrongylus cantonensis) is a parasitic nematode that causes rat lungworm disease. It is the leading cause of eosinophilic meningitis and is a zoonotic health risk. We confirmed the presence of A. cantonensis using species-specific, quantitative PCR in 18 of 50 (36%) giant African land snails (Lissachatina fulica) collected from Miami, Florida, US in May 2013. These snails were collected from seven of 21 core areas that the Florida Department of Agriculture and Consumer Services monitor weekly. Rat lungworms have not previously been identified in these areas. Duplicate DNA extractions of foot muscle tissue from each snail were tested. Of the seven core areas we examined, six were positive for A. cantonensis and prevalence of infection ranged from 27% to 100%. Of the 18 positive snails, only five were positive in both extractions. Our results confirm an increase in the range and prevalence of rat lungworm infection in Miami. We also emphasize the importance of extracting sufficient host tissue to minimize false negatives. C1 [Iwanowicz, Deborah D.; Schill, W. Bane] US Geol Survey, Fish Hlth Branch, Kearneysville, WV 25430 USA. [Sanders, Lakyn R.] US Geol Survey, Cherokee Nation Technol Solut, Fish Hlth Branch, Kearneysville, WV 25430 USA. [Xayavong, Maniphet V.] Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Ctr Global Hlth, Atlanta, GA 30329 USA. [da Silva, Alexandre J.; Qvarnstrom, Yvonne] US FDA, Div Virulence Assessment, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Smith, Trevor] Florida Dept Agr & Consumer Serv, Gainesville, FL 32608 USA. RP Iwanowicz, DD (reprint author), US Geol Survey, Fish Hlth Branch, 11649 Leetown Rd, Kearneysville, WV 25430 USA. EM diwanowicz@usgs.gov OI Schill, William/0000-0002-9217-984X NR 14 TC 5 Z9 5 U1 1 U2 6 PU WILDLIFE DISEASE ASSOC, INC PI LAWRENCE PA 810 EAST 10TH ST, LAWRENCE, KS 66044-8897 USA SN 0090-3558 EI 1943-3700 J9 J WILDLIFE DIS JI J. Wildl. Dis. PD JUL PY 2015 VL 51 IS 3 BP 749 EP 753 DI 10.7589/2014-06-160 PG 5 WC Veterinary Sciences SC Veterinary Sciences GA CM5YR UT WOS:000357765400026 PM 25973628 ER PT J AU Li, Q Gavrielides, MA Sahiner, B Myers, KJ Zeng, RP Petrick, N AF Li, Qin Gavrielides, Marios A. Sahiner, Berkman Myers, Kyle J. Zeng, Rongping Petrick, Nicholas TI Statistical analysis of lung nodule volume measurements with CT in a large-scale phantom study SO MEDICAL PHYSICS LA English DT Article DE quantitative image biomarker; lung nodule volumetry; computed tomography; phantom study ID PULMONARY NODULES; THORACIC CT; SIZE ESTIMATION; RECONSTRUCTION AB Purpose: To determine inter-related factors that contribute substantially to measurement error of pulmonary nodule measurements with CT by assessing a large-scale dataset of phantom scans and to quantitatively validate the repeatability and reproducibility of a subset containing nodules and CT acquisitions consistent with the Quantitative Imaging Biomarker Alliance (QIBA) metrology recommendations. Methods: The dataset has about 40 000 volume measurements of 48 nodules (5-20 mm, four shapes, three radiodensities) estimated by a matched-filter estimator from CT images involving 72 imaging protocols. Technical assessment was performed under a framework suggested by QIBA, which aimed to minimize the inconsistency of terminologies and techniques used in the literature. Accuracy and precision of lung nodule volume measurements were examined by analyzing the linearity, bias, variance, root mean square error (RMSE), repeatability, reproducibility, and significant and substantial factors that contribute to the measurement error. Statistical methodologies including linear regression, analysis of variance, and restricted maximum likelihood were applied to estimate the aforementioned metrics. The analysis was performed on both the whole dataset and a subset meeting the criteria proposed in the QIBA Profile document. Results: Strong linearity was observed for all data. Size, slice thickness x collimation, and randomness in attachment to vessels or chest wall were the main sources of measurement error. Grouping the data by nodule size and slice thickness x collimation, the standard deviation (3.9%-28%), and RMSE (4.4%-68%) tended to increase with smaller nodule size and larger slice thickness. For 5, 8, 10, and 20 mm nodules with reconstruction slice thickness <= 0.8, 3, 3, and 5 mm, respectively, the measurements were almost unbiased (-3.0% to 3.0%). Repeatability coefficients (RCs) were from 6.2% to 40%. Pitch of 0.9, detail kernel, and smaller slice thicknesses yielded better (smaller) RCs than those from pitch of 1.2, medium kernel, and larger slice thicknesses. Exposure showed no impact on RC. The overall reproducibility coefficient (RDC) was 45%, and reduced to about 20%-30% when the slice thickness and collimation were fixed. For nodules and CT imaging complying with the QIBA Profile (QIBA Profile subset), the measurements were highly repeatable and reproducible in spite of variations in nodule characteristics and imaging protocols. The overall measurement error was small and mostly due to the randomness in attachment. The bias, standard deviation, and RMSE grouped by nodule size and slice thickness x collimation in the QIBA Profile subset were within +/-3%, 4%, and 5%, respectively. RCs are within 11% and the overall RDC is equal to 11%. Conclusions: The authors have performed a comprehensive technical assessment of lung nodule volumetry with a matched-filter estimator from CT scans of synthetic nodules and identified the main sources of measurement error among various nodule characteristics and imaging parameters. The results confirm that the QIBA Profile set is highly repeatable and reproducible. These phantom study results can serve as a bound on the clinical performance achievable with volumetric CT measurements of pulmonary nodules. C1 [Li, Qin; Gavrielides, Marios A.; Sahiner, Berkman; Myers, Kyle J.; Zeng, Rongping; Petrick, Nicholas] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Li, Q (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM qin.li1@fda.hhs.gov NR 25 TC 5 Z9 5 U1 0 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 JUL PY 2015 VL 42 IS 7 BP 3932 EP 3947 DI 10.1118/1.4921734 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CM4WN UT WOS:000357686400015 PM 26133594 ER PT J AU Butler, KS Peeler, DJ Casey, BJ Dair, BJ Elespuru, RK AF Butler, Kimberly S. Peeler, David J. Casey, Brendan J. Dair, Benita J. Elespuru, Rosalie K. TI Silver nanoparticles: correlating nanoparticle size and cellular uptake with genotoxicity SO MUTAGENESIS LA English DT Article ID IN-VITRO; ANTIBACTERIAL ACTIVITY; ESCHERICHIA-COLI; OXIDATIVE STRESS; ANTIMICROBIAL ACTIVITY; MAMMALIAN-CELLS; NANO-SILVER; TOXICITY; IONS; CYTOTOXICITY AB The focus of this research was to develop a better understanding of the pertinent physico-chemical properties of silver nanoparticles (AgNPs) that affect genotoxicity, specifically how cellular uptake influences a genotoxic cell response. The genotoxicity of AgNPs was assessed for three potential mechanisms: mutagenicity, clastogenicity and DNA strand-break-based DNA damage. Mutagenicity (reverse mutation assay) was assessed in five bacterial strains of Salmonella typhimurium and Echerichia coli, including TA102 that is sensitive to oxidative DNA damage. AgNPs of all sizes tested (10, 20, 50 and 100 nm), along with silver nitrate (AgNO3), were negative for mutagenicity in bacteria. No AgNPs could be identified within the bacteria cells using transmission electron microscopy (TEM), indicating these bacteria lack the ability to actively uptake AgNPs 10 nm or larger. Clastogenicity (flow cytometry-based micronucleus assay) and intermediate DNA damage (DNA strand breaks as measured in the Comet assay) were assessed in two mammalian white blood cell lines: Jurkat Clone E6-1 and THP-1. It was observed that micronucleus and Comet assay end points were inversely correlated with AgNP size, with smaller NPs inducing a more genotoxic response. TEM results indicated that AgNPs were confined within intracellular vesicles of mammalian cells and did not penetrate the nucleus. The genotoxicity test results and the effect of AgNO3 controls suggest that silver ions may be the primary, and perhaps only, cause of genotoxicity. Furthermore, since AgNO3 was not mutagenic in the gram-negative bacterial Ames strains tested, the lack of bacterial uptake of the AgNPs may not be the major reason for the lack of genotoxicity observed. C1 [Butler, Kimberly S.; Peeler, David J.; Casey, Brendan J.; Dair, Benita J.; Elespuru, Rosalie K.] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, Silver Spring, MD 20993 USA. RP Elespuru, RK (reprint author), US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, 10933 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Rosalie.Elespuru@fda.hhs.gov RI Peeler, David/M-2673-2014 OI Peeler, David/0000-0003-2441-6409 FU National Cancer Institute Interagency Oncology Taskforce; Office of Science and Engineering Laboratories, CDRH, U.S. Food and Drug Administration; U.S. Department of Energy; U.S. Food and Drug Administration FX This study was supported by funds provided by the National Cancer Institute Interagency Oncology Taskforce and the Office of Science and Engineering Laboratories, CDRH, U.S. Food and Drug Administration. This project was supported in part by an appointment to the Research Participation Program at the Office of Science and Engineering Laboratories, 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 U.S. Food and Drug Administration. NR 59 TC 8 Z9 8 U1 6 U2 60 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 JUL PY 2015 VL 30 IS 4 BP 577 EP 591 DI 10.1093/mutage/gev020 PG 15 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CM7PB UT WOS:000357885900013 PM 25964273 ER PT J AU Strong, DR Hartman, SJ Nodora, J Messer, K James, L White, M Portnoy, DB Choiniere, CJ Vullo, GC Pierce, J AF Strong, David R. Hartman, Sheri J. Nodora, Jesse Messer, Karen James, Lisa White, Martha Portnoy, David B. Choiniere, Conrad J. Vullo, Genevieve C. Pierce, John TI Predictive Validity of the Expanded Susceptibility to Smoke Index SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID ADOLESCENT CIGARETTE-SMOKING; ACADEMIC-PERFORMANCE; SUBSTANCE USE; INITIATION; RISK; ACHIEVEMENT; VALIDATION; CURIOSITY; BEHAVIOR AB Objectives: The susceptibility to smoking index can be improved as it only identifies one third of future adult smokers. Adding curiosity to this index may increase the identification of future smokers and improve the identification of effective prevention messages. Methods: Analyses used data from the California Longitudinal Study of Smoking Transitions in Youth, for whom tobacco use behaviors, attitudes, and beliefs were assessed at 3 time points from age 12 through early adulthood. Logistic regressions were used to evaluate whether baseline curiosity about smoking was predictive of smoking during the 6-year follow-up period and whether curiosity about smoking provided evidence of incremental validity over existing measures of susceptibility to smoking. Results: Compared to those who were classified as definitely not curious about smoking, teens who were classified as probably not curious (ORadj = 1.90, 95% CI = 1.28-2.81) and those classified as definitely curious (ORadj = 2.38, 95% CI= 1.49-3.79) had an increase in the odds of becoming a young adult smoker. Adding curiosity to the original susceptibility to smoking index increased the sensitivity of the enhanced susceptibility index to 78.9% compared to 62.2% identified by the original susceptibility index. However, a loss of specificity meant there was no improvement in the positive predictive value. Conclusions: The enhanced susceptibility index significantly improves identification of teens at risk for becoming young adult smokers. Thus, this enhanced index is preferred for identifying and testing potentially effective prevention messages. C1 [Strong, David R.; Hartman, Sheri J.; Nodora, Jesse; Messer, Karen; James, Lisa; White, Martha; Pierce, John] Univ Calif San Diego, Moores UCSD Canc Ctr, Canc Prevent & Control Program, La Jolla, CA 92093 USA. [Portnoy, David B.; Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. [Vullo, Genevieve C.] Kelly Govt Solut, Rockville, MD USA. RP Strong, DR (reprint author), Univ Calif San Diego, Moores UCSD Canc Ctr, Canc Prevent & Control Program, 3855 Hlth Sci Dr MC 0901, La Jolla, CA 92093 USA. EM dstrong@ucsd.edu OI Portnoy, David/0000-0003-2175-9457 FU California Department of Health Services [95-23211]; Robert Wood Johnson Foundation [044244]; National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; Tobacco Related Disease Research Program [21RT-01335, 21XT-0076] FX This work was supported by the California Department of Health Services (contract number 95-23211) and by a grant from the Robert Wood Johnson Foundation (grant number 044244) Funding for this analysis and manuscript preparation has been funded with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services. (contract number HHSN271201100027C), and Tobacco Related Disease Research Program (grant numbers 21RT-01335, 21XT-0076). The views and opinions expressed in this article are those of the authors only and do not necessarily represent the views, official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies. NR 44 TC 6 Z9 6 U1 2 U2 5 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 2015 VL 17 IS 7 BP 862 EP 869 DI 10.1093/ntr/ntu254 PG 8 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CM7PX UT WOS:000357888500014 PM 25481915 ER PT J AU Lu, TP Chen, JJ AF Lu, Tzu-Pin Chen, James J. TI Identification of drug-induced toxicity biomarkers for treatment determination SO PHARMACEUTICAL STATISTICS LA English DT Article DE biomarkers of response; biomarkers of susceptibility; classification; safety assessment; subgroup identification; susceptible subpopulation ID CLINICAL-TRIAL DESIGNS; EARLY PREDICTIVE BIOMARKER; ADAPTIVE SIGNATURE DESIGN; SUBGROUP IDENTIFICATION; DECISION-MAKING; BREAST-CANCER; MEDICINE; VALIDATION; TOXICOGENOMICS; CLASSIFICATION AB Drug-induced organ toxicity (DIOT) that leads to the removal of marketed drugs or termination of candidate drugs has been a leading concern for regulatory agencies and pharmaceutical companies. In safety studies, the genomic assays are conducted after the treatment so that drug-induced adverse effects can occur. Two types of biomarkers are observed: biomarkers of susceptibility and biomarkers of response. This paper presents a statistical model to distinguish two types of biomarkers and procedures to identify susceptible subpopulations. The biomarkers identified are used to develop classification model to identify susceptible subpopulation. Two methods to identify susceptibility biomarkers were evaluated in terms of predictive performance in subpopulation identification, including sensitivity, specificity, and accuracy. Method 1 considered the traditional linear model with a variable-by-treatment interaction term, and Method 2 considered fitting a single predictor variable model using only treatment data. Monte Carlo simulation studies were conducted to evaluate the performance of the two methods and impact of the subpopulation prevalence, probability of DIOT, and sample size on the predictive performance. Method 2 appeared to outperform Method 1, which was due to the lack of power for testing the interaction effect. Important statistical issues and challenges regarding identification of preclinical DIOT biomarkers were discussed. In summary, identification of predictive biomarkers for treatment determination highly depends on the subpopulation prevalence. When the proportion of susceptible subpopulation is 1% or less, a very large sample size is needed to ensure observing sufficient number of DIOT responses for biomarker and/or subpopulation identifications. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Lu, Tzu-Pin; Chen, James J.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lu, Tzu-Pin] Natl Taiwan Univ, Inst Epidemiol & Prevent Med, Dept Publ Hlth, Taipei 10764, Taiwan. RP Chen, JJ (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM jamesj.chen@fda.hhs.gov OI LU, TZU-PIN/0000-0003-3697-0386 NR 54 TC 1 Z9 1 U1 0 U2 3 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 2015 VL 14 IS 4 BP 284 EP 293 DI 10.1002/pst.1684 PG 10 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CM7QZ UT WOS:000357892000002 PM 25914330 ER PT J AU Scott, DE Epstein, JS AF Scott, Dorothy E. Epstein, Jay S. TI Hemolytic adverse events with immune globulin products: product factors and patient risks SO TRANSFUSION LA English DT Editorial Material ID INTRAVENOUS GAMMA-GLOBULIN; SERUM GLOBULIN; IMMUNOGLOBULIN; PLASMA; DISEASE; IMMUNODEFICIENCY; FRACTIONATION C1 [Scott, Dorothy E.; Epstein, Jay S.] US FDA, OBRR, CBER, Silver Spring, MD 20851 USA. RP Scott, DE (reprint author), US FDA, OBRR, CBER, Bldg 52,Room 4124,10903 New Hampshire Ave, Silver Spring, MD 20851 USA. EM Dorothy.scott@fda.hhs.gov NR 29 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2015 VL 55 SU 2 SI SI BP S2 EP S5 DI 10.1111/trf.13148 PG 4 WC Hematology SC Hematology GA CM9FE UT WOS:000358011800003 PM 26174893 ER PT J AU Scott, DE Epstein, JS AF Scott, Dorothy E. Epstein, Jay S. TI Safeguarding immune globulin recipients against hemolysis: what do we know and where do we go? SO TRANSFUSION LA English DT Article ID TRANSFUSION C1 [Scott, Dorothy E.; Epstein, Jay S.] US FDA, OBRR, CBER, Silver Spring, MD 20993 USA. RP Scott, DE (reprint author), US FDA, OBRR, CBER, Bldg 52,Room 4124,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Dorothy.scott@fda.hhs.gov NR 23 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2015 VL 55 SU 2 SI SI BP S122 EP S126 DI 10.1111/trf.13196 PG 5 WC Hematology SC Hematology GA CM9FE UT WOS:000358011800021 PM 26174890 ER PT J AU Winiecki, S Baer, B Chege, W Jankosky, C Mintz, P Baker, M Woodworth, T Nguyen, M AF Winiecki, Scott Baer, Bethany Chege, Wambui Jankosky, Christopher Mintz, Paul Baker, Meghan Woodworth, Tiffany Nguyen, Michael TI Complementary use of passive surveillance and Mini-Sentinel to better characterize hemolysis after immune globulin SO TRANSFUSION LA English DT Article ID INFLAMMATORY DEMYELINATING POLYNEUROPATHY; INTRAVENOUS IMMUNOGLOBULIN; ANTI-A; DISEASE; TRANSFUSION; POPULATION; COMMITTEE; PRODUCTS; PROGRAM; FOOD AB BACKGROUNDHemolysis after intravenous immune globulins (IGIVs) is a known complication, but expanding indications and recent manufacturing changes warrant ongoing postmarketing surveillance. Characterization of post-IGIV hemolysis to date has been limited to small case series. STUDY DESIGN AND METHODSWe queried the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) from 2007 to 2014. All reported post-IGIV hemolysis cases were classified using a prespecified case definition and a case series analysis performed. We also conducted two assessments using FDA's Mini-Sentinel (MS) system to quantify the risk of hemolysis by six product indications and by IGIV formulation and evaluate the onset interval. RESULTSA total of 109 FAERS cases met our definition. For cases with available information, 83% (66/80) received IGIV doses of at least 2 g/kg, 98.1% (51/52) had non-O blood group, and 75% (64/85) of events occurred within 4 days of IGIV exposure. We identified 313,045 treatment episodes and 337 post-IGIV hemolytic events in MS from 2006 to 2014, with 72% occurring within 2 days. Rates of hemolysis were highest among patients with Kawasaki disease (KD) and immune thrombocytopenia (ITP). The risk among patients receiving nonlyophilized products was 2.3 times higher than that in patients receiving lyophilized products. CONCLUSIONWith the largest case series to date, FAERS data support that higher doses and non-O blood group are key risk factors. The incident rate of post-IGIV hemolysis is estimated at one per 1000 IGIV treatment episodes, with most occurring within 2 days of exposure. The risk is higher in patients with KD and ITP and after receipt of nonlyophilized IGIV. C1 [Winiecki, Scott; Baer, Bethany; Chege, Wambui; Jankosky, Christopher; Nguyen, Michael] US FDA, Div Epidemiol, Off Biostat & Epidemiol, Silver Spring, MD USA. [Mintz, Paul] US FDA, Div Hematol Clin Review, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Baker, Meghan; Woodworth, Tiffany] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Baker, Meghan; Woodworth, Tiffany] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Baker, Meghan] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. RP Winiecki, S (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,WO71-1025, Silver Spring, MD 20993 USA. EM scott.winiecki@fda.hhs.gov FU FDA through the Department of Health and Human Services Contract [HHSF223200910006I] FX The Mini-Sentinel program is funded by the FDA through the Department of Health and Human Services Contract; contract grant number: HHSF223200910006I. NR 28 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2015 VL 55 SU 2 SI SI BP S28 EP S35 DI 10.1111/trf.13116 PG 8 WC Hematology SC Hematology GA CM9FE UT WOS:000358011800007 PM 26174895 ER PT J AU Mebazaa, A Longrois, D Metra, M Mueller, C Richards, AM Roessig, L Seronde, MF Sato, N Stockbridge, NL Stough, WG Alonso, A Cody, RJ Bruns, NC Gheorghiade, M Holzmeister, J Laribi, S Zannad, F AF Mebazaa, Alexandre Longrois, Dan Metra, Marco Mueller, Christian Richards, Arthur Mark Roessig, Lothar Seronde, Marie France Sato, Naoki Stockbridge, Norman L. Stough, Wendy Gattis Alonso, Angeles Cody, Robert J. Bruns, Nancy Cook Gheorghiade, Mihai Holzmeister, Johannes Laribi, Said Zannad, Faiez TI Agents with vasodilator properties in acute heart failure: how to design successful trials SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Review DE Acute heart failure; Vasodilator; Clinical trials ID PULMONARY ARTERIAL-HYPERTENSION; RANDOMIZED CONTROLLED TRIAL; ACUTE MYOCARDIAL-INFARCTION; SOLUBLE GUANYLATE-CYCLASE; SYSTOLIC BLOOD-PRESSURE; ARRESTIN-BIASED LIGAND; QUALITY-OF-CARE; RENAL-FUNCTION; RELAX-AHF; SODIUM-NITROPRUSSIDE AB Agents with vasodilator properties (AVDs) are frequently used in the treatment of acute heart failure (AHF). AVDs rapidly reduce preload and afterload, improve left ventricle to aorta and right ventricle to pulmonary artery coupling, and may improve symptoms. Early biomarker changes after AVD administration have suggested potentially beneficial effects on cardiac stretch, vascular tone, and renal function. AVDs that reduce haemodynamic congestion without causing hypoperfusion might be effective in preventing worsening organ dysfunction. Existing AVDs have been associated with different results on outcomes in randomized clinical trials, and observational studies have suggested that AVDs may be associated with a clinical outcome benefit. Lessons have been learned from past AVD trials in AHF regarding preventing hypotension, selecting the optimal endpoint, refining dyspnoea measurements, and achieving early randomization and treatment initiation. These lessons have been applied to the design of ongoing pivotal clinical trials, which aim to ascertain if AVDs improve clinical outcomes. The developing body of evidence suggests that AVDs may be a clinically effective therapy to reduce symptoms, but more importantly to prevent end-organ damage and improve clinical outcomes for specific patients with AHF. The results of ongoing trials will provide more clarity on the role of AVDs in the treatment of AHF. C1 [Mebazaa, Alexandre] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Mebazaa, Alexandre] AP HP, INSERM, U942, Paris, France. [Mebazaa, Alexandre] Hop Univ St Louis Lariboisiere, AP HP, Dept Anesthesia & Crit Care, Paris, France. [Longrois, Dan] Univ Paris Diderot, Hop Bichat Claude Bernard, Sorbonne Paris Cite, Dept Anesthesie Reanimat,INSERM,U1148, Paris, France. [Metra, Marco] Univ Brescia, Cardiol, Brescia, Italy. [Mueller, Christian] Univ Basel Hosp, Dept Cardiol, CH-4031 Basel, Switzerland. [Richards, Arthur Mark] Natl Univ Singapore, Cardiovasc Res Inst, Singapore 117548, Singapore. [Richards, Arthur Mark] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore, Singapore. [Roessig, Lothar; Bruns, Nancy Cook] Bayer Pharma AG, Global Clin Dev, Berlin, Germany. [Seronde, Marie France] Univ Hosp Besancon, Dept Cardiol, INSERM, U942, Besancon, France. [Sato, Naoki] Musashi Kosugi Hosp, Nippon Med Sch, Internal Med Cardiol & Intens Care Med, Kawasaki, Kanagawa, Japan. [Stockbridge, Norman L.] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Stough, Wendy Gattis] Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. [Alonso, Angeles] Sci Advice Working Party European Med Agcy, Madrid, Spain. [Cody, Robert J.] Janssen Res & Dev, Raritan, NJ USA. [Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Dept Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Holzmeister, Johannes] Cardiorentis AG, Zug, Switzerland. [Laribi, Said] Hop Univ St Louis Lariboisiere, AP HP, Dept Emergency Med, INSERM,U942, Paris, France. [Zannad, Faiez] Univ Lorraine, Nancy Univ, INSERM, Ctr Invest Clin 9501, Nancy, France. [Zannad, Faiez] Univ Lorraine, Nancy Univ, Ctr Hosp Univ, Unite 961, Nancy, France. [Zannad, Faiez] Univ Lorraine, Nancy Univ, Dept Cardiol, Nancy, France. RP Mebazaa, A (reprint author), Univ Paris Diderot, Hop Univ St Louis Lariboisiere, AP HP, Dept Anesthesiol & Crit Care Med,PRES Sorbonne Pa, Paris, France. EM alexandre.mebazaa@lrb.aphp.fr RI Stough, Wendy/R-4287-2016; Laribi, said/S-3693-2016 OI Stough, Wendy/0000-0001-8290-1205; NR 94 TC 9 Z9 9 U1 5 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1388-9842 EI 1879-0844 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD JUL PY 2015 VL 17 IS 7 BP 652 EP 664 DI 10.1002/ejhf.294 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CM2OC UT WOS:000357519700005 PM 26040488 ER PT J AU Cheetham, TC Marcy, SM Tseng, HF Sy, LS Liu, ILA Bixler, F Baxter, R Donahue, JG Naleway, AL Jacobsen, SJ AF Cheetham, T. Craig Marcy, S. Michael Tseng, Hung-Fu Sy, Lina S. Liu, In-Lu Amy Bixler, Felicia Baxter, Roger Donahue, James G. Naleway, Allison L. Jacobsen, Steven J. TI Risk of Herpes Zoster and Disseminated Varicella Zoster in Patients Taking Immunosuppressant Drugs at the Time of Zoster Vaccination SO MAYO CLINIC PROCEEDINGS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; NECROSIS FACTOR THERAPY; RHEUMATOID-ARTHRITIS; COMPLICATION RATES; OLDER-ADULTS; ASSOCIATION; IMMUNIZATION; INFECTION; DISEASE; VIRUS AB Objective: To determine the risks associated with zoster vaccine when administered to patients taking immunosuppressant medications. Patients and Methods: Patients enrolled in 1 of 7 managed care organizations affiliated with the Vaccine Safety Datalink between January 1, 2006, and December 31, 2009, were eligible. The exposure of interest was zoster vaccination in patients with current or remote immunosuppressant drug use. The primary outcomes were disseminated varicella zoster virus (VZV) and herpes zoster in the 42 days after vaccination. Automated data were collected on immunosuppressant drugs and baseline medical conditions. A logistic regression model using inverse probability treatment weights was used to estimate the odds of developing VZV or herpes zoster. Results: A total of 14,554 individuals had an immunosuppressant medication dispensed around the time of vaccination, including 4826 with current use and 9728 with remote use. Most patients were taking low-dose corticosteroids. No cases of disseminated VZV were found in the current or remote users. The risk of herpes zoster was elevated in the 42 days after vaccination in current vs remote users (adjusted odds ratio, 2.99; 95% CI, 1.58-5.70). Conclusion: We found that patients taking immunosuppressant medications at the time of vaccination had a modest increased risk of herpes zoster in the 42 days after vaccination. The development of herpes zoster within 42 days after vaccination suggests that this is more likely due to reactivation of latent zoster virus than dissemination of the vaccine-derived varicella virus. These findings support the current zoster vaccination guidelines. (C) 2015 Mayo Foundation for Medical Education and Research C1 [Cheetham, T. Craig; Marcy, S. Michael; Tseng, Hung-Fu; Sy, Lina S.; Liu, In-Lu Amy; Bixler, Felicia; Jacobsen, Steven J.] Kaiser Permanente So Calif, Ctr Biol Evaluat & Res, Res & Evaluat, Pasadena, CA 91101 USA. [Baxter, Roger] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Donahue, James G.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Naleway, Allison L.] Kaiser Permanente Northwest, Portland, OR USA. RP Cheetham, TC (reprint author), So Calif Permanente Med Grp, 100 S Los Robles Ave,2nd Floor, Pasadena, CA 91101 USA. EM craig.t.cheetham@kp.org OI Jacobsen, Steven/0000-0002-8174-8533 FU America's Health Insurance Plans from the Centers for Disease Control and Prevention [200-2002-00732] FX This study was funded through a subcontract with America's Health Insurance Plans under contract 200-2002-00732 from the Centers for Disease Control and Prevention. NR 28 TC 10 Z9 10 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD JUL PY 2015 VL 90 IS 7 BP 865 EP 873 DI 10.1016/j.mayocp.2015.04.021 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CM2PY UT WOS:000357525000007 PM 26051268 ER PT J AU Davis, RL Gallagher, MA Asgari, MM Eide, MJ Margolis, DJ Macy, E Burmester, JK Selvam, N Boscarino, JA Cromwell, LF Feigelson, HS Kuntz, JL Pawloski, PA Penfold, RB Raebel, MA Sridhar, G Wu, A La Grenade, LA Pacanowski, MA Pinheiro, SP AF Davis, Robert L. Gallagher, Mia A. Asgari, Maryam M. Eide, Melody J. Margolis, David J. Macy, Eric Burmester, James K. Selvam, Nandini Boscarino, Joseph A. Cromwell, Lee F. Feigelson, Heather S. Kuntz, Jennifer L. Pawloski, Pamala A. Penfold, Robert B. Raebel, Marsha A. Sridhar, Gayathri Wu, Ann La Grenade, Lois A. Pacanowski, Michael A. Pinheiro, Simone P. TI Identification of Stevens-Johnson syndrome and toxic epidermal necrolysis in electronic health record databases SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE Stevens-Johnson syndrome; toxic epidermal necrolysis; pharmacoepidemiology ID ADVERSE DRUG-REACTIONS; HLA-B-ASTERISK-1502 ALLELE; ERYTHEMA MULTIFORME; THAI POPULATION; CLAIMS DATA; CARBAMAZEPINE; ASSOCIATION; HLA-A-ASTERISK-3101; RISK AB BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) carry a high mortality risk. While identifying clinical and genetic risk factors for these conditions has been hindered by their rarity, large electronic health databases hold promise for identifying large numbers of cases for study, especially with the introduction in 2008 of ICD-9 codes more specific for these conditions. ObjectiveThe objective of this study is to estimate the validity of ICD-9 codes for ascertaining SJS/TEN in 12 collaborating research units in the USA, covering almost 60 million lives. MethodsFrom the electronic databases at each site, we ascertained potential cases of SJS/TEN using ICD-9 codes. At five sites, a subset of medical records was abstracted and standardized criteria applied by board-certified dermatologists to adjudicate diagnoses. Multivariate logistic regression was used to identify factors independently associated with validated SJS/TEN cases. ResultsA total of 56591 potential cases of SJS/TEN were identified. A subset of 276 charts was selected for adjudication and 39 (of the 276) were confirmed as SJS/TEN. Patients with the ICD-9 codes introduced after 2008 were more likely to be confirmed as cases (OR 3.32; 95%CI 0.82, 13.47) than those identified in earlier years. Likelihood of case status increased with length of hospitalization. Applying the probability of case status to the 56591 potential cases, we estimated 475-875 to be valid SJS/TEN cases. ConclusionNewer ICD-9 codes, along with length of hospitalization, identified patients with a high likelihood of SJS/TEN. This is important for identification of subjects for future pharmacogenomics studies. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Davis, Robert L.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Davis, Robert L.; Gallagher, Mia A.; Cromwell, Lee F.] Kaiser Permanente Georgia, Atlanta, GA USA. [Asgari, Maryam M.] Kaiser Permanente Northern Calif, Oakland, CA USA. [Eide, Melody J.] Henry Ford Hosp, Detroit, MI 48202 USA. [Margolis, David J.] Univ Penn, Philadelphia, PA 19104 USA. [Macy, Eric] Kaiser Permanente So Calif, Pasadena, CA 91101 USA. [Burmester, James K.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Selvam, Nandini; Sridhar, Gayathri] Healthcore, Wilmington, DE USA. [Boscarino, Joseph A.] Geisinger Hlth Syst, Danville, PA USA. [Feigelson, Heather S.; Raebel, Marsha A.] Kaiser Permanente Colorado, Denver, CO USA. [Kuntz, Jennifer L.] Kaiser Permanente Northwest, Portland, OR USA. [Pawloski, Pamala A.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Penfold, Robert B.] Grp Hlth Res Inst, Seattle, WA USA. [Wu, Ann] Harvard Pilgrim Hlth Care, Boston, MA USA. [La Grenade, Lois A.; Pacanowski, Michael A.; Pinheiro, Simone P.] US FDA, Silver Spring, MD USA. RP Davis, RL (reprint author), UTHSC ORNL, Ctr Biomed Informat, 50N Dunlap Ave,Rm 524R, Memphis, TN 38103 USA. EM rdavis88@uthsc.edu RI Asgari, Maryam/O-4947-2016 FU FDA [HHSF223201000009I] FX Funding was provided by FDA under contract HHSF223201000009I. We would like to thank the project staff at each of the sites, especially Mary Ann Blosky (Geisinger), Hozefa Divan (HealthCore), Kristin Goddard (KP Colorado), Michelle Groesbeck (Henry Ford), Terrie Kitchner (Marshfield), Jill Mesa (KP Northwest), Brian Owens (HealthPartners), Cristy Geno Rasmussen (KP Colorado), Donna Rusinak (Harvard Pilgrim), Monica Sokil (KP Northern California), and Linda Wehnes (Group Health). NR 18 TC 5 Z9 5 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 JUL PY 2015 VL 24 IS 7 BP 684 EP 692 DI 10.1002/pds.3778 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA CL9VC UT WOS:000357325200003 PM 25914229 ER PT J AU Gooch, B Goodman, J Gracia, JN Griffin, SO Grummer-Strawn, L Hirschman, J Hyman, F Iafolla, T Kohn, W Lester, AM Makrides, NS Manski, R Osorio, AM Silverman, B Sinks, T AF Gooch, Barbara Goodman, Jesse Gracia, J. Nadine Griffin, Susan O. Grummer-Strawn, Laurence Hirschman, Jay Hyman, Frederick Iafolla, Timothy Kohn, William Lester, Arlene M. Makrides, Nicholas S. Manski, Richard Osorio, Ana Maria Silverman, Benson Sinks, Thomas CA US Dept Hlth Human Serv Federal Pa TI US Public Health Service Recommendation for Fluoride Concentration in Drinking Water for the Prevention of Dental Caries SO PUBLIC HEALTH REPORTS LA English DT Article ID UNITED-STATES; ENAMEL FLUOROSIS; INFANT FORMULA; CHILDRENS INTELLIGENCE; RISK-FACTORS; ORAL-HEALTH; OSTEOSARCOMA; COMMUNITY; IMPACT; NEEDS C1 [Gooch, Barbara; Griffin, Susan O.; Kohn, William] US Dept HHS, Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Oral Hlth, Washington, DC USA. [Goodman, Jesse] US Dept HHS, Sci & Publ Hlth, US FDA, Washington, DC USA. [Gracia, J. Nadine] US Dept HHS, Off Assistant Secretary Hlth, Washington, DC USA. [Grummer-Strawn, Laurence] US Dept HHS, Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Nutr Phys Act & Obes,Maternal & Child Nutr Br, Washington, DC USA. [Hirschman, Jay] Food & Nutr Serv, USDA, Off Res & Anal, Washington, DC USA. [Hyman, Frederick] US Dept HHS, US FDA, Ctr Drug Evaluat & Res, Div Dermatol & Dent Prod, Washington, DC USA. [Iafolla, Timothy] Natl Inst Dent & Craniofacial Res, US Dept HHS, NIH, Off Sci & Policy Anal, Washington, DC USA. [Lester, Arlene M.; Makrides, Nicholas S.] US PHS, Washington, DC USA. [Lester, Arlene M.] US Dept HHS, Off Secretary, Washington, DC USA. [Makrides, Nicholas S.] US Dept Justice, Fed Bur Prisons, Washington, DC USA. [Manski, Richard] US Dept HHS, Agcy Healthcare Res & Qual, Ctr Financing Access & Cost Trends, Washington, DC USA. [Osorio, Ana Maria] US PHS, US Dept HHS, Off Assistant Secretary Hlth, Washington, DC USA. [Silverman, Benson] US Dept HHS, US FDA, Ctr Food Safety & Appl Nutr, Washington, DC USA. [Sinks, Thomas] US Dept HHS, Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Agcy Tox Subst & Dis Registry, Washington, DC USA. RP Gooch, B (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Oral Hlth, 4770 Buford Hwy NE,MS F-80, Atlanta, GA 30341 USA. EM bgooch@cdc.gov NR 90 TC 0 Z9 0 U1 5 U2 17 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 JUL-AUG PY 2015 VL 130 IS 4 BP 318 EP 331 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CM5DN UT WOS:000357707100008 ER PT J AU Jacobs, AC Brown, PC AF Jacobs, Abigail C. Brown, Paul C. TI Regulatory Forum Opinion Piece*: Transgenic/Alternative Carcinogenicity Assays: A Retrospective Review of Studies Submitted to CDER/FDA 1997-2014 SO TOXICOLOGIC PATHOLOGY LA English DT Article DE carcinogenicity; transgenic; regulatory; FDA AB The International Conference on Harmonization (ICH; S1B of 1997) allows a second species carcinogenicity study to be an alternative to one of the traditional 2-year studies. In the past 17 years, the FDA's Center for Drug Evaluation and Research's (CDER) Executive Carcinogenicity Assessment Committee received 269 alternative carcinogenicity assay protocols for review. This committee's recommendations regarding choice of animal model and dose selection are generally followed by sponsors conducting these studies to increase the acceptability of such studies. The P53(+/-) assay is generally considered appropriate for genotoxic products, and the TgRasH2 assay is appropriate for non-genotoxic or genotoxic drugs. In the United States, the TgAC assay is not used any more and the animals are no longer available. The TgAC assay can detect both tumor promoters and complete carcinogens, and consequently more than half of the dermal TgAC assays resulted in a positive assessment. Currently, more than 75% of mouse carcinogenicity studies are conducted in TgRasH2 mice. Behavior of genotoxic and non-genotoxic drugs in the various assays is reviewed. C1 [Jacobs, Abigail C.; Brown, Paul C.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Jacobs, AC (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Abigail.Jacobs@fda.hhs.gov NR 5 TC 4 Z9 4 U1 0 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2015 VL 43 IS 5 BP 605 EP 610 DI 10.1177/0192623314566241 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA CM2UI UT WOS:000357537400001 PM 25630682 ER PT J AU Rouse, R Min, M Francke, S Mog, S Zhang, J Shea, K Stewart, S Colatsky, T AF Rouse, Rodney Min, Min Francke, Sabine Mog, Steven Zhang, Jun Shea, Katherine Stewart, Sharron Colatsky, Thomas TI Impact of Pathologists and Evaluation Methods on Performance Assessment of the Kidney Injury Biomarker, Kim-1 SO TOXICOLOGIC PATHOLOGY LA English DT Article DE methods; biomarker; qualification; histopathology; nephrotoxicity; cisplatin; Kim-1 ID CISPLATIN; HISTOPATHOLOGY; QUALIFICATION; KAPPA; RATS AB Attempts to characterize and formally qualify biomarkers for regulatory purposes have raised questions about how histological and histopathological methods impact the evaluation of biomarker performance. A group of pathologists was asked to analyze digitized images prepared from rodent kidney injury experiments in studies designed to investigate sources of variability in histopathology evaluations. Study A maximized variability by using samples from diverse studies and providing minimal guidance, contextual information, or opportunities for pathologist interaction. Study B was designed to limit interpathologist variability by using more uniform image sets from different locations within the same kidneys and allowing pathologist selected interactions to discuss and identify the location and injury to be evaluated but without providing a lexicon or peer review. Results from this study suggest that differences between pathologists and across models of disease are the largest sources of variability in evaluations and that blind evaluations do not generally make a significant difference. Results of this study generally align with recommendations from both industry and the U.S. Food and Drug Administration and should inform future studies examining the effects of common lexicons and scoring criteria, peer review, and blind evaluations in the context of biomarker performance assessment. C1 [Rouse, Rodney; Zhang, Jun; Shea, Katherine; Stewart, Sharron; Colatsky, Thomas] US FDA, Div Appl Regulatory Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Min, Min] US FDA, Div Biometr 6, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Francke, Sabine; Mog, Steven] US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, Silver Spring, MD 20993 USA. RP Rouse, R (reprint author), US FDA, Div Appl Regulatory Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM rodney.rouse@fda.hhs.gov NR 21 TC 0 Z9 0 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2015 VL 43 IS 5 BP 662 EP 674 DI 10.1177/0192623314562072 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA CM2UI UT WOS:000357537400007 PM 25520306 ER PT J AU Zusterzeel, R Canos, DA Sanders, WE Silverman, H MaCurdy, TE Worrall, CM Kelman, J Marinac-Dabic, D Strauss, DG AF Zusterzeel, Robbert Canos, Daniel A. Sanders, William E. Silverman, Henry MaCurdy, Thomas E. Worrall, Christopher M. Kelman, Jeffrey Marinac-Dabic, Danica Strauss, David G. TI Comparative Effectiveness of Cardiac Resynchronization Therapy Defibrillators Versus Standard Implantable Defibrillators in Medicare Patients SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID BUNDLE-BRANCH BLOCK; HEART-FAILURE; QRS MORPHOLOGY; MADIT-CRT; WOMEN; MEN; PREDICTORS; DURATION; TRIAL; METAANALYSIS AB Previous analyses have shown that there is lower mortality with cardiac resynchronization therapy defibrillators (CRT-D) in patients with left bundle branch block (LBBB) but demonstrated mixed results in patients without LBBB. We evaluated the comparative effectiveness of CRT-D versus standard implantable defibrillators (ICDs) separately in patients with LBBB and right bundle branch block (RBBB) using Medicare claims data. Medicare records from CRT-D and ICD recipients from 2002 to 2009 that were followed up for up to 48 months were analyzed. We used propensity scores to match patients with ICD to those with CRT-D. In LBBB, 1:1 matching with replacement resulted in 54,218 patients with CRT-D and 20,763 with ICD, and in RBBB, 1:1 matching resulted in 7,298 patients with CRT-D and 7,298 with ICD. In LBBB, CRT-D had a 12% lower risk of heart failure hospitalization or death (hazard ratio [HR] 0.88, 95% confidence interval 0.86 to 0.90) and 5% lower death risk (HR 0.95, 0.92 to 0.97) compared with ICD. In RBBB, CRT-D had a 15% higher risk of heart failure hospitalization or death (FIR 1.15, 1.10 to 1.20) and 13% higher death risk (HR 1.13, 1.07 to 1.18). Sensitivity analysis revealed that accounting for covariates not captured in the Medicare database may lead to increased benefit with CRT-D in LBBB and no difference in RBBB. In conclusion, in a large Medicare population, CRT-D was associated with lower mortality in LBBB but higher mortality in RBBB. The absence of certain covariates, in particular those that determine treatment selection, may affect the results of comparative effectiveness studies using claims data. Published by Elsevier Inc. C1 [Zusterzeel, Robbert; Canos, Daniel A.; Sanders, William E.; Marinac-Dabic, Danica; Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Silverman, Henry; MaCurdy, Thomas E.] Acumen LLC, SafeRx, Burlingame, CA USA. [Worrall, Christopher M.; Kelman, Jeffrey] Ctr Med & Medicaid Serv, Baltimore, MD USA. RP Strauss, DG (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM david.strauss@fda.hhs.gov FU SafeRx Project; Oak Ridge Institute for Science and Education (Oak Ridge, Tennessee) through US Department of Energy; Oak Ridge Institute for Science and Education (Oak Ridge, Tennessee) through USFDA FX This project was supported by the SafeRx Project, a joint initiative of the CMS (Baltimore, Maryland), USFDA (Silver Spring, Maryland), and the US Department of Health and Human Services Office of the Assistant Secretary for Planning and Evaluation and by a research fellowship from the Oak Ridge Institute for Science and Education (Oak Ridge, Tennessee) through an interagency agreement between the US Department of Energy and the USFDA. Acumen LLC is a contractor to CMS. The authors have no conflicts of interest to disclose. NR 25 TC 0 Z9 0 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 1 PY 2015 VL 116 IS 1 BP 79 EP 84 DI 10.1016/j.amjcard.2015.03.037 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CL8PI UT WOS:000357236200012 PM 25933736 ER PT J AU Lozzi, A Agrawal, A Boretsky, A Welle, CG Hammer, DX AF Lozzi, Andrea Agrawal, Anant Boretsky, Adam Welle, Cristin G. Hammer, Daniel X. TI Image quality metrics for optical coherence angiography SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID SPECKLE VARIANCE OCT; TOMOGRAPHY; MICROVASCULATURE; RETINA AB We characterized image quality in optical coherence angiography (OCA) en face planes of mouse cortical capillary network in terms of signal-to-noise ratio (SNR) and Weber contrast (W-c) through a novel mask-based segmentation method. The method was used to compare two adjacent B-scan processing algorithms, (1) average absolute difference (AAD) and (2) standard deviation (SD), while varying the number of lateral cross-sections acquired (also known as the gate length, N). AAD and SD are identical at N = 2 and exhibited similar image quality for N<10. However, AAD is relatively less susceptible to bulk tissue motion artifact than SD. SNR and Wc were 15% and 35% higher for AAD from N = 25 to 100. In addition data sets were acquired with two objective lenses with different magnifications to quantify the effect of lateral resolution on fine capillary detection. The lower power objective yielded a significant mean broadening of 17% in Full Width Half Maximum (FWHM) diameter. These results may guide study and device designs for OCA capillary and blood flow quantification. (C)2015 Optical Society of America C1 [Lozzi, Andrea; Agrawal, Anant; Boretsky, Adam; Welle, Cristin G.; Hammer, Daniel X.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Lozzi, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM lozziandrea88@gmail.com; daniel.hammer@fda.hhs.gov OI Welle, Cristin/0000-0001-8735-0983 FU interagency agreement with DARPA (RE-NET Program, Microsystems Technology Office); FDA Medical Counter Measures Initiative and Critical Path Initiative FX This work was funded by an interagency agreement with DARPA (RE-NET Program, Microsystems Technology Office) and grants from the FDA Medical Counter Measures Initiative and Critical Path 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 US Department of Health and Human Services. NR 25 TC 8 Z9 8 U1 1 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUL 1 PY 2015 VL 6 IS 7 BP 2435 EP 2447 DI 10.1364/BOE.6.002435 PG 13 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA CM1IT UT WOS:000357435200012 PM 26203372 ER PT J AU Strong, DR Messer, K Hartman, SJ Conway, KP Hoffman, AC Pharris-Ciurej, N White, M Green, VR Compton, WM Pierce, J AF Strong, David R. Messer, Karen Hartman, Sheri J. Conway, Kevin P. Hoffman, Allison C. Pharris-Ciurej, Nikolas White, Martha Green, Victoria R. Compton, Wilson M. Pierce, John TI Measurement of multiple nicotine dependence domains among cigarette, non-cigarette and poly-tobacco users: Insights from item response theory SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Nicotine dependence; Poly-tobacco use; Item response theory; Tobacco ID SYNDROME SCALE; SMOKERS; CONTINUUM; SYMPTOMS AB Background: Nicotine dependence (ND) is a key construct that organizes physiological and behavioral symptoms associated with persistent nicotine intake. Measurement of ND has focused primarily on cigarette smokers. Thus, validation of brief instruments that apply to a broad spectrum of tobacco product users is needed. Methods: We examined multiple domains of ND in a longitudinal national study of the United States population, the United States National Epidemiological Survey of Alcohol and Related Conditions (NESARC). We used methods based in item response theory to identify and validate increasingly brief measures of ND that included symptoms to assess ND similarly among cigarette, cigar, smokeless, and poly tobacco users. Results: Confirmatory factor analytic models supported a single, primary dimension underlying symptoms of ND across tobacco use groups. Differential Item Functioning (DIF) analysis generated little support for systematic differences in response to symptoms of ND across tobacco use groups. We established significant concurrent and predictive validity of brief 3- and 5-symptom indices for measuring ND. Conclusions: Measuring ND across tobacco use groups with a common set of symptoms facilitates evaluation of tobacco use in an evolving marketplace of tobacco and nicotine products. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Strong, David R.; Messer, Karen; Hartman, Sheri J.; White, Martha; Pierce, John] Moores UC San Diego Canc Ctr, Canc Prevent & Control Program, La Jolla, CA 92093 USA. [Strong, David R.; Messer, Karen; Hartman, Sheri J.; White, Martha; Pierce, John] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Hoffman, Allison C.; Pharris-Ciurej, Nikolas] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Conway, Kevin P.; Green, Victoria R.; Compton, Wilson M.] NIDA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Green, Victoria R.] Kelly Govt Solut, Bethesda, MD USA. RP Strong, DR (reprint author), Univ Calif San Diego, Canc Prevent & Control Program, Moores UC San Diego Canc Ctr, La Jolla, CA 92093 USA. EM dstrong@ucsd.edu OI Conway, Kevin/0000-0002-7638-339X FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; National Cancer Institute [1R01CA172058-1]; UC Tobacco-Related Disease Research Program [21XT-0076, 21RT-0135] FX This project has been funded with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under Contract No. HHSN271201100027C. In addition, Drs. Strong, Pierce, Messer, Hartman, and Ms. White were partially supported on National Cancer Institute (1R01CA172058-1) and UC Tobacco-Related Disease Research Program grants (21XT-0076; 21RT-0135). The role of Drs. Hoffman, Pharris-Ciurej, Conway, Compton, and Ms. Green on this paper were through their involvement on contract no. HHSN271201100027C. They had no involvement in the cited grants. NR 34 TC 1 Z9 1 U1 2 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2015 VL 152 BP 185 EP 193 DI 10.1016/j.drugalcdep.2015.03.040 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CL1XN UT WOS:000356738300025 PM 26005043 ER PT J AU Azizian, H Mossoba, MM Fardin-Kia, AR Delmonte, P Karunathilaka, SR Kramer, JKG AF Azizian, Hormoz Mossoba, Magdi M. Fardin-Kia, Ali Reza Delmonte, Pierluigi Karunathilaka, Sanjeewa R. Kramer, John K. G. TI Novel, Rapid Identification, and Quantification of Adulterants in Extra Virgin Olive Oil Using Near-Infrared Spectroscopy and Chemometrics SO LIPIDS LA English DT Article DE FT-NIR; PLS; Extra virgin olive oil; FA markers; Volatile compounds ID FTIR SPECTROSCOPY; VEGETABLE-OILS; FATTY-ACIDS; SUNFLOWER OIL; EDIBLE OILS; CORN-OIL; AUTHENTICATION; TRIGLYCERIDES; QUALITY; MODELS AB A new, rapid Fourier transform near infrared (FT-NIR) spectroscopic procedure is described to screen for the authenticity of extra virgin olive oils (EVOO) and to determine the kind and amount of an adulterant in EVOO. To screen EVOO, a partial least squares (PLS1) calibration model was developed to estimate a newly created FT-NIR index based mainly on the relative intensities of two unique carbonyl overtone absorptions in the FT-NIR spectra of EVOO and other mixtures attributed to volatile (5280 cm(-1)) and non-volatile (5180 cm(-1)) components. Spectra were also used to predict the fatty acid (FA) composition of EVOO or samples spiked with an adulterant using previously developed PLS1 calibration models. Some adulterated mixtures could be identified provided the FA profile was sufficiently different from those of EVOO. To identify the type and determine the quantity of an adulterant, gravimetric mixtures were prepared by spiking EVOO with different concentrations of each adulterant. Based on FT-NIR spectra, four PLS1 calibration models were developed for four specific groups of adulterants, each with a characteristic FA composition. Using these different PLS1 calibration models for prediction, plots of predicted vs. gravimetric concentrations of an adulterant in EVOO yielded linear regression functions with four unique sets of slopes, one for each group of adulterants. Four corresponding slope rules were defined that allowed for the determination of the nature and concentration of an adulterant in EVOO products by applying these four calibration models. The standard addition technique was used for confirmation. C1 [Azizian, Hormoz] NIR Technol Inc, Oakville, ON L6M 2M2, Canada. [Mossoba, Magdi M.; Fardin-Kia, Ali Reza; Delmonte, Pierluigi; Karunathilaka, Sanjeewa R.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD USA. RP Azizian, H (reprint author), NIR Technol Inc, Oakville, ON L6M 2M2, Canada. EM hazizian@nirtechnologies.com; magdi.mossoba@fda.hhs.gov; jkgkramer@rogers.com NR 36 TC 9 Z9 9 U1 11 U2 40 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 EI 1558-9307 J9 LIPIDS JI Lipids PD JUL PY 2015 VL 50 IS 7 BP 705 EP 718 DI 10.1007/s11745-015-4038-4 PG 14 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA CL9FC UT WOS:000357280200010 PM 26050093 ER PT J AU Khozin, S Jarow, JP Pazdur, R Liu, K AF Khozin, Sean Jarow, Jonathan P. Pazdur, Richard Liu, Ke TI Why do oncology drugs fail to gain US regulatory approval? SO NATURE REVIEWS DRUG DISCOVERY LA English DT News Item C1 [Khozin, Sean; Jarow, Jonathan P.; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Liu, Ke] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Khozin, S (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sean.khozin@fda.hhs.gov NR 0 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD JUL PY 2015 VL 14 IS 7 BP 450 EP U157 DI 10.1038/nrd4651 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA CL8BX UT WOS:000357198300007 PM 26000722 ER PT J AU Huang, S Fisher, JAN Ye, MJ Nabili, M Kim, Y Ma, R Kim, YS Coleman, T Civillico, EF Krauthamer, V Myers, M Welle, C AF Huang, Stanley Fisher, Jonathan A. N. Ye, Meijun Nabili, Marjan Kim, Yeonho Ma, Rui Kim, Yun Soung Coleman, Todd Civillico, Eugene F. Krauthamer, Victor Myers, Matthew Welle, Cristin TI Detecting Ultrasound-Induced Brain Injury in the Mouse with a Novel Flexible Epidermal Electrode Array SO NEUROTHERAPEUTICS LA English DT Meeting Abstract C1 [Huang, Stanley; Ye, Meijun] US FDA, Rockville, MD 20857 USA. [Fisher, Jonathan A. N.] New York Med Coll, Valhalla, NY 10595 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2015 VL 12 IS 3 BP 683 EP 684 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CL9WP UT WOS:000357329600030 ER PT J AU Knaack, GL Ruda, K Jain, A Wachrathit, KT Krauthamer, V Pancrazio, JJ Civillico, EF Welle, CG AF Knaack, Gretchen L. Ruda, Kiersten Jain, Anjuli Wachrathit, Kelliann T. Krauthamer, Victor Pancrazio, Joseph J. Civillico, Eugene F. Welle, Cristin G. TI Assessment of the Neuroinflammatory Response to Chronic Cortical Implants Intended for Therapeutic Applications SO NEUROTHERAPEUTICS LA English DT Meeting Abstract C1 [Knaack, Gretchen L.; Ruda, Kiersten; Jain, Anjuli; Wachrathit, Kelliann T.] US FDA, Rockville, MD 20857 USA. RI Pancrazio, Joseph/M-3206-2015 OI Pancrazio, Joseph/0000-0001-8276-3690 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 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2015 VL 12 IS 3 BP 684 EP 684 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CL9WP UT WOS:000357329600031 ER PT J AU Ye, MJ Nabili, M Fishser, J Huang, S Kim, Y Civillico, E Krauthamer, V Myers, M AF Ye, Meijun Nabili, Marjan Fishser, Jonathan Huang, Stanley Kim, Yeonho Civillico, Eugene Krauthamer, Victor Myers, Matthew TI ElectrophySiological Signatures of Mild Brain injury in a Novel Mouse Model SO NEUROTHERAPEUTICS LA English DT Meeting Abstract C1 [Ye, Meijun; Nabili, Marjan; Fishser, Jonathan; Huang, Stanley] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2015 VL 12 IS 3 BP 685 EP 685 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CL9WP UT WOS:000357329600032 ER PT J AU Burotto, M Edgerly, M Poruchynsky, M Velarde, M Wilkerson, J Kotz, H Bates, S Balasubramaniam, S Fojo, T AF Burotto, Mauricio Edgerly, Maureen Poruchynsky, Marianne Velarde, Margarita Wilkerson, Julia Kotz, Herb Bates, Susan Balasubramaniam, Sanjeeve Fojo, Tito TI Phase II Clinical Trial of Ixabepilone in Metastatic Cervical Carcinoma SO ONCOLOGIST LA English DT Article ID RENAL-CELL CARCINOMA; EPOTHILONE-B ANALOG; RADIATION RECALL; PACLITAXEL; BMS-247550; CANCER AB Background. Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC. Methods. Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot. Results. In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naive, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated. Conclusion. Ixabepilone was well tolerated but showed very modest activity in second-or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC. C1 [Burotto, Mauricio; Edgerly, Maureen; Poruchynsky, Marianne; Velarde, Margarita; Wilkerson, Julia; Kotz, Herb; Bates, Susan; Fojo, Tito] NCI, NIH, Bethesda, MD 20892 USA. [Balasubramaniam, Sanjeeve] Food & Drug Adm, Silver Spring, MD USA. RP Burotto, M (reprint author), NCI, NIH, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM mburotto@alemana.cl OI Wilkerson, Julia/0000-0002-6965-0867; Balasubramaniam, Sanjeeve/0000-0002-0643-2117 FU Cancer Therapy Evaluation Program (CTEP) FX Cancer Therapy Evaluation Program (CTEP) NR 13 TC 1 Z9 1 U1 0 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 JUL PY 2015 VL 20 IS 7 BP 725 EP 726 DI 10.1634/theoncologist.2015-0104 PG 2 WC Oncology SC Oncology GA CL9DK UT WOS:000357275500008 PM 26040622 ER PT J AU Lynch, PJ Thompson, EE McGinnis, K Gonzalez, YI Lo Surdo, J Bauer, SR Hursh, DA AF Lynch, Patrick J. Thompson, Elaine E. McGinnis, Kathleen Rovira Gonzalez, Yazmin I. Lo Surdo, Jessica Bauer, Steven R. Hursh, Deborah A. TI Chromatin Changes at the PPAR-gamma 2 Promoter During Bone Marrow-Derived Multipotent Stromal Cell Culture Correlate With Loss of Gene Activation Potential SO STEM CELLS LA English DT Article DE Mesenchymal stromal cells; Chromatin; Gene expression regulation; Cell differentiation; Epigenomics; Immunomodulation ID MESENCHYMAL STEM-CELLS; HISTONE METHYLTRANSFERASE ACTIVITY; CHIP-CHIP DATA; REPLICATIVE SENESCENCE; LYSINE-27 METHYLATION; EPIGENOMIC ANALYSIS; SELF-RENEWAL; ISING-MODEL; GENOME; DIFFERENTIATION AB Bone marrow-derived multipotent stromal cells (BM-MSCs) display a broad range of therapeutically valuable properties, including the capacity to form skeletal tissues and dampen immune system responses. However, to use BM-MSCs in a clinical setting, amplification is required, which may introduce epigenetic changes that affect biological properties. Here we used chromatin immunoprecipitation to compare post-translationally modified histones at a subset of gene promoters associated with developmental and environmental plasticity in BM-MSCs from multiple donors following culture expansion. At many locations, we observed localization of both transcriptionally permissive (H3K4me3) and repressive (H3K27me3) histone modifications. These chromatin signatures were consistent among BM-MSCs from multiple donors. Since promoter activity depends on the relative levels of H3K4me3 and H3K27me3, we examined the ratio of H3K4me3 to H3K27me3 (K4/K27) at promoters during culture expansion. The H3K4me3 to H3K27me3 ratios were maintained at most assayed promoters over time. The exception was the adipose-tissue specific promoter for the PPAR-2 isoform of PPAR-, which is a critical positive regulator of adipogenesis. At PPAR-2, we observed a change in K4/K27 levels favoring the repressed chromatin state during culture. This change correlated with diminished promoter activity in late passage cells exposed to adipogenic stimuli. In contrast to BM-MSCs and osteoblasts, lineage-restricted preadipocytes exhibited levels of H3K4me3 and H3K27me3 that favored the permissive chromatin state at PPAR-2. These results demonstrate that locus-specific changes in H3K4me3 and H3K27me3 levels can occur during BM-MSC culture that may affect their properties. Stem Cells 2015;33:2169-2181 C1 [Lynch, Patrick J.; Thompson, Elaine E.; McGinnis, Kathleen; Rovira Gonzalez, Yazmin I.; Lo Surdo, Jessica; Bauer, Steven R.; Hursh, Deborah A.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Cellular & Tissue Therapies Branch, Silver Spring, MD 20993 USA. RP Hursh, DA (reprint author), US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave Bldg 72,Rm 3216, Silver Spring, MD 20993 USA. EM Deborah.Hursh@fda.hhs.gov OI Thompson, Elaine/0000-0001-8633-2417 FU U.S. Department of Energy; U.S. Food and Drug Administration; U.S. Food and Drug Administration Modernizing Science Initiative; Medical Countermeasures Initiative FX Patrick Lynch, Elaine Thompson, Kathleen McGinnis, and Yazmin Rovira Gonzalez 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 the members of the FDA's MSC Consortium for their valuable insights and discussions of this work. We also thank Drs. Carl Gregory, Mark Mortin, Bharat Joshi, Malcolm Moos, and Kristen Nickens for critical reviews of this manuscript and Brian Stultz for technical support. This project was supported by grants from the U.S. Food and Drug Administration Modernizing Science Initiative and the Medical Countermeasures Initiative. NR 74 TC 4 Z9 4 U1 0 U2 0 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 JUL PY 2015 VL 33 IS 7 BP 2169 EP 2181 DI 10.1002/stem.1967 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA CL0YE UT WOS:000356668200009 PM 25640287 ER PT J AU Geanacopoulos, M Barratt, R AF Geanacopoulos, Mark Barratt, Ruth TI How the Critical Path Initiative Addresses CDER's Regulatory Science Needs: Some Illustrative Examples SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Review DE regulatory science; critical path initiative; drugs; CDER's science and research needs; research AB Since 2008, the Critical Path Initiative has supported FDA's program of intramural research projects in regulatory science, with the goal of improving translation of advances in emerging sciences to the development of safe and effective medical products. Since 2011, the research of FDA's Center for Drug Evaluation and Research (CDER), including the work supported by the Critical Path Initiative, has been guided by the regulatory science needs identified in the CDER science and research needs report. In this review, the authors highlight a few of CDER'S Critical Path Initiative research projects, each addressing a different regulatory science need, to illustrate the diversity of regulatory science at CDER. They also describe elements common to these research projects, including broad collaboration with external partners, an increasing dependence on large data sets and computational models, and requirements for resources or perspectives specific to FDA. C1 [Geanacopoulos, Mark; Barratt, Ruth] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Silver Spring, MD USA. RP Barratt, R (reprint author), Ctr Drug Evaluat & Res, Off Translat Sci, Bldg 21,Room 4540,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Ruth.Barratt@fda.hhs.gov NR 13 TC 1 Z9 1 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD JUL PY 2015 VL 49 IS 4 BP 466 EP 472 DI 10.1177/2168479014567323 PG 7 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CL9LM UT WOS:000357300100002 ER PT J AU Sullivan, HW O'Donoghue, AC Aikin, KJ AF Sullivan, Helen W. O'Donoghue, Amie C. Aikin, Kathryn J. TI Communicating Benefit and Risk Information in Direct-to-Consumer Print Advertisements: A Randomized Study SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE direct-to-consumer; advertising; prescription drugs; risk communication; quantitative information ID DRUG FACTS BOX; NUMERACY; HARMS AB Background: Previous research demonstrated that providing qualitative and quantitative information in a drug facts box may help individuals understand prescription drug information in print-based direct-to-consumer advertisements. The authors sought to determine whether qualitative, quantitative, or a combination thereof best communicates benefit and risk information. Methods: To replicate and extend previous research, the authors used simple quantitative drug information. A randomized controlled study was conducted with 5067 Internet panelists with heartburn. Participants viewed a drug facts box with benefit and risk information that varied the presence or absence of qualitative summaries and absolute frequencies, percentages, and absolute differences. Measures included knowledge of drug benefits and risks, perceptions, and intentions. Results: Providing absolute frequencies and percentages most improved participants' drug knowledge and affected perceptions and intentions. Conclusions: The study findings suggest that, for simple drug information, adding absolute frequencies and percentages to direct-to-consumer advertisements may benefit consumers. Absolute differences and qualitative labels may not be needed. C1 [Sullivan, Helen W.; O'Donoghue, Amie C.; Aikin, Kathryn J.] US FDA, Silver Spring, MD 20993 USA. RP Sullivan, HW (reprint author), US FDA, Off Prescript Drug Promot, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Helen.Sullivan@fda.hhs.gov FU FDA FX The authors received no external financial support. The study was funded by FDA, employer of the authors. NR 28 TC 4 Z9 4 U1 1 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 JUL PY 2015 VL 49 IS 4 BP 493 EP 502 DI 10.1177/2168479015572370 PG 10 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CL9LM UT WOS:000357300100005 ER PT J AU Stockbridge, MD Taylor, K AF Stockbridge, Melissa D. Taylor, Kellie TI A Method of Addressing Proprietary Name Similarity for US Prescription Drugs SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Review DE medication error; error review; prescription; brand name; trade name ID LOOK-ALIKE; ERRORS AB There is an increased risk of medication error and harm to a patient whenever 2 or more drug product names appear alike in sound, look, or meaning. Any ambiguity of the proprietary name (trade or brand name) of a drug product can lead to errors in ordering, dispensing, or administering medication. A drug's name is a critical identifier, and correct product identification is important to the responsible administration of medicine. This article describes a series of tools created for regulatory reviewers to enhance the review of proprietary names under current federal regulations, with the goal of encouraging further innovation toward the goal of medication safety. These tools include measures of orthographic, phonetic, and semantic similarities and are designed be used together with the existing computerized measures of similarity. It is the hope that highlighting the importance of medication error reporting for the safety review process will further encourage health care professionals to provide adequate and detailed reporting regarding medication errors, which will lead to improvements in the overall safety review process. C1 [Stockbridge, Melissa D.] Univ Maryland, College Pk, MD 20742 USA. [Taylor, Kellie] Ctr Drug Evaluat & Res, Div Medicat Error Prevent & Anal, White Oak, MD USA. RP Stockbridge, MD (reprint author), Univ Maryland, Dept Hearing & Speech Sci, 0100 Samuel J LeFrak Hall, College Pk, MD 20742 USA. EM mdstock@umd.edu OI Stockbridge, Melissa/0000-0001-9069-1236 NR 17 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD JUL PY 2015 VL 49 IS 4 BP 524 EP 529 DI 10.1177/2168479015570331 PG 6 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CL9LM UT WOS:000357300100009 ER PT J AU Forbes, B Backman, P Christopher, D Dolovich, M Li, BV Morgan, B AF Forbes, Ben Backman, Per Christopher, David Dolovich, Myrna Li, Bing V. Morgan, Beth TI In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches SO AAPS JOURNAL LA English DT Review DE aerosol; bioequivalence; deposition; dissolution; in vitro-in vivo correlation; inhaler; regulatory; statistics and data analysis ID COMPUTATIONAL FLUID-DYNAMICS; POSITRON-EMISSION-TOMOGRAPHY; PARTICLE-SIZE DISTRIBUTION; REGIONAL LUNG DEPOSITION; PERFUSED RAT LUNG; DRUG-DELIVERY; COMPUTED-TOMOGRAPHY; FLUTICASONE PROPIONATE; INHALATION PRODUCTS; AEROSOL DEPOSITION AB This article is part of a series of reports from the "Orlando Inhalation Conference-Approaches in International Regulation" which was held in March 2014, and coorganized by the University of Florida and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of the conference was to foster the exchange of ideas and knowledge across the global scientific and regulatory community in order to identify and help move towards strategies for internationally harmonized, science-based regulatory approaches for the development and marketing approval of inhalation medicines, including innovator and second entry products. This article provides an integrated perspective of case studies and discussion related to in vitro testing of orally inhaled products, including in vitro-in vivo correlations and requirements for in vitro data and statistical analysis that support quality or bioequivalence for regulatory applications. C1 [Forbes, Ben] Kings Coll London, Inst Pharmaceut Sci, London SE1 9NH, England. [Backman, Per] AstraZeneca R&D, Molndal, Sweden. [Christopher, David] Merck Res Labs, West Point, PA USA. [Dolovich, Myrna] McMaster Univ, Hamilton, ON, Canada. [Li, Bing V.] US FDA, Silver Spring, MD USA. [Morgan, Beth] GlaxoSmithKline, Zebulon, NC USA. RP Forbes, B (reprint author), Kings Coll London, Inst Pharmaceut Sci, 150 Stamford St, London SE1 9NH, England. EM Ben.forbes@kcl.ac.uk NR 113 TC 7 Z9 7 U1 1 U2 12 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 2015 VL 17 IS 4 BP 837 EP 852 DI 10.1208/s12248-015-9763-3 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL0DV UT WOS:000356610300007 PM 25940082 ER PT J AU Jiang, WL Makhlouf, F Schuirmann, DJ Zhang, XY Zheng, N Conner, D Yu, LX Lionberger, R AF Jiang, Wenlei Makhlouf, Fairouz Schuirmann, Donald J. Zhang, Xinyuan Zheng, Nan Conner, Dale Yu, Lawrence X. Lionberger, Robert TI A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion SO AAPS JOURNAL LA English DT Article DE generic drugs; narrow therapeutic index (NTI) drugs; reference-scaled average bioequivalence; within-subject variability ID HIGHLY VARIABLE DRUGS; PRODUCTS AB Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00-125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD's within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion. C1 [Jiang, Wenlei; Zhang, Xinyuan; Zheng, Nan; Conner, Dale; Lionberger, Robert] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Makhlouf, Fairouz; Schuirmann, Donald J.] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yu, Lawrence X.] US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Lionberger, R (reprint author), US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. EM robert.lionberger@fda.hhs.gov NR 17 TC 7 Z9 8 U1 1 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 JUL PY 2015 VL 17 IS 4 BP 891 EP 901 DI 10.1208/s12248-015-9753-5 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL0DV UT WOS:000356610300011 PM 25840883 ER PT J AU Papich, MG Martinez, MN AF Papich, Mark G. Martinez, Marilyn N. TI Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls SO AAPS JOURNAL LA English DT Article DE BCS; dogs; canine; permeability; solubility ID WATER-SOLUBLE DRUGS; IN-VITRO; HEALTHY DOGS; DOSAGE FORMS; BIOWAIVER MONOGRAPHS; 1ST-PASS METABOLISM; CACO-2 MONOLAYERS; P-GLYCOPROTEIN; ANIMAL-MODEL; CELL-LINE AB The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential effects of formulation on the human drug oral bioavailability. When used in conjunction with in vitro dissolution tests, the BCS can support the prediction of in vivo product performance and the development of mechanistic models that support formulation assessments through the generation of "what if" scenarios. To date, the applicability of existing human BCS criteria has not been evaluated in dogs, thereby limiting its use in canine drug development. Therefore, we examined 50 drugs for which absolute bioavailability (F) was available both in dogs and humans. The drugs were also evaluated for any potential association between solubility (calculated from the dose number, Do) or lipophilicity (LogP) and F in dogs. In humans, solubility is determined in 250 mL of fluid. However, the appropriate volume for classifying drug solubility in dogs has not been established. In this analysis, the estimated volume of a water flush administered to fasted dogs (6 mL) and a volume of 250 mL scaled to a Beagle dog (35 mL) were examined. In addition, in humans, a Do value greater than 1.0 is used to define a compound as highly soluble and a LogP value greater than 1.72 as high permeability. These same criteria were applied for defining highly soluble and highly permeable in dogs. Whether using 35 or 6 mL to determine Do, the canine solubility classification remained unchanged for all but seven compounds. There were no clear associations between a drug's F in dogs and humans or between the canine value of F and either its human BCS classification, its LogP value, or the canine Do estimate. There was a tendency for those drugs with canine values of F equal to or greater than 80% to have LogP values equal to or greater than 1.0. Exceptions to this observation tended to be those compounds known to be absorbed via mechanisms other than passive diffusion (e.g., via transporters or paracellular transporters). Although there are limitations to the approach used in this study, the results of our assessment strongly suggest that the human BCS classification system requires substantial modification before it can be reliably applied to dogs. C1 [Papich, Mark G.] N Carolina State Univ, Coll Vet Med, Raleigh, NC 27607 USA. [Martinez, Marilyn N.] US FDA, Ctr Vet Med, Rockville, MD 20855 USA. RP Papich, MG (reprint author), N Carolina State Univ, Coll Vet Med, 1060 William Moore Dr, Raleigh, NC 27607 USA. EM mgpapich@ncsu.edu FU United States Pharmacopeia FX The authors would like to thank Robyn Martinez for her help collecting data for this manuscript. They also appreciate the support from the United States Pharmacopeia in the early stages of this project. The authors also acknowledge the advice and recommendations from Dr. G.L. Amidon and Dr. James Polli in the analysis of these data. NR 99 TC 2 Z9 2 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JUL PY 2015 VL 17 IS 4 BP 948 EP 964 DI 10.1208/s12248-015-9743-7 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL0DV UT WOS:000356610300016 PM 25916691 ER PT J AU Yu, LX Baker, J Berlam, SC Boam, A Brandreth, EJ Buhse, L Cosgrove, T Doleski, D Ensor, L Famulare, J Ganapathy, M Grampp, G Hussong, D Iser, R Johnston, G Kesisoglou, F Khan, M Kozlowski, S Lacana, E Lee, SL Miller, S Miksinski, SP Moore, CMV Mullin, T Raju, GK Raw, A Rosencrance, S Rosolowsky, M Stinavage, P Thomas, H Wesdyk, R Windisch, J Vaithiyalingam, S AF Yu, Lawrence X. Baker, Jeffrey Berlam, Susan C. Boam, Ashley Brandreth, E. J. Buhse, Lucinda Cosgrove, Thomas Doleski, David Ensor, Lynne Famulare, Joseph Ganapathy, Mohan Grampp, Gustavo Hussong, David Iser, Robert Johnston, Gordon Kesisoglou, Filippos Khan, Mansoor Kozlowski, Steven Lacana, Emanuela Lee, Sau L. Miller, Stephen Miksinski, Sarah Pope Moore, Christine M. V. Mullin, Theresa Raju, G. K. Raw, Andre Rosencrance, Susan Rosolowsky, Mark Stinavage, Paul Thomas, Hayden Wesdyk, Russell Windisch, Joerg Vaithiyalingam, Sivakumar TI Advancing Product Quality: a Summary of the Inaugural FDA/PQRI Conference SO AAPS JOURNAL LA English DT Article ID CLASSIFICATION; DISSOLUTION; DESIGN AB On September 16 and 17, 2014, the Food and Drug Administration (FDA) and Product Quality Research Institute (PQRI) inaugurated their Conference on Evolving Product Quality. The Conference is conceived as an annual forum in which scientists from regulatory agencies, industry, and academia may exchange viewpoints and work together to advance pharmaceutical quality. This Conference Summary Report highlights key topics of this conference, including (1) risk-based approaches to pharmaceutical development, manufacturing, regulatory assessment, and post-approval changes; (2) FDA-proposed quality metrics for products, facilities, and quality management systems; (3) performance-based quality assessment and clinically relevant specifications; (4) recent developments and implementation of continuous manufacturing processes, question-based review, and European Medicines Agency (EMA)-FDA pilot for Quality-by-Design (QbD) applications; and (5) breakthrough therapies, biosimilars, and international harmonization, focusing on ICH M7 and Q3D guidelines. The second FDA/PQRI conference on advancing product quality is planned for October 5-7, 2015. C1 [Yu, Lawrence X.; Baker, Jeffrey; Boam, Ashley; Buhse, Lucinda; Cosgrove, Thomas; Doleski, David; Ensor, Lynne; Hussong, David; Iser, Robert; Khan, Mansoor; Kozlowski, Steven; Lacana, Emanuela; Lee, Sau L.; Miller, Stephen; Miksinski, Sarah Pope; Moore, Christine M. V.; Mullin, Theresa; Raw, Andre; Rosencrance, Susan; Wesdyk, Russell] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Berlam, Susan C.] Pfizer Inc, Groton, CT 06340 USA. [Brandreth, E. J.] Inovio, Plymouth Meeting, PA 19462 USA. [Famulare, Joseph] Genentech Roche, San Francisco, CA 94080 USA. [Grampp, Gustavo; Johnston, Gordon] Amgen Inc, Thousand Oaks, CA 91320 USA. [Kesisoglou, Filippos] Gener Pharmaceut Assoc GPhA, Washington, DC 20001 USA. [Ganapathy, Mohan] Merck & Co Inc, West Point, PA 19486 USA. [Raju, G. K.] MIT, Cambridge, MA 02139 USA. [Raju, G. K.] Light Pharm Inc, Cambridge, MD 02142 USA. [Rosolowsky, Mark] Bristol Myers Squibb Co, Princeton, NJ 08540 USA. [Stinavage, Paul] Pfizer Global Mfg, Kalamazoo, MI 49001 USA. [Thomas, Hayden] Vertex Pharmaceut, Boston, MD 02210 USA. [Windisch, Joerg] Sandoz Biopharmaceut, Princeton, NJ 08540 USA. [Vaithiyalingam, Sivakumar] Teva Pharmaceut USA, Pomona, NY 10970 USA. RP Yu, LX (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM lawrence.yu@fda.hhs.gov NR 22 TC 2 Z9 3 U1 1 U2 13 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 2015 VL 17 IS 4 BP 1011 EP 1018 DI 10.1208/s12248-015-9754-4 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL0DV UT WOS:000356610300021 PM 25840884 ER PT J AU Kelley, M Stevenson, L Golob, M Devanarayan, V Pedras-Vasconcelos, J Staack, RF Jenkins, R Booth, B Wakshull, E Bowsher, R Rock, M Dudal, S DeSilva, B AF Kelley, Marian Stevenson, Lauren Golob, Michaela Devanarayan, Viswanath Pedras-Vasconcelos, Joao Staack, Roland F. Jenkins, Rand Booth, Brian Wakshull, Eric Bowsher, Ronald Rock, Marie Dudal, Sherri DeSilva, Binodh TI Workshop Report: AAPS Workshop on Method Development, Validation, and Troubleshooting of Ligand-Binding Assays in the Regulated Environment SO AAPS JOURNAL LA English DT Article DE antibody; bioanalytical; biomarker; ligand-binding assays; immunogenicity ID BIOANALYTICAL METHOD VALIDATION; MACROMOLECULES; QUANTIFICATION AB A novel format was introduced at the recent AAPS NBC Workshop on Method Development, Validation and Troubleshooting in San Diego on 18th May 2014. The workshop format was initiated by Binodh De Silva; Marie Rock and Sherri Dudal joined the initiative to develop and chair the workshop. Questions were solicited by a variety of avenues, including a Linked-In Discussion Group. Once collated and clarified, the topics covered assay development, validation, and analysis of PK, Immunogenicity, and Biomarkers with an additional topic on alternative bioanalytical technologies. A panel of experts (workshop report co-authors) was assigned to each topic to bring forward thought-provoking aspects of each topic. The format of the workshop was developed to target the needs of bioanalytical scientists with intermediate to advanced experience in the field ranging to enable robust discussion and to delve deeper into the current bioanalytical hot topics. While the new format allowed for an interactive session with the topical discussion driven by the audience members, it did not foster equal discussion time for all of the proposed topics, especially Biomarkers and alternative LBA technologies. C1 [Kelley, Marian] MKelley Consulting LLC, W Chester, PA USA. [Stevenson, Lauren] Biogen Idec Inc, Translat Sci, Cambridge, MA USA. [Golob, Michaela] Merck KGaA, Quantitat Pharmacol & Drug Disposit, Grafing, Germany. [Devanarayan, Viswanath] AbbVie Inc, Exploratory Stat & BioInformat, N Chicago, IL 60064 USA. [Pedras-Vasconcelos, Joao] FDA CDER DTP, Silver Spring, MD USA. [Staack, Roland F.] Roche Innovat Ctr Penzberg, DMPK, Pharmaceut Sci, Penzberg, Germany. [Staack, Roland F.] Roche Innovat Ctr Penzberg, BA R&D, Pharmaceut Sci, Penzberg, Germany. [Jenkins, Rand] PPD Bioanalyt Labs, Chromatog Sci, Richmond, VA USA. [Booth, Brian] US FDA, Silver Spring, MD USA. [Wakshull, Eric] Genentech Inc, Bioanalyt Sci, San Francisco, CA 94080 USA. [Bowsher, Ronald] B2S Consulting, Indianapolis, IN 46327 USA. [Rock, Marie] WIL Res, Skokie, IL USA. [Dudal, Sherri] Roche Innovat Ctr Basel, DMPK, Pharmaceut Sci, Basel, Switzerland. [Dudal, Sherri] Roche Innovat Ctr Basel, BA R&D, Pharmaceut Sci, Basel, Switzerland. [DeSilva, Binodh] Bristol Myers Squibb Co, Bioanalyt Sci Biol, Princeton, NJ 08540 USA. RP DeSilva, B (reprint author), Bristol Myers Squibb Co, Bioanalyt Sci Biol, Princeton, NJ 08540 USA. EM binodh.desilva@bms.com NR 9 TC 1 Z9 1 U1 1 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 JUL PY 2015 VL 17 IS 4 BP 1019 EP 1024 DI 10.1208/s12248-015-9767-z PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL0DV UT WOS:000356610300022 PM 25921938 ER PT J AU Polak, S Pugsley, MK Stockbridge, N Garnett, C Wisniowska, B AF Polak, Sebastian Pugsley, Michael K. Stockbridge, Norman Garnett, Christine Wisniowska, Barbara TI Early Drug Discovery Prediction of Proarrhythmia Potential and Its Covariates SO AAPS JOURNAL LA English DT Article ID TORSADE-DE-POINTES; QT INTERVAL PROLONGATION; CELL-DERIVED CARDIOMYOCYTES; PIG VENTRICULAR MYOCYTES; IN-VITRO DATA; CARDIAC-ARRHYTHMIAS; EARLY AFTERDEPOLARIZATIONS; SAFETY PHARMACOLOGY; NONCARDIAC DRUGS; HERG CHANNEL C1 [Garnett, Christine] Certara, St Louis, MO USA. [Polak, Sebastian] Simcyp Part Certara, Sheffield, S Yorkshire, England. [Polak, Sebastian; Wisniowska, Barbara] Jagiellonian Univ, Coll Med, Krakow, Poland. [Pugsley, Michael K.] Janssen Pharmaceut LLC, Dept Global Safety Pharmacol & Toxicol Pathol, Raritan, NJ 08869 USA. [Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Polak, S (reprint author), Simcyp Part Certara, Sheffield, S Yorkshire, England. EM spolak@cm-uj.krakow.pl NR 75 TC 3 Z9 3 U1 0 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 2015 VL 17 IS 4 BP 1025 EP 1032 DI 10.1208/s12248-015-9773-1 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL0DV UT WOS:000356610300023 PM 25940083 ER PT J AU Kaur, P Jiang, XJ Duan, J Stier, E AF Kaur, Paramjeet Jiang, Xiaojian Duan, John Stier, Ethan TI Applications of In Vitro-In Vivo Correlations in Generic Drug Development: Case Studies SO AAPS JOURNAL LA English DT Article DE bioequivalence; extended; release drug products; generics; IVIVC; SUPAC AB In vitro-in vivo correlation (IVIVC) is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. The main objective of an IVIVC is to serve as a surrogate for human bioequivalence (BE) studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and postapproval changes. The US Food and Drug Administration (FDA) published a regulatory guidance related to development, evaluation, and applications of IVIVC for extended-release (ER) oral dosage forms in September 1997. Despite the publication of this guidance, the deficiencies related to IVIVC are still identified by the Division of Bioequivalence in the process of Abbreviated New Drug Application (ANDA) review. Thus, the main objective of this article is to present the most commonly occurring deficiencies associated with IVIVCs via selected case studies from the AND As for oral ER drug products only. We searched internal FDA databases from January 1996 to December 2014 to identify the ANDAs for proposed generic oral ER drug products containing IVIVC. Only 14 ANDA submissions had IVIVC data, and most were not acceptable. Only one ANDA submission included adequate information related to IVIVC data enabling the completion of BE review within first review cycle. It is hoped that awareness of the deficiencies presented in our article would help the generic drug applicants to submit complete and appropriate information related to IVIVC data, ultimately, resulting in a more timely approval of ANDAs. C1 [Kaur, Paramjeet; Jiang, Xiaojian; Stier, Ethan] US FDA, Div Bioequivalence 2, Off Gener Drugs, Silver Spring, MD 20993 USA. [Duan, John] US FDA, Off New Drug Qual Assessment, Off Pharmaceut Sci, Silver Spring, MD 20993 USA. RP Kaur, P (reprint author), US FDA, Div Bioequivalence 2, Off Gener Drugs, Silver Spring, MD 20993 USA. EM Paramjeet.Kaur@fda.hhs.gov NR 16 TC 3 Z9 3 U1 1 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 2015 VL 17 IS 4 BP 1035 EP 1039 DI 10.1208/s12248-015-9765-1 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL0DV UT WOS:000356610300025 PM 25896303 ER PT J AU Broussard, CS Sahin, L Tassinari, MS AF Broussard, Cheryl S. Sahin, Leyla Tassinari, Melissa S. TI Getting to safer and smarter medication use during pregnancy REPLY SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Broussard, Cheryl S.] Natl Ctr Birth Defects & Dev Disabil, Ctr Dis Control & Prevent, Div Birth Defects & Dev Disabil, Atlanta, GA 30329 USA. [Sahin, Leyla; Tassinari, Melissa S.] Ctr Drug Evaluat & Res, Food & Drug Adm, Div Pediat & Maternal Hlth, Off New Drugs, Silver Spring, MD USA. RP Broussard, CS (reprint author), Natl Ctr Birth Defects & Dev Disabil, Ctr Dis Control & Prevent, Div Birth Defects & Dev Disabil, Atlanta, GA 30329 USA. FU Intramural CDC HHS [CC999999] NR 3 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 2015 VL 213 IS 1 BP 116 EP 116 DI 10.1016/j.ajog.2014.12.036 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CL3FQ UT WOS:000356836200049 PM 25557207 ER PT J AU Roscoe, DM Hu, YF Philip, R AF Roscoe, Donna M. Hu, Yun-Fu Philip, Reena TI Companion diagnostics: a regulatory perspective from the last 5 years of molecular companion diagnostic approvals SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE approval; cancer; companion diagnostics; FDA; personalized medicine ID CELL LUNG-CANCER; COLORECTAL-CANCER; METASTATIC MELANOMA; RAS MUTATIONS; VEMURAFENIB; CHALLENGES; EFFICACY; ASSAY; BRAF(V600E); PERFORMANCE AB Companion diagnostics are essential for the safe and effective use of the corresponding therapeutic products. The US FDA has approved a number of companion diagnostics used to select cancer patients for treatment with contemporaneously approved novel therapeutics. The processes of co-development and co-approval of a therapeutic product and its companion diagnostic have been a learning experience that continues to evolve. Using several companion diagnostics as examples, this article describes the challenges associated with the scientific, clinical and regulatory hurdles faced by FDA and industry alike. Taken together, this discussion is intended to assist manufacturers toward a successful companion diagnostics development plan. C1 [Roscoe, Donna M.; Hu, Yun-Fu; Philip, Reena] US FDA, Div Mol Genet & Pathol, Off Vitro Diagnost & Radiol Hlth OIR, CDRH, Silver Spring, MD 20993 USA. RP Philip, R (reprint author), US FDA, Div Mol Genet & Pathol, Off Vitro Diagnost & Radiol Hlth OIR, CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Reena.Philip@fda.hhs.gov NR 27 TC 3 Z9 3 U1 1 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUL PY 2015 VL 15 IS 7 BP 869 EP 880 DI 10.1586/14737159.2015.1045490 PG 12 WC Pathology SC Pathology GA CL4OS UT WOS:000356933200004 PM 26109316 ER PT J AU Breger, JC Fisher, B Samy, R Pollack, S Wang, NS Isayeva, I AF Breger, Joyce C. Fisher, Benjamin Samy, Raghu Pollack, Steven Wang, Nam Sun Isayeva, Irada TI Synthesis of "click" alginate hydrogel capsules and comparison of their stability, water swelling, and diffusion properties with that of Ca+2 crosslinked alginate capsules SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE alginate; hydrogels; "click" chemistry; NMR; bioartificial pancreas; cell encapsulation; stability; diffusion; EDTA titration ID MECHANICAL-PROPERTIES; IONIC GELS; CHEMISTRY; MICROENCAPSULATION; TRANSPLANTATION; MICROCAPSULES; SPECTROSCOPY; SCAFFOLDS; POLYMER; SYSTEM AB Ionically crosslinked alginate hydrogels have been extensively explored for encapsulation and immunoisolation of living cells/tissues to develop implantable cell therapies, such as islet encapsulation for bioartificial pancreas. Chemical instability of these hydrogels during long-term implantation hinders the development of viable cell therapy. The exchange between divalent crosslinking ions (e.g., Ca+2) with monovalent ions from physiological environment causes alginate hydrogels to degrade, resulting in exposure of the donor tissue to the host's immune system and graft failure. The goal of this study was to improve stability of alginate hydrogels by utilizing covalent click crosslinking while preserving other biomedically viable hydrogel properties. Alginate was first functionalized to contain either pendant alkyne or azide functionalities, and subsequently reacted via click chemistry to form click gel capsules. Alginate functionalization was confirmed by NMR and gel permeation chromatography. When compared with Ca+2 capsules, click capsules exhibited superior stability in ionic media, while showing higher permeability to small size diffusants and similar molecular weight cut-off and water swelling. Physicochemical properties of click alginate hydrogels demonstrate their potential utility for therapeutic cell encapsulation and other biomedical applications. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 1120-1132, 2015. C1 [Breger, Joyce C.; Fisher, Benjamin; Samy, Raghu; Pollack, Steven; Isayeva, Irada] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Breger, Joyce C.; Wang, Nam Sun] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Sci, Off Gener Drugs,Div Chem 3, Silver Spring, MD 20993 USA. RP Isayeva, I (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM nsw@umd.edu; irada.isayeva@fda.hhs.gov RI Wang, Nam Sun/E-4253-2016 FU Food and Drug Administration FX Sponsor: Food and Drug Administration, Administered by the Oak Ridge Institute for Science and Education through an agreement between the Department of Energy and FDA NR 42 TC 3 Z9 3 U1 11 U2 65 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 2015 VL 103 IS 5 BP 1120 EP 1132 DI 10.1002/jbm.b.33282 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CL0ZO UT WOS:000356671800019 PM 25286444 ER PT J AU Lum, F Tarver, ME Kahook, MY Oetting, TA Rorer, E Hilmantel, G Calogero, D Kiang, T Berdahl, JP Coleman, AL Eydelman, MB AF Lum, Flora Tarver, Michelle E. Kahook, Malik Y. Oetting, Thomas A. Rorer, Eva Hilmantel, Gene Calogero, Don Kiang, Tina Berdahl, John P. Coleman, Anne L. Eydelman, Malvina B. CA Amer Acad Ophthalmology TI Special Commentary: Food and Drug Administration and American Academy of Ophthalmology Sponsored Developing Novel End Points for Premium Intraocular Lenses Workshop SO OPHTHALMOLOGY LA English DT Editorial Material ID QUALITY-OF-LIFE; VISUAL FUNCTION QUESTIONNAIRE; BILATERAL CATARACT-SURGERY; ACCOMMODATION MEASUREMENTS; PSEUDOPHAKIC PATIENTS; RANDOMIZED-TRIAL; REFRACTIVE ERROR; LONG-TERM; VISION; DYSPHOTOPSIA C1 [Lum, Flora] Amer Acad Ophthalmol, MD Ctr Qual Eye Care, San Francisco, CA USA. [Tarver, Michelle E.; Rorer, Eva; Hilmantel, Gene; Calogero, Don; Kiang, Tina; Eydelman, Malvina B.] Ctr Devices & Radiol Hlth Food & Drug Adm, Off Device Evaluat, Silver Spring, MD USA. [Kahook, Malik Y.] Univ Colorado, Sch Med, Dept Ophthalmol, Aurora, CO USA. [Oetting, Thomas A.] Univ Iowa, Dept Ophthalmol, Iowa City, IA USA. [Berdahl, John P.] Univ S Dakota, Sch Med, Sioux Falls, SD USA. [Coleman, Anne L.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Coleman, Anne L.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. RP Eydelman, MB (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 45 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2015 VL 122 IS 7 BP 1522 EP 1531 DI 10.1016/j.ophtha.2015.02.038 PG 10 WC Ophthalmology SC Ophthalmology GA CL0HI UT WOS:000356621700035 PM 25896896 ER PT J AU Nagaraja, S Awada, HK Dreher, ML AF Nagaraja, S. Awada, H. K. Dreher, M. L. TI Vertebroplasty increases trabecular microfractures in elderly female cadaver spines SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Biomechanics; Microfractures; Osteoporosis; Trabecular bone; Vertebroplasty ID PERCUTANEOUS VERTEBROPLASTY; COMPRESSION FRACTURES; DAMAGE MORPHOLOGY; FINITE-ELEMENT; VERTEBRAL BODY; BONE; ADJACENT; ACCUMULATION; MICRODAMAGE; STRESS AB This study assessed whether vertebroplasty increases trabecular bone microfractures in adjacent vertebrae of elderly female cadavers. Results indicated microfractures were almost two times greater in superior adjacent vertebrae for vertebroplasty treated spines compared to non-treated controls. This finding may aid in developing improved treatments for osteoporotic women with vertebral fractures. Introduction Although vertebroplasty may stabilize compression fractures and reduce pain, subsequent vertebral fractures occur in approximately 25 % of patients, reducing the overall safety of this procedure. This is particularly a concern in vertebrae surrounding the treated level where bone cement may cause abnormal transfer of forces to adjacent spinal structures. Therefore, the objective of this study was to quantify the effects of vertebroplasty on local trabecular bone damage in adjacent vertebrae. Methods Five level motion segments (T-11-L-3) from osteopenic/osteoporotic female cadaver spines (T-score -2.9 +/- 1.0) were assigned into either vertebroplasty or control (no vertebroplasty) groups (n = 10/group) such that T-score, trabecular microarchitecture, and age were similar between groups. Compression fractures were created in the L (1) vertebra of all specimens and PMMA bone cement was injected into the fractured vertebra of vertebroplasty specimens. All spine segments were subjected to cyclic axial compression (685-1370 N) for 115,000 cycles. Post-testing, trabecular cubes were cut from adjacent (T-12 and L-2) vertebral bodies and histologically processed. Trabecular microfractures were identified and normalized by bone area in each section. Results There were significantly more trabecular microfractures (p < 0.001) in superior adjacent vertebral bodies of the vertebroplasty group (0.091 +/- 0.025 microfractures/mm(2)) when compared to the control group (0.049 +/- 0.018 microfractures/mm(2)). However, there was no difference in trabecular microfractures (p = 0.835) between vertebroplasty (0.045 +/- 0.022 microfractures/mm(2)) and control groups (0.035 +/- 0.013 microfractures/mm(2)) for inferior adjacent vertebral bodies. Conclusions Vertebroplasty specifically impacts the superior adjacent vertebrae of elderly female spines resulting in almost two times more trabecular microfractures when compared to non-treated controls. C1 [Nagaraja, S.; Awada, H. K.; Dreher, M. L.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Appl Mech, Silver Spring, MD 20993 USA. RP Nagaraja, S (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Appl Mech, 10903 New Hampshire Ave,Bldg 62,Room 2210, Silver Spring, MD 20993 USA. EM srinidhi.nagaraja@fda.hhs.gov FU FDA's Office of Women's Health FX This research study was funded by a grant through the FDA's Office of Women's Health. The authors would like to thank Ronald Wade and Anthony Pleasant for cadaver procurement, and Steven Kaplan and Sarah Schmiedel for histology of trabecular cores. NR 20 TC 0 Z9 0 U1 1 U2 5 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUL PY 2015 VL 26 IS 7 BP 2029 EP 2034 DI 10.1007/s00198-015-3105-2 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CL4VR UT WOS:000356954500019 PM 25792494 ER PT J AU Heller, S Darpo, B Mitchell, MI Linnebjerg, H Leishman, DJ Mehrotra, N Zhu, H Koerner, J Fiszman, ML Balakrishnan, S Xiao, S Todaro, TG Hensley, I Guth, BD Michelson, EL Sager, P AF Heller, Simon Darpoe, Boerje Mitchell, Malcolm I. Linnebjerg, Helle Leishman, Derek J. Mehrotra, Nitin Zhu, Hao Koerner, John Fiszman, Monica L. Balakrishnan, Suchitra Xiao, Shen Todaro, Thomas G. Hensley, Ingrid Guth, Brian D. Michelson, Eric L. Sager, Philip TI Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: A report from the Cardiac Safety Research Consortium SO AMERICAN HEART JOURNAL LA English DT Article ID QT INTERVAL PROLONGATION; TYPE-1 DIABETIC-PATIENTS; CORONARY-ARTERY-DISEASE; TORSADES-DE-POINTES; THOROUGH QT; HEALTHY-SUBJECTS; INSULIN-SECRETION; NOCTURNAL HYPOGLYCEMIA; AUTONOMIC NEUROPATHY; CLINICAL DEVELOPMENT AB Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic parameters affected by antidiabetes drugs may prolong the QT interval and thus confound QT/corrected QT assessments. This review discusses potential mechanisms for QT/corrected QT interval prolongation with antidiabetes drugs and offers practical considerations for assessing antidiabetes drugs in thorough QT studies. This article represents collaborative discussions among key stakeholders from academia, industry, and regulatory agencies participating in the Cardiac Safety Research Consortium. It does not represent regulatory policy. C1 [Heller, Simon] Univ Sheffield, Sheffield, S Yorkshire, England. [Darpoe, Boerje] Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden. [Darpoe, Boerje] Cardiac Technol, Rochester, NY USA. [Mitchell, Malcolm I.; Linnebjerg, Helle; Leishman, Derek J.; Hensley, Ingrid] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Mehrotra, Nitin; Zhu, Hao; Koerner, John; Fiszman, Monica L.; Balakrishnan, Suchitra; Xiao, Shen] US FDA, Silver Spring, MD USA. [Todaro, Thomas G.] Medpace Inc, Cincinnati, OH USA. [Guth, Brian D.] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Michelson, Eric L.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Sager, Philip] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Sager, Philip] Cardiac Safety Res Consortium, Durham, NC USA. [Michelson, Eric L.] AstraZeneca Pharmaceut LP, Wilmington, DE USA. RP Linnebjerg, H (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. EM linnebjerg_helle@lilly.com OI Heller, Simon/0000-0002-2425-9565 FU Eli Lilly; Novo Nordisk; Takeda; Medtronic Inc; Eli Lilly and Company; NovoNordisk; BI; MSD FX Simon Heller, FRCP, has consulted for the following companies for which his academic institution has received payment: Eli Lilly, Novo Nordisk, and Takeda. He has received research support from Medtronic Inc and has given talks for the following companies for which he has received payment: Eli Lilly and Company, NovoNordisk, Takeda, BI, and MSD. Borje Darpo, MD, PhD, holds stock and stock options in iCardiac Technologies. Philip Sager, MD, FACC, FAHA, FHRS, is not a member of any speakers' bureaus and has declared no research funding. He is a safety consultant (member of DSMB, CV endpoint committee, consultant, or advisory board) to Shire Pharmaceuticals, Chemo, Helssin, Milestone, Medtronic, Aerpio, SK Science, Viamet, SNBL, Biomedical Systems, iCardiac, Celgene, and Genentech. He is a member of the FDA Cardiovascular and Renal Drugs Advisory Committee and the CSRC Executive Committee, and serves on the Board of Directors of Anthera, Inc. Eric L. Michelson, MD, FACC, is a former employee of AstraZeneca Pharmaceuticals LP. Malcolm I. Mitchell, MBBS, MFPM; Helle Linnebjerg, PhD; Derek J. Leishman, PhD, DSP; and Ingrid Hensley, PhD, are employees and stockholders of Eli Lilly and Company. No other disclosures or potential conflicts of interest pertinent to this article were declared. NR 85 TC 3 Z9 3 U1 0 U2 1 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 2015 VL 170 IS 1 BP 23 EP 35 DI 10.1016/j.ahj.2015.03.007 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK7YJ UT WOS:000356452700004 PM 26093861 ER PT J AU Pouillot, R Van Doren, JM Woods, J Plante, D Smith, M Goblick, G Roberts, C Locas, A Hajen, W Stobo, J White, J Holtzman, J Buenaventura, E Burkhardt, W Catford, A Edwards, R DePaola, A Calci, KR AF Pouillot, Regis Van Doren, Jane M. Woods, Jacquelina Plante, Daniel Smith, Mark Goblick, Gregory Roberts, Christopher Locas, Annie Hajen, Walter Stobo, Jeffrey White, John Holtzman, Jennifer Buenaventura, Enrico Burkhardt, William, III Catford, Angela Edwards, Robyn DePaola, Angelo Calci, Kevin R. TI Meta-Analysis of the Reduction of Norovirus and Male-Specific Coliphage Concentrations in Wastewater Treatment Plants SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID REVERSE TRANSCRIPTION-PCR; NORWALK-LIKE VIRUSES; SEWAGE-TREATMENT PLANT; HUMAN ENTERIC VIRUSES; RIO-DE-JANEIRO; UNITED-STATES; MOLECULAR CHARACTERIZATION; BACTERIAL INDICATORS; FOODBORNE ILLNESS; VIRAL PATHOGENS AB Human norovirus (NoV) is the leading cause of foodborne illness in the United States and Canada. Wastewater treatment plant (WWTP) effluents impacting bivalve mollusk-growing areas are potential sources of NoV contamination. We have developed a meta-analysis that evaluates WWTP influent concentrations and log(10) reductions of NoV genotype I (NoV GI; in numbers of genome copies per liter [gc/liter]), NoV genotype II (NoV GII; in gc/liter), and male-specific coliphage (MSC; in number of PFU per liter), a proposed viral surrogate for NoV. The meta-analysis included relevant data (2,943 measurements) reported in the scientific literature through September 2013 and previously unpublished surveillance data from the United States and Canada. Model results indicated that the mean WWTP influent concentration of NoV GII (3.9 log(10) gc/liter; 95% credible interval [ CI], 3.5, 4.3 log(10) gc/liter) is larger than the value for NoV GI (1.5 log(10) gc/liter; 95% CI, 0.4, 2.4 log(10) gc/liter), with large variations occurring from one WWTP to another. For WWTPs with mechanical systems and chlorine disinfection, mean log(10) reductions were -2.4 log(10) gc/liter (95% CI, -3.9, -1.1 log(10) gc/liter) for NoV GI, -2.7 log(10) gc/liter (95% CI, -3.6, -1.9 log(10) gc/liter) for NoV GII, and -2.9 log(10) PFU per liter (95% CI, -3.4, -2.4 log(10) PFU per liter) for MSCs. Comparable values for WWTPs with lagoon systems and chlorine disinfection were -1.4 log(10) gc/liter (95% CI, -3.3, 0.5 log(10) gc/liter) for NoV GI, -1.7 log(10) gc/liter (95% CI, -3.1, -0.3 log(10) gc/liter) for NoV GII, and -3.6 log(10) PFU per liter (95% CI, -4.8, -2.4 PFU per liter) for MSCs. Within WWTPs, correlations exist between mean NoV GI and NoV GII influent concentrations and between the mean log(10) reduction in NoV GII and the mean log(10) reduction in MSCs. C1 [Pouillot, Regis; Van Doren, Jane M.; Goblick, Gregory] US FDA, College Pk, MD USA. [Woods, Jacquelina; Burkhardt, William, III; DePaola, Angelo; Calci, Kevin R.] US FDA, Dauphin Isl, AL 36528 USA. [Plante, Daniel] Hlth Canada, Longueuil, Qld, Australia. [Smith, Mark; Holtzman, Jennifer; Buenaventura, Enrico; Catford, Angela] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Roberts, Christopher; Stobo, Jeffrey] Environm Canada, Dartmouth, NS, Canada. [Locas, Annie; White, John; Edwards, Robyn] Canadian Food Inspect Agcy, Ottawa, ON, Canada. [Hajen, Walter] Environm Canada, N Vancouver, BC, Canada. RP Calci, KR (reprint author), US FDA, Dauphin Isl, AL 36528 USA. EM Kevin.Calci@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 NR 68 TC 6 Z9 6 U1 0 U2 10 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 2015 VL 81 IS 14 BP 4669 EP 4681 DI 10.1128/AEM.00509-15 PG 13 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CK8ZE UT WOS:000356528200012 PM 25934626 ER PT J AU Testoni, D Hornik, CP Neely, ML Yang, QH McMahon, AW Clark, RH Smith, PB AF Testoni, Daniela Hornik, Christoph P. Neely, Megan L. Yang, Qinghong McMahon, Ann W. Clark, Reese H. Smith, P. Brian CA Best Pharmaceuticals Children Act TI Safety of octreotide in hospitalized infants SO EARLY HUMAN DEVELOPMENT LA English DT Article DE Octreotide; Safety; Infant; Drug toxicity ID ASPARAGINASE-ASSOCIATED PANCREATITIS; ACUTE LYMPHOBLASTIC-LEUKEMIA; NECROTIZING ENTEROCOLITIS; CONGENITAL HYPERINSULINISM; PEDIATRIC-PATIENTS; SMS 201-995; SOMATOSTATIN; CHILDREN; CHYLOTHORAX; THERAPY AB Background: Octreotide is used off-label in infants for treatment of chylothorax, congenital hyperinsulinism, and gastrointestinal bleeding. The safety profile of octreotide in hospitalized infants has not been described; we sought to fill this information gap. Methods: We identified all infants exposed to at least 1 dose of octreotide from a cohort of 887,855 infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. We collected laboratory and clinical information while infants were exposed to octreotide and described the frequency of baseline diagnoses, laboratory abnormalities, and clinical adverse events (AEs). Results: A total of 428 infants received 490 courses of octreotide. The diagnoses most commonly associated with octreotide use were chylothorax (50%), pleural effusion (32%), and hypoglycemia (22%). The most common laboratory AEs that occurred during exposure to octreotide were thrombocytopenia (47/1000 infant-days), hyperkalemia (21/1000 infant-days), and leukocytosis (20/1000 infant-days). Hyperglycemia occurred in 1/1000 infant-days and hypoglycemia in 3/1000 infant-days. Hypotension requiring pressors (12%) was the most common clinical AE that occurred during exposure to octreotide. Necrotizing enterocolitis was observed in 9/490 (2%) courses, and death occurred in 11(3%) infants during octreotide administration. Conclusion: Relatively few AEs occurred during off-label use of octreotide in this cohort of infants. Additional studies are needed to further evaluate the safety, dosing, and efficacy of this medication in infants. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Testoni, Daniela; Hornik, Christoph P.; Neely, Megan L.; Yang, Qinghong; Smith, P. Brian] Duke Clin Res Inst, Durham, NC 27715 USA. [Testoni, Daniela] Univ Fed Sao Paulo, Escola Paulista Med, Div Neonatal Med, Sao Paulo, Brazil. [Hornik, Christoph P.; Smith, P. Brian] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Neely, Megan L.] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [McMahon, Ann W.] US FDA, Off Pediat Therapeut, Silver Spring, MD USA. [Clark, Reese H.] Pediatrix Obstetrix Ctr Res & Educ, Sunrise, FL USA. RP Smith, PB (reprint author), Duke Clin Res Inst, Box 17969, Durham, NC 27715 USA. EM brian.smith@duke.edu FU National Institute of Child Health and Human Development [HHSN27500016]; American Recovery and Reinvestment Act [DHHS-1R18AE000028-01]; National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) [UL1TR001117] FX This work was funded under National Institute of Child Health and Human Development contract HHSN27500016 for the Pediatric Trials Network. This work was also supported by the American Recovery and Reinvestment Act (DHHS-1R18AE000028-01) (P.B.S.). Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 40 TC 5 Z9 6 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-3782 EI 1872-6232 J9 EARLY HUM DEV JI Early Hum. Dev. PD JUL PY 2015 VL 91 IS 7 BP 387 EP 392 DI 10.1016/j.earlhumdev.2015.04.008 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CK9GX UT WOS:000356549700002 PM 25968047 ER PT J AU Camacho, L Basavarajappa, MS Chang, CW Han, T Kobets, T Koturbash, I Surratt, G Lewis, SM Vanlandingham, MM Fuscoe, JC da Costa, GG Pogribny, IP Delclos, KB AF Camacho, Luisa Basavarajappa, Mallikarjuna S. Chang, Ching-Wei Han, Tao Kobets, Tetyana Koturbash, Igor Surratt, Gordon Lewis, Sherry M. Vanlandingham, Michelle M. Fuscoe, James C. da Costa, Goncalo Gamboa Pogribny, Igor P. Delclos, K. Barry TI Effects of oral exposure to bisphenol A on gene expression and global genomic DNA methylation in the prostate, female mammary gland, and uterus of NCTR Sprague-Dawley rats SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Bisphenol A; Ethinyl estradiol; Global genomic DNA methylation; Microarray; Prostate; Mammary gland ID FALSE DISCOVERY RATE; BREAST-CANCER CELLS; ENVIRONMENTAL ESTROGENS; REPRODUCTIVE TOXICITY; ENDOCRINE DISRUPTORS; RECEPTOR EXPRESSION; ETHINYL ESTRADIOL; PITUITARY-CELLS; MOUSE UTERUS; INCREASES AB Bisphenol A (BPA), an industrial chemical used in the manufacture of polycarbonate and epoxy resins, binds to the nuclear estrogen receptor with an affinity 4-5 orders of magnitude lower than that of estradiol. We reported previously that "high BPA" [100,000 and 300,000 mu g/kg body weight (bw)/day], but not "low BPA" (2.5-2700 mu g/kg bw/day), induced clear adverse effects in NCTR Sprague-Dawley rats gavaged daily from gestation day 6 through postnatal day (PND) 90. The "high BPA" effects partially overlapped those of ethinyl estradiol (EE2, 0.5 and 5.0 mu g/kg bw/day). To evaluate further the potential of "low BPA" to induce biological effects, here we assessed the global genomic DNA methylation and gene expression in the prostate and female mammary glands, tissues identified previously as potential targets of BPA, and uterus, a sensitive estrogen-responsive tissue. Both doses of EE2 modulated gene expression, including of known estrogen-responsive genes, and PND 4 global gene expression data showed a partial overlap of the "high BPA" effects with those of EE2. The "low BPA" doses modulated the expression of several genes; however, the absence of a dose response reduces the likelihood that these changes were causally linked to the treatment. These results are consistent with the toxicity outcomes. Published by Elsevier Ltd. C1 [Camacho, Luisa; Basavarajappa, Mallikarjuna S.; Kobets, Tetyana; Koturbash, Igor; Surratt, Gordon; Vanlandingham, Michelle M.; da Costa, Goncalo Gamboa; Pogribny, Igor P.; Delclos, K. Barry] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chang, Ching-Wei] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Han, Tao; Fuscoe, James C.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lewis, Sherry M.] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Camacho, L (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM luisa.camacho@fda.hhs.gov FU FDA [224-12-0003/NIEHS]; National Institute of Environmental Health Sciences (NIEHS) [AES12013] FX The authors would like to thank Dr. Ana M. Soto (Tufts University), Dr. Gail S. Prins (University of Illinois at Chicago), Drs. Shuk-Mei Ho and Yuet-Kin Leung (University of Cincinnati), and Dr. Toshihiro Shioda (Massachusetts General Hospital) for their constructive input during the preparation of the manuscript. MSB, TK, and IK were supported by appointments to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement (IAG) between the US Department of Energy and the US Food and Drug Administration (FDA). This study was conducted under the auspices of the US National Toxicology Program (NTP) under an IAG between the FDA and the National Institute of Environmental Health Sciences (NIEHS) (FDA IAG # 224-12-0003/NIEHS IAG # AES12013). The views presented in this article do not necessarily reflect those of the FDA. NR 66 TC 6 Z9 6 U1 3 U2 22 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 JUL PY 2015 VL 81 BP 92 EP 103 DI 10.1016/j.fct.2015.04.009 PG 12 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CL1YJ UT WOS:000356740500011 PM 25862956 ER PT J AU Portnoy, DB Loud, JT Han, PKJ Mai, PL Greene, MH AF Portnoy, David B. Loud, Jennifer T. Han, Paul K. J. Mai, Phuong L. Greene, Mark H. TI Effects of False-Positive Cancer Screenings and Cancer Worry on Risk-Reducing Surgery Among BRCA1/2 Carriers SO HEALTH PSYCHOLOGY LA English DT Article DE BRCA1/2; risk perception; cancer worry; false-positive; cancer screening; risk-reducing surgery ID QUALITY-OF-LIFE; BREAST-CANCER; OVARIAN-CANCER; MUTATION CARRIERS; PROPHYLACTIC OOPHORECTOMY; SALPINGO-OOPHORECTOMY; INFLUENZA VACCINATION; HEALTH BEHAVIOR; FAMILY-HISTORY; WOMEN AB Objective: Female BRCA1/2 mutation carriers are at increased risk of breast and ovarian cancer. Annual breast and semiannual ovarian cancer screening is recommended for early detection, which frequently leads to false-positive test results (FPTR). FPTR may influence cancer risk perceptions and worry, which in turn may affect an individual's decision to undergo risk-reducing bilateral salpingo-oophorectomy (RRSO) or risk-reducing bilateral mastectomy (RRBM). The purpose of this study was to examine: (a) the effect of false-positive breast and ovarian cancer screening test results on perceived cancer risk and cancer worry, and (b) the joint effects of FPTR, risk perceptions, and worry on the choice of risk-reducing surgery among BRCA1/2 mutation carriers undergoing an intensive cancer screening protocol. Method: BRCA1/2 mutation carriers (N = 170) reported cancer risk perceptions and cancer worry during a prospective 4-year screening protocol (2001-2007) at the U.S. National Cancer Institute. FPTR and risk-reducing surgeries were objectively recorded. Results: FPTR at baseline were associated with transient elevations in worry; cumulative FPTR across the entire study were not associated with opting for risk-reducing surgery. However, cancer-specific worry was a strong predictor of surgery (RRSO: OR = 6.15; RRBM: OR = 4.27). Conclusions: In women at inherited risk of breast and ovarian cancer, FPTR were not associated with large increases in cancer risk perception, cancer worry, or increased uptake of risk-reducing surgery. However, cancer-specific worry was an independent predictor of uptake of risk-reducing surgery and warrants consideration when counseling high-risk women regarding risk-reducing interventions. C1 [Portnoy, David B.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training & Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Loud, Jennifer T.; Mai, Phuong L.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04102 USA. RP Portnoy, DB (reprint author), US FDA, Ctr Tobacco Prod, Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457; Han, Paul/0000-0003-0165-1940 FU Intramural Research Program of the NIH; National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH and the National Cancer Institute. The views expressed do not necessarily reflect those of the Food and Drug Administration or the Federal Government. The authors wish to acknowledge Ruthann Giusti, Sheila Prindiville, and June Peters for their contributions to the original design and implementation of the Breast Imaging Study. NR 46 TC 1 Z9 1 U1 0 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD JUL PY 2015 VL 34 IS 7 BP 709 EP 717 DI 10.1037/hea0000156 PG 9 WC Psychology, Clinical; Psychology SC Psychology GA CK9XO UT WOS:000356593100003 PM 25243716 ER PT J AU Desai, D Wong, B Huang, YD Ye, QM Guo, H Huang, M Timmins, P AF Desai, Divyakant Wong, Benjamin Huang, Yande Ye, Qingmei Guo, Hang Huang, Ming Timmins, Peter TI Wetting Effects Versus Ion Pairs Diffusivity: Interactions of Anionic Surfactants with Highly Soluble Cationic Drugs and Its Impact on Tablet Dissolution SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE sodium alkyl sulfate; dissolution; critical micelle concentration; solubility; metformin salts; wetting; diffusion; NMR ID METFORMIN HYDROCHLORIDE; SULFATE AB A study was conducted to develop a mechanistic understanding of dissolution of a highly soluble cationic drug, metformin hydrochloride, under the influence of anionic surfactants, sodium alkyl sulfates. The surfactants did not influence the saturated solubility of the drug, but reduced the surface tension of the dissolution media as the alkyl chain length increased. Their influence on tablet wetting based on the contact angles did not show any trend. The dissolution of 850 mg metformin hydrochloride tablets in 0.1 N HCl and pH 4.5 acetate buffer with 0.01% (w/v) sodium n-octyl sulfate (C8), sodium n-decyl sulfate (C10), or sodium n-tetradecyl sulfate (C14) was similar to the control, but was enhanced by sodium lauryl sulfate (C12). At 0.1% (w/v) concentration, the dissolution was not enhanced by C12 because the reduction in surface tension was counterbalanced by an increase in hydrophobic ion pairs that showed slower diffusivity by nuclear magnetic resonance. At 0.1% (w/v), metformin also formed an insoluble salt (1:2 molar ratios) with C10 (pH 1.2), C12, and C14 (pH 1.2 and 4.5) but not with C8. Three competing factors influenced the drug dissolution by surfactants: reduction in surface tension of the dissolution media, ion pairs with low diffusivity, and formation of an insoluble salt. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2255-2265, 2015 C1 [Desai, Divyakant; Wong, Benjamin; Guo, Hang] Bristol Myers Squibb Co, Drug Product Sci & Technol, New Brunswick, NJ 08903 USA. [Huang, Yande; Ye, Qingmei; Huang, Ming] Bristol Myers Squibb Co, Analyt & Bioanalyt Dev, New Brunswick, NJ 08903 USA. [Guo, Hang] FDA, CDER, Silver Spring, MD USA. [Timmins, Peter] Bristol Myers Squibb, Drug Product Sci & Technol, Moreton CII46 1QW, Merseyside, England. RP Desai, D (reprint author), Bristol Myers Squibb Co, Drug Product Sci & Technol, New Brunswick, NJ 08903 USA. EM divyakant.desai@bms.com NR 17 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD JUL PY 2015 VL 104 IS 7 BP 2255 EP 2265 DI 10.1002/jps.24478 PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CL1LT UT WOS:000356705500016 PM 26017286 ER PT J AU Delnevo, CD Giovenco, DP Ambrose, BK Corey, CG Conway, KP AF Delnevo, Cristine D. Giovenco, Daniel P. Ambrose, Bridget K. Corey, Catherine G. Conway, Kevin P. TI Preference for flavoured cigar brands among youth, young adults and adults in the USA SO TOBACCO CONTROL LA English DT Article ID TOBACCO PRODUCTS; UNITED-STATES; SMOKING; SMOKERS; ADOLESCENTS; PREVALENCE; CALIFORNIA; MARIJUANA; PATTERNS; STUDENTS AB Background While cigarette consumption in the USA continues to decline, cigar consumption has increased. Tobacco-trade publications suggest that flavoured cigars are driving the recent growth in cigar consumption. Limited survey data exist to explore flavoured cigar preferences among youth and adults. Methods This study used the 2010-2011 National Survey on Drug Use and Health (NSDUH) and Nielsen market scanner data. The NSDUH sample consisted of 6678 past 30-day cigar smokers who reported smoking a usual brand of cigars. NSDUH contains a measure on usual cigar brand smoked and was merged with Nielsen data to estimate the per cent of each cigar brand's market share that is flavoured. Results Multivariate analyses indicate that youth, young adults, females, blacks, cigarette smokers, blunt users and daily cigar smokers are significantly more likely to report a usual cigar brand that is flavoured. Preference for a usual brand that produces flavoured cigars decreases significantly with age. Conclusions This study finds recent growth in flavoured cigar consumption and preference among youth and young adults for cigar brands that are flavoured. These findings underscore the need to expand monitoring of product attributes as well as individual-level cigar use behaviours captured through population surveillance. C1 [Delnevo, Cristine D.; Giovenco, Daniel P.] Rutgers Sch Publ Hlth, Ctr Tobacco Surveillance & Evaluat Res, New Brunswick, NJ 08854 USA. [Ambrose, Bridget K.; Corey, Catherine G.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Conway, Kevin P.] NIDA, Div Epidemiol Serv & Prevent Res, Rockville, MD USA. RP Delnevo, CD (reprint author), Rutgers Sch Publ Hlth, Ctr Tobacco Surveillance & Evaluat Res, New Brunswick, NJ 08854 USA. OI Conway, Kevin/0000-0002-7638-339X FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C] FX This project has been funded in part with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under contract no. HHSN271201100027C. NR 39 TC 37 Z9 37 U1 1 U2 5 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 JUL PY 2015 VL 24 IS 4 BP 389 EP 394 DI 10.1136/tobaccocontrol-2013-051408 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL0BS UT WOS:000356604100019 PM 24721967 ER PT J AU Kim, SJ Kweon, O Sutherland, JB Kim, HL Jones, RC Burback, BL Graves, SW Psurny, E Cerniglia, CE AF Kim, Seong-Jae Kweon, Ohgew Sutherland, John B. Kim, Hyun-Lee Jones, Richard C. Burback, Brian L. Graves, Steven W. Psurny, Edward Cerniglia, Carl E. TI Dynamic Response of Mycobacterium vanbaalenii PYR-1 to BP Deepwater Horizon Crude Oil SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBON; SP STRAIN PYR-1; ALKANE HYDROXYLASE SYSTEMS; LOUISIANA SALT MARSHES; DEGRADING BACTERIA; METABOLIC NETWORK; MICROBIAL-DEGRADATION; MOLECULAR-CLONING; COASTAL WETLANDS; SPILL AB We investigated the response of the hydrocarbon-degrading Mycobacterium vanbaalenii PYR-1 to crude oil from the BP Deepwater Horizon (DWH) spill, using substrate depletion, genomic, and proteome analyses. M. vanbaalenii PYR-1 cultures were incubated with BP DWH crude oil, and proteomes and degradation of alkanes and polycyclic aromatic hydrocarbons (PAHs) were analyzed at four time points over 30 days. Gas chromatography-mass spectrometry (GC-MS) analysis showed a chain length-dependent pattern of alkane degradation, with C-12 and C-13 being degraded at the highest rate, although alkanes up to C-28 were degraded. Whereas phenanthrene and pyrene were completely degraded, a significantly smaller amount of fluoranthene was degraded. Proteome analysis identified 3,948 proteins, with 876 and 1,859 proteins up-and downregulated, respectively. We observed dynamic changes in protein expression during BP crude oil incubation, including transcriptional factors and transporters potentially involved in adaptation to crude oil. The proteome also provided a molecular basis for the metabolism of the aliphatic and aromatic hydrocarbon components in the BP DWH crude oil, which included upregulation of AlkB alkane hydroxylase and an expression pattern of PAH-metabolizing enzymes different from those in previous proteome expression studies of strain PYR-1 incubated with pure or mixed PAHs, particularly the ring-hydroxylating oxygenase (RHO) responsible for the initial oxidation of aromatic hydrocarbons. Based on these results, a comprehensive cellular response of M. vanbaalenii PYR-1 to BP crude oil was proposed. This study increases our fundamental understanding of the impact of crude oil on the cellular response of bacteria and provides data needed for development of practical bioremediation applications. C1 [Kim, Seong-Jae; Kweon, Ohgew; Sutherland, John B.; Kim, Hyun-Lee; Cerniglia, Carl E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Jones, Richard C.] MS Bioworks LLC, Ann Arbor, MI USA. [Burback, Brian L.; Graves, Steven W.; Psurny, Edward] Battelle Mem Inst, Life Sci Res, Columbus, OH 43201 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 63 TC 2 Z9 2 U1 12 U2 56 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 2015 VL 81 IS 13 BP 4263 EP 4276 DI 10.1128/AEM.00730-15 PG 14 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CJ9TC UT WOS:000355844800005 PM 25888169 ER PT J AU Yan, QQ Wang, J Gangiredla, J Cao, Y Martins, M Gopinath, GR Stephan, R Lampel, K Tall, BD Fanning, S AF Yan, Qiongqiong Wang, Juan Gangiredla, Jayanthi Cao, Yu Martins, Marta Gopinath, Gopal R. Stephan, Roger Lampel, Keith Tall, Ben D. Fanning, Seamus TI Comparative Genotypic and Phenotypic Analysis of Cronobacter Species Cultured from Four Powdered Infant Formula Production Facilities: Indication of Pathoadaptation along the Food Chain SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID COMPLETE GENOME SEQUENCE; ENTEROBACTER-SAKAZAKII; NEONATAL MENINGITIS; VI SECRETION; COMB. NOV.; GEN. NOV; TURICENSIS; IDENTIFICATION; SPP.; ENVIRONMENTS AB Cronobacter species are opportunistic pathogens commonly found in the environment. Among the seven Cronobacter species, Cronobacter sakazakii sequence type 4 (ST-4) is predominantly associated with recorded cases of infantile meningitis. This study reports on a 26-month powdered infant formula (PIF) surveillance program in four production facilities located in distinct geographic regions. The objective was to identify the ST(s) in PIF production environments and to investigate the phenotypic features that support their survival. Of all 168 Cronobacter isolates, 133 were recovered from a PIF production environment, 31 were of clinical origin, and 4 were laboratory type strains. Sequence type 1 (n = 84 isolates; 63.9%) was the dominant type in PIF production environments. The majority of these isolates clustered with an indistinguishable pulsotype and persisted for at least an 18-month period. Moreover, DNA microarray results identified two phylogenetic lineages among ST-4 strains tested. Thereafter, the ST-1 and -4 isolates were phenotypically compared. Differences were noted based on the phenotypes expressed by these isolates. The ST-1 PIF isolates produced stronger biofilms at both 28 degrees C and 37 degrees C, while the ST-4 clinical isolates exhibited greater swimming activity and increased binding to Congo red dye. Given the fact that PIF is a low-moisture environment and that the clinical environment provides for an interaction between the pathogen and its host, these differences may be consistent with a form of pathoadaptation. These findings help to extend our current understanding of the epidemiology and ecology of Cronobacter species in PIF production environments. C1 [Yan, Qiongqiong; Wang, Juan; Cao, Yu; Martins, Marta; Fanning, Seamus] Univ Coll Dublin, Sch Publ Hlth Physiotherapy & Populat Sci, WHO Collaborating Ctr Res Reference & Training Cr, UCD Ctr Food Safety, Dublin 2, Ireland. [Gangiredla, Jayanthi; Gopinath, Gopal R.; Lampel, Keith; Tall, Ben D.] US FDA, OARSA, Ctr Food Safety & Appl Nutr, Silver Spring, MD USA. [Stephan, Roger] Univ Zurich, Vetsuisse Fac, Inst Food Safety & Hyg, Zurich, Switzerland. RP Fanning, S (reprint author), Univ Coll Dublin, Sch Publ Hlth Physiotherapy & Populat Sci, WHO Collaborating Ctr Res Reference & Training Cr, UCD Ctr Food Safety, Dublin 2, Ireland. EM sfanning@ucd.ie RI Wang, Juan/C-4248-2016; OI Fanning, Seamus/0000-0002-1922-8836; Tall, Ben/0000-0003-0399-3629 NR 53 TC 3 Z9 3 U1 2 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 JUL PY 2015 VL 81 IS 13 BP 4388 EP 4402 DI 10.1128/AEM.00359-15 PG 15 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CJ9TC UT WOS:000355844800017 PM 25911470 ER PT J AU Harinstein, ME Butler, J Greene, SJ Fonarow, GC Stockbridge, NL O'Connor, CM Pfeffer, MA Mehra, MR Solomon, SD Yancy, CW Fiuzat, M Mentz, RJ Collins, SP McMurray, JJV Vaduganathan, M Dunnmon, PM Rosano, GMC Dinh, W Misselwitz, F Bonow, RO Gheorghiade, M AF Harinstein, Matthew E. Butler, Javed Greene, Stephen J. Fonarow, Gregg C. Stockbridge, Norman L. O'Connor, Christopher M. Pfeffer, Marc A. Mehra, Mandeep R. Solomon, Scott D. Yancy, Clyde W. Fiuzat, Mona Mentz, Robert J. Collins, Sean P. McMurray, John J. V. Vaduganathan, Muthiah Dunnmon, Preston M. Rosano, Giuseppe M. C. Dinh, Wilfried Misselwitz, Frank Bonow, Robert O. Gheorghiade, Mihai TI Site selection for heart failure clinical trials in the USA SO HEART FAILURE REVIEWS LA English DT Article DE Clinical trials; Site selection; Heart failure; United States; Outcomes ID PRESERVED EJECTION FRACTION; VASOPRESSIN ANTAGONISM; MYOCARDIAL-INFARCTION; THROMBUS ASPIRATION; EVEREST EFFICACY; UNITED-STATES; OUTCOMES; TOLVAPTAN; REGISTRY; PROGRAM AB There are more than 1 million primary hospitalizations for heart failure (HF) annually in the USA alone, and post-discharge outcomes remain persistently poor despite available therapies and quality improvement initiatives. Recent international randomized clinical trials in hospitalized HF have repeatedly failed to improve this post-discharge event rate. A potential reason for this persistent lack of clinical trial success that has not previously received significant attention relates to site selection and the generally low level of patient enrollment from the USA. Only similar to 5 % of US hospitals participate in clinical trials, and in four recent randomized trials of hospitalized HF, only one-third of patients were enrolled in North America. This poor participation among US centers has necessitated disproportionate enrollment from non-US sites. Regional variations in HF patient characteristics and clinical outcomes are well documented, and a lack of US patient representation in clinical trials limits the generalizability of results and presents obstacles for US regulatory agency approval. There are multiple impediments to successful US enrollment including a lack of incentive for investigators and institutions, the relative value unit-based compensation system, poor institutional framework for identification of appropriate patients, and increasing liability to conduct trials. In this manuscript, we specifically identify barriers to successful hospitalized HF clinical trial participation in the USA and suggest possible solutions. C1 [Harinstein, Matthew E.] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA USA. [Butler, Javed] SUNY Stony Brook, Sch Med, Div Cardiol, Stony Brook, NY 11794 USA. [Greene, Stephen J.; Bonow, Robert O.; Gheorghiade, Mihai] Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, Chicago, IL 60611 USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Stockbridge, Norman L.] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [O'Connor, Christopher M.; Fiuzat, Mona; Mentz, Robert J.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Pfeffer, Marc A.; Mehra, Mandeep R.; Solomon, Scott D.] Brigham & Womens Hosp, Heart & Vasc Ctr, Boston, MA 02115 USA. [Pfeffer, Marc A.; Mehra, Mandeep R.; Solomon, Scott D.] Harvard Univ, Sch Med, Boston, MA USA. [Yancy, Clyde W.] Northwestern Univ, Div Cardiol, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Collins, Sean P.] Vanderbilt Univ, Sch Med, Dept Emergency Med, Nashville, TN 37212 USA. [McMurray, John J. V.] Univ Glasgow, British Heart Fdn, Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Vaduganathan, Muthiah] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Dunnmon, Preston M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Rosano, Giuseppe M. C.] IRCC San Raffaele, Div Cardiol, Rome, Italy. [Dinh, Wilfried; Misselwitz, Frank] Bayer Pharma AG, Global Drug Discovery, Clin Sci, Expt Med, Berlin, Germany. [Dinh, Wilfried] Univ Witten Herdecke, Dept Cardiol, Witten, Germany. RP Gheorghiade, M (reprint author), Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, 201 East Huron St,Galter 3-150, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu OI Mehra, Mandeep/0000-0001-8683-7044; mcmurray, john/0000-0002-6317-3975 FU National Institutes of Health; European Union; Health Resource Services Administration; Food and Drug Administration; Amgen; Celladon; Novartis; Sanofi-Aventis; AstraZeneca; Bristol-Myers Squibb; GlaxoSmithKline; Gilead; Otsuka; ResMed; NIH/NHLBI; Medtronic; Cardiorentis; Abbott Point-of-Care; Medicines Company; Astellas; Bayer Schering Pharma AG; DebioPharm S.A.; Novartis Pharma AG; Otsuka Pharmaceuticals; Sigma Tau; Solvay Pharmaceuticals; Sticares InterACT; Takeda Pharmaceuticals North America, Inc. FX JB.: Research support: National Institutes of Health, European Union, Health Resource Services Administration, Food and Drug Administration, Consultant: Amgen, Bayer, Celladon, Gambro, GE Healthcare, Janssen, Medtronic, Novartis, Ono, Relypsa, Trevena, Stock options: Stemedica; G. C. F.: Research AHRQ significant, NHLBI significant, Consultant: Novartis significant, Medtronic modest, Bayer modest, Gambro modest, Janssen modest; C. M. O.: none; M.A.P.: Research Support: Amgen, Celladon, Novartis, Sanofi-Aventis, Consultant: Aastrom, Abbott Vascular, Amgen, Cerenis, Concert, Fibrogen, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Roche, Servier, Teva, University of Oxford; M. R. M.: Consultant: Boston Scientific, St. Jude's, Medtronic, Johnson and Johnson, ABIM, NIH/NHLBI, Baxter, Abbott Vascular, Thoratec; R. J. M. receives research support from Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, Otsuka, and ResMed; honoraria from Thoratec; and has served on an advisory board for Luitpold Pharmaceuticals, Inc; S. P. C.: Research support: NIH/NHLBI, Medtronic, Cardiorentis, Abbott Point-of-Care, Novartis, The Medicines Company, Astellas, Consultant: Trevena, Novartis, Otsuka, Radiometer, The Medicines Company, Medtronic, BRAHMS, Insys; J. J. V. M.: none; W. D. is a full time employee of Bayer Pharma; F. M. is a full time employee of Bayer Pharma; M. G.: Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S. A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, INC, Johnson and Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT,Takeda Pharmaceuticals North America, Inc and Trevena Therapeutics; and has received significant (>$10,000) support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT and Takeda Pharmaceuticals North America, Inc. All others authors report no conflicts of interest. NR 43 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1382-4147 EI 1573-7322 J9 HEART FAIL REV JI Heart Fail. Rev. PD JUL PY 2015 VL 20 IS 4 BP 375 EP 383 DI 10.1007/s10741-015-9473-z PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK2KK UT WOS:000356039000001 PM 25649127 ER PT J AU Hillebrenner, E Litwack, E Bradley, P Donigan, K Lowe, T Serrano, K Kelm, K Mansfield, E Gutierrez, A AF Hillebrenner, E. Litwack, E. Bradley, P. Donigan, K. Lowe, T. Serrano, K. Kelm, K. Mansfield, E. Gutierrez, A. TI FDA oversight of laboratory-developed tests will facilitate adoption of pharmacogenetic testing into routine clinical care SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Editorial Material ID DISEASE C1 [Hillebrenner, E.; Litwack, E.; Bradley, P.; Donigan, K.; Lowe, T.; Serrano, K.; Kelm, K.; Mansfield, E.; Gutierrez, A.] US FDA, Ctr Diagnost & Radiol Hlth, Off Vitro Diagnost & Radiol Hlth, Silver Spring, MD USA. RP Hillebrenner, E (reprint author), WO66 RM4502,10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM elizabeth.hillebrenner@fda.hhs.gov NR 6 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUL PY 2015 VL 55 IS 7 BP 728 EP 730 DI 10.1002/jcph.521 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CK0AJ UT WOS:000355865700003 PM 26053648 ER PT J AU Yoshitomi, KJ Jinneman, KC Orlandi, PA Weagant, SD Zapata, R Fedio, WM AF Yoshitomi, K. J. Jinneman, K. C. Orlandi, P. A. Weagant, S. D. Zapata, R. Fedio, W. M. TI Evaluation of rapid screening techniques for detection of Salmonella spp. from produce samples after pre-enrichment according to FDA BAM and a short secondary enrichment SO LETTERS IN APPLIED MICROBIOLOGY LA English DT Article DE lateral flow device; produce; rapid screening; Salmonella; VIDAS ID UNITED-STATES; FOODBORNE OUTBREAKS; FRESH PRODUCE; CONSUMPTION; FOODS AB Conventional detection of Salmonella from foods involves enrichment and isolation on selective media which can significantly lengthen time to result. The objective of this study was to evaluate the utility of an accelerated plating procedure and the use of rapid screening devices for Salmonella detection. Fresh produce was inoculated with Salmonella at similar to 25, similar to 75 and similar to 25CFUsample(-1). After 24h pre-enrichment, subcultures were made into TT and RV broths and further incubated at 42 degrees C for an additional 7 and 24h. Enrichments were streaked for isolation of Salmonella as well as tested by rapid screening methods. The 7-h accelerated plating procedure worked well from 4/6 to 6/6 in all produce samples inoculated at the lowest level. Both the RapidChek and Neogen Reveal tests worked as well as the VIDAS-SLM after 24h secondary enrichment, but failed to detect the pathogen after 7h selective enrichment in romaine lettuce and tomatoes, while fractional detection was observed in cilantro and jalapenos. Both devices detected Salmonella on cantaloupe at the lowest level of inoculation. An abbreviated selective enrichment procedure worked well to accelerate the isolation of colonies of Salmonella from contaminated samples providing isolates for further characterization 1day earlier than standard analysis. Significance and Impact of the StudyIn the event of a foodborne disease outbreak, rapid identification and characterization of the pathogen is essential to prevent the spread of disease and reduce the number of illnesses. This study reports the utility of an abbreviated secondary enrichment for the isolation of Salmonella in artificially contaminated fresh produce at very low levels. In addition, incorporation of rapid, easy-to-use lateral flow devices to screen enrichments can provide a low cost (equipment and highly trained personnel), high return (rapid identification of contaminated food) investment in the timely pathogen screening of fresh produce. Significance and Impact of the Study: In the event of a foodborne disease outbreak, rapid identification and characterization of the pathogen is essential to prevent the spread of disease and reduce the number of illnesses. This study reports the utility of an abbreviated secondary enrichment for the isolation of Salmonella in artificially contaminated fresh produce at very low levels. In addition, incorporation of rapid, easy-to-use lateral flow devices to screen enrichments can provide a low cost (equipment and highly trained personnel), high return (rapid identification of contaminated food) investment in the timely pathogen screening of fresh produce. C1 [Yoshitomi, K. J.; Jinneman, K. C.] US FDA, Bothell, WA USA. [Orlandi, P. A.] US FDA, Rockville, MD 20857 USA. [Weagant, S. D.] Weagant Consulting, Poulsbo, WA USA. [Zapata, R.; Fedio, W. M.] New Mexico State Univ, Food Safety Lab, Las Cruces, NM 88003 USA. RP Fedio, WM (reprint author), New Mexico State Univ, MSC 3BF,POB 30003, Las Cruces, NM 88003 USA. EM wfedio@nmsu.edu NR 17 TC 0 Z9 0 U1 3 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0266-8254 EI 1472-765X J9 LETT APPL MICROBIOL JI Lett. Appl. Microbiol. PD JUL PY 2015 VL 61 IS 1 BP 7 EP 12 DI 10.1111/lam.12422 PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CK0FV UT WOS:000355881800002 PM 25809127 ER PT J AU Thomas, A Chen, YB Yu, TH Gill, A Prasad, V AF Thomas, Anish Chen, Yuanbin Yu, Tinghui Gill, Ammara Prasad, Vinay TI Distinctive clinical characteristics of malignant mesothelioma in young patients SO ONCOTARGET LA English DT Article DE mesothelioma; SEER analysis; incidence among the young; asbestos ID EXPANDED ACCESS PROGRAM; GERMLINE BAP1 MUTATIONS; PERITONEAL MESOTHELIOMA; PLEURAL MESOTHELIOMA; ASBESTOS; COMBINATION; SURVIVAL; CANCER; CARCINOGENESIS; CISPLATIN AB Although considered a disease of the elderly, a subset of patients with mesothelioma are young (<40 years). The goal of this study was to understand their characteristics and outcomes. The Surveillance, Epidemiology, and End Results (SEER) database was used to extract mesothelioma cases (1990-2010). We modeled Kaplan-Meyer survival curves stratified by site of disease, and age of presentation. 2% (207 of 12345) of mesothelioma patients are young. Sex distribution is comparable among the young (51% males, 49% females); males predominated (78%, 22%) in the older cohort. Frequency of pleural and peritoneal mesothelioma are similar in the young (47%, 48% respectively); pleural disease predominated in the old (90%, 9%). Cancer-directed surgeries are more frequent in the young. Regardless of histologic subtype, young patients with pleural (11 vs. 8 months) and peritoneal (not reached vs. 10 months) mesothelioma had significantly improved overall survival. In multivariate analysis, younger age was an independent prognostic factor. Although rare, mesothelioma do occur in the young; their characteristics are distinct from those of older patients. Further studies are needed to understand the interplay between genetic susceptibility and mineral fiber carcinogenesis in the pathogenesis of mesothelioma in the young. C1 [Thomas, Anish; Chen, Yuanbin] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Yu, Tinghui] US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Gill, Ammara] Meyer Orthoped & Rehabil Hosp, Springfield, MO USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Thomas, Anish/0000-0003-3293-3115 FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 27 TC 2 Z9 2 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUN 30 PY 2015 VL 6 IS 18 BP 16766 EP 16773 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2UL UT WOS:000359012000097 PM 26202904 ER PT J AU Price, DL Wang, Y AF Price, Dionne L. Wang, Yan TI Commentary on "Joint modeling of survival and longitudinal non-survival data: current methods and issues' SO STATISTICS IN MEDICINE LA English DT Editorial Material C1 [Price, Dionne L.; Wang, Yan] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. RP Price, DL (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Bldg 21,Room 3508,10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM dionne.price@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUN 30 PY 2015 VL 34 IS 14 BP 2200 EP 2201 DI 10.1002/sim.6331 PG 2 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CJ7JY UT WOS:000355672400004 PM 26032838 ER PT J AU Li, MJ Yu, TH Hu, YF AF Li, Meijuan Yu, Tinghui Hu, Yun-Fu TI The impact of companion diagnostic device measurement performance on clinical validation of personalized medicine SO STATISTICS IN MEDICINE LA English DT Article DE biomarker; companion diagnostic device; analytical accuracy; imprecision; positive and negative percentage agreements; positive and negative predictive values; clinical validation trial ID PREDICTIVE BIOMARKER VALIDATION; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; TRIAL DESIGNS AB A key component of personalized medicine is companion diagnostics that measure biomarkers, for example,protein expression, gene amplification or specific mutations. Most of the recent attention concerning molecular cancer diagnostics has been focused on the biomarkers of response to therapy, such as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in metastatic colorectal cancer, epidermal growth factor receptor mutations in metastatic malignant melanoma. The presence or absence of these markers is directly linked to the response rates of particular targeted therapies with small-molecule kinase inhibitors or antibodies. Therefore, testing for these markers has become a critical step in the target therapy of the aforementioned tumors. The core capability of personalized medicine is the companion diagnostic devices' (CDx) ability to accurately and precisely stratify patients by their likelihood of benefit (or harm) from a particular therapy. There is no reference in the literature discussing the impact of device's measurement performance, for example,analytical accuracy and precision on treatment effects, variances, and sample sizes of clinical trial for the personalized medicine. In this paper, using both analytical and estimation method, we assessed the impact of CDx measurement performance as a function of positive and negative predictive values and imprecision (standard deviation) on treatment effects, variances of clinical outcome, and sample sizes for the clinical trials. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Li, Meijuan; Yu, Tinghui] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Hu, Yun-Fu] US FDA, Div Mol Genet & Pathol, Off Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Li, MJ (reprint author), US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM meijuan.li@fda.hhs.gov NR 13 TC 2 Z9 3 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUN 30 PY 2015 VL 34 IS 14 BP 2222 EP 2234 DI 10.1002/sim.6476 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 CJ7JY UT WOS:000355672400007 PM 25779099 ER PT J AU Pfeiffer, CM Sternberg, MR Fazili, Z Lacher, DA Zhang, M Johnson, CL Hamner, HC Bailey, RL Rader, JI Yamini, S Berry, RJ Yetley, EA AF Pfeiffer, Christine M. Sternberg, Maya R. Fazili, Zia Lacher, David A. Zhang, Mindy Johnson, Clifford L. Hamner, Heather C. Bailey, Regan L. Rader, Jeanne I. Yamini, Sedigheh Berry, R. J. Yetley, Elizabeth A. TI Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2 SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE National Health and Nutrition Examination Survey; Folate vitamers; 5-Methyltetrahydrofolate; Unmetabolised folic acid; Non-methyl folate; Folate oxidation products; Liquid chromatography-MS/MS ID TANDEM MASS-SPECTROMETRY; UNMETABOLIZED FOLIC-ACID; LIFE-STYLE VARIABLES; NEURAL-TUBE DEFECTS; MICROBIOLOGIC ASSAY; NHANES 1988-2010; RBC FOLATE; LC-MS/MS; BIOMARKERS; RADIOASSAY AB Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population >= 1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011-2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37.5 nmol/l; 100 %), UMFA (1.21 nmol/l; 99.9 %), MeFox (1.53 nmol/l; 98.8 %), and THF (1.01 nmol/l; 85.2 %) were mostly detectable. 5-FormylTHF (3.6 %) and 5,10-methenylTHF (4.4 %) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86.7 %); UMFA (4.0 %), non-methyl folate (4.7 %) and MeFox (4.5 %) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's r < 0.4) but significant (P < 0.05) correlations with physiological and lifestyle variables. Fasting, kidney function, smoking and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics. C1 [Pfeiffer, Christine M.; Sternberg, Maya R.; Fazili, Zia; Zhang, Mindy] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Lacher, David A.; Johnson, Clifford L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Hamner, Heather C.; Berry, R. J.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Bailey, Regan L.; Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Rader, Jeanne I.; Yamini, Sedigheh] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Pfeiffer, CM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. EM cpfeiffer@cdc.gov OI Berry, Robert/0000-0002-7162-5046 FU Office of Dietary Supplements, NIH FX Data collection and laboratory analyses of folate supported by funding from the Office of Dietary Supplements, NIH. None of the authors has reported a conflict of interest. NR 45 TC 13 Z9 13 U1 2 U2 13 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD JUN 28 PY 2015 VL 113 IS 12 BP 1965 EP 1977 DI 10.1017/S0007114515001142 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CM7PR UT WOS:000357887800014 PM 25917925 ER PT J AU Zhang, WQ Yu, Y Hertwig, F Thierry-Mieg, J Zhang, WW Thierry-Mieg, D Wang, J Furlanello, C Devanarayan, V Cheng, J Deng, YP Hero, B Hong, HX Jia, MW Li, L Lin, SM Nikolsky, Y Oberthuer, A Qing, T Su, ZQ Volland, R Wang, C Wang, MD Ai, JM Albanese, D Asgharzadeh, S Avigad, S Bao, WJ Bessarabova, M Brilliant, MH Brors, B Chierici, M Chu, TM Zhang, JB Grundy, RG He, MM Hebbring, S Kaufman, HL Lababidi, S Lancashire, LJ Li, Y Lu, XX Luo, H Ma, XW Ning, BT Noguera, R Peifer, M Phan, JH Roels, F Rosswog, C Shao, SS Shen, J Theissen, J Tonini, GP Vandesompele, J Wu, PY Xiao, WZ Xu, JS Xu, WH Xuan, JK Yang, Y Ye, Z Dong, ZR Zhang, KK Yin, Y Zhao, C Zheng, YT Wolfinger, RD Shi, TL Malkas, LH Berthold, F Wang, J Tong, WD Shi, LM Peng, ZY Fischer, M AF Zhang, Wenqian Yu, Ying Hertwig, Falk Thierry-Mieg, Jean Zhang, Wenwei Thierry-Mieg, Danielle Wang, Jian Furlanello, Cesare Devanarayan, Viswanath Cheng, Jie Deng, Youping Hero, Barbara Hong, Huixiao Jia, Meiwen Li, Li Lin, Simon M. Nikolsky, Yuri Oberthuer, Andre Qing, Tao Su, Zhenqiang Volland, Ruth Wang, Charles Wang, May D. Ai, Junmei Albanese, Davide Asgharzadeh, Shahab Avigad, Smadar Bao, Wenjun Bessarabova, Marina Brilliant, Murray H. Brors, Benedikt Chierici, Marco Chu, Tzu-Ming Zhang, Jibin Grundy, Richard G. He, Min Max Hebbring, Scott Kaufman, Howard L. Lababidi, Samir Lancashire, Lee J. Li, Yan Lu, Xin X. Luo, Heng Ma, Xiwen Ning, Baitang Noguera, Rosa Peifer, Martin Phan, John H. Roels, Frederik Rosswog, Carolina Shao, Susan Shen, Jie Theissen, Jessica Tonini, Gian Paolo Vandesompele, Jo Wu, Po-Yen Xiao, Wenzhong Xu, Joshua Xu, Weihong Xuan, Jiekun Yang, Yong Ye, Zhan Dong, Zirui Zhang, Ke K. Yin, Ye Zhao, Chen Zheng, Yuanting Wolfinger, Russell D. Shi, Tieliu Malkas, Linda H. Berthold, Frank Wang, Jun Tong, Weida Shi, Leming Peng, Zhiyu Fischer, Matthias TI Comparison of RNA-seq and microarray-based models for clinical endpoint prediction SO GENOME BIOLOGY LA English DT Article ID EXPRESSION-BASED CLASSIFICATION; GENE-EXPRESSION; NEUROBLASTOMA PATIENTS; RISK STRATIFICATION; PROSTATE-CANCER; BREAST-CANCER; TRANSCRIPTOME; SIGNATURE; DIFFERENTIATION; REPRODUCIBILITY AB Background: Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. Results: We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. Conclusions: We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice. C1 [Zhang, Wenqian; Zhang, Wenwei; Zhang, Jibin; Dong, Zirui; Yin, Ye; Wang, Jun] BGI Shenzhen, Shenzhen 518083, Guangdong, Peoples R China. [Yu, Ying; Jia, Meiwen; Qing, Tao; Zhao, Chen; Zheng, Yuanting; Shi, Leming] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Yu, Ying; Jia, Meiwen; Qing, Tao; Zhao, Chen; Zheng, Yuanting; Shi, Leming] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 201203, Peoples R China. [Yu, Ying; Jia, Meiwen; Qing, Tao; Zhao, Chen; Zheng, Yuanting; Shi, Leming] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China. [Hertwig, Falk; Hero, Barbara; Oberthuer, Andre; Volland, Ruth; Roels, Frederik; Rosswog, Carolina; Theissen, Jessica; Berthold, Frank; Fischer, Matthias] Univ Childrens Hosp Cologne, Dept Pediat Oncol & Hematol, D-50924 Cologne, Germany. [Hertwig, Falk; Peifer, Martin; Roels, Frederik; Berthold, Frank; Fischer, Matthias] Univ Cologne, Fac Med, Ctr Mol Med CMMC, D-50924 Cologne, Germany. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] NIH NCBI, Bethesda, MD 20894 USA. [Wang, Jian; Yang, Yong] Eli Lilly & Co Res Informat, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Furlanello, Cesare; Chierici, Marco] FBK, I-38123 Trento Povo, TN, Italy. [Devanarayan, Viswanath] AbbVie Inc, Global Pharmaceut R&D, Souderton, PA 18964 USA. [Cheng, Jie] GlaxoSmithKline, Discovery Analyt, Collegeville, PA 19426 USA. [Deng, Youping; Ai, Junmei; Kaufman, Howard L.; Li, Yan] Rush Univ, Ctr Canc, Dept Internal Med, Chicago, IL 60612 USA. [Hong, Huixiao; Su, Zhenqiang; Luo, Heng; Ning, Baitang; Shen, Jie; Xu, Joshua; Xuan, Jiekun; Tong, Weida; Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, Li; Bao, Wenjun; Chu, Tzu-Ming; Shao, Susan; Wolfinger, Russell D.] SAS Inst Inc, Cary, NC 27513 USA. [Lin, Simon M.; He, Min Max; Ye, Zhan] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI 54449 USA. [Nikolsky, Yuri; Bessarabova, Marina; Lancashire, Lee J.] Thomson Reuters IP & Sci, Carlsbad, CA 92008 USA. [Wang, Charles] Loma Linda Univ, Ctr Genom, Loma Linda, CA 92350 USA. [Wang, Charles] Loma Linda Univ, Sch Med, Div Microbiol & Mol Genet, Loma Linda, CA 92350 USA. [Wang, May D.; Phan, John H.] GeorgiaTech, Dept Biomed Engn, Atlanta, GA 30332 USA. [Wang, May D.; Phan, John H.] Emory Univ, Atlanta, GA 30332 USA. [Albanese, Davide] CRI CBC, Fdn Edmund Mach, San Michele All Adige, TN, Italy. [Asgharzadeh, Shahab] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Avigad, Smadar] Schneider Childrens Med Ctr Israel, Felsenstein Med Res Ctr, Dept Pediat Hematol Oncol, Mol Oncol, IL-49202 Petah Tiqwa, Israel. [Brilliant, Murray H.; Hebbring, Scott] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI 54449 USA. [Brors, Benedikt] German Canc Res Ctr, Dept Theoret Bioinformat, D-69120 Heidelberg, Germany. [Grundy, Richard G.] Univ Nottingham, Queens Med Ctr, Childrens Brain Tumour Res Ctr, Nottingham NG7 2UH, England. [Lababidi, Samir] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Lu, Xin X.] AbbVie Inc, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA. [Luo, Heng] Univ Arkansas, UALR UAMS Joint Bioinformat Grad Program, Little Rock, AR 72204 USA. [Ma, Xiwen] Eli Lilly & Co, Lilly Corp Ctr, Discovery Stat, Indianapolis, IN 46285 USA. [Noguera, Rosa] Univ Valencia, Sch Med, Dept Pathol, Valencia 46010, Spain. [Peifer, Martin] Univ Cologne, Dept Translat Genom, D-50924 Cologne, Germany. [Tonini, Gian Paolo] Univ Padua, Pediat Res Inst, SDB Dept, Neuroblastoma Lab,Onco Hematol Lab, Padua, Italy. [Vandesompele, Jo] Univ Ghent, Ctr Med Genet, Dept Pediat & Genet, B-9000 Ghent, Belgium. [Wu, Po-Yen] Georgia Inst Technol, Sch Elect & Comp Engn, Atlanta, GA 30332 USA. [Xiao, Wenzhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Xu, Weihong] Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. [Zhang, Ke K.] Univ N Dakota, Sch Med, Dept Pathol, Grand Forks, ND 58202 USA. [Shi, Tieliu] E China Normal Univ, Ctr Bioinformat & Computat Biol, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China. [Shi, Tieliu] Sch Life Sci, Shanghai 200241, Peoples R China. [Malkas, Linda H.] City Hope Comprehens Canc Ctr, Beckman Res Inst, Dept Mol & Cellular Biol, Duarte, CA 91010 USA. [Wang, Jun] Univ Copenhagen, Dept Biol, DK-2200 Copenhagen, Denmark. [Wang, Jun] King Abdulaziz Univ, Jeddah 21589, Saudi Arabia. [Wang, Jun] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark. [Peng, Zhiyu] Guangzhou Higher Educ Mega Ctr, BGI Guangzhou, Guangzhou 510006, Guangdong, Peoples R China. RP Shi, LM (reprint author), Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. EM lemingshi@fudan.edu.cn; pengzhiyu@genomics.org.cn; matthias.fischer@uk-koeln.de RI Brors, Benedikt/E-5620-2013; Wang, Jun/C-8434-2016; Luo, Heng/D-3616-2016; THIERRY-MIEG, Jean/F-1975-2017; Wang, Jun/B-9503-2016; OI Brors, Benedikt/0000-0001-5940-3101; Wang, Jun/0000-0002-8540-8931; Luo, Heng/0000-0001-5192-8878; THIERRY-MIEG, Jean/0000-0002-0396-6789; Chierici, Marco/0000-0001-9791-9301; Wang, Jun/0000-0002-2113-5874; Hertwig, Falk/0000-0003-4784-6516 FU National High Technology Research and Development Program of China - 863 Program [2015AA020104, 2012AA02A201]; National Science Foundation of China [31471239]; Intramural Research Program of the NIH, National Library of Medicine (USA); Cologne Center for Molecular Medicine; Bundesministerium fur Bildung und Forschung (BMBF) through the National Genome Research Network plus (NGFNplus) [01GS0895]; German Cancer Aid (Deutsche Krebshilfe) [110122]; Fordergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V.; National Institutes of Health [U54CA119338, 1RC2CA148265, R01CA163256]; Georgia Cancer Coalition; BMBF through the Competence Network Pediatric Oncology and Hematology (KPOH); Italian Neuroblastoma Foundation; China National Supercomputing Center in Guangzhou; China National Supercomputing Center in Tianjin FX We are grateful to Yvonne Kahlert, Anne Engesser, and Simona Coco for technical assistance. This work was supported by grants from the National High Technology Research and Development Program of China - 863 Program (2015AA020104 to LS and 2012AA02A201 to TS), the National Science Foundation of China (31471239 to LS), the Intramural Research Program of the NIH, National Library of Medicine (USA), the Cologne Center for Molecular Medicine (to MF), the Bundesministerium fur Bildung und Forschung (BMBF) through the National Genome Research Network plus (NGFNplus, grant 01GS0895 to MF), the German Cancer Aid (Deutsche Krebshilfe, grant 110122 to MF), the Fordergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V. (to FB and MF), and the National Institutes of Health (U54CA119338, 1RC2CA148265, and R01CA163256) and Georgia Cancer Coalition (to MDW). Tumor sample collection was supported by the BMBF through the Competence Network Pediatric Oncology and Hematology (KPOH) and by the Italian Neuroblastoma Foundation. We gratefully acknowledge support by China's National Supercomputing Centers in Guangzhou and Tianjin. NR 39 TC 12 Z9 12 U1 3 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD JUN 25 PY 2015 VL 16 AR 133 DI 10.1186/s13059-015-0694-1 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CN0PZ UT WOS:000358117100001 PM 26109056 ER PT J AU Guo, XQ Chen, S Zhang, ZH Dobrovolsky, VN Dial, SL Guo, L Mei, N AF Guo, Xiaoqing Chen, Si Zhang, Zhuhong Dobrovolsky, Vasily N. Dial, Stacey L. Guo, Lei Mei, Nan TI Reactive oxygen species and c-Jun N-terminal kinases contribute to TEMPO-induced apoptosis in L5178Y cells SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Nitroxide; TEMPO; Reactive oxygen species; Apoptosis; MAPK pathway ID NITROXIDE-FREE-RADICALS; BREAST-CANCER CELLS; OXIDATIVE STRESS; HEPATIC CELLS; SIGNALING PATHWAYS; CASPASE ACTIVATION; BAX TRANSLOCATION; MELANOMA-CELLS; MAP KINASES; BCL-2 AB The biological consequences of exposure to piperidine nitroxides is a concern, given their widespread use in manufacturing processes and their potential use in clinical applications. Our previous study reported that TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), a low molecular weight free radical, possesses pro-oxidative activity in L5178Y cells. In this study, we investigated and characterized the role of reactive oxygen species (ROS) in TEMPO-induced toxicity in L5178Y cells. We found that TEMPO induced time- and concentration-dependent intracellular ROS production and glutathione depletion. TEMPO also induced apoptosis as demonstrated by increased caspase-3/7 activity, an increased proportion of annexin V stained cells, and decreased expression of anti-apoptotic proteins including Bcl-2, Bcl-xL and Mcl-1. N-acetylcysteine, a ROS scavenger, attenuated the ROS production and apoptosis induced by TEMPO. Moreover, Western blot analyses revealed that TEMPO activated gamma-H2A.X, a hallmark of DNA damage, and c-Jun N-terminal kinases (JNK), a key member in the mitogen-activated protein kinase (MAPK) signaling pathway. Addition of SP600125, a JNK-specific inhibitor, blocked TEMPO-mediated JNK phosphorylation and also attenuated TEMPO-induced apoptosis. These findings indicate that both ROS production and JNK activation are involved in TEMPO-induced apoptosis, and may contribute to the toxicity of TEMPO in L5178Y cells. Published by Elsevier Ireland Ltd. C1 [Guo, Xiaoqing; Zhang, Zhuhong; Dobrovolsky, Vasily N.; Dial, Stacey L.; Mei, Nan] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Chen, Si; Guo, Lei] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Zhang, Zhuhong] Tianjin Med Univ, Gen Hosp, Tianjin 300052, Peoples R China. 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 National Center for Toxicological Research (NCTR) FX This research was partly supported by an appointment (S.C. and Z.Z.) to the Postdoctoral Research Program at the National Center for Toxicological Research (NCTR) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Entergy and the U.S. Food and Drug Administration (FDA). We thank Drs. Barbara L. Parsons and Page B. Mckinzie for their helpful discussions and comments. The information in this paper is not a formal dissemination of information by the U.S. FDA and does not represent the agency position or policy. NR 59 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUN 25 PY 2015 VL 235 BP 27 EP 36 DI 10.1016/j.cbi.2015.04.009 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA CK0HE UT WOS:000355885500004 PM 25882087 ER PT J AU Nishshanka, U Chu, PS Evans, E Reimschuessel, R Hasbrouck, N Amarasinghe, K Jayasuriya, H AF Nishshanka, Upul Chu, Pak-Sin Evans, Eric Reimschuessel, Renate Hasbrouck, Nicholas Amarasinghe, Kande Jayasuriya, Hiranthi TI Tentative Structural Assignment of a Glucuronide Metabolite of Methyltestosterone in Tilapia Bile by Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE methyltestosterone; MT-glu; OHMT-glu; QTOF; MS/MS; tilapia; bile ID COLLISION-INDUCED DISSOCIATION; ANABOLIC-STEROIDS; 17-ALPHA-METHYLTESTOSTERONE; BIOTRANSFORMATION; IDENTIFICATION; FISH AB Methyltestosterone (MT), a strong androgenic steroid, is not approved for use in fish aquaculture in the United States. It is used in the U.S. under an investigational new animal drug exemption (INAD) only during the early life stages of fish. There is a possibility that farmers feed fish with MT to enhance production for economic gains. Therefore, there is a need to develop methods for the detection of MT and its metabolite residues in fish tissue for monitoring purposes. Previously, our laboratory developed a liquid chromatography-quadrupole time-Of-flight (LC-QTOF) method for characterization of 17-O-glucuronide metabolite (MT-glu) in bile of tilapia dosed with MT. The system used was an Agilent 6530 Q-TOF equipped with electrospray jet stream technology, operating in positive ion mode. Retrospective analysis of the data generated in that experiment by a feature-finding algorithm, combined with a search against an in-house library of possible MT-metabolites, resulted in the discovery of a major glocuronide metabolite of MT in the bile extracts. Preliminary data indicate it to be a glucuronide of a hydroxylated MT (OHMT-glu) which persists in tilapia bile for at least 2 weeks after dosing. We present the tentative structural assignment of the OHMT-glu in tilapia bile and time course of development. This glucuronide can serve as a marker to monitor illegal use of MT in tilapia culture. C1 [Nishshanka, Upul; Chu, Pak-Sin; Evans, Eric; Reimschuessel, Renate; Hasbrouck, Nicholas; Amarasinghe, Kande; Jayasuriya, Hiranthi] US FDA, Ctr Vet Med, Laurel, MD 20708 USA. RP Jayasuriya, H (reprint author), US FDA, Ctr Vet Med, Laurel, MD 20708 USA. EM hiranthi.jayasuriya@fda.hhs.gov NR 16 TC 1 Z9 1 U1 4 U2 6 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 24 PY 2015 VL 63 IS 24 BP 5753 EP 5760 DI 10.1021/jf506151g PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CL6FJ UT WOS:000357062700006 PM 25980472 ER PT J AU Merrill, SJ Mu, Y AF Merrill, Stephen J. Mu, Ying TI Thyroid autoimmunity as a window to autoimmunity: An explanation for sex differences in the prevalence of thyroid autoimmunity SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Leptin; Adipokines; Hashimoto's thyroiditis; Graves' disease; PAMP's ID POLYGLANDULAR SYNDROME TYPE-2; SERUM LEPTIN LEVELS; BODY-MASS INDEX; GENDER-DIFFERENCES; HASHIMOTOS-THYROIDITIS; CROSS-REACTIVITY; IMMUNE-RESPONSE; TNF-ALPHA; DISEASES; INFLAMMATION AB Autoimmune thyroid diseases (AITDs), predominately Graves' disease and Hashimoto's thyroiditis, comprise the most common autoimmune diseases in humans. Both have the production of anti-thyroid antibody as an important aspect and both are much more prevalent in females, being at least 10 times more common than in males. Using these two clues, a hypothesis for the initiation of thyroid autoimmunity is proposed that helps to make the case that the thyroid is one of the most sensitive sites for autoimmunity and helps account for the prevalence and the observed sex differences in AITDs and associated diseases, such as type 1 diabetes and Latent Autoimmune Diabetes in Adults (LADA). The primary mechanisms proposed involve the underlying state of inflammation as a result of the adipokines, especially leptin, TNF-alpha, and IL-6, and the receptors able to recognize pathogen-associated molecular patterns (PAMP's) and damage-associated molecular patterns (DAMP's) through Toll-like receptors (TLR) and others receptors present on thyrocytes. The adipokines are produced by adipose tissue, but have hormone-like and immune modulating properties. As the levels of leptin are significantly higher in females, an explanation for the sex difference in thyroid autoimmunity emerges. The ability of the thyrocytes to participate in innate immunity through the TLR provides an adjuvant-like signal and allows for the action of other agents, such as environmental factors, viruses, bacteria, and even stress to provide the initiation step to break tolerance to thyroid self-antigens. Seeing the thyroid as one of the most sensitive sites for autoimmunity, means that for many autoimmune disorders, if autoimmunity is present, it is likely to also be present in the thyroid - and that that condition in the thyroid was probably earlier. The evidence is seen in multiple autoimmune syndrome. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Merrill, Stephen J.; Mu, Ying] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Merrill, Stephen J.] Marquette Univ, Dept Math Stat & Comp Sci, Milwaukee, WI 53201 USA. RP Merrill, SJ (reprint author), Marquette Univ, Dept MSCS, Milwaukee, WI 53201 USA. EM stephen.merrill@marquette.edu FU Research Participation Program at the Center for Devices and Radiological Health; U.S. Department of Energy; U.S. Food and Drug Administration FX SJM is supported by the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 78 TC 1 Z9 1 U1 1 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD JUN 21 PY 2015 VL 375 SI SI BP 95 EP 100 DI 10.1016/j.jtbi.2014.12.015 PG 6 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA CI5WO UT WOS:000354830700012 PM 25576242 ER PT J AU Jeffrey, M Piccardo, P Ritchie, DL Ironside, JW Green, AJE McGovern, G AF Jeffrey, Martin Piccardo, Pedro Ritchie, Diane L. Ironside, James W. Green, Alison J. E. McGovern, Gillian TI A Naturally Occurring Bovine Tauopathy Is Geographically Widespread in the UK SO PLOS ONE LA English DT Article ID STEM NEURONAL CHROMATOLYSIS; PARKINSONS-DISEASE; SPONGIFORM ENCEPHALOPATHY; PRION PROTEIN; NEUROFIBRILLARY TANGLES; PESTICIDE EXPOSURE; CEREBRAL-CORTEX; TAU; BRAIN; SHEEP AB Many human neurodegenerative diseases are associated with hyperphosphorylation and widespread intra-neuronal and glial associated aggregation of the microtubule associated protein tau. In contrast, animal tauopathies are not reported with only senescent animals showing inconspicuous tau labelling of fine processes albeit significant tau aggregation may occur in some experimental animal disease. Since 1986, an idiopathic neurological condition of adult cattle has been recognised in the UK as a sub-set of cattle slaughtered as suspect bovine spongiform encephalopathy cases. This disorder is characterised by brainstem neuronal chromatolysis and degeneration with variable hippocampal sclerosis and spongiform change. Selected cases of idiopathic brainstem neuronal chromatolysis (IBNC) were identified from archive material and characterised using antibodies specific to several tau hyperphosphorylation sites or different isoforms of the tau microtubule binding region. Labelling was also carried out for alpha synuclein, ubiquitin, TDP43, A beta(1-42), A beta(1-40). Widespread tau labelling was identified in all IBNC brains examined and with each of seven tau antibodies recognising different hyperphosphorylated sites. Labelling with each antibody was associated with dendrites, neuronal perikarya and glia. Thus IBNC is a sporadic, progressive neurological disease predominantly affecting aged cattle that occurs throughout the UK and is associated with hyperphosphorylation of tau, a rare example of a naturally-occurring tauopathy in a non-primate species. Secondary accumulation of alpha synuclein and ubiquitin was also present. The neuropathology does not precisely correspond with any human tauopathy. The cause of IBNC remains undetermined but environmental factors and exposure to agrochemicals needs to be considered in future aetiological investigations. C1 [Jeffrey, Martin; McGovern, Gillian] Anim & Plant Hlth Agcy, Lasswade Vet Lab, Penicuik, Midlothian, Scotland. [Piccardo, Pedro] Food & Drug Adm, Lab Bacterial & TSE Agents, Rockville, MD USA. [Ritchie, Diane L.; Ironside, James W.; Green, Alison J. E.] Univ Edinburgh, Western Gen Hosp, Natl CJD Res & Surveillance Unit, Ctr Clin Brain Sci,Sch Clin Sci, Edinburgh, Midlothian, Scotland. RP McGovern, G (reprint author), Anim & Plant Hlth Agcy, Lasswade Vet Lab, Pentlands Sci Pk, Penicuik, Midlothian, Scotland. EM gillian.mcgovern@apha.gsi.gov.uk RI APHA, Staff publications/E-6082-2010; OI Ironside, James/0000-0001-5869-2108 FU UK Department of farming and rural affairs grant [Se1957]; NIH-NIAID Agreement [Y1-AI-4893-02]; FDA Agreement [224-05-1307] FX These studies were partly funded by UK Department of farming and rural affairs grant Se1957 and NIH-NIAID Agreement No. Y1-AI-4893-02 and FDA Agreement No. 224-05-1307. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 0 Z9 0 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 JUN 19 PY 2015 VL 10 IS 6 AR e0129499 DI 10.1371/journal.pone.0129499 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL3FE UT WOS:000356835000047 PM 26091261 ER PT J AU Vassell, R He, Y Vennakalanti, P Dey, AK Zhuang, M Wang, W Sun, Y Biron-Sorek, Z Srivastava, IK LaBranche, CC Montefiori, DC Barnett, SW Weiss, CD AF Vassell, Russell He, Yong Vennakalanti, Prasad Dey, Antu K. Zhuang, Min Wang, Wei Sun, Yide Biron-Sorek, Zohar Srivastava, Indresh K. LaBranche, Celia C. Montefiori, David C. Barnett, Susan W. Weiss, Carol D. TI Immunogens Modeling a Fusion-Intermediate Conformation of gp41 Elicit Antibodies to the Membrane Proximal External Region of the HIV Envelope Glycoprotein SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BROADLY NEUTRALIZING ANTIBODIES; HUMAN MONOCLONAL-ANTIBODY; CELL-CELL FUSION; TYPE-1 GP41; VACCINE DESIGN; POTENT NEUTRALIZATION; ANTIGENIC PROPERTIES; LENTIVIRAL VECTOR; EPITOPE-SCAFFOLDS AB The membrane proximal external region (MPER) of the gp41 subunit of the HIV-1 envelope glycoprotein (Env) contains determinants for broadly neutralizing antibodies and has remained an important focus of vaccine design. However, creating an immunogen that elicits broadly neutralizing antibodies to this region has proven difficult in part due to the relative inaccessibility of the MPER in the native conformation of Env. Here, we describe the antigenicity and immunogenicity of a panel of oligomeric gp41 immunogens designed to model a fusion-intermediate conformation of Env in order to enhance MPER exposure in a relevant conformation. The immunogens contain segments of the gp41 N- and C-heptad repeats to mimic a trapped intermediate, followed by the MPER, with variations that include different N-heptad lengths, insertion of extra epitopes, and varying C-termini. These well-characterized immunogens were evaluated in two different immunization protocols involving gp41 and gp140 proteins, gp41 and gp160 DNA primes, and different immunization schedules and adjuvants. We found that the immunogens designed to reduce extension of helical structure into the MPER elicited the highest MPER antibody binding titers, but these antibodies lacked neutralizing activity. The gp41 protein immunogens also elicited higher MPER titers than the gp140 protein immunogen. In prime-boost studies, the best MPER responses were seen in the groups that received DNA priming with gp41 vectors followed by gp41 protein boosts. Finally, although titers to the entire protein immunogen were similar in the two immunization protocols, MPER-specific titers differed, suggesting that the immunization route, schedule, dose, or adjuvant may differentially influence MPER immunogenicity. These findings inform the design of future MPER immunogens and immunization protocols. C1 [Vassell, Russell; He, Yong; Vennakalanti, Prasad; Zhuang, Min; Wang, Wei; Weiss, Carol D.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Dey, Antu K.; Sun, Yide; Biron-Sorek, Zohar; Srivastava, Indresh K.; Barnett, Susan W.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Zhuang, Min] Harbin Med Univ, Dept Microbiol, Heilongjiang, Peoples R China. [LaBranche, Celia C.; Montefiori, David C.] Duke Med Ctr, Dept Surg, Durham, NC USA. RP Weiss, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM carol.weiss@fda.hhs.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [P01 AI066287, RFA/PA PAR03-094]; Novartis Vaccines and Diagnostics FX National Institutes of Health, National Institute of Allergy and Infectious Diseases grant P01 AI066287 to SWB responsive to RFA/PA PAR03-094. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. FDA institutional funds to CDW: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors clarify that Novartis Vaccines and Diagnostics provided support in the form of salaries for authors AKD, YS, ZB-S, IKS and SWB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 97 TC 1 Z9 1 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2015 VL 10 IS 6 AR e0128562 DI 10.1371/journal.pone.0128562 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CK9NT UT WOS:000356567500017 PM 26087072 ER PT J AU Lee, HZ Kwitkowski, VE Del Valle, PL Ricci, MS Saber, H Habtemariam, BA Bullock, J Bloomquist, E Shen, YL Chen, XH Brown, J Mehrotra, N Dorff, S Charlab, R Kane, RC Kaminskas, E Justice, R Farrell, AT Pazdur, R AF Lee, Hyon-Zu Kwitkowski, Virginia E. Del Valle, Pedro L. Ricci, M. Stacey Saber, Haleh Habtemariam, Bahru A. Bullock, Julie Bloomquist, Erik Shen, Yuan Li Chen, Xiao-Hong Brown, Janice Mehrotra, Nitin Dorff, Sarah Charlab, Rosane Kane, Robert C. Kaminskas, Edvardas Justice, Robert Farrell, Ann T. Pazdur, Richard TI FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article AB On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered intravenously at a dose of 1000 mg/m(2) over 30 minutes once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiology readings by an independent review committee. The ORR was 25.8% [ 95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathology Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), respectively. The median duration of response, the key secondary efficacy endpoint, was 8.4 months (95% CI, 4.5-29.4). The most common adverse reactions (> 25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (>= 5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL. (C)2015 AACR. C1 [Lee, Hyon-Zu; Kwitkowski, Virginia E.; Del Valle, Pedro L.; Ricci, M. Stacey; Saber, Haleh; Kane, Robert C.; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T.; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Off New Drugs, Silver Spring, MD 20993 USA. [Habtemariam, Bahru A.; Bullock, Julie; Mehrotra, Nitin; Dorff, Sarah; Charlab, Rosane] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD 20993 USA. [Bloomquist, Erik; Shen, Yuan Li] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD 20993 USA. [Chen, Xiao-Hong; Brown, Janice] US FDA, Ctr Drug Evaluat & Res, Off New Drug Qual Assessment, Silver Spring, MD 20993 USA. RP Lee, HZ (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Hyon.Lee@fda.hhs.gov NR 9 TC 39 Z9 40 U1 1 U2 3 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 15 PY 2015 VL 21 IS 12 BP 2666 EP 2670 DI 10.1158/1078-0432.CCR-14-3119 PG 5 WC Oncology SC Oncology GA CL9YZ UT WOS:000357336600004 PM 25802282 ER PT J AU Wu, YF Beland, FA Chen, S Liu, F Guo, L Fang, JL AF Wu, Yuanfeng Beland, Frederick A. Chen, Si Liu, Fang Guo, Lei Fang, Jia-Long TI Mechanisms of tolvaptan-induced toxicity in HepG2 cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Tolvaptan; Liver injury; DNA damage; Apoptosis; Proteasome; Autophagy ID KINASE SIGNALING CASCADES; BCL-2 FAMILY-MEMBERS; HEPATIC CELLS; MITOCHONDRIAL DYSFUNCTION; INDUCED HEPATOTOXICITY; PROTEASOME INHIBITOR; UBIQUITIN LIGASES; HEALTHY-SUBJECTS; CDK1 ACTIVITY; CYCLE CONTROL AB Tolvaptan, a vasopressin receptor 2 antagonist used to treat hyponatremia, has recently been reported to be associated with an increased risk of liver injury. In this study, we explored the underlying mechanisms of hepatotoxicity of tolvaptan using human HepG2 cells. Tolvaptan inhibited cell growth and caused cell death in a concentration- and time-dependent manner. Tolvaptan treatment led to delayed cell cycle progression, accompanied by decreased levels of several cyclins and cyclin-dependent kinases. Tolvaptan was found to cause DNA damage, as assessed by alkaline comet assays; this was confirmed by increased levels of 8-oxoguanine and phosphorylation of histone H2AX. Exposure HepG2 cells to tolvaptan enhanced cytochrome C release and triggered apoptosis by modulating Bcl-2 family members. The activation of p38 contributed to tolvaptan-mediated apoptosis via downregulation of Bcl-2. Proteasome inhibition altered tolvaptan-induced cell cycle deregulation and enhanced tolvaptan-induced apoptosis and cytotoxicity. Moreover, tolvaptan treatment induced autophagy. Inhibition of autophagy by knocking-down an autophagy-related gene increased tolvaptaninduced apoptosis and cytotoxicity. Taken together, our findings suggest that the cytotoxicity of tolvaptan results from delayed cell cycle progression, the induction of DNA damage, and the execution of apoptosis. In addition, a number of signaling pathways were perturbed by tolvaptan and played an important rnIP in its rytotoxirity. Published by Elsevier Inc. C1 [Wu, Yuanfeng; Beland, Frederick A.; Chen, Si; Guo, Lei; Fang, Jia-Long] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Liu, Fang] US FDA, Div Neurotoxicol, 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 NR 65 TC 7 Z9 7 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUN 15 PY 2015 VL 95 IS 4 BP 324 EP 336 DI 10.1016/j.bcp.2015.03.015 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL0PN UT WOS:000356644700010 PM 25858412 ER PT J AU Troy, SB Kouiavskaia, D Siik, J Kochba, E Beydoun, H Mirochnitchenko, O Levin, Y Khardori, N Chumakov, K Maldonado, Y AF Troy, Stephanie B. Kouiavskaia, Diana Siik, Julia Kochba, Efrat Beydoun, Hind Mirochnitchenko, Olga Levin, Yotam Khardori, Nancy Chumakov, Konstantin Maldonado, Yvonne TI Comparison of the Immunogenicity of Various Booster Doses of Inactivated Polio Vaccine Delivered Intradermally Versus Intramuscularly to HIV-Infected Adults SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE intradermal; fractional dose; inactivated polio vaccine; HIV; polio; vaccine ID RANDOMIZED CONTROLLED-TRIAL; HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIBODY-RESPONSE; WILD POLIOVIRUS; IMMUNE-RESPONSE; CLINICAL-TRIAL; POLIOMYELITIS; CHILDREN; ERADICATION; WORLDWIDE AB Background. Inactivated polio vaccine (IPV) is necessary for global polio eradication because oral polio vaccine can rarely cause poliomyelitis as it mutates and may fail to provide adequate immunity in immunocompromised populations. However, IPV is unaffordable for many developing countries. Intradermal IPV shows promise as a means to decrease the effective dose and cost of IPV, but prior studies, all using 20% of the standard dose used in intramuscular IPV, resulted in inferior antibody titers. Methods.aEuro integral We randomly assigned 231 adults with well-controlled human immunodeficiency virus infection at a ratio of 2:2:2:1 to receive 40% of the standard dose of IPV intradermally, 20% of the standard dose intradermally, the full standard dose intramuscularly, or 40% of the standard dose intramuscularly. Intradermal vaccination was done using the NanoPass MicronJet600 microneedle device. Results.aEuro integral Baseline immunity was 87%, 90%, and 66% against poliovirus serotypes 1, 2, and 3, respectively. After vaccination, antibody titers increased a median of 64-fold. Vaccine response to 40% of the standard dose administered intradermally was comparable to that of the standard dose of IPV administered intramuscularly and resulted in higher (although not significantly) antibody titers. Intradermal administration had higher a incidence of local side effects (redness and itching) but a similar incidence of systemic side effects and was preferred by study participants over intramuscular administration. Conclusions.aEuro integral A 60% reduction in the standard IPV dose without reduction in antibody titers is possible through intradermal administration. C1 [Troy, Stephanie B.; Siik, Julia; Khardori, Nancy] Eastern Virginia Med Sch, Dept Internal Med, Norfolk, VA 23501 USA. [Beydoun, Hind] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Kouiavskaia, Diana; Mirochnitchenko, Olga; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Maldonado, Yvonne] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Kochba, Efrat; Levin, Yotam] NanoPass Technol, Ness Ziona, Israel. RP Troy, SB (reprint author), Eastern Virginia Med Sch, 825 Fairfax Ave,Ste 572, Norfolk, VA 23501 USA. EM amadapaah@gmail.com FU Doris Duke Charitable Foundation [2012061]; National Institutes of Health [5K23AI093678] FX Financial support. This work was supported by the Doris Duke Charitable Foundation (Clinical Scientist Development Award 2012061 [principal investigator, S. B. T.]). S. B. T. also received salary support while working on this project from the National Institutes of Health (Career Development Award 5K23AI093678 [principal investigator, S. B. T.]). NR 40 TC 11 Z9 11 U1 1 U2 8 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 15 PY 2015 VL 211 IS 12 BP 1969 EP 1976 DI 10.1093/infdis/jiu841 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CJ7LC UT WOS:000355675600015 PM 25567841 ER PT J AU Rasooly, R Balsam, J Hernlem, BJ Rasooly, A AF Rasooly, Reuven Balsam, Josh Hernlem, Bradley J. Rasooly, Avraham TI Sensitive detection of active Shiga toxin using low cost CCD based optical detector SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Food; Shiga toxin; CCD camera; Adenovirus ID LINKED-IMMUNOSORBENT-ASSAY; ESCHERICHIA-COLI O157-H7; STAPHYLOCOCCAL-ENTEROTOXIN; UNITED-STATES; FOOD; PCR AB To reduce the sources and incidence of food-borne illness there is a need to develop affordable, sensitive devices for detection of active toxins, such as Shiga toxin type 2 (Stx2). Currently the widely used methods for measuring Shiga toxin are immunoassay that cannot distinguish between the active form of the toxin, which poses a threat to life, to the inactive form which can bind to antibodies but show no toxicity. In this work, we determine toxin activity based on Shiga toxin inhibition of green fluorescent protein (GFP) combined with low cost charge-coupled device (CCD) fluorescence detection, which is more clinically relevant than immunoassay. For assay detection, a simple low cost fluorescence detection system was constructed using a CCD camera and light emitting diode (LED) excitation source, to measure GFP expression. The system was evaluated and compared to a commercial fluorometer using photo-multiplier detection for detecting active Stx2 in the range 100 ng/mL-0.01 pg/mL. The result shows that there is a negative linear relationship between Stx2 concentrations and luminous intensity of GFP, imaged by the CCD camera (R-2=0.85) or fluorometer (R-2=0.86). The low cost (similar to$300) CCD camera is capable of detecting Shiga toxin activity at comparable levels as a more expensive (similar to$30,000) fluorometer. These results demonstrate the utility and the potential of low cost detectors for toxin activity; this approach may increase the availability of foodborne bacterial toxin diagnostics in regions where there are limited resources and could be readily adapted to the detection of other food-borne toxins. Published by Elsevier B.V. C1 [Rasooly, Reuven; Hernlem, Bradley J.] ARS, Western Reg Res Ctr, USDA, Albany, CA 94710 USA. [Balsam, Josh; Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Balsam, Josh] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Off Canc Complementary & Alternat Med, Rockville, MD 20850 USA. RP Rasooly, R (reprint author), ARS, Western Reg Res Ctr, USDA, Albany, CA 94710 USA. EM reuven.rasooly@ars.usda.gov NR 20 TC 3 Z9 3 U1 5 U2 47 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 EI 1873-4235 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD JUN 15 PY 2015 VL 68 BP 705 EP 711 DI 10.1016/j.bios.2015.01.065 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA CD7CL UT WOS:000351248300100 PM 25677808 ER PT J AU Wu, HQ Lyon, RC Khan, MA Voytilla, RJ Drennen, JK AF Wu, Huiquan Lyon, Robbe C. Khan, Mansoor A. Voytilla, Randall J. Drennen, James K., III TI Integration of Near-Infrared Spectroscopy and Mechanistic Modeling for Predicting Film-Coating and Dissolution of Modified Release Tablets SO INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH LA English DT Article ID PROCESS ANALYTICAL TECHNOLOGY; DATA PREPROCESSING METHODS; DRUG-RELEASE; DOSAGE FORMS; NIR SPECTROSCOPY; SPECTRA; PAT; FORMULATION; PARAMETERS; THICKNESS AB This study demonstrates the feasibility of predicting polymeric film coating and dissolution of theophylline (active pharmateutical ingredients, API) tablets based on integration of multivariate data analysis of near-infrared (NIR) spectra and first-principal modeling. Tablets of various API strengths were manufactured and were spray-coated in a fluid bed using a mixture of ethyl cellulose and hydroxypropyl methylcellulose. Tablets were subjected in NIR spectroscopy and in vitro USP dissolution testing. The characteristic peaks of coating materials were identified via Norris Gap second derivative preprocessing of the NIR spectra of coated tablets. Principal component analysis revealed a linear relationship between PC1 score and tablet coating level. Principal component regression and partial least squares calibration models were developed to correlate the NIR spectra with the dissolution data within the time window of 10-120 min. A linear relationship between tablet initial dissolution rate and tablet coating level was found with a slope of S. On the basis of a Fickian diffusion model, a mathematical equation was derived to relate S to the diffusion coefficient (D) of the drug across the polymeric film. The mechanistic modeling of the film-coated theophylline tablet dissolution profiles suggested that the film-coated tablet dissolution process might be governed by Fick diffusion control for the initial and early release, and governed by the Hixson and Crowell first order kinetics for the late release stage. Finally, some of the current challenges and future outlook on development of such a hybrid modeling approach for characterizing and understanding film-coated tablet manufacturing and dissolution via process analytical technology implementation was discussed from both a technical and a regulatory science perspective. C1 [Wu, Huiquan; Lyon, Robbe C.; Khan, Mansoor A.] US FDA, Div Product Qual Res, Off Testing & Res, Off Pharmaceut Qual,CDER,HFD 940, Silver Spring, MD 20993 USA. [Wu, Huiquan] US FDA, Proc Assessment Branch 2, Div Proc Assessment 1, Off Proc & Facil,Off Pharmaceut Qual,CDER, Silver Spring, MD 20993 USA. [Voytilla, Randall J.; Drennen, James K., III] Duquesne Univ, Duquesne Ctr Pharmaceut Technol, Pittsburgh, PA 15282 USA. RP Wu, HQ (reprint author), US FDA, Div Product Qual Res, Off Testing & Res, Off Pharmaceut Qual,CDER,HFD 940, White Oak Life Sci Bldg 64,10903 New Hampshire Av, Silver Spring, MD 20993 USA. EM Huiquan.wu@fda.hhs.gov FU FDA CDER Regulatory Science and Review (RSR) Grant [04-16] FX This work was partially supported by FDA CDER Regulatory Science and Review (RSR) Grant 04-16. Duquesne Center of Pharmaceutical Technology (Pittsburgh, PA) is graciously acknowledged for part of the work. NR 55 TC 0 Z9 0 U1 2 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0888-5885 J9 IND ENG CHEM RES JI Ind. Eng. Chem. Res. PD JUN 10 PY 2015 VL 54 IS 22 BP 6012 EP 6023 DI 10.1021/ie504680m PG 12 WC Engineering, Chemical SC Engineering GA CK6CW UT WOS:000356317100018 ER PT J AU Lurie, P Chahal, HS Sigelman, DW Stacy, S Sclar, J Ddamulira, B AF Lurie, Peter Chahal, Harinder S. Sigelman, Daniel W. Stacy, Sylvie Sclar, Joshua Ddamulira, Barbara TI Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article AB OBJECTIVES To describe the content of non-public complete response letters issued by the US Food and Drug Administration (FDA) when they do not approve marketing applications from sponsors (drug companies) and to compare them with the content any subsequent press releases issued by those sponsors Design Cross sectional study. Data sources All applications for which FDA's Center for Drug Evaluation and Research initially issued complete response letters (n=61) from 11 August 2008 to 27 June 2013. Complete response letters and press releases were divided into discrete statements related to seven domains and 64 subdomains and assessed to determine whether they matched. Results 48% (29) of complete response letters cited deficiencies in both the safety and efficacy domains, and only 13% cited neither safety nor efficacy deficiencies. No press release was issued for 18% (11) of complete response letters, and 21% (13) of press releases did not match any statements from the letters. Press release statements matched 93 of the 687 statements (14%), including 16% (30/191) of efficacy and 15% (22/150) of safety statements. Of 32 complete response letters that called for a new clinical trial for safety or efficacy, 59% (19) had matching press release statements. Seven complete response letters reported higher mortality rates in treated participants; only one associated press release mentioned this fact. Conclusions FDA generally issued complete response letters to sponsors for multiple substantive reasons, most commonly related to safety and/or efficacy deficiencies. In many cases, press releases were not issued in response to those letters and, when they were, omitted most of the statements in the complete response letters. Press releases are incomplete substitutes for the detailed information contained in complete response letters. C1 [Lurie, Peter; Chahal, Harinder S.; Sigelman, Daniel W.; Stacy, Sylvie; Sclar, Joshua; Ddamulira, Barbara] US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, Silver Spring, MD 20993 USA. RP Lurie, P (reprint author), US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM peter.lurie@fda.hhs.gov NR 16 TC 7 Z9 7 U1 0 U2 2 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 JUN 10 PY 2015 VL 350 AR h2758 DI 10.1136/bmj.h2758 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CK7CZ UT WOS:000356389600005 PM 26063327 ER PT J AU Ludeke, CHM Gonzalez-Escalone, N Fischer, M Jones, JL AF Luedeke, Catharina H. M. Gonzalez-Escalone, Narjol Fischer, Markus Jones, Jessica L. TI Examination of clinical and environmental Vibrio parahaemolyticus isolates by multi-locus sequence typing (MLST) and multiple-locus variable-number tandem-repeat analysis (MLVA) SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Vibrio parahaemolyticus; phylogenetics; MLVA; MLST; HRM ID FIELD GEL-ELECTROPHORESIS; PACIFIC-NORTHWEST; STRAINS; IDENTIFICATION; EPIDEMIOLOGY; GENOMICS AB Vibrio parahaemolyticus is a leading cause of seafood-borne infections in the US. This organism has a high genetic diversity that complicates identification of strain relatedness and epidemiological investigations. However, sequence-based analysis methods are promising tools for these identifications. In this study, Multi-Locus Sequence Typing (MLST) and Multiple-Locus Variable-Number Tandem-Repeat Analysis (MLVA) was performed on 58 Vibrio parahaemolyticus isolates (28 of oyster and 30 of clinical origin), to identify differences in phylogeny. The results obtained by both methods were compared to Pulsed-Field Gel Electrophoresis (PFGE) patterns determined in a previous study. Forty-one unique sequence types (STs) were identified by MLST among the 58 isolates. Almost half of the isolates (22) belonged to a new ST and added to the MLST database. A ST could not be generated for 5 (8.6%) isolates, primarily due to an untypable recA locus. Analysis with eBURST did not identify any clonal complex among the strains analyzed and revealed 37 singeltons with 4 of them forming 2 groups (1 of them SLV, and the other a DLV). An established MLVA assay, targeting 12 total genes through three separate 4-plex PCRs, was successfully adapted to high resolution melt (HRM) analysis with faster and easier experimental setup; resulting in 58 unique melt curve patterns. HRM-MLVA was capable of differentiating isolates within the same PFGE cluster and having the same ST. Conclusively, combining the three methods PFGE, MLST, and HRM-MLVA, for the phylogenetic analysis of Vibrio parahaemolyticus resulted in a high resolution subtyping scheme for Vibrio parahaemolyticus. This scheme will be useful as a phylogenetic research tool and as an improved method for outbreak investigations for Vibrio parahaemolyticus. C1 [Luedeke, Catharina H. M.; Jones, Jessica L.] US FDA, Gulf Coast Seafood Lab, Div Seafood Sci & Technol, Dauphin Isl, AL 36528 USA. [Luedeke, Catharina H. M.; Fischer, Markus] Univ Hamburg, Hamburg Sch Food Sci, Hamburg, Germany. [Gonzalez-Escalone, Narjol] US FDA, Div Microbiol, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Jones, JL (reprint author), US FDA, Gulf Coast Seafood Lab, Div Seafood Sci & Technol, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM jessica.jones@fda.hhs.gov OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 FU Research Fellowship Program for the Center for Food Safety; FDA FX This project was supported by an appointment of CL to the Research Fellowship Program for the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Associated Universities through a contract with the FDA. NR 29 TC 3 Z9 3 U1 3 U2 16 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD JUN 10 PY 2015 VL 6 AR 564 DI 10.3389/fmicb.2015.00564 PG 10 WC Microbiology SC Microbiology GA CK6PT UT WOS:000356350700001 PM 26113844 ER PT J AU Jorge-Mustonen, PS Oelbermann, M Kass, DCL AF Jorge-Mustonen, P. S. Oelbermann, M. Kass, D. C. L. TI Biomass Production and Phosphorus Use Efficiency in Two Tithonia Diversifolia (Hemsl.) Gray Genotypes SO JOURNAL OF PLANT NUTRITION LA English DT Article DE phosphorus uptake; Asteraceae; genotype; root length; agroforestry practices; organic amendments; diameter ID LEAF NUTRIENT CONCENTRATION; MAIZE ZEA-MAYS; CROTALARIA-JUNCEA; SOIL-PHOSPHORUS; P AVAILABILITY; GROWTH; ROOT; FERTILIZERS; IMPROVEMENT; RESPONSES AB Little information exists on the phosphorus (P) use efficiency of Tithonia diversifolia under varying levels of soil P availability. This study evaluated biomass production, changes in tissue P concentration, P uptake, and P uptake and utilization efficiencies in a Costa Rican and Colombian T. diversifolia genotype when 0, 0.3, 5, and 30mg P g(-1) were available. Biomass, root length and tissue P concentration increased significantly (P < 0.05) with increasing levels of P availability and with time. Phosphorus uptake (mg plant(-1)) was significantly higher (P < 0.05) at 30mg P g(-1). Phosphorus uptake (mg P mg(-1) P-f) and utilization (mg mg(-1) P) efficiencies were greatest at 0.3 and 5mg P g(-1). Differences between genotypes showed that T. diversofilia from Colombia had a significantly higher (P < 0.05) biomass, tissue P concentration, root length, and a more effective uptake and utilization of P when availability of this nutrient was low. C1 [Jorge-Mustonen, P. S.] Jorge & Mustonen SRL, Dept Agron, Santo Domingo, Dominican Rep. [Oelbermann, M.] Univ Waterloo, Dept Environm & Resource Studies, Waterloo, ON N2L 3G1, Canada. [Kass, D. C. L.] US FDA, Northeast Reg Lab, Jamaica, NY USA. RP Oelbermann, M (reprint author), Univ Waterloo, Dept Environm & Resource Studies, 200 Univ Ave West, Waterloo, ON N2L 3G1, Canada. EM moelber-mann@uwaterloo.ca NR 29 TC 0 Z9 0 U1 3 U2 11 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0190-4167 EI 1532-4087 J9 J PLANT NUTR JI J. Plant Nutr. PD JUN 7 PY 2015 VL 38 IS 7 BP 1083 EP 1096 DI 10.1080/01904167.2014.957397 PG 14 WC Plant Sciences SC Plant Sciences GA CJ1LE UT WOS:000355244300008 ER PT J AU Cinar, HN Gopinath, G Jarvis, K Murphy, HR AF Cinar, Hediye Nese Gopinath, Gopal Jarvis, Karen Murphy, Helen R. TI The Complete Mitochondrial Genome of the Foodborne Parasitic Pathogen Cyclospora cayetanensis SO PLOS ONE LA English DT Article ID MOLECULAR CHARACTERIZATION; PLASMODIUM-FALCIPARUM; SEQUENCE; APICOMPLEXA; ALIGNMENT; HUMANS AB Cyclospora cayetanensis is a human-specific coccidian parasite responsible for several food and water-related outbreaks around the world, including the most recent ones involving over 900 persons in 2013 and 2014 outbreaks in the USA. Multicopy organellar DNA such as mitochondrion genomes have been particularly informative for detection and genetic traceback analysis in other parasites. We sequenced the Cyclospora cayetanensis genomic DNA obtained from stool samples from patients infected with Cyclospora in Nepal using the Illumina MiSeq platform. By bioinformatically filtering out the metagenomic reads of non-coccidian origin sequences and concentrating the reads by targeted alignment, we were able to obtain contigs containing Eimeria-like mitochondrial, apicoplastic and some chromosomal genomic fragments. A mitochondrial genomic sequence was assembled and confirmed by cloning and sequencing targeted PCR products amplified from Cyclospora DNA using primers based on our draft assembly sequence. The results show that the Cyclospora cayetanensis mitochondrion genome is 6274 bp in length, with 33% GC content, and likely exists in concatemeric arrays as in Eimeria mitochondrial genomes. Phylogenetic analysis of the Cyclospora cayetanensis mitochondrial genome places this organism in a tight cluster with Eimeria species. The mitochondrial genome of Cyclospora cayetanensis contains three protein coding genes, cytochrome (cytb), cytochrome C oxidase subunit 1 (cox1), and cytochrome C oxidase subunit 3 (cox3), in addition to 14 large subunit (LSU) and nine small subunit (SSU) fragmented rRNA genes. C1 [Cinar, Hediye Nese; Gopinath, Gopal; Jarvis, Karen; Murphy, Helen R.] US FDA, Ctr Food Safety & Nutr, Off Appl Res, Div Virulence Assessment, Laurel, MD 20708 USA. RP Cinar, HN (reprint author), US FDA, Ctr Food Safety & Nutr, Off Appl Res, Div Virulence Assessment, Laurel, MD 20708 USA. EM hediye.cinar@fda.hhs.gov NR 29 TC 0 Z9 0 U1 3 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 4 PY 2015 VL 10 IS 6 AR UNSP e0128645 DI 10.1371/journal.pone.0128645 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7TC UT WOS:000355701600057 PM 26042787 ER PT J AU Litwack, ED Mansfield, E Shuren, J AF Litwack, E. David Mansfield, Elizabeth Shuren, Jeffrey TI The FDA and Genetic Testing SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Litwack, E. David; Mansfield, Elizabeth; Shuren, Jeffrey] US FDA, Silver Spring, MD 20993 USA. RP Litwack, ED (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 4 TC 4 Z9 4 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 4 PY 2015 VL 372 IS 23 BP 2273 EP 2274 DI 10.1056/NEJMc1504604 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CK1GK UT WOS:000355955100031 PM 26014594 ER PT J AU Robbins, KS Shah, R MacMahon, S de Jager, LS AF Robbins, Katherine S. Shah, Romina MacMahon, Shaun de Jager, Lowri S. TI Development of a Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Sulfite in Food SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE LC-MS/MS; sulfites; food additives ID INJECTION ANALYSIS SYSTEM; REVERSIBLY BOUND SULFITE; SULFUR-DIOXIDE; WINES; SO2; GRAPES; PHASE AB Sulfites are widely used food preservatives that can cause severe reactions in sensitive individuals. As a result, the U.S. FDA requires that sulfites be listed on the label of any food product containing >10 mg/kg (ppm) sulfite (measured as sulfur dioxide). Currently, the optimized Monier-Williams (MW) method (AOAC Official Method 990.28) is the most common approach for determining sulfite concentrations in food samples. However, this method is time-consuming and lacks specificity in certain matrices. An improved rapid, sensitive, and selective method has been developed using electrospray ionization (ESI) high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of sulfite in various food matrices. A total of 12 different types of foods were evaluated. These included dried fruits and vegetables, frozen seafood, sweeteners, and juices. The matrix is extracted with a buffered formaldehyde solution, converting free and reversibly bound sulfite to the stable formaldehyde adduct, hydroxymethylsulfonate (HMS). Extracts are prepared for injection using a C18 SPE cartridge to remove any lipophilic compounds. HMS is then separated from other matrix components using hydrophilic interaction chromatography (HILIC) and detected using multiple reaction monitoring (MRM). The method was validated at 5 concentrations in 12 food matrices. Accuracy data showed spiked recoveries ranging from 84 to 115% in representative foods. Six commercially available sulfited products were analyzed using the LC-MS/MS method, as well as the MW method, to determine if differences exist. C1 [Robbins, Katherine S.; Shah, Romina; MacMahon, Shaun; de Jager, Lowri S.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Robbins, KS (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 706, College Pk, MD 20740 USA. EM Katherine.robbins@fda.hhs.gov NR 26 TC 2 Z9 2 U1 9 U2 54 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 3 PY 2015 VL 63 IS 21 BP 5126 EP 5132 DI 10.1021/jf505525z PG 7 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CK0JG UT WOS:000355890900005 PM 25695590 ER PT J AU Yang, P Chang, JS Wong, JW Zhang, K Krynitsky, AJ Bromirski, M Wang, J AF Yang, Paul Chang, James S. Wong, Jon W. Zhang, Kai Krynitsky, Alexander J. Bromirski, Maciej Wang, Jian TI Effect of Sample Dilution on Matrix Effects in Pesticide Analysis of Several Matrices by Liquid Chromatography High-Resolution Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE matrix effects; multiresidue pesticides analysis; high-performance liquid chromatography (HPLC); Orbitrap mass spectrometry (Orbitrap MS) ID LC-ESI-MS; ELECTROSPRAY-IONIZATION; MULTIRESIDUE ANALYSIS; VETERINARY DRUGS; EXTRACTION; PHASE; MYCOTOXINS; VEGETABLES; ORBITRAP; PLASMA AB This study used two LC columns of different adsorbents and liquid chromatography-electrospray ionization-high-resolution mass spectrometry to study the relationship between matrix effects (ME), the LC separations, and elution patterns of pesticides and those of matrix components. Using calibration standards of 381 pesticides at three dilution levels of 1x, 1/10x, and 1/100x, 108 samples were prepared in solvent and five different sample matrices for the study. Results obtained from principal component analysis and slope ratios of calibration curves provided measurements of the ME and showed the 1/100X sample dilution could minimize suppression ME for most pesticides analyzed. Should a pesticide coeluting with Matrix components have a peak intensity of 25 times or higher, the suppression for that pesticide would persist even at 1/100X dilution. The number Of pesticides had enhancement ME increased with increasing dilution from 1x to 1/100X, with those early eluting, hydrophilic pesticides affected the most. C1 [Yang, Paul] Ontario Minist Environm & Climate Change, Lab Serv Branch, Etobicoke, ON M9P 3V6, Canada. [Chang, James S.] ThermoFisher Sci, San Jose, CA 95134 USA. [Wong, Jon W.; Zhang, Kai; Krynitsky, Alexander J.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Bromirski, Maciej] ThermoFisher Sci, D-28199 Bremen, Germany. [Wang, Jian] Canadian Food Inspect Agcy, Calgary Lab, Calgary, AB T2L 2L1, Canada. RP Yang, P (reprint author), Ontario Minist Environm & Climate Change, Lab Serv Branch, 125 Resources Rd, Etobicoke, ON M9P 3V6, Canada. EM paul.yang@ontario.ca NR 31 TC 7 Z9 7 U1 2 U2 19 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 3 PY 2015 VL 63 IS 21 BP 5169 EP 5177 DI 10.1021/jf505168v PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CK0JG UT WOS:000355890900011 PM 25620499 ER PT J AU George, NI Bowyer, JF Crabtree, NM Chang, CW AF George, Nysia I. Bowyer, John F. Crabtree, Nathaniel M. Chang, Ching-Wei TI An Iterative Leave-One-Out Approach to Outlier Detection in RNA-Seq Data SO PLOS ONE LA English DT Article ID DIFFERENTIAL EXPRESSION; DISPERSION AB The discrete data structure and large sequencing depth of RNA sequencing (RNA-seq) experiments can often generate outlier read counts in one or more RNA samples within a homogeneous group. Thus, how to identify and manage outlier observations in RNA-seq data is an emerging topic of interest. One of the main objectives in these research efforts is to develop statistical methodology that effectively balances the impact of outlier observations and achieves maximal power for statistical testing. To reach that goal, strengthening the accuracy of outlier detection is an important precursor. Current outlier detection algorithms for RNA-seq data are executed within a testing framework and may be sensitive to sparse data and heavy-tailed distributions. Therefore, we propose a univariate algorithm that utilizes a probabilistic approach to measure the deviation between an observation and the distribution generating the remaining data and implement it within in an iterative leave-one-out design strategy. Analyses of real and simulated RNA-seq data show that the proposed methodology has higher outlier detection rates for both non-normalized and normalized negative binomial distributed data. C1 [George, Nysia I.; Chang, Ching-Wei] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Bowyer, John F.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Crabtree, Nathaniel M.] Univ Arkansas, Joint Bioinformat Grad Program, Little Rock, AR 72204 USA. [Crabtree, Nathaniel M.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. RP Chang, CW (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Ching-Wei.Chang@fda.hhs.gov NR 17 TC 3 Z9 3 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 3 PY 2015 VL 10 IS 6 AR UNSP e0125224 DI 10.1371/journal.pone.0125224 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ7ST UT WOS:000355700700008 PM 26039068 ER PT J AU Ntim, SA Thomas, TA Begley, TH Noonan, GO AF Ntim, Susana Addo Thomas, Treye A. Begley, Timothy H. Noonan, Gregory O. TI Characterisation and potential migration of silver nanoparticles from commercially available polymeric food contact materials SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE silver nanoparticles; AF(4); characterisation; food contact materials; migration ID EXPOSURE ASSESSMENT; ORANGE JUICE; NANOCOMPOSITES; POLYETHYLENE; CONTAINERS; PARTICLES; SIMULANTS; ZNO; AG AB The potential for consumer exposure to nano-components in food contact materials (FCMs) is dependent on the migration of nanomaterials into food. Therefore, characterising the physico-chemical properties and potential for migration of constituents is an important step in assessing the safety of FCMs. A number of commercially available food storage products, purchased domestically within the United States and internationally, that claim to contain nanosilver were evaluated. The products were made of polyethylene, polypropylene and polyphenylene ether sulfone and all contained silver (0.001-36mgkg(-1) of polymer). Silver migration was measured under various conditions, including using 3% acetic acid and water as food simulants. Low concentrations (sub-ppb levels) of silver were detected in the migration studies generally following a trend characterised by a surface desorption phenomenon, where the majority of the silver migration occurred in the first of three consecutive exposures. Silver nanoparticles were not detected in food simulants, suggesting that the silver migration may be due solely to ionic silver released into solution from oxidation of the silver nanoparticle surface. The absence of detectable silver nanoparticles was consistent with expectations from a physico-chemical view point. For the products tested, current USFDA guidance for evaluating migration from FCMs was applicable. C1 [Ntim, Susana Addo; Begley, Timothy H.; Noonan, Gregory O.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Thomas, Treye A.] US Consumer Prod Safety Commiss, Off Hazard Identificat & Reduct, Bethesda, MD USA. RP Ntim, SA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM susana.addontim@fda.hhs.gov FU Center for Food Safety and Applied Nutrition FX This project was supported in part by an appointment to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Consumer Product Safety Commission and the USFDA. NR 21 TC 8 Z9 8 U1 2 U2 34 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 JUN 3 PY 2015 VL 32 IS 6 BP 1003 EP 1011 DI 10.1080/19440049.2015.1029994 PG 9 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA CH5YP UT WOS:000354112400019 ER PT J AU Varma, V Boros, LG Nolen, GT Chang, CW Wabitsch, M Beger, RD Kaput, J AF Varma, Vijayalakshmi Boros, Laszlo G. Nolen, Greg T. Chang, Ching-Wei Wabitsch, Martin Beger, Richard D. Kaput, Jim TI Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One-Carbon Cycle Energy Producing Pathway SO METABOLITES LA English DT Article DE human adipocytes; fructose; glucose; [1,2-C-13(2)]-D-glucose; targeted tracer fate association study (TTFAS); SOGC pathway ID MASS ISOTOPOMER ANALYSIS; FATTY-ACID; ADIPOSE-TISSUE; DIETARY FRUCTOSE; SERUM FRUCTOSE; CELLS; INSULIN; RAT; CANCER; REQUIREMENTS AB Increased consumption of sugar and fructose as sweeteners has resulted in the utilization of fructose as an alternative metabolic fuel that may compete with glucose and alter its metabolism. To explore this, human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes were differentiated to adipocytes in the presence of 0, 1, 2.5, 5 or 10 mM of fructose added to a medium containing 5 mM of glucose representing the normal blood glucose concentration. Targeted tracer [1,2-C-13(2)]-D-glucose fate association approach was employed to examine the influence of fructose on the intermediary metabolism of glucose. Increasing concentrations of fructose robustly increased the oxidation of [1,2-C-13(2)]-D-glucose to (CO2)-C-13 (p < 0.000001). However, glucose-derived (CO2)-C-13 negatively correlated with C-13 labeled glutamate, C-13 palmitate, and M+1 labeled lactate. These are strong markers of limited tricarboxylic acid (TCA) cycle, fatty acid synthesis, pentose cycle fluxes, substrate turnover and NAD(+)/NADP(+) or ATP production from glucose via complete oxidation, indicating diminished mitochondrial energy metabolism. Contrarily, a positive correlation was observed between glucose-derived (CO2)-C-13 formed and C-13 oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage. Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD(+)/NADP(+) production that is utilized in fructose-induced lipogenesis and storage in adipocytes. C1 [Varma, Vijayalakshmi; Nolen, Greg T.; Beger, Richard D.] Natl Ctr Toxicol Res, Biomarkers & Alternate Models Branch, Div Syst Biol, Jefferson, AR 72079 USA. [Chang, Ching-Wei] Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Boros, Laszlo G.] SiDMAP LLC, Los Angeles, CA 90064 USA. [Boros, Laszlo G.] Los Angeles Biomed Res Inst LABIOMED, Torrance, CA 90502 USA. [Boros, Laszlo G.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Wabitsch, Martin] Univ Ulm, Div Pediat Endocrinol & Diabetol, D-89075 Ulm, Germany. RP Varma, V (reprint author), Natl Ctr Toxicol Res, Biomarkers & Alternate Models Branch, Div Syst Biol, Jefferson, AR 72079 USA. EM vijayalakshmi.varma@fda.hhs.gov; lboros@sidmap.com; greg.nolen@fda.hhs.gov; ching-wei.chang@fda.hhs.gov; martin.wabitsch@uniklinik-ulm.de; richard.beger@fda.hhs.gov; james.kaput@rd.nestle.com FU NCATS NIH HHS [UL1 TR000124]; NCCIH NIH HHS [P01 AT003960] NR 63 TC 1 Z9 1 U1 0 U2 3 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2218-1989 J9 METABOLITES JI Metabolites PD JUN PY 2015 VL 5 IS 2 BP 364 EP 385 DI 10.3390/metabo5020364 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU0LG UT WOS:000363207300010 PM 26087138 ER PT J AU Viazis, S Beal, JK Monahan, C Lanier, WA Kreil, KR Melka, DC Boden, WD Dion, JL Miller, ZA Nguyen, TA Gieraltowski, LB Zink, DL AF Viazis, Stelios Beal, Jennifer K. Monahan, Caitlin Lanier, William A. Kreil, Katherine R. Melka, David C. Boden, William D. Dion, Jamie L. Miller, Zachary A. Thai-An Nguyen Gieraltowski, Laura B. Zink, Donald L. TI Laboratory, Environmental, and Epidemiologic Investigation and Regulatory Enforcement Actions in Response to an Outbreak of Salmonella Bredeney Infections Linked to Peanut Butter SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE food safety; outbreak; peanut butter; Salmonella ID UNITED-STATES AB Background. In September 2012, the Centers for Disease Control and Prevention (CDC), U.S. Food and Drug Administration (FDA), and state and local partners investigated an outbreak of Salmonella enterica serovar Bredeney linked to peanut butter (PB). Methods. A case was defined as infection with the outbreak strain of Salmonella Bredeney between June 1, 2012 and October 31, 2012. Food exposure questionnaires were analyzed by the CDC to determine the food vehicle. The FDA reviewed production information from Retail Chain A's sole supplier of PB, Company A. The PB samples collected from case-patients and Company A were tested for Salmonella. Results. Forty-two case-patients from 20 states were identified. Of 33 case-patients from whom food exposure information was obtained, 25 (76%) shopped at Retail Chain A and 25 (100%) purchased Company A PB. Three state health departments isolated the outbreak strain from opened jars of PB collected from case-patients. The FDA investigators identified multiple deficiencies in current Good Manufacturing Practices (cGMPs) in Company A's manufacturing facility and determined that internal controls were insufficient to prevent shipment of contaminated product. The FDA isolated the outbreak strain of Salmonella Bredeney from implicated product collected at the firm and the environment of the firm's food production facility. Conclusions. Timely laboratory, investigational, and epidemiologic data led to the voluntary recall of PB by Company A. The FDA suspended Company A's food facility registration, prohibiting the firm from introducing food into interstate commerce. This outbreak underscores the need for effective preventive controls, including robust internal environmental monitoring programs, appropriate action in response to contamination findings, and an improved understanding of food safety at the managerial and corporate levels. C1 [Viazis, Stelios; Beal, Jennifer K.; Monahan, Caitlin; Lanier, William A.; Kreil, Katherine R.] US FDA, Coordinated Outbreak Response & Evaluat Network, College Pk, MD 20740 USA. [Melka, David C.; Zink, Donald L.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Boden, William D.; Dion, Jamie L.] US FDA, Denver Dist Off, Denver, CO USA. [Miller, Zachary A.] US FDA, Denver Lab, Denver, CO USA. [Thai-An Nguyen; Gieraltowski, Laura B.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. RP Viazis, S (reprint author), US FDA, Coordinated Outbreak Response & Evaluat Network, 4300 River Rd, College Pk, MD 20740 USA. EM stelios.viazis@fda.hhs.gov NR 20 TC 1 Z9 1 U1 0 U2 4 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 SUM PY 2015 VL 2 IS 3 DI 10.1093/ofid/ofv114 PG 8 WC Infectious Diseases SC Infectious Diseases GA CX6BP UT WOS:000365786500038 ER PT J AU Bai, YP Bourne, D Wang, Y Choi, S Kompella, UB AF Bai, Yunpeng Bourne, David Wang, Yan Choi, Stephanie Kompella, Uday B. TI Sustained Release Dexamethasone Implants for In Vitro - In Vivo Correlations SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 03-07, 2015 CL Denver, CO SP Assoc Res Vis & Ophthalmol C1 [Bai, Yunpeng; Bourne, David; Kompella, Uday B.] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. [Wang, Yan; Choi, Stephanie] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2015 VL 56 IS 7 MA 4154 PG 2 WC Ophthalmology SC Ophthalmology GA CT5ZY UT WOS:000362891102355 ER PT J AU Bourne, D Vooturi, S Panda, J Choi, S Kim, H Yandrapu, S Kompella, UB AF Bourne, David Vooturi, Sunil Panda, Jiban Choi, Stephanie Kim, Hyewon Yandrapu, Sarath Kompella, Uday B. TI Effect of Particle Size and Viscosity of Ophthalmic Suspensions on Ocular Bioavailability SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 03-07, 2015 CL Denver, CO SP Assoc Res Vis & Ophthalmol C1 [Bourne, David; Vooturi, Sunil; Panda, Jiban; Yandrapu, Sarath; Kompella, Uday B.] CU SOP, Pharmaceut Sci, Aurora, CO USA. [Choi, Stephanie; Kim, Hyewon] FDA, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2015 VL 56 IS 7 MA 5722 PG 2 WC Ophthalmology SC Ophthalmology GA CT5ZY UT WOS:000362891106219 ER PT J AU Ramella-Roman, JC Rodriguez, D Wang, QZ Pfefer, J AF Ramella-Roman, J. C. Rodriguez, Daniel Wang, Quanzeng Pfefer, Joshua TI Error analysis of two-wavelength algorithms for retinal oximetry SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 03-07, 2015 CL Denver, CO SP Assoc Res Vis & Ophthalmol C1 [Ramella-Roman, J. C.] Florida Int Univ, BME, Miami, FL 33199 USA. [Ramella-Roman, J. C.] Florida Int Univ, Herbert Wertheim Coll Medi, Miami, FL 33199 USA. [Ramella-Roman, J. C.; Rodriguez, Daniel] Florida Int Univ, Biomed Engieneering Dept, Miami, FL 33199 USA. [Wang, Quanzeng; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2015 VL 56 IS 7 MA 3307 PG 2 WC Ophthalmology SC Ophthalmology GA CT5ZY UT WOS:000362891100178 ER PT J AU Li, YC Fariss, RN Cohen, ED Qian, HH AF Li, Yichao Fariss, Robert N. Cohen, Ethan D. Qian, Haohua TI Light-induced thickening of photoreceptor outer segment layer detected by ultrahigh resolution OCT imaging SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 03-07, 2015 CL Denver, CO SP Assoc Res Vis & Ophthalmol C1 [Li, Yichao; Qian, Haohua] NEI, Visual Funct Core, NIH, Rockville, MD USA. [Fariss, Robert N.] NEI, Biol Imaging core, NIH, Rockville, MD USA. [Cohen, Ethan D.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2015 VL 56 IS 7 MA 1307 PG 2 WC Ophthalmology SC Ophthalmology GA CT5WQ UT WOS:000362882203209 ER PT J AU Winchell, CJ AF Winchell, C. J. TI PATTERNS OF ALCOHOL CONSUMPTION AS SURROGATE ENDPOINTS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 38th Annual Scientific Meeting of the Research-Society-on-Alcoholism CY JUN 20-24, 2015 CL San Antonio, TX SP Res Soc Alcoholism C1 [Winchell, C. J.] US FDA, Div Anesthesia Analgesia & Addict Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2015 VL 39 SU 1 SI SI MA 105 BP 276A EP 276A PG 1 WC Substance Abuse SC Substance Abuse GA CR8XG UT WOS:000361637101583 ER PT J AU Cokic, V Mossuz, P Puri, R Beleslin-Cokic, B Mitrovic-Ajtic, O Suboticki, T Diklic, M Lekovic, D Gotic, M AF Cokic, V. Mossuz, P. Puri, R. Beleslin-Cokic, B. Mitrovic-Ajtic, O. Suboticki, T. Diklic, M. Lekovic, D. Gotic, M. TI GENE AND PROTEIN EXPRESSION ANALYSES OF THE MTOR SIGNALING PATHWAY IN MYELOPROLIFERATIVE NEOPLASMS SO HAEMATOLOGICA LA English DT Meeting Abstract CT 20th Congress of European-Hematology-Association CY JUN 11-14, 2015 CL Vienna, AUSTRIA C1 [Cokic, V.; Mitrovic-Ajtic, O.; Suboticki, T.; Diklic, M.] Univ Belgrade, Inst Med Res, Belgrade, Serbia. [Mossuz, P.] CHU Grenoble, Inst Biol & Pathol, Dept Hematol, F-38043 Grenoble, France. [Puri, R.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Beleslin-Cokic, B.] Clin Ctr Serbia, Clin Endocrinol Diabet & Dis Metab, Belgade, Serbia. [Lekovic, D.; Gotic, M.] Clin Ctr Serbia, Clin Hematol, Belgrade, Serbia. [Gotic, M.] Univ Belgrade, Fac Med, Belgrade, Serbia. NR 0 TC 0 Z9 0 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUN PY 2015 VL 100 SU 1 MA E1319 BP 528 EP 528 PG 1 WC Hematology SC Hematology GA CR3BJ UT WOS:000361204903302 ER PT J AU Siegelman, JW Supanich, MP Gavrielides, MA AF Siegelman, Jenifer W. Supanich, Mark P. Gavrielides, Marios A. TI Pulmonary Nodules With Ground-Glass Opacity Can Be Reliably Measured With Low-Dose Techniques Regardless of Iterative Reconstruction: Results of a Phantom Study SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE ground-glass opacity; lung cancer; pulmonary nodule; quantitative imaging; volume measurement ID LUNG SCREENING TRIAL; SIZE ESTIMATION; SOLID TUMORS; THORACIC CT; VOLUMETRY; CANCER; ADENOCARCINOMA; CLASSIFICATION; PARAMETERS; INCREASE AB OBJECTIVE. Pulmonary nodules of ground-glass opacity represent one imaging manifestation of a slow-growing variant of lung cancer. The objective of this phantom study was to quantify the effect of the radiation dose used for the examination (volume CT dose index [CTDI vol]), type of reconstruction algorithm, and choice of postreconstruction enhancement algorithms on the measurement error when assessing the volume of simulated lung nodules with CT, focusing on two radiodensity levels. MATERIALS AND METHODS. Twelve synthetic nodules of two radiodensities (-630 and -10 HU), three shapes (spherical, lobulated, and spiculated), and two sizes (nominal diameters of 5 and 10 mm) were inserted into an anthropomorphic chest phantom and scanned with techniques varying in CTDI vol (from subscreening dose [0.8 mGy] to diagnostic levels [6.5 mGy]), reconstruction algorithms (iterative reconstruction and filtered back projection), and different postreconstruction enhancement algorithms. Nodule volume was measured from the resulting reconstructed CT images with a matched filter estimator. RESULTS. No significant over-or underestimation of nodule volume was observed across individual variables, with low percentage error overall (-1.4%) and for individual variables (range, -3.4% to 0.4%). The magnitude of percentage error was also low (overall average percentage error < 6% and SD values < 4.5%) and for individual variables (absolute percentage error range 3.3-5.6%). No clinically significant differences were observed between different levels of CTDI vol, use of iterative reconstruction algorithms, or use of different postreconstruction enhancement algorithms. CONCLUSION. These results indicate that, if validated for other measurement tools and scanners, lung nodule volume measurements from scans acquired and reconstructed with significantly different acquisition and reconstruction techniques can be reliably compared. C1 [Siegelman, Jenifer W.] Harvard Univ, Sch Med, Dept Radiol, Brigham & Womens Hosp,Ctr Evidence Based Imaging, Brookline, MA 02445 USA. [Supanich, Mark P.] Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60612 USA. [Gavrielides, Marios A.] US FDA, Div Imaging Diagnost & Software Reliabil DIDSR, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Siegelman, JW (reprint author), Harvard Univ, Sch Med, Dept Radiol, Brigham & Womens Hosp,Ctr Evidence Based Imaging, 20 Kent St, Brookline, MA 02445 USA. EM jsiegelman1@partners.org FU NIH-NLM [R01LM010679-01]; Elucid Bioimaging; FDA Critical Path Initiative; Siemens Healthcare FX J. W. Siegelman has received grant funding from NIH-NLM R01LM010679-01 and research funding from Elucid Bioimaging, which did not contribute to this study, and is a consultant for Bayer HealthCare and for Siemens Healthcare. No Bayer HealthCare or Siemens Healthcare products were used in this study.; This work was supported in part by funding from the FDA Critical Path Initiative.; M. P. Supanich has a research grant from Siemens Healthcare. No Siemens Healthcare products were used in this study. NR 27 TC 5 Z9 5 U1 1 U2 3 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 JUN PY 2015 VL 204 IS 6 BP 1242 EP 1247 DI 10.2214/AJR.14.13820 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CQ2ZU UT WOS:000360472100037 PM 26001234 ER PT J AU Gilchrist, MA Chen, WC Shah, P Landerer, CL Zaretzki, R AF Gilchrist, Michael A. Chen, Wei-Chen Shah, Premal Landerer, Cedric L. Zaretzki, Russell TI Estimating Gene Expression and Codon-Specific Translational Efficiencies, Mutation Biases, and Selection Coefficients from Genomic Data Alone SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE synonymous codon usage; translation efficiency; mutation bias; population genetics; selection coefficient; codon usage bias ID CODING-SEQUENCE EVOLUTION; SACCHAROMYCES-CEREVISIAE; UNICELLULAR ORGANISMS; PROTEIN TRANSLATION; ESCHERICHIA-COLI; USAGE PATTERNS; REGULATORY ELEMENTS; SYNONYMOUS SITES; WIDE ANALYSIS; TRANSFER-RNAS AB Extracting biologically meaningful information from the continuing flood of genomic data is a major challenge in the life sciences. Codon usage bias (CUB) is a general feature of most genomes and is thought to reflect the effects of both natural selection for efficient translation and mutation bias. Here we present a mechanistically interpretable, Bayesian model (ribosome overhead costs Stochastic Evolutionary Model of Protein Production Rate [ ROC SEMPPR]) to extract meaningful information from patterns of CUB within a genome. ROC SEMPPR is grounded in population genetics and allows us to separate the contributions of mutational biases and natural selection against translational in efficiency on a gene-by-gene and codon-by-codon basis. Until now, the primary disadvantage of similar approaches was the need for genome scale measurements of gene expression. Here, we demonstrate that it is possible to both extract accurate estimates of codon-specific mutation biases and translational efficiencies while simultaneously generating accurate estimates of gene expression, rather than requiring such information. We demonstrate the utility of ROC SEMPPR using the Saccharomyces cerevisiae S288c genome. When we compare our model fits with previous approaches we observe an exceptionally high agreement between estimates of both codon-specific parameters and gene expression levels (rho > 0: 99 in all cases). We also observe strong agreement between our parameter estimates and those derived from alternative data sets. For example, our estimates of mutation bias and those from mutational accumulation experiments are highly correlated (rho = 0: 95). Our estimates of codon-specific translational inefficiencies and tRNA copy number-based estimates of ribosome pausing time (rho = 0: 64), and mRNA and ribosome profiling footprint-based estimates of gene expression (rho = 0:53 - 0:74) are also highly correlated, thus supporting the hypothesis that selection against translational inefficiency is an important forcedriving the evolution of CUB. Surprisingly, we find that for particular amino acids, codon usage in highly expressed genes can still be largely driven by mutation bias and that failing to take mutation bias into account can lead to the misidentification of an amino acid's "optimal" codon. In conclusion, our method demonstrates that an enormous amount of biologically important information is encoded within genome scale patterns of codon usage, accessing this information does not require gene expression measurements, but instead carefully formulated biologically interpretable models. C1 [Gilchrist, Michael A.; Chen, Wei-Chen; Landerer, Cedric L.] Univ Tennessee, Dept Ecol & Evolutionary Biol, Knoxville, TN 37996 USA. [Gilchrist, Michael A.; Zaretzki, Russell] Natl Inst Math & Biol Synth, Knoxville, TN USA. [Shah, Premal] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Zaretzki, Russell] Univ Tennessee, Dept Business Analyt & Stat, Knoxville, TN USA. [Chen, Wei-Chen] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Gilchrist, MA (reprint author), Univ Tennessee, Dept Ecol & Evolutionary Biol, Knoxville, TN 37996 USA. EM mikeg@utk.edu FU NSF [MCB-1120370, EOB-1355033]; Burroughs Wellcome Fund; David and Lucile Packard Foundation; US Army Research Office [W911NF-12-1-0552]; National Institute for Mathematical and Biological Synthesis [NSF:DBI-1300426]; University of Tennessee FX The authors acknowledge financial support for this project from NSF grants MCB-1120370 (M.A.G. and R.Z.) and EOB-1355033 (Brian O'Meara, M.A.G., and R.Z.). P.S. was supported by Burroughs Wellcome Fund, the David and Lucile Packard Foundation, and US Army Research Office Grant W911NF-12-1-0552 awarded to Joshua Plotkin. Additional support was also provided by the National Institute for Mathematical and Biological Synthesis (NSF:DBI-1300426 with additional support from the University of Tennessee). They are grateful to the RDAV group at the National Institute for Computational Sciences: George Ostrouchov, Drew Schmidt, and Pragnesh Patel who contributed to an earlier attempt to address this problem. They also thank W. Preston Hewgley, Brian O'Meara, Ivan Erill, and Patrick O'Neill for their helpful discussions and suggestions and Laura Kubatko for providing the FMutSel output. Finally, they thank their two anonymous reviewers whose comments and suggestions greatly improved the quality of this article. NR 85 TC 2 Z9 2 U1 3 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PD JUN PY 2015 VL 7 IS 6 BP 1559 EP 1579 DI 10.1093/gbe/evv087 PG 21 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA CN9WB UT WOS:000358800100012 PM 25977456 ER PT J AU Alam, MS Costales, MG Cavanaugh, C Williams, K AF Alam, M. Samiul Costales, Matthew G. Cavanaugh, Christopher Williams, Kristina TI Extracellular Adenosine Generation in the Regulation of Pro-Inflammatory Responses and Pathogen Colonization SO BIOMOLECULES LA English DT Review ID CD4 T-CELLS; NITRIC-OXIDE SYNTHASE; NATURAL-KILLER-CELLS; HUMAN GASTRIC-MUCOSA; HELICOBACTER-PYLORI; ECTO-5'-NUCLEOTIDASE CD73; IMMUNE-RESPONSE; SALMONELLA-TYPHIMURIUM; LEGIONELLA-PNEUMOPHILA; NUCLEOTIDE-METABOLISM AB Adenosine, an immunomodulatory biomolecule, is produced by the ecto-enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5'-nucleotidase) by dephosphorylation of extracellular ATP. CD73 is expressed by many cell types during injury, infection and during steady-state conditions. Besides host cells, many bacteria also have CD39-CD73-like machinery, which helps the pathogen subvert the host inflammatory response. The major function for adenosine is anti-inflammatory, and most recent research has focused on adenosine's control of inflammatory mechanisms underlying various autoimmune diseases (e.g., colitis, arthritis). Although adenosine generated through CD73 provides a feedback to control tissue damage mediated by a host immune response, it can also contribute to immunosuppression. Thus, inflammation can be a double-edged sword: it may harm the host but eventually helps by killing the invading pathogen. The role of adenosine in dampening inflammation has been an area of active research, but the relevance of the CD39/CD73-axis and adenosine receptor signaling in host defense against infection has received less attention. Here, we review our recent knowledge regarding CD73 expression during murine Salmonellosis and Helicobacter-induced gastric infection and its role in disease pathogenesis and bacterial persistence. We also explored a possible role for the CD73/adenosine pathway in regulating innate host defense function during infection. C1 [Alam, M. Samiul; Costales, Matthew G.; Cavanaugh, Christopher; Williams, Kristina] US FDA, Immunobiol Branch, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Alam, MS (reprint author), US FDA, Immunobiol Branch, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM Mohammad.alam@fda.hhs.gov; matthew.costales@gmail.com; Christopher.Cavanaugh@fda.hhs.gov; Kristina.Williams@fda.hhs.gov NR 114 TC 4 Z9 4 U1 2 U2 4 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2218-273X J9 BIOMOLECULES JI Biomolecules PD JUN PY 2015 VL 5 IS 2 BP 775 EP 792 DI 10.3390/biom5020775 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CM4FV UT WOS:000357640800024 PM 25950510 ER PT J AU Lansdowne, K Scully, CG Galeotti, L Schwartz, S Marcozzi, D Strauss, DG AF Lansdowne, Krystal Scully, Christopher G. Galeotti, Loriano Schwartz, Suzanne Marcozzi, David Strauss, David G. TI Recent Advances in Medical Device Triage Technologies for Chemical, Biological, Radiological, and Nuclear Events SO PREHOSPITAL AND DISASTER MEDICINE LA English DT Article DE mass-casualty incidents; patient monitoring; triage; weapons of mass destruction ID SYSTEM; CARE AB In 2010, the US Food and Drug Administration (Silver Spring, Maryland USA) created the Medical Countermeasures Initiative with the mission of development and promoting medical countermeasures that would be needed to protect the nation from identified, high-priority chemical, biological, radiological, or nuclear (CBRN) threats and emerging infectious diseases. The aim of this review was to promote regulatory science research of medical devices and to analyze how the devices can be employed in different CBRN scenarios. Triage in CBRN scenarios presents unique challenges for first responders because the effects of CBRN agents and the clinical presentations of casualties at each triage stage can vary. The uniqueness of a CBRN event can render standard patient monitoring medical device and conventional triage algorithms ineffective. Despite the challenges, there have been recent advances in CBRN triage technology that include: novel technologies; mobile medical applications ("medical apps") for CBRN disasters; electronic triage tags, such as eTriage; diagnostic field devices, such as the Joint Biological Agent Identification System; and decision support systems, such as the Chemical Hazards Emergency Medical Management Intelligent Syndromes Tool (CHEMM-IST). Further research and medical device validation can help to advance prehospital triage technology for CBRN events. Lansdowne K, Scully CG, Galeotti L, Schwartz S, Marcozzi D, Strauss DG. Recent advances in medical device triage technologies for chemical, biological, radiological, and nuclear events. C1 [Lansdowne, Krystal; Scully, Christopher G.; Galeotti, Loriano; Schwartz, Suzanne; Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Marcozzi, David] US Dept HHS, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. RP Strauss, DG (reprint author), 10903 New Hampshire Ave,WO62-1126, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov NR 19 TC 1 Z9 1 U1 1 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1049-023X EI 1945-1938 J9 PREHOSPITAL DISASTER JI Prehospital Disaster Med. PD JUN PY 2015 VL 30 IS 3 BP 320 EP 323 DI 10.1017/S1049023X15004641 PG 4 WC Emergency Medicine SC Emergency Medicine GA CN4OP UT WOS:000358410000017 PM 25868677 ER PT J AU Parshikov, IA Sutherland, JB AF Parshikov, Igor A. Sutherland, John B. TI Biotransformation of Steroids and Flavonoids by Cultures of Aspergillus niger SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY LA English DT Article DE Aspergillus niger; Biotransformation; Flavonoids; Organic compounds; Steroids ID PENICILLIUM-CHERMESINUM CULTURES; IMMOBILIZED FILAMENTOUS FUNGI; MICROBIAL TRANSFORMATIONS; MICROBIOLOGICAL TRANSFORMATION; FOOD MICROORGANISMS; PANAX-GINSENG; METABOLITES; CONVERSION; ALGINATE; 6-HYDROXYFLAVANONE AB Steroids are derivatives of the triterpenoid squalene, containing three fused cyclohexane rings and a cyclopentane ring, and flavonoids are derivatives of L-phenylalanine, containing two aromatic rings joined by a three-carbon bridge that may form part of a heterocyclic ring. A great variety of steroids and flavonoids are produced by plants, and many additional steroids are produced by animals or fungi. Because these compounds have many nutritional and pharmaceutical values, and many of them cannot be produced by chemical synthesis, biotechnological processes are being developed that use cultures of Aspergillus niger and other fungi to transform steroids and flavonoids to a variety of metabolites. These biochemical reactions, including hydroxylation, dehydrogenation, O-methylation, demethylation, cleavage of rings, epoxide hydrolysis, double bond reduction, and others, may be used for the production of higher-value compounds. C1 [Parshikov, Igor A.] Russian Acad Sci, Inst Appl Mech, Moscow 119991, Russia. [Sutherland, John B.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Sutherland, JB (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM john.sutherland@fda.hhs.gov OI Parshikov, Igor/0000-0003-1466-1128 NR 69 TC 4 Z9 4 U1 13 U2 47 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0273-2289 EI 1559-0291 J9 APPL BIOCHEM BIOTECH JI Appl. Biochem. Biotechnol. PD JUN PY 2015 VL 176 IS 3 BP 903 EP 923 DI 10.1007/s12010-015-1619-x PG 21 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA CN1JK UT WOS:000358175400017 PM 25951777 ER PT J AU Zabala-Travers, S Choi, M Cheng, WC Badano, A AF Zabala-Travers, Silvina Choi, Mina Cheng, Wei-Chung Badano, Aldo TI Effect of color visualization and display hardware on the visual assessment of pseudocolor medical images SO MEDICAL PHYSICS LA English DT Article DE color imaging; color visualization; color display; color scale; functional imaging ID HAND-HELD DEVICES; DETECTION PERFORMANCE; AMBIENT ILLUMINATION; LUMPY BACKGROUNDS; PROSTATE-CANCER; CONTRAST; OBSERVER; HETEROGENEITY; MANIPULATION; RAINBOW AB Purpose: Even though the use of color in the interpretation of medical images has increased significantly in recent years, the ad hoc manner in which color is handled and the lack of standard approaches have been associated with suboptimal and inconsistent diagnostic decisions with a negative impact on patient treatment and prognosis. The purpose of this study is to determine if the choice of color scale and display device hardware affects the visual assessment of patterns that have the characteristics of functional medical images. Methods: Perfusion magnetic resonance imaging (MRI) was the basis for designing and performing experiments. Synthetic images resembling brain dynamic-contrast enhanced MRI consisting of scaled mixtures of white, lumpy, and clustered backgrounds were used to assess the performance of a rainbow ("jet"), a heated black-body ("hot"), and a gray ("gray") color scale with display. devices of different quality on the detection of small changes in color intensity. The authors used a two-alternative, forced-choice design where readers were presented with 600 pairs of images. Each pair consisted of two images of the same pattern flipped along the vertical axis with a small difference in intensity. Readers were asked to select the image with the highest intensity. Three differences in intensity were tested on four display devices: a medical-grade three-million-pixel display, a consumer-grade monitor, a tablet device, and a phone. Results: The estimates of percent correct show that jet outperformed hot and gray in the high and low range of the color scales for all devices with a maximum difference in performance of 18% (confidence intervals: 6%, 30%). Performance with hot was different for high and low intensity, comparable to jet for the high range, and worse than gray for lower intensity values. Similar performance was seen between deviees using jet and hot, while gray performance was better for handheld devices. Time of performance was shorter with jet. Conclusions: Our findings demonstrate that the choice of color scale and display hardware affects the visual comparative analysis of pseudocolor images. Follow-up studies in clinical settings are being considered to confirm the results with patient images. C1 [Zabala-Travers, Silvina; Choi, Mina; Cheng, Wei-Chung; Badano, Aldo] OSEL CDRH FDA, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. RP Badano, A (reprint author), OSEL CDRH FDA, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 52 TC 1 Z9 1 U1 1 U2 5 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2015 VL 42 IS 6 BP 2942 EP 2954 DI 10.1118/1.4921125 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL5KH UT WOS:000356998300022 PM 26127048 ER PT J AU Myers, K Stierstorfer, K Hsieh, J Wang, W Halliburton, S Pelc, N AF Myers, K. Stierstorfer, K. Hsieh, J. Wang, W. Halliburton, S. Pelc, N. TI Iterative Reconstruction in CT SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 12-16, 2015 CL Anaheim, CA SP Amer Assoc Physicists Med C1 [Myers, K.] US FDA, Off Sci & Engn Labs, Rockville, MD 20857 USA. [Stierstorfer, K.] Siemens, Hyderabad, Andhra Pradesh, India. [Hsieh, J.] GE Healthcare Technol, Hyderabad, Andhra Pradesh, India. [Wang, W.] Toshiba Med Res Inst, Vernon Hills, IL USA. [Halliburton, S.] Philips Healthcare, Baltimore, MD USA. [Pelc, N.] Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 JUN PY 2015 VL 42 IS 6 BP 3558 EP 3559 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL5KH UT WOS:000356998302642 PM 26128643 ER PT J AU Zeng, R Park, S Badano, A Myers, K AF Zeng, R. Park, S. Badano, A. Myers, K. TI Effect of Reconstruction Methods On the Evaluation of Digital Breast Tomosynthesis (DBT) Acquisition Parameters Using Human and Model Observers SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 12-16, 2015 CL Anaheim, CA SP Amer Assoc Physicists Med C1 [Zeng, R.; Park, S.; Badano, A.; Myers, K.] Food & Drug Adm, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2015 VL 42 IS 6 BP 3611 EP 3611 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL5KH UT WOS:000356998303092 PM 26128926 ER PT J AU Luetmer, P Badano, A Walz-Flannigan, A Walz-Flannigan, A AF Luetmer, P. Badano, A. Walz-Flannigan, A. Walz-Flannigan, A. TI Mobile Viewing Devices SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) CY JUL 12-16, 2015 CL Anaheim, CA SP Amer Assoc Physicists Med C1 [Luetmer, P.; Walz-Flannigan, A.; Walz-Flannigan, A.] Mayo Clin, Rochester, MN USA. [Badano, A.] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 JUN PY 2015 VL 42 IS 6 BP 3698 EP 3698 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CL5KH UT WOS:000356998303386 PM 26129404 ER PT J AU Minor, T Lasher, A Klontz, K Brown, B Nardinelli, C Zorn, D AF Minor, Travis Lasher, Angela Klontz, Karl Brown, Bradley Nardinelli, Clark Zorn, David TI The Per Case and Total Annual Costs of Foodborne Illness in the United States SO RISK ANALYSIS LA English DT Article DE Foodborne illness; QALY ID WILLINGNESS-TO-PAY; CAMPYLOBACTER-JEJUNI INFECTION; HEMOLYTIC-UREMIC SYNDROME; GUILLAIN-BARRE-SYNDROME; YERSINIA-ENTEROCOLITICA; VIBRIO INFECTIONS; STATISTICAL LIFE; ECONOMIC BURDEN; OUTBREAK; HEALTH AB We present an economic welfare-based method to estimate the health costs associated with foodborne illness caused by known viruses, bacteria, parasites, allergens, two marine biotoxins, and unspecified agents. The method generates health costs measured in both quality-adjusted life years and in dollars. We calculate the reduction in quality-adjusted life days caused by the illness and add reductions in quality-adjusted life years from any secondary effects that are estimated to occur. For fatal cases, we calculate the life years lost due to premature death. We add direct medical expenses to the monetary costs as derived from estimates of willingness to pay to reduce health risks. In total, we estimate that foodborne illness represents an annual burden to society of approximately $36 billion, with an average identified illness estimated to reduce quality-adjusted life days by 0.84, which is monetized and included in the average cost burden per illness of $3,630. C1 [Minor, Travis; Lasher, Angela; Klontz, Karl; Brown, Bradley] US FDA, College Pk, MD 20740 USA. [Nardinelli, Clark] US FDA, Silver Spring, MD USA. [Zorn, David] US FDA, Springfield, VA USA. RP Minor, T (reprint author), US FDA, HFS-020,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Travis.Minor@fda.hhs.gov NR 77 TC 3 Z9 3 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0272-4332 EI 1539-6924 J9 RISK ANAL JI Risk Anal. PD JUN PY 2015 VL 35 IS 6 SI SI BP 1125 EP 1139 DI 10.1111/risa.12316 PG 15 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA CN0SD UT WOS:000358122800011 PM 25557397 ER PT J AU Anez, G AF Anez, German TI Flying pain SO MEDICAL HUMANITIES LA English DT Poetry DE arthritis; pain; chikungunya virus; mosquito-borne virus C1 [Anez, German] US FDA, Silver Spring, MD USA. RP Anez, G (reprint author), 10903 New Hampshire Av,Bldg 52-72,Room 5216, Silver Spring, MD 20993 USA. EM german.anez@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1468-215X EI 1473-4265 J9 MED HUMANIT JI Med. Humanit. PD JUN PY 2015 VL 41 IS 1 BP E12 EP E12 DI 10.1136/medhum-2014-010657 PG 1 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA CM2RV UT WOS:000357530700012 PM 26052124 ER PT J AU Depasquale, R Lee, SL Saluja, B Shur, J Price, R AF Depasquale, Roberto Lee, Sau L. Saluja, Bhawana Shur, Jagdeep Price, Robert TI The Influence of Secondary Processing on the Structural Relaxation Dynamics of Fluticasone Propionate SO AAPS PHARMSCITECH LA English DT Article DE cohesive-adhesive balance; laagering; mechanical activation; particle adhesion; process-induced structural disorder ID POWDER INHALER FORMULATIONS; COHESIVE-ADHESIVE BALANCES; MECHANICAL ACTIVATION; PHYSICAL STABILITY; SALBUTAMOL SULFATE; QUANTIFICATION; PERFORMANCE AB This study investigated the structural relaxation of micronized fluticasone propionate (FP) under different lagering conditions and its influence on aerodynamic particle size distribution (APSD) of binary and tertiary carrier-based dry powder inhaler (DPI) formulations. Micronized FP was lagered under low humidity (LH 25 C, 33% RH [relative humidity]), high humidity (HH 25 degrees C, 75% RH) for 30, 60, and 90 days, respectively, and high temperature (HT 60 degrees C, 44% RH) for 14 days. Physicochemical, surface interfacial properties via cohesive-adhesive balance (CAB) measurements and amorphous disorder levels of the FP samples were characterized. Particle size, surface area, and rugosity suggested minimal morphological changes of the lagered FP samples, with the exception of the 90-day HH (HH90) sample. HH90 FP samples appeared to undergo surface reconstruction with a reduction in surface rugosity. LH and HH lagering reduced the levels of amorphous content over 90-day exposure, which influenced the CAB measurements with lactose monohydrate and salmeterol xinafoate (SX). CAB analysis suggested that LH and HH lagering led to different interfacial interactions with lactose monohydrate but an increasing adhesive affinity with SX. HT lagering led to no detectable levels of the amorphous disorder, resulting in an increase in the adhesive interaction with lactose monohydrate. APSD analysis suggested that the fine particle mass of FP and SX was affected by the lagering of the FP. In conclusion, environmental conditions during the lagering of FP may have a profound effect on physicochemical and interfacial properties as well as product performance of binary and tertiary carrier-based DPI formulations. C1 [Depasquale, Roberto; Shur, Jagdeep; Price, Robert] Univ Bath, Dept Pharm & Pharmacol, Pharmaceut Surface Sci Res Grp, Bath BA2 7AY, Avon, England. [Lee, Sau L.] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Saluja, Bhawana] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Price, R (reprint author), Univ Bath, Dept Pharm & Pharmacol, Pharmaceut Surface Sci Res Grp, Bath BA2 7AY, Avon, England. EM r.price@bath.ac.uk NR 20 TC 0 Z9 0 U1 2 U2 5 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 2015 VL 16 IS 3 BP 589 EP 600 DI 10.1208/s12249-014-0222-8 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CM3FP UT WOS:000357567600012 PM 25398478 ER PT J AU Betts, KR Hinsz, VB AF Betts, Kevin R. Hinsz, Verlin B. TI Mindful Attention and Awareness Predict Self-Reported Food Safety Practices in the Food Service Industry SO CURRENT PSYCHOLOGY LA English DT Article DE Food safety; Food service; Mindfulness; Effective work practices; Training ID KNOWLEDGE; PERSISTENCE; ATTITUDES; HANDLERS; BEHAVIOR AB We examine relationships between dispositional mindfulness, food safety knowledge, and self-reported food safety practices in the food service industry. Mindfulness refers to the state of being attentive to and aware of what is taking place in the present. Mindfulness is relevant to food service work because employees often work in hectic environments that can detract attention and awareness away from threats to food safety and protocols that help manage such threats. Food service workers (N=428) from a wide variety of establishments were surveyed to gather their dispositional mindfulness as well as food safety knowledge and practices. Analyses reveal that mindfulness explains variance in self-reported food safety practices beyond that of food safety knowledge, with stronger relationships for workers having lower levels of food safety knowledge. Implications are considered within the context of an emerging literature that emphasizes the relationship between psychological constructs and food safety practices. C1 [Betts, Kevin R.] US FDA, Silver Spring, MD 20993 USA. [Hinsz, Verlin B.] N Dakota State Univ, Fargo, ND 58105 USA. RP Betts, KR (reprint author), US FDA, Silver Spring, MD 20993 USA. EM Kevin.Betts@fda.hhs.gov FU Cooperative State Research, Education and Extension Service, U.S. Department of Agriculture FX Address correspondence to Kevin R. Betts, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993; or email Kevin. Betts@fda.hhs.gov. Preparation of this report was supported by grants from the Cooperative State Research, Education and Extension Service, U.S. Department of Agriculture awarded to the second author. A portion of the data reported in this paper regarding food safety knowledge and practices was previously published as part of a chapter in an edited book (Betts and Hinsz 2010). The views expressed in this article do not represent the views of the U.S. Food and Drug Administration or the United States. NR 37 TC 0 Z9 1 U1 4 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1046-1310 EI 1936-4733 J9 CURR PSYCHOL JI Curr. Psychol. PD JUN PY 2015 VL 34 IS 2 BP 191 EP 206 DI 10.1007/s12144-014-9251-4 PG 16 WC Psychology, Multidisciplinary SC Psychology GA CM2AR UT WOS:000357482400001 ER PT J AU Pearce, N Blair, A Vineis, P Ahrens, W Andersen, A Anto, JM Armstrong, BK Baccarelli, AA Beland, FA Berrington, A Bertazzi, PA Birnbaum, LS Brownson, RC Bucher, JR Cantor, KP Cardis, E Cherrie, JW Christiani, DC Cocco, P Coggon, D Comba, P Demers, PA Dement, JM Douwes, J Eisen, EA Engel, LS Fenske, RA Fleming, LE Fletcher, T Fontham, E Forastiere, F Frentzel-Beyme, R Fritschi, L Gerin, M Goldberg, M Grandjean, P Grimsrud, TK Gustavsson, P Haines, A Hartge, P Hansen, J Hauptmann, M Heederik, D Hemminki, K Hemon, D Hertz-Picciotto, I Hoppin, JA Huff, J Jarvholm, B Kang, D Karagas, MR Kjaerheim, K Kjuus, H Kogevinas, M Kriebel, D Kristensen, P Kromhout, H Laden, F Lebailly, P LeMasters, G Lubin, JH Lynch, CF Lynge, E Mannetje, A McMichael, AJ McLaughlin, JR Marrett, L Martuzzi, M Merchant, JA Merler, E Merletti, F Miller, A Mirer, FE Monson, R Nordby, KC Olshan, AF Parent, ME Perera, FP Perry, MJ Pesatori, AC Pirastu, R Porta, M Pukkala, E Rice, C Richardson, DB Ritter, L Ritz, B Ronckers, CM Rushton, L Rusiecki, JA Rusyn, I Samet, JM Sandler, DP de Sanjose, S Schernhammer, E Costantini, AS Seixas, N Shy, C Siemiatycki, J Silverman, DT Simonato, L Smith, AH Smith, MT Spinelli, JJ Spitz, MR Stallones, L Stayner, LT Steenland, K Stenzel, M Stewart, BW Stewart, PA Symanski, E Terracini, B Tolbert, PE Vainio, H Vena, J Vermeulen, R Victora, CG Ward, EM Weinberg, CR Weisenburger, D Wesseling, C Weiderpass, E Zahm, SH AF Pearce, Neil Blair, Aaron Vineis, Paolo Ahrens, Wolfgang Andersen, Aage Anto, Josep M. Armstrong, Bruce K. Baccarelli, Andrea A. Beland, Frederick A. Berrington, Amy Bertazzi, Pier Alberto Birnbaum, Linda S. Brownson, Ross C. Bucher, John R. Cantor, Kenneth P. Cardis, Elisabeth Cherrie, John W. Christiani, David C. Cocco, Pierluigi Coggon, David Comba, Pietro Demers, Paul A. Dement, John M. Douwes, Jeroen Eisen, Ellen A. Engel, Lawrence S. Fenske, Richard A. Fleming, Lora E. Fletcher, Tony Fontham, Elizabeth Forastiere, Francesco Frentzel-Beyme, Rainer Fritschi, Lin Gerin, Michel Goldberg, Marcel Grandjean, Philippe Grimsrud, Tom K. Gustavsson, Per Haines, Andy Hartge, Patricia Hansen, Johnni Hauptmann, Michael Heederik, Dick Hemminki, Kari Hemon, Denis Hertz-Picciotto, Irva Hoppin, Jane A. Huff, James Jarvholm, Bengt Kang, Daehee Karagas, Margaret R. Kjaerheim, Kristina Kjuus, Helge Kogevinas, Manolis Kriebel, David Kristensen, Petter Kromhout, Hans Laden, Francine Lebailly, Pierre LeMasters, Grace Lubin, Jay H. Lynch, Charles F. Lynge, Elsebeth Mannetje, Andrea 't McMichael, Anthony J. McLaughlin, John R. Marrett, Loraine Martuzzi, Marco Merchant, James A. Merler, Enzo Merletti, Franco Miller, Anthony Mirer, Franklin E. Monson, Richard Nordby, Karl-Cristian Olshan, Andrew F. Parent, Marie-Elise Perera, Frederica P. Perry, Melissa J. Pesatori, Angela Cecilia Pirastu, Roberta Porta, Miquel Pukkala, Eero Rice, Carol Richardson, David B. Ritter, Leonard Ritz, Beate Ronckers, Cecile M. Rushton, Lesley Rusiecki, Jennifer A. Rusyn, Ivan Samet, Jonathan M. Sandler, Dale P. de Sanjose, Silvia Schernhammer, Eva Costantini, Adele Seniori Seixas, Noah Shy, Carl Siemiatycki, Jack Silverman, Debra T. Simonato, Lorenzo Smith, Allan H. Smith, Martyn T. Spinelli, John J. Spitz, Margaret R. Stallones, Lorann Stayner, Leslie T. Steenland, Kyle Stenzel, Mark Stewart, Bernard W. Stewart, Patricia A. Symanski, Elaine Terracini, Benedetto Tolbert, Paige E. Vainio, Harri Vena, John Vermeulen, Roel Victora, Cesar G. Ward, Elizabeth M. Weinberg, Clarice R. Weisenburger, Dennis Wesseling, Catharina Weiderpass, Elisabete Zahm, Shelia Hoar TI IARC Monographs: 40 Years of Evaluating Carcinogenic Hazards to Humans SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID PRINCIPLES UNDERLYING SCIENCE; PUBLIC-HEALTH; EPIDEMIOLOGIC ENTERPRISE; CANCER-EPIDEMIOLOGY; PLEA; POLICY; FALSE; ADHERENCE; PROGRAM; RECIPE AB BACKGROUND: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans. OBJECTIVES: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed. DISCUSSION: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed. CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health. C1 [Pearce, Neil] London Sch Hyg & Trop Med, Dept Med Stat, London WC1E 7HT, England. [Blair, Aaron; Berrington, Amy; Hartge, Patricia; Lubin, Jay H.; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, London, England. [Ahrens, Wolfgang] Leibniz Inst Prevent Res & Epidemiol BIPS, Bremen, Germany. [Andersen, Aage; Grimsrud, Tom K.; Kjaerheim, Kristina] Canc Registry Norway, Dept Res, Oslo, Norway. [Anto, Josep M.] Univ Pompeu Fabra, Ctr Res Environm Epidemiol CREAL, IMIM Hosp Mar Med Res Inst, Barcelona, Spain. [Anto, Josep M.] CIBERESP, Barcelona, Spain. [Armstrong, Bruce K.] Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Armstrong, Bruce K.] Sax Inst, Sydney, NSW, Australia. [Baccarelli, Andrea A.; Christiani, David C.; Laden, Francine; Monson, Richard; Schernhammer, Eva] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Baccarelli, Andrea A.; Christiani, David C.; Laden, Francine; Monson, Richard; Schernhammer, Eva] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Bertazzi, Pier Alberto; Pesatori, Angela Cecilia] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Bertazzi, Pier Alberto; Pesatori, Angela Cecilia] IRCCS Fdn Ca Granda, Osped Maggiore Policlin, Milan, Italy. [Birnbaum, Linda S.] NCI, NIH, DHHS, Res Triangle Pk, NC USA. [Brownson, Ross C.] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA. [Brownson, Ross C.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. [Bucher, John R.] NIEHS, Div Natl Toxicol Program, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Cantor, Kenneth P.] KP Cantor Environm LLC, Silver Spring, MD USA. [Cardis, Elisabeth] CREAL, IMIM, Barcelona, Spain. [Cardis, Elisabeth] CIBERESP, Barcelona, Spain. [Cherrie, John W.] Inst Occupat Med, Edinburgh, Midlothian, Scotland. [Cocco, Pierluigi] Univ Cagliari Monserrato, Dept Publ Hlth Clin & Mol Med, Cagliari, Italy. [Coggon, David] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Comba, Pietro; Pirastu, Roberta] Charles Darwin Sapienza Rome Univ, Dept Biol & Biotechnol, Rome, Italy. [Demers, Paul A.] Canc Care Ontario, Occupat Canc Res Ctr, Toronto, ON, Canada. [Dement, John M.] Duke Univ, Med Ctr, Div Occupat & Environm Med, Durham, NC USA. [Douwes, Jeroen; Mannetje, Andrea 't] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Eisen, Ellen A.] Univ Calif Berkeley, Sch Publ Hlth, Dept Environm Hlth Sci, Berkeley, CA 94720 USA. [Eisen, Ellen A.] Univ Calif Berkeley, Sch Publ Hlth, Dept Epidemiol, Berkeley, CA 94720 USA. [Engel, Lawrence S.; Olshan, Andrew F.; Richardson, David B.; Shy, Carl] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Fenske, Richard A.; Seixas, Noah] Univ Washington, Sch Publ Hlth, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Fleming, Lora E.] Univ Exeter, Sch Med, European Ctr Environm & Human Hlth, Truro, Cornwall, England. London Sch Hyg & Trop Med, Dept Social & Environm Hlth Res, London WC1, England. [Fontham, Elizabeth] Louisiana State Univ, Sch Publ Hlth, New Orleans, LA USA. [Forastiere, Francesco] Lazio Reg Hlth Serv, Dept Epidemiol, Rome, Italy. [Frentzel-Beyme, Rainer] Univ Bremen, Ctr Environm Res & Sustainable Technol UFT, D-28359 Bremen, Germany. [Fritschi, Lin] Curtin Univ, Sch Publ Hlth, Perth, WA 6845, Australia. [Gerin, Michel] Univ Montreal, Ecole Sante Publ, Dept Environm & Occupat Hlth, Montreal, PQ, Canada. [Goldberg, Marcel] INSERM, UMS 011, Populat Based Epidemiol Cohorts Unit, Villejuif, France. [Grandjean, Philippe] Univ Southern Denmark, Dept Environm Med, Odense, Denmark. Karolinska Inst, Inst Environm Med IMM, Stockholm, Sweden. [Hansen, Johnni] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Hauptmann, Michael] Netherlands Canc Inst, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Heederik, Dick; Kromhout, Hans; Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, Utrecht, Netherlands. [Hemminki, Kari] German Canc Res Ctr, Heidelberg, Germany. [Hemon, Denis] Paris Descartes Univ, Epidemiol & Biostat Sorbonne Paris Cite Ctr CRESS, Epidemiol Childhood & Adolescent Canc Res Grp EPI, INSERM,UMR 1153, F-75015 Paris, France. [Hertz-Picciotto, Irva] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. 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EM neil.pearce@lshtm.ac.uk RI Anto, J/H-2676-2014; bertazzi, pietro alberto/D-5039-2017; Fritschi, Lin /K-2096-2012; Porta, Miquel/B-5787-2008; Armstrong, Bruce/K-9464-2015; LEBAILLY, Pierre/L-7351-2015; de Sanjose Llongueras, Silvia/H-6339-2014; Forastiere, Francesco/J-9067-2016; Weiderpass, Elisabete/M-4029-2016; Rusyn, Ivan/S-2426-2016; Victora, Cesar/D-4476-2013; Cardis, Elisabeth/C-3904-2017; Kogevinas, Manolis/C-3918-2017; Vermeulen, Roel/F-8037-2011 OI Engel, Lawrence/0000-0001-9268-4830; Anto, J/0000-0002-4736-8529; bertazzi, pietro alberto/0000-0003-3475-2449; Pirastu, Roberta/0000-0003-1192-2732; Baccarelli, Andrea/0000-0002-3436-0640; Douwes, Jeroen/0000-0003-3599-4036; Lynge, Elsebeth/0000-0003-4785-5236; Kjaerheim, Kristina/0000-0003-0691-3735; pesatori, angela/0000-0002-0261-3252; Victora, Cesar/0000-0002-2465-2180; Ahrens, Wolfgang/0000-0003-3777-570X; Sandler, Dale/0000-0002-6776-0018; Fritschi, Lin /0000-0002-7692-3560; Porta, Miquel/0000-0003-1684-7428; Armstrong, Bruce/0000-0001-8940-7525; Forastiere, Francesco/0000-0002-9162-5684; Weiderpass, Elisabete/0000-0003-2237-0128; Vermeulen, Roel/0000-0003-4082-8163 FU NIH (NCI); NIH (NIEHS) FX This work was conducted with no direct funding, but was supported in part by the Intramural Research Program of the NIH (NCI and NIEHS). NR 43 TC 8 Z9 9 U1 4 U2 36 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 JUN PY 2015 VL 123 IS 6 BP 507 EP 514 DI 10.1289/ehp.1409149 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CL9KD UT WOS:000357296200010 PM 25712798 ER PT J AU Goodson, WH Lowe, L Carpenter, DO Gilbertson, M Ali, AM Salsamendi, ALD Lasfar, A Carnero, A Azqueta, A Amedei, A Charles, AK Collins, AR Ward, A Salzberg, AC Colacci, A Olsen, AK Berg, A Barclay, BJ Zhou, BHP Blanco-Aparicio, C Baglole, CJ Dong, CF Mondello, C Hsu, CW Naus, CC Yedjou, C Curran, CS Laird, DW Koch, DC Carlin, DJ Felsher, DW Roy, D Brown, DG Ratovitski, E Ryan, EP Corsini, E Rojas, E Moon, EY Laconi, E Marongiu, F Al-Mulla, F Chiaradonna, F Darroudi, F Martin, FL Van Schooten, FJ Goldberg, GS Wagemaker, G Nangami, G Calaf, GM Williams, G Wolf, GT Koppen, G Brunborg, G Lyerly, HK Krishnan, H Ab Hamid, H Yasaei, H Sone, H Kondoh, H Salem, HK Hsu, HY Park, HH Koturbash, I Miousse, IR Scovassi, AI Klaunig, JE Vondracek, J Raju, J Roman, J Wise, JP Whitfield, JR Woodrick, J Christopher, JA Ochieng, J Martinez-Leal, JF Weisz, J Kravchenko, J Sun, J Prudhomme, KR Narayanan, KB Cohen-Solal, KA Moorwood, K Gonzalez, L Soucek, L Jian, L D'Abronzo, LS Lin, LT Li, L Gulliver, L McCawley, LJ Memeo, L Vermeulen, L Leyns, L Zhang, LP Valverde, M Khatami, M Romano, MF Chapellier, M Williams, MA Wade, M Manjili, MH Lleonart, M Xia, MH Gonzalez, MJ Karamouzis, MV Kirsch-Volders, M Vaccari, M Kuemmerle, NB Singh, N Cruickshanks, N Kleinstreuer, N van Larebeke, N Ahmed, N Ogunkua, O Krishnakumar, PK Vadgama, P Marignani, PA Ghosh, PM Ostrosky-Wegman, P Thompson, P Dent, P Heneberg, P Darbre, P Leung, PS Nangia-Makker, P Cheng, Q Robey, RB Al-Temaimi, R Roy, R Andrade-Vieira, R Sinha, RK Mehta, R Vento, R Di Fiore, R Ponce-Cusi, R Dornetshuber-Fleiss, R Nahta, R Castellino, RC Palorini, R Abd Hamid, R Langie, SAS Eltom, S Brooks, SA Ryeom, S Wise, SS Bay, SN Harris, SA Papagerakis, S Romano, S Pavanello, S Eriksson, S Forte, S Casey, SC Luanpitpong, S Lee, TJ Otsuki, T Chen, T Massfelder, T Sanderson, T Guarnieri, T Hultman, T Dormoy, V Odero-Marah, V Sabbisetti, V Maguer-Satta, V Rathmell, WK Engstrom, W Decker, WK Bisson, WH Rojanasakul, Y Luqmani, Y Chen, ZB Hu, ZW AF Goodson, William H., III Lowe, Leroy Carpenter, David O. Gilbertson, Michael Ali, Abdul Manaf de Cerain Salsamendi, Adela Lopez Lasfar, Ahmed Carnero, Amancio Azqueta, Amaya Amedei, Amedeo Charles, Amelia K. Collins, Andrew R. Ward, Andrew Salzberg, Anna C. Colacci, Annamaria Olsen, Ann-Karin Berg, Arthur Barclay, Barry J. Zhou, Binhua P. Blanco-Aparicio, Carmen Baglole, Carolyn J. Dong, Chenfang Mondello, Chiara Hsu, Chia-Wen Naus, Christian C. Yedjou, Clement Curran, Colleen S. Laird, Dale W. Koch, Daniel C. Carlin, Danielle J. Felsher, Dean W. Roy, Debasish Brown, Dustin G. Ratovitski, Edward Ryan, Elizabeth P. Corsini, Emanuela Rojas, Emilio Moon, Eun-Yi Laconi, Ezio Marongiu, Fabio Al-Mulla, Fahd Chiaradonna, Ferdinando Darroudi, Firouz Martin, Francis L. Van Schooten, Frederik J. Goldberg, Gary S. Wagemaker, Gerard Nangami, Gladys Calaf, Gloria M. Williams, Graeme Wolf, Gregory T. Koppen, Gudrun Brunborg, Gunnar Lyerly, H. Kim Krishnan, Harini Ab Hamid, Hasiah Yasaei, Hemad Sone, Hideko Kondoh, Hiroshi Salem, Hosni K. Hsu, Hsue-Yin Park, Hyun Ho Koturbash, Igor Miousse, Isabelle R. Scovassi, A. Ivana Klaunig, James E. Vondracek, Jan Raju, Jayadev Roman, Jesse Wise, John Pierce, Sr. Whitfield, Jonathan R. Woodrick, Jordan Christopher, Joseph A. Ochieng, Josiah Fernando Martinez-Leal, Juan Weisz, Judith Kravchenko, Julia Sun, Jun Prudhomme, Kalan R. Narayanan, Kannan Badri Cohen-Solal, Karine A. Moorwood, Kim Gonzalez, Laetitia Soucek, Laura Jian, Le D'Abronzo, Leandro S. Lin, Liang-Tzung Li, Lin Gulliver, Linda McCawley, Lisa J. Memeo, Lorenzo Vermeulen, Louis Leyns, Luc Zhang, Luoping Valverde, Mahara Khatami, Mahin Romano, Maria Fiammetta Chapellier, Marion Williams, Marc A. Wade, Mark Manjili, Masoud H. Lleonart, Matilde Xia, Menghang Gonzalez, Michael J. Karamouzis, Michalis V. Kirsch-Volders, Micheline Vaccari, Monica Kuemmerle, Nancy B. Singh, Neetu Cruickshanks, Nichola Kleinstreuer, Nicole van Larebeke, Nik Ahmed, Nuzhat Ogunkua, Olugbemiga Krishnakumar, P. K. Vadgama, Pankaj Marignani, Paola A. Ghosh, Paramita M. Ostrosky-Wegman, Patricia Thompson, Patricia Dent, Paul Heneberg, Petr Darbre, Philippa Leung, Po Sing Nangia-Makker, Pratima Cheng, Qiang (Shawn) Robey, R. Brooks Al-Temaimi, Rabeah Roy, Rabindra Andrade-Vieira, Rafaela Sinha, Ranjeet K. Mehta, Rekha Vento, Renza Di Fiore, Riccardo Ponce-Cusi, Richard Dornetshuber-Fleiss, Rita Nahta, Rita Castellino, Robert C. Palorini, Roberta Abd Hamid, Roslida Langie, Sabine A. S. Eltom, Sakina Brooks, Samira A. Ryeom, Sandra Wise, Sandra S. Bay, Sarah N. Harris, Shelley A. Papagerakis, Silvana Romano, Simona Pavanello, Sofia Eriksson, Staffan Forte, Stefano Casey, Stephanie C. Luanpitpong, Sudjit Lee, Tae-Jin Otsuki, Takemi Chen, Tao Massfelder, Thierry Sanderson, Thomas Guarnieri, Tiziana Hultman, Tove Dormoy, Valerian Odero-Marah, Valerie Sabbisetti, Venkata Maguer-Satta, Veronique Rathmell, W. Kimryn Engstrom, Wilhelm Decker, William K. Bisson, William H. Rojanasakul, Yon Luqmani, Yunus Chen, Zhenbang Hu, Zhiwei TI Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead SO CARCINOGENESIS LA English DT Review ID BREAST-CANCER CELLS; ESTROGEN-RECEPTOR-ALPHA; EPITHELIAL-MESENCHYMAL TRANSITION; VASCULAR ENDOTHELIAL-CELLS; ARYL-HYDROCARBON RECEPTOR; ACTIVATED PROTEIN-KINASES; POLYBROMINATED DIPHENYL ETHERS; ENDOCRINE-DISRUPTING CHEMICALS; BISPHENOL-A EXPOSURE; SPRAGUE-DAWLEY RATS AB Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. C1 [Goodson, William H., III] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94115 USA. 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[Vondracek, Jan] Acad Sci Czech Republic, Inst Biophys, Dept Cytokinet, CZ-61265 Brno, Czech Republic. [Raju, Jayadev; Mehta, Rekha] Hlth Canada, Regulatory Toxicol Res Div, Bur Chem Safety, Food Directorate, Ottawa, ON K1A 0K9, Canada. [Roman, Jesse] Univ Louisville, Dept Med, Louisville, KY 40202 USA. [Roman, Jesse] Robley Rex VA Med Ctr, Louisville, KY 40202 USA. [Wise, John Pierce, Sr.; Wise, Sandra S.] Univ So Maine, Dept Appl Sci Med, Portland, ME 04104 USA. [Whitfield, Jonathan R.; Soucek, Laura] Vall dHebron Inst Oncol VHIO, Mouse Models Canc Therapies Grp, Barcelona 08035, Spain. [Woodrick, Jordan; Roy, Rabindra] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Christopher, Joseph A.] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England. [Fernando Martinez-Leal, Juan] Pharmamar SAU, Dept Cell Biol, Madrid 28770, Spain. [Weisz, Judith] Penn State Univ, Coll Med, Dept Obstet & Gynecol, Hershey, PA 17033 USA. [Weisz, Judith] Penn State Univ, Coll Med, Dept Pathol, Hershey, PA 17033 USA. [Sun, Jun] Rush Univ, Dept Biochem, Chicago, IL 60612 USA. [Prudhomme, Kalan R.; Bisson, William H.] Oregon State Univ, Environm Hlth Sci Ctr, Environm & Mol Toxicol, Corvallis, OR 97331 USA. [Cohen-Solal, Karine A.] Rutgers Canc Inst New Jersey, Dept Med Med Oncol, New Brunswick, NJ 08903 USA. [Gonzalez, Laetitia; Leyns, Luc; Kirsch-Volders, Micheline] Vrije Univ Brussel, Lab Cell Genet, B-1050 Brussels, Belgium. [Soucek, Laura] Catalan Inst Res & Adv Studies ICREA, Barcelona 08010, Spain. [Jian, Le] Curtin Univ, Sch Publ Hlth, Bentley, WA 6102, Australia. [Jian, Le] Govt Western Australia, Dept Hlth, Publ Hlth & Clin Serv Div, Perth, WA 6004, Australia. [D'Abronzo, Leandro S.; Ghosh, Paramita M.] Univ Calif Davis, Dept Urol, Sacramento, CA 95817 USA. [Lin, Liang-Tzung] Taipei Med Univ, Sch Med, Dept Microbiol & Immunol, Coll Med, Taipei 11031, Taiwan. [Li, Lin; Leung, Po Sing] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Gulliver, Linda] Univ Otago, Fac Med, Dunedin 9054, New Zealand. [McCawley, Lisa J.] Vanderbilt Univ, Dept Biomed Engn & Canc Biol, Nashville, TN 37235 USA. [Memeo, Lorenzo; Forte, Stefano] Mediterranean Inst Oncol, Dept Expt Oncol, I-95029 Viagrande, CT, Italy. [Vermeulen, Louis] Univ Amsterdam, Acad Med Ctr, Ctr Expt Mol Med, NL-1105 AZ Amsterdam, Netherlands. [Zhang, Luoping] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Khatami, Mahin] NCI, Inflammat & Canc Res, NIH, Bethesda, MD 20892 USA. [Romano, Maria Fiammetta; Romano, Simona] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy. [Chapellier, Marion] Ctr Rech Cancerol, U1052, UMR5286, Lyon, France. [Williams, Marc A.; Maguer-Satta, Veronique] US Army, Inst Publ Hlth, Toxicol Portfolio Hlth Effects Res Program, Edgewood, MD 21010 USA. [Wade, Mark] Fdn Ist Italiano Tecnol, Ctr Genom Sci IIT SEMM, I-20139 Milan, Italy. [Manjili, Masoud H.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Massey Canc Ctr, Richmond, VA 23298 USA. [Lleonart, Matilde] Inst Recerca Hosp Vall DHebron, Barcelona 08035, Spain. [Gonzalez, Michael J.] Univ Puerto Rico, Nutr Program, Sch Publ Hlth, San Juan, PR 00921 USA. [Karamouzis, Michalis V.] Univ Athens, Sch Med, Dept Biol Chem, Inst Mol Med & Biomed Res, Athens 10676, Greece. [Kuemmerle, Nancy B.; Robey, R. Brooks] White River Junction Vet Affairs Med Ctr, White River Jct, VT 05009 USA. [Kuemmerle, Nancy B.; Robey, R. Brooks] Geisel Sch Med Dartmouth, Hanover, NH 03755 USA. [Singh, Neetu] King Georges Med Univ, Adv Mol Sci Res Ctr, Ctr Adv Res, Lucknow 226003, Uttar Pradesh, India. [Cruickshanks, Nichola; Dent, Paul] Virginia Commonwealth Univ, Dept Neurosurg, Richmond, VA 23298 USA. [Cruickshanks, Nichola; Dent, Paul] Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA. [Cruickshanks, Nichola; Dent, Paul] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA. [Kleinstreuer, Nicole] Integrated Lab Syst Inc, Support Natl Toxicol Program Interagency Ctr Eval, Res Triangle Pk, NC 27709 USA. [van Larebeke, Nik] Vrije Univ Brussel, Milieu Geochem, Analyt, B-1050 Brussels, Belgium. [Ahmed, Nuzhat] Univ Melbourne, Dept Obstet & Gynecol, Parkville, Vic 3052, Australia. [Krishnakumar, P. K.] King Fahd Univ Petr & Minerals, Res Inst, Ctr Environm & Water, Dhahran 3126, Saudi Arabia. [Vadgama, Pankaj] Queen Mary Univ London, Sch Engn & Mat Sci, London E1 4NS, England. [Marignani, Paola A.; Andrade-Vieira, Rafaela] Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS B3H 4R2, Canada. [Thompson, Patricia] SUNY Stony Brook, Stony Brook Sch Med, Dept Pathol, Stony Brook, NY 11794 USA. [Heneberg, Petr] Charles Univ Prague, Fac Med 3, CZ-10000 Prague 10, Czech Republic. [Darbre, Philippa] Univ Reading, Sch Biol Sci, Reading RG6 6UB, Berks, England. [Nangia-Makker, Pratima] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. [Cheng, Qiang (Shawn)] So Illinois Univ, Dept Comp Sci, Carbondale, IL 62901 USA. [Al-Temaimi, Rabeah] Kuwait Univ, Dept Pathol, Human Genet Unit, Fac Med, Jabriya 13110, Kuwait. [Sinha, Ranjeet K.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Vento, Renza; Di Fiore, Riccardo] Univ Palermo, Dept Biol Chem & Pharmaceut Sci & Technol, Polyclin Plexus, I-90127 Palermo, Italy. [Vento, Renza] Temple Univ, Sbarro Inst Canc Res & Mol Med, Philadelphia, PA 19122 USA. [Dornetshuber-Fleiss, Rita] Univ Vienna, Dept Pharmacol & Toxicol, A-1090 Vienna, Austria. [Dornetshuber-Fleiss, Rita] Med Univ Vienna, Dept Med, Inst Canc Res, A-1090 Vienna, Austria. [Nahta, Rita] Emory Univ, Dept Pharmacol, Sch Med, Atlanta, GA 30322 USA. [Nahta, Rita] Emory Univ, Dept Hematol & Med Oncol, Sch Med, Atlanta, GA 30322 USA. [Nahta, Rita] Winship Canc Inst, Atlanta, GA 30322 USA. [Castellino, Robert C.] Childrens Healthcare Atlanta, Div Hematol & Oncol, Dept Pediat, Atlanta, GA 30322 USA. [Castellino, Robert C.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Brooks, Samira A.; Rathmell, W. Kimryn] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Ryeom, Sandra] Univ Penn, Dept Canc Biol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bay, Sarah N.] Emory Univ, Grad Div Biol & Biomed Sci, Program Genet & Mol Biol, Atlanta, GA 30322 USA. [Harris, Shelley A.] Canc Care Ontario, Res Prevent & Canc Control, Populat Hlth & Prevent, Toronto, ON M5G 2L7, Canada. [Harris, Shelley A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Dept Epidemiol, Toronto, ON M5T 3M7, Canada. [Harris, Shelley A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Dept Occupat & Environm Hlth, Toronto, ON M5T 3M7, Canada. [Pavanello, Sofia] Univ Padua, Unit Occupat Med, Dept Cardiac Thorac & Vasc Sci, I-35128 Padua, Italy. [Eriksson, Staffan] Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, VHC, SE-75651 Uppsala, Sweden. [Luanpitpong, Sudjit] Mahidol Univ, Fac Med, Siriraj Hosp, Siriraj Ctr Excellence Stem Cell Res, Bangkok 10700, Thailand. [Lee, Tae-Jin] Yeungnam Univ, Dept Anat, Coll Med, Daegu 705717, South Korea. [Otsuki, Takemi] Kawasaki Med Univ, Dept Hyg, Okayama 7010192, Japan. [Chen, Tao] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Massfelder, Thierry; Dormoy, Valerian] Univ Strasbourg, INSERM, Fac Med,U1113, Team Cell Signalling & Commun Kidney & Prostate C, F-67085 Strasbourg, France. [Sanderson, Thomas] Univ Quebec, Inst Armand Frappier, INRS, Laval, PQ H7V 1B7, Canada. [Guarnieri, Tiziana] Alma Mater Studiorum Univ Bologna, Dept Biol Geol & Environm Sci, I-40126 Bologna, Italy. [Guarnieri, Tiziana] S Orsola Malpighi Univ Hosp, Ctr Appl Biomed Res, I-40126 Bologna, Italy. [Guarnieri, Tiziana] Natl Inst Biostruct & Biosyst, I-00136 Rome, Italy. [Hultman, Tove; Engstrom, Wilhelm] Swedish Univ Agr Sci, Fac Vet Med, Dept Biosci & Vet Publ Hlth, S-75007 Uppsala, Sweden. [Dormoy, Valerian] Univ Calif Irvine, Dept Cell & Dev Biol, Irvine, CA 92697 USA. [Odero-Marah, Valerie] Clark Atlanta Univ, Dept Biol, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA. [Sabbisetti, Venkata] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Decker, William K.] Baylor Coll Med, Houston, TX 77030 USA. [Rojanasakul, Yon] W Virginia Univ, Dept Pharmaceut Sci, Morgantown, WV 26506 USA. [Luqmani, Yunus] Kuwait Univ, Fac Pharm, Dept Pharmaceut Chem, Safat 13110, Kuwait. [Hu, Zhiwei] Ohio State Univ, Coll Med, Dept Surg, James Comprehens Canc Ctr, Columbus, OH 43210 USA. RP Goodson, WH (reprint author), Calif Pacific Med Ctr, Res Inst, 2100 Webster St 401, San Francisco, CA 94115 USA. EM whg3md@att.net; leroy.lowe@gettingtoknowcancer.org RI Vermeulen, Louis/B-7488-2008; Hu, Zhiwei/L-3727-2013; Wade, Mark /B-6719-2009; Lopez de Cerain, Adela/L-4572-2014; IBIS, CANCER/P-3323-2015; CHIARADONNA, Ferdinando/K-4959-2016; Gonzalez, Laetitia/F-5116-2011; Leung, Po Sing/P-5758-2014; Heneberg, Petr/C-1881-2012; Vondracek, Jan/J-3037-2012; Jian, Le/B-9180-2012; Laird, Dale /E-4176-2015; Mondello, Chiara/B-8305-2015; Massfelder, Thierry/I-1260-2016; Dormoy, Valerian/P-5109-2016; Marongiu, Fabio/E-6294-2016; Robey, R. Brooks/J-7099-2013; Forte, Stefano/D-3645-2013; OI Vermeulen, Louis/0000-0002-6066-789X; Hu, Zhiwei/0000-0002-0023-1170; Wade, Mark /0000-0002-2688-5965; Lopez de Cerain, Adela/0000-0002-2085-1289; CHIARADONNA, Ferdinando/0000-0001-8529-2732; Gonzalez, Laetitia/0000-0003-4182-3428; Heneberg, Petr/0000-0002-0703-951X; Vondracek, Jan/0000-0003-4071-1969; Nangia-Makker, Pratima/0000-0002-1917-169X; Blanco-Aparicio, Carmen/0000-0002-3249-6595; Soucek, Laura/0000-0002-4750-7971; Whitfield, Jonathan/0000-0002-4925-7283; Barclay, Barry/0000-0002-8325-115X; Mondello, Chiara/0000-0002-8379-9246; Scovassi, Anna Ivana/0000-0003-3484-9881; L Martin, Francis/0000-0001-8562-4944; Kleinstreuer, Nicole/0000-0002-7914-3682; Marongiu, Fabio/0000-0001-5860-4227; Robey, R. Brooks/0000-0001-5059-3965; Forte, Stefano/0000-0001-5746-7451; Roy, Debasish/0000-0001-6590-0569; Valverde, Mahara/0000-0001-6975-1185; Luanpitpong, Sudjit/0000-0002-1639-4935 FU National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) [R13ES023276]; California Breast Cancer Research Program; Clarence Heller Foundation; California Pacific Medical Center Foundation; University of Sultan Zainal Abidin, Malaysia; Rutgers Cancer Institute of New Jersey; Research Council of Norway (RCN) through its Centres of Excellence funding scheme [223268/F50]; Spanish Ministry of Economy and Competitivity, ISCIII [Fis: PI12/00137, RTICC: RD12/0036/0028]; FEDER from Regional Development European Funds (European Union); Consejeria de Ciencia e Innovacion [CTS-1848]; Consejeria de Salud of the Junta de Andalucia [PI-0306-2012]; Ministerio de Educacion y Ciencia (Juande la Cierva' programme) of the Spanish Government; Italian Ministry of University and Research [2009FZZ4XM_002]; University of Florence; University of Oslo; Emilia-Romagna Region - Project 'Supersite' in Italy; Fonds de recherche du Quebec-Sante (FRQ-S); Fondazione Cariplo in Milan, Italy [2011-0370]; National Institutes of Health (NIH-NIMHD) [G12MD007581]; Burroughs Wellcome Fund Postdoctoral Enrichment Award; Timor Biology Training grant [NIH T32CA09151]; United States Department of Health and Human Services, NIH [R01 CA170378 PQ22, RO1 CA184384, U54 CA149145, U54 CA151459, P50 CA114747, 1121 CA169964]; CONACyT [152473]; AIRC (Italian Association for Cancer Research) [IG 14640]; Sardinian Regional Government (RAS); Public Problem-Solving Program [NRF-015M3C8A6A06014500]; National Research Foundation of Korea (NRF) [2013M2B2A9A03051296, 2010-0018545]; Ministry of Education, Science and Technology (MEST) in Korea; Kuwait Foundation for the Advancement of Sciences [2011-1302-06]; SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI); AIRC (Associazione Italiana Ricerca sul Cancro) [IG 15364]; Rosemere Cancer Foundation; New Jersey Health Foundation; Fondo Nacional de Ciencia y Tecnologia (FONDECYT), Ministerio de Educacion de Chile (MINEDUC), Universidad de Tarapao (UTA); Flemish Institute for Technological Research (VITO), Belgium; National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research [NC.K500045.1, G0800697]; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Japan Science and Technology Agency; JST, CREST; Ministry of Science and Technology of Taiwan [NSC93-2314-B-320-006, NSC94-2314-B-320-002]; National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology [2012R1A2A2A01010870]; Ministry of Health and Welfare, Republic of Korea [HI13C1449]; UAMS/NIH Clinical and Translational Science Award [UL1TR000039, KL2TR000063]; Arkansas Biosciences Institute; Czech Science Foundation [13-07711S]; NIH [CA116812]; National Institute of Environmental Health Sciences [ES016893]; Maine Center for Toxicology and Environmental Health; FERO Foundation in Barcelona, Spain; Cancer Research UK; International Journal of Experimental Pathology; Swim Across America Cancer Research Award; American Cancer Society [116683-RSG-09-087-01-TBE]; Fund for Scientific Research-Flanders (FWO-Vlaanderen); Inter University Attraction Pole grant [IAP-P7-07]; Miguel Servet Research Contract Program [CP10/00656]; Taipei Medical University [TMU101-AE3-Y19]; Genesis Oncology Trust (NZ) Professional Development Grant; Faculty of Medicine, University of Otago, Dunedin, New Zealand; Dutch Cancer Society [UVA2011-4969]; AICR [14-1164]; Breast Cancer Research Program [W81XWH-14-1-0087]; Department of Science and Technology, Government of India [SR/FT/LS-063/2008]; NIEHS contracts [N01-ES 35504, HHSN27320140003C]; King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia [T.K. 11-0629]; Dalhousie Medical Research Foundation; Beatrice Hunter Cancer Institute; CIHR; Nova Scotia Lung Association; PHS grants from the NIH [R01-CA141704, R01-CA150214, R01-DK52825, R01-CA61774]; Charles University in Prague [UNCE 204015, PRVOUK P31/2012]; Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region [10110021]; [PI12/01104]; [CP03/00101] FX We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276); Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript; William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation; Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia; Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey; Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Camaro's lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012); Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (Juande la Cierva' programme, 2009) of the Spanish Government for personal support; Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012); Andrew R.Collins was supported by the University of Oslo; Annamaria Colacci was supported by the Emilia-Romagna Region - Project 'Supersite' in Italy; Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S); Chiara Mondello's laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370); Christian C.Naus holds a Canada Research Chair; Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581); Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Timor Biology Training grant: NIH T32CA09151; Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, RO1 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and 1121 CA169964); Emilio Rojas would like to thank CONACyT support 152473; Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS); Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea; Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06); Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro; IG 15364); Francis L.Martin acknowledges funding from Rosemere Cancer Foundation; he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years; Gary S.; Goldberg would like to acknowledge the support of the New Jersey Health Foundation; Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnologia (FONDECYT), Ministerio de Educacion de Chile (MINEDUC), Universidad de Tarapac6 (UTA); Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium; Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697); Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST; Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002); Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449); Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000; Jan VondrLek acknowledges funding from the Czech Science Foundation (13-07711S); Jesse Roman thanks the NIH for their support (CA116812); John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health; Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain; Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology; Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback; Jun Sun is supported by a Swim Across America Cancer Research Award; Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE); Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research-Flanders (FWO-Vlaanderen) and support by an Inter University Attraction Pole grant (IAP-P7-07); Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain; Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19); Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand; Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14-1164); Mahara Valverde would like to thank CONACyT support 153781; Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India; Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C); P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia; Paola A.; Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association; Paul Dent is the holder of the Universal Inc. Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774); Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y; Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021; Qiang Cheng was supported in part by grant NSF IIS4218712; R. Brooks Robey is supported by the United States Department of Veterans Affairs; Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447); Rafaela AndradeVieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation; Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007-13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007-13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007; Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007-2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007-2013); Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung; Roberta Palorini is supported by a SysBioNet fellowship; Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165; Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013; Sakina Eltom is supported by NIH grant SC1CA153326; Samira A. Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship; Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation; Thierry Massfelder was supported by the Institut National de la Sante et de la Recherche Medicale INSERM and Universite de Strasbourg; Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR; MOP115019), the Natural Sciences and Engineering Council of Canada (NSERC; 313313) and the California Breast Cancer Research Program (CBCRP; 17UB-8703); Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy; W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society; William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas; William H.; Bisson was supported with funding from the NIH P30 ES000210; Yon Rojanasakul was supported with NIH grant R01-ES022968; Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593); Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program, NR 508 TC 34 Z9 36 U1 14 U2 73 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 JUN PY 2015 VL 36 SU 1 BP S254 EP S296 DI 10.1093/carcin/bgv039 PG 43 WC Oncology SC Oncology GA CL6AQ UT WOS:000357048100013 PM 26106142 ER PT J AU Langie, SAS Koppen, G Desaulniers, D Al-Mulla, F Al-Temaimi, R Amedei, A Azqueta, A Bisson, WH Brown, D Brunborg, G Charles, AK Chen, T Colacci, A Darroudi, F Forte, S Gonzalez, L Hamid, RA Knudsen, LE Leyns, L Salsamendi, ALD Memeo, L Mondello, C Mothersill, C Olsen, AK Pavanello, S Raju, J Rojas, E Roy, R Ryan, E Ostrosky-Wegman, P Salem, HK Scovassi, I Singh, N Vaccari, M Van Schooten, FJ Valverde, M Woodrick, J Zhang, LP van Larebeke, N Kirsch-Volders, M Collins, AR AF Langie, Sabine A. S. Koppen, Gudrun Desaulniers, Daniel Al-Mulla, Fahd Al-Temaimi, Rabeah Amedei, Amedeo Azqueta, Amaya Bisson, William H. Brown, Dustin Brunborg, Gunnar Charles, Amelia K. Chen, Tao Colacci, Annamaria Darroudi, Firouz Forte, Stefano Gonzalez, Laetitia Hamid, Roslida A. Knudsen, Lisbeth E. Leyns, Luc de Cerain Salsamendi, Adela Lopez Memeo, Lorenzo Mondello, Chiara Mothersill, Carmel Olsen, Ann-Karin Pavanello, Sofia Raju, Jayadev Rojas, Emilio Roy, Rabindra Ryan, Elizabeth Ostrosky-Wegman, Patricia Salem, Hosni K. Scovassi, Ivana Singh, Neetu Vaccari, Monica Van Schooten, Frederik J. Valverde, Mahara Woodrick, Jordan Zhang, Luoping van Larebeke, Nik Kirsch-Volders, Micheline Collins, Andrew R. TI Causes of genome instability: the effect of low dose chemical exposures in modern society SO CARCINOGENESIS LA English DT Review ID NUCLEOTIDE-EXCISION-REPAIR; TITANIUM-DIOXIDE NANOPARTICLES; BREAST-CANCER CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; OXIDATIVE DNA-DAMAGE; NF-KAPPA-B; POLYCYCLIC AROMATIC-HYDROCARBONS; VASCULAR ENDOTHELIAL-CELLS; MERCURY-INDUCED APOPTOSIS; TUNGSTEN ALLOY PARTICLES AB In this review, we focus on some 'chemical disruptors' and how they add to the burden of genome instability, thereby increasing cancer incidence risk.Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis. C1 [Langie, Sabine A. S.; Koppen, Gudrun] Flemish Inst Technol Res VITO, Environm Risk & Hlth Unit, B-2400 Mol, Belgium. [Desaulniers, Daniel] Hlth Canada, Environm Hlth Sci & Res Bur, Ctr Environm Hlth, Ottawa, ON K1A0K9, Canada. [Al-Mulla, Fahd; Al-Temaimi, Rabeah] Kuwait Univ, Dept Pathol, Safat 13110, Kuwait. [Amedei, Amedeo] Univ Firenze, Dept Expt & Clin Med, I-50134 Florence, Italy. [Azqueta, Amaya; de Cerain Salsamendi, Adela Lopez] Univ Navarra, Fac Pharm, Dept Pharmacol & Toxicol, Pamplona 31009, Spain. [Bisson, William H.] Oregon State Univ, Environm Hlth Sci Ctr, Environm & Mol Toxicol, Corvallis, OR 97331 USA. [Brown, Dustin; Ryan, Elizabeth] Colorado State Univ, Colorado Sch Publ Hlth, Coll Vet Med & Biomed Sci, Dept Environm & Radiol Hlth Sci Food Sci & Human, Ft Collins, CO 80523 USA. [Brunborg, Gunnar; Olsen, Ann-Karin] Norwegian Inst Publ Hlth, Div Environm Med, Dept Chem & Radiat, N-0403 Oslo, Norway. [Charles, Amelia K.] Univ Reading, Sch Biol Sci, Reading RG6 6UB, Berks, England. [Chen, Tao] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Colacci, Annamaria; Vaccari, Monica] Environm Protect & Hlth Prevent Agcy, Ctr Environm Carcinogenesis & Risk Assessment, I-40126 Bologna, Italy. [Darroudi, Firouz] Coll North Atlantic, Dept Hlth Sci, Human & Environm Safety Res, Doha, State Of Qatar, Qatar. [Forte, Stefano; Memeo, Lorenzo] Mediterranean Inst Oncol, I-95029 Viagrande, Italy. [Gonzalez, Laetitia; Leyns, Luc; Kirsch-Volders, Micheline] Vrije Univ Brussel, Lab Cell Genet, B-1050 Brussels, Belgium. [Hamid, Roslida A.] Univ Putra Malaysia, Dept Biomed Sci, Fac Med & Hlth Sci, Serdang 43400, Selangor, Malaysia. [Knudsen, Lisbeth E.] Univ Copenhagen, Dept Publ Hlth, DK-1353 Copenhagen, Denmark. [Mondello, Chiara; Scovassi, Ivana] CNR, Inst Mol Genet, I-27100 Pavia, Italy. [Mothersill, Carmel] McMaster Univ, Med Phys & Appl Radiat Sci, Hamilton, ON L8S 4L8, Canada. [Pavanello, Sofia] Univ Padua, Unit Occupat Med, Dept Cardiac Thorac & Vasc Sci, I-35128 Padua, Italy. [Raju, Jayadev] Hlth Canada, Toxicol Res Div, Bur Chem Safety, Food Directorate,Hlth Prod & Food Branch, Ottawa, ON K1A0K9, Canada. [Rojas, Emilio; Ostrosky-Wegman, Patricia; Valverde, Mahara] Univ Nacl Autonoma Mexico, Inst Invest Biomed, Dept Med Genom & Toxicol Ambiental, Mexico City 04510, DF, Mexico. [Roy, Rabindra; Woodrick, Jordan] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Salem, Hosni K.] Cairo Univ, Kasr Al Ainy Sch Med, Dept Urol, Cairo 12515, Egypt. [Singh, Neetu] King Georges Med Univ, Ctr Adv Res, Lucknow 226003, Uttar Pradesh, India. [Van Schooten, Frederik J.] Maastricht Univ, NUTRIM Sch Nutr Toxicol & Metab, Dept Toxicol, NL-6200 MD Maastricht, Netherlands. [Zhang, Luoping] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [van Larebeke, Nik] Vrije Univ Brussel, Lab Analyt & Environm Chem, B-1050 Brussels, Belgium. [van Larebeke, Nik] Univ Ghent, Study Ctr Carcinogenesis & Primary Prevent Canc, B-9000 Ghent, Belgium. [Collins, Andrew R.] Univ Oslo, Dept Nutr, N-0316 Oslo, Norway. RP Koppen, G (reprint author), Flemish Inst Technol Res VITO, Environm Risk & Hlth Unit, Boeretang 200, B-2400 Mol, Belgium. EM gudrun.koppen@vito.be RI Gonzalez, Laetitia/F-5116-2011; Lopez de Cerain, Adela/L-4572-2014; Forte, Stefano/D-3645-2013; Mondello, Chiara/B-8305-2015; OI Gonzalez, Laetitia/0000-0003-4182-3428; Lopez de Cerain, Adela/0000-0002-2085-1289; Forte, Stefano/0000-0001-5746-7451; Valverde, Mahara/0000-0001-6975-1185; Mondello, Chiara/0000-0002-8379-9246; Scovassi, Anna Ivana/0000-0003-3484-9881 FU Flemish Institute for Technological Research (VITO, Belgium); National Institute of Health-National Institute of Environmental Health Sciences [R01ES017452]; University of Padova, Italy [prot. 60A07-5397/13]; University of Padova, Italy (CONACyT) [153781]; Ministerio de Educacion y Ciencia ('Juan de la Cierva' programme) of the Spanish Government; Innoviris (NanoIris project); Belgian Science Policy Office [IUAP P7/07 DevRepair]; Research Fund Flanders, Belgium (FWO-Vlaanderen); Fondazione Cariplo [2011-0370]; Kuwait Institute for the Advancement of Sciences [2011-1302-06]; Grant University Scheme (RUGs) Ministry of Education Malaysia [04-02-12-2099RU]; Italian Ministry of University and Research [2009FZZ4XM_002]; University of Florence; US Public Health Service Grants [RO1 CA92306, RO1 CA92306-S1, RO1 CA113447]; Department of Science and Technology, Government of India [SR/FT/LS-063/2008] FX Flemish Institute for Technological Research (VITO, Belgium); National Institute of Health-National Institute of Environmental Health Sciences (R01ES017452 and travel grant support); University of Padova, Italy (prot. 60A07-5397/13, CONACyT # 153781); Ministerio de Educacion y Ciencia ('Juan de la Cierva' programme, 2009) of the Spanish Government; Innoviris (NanoIris project); Belgian Science Policy Office (IUAP P7/07 DevRepair); Research Fund Flanders, Belgium (FWO-Vlaanderen); Fondazione Cariplo (2011-0370 to C.M.); Kuwait Institute for the Advancement of Sciences (2011-1302-06 to F.Al-M.); Grant University Scheme (RUGs) Ministry of Education Malaysia (04-02-12-2099RU to R.A.H.); Italian Ministry of University and Research (2009FZZ4XM_002 to A.A.); University of Florence (ex60% 2012 to A.A.); US Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1, RO1 CA113447 to R.R.); Department of Science and Technology, Government of India (SR/FT/LS-063/2008 to N.S.). NR 535 TC 16 Z9 16 U1 2 U2 27 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 JUN PY 2015 VL 36 SU 1 BP S61 EP S88 DI 10.1093/carcin/bgv031 PG 28 WC Oncology SC Oncology GA CL6AQ UT WOS:000357048100005 PM 26106144 ER PT J AU Khozin, S Blumenthal, GM Zhang, LJ Tang, SH Brower, M Fox, E Helms, W Leong, R Song, PF Pan, YZ Liu, Q Zhao, P Zhao, H Lu, DH Tang, Z Al Hakim, A Boyd, K Keegan, P Justice, R Pazdur, R AF Khozin, Sean Blumenthal, Gideon M. Zhang, Lijun Tang, Shenghui Brower, Margaret Fox, Emily Helms, Whitney Leong, Ruby Song, Pengfei Pan, Yuzhuo Liu, Qi Zhao, Ping Zhao, Hong Lu, Donghao Tang, Zhe Al Hakim, Ali Boyd, Karen Keegan, Patricia Justice, Robert Pazdur, Richard TI FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CRIZOTINIB; RESISTANCE; SURVIVAL; TRIALS; GENE AB On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA; Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee was 44% (95% CI, 36-52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to adverse reactions, the discontinuation rate due to adverse reactions was low (10%). With this safety profile, the benefit-risk analysis was considered favorable because of the clinically meaningful ORR and DOR. (C) 2015 AACR. C1 [Khozin, Sean; Blumenthal, Gideon M.; Brower, Margaret; Fox, Emily; Helms, Whitney; Boyd, Karen; Keegan, Patricia; Justice, Robert; Pazdur, Richard] FDA, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. [Zhang, Lijun; Tang, Shenghui] FDA, Off Biostat, Silver Spring, MD 20993 USA. [Leong, Ruby; Song, Pengfei; Pan, Yuzhuo; Liu, Qi; Zhao, Ping; Zhao, Hong] FDA, Off Translat Sci, Silver Spring, MD 20993 USA. [Lu, Donghao; Tang, Zhe; Al Hakim, Ali] FDA, Off New Drug Qual Assessment, Silver Spring, MD 20993 USA. RP Khozin, S (reprint author), FDA, 10903 New Hampshire Ave,Bldg 22,Room 2322, Silver Spring, MD 20993 USA. EM Sean.Khozin@fda.hhs.gov NR 24 TC 34 Z9 37 U1 1 U2 13 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 2015 VL 21 IS 11 BP 2436 EP 2439 DI 10.1158/1078-0432.CCR-14-3157 PG 4 WC Oncology SC Oncology GA CL9YT UT WOS:000357335800005 PM 25754348 ER PT J AU Podoplelova, N Sveshnikova, A Kurasawa, J Sarafanov, A Ataullakhanov, F Panteleev, M AF Podoplelova, N. Sveshnikova, A. Kurasawa, J. Sarafanov, A. Ataullakhanov, F. Panteleev, M. TI Hysteresis-like binding of coagulation factor X/XA to lipids protects from blood flow SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Podoplelova, N.; Sveshnikova, A.; Ataullakhanov, F.; Panteleev, M.] Moscow MV Lomonosov State Univ, Fed Sci Clin Ctr Pediat Hematol Oncol & Immunol, Moscow, Russia. [Podoplelova, N.; Ataullakhanov, F.; Panteleev, M.] Moscow MV Lomonosov State Univ, Natl Res Ctr Haematol, Moscow, Russia. [Sveshnikova, A.; Ataullakhanov, F.; Panteleev, M.] Moscow MV Lomonosov State Univ, Dept Phys, Moscow, Russia. [Kurasawa, J.; Sarafanov, A.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Ataullakhanov, F.; Panteleev, M.] Ctr Theoret Problems Physicochem Pharmacol, Moscow, Russia. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2015 VL 13 SU 2 SI SI MA AS142 BP 51 EP 52 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426901138 ER PT J AU Kurasawa, JH Shestopal, SA Lee, TK Sarafanov, AG AF Kurasawa, J. H. Shestopal, S. A. Lee, T. K. Sarafanov, A. G. TI Characterization of interactive sites of activated coagulation factor VIII and low-density lipoprotein receptor-related protein 1 SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Kurasawa, J. H.; Shestopal, S. A.; Lee, T. K.; Sarafanov, A. G.] US FDA, CBER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2015 VL 13 SU 2 SI SI MA OR163 BP 157 EP 157 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426901413 ER PT J AU De Paoli, SH Tegegn, TZ Strader, M Tarandovskiy, I Orecna, M Elhelu, O Ovanesov, MV Alayash, A Simak, J AF De Paoli, S. H. Tegegn, T. Z. Strader, M. Tarandovskiy, I Orecna, M. Elhelu, O. Ovanesov, M., V Alayash, A. Simak, J. TI Analysis of exosome-like membrane microparticles released from TRAP-activated platelets SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [De Paoli, S. H.; Tegegn, T. Z.; Strader, M.; Tarandovskiy, I; Orecna, M.; Elhelu, O.; Ovanesov, M., V; Alayash, A.; Simak, J.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2015 VL 13 SU 2 SI SI MA OR174 BP 161 EP 161 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426901424 ER PT J AU Young, P Migliorini, M Prasad, J Sarafanov, A Strickland, DK AF Young, P. Migliorini, M. Prasad, J. Sarafanov, A. Strickland, D. K. TI Characterizing mechanisms of factor VIII binding to the low-density lipoprotein receptor-related protein 1 SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Young, P.; Migliorini, M.; Prasad, J.; Strickland, D. K.] Univ Maryland, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA. [Sarafanov, A.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2015 VL 13 SU 2 SI SI MA PO493-MON BP 440 EP 440 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426903105 ER PT J AU Shibeko, AM Rezaie, AR Lee, TK Ovanesov, MV AF Shibeko, A. M. Rezaie, A. R. Lee, T. K. Ovanesov, M., V TI Soluble tissue factor improves detection of thrombin generation responses to wide range of factor VIIA doses SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Shibeko, A. M.; Lee, T. K.; Ovanesov, M., V] US FDA, Off Blood Res & Review, CBER, Silver Spring, MD USA. [Rezaie, A. R.] St Louis Univ, Sch Med, St Louis, MO 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 JUN PY 2015 VL 13 SU 2 SI SI MA PO560-MON BP 464 EP 464 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426903171 ER PT J AU Liang, Y Struble, EB Chang, WC Scott, D Ovanesov, MV AF Liang, Y. Struble, E. B. Chang, W. C. Scott, D. Ovanesov, M., V TI Evaluation of factor xia pharmacokinetics in mice with a thrombin generation assay SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Liang, Y.; Struble, E. B.; Chang, W. C.; Scott, D.; Ovanesov, M., V] US FDA, Off Blood Res & Review, CBER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2015 VL 13 SU 2 SI SI MA PO008-TUE BP 511 EP 511 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426903296 ER PT J AU Galanakis, D Zhang, I Rafailovich, M Case, B AF Galanakis, D. Zhang, I Rafailovich, M. Case, B. TI Non-enzymatic fibrinogen self-assembly unveiled SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Galanakis, D.] SUNY Stony Brook, Pathol, Stony Brook, NY 11794 USA. [Zhang, I; Rafailovich, M.] SUNY Stony Brook, Mat Sci & Engn, Stony Brook, NY 11794 USA. [Zhang, I; Case, B.] US FDA, Div Biol Chem & Mat Sci, Silver Spring, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 4 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 JUN PY 2015 VL 13 SU 2 SI SI MA PO202-TUE BP 581 EP 581 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426903490 ER PT J AU Fijalkowska, I Dollins, C AF Fijalkowska, I Dollins, C. TI Blood coagulation tests: review of validation requirements for FDA clearance SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Fijalkowska, I; Dollins, C.] US FDA, Div Immunoil & Hematol Devices, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2015 VL 13 SU 2 SI SI MA PO154-WED BP 808 EP 808 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426904549 ER PT J AU Shestopal, SA Kurasawa, JH Karnaukhova, E McVey, J Lee, TK Sarafanov, AG AF Shestopal, S. A. Kurasawa, J. H. Karnaukhova, E. McVey, J. Lee, T. K. Sarafanov, A. G. TI Expression, purification and characterization of codon optimized coagulation factor VIII SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Shestopal, S. A.; Kurasawa, J. H.; Karnaukhova, E.; Lee, T. K.; Sarafanov, A. G.] US FDA, CBER, Silver Spring, MD USA. [McVey, J.] Univ Surrey, Cardiovasc Biol, Guildford GU2 5XH, Surrey, England. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2015 VL 13 SU 2 SI SI MA PO196-WED BP 822 EP 823 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426905035 ER PT J AU Tegegn, TZ De Paoli, SH Orecna, M Elhelu, O Woodle, SA Tarandovskiy, I Ovanesov, MV Simak, J AF Tegegn, T. Z. De Paoli, S. H. Orecna, M. Elhelu, O. Woodle, S. A. Tarandovskiy, I Ovanesov, M., V Simak, J. TI Analysis of membrane microparticles and thrombin generation activity of DMSO cryopreserved platelets SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Tegegn, T. Z.; De Paoli, S. H.; Orecna, M.; Elhelu, O.; Woodle, S. A.; Tarandovskiy, I; Ovanesov, M., V; Simak, J.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2015 VL 13 SU 2 SI SI MA PO603-WED BP 970 EP 970 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CK7QJ UT WOS:000356426905440 ER PT J AU Garber, EAE Thole, J AF Garber, Eric A. E. Thole, Joseph TI Application of Microwave Irradiation and Heat to Improve Gliadin Detection and Ricin ELISA Throughput with Food Samples SO TOXINS LA English DT Article DE microwave; ELISA; ricin; gluten ID PROTEIN; TECHNOLOGY; ASSAY; OVEN AB The utility of microwave irradiation to accelerate the onset of equilibrium and improve ELISA performance was examined using ELISAs for the detection of the plant toxin ricin and gliadin. The ricin ELISA normally requires several one hour incubations at 37 degrees C, a total assay time of approximately five hours, and employs a complex buffer containing PBS, Tween-20((R)), and non-fat milk. Different energy levels and pulse designs were compared to the use of abbreviated incubation times at 37 degrees C for the detection of ricin in food. The use of microwave irradiation had no significant advantage over the application of heat using an oven incubator and performed worse with some foods. In contrast, a gliadin ELISA that relied on 30 min incubation steps at room temperature and a salt-based buffer performed better upon irradiation but also displayed improvement upon incubating the microtiter plate at 37 degrees C. Whether microwave irradiation was advantageous compared to incubation in an oven was inconclusive. However, by abbreviating the incubation time of the ricin ELISA, it was possible to cut the assay time to less than 2 hours and still display LOD values < 10 ppb and recoveries of 78%-98%. C1 [Garber, Eric A. E.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Thole, Joseph] Univ Maryland, JIFSAN, College Pk, MD 20742 USA. RP Garber, EAE (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM eric.garber@fda.hhs.gov; jthole@terpmail.umd.edu NR 22 TC 2 Z9 2 U1 4 U2 15 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD JUN PY 2015 VL 7 IS 6 BP 2135 EP 2144 DI 10.3390/toxins7062135 PG 10 WC Toxicology SC Toxicology GA CL9FT UT WOS:000357282600016 PM 26110503 ER PT J AU Fu, P AF Fu, Peter TI Introduction to Dr. Jerzy Leszczynski SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Editorial Material C1 US FDA, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. RP Fu, P (reprint author), US FDA, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. EM fupeter@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU FOOD & DRUG ADMINSTRATION PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD JUN PY 2015 VL 23 IS 2 BP 167 EP 167 DI 10.1016/j.jfda.2015.04.001 PG 1 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA CL2AH UT WOS:000356745500001 ER PT J AU Jiang, X Wang, SG Zhao, YW Xia, QS Cai, LN Sun, X Fu, PP AF Jiang, Xiao Wang, Shuguang Zhao, Yuewei Xia, Qingsu Cai, Lining Sun, Xin Fu, Peter P. TI Absolute configuration, stability, and interconversion of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine valine adducts and their phenylthiohydantoin derivatives SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Article DE 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP); DHP-valine adducts; DHP-valine-phenyl isothiocyanate adducts; interconversion; liquid chromatography-electrospray tandem mass spectrometry; phenylthiohydantoin adducts; pyrrolizidine alkaloid ID PYRROLIZIDINE ALKALOIDS; DNA-ADDUCTS; DEHYDROPYRROLIZIDINE ALKALOIDS; METABOLIC-ACTIVATION; IN-VIVO; PLANTS; TUMORIGENICITY; MECHANISMS AB Pyrrolizidine alkaloid-containing plants are widespread in the world and probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolic activation to form dehydropyrrolizidine alkaloids that bind to cellular proteins and DNA leading to hepatotoxicity, genotoxicity, and tumorigenicity. At present, it is not clear how dehydropyrrolizidine alkaloids bind to cellular amino acids and proteins to induced toxicity. We previously reported that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived valine (DHP-valine) adducts that upon reaction with phenyl isothiocyanate (PITC) formed four DHP-valine-PITC adduct isomers. In this study, we report the absolute configuration and stability of DHP-valine and DHP-valine-PITC adducts, and the mechanism of interconversion between DHP-valine-PITC adducts. Copyright (C) 2015, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. C1 [Jiang, Xiao; Wang, Shuguang; Zhao, Yuewei; Xia, Qingsu; Fu, Peter P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Jiang, Xiao; Sun, Xin] Chinese Ctr Dis Control & Prevent, Natl Inst Occupat Hlth & Poison Control, Beijing, Peoples R China. [Cai, Lining] Biotranex LLC, Monmouth Jct, NJ USA. RP Fu, PP (reprint author), Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov NR 19 TC 3 Z9 3 U1 0 U2 1 PU FOOD & DRUG ADMINSTRATION PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD JUN PY 2015 VL 23 IS 2 BP 318 EP 326 DI 10.1016/j.jfda.2015.01.004 PG 9 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA CL2AH UT WOS:000356745500019 ER PT J AU Hansen, AR Cook, N Ricci, MS Razak, A Le Tourneau, C McKeever, K Roskos, L Dixit, R Siu, LL Hinrichs, AJ AF Hansen, Aaron R. Cook, Natalie Ricci, M. Stacey Razak, Albiruni Le Tourneau, Christophe McKeever, Kathleen Roskos, Lorin Dixit, Rakesh Siu, Lillian L. Hinrichs, Mary Jane TI Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials SO ONCOLOGIST LA English DT Article DE Starting dose; Biotechnology derived products; Animal toxicology studies; Phase I clinical trials; Highest nonseverely toxic dose ID REGULATORY FRAMEWORK; DRUG DEVELOPMENT; TOXICOLOGY; SAFETY; AGENTS AB Background. First-in-human (FIH) trials of low-molecular-weight anticancer agents conventionally derive a safe start dose(SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs). Materials and Methods. A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial. Results. The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the actual FIH SD was 36 (range, 8-500). Only 2 BDPs reached the MTD. Hypothetical use of one-sixth HNSTD (allometrically scaled to humans) would not have exceeded the MTD or MAD for all 23 BDPs and would have reduced the median ratio of the MTD or MAD to a SD to 6.1 (range, 3.5-55.3). Pharmacodynamic (PD) markers were included in some animal toxicology studies and were useful to confirm the hypothetical SD of one-sixth HNSTD. Conclusion. One-sixth HNSTD would not have resulted in unacceptable toxicities in the data available. Supporting its use could reduce the number of dose escalations needed to reach the recommended dose. A low incidence of toxicities in animals and humans underscores the need to identify the pharmacokinetic and PD parameters to guide SD selection of BDPs for FIH cancer trials. C1 [Hansen, Aaron R.; Cook, Natalie; Razak, Albiruni; Siu, Lillian L.] Princess Margaret Canc Ctr, Drug Dev Program, Toronto, ON M5G 2M9, Canada. [Ricci, M. Stacey] US FDA, Div Hematol & Oncol Toxicol, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Le Tourneau, Christophe] Inst Curie, Dept Med Oncol, Paris, France. [Le Tourneau, Christophe] Inst Curie, Dept Med Oncol, St Cloud, France. [Le Tourneau, Christophe] Inst Curie, INSERM, U900, Paris, France. [McKeever, Kathleen; Roskos, Lorin; Dixit, Rakesh; Hinrichs, Mary Jane] MedImmune LLC, Translat Sci, Gaithersburg, MD USA. RP Siu, LL (reprint author), Princess Margaret Canc Ctr, Drug Dev Program, 610 Univ Ave,Suite 5-718, Toronto, ON M5G 2M9, Canada. EM lillian.siu@uhn.ca RI Cook, Natalie/O-4871-2015 OI Cook, Natalie/0000-0003-2606-1082 FU Pfizer; Novartis; Karyopahrm; Bristol-Myers Squibb FX Albiruni Razak: Pfizer, Novartis, Karyopahrm, Bristol-Myers Squibb (RF); Kathleen McKeever: Ultragenyx (January 2015 to present), MedImmune/AstraZeneca (formerly employed) (E), AstraZeneca, Ultragenyx (OI); Lorin Roskos: AstraZeneca (E, OI); Lillian L. Siu: Novartis, Roche/Genentech, GlaxoSmithKline, Pfizer, Bayer, Karyopharm, Boehringer Ingelheim, AstraZeneca/MedImmune, Merck, Bristol-Myers Squibb, Regeneron (RF); Mary Jane Hinrichs: MedImmune (E, OI). The other authors indicated no financial relationships.; (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board NR 20 TC 0 Z9 0 U1 1 U2 10 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 JUN PY 2015 VL 20 IS 6 BP 653 EP 659 DI 10.1634/theoncologist.2015-0008 PG 7 WC Oncology SC Oncology GA CL1EC UT WOS:000356684400017 PM 25964306 ER PT J AU Manjanatha, MG Guo, LW Shelton, SD Doerge, DR AF Manjanatha, Mugimane G. Guo, Li-Wu Shelton, Sharon D. Doerge, Daniel R. TI Acrylamide-induced carcinogenicity in mouse lung involves mutagenicity: cII gene mutations in the lung of big blue mice exposed to acrylamide and glycidamide for up to 4 weeks SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE acrylamide; glycidamide; cII mutant frequency; DNA adducts; carcinogenicity ID HEMOGLOBIN ADDUCT FORMATION; B6C3F(1) MICE; IN-VIVO; N-METHYLOLACRYLAMIDE; MAMMALIAN-CELLS; TRANSGENIC MICE; DRINKING-WATER; DNA; RATS; TOXICOKINETICS AB Potential health risks for humans from exposure to acrylamide (AA) and its epoxide metabolite glycidamide (GA) have garnered much attention lately because substantial amounts of AA are present in a variety of fried and baked starchy foods. AA is tumorigenic in rodents, and a large number of in vitro and in vivo studies indicate that AA is genotoxic. A recent cancer bioassay on AA demonstrated that the lung was one of the target organs for tumor induction in mice; however, the mutagenicity of AA in this tissue is unclear. Therefore, to investigate whether or not gene mutation is involved in the etiology of AA- or GA-induced mouse lung carcinogenicity, we screened for cII mutant frequency (MF) in lungs from male and female Big Blue (BB) mice administered 0, 1.4, and 7.0 mM AA or GA in drinking water for up to 4 weeks (19-111 mg/kg bw/days). Both doses of AA and GA produced significant increases in cII MFs, with the high doses producing responses 2.7-5.6-fold higher than the corresponding controls (P0.05; control MFs=17.2 +/- 2.2 and 15.8 +/- 3.5 x 10(-6) in males and females, respectively). Molecular analysis of the mutants from high doses indicated that AA and GA produced similar mutation spectra and that these spectra were significantly different from the spectra in control mice (P0.01). The predominant types of mutations in the lung cII gene from AA- and GA-treated mice were A:T T:A, and G:C C:G transversions, and -1/+1 frameshifts at a homopolymeric run of Gs. The MFs and types of mutations induced by AA and GA in the lung are consistent with AA exerting its genotoxicity via metabolism to GA. These results suggest that AA is a mutagenic carcinogen in mouse lungs and therefore further studies on its potential health risk to humans are warranted. Environ. Mol. Mutagen. 56:446-456, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Manjanatha, Mugimane G.; Guo, Li-Wu; Shelton, Sharon D.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Doerge, Daniel R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Manjanatha, MG (reprint author), Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM mugimane.manjanatha@fda.hhs.gov FU NCTR/FDA, the National Institute for Environmental Health Sciences/National Toxicology Program [224-93-0001] FX Grant sponsor: NCTR/FDA, the National Institute for Environmental Health Sciences/National Toxicology Program; Grant number: 224-93-0001. NR 43 TC 5 Z9 5 U1 2 U2 14 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 JUN PY 2015 VL 56 IS 5 BP 446 EP 456 DI 10.1002/em.21939 PG 11 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CK7QC UT WOS:000356426200003 PM 25639614 ER PT J AU Zhu, JM Pouillot, R Kwegyir-Afful, EK Luccioli, S Gendel, SM AF Zhu, Jianmei Pouillot, Regis Kwegyir-Afful, Ernest K. Luccioli, Stefano Gendel, Steven M. TI A retrospective analysis of allergic reaction severities and minimal eliciting doses for peanut, milk, egg, and soy oral food challenges SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Food allergen; Oral food challenges; Eliciting dose; Reaction severity ID SKIN PRICK TESTS; DOUBLE-BLIND; COWS MILK; TOLERANCE INDUCTION; ATOPIC-DERMATITIS; HYPERSENSITIVITY REACTIONS; CLINICAL IMMUNOLOGY; SENSITIZED CHILDREN; ELIMINATION DIETS; EUROPEAN ACADEMY AB Food allergy is a public health concern, affecting up to 6% of children and 2% of adults. The severity of allergic reactions can range from mild to potentially life-threatening. In addition, the minimum amount of protein needed to provoke an allergic reaction in an individual patient (the minimal eliciting dose (MED)) ranges from a few micrograms to several grams. To determine whether a retrospective analysis of published data from oral food challenges could be used to assess the potential relationship between MEDs and reaction severities at the MEDs, a three class (mild, moderate, severe) reaction grading system was developed by integrating previously published reaction grading systems. MEDs and symptoms were collected from food challenge studies and each reaction was graded using the integrated grading system. Peanut allergic patients who experienced severe reactions had significantly higher MEDs and threshold distribution doses than those who experienced mild and moderate reactions. No significant differences in threshold distributions according to the severity grading were found for milk, egg and soy. The relationship between threshold dose distribution and reaction severity based on these grading criteria differed between peanut and other allergens, and severe reactions were found to occur in some patients at low MEDs for all of these food allergens. Published by Elsevier Ltd. C1 [Zhu, Jianmei; Pouillot, Regis; Kwegyir-Afful, Ernest K.; Luccioli, Stefano; Gendel, Steven M.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Gendel, SM (reprint author), 5100 Paint Branch Pkwy,HFS-200, College Pk, MD 20740 USA. EM steven.gendel@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 NR 85 TC 9 Z9 10 U1 2 U2 16 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 2015 VL 80 BP 92 EP 100 DI 10.1016/j.fct.2015.02.023 PG 9 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CK3HP UT WOS:000356107500011 PM 25748389 ER PT J AU Jackson, LS Triplett, OA Tolleson, WH AF Jackson, Lauren S. Triplett, Odbert A. Tolleson, William H. TI Influence of yogurt fermentation and refrigerated storage on the stability of protein toxin contaminants SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Yogurt; Ricin; Abrin; Stability; Dairy; Manufacture ID ESCHERICHIA-COLI; THERMAL INACTIVATION; BIOLOGICAL-ACTIVITY; DAIRY-PRODUCTS; RICIN TOXICITY; APPLE JUICES; INHIBITION; MILK; PASTEURIZATION; INDUSTRY AB Dairy products sold in a ready-to-eat form present the risk that adulterants persisting through manufacturing, storage, and distribution would reach consumers. Pathogenic microbes, including shigatoxigenic strains of Escherichia coil and the toxins they produce, are common food safety hazards associated with dairy products. Ricin and abrin are plant-derived ribosome-inactivating protein toxins related to the shiga-like toxins produced by E. coil. Limited information exists on the effects of manufacturing processes on the stabilities of these heat-resistant ribosome-inactivating proteins in the presence of foods. The goal of this study was to determine how typical yogurt manufacturing and storage processes influence ribosome-inactivating protein toxins. Ricin and abrin were added to skim or whole milk and batch pasteurized. Complete inactivation of both toxins was observed after 30 minutes at 85 degrees C. If the toxins were added after pasteurization, the levels of ricin and abrin in yogurt and their cytotoxic activities did not change significantly during fermentation or refrigerated storage for 4 weeks. The activities of ricin and abrin were inhibited by skim milk, nonfat yogurt, whole milk, and whole milk yogurt. The results showed minimal effects of the toxins on yogurt pH and %titratable acidity but inhibitory effects of yogurt on toxin activity. Published by Elsevier Ltd. C1 [Jackson, Lauren S.] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Triplett, Odbert A.; Tolleson, William H.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Tolleson, WH (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM william.tolleson@fda.hhs.gov FU National Center for Food Protection and Defense FX The contents of this manuscript do not necessarily reflect the views and policies of the U.S. Food and Drug Administration, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. This project was funded in part by a grant from the National Center for Food Protection and Defense. NR 30 TC 0 Z9 0 U1 3 U2 18 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 2015 VL 80 BP 101 EP 107 DI 10.1016/j.fct.2015.03.003 PG 7 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CK3HP UT WOS:000356107500012 PM 25772284 ER PT J AU Tkachenko, A Clark, J Knutson, N Wallace, B Bomba, M Yacopucci, M Rhodes, B Nemser, SM Guag, J Reimschuessel, R AF Tkachenko, Andriy Clark, James Knutson, Natalie Wallace, Betzy Bomba, Malgorzata Yacopucci, Michele Rhodes, Blaine Nemser, Sarah M. Guag, Jake Reimschuessel, Renate TI Investigation of melamine and cyanuric acid deposition in pig tissues using LC-MS/MS methods SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Mass spectrometry; Melamine; Cyanuric acid; Residues; Pig ID RESIDUE DEPLETION; MASS-SPECTROMETRY; EXPOSURE; RATS AB Four LC-MS/MS methods were developed to quantify melamine (MEL) and cyanuric acid (CYA) in various pig tissues at or above the level of concern (2.5 mg/kg). Pigs treated with 200 mg/kg bw/day CYA daily for 7 days did not accumulate significant residue concentrations in muscle, liver or kidney. Pigs treated with 200 mg/kg bw MEL daily for 7 or 28 days had MEL residues in muscles (3-13 ppm), liver (2.8-14.1 ppm) and kidney (9.4-27.2 ppm). Treatment with MEL and CYA at 100 mg/kg bw of each triazine daily for 7 days resulted in MEL (26-59 ppm in muscle, 30-49 ppm in liver and 367-6300 ppm in kidney) and CYA (1.8-5.8 ppm in muscle, 2.6-6.5 ppm in liver and 303-7100 ppm in kidney). Treatment with MEL and CYA at 1, 3 or 10 mg/kg bw/day for 7 days did not result in residues greater than the level of concern in all tissues tested. Pigs dosed with 33 mg/kg bw/day of MEL + CYA for 7 days contained residues above the level of concern only in kidney. Deposition of MEL and CYA depends on the tissue type (muscles, liver and kidney), dosage and whether the triazines are given alone or in combination. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Tkachenko, Andriy; Nemser, Sarah M.; Guag, Jake; Reimschuessel, Renate] US FDA, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. [Clark, James; Knutson, Natalie] Arizona Dept Hlth Serv, State Lab, Phoenix, AZ 85007 USA. [Wallace, Betzy; Bomba, Malgorzata; Yacopucci, Michele] New Hampshire State Publ Hlth Lab, Concord, NH 03301 USA. [Rhodes, Blaine] Washington State Publ Hlth Lab, Shoreline, WA 98155 USA. RP Reimschuessel, R (reprint author), US FDA, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM renate.reimschuessel@fda.hhs.gov FU DOE; USFDA FX This project was supported in part by an appointment to the Research Participation Program in the Center for Veterinary Medicine administered by the Oak Ridge Institute for Science and education through an interagency agreement between DOE and USFDA. NR 29 TC 2 Z9 2 U1 6 U2 17 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 2015 VL 80 BP 310 EP 318 DI 10.1016/j.fct.2015.03.007 PG 9 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CK3HP UT WOS:000356107500034 PM 25818466 ER PT J AU Hall, DG Rohrig, E AF Hall, David G. Rohrig, Eric TI Bionomics of Asian Citrus Psyllid (Hemiptera: Liviidae) Associated with Orange Jasmine Hedges in Southeast Central Florida, with Special Reference to Biological Control by Tamarixia radiata SO JOURNAL OF ECONOMIC ENTOMOLOGY LA English DT Article DE greening disease; huanglongbing; Murraya; Diaphorina citri ID CANDIDATUS LIBERIBACTER ASIATICUS; DIAPHORINA-CITRI; MURRAYA-PANICULATA; HYMENOPTERA EULOPHIDAE; SEASONAL ABUNDANCE; HOMOPTERA; DISEASE AB The Asian citrus psyllid, Diaphorina citri Kuwayama, is an important pest in Florida because it transmits bacteria responsible for citrus huanglongbing disease. In addition to infesting citrus, orange jasmine (Murraya exotica L.) is one of Asian citrus psyllid's preferred host plants and is widely grown as an ornamental hedge. We report on Asian citrus psyllid bionomics over three years at five urban plantings of orange jasmine and on biological control of Asian citrus psyllid by a parasitoid Tamarixia radiata (Waterston). T. radiata had been released in Florida shortly after Asian citrus psyllid was first found, and the parasitoid was known to be established at each planting. Additionally, three new T. radiata haplotypes were released every 3 wk at three plantings during the first study year (one haplotype per planting, over all releases an average of 17 parasitoids per linear meter of hedge); all three haplotypes were released at a fourth planting beginning midway through the study (over all releases, an average combined total of 202 parasitoids per linear meter of hedge). Asian citrus psyllid populations were present year-round at each planting, often at large levels. Such plantings may pose risk to commercial citrus as Asian citrus psyllid reservoirs. Releases of the new haplotypes did not cause any measurable reduction in Asian citrus psyllid population levels during the study, and ironically percentage parasitism was generally highest at a planting where no releases were made. Higher release rates might have been more effective. The probability is discussed that repetitive pruning of orange jasmine reduced the full potential of T. radiata against Asian citrus psyllid in this study. C1 [Hall, David G.] USDA ARS, Ft Pierce, FL 34945 USA. [Rohrig, Eric] FDACS DPI, Gainesville, FL 32614 USA. RP Hall, DG (reprint author), USDA ARS, 2001 South Rock Rd, Ft Pierce, FL 34945 USA. EM david.hall@ars.usda.gov NR 24 TC 3 Z9 3 U1 1 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-0493 EI 1938-291X J9 J ECON ENTOMOL JI J. Econ. Entomol. PD JUN PY 2015 VL 108 IS 3 BP 1198 EP 1207 DI 10.1093/jee/tov052 PG 10 WC Entomology SC Entomology GA CK5CF UT WOS:000356239000045 PM 26470246 ER PT J AU Chen, XR Hansen, DK Merry, G DeJarnette, C Nolen, G Sloper, D Fisher, JE Harrouk, W Tassinari, MS Inselman, AL AF Chen, Xinrong Hansen, Deborah K. Merry, Gwenn DeJarnette, Christian Nolen, Greg Sloper, Daniel Fisher, J. Edward Harrouk, Wafa Tassinari, Melissa S. Inselman, Amy L. TI Developing osteoblasts as an endpoint for the mouse embryonic stem cell test SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Osteoblast; Cardiomyocyte; Embryonic stem cell test; Embryotoxicity; Alternative model; In vitro ID VITRO EMBRYOTOXICITY TESTS; IN-VITRO; DEVELOPMENTAL TOXICITY; OSTEOCALCIN GENE; BONE-FORMATION; DIFFERENTIATION; VALIDATION; ACETAZOLAMIDE; AZATHIOPRINE; CULTURE AB The mouse Embryonic Stem cell Test (EST) using cardiomyocyte differentiation is a promising in vitro assay for detecting potential embryotoxicity; however, the addition of another differentiation endpoint, such as osteoblasts, may improve the predictive value of the test. A number of variables such as culture conditions and starting cell number were investigated. A 14 day direct plating method of 03 mouse embryonic stem cells (mESCs) was used to test the predictivity of osteoblast differentiation as an endpoint in the EST. Twelve compounds were tested using the prediction model developed in the ECVAM validation study. Eight of the compounds selected from the EST validation study served as model compounds; four additional compounds known to produce skeletal defects were also tested. Our results indicate comparable chemical classification between the validated cardiomyocyte endpoint and the osteoblast endpoint. These results suggest that differentiation to osteoblasts may provide confirmatory information in predicting embryotoxicity. Published by Elsevier Inc. C1 [Chen, Xinrong; Hansen, Deborah K.; Merry, Gwenn; Nolen, Greg; Sloper, Daniel; Inselman, Amy L.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. [DeJarnette, Christian] Lee Univ, Cleveland, TN USA. [Fisher, J. Edward; Harrouk, Wafa; Tassinari, Melissa S.] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Chen, XR (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. EM Xinrong.chen@fda.hhs.gov; Deborah.Hansen@fda.hhs.gov; Gwenn.Merry@fda.hhs.gov; Christiandelarnette@comcast.net; Vivian_nolen@att.net; Daniel.Sloper@fda.hhs.gov; Jedward.fisher@fda.hhs.gov; Wafa.Harrouk@fda.hhs.gov; Melissa.Tassinari@fda.hhs.gov; Amy.Inselman@fda.hhs.gov FU FDA/NCTR [E7354]; FDA/NCTR Summer Student Research Program FX This study was funded by FDA/NCTR under E7354 and by FDA/NCTR Summer Student Research Program provided to Christian DeJarnette. NR 40 TC 0 Z9 0 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUN PY 2015 VL 53 BP 131 EP 140 DI 10.1016/j.reprotox.2015.04.008 PG 10 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA CK6DO UT WOS:000356318900019 PM 25929818 ER PT J AU Hamburg, M AF Hamburg, Margaret TI Foreword: The Global Pandemic of Falsified Medicines: Laboratory and Field Innovations and Policy Implications SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Editorial Material C1 [Hamburg, Margaret] US FDA, Silver Spring, MD USA. RP Hamburg, M (reprint author), 10903 New Hampshire Ave,Bldg 1,Room 2217, Silver Spring, MD 20903 USA. EM commissioner@fda.hhs.gov NR 0 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2015 VL 92 IS 6 SU S BP 1 EP 1 DI 10.4269/ajtmh.15-0046 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CJ8XA UT WOS:000355785600001 ER PT J AU Green, MD Hostetler, DM Nettey, H Swamidoss, I Ranieri, N Newton, PN AF Green, Michael D. Hostetler, Dana M. Nettey, Henry Swamidoss, Isabel Ranieri, Nicola Newton, Paul N. TI Integration of Novel Low-Cost Colorimetric, Laser Photometric, and Visual Fluorescent Techniques for Rapid Identification of Falsified Medicines in Resource-Poor Areas: Application to Artemether-Lumefantrine SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID COUNTERFEIT ANTIMALARIAL TABLETS; SOUTHEAST-ASIA; ARTESUNATE; QUALITY; DRUGS; SPECTROSCOPY; AFRICA; SOLD AB The availability of falsified antimalarial drugs can be reduced with effective drug regulatory agencies and proper enforcement. Fundamental to these agencies taking action, rapid identification must be made as soon as they appear in the market place. Since falsified antimalarials occur mostly in developing countries, performing drug analysis presents itself with unique challenges. A fundamental factor in choosing a useful technique is affordability and simplicity. Therefore, we suggest a three-tiered drug evaluation strategy for identifying a falsified drug in resource-poor areas. Tier I is a simple comparison of a tablet's weight and dimensions with official specifications. Tier II uses inexpensive photometric devices (laser and fluorescence) to evaluate a tablet. Suspicious samples from Tier I and II assessments are then subjected to a colorimetric assay for active ingredients identification and quantification. In this article, we evaluate a novel colorimetric assay for the simultaneous assessment of both lumefantrine and artemether in co-formulated Coartem (TM) tablets, and integrate the method with two novel, low-cost, fluorescence and laser photometric devices. Image analysis software is used for the assessments. Although artemether-lumefantrine is used as an example, the strategy may be adapted to other medicines. C1 [Green, Michael D.; Hostetler, Dana M.; Swamidoss, Isabel] CDC, Div Parasit Dis & Malaria, Atlanta, GA 30333 USA. [Nettey, Henry] Univ Ghana, Coll Hlth Sci, Sch Pharm, Dept Pharmaceut & Microbiol, Legon, Ghana. [Ranieri, Nicola] US FDA, Forens Chem Ctr, Cincinnati, OH USA. [Newton, Paul N.] Mahosot Hosp, Microbiol Lab, Lao Oxford Mahosot Hosp Wellcome Trust Res Unit, Viangchan, Laos. [Newton, Paul N.] Univ Oxford, Churchill Hosp, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England. RP Green, MD (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd,Mailstop F12, Atlanta, GA 30333 USA. EM mgreen@cdc.gov; danahostetler@gmail.com; hnettey@msn.com; gtz8@cdc.gov; nicola.ranieri@fda.hhs.gov; paul.newton@tropmedres.ac NR 29 TC 7 Z9 7 U1 2 U2 10 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2015 VL 92 IS 6 SU S BP 8 EP 16 DI 10.4269/ajtmh.14-0832 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CJ8XA UT WOS:000355785600003 PM 25897066 ER PT J AU Dave, VS Fahmy, RM Hoag, SW AF Dave, Vivek S. Fahmy, Raafat M. Hoag, Stephen W. TI Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Matrix tablets; near-infrared; plasticizer; roller compaction; sintering temperature ID DIFFUSE-REFLECTANCE SPECTROSCOPY; ANALYTICAL TECHNOLOGY APPROACH; DRIED INJECTION PRODUCT; HARD GELATIN CAPSULES; FILM COATING PROCESS; NONDESTRUCTIVE METHOD; MOISTURE-CONTENT; CONTENT UNIFORMITY; BLEND HOMOGENEITY; NIR SPECTROSCOPY AB The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit (R) RL PO or Eudragit (R) RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5: 1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 degrees C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly increased with increasing plasticizer levels and with increases in the sintering temperature. An increase in tablet hardness produced an upward shift (increase in absorbance) in the NIR spectra. The principle component analysis (PCA) of the spectra was able to distinguish samples with different plasticizer levels and sintering temperatures. In addition, a 9-factor partial least squares (PLS) regression model for tablets containing Eudragit (R) RL PO had an r(2) of 0.9797, a standard error of calibration of 0.6255 and a standard error of cross validation (SECV) of 0.7594. Similar analysis of tablets containing Eudragit (R) RS PO showed an r(2) of 0.9831, a standard error of calibration of 0.9711 and an SECV of 1.192. C1 [Dave, Vivek S.] St John Fisher Coll, Wegmans Sch Pharm, Rochester, NY 14618 USA. [Fahmy, Raafat M.] US FDA, Rockville, MD USA. [Hoag, Stephen W.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP Hoag, SW (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, 20 North Pine St, Baltimore, MD 21201 USA. EM shoag@rx.umaryland.edu FU CIPET FX The authors report no declarations of interest. Some of the contents of this article were part of the graduate thesis dissertation submitted by Vivek S. Dave to the faculty of the School of Pharmacy, University of Maryland, Baltimore in partial fulfillment of the requirements for the doctorate degree. The authors gratefully acknowledge the financial support of CIPET. NR 65 TC 1 Z9 1 U1 4 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0363-9045 EI 1520-5762 J9 DRUG DEV IND PHARM JI Drug Dev. Ind. Pharm. PD JUN PY 2015 VL 41 IS 6 BP 898 EP 905 DI 10.3109/03639045.2014.911883 PG 8 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CK1QG UT WOS:000355981400003 PM 24785574 ER PT J AU Siddiqui, A Rahman, Z Khan, MA AF Siddiqui, Akhtar Rahman, Ziyaur Khan, Mansoor A. TI Application of chemometric methods to differential scanning calorimeter (DSC) to estimate nimodipine polymorphs from cosolvent system SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Chemometrics; DSC; nimodipine; PCS; PLS; polymorphs ID VIRGIN OLIVE OIL; SOLID DISPERSIONS; GRANULATION; PREDICTION; STATE AB The focus of this study was to evaluate the applicability of chemometrics to differential scanning calorimetry data (DSC) to evaluate nimodipine polymorphs. Multivariate calibration models were built using DSC data from known mixtures of the nimodipine modification. The linear baseline correction treatment of data was used to reduce dispersion in thermograms. Principal component analysis of the treated and untreated data explained 96% and 89% of the data variability, respectively. Score and loading plots correlated variability between samples with change in proportion of nimodipine modifications. The R-2 for principal component regression (PCR) and partial lease square regression (PLS) were found to be 0.91 and 0.92. The root mean square of standard error of the treated samples for calibration and validation in PCR and PLS was found to be lower than the untreated sample. These models were applied to samples recrystallized from a cosolvent system, which indicated different proportion of modifications in the mixtures than those obtained by placing samples under different storage conditions. The model was able to predict the nimodipine modifications with known margin of error. Therefore, these models can be used as a quality control tool to expediently determine the nimodipine modification in an unknown mixture. C1 [Siddiqui, Akhtar; Rahman, Ziyaur; Khan, Mansoor A.] CDER, FDA, OPS, Div Prod Qual Res,Off Testing & Res, Silver Spring, MD 20993 USA. RP Khan, MA (reprint author), CDER, DPQR, FDA, LS Bldg 64,Room 1070,New Hampshire Ave, Silver Spring, MD 20993 USA. EM mansoor.khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X FU Oak Ridge Institute for Science and Education (ORISE) FX The authors would like to thank Medical Counter Measure Initiative (MCMi) for infrastructure support and Oak Ridge Institute for Science and Education (ORISE) for supporting post-doctoral research program. NR 21 TC 0 Z9 0 U1 1 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0363-9045 EI 1520-5762 J9 DRUG DEV IND PHARM JI Drug Dev. Ind. Pharm. PD JUN PY 2015 VL 41 IS 6 BP 995 EP 999 DI 10.3109/03639045.2014.922571 PG 5 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CK1QG UT WOS:000355981400014 PM 24856323 ER PT J AU Sharfstein, JM AF Sharfstein, Joshua M. TI Electronic Cigarettes: Gateway to Understanding the FDA? SO MILBANK QUARTERLY LA English DT Article C1 [Sharfstein, Joshua M.] Johns Hopkins Bloomberg Sch Publ Hlth, Publ Hlth Practice & Training, Baltimore, MD 21205 USA. [Sharfstein, Joshua M.] Maryland Dept Hlth & Mental Hyg, Baltimore, MD 21201 USA. [Sharfstein, Joshua M.] US FDA, Rockville, MD 20857 USA. [Sharfstein, Joshua M.] US House Representat, Comm Govt Reform, Washington, DC USA. [Sharfstein, Joshua M.] Inst Med, Board Populat Hlth & Publ Hlth Practice, Washington, DC USA. RP Sharfstein, JM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 615 North Wolfe St,Ste W1033D, Baltimore, MD 21205 USA. EM Joshua.Sharfstein@jhu.edu NR 3 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-378X EI 1468-0009 J9 MILBANK Q JI Milbank Q. PD JUN PY 2015 VL 93 IS 2 BP 251 EP 254 DI 10.1111/1468-0009.12119 PG 4 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CK1XH UT WOS:000356002000007 PM 26044627 ER PT J AU Rubio, T AF Rubio, Teresa TI Summaries of Safety Labeling Changes Approved By FDA-Boxed Warnings Highlights January-March 2015 SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT News Item C1 US FDA, Off Hlth & Constituent Affairs, Rockville, MD 20857 USA. RP Rubio, T (reprint author), US FDA, Off Hlth & Constituent Affairs, Rockville, MD 20857 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUN 1 PY 2015 VL 72 IS 11 BP 900 EP + DI 10.2146/news150039 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CJ8VW UT WOS:000355782600004 PM 25987678 ER PT J AU Khurana, M Vaidyanathan, J Marathe, A Mehrotra, N Sahajwalla, CG Zineh, I Jain, L AF Khurana, Manoj Vaidyanathan, Jayabharathi Marathe, Anshu Mehrotra, Nitin Sahajwalla, Chandrahas G. Zineh, Issam Jain, Lokesh TI Canagliflozin Use in Patients With Renal Impairment-Utility of Quantitative Clinical Pharmacology Analyses in Dose Optimization SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE SGLT2; diabetes; canagliflozin; renal impairment; regulatory AB Canagliflozin (INVOKANA (TM)) is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Canagliflozin inhibits renal sodium-glucose co-transporter 2 (SGLT2), thereby, reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Given the mechanism of action of SGLT2 inhibitors, we assessed the interplay between renal function, efficacy (HbA1c reduction), and safety (renal adverse reactions). The focus of this article is to highlight the FDA's quantitative clinical pharmacology analyses that were conducted to support the regulatory decision on dosing in patients with renal impairment (RI). The metrics for assessment of efficacy for T2DM drugs is standard; however, there is no standard method for evaluation of renal effects for diabetes drugs. Therefore, several analyses were conducted to assess the impact of canagliflozin on renal function (as measured by eGFR) based on available data. These analyses provided support for approval of canagliflozin in T2DM patients with baseline eGFR >= 45 mL/min/1.73m(2), highlighting a data-driven approach to dose optimization. The availability of a relatively rich safety dataset (ie, frequent and early measurements of laboratory markers) in the canagliflozin clinical development program enabled adequate assessment of benefit-risk balance in various patient subgroups based on renal function. C1 [Khurana, Manoj; Vaidyanathan, Jayabharathi; Marathe, Anshu; Mehrotra, Nitin; Sahajwalla, Chandrahas G.; Zineh, Issam; Jain, Lokesh] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Khurana, M (reprint author), Ctr Drug Evaluat & Res, Div Clin Pharmacol 2, Off Translat Sci, 10903 New Hampshire Ave,Room 3158,Bldg 51, Silver Spring, MD 20993 USA. EM Manoj.Khurana@fda.hhs.gov NR 3 TC 2 Z9 2 U1 0 U2 3 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 2015 VL 55 IS 6 BP 647 EP 656 DI 10.1002/jcph.466 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CK0BO UT WOS:000355869100005 PM 25612234 ER PT J AU Mahmood, I AF Mahmood, Iftekhar TI Mechanistic Versus Allometric Models for the Prediction of Drug Clearance in Neonates (< 3 Months of Age) SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Letter ID EXPONENT; CHILDREN; ADULTS C1 US FDA, Div Hematol Clin Review, OBRR, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Mahmood, I (reprint author), US FDA, Div Hematol Clin Review, OBRR, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Iftekhar.mahmood@fda.hhs.gov NR 14 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUN PY 2015 VL 55 IS 6 BP 718 EP 720 DI 10.1002/jcph.487 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CK0BO UT WOS:000355869100013 PM 25943826 ER PT J AU Cheng, CM Doran, T Lin, W Chen, KS Williams-Hill, D Pamboukian, R AF Cheng, Chorng-Ming Doran, Tara Lin, Wen Chen, Kai-Shun Williams-Hill, Donna Pamboukian, Ruiqing TI Interlaboratory Validation for a Real-Time PCR Salmonella Detection Method Using the ABI 7500 FAST Real-Time PCR System SO JOURNAL OF FOOD PROTECTION LA English DT Article ID POLYMERASE-CHAIN-REACTION; GENE; AMPLIFICATION; TYPHIMURIUM; FOODS AB Sixteen FERN (Food Emergency Response Network) member laboratories collaborated in this study to verify extension of the real-time PCR Salmonella detection method originally designed for the single-tube Cepheid SmartCycler II and validated against the Salmonella method of the U.S. Food and Drug Administration Bacteriological Analytical Manual to the Applied Biosystems (ABI) 7500 FAST Real-Time PCR system multiwell plate platform. Four foods were selected for this study: chili powder, soft cheese, fish, and tomatoes; these foods represent products that are commonly analyzed for the presence of Salmonella for regulatory purposes. Each food consisted of six uninoculated control samples, six samples inoculated with low Salmonella levels (target 1 to 5 CFU/25 g), and six samples inoculated with high levels (target 10 to 50 CFU/25 g). All samples were tested for Salmonella using the 24-h quantitative PCR (qPCR) method for detecting Salmonella, which utilizes modified buffered peptone water as the sole enrichment medium and an internal control for the qPCR. Each of these 18 samples was individually analyzed for Salmonella by the collaborating laboratories using both the ABI 7500 FAST system (alternative method) and the SmartCycler LE system (reference method). Statistical analysis of the data revealed no significant difference (P >= 0.05) between these two qPCR platforms except for the chili powder samples. The differences noted with chili powder (P = 0.0455) were attributed to the enhanced sensitivity of the ABI 7500 FAST system compared with the SmartCycler II system. The detection limit of both qPCR methods was 0.02 to 0.15 CFU/g. These results provide a solid basis for extending the 24-h qPCR Salmonella method to the ABI 7500 FAST system for high-throughput detection of Salmonella in foods: C1 [Cheng, Chorng-Ming; Chen, Kai-Shun; Williams-Hill, Donna] US FDA, Off Regulatory Affairs, Pacific Reg Lab Southwest, Irvine, CA 92612 USA. [Doran, Tara] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Lin, Wen; Pamboukian, Ruiqing] US FDA, Off Regulatory Affairs, Off Regulatory Sci, Rockville, MD 20857 USA. RP Chen, KS (reprint author), US FDA, Off Regulatory Affairs, Pacific Reg Lab Southwest, 19701 Fairchild, Irvine, CA 92612 USA. EM kai-shun.chen@fda.hhs.gov NR 15 TC 1 Z9 1 U1 4 U2 12 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD JUN PY 2015 VL 78 IS 6 BP 1119 EP 1124 DI 10.4315/0362-028X.JFP-14-244 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CJ8UW UT WOS:000355780000008 PM 26038901 ER PT J AU Panda, R Zoerb, HF Cho, CY Jackson, LS Garber, EAE AF Panda, Rakhi Zoerb, Hans F. Cho, Chung Y. Jackson, Lauren S. Garber, Eric A. E. TI Detection and Quantification of Gluten during the Brewing and Fermentation of Beer Using Antibody-Based Technologies SO JOURNAL OF FOOD PROTECTION LA English DT Article ID MONOCLONAL-ANTIBODIES; ENZYME-IMMUNOASSAY; CELIAC PATIENTS; FOODS; WHEAT; GLIADIN; FRACTIONS; PEPTIDE; ELISA AB 2013 the U.S. Food and Drug Administration (FDA) defined the term "gluten-free" and identified a gap in the analytical methodology for detection and quantification of gluten in foods subjected to fermentation and hydrolysis. To ascertain the ability of current enzyme-linked immunosorbent assays (ELISAs) to detect and quantify gluten in fermented and hydrolyzed products, sorghum beer was spiked in the initial phases of production with 0, 20, and 200 mu g/ml wheat gluten, and samples were collected throughout the beer production process. The samples were analyzed using five sandwich ELISAs and two competitive ELISAs and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western analysis employing four antibodies (MIoBS, R5, G12, and Skerritt). The sensitivity of the MIoBS ELISA (0.25 ppm) enabled the reliable detection of gluten throughout the manufacturing process, including fermentation, when the initial concentration of 20 mu g/ml dropped to 2 mu g/ml. The R5 antibody-based and G12 antibody-based sandwich ELISAs were unable to reliably detect gluten, initially at 20 mu g/ml, after the onset of production. The Skerritt antibody-based sandwich ELISA overestimated the gluten concentration in all samples. The R5 antibody-based and G12 antibody-based competitive ELISAs were less sensitive than the sandwich ELISAs and did not provide accurate results for quantifying gluten concentration. The Western analyses were able to detect gluten at less than 5 mu g/ml in the samples and confirmed the results of the ELISAs. Although further research is necessary before all problems associated with detection and quantification of hydrolyzed and fermented gluten are resolved, the analytical methods recommended by the FDA for regulatory samples can detect >= 20 mu g/ml gluten that has undergone brewing and fermentation processes associated with the manufacture of beer. C1 [Panda, Rakhi; Cho, Chung Y.; Garber, Eric A. E.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Bioanalyt Chem, College Pk, MD 20740 USA. [Zoerb, Hans F.] Univ Wisconsin, Dept Food Sci, Madison, WI 53706 USA. [Jackson, Lauren S.] US FDA, Ctr Food Safety & Appl Nutr, Off Food Safety, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. RP Garber, EAE (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Bioanalyt Chem, College Pk, MD 20740 USA. EM eric.garber@fda.hhs.gov NR 27 TC 4 Z9 4 U1 6 U2 36 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 JUN PY 2015 VL 78 IS 6 BP 1167 EP 1177 DI 10.4315/0362-028X.JFP-14-546 PG 11 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CJ8UW UT WOS:000355780000015 PM 26038908 ER PT J AU Garber, EAE Panda, R Shireen, KF AF Garber, Eric A. E. Panda, Rakhi Shireen, Kaniz F. TI Survey of Tea for the Presence of Gluten SO JOURNAL OF FOOD PROTECTION LA English DT Article ID CELIAC-DISEASE; MONOCLONAL-ANTIBODY; ENZYME-IMMUNOASSAY; FOODS; WHEAT; GLIADIN; FRACTIONS; MODEL AB In 2013, the U.S. Food and Drug Administration conducted a survey of green and white teas marketed in the northeastern United States for the presence of undeclared wheat. Based on the requirement for concurrence between the RIDASCREEN gliadin (R5) enzyme-linked immunosorbent assay (ELISA) and the Morinaga Institutes of Biological Science (MIoBS) wheat protein ELISA, none of the 20 products included in the survey tested positive for wheat, rye, barley, or gluten. However, eight of the teas generated responses indicative of the presence of gluten with the RIDASCREEN gliadin (R5), AgraQuant gluten G12, and Aller-Tek (Skerritt) sandwich ELISAs. Five of the eight teas generated responses indicative of >20 ppm of gluten using the RIDASCREEN and AgraQuant ELISA test kits, and all eight had >= 20 ppm based on the Aller-Tek ELISA. Extracts prepared using the REDASCREEN validated protocol and the MIoBS validated sodium dodecyl sulfate plus beta-mercaptoethanol (overnight) protocol were analyzed using both test kits. The extracts prepared using the RIDASCREEN protocol tested positive for gluten with both test kits. Western blot analyses of the two sets of extracts using the R5 and MdoBS antibodies to visualize the bands revealed the presence of antigenic proteins in both sets of extracts, although the profiles and band intensities were different and inconsistent with the ELISA results. These results raise questions regarding the screening procedures used to detect gluten and how the observation of a homologous antigenic element is defined. C1 [Garber, Eric A. E.; Panda, Rakhi] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Shireen, Kaniz F.] US FDA, Off Compliance, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Garber, EAE (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM eric.garber@fda.hhs.gov NR 23 TC 0 Z9 0 U1 0 U2 7 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD JUN PY 2015 VL 78 IS 6 BP 1237 EP 1243 DI 10.4315/0362-028X.JFP-14-575 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CJ8UW UT WOS:000355780000027 PM 26038920 ER PT J AU Xu, ZH Kass-Hout, T Anderson-Smits, C Gray, G AF Xu, Zhiheng Kass-Hout, Taha Anderson-Smits, Colin Gray, Gerry TI Signal detection using change point analysis in postmarket surveillance SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE change point analysis; adverse event; signal detection; pharmacoepidemiology ID REPORTING SYSTEM; FDA; ALGORITHMS AB PurposeSignal detection methods have been used extensively in postmarket surveillance to identify elevated risks of adverse events associated with medical products (drugs, vaccines, and devices). However, current popular disproportionality methods ignore useful information such as trends when the data are aggregated over time for signal detection. MethodsIn this paper, we applied change point analysis (CPA) to trend analysis of medical products in a spontaneous adverse event reporting system. CPA was used to detect the time point at which statistical properties of a sequence of observations change over time. Two CPA approaches, change in mean and change in variance, were demonstrated by an example using neurostimulator adverse event dataset. ResultsTwo significant change points associated with upward trends were detected in June 2008 (n=20, p<0.001) and May 2011 (n=51, p=0.003). Further investigation confirmed battery issues and expansion of the indication for use could be possible causes for the occurrence of these change points. Two time points showed extremely low number of loss of therapy events, two cases in October 2009 and three in November 2009, which could be the result of reporting issues such as underreporting. ConclusionAs a complimentary tool to current signal detection efforts at FDA, CPA can be used to detect changes in the association between medical products and adverse events over time. Detecting these changes could be critical for public health regulation, adverse events surveillance, product recalls, and regulators' understanding of the connection between adverse events and other events regarding regulated products. (c) 2015 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd. C1 [Xu, Zhiheng; Gray, Gerry] US FDA, Div Biostat, Silver Spring, MD 20993 USA. [Kass-Hout, Taha] US FDA, Off Informat & Technol Innovat, Operat Off, Off Commissioner, Silver Spring, MD USA. [Anderson-Smits, Colin] US FDA, Div Epidemiol, Silver Spring, MD USA. RP Xu, ZH (reprint author), US FDA, Div Biostat, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiheng.xu@fda.hhs.gov OI Kass-Hout, Taha/0000-0002-0123-5157 NR 18 TC 0 Z9 0 U1 1 U2 6 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 JUN PY 2015 VL 24 IS 6 BP 663 EP 668 DI 10.1002/pds.3783 PG 6 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA CK0CV UT WOS:000355872900013 PM 25903221 ER PT J AU Sarich, TC Seltzer, JH Berkowitz, SD Costin, J Curnutte, JT Gibson, CM Hoffman, M Kaminskas, E Krucoff, MW Levy, JH Mintz, PD Reilly, PA Sager, PT Singer, DE Stockbridge, N Weitz, JI Kowey, PR AF Sarich, Troy C. Seltzer, Jonathan H. Berkowitz, Scott D. Costin, James Curnutte, John T. Gibson, C. Michael Hoffman, Maureane Kaminskas, Edvardas Krucoff, Mitchell W. Levy, Jerrold H. Mintz, Paul D. Reilly, Paul A. Sager, Philip T. Singer, Daniel E. Stockbridge, Norman Weitz, Jeffrey I. Kowey, Peter R. TI Novel oral anticoagulants and reversal agents: Considerations for clinical development SO AMERICAN HEART JOURNAL LA English DT Article ID VITAMIN-K ANTAGONISTS; ATRIAL-FIBRILLATION; WARFARIN; DABIGATRAN; EFFICACY; THERAPY; STROKE; TRIAL; RIVAROXABAN; MANAGEMENT AB This white paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co-sponsored by the Cardiac Safety Research Consortium and the US Food and Drug Administration (FDA) at the FDA's White Oak Headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists, although NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular clinical trials and cardiovascular safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies; regulatory agencies; end point adjudication specialist groups; contract research organizations; and active, academically based physicians. There was wide and solid consensus that NOACs overall offer improvements in convenience, efficacy, and safety compared with warfarin, even without reversal agents. Still, it was broadly accepted that it would be helpful to have reversal agents available for clinicians to use. Because it is not feasible to do definitive outcomes studies demonstrating a reversal agent's clinical benefits, it was felt that these agents could be approved for use in life-threatening bleeding situations if the molecules were well characterized preclinically, their pharmacodynamic and pharmacokinetic profiles were well understood, and showed no harmful adverse events in early human testing. There was also consensus that after such approval, efforts should be made to augment the available clinical information until such time as there is a body of evidence to demonstrate real-world clinical outcomes with the reversal agents. No recommendations were made for more generalized use of these agents in the setting of non-life-threatening situations. This article reflects the views of the authors and should not be construed to represent FDA's views or policies. C1 [Sarich, Troy C.] Janssen Sci Affairs LLC, Titusville, NJ USA. [Seltzer, Jonathan H.] ACI Clin & Lankenau Heart Inst, Wynnewood, PA USA. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut Inc, Whippany, NJ USA. [Costin, James] Perosphere Inc, Danbury, CT USA. [Curnutte, John T.] Portola Pharmaceut Inc, San Francisco, CA USA. [Gibson, C. Michael] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Hoffman, Maureane] Durham Vet Affairs Med Ctr, Pathol & Lab Med Serv, Durham, NC USA. [Kaminskas, Edvardas] US FDA, Div Hematol Prod, CDER, Silver Spring, MD USA. [Krucoff, Mitchell W.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Levy, Jerrold H.] Duke Univ, Sch Med, Durham, NC USA. [Mintz, Paul D.] US FDA, Div Hematol Clin Review, Off Blood Res & Review, CBER, Silver Spring, MD USA. [Reilly, Paul A.] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Sager, Philip T.] Stanford Univ, San Francisco, CA USA. [Sager, Philip T.] Sager Consulting Experts, San Francisco, CA USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, CDER, Silver Spring, MD USA. [Weitz, Jeffrey I.] McMaster Univ, Hamilton, ON, Canada. [Weitz, Jeffrey I.] Thrombosis & Atherosclerosis Res Inst, Hamilton, ON, Canada. [Kowey, Peter R.] Lankenau Heart Inst, Philadelphia, PA USA. [Kowey, Peter R.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. RP Sarich, TC (reprint author), Janssen Sci Affairs LLC, Real World Evidence, Titusville, NJ 08560 USA. EM tsarich@its.jnj.com OI Hoffman, Maureane/0000-0001-7123-0100 NR 15 TC 21 Z9 23 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JUN PY 2015 VL 169 IS 6 BP 751 EP 757 DI 10.1016/j.ahj.2015.03.010 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CJ1AK UT WOS:000355213300002 PM 26027611 ER PT J AU Flores, KF Robledo, CA Hwang, BS Leishear, K Grantz, KL Mendola, P AF Flores, Katrina F. Robledo, Candace A. Hwang, Beom Seuk Leishear, Kira Grantz, Katherine Laughon Mendola, Pauline TI Does maternal asthma contribute to racial/ethnic disparities in obstetrical and neonatal complications? SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Asthma; Pregnancy; Infant; Ethnic groups; Health disparities ID BLACK WOMENS HEALTH; PERINATAL OUTCOMES; PRETERM BIRTH; RACIAL-DISCRIMINATION; DEPRESSIVE SYMPTOMS; ETHNIC DISPARITIES; AFRICAN-AMERICAN; INFANT-MORTALITY; PREGNANT-WOMEN; UNITED-STATES AB Purpose: To examine whether maternal asthma contributes to racial/ethnic differences in obstetrical and neonatal complications. Methods: Data on white (n = 110,603), black (n = 50,284), and Hispanic (n = 38,831) singleton deliveries came from the Consortium on Safe Labor. Multilevel logistic regression models, with an interaction term for asthma and race/ethnicity, estimated Within-group adjusted odds ratios (aORs) for gestational diabetes, gestational hypertension, pre-eclampsia, placental abruption, premature rupture of membranes, preterm delivery, maternal hemorrhage, neonatal intensive care unit admissions, small for gestational age, apnea, respiratory distress syndrome, transient tachypnea of the newborn, anemia, and hyperbilirubinemia after adjustment for clinical and demographic confounders. Nonasthmatics of the same racial/ethnic group were the reference group. Results: Compared with nonasthmatics, white asthmatics had increased odds of pre-eclampsia (aOR, 1.28; 95% confidence interval [CI], 1.15-1.43) and maternal hemorrhage (aOR, 1.14; 95% Cl, 1.04-1.23). White and Hispanic infants were more likely to have neonatal intensive care unit admissions (aOR, 1.19; 95% Cl, 1.11-1.28; aOR, 1.16; 95% Cl, 1.02-1.32, respectively) and be small for gestational age (aOR, 1.11; 95% Cl, 1.02-1.20; aOR, 1.26; 95% Cl, 1.10-1.44, respectively), and Hispanic infants were more likely to have apnea (aOR, 1.32; 95% Cl, 1.02-1.69). Conclusions: Maternal asthma did not affect most obstetrical and neonatal complication risks within racial/ethnic groups. Despite their increased risk for both asthma and many complications, our findings for black women were null. Asthma did not contribute to racial/ethnic disparities in complications. Published by Elsevier Inc. C1 [Flores, Katrina F.; Robledo, Candace A.; Grantz, Katherine Laughon; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Hwang, Beom Seuk] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Leishear, Kira] US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Off Pharmacovigilance & Epidemiol,Ctr Drug Evalua, Silver Spring, MD USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B03F, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Grantz, Katherine/0000-0003-0276-8534; Mendola, Pauline/0000-0001-5330-2844 FU Intramural Research Program of the National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Intramural Research Program of the NIH, NICHD [HHSN267200603425C] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The data included in this article were obtained from the Consortium on Safe Labor, supported by the Intramural Research Program of the NIH, NICHD, through contract number HHSN267200603425C. NR 41 TC 0 Z9 0 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JUN PY 2015 VL 25 IS 6 BP 392 EP 397 DI 10.1016/j.annepidem.2015.01.011 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI8KM UT WOS:000355021200002 PM 25724829 ER PT J AU Chambers, CE Miller, DL AF Chambers, Charles E. Miller, Donald L. TI Radiation safety: Patients First "Where Is the Radiation Needle on the Ethical Compass?" SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material C1 [Chambers, Charles E.] Penn State Univ, Coll Med, Cardiol, Hershey, PA USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Chambers, CE (reprint author), Hershey Med Ctr, Cardiol, 500 Univ Dr,MCH047, Hershey, PA 17033 USA. EM cchambers@hmc.pus.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUN PY 2015 VL 85 IS 7 BP 1171 EP 1172 DI 10.1002/ccd.25976 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CI8DU UT WOS:000355000100016 PM 25999276 ER PT J AU Kesselheim, AS Campbell, EG Schneeweiss, S Rausch, P Lappin, BM Zhou, EH Seeger, JD Brownstein, JS Woloshin, S Schwartz, LM Toomey, T Dal Pan, GJ Avorn, J AF Kesselheim, Aaron S. Campbell, Eric G. Schneeweiss, Sebastian Rausch, Paula Lappin, Brian M. Zhou, Esther H. Seeger, John D. Brownstein, John S. Woloshin, Steven Schwartz, Lisa M. Toomey, Timothy Dal Pan, Gerald J. Avorn, Jerry TI Methodological Approaches to Evaluate the Impact of FDA Drug Safety Communications SO DRUG SAFETY LA English DT Article ID NEWS MEDIA COVERAGE; PRESCRIPTION MEDICATIONS; PRIOR AUTHORIZATION; TIME-SERIES; HEALTH; ZOLPIDEM; INFORMATION; MAMMOGRAPHY; WARNINGS; INTERNET AB When the US FDA approves a new prescription drug there is still a great deal remaining to be learned about the safe and proper use of that product. When new information addressing these topics emerges post-approval, the FDA may issue a Drug Safety Communication (DSC) to alert patients and physicians. The effectiveness of the communication-how drug safety messaging conveyed in FDA DSCs changes patient or prescriber behavior-may depend on multiple factors, including the way physicians and patients learn about the information, their understanding of the issues conveyed, and their perception of the importance of the information. In 2013, the FDA issued two DSCs addressing critical new warnings related to products containing the sedative/hypnotic zolpidem. In this article, we describe a core set of research initiatives that can be used to study how zolpidem-related DSCs affected subsequent physician and patient decision making. These research initiatives include analyzing drug utilization patterns and related health outcomes; comparing zolpidem-containing products against a comparator with similar indications [eszopiclone (Lunesta)] not covered by the 2013 DSCs; and surveying patients and qualitatively evaluating the dissemination of information regarding these drugs in traditional and social-media channels. Using an integrated, multidisciplinary approach, we can obtain information that can be used to optimize regulatory communications by seeking to understand the impact of the information contained in FDA risk communications. C1 [Kesselheim, Aaron S.; Schneeweiss, Sebastian; Seeger, John D.; Toomey, Timothy; Avorn, Jerry] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, PORTAL, Boston, MA 02120 USA. [Kesselheim, Aaron S.; Campbell, Eric G.; Schneeweiss, Sebastian; Seeger, John D.; Brownstein, John S.; Toomey, Timothy; Avorn, Jerry] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy Res, Boston, MA 02114 USA. [Rausch, Paula] US FDA, Off Commun, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Lappin, Brian M.] US FDA, Off Planning, Off Commissioner, Silver Spring, MD 20993 USA. [Zhou, Esther H.; Dal Pan, Gerald J.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Brownstein, John S.] Boston Childrens Hosp, Childrens Hosp, Epidemiol Grp, Boston, MA USA. [Woloshin, Steven; Schwartz, Lisa M.] Dartmouth Inst Hlth Policy & Clin Practice, Ctr Med & Media, Lebanon, NH USA. RP Kesselheim, AS (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, PORTAL, Suite 3030,1620 Tremont St, Boston, MA 02120 USA. EM akesselheim@partners.org RI Schneeweiss, Sebastian/C-2125-2013 FU Informulary, Inc. FX Sebastian Schneeweiss is a consultant to WHISCON LLC, a consulting company specializing in the conduct of drug safety database studies. He is also a consultant to, and owns some equities in, Aetion, Inc., a software company specializing in the analyses of healthcare databases. Paula Rausch, Brian M. Lappin, Esther H. Zhou, and Gerald J. Dal Pan are employed by the FDA, which commissioned this study. John D. Seeger is a consultant to both WHISCON LLC and Optum. John S. Brownstein owns shares in, and is employed as consultant to, Epidemico, Inc., a technology company that develops social-media mining tools for drug safety. Steven Woloshin and Lisa M. Schwartz were paid under a subcontract for work on this project and are co-founders of Informulary, Inc., a company that provides data regarding the benefit, harms, and uncertainties of prescription drugs. Aaron S. Kesselheim, Eric G. Campbell, Timothy Toomey, and Jerry Avorn have no conflicts of interest that are directly relevant to the content of this study. NR 56 TC 3 Z9 3 U1 2 U2 11 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 2015 VL 38 IS 6 BP 565 EP 575 DI 10.1007/s40264-015-0291-y PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA CJ0ZV UT WOS:000355211500006 PM 25968811 ER PT J AU Sun, HH Papadopoulos, EJ Hyams, JS Griebel, D Lee, JJ Tomaino, J Mulberg, AE AF Sun, Haihao Papadopoulos, Elektra J. Hyams, Jeffrey S. Griebel, Donna Lee, Jessica J. Tomaino, Juli Mulberg, Andrew E. TI Well-Defined and Reliable Clinical Outcome Assessments for Pediatric Crohn Disease: A Critical Need for Drug Development SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE clinical outcome assessment; clinical trials; disease activity index; pediatric Crohn disease; study endpoint ID INFLAMMATORY-BOWEL-DISEASE; ACTIVITY INDEX; ULCERATIVE-COLITIS; TASK-FORCE; MULTICENTER TRIAL; PRO INSTRUMENTS; END-POINTS; CHILDREN; EFFICACY; MODERATE AB Objectives: The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD). Methods: The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient-reported outcome (PRO) development. Results: The Pediatric Crohn's Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) Were reviewed. The Crohn's Disease Activity Index (CDAI) and Harvey-Bradshaw index (RBI), designed for adult patients, have been adapted for use in a few pediatric CD studies. The use of PCDAI as an endpoint in Remicade and Humira trials led to the Food and Drug Administration approved indication in pediatric CD. Common issues in measurement properties of COA tools included the absence of direct patient or caregivers' input to generate the items measuring signs and symptoms; absence of evidence demonstrating correlation with clinically relevant inflammation observed with endoscopic measures; lack of standardization in measurement, age-appropriate interviewer script, and response rating criteria for the physician interviewer. Conclusions: Available evidence indicates that CDAI, HBI, and 5 versions of the PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials intended to support approval of products intended to treat pediatric CD. In order to facilitate pediatric drug development, a well-defined, reliable, sensitive, and globally recognized PRO that measures signs and symptoms in children with CD and that can be used in conjunction with endoscopy-based endpoints and/or biomarkers is sorely needed. C1 [Sun, Haihao] US FDA, Off Pediat Therapeut, Off Commissioner, Silver Spring, MD 20993 USA. [Papadopoulos, Elektra J.] US FDA, Study Endpoint & Labeling Dev, Off New Drugs, Ctr Drug Res & Evaluat, Silver Spring, MD 20993 USA. [Hyams, Jeffrey S.] Connecticut Childrens Med Ctr, Hartford, CT USA. [Griebel, Donna; Lee, Jessica J.; Tomaino, Juli; Mulberg, Andrew E.] US FDA, Div Gastroenterol & Inborn Errors Prod, Off New Drugs, Ctr Drug Res & Evaluat, Silver Spring, MD 20993 USA. RP Mulberg, AE (reprint author), US FDA, Div Gastroenterol & Inborn Errors Prod, Off New Drugs, Ctr Drug Res & Evaluat, 10903 New Hampshire Ave,Bldg 22,Room 5120, Silver Spring, MD 20993 USA. EM Andrew.Mulberg@fda.hhs.gov NR 33 TC 2 Z9 2 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JUN PY 2015 VL 60 IS 6 BP 729 EP 736 DI 10.1097/MPG.0000000000000793 PG 8 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA CJ1KI UT WOS:000355242100007 PM 25793905 ER PT J AU Zenarruzabeitia, O Vitalle, J Eguizabal, C Simhadri, VR Borrego, F AF Zenarruzabeitia, Olatz Vitalle, Joana Eguizabal, Cristina Simhadri, Venkateswara R. Borrego, Francisco TI The Biology and Disease Relevance of CD300a, an Inhibitory Receptor for Phosphatidylserine and Phosphatidylethanolamine SO JOURNAL OF IMMUNOLOGY LA English DT Review ID HYPOXIA-INDUCIBLE GENE; ENVELOPED-VIRUS ENTRY; APOPTOTIC CELLS; NK CELLS; HUMAN MONOCYTES; IRP60 CD300A; IMMUNOGLOBULIN SUPERFAMILY; PSORIASIS SUSCEPTIBILITY; CMRF-35-LIKE MOLECULE-1; SIGNALING PATHWAYS AB The CD300a inhibitory receptor belongs to the CD300 family of cell surface molecules that regulate a diverse array of immune cell processes. The inhibitory signal of CD300a depends on the phosphorylation of tyrosine residues embedded in ITIMs of the cytoplasmic tail. CD300a is broadly expressed on myeloid and lymphoid cells, and its expression is differentially regulated depending on the cell type. The finding that CD300a recognizes phosphatidylserine and phosphatidylethanolamine, two aminophospholipids exposed on the outer leaflet of dead and activated cells, has shed new light on its role in the modulation of immune functions and in its participation in the host response to several diseases states, such as infectious diseases, cancer, allergy, and chronic inflammatory diseases. This review summarizes the literature on CD300a expression, regulation, signaling pathways, and ligand interaction, as well as its role in fine tuning immune cell functions and its clinical relevance. C1 [Zenarruzabeitia, Olatz; Vitalle, Joana; Borrego, Francisco] BioCruces Hlth Res Inst, Immunopathol Grp, Baracaldo 48903, Spain. [Eguizabal, Cristina] Basque Ctr Transfus & Human Tissues, Cell Therapy & Stem Cell Grp, Galdakao 48960, Spain. [Simhadri, Venkateswara R.] US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod Review & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Borrego, Francisco] Ikerbasque, Basque Fdn Sci, Bilbao 48903, Spain. RP Borrego, F (reprint author), BioCruces Hlth Res Inst, Immunopathol Grp, Plaza Cruces S-N, Baracaldo 48903, Spain. EM francisco.borregorabasco@osakidetza.eus FU Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Gobierno de Espana [PI13/00889]; Marie Curie Actions, Career Integration Grant, European Commission [CIG 631674]; SAIOTEK, Departamento de Desarrollo Economico y Competitividad, Gobierno Vasco [SAIO13-PE13BF005] FX This work was supported by the Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Gobierno de Espana (PI13/00889); the Marie Curie Actions, Career Integration Grant, European Commission (CIG 631674); and SAIOTEK, Departamento de Desarrollo Economico y Competitividad, Gobierno Vasco (SAIO13-PE13BF005). NR 83 TC 12 Z9 12 U1 3 U2 7 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 2015 VL 194 IS 11 BP 5053 EP 5060 DI 10.4049/jimmunol.1500304 PG 8 WC Immunology SC Immunology GA CI6WS UT WOS:000354905300006 PM 25980030 ER PT J AU Agarabi, CD Schiel, JE Lute, SC Chavez, BK Boyne, MT Brorson, KA Khan, MA Read, EK AF Agarabi, Cyrus D. Schiel, John E. Lute, Scott C. Chavez, Brittany K. Boyne, Michael T., II Brorson, Kurt A. Khan, Mansoor A. Read, Erik K. TI Bioreactor Process Parameter Screening Utilizing a Plackett-Burman Design for a Model Monoclonal Antibody SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE biotechnology; glycoprotein; mass spectrometry; glycosylation; monoclonal antibody; quality by design (QbD); cell culture; design of experiments (DoE); Plackett-Burman; glycan profiling ID DEPENDENT CELLULAR CYTOTOXICITY; EXPRESSING CHO-CELLS; HAMSTER OVARY CELLS; FATTY-ACIDS; SIALIC-ACID; CULTURE; HYBRIDOMA; QUALITY; PRODUCTIVITY; GLYCOSYLATION AB Consistent high-quality antibody yield is a key goal for cell culture bioprocessing. This endpoint is typically achieved in commercial settings through product and process engineering of bioreactor parameters during development. When the process is complex and not optimized, small changes in composition and control may yield a finished product of less desirable quality. Therefore, changes proposed to currently validated processes usually require justification and are reported to the US FDA for approval. Recently, design-of-experiments-based approaches have been explored to rapidly and efficiently achieve this goal of optimized yield with a better understanding of product and process variables that affect a product's critical quality attributes. Here, we present a laboratory-scale model culture where we apply a Plackett-Burman screening design to parallel cultures to study the main effects of 11 process variables. This exercise allowed us to determine the relative importance of these variables and identify the most important factors to be further optimized in order to control both desirable and undesirable glycan profiles. We found engineering changes relating to culture temperature and nonessential amino acid supplementation significantly impacted glycan profiles associated with fucosylation, -galactosylation, and sialylation. All of these are important for monoclonal antibody product quality. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1919-1928, 2015 C1 [Agarabi, Cyrus D.; Khan, Mansoor A.] US FDA, Div Prod Qual Res, Off Testing & Res, OPS,CDER, Silver Spring, MD 20993 USA. [Schiel, John E.] NIST, Biomol Measurement Div, Bioanalyt Sci Grp, Gaithersburg, MD 20899 USA. [Lute, Scott C.; Chavez, Brittany K.; Brorson, Kurt A.; Read, Erik K.] US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, OPS,CDER, Silver Spring, MD USA. [Boyne, Michael T., II] US FDA, Div Pharmaceut Anal, Off Testing & Res, OPS,CDER, St Louis, MO USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual Res, Off Testing & Res, OPS,CDER, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov FU CDER Critical Path Program; Medical Counter Measure Initiative FX The authors would like to thank Dr. Michael Tarlov and Dr. Karen Phinney from National Institute for Standards and Technology for their support and input. Partial internal funding was provided for this work by the CDER Critical Path Program (K.B. and M.T.B.) and The Medical Counter Measure Initiative (MAK). NR 48 TC 10 Z9 12 U1 3 U2 25 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 2015 VL 104 IS 6 BP 1919 EP 1928 DI 10.1002/jps.24420 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CI0WB UT WOS:000354458800006 PM 25762022 ER PT J AU Krause, PR Cavaleri, M Coleman, G Gruber, MF AF Krause, Philip R. Cavaleri, Marco Coleman, Gina Gruber, Marion F. TI Approaches to demonstration of Ebola virus vaccine efficacy SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material C1 [Krause, Philip R.; Gruber, Marion F.] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Cavaleri, Marco] European Med Agcy, Antiinfect & Vaccines, London, England. [Coleman, Gina] Hlth Canada, Clin Evaluat Div Vaccines, Ottawa, ON K1A 0L2, Canada. RP Krause, PR (reprint author), US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM philip.krause@fda.hhs.gov NR 3 TC 3 Z9 3 U1 0 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2015 VL 15 IS 6 BP 627 EP 629 DI 10.1016/S1473-3099(15)70033-2 PG 4 WC Infectious Diseases SC Infectious Diseases GA CI3HI UT WOS:000354638000010 PM 26008825 ER PT J AU Nachman, S Ahmed, A Amanullah, F Becerra, MC Botgros, R Brigden, G Browning, R Gardiner, E Hafner, R Hesseling, A How, C Jean-Philippe, P Lessem, E Makhene, M Mbelle, N Marais, B McIlleron, H McNeeley, DF Mendel, C Murray, S Navarro, E Anyalechi, EG Porcalla, AR Powell, C Powell, M Rigaud, M Rouzier, V Samson, P Schaaf, HS Shah, S Starke, J Swaminathan, S Wobudeya, E Worrell, C AF Nachman, Sharon Ahmed, Amina Amanullah, Farhana Becerra, Mercedes C. Botgros, Radu Brigden, Grania Browning, Renee Gardiner, Elizabeth Hafner, Richard Hesseling, Anneke How, Cleotilde Jean-Philippe, Patrick Lessem, Erica Makhene, Mamodikoe Mbelle, Nontombi Marais, Ben McIlleron, Helen McNeeley, David F. Mendel, Carl Murray, Stephen Navarro, Eileen Anyalechi, E. Gloria Porcalla, Ariel R. Powell, Clydette Powell, Mair Rigaud, Mona Rouzier, Vanessa Samson, Pearl Schaaf, H. Simon Shah, Seema Starke, Jeff Swaminathan, Soumya Wobudeya, Eric Worrell, Carol TI Towards early inclusion of children in tuberculosis drugs trials: a consensus statement SO LANCET INFECTIOUS DISEASES LA English DT Review ID MULTIDRUG-RESISTANT TUBERCULOSIS; SOUTH-AFRICAN CHILDREN; CHILDHOOD TUBERCULOSIS; ANTITUBERCULOSIS AGENTS; MANAGEMENT CHALLENGES; WESTERN CAPE; RISK-FACTORS; HIV; RECOMMENDATIONS; MORTALITY AB Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained. C1 [Nachman, Sharon] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Ahmed, Amina] Carolinas Med Ctr, Levine Childrens Hosp, Charlotte, NC 28203 USA. [Amanullah, Farhana] Indus Hosp, Karachi, Pakistan. [Becerra, Mercedes C.] Harvard Univ, Sch Med, Boston, MA USA. [Botgros, Radu; Powell, Mair] European Med Agcy, London, England. [Brigden, Grania] Access Campaign, Medecins Sans Frontieres, Geneva, Switzerland. [Browning, Renee; Hafner, Richard; Makhene, Mamodikoe] NIAID, NIH, Div Aids, Bethesda, MD 20892 USA. [Gardiner, Elizabeth; Mendel, Carl; Murray, Stephen] TB Alliance, New York, NY USA. [Hesseling, Anneke; Schaaf, H. Simon] Univ Stellenbosch, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Cape Town, South Africa. [How, Cleotilde] Univ Philippines, Dept Pharmacol & Toxicol, Manila, Philippines. [Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn, Div Aids, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lessem, Erica] Treatment Act Grp, New York, NY USA. [Mbelle, Nontombi] Univ Pretoria, Dept Med Microbiol, ZA-0002 Pretoria, South Africa. [Marais, Ben] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Marais, Ben] Univ Sydney, Sydney Emerging Infect Dis & Biosecur Inst, Sydney, NSW 2006, Australia. [Marais, Ben] Univ Sydney, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [McIlleron, Helen] Univ Cape Town, Dept Med, Div Clin Pharmacol, ZA-7700 Rondebosch, South Africa. [McNeeley, David F.] Novartis Pharmaceut, E Hanover, NJ USA. [Navarro, Eileen; Porcalla, Ariel R.] US FDA, Div Antiinfect Prod, Off Antimicrobial Prod, Off New Drugs, Silver Spring, MD USA. [Anyalechi, E. Gloria] US Ctr Dis Control & Prevent, Div TB Eliminat, Int Res & Programs Branch, Atlanta, GA USA. [Powell, Clydette] Agcy Int Dev, Washington, DC USA. [Rigaud, Mona] NYU, Sch Med, New York, NY 10003 USA. [Rouzier, Vanessa] GHESKIO, Port Au Prince, Haiti. [Samson, Pearl] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res & Frontier Sci, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Shah, Seema] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Starke, Jeff] Baylor Coll Med, Houston, TX 77030 USA. [Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Wobudeya, Eric] Makerere Univ Johns Hopkins Res Collaborat, Kampala, Uganda. [Wobudeya, Eric] Mulago Natl Referral Hosp, Kampala, Uganda. [Worrell, Carol] Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, NIH, Rockville, MD USA. RP Nachman, S (reprint author), Hlth Sci SUNY Stony Brook, Stony Brook Childrens Hosp, Dept Pediat, Stony Brook, NY 11794 USA. EM sharon.nachman@stonybrook.edu OI wobudeya, eric/0000-0001-9574-5539; McIlleron, Helen/0000-0002-0982-6226 FU National Institute of Allergy and Infectious Diseases; National Institute of Health; Department of Health and Human Services; HHS FX We thank the following individuals for assistance in the planning and conduct of the workshop or drafting of the manuscript, or both: Sheryl Zwerski, Sarah Read, Larry Fox, Devasena Gnanashanmugam, Judi Miller, Ellen O'Gara, Paul Sato, Peter Kim, Tyseaia Squirewell McFarlane, Rahel Abebe, and Andrea Williams. This work was funded by National Institute of Allergy and Infectious Diseases and National Institute of Health. This project has also been funded in part with federal funds from the Department of Health and Human Services. The views expressed in written conference materials or publications and by speakers and moderators at HHS-sponsored conferences, do not necessarily show the official policies of the Department of Health and Human Services (DHHS) or individual DHHS or other US government agencies including the National Institute of Health, the Center for Disease Control and Prevention, the Food and Drug Administration or the US Agency for International Development; nor does mention of trade names, commercial practices, or organisations imply endorsement by the US Government. The views expressed in this consensus statement are the personal views of the authors and cannot be understood or quoted as made on behalf of the position of the European Medicines Agency, or one of its committees or working parties. NR 75 TC 21 Z9 21 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JUN PY 2015 VL 15 IS 6 BP 711 EP 720 DI 10.1016/S1473-3099(15)00007-9 PG 10 WC Infectious Diseases SC Infectious Diseases GA CI3HI UT WOS:000354638000036 PM 25957923 ER PT J AU Lee, SJ Wolff, D Kitko, C Koreth, J Inamoto, Y Jagasia, M Pidala, J Olivieri, A Martin, PJ Przepiorka, D Pusic, I Dignan, F Mitchell, SA Lawitschka, A Jacobsohn, D Hall, AM Flowers, MED Schultz, KR Vogelsang, G Pavletic, S AF Lee, Stephanie J. Wolff, Daniel Kitko, Carrie Koreth, John Inamoto, Yoshihiro Jagasia, Madan Pidala, Joseph Olivieri, Attilio Martin, Paul J. Przepiorka, Donna Pusic, Iskra Dignan, Fiona Mitchell, Sandra A. Lawitschka, Anita Jacobsohn, David Hall, Anne M. Flowers, Mary E. D. Schultz, Kirk R. Vogelsang, Georgia Pavletic, Steven TI Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response Criteria Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Response criteria; Consensus; Guidelines ID STEM-CELL TRANSPLANTATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; BONE-MARROW-TRANSPLANTATION; CHRONIC GVHD CONSORTIUM; 6-MINUTE WALK TEST; OBLITERANS ORGANIZING PNEUMONIA; HUMAN ACTIVITY PROFILE; FAILURE-FREE SURVIVAL; SLEEP QUALITY INDEX; RHEUMATOID-ARTHRITIS AB In 2005, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. Published by Elsevier Inc. C1 [Lee, Stephanie J.; Martin, Paul J.; Hall, Anne M.; Flowers, Mary E. D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Wolff, Daniel] Univ Regensburg, Dept Internal Med 3, D-93053 Regensburg, Germany. [Kitko, Carrie] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Koreth, John] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Jagasia, Madan] Vanderbilt Univ, Div Hematol Oncol, Nashville, TN 37235 USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Olivieri, Attilio] Univ Ancona, Dept Clin & Mol Sci, Ancona, Italy. [Przepiorka, Donna] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pusic, Iskra] Washington Univ, Dept Med, St Louis, MO USA. [Dignan, Fiona] Univ Manchester, Dept Clin Haematol, Manchester, Lancs, England. [Mitchell, Sandra A.; Pavletic, Steven] NCI, Outcomes Res Branch, Bethesda, MD 20852 USA. [Lawitschka, Anita] Med Univ Vienna, St Anna Childrens Hosp, Stem Cell Transplant Unit, Vienna, Austria. [Jacobsohn, David] Childrens Natl Hlth Syst, Div Blood & Marrow Transplantat, Washington, DC USA. [Schultz, Kirk R.] Univ British Columbia, BC Childrens Hosp, Vancouver, BC V5Z 1M9, Canada. [Vogelsang, Georgia] Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21205 USA. RP Pavletic, S (reprint author), NCI, GVHD & Autoimmun Unit, Expt Transplantat & Immunol Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Bldg 10,Room CRC 4-3130, Bethesda, MD 20852 USA. EM pavletis@mail.nih.gov FU Millenium; Otsuka Pharmaceuticals; Prometheus Labs Inc.; Therakos; Johnson and Johnson company FX S.L. scientific advisory board meeting: Bristol Myers Squibb, Kadmon Corp. J.K., research funding: Millenium, Otsuka Pharmaceuticals, Prometheus Labs Inc.; scientific advisory board: Kadmon Corp, Amgen, Takeda Pharmaceuticals. P.M., scientific advisory board meeting: Pharmacyclics. F.D., received research funding, honoraria and speaker fees: Therakos, a Johnson and Johnson company. NR 119 TC 22 Z9 23 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUN PY 2015 VL 21 IS 6 BP 984 EP 999 DI 10.1016/j.bbmt.2015.02.025 PG 16 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CI3SO UT WOS:000354667900004 PM 25796139 ER PT J AU Patro, JN Ramachandran, P Lewis, JL Mammel, MK Barnaba, T Pfeiler, EA Elkins, CA AF Patro, J. N. Ramachandran, P. Lewis, J. L. Mammel, M. K. Barnaba, T. Pfeiler, E. A. Elkins, C. A. TI Development and utility of the FDA "GutProbe' DNA microarray for identification, genotyping and metagenomic analysis of commercially available probiotics SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE genotyping; lactic acid bacteria; Lactobacillus; microarray; probiotics ID DIVERSITY; ACCURACY; PRODUCTS; FOOD AB AimLactic acid bacteria are beneficial microbes added to many food products and dietary supplements for their purported health benefits. Proper identification of bacteria is important to assess safety as well as proper product labelling. A custom microarray (FDA GutProbe) was developed to verify accurate labelling in commercial dietary supplements. Methods and ResultsStrain-specific attribution was achieved with GutProbe array which contains genes from the most commonly found species in probiotic supplements and food ingredients. Applied utility of the array was assessed with direct from product DNA hybridization to determine (i) if identification of multiple strains in one sample can be conducted and (ii) if any lot-to-lot variations exist with eight probiotics found on the US market. ConclusionsGutProbe is a useful tool in identifying a mixture of microbials in probiotics and did reveal some product variations. In addition, the array is able to identify lot-to-lot differences in these products. These strain level attribution may be useful for routine monitoring of batch variation as part of a Good Manufacturing Practices' process. Significance and Impact of the StudyThe FDA GutProbe is an efficient and reliable platform to identify the presence of microbial ingredients and determining microbe differences in dietary supplements. The GutProbe is a fast, rapid method for direct community profiling or food matrix sampling. C1 [Patro, J. N.; Ramachandran, P.; Lewis, J. L.; Mammel, M. K.; Barnaba, T.; Pfeiler, E. A.; Elkins, C. A.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Elkins, CA (reprint author), Ctr Food Safety & Appl Nutr, Div Mol Biolofy, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM chris.elkins@fda.hhs.gov FU Center for Food Safety and Applied Nutrition FX The authors thank David W. Lacher and Isha R. Patel for their discussions and guidance in completing the microarray analysis. This study was funded by the Center for Food Safety and Applied Nutrition. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 24 TC 11 Z9 11 U1 1 U2 11 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 JUN PY 2015 VL 118 IS 6 BP 1478 EP 1488 DI 10.1111/jam.12795 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CI2IT UT WOS:000354570600022 PM 25766767 ER PT J AU Kim, JM Ahn, Y LiPuma, JJ Hussong, D Cerniglia, CE AF Kim, Jeong Myeong Ahn, Youngbeom LiPuma, John J. Hussong, David Cerniglia, Carl E. TI Survival and susceptibility of Burkholderia cepacia complex in chlorhexidine gluconate and benzalkonium chloride SO JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY LA English DT Article DE Burkholderia cepacia complex; Chlorhexidine gluconate; Benzalkonium chloride; Survival; Susceptibility ID PSEUDOMONAS-CEPACIA; CYSTIC-FIBROSIS; DISTILLED WATER; SELECTIVE MEDIA; CONTAMINATION; RESISTANCE; BACTERIA; DISINFECTANTS; PSEUDOMALLEI; CENOCEPACIA AB The Burkholderia cepacia complex (BCC) includes opportunistic pathogenic bacteria that have occasionally been recovered from various pharmaceutical products, including antiseptics and disinfectants. Plausible reasons for the contamination include intrinsic sources, such as inadequate process controls, especially for water or equipment used during product manufacture, or extrinsic sources, such as improper handling and dilution or distribution in contaminated containers. Because the survival of BCC in antiseptics is a concern to the public health and pharmaceutical industry, we determined minimum inhibitory concentrations (MICs) of 36 BCC strains against the antiseptics, following exposure to chlorhexidine gluconate (CHX) and benzalkonium chloride (BZK) solutions (1-500 A mu g/ml for each chemical). Susceptibility to CHX and BZK varied across the BCC strains and was recorded as mean 90.3 and 111.1 A mu g/ml, respectively, at initial inoculation, which was significantly higher than the 46.4 and 61.1 A mu g/ml levels measured for BCC incubated in water for 40 days. After determining antiseptic MICs of individual BCC strains, BCC recovery was measured on Tryptic Soy Agar (TSA), Reasoner's Second Agar (R2A) and diluted preparations of these media under their sub-MICs. The survival of BCC was monitored for 14 days (336 h) in sub-MICs diluted to less than their antiseptic susceptible concentration value. Diluted TSA and R2A media exhibited greater efficiency of recovery for most BCC strains from the CHX and BZK solutions than full strength TSA or R2A. For BCC survival in antiseptic solutions, the cell number of BCC decreased rapidly within the first 20 min in both antiseptics, but after this, recovery remained constant in CHX and increased in BZK over the 14 day incubation period. The results indicate that BCC in water can remain viable with low susceptibility to antiseptics for 14 days, which suggests the necessity for improved detection methods and control measures to monitor BCC contamination in pharmaceutical products. C1 [Kim, Jeong Myeong; Ahn, Youngbeom; Cerniglia, Carl E.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [LiPuma, John J.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Hussong, David] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Sci, Silver Spring, MD USA. RP Ahn, Y (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM young.ahn@fda.hhs.gov FU US Department of Energy; US Food and Drug Administration FX We thank Dr. John Sutherland and Dr. Kuppan Gokulan for reviewing the manuscript. This work was supported in part by an interagency agreement between the US Department of Energy and the US Food and Drug Administration to the Postgraduate Research Fellowship Program (J. M. Kim) at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science and Education. The views presented in this article do not necessarily reflect those of the Food and Drug Administration. NR 50 TC 3 Z9 3 U1 0 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1367-5435 EI 1476-5535 J9 J IND MICROBIOL BIOT JI J. Ind. Microbiol. Biotechnol. PD JUN PY 2015 VL 42 IS 6 BP 905 EP 913 DI 10.1007/s10295-015-1605-x PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CI0CA UT WOS:000354402100008 PM 25794566 ER PT J AU Dykstra, K Mehrotra, N Tornoe, CW Kastrissios, H Patel, B Al-Huniti, N Jadhav, P Wang, YN Byon, W AF Dykstra, Kevin Mehrotra, Nitin Tornoe, Christoffer Wenzel Kastrissios, Helen Patel, Bela Al-Huniti, Nidal Jadhav, Pravin Wang, Yaning Byon, Wonkyung TI Reporting guidelines for population pharmacokinetic analyses SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Pharmacometrics; Population pharmacokinetics; PK reporting; Regulatory submission; Best practices ID PERSPECTIVE; MODEL AB The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including PKPD and simulation reports. C1 [Dykstra, Kevin] qPharmetra LLC, Andover, MA 01810 USA. [Mehrotra, Nitin; Wang, Yaning] US FDA, Div Pharmacometr, Silver Spring, MD USA. [Tornoe, Christoffer Wenzel] Novo Nordisk, Clin Reporting, Copenhagen, Denmark. [Kastrissios, Helen] Certara, Pharsight Consulting Serv, St Louis, MO USA. [Patel, Bela] GlaxoSmithKline, Quantitat Sci, Clin Pharmacol, King Of Prussia, PA USA. [Al-Huniti, Nidal] AstraZeneca, Quantitat Clin Pharmacol, Waltham, MA USA. [Jadhav, Pravin] Merck & Co Inc, Quantitat Pharmacol & Pharmacometr, Whitehouse Stn, NJ USA. [Byon, Wonkyung] Pfizer Inc, Global Innovat Pharma Business Clin Pharmacol, Groton, CT 06340 USA. RP Dykstra, K (reprint author), qPharmetra LLC, Andover, MA 01810 USA. EM kevin.dykstra@qpharmetra.com NR 11 TC 1 Z9 1 U1 1 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD JUN PY 2015 VL 42 IS 3 BP 301 EP 314 DI 10.1007/s10928-015-9417-1 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CI1GW UT WOS:000354492800009 PM 25925797 ER PT J AU Basch, E Geoghegan, C Coons, SJ Gnanasakthy, A Slagle, AF Papadopoulos, EJ Kluetz, PG AF Basch, Ethan Geoghegan, Cindy Coons, Stephen Joel Gnanasakthy, Ari Slagle, Ashley F. Papadopoulos, Elektra J. Kluetz, Paul G. TI Patient-Reported Outcomes in Cancer Drug Development and US Regulatory Review Perspectives From Industry, the Food and Drug Administration, and the Patient SO JAMA ONCOLOGY LA English DT Article ID CLINICAL-TRIALS; LABELING CLAIMS; UNITED-STATES; ONCOLOGY; GUIDANCE AB Data reported directly by patients about how they feel and function are rarely included in oncology drug labeling in the United States, in contrast to Europe and to nononcology labeling in the United States, where this practice is more common. Multiple barriers exist, including challenges unique to oncology trials, and industry's concerns regarding cost, logistical complexities, and the Food and Drug Administration's (FDA's) rigorous application of its 2009 guidance on the use of patient-reported outcome (PRO) measures. A panel consisting of representatives of industry, FDA, the PRO Consortium, clinicians, and patients was assembled at a 2014 workshop cosponsored by FDA to identify practical recommendations for overcoming these barriers. Key recommendations included increasing proactive encouragement by FDA to clinical trial sponsors for including PROs in drug development programs; provision of comprehensive PRO plans by sponsors to FDA early in drug development; promotion of an oncology-specific PRO research agenda; development of an approach to existing ("legacy") PRO measures, when appropriate (focused initially on symptoms and functional status); and increased FDA and industry training in PRO methodology. FDA has begun implementing several of these recommendations. C1 [Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Geoghegan, Cindy] Patient & Partners LLC, Madison, CT USA. [Coons, Stephen Joel] Crit Path Inst, Patient Reported Outcome Consortium, Tucson, AZ USA. [Gnanasakthy, Ari] Novartis Pharmaceut, E Hanover, NJ USA. [Slagle, Ashley F.; Papadopoulos, Elektra J.] US FDA, Study Endpoints Team, Study Endpoints & Labeling Dev, Off New Drugs,Immediate Off,Ctr Drug Evaluat & Re, Silver Spring, MD USA. [Kluetz, Paul G.] US FDA, Off Hematol & Oncol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Basch, E (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Canc Outcomes Res Program, 170 Manning Dr, Chapel Hill, NC 27599 USA. EM ebasch@med.unc.edu FU National Cancer Institute; US Food and Drug Administration (FDA) [1U18FD005320] FX Dr Basch is an employee of the University of North Carolina with grant funding from the National Cancer Institute and membership on the Methodology Committee of the Patient-Centered Outcomes Research Institute. Dr Coons is an employee of the Critical Path Institute, which is supported, in part, by grant 1U18FD005320 from the US Food and Drug Administration (FDA). During preparation of this manuscript, Mr Gnanasakthy was an employee of Novartis, and he is currently an employee of RTI Health Solutions. Drs Slagle, Papadopoulos, and Kluetz are employees of FDA. No other disclosures are reported. NR 13 TC 16 Z9 16 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA EI 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUN PY 2015 VL 1 IS 3 BP 375 EP 379 DI 10.1001/jamaoncol.2015.0530 PG 5 WC Oncology SC Oncology GA DW5FQ UT WOS:000383669100024 PM 26181187 ER PT J AU Varma, V Boros, LG Nolen, GT Chang, CW Wabitsch, M Beger, RD Kaput, J AF Varma, Vijayalakshmi Boros, Laszlo G. Nolen, Greg T. Chang, Ching-Wei Wabitsch, Martin Beger, Richard D. Kaput, Jim TI Metabolic fate of fructose in human adipocytes: a targeted C-13 tracer fate association study SO METABOLOMICS LA English DT Article DE Human adipocytes; Fructose metabolism; C-13 labeled fructose; Isobolomics; Targeted tracer fate association study; Fatty acids ID MASS ISOTOPOMER ANALYSIS; HUMAN ADIPOSE-TISSUE; GLUCOSE-METABOLISM; SERUM FRUCTOSE; DIFFERENT SIZE; NORMAL RATS; CORN SYRUP; OBESITY; CONSUMPTION; ACID AB The development of obesity is becoming an international problem and the role of fructose is unclear. Studies using liver tissue and hepatocytes have contributed to the understanding of fructose metabolism. Excess fructose consumption also affects extra hepatic tissues including adipose tissue. The effects of fructose on human adipocytes are not yet fully characterized, although in vivo studies have noted increased adiposity and weight gain in response to fructose sweetened-beverages. In order to understand and predict the metabolic responses of adipocytes to fructose, this study examined differentiating and differentiated human adipocytes in culture, exposed to a range of fructose concentrations equivalent to that reported in blood after consuming fructose. A stable isotope based dynamic profiling method using [U-C-13(6)]-d-fructose tracer was used to examine the metabolism and fate of fructose. A targeted stable isotope tracer fate association method was used to analyze metabolic fluxes and flux surrogates with exposure to escalating fructose concentration. This study demonstrated that fructose stimulates anabolic processes in adipocytes robustly, including glutamate and de novo fatty acid synthesis. Furthermore, fructose also augments the release of free palmitate from fully differentiated adipocytes. These results imply that in the presence of fructose, the metabolic response of adipocytes in culture is altered in a dose dependent manner, particularly favoring increased glutamate and fatty acid synthesis and release, warranting further in vivo studies. C1 [Varma, Vijayalakshmi; Nolen, Greg T.; Beger, Richard D.; Kaput, Jim] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Boros, Laszlo G.] SiDMAP LLC, Los Angeles, CA 90064 USA. [Boros, Laszlo G.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst LABIOMED, Torrance, CA 90502 USA. [Boros, Laszlo G.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Chang, Ching-Wei] Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Wabitsch, Martin] Univ Ulm, Div Pediat Endocrinol & Diabetol, D-89069 Ulm, Germany. [Kaput, Jim] Nestle Inst Hlth Sci, Syst Nutr & Hlth, Lausanne, Switzerland. RP Varma, V (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM vijayalakshmi.varma@fda.hhs.gov FU National Center for Toxicological Research [E0740401]; Food and Drug Administration; Hirshberg Foundation for Pancreatic Cancer Research; NCI [P01-AT003960-01A1]; UCLA Clinical & Translational Science Institute [UL1TR000124] FX This study was supported by the National Center for Toxicological Research (Protocol E0740401) (VV), Food and Drug Administration. SGBS isobolome interpretations and central processing unit (CPU) time for GC-MS data with functional markers of 13C-tracer to products were supported by the Hirshberg Foundation for Pancreatic Cancer Research, the NCI [Grant P01-AT003960-01A1] and the UCLA Clinical & Translational Science Institute [Grant UL1TR000124] to LGB. The authors wish to acknowledge assistance by Ferenc Nadudvari, Maria Csikos, Csaba Geri and Ana Geri for informatics cohort processing work. The authors would also like to thank Dr. Laura Schnackenberg and Dr. Deborah Hansen for reviewing the manuscript and providing their critical comments and suggestions. The title and abstract of this article are included in (1) the SCHOLARLY DEVELOPMENT REPORT-JULY, 2014 of the Department of Pediatrics, Harbor-UCLA Medical Center, available at the ELEARNING website http://www.LEARN.HARBORPEDS.ORG and (2) in the US West Coast Club of Hungarian Scientist open archive for educational credits in Functional Biochemistry, Systems Biology, Molecular Medicine and Metabolic Control Analysis (MCA), which partially cover Scientific Information (Thomson ISI) fields in Biology & Biochemistry, Clinical Medicine, as well as Pharmacology & Toxicology. NR 70 TC 1 Z9 1 U1 0 U2 11 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 JUN PY 2015 VL 11 IS 3 BP 529 EP 544 DI 10.1007/s11306-014-0716-0 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CH6HL UT WOS:000354137100003 PM 25972768 ER PT J AU Tong, WD Ostroff, S Blais, B Silva, P Dubuc, M Healy, M Slikker, W AF Tong, Weida Ostroff, Stephen Blais, Burton Silva, Primal Dubuc, Martine Healy, Marion Slikker, William TI Genomics in the land of regulatory science SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Genomics; Regulatory science; Next generation sequencing ID GLOBAL-SUMMIT; CHALLENGES AB Genomics science has played a major role in the generation of new knowledge in the basic research arena, and currently question arises as to its potential to support regulatory processes. However, the integration of genomics in the regulatory decision-making process requires rigorous assessment and would benefit from consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) hosted the fourth Global Summit on Regulatory Science (GSRS2014) to discuss the role of genomics in regulatory decision making, with a specific emphasis on applications in food safety and medical product development. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the analysis, interpretation and reporting of genomics data with an emphasis on transparency, traceability and "fitness for purpose" for the intended application. It was recognized that there is a need for a global path in the establishment of a regulatory bioinformatics framework for the development of transparent, reliable, reproducible and auditable processes in the management of food and medical product safety risks. It was also recognized that training is an important mechanism in achieving internationally consistent outcomes. GSRS2014 provided an effective venue for regulators and researchers to meet, discuss common issues, and develop collaborations to address the challenges posed by the application of genomics to regulatory science, with the ultimate goal of wisely integrating novel technical innovations into regulatory decision-making. Published by Elsevier Inc. C1 [Tong, Weida; Slikker, William] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ostroff, Stephen] US FDA, Off Chief Scientist, Silver Spring, MD USA. [Blais, Burton; Silva, Primal; Dubuc, Martine] Canadian Food Inspect Agcy, Ottawa, ON, Canada. [Healy, Marion] Foods Stand Australia New Zealand, Canberra, ACT, Australia. RP Tong, WD (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Weida.tong@fda.hhs.gov; William.slikker@fda.hhs.gov FU Canadian Food Inspection Agency (CFIA), Food and Drug Administration (FDA), Genome Quebec, Genome Canada, McGill University; Genome Quebec Innovation Centre, University of Arkansas for Medical Sciences (UAMS) Regulatory Science Certificate Program FX GSRS2014 was sponsored by Canadian Food Inspection Agency (CFIA), Food and Drug Administration (FDA), Genome Quebec, Genome Canada, McGill University and Genome Quebec Innovation Centre, University of Arkansas for Medical Sciences (UAMS) Regulatory Science Certificate Program. We would also like to thanks all the speakers and organizing committees to contribute to the conference, which can be found from http://www.fda.gov/AboutFDA/CentersOffices/OC/OfficeofScientificandMedic alPrograms/NCTR/WhatWeDo/ucm334155.htm). NR 12 TC 4 Z9 4 U1 1 U2 6 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 2015 VL 72 IS 1 BP 102 EP 106 DI 10.1016/j.yrtph.2015.03.008 PG 5 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CG9WI UT WOS:000353670400013 PM 25796433 ER PT J AU Zhang, Y Newton, B Lewis, E Fu, PP Kafoury, R Ray, PC Yu, HT AF Zhang, Ying Newton, Brandon Lewis, Eybriunna Fu, Peter P. Kafoury, Ramzi Ray, Paresh C. Yu, Hongtao TI Cytotoxicity of organic surface coating agents used for nanoparticles synthesis and stability SO TOXICOLOGY IN VITRO LA English DT Article DE Surface coating agents; Nanoparticle; Cytotoxicity; Aliphatic amines; SDS ID HUMAN SKIN KERATINOCYTES; LIPID OZONATION PRODUCTS; TRANSITION-METAL OXIDES; AIRWAY EPITHELIAL-CELLS; NICKEL NANOPARTICLES; MAGNETIC-PROPERTIES; SILVER NANOPARTICLES; GOLD NANOPARTICLES; OPTICAL-PROPERTIES; SELF-ORGANIZATION AB Impact on health by nanomaterials has become a public concern with the great advances of nanomaterials for various applications. Surface coating agents are an integral part of nanoparticles, but not enough attention has been paid during toxicity tests of nanopartides. As a result, there are inconsistent toxicity results for certain nanomaterials. In this study, we explored the cytotoxicity of eleven commonly used surface coating agents in two cell lines, human epidermal keratinocyte (HaCaT) and lung fibroblast (CRL-1490) cells, at surface coating agent concentrations of 3, 10, 30, and 100 mu M. Two exposure time points, 2 h and 24 h, were employed for the study. Six of the eleven surface coating agents are cytotoxic, especially those surfactants with long aliphatic chains, both cationic (cetyltrimethylammonium bromide, oleylamine, tetraoctylammonium bromide, and hexadecylamine) and anionic (sodium dodecylsulfate). In addition, exposure time and the use of different cell lines also affect the cytotoxicity results. Therefore, factors such as cell lines used and exposure times must be considered when conducting toxicity tests or comparing cytotoxicity results. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Zhang, Ying; Newton, Brandon; Lewis, Eybriunna; Ray, Paresh C.; Yu, Hongtao] Jackson State Univ, Dept Chem, Jackson, MS 39127 USA. [Zhang, Ying; Newton, Brandon; Lewis, Eybriunna; Ray, Paresh C.; Yu, Hongtao] Jackson State Univ, Dept Biochem, Jackson, MS 39127 USA. [Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Kafoury, Ramzi] Jackson State Univ, Dept Biol, Jackson, MS 39127 USA. RP Yu, HT (reprint author), Jackson State Univ, Dept Chem, Jackson, MS 39127 USA. EM yu@jsums.edu FU NSF for the Partnership for Research and Education in Materials [DMR-0611539]; NSF [CHE-0840450]; NIH [NCRR 2G12RR013459-11] FX This research was supported in part by NSF for the Partnership for Research and Education in Materials (DMR-0611539). Core research facilities were supported by Grants from the NSF (CHE-0840450) and NIH (NCRR 2G12RR013459-11). This article is not an official U.S. Food and Drug Administration guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 62 TC 6 Z9 6 U1 3 U2 32 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 JUN PY 2015 VL 29 IS 4 BP 762 EP 768 DI 10.1016/j.tiv.2015.01.017 PG 7 WC Toxicology SC Toxicology GA CH1AV UT WOS:000353754400014 PM 25746383 ER PT J AU Sussman, EM Casey, BJ Dutta, D Dair, BJ AF Sussman, Eric M. Casey, Brendan J. Dutta, Debargh Dair, Benita J. TI Different cytotoxicity responses to antimicrobial nanosilver coatings when comparing extract-based and direct-contact assays SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE nanosilver; cytotoxicity; direct-contact; extract; biocompatibility; antibacterial; medical device coating ID COLON CACO2 CELLS; HUMAN LIVER HEPG2; SILVER NANOPARTICLES; IN-VITRO; NANOCRYSTALLINE SILVER; IONS; GENOTOXICITY; POLYURETHANE; DEPOSITION; TOXICITY AB This study was performed to understand how the choice of cytotoxicity assay format affects the observed biocompatibility of nanosilver (nAg). nAg coatings are physical coatings containing silver (Ag) that have feature sizes of 100nm or less, often in the form of nanoparticles or grains. They are used on medical devices to prevent infection, but in spite of this intended benefit, observations of potential cytotoxicity from nAg have been reported in numerous published studies. For medical device regulation, cytotoxicity testing is part of a biocompatibility evaluation, in which specific test methods are chosen based on the technological characteristics and intended use of a device. For this study, nAg-coated tissue culture polystyrene surfaces were prepared using magnetron sputter coating, resulting in nAg films of 0.2 to 311 mu gcm(-2) Ag. These coatings exhibited nanometer-scale morphologies and demonstrated a>4log(10) reduction in Escherichia coli viability. It was observed that extracts of nAg caused no cytotoxicity to L929 mouse fibroblasts, but cells cultured directly on nAg coatings (direct-contact assay format) showed a dose-dependent reduction in viability by up to 100% (P<0.001). Results using inductively coupled plasma mass spectrometry to measure Ag release suggested that extracts of nAg are not toxic because the dissolved Ag in those samples becomes less cytotoxic over time, probably owing to the reaction with cell culture media and serum (six-fold cytotoxicity reductions observed over a 24-h period). These findings highlight the potential value of direct-contact cytotoxicity testing for nAg in predicting biological interactions with cells or tissue in vivo. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Sussman, Eric M.; Casey, Brendan J.; Dutta, Debargh; Dair, Benita J.] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Sussman, EM (reprint author), US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM eric.sussman@fda.hhs.gov RI Dutta, Debargh/J-6086-2015 OI Dutta, Debargh/0000-0003-1517-0670 FU FDA Nanotechnology Initiative; Maryland NanoCenter and its NispLab; U.S. Department of Energy; U.S. Food and Drug Administration FX The authors wish to thank Jiwen Zheng and Joshua Silverstein for their assistance in using the ICP-MS and AFM. The authors would like to acknowledge the FDA White Oak Nanotechnology Core Facility for instrument use, scientific and technical assistance. The authors acknowledge the use of the University of Maryland Nanoscale Imaging Spectroscopy and Properties Laboratory for FESEM imaging and the FDA Nanotechnology Initiative for funding this research. We acknowledge the support of the Maryland NanoCenter and its NispLab. This project was supported in part by an appointment to the Research Participation Program administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 61 TC 3 Z9 3 U1 3 U2 34 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 JUN PY 2015 VL 35 IS 6 BP 631 EP 639 DI 10.1002/jat.3104 PG 9 WC Toxicology SC Toxicology GA CG5SZ UT WOS:000353356300008 PM 25645305 ER PT J AU Srigley, CT Haile, EA AF Srigley, Cynthia T. Haile, Ermias A. TI Quantification of plant sterols/stanols in foods and dietary supplements containing added phytosterols SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE Dietary supplement; Food analysis; Food composition; Gas chromatography; Health claim; Method validation; Phytostanol; Phytosterol; United States Food and Drug Administration ID LDL-CHOLESTEROL CONCENTRATIONS; CARDIOVASCULAR-DISEASE; HYPERCHOLESTEROLEMIC SUBJECTS; QUANTITATIVE-ANALYSIS; ENRICHED MARGARINES; HUMAN-NUTRITION; RAW-MATERIALS; STEROLS; STANOLS; ESTERS AB Plant sterols and plant stanols, collectively referred to as phytosterols, are currently added to conventional foods and dietary supplements for the purpose of reducing the risk of coronary heart disease (CHD). The objective of the present study was to validate a method for the determination of the content and composition of plant sterols/stanols in foods and dietary supplements containing added phytosterols. Chromatographic conditions with this method permitted the near-baseline resolution of the five major phytosterols (campesterol, campestanol, stigmasterol, beta-sitosterol, sitostanol) that are the subject of the United States Food and Drug Administration's (FDA) health claim on the relationship between phytosterols and reduced risk of CHD. Analyzed samples (n = 25) showed total phytosterol contents that varied from 0.2 to 55.2 g/100 g, or 0.02 to 2.3 g/serving. The mean total phytosterol content was 105 +/- 14% of label declarations (range: 83-137%). Thirteen (13) products (52%) carried the FDA's health claim. This work is the first to evaluate the content and composition of phytosterols from the wide variety of products containing added phytosterols currently available in the United States and their use of the FDA's health claim for phytosterols and reduced risk of CHD. Published by Elsevier Inc. C1 [Srigley, Cynthia T.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Haile, Ermias A.] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. RP Srigley, CT (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM cynthia.srigley@fda.hhs.gov FU Joint Institute for Food Safety and Applied Nutrition (JIFSAN) [FDU001418]; FDA [FDU001418] FX This project was funded in part by the Joint Institute for Food Safety and Applied Nutrition (JIFSAN) through a cooperative agreement with the FDA (#FDU001418). The authors would also like to acknowledge Dr. Jeanne I. Rader (retired) for helpful discussions during the planning and development of the current method. NR 47 TC 7 Z9 7 U1 7 U2 41 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1575 EI 1096-0481 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD JUN PY 2015 VL 40 BP 163 EP 176 DI 10.1016/j.jfca.2015.01.008 PG 14 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA CG3KR UT WOS:000353179600024 ER PT J AU Wokovich, AM Strasinger, C Kessler, J Cai, B Westenberger, B Rhee, MJ Raw, A Buhse, LF AF Wokovich, Anna M. Strasinger, Caroline Kessler, Jennifer Cai, Bing Westenberger, Benjamin Rhee, Moo Jhong Raw, Andre Buhse, Lucinda F. TI Cold flow measurement of transdermal drug delivery systems (TDDS) SO INTERNATIONAL JOURNAL OF ADHESION AND ADHESIVES LA English DT Article DE Transdermal drug delivery system; Transdermal; Cold flow; Shear ID PRESSURE-SENSITIVE ADHESIVES; PATCHES AB Cold flow, the movement of adhesive beyond the edge of a transdermal drug delivery system (TDDS) or between the release liner slit, can affect the quality of the drug product and result in patient use issues such as difficulty in removal from packaging and unintentional removal of the product during wear due to increased tackiness on the edge and backing of the TDDS. In this study, different techniques for measuring cold flow of United States marketed transdermal drug delivery systems are assessed including a wiping method with various ways of calculating cold flow, a macroscopic rating method and a microscope evaluation. The amount of cold flow measured from the wiping method was dependent upon the calculation method. Assessment of cold flow may be a combination of quantitative and qualitative methods. Appearance criteria can assess potential use issues caused by cold flow if TDDS are difficult to remove from pouches and if release liners detach from the adhesive matrix during attempted removal due to cold flow adhering the backing to the pouch. A quantitative cold flow method captures the degree to which cold flow extends beyond the perimeter of the backing and through the release liner slit. The method(s) selected by a TDDS manufacturer to measure cold flow should be applicable to the individual product and scientifically justified. Published by Elsevier Ltd. C1 [Wokovich, Anna M.; Westenberger, Benjamin; Buhse, Lucinda F.] US FDA, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. [Strasinger, Caroline; Kessler, Jennifer; Rhee, Moo Jhong] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Cai, Bing; Raw, Andre] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20855 USA. RP Wokovich, AM (reprint author), US FDA, Ctr Drug Evaluat & Res, 645 South Newstead, St Louis, MO 63110 USA. EM anna.wokovich@fda.hhs.gov FU FDA Center for Drug Evaluation and Research (CDER) Regulatory Science and Review Enhancement (RSR) program [RSR 11-09] FX The authors thank the FDA Center for Drug Evaluation and Research (CDER) Regulatory Science and Review Enhancement (RSR) program for funding this project, RSR 11-09. NR 40 TC 0 Z9 0 U1 1 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0143-7496 EI 1879-0127 J9 INT J ADHES ADHES JI Int. J. Adhes. Adhes. PD JUN PY 2015 VL 59 BP 71 EP 76 DI 10.1016/j.ijadhadh.2015.02.002 PG 6 WC Engineering, Chemical; Materials Science, Multidisciplinary SC Engineering; Materials Science GA CG1AT UT WOS:000353006100009 ER PT J AU Fleischman, GJ AF Fleischman, Gregory J. TI Reducing the experimental effort in measuring D and z values for microorganism inactivation kinetics SO JOURNAL OF FOOD ENGINEERING LA English DT Article DE Bacterial destruction; Thermal inactivation; D value; z value ID THERMAL INACTIVATION; PEANUT BUTTER; SALMONELLA; PARAMETERS; RESISTANCE; FOODS; MODEL; TIME AB For those microorganisms exhibiting log linear inactivation kinetics, the D and z values describing their inactivation are typically measured in a series of isothermal experiments, each measuring log reductions with time. This paper examines the mathematics of D and z measurement in order to show how both values could be obtained in fewer isothermal experiments than are traditionally performed. Additionally, a similar analysis of a non-isothermal experimental approach shows how even a minimum of 3 data points in one experiment can be used to determine both parameters. This latter approach, though discussed previously in the literature, is given an analysis in this paper which reveals previously unrecognized details of the method and its performance in extracting D and z values from experimental data. Published by Elsevier Ltd. C1 US FDA, Inst Food Safety & Technol, Bedford Pk, IL 60501 USA. RP Fleischman, GJ (reprint author), US FDA, Inst Food Safety & Technol, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. EM gregory.fleischman@fda.hhs.gov NR 25 TC 1 Z9 1 U1 0 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0260-8774 EI 1873-5770 J9 J FOOD ENG JI J. Food Eng. PD JUN PY 2015 VL 155 BP 1 EP 9 DI 10.1016/j.jfoodeng.2014.12.023 PG 9 WC Engineering, Chemical; Food Science & Technology SC Engineering; Food Science & Technology GA CF0QD UT WOS:000352248400001 ER PT J AU Westgeest, KB Bestebroer, TM Spronken, MIJ Gao, J Couzens, L Osterhaus, ADME Eichelberger, M Fouchier, RAM de Graaf, M AF Westgeest, Kim B. Bestebroer, Theo M. Spronken, Monique I. J. Gao, Jin Couzens, Laura Osterhaus, Albert D. M. E. Eichelberger, Maryna Fouchier, Ron A. M. de Graaf, Miranda TI Optimization of an enzyme-linked lectin assay suitable for rapid antigenic characterization of the neuraminidase of human influenza A(H3N2) viruses SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Influenza; Neuraminidase; Antigenic drift; ELLA ID MANNOSE-BINDING LECTINS; A VIRUS; HEMAGGLUTINATION INHIBITION; 3-DIMENSIONAL STRUCTURE; ANTIBODY-RESPONSES; BETA-INHIBITORS; SERUM; VACCINE; REPLICATION; INFECTION AB Antibodies to neuraminidase (NA), the second most abundant surface protein of the influenza virus, contribute to protection against influenza virus infection. Although traditional and miniaturized thiobarbituric acid (TBA) neuraminidase inhibition (NI) assays have been successfully used to characterize the antigenic properties of NA, these methods are cumbersome and not easily amendable to rapid screening. An additional difficulty of the NI assay is the interference by hemagglutinin (HA)-specific antibodies. To prevent interference of HA-specific antibodies, most NI assays are performed with recombinant viruses containing a mismatched HA. However, generation of these viruses is time consuming and unsuitable for large-scale surveillance. The feasibility of using the recently developed enzyme-linked lectin assay (ELLA) to evaluate the antigenic relatedness of NA of wild type A(H3N2) viruses was assessed. Rather than using recombinant viruses, wild type A(H3N2) viruses were used as antigen with ferret sera elicited against recombinant viruses with a mismatched HA. In this study, details of the critical steps that are needed to modify and optimize the NI ELLA in a format that is reproducible, highly sensitive, and useful for influenza virus surveillance to monitor antigenic drift of NA are provided. (C) 2015 Elsevier B.V. All rights reserved. C1 [Westgeest, Kim B.; Bestebroer, Theo M.; Spronken, Monique I. J.; Osterhaus, Albert D. M. E.; Fouchier, Ron A. M.; de Graaf, Miranda] Erasmus MC, Dept Virosci, Rotterdam, Netherlands. [Gao, Jin; Couzens, Laura; Eichelberger, Maryna] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP de Graaf, M (reprint author), Erasmus MC, Dept Virosci, Rotterdam, Netherlands. EM m.degraaf@erasmusmc.nl RI Fouchier, Ron/A-1911-2014 OI Fouchier, Ron/0000-0001-8095-2869 FU NWO VICI [918.96.613]; NIH [HHSN266200700010C] FX This work was supported by an NWO VICI (918.96.613) and NIH contract no. HHSN266200700010C. We gratefully thank Geert van Amerongen, Sander Herfst, Eetie Schrauwen, Oanh Vuong, Martin Linster and Ruud van Beek for excellent technical assistance. NR 61 TC 3 Z9 3 U1 2 U2 11 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 JUN 1 PY 2015 VL 217 BP 55 EP 63 DI 10.1016/j.jviromet.2015.02.014 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA CG2FV UT WOS:000353091200010 PM 25712563 ER PT J AU Burall, LS Simpson, AC Chou, L Laksanalamai, P Datta, AR AF Burall, Laurel S. Simpson, Alexandra C. Chou, Luoth Laksanalamai, Pongpan Datta, Atin R. TI A novel gene, lstC, of Listeria monocytogenes is implicated in high salt tolerance SO FOOD MICROBIOLOGY LA English DT Article DE Listeria monocytogenes; Salt growth; Stress adaptation; Food preservation ID ALTERNATIVE SIGMA-FACTORS; N-ACETYLTRANSFERASE; GLYCINE BETAINE; TRANSPOSON INSERTION; BACILLUS-SUBTILIS; GNAT SUPERFAMILY; ACID TOLERANCE; STRESS; VIRULENCE; GROWTH AB Listeria monocytogenes, causative agent of human listeriosis, has been isolated from a wide variety of foods including deli meats, soft cheeses, cantaloupes, sprouts and canned mushrooms. Standard control measures for restricting microbial growth such as refrigeration and high salt are often inadequate as L. monocytogenes grows quite well in these environments. In an effort to better understand the genetic and physiological basis by which L. monocytogenes circumvents these controls, a transposon library of L. monocytogenes was screened for changes in their ability to grow in 7% NaCl and/ or at 5 degrees C. This work identified a transposon insertion upstream of an operon, here named lstABC, that led to a reduction in growth in 7% NaCl. In-frame deletion studies identified lstC which codes for a GNAT-acetyltransferase being responsible for the phenotype. Transcriptomic and RT-PCR analyses identified nine genes that were upregulated in the presence of high salt in the Delta lstC mutant. Further analysis of lstC and the genes affected by Delta lstC is needed to understand LstC's role in salt tolerance. Published by Elsevier Ltd. C1 [Burall, Laurel S.; Simpson, Alexandra C.; Chou, Luoth; Laksanalamai, Pongpan; Datta, Atin R.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Datta, AR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM atin.datta@fda.hhs.gov NR 61 TC 2 Z9 2 U1 0 U2 28 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 2015 VL 48 BP 72 EP 82 DI 10.1016/j.fm.2014.12.008 PG 11 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA CD7UQ UT WOS:000351299900011 PM 25790994 ER PT J AU Kumar, S Shen, J Zolnik, B Sadrieh, N Burgess, DJ AF Kumar, Sumit Shen, Jie Zolnik, Banu Sadrieh, Nakissa Burgess, Diane J. TI Optimization and dissolution performance of spray-dried naproxen nano-crystals SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Nano-suspension; Spray drying; Re-dispersion; DoE; Nano-crystalline; Spray-dried powder ID PARTICLE-SIZE REDUCTION; DRUG NANOSUSPENSIONS; BEAGLE DOGS; SOLUBILITY; PERMEABILITY; DISCOVERY AB The purpose of this study was to investigate the in vitro dissolution performance of the different sized spray-dried nano-crystalline powders of naproxen. A DoE approach was used to formulate and optimize nano-crystalline suspensions. The critical wet milling operation parameters were i.e., drug concentration, drug-to-stabilizer ratio, stabilizer type (HPMC E15 or Tween 80) and milling intensity. The nano-crystalline suspensions were optimized for size and physical stability and then spray-dried to obtain nano-crystalline powders. Trehalose and lactose were investigated as spray-drying auxiliary excipients to achieve non-aggregating powders. Particle size, DSC and PXRD were utilized for characterization of powder formulations. A modified USP apparatus II was utilized to determine the in vitro release/dissolution of powder formulations. The size of the nano-crystalline suspensions was dependent on drug concentration and milling intensity. HPMC E15 containing formulations were better in terms of the spray-dried powder yield compared to Tween 80 containing formulations. Trehalose was selected to formulate non-aggregating nano-crystalline powders. No polymorphic changes were observed following the wet milling and spray-drying processes. Size dependent in vitro dissolution profiles, utilizing a dialysis sac method were obtained for the crystalline powders. (C) 2015 Elsevier B.V. All rights reserved. C1 [Kumar, Sumit; Shen, Jie; Burgess, Diane J.] Univ Connecticut, Sch Pharm, Storrs, CT 06269 USA. [Zolnik, Banu; Sadrieh, Nakissa] US FDA, CDER, OPS, Silver Spring, MD 20993 USA. RP Burgess, DJ (reprint author), Univ Connecticut, Sch Pharm, Dept Pharmaceut Sci, Storrs, CT 06269 USA. EM d.burgess@uconn.edu FU FDA/CDER/OPS [HHSF223201110077A] FX This current research was funded and supported by FDA/CDER/OPS (Contract number HHSF223201110077A). NR 21 TC 1 Z9 1 U1 2 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD MAY 30 PY 2015 VL 486 IS 1-2 BP 159 EP 166 DI 10.1016/j.ijpharm.2015.03.047 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CH4JF UT WOS:000353999100018 PM 25814034 ER PT J AU Wozniak, KM Vornov, JJ Mistry, BM Wu, Y Rais, R Slusher, BS AF Wozniak, Krystyna M. Vornov, James J. Mistry, Bipin M. Wu, Ying Rais, Rana Slusher, Barbara S. TI Gastrointestinal delivery of propofol from fospropofol: its bioavailability and activity in rodents and human volunteers SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Propofol; Prodrug; Non-IV; Pain; Hyperalgesia ID PRODRUG GPI 15715; SEE VOL. 112; NEUROPATHIC PAIN; PG. 1058; RATS; PHARMACOKINETICS; PHARMACODYNAMICS; RECEPTORS; PRURITUS; SYNAPTOSOMES AB Background: Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605: 1-8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes. Methods: Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers. Results: In rats, bioavailability of propofol from fospropofol delivered orally was found to be appreciable, in the order of around 20-70%, depending on dose. Availability was especially marked following fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements. Conclusions: These data suggest potential utility of oral administration of fospropofol for various therapeutic indications previously considered for propofol. C1 [Wozniak, Krystyna M.; Vornov, James J.; Mistry, Bipin M.; Wu, Ying; Slusher, Barbara S.] Eisai Inc, Baltimore, MD 21224 USA. [Wozniak, Krystyna M.; Vornov, James J.; Wu, Ying; Rais, Rana; Slusher, Barbara S.] Johns Hopkins Sch Med, Johns Hopkins Drug Discovery, Baltimore, MD 21205 USA. [Rais, Rana; Slusher, Barbara S.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Slusher, Barbara S.] Johns Hopkins Sch Med, Dept Psychiat & Neurosci, Baltimore, MD USA. [Vornov, James J.] Medpace, Cincinnati, OH USA. [Mistry, Bipin M.] FDA, Ctr Vet Med, Derwood, MD USA. RP Slusher, BS (reprint author), Eisai Inc, Baltimore, MD 21224 USA. EM bslusher@jhmi.edu NR 49 TC 1 Z9 1 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAY 29 PY 2015 VL 13 AR 170 DI 10.1186/s12967-015-0526-9 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CK3VD UT WOS:000356143400002 PM 26021605 ER PT J AU Lumen, A McNally, K George, N Fisher, JW Loizou, GD AF Lumen, Annie McNally, Kevin George, Nysia Fisher, Jeffrey W. Loizou, George D. TI Quantitative global sensitivity analysis of a biologically based dose-response pregnancy model for the thyroid endocrine system SO FRONTIERS IN PHARMACOLOGY LA English DT Article DE global sensitivity analysis; BBDR; PBPK; pregnancy; thyroid; thyroid hormones; iodide; modeling ID RISK-ASSESSMENT; PBPK MODELS; MATERNAL HYPOTHYROXINEMIA; THYROXINE TURNOVER; IODIDE DEFICIENCY; GESTATIONAL-AGE; NEONATAL-PERIOD; DIETARY IODIDE; PERCHLORATE; RAT AB A deterministic biologically based dose-response model for the thyroidal system in a near-term pregnant woman and the fetus was recently developed to evaluate quantitatively thyroid hormone perturbations. The current work focuses on conducting a quantitative global sensitivity analysis on this complex model to identify and characterize the sources and contributions of uncertainties in the predicted model output. The workflow and methodologies suitable for computationally expensive models, such as the Morris screening method and Gaussian Emulation processes, were used for the implementation of the global sensitivity analysis. Sensitivity indices, such as main, total and interaction effects, were computed for a screened set of the total thyroidal system descriptive model input parameters. Furthermore, a narrower sub-set of the most influential parameters affecting the model output of maternal thyroid hormone levels were identified in addition to the characterization of their overall and pair-wise parameter interaction quotients. The characteristic trends of influence in model output for each of these individual model input parameters over their plausible ranges were elucidated using Gaussian Emulation processes. Through global sensitivity analysis we have gained a better understanding of the model behavior and performance beyond the domains of observation by the simultaneous variation in model inputs over their range of plausible uncertainties. The sensitivity analysis helped identify parameters that determine the driving mechanisms of the maternal and fetal iodide kinetics, thyroid function and their interactions, and contributed to an improved understanding of the system modeled. We have thus demonstrated the use and application of global sensitivity analysis for a biologically based dose-response model for sensitive life-stages such as pregnancy that provides richer information on the model and the thyroidal system modeled compared to local sensitivity analysis. C1 [Lumen, Annie; Fisher, Jeffrey W.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [McNally, Kevin; Loizou, George D.] Hlth & Safety Lab, Buxton, England. [George, Nysia] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Lumen, A (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 110, Jefferson, AR 72079 USA. EM annie.lumen@fda.hhs.gov; kevin.mcnally@hsl.gsi.gov.uk FU U.S. Food and Drug Administration Office of Women's Health; National Center for Toxicological Research FX This manuscript does not necessarily reflect the views of the U.S. Food and Drug Administration or the Health and Safety Laboratory. We appreciate Drs. William Tolleson, Xiaoxia Yang, and Frederick A. Beland for critically reviewing this manuscript. This work was supported by the U.S. Food and Drug Administration Office of Women's Health and the National Center for Toxicological Research. NR 69 TC 4 Z9 4 U1 4 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD MAY 27 PY 2015 VL 6 AR 107 DI 10.3389/fphar.2015.00107 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CW5MO UT WOS:000365039700001 PM 26074819 ER PT J AU Thomas, A Chen, YB Yu, TH Jakopovic, M Giaccone, G AF Thomas, Anish Chen, Yuanbin Yu, Tinghui Jakopovic, Marko Giaccone, Giuseppe TI Trends and characteristics of young non-small cell lung cancer patients in the United States SO FRONTIERS IN ONCOLOGY LA English DT Article DE non-small cell lung cancer; SEER; young; population-based studies; disparities ID AGE; SMOKING; EPIDEMIOLOGY; SURVEILLANCE; CARCINOMA; DIAGNOSIS; OUTCOMES; ADULTS; TUMORS; RATES AB Background: Although the median age at diagnosis of non-small cell lung cancer (NSCLC) is 70 years, a subset of patients with NSCLC present at a younger age (<40 years). Little is known about the time-trends in incidence of NSCLC in the young, their characteristics and outcomes. Methods: The surveillance, epidemiology, and end results database was used to extract NSCLC cases from 1978 to 2010. Yearly incidence rates in various age groups, race, site of disease, histology, treatment patterns, and outcomes were assessed. We modeled Kaplan Meyer survival curves stratified by age of presentation. Results: Young patients represented 0.6% of incident NSCLC from 1978 to 2010. The incidence of young NSCLC declined significantly during this time-period. Young NSCLCs had a higher proportion of women (51%), Asians or Pacific Islanders (14%), adenocarcinoma histology (59%) and were more likely to present with distant metastases (68%). The young had better all cause and lung cancer-specific survival than the older patients (median survival for localized, regional, and distant disease: not reached, 28, 9 vs. 46, 17, 5 months; p <0.001 for all groups). Male sex, non-adenocarcinoma histology, and main bronchial primary were independent negative prognostic factors among the young. In contrast to the overall population, black race was a poor prognostic factor among the young. Conclusion: The incidence of NSCLC in the young decreased from 1978 to 2010. The clinical characteristics of NSCLC in the young, including demographic distribution, treatment, and outcomes are different from those observed in the older patients. C1 [Thomas, Anish; Chen, Yuanbin] NCI, Natl Inst Hlth, Med Oncol Branch, Bethesda, MD 20892 USA. [Yu, Tinghui] Fed Drug Adm, Off Surveillance & Biometr Devices & Radiol, Silver Spring, MD USA. [Jakopovic, Marko] Univ Zagreb, Univ Hosp Ctr Zagreb, Sch Med, Dept Resp Dis, Zagreb 41000, Croatia. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20057 USA. RP Giaccone, G (reprint author), Georgetown Univ, Lombardi Canc Ctr, Res Bldg RoomW503,3970Reservoir Rd NW, Washington, DC 20057 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 NR 37 TC 9 Z9 10 U1 1 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD MAY 26 PY 2015 VL 5 AR 113 DI 10.3389/fonc.2015.00113 PG 7 WC Oncology SC Oncology GA CO4OE UT WOS:000359139500001 PM 26075181 ER PT J AU Sharfstein, JM AF Sharfstein, Joshua M. TI Using Health Care Data to Track and Improve Public Health SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT News Item C1 [Sharfstein, Joshua M.] Johns Hopkins Bloomberg Sch Publ Hlth, Publ Hlth Practice & Training, Baltimore, MD 21205 USA. [Sharfstein, Joshua M.] Maryland Dept Hlth & Mental Hyg, Baltimore, MD 21201 USA. [Sharfstein, Joshua M.] US FDA, Rockville, MD 20857 USA. [Sharfstein, Joshua M.] Hlth Baltimore, Baltimore, MD USA. RP Sharfstein, JM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Publ Hlth Practice & Training, Baltimore, MD 21205 USA. EM joshua.sharfstein@jhu.edu NR 0 TC 4 Z9 4 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 26 PY 2015 VL 313 IS 20 BP 2012 EP 2013 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CJ0DC UT WOS:000355142400002 PM 26010618 ER PT J AU Bates, SE Lindenberg, ML Bryla, C Pichun, MEB Patronas, N Amiri-Kordestani, L Gonzalez, EM Fojo, T Balasubramaniam, S Choyke, PL AF Bates, Susan Elaine Lindenberg, Maria Liza Bryla, Christine Pichun, Mauricio Emmanuel Burotto Patronas, Nicholas Amiri-Kordestani, Laleh Gonzalez, Esther Mena Fojo, Tito Balasubramaniam, Sanjeeve Choyke, Peter L. TI ANG1005 for brain metastases from breast cancer: 18F-FLT-PET and MRI as complementary approaches to response assessment. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NIH, Dept Radiol, Bethesda, MD 20892 USA. US FDA, Bethesda, MD 20014 USA. Johns Hopkins Univ, Div Nucl Med, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 4 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 20 PY 2015 VL 33 IS 15 SU S MA 2552 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900585 ER PT J AU Jin, RY Li, HS Zhang, LH Zhao, H Fashoyin-Aje, L Lemery, S Keegan, P Booth, B Rahman, NA Wang, YN Sinha, V Zhao, L AF Jin, Runyan Li, Hongshan Zhang, Lillian H. Zhao, Hong Fashoyin-Aje, Lola Lemery, Steven Keegan, Patricia Booth, Brian Rahman, Nam Atiqur Wang, Yaning Sinha, Vikram Zhao, Liang TI Exposure- response (E-R) and case-control analyses of ramucirumab leading to recommendation for dosing optimization in patients with gastric cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 [Jin, Runyan; Li, Hongshan; Zhang, Lillian H.; Zhao, Hong; Fashoyin-Aje, Lola; Lemery, Steven; Keegan, Patricia; Booth, Brian; Rahman, Nam Atiqur; Wang, Yaning; Sinha, Vikram; Zhao, Liang] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 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 20 PY 2015 VL 33 IS 15 SU S MA 2578 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900611 ER PT J AU Kazandjian, DG Blumenthal, GM Fernandes, L Mathieu, LN Tang, SH Sridhara, R Kluetz, PG Keegan, P Pazdur, R AF Kazandjian, Dickran Gano Blumenthal, Gideon Michael Fernandes, Laura Mathieu, Luckson Noe Tang, Shenghui Sridhara, Rajeshwari Kluetz, Paul Gustav Keegan, Patricia Pazdur, Richard TI The relationship of delay in time to deterioration of chest pain, cough and dyspnea with radiographic response with targeted therapies (TT) and chemotherapy (CT) in NSCLC. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 US FDA, Rockville, MD 20857 USA. NIH, Potomac, MD USA. US FDA, Silver Spring, MD USA. US FDA, Silver Spring, MD USA. FDA, Kensington, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2015 VL 33 IS 15 SU S MA e19052 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903906 ER PT J AU Leong, R Song, PF Liu, Q Zhao, H Blumenthal, GM Khozin, S Pan, YZ Zhao, P Keegan, P Booth, B Rahman, NA AF Leong, Ruby Song, Pengfei Liu, Qi Zhao, Hong Blumenthal, Gideon Michael Khozin, Sean Pan, Yuzhuo Zhao, Ping Keegan, Patricia Booth, Brian Rahman, Nam Atiqur TI Recommendations in a new drug application review for dose optimization to potentially improve gastrointestinal tolerability of a tyrosine kinase inhibitor. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 [Leong, Ruby; Song, Pengfei; Liu, Qi; Zhao, Hong; Blumenthal, Gideon Michael; Khozin, Sean; Pan, Yuzhuo; Zhao, Ping; Keegan, Patricia; Booth, Brian; Rahman, Nam Atiqur] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 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 20 PY 2015 VL 33 IS 15 SU S MA 2574 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900607 ER PT J AU Okusanya, OO Dinndorf, PA Bullock, J Habtemariam, BA Mehrotra, N Deisseroth, AB Reaman, GH Rahman, NA Farrell, AT AF Okusanya, Olanrewaju O. Dinndorf, Patricia A. Bullock, Julie Habtemariam, Bahru A. Mehrotra, Nitin Deisseroth, Albert B. Reaman, Gregory H. Rahman, Nam Atiqur Farrell, Ann T. TI Intramuscular (IM) or intravenous (IV): Impact of Erwinia asparaginase route of administration on asparaginase activity. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 US FDA, Silver Spring, MD USA. D3medicine, Parsippany, NJ USA. NR 0 TC 0 Z9 0 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 20 PY 2015 VL 33 IS 15 SU S MA 10031 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900037 ER PT J AU Shord, SS Schrieber, SJ Zhao, H Booth, B Rahman, NA AF Shord, Stacy Shifflett Schrieber, Sarah J. Zhao, Hong Booth, Brian Rahman, Nam Atiqur TI Regulatory considerations for clinical pharmacology during development of antibody-drug conjugates. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 [Shord, Stacy Shifflett; Schrieber, Sarah J.; Zhao, Hong; Booth, Brian; Rahman, Nam Atiqur] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 20 PY 2015 VL 33 IS 15 SU S MA 2569 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036900602 ER PT J AU Sridhara, R Chen, HY Wang, Y Mushti, S Khozin, S Maher, VE Pazdur, R AF Sridhara, Rajeshwari Chen, Huanyu Wang, Yun Mushti, Sirisha Khozin, Sean Maher, Virginia Ellen Pazdur, Richard TI Collection of grade 3/4 adverse event (AE) data in a subgroup of patients in cancer clinical trials supporting supplemental indications: A comprehensive analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2015 CL Chicago, IL SP Amer Soc Clin Oncol C1 [Sridhara, Rajeshwari; Chen, Huanyu; Wang, Yun; Mushti, Sirisha; Khozin, Sean; Maher, Virginia Ellen; Pazdur, Richard] US FDA, Silver Spring, MD USA. RI Mushti, Sirisha/K-3519-2016 NR 0 TC 0 Z9 0 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 20 PY 2015 VL 33 IS 15 SU S MA e17640 PG 1 WC Oncology SC Oncology GA CM9OA UT WOS:000358036903598 ER PT J AU Lohne, JJ Turnipseed, SB Andersen, WC Storey, J Madson, MR AF Lohne, Jack J. Turnipseed, Sherri B. Andersen, Wendy C. Storey, Joseph Madson, Mark R. TI Application of Single-Stage Orbitrap Mass Spectrometry and Differential Analysis Software to Nontargeted Analysis of Contaminants in Dog Food: Detection, Identification, and Quantification of Glycoalkaloids SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE glycoalkaloids; HRMS; nontargeted search; Orbitrap; Sieve; dog food ID HIGH-RESOLUTION; POTATO GLYCOALKALOIDS; CHALLENGES; CULTIVARS; SAFETY; MS AB The objective of this study was to perform a preliminary investigation of the nontargeted search and quantitative capabilities of a single-stage Exactive High-Resolution Mass Spectrometer (HRMS). To do this, the instrument and its associated software performed a non-targeted search for deleterious substances in a dog food sample suspected of causing gastrointestinal problems in dogs. A single-stage Orbitrap/high-performance liquid chromatography method and differential expression analysis software (Sieve) was used to detect and identify, and subsequently quantify, nontargeted compounds occurring only in the suspect dog food sample. When combined with an online database (ChemSpider), a preliminary identification of one of the nontargeted compounds was determined to be potato glycoalkaloids. The diagnostic product ion ratios and quantitative data accuracy generated by the single-stage Orbitrap MS were shown to be similar to results obtained using a triple quadrupole LC-MS/MS. Additionally, the ability of the single-stage Orbitrap instrument to provide precursor and product ion accurate masses and isotope patterns was also investigated. C1 [Lohne, Jack J.; Turnipseed, Sherri B.; Andersen, Wendy C.; Storey, Joseph; Madson, Mark R.] US FDA, Anim Drugs Res Ctr, Denver, CO 80225 USA. [Madson, Mark R.] US FDA, Denver Lab, Denver, CO 80225 USA. RP Lohne, JJ (reprint author), US FDA, Anim Drugs Res Ctr, Denver Fed Ctr Bldg 20, Denver, CO 80225 USA. EM Jack.Lohne@fda.hhs.gov NR 32 TC 6 Z9 7 U1 2 U2 19 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 MAY 20 PY 2015 VL 63 IS 19 BP 4790 EP 4798 DI 10.1021/acs.jafc.5b00959 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CJ0GS UT WOS:000355154400012 PM 25912523 ER PT J AU Crim, SM Griffin, PM Tauxe, R Marder, EP Gilliss, D Cronquist, AB Cartter, M Tobin-D'Angelo, M Blythe, D Smith, K Lathrop, S Zansky, S Cieslak, PR Dunn, J Holt, KG Wolpert, B Henao, OL AF Crim, Stacy M. Griffin, Patricia M. Tauxe, Robert Marder, Ellyn P. Gilliss, Debra Cronquist, Alicia B. Cartter, Matthew Tobin-D'Angelo, Melissa Blythe, David Smith, Kirk Lathrop, Sarah Zansky, Shelley Cieslak, Paul R. Dunn, John Holt, Kristin G. Wolpert, Beverly Henao, Olga L. TI Preliminary Incidence and Trends of Infection with Pathogens Transmitted Commonly Through Food - Foodborne Diseases Active Surveillance Network, 10 US Sites, 2006-2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID UNITED-STATES C1 [Crim, Stacy M.; Griffin, Patricia M.; Tauxe, Robert; Marder, Ellyn P.; Henao, Olga L.] CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Marder, Ellyn P.] Atlanta Res & Educ Fdn, Atlanta, GA USA. [Gilliss, Debra] Calif Dept Publ Hlth, Richmond, CA USA. [Cronquist, Alicia B.] Colorado Dept Publ Hlth & Environm, Denver, CO USA. [Cartter, Matthew] Connecticut Dept Publ Hlth, Hartford, CT USA. [Tobin-D'Angelo, Melissa] Georgia Dept Publ Hlth, Marietta, GA USA. [Blythe, David] 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. [Cieslak, Paul R.] Oregon Hlth Author, Portland, OR USA. [Dunn, John] Tennessee Dept Hlth, Nashville, TN USA. [Holt, Kristin G.] Food Safety & Inspect Serv, USDA, Washington, DC USA. [Wolpert, Beverly] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Henao, OL (reprint author), CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM ohenao@cdc.gov NR 9 TC 26 Z9 27 U1 1 U2 13 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 MAY 15 PY 2015 VL 64 IS 18 BP 495 EP 499 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI4AK UT WOS:000354688400003 PM 25974634 ER PT J AU Sukumaran, L McNeil, MM Moro, PL Lewis, PW Winiecki, SK Shimabukuro, TT AF Sukumaran, Lakshmi McNeil, Michael M. Moro, Pedro L. Lewis, Paige W. Winiecki, Scott K. Shimabukuro, Tom T. TI Adverse Events Following Measles, Mumps, and Rubella Vaccine in Adults Reported to the Vaccine Adverse Event Reporting System (VAERS), 2003-2013 SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE measles; mumps; rubella; MMR vaccine; Vaccine Adverse Event Reporting System (VAERS) ID IMMUNIZATION SAFETY DATA; GUILLAIN-BARRE-SYNDROME; SCHEDULE-UNITED-STATES; FEBRILE SEIZURES; CASE DEFINITIONS; COLLECTION; GUIDELINES; JANUARY; RISK AB Background. Limited data exist on the safety of the measles, mumps, and rubella (MMR) vaccine in adults. We reviewed reports of adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS) to assess safety in this previously understudied group. Methods. VAERS is the national spontaneous vaccine safety surveillance system coadministered by the Centers for Disease Control and Prevention and the US Food and Drug Administration. We searched the VAERS database for US reports of adults aged >= 19 years who received the MMR vaccine from 1 January 2003 to 31 July 2013. We clinically reviewed reports and available medical records for serious AEs, pregnancy reports, and reports for selected prespecified outcomes. Results. During this period, VAERS received 3175 US reports after MMR vaccine in adults. Of these, 168 (5%) were classified as serious, including 7 reports of death. Females accounted for 77% of reports. The most common signs and symptoms for all reports were pyrexia (19%), rash (17%), pain (13%), and arthralgia (13%). We did not detect any new safety findings in empirical Bayesian data mining. We identified 131 reports of MMR vaccine administered to a pregnant woman; the majority of these vaccinations were in the first trimester and in 83 (62%), no AE was reported. Conclusions. In our review of VAERS data, we did not detect any new or unexpected safety concerns for MMR vaccination in adults. We identified reports of pregnant women exposed to MMR, which is a group in whom the vaccine is contraindicated, suggesting the need for continued provider education on vaccine recommendations and screening. C1 [Sukumaran, Lakshmi; McNeil, Michael M.; Moro, Pedro L.; Lewis, Paige W.; Shimabukuro, Tom T.] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Immunizat Safety Off, Atlanta, GA 30333 USA. [Sukumaran, Lakshmi] Emory Univ, Sch Med, Atlanta, GA USA. [Winiecki, Scott K.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Sukumaran, L (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd NE,MS D-26, Atlanta, GA 30333 USA. EM xfq3@cdc.gov FU NIAID [T32AI074492] FX This work was supported by the NIAID (award number T32AI074492). NR 29 TC 6 Z9 6 U1 2 U2 22 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 MAY 15 PY 2015 VL 60 IS 10 BP E58 EP E65 DI 10.1093/cid/civ061 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CH0ON UT WOS:000353721300002 PM 25637587 ER PT J AU De Pascalis, R Mittereder, L Chou, AY Kennett, NJ Elkins, KL AF De Pascalis, Roberto Mittereder, Lara Chou, Alicia Y. Kennett, Nikki J. Elkins, Karen L. TI Francisella tularensis Vaccines Elicit Concurrent Protective T- and B-Cell Immune Responses in BALB/cByJ Mice SO PLOS ONE LA English DT Article ID STRAIN INFECTION; PASTEURELLA-TULARENSIS; MEDIATED IMMUNITY; GAMMA-INTERFERON; HUMORAL IMMUNITY; LVS INFECTION; LIVE; TULAREMIA; ANTIBODIES; IMMUNIZATION AB In the last decade several new vaccines against Francisella tularensis, which causes tularemia, have been characterized in animal models. Whereas many of these vaccine candidates showed promise, it remains critical to bridge the preclinical studies to human subjects, ideally by taking advantage of correlates of protection. By combining in vitro intramacrophage LVS replication with gene expression data through multivariate analysis, we previously identified and quantified correlative T cell immune responses that discriminate vaccines of different efficacy. Further, using C57BL/6J mice, we demonstrated that the relative levels of gene expression vary according to vaccination route and between cell types from different organs. Here, we extended our studies to the analysis of T cell functions of BALB/cByJ mice to evaluate whether our approach to identify correlates of protection also applies to a Th2 dominant mouse strain. BALB/cByJ mice had higher survival rates than C57BL/6J mice when they were immunized with suboptimal vaccines and challenged. However, splenocytes derived from differentially vaccinated BALB/cByJ mice controlled LVS intramacrophage replication in vitro in a pattern that reflected the hierarchy of protection observed in C57BL/6J mice. In addition, gene expression of selected potential correlates revealed similar patterns in splenocytes of BALB/cByJ and C57BL/6J mice. The different survival patterns were related to B cell functions, not necessarily to specific antibody production, which played an important protective role in BALB/cByJ mice when vaccinated with suboptimal vaccines. Our studies therefore demonstrate the range of mechanisms that operate in the most common mouse strains used for characterization of vaccines against F. tularensis, and illustrate the complexity necessary to define a comprehensive set of correlates. C1 [De Pascalis, Roberto; Mittereder, Lara; Chou, Alicia Y.; 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 20993 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 20993 USA. EM roberto.depascalis@fda.hhs.gov FU CBER/FDA (U.S. government) FX This work was funded by internal CBER/FDA (U.S. government) operating funds. NR 48 TC 2 Z9 2 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 14 PY 2015 VL 10 IS 5 AR e0126570 DI 10.1371/journal.pone.0126570 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI2AC UT WOS:000354545600060 PM 25973794 ER PT J AU Li, ZG Qin, TC Wang, KJ Hackenberg, M Yan, J Gao, Y Yu, LR Shi, LM Su, ZQ Chen, T AF Li, Zhiguang Qin, Taichun Wang, Kejian Hackenberg, Michael Yan, Jian Gao, Yuan Yu, Li-Rong Shi, Leming Su, Zhenqiang Chen, Tao TI Integrated microRNA, mRNA, and protein expression profiling reveals microRNA regulatory networks in rat kidney treated with a carcinogenic dose of aristolochic acid SO BMC GENOMICS LA English DT Article DE Aristolochic acid; Carcinogenesis; Kidney tumor; microRNA; Proteomics; Deep-Sequencing; RNA array; Target prediction; Rat ID RENAL-CELL CARCINOMA; CANCER; NEPHROPATHY; TARGETS; GENOME; LIVER; TOOL; TRANSLATION; ACTIVATION; MUTATIONS AB Background: Aristolochic Acid (AA), a natural component of Aristolochia plants that is found in a variety of herbal remedies and health supplements, is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Given that microRNAs (miRNAs) are involved in cancer initiation and progression and their role remains unknown in AA-induced carcinogenesis, we examined genome-wide AA-induced dysregulation of miRNAs as well as the regulation of miRNAs on their target gene expression in rat kidney. Results: We treated rats with 10 mg/kg AA and vehicle control for 12 weeks and eight kidney samples (4 for the treatment and 4 for the control) were used for examining miRNA and mRNA expression by deep sequencing, and protein expression by proteomics. AA treatment resulted in significant differential expression of miRNAs, mRNAs and proteins as measured by both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Specially, 63 miRNAs (adjusted p value < 0.05 and fold change > 1.5), 6,794 mRNAs (adjusted p value < 0.05 and fold change > 2.0), and 800 proteins (fold change > 2.0) were significantly altered by AA treatment. The expression of 6 selected miRNAs was validated by quantitative real-time PCR analysis. Ingenuity Pathways Analysis (IPA) showed that cancer is the top network and disease associated with those dysregulated miRNAs. To further investigate the influence of miRNAs on kidney mRNA and protein expression, we combined proteomic and transcriptomic data in conjunction with miRNA target selection as confirmed and reported in miRTarBase. In addition to translational repression and transcriptional destabilization, we also found that miRNAs and their target genes were expressed in the same direction at levels of transcription (169) or translation (227). Furthermore, we identified that up-regulation of 13 oncogenic miRNAs was associated with translational activation of 45 out of 54 cancer-related targets. Conclusions: Our findings suggest that dysregulated miRNA expression plays an important role in AA-induced carcinogenesis in rat kidney, and that the integrated approach of multiple profiling provides a new insight into a post-transcriptional regulation of miRNAs on their target repression and activation in a genome-wide scale. C1 [Li, Zhiguang] Dalian Med Univ, Ctr Canc, Affiliated Hosp 2, Inst Canc Stem Cell, Dalian 116044, Peoples R China. [Qin, Taichun; Yan, Jian; Chen, Tao] Natl Ctr Toxicol Res Food & Drug Adm, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Wang, Kejian; Gao, Yuan; Yu, Li-Rong; Shi, Leming; Su, Zhenqiang] Natl Ctr Toxicol Res Food & Drug Adm, Div Syst Biol, Jefferson, AR 72079 USA. [Hackenberg, Michael] Univ Granada, Fac Ciencias, Dept Genet, E-18071 Granada, Spain. RP Chen, T (reprint author), Natl Ctr Toxicol Res Food & Drug Adm, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM tao.chen@fda.hhs.gov RI Hackenberg, Michael/A-2503-2009 OI Hackenberg, Michael/0000-0003-2248-3114 FU National Center for Toxicological Research FX ZL and TQ are supported by the appointment to the Postgraduate Research Program at the National Center for Toxicological Research administered by OAK Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. We cherish all sequencing support from University of Texas Southwestern Medical Center Microarray Core Facility. This article is not an official U.S. Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 52 TC 8 Z9 9 U1 6 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 8 PY 2015 VL 16 AR 365 DI 10.1186/s12864-015-1516-2 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CK1KH UT WOS:000355965700001 PM 25952319 ER PT J AU Bell, RL Zheng, J Burrows, E Allard, S Wang, CY Keys, CE Melka, DC Strain, E Luo, Y Allard, MW Rideout, S Brown, EW AF Bell, Rebecca L. Zheng, Jie Burrows, Erik Allard, Sarah Wang, Charles Y. Keys, Christine E. Melka, David C. Strain, Errol Luo, Yan Allard, Marc W. Rideout, Steven Brown, Eric W. TI Ecological prevalence, genetic diversity, and epidemiological aspects of Salmonella isolated from tomato agricultural regions of the Virginia Eastern Shore SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Salmonella Newport; tomatoes; environmental reservoirs; epidemiological impact; prevalence and diversity ID REAL-TIME PCR; ENTERICA SEROVAR TYPHIMURIUM; UNITED-STATES; ESCHERICHIA-COLI; FRESH PRODUCE; IRRIGATION WATER; CONTAMINATION; PATHOGENS; OUTBREAKS; SURVIVAL AB Virginia is the third largest producer of fresh-market tomatoes in the United States. Tomatoes grown along the eastern shore of Virginia are implicated almost yearly in Salmonella illnesses. Traceback implicates contamination occurring in the pre-harvest environment. To get a better understanding of the ecological niches of Salmonella in the tomato agricultural environment, a 2-year study was undertaken at a regional agricultural research farm in Virginia. Environmental samples, including tomato (fruit, blossoms, and leaves), irrigation water, surface water and sediment, were collected over the growing season. These samples were analyzed for the presence of Salmonella using modified FDA-BAM methods. Molecular assays were used to screen the samples. Over 1500 samples were tested. Seventy-five samples tested positive for Salmonella yielding over 230 isolates. The most commonly isolated serovars were S. Newport and S. Javiana with pulsed-field gel electrophoresis yielding 39 different patterns. Genetic diversity was further underscored among many other serotypes, which showed multiple PFGE subtypes. Whole genome sequencing (WGS) of several S. Newport isolates collected in 2010 compared to clinical isolates associated with tomato consumption showed very few single nucleotide differences between environmental isolates and clinical isolates suggesting a source link to Salmonella contaminated tomatoes. Nearly all isolates collected during two growing seasons of surveillance were obtained from surface water and sediment sources pointing to these sites as long-term reservoirs for persistent and endemic contamination of this environment. C1 [Bell, Rebecca L.; Zheng, Jie; Burrows, Erik; Allard, Sarah; Wang, Charles Y.; Keys, Christine E.; Melka, David C.; Strain, Errol; Luo, Yan; Allard, Marc W.; Brown, Eric W.] US FDA, Div Microbiol, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Rideout, Steven] Virginia Tech, Eastern Shore Agr Res & Extens Ctr, Painter, VA USA. RP Bell, RL (reprint author), Ctr Food Safety & Appl Nutr, Div Microbiol, Off Regulatory Sci, 5100 Paint Branch Pkwy,HSF 712, College Pk, MD 20704 USA. EM rebecca.bell@fda.hhs.gov FU Research Participation Program at the Center for Food Safety and Applied Nutrition FX We are grateful to M. Mahovic, M. Fatica and R. Timme for insightful comments and discussions. We are appreciative of the assistance of Stuart Chirtel for the statistical analyses. We are especially indebted to Capt. T. Hill for championing this work throughout his career. We acknowledge the U.S. Center for Disease Control and Prevention PulseNet Team for their dedication and hard work in administering, maintaining and monitoring of the PulseNet database. EB, SA, and CW were funded in part by an appointment with the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by Oak Ridge Institute for Science and Education through and interagency agreement between the U.S. Department of Energy and The U.S. Food and Drug Administration. NR 54 TC 6 Z9 6 U1 3 U2 25 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD MAY 7 PY 2015 VL 6 AR 415 DI 10.3389/fmicp.2015.00415 PG 15 WC Microbiology SC Microbiology GA CJ6TO UT WOS:000355627000001 PM 25999938 ER PT J AU Krause, PR Bryant, PR Clark, T Dempsey, W Henchal, E Michael, NL Regules, JA Gruber, MF AF Krause, Philip R. Bryant, Paula R. Clark, Thomas Dempsey, Walla Henchal, Erik Michael, Nelson L. Regules, Jason A. Gruber, Marion F. TI Immunology of protection from Ebola virus infection SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NONHUMAN-PRIMATES; WEST-AFRICA; IMMUNITY; ANTIBODIES; CHALLENGE; DISEASE AB A December 2014 meeting reviewed Ebola virus immunology relevant to vaccine development, including Ebola prevention, immunity, assay standardization, and regulatory considerations. Vaccinated humans appear to achieve immune responses comparable in magnitude with those associated with protection in nonhuman primates, suggesting that immunological data could be used to demonstrate vaccine efficacy. C1 [Krause, Philip R.; Henchal, Erik; Gruber, Marion F.] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Bryant, Paula R.; Dempsey, Walla] NIAID, Div Microbial & Infect Dis, NIH, Bethesda, MD 20892 USA. [Clark, Thomas] Ctr Dis Control & Prevent, Atlanta, GA USA. [Michael, Nelson L.; Regules, Jason A.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Krause, PR (reprint author), US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM philip.krause@fda.hhs.gov FU FDA; NIAID; CDC; Biomedical Advanced Research and Development Authority; U.S. Department of Defense FX We appreciate financial and logistical support for the meeting from FDA, NIAID, CDC, Biomedical Advanced Research and Development Authority, and U.S. Department of Defense. NR 25 TC 2 Z9 2 U1 1 U2 15 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 6 PY 2015 VL 7 IS 286 AR 286ps11 DI 10.1126/scitranslmed.aaa8202 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CI0MP UT WOS:000354431600003 PM 25947159 ER PT J AU McNally, EM Kaltman, JR Benson, DW Canter, CE Cripe, LH Duan, DS Finder, JD Hoffman, EP Judge, DP Kertesz, N Kinnett, K Kirsch, R Metzger, JM Pearson, GD Rafael-Fortney, JA Raman, SV Spurney, CF Targum, SL Wagner, KR Markham, LW AF McNally, Elizabeth M. Kaltman, Jonathan R. Benson, D. Woodrow Canter, Charles E. Cripe, Linda H. Duan, Dongsheng Finder, Jonathan D. Hoffman, Eric P. Judge, Daniel P. Kertesz, Naomi Kinnett, Kathi Kirsch, Roxanne Metzger, Joseph M. Pearson, Gail D. Rafael-Fortney, Jill A. Raman, Subha V. Spurney, Christopher F. Targum, Shari L. Wagner, Kathryn R. Markham, Larry W. TI Contemporary Cardiac Issues in Duchenne Muscular Dystrophy SO CIRCULATION LA English DT Article DE cardiomyopathy; dystrophin; heart failure; magnetic resonance imaging; muscular dystrophy ID CONVERTING-ENZYME-INHIBITORS; MDX MOUSE MODEL; DEFICIENT CARDIOMYOPATHY; HEART-FAILURE; VENTRICULAR DYSFUNCTION; DILATED CARDIOMYOPATHY; STEROID-THERAPY; SKELETAL-MUSCLE; LIFE EXPECTANCY; BETA-BLOCKERS C1 [McNally, Elizabeth M.] Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Kaltman, Jonathan R.; Pearson, Gail D.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20817 USA. [Benson, D. Woodrow] Childrens Hosp Wisconsin, Div Cardiol, Milwaukee, WI 53201 USA. [Canter, Charles E.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Cripe, Linda H.; Kertesz, Naomi] Nationwide Childrens Hosp, Ctr Heart, Columbus, OH USA. [Duan, Dongsheng] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. [Finder, Jonathan D.] Childrens Hosp Pittsburgh, Div Pulm Med, Pittsburgh, PA USA. [Hoffman, Eric P.] Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC USA. [Spurney, Christopher F.] Childrens Natl Hlth Syst, Div Cardiol, Childrens Natl Heart Inst, Med Genet Res Ctr, Washington, DC USA. [Judge, Daniel P.] Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. [Kinnett, Kathi] Parent Project Muscular Dystrophy, Middletown, OH USA. [Kirsch, Roxanne] Childrens Hosp Philadelphia, Div Cardiac Crit Care, Philadelphia, PA USA. [Metzger, Joseph M.] Univ Minnesota, Sch Med, Dept Integrat Biol & Physiol, Minneapolis, MN 55455 USA. [Rafael-Fortney, Jill A.] Ohio State Univ, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. [Raman, Subha V.] Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA. [Targum, Shari L.] US FDA, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Wagner, Kathryn R.] Kennedy Krieger Inst, Hugo W Moser Res Inst, Baltimore, MD USA. [Markham, Larry W.] Vanderbilt Univ, Dept Pediat, Div Pediat Cardiol, Nashville, TN 37232 USA. RP McNally, EM (reprint author), Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, 303 E Super St,7-123, Chicago, IL 60611 USA. EM Elizabeth.mcnally@northwestern.edu; kaltmanj@nhlbi.nih.gov; larry.markham@Vanderbilt.Edu FU Siemens FX The views expressed in this article do not necessarily relied those of the National Heart, Lung, and Blood Institute; US Food and Drug Administration; or National Institutes of Health. This article reflects the views of the author and should not be construed to represent the US Food and Drug Administration's views or policies. Dr Raman receives institutional research support from Siemens. Dr Duan is a member of the Scientific Advisory Board for Solid GT, LLC, a venture company founded to advance gene therapy for DMD, Working Group members: co-chairs: Elizabeth McNally, MD, PhD, University of Chicago; Larry Markham, MD, Vanderbilt University. Members: D. Woodrow Benson, MD, PhD, Children's Hospital of Wisconsin: Charles Canter, MD, St. Louis Children's Hospital; Linda Cripe, MD, Nation id Children's Hospital; Dongshene Duan, PhD, University of Missouri; Jonathan Finder, MD, Children's Hospital of Pittsburgh: William Groh, MD, MPH, Krannert Institute of Cardiology; Eric Hoffman, PhD, Children's National Medical Center; Daniel Judge, MD, Johns Hopkins University; David Kass, MD, Johns Hopkins University; Naomi Keriesz, MD, Nationwide Children's Hospital; Roxanne Kirsch, MD, Children's Hospital of Philadelphia; Joseph M. Metzger, PhD, University of Minnesota; Jill Rafael-Fortney, PhD, Ohio State University; Subha Raman, MD, Ohio State University; Christopher Spurney, MD, Children's National Medical Center; Lee Sweeney, PhD, Penn Rare Disease Center; Shari Targum, MD, Food and Drug Administration; Kathryn Wagner, MD, PhD, Johns Hopkins University. Parent Project Muscular Dystrophy staff: Brian Denger; Pat Furlong; Sharon Hesterlee, PhD: Kathi Kinnett, MSN, CNP. National Institutes of Health staff: Kristin Burns, MD; Jonathan Kaltman, MD; Glen Nuckolls, PhD; Gail Pearson, MD, ScR John Porter, PhD. The other authors report no conflicts. NR 77 TC 25 Z9 25 U1 0 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 5 PY 2015 VL 131 IS 18 BP 1590 EP 1598 DI 10.1161/CIRCULATIONAHA.114.015151 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CH2ZO UT WOS:000353895100012 PM 25940966 ER PT J AU Verma, RP Matthews, EJ AF Verma, R. P. Matthews, E. J. TI An in silico expert system for the identification of eye irritants SO SAR AND QSAR IN ENVIRONMENTAL RESEARCH LA English DT Article DE in silico; molecular weight; eye irritation; number of hydrogen bond donors; Draize test; decision support system; number of hydrogen bond acceptors; polarizability; physicochemical exclusion rules; hydrophobicity; expert rule ID DECISION-SUPPORT-SYSTEM; EVIDENCE WOE BATTERY; ALTERNATIVE METHODS; TESTING STRATEGIES; IRRITATION; MODELS; CHEMICALS AB This report describes development of an in silico, expert rule-based method for the classification of chemicals into irritants or non-irritants to eye, as defined by the Draize test. This method was developed to screen data-poor cosmetic ingredient chemicals for eye irritancy potential, which is based upon exclusion rules of five physicochemical properties - molecular weight (MW), hydrophobicity (log P), number of hydrogen bond donors (HBD), number of hydrogen bond acceptors (HBA) and polarizability (Pol). These rules were developed using the ADMET Predictor software and a dataset of 917 eye irritant chemicals. The dataset was divided into 826 (90%) chemicals used for training set and 91 (10%) chemicals used for external validation set (every 10th chemical sorted by molecular weight). The sensitivity of these rules for the training and validation sets was 72.3% and 71.4%, respectively. These rules were also validated for their specificity using an external validation set of 2011 non-irritant chemicals to the eye. The specificity for this validation set was revealed as 77.3%. This method facilitates rapid screening and prioritization of data poor chemicals that are unlikely to be tested for eye irritancy in the Draize test. C1 [Verma, R. P.] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Matthews, E. J.] US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Verma, RP (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Rajeshwar.Verma@fda.hhs.gov FU Office of Cosmetics and Colors (OCAC) at the Center for Food Safety and Applied Nutrition at the US Food and Drug Administration through the Oak Ridge Institute for Science and Education (ORISE); Office of Cosmetics and Colors (OCAC) at the Center for Food Safety and Applied Nutrition at the US Food and Drug Administration through Goldbelt Falcon/C6 FX One of the authors (Dr Rajeshwar P. Verma) is grateful to the Office of Cosmetics and Colors (OCAC) at the Center for Food Safety and Applied Nutrition at the US Food and Drug Administration for financial support through the Oak Ridge Institute for Science and Education (ORISE) and Goldbelt Falcon/C6. NR 29 TC 1 Z9 1 U1 0 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1062-936X EI 1029-046X J9 SAR QSAR ENVIRON RES JI SAR QSAR Environ. Res. PD MAY 4 PY 2015 VL 26 IS 5 BP 383 EP 395 DI 10.1080/1062936X.2015.1039578 PG 13 WC Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications; Environmental Sciences; Mathematical & Computational Biology; Toxicology SC Chemistry; Computer Science; Environmental Sciences & Ecology; Mathematical & Computational Biology; Toxicology GA CI4IV UT WOS:000354712800002 PM 25967253 ER PT J AU Storey, JM Andersen, WC Heise, A Turnipseed, SB Lohne, J Thomas, T Madson, M AF Storey, Joseph M. Andersen, Wendy C. Heise, Andrea Turnipseed, Sherri B. Lohne, Jack Thomas, Terri Madson, Mark TI A rapid liquid chromatography determination of free formaldehyde in cod SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE liquid chromatography; cod; formaldehyde; 2,4-dinitrophenylhydrazine ID EXTRACTION; SQUID; FISH AB A rapid method for the determination of free formaldehyde in cod is described. It uses a simple water extraction of formaldehyde which is then derivatised with 2,4-dinitrophenylhydrazine (DNPH) to form a sensitive and specific chromophore for high-performance liquid chromatography (HPLC) detection. Although this formaldehyde derivative has been widely used in past tissue analysis, this paper describes an improved derivatisation procedure. The formation of the DNPH formaldehyde derivative has been shortened to 2min and a stabilising buffer has been added to the derivative to increase its stability. The average recovery of free formaldehyde in spiked cod was 63% with an RSD of 15% over the range of 25-200mgkg(-1) (n=48). The HPLC procedure described here was also compared to a commercial qualitative procedure - a swab test for the determination of free formaldehyde in fish. Several positive samples were compared by both methods. C1 [Storey, Joseph M.; Andersen, Wendy C.; Turnipseed, Sherri B.; Lohne, Jack; Madson, Mark] US FDA, Anim Drugs Res Ctr, Denver, CO 80225 USA. [Heise, Andrea; Thomas, Terri; Madson, Mark] US FDA, Denver Lab, Denver, CO 80225 USA. RP Storey, JM (reprint author), US FDA, Anim Drugs Res Ctr, Denver, CO 80225 USA. EM joseph.storey@fda.hhs.gov NR 23 TC 0 Z9 0 U1 4 U2 23 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD MAY 4 PY 2015 VL 32 IS 5 BP 657 EP 664 DI 10.1080/19440049.2015.1020530 PG 8 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA CE5ZY UT WOS:000351916300004 PM 25719953 ER PT J AU Li, MJ AF Li, Meijuan TI Statistical Consideration and Challenges in Bridging Study of Personalized Medicine SO Journal of Biopharmaceutical Statistics LA English DT Article DE Companion diagnostic assay; Clinical trial assay; Personalized medicine; Drug efficacy; Bridging study; Device-drug pivotal clinical trial; Device's intended use population ID MISSING DATA; BOOTSTRAP; TESTS AB Applications of personalized medicine are becoming increasingly prominent. A well-characterized market-ready companion diagnostic assay (CDx) is often desired for patient enrollment in device-drug pivotal clinical trial(s) so that Food and Drug Administration can ensure that appropriate clinical and analytical validation studies are planned and carried out for CDx. However, such a requirement may be difficult or impractical to accomplish. A clinical trial assay (CTA) instead of CDx may be used for patient enrollment in the clinical trial. A concordance study (or bridging study) will be required to assess the agreement between CDx and CTA in order to bridge the clinical data (e.g. overall survival) from CTA to CDx and to evaluate the drug efficacy in CDx intended use population. In this article, we will discuss statistical challenges in study design and data analysis for bridging study. Particularly, we aimed to provide statistical methods on how to estimate the drug efficacy in CDx intended use population using results from bridging study and CTA-drug pivotal clinical trial. C1 US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Li, MJ (reprint author), US FDA, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM meijuan.li@fda.hhs.gov NR 17 TC 5 Z9 6 U1 2 U2 3 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 MAY 4 PY 2015 VL 25 IS 3 BP 397 EP 407 DI 10.1080/10543406.2014.920340 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CG6DQ UT WOS:000353386300002 PM 24897254 ER PT J AU Qu, YP Meeden, GD Zhang, B AF Qu, Yanping Meeden, Glen D. Zhang, Bo TI An objective stepwise Bayes approach to small area estimation SO JOURNAL OF STATISTICAL COMPUTATION AND SIMULATION LA English DT Article; Proceedings Paper CT 7th International Conference on Sensitivity Analysis of Model Output (SAMO 2013) CY JUL 01-04, 2013 CL Univ Nice, Nice, FRANCE HO Univ Nice DE auxiliary variable; Polya posterior; noninformative Bayes; sample survey ID MODEL AB The term 'small area' or 'small domain' is commonly used to denote a small geographical area that has a small subpopulation of people within a large area. Small area estimation is an important area in survey sampling because of the growing demand for better statistical inference for small areas in public or private surveys. In small area estimation problems the focus is on how to borrow strength across areas in order to develop a reliable estimator and which makes use of available auxiliary information. Some traditional methods for small area problems such as empirical best linear unbiased prediction borrow strength through linear models that provide links to related areas, which may not be appropriate for some survey data. In this article, we propose a stepwise Bayes approach which borrows strength through an objective posterior distribution. This approach results in a generalized constrained Dirichlet posterior estimator when auxiliary information is available for small areas. The objective posterior distribution is based only on the assumption of exchangeability across related areas and does not make any explicit model assumptions. The form of our posterior distribution allows us to assign a weight to each member of the sample. These weights can then be used in a straight forward fashion to make inferences about the small area means. Theoretically, the stepwise Bayes character of the posterior allows one to prove the admissibility of the point estimators suggesting that inferential procedures based on this approach will tend to have good frequentist properties. Numerically, we demonstrate in simulations that the proposed stepwise Bayes approach can have substantial strengths compared to traditional methods. C1 [Qu, Yanping] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Meeden, Glen D.] Univ Minnesota, Sch Stat, Minneapolis, MN 55455 USA. [Zhang, Bo] Oregon State Univ, Biostat Core, Sch Biol & Populat Hlth Sci, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. RP Meeden, GD (reprint author), Univ Minnesota, Sch Stat, Minneapolis, MN 55455 USA. EM glen@stat.umn.edu NR 14 TC 1 Z9 1 U1 2 U2 9 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0094-9655 EI 1563-5163 J9 J STAT COMPUT SIM JI J. Stat. Comput. Simul. PD MAY 3 PY 2015 VL 85 IS 7 SI SI BP 1474 EP 1494 DI 10.1080/00949655.2013.879589 PG 21 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA CA7HC UT WOS:000349087400011 ER PT J AU Kress, WJ Jones, FA Swenson, NG Erickson, DL AF Kress, W. John Jones, F. Andrew Swenson, Nathan G. Erickson, David L. TI Tracking evolutionary diversity and phylogenetic structure across global forest dynamics plots using plant DNA barcodes SO GENOME LA English DT Meeting Abstract C1 [Kress, W. John] Smithsonian Inst, Natl Museum Nat Hist, Washington, DC 20013 USA. [Jones, F. Andrew] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Swenson, Nathan G.] Univ Maryland, Dept Plant Biol, College Pk, MD 20742 USA. [Erickson, David L.] US FDA, Beltsville, MD USA. EM kressj@si.edu NR 0 TC 0 Z9 0 U1 1 U2 4 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 65 AURIGA DR, SUITE 203, OTTAWA, ON K2E 7W6, CANADA SN 0831-2796 EI 1480-3321 J9 GENOME JI Genome PD MAY PY 2015 VL 58 IS 5 BP 239 EP 239 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CQ8MF UT WOS:000360861200205 ER PT J AU Lyn-Cook, B Word, B Joseph, S AF Lyn-Cook, B. Word, B. Joseph, S. TI Promoter methylation of genes in the innate immune system and microRNA 146a expression in systemic lupus erythematosus: Potential new therapeutic targets SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Article; Proceedings Paper CT 11th International Congress on Systemic Lupus Erythematosus CY SEP 02-06, 2015 CL Vienna, AUSTRIA C1 [Lyn-Cook, B.; Word, B.; Joseph, S.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAY-JUN PY 2015 VL 33 IS 3 SU 90 MA P3.36 BP S26 EP S26 PG 1 WC Rheumatology SC Rheumatology GA CQ2HY UT WOS:000360421900096 ER PT J AU Krutzke, L Prill, JM Engler, T Hoffmeister, A Schmidt, CQ Xu, ZL Byrnes, AP Kochanek, S Kreppel, F AF Krutzke, Lea Prill, Jan-Michael Engler, Tatjana Hoffmeister, Andrea Schmidt, Christoph Q. Xu, Zhili Byrnes, Andrew P. Kochanek, Stefan Kreppel, Florian TI Shielding of Ad5 by Minimal Geneti-Chemical Modification: Preventing Clearance While Preserving Infectivity SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Krutzke, Lea; Prill, Jan-Michael; Engler, Tatjana; Hoffmeister, Andrea; Kochanek, Stefan; Kreppel, Florian] Univ Ulm, Gene Therapy, D-89069 Ulm, Germany. [Schmidt, Christoph Q.] Univ Ulm, Pharmacol Nat Prod & Clin Pharmacol, D-89069 Ulm, Germany. [Xu, Zhili; Byrnes, Andrew P.] US FDA, Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 2015 VL 23 SU 1 MA 46 BP S20 EP S20 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700048 ER PT J AU Pripuzova, NS Getie-Kebtie, M Grunseich, C Sweeney, C Malech, H Alterman, MA AF Pripuzova, Natalia S. Getie-Kebtie, Melkamu Grunseich, Christopher Sweeney, Colin Malech, Harry Alterman, Michail A. TI Development of a protein marker panel for characterization of human induced pluripotent stem cells (hiPSCs) using global quantitative proteome analysis SO STEM CELL RESEARCH LA English DT Article ID HUMAN PERIPHERAL-BLOOD; HUMAN SOMATIC-CELLS; IPS CELLS; EPIGENETIC MEMORY; ENERGY-METABOLISM; GENE-EXPRESSION; MS/MS ANALYSIS; STROMAL CELLS; HUMAN ES; GENERATION AB The emergence of new methods for reprogramming of adult somatic cells into induced pluripotent stem cells (iPSC) led to the development of new approaches in drug discovery and regenerative medicine. Investigation of the molecular mechanisms underlying the self-renewal, expansion and differentiation of human iPSC (hiPSC) should lead to improvements in the manufacture of safe and reliable cell therapy products. The goal of our study was qualitative and quantitative proteomic characterizations of hiPSC by means of electrospray ionization (ESI)-MSe and MALDI-TOF/TOF mass spectrometry (MS). Proteomes of hiPSCs of different somatic origins: fibroblasts and peripheral blood CD34(+) cells, reprogrammed by the same technique, were compared with the original somatic cells and hESC. Quantitative proteomic comparison revealed approximately 220 proteins commonly up-regulated in all three pluripotent stem cell lines compared to the primary cells. Expression of 21 proteins previously reported as pluripotency markers was up-regulated in both hiPSCs (8 were confirmed by Western blot). A number of novel candidate marker proteins with the highest fold-change difference between hiPSCs/hESC and somatic cells discovered by MS were confirmed by Western blot. A panel of 22 candidate marker proteins of hiPSC was developed and expression of these proteins was confirmed in 8 additional hiPSC lines. Published by Elsevier B.V. C1 [Pripuzova, Natalia S.; Getie-Kebtie, Melkamu; Alterman, Michail A.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Grunseich, Christopher] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Sweeney, Colin; Malech, Harry] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP Alterman, MA (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM Michail.Alterman@fda.hhs.gov OI Malech, Harry/0000-0001-5874-5775 NR 59 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD MAY PY 2015 VL 14 IS 3 BP 323 EP 338 DI 10.1016/j.scr.2015.01.009 PG 16 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA CP6JR UT WOS:000359993400007 PM 25840413 ER PT J AU McConathy, J Gauvain, K Barone, A Grimaldi, M Parent, E Ponisio, M Leeds, H Rubin, J AF McConathy, Jonathan Gauvain, Karen Barone, Amy Grimaldi, Michael Parent, Ephraim Ponisio, Maria Leeds, Hayden Rubin, Joshua TI FDOPA-PET/MRI for Recurrent Pediatric Brain Tumors: Initial Results SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [McConathy, Jonathan; Parent, Ephraim; Ponisio, Maria; Leeds, Hayden] Washington Univ, Radiol, St Louis, MO USA. [Grimaldi, Michael] Commonwealth Med Coll, Scranton, PA USA. [Gauvain, Karen; Rubin, Joshua] Washington Univ, Pediat, St Louis, MO USA. [Barone, Amy] FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 160 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800161 ER PT J AU Ferguson, S Law, D Sarkar, S AF Ferguson, Sherry Law, Delbert Sarkar, Sumit TI Chronic MPTP treatment produces hyperactivity in male mice which is not alleviated by concurrent trehalose treatment SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 39th Annual Meeting of the Neurobehavioral-Teratology-Society (NBTS) / 15th Biennial Meeting of the International-Neurotoxicology-Association (INA) Held in Conjunction with the 55th Annual Meeting of the Teratology-Society CY JUN 27-JUL 01, 2015 CL Montreal, CANADA SP Neurobehavioral Teratol Soc, Int Neurotoxicol Assoc, Teratol Soc C1 [Ferguson, Sherry; Law, Delbert; Sarkar, Sumit] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 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 2015 VL 49 MA NTX98 BP 132 EP 133 DI 10.1016/j.ntt.2015.04.104 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CL7HI UT WOS:000357142700108 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 plus nitrous oxide SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 39th Annual Meeting of the Neurobehavioral-Teratology-Society (NBTS) / 15th Biennial Meeting of the International-Neurotoxicology-Association (INA) Held in Conjunction with the 55th Annual Meeting of the Teratology-Society CY JUN 27-JUL 01, 2015 CL Montreal, CANADA SP Neurobehavioral Teratol Soc, Int Neurotoxicol Assoc, 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, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 3 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 2015 VL 49 MA NTX137 BP 145 EP 145 DI 10.1016/j.ntt.2015.04.143 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CL7HI UT WOS:000357142700147 ER PT J AU Boison, JO Turnipseed, SB AF Boison, Joe O. Turnipseed, Sherri B. TI Methods of Analysis for Residues and Chemical Contaminants in Aquaculture SO JOURNAL OF AOAC INTERNATIONAL LA English DT Editorial Material C1 [Boison, Joe O.] CFIA, Ctr Vet Drug Residues CVDR Lab, Ottawa, ON, Canada. [Turnipseed, Sherri B.] US FDA, Anim Drugs Res Ctr, Rockville, MD 20857 USA. RP Boison, JO (reprint author), CFIA, Ctr Vet Drug Residues CVDR Lab, Ottawa, ON, Canada. EM Joe.Boison@inspection.gc.ca; Sherri.Turnipseed@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD MAY-JUN PY 2015 VL 98 IS 3 BP 539 EP 540 DI 10.5740/jaoacint.SGE_Boison_Intro PG 2 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400001 PM 26024758 ER PT J AU Boison, JO Turnipseed, SB AF Boison, Joe O. Turnipseed, Sherri B. TI A Review of Aquaculture Practices and Their Impacts on Chemical Food Safety from a Regulatory Perspective SO JOURNAL OF AOAC INTERNATIONAL LA English DT Review ID OMEGA-3-FATTY-ACIDS; DISORDERS; PONDS AB Aquaculture is currently one of the most rapidly growing food production industries in the world. The increasing global importance for this industry stems primarily from the fact that it is reducing the gap between the supply and demand for fish products. Commercial aquaculture contributes significantly to the economies of many countries since high-value fish species are a major source of foreign exchange. This review looks at the aquaculture industry, the issues raised by the production of fish through aquaculture for food security, the sustainability of the practice to agriculture, what the future holds for the industry in the next 10-20 years, and why there is a need to have available analytical procedures to regulate the safe use of chemicals and veterinary drugs in aquaculture. C1 [Boison, Joe O.] CFIA, Ctr Vet Drug Residues CVDR Lab, Saskatoon, SK S7N 2R3, Canada. [Turnipseed, Sherri B.] US FDA, Off Regulatory Affairs, Anim Drugs Res Ctr, Denver, CO 80225 USA. RP Boison, JO (reprint author), CFIA, Ctr Vet Drug Residues CVDR Lab, 116 Vet Rd, Saskatoon, SK S7N 2R3, Canada. EM joe.boison@inspection.gc.ca NR 21 TC 0 Z9 0 U1 2 U2 12 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 2015 VL 98 IS 3 BP 541 EP 549 DI 10.5740/jaoacint.15-033 PG 9 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400002 PM 26024870 ER PT J AU Turnipseed, SB Lohne, JJ Boison, JO AF Turnipseed, Sherri B. Lohne, Jack J. Boison, Joe O. TI Review: Application of High Resolution Mass Spectrometry to Monitor Veterinary Drug Residues in Aquacultured Products SO JOURNAL OF AOAC INTERNATIONAL LA English DT Review ID POLYBROMINATED DIPHENYL ETHERS; POLYCYCLIC AROMATIC-HYDROCARBONS; PERSISTENT ORGANIC POLLUTANTS; FOOD CONTAMINANT ANALYSIS; LIQUID-CHROMATOGRAPHY; ION-TRAP; BIOLOGICAL SAMPLES; TILAPIA FILLETS; QTOF-MS; FISH AB High resolution MS (HRMS) instruments provide accurate mass measurements. With HRMS, virtually an unlimited number of compounds can be analyzed simultaneously because full-scan data are collected, rather than preselected ion transitions corresponding to specific compounds. This enables the development of methods that can monitor for a wide scope of residues and contaminants in aquacultured fish and shellfish including antibiotics, metabolites, and emerging contaminants. Applications of HRMS to the analysis of veterinary drug residues in aquacultured products are summarized in this review including methods for screening, quantifying, and identifying drug residues in these matrixes. The use of targeted, semi-targeted, and nontargeted analysis of HRMS data and the implications to the global aquaculture industry are also reviewed. C1 [Turnipseed, Sherri B.; Lohne, Jack J.] US FDA, Anim Drugs Res Ctr, Denver Fed Ctr, Denver, CO 80225 USA. [Boison, Joe O.] Canadian Food Inspect Agcy, Ctr Vet Drug Residues CVDR Lab, Saskatoon, SK S7N 2R3, Canada. RP Turnipseed, SB (reprint author), US FDA, Anim Drugs Res Ctr, Denver Fed Ctr, POB 25087, Denver, CO 80225 USA. EM Sherri.turnipseed@fda.hhs.gov NR 61 TC 4 Z9 4 U1 9 U2 41 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 2015 VL 98 IS 3 BP 550 EP 558 DI 10.5740/jaoacint.14-265 PG 9 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400003 PM 26025003 ER PT J AU Veach, BT Baker, CA Kibbey, JH Fong, A Broadaway, BJ Drake, CP AF Veach, Brian T. Baker, Chris A. Kibbey, John H. Fong, Andrew Broadaway, Bryanna J. Drake, Connie P. TI Quantitation of Chloramphenicol and Nitrofuran Metabolites in Aquaculture Products Using Microwave-Assisted Derivatization, Automated SPE, and LC-MS/MS SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID MASS-SPECTROMETRY; RESIDUES; 3-AMINO-2-OXAZOLIDINONE; FURAZOLIDONE AB This paper describes a rapid and robust method utilizing microwave-assisted derivatization, automated SPE, and LC-MS/MS for the quantitation and confirmation of chloramphenicol (CAP) and nitrofuran metabolites in various aquaculture matrixes. The use of equipment presented in this work allowed extractions to be completed on average within 6 h, with quantitation accuracy ranging from 89 to 107% and RSD <= 8.3%. The demonstrated detection limits for all the nitrofuran metabolites of interest in three different matrixes were <= 0.06 ng/g, with a quantitation limit of <= 0.2 ng/g. Additionally, the method exhibited a CAP detection limit for all matrixes <= 0.01 ng/g and an LOQ of <= 0.03 ng/g. C1 [Veach, Brian T.; Baker, Chris A.; Kibbey, John H.; Fong, Andrew; Broadaway, Bryanna J.; Drake, Connie P.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. RP Veach, BT (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM brian.veach@fda.hhs.gov NR 17 TC 2 Z9 3 U1 4 U2 10 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 2015 VL 98 IS 3 BP 588 EP 594 DI 10.5740/jaoacint.14-271 PG 7 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400008 PM 26025616 ER PT J AU El-Demerdash, A Song, FH Reel, RK Hillegas, J Smith, RE AF El-Demerdash, Aref Song, Fenhong Reel, Robin K. Hillegas, Judy Smith, Robert E. TI Simultaneous Determination of Nitrofuran Metabolites and Chloramphenicol in Shrimp with a Single Extraction and LC-MS/MS Analysis SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID TANDEM MASS-SPECTROMETRY; TISSUE-BOUND METABOLITES; LIQUID-CHROMATOGRAPHY; ANTIMICROBIAL AGENTS; PORCINE TISSUES; POULTRY MUSCLE; RESIDUES; CONFIRMATION; HONEY; MILK AB A method has been developed to quantify the nitrofuran metabolites 3-amino-5-morphorinomethyl-1,3-oxazolidinone, 3-amino-oxazolidinone, 1-aminohydantoin, and semicarbazide, as well as chloramphenicol in shrimp with a single extraction procedure followed by LC-MS/MS analysis. Dynamic selected reaction monitoring with positive and negative ionization mode switching was used. The method LODs were 0.5 ng/g for the nitrofuran metabolites and 0.3 ng/g for chloramphenicol. C1 [El-Demerdash, Aref; Reel, Robin K.; Hillegas, Judy; Smith, Robert E.] US FDA, Lenexa, KS 66214 USA. [Song, Fenhong] US FDA, ORA ORS MPTSS, Rockville, MD 20857 USA. RP El-Demerdash, A (reprint author), US FDA, 11510 W 80th St, Lenexa, KS 66214 USA. EM aref.el-demerdash@fda.hhs.gov; robert.smith@fda.hhs.gov NR 27 TC 1 Z9 2 U1 6 U2 20 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 2015 VL 98 IS 3 BP 595 EP 601 DI 10.5740/jaoacint.14-261 PG 7 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400009 PM 26025729 ER PT J AU An, HJ Parrales, L Wang, K Cain, T Hollins, R Forrest, D Liao, B Paek, HC Sram, J AF An, Haejung Parrales, Lenin Wang, Kai Cain, Teresa Hollins, Ralph Forrest, Douglas Liao, Benjamin Paek, Han Chol Sram, Jacqueline TI Quantitative Analysis of Nitrofuran Metabolites and Chloramphenicol in Shrimp Using Acetonitrile Extraction and Liquid Chromatograph-Tandem Mass Spectrometric Detection: A Single Laboratory Validation SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID ANTIBIOTIC USE; HEALTH; RESIDUES; FURAZOLIDONE; AQUACULTURE; FOOD AB A method was developed and validated for the simultaneous analysis of chloramphenicol and nitrofuran metabolites in shrimp according to the guideline established by the U.S. Food and Drug Administration Office of Foods and Veterinary Medicine. The extraction steps following the overnight hydrolysis and derivatization are simpler than the conventional ethyl acetate extraction method. The main steps are neutralization of hydrolysates, addition of acetonitrile for extraction, and salting out of organic phase from the acetonitrile-aqueous mixture. Extracts are analyzed for chloramphenicol and nitrofuran metabolites by LC-MS/MS in a single injection with polarity switching between the positive electrospray ionization (ESI) mode for the nitrofurans and the negative ESI mode for chloramphenicol. Recoveries calculated using an extracted matrix calibration curve and labeled internal standards for chloramphenicol and nitrofurans ranged from 98.6 to 109.2% with RSDs less than 18%. This method that combines the analysis of chloramphenicol with the nitrofurans was shown to generate analytical results similar to those obtained using the individual drug-class analytical methods currently used for the analysis of chloramphenicol or nitrofurans in shrimp. C1 [An, Haejung; Parrales, Lenin; Wang, Kai; Cain, Teresa; Hollins, Ralph; Forrest, Douglas; Liao, Benjamin; Paek, Han Chol; Sram, Jacqueline] US FDA, Pacific Reg Lab Southwest, Irvine, CA 92612 USA. RP An, HJ (reprint author), US FDA, Pacific Reg Lab Southwest, Irvine, CA 92612 USA. EM Haejung.An@fda.hhs.gov NR 22 TC 2 Z9 3 U1 1 U2 8 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 2015 VL 98 IS 3 BP 602 EP 608 DI 10.5740/jaoacint.14-262 PG 7 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400010 PM 26025834 ER PT J AU Bjornsdottir-Butler, K Bencsath, FA Benner, RA AF Bjornsdottir-Butler, Kristin Bencsath, F. Aladar Benner, Ronald A., Jr. TI Modification and Single-Laboratory Validation of AOAC Official Method 977.13 for Histamine in Seafood to Improve Sample Throughput SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID TANDEM MASS-SPECTROMETRY; SOLID-PHASE EXTRACTION; BIOGENIC-AMINES; FISH PRODUCTS; FLUOROMETRIC-DETERMINATION; RAPID-DETERMINATION; KATSUWONUS-PELAMIS; TUNA; ELISA; HPLC AB Histamine is the main causative agent in scombrotoxin fish poisoning, the most frequently reported illness related to fish consumption. The AOAC official method for histamine determination in fish is the fluorometric method AOAC 977.13, which is sensitive and reproducible but somewhat labor intensive and time consuming. We investigated multiple modifications to this method in an attempt to reduce assay time and increase sample throughput while maintaining the performance of the original method. Some of the attempted modifications negatively affected the performance characteristics of the method. However, omitting the heating step during extraction and replacing the cuvette style fluorometer with a microplate reader retained method performance while increasing sample throughput. Therefore, we adopted these modifications and conducted a single-laboratory validation. The recovery, precision (RSD), and LOD of the modified method assessed by the single-laboratory validation ranged from 92 to 105%, 1 to 3%, and 0.2 to 0.5 ppm, respectively, in tuna, mahi-mahi, and Spanish mackerel samples. We conclude that the AOAC 977.13 fluorometric method, modified as described, will improve assay time and sample throughput efficiency cumulatively, as the number of sample units analyzed increases. We anticipate that this modified method could be used by regulatory agencies and other laboratories following successful multilaboratory validation. C1 [Bjornsdottir-Butler, Kristin; Bencsath, F. Aladar; Benner, Ronald A., Jr.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Bjornsdottir-Butler, K (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. EM Kristin.Butler@fda.hhs.gov NR 27 TC 0 Z9 0 U1 3 U2 5 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 2015 VL 98 IS 3 BP 622 EP 627 DI 10.5740/jaoacint.14-194 PG 6 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400012 PM 26086251 ER PT J AU Andersen, WC Casey, CR Schneider, MJ Turnipseed, SB AF Andersen, Wendy C. Casey, Christine R. Schneider, Marilyn J. Turnipseed, Sherri B. TI Expansion of the Scope of AOAC First Action Method 2012.25-Single-Laboratory Validation of Triphenylmethane Dye and Leuco Metabolite Analysis in Shrimp, Tilapia, Catfish, and Salmon by LC-MS/MS SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID TANDEM MASS-SPECTROMETRY; MALACHITE GREEN; LIQUID-CHROMATOGRAPHY; GENTIAN-VIOLET; LEUCOMALACHITE GREEN; AQUACULTURE PRODUCTS; BRILLIANT GREEN; CRYSTAL VIOLET; FISH-TISSUES; RESIDUES AB Prior to conducting a collaborative study of AOAC First Action 2012.25 LC-MS/MS analytical method for the determination of residues of three triphenylmethane dyes (malachite green, crystal violet, and brilliant green) and their metabolites (leucomalachite green and leucocrystal violet) in seafood, a single-laboratory validation of method 2012.25 was performed to expand the scope of the method to other seafood matrixes including salmon, catfish, tilapia, and shrimp. The validation included the analysis of fortified and incurred residues over multiple weeks to assess analyte stability in matrix at -80 degrees C, a comparison of calibration methods over the range 0.25 to 4 mu g/kg, study of matrix effects for analyte quantification, and qualitative identification of targeted analytes. Method accuracy ranged from 88 to 112% with 13% RSD or less for samples fortified at 0.5, 1.0, and 2.0 mu g/kg. Analyte identification and determination limits were determined by procedures recommended both by the U.S. Food and Drug Administration and the European Commission. Method detection limits and decision limits ranged from 0.05 to 0.24 mu g/kg and 0.08 to 0.54 mu g/kg, respectively. AOAC First Action Method 2012.25 with an extracted matrix calibration curve and internal standard correction is suitable for the determination of triphenylmethane dyes and leuco metabolites in salmon, catfish, tilapia, and shrimp by LC-MS/MS at a residue determination level of 0.5 mu g/kg or below. C1 [Andersen, Wendy C.; Turnipseed, Sherri B.] US FDA, Off Regulatory Affairs, Anim Drugs Res Ctr, Denver, CO 80225 USA. [Casey, Christine R.] US FDA, Off Regulatory Affairs, Denver Lab, Denver, CO 80225 USA. [Schneider, Marilyn J.] ARS, USDA, Eastern Reg Res Ctr, Wyndmoor, PA 19038 USA. RP Andersen, WC (reprint author), US FDA, Off Regulatory Affairs, Anim Drugs Res Ctr, Denver Fed Ctr Bldg 20,W 6th Ave & Kipling St, Denver, CO 80225 USA. EM wendy.andersen@fda.hhs.gov NR 21 TC 1 Z9 1 U1 2 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 2015 VL 98 IS 3 BP 636 EP 648 DI 10.5740/jaoacint.14-264 PG 13 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400014 PM 26024871 ER PT J AU Schneider, MJ Andersen, WC AF Schneider, Marilyn J. Andersen, Wendy C. TI Determination of Triphenylmethane Dyes and Their Metabolites in Salmon, Catfish, and Shrimp by LC-MS/MS Using AOAC First Action Method 2012.25: Collaborative Study SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID MALACHITE GREEN; LEUCOMALACHITE GREEN; BRILLIANT GREEN; CRYSTAL VIOLET; RATS AB A collaborative study was conducted to evaluate the AOAC First Action 2012.25 LC-MS/MS analytical method for the determination of residues of three triphenylmethane dyes (malachite green, crystal violet, and brilliant green) and their metabolites (leucomalachite green and leucocrystal violet) in seafood. Fourteen laboratories from the United States, Canada, and the European Union member states participated in the study including national and state regulatory laboratories, university and national research laboratories, and private analytical testing laboratories. A variety of LC-MS/MS instruments were used for the analysis. Each participating laboratory received blinded test samples in duplicate of salmon, catfish, and shrimp consisting of negative control matrix; matrix fortified with residues at 0.42, 0.90, and 1.75 mu g/kg; and samples of incurred matrix. The analytical results from each participating laboratory were evaluated for both quantitative residue determination and qualitative identification of targeted analytes. Results from statistical analysis showed that this method provided excellent trueness (generally >= 90% recovery) and precision (RSDr generally <= 10%, HorRat <1). The Study Directors recommend Method 2012.25 for Final Action status. C1 [Schneider, Marilyn J.] ARS, USDA, Eastern Reg Res Ctr, Wyndmoor, PA 19038 USA. [Andersen, Wendy C.] US FDA, Off Regulatory Affairs, Anim Drugs Res Ctr, Denver, CO 80225 USA. RP Andersen, WC (reprint author), US FDA, Off Regulatory Affairs, Anim Drugs Res Ctr, Denver Fed Ctr Bldg 20,W 6th Ave & Kipling St, Denver, CO 80225 USA. EM wendy.andersen@fda.hhs.gov NR 17 TC 2 Z9 2 U1 3 U2 5 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 2015 VL 98 IS 3 BP 658 EP 670 DI 10.5740/jaoacint.14-263 PG 13 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400016 PM 26025133 ER PT J AU Vega, VA Young, M Dorsey, L AF Vega, Victor A. Young, Michelle Dorsey, LaTisha TI A Quick Assay for the Quantitation of Deoxynivalenol in Grain Samples by Liquid Chromatography with UV Detection SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article AB A quick and effective extraction of deoxynivalenol (DON) in food samples is described. The samples were extracted using 80% acetonitrile water solution, followed by a second extraction using an 80% methanol water solution. The extract was then subjected to an immunoaffinity column (IAC) cleanup. Quantification of isolated analyte was obtained by LC with UV detection at 220 nm. LC-UV parameters were optimized with a C18 LC column resulting in a 6 min run time. Certified reference materials (CRMs) of three different matrixes at three different levels were analyzed. Wheat, barley, and corn samples containing 0.5, 1.0, and 1.9 mg/kg, respectively, were analyzed. Recoveries from all CRM samples were calculated using an external standard curve (Figure 1) and ranged from 80 to 102%. Confirmation of DON in the sample extracts was accomplished using LC/MS. This method provides a rapid, specific, and robust assay for the analysis of DON with an uncertainty measurement of 12.2% and method detention limit of less than 0.125 mg/kg. Other methods that do not use an IAC produce dirty extracts that sometimes require washing the chromatographic column after each sample injection. The method presented here does not require washing the column, which leads to faster LC analysis time/sample. C1 [Vega, Victor A.; Young, Michelle; Dorsey, LaTisha] 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 7 TC 0 Z9 0 U1 2 U2 10 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 2015 VL 98 IS 3 BP 806 EP 809 DI 10.5740/jaoacint.14-241 PG 4 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CL4DS UT WOS:000356903400038 PM 26086259 ER PT J AU Iskra, T Sacramo, A Gallo, C Godavarti, R Chen, S Lute, S Brorson, K AF Iskra, Timothy Sacramo, Ashley Gallo, Chris Godavarti, Ranga Chen, Shuang Lute, Scott Brorson, Kurt TI Development of a Modular Virus Clearance Package for Anion Exchange Chromatography Operated in Weak Partitioning Mode SO BIOTECHNOLOGY PROGRESS LA English DT Article DE monoclonal antibody; purification; anion-exchange chromatography; viral clearance ID FAST-FLOW CHROMATOGRAPHY; VIRAL CLEARANCE; MONOCLONAL-ANTIBODIES; MEMBRANE ADSORBERS; PURIFICATION; REMOVAL; PROTEIN; FILTER; SEPARATIONS; FILTRATION AB Anion exchange chromatography (AEX) operated under weak partitioning mode has been proven to be a powerful polishing step as well as a robust viral clearance step in Pfizer's monoclonal antibody (mAb) platform purification process. A multivariate design of experiment (DoE) study was conducted to understand the impact of operating parameters and feedstream impurity levels on viral clearance by weak partitioning mode AEX. Bacteriophage was used initially as a surrogate for neutral and acidic isoelectric point mammalian viruses (e.g., retrovirus and parvovirus). Five different mAbs were used in the evaluation of process parameters such as load challenge (both product and impurities), load pH, load conductivity, and contact time (bed height and flow-rate). The operating ranges obtained from phage clearance studies and Pfizer's historical data were used to define an appropriate operating range for a subsequent clearance study with model retrovirus and parvovirus. Both phage and virus clearance evaluations included feedstreams containing different levels of impurities such as high molecular mass species (HMMS), host cell proteins (HCPs), and host cell DNA. For all the conditions tested, over 5 log(10) of clearance for both retrovirus and parvovirus was achieved. The results demonstrated that weak partitioning mode AEX chromatography is a robust step for viral clearance and has the potential to be included as part of the modular viral clearance approach. (C) 2015 American Institute of Chemical Engineers C1 [Iskra, Timothy; Sacramo, Ashley; Gallo, Chris; Godavarti, Ranga] Pfizer Inc, Purificat Proc Dev, Andover, MA 01810 USA. [Chen, Shuang] Pfizer Inc, Purificat Proc Dev, Chesterfield, MO 63017 USA. [Lute, Scott; Brorson, Kurt] CDER FDA, Off Biotechnol Prod, Silver Spring, MD 20903 USA. RP Godavarti, R (reprint author), Pfizer Inc, Purificat Proc Dev, Andover, MA 01810 USA. EM ranga.godavarti@pfizer.com NR 26 TC 1 Z9 1 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8756-7938 EI 1520-6033 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD MAY-JUN PY 2015 VL 31 IS 3 BP 750 EP 757 DI 10.1002/btpr.2080 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CL0ZD UT WOS:000356670700017 PM 25826186 ER PT J AU Zhao, SH Mukherjee, S Chen, YS Li, C Young, S Warren, M Abbott, J Friedman, S Kabera, C Karlsson, M McDermott, PF AF Zhao, Shaohua Mukherjee, Sampa Chen, Yuansha Li, Cong Young, Shenia Warren, Melissa Abbott, Jason Friedman, Sharon Kabera, Claudine Karlsson, Maria McDermott, Patrick F. TI Novel gentamicin resistance genes in Campylobacter isolated from humans and retail meats in the USA SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE Campylobacter; gentamicin resistance; NARMS; PCR; WGS ID AMINOGLYCOSIDE RESISTANCE; UNITED-STATES; ANTIMICROBIAL RESISTANCE; ENTEROCOCCUS-FAECALIS; JEJUNI; IDENTIFICATION; ANTIBIOTICS; DIVERSITY; GENETICS; PLASMID AB Objectives: To understand the molecular epidemiology of gentamicin-resistant Campylobacter and investigate aminoglycoside resistance mechanisms. Methods: One-hundred-and-fifty-one gentamicin-resistant Campylobacter isolates from humans (n = 38 Campylobacter jejuni; n = 41, Campylobacter coli) and retail chickens (n = 72 C. coli), were screened for the presence of gentamicin resistance genes by PCR and subtyped using PFGE. A subset of the isolates (n = 41) was analysed using WGS. Results: Nine variants of gentamicin resistance genes were identified: aph(2 ''')-Ib, Ic, Ig, If, If1, If(3), Ih, aac(6')-Ie/aph(2 '')-Ia and aac(6')-Ie/aph(2 '')-If(2). The aph(2 '')-Ib, Ic, If1, If(3), Ih and aac(6')-Ie/aph(2 '')-If(2) variants were identified for the first time in Campylobacter. Human isolates showed more diverse aminoglycoside resistance genes than did retail chicken isolates, in which only aph(2 '')-Ic and -Ig were identified. The aph(2 '')-Ig gene was only gene shared by C. coli isolates from human (n = 27) and retail chicken (n = 69). These isolates displayed the same resistance profile and similar PFGE patterns, suggesting that contaminated retail chicken was probably the source of human C. coli infections. Human isolates were genetically diverse and generally more resistant than the retail chicken isolates. The most frequent co-resistance was to tetracycline (78/79, 98.7%), followed by ciprofloxacin/nalidixic acid (46/79, 58.2%), erythromycin and azithromycin (36/79, 45.6%), telithromycin (32/79, 40.5%) and clindamycin (18/79, 22.8%). All human and retail meat isolates were susceptible to florfenicol. Conclusions: This study demonstrated that several new aminoglycoside resistance genes underlie the recent emergence of gentamicin-resistant Campylobacter, and that, in addition to contaminated retail chicken, other sources have also contributed to gentamicin-resistant Campylobacter infections in humans. C1 [Zhao, Shaohua; Mukherjee, Sampa; Chen, Yuansha; Li, Cong; Young, Shenia; Warren, Melissa; Abbott, Jason; Friedman, Sharon; Kabera, Claudine; McDermott, Patrick F.] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD USA. [Karlsson, Maria] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. RP Zhao, SH (reprint author), US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD USA. EM shaohua.zhao@fda.hhs.gov NR 32 TC 3 Z9 3 U1 3 U2 8 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 MAY PY 2015 VL 70 IS 5 BP 1314 EP 1321 DI 10.1093/jac/dkv001 PG 8 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA CK0YW UT WOS:000355932800007 PM 25645207 ER PT J AU Li, HB Shi, Q AF Li, Haibo Shi, Qiang TI Drugs and Diseases Interacting with Cigarette Smoking in US Prescription Drug Labelling SO CLINICAL PHARMACOKINETICS LA English DT Review ID EVENT REPORTING SYSTEM; TOBACCO SMOKING; LIVER AB The US Food and Drug Administration (FDA) draft guidance for industry on drug interaction studies recommends, but does not mandate, that both cigarette smokers and non-smokers can be used to study drug metabolism in clinical trials, and that important results related to smoking should be included in drug labelling to guide medication usage. This study aimed to provide a comprehensive review of drugs or diseases interacting with smoking, as presented in all US drug labelling. The 62,857 drug labels deposited in the FDA Online Label Repository were searched using the keywords 'smoke', 'smoker(s)', 'smoking', 'tobacco' and 'cigarette(s)' on 19 June 2014. The resultant records were refined to include only human prescription drug labelling, for manual examination. For 188 single-active-ingredient drugs and 36 multiple-active-ingredient drugs, the labelling was found to contain smoking-related information. The pharmacokinetics of 29 and 21 single-active-ingredient drugs were affected and unaffected, respectively, by smoking. For the remaining drugs, the provided information related to smoking affecting efficacy, safety or diseases but not pharmacokinetics. Depending on the nature of specific drugs, the perturbation in pharmacokinetic parameters in smokers ranged from 13 to 500 %, in comparison with non-smokers. Dosage modifications in smokers are necessary for four drugs and may be necessary for six drugs, but are unnecessary for seven drugs although the pharmacokinetic parameters of four of them are affected by smoking. Cigarette smoking is a risk factor for 16 types of diseases or adverse drug reactions. For one single-active-ingredient contraceptive drug and 10 multiple-active-ingredient contraceptive drugs, a black box warning (the FDA's strongest safety warning) is included in the labelling for increased risks of heart attacks and strokes in female smokers, and "women are strongly advised not to smoke" when using these drugs. This study presents the first comprehensive overview of cigarette smoking interacting with drugs and/or diseases, as presented in US drug labelling. C1 [Li, Haibo] Nantong Ctr Dis Control & Prevent, Dept Microbiol, Nantong 226007, Jiangsu, Peoples R China. [Li, Haibo; Shi, Qiang] Food & Drug Adm, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. RP Shi, Q (reprint author), Food & Drug Adm, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM qiang.shi@fda.hhs.gov FU Research Participation Program at the National Center for Toxicological Research; US Department of Energy; US FDA; International Cooperation and Exchanges Program of the Department of Health in Jiangsu Province, China FX Dr. Haibo Li's work was supported by the Research Participation Program at the National Center for Toxicological Research, administrated by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US FDA. Dr. Li's work was also supported by the International Cooperation and Exchanges (2012) Program of the Department of Health in Jiangsu Province, China. Dr. Li now works in the Department of Clinical Laboratory Medicine, Nantong Maternal and Child Health Hospital, 399 Century Avenue, Nantong, Jiangsu 226018, China. NR 21 TC 4 Z9 4 U1 0 U2 5 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 MAY PY 2015 VL 54 IS 5 BP 493 EP 501 DI 10.1007/s40262-015-0246-6 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CJ2TX UT WOS:000355338600003 PM 25701380 ER PT J AU Speit, G Kojima, H Burlinson, B Collins, AR Kasper, P Plappert-Helbig, U Uno, Y Vasquez, M Beevers, C De Boeck, M Escobark, PA Kitamoto, S Pant, K Pfuhler, S Tanaka, J Levy, DD AF Speit, Guenter Kojima, Hajime Burlinson, Brian Collins, Andrew R. Kasper, Peter Plappert-Helbig, Ulla Uno, Yoshifumi Vasquez, Marie Beevers, Carol De Boeck, Marlies Escobark, Patricia A. Kitamoto, Sachiko Pant, Kamala Pfuhler, Stefan Tanaka, Jin Levy, Dan D. TI Critical issues with the in vivo comet assay: A report of the comet assay working group in the 6th International Workshop on Genotoxicity Testing (IWGT) SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article; Proceedings Paper CT 6th International Workshop on Genotoxicity Testing (IWGT) CY OCT 31-NOV 01, 2013 CL Foz do Iguacu, BRAZIL DE Genotoxicity testing; Laboratory proficiency; Test protocol; Tissue toxicity ID DNA-DAMAGE; CELLS; RAT; REPAIR; RECOMMENDATIONS; CYTOTOXICITY; CARCINOGENS; VITRO; VARIABILITY; ORGANS AB As a part of the 6th IWGT, an expert working group on the comet assay evaluated critical topics related to the use of the in vivo comet assay in regulatory genotoxicity testing. The areas covered were: identification of the domain of applicability and regulatory acceptance, identification of critical parameters of the protocol and attempts to standardize the assay, experience with combination and integration with other in vivo studies, demonstration of laboratory proficiency, sensitivity and power of the protocol used, use of different tissues, freezing of samples, and choice of appropriate measures of cytotoxicity. The standard protocol detects various types of DNA lesions but it does not detect all types of DNA damage. Modifications of the standard protocol may be used to detect additional types of specific DNA damage (e.g., cross-links, bulky adducts, oxidized bases). In addition, the working group identified critical parameters that should be carefully controlled and described in detail in every published study protocol. In vivo comet assay results are more reliable if they were obtained in laboratories that have demonstrated proficiency. This includes demonstration of adequate response to vehicle controls and an adequate response to a positive control for each tissue being examined. There was a general agreement that freezing of samples is an option but more data are needed in order to establish generally accepted protocols. With regard to tissue toxicity, the working group concluded that cytotoxicity could be a confounder of comet results. It is recommended to look at multiple parameters such as histopathological observations, organ-specific clinical chemistry as well as indicators of tissue inflammation to decide whether compound-specific toxicity might influence the result. The expert working group concluded that the alkaline in vivo comet assay is a mature test for the evaluation of genotoxicity and can be recommended to regulatory agencies for use. (C) 2014 Elsevier B.V. All rights reserved. C1 [Speit, Guenter] Univ Ulm, Inst Human Genet, D-89069 Ulm, Germany. [Kojima, Hajime] Natl Inst Hlth Sci, Japanese Ctr Validat Alternat Methods, Tokyo, Japan. [Burlinson, Brian] Huntingdon Life Sci, Huntingdon, England. [Collins, Andrew R.] Univ Oslo, Dept Nutr, Oslo, Norway. [Kasper, Peter] Fed Inst Drugs & Med Devices BfArM, Bonn, Germany. [Plappert-Helbig, Ulla] Novartis Inst BioMed Res, Preclin Safety, Basel, Switzerland. [Uno, Yoshifumi] Mitsubishi Tanabe Pharma Co, Chiba, Japan. [Vasquez, Marie] Helix3 Inc, RTP, Morrisville, NC USA. [Beevers, Carol] Covance Labs Ltd, Harrogate, Yorks, England. [De Boeck, Marlies] Janssen Res & Dev, Beerse, Belgium. [Escobark, Patricia A.] Boehringer Ingelheim Pharmaceut Inc, Nonclin Drug Safety, Ridgefield, CT 06877 USA. [Kitamoto, Sachiko] Sumitomo Chem Co Ltd, Osaka, Japan. [Pant, Kamala] BioReliance SAFC, Rockville, MD USA. [Pfuhler, Stefan] Procter & Gamble Co, Global Prod Stewardship, Mason, OH USA. [Tanaka, Jin] Public Interest Inc Fdn Biosafety Res Ctr, Shizuoka, Japan. [Levy, Dan D.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Speit, G (reprint author), Univ Ulm, Inst Human Genet, D-89069 Ulm, Germany. EM guenter.speit@uni-ulm.de NR 46 TC 8 Z9 9 U1 3 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 1 PY 2015 VL 783 SI SI BP 6 EP 12 DI 10.1016/j.mrgentox.2014.09.006 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CJ2YX UT WOS:000355351700002 PM 25953395 ER PT J AU Gollapudi, BB Lynch, AM Heflich, RH Dertinger, SD Dobrovolsky, VN Froetschl, R Horibata, K Kenyon, MO Kimoto, T Lovell, DP Stankowski, LF White, PA Witt, KL Tanir, JY AF Gollapudi, B. Bhaskar Lynch, Anthony M. Heflich, Robert H. Dertinger, Stephen D. Dobrovolsky, Vasily N. Froetschl, Roland Horibata, Katsuyoshi Kenyon, Michelle O. Kimoto, Takafumi Lovell, David P. Stankowski, Leon F., Jr. White, Paul A. Witt, Kristine L. Tanir, Jennifer Y. TI The in vivo Pig-a assay: A report of the International Workshop On Genotoxicity Testing (IWGT) Workgroup SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article; Proceedings Paper CT 6th International Workshop on Genotoxicity Testing (IWGT) CY OCT 31-NOV 01, 2013 CL Foz do Iguacu, BRAZIL DE Red blood cells; Reticulocytes; Glycosylphosphatidylinositol; Flow cytometry; CD59; Mutation ID GENE MUTATION ASSAY; ETHYL-N-NITROSOUREA; RED-BLOOD-CELLS; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; SPLEEN T-CELLS; FLOW-CYTOMETRIC DETECTION; BONE-MARROW ERYTHROIDS; LESCH-NYHAN-SYNDROME; END-POINTS; 1,3-PROPANE SULTONE AB The in vivo Pig-a assay uses flow cytometry to measure phenotypic variants for antibody binding to cell surface glycosylphosphatidylinositol (GPI)-anchored proteins. There is good evidence suggesting that the absence of antibody binding is the result of a mutation in the endogenous X-linked Pig-a gene, which forms the rationale for the assay. Although the assay has been performed with several types of hematopoietic cells and in a variety of mammalian species, including humans, currently it' is optimized only for measuring CD59-deficient (presumed Pig-a mutant) erythrocytes in the peripheral blood of rats. An expert workgroup formed by the International Workshop on Genotoxicity Testing considered the state of assay development and the potential of the assay for regulatory use. Consensus was reached on what is known about the Pig-a assay and how it should be conducted, and recommendations were made on additional data and refinements that would help to further enhance the assay for use in hazard identification and risk assessment. Published by Elsevier B.V. C1 [Gollapudi, B. Bhaskar] Exponent, Midland, MI USA. [Lynch, Anthony M.] GlaxoSmithKline, Stevenage, Herts, England. [Heflich, Robert H.; Dobrovolsky, Vasily N.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Dertinger, Stephen D.] Litron Labs, Rochester, NY USA. [Froetschl, Roland] Fed Inst Drugs & Med Devices, Bonn, Germany. [Horibata, Katsuyoshi] Natl Inst Hlth Sci, Tokyo, Japan. [Kenyon, Michelle O.] Pfizer Global Res & Dev, Groton, CT USA. [Kimoto, Takafumi] Teijin Pharma, Tokyo, Japan. [Lovell, David P.] Univ London, London WC1E 7HU, England. [Stankowski, Leon F., Jr.] BioReliance, Rockville, MD USA. [White, Paul A.] Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. [Witt, Kristine L.] NIEHS, NIH, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Tanir, Jennifer Y.] Hlth & Environm Sci Inst, Washington, DC USA. RP Heflich, RH (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM robert.heflich@fda.hhs.gov OI white, paul/0000-0001-5853-4759 FU National Institute of Health/National Institute of Environmental Health Sciences (NIEHS) [R44ES021973] FX The views expressed in this report are not necessarily shared by the institutions at which the workgroup members are employed. The information in these materials is not a formal dissemination of information by the U.S. Food and Drug Administration and does not represent agency position or policy. Data presented in this communication were partially funded by a grant from the National Institute of Health/National Institute of Environmental Health Sciences (NIEHS; grant no. R44ES021973). The contents of this report are solely the responsibility of the authors, and do not necessarily represent the official views of the NIEHS. NR 66 TC 34 Z9 34 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 1 PY 2015 VL 783 SI SI BP 23 EP 35 DI 10.1016/j.mrgentox.2014.09.007 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CJ2YX UT WOS:000355351700005 PM 25953398 ER PT J AU MacGregor, JT Frotschl, R White, PA Crump, KS Eastmond, DA Fukushima, S Gueard, M Hayashi, M Soeteman-Hernadez, LG Kasamatsu, T Levy, DD Morita, T Muller, L Schoeny, R Schuler, MJ Thybaud, V Johnson, GE AF MacGregor, James T. Froetschl, Roland White, Paul A. Crump, Kenny S. Eastmond, David A. Fukushima, Shoji Guerard, Melanie Hayashi, Makoto Soeteman-Hernandez, Lya G. Kasamatsu, Toshio Levy, Dan D. Morita, Takeshi Mueller, Lutz Schoeny, Rita Schuler, Maik J. Thybaud, Veronique Johnson, George E. TI IWGT report on quantitative approaches to genotoxicity risk assessment I. Methods and metrics for defining exposure-response relationships and points of departure (PoDs) SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article; Proceedings Paper CT 6th International Workshop on Genotoxicity Testing (IWGT) CY OCT 31-NOV 01, 2013 CL Foz do Iguacu, BRAZIL DE Genotoxicity; Quantitative risk assessment; Points of departure; Benchmark dose ID PREDICTING RODENT CARCINOGENICITY; GENETIC TOXICITY ASSAYS; CONTINUOUS END-POINTS; THRESHOLD; TOXICOLOGY; POTENCY; CHEMICALS; LIMITS AB This report summarizes the discussion, conclusions, and points of consensus of the IWGT Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (QWG) based on a meeting in Foz do Iguacu, Brazil October 31 November 2, 2013. Topics addressed included (1) the need for quantitative dose response analysis, (2) methods to analyze exposure response relationships & derive point of departure (PoD) metrics, (3) points of departure (PoD) and mechanistic threshold considerations, (4) approaches to define exposure-related risks, (5) empirical relationships between genetic damage (mutation) and cancer, and (6) extrapolations across test systems and species. This report discusses the first three of these topics and a companion report discusses the latter three. The working group critically examined methods for determining point of-departure metrics (PoDs) that could be used to estimate low-dose risk of genetic damage and from which extrapolation to acceptable exposure levels could be made using appropriate mode of action information and uncertainty factors. These included benchmark doses (BMDs) derived from fitting families of exponential models, the No Observed Genotoxic Effect Level (NOGEL), and "threshold" or breakpoint dose (BPD) levels derived from bilinear models when mechanistic data supported this approach. The QWG recognizes that scientific evidence suggests that thresholds below which genotoxic effects do not occur likely exist for both DNA-reactive and DNA-nonreactive substances, but notes that small increments of the spontaneous level cannot be unequivocally excluded either by experimental measurement or by mathematical modeling. Therefore, rather than debating the theoretical possibility of such low-dose effects, emphasis should be placed on determination of PoDs from which acceptable exposure levels can be determined by extrapolation using available mechanistic information and appropriate uncertainty factors. This approach places the focus on minimization of the genotoxic risk, which protects against the risk of the development of diseases resulting from the genetic damage. Based on analysis of the strengths and weaknesses of each method, the QWG concluded that the order of preference of PoD metrics is the statistical lower bound on the BMD > the NOGEL > a statistical lower bound on the BPD. A companion report discusses the use of these metrics in genotoxicity risk assessment, including scaling and uncertainty factors to be considered when extrapolating below the PoD and/or across test systems and to the human. (C) 2014 The Authors. Published by Elsevier B.V. C1 [MacGregor, James T.] Toxicol Consulting Serv, Bonita Springs, FL 14620 USA. [Froetschl, Roland] Bundesinst Arzneimittel & Medizinprod, Bonn, Germany. [White, Paul A.] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Eastmond, David A.] Univ Calif Riverside, Riverside, CA 92521 USA. [Fukushima, Shoji] Japan Bioassay Res Ctr, Hadano, Kanagawa, Japan. [Guerard, Melanie] F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland. [Hayashi, Makoto] Biosafety Res Ctr Foods Drugs & Pesticides, Shizuoka, Japan. [Soeteman-Hernandez, Lya G.] RIVM Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. [Kasamatsu, Toshio] Kao Corp, Haga Gun, Tochigi, Japan. [Levy, Dan D.] US FDA, College Pk, MD USA. [Morita, Takeshi] Natl Inst Hlth Sci, Tokyo, Japan. [Mueller, Lutz] Hoffmann La Roche AG, Basel, Switzerland. [Schoeny, Rita] US EPA, Washington, DC 20460 USA. [Schuler, Maik J.] Pfizer Inc, Groton, CT 06340 USA. [Thybaud, Veronique] Sanofi Rech, Vitry Sur Seine, France. [Johnson, George E.] Swansea Univ, Swansea, W Glam, Wales. RP MacGregor, JT (reprint author), Toxicol Consulting Serv, Bonita Springs, FL 14620 USA. EM jtmacgregor@earthlink.net; paul.white@hc-sc.gc.ca OI white, paul/0000-0001-5853-4759; Johnson, George/0000-0001-5643-9942 FU National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/K500033/1]; Health Canada under the Chemicals Management Plan Research Fund FX We acknowledge support from the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs, contract number NC/K500033/1) for Dr. Johnson. Funding for the development of the G4 genetic toxicity dose-response database described by Gollapudi et al. [29] and Johnson et al. [30] and of R-based procedures for derivation of genetic toxicology PoDs (i.e., drsmooth), and for support of open access of this publication, was provided by Health Canada under the Chemicals Management Plan Research Fund. We thank the ILSI/HESI Quantitative Working Group for sharing data and analyses collected and employed by that Working Group, and note that their analyses were a critical component of our deliberations. NR 64 TC 17 Z9 17 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 1 PY 2015 VL 783 SI SI BP 55 EP 65 DI 10.1016/j.mrgentox.2014.09.011 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CJ2YX UT WOS:000355351700007 PM 25953400 ER PT J AU MacGregor, JT Frotschl, R White, PA Crump, KS Eastmond, DA Fukushima, S Guerard, M Hayashi, M Soeteman-Hernandez, LG Johnson, GE Kasamatsu, T Levy, DD Morita, T Muller, L Schoeny, R Schuler, MJ Thybaud, V AF MacGregor, James T. Froetschl, Roland White, Paul A. Crump, Kenny S. Eastmond, David A. Fukushima, Shoji Guerard, Melanie Hayashi, Makoto Soeteman-Hernandez, Lya G. Johnson, George E. Kasamatsu, Toshio Levy, Dan D. Morita, Takeshi Mueller, Lutz Schoeny, Rita Schuler, Maik J. Thybaud, Veronique TI IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article; Proceedings Paper CT 6th International Workshop on Genotoxicity Testing (IWGT) CY OCT 31-NOV 01, 2013 CL Foz do Iguacu, BRAZIL DE Genotoxic risk assessment; Point of departure; Benchmark dose; Breakpoint dose; Extrapolation; Low-dose risk ID DOSE-RESPONSE RELATIONSHIPS; SALMONELLA-MICROSOME TEST; GENETIC TOXICITY ASSAYS; DNA ADDUCT DATA; IN-VITRO; HEMOGLOBIN ADDUCTS; RODENT CARCINOGENICITY; 21ST-CENTURY ROADMAP; CREATING CONTEXT; END-POINTS AB This is the second of two reports from the International Workshops on Genotoxicity Testing (IWGT) Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized the discussions and recommendations of the QWG related to the need for quantitative dose-response analysis of genetic toxicology data, the existence and appropriate evaluation of threshold responses, and methods to analyze exposure-response relationships and derive points of departure (PoDs) from which acceptable exposure levels could be determined. This report summarizes the QWG discussions and recommendations regarding appropriate approaches to evaluate exposure-related risks of genotoxic damage, including extrapolation below identified PoDs and across test systems and species. Recommendations include the selection of appropriate genetic endpoints and target tissues, uncertainty factors and extrapolation methods to be considered, the importance and use of information on mode of action, toxicokinetics, metabolism, and exposure biomarkers when using quantitative exposure-response data to determine acceptable exposure levels in human populations or to assess the risk associated with known or anticipated exposures. The empirical relationship between genetic damage (mutation and chromosomal aberration) and cancer in animal models was also examined. It was concluded that there is a general correlation between cancer induction and mutagenic and/or clastogenic damage for agents thought to act via a genotoxic mechanism, but that the correlation is limited due to an inadequate number of cases in which mutation and cancer can be compared at a sufficient number of doses in the same target tissues of the same species and strain exposed under directly comparable routes and experimental protocols. (C) 2014 The Authors. Published by Elsevier B.V. C1 [MacGregor, James T.] Toxicol Consulting Serv, Bonita Springs, FL USA. [Froetschl, Roland] Bundesinst Arzneimittel & Medizinprod, Bonn, Germany. [White, Paul A.] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Eastmond, David A.] Univ Calif Riverside, Riverside, CA 92521 USA. [Fukushima, Shoji] Japan Bioassay Res Ctr, Haden, Kanagawa, Japan. [Guerard, Melanie; Mueller, Lutz] F Hoffmann La Roche & Co Ltd, Pharmaceut Sci & Early Dev Innovat Ctr, Basel, Switzerland. [Hayashi, Makoto] Publ Interest Inc Fdn BioSafety Res Ctr, Shizuoka, Japan. [Soeteman-Hernandez, Lya G.] RIVM Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. [Johnson, George E.] Swansea Univ, Coll Med, Inst Life Sci, Swansea SA2 8PP, W Glam, Wales. [Kasamatsu, Toshio] Kao Corp, Haga Gun, Tochigi, Japan. [Levy, Dan D.] US FDA, College Pk, MD USA. [Morita, Takeshi] Natl Inst Hlth Sci, Tokyo, Japan. [Schoeny, Rita] US EPA, Washington, DC 20460 USA. [Schuler, Maik J.] Pfizer Inc, Groton, CT 06340 USA. [Thybaud, Veronique] Sanofi Rech, Vitry Sur Seine, France. RP MacGregor, JT (reprint author), Toxicol Consulting Serv, Bonita Springs, FL USA. EM jtmacgregor@earthlink.net OI white, paul/0000-0001-5853-4759; Johnson, George/0000-0001-5643-9942 NR 110 TC 18 Z9 18 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 1 PY 2015 VL 783 SI SI BP 66 EP 78 DI 10.1016/j.mrgentox.2014.10.008 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CJ2YX UT WOS:000355351700008 PM 25953401 ER PT J AU Bento, JC Lane, KD Read, EK Cerca, N Christie, GE AF Bento, Joana C. Lane, Kristin D. Read, Erik K. Cerca, Nuno Christie, Gail E. TI sequence determinants for DNA packaging specificity in the S. aureus Pathogenicity Island SaPI1 (vol 71, pg 8, 2014) SO PLASMID LA English DT Correction C1 [Bento, Joana C.; Lane, Kristin D.; Christie, Gail E.] Virginia Commonwealth Univ, Sch Med, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Bento, Joana C.; Cerca, Nuno] Univ Minho, Inst Biotechnol & Bioengn, Ctr Biol Engn, P-4710057 Braga, Portugal. [Read, Erik K.] US FDA, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Bento, JC (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Microbiol & Immunol, POB 980678, Richmond, VA 23298 USA. EM christie@vcu.edu NR 1 TC 0 Z9 0 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 0147-619X EI 1095-9890 J9 PLASMID JI Plasmid PD MAY PY 2015 VL 79 BP 54 EP 54 DI 10.1016/j.plasmid.2015.03.003 PG 1 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA CJ5ZY UT WOS:000355574000008 ER PT J AU Heflich, RH Dobrovolsky, VN Dertinger, SD AF Heflich, Robert H. Dobrovolsky, Vasily N. Dertinger, Stephen D. TI Continued progress in developing the Pig-a gene mutation assay SO MUTAGENESIS LA English DT Editorial Material ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; ANCHOR BIOSYNTHESIS; LOCUS; CELLS; RAT AB The Pig-a assay has shown promise as a regulatory assay for evaluating in vivo gene mutation. A recent International Workshop on Genotoxicity Testing workgroup discussed the state of the assay and identified several knowledge gaps in assay development. This Mutagenesis Special Topic includes a collection of reports that addresses some of these knowledge gaps, including identifying the mutations responsible for the Pig-a mutant phenotype, the effect of sex on the response, probing the robustness of the assay and expanding the number of agents tested in the assay, especially agents expected to yield negative responses. C1 [Heflich, Robert H.; Dobrovolsky, Vasily N.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Dertinger, Stephen D.] Litron Labs, Rochester, NY 14623 USA. RP Heflich, RH (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. EM robert.heflich@fda.hhs.gov NR 15 TC 3 Z9 3 U1 0 U2 3 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 2015 VL 30 IS 3 BP 313 EP 314 DI 10.1093/mutage/geu082 PG 2 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CJ2MB UT WOS:000355317800001 PM 25934984 ER PT J AU Revollo, J Pearce, MG Petibone, DM Mittelstaedt, RA Dobrovolsky, VN AF Revollo, Javier Pearce, Mason G. Petibone, Dayton M. Mittelstaedt, Roberta A. Dobrovolsky, Vasily N. TI Confirmation of Pig-a mutation in flow cytometry-identified CD48-deficient T-lymphocytes from F344 rats SO MUTAGENESIS LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; ETHYL-N-NITROSOUREA; IN-VIVO MUTATION; GENE MUTATION; CELLS; ASSAY; BIOSYNTHESIS; DISEASE; CDNA; MICE AB The Pig-a assay is used for monitoring somatic cell mutation in laboratory animals and humans. The assay detects haematopoietic cells deficient in glycosylphosphatidylinositol (GPI)-anchored protein surface markers using flow cytometry. However, given that synthesis of the protein markers (and the expression of their genes) is independent of the expression of the X-linked Pig-a gene and the function of its enzyme product, the deficiency of markers at the surface of the cells may be caused by a number of events (e.g. by mutation or epigenetic silencing in the marker gene itself or in any of about two dozen autosomal genes involved in the synthesis of GPI). Here we provide direct evidence that the deficiency of the GPI-anchored surface marker CD48 in rat T-cells is accompanied by mutation in the endogenous X-linked Pig-a gene. We treated male F344 rats with N-ethyl-N-nitrosourea (ENU), and established colonies from flow cytometry-identified and sorted CD48-deficient spleen T-lymphocytes. Molecular analysis confirmed that the expanded sorted cells have mutations in the Pig-a gene. The spectrum of Pig-a mutation in our model was consistent with the spectrum of ENU-induced mutation determined in other in vivo models, mostly base-pair substitutions at A:T with the mutated T on the non-transcribed strand of Pig-a genomic DNA. We also used next generation sequencing to derive a similar mutational spectrum from a pool of 64 clones developed from flow-sorted CD48-deficient lymphocytes. Our findings confirm that Pig-a assays detect what they are designed to detect-gene mutation in the Pig-a gene. C1 [Revollo, Javier; Pearce, Mason G.; Petibone, Dayton M.; Mittelstaedt, Roberta A.; Dobrovolsky, Vasily N.] US FDA, Jefferson, AR 72079 USA. [Revollo, Javier; Pearce, Mason G.; Petibone, Dayton M.; Mittelstaedt, Roberta A.; Dobrovolsky, Vasily N.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Revollo, J (reprint author), US FDA, 3900 NCTR Rd,HFT 120, Jefferson, AR 72079 USA. EM vasily.dobrovolsky@fda.hhs.gov NR 17 TC 7 Z9 8 U1 0 U2 3 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 2015 VL 30 IS 3 BP 315 EP 324 DI 10.1093/mutage/geu030 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CJ2MB UT WOS:000355317800002 PM 25820172 ER PT J AU Campbell, ML Beardsley, RS Shaya, FT Pradel, FG AF Campbell, M. L. Beardsley, R. S. Shaya, F. T. Pradel, F. G. TI SELF-EFFICACY, HEALTH LITERACY AND ADHERENCE TO SELF-CARE BEHAVIORS IN KIDNEY TRANSPLANT RECIPIENTS SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Campbell, M. L.] US FDA, Silver Spring, MD USA. [Beardsley, R. S.; Shaya, F. T.; Pradel, F. G.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 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 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2015 VL 18 IS 3 MA PUK14 BP A188 EP A188 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498503115 ER PT J AU Du, D McKean, S Kelman, JA Laschinger, J Johnson, C Warnock, R Worrall, CM Sedrakyan, A Liu, X Encinosa, W MaCurdy, TE Izurieta, HS AF Du, D. McKean, S. Kelman, J. A. Laschinger, J. Johnson, C. Warnock, R. Worrall, C. M. Sedrakyan, A. Liu, X. Encinosa, W. MaCurdy, T. E. Izurieta, H. S. TI COMPARE EARLY MORTALITY AFTER AORTIC VALVE REPLACEMENT WITH MECHANICAL PROSTHETIC VS BIOPROSTHETIC VALVES AMONG MEDICARE BENEFICIARIES SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Du, D.; Laschinger, J.; Izurieta, H. S.] US FDA, Silver Spring, MD USA. [McKean, S.; Johnson, C.; Warnock, R.] Acumen LLC, Burlingame, CA USA. [Kelman, J. A.; Liu, X.] CMS, Washington, DC USA. [Worrall, C. M.] CMS, Baltimore, MD USA. [MaCurdy, T. E.] Weill Cornell Med Coll, New York, NY USA. [Encinosa, W.] Agcy Healthcare Res & Qual, Rockville, 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 2015 VL 18 IS 3 MA PCV22 BP A133 EP A133 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498502116 ER PT J AU Hwang, CS Rutkow, L Turner, L Lucas, E Alexander, GC AF Hwang, C. S. Rutkow, L. Turner, L. Lucas, E. Alexander, G. C. TI USE OF PRESCRIPTION MONITORING PROGRAMS BY PRIMARY CARE PHYSICIANS: RESULTS OF A NATIONAL SURVEY SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Hwang, C. S.] US FDA, Silver Spring, MD USA. [Rutkow, L.; Turner, L.; Lucas, E.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Alexander, G. C.] Johns Hopkins Ctr Drug Safety & Effectiveness, Baltimore, 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 2015 VL 18 IS 3 MA PHS149 BP A272 EP A272 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498504262 ER PT J AU Menis, M Forshee, RA McKean, S Warnock, R Verma, S Izurieta, HS Mintz, PD Worrall, CM Kelman, JA Anderson, SA AF Menis, M. Forshee, R. A. McKean, S. Warnock, R. Verma, S. Izurieta, H. S. Mintz, P. D. Worrall, C. M. Kelman, J. A. Anderson, S. A. TI TRANSFUSION-RELATED ACUTE LUNG INJURY (TRALI) OCCURRENCE AMONG INPATIENT MEDICAID BENEFICIARIES, UNDER 65 YEARS OF AGE, AS RECORDED BY LARGE ADMINISTRATIVE DATABASES DURING 2007-2010 SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Menis, M.; Forshee, R. A.; Izurieta, H. S.; Mintz, P. D.; Anderson, S. A.] US FDA, Silver Spring, MD USA. [McKean, S.; Warnock, R.; Verma, S.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.] CMS, Baltimore, MD USA. [Kelman, J. A.] CMS, Washington, DC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2015 VL 18 IS 3 MA PRS1 BP A169 EP A169 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498503010 ER PT J AU Li, Q Kappil, M Li, A Dassanayke, PS Darrah, T Friedman, AE Friedman, M Lambertini, L Landrigan, P Stodgell, CJ Aagaard, K Schadt, E Murray, J Clark, EB Dole, N Culhane, J Swanson, J Varner, M Moye, J Kasten, C Miller, RK Chen, J AF Li, Q. Kappil, M. Li, A. Dassanayke, P. S. Darrah, T. Friedman, A. E. Friedman, M. Lambertini, L. Landrigan, P. Stodgell, C. J. Aagaard, K. Schadt, E. Murray, J. Clark, E. B. Dole, N. Culhane, J. Swanson, J. Varner, M. Moye, J. Kasten, C. Miller, R. K. Chen, J. CA Natl Childrens Study Consortium TI Exploring the Associations between microRNA Expression Profiles and Environmental Pollutants in Human Placenta from the National Children's Study (NCS) SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Li, Q.; Kappil, M.; Lambertini, L.; Landrigan, P.; Schadt, E.; Chen, J.] Mt Sinai, Ichan Sch Med, New York, NY USA. [Li, A.; Dassanayke, P. S.] Univ Illinois, Chicago, IL USA. [Darrah, T.] Ohio State Univ, Columbus, OH 43210 USA. [Friedman, A. E.; Friedman, M.; Stodgell, C. J.; Miller, R. K.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Aagaard, K.] Baylor Sch Med, Houston, TX USA. [Murray, J.] Univ Iowa, Iowa City, IA USA. [Clark, E. B.; Varner, M.] Univ Utah, Salt Lake City, UT USA. [Dole, N.] Univ N Carolina, Chapel Hill, NC USA. [Culhane, J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Swanson, J.] Univ Calif Irvine, Irvine, CA USA. [Moye, J.; Natl Childrens Study Consortium] NIH, Bethesda, MD 20892 USA. [Kasten, C.] US FDA, Silver Spring, MD USA. OI Li, An/0000-0002-8476-8783 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA 5 BP 378 EP 378 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400055 ER PT J AU Piersma, AH Theunissen, PT Beken, S Cappon, GD Chen, C Harrouk, W Hoberman, AM Van der Laan, JW Stewart, J AF Piersma, A. H. Theunissen, P. T. Beken, S. Cappon, G. D. Chen, C. Harrouk, W. Hoberman, A. M. Van der Laan, J. W. Stewart, J. TI A Comparison of Rat and Rabbit Developmental Toxicity Study Outcomes of More Than 400 Pharmaceutical Compounds SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Piersma, A. H.] RIVM, Bilthoven, Netherlands. [Theunissen, P. T.; Van der Laan, J. W.] CBG MEB, Utrecht, Netherlands. [Cappon, G. D.] Pfizer Inc, Groton, CT 06340 USA. [Beken, S.] FAMHP, Brussels, Belgium. [Chen, C.] ILSI HESI, Washington, DC USA. [Hoberman, A. M.] Charles River Labs, Horsham, PA USA. [Stewart, J.] AstaZeneca, Macclesfield, Cheshire, England. [Piersma, A. H.] IRAS, Utrecht, Netherlands. [Harrouk, W.] US FDA, Washington, DC 20204 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 2015 VL 103 IS 5 MA 30 BP 390 EP 390 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400079 ER PT J AU Sahin, L Hammad, H Bird, S Gelperin, K Hampp, C Leishear, K Taylor, L AF Sahin, L. Hammad, H. Bird, S. Gelperin, K. Hampp, C. Leishear, K. Taylor, L. TI US Food and Drug Administration Systematic Review of Pregnancy Registries: Follow-up Analysis SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Sahin, L.] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Div Pediat & Maternal Hlth, Silver Spring, MD USA. [Hammad, H.; Bird, S.; Gelperin, K.; Hampp, C.; Leishear, K.; Taylor, L.] US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Div Epidemiol 1, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 4 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 2015 VL 103 IS 5 MA 31 BP 391 EP 391 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400080 ER PT J AU Xu, Y Stuart, C Dahlen, S Zhang, P Struble, EB AF Xu, Y. Stuart, C. Dahlen, S. Zhang, P. Struble, E. B. TI A Biodistribution and Mechanistic Analysis of FcRn-Mediated Transplacental Transfer of Therapeutic Antibodies In Vitro and In Vivo SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Xu, Y.; Stuart, C.; Dahlen, S.; Zhang, P.; Struble, E. B.] US FDA, CBER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA P27 BP 415 EP 415 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400127 ER PT J AU Nakamura, N Inselman, AL Han, T Fuscoe, JC Harrouk, W Mcintyre, B Foster, PM Hansen, DK AF Nakamura, N. Inselman, A. L. Han, T. Fuscoe, J. C. Harrouk, W. Mcintyre, B. Foster, P. M. Hansen, D. K. TI Gene Expression Changes in the Testes and Prostate from Postnatal Day 30 Sprague-Dawley Rats Dosed Perinatally with Oxybenzone-Preliminary Study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Nakamura, N.; Inselman, A. L.; Han, T.; Fuscoe, J. C.; Hansen, D. K.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Harrouk, W.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Mcintyre, B.; Foster, P. M.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 8 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 2015 VL 103 IS 5 MA P40 BP 422 EP 422 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400140 ER PT J AU Inselman, AL Hansen, DK Harrouk, W Fisher, JE Tassinari, MS Nolen, GT Merry, GE Chen, X AF Inselman, A. L. Hansen, D. K. Harrouk, W. Fisher, J. E. Tassinari, M. S. Nolen, G. T. Merry, G. E. Chen, X. TI Investigating Additional Differentiation Endpoints in the Mouse Embryonic Stem Cell Test SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Inselman, A. L.; Hansen, D. K.; Nolen, G. T.; Merry, G. E.; Chen, X.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Harrouk, W.; Fisher, J. E.; Tassinari, M. S.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA P59 BP 431 EP 431 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400159 ER PT J AU Hur, J Zhao, CS Bai, JPF AF Hur, Junguk Zhao, ChunSheng Bai, Jane P. F. TI Systems Pharmacological Analysis of Drugs Inducing Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID LARGE GENE LISTS; HYPERSENSITIVITY REACTIONS; BIOLOGICAL NETWORKS; CARBAMAZEPINE; HLA; UPDATE AB Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious cutaneous adverse reactions. We mined the approved labels in Drugs@FDA, identified the SJS/TEN list of 259 small molecular drugs and biologics, and conducted systems pharmacological network analyses. Pharmacological network analysis revealed that drugs with treatment-related SJS and/or TEN are pharmacologically diverse and that the largest subnetwork is associated with antiepileptic drugs and their pharmacological targets. Our pharmacological network analysis identified CTNNB1 [catenin (cadherin-associated protein), beta 1, 88 kDa] as a significant intermediator. This protein is involved in maintaining the functional integrity of the epithelium through regulating cell growth and adhesion between cells in various organs, including the skin. Leveraging a publicly accessible genome-wide transcriptional expression database, we found that human leukocyte antigen-related (HLA) genes were significantly perturbed by various SJS/TEN-inducing drugs. Notably, carbamazepine (CBZ) perturbed several HLA genes, among which HLA-DQB1*0201 was reportedly shown to be associated with CBZ-induced SJS/TEN in caucasians. In short, systems analysis by leveraging a publicly accessible knowledge base and databases could produce meaningful results for further mechanistic investigation. Our study sheds light on the utility of systems pharmacology analysis for gaining insight into clinical drug toxicity. C1 [Hur, Junguk] Univ N Dakota, Sch Med & Hlth Sci, Dept Basic Sci, Grand Forks, ND 58502 USA. [Hur, Junguk] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Zhao, ChunSheng; Bai, Jane P. F.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Hur, J (reprint author), Univ N Dakota, Sch Med & Hlth Sci, Dept Basic Sci, Grand Forks, ND 58502 USA. EM junguk.hur@med.und.edu; jane.bai@fda.hhs.gov OI Hur, Junguk/0000-0002-0736-2149 FU ORISE through a Critical Path Grant from the Center for Drug Evaluation and Research; Juvenile Diabetes Research Foundation FX C.Z. was supported as an ORISE through a Critical Path Grant from the Center for Drug Evaluation and Research to J.P.F.B. and by a Postdoctoral Fellowship from the Juvenile Diabetes Research Foundation to J.H. NR 29 TC 5 Z9 5 U1 1 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 MAY PY 2015 VL 28 IS 5 BP 927 EP 934 DI 10.1021/tx5005248 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA CI6XM UT WOS:000354907500010 PM 25811541 ER PT J AU Gelderman, MP Baek, JH Yalamanoglu, A Puglia, M Vallelian, F Burla, B Vostal, J Schaer, DJ Buehler, PW AF Gelderman, Monique P. Baek, Jin Hyen Yalamanoglu, Ayla Puglia, Michele Vallelian, Florence Burla, Bo Vostal, Jaroslav Schaer, Dominik J. Buehler, Paul W. TI Reversal of hemochromatosis by apotransferrin in non-transfused and transfused Hbb(th3/+) (heterozygous b1/b2 globin gene deletion) mice SO HAEMATOLOGICA LA English DT Article ID BETA-THALASSEMIC MICE; IRON-OVERLOAD CARDIOMYOPATHY; TRANSFERRIN-BOUND IRON; INEFFECTIVE ERYTHROPOIESIS; HEMOGLOBIN-SYNTHESIS; CA2+ CHANNELS; MURINE MODEL; MOUSE MODEL; SERUM IRON; RECEPTOR 2 AB Intermediate beta-thalassemia has a broad spectrum of sequelae and affected subjects may require occasional blood transfusions over their lifetime to correct anemia. Iron overload in intermediate beta-thalassemia results from a paradoxical intestinal absorption, iron release from macrophages and hepatocytes, and sporadic transfusions. Pathological iron accumulation in parenchyma is caused by chronic exposure to non-transferrin bound iron in plasma. The iron scavenger and transport protein transferrin is a potential treatment being studied for correction of anemia. However, transferrin may also function to prevent or reduce iron loading of tissues when exposure to non-transferrin bound iron increases. Here we evaluate the effects of apotransferrin administration on tissue iron loading and early tissue pathology in non-transfused and transfused Hbb(th3/+) mice. Mice with the Hbb(th3/+) phenotype have mild to moderate anemia and consistent tissue iron accumulation in the spleen, liver, kidneys and myocardium. Chronic apotransferrin administration resulted in normalization of the anemia. Furthermore, it normalized tissue iron content in the liver, kidney and heart and attenuated early tissue changes in non-transfused Hbb(th3/+) mice. Apotransferrin treatment was also found to attenuate transfusion-mediated increases in plasma non-transferrin bound iron and associated excess tissue iron loading. These therapeutic effects were associated with normalization of transferrin saturation and suppressed plasma non-transferrin bound iron. Apotransferrin treatment modulated a fundamental iron regulatory pathway, as evidenced by decreased erythroid Fam132b gene (erythroferrone) expression, increased liver hepcidin gene expression and plasma hepcidin-25 levels and consequently reduced intestinal ferroportin-1 in apotransferrin-treated thalassemic mice. C1 [Gelderman, Monique P.; Vostal, Jaroslav] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Baek, Jin Hyen; Yalamanoglu, Ayla; Buehler, Paul W.] US FDA, Lab Cellular Hematol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Puglia, Michele] Univ Zurich, Swiss Fed Inst Technol Zurich, Funct Genom Ctr Zurich, CH-8006 Zurich, Switzerland. [Yalamanoglu, Ayla; Puglia, Michele; Vallelian, Florence; Burla, Bo; Schaer, Dominik J.] Univ Zurich, Div Internal Med, CH-8006 Zurich, Switzerland. [Schaer, Dominik J.] Univ Zurich, Ctr Evolutionary Med, CH-8006 Zurich, Switzerland. RP Buehler, PW (reprint author), US FDA, Lab Cellular Hematol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM dominik.schaer@usz.ch; paul.buehler@fda.hhs.gov FU FDA internal funding; Swiss National Science Foundation [310030/120658, 31003A/138500]; University of Zurich Research Priority Program "Integrative Human Physiology"; Swiss Federal Commission for Technology and Innovation (CTI) FX This work was supported by FDA internal funding to PWB and JV and by the Swiss National Science Foundation (grants 310030/120658 and 31003A/138500 to DJS), the University of Zurich Research Priority Program "Integrative Human Physiology" and the Swiss Federal Commission for Technology and Innovation (CTI). NR 47 TC 7 Z9 7 U1 1 U2 7 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAY PY 2015 VL 100 IS 5 BP 611 EP 622 DI 10.3324/haematol.2014.117325 PG 12 WC Hematology SC Hematology GA CI5IE UT WOS:000354788000026 PM 25616571 ER PT J AU Smith, SM Paillard, F McKeown, A Burke, LB Edwards, RR Katz, NP Papadopoulos, EJ Rappaport, BA Slagle, A Strain, EC Wasan, AD Turk, DC Dworkin, RH AF Smith, Shannon M. Paillard, Florence McKeown, Andrew Burke, Laurie B. Edwards, Robert R. Katz, Nathaniel P. Papadopoulos, Elektra J. Rappaport, Bob A. Slagle, Ashley Strain, Eric C. Wasan, Ajay D. Turk, Dennis C. Dworkin, Robert H. TI Instruments to Identify Prescription Medication Misuse, Abuse, and Related Events in Clinical Trials: An ACTTION Systematic Review SO JOURNAL OF PAIN LA English DT Review DE Abuse potential; misuse; clinical trial; measurement properties ID CHRONIC PAIN PATIENTS; ADDICTION SEVERITY INDEX; DISORDERS IDENTIFICATION TEST; ALCOHOLISM SCREENING-TEST; ABERRANT DRUG BEHAVIOR; CHRONIC OPIOID THERAPY; CHRONIC NONCANCER PAIN; SUBSTANCE-ABUSE; PSYCHOMETRIC PROPERTIES; NONMALIGNANT PAIN AB Measurement of inappropriate medication use events (eg, abuse or misuse) in clinical trials is important in characterizing a medication's abuse potential. However, no gold standard assessment of inappropriate use events in clinical trials has been identified. In this systematic review, we examine the measurement properties (ie, content validity, cross-sectional reliability and construct validity, longitudinal construct validity, ability to detect change, and responder definitions) of instruments assessing inappropriate use of opioid and nonopioid prescription medications to identify any that' meet U.S. and European regulatory agencies' rigorous standards for outcome measures in clinical trials. Sixteen published instruments were identified, most of which were not designed for the selected concept of interest and context of use. For this reason, many instruments were found to lack adequate content validity (or documentation of content validity) to evaluate current inappropriate medication use events; for example, evaluating inappropriate use across the life span rather than current use, including items that did not directly assess inappropriate use (eg, questions about anger), or failing to capture information pertinent to inappropriate use events (eg, intention and route of administration). In addition, the psychometric data across all instruments were generally limited in scope. A further limitation is the heterogeneous, nonstandardized use of inappropriate medication use terminology. These observations suggest that available instruments are not well suited for assessing current inappropriate medication use within the specific context of clinical trials. Further effort is needed to develop reliable and valid instruments to measure current inappropriate medication use events in clinical trials. Perspective: This systematic review evaluates the measurement properties of inappropriate medication use (eg, abuse or misuse) instruments to determine whether any meet regulatory standards for clinical trial outcome measures to assess abuse potential. (C) 2015 by the American Pain Society C1 [Smith, Shannon M.; McKeown, Andrew; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14642 USA. [Paillard, Florence] Focus Biocom, Durango, CO USA. [Burke, Laurie B.] LORA Grp LLC, Royal Oak, MD USA. [Edwards, Robert R.] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Katz, Nathaniel P.] Tufts Univ, Dept Anesthesia, Boston, MA 02111 USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Papadopoulos, Elektra J.; Rappaport, Bob A.; Slagle, Ashley] US FDA, Silver Spring, MD USA. [Strain, Eric C.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Ctr Human Expt Therapeut, Rochester, NY 14642 USA. RP Smith, SM (reprint author), Univ Rochester, Sch Med & Dent, Dept Anesthesiol, 601 Elmwood Ave,Box 604, Rochester, NY 14642 USA. EM shannon1_smith@urmc.rochester.edu NR 63 TC 4 Z9 4 U1 4 U2 8 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD MAY PY 2015 VL 16 IS 5 BP 389 EP 411 DI 10.1016/j.jpain.2015.01.009 PG 23 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CH6KA UT WOS:000354144300001 PM 25660826 ER PT J AU Yang, Z Wilsey, B Bohm, M Weyrich, M Roy, K Ritley, D Jones, C Melnikow, J AF Yang, Zhuo Wilsey, Barth Bohm, Michele Weyrich, Meghan Roy, Kakoli Ritley, Dominique Jones, Christopher Melnikow, Joy TI Defining Risk of Prescription Opioid Overdose: Pharmacy Shopping and Overlapping Prescriptions Among Long-Term Opioid Users in Medicaid SO JOURNAL OF PAIN LA English DT Article DE Prescription opioids; overlapping prescriptions; pharmacy shopping; overdose risk factors ID NONCANCER PAIN; CONTROLLED SUBSTANCES; THERAPY; DEATHS; TROUP; BENZODIAZEPINES; ENROLLEES; BEHAVIOR; COHORT; TRENDS AB Use of multiple pharmacies concurrently (pharmacy shopping) and overlapping prescriptions may be indicators of potential misuse or abuse of prescription opioid medications. To evaluate strategies for identifying patients at high risk, we first compared different definitions of pharmacy shopping and then added the indicator of overlapping opioid prescriptions. We identified a cohort of 90,010 Medicaid enrollees who used >= 3 opioid prescriptions for >= 90 days during 2008 to 2010 from a multistate Medicaid claims database. We compared the diagnostic odds ratios for opioid overdose events of 9 pharmacy shopping definitions. Within a 90-day interval, a threshold of 4 pharmacies had the highest diagnostic odds ratio and was used to define pharmacy shopping. The overdose rate was higher in the subgroup with overlapping prescriptions (18.5 per 1,000 person-years [PYs]) than in the subgroup with pharmacy shopping as the sole indicator (10.7 per 1,000 PYs). Among the subgroup with both conditions, the overdose rate was 26.3 per 1,000 PYs, compared with 4.3 per 1,000 PYs for those with neither condition. Overlapping opioid prescriptions and pharmacy shopping measures had adjusted hazard ratios of 3.0 and 1.8, respectively, for opioid overdose. Using these measures will improve accurate identification of patients at highest risk of opioid overdose, the first step in implementing targeted prevention policies. Perspective: Long-term prescription opioid use may lead to adverse events, including overdose. Both pharmacy shopping and overlapping opioid prescriptions are associated with adverse outcomes. This study demonstrates that using both indicators will better identify those at high risk of overdose. Published by Elsevier Inc. on behalf of the American Pain Society C1 [Yang, Zhuo; Roy, Kakoli] Ctr Dis Control & Prevent, Off Associate Director Policy, Atlanta, GA 30333 USA. [Wilsey, Barth] VA Northern Calif Hlth Care Syst, Dept Phys Med, Mather, CA USA. [Wilsey, Barth] VA Northern Calif Hlth Care Syst, Dept Rehabil, Mather, CA USA. [Wilsey, Barth] Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA. [Bohm, Michele] Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. [Weyrich, Meghan; Ritley, Dominique; Melnikow, Joy] Univ Calif Davis, Sch Med, Ctr Healthcare Policy & Res, Sacramento, CA 95817 USA. [Jones, Christopher] US FDA, Off Commissioner, Silver Spring, MD USA. RP Yang, Z (reprint author), Ctr Dis Control & Prevent, Policy Res Anal & Dev Off, Off Associate Director Policy, 1600 Clifton Rd,MS D-28, Atlanta, GA 30333 USA. EM xco2@cdc.gov FU ODCDC CDC HHS [1U58CD001370-01] NR 28 TC 8 Z9 8 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD MAY PY 2015 VL 16 IS 5 BP 445 EP 453 DI 10.1016/j.jpain.2015.01.475 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CH6KA UT WOS:000354144300005 PM 25681095 ER PT J AU Pignatti, F Jonsson, B Blumenthal, G Justice, R AF Pignatti, Francesco Jonsson, Bertil Blumenthal, Gideon Justice, Robert TI Assessment of benefits and risks in development of targeted therapies for cancer - The view of regulatory authorities SO MOLECULAR ONCOLOGY LA English DT Review DE Targeted therapies; Drug regulation; Benefit-risk balance ID METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; PHASE-III TRIAL; DRUG APPROVAL; BREAST-CANCER; ACCELERATED APPROVAL; ONCOLOGY DRUGS; CHEMOTHERAPY; BEVACIZUMAB; PREFERENCES AB Drug licensing and approval decisions involve the balancing of benefits against the risks (harms) in the presence of uncertainty. Typically, the benefits are estimated from primary efficacy endpoints from confirmatory (phase III) clinical trials although exceptions where promising early data from single-arm studies have led to accelerated approvals are not uncommon, particularly for cancer drugs. The challenge for regulators is to balance early evidence of efficacy that might support approval versus the need to establish clinical benefit based on conclusive evidence. Targeted agents offer the promise that knowledge about the mechanism of the disease will help identify patients with tumors likely to respond, resulting in higher efficacy and less toxicity, and earlier regulatory decisions based on convincing evidence of clinical benefit. In this paper, we describe methods and examples of benefit-risk assessment of targeted drugs, recent initiatives from EMA and FDA on improving communication about benefits and risks, and discuss future steps. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies. C1 [Pignatti, Francesco] European Med Agcy, London E14 4HB, England. [Jonsson, Bertil] Lakemedelsverket, Uppsala, Sweden. [Blumenthal, Gideon; Justice, Robert] US FDA, Silver Spring, MD USA. RP Pignatti, F (reprint author), European Med Agcy, 7 Westferry Circus, London E14 4HB, England. EM francesco.pignatti@ema.europa.eu NR 58 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 1574-7891 EI 1878-0261 J9 MOL ONCOL JI Mol. Oncol. PD MAY PY 2015 VL 9 IS 5 BP 1034 EP 1041 DI 10.1016/j.molonc.2014.10.003 PG 8 WC Oncology SC Oncology GA CI8TB UT WOS:000355043500011 PM 25481691 ER PT J AU Williams, K Milner, J Boudreau, MD Gokulan, K Cerniglia, CE Khare, S AF Williams, Katherine Milner, Jessica Boudreau, Mary D. Gokulan, Kuppan Cerniglia, Carl E. Khare, Sangeeta TI Effects of subchronic exposure of silver nanoparticles on intestinal microbiota and gut-associated immune responses in the ileum of Sprague-Dawley rats SO NANOTOXICOLOGY LA English DT Article DE Bacteria; microbiome; mucosal immunity ID ORAL-EXPOSURE; TOXICITY; EXPRESSION; PARTICLES; DIVERSITY; DYNAMICS; MICE; PCR AB Silver nanoparticles (AgNP) are widely used for their antibacterial properties. Incorporation of AgNP into food-related products and health supplements represents a potential route for oral exposure to AgNP; however, the effects of such exposure on the gastrointestinal system are mostly unknown. This study evaluated changes in the populations of intestinal-microbiota and intestinal-mucosal gene expression in Sprague-Dawley rats (both male and female) that were gavaged orally with discrete sizes of AgNP (10, 75 and 110 nm) and silver acetate. Doses of AgNP (9, 18 and 36 mg/kg body weight/day) and silver acetate (100, 200 and 400 mg/kg body weight/day) were divided and administered to rats twice daily (similar to 10 h apart) for 13 weeks. The results indicate that AgNP prompted size-and dose-dependent changes to ilealmucosal microbial populations, as well as, intestinal gene expression and induced an apparent shift in the gut microbiota toward greater proportions of Gram-negative bacteria. DNA-based analyses revealed that exposure to 10nm AgNP and low-dose silver acetate caused a decrease in populations of Firmicutes phyla, along with a decrease in the Lactobacillus genus. Analysis of host gene expression demonstrated that smaller sizes and lower doses of AgNP exposure prompted the decreased expression of important immunomodulatory genes, including MUC3, TLR2, TLR4, GPR43 and FOXP3. Gender-specific effects to AgNP exposure were more prominent for the gut-associated immune responses. These results indicate that the oral exposure to AgNP alter mucosa-associated microbiota and modulate the gut-associated immune response and the overall homeostasis of the intestinal tract. C1 [Williams, Katherine; Milner, Jessica; Gokulan, Kuppan; Cerniglia, Carl E.; Khare, Sangeeta] Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Boudreau, Mary D.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Khare, S (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM sangeeta.khare@fda.hhs.gov FU US Food and Drug Administration; National Institute of Environmental Health Sciences (FDA IAG) [224-12-003/NIEHS IAG, AES12013]; NCTR-US Food and Drug Administration [E07506]; Oak Ridge Institute for Science and Education FX This study was supported, in part, by an Interagency Agreement between the US Food and Drug Administration and the National Institute of Environmental Health Sciences (FDA IAG #224-12-003/NIEHS IAG #AES12013) and by the NCTR-US Food and Drug Administration (E07506). Ms. Katherine Williams, Ms. Jessica Milner and Dr. Kuppan Gokulan are supported through the Oak Ridge Institute for Science and Education. NR 38 TC 14 Z9 14 U1 7 U2 41 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1743-5390 EI 1743-5404 J9 NANOTOXICOLOGY JI Nanotoxicology PD MAY PY 2015 VL 9 IS 3 BP 279 EP 289 DI 10.3109/17435390.2014.921346 PG 11 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA CI7WI UT WOS:000354975400002 PM 24877679 ER PT J AU Ellson, G Di Prima, M Ware, T Tang, XL Voit, W AF Ellson, Gregory Di Prima, Matthew Ware, Taylor Tang, Xiling Voit, Walter TI Tunable thiol-epoxy shape memory polymer foams SO SMART MATERIALS AND STRUCTURES LA English DT Article DE shape memory polymer; foam; thiol-epoxy ID THERMOMECHANICAL PROPERTIES; BIOMEDICAL APPLICATIONS; RECOVERY; NETWORKS; BEHAVIOR; DENSITY AB Shape memory polymers (SMPs) are uniquely suited to a number of applications due to their shape storage and recovery abilities and the wide range of available chemistries. However, many of the desired performance properties are tied to the polymer chemistry which can make optimization difficult. The use of foaming techniques is one way to tune mechanical response of an SMP without changing the polymer chemistry. In this work, a novel thiol-epoxy SMP was foamed using glass microspheres (40 and 50% by volume Q-Cel 6019), using expandable polymer microspheres (1% 930 DU 120), and by a chemical blowing agent (1% XOP-341). Each approach created SMP foam with a differing density and microstructure from the others. Thermal and thermomechanical analysis was performed to observe the behavioral difference between the foaming techniques and to confirm that the glass transition (T-g) was relatively unchanged near 50 degrees C while the glassy modulus varied from 19.1 to 345 MPa and the rubbery modulus varied from 0.04 to 2.2 MPa. The compressive behavior of the foams was characterized through static compression testing at different temperatures, and cyclic compression testing at T-g. Constrained shape recovery testing showed a range of peak recovery stress from 5 MPa for the syntactic Q-Cel foams to similar to 0.1 MPa for the chemically blown XOP-341 foam. These results showed that multiple foaming approaches can be used with a novel SMP to vary the mechanical response independent of T-g and polymer chemistry. C1 [Ellson, Gregory; Di Prima, Matthew; Ware, Taylor; Tang, Xiling; Voit, Walter] Univ Texas Dallas, Dept Mat Sci & Engn, Richardson, TX 75083 USA. [Di Prima, Matthew] US FDA, US Dept HHS, Rockville, MD 20857 USA. RP Ellson, G (reprint author), Univ Texas Dallas, Dept Mat Sci & Engn, Richardson, TX 75083 USA. EM Gregory.Ellson@utdallas.edu; Walter.Voit@utdallas.edu RI Ware, Taylor/A-7130-2017 OI Ware, Taylor/0000-0001-7996-7393 FU DARPA Young Faculty Award; University of Texas at Dallas FX This work was supported by the DARPA Young Faculty Award and the University of Texas at Dallas. The opinions and/or conclusions expressed are solely those of the authors and in no way imply a policy or position of the Food and Drug Administration. NR 30 TC 3 Z9 3 U1 9 U2 54 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0964-1726 EI 1361-665X J9 SMART MATER STRUCT JI Smart Mater. Struct. PD MAY PY 2015 VL 24 IS 5 AR 055001 DI 10.1088/0964-1726/24/5/055001 PG 11 WC Instruments & Instrumentation; Materials Science, Multidisciplinary SC Instruments & Instrumentation; Materials Science GA CI5VK UT WOS:000354827700001 ER PT J AU Bencsath, FA Benner, RA Abraham, A Wang, YS El Said, KR Jester, ELE Plakas, SM AF Bencsath, F. Aladar Benner, Ronald A., Jr. Abraham, Ann Wang, Yuesong El Said, Kathleen R. Jester, Edward L. E. Plakas, Steven M. TI Screening for petrochemical contamination in seafood by headspace solid-phase microextraction gas chromatography-mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Seafood; Petrochemical taint; VOCs; Headspace; Solid-phase microextraction; GC-MS ID DRINKING-WATER; OIL-SPILL; FISH; BIOTRANSFORMATION; HYDROCARBONS; EXTRACTION; VOLATILES; SPME; WINE AB A headspace solid-phase microextraction gas chromatography-mass spectrometry (SPME GC-MS) method is described, to screen seafood for volatile organic compounds (VOCs) associated with petrochemical taint. VOCs are extracted from the headspace of heated sample homogenates by adsorption onto a SPME fiber and desorbed for analysis by GC-MS. Targeted compounds are determined semi-quantitatively using representative calibration standards for the various classes (alkanes, alkylbenzenes, indanes/tetralins, and naphthalenes) of VOCs analyzed. Sample preparation is minimal, and the analyses are rapid and automated with a capacity of 50 samples per day. The method was optimized in terms of headspace temperature, sample heating time, extraction time, and desorption time using oyster samples fortified with target compounds. Calibrations for hydrocarbon components were linear in the range of 8.3-167 ng/g; the limit of detection ranged between 0.05 and 0.21 ng/g, and the limit of quantitation between 0.16 and 0.69 ng/g. Good precision (RSD < 10 % at 16.7 ng/g for individual VOCs) and accuracy (recovery range 89-118 % at 25 ng/g) were obtained in oyster, crab, shrimp, and finfish matrices. The trueness of the method was demonstrated by quantifying VOCs at 1-2-ppb levels in oyster fortified with certified reference material NIST SRM 1491a. Following single laboratory validation, the method was employed for the determination of VOCs in seafood exposed to oil contaminated seawater and for the determination of background VOC levels in seafood species from the Gulf of Mexico and local food stores. The method as described can be used to supplement human sensory testing for petrochemical taint in seafood. C1 [Bencsath, F. Aladar; Benner, Ronald A., Jr.; Abraham, Ann; Wang, Yuesong; El Said, Kathleen R.; Jester, Edward L. E.; Plakas, Steven M.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Bencsath, FA (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, One Iberville Dr, Dauphin Isl, AL 36528 USA. EM ferenc.bencsath@fda.hhs.gov NR 29 TC 3 Z9 3 U1 8 U2 37 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 MAY PY 2015 VL 407 IS 14 BP 4079 EP 4090 DI 10.1007/s00216-015-8624-3 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CH7BJ UT WOS:000354190300019 PM 25796529 ER PT J AU Cho, CY Nowatzke, W Oliver, K Garber, EAE AF Cho, Chung Y. Nowatzke, William Oliver, Kerry Garber, Eric A. E. TI Multiplex detection of food allergens and gluten SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Food allergens; Gluten; Detection; Multiplex; Luminex; BioPlex ID CRUSTACEAN PROTEIN; PROCESSED FOODS; IMMUNOASSAY; SYSTEM AB To help safeguard the food supply and detect the presence of undeclared food allergens and gluten, most producers and regulatory agencies rely on commercial test kits. Most of these are ELISAs with a few being PCR-based. These methods are very sensitive and analyte specific, requiring different assays to detect each of the different food allergens. Mass spectrometry offers an alternative approach whereby multiple allergens may be detected simultaneously. However, mass spectrometry requires expensive equipment, highly trained analysts, and several years before a quantitative approach can be achieved. Using multianalyte profiling (xMAPA (R)) technology, a commercial multiplex test kit based on the use of established antibodies was developed for the simultaneous detection of up to 14 different food allergens plus gluten. The assay simultaneously detects crustacean seafood, egg, gluten, milk, peanut, soy, and nine tree nuts (almond, Brazil nut, cashew, coconut, hazelnut, macadamia, pine nut, pistachio, and walnut). By simultaneously performing multiple tests (typically two) for each analyte, this magnetic bead-based assay offers built-in confirmatory analyses without the need for additional resources. Twenty-five of the assays were performed on buffer extracted samples, while five were conducted on samples extracted using reduced-denatured conditions. Thus, complete analysis for all 14 allergens and gluten requires only two wells of a 96-well microtiter plate. This makes it possible to include in a single analytical run up to 48 samples. All 30 bead sets in this multiplex assay detected 5 ng/mL of food allergen and gluten with responses greater than background. In addition, 26 of the bead sets displayed signal/noise ratios of five or greater. The bead-based design makes this 30-plex assay expandable to incorporate new antibodies and capture/detector methodologies by ascribing these new detectors to any of the unassigned bead sets that are commercially available. C1 [Cho, Chung Y.; Garber, Eric A. E.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr CFSAN, College Pk, MD 20740 USA. [Nowatzke, William; Oliver, Kerry] Radix BioSolut, Georgetown, TX 78626 USA. RP Garber, EAE (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr CFSAN, College Pk, MD 20740 USA. EM Eric.Garber@fda.hhs.gov NR 21 TC 12 Z9 12 U1 10 U2 55 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 MAY PY 2015 VL 407 IS 14 BP 4195 EP 4206 DI 10.1007/s00216-015-8645-y PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CH7BJ UT WOS:000354190300030 PM 25814275 ER PT J AU Nelson, RM AF Nelson, Robert M. TI What Counts as Equipoise? Reply SO HASTINGS CENTER REPORT LA English DT Editorial Material AB A response to What Counts as Equipoise? by Henry J. Silverman and Didier Dreyfuss. C1 US FDA, Rockville, MD 20857 USA. RP Nelson, RM (reprint author), US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAY-JUN PY 2015 VL 45 IS 3 BP 4 EP 4 DI 10.1002/hast.438 PG 1 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA CH8DC UT WOS:000354265300005 PM 25944196 ER PT J AU Kouiavskaia, D Mirochnitchenko, O Dragunsky, E Kochba, E Levin, Y Troy, S Chumakov, K AF Kouiavskaia, Diana Mirochnitchenko, Olga Dragunsky, Eugenia Kochba, Efrat Levin, Yotam Troy, Stephanie Chumakov, Konstantin TI Intradermal Inactivated Poliovirus Vaccine: A Preclinical Dose-Finding Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE inactivated poliovirus vaccine; intradermal; immunogenicity; dose sparing ID ERADICATION; DELIVERY; ADULTS AB Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. C1 [Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Kochba, Efrat; Levin, Yotam] NanoPass Technol, Ness Ziona, Israel. [Troy, Stephanie] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. RP Chumakov, K (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52,Rm 1128, Silver Spring, MD 20993 USA. EM konstantin.chumakov@fda.hhs.gov FU US Food and Drug Administration; National Institute of Allergy and Infectious Diseases [K23 AI093678]; Doris Duke Charitable Foundation [2012061] FX The work was funded by the intramural research program of the US Food and Drug Administration; the National Institute of Allergy and Infectious Diseases (grant number K23 AI093678); and the Doris Duke Charitable Foundation (grant number 2012061) to S. T. NR 15 TC 4 Z9 4 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 MAY 1 PY 2015 VL 211 IS 9 BP 1447 EP 1450 DI 10.1093/infdis/jiu624 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CI4LZ UT WOS:000354722000012 PM 25391313 ER PT J AU Shen, MY Russek-Cohen, E Slud, EV AF Shen, Meiyu Russek-Cohen, Estelle Slud, Eric V. TI Letter to the editor by the authors of Exact Calculation of Power and Sample Size in Bioequivalence Studies Using Two One-sided Tests, Pharmaceutical Statistics, DOI:10.1002/pst.1666 SO PHARMACEUTICAL STATISTICS LA English DT Letter AB This article reflects the views of the authors and should not be construed to be those of the US Food and Drug Administration. Copyright (c) 2015John Wiley & Sons, Ltd. C1 [Shen, Meiyu] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Russek-Cohen, Estelle] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Slud, Eric V.] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Slud, Eric V.] US Bur Census, Ctr Stat Res, Washington, DC 20233 USA. [Slud, Eric V.] US Bur Census, Methodol Res & Methodol Directorate, Washington, DC 20233 USA. RP Shen, MY (reprint author), US FDA, DBVI, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM meiyu.shen@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 1 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 MAY-JUN PY 2015 VL 14 IS 3 BP 272 EP 272 DI 10.1002/pst.1677 PG 1 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CI0HF UT WOS:000354417000013 PM 25807931 ER PT J AU Lu, DM Lee, SL Lionberger, RA Choi, S Adams, W Caramenico, HN Chowdhury, BA Conner, DP Katial, R Limb, S Peters, JR Yu, L Seymour, S Li, BV AF Lu, Dongmei Lee, Sau L. Lionberger, Robert A. Choi, Stephanie Adams, Wallace Caramenico, Hoainhon N. Chowdhury, Badrul A. Conner, Dale P. Katial, Rohit Limb, Susan Peters, John R. Yu, Lawrence Seymour, Sally Li, Bing V. TI International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences SO AAPS JOURNAL LA English DT Review DE bioequivalence; exhaled nitric oxide; generic; guidelines; orally inhaled drugs AB International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and/or subsequent entry OIDPs. They are Therapeutic GoodsAdministration (TGA) in Australia, Health Canada (HC) in Canada, European Medicines Association (EMA) of European Union (EU), and the Food and Drug Administration (FDA) in the United States of America (USA). The comparisons of these bioequivalence (BE) recommendations are based on selection of reference products, formulation and inhaler device comparisons, and in vitro tests and in vivo studies, including pharmacokinetic (PK), pharmacodynamics (PD), and clinical studies. For the in vivo studies, the study design, choices of dose, subject inclusion/exclusion criteria, study period, study endpoint, and equivalence criteria are elaborated in details. The bioequivalence on multiple-strength products and waiver options are also discussed. C1 [Lu, Dongmei; Caramenico, Hoainhon N.; Conner, Dale P.; Peters, John R.; Li, Bing V.] US FDA, Off Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Lee, Sau L.; Yu, Lawrence] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Lionberger, Robert A.; Choi, Stephanie; Adams, Wallace] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Chowdhury, Badrul A.; Limb, Susan; Seymour, Sally] US FDA, Div Pulm Allergy & Rheumatol Prod, Off Drug Evaluat, Off New Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Katial, Rohit] Natl Jewish Hlth, Weinberg Clin Res Unit, Denver, CO USA. RP Li, BV (reprint author), US FDA, Off Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM bing.li@fda.hhs.gov NR 14 TC 4 Z9 4 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 MAY PY 2015 VL 17 IS 3 BP 546 EP 557 DI 10.1208/s12248-015-9733-9 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CG8LY UT WOS:000353560700006 PM 25758352 ER PT J AU Zeng, K Geerlof-Vidavisky, I Gucinski, A Jiang, XH Boyneii, MT AF Zeng, Kui Geerlof-Vidavisky, Ilan Gucinski, Ashley Jiang, Xiaohui Boyneii, Michael T. TI Liquid Chromatography-High Resolution Mass Spectrometry for Peptide Drug Quality Control SO AAPS JOURNAL LA English DT Article DE High resolution mass spectrometry; impurity profiling; LC-HRMS; peptide drug ID LC-MS TECHNIQUE; PROTEIN THERAPEUTICS; FUTURE-DIRECTIONS; BIOANALYSIS; QUANTIFICATION; IMPURITIES; EXENATIDE AB A liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed using three peptide drugs: salmon calcitonin, bivalirudin, and exenatide as model systems to assess the suitability of this approach for monitoring peptide drug product quality. Calcitonin and its related impurities displayed linear responses over the range from 0.1 to 10 mu M (R-2 values for calcitonin salmon, Glu(14)-calcitonin, and acetyl-calcitonin were 0.995, 0.996, and 0.993, respectively). Intra-assay precision in terms of relative standard deviation (%RSD) was less than 10% at all tested concentrations. The accuracy of the method was greater than 85% as measured by spiking 0.1, 0.3, and 1% of Glu(14)-calcitonin and acetyl-calcitonin into a stock calcitonin solution. Limits of detection for calcitonin, Glu(14)-calcitonin, and acetyl-calcitonin were 0.02, 0.03, and 0.04 mu M, respectively, indicating that an impurity present at less than 0.1% (0.1 mu M) of the drug product API concentration (107 mu M) could be detected. Method validation studies analyzing bivalirudin and exenatide drug products exhibited similar results to calcitonin salmon in regard to high selectivity, sensitivity, precision, and linearity. Added benefits of using LC-HRMS-based methods are the ability to also determine amino acid composition, confirm peptide sequence, and quantify impurities, even when they are co-eluting, within a single experiment. LC-HRMS represents a promising approach for the quality control of peptides including the measurement of any peptide-related impurities. While the development work performed here is focus on peptide drug products, the principles could be adapted to peptide drug substance. C1 [Zeng, Kui; Geerlof-Vidavisky, Ilan; Gucinski, Ashley; Boyneii, Michael T.] US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. [Jiang, Xiaohui] US FDA, Off Res Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, St Louis, MO USA. [Boyneii, Michael T.] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Pharmaceut Anal, Silver Spring, MD 20993 USA. RP Boyneii, MT (reprint author), US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. EM michael.boyne@fda.hhs.gov FU CDER Critical Path Program; Office of Generic Drugs FX Internal funding for this work was provided by the CDER Critical Path Program and the Office of Generic Drugs (MTB). NR 20 TC 1 Z9 1 U1 6 U2 17 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 2015 VL 17 IS 3 BP 643 EP 651 DI 10.1208/s12248-015-9730-z PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CG8LY UT WOS:000353560700013 PM 25716148 ER PT J AU Hochhaus, G Horhota, S Hendeles, L Suarez, S Rebello, J AF Hochhaus, Guenther Horhota, Stephen Hendeles, Leslie Suarez, Sandra Rebello, Juliet TI Pharmacokinetics of Orally Inhaled Drug Products SO AAPS JOURNAL LA English DT Article ID DEPOSITION; AIRWAY; LUNG AB The presentations at the Orlando Inhalation Conference on pharmacokinetic (PK) studies indicated that PK is the most sensitive methodology for detecting formulation differences of oral inhaled drug products (OIDPs) that have negligible gastrointestinal bioavailability or for which oral absorption can be prevented (e.g., ingestion of charcoal). PK studies, therefore, may represent the most appropriate methodology for assessing local and systemic bioequivalence (BE). It was believed by many (but not all participants) that potential differences between formulations are more likely to be detected in healthy adult volunteers, as variability is reduced while deposition to peripheral areas is not restricted. A study design allowing assessment and statistical consideration of intra-subject and inter-batch variability within the evaluation of BE studies was suggested, while optimal inhalation technique during PK studies should be enforced to decrease variability. Depending on the drug and in vitro method, in vitro tests may not detect differences in PK parameters. Harmonization of BE testing requirements among different countries should be encouraged to improve global availability of low cost OIDPs and decrease industry burden. C1 [Hochhaus, Guenther] Univ Florida, Pharmaceut, Gainesville, FL 32610 USA. [Horhota, Stephen] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Hendeles, Leslie] Univ Florida, Pharmacotherapy & Translat Res, Gainesville, FL 32610 USA. [Suarez, Sandra] US FDA, Silver Spring, MD USA. [Rebello, Juliet] Cipla, Clin Res Resp, Bombay, Maharashtra, India. RP Hochhaus, G (reprint author), Univ Florida, Pharmaceut, POB 100494, Gainesville, FL 32610 USA. EM hochhaus@cop.ufl.edu NR 22 TC 6 Z9 6 U1 0 U2 5 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 2015 VL 17 IS 3 BP 769 EP 775 DI 10.1208/s12248-015-9736-6 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CG8LY UT WOS:000353560700025 PM 25762449 ER PT J AU Anderson, KM Abbott, J Zhao, SH Liu, E Himathongkham, S AF Anderson, Kimberly M. Abbott, Jason Zhao, Shaohua Liu, Eileen Himathongkham, Sunee TI Molecular Subtyping of Shiga Toxin-Producing Escherichia coli Using a Commercial Repetitive Sequence-Based PCR Assay SO JOURNAL OF FOOD PROTECTION LA English DT Article ID FIELD GEL-ELECTROPHORESIS; SEMIAUTOMATED REP-PCR; UNITED-STATES; MULTISTATE OUTBREAK; O157-H7 INFECTIONS; DIVERSILAB SYSTEM; TYPING METHODS; DNA-SEQUENCES; STRAINS; CONSUMPTION AB PCR-based typing methods, such as repetitive sequence based PCR (rep-PCR), may facilitate the identification of Shiga toxin producing Escherichia coli (STEC) by serving as screening methods to reduce the number of isolates to be processed for further confirmation. In this study, we used a commercial rep-PCR typing system to generate DNA fingerprint profiles for STEC O157 (n = 60) and non-O157 (n = 91) isolates from human, food, and animal samples and then compared the results with those obtained from pulsed-field gel electrophoresis (PFGE). Fifteen serogroups were analyzed using the Kullback Leibler or extended Jaccard statistical method, and the unweighted pair group method of averages algorithm was used to create dendrograms. Among the 151 STEC isolates tested, all were typeable by rep-PCR. Among the non-O157 isolates, rep-PCR clustered 79 (88.8%) of 89 isolates according to serogroup status, with peak differences ranging from 1 (96.4% similarity) to 12 (58.7% similarity). The genetic relatedness of the non-O157 serogroups mirrored the branching of distinct clonal groups elucidated by other investigators. Although the discriminatory power of rep-PCR (Simpson's index of diversity [SID] = 0.954) for the O157 isolates was less than that of PFGE (SID = 0.993), rep-PCR was able to identify 29 pattern types, suggesting that this method can be used for strain typing, although not to the same level as PFGE. Similar results were obtained from analysis of the non-O157 isolates. With rep-PCR, we assigned non-O157 isolates to 46 pattern types with a SID of 0.977. By PFGE, non-O157 STEC strains were divided into 77 pattern types with a SID of 0.996. Together, these results indicate the ability of the rep-PCR typing system to distinguish between and within O157 and non-O157 STEC groups. Rapid PCR-based typing methods could be invaluable tools for use in outbreak investigations by excluding unrelated STEC isolates within 24 h. C1 [Anderson, Kimberly M.; Liu, Eileen] US FDA, Off Regulatory Affairs, San Francisco Dist Lab, Alameda, CA 94502 USA. [Abbott, Jason; Zhao, Shaohua] US FDA, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. [Himathongkham, Sunee] US FDA, Off Regulatory Affairs, Off Regulatory Sci, Rockville, MD 20857 USA. RP Anderson, KM (reprint author), US FDA, Off Regulatory Affairs, San Francisco Dist Lab, Alameda, CA 94502 USA. EM kimberly.anderson@fda.hhs.gov FU U.S. Food and Drug Administration (FDA), Office of Regulatory Affairs, San Francisco District Laboratory; FDA Commissioner's Fellowship Program FX The authors thank the U.S. Food and Drug Administration (FDA), Office of Regulatory Affairs, San Francisco District Laboratory, especially Capt. David K. Lau, for support of this research and for generously sharing their bacterial cultures. Funding for this research was provided by the FDA Commissioner's Fellowship Program. NR 44 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 2015 VL 78 IS 5 BP 902 EP 911 DI 10.4315/0362-028X.JFP-14-430 PG 10 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CH6KR UT WOS:000354146000005 PM 25951383 ER PT J AU Zhang, JN Chen, HF Tsong, Y Stockbridge, N AF Zhang, Joanne Chen, Huifang Tsong, Yi Stockbridge, Norman TI Lessons Learned From Hundreds of Thorough QT Studies SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE relationship; QTc; drug plasma concentration; coherence; sensitivity; specificity AB Background: The coherence between the relationship of QTc and drug plasma concentration (this relationship is measured through the slope) and ICH E14 findings based on hundreds of QT study reports was studied. Results: Based on ICH E14 analysis, our findings indicate that if the slope was not positive, in most cases (86%) the corresponding QT studies were also negative. If the slope was positive, 92% of the corresponding QT studies were also positive. Conclusions: In exploring whether a thorough QT (TQT) study may be needed, we recommend that the relationship analysis between QTc and drug plasma concentration be performed when proper single ascending dose (SAD) and multiple ascending dose (MAD) studies are available. If the relationship cannot be detected and the 90% upper confidence interval at a fixed concentration level (50th or 75th percentile, or mean peak plasma concentration [C-max]) is below a certain threshold level (eg, 10 milliseconds), then a TQT study might be unnecessary. If the relationship can be established and the 90% lower confidence interval at a fixed concentration level (eg, mean C-max) is greater than 10 milliseconds, further investigation is needed. If the signal is real, one might choose intensive safety monitoring during later drug development instead of a TQT study for a good compound. However, there are still some gray areas in which this analysis alone cannot determine the potential QT liability of the drug, and a TQT type of study might be worth considering. C1 [Zhang, Joanne; Chen, Huifang; Tsong, Yi] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Div Biometr 4, Silver Spring, MD 20993 USA. [Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Div Cardiovasc & Renal Prod, Silver Spring, MD 20993 USA. RP Zhang, JN (reprint author), US FDA, WO21 RM4673 HFD 705,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM joanne.zhang@fda.hhs.gov NR 8 TC 3 Z9 3 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD MAY PY 2015 VL 49 IS 3 BP 392 EP 397 DI 10.1177/2168479014563549 PG 6 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CH4CS UT WOS:000353979600012 ER PT J AU Vu, HH Pariser, AR AF Vu, Hong H. Pariser, Anne R. TI Pre-Investigational New Drug Meetings With the FDA: Evaluation of Meeting Content and Characteristics of Applications for New Drug and Biologic Products SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE drug approval process; rare diseases; orphan drugs; FDA AB Introduction: Prior studies suggested that holding preinvestigational new drug application (PIND) meetings with FDA has a positive effect on clinical development time (CDT). Methods: New product marketing applications submitted to FDA CDER during fiscal years 2008-2012 were assessed for whether a PIND meeting was held and, if so, a qualitative assessment of meeting content was performed. Results: Discussions contained in the PIND meeting minutes tended to reflect topics appropriate to an early phase of drug development, including chemistry, manufacturing, and controls (CMC) and safety topics (eg, nonclinical and clinical domains). Additionally, FDA commonly provided additional advice most often in the clinical and CMC domains. Applications for which a PIND meeting was held during drug development had shorter CDTs than those that did not. Conclusions: This analysis showed the importance of early communication with FDA during development, and small companies with limited regulatory experience may gain the greatest benefit from early communication with FDA. C1 [Vu, Hong H.; Pariser, Anne R.] US FDA, Off New Drugs, Rare Dis Program, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Vu, HH (reprint author), 10903 New Hampshire Ave,Bldg 22,Room 64, Silver Spring, MD 20993 USA. EM hong.vu@fda.hhs.gov NR 10 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD MAY PY 2015 VL 49 IS 3 BP 434 EP 442 DI 10.1177/2168479014558275 PG 9 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CH4CS UT WOS:000353979600017 ER PT J AU Wiegmann, TL Mintz, PD AF Wiegmann, Theresa L. Mintz, Paul D. TI The growing role of AABB clinical practice guidelines in improving patient care SO TRANSFUSION LA English DT Editorial Material ID TRANSFUSION C1 [Wiegmann, Theresa L.] AABB, Publ Policy, Bethesda, MD 20814 USA. [Mintz, Paul D.] US FDA, Div Hematol Clin Review, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Wiegmann, TL (reprint author), AABB, Publ Policy, Bethesda, MD 20814 USA. EM Paul.Mintz@fda.hhs.gov NR 6 TC 3 Z9 3 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 MAY PY 2015 VL 55 IS 5 BP 935 EP 936 DI 10.1111/trf.13093 PG 2 WC Hematology SC Hematology GA CH8JB UT WOS:000354281500003 PM 25959216 ER PT J AU Gonzalez, C Rosas-Hernandez, H Jurado-Manzano, B Ramirez-Lee, MA Salazar-Garcia, S Martinez-Cuevas, PP Velarde-Salcedo, AJ Morales-Loredo, H Espinosa-Tanguma, R Ali, SF Rubio, R AF Gonzalez, Carmen Rosas-Hernandez, Hector Jurado-Manzano, Brenda Alejandro Ramirez-Lee, Manuel Salazar-Garcia, Samuel Pablo Martinez-Cuevas, Pedro Jimena Velarde-Salcedo, Ada Morales-Loredo, Humberto Espinosa-Tanguma, Ricardo Ali, Syed F. Rubio, Rafael TI The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings SO ACTA PHARMACOLOGICA SINICA LA English DT Article DE endothelium; growth hormones; placental lactogen; prolactin; eNOS; NO; prostaglandins; aortic rings; aortic endothelial cells ID NITRIC-OXIDE SYNTHASE; CARDIOVASCULAR RISK-FACTORS; GROWTH-HORMONE; BLOOD-PRESSURE; ANGIOTENSIN-II; DEPENDENT VASORELAXATION; ANESTHETIZED PIGS; INOTROPIC ACTION; ENOS ACTIVATION; HEART-FAILURE AB Aim: Prolactin family hormones include growth hormone, placental lactogen and prolactin, which are able to regulate angiogenesis via NO and prostaglandins. However, their effects on vascular tone are not fully understood. The aim of this study was to evaluate the effects of prolactin family hormones on rat vascular tone in vitro. Methods: Aortic rings were prepared from adult male rats and precontracted with phenylephrine, then treated with the hormones and drugs. The tension was measured with isometric force displacement transducer connected to a polygraph. NO production and prostacyclin release in physiological solution was determined. Cultured rat aortic endothelial cells (RAECs) were treated with the hormones and drugs, and the phosphorylation of eNOS at serine 1177 was assessed using Western bolt analysis. Results: Administration of growth hormone or placental lactogen (0.01-100 nmol/L) induced endothelium-dependent vasodilation. Both the hormones significantly increased the phosphorylation of eNOS in RAECs and NO level in physiological solution. Preincubation with L-NAME blocked growth hormone-or placental lactogen-induced vasodilation and NO production. Preincubation with an antibody against growth hormone receptors blocked growth hormone-and placental lactogen-induced vasodilation. Addition of a single dose of prolactin (0.01 nmol/L) induced sustained vessel relaxation, whereas multiple doses of prolactin induced a biphasic contraction-relaxation effect. The vascular effects of prolactin depended on endothelium. Prolactin significantly increased the level of prostacyclin I-2 in physiological solution. Preincubation with indomethacin or an antibody against prolactin receptors blocked prolactin-induced vasodilation. Conclusion: The prolactin family hormones regulate rat vascular tone, selectively promoting either relaxation or contraction of vascular smooth muscle via activation of either growth hormone receptors or prolactin receptors within the endothelium. C1 [Gonzalez, Carmen; Rosas-Hernandez, Hector; Jurado-Manzano, Brenda; Alejandro Ramirez-Lee, Manuel; Salazar-Garcia, Samuel; Pablo Martinez-Cuevas, Pedro; Jimena Velarde-Salcedo, Ada] Univ Autonoma San Luis Potosi, Fac Ciencias Quim, San Luis Potosi 78210, Mexico. [Morales-Loredo, Humberto; Espinosa-Tanguma, Ricardo; Rubio, Rafael] Univ Autonoma San Luis Potosi, Fac Med, San Luis Potosi 78210, Mexico. [Rosas-Hernandez, Hector; Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Gonzalez, C (reprint author), Univ Autonoma San Luis Potosi, Fac Ciencias Quim, San Luis Potosi 78210, Mexico. EM cgonzalez.uaslp@gmail.com RI Hector, Rosas-Hernandez/J-5130-2015; OI Rosas-Hernandez, Hector/0000-0002-2736-8302 FU Consejo Nacional de Ciencia y Tecnologia CONACYT-Mexico [84576, 134595]; Academic and Research Support Program [PROMEP-103.5/08/5637, C08-FAI-10-13.49, CO8-PIFI-05-4.4, C14-PIFI-08-06.06]; Research Participation Program at the National Center for Toxicological Research; US Department of Energy; US Food and Drug Administration; PROMEP [PROMEP/103.5/07/2574]; CONACyT [317768, 55849, 278347, 257942] FX This study was supported by the Consejo Nacional de Ciencia y Tecnologia CONACYT-Mexico (84576 and 134595) and the Academic and Research Support Program (PROMEP-103.5/08/5637, C08-FAI-10-13.49, CO8-PIFI-05-4.4, and C14-PIFI-08-06.06), and was also supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research, administered by the Oak Ridge Institute for Science and Education, through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. Hector ROSAS-HERNANDEZ would like to thank PROMEP (PROMEP/103.5/07/2574) and CONACyT (317768) for the fellowships that each provided; Brenda JURADO-MANZANO, Samuel SALAZAR-GARCIA and Manuel Alejandro RAMIREZ-LEE would like to thank CONACyT for the No 55849; 278347 and 257942 fellowships. NR 66 TC 3 Z9 3 U1 3 U2 8 PU ACTA PHARMACOLOGICA SINICA PI SHANGHAI PA 294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA SN 1671-4083 EI 1745-7254 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD MAY PY 2015 VL 36 IS 5 BP 572 EP 586 DI 10.1038/aps.2014.159 PG 15 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA CH2YY UT WOS:000353893100005 PM 25891087 ER PT J AU Paczesny, S Hakim, FT Pidala, J Cooke, KR Lathrop, J Griffith, LM Hansen, J Jagasia, M Miklos, D Pavletic, S Parkman, R Russek-Cohen, E Flowers, MED Lee, S Martin, P Vogelsang, G Walton, M Schultz, KR AF Paczesny, Sophie Hakim, Frances T. Pidala, Joseph Cooke, Kenneth R. Lathrop, Julia Griffith, Linda M. Hansen, John Jagasia, Madan Miklos, David Pavletic, Steven Parkman, Robertson Russek-Cohen, Estelle Flowers, Mary E. D. Lee, Stephanie Martin, Paul Vogelsang, Georgia Walton, Marc Schultz, Kirk R. TI National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Biomarkers; National Institutes of Health; Consensus ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; REGULATORY T-CELLS; PARAFFIN-EMBEDDED TISSUE; CHILDRENS ONCOLOGY GROUP; SERUM CYTOKINE LEVELS; PREDICT CHRONIC GVHD; PERIPHERAL-BLOOD; GENE POLYMORPHISMS; INCIDENTAL FINDINGS AB Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, or of a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include the following: (1) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity; (2) prognostic risk to develop chronic GVHD; and (3) prediction of response to therapy. Sample collection for chronic GVHD biomarkers studies should be well documented following established quality control guidelines for sample acquisition, processing, preservation, and testing, at,intervals that are both calendar and event driven. The consistent therapeutic treatment of subjects and standardized documentation needed to support biomarker studies are most likely to be provided in prospective clinical trials. To date, no chronic GVHD biomarkers have been qualified for use in clinical applications. Since our previous chronic GVHD Biomarkers Working Group report in 2005, an increasing number of chronic GVHD candidate biomarkers are available for further investigation. This paper provides a 4-part framework for biomarker investigations: identification, verification, qualification, and application with terminology based on Food and Drug Administration and European Medicines Agency guidelines. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Paczesny, Sophie] Indiana Univ Med, Dept Pediat & Immunol, Indianapolis, IN USA. [Hakim, Frances T.; Pavletic, Steven] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Pidala, Joseph] H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplantat, Tampa, FL USA. [Cooke, Kenneth R.; Vogelsang, Georgia] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA. [Lathrop, Julia] Ctr Devices & Radiol Hlth Food & Drug Adm, Off Vitro Diagnost & Radiol Hlth, Silver Spring, MD USA. [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Hansen, John; Flowers, Mary E. D.; Lee, Stephanie; Martin, Paul] Univ Washington, Sch Med, Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98195 USA. [Hansen, John; Flowers, Mary E. D.; Lee, Stephanie; Martin, Paul] Univ Washington, Sch Med, Div Med Oncol, Seattle, WA 98195 USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Miklos, David] Stanford Univ, Stanford Bone Marrow Transplant Cellular Therapy, Stanford, CA 94305 USA. [Parkman, Robertson] Univ So Calif, Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA USA. [Russek-Cohen, Estelle] Ctr Biol Food & Drug Adm, Div Biostat, Silver Spring, MD USA. [Walton, Marc] Ctr Drug Evaluat & Res Food & Drug Adm, Off Translat Sci, Silver Spring, MD USA. [Schultz, Kirk R.] BC Childrens Hosp, Michael Cuccione Childhood Canc Res Program, Vancouver, BC, Canada. [Schultz, Kirk R.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. RP Paczesny, S (reprint author), 1044 W Walnut St,Room R4-425, Indianapolis, IN 46202 USA. EM sophpacz@iu.edu FU National Institutes of Health's (NIH's) National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources; Office of Rare Diseases Research/National Center for Advancing Translational Sciences and National Cancer Institute FX This project Was supported by the National Institutes of Health's (NIH's) National Cancer Institute, Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research, National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources. The authors acknowledge the following individuals and organizations that, by their participation, made this project possible: American Society for Blood and Marrow Transplantation, Center for International Bone and Marrow Transplant Research, US Chronic GVHD Consortium (supported by Office of Rare Diseases Research/National Center for Advancing Translational Sciences and National Cancer Institute), German-Austrian-Swiss chronic GVHD Consortium, National Marrow Donor Program, the Health Resources and Services Administration, Division of Transplantation, US Department of Human Health and Services, Canadian Blood and Marrow Transplant Group, European Group for Blood and Marrow Transplantation, Pediatric Blood and Marrow Transplant Consortium, and the representatives of the Brazilian Chronic GVHD consortium (Drs. Maria Claudia Moreira, Marcia de Matos Silva and Vaneuza Funke) and Deutsche Jose Carreras Leukamie-Stiftung. The authors thank Dr. Joseph Antin (Dana Farber Cancer Center, Boston, MA), Dr. Hildegard Greinix (Medical University of Vienna, Vienna, Austria), and Dr. Gerard Socie (University Paris VII & AP-HP, Hospital Saint Louis, Paris, France) for their critical review of the manuscript. The organizers are in debt to patients and patient and research advocacy groups, who made this process much more meaningful by their engagement. Acknowledgement goes to the Meredith Cowden GVHD foundation for facilitating the initial planning meeting in Cleveland in November of 2013 in conjunction with the National GVHD Symposium. The project group also recognizes the contributions of numerous colleagues in the field of blood and marrow transplantation in the United States and internationally, medical specialists and consultants, the pharmaceutical industry, and the NIH and US Food and Drug Administration professional staff for their intellectual input, dedication, and enthusiasm on the road to completion of these documents. For their expert contributions to this 2014 NIH Biomarkers Consensus Working Group document, special acknowledgements to Ms. Licia Masuch, Ms. Kristie Bradley, and Ms. Linda Henson for assistance in the manuscript preparation. The opinions expressed are those of the authors and do not represent the position of the National Cancer Institute; the National Heart, Lung and Blood Institute; the National Institute of Allergy and Infectious Diseases; the National Institutes of Health; the Food and Drug Administration; or the United States government. NR 97 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAY PY 2015 VL 21 IS 5 BP 780 EP 792 DI 10.1016/j.bbna.2015.01.003 PG 13 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CH2LM UT WOS:000353856700002 PM 25644957 ER PT J AU Wang, QS Qian, L Chen, SH Chu, CH Wilson, B Oyarzabal, E Ali, S Robinson, B Rao, D Hong, JS AF Wang, Qingshan Qian, Li Chen, Shih-Heng Chu, Chun-Hsien Wilson, Belinda Oyarzabal, Esteban Ali, Syed Robinson, Bonnie Rao, Deepa Hong, Jau-Shyong TI Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson's disease models SO BRAIN LA English DT Article DE Parkinson's disease; microglia; NADPH oxidase; neuroinflammation; superoxide ID DOPAMINERGIC NEURODEGENERATION; MPTP MODEL; CHRONIC NEUROINFLAMMATION; MICROGLIAL ACTIVATION; REACTIVE MICROGLIOSIS; OXIDATIVE STRESS; ALPHA-SYNUCLEIN; ANIMAL-MODEL; NOX ENZYMES; NEUROPROTECTION AB Nicotinamide adenine dinucleotide phosphate oxidase, a key superoxide-producing enzyme, plays a critical role in microglia-mediated chronic neuroinflammation and subsequent progressive dopaminergic neurodegeneration in Parkinson's disease. Although nicotinamide adenine dinucleotide phosphate oxidase-targeting anti-inflammatory therapy for Parkinson's disease has been proposed, its application in translational research remains limited. The aim of this study was to obtain preclinical evidence supporting this therapeutic strategy by testing the efficacy of an ultra-low dose of the nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium in both endotoxin (lipopolysaccharide)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using post-treatment regimens. Our data revealed that post-treatment with diphenyleneiodonium significantly attenuated progressive dopaminergic degeneration and improved rotarod activity. Remarkably, post-treatment with diphenyleneiodonium 10 months after lipopolysaccharide injection when mice had 30% loss of nigral dopaminergic neurons, showed high efficacy in protecting the remaining neuronal population and restoring motor function. Diphenyleneiodonium-elicited neuroprotection was associated with the inhibition of microglial activation, a reduction in the expression of proinflammatory factors and an attenuation of alpha-synuclein aggregation. A pathophysiological evaluation of diphenyleneiodonium-treated mice, including assessment of body weight, organs health, and neuronal counts, revealed no overt signs of toxicity. In summary, infusion of ultra-low dose diphenyleneiodonium potently reduced microglia-mediated chronic neuroinflammation by selectively inhibiting nicotinamide adenine dinucleotide phosphate oxidase and halted the progression of neurodegeneration in mouse models of Parkinson's disease. The robust neuroprotective effects and lack of apparent toxic side effects suggest that diphenyleneiodonium at ultra-low dose may be a promising candidate for future clinical trials in Parkinson's disease patients. C1 [Wang, Qingshan; Qian, Li; Chen, Shih-Heng; Chu, Chun-Hsien; Wilson, Belinda; Oyarzabal, Esteban; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Ali, Syed; Robinson, Bonnie] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Rao, Deepa] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Wang, QS (reprint author), NIEHS, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wangq4@niehs.nih.gov; hong3@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences NR 49 TC 5 Z9 6 U1 0 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD MAY 1 PY 2015 VL 138 BP 1247 EP 1262 DI 10.1093/brain/awv034 PN 5 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CH2DB UT WOS:000353834100022 PM 25716193 ER PT J AU Kim, YJ Oh, DH Song, BR Heo, EJ Lim, JS Moon, JS Park, HJ Wee, SH Sung, K AF Kim, Young Jo Oh, Deog Hwan Song, Bo Ra Heo, Eun Jeong Lim, Jong Su Moon, Jin San Park, Hyun Jung Wee, Sung Hwan Sung, Kidon TI Molecular Characterization, Antibiotic Resistance, and Virulence Factors of Methicillin-Resistant Staphylococcus aureus Strains Isolated from Imported and Domestic Meat in Korea SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID MULTIPLEX PCR ASSAY; RETAIL MEAT; GENES; INFECTIONS; SEQUENCE; PREVALENCE; MUTATIONS; GRLA; GYRA; MRSA AB During a nationwide surveillance in Korea, 13 methicillin-resistant Staphylococcus aureus (MRSA) strains were isolated from imported and domestic meat between 2009 and 2011. The predominant MRSA genotype was SCCmec type V, and only two agr types (I and II) were found. Unexpectedly, sequence type ST72 comprised more than 50% of the isolates; this is the first instance of type ST72 in food from Canada. Two Spanish pork isolates were ST398, which caused human disease in Europe, and they carried leukotoxin genes, lukS, lukF, and lukE-lukD. Furthermore, P71 and P6 harbored all of the known leukocidin genes, lukS-lukF-lukE-lukD-lukM. Our collected MRSA strains were multidrug resistant with various antimicrobial and heavy-metal resistance genes. Toxin genes that are commonly found in clinical MRSA also were detected in our meat strains. One MRSA strain exhibited an uncommon type of enterotoxin, sec-see-seg-sei-sel-sem-sen-seo-sep. Plasmids (1.5-15.0 kb) were found in 12 of the 13 MRSA isolates. Repetitive sequence-based polymerase chain reaction of the genomic DNA showed 3 clusters with 95% similarity. The presence of multidrug-resistant and toxigenic MRSA in meat products suggests that comprehensive surveillance should be continued for imported meats in Korea. C1 [Kim, Young Jo] Minist Food & Drug Safety, Food Consumpt Safety Div, Cheongwon, South Korea. [Oh, Deog Hwan] Kangwon Natl Univ, Dept Food Sci & Biotechnol, Coll Biotechnol & Bioengn, Chunchon, South Korea. [Oh, Deog Hwan] Kangwon Natl Univ, Inst Biosci & Biotechnol, Chunchon, South Korea. [Song, Bo Ra; Heo, Eun Jeong] Minist Food & Drug Safety, Food Microbiol Div, Cheongwon, South Korea. [Lim, Jong Su] Konkuk Univ, Coll Vet Med, Seoul, South Korea. [Moon, Jin San; Wee, Sung Hwan] Anim & Plant Quarantine Agcy, Vet Pharmaceut Management Div, Anyang, South Korea. [Park, Hyun Jung] Minist Food & Drug Safety, Agrolivestock & Fishery Prod Policy Div, Cheongwon, South Korea. [Sung, Kidon] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Sung, K (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Dr, Jefferson, AR 72079 USA. EM kidon.sung@fda.hhs.gov FU Ministry of Food and Drug Safety, Korea [13161MFDS923] FX We thank Drs. Carl E. Cerniglia, John B. Sutherland, and Fatemeh Rafii for critical review of the manuscript. This work was supported by a grant (13161MFDS923) from the Ministry of Food and Drug Safety, Korea. The views presented here do not necessarily reflect those of the U.S. Food and Drug Administration. NR 50 TC 6 Z9 6 U1 1 U2 17 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 1 PY 2015 VL 12 IS 5 BP 390 EP 398 DI 10.1089/fpd.2014.1885 PG 9 WC Food Science & Technology SC Food Science & Technology GA CH1JO UT WOS:000353777800003 PM 25789540 ER PT J AU Ogedengbe, ME Qvarnstrom, Y da Silva, AJ Arrowood, MJ Barta, JR AF Ogedengbe, Mosun E. Qvarnstrom, Yvonne da Silva, Alexandre J. Arrowood, Michael J. Barta, John R. TI A linear mitochondrial genome of Cyclospora cayetanensis (Eimeriidae, Eucoccidiorida, Coccidiasina, Apicomplexa) suggests the ancestral start position within mitochondrial genomes of eimeriid coccidia SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Mitochondrial genome; Eimeriidae; Cyclospora cayetanensis; Apicomplexa; Linear genome; Genomics ID MOLECULAR CHARACTERIZATION; DNA; PARASITES; SEQUENCES; BABESIA AB The near complete mitochondria] genome for Cyclospora cayetanensis is 6184 bp in length with three protein-coding genes (Cox1, Cox3, CytB) and numerous lsrDNA and ssrDNA fragments. Gene arrangements were conserved with other coccidia in the Eimeriidae, but the C. cayetanensis mitochondrial genome is not circular-mapping. Terminal transferase tailing and nested PCR completed the 5'-terminus of the genome starting with a 21 bp A/T-only region that forms a potential stem-loop. Regions homologous to the C. cayetanensis mitochondrial genome 5'-terminus are found in all eimeriid mitochondrial genomes available and suggest this may be the ancestral start of eimeriid mitochondrial genomes. (C) 2015 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. C1 [Ogedengbe, Mosun E.; Barta, John R.] Univ Guelph, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. [Qvarnstrom, Yvonne; da Silva, Alexandre J.; Arrowood, Michael J.] US Ctr Dis Control & Prevent, Atlanta, GA USA. [da Silva, Alexandre J.] US FDA, Laurel, MD USA. RP Barta, JR (reprint author), Univ Guelph, Dept Pathobiol, 50 Stone Rd East, Guelph, ON N1G 2W1, Canada. EM jbarta@uoguelph.ca OI Barta, John/0000-0001-6896-2271 FU Ontario Veterinary College, Canada; Natural Sciences and Engineering Research Council of Canada (NSERC) [DG 400566]; Centers for Disease Control (CDC) Initiative for Advanced Molecular Detection and Response to Infectious Disease Outbreak, USA FX This work was supported by scholarship support to M.E.O. from the Ontario Veterinary College, Canada and a Discovery Grant (DG 400566) from the Natural Sciences and Engineering Research Council of Canada (NSERC) to J.R.B. This work was supported by the Centers for Disease Control (CDC) Initiative for Advanced Molecular Detection and Response to Infectious Disease Outbreak, USA. The authors acknowledge Julia Whale for her technical support. NR 25 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-7519 EI 1879-0135 J9 INT J PARASITOL JI Int. J. Parasit. PD MAY PY 2015 VL 45 IS 6 BP 361 EP 365 DI 10.1016/j.ijpara.2015.02.006 PG 5 WC Parasitology SC Parasitology GA CH0WP UT WOS:000353743400002 PM 25812835 ER PT J AU Nawaz, M Sung, KD Kweon, O Khan, S Nawaz, S Steele, R AF Nawaz, Mohamed Sung, Kidon Kweon, Ohgew Khan, Saeed Nawaz, Samia Steele, Roger TI Characterisation of novel mutations involved in quinolone resistance in Escherichia coli isolated from imported shrimp SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Article DE Quinolone resistance; Escherichia coli; Imported shrimp ID MOLECULAR CHARACTERIZATION; UNITED-STATES; DNA GYRASE; MECHANISMS; FLUOROQUINOLONES; TETRACYCLINE; AQUACULTURE; INTEGRONS; CHEMICALS; IMPACT AB Fifty-five nalidixic acid-resistant Escherichia coli strains were isolated from imported shrimp. Purified PCR amplicons of gyrA, gyrB, parC and parE from the template DNA of all isolates were sequenced and analysed for point mutations that confer resistance to nalidixic acid and ciprofloxacin. Point mutations in the quinolone resistance-determining regions (QRDRs) of GyrA at positions 68, 83 and 87 and in ParC at positions 80 and 84 as well as in the non-QRDR of GyrA at positions 112, 127, 128 and 154 along with point mutations in parE at position 476 conferred resistance to these antibiotics. Computational modelling and analysis of the different point mutations and their role in the enhanced resistance to these antibiotics indicated that only mutation at codons 83 (Ser -> Ile) and 87 (Asp -> Asn) played a vital role in increasing the minimum inhibitory concentration (MIC) to these drugs compared with other mutations. Ethidium bromide experiments indicated higher efflux pump activities in quinolone-resistant E. coli strains compared with their quinolone-sensitive counterparts. Class 1 integrons measuring 0.7-2.3 kb were amplified and sequenced from the template DNA of the isolates. Sequence analysis of the 2.0 kb and 1.7 kb integrons indicated the presence of resistance determinants for trimethoprim (dfrA12 and dfrA17) and aminoglycosides (aadA2 and aadA5). These results indicate that use of nalidixic acid, ciprofloxacin and other antibiotics in shrimp aquaculture ponds may select E. coli resistant to these antibiotics and that imported shrimp is a reservoir of multiple antibiotic-resistant E. coli. Published by Elsevier B.V. on behalf of International Society of Chemotherapy C1 [Nawaz, Mohamed; Sung, Kidon; Kweon, Ohgew; Khan, Saeed; Steele, Roger] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Nawaz, Samia] Hendrix Coll, Conway, AR 72032 USA. RP Nawaz, M (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Mohamed.Nawaz@fda.hhs.gov FU National Center for Toxicological Research, US Food and Drug Administration (FDA) FX This work was supported by the National Center for Toxicological Research, US Food and Drug Administration (FDA); the views presented here do not necessarily reflect those of the FDA. NR 30 TC 4 Z9 4 U1 0 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 EI 1872-7913 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD MAY PY 2015 VL 45 IS 5 BP 471 EP 476 DI 10.1016/j.ijantimicag.2014.11.010 PG 6 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA CG6AR UT WOS:000353377800005 PM 25631675 ER PT J AU Winnenburg, R Sorbello, A Bodenreider, O AF Winnenburg, Rainer Sorbello, Alfred Bodenreider, Olivier TI Exploring adverse drug events at the class level SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Adverse drug events; Drug classes; Anatomical Therapeutic Chemical (ATC) drug classification system; Class effect; Heat maps; Pharmacovigilance ID REPORTING SYSTEM AB Background: While the association between a drug and an adverse event (ADE) is generally detected at the level of individual drugs, ADEs are often discussed at the class level, i.e., at the level of pharmacologic classes (e.g., in drug labels). We propose two approaches, one visual and one computational, to exploring the contribution of individual drugs to the class signal. Methods: Having established a dataset of ADEs from MEDLINE, we aggregate drugs into ATC classes and ADEs into high-level MeSH terms. We compute statistical associations between drugs and ADEs at the drug level and at the class level. Finally, we visualize the signals at increasing levels of resolution using heat maps. We also automate the exploration of drug-ADE associations at the class level using clustering techniques. Results: Using our visual approach, we were able to uncover known associations, e.g., between fluoroquinolones and tendon injuries, and between statins and rhabdomyolysis. Using our computational approach, we systematically analyzed 488 associations between a drug class and an ADE. Conclusions: The findings gained from our exploratory techniques should be of interest to the curators of ADE repositories and drug safety professionals. Our approach can be applied to different drug-ADE datasets, using different drug classification systems and different signal detection algorithms. C1 [Winnenburg, Rainer] Stanford Univ, Ctr Biomed Informat Res, Stanford, CA 94305 USA. [Sorbello, Alfred] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Bodenreider, Olivier] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20892 USA. RP Bodenreider, O (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20892 USA. EM obodenreider@mail.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine (NLM); US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) Critical Path Program [XLM12011 001]; Office of Translational Sciences at CDER; U.S. Department of Energy; National Library of Medicine FX A preliminary version of this work was presented to the Vaccine and Drug Ontology Studies (VDOS-2014) workshop. This work was supported by the Intramural Research Program of the NIH, National Library of Medicine (NLM). This work also received support from the US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) Critical Path Program [interagency agreement with NLM (XLM12011 001)] and from the Office of Translational Sciences at CDER. While conducting this research, RW was supported by an appointment to the NLM Research Participation Program administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the National Library of Medicine. The authors want to thank Ana Szarfman, Rave Harpaz and Anna Ripple for useful discussions. NR 24 TC 2 Z9 2 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD MAY 1 PY 2015 VL 6 AR 18 DI 10.1186/s13326-015-0017-1 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CH0BP UT WOS:000353684200001 PM 25937884 ER PT J AU Hampshire, V Rippy, M AF Hampshire, Victoria Rippy, Marian TI Optimizing research animal necropsy and histology practices SO LAB ANIMAL LA English DT Editorial Material AB Reduction in animal numbers is an important tenet of laboratory animal research. Research animals should undergo complete necropsy at the close of a study to yield valuable information about the effects and safety of experimental manipulations. Proper and thorough tissue collection, storage and assessment are paramount in attaining the most efficient use of animals in research. C1 [Hampshire, Victoria; Rippy, Marian] US FDA, Silver Spring, MD 20993 USA. RP Hampshire, V (reprint author), US FDA, Silver Spring, MD 20993 USA. EM vahampshire@gmail.com NR 6 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD MAY PY 2015 VL 44 IS 5 BP 170 EP 172 PG 3 WC Veterinary Sciences SC Veterinary Sciences GA CH2QK UT WOS:000353869500017 PM 25897936 ER PT J AU Messer, K White, MM Strong, DR Wang, B Shi, Y Conway, KP Pierce, JP AF Messer, Karen White, Martha M. Strong, David R. Wang, Baoguang Shi, Yuyan Conway, Kevin P. Pierce, John P. TI Trends in Use of Little Cigars or Cigarillos and Cigarettes among U.S. Smokers, 2002-2011 SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID TOBACCO PRODUCTS; UNITED-STATES; ADOLESCENTS; PREVALENCE; CALIFORNIA; PATTERNS; EXPLAINS; SMOKING AB Objectives: Little cigars and cigarillos may resemble cigarettes, but may be less expensive and can be purchased singly and in flavored varieties. We used two major U.S. surveys to investigate use of cigarillos and cigarettes. Methods: The 2010/2011 Tobacco Use Supplement to the Current Population Survey ascertained cigar use by brand and type (little cigars/cigarillos or large/regular). The annual National Survey on Drug Use and Health (NSDUH) assessed cigar use by brand, 2002-2011. We used the available data to classify cigars by type among males in the NSDUH. Results: Estimated prevalence of little cigar use among male cigar smokers was similar using the two surveys. From 2002 to 2011, past-30-day cigarette smoking declined for all age groups and genders, but among young adult men (aged 18-25) little cigar smoking remained steady at nearly 9%. "Cigarette and/or cigar" smoking was 44% among young adult men in 2011, and was consistently 6 percentage points higher than cigarette-only smoking, from 2002 to 2011. Over 60% of male and 70% of female adolescent/young adult cigar smokers also smoked cigarettes in 2011. Most male adolescents preferred little cigars to traditional cigars. Among males, most lower income or less educated cigar smokers preferred little cigars, compared to only 16% of those with higher education. Conclusions: These patterns indicate that little cigar/cigarillo use may promote initiation and maintenance of cigarette smoking, particularly among younger and less advantaged populations. Population-level data are urgently needed to better assess type of cigar smoked and reasons for use. C1 [Messer, Karen; White, Martha M.; Strong, David R.; Shi, Yuyan; Pierce, John P.] Univ Calif San Diego, Canc Prevent & Control Div, Moores UCSD Canc Ctr, La Jolla, CA 92093 USA. [Wang, Baoguang] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Conway, Kevin P.] Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Rockville, MD USA. RP Messer, K (reprint author), Univ Calif San Diego, Div Biostat, Dept Family & Prevent Med, 3855 Hlth Sci Dr,0901, La Jolla, CA 92093 USA. EM kmesser@ucsd.edu OI Conway, Kevin/0000-0002-7638-339X FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration; Department of Health and Human Services [HHSN271201100027C]; UC Tobacco-Related Disease Research Program [21RT-0135, 21XT-0076]; National Cancer Institute [1R01CA172058-01] FX This project has been funded in whole or in part with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under Contract No. HHSN271201100027C, UC Tobacco-Related Disease Research Program grants 21RT-0135 and 21XT-0076, and National Cancer Institute grant No. 1R01CA172058-01. The views and opinions expressed in this presentation are those of the authors only and do not necessarily represent the views, official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies. NR 26 TC 5 Z9 5 U1 3 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD MAY PY 2015 VL 17 IS 5 BP 515 EP 523 DI 10.1093/ntr/ntu179 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CH3CL UT WOS:000353904000003 PM 25239955 ER PT J AU Wang, MO Piard, CM Melchiorri, A Dreher, ML Fisher, JP AF Wang, Martha O. Piard, Charlotte M. Melchiorri, Anthony Dreher, Maureen L. Fisher, John P. TI Evaluating Changes in Structure and Cytotoxicity During In Vitro Degradation of Three-Dimensional Printed Scaffolds SO TISSUE ENGINEERING PART A LA English DT Article ID POLY(PROPYLENE FUMARATE); CROSS-LINKING; MECHANICAL-PROPERTIES; CANCELLOUS BONE; BIOMATERIALS; POLYMERS; DESIGN; FUMARATE)-DIACRYLATE; NETWORKS; TOXICITY AB This study evaluated the structural, mechanical, and cytocompatibility changes of three-dimensional (3D) printed porous polymer scaffolds during degradation. Three porous scaffold designs were fabricated from a poly(propylene fumarate) (PPF) resin. PPF is a hydrolytically degradable polymer that has been well characterized for applications in bone tissue engineering. Over a 224 day period, scaffolds were hydrolytically degraded and changes in scaffold parameters, such as porosity and pore size, were measured nondestructively using micro-computed tomography. In addition, changes in scaffold mechanical properties were also measured during degradation. Scaffold degradation was verified through decreasing pH and increasing mass loss as well as the formation of micropores and surface channels. Current methods to evaluate polymer cytotoxicity have been well established; however, the ability to evaluate toxicity of an absorbable polymer as it degrades has not been well explored. This study, therefore, also proposes a novel method to evaluate the cytotoxicity of the absorbable scaffolds using a combination of degradation extract, phosphate-buffered saline, and cell culture media. Fibroblasts were incubated with this combination media, and cytotoxicity was evaluated using XTT assay and fluorescence imaging. Cell culture testing demonstrated that the 3D-printed scaffold extracts did not induce significant cell death. In addition, results showed that over a 224 day time period, porous PPF scaffolds provided mechanical stability while degrading. Overall, these results show that degradable, 3D-printed PPF scaffolds are suitable for bone tissue engineering through the use of a novel toxicity during degradation assay. C1 [Wang, Martha O.; Piard, Charlotte M.; Melchiorri, Anthony; Fisher, John P.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Dreher, Maureen L.] US FDA, Div Appl Mech, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Fisher, JP (reprint author), Univ Maryland, Bioengn, Fischell Dept Bioengn, College Pk, MD 20742 USA. EM jpfisher@umd.edu FU National Institutes of Health [R01-DE013740]; Food and Drug Administration Center of Excellence in Regulatory Science and Innovation (CERSI) grant FX This research was supported, in part, by the National Institutes of Health (R01-DE013740) and a Food and Drug Administration Center of Excellence in Regulatory Science and Innovation (CERSI) grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 40 TC 4 Z9 4 U1 9 U2 32 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD MAY 1 PY 2015 VL 21 IS 9-10 BP 1642 EP 1653 DI 10.1089/ten.tea.2014.0495 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA CH3TD UT WOS:000353952300016 PM 25627168 ER PT J AU Simon, R Blumenthal, GM Rothenberg, ML Sommer, J Roberts, SA Armstrong, DK LaVange, LM Pazdur, R AF Simon, R. Blumenthal, G. M. Rothenberg, M. L. Sommer, J. Roberts, S. A. Armstrong, D. K. LaVange, L. M. Pazdur, R. TI The Role of Nonrandomized Trials in the Evaluation of Oncology Drugs SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ADMINISTRATION APPROVAL; CLINICAL-TRIALS; END-POINTS; PHASE-II; SURVIVAL; CANCER; THERAPIES AB Although randomized trials provide the most reliable evidence of a drug's safety and efficacy, there are situations where randomized trials are not possible or ethical. In this article we discuss when and how single-arm trials can be used to support full approval of oncology drugs. These include situations in which an unprecedented effect on tumor response is observed in a setting of high unmet medical need, clinical trial patients have been well characterized, enabling a target population to be clearly defined, experience exists in a sufficient number of patients to allow adequate assessment of the risk:benefit relationship, and a proper historical context can be provided for analysis. We also discuss how response rates might be considered predictive of long-term outcomes or clinically meaningful in and of themselves in certain contexts. C1 [Simon, R.] NCI, Bethesda, MD 20892 USA. [Blumenthal, G. M.; LaVange, L. M.] US FDA, Silver Spring, MD USA. [Rothenberg, M. L.; Pazdur, R.] Pfizer Inc, New York, NY USA. [Sommer, J.] Chordoma Fdn, Durham, NC USA. [Roberts, S. A.] Friends Canc Res, Washington, DC 20036 USA. [Armstrong, D. K.] Johns Hopkins Kimmel Canc Ctr, Baltimore, MD USA. RP Roberts, SA (reprint author), Friends Canc Res, Washington, DC 20036 USA. EM sroberts@focr.org FU American Society of Clinical Oncology; Susan G. Komen for the Cure FX This article was developed as an issue brief for the seventh annual Friends of Cancer Research-Brookings Institution Conference on Clinical Cancer Research, held on November 21, 2014. The authors thank the American Society of Clinical Oncology and Susan G. Komen for the Cure for their generous financial support of this conference. We also thank staff at Friends of Cancer Research and the Brookings Institution for their expertise and logistical support, in particular Marina Kozak at Friends of Cancer Research for thoughtful input on the article. NR 20 TC 11 Z9 11 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAY PY 2015 VL 97 IS 5 BP 502 EP 507 DI 10.1002/cpt.86 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CG4DT UT WOS:000353233900011 PM 25676488 ER PT J AU Bohn, J Kortepeter, C Munoz, M Simms, K Montenegro, S Dal Pan, G AF Bohn, J. Kortepeter, C. Munoz, M. Simms, K. Montenegro, S. Dal Pan, G. TI Patterns in Spontaneous Adverse Event Reporting Among Branded and Generic Antiepileptic Drugs SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID EPILEPSY AB Spontaneous adverse event reports constitute an important source of information on previously unknown adverse reactions to marketed medicines. However, the dynamics of such reporting following generic introduction are poorly understood. Using adverse event reports on five antiepileptic drugs from the US Food and Drug Administration's Adverse Event Reporting System, we describe temporal trends in adverse event reporting before and after generic introduction, and survey the quality of product-identifying information contained therein. The majority of reports were sent by innovator drug manufacturers while few were sent by generic manufacturers, even when generics accounted for >90% of dispensed prescriptions. We manually reviewed narratives from 2,500 reports and found that the suspect product type (brand or generic) could not be determined in 84% of reports, while generic products (16%) were identified more often than brand-name products (<1%). These results suggest that pharmacovigilance stakeholders should act to promote more detailed reporting practices. C1 [Bohn, J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bohn, J.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Bohn, J.; Kortepeter, C.; Munoz, M.; Simms, K.; Montenegro, S.; Dal Pan, G.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. RP Bohn, J (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM jmb619@mail.harvard.edu FU Oak Ridge Institute for Science and Education (ORISE) FX This project was partially supported by funds from the Oak Ridge Institute for Science and Education (ORISE) to J.B. NR 17 TC 2 Z9 2 U1 0 U2 5 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 MAY PY 2015 VL 97 IS 5 BP 508 EP 517 DI 10.1002/cpt.81 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CG4DT UT WOS:000353233900012 PM 25670505 ER PT J AU Ding, W Levy, DD Bishop, ME Pearce, MG Davis, KJ Jeffrey, AM Duan, JD Williams, GM White, GA Lyn-Cook, LE Manjanatha, MG AF Ding, Wei Levy, Dan D. Bishop, Michelle E. Pearce, Mason G. Davis, Kelly J. Jeffrey, Alan M. Duan, Jian-Dong Williams, Gary M. White, Gene A. Lyn-Cook, Lascelles E. Manjanatha, Mugimane G. TI In Vivo Genotoxicity of Estragole in Male F344 Rats SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE In vivo comet assay; direct DNA damage; oxidative DNA damage; inflammation; cell proliferation ID NATURALLY-OCCURRING ALKENYLBENZENES; UNSCHEDULED DNA-SYNTHESIS; POST-LABELING ANALYSIS; COMET ASSAY; POSSIBLE INVOLVEMENT; OXIDATIVE DAMAGE; FISCHER-344 RAT; SAFROLE; LIVER; ADDUCTS AB Estragole, a naturally occurring constituent of various herbs and spices, is a rodent liver carcinogen which requires bio-activation. To further understand the mechanisms underlying its carcinogenicity, genotoxicity was assessed in F344 rats using the comet, micronucleus (MN), and DNA adduct assays together with histopathological analysis. Oxidative damage was measured using human 8-oxoguanine-DNA-N-glycosylase (hOGG1) and EndonucleaseIII (EndoIII)-modified comet assays. Results with estragole were compared with the structurally related genotoxic carcinogen, safrole. Groups of seven-week-old male F344 rats received corn oil or corn oil containing 300, 600, or 1,000 mg/kg bw estragole and 125, 250, or 450 mg/kg bw safrole by gavage at 0, 24, and 45 hr and terminated at 48 hr. Estragole-induced dose-dependent increases in DNA damage following EndoIII or hOGG1 digestion and without enzyme treatment in liver, the cancer target organ. No DNA damage was detected in stomach, the non-target tissue for cancer. No elevation of MN was observed in reticulocytes sampled from peripheral blood. Comet assays, both without digestion or with either EndoIII or hOGG1 digestion, also detected DNA damage in the liver of safrole-dosed rats. No DNA damage was detected in stomach, nor was MN elevated in peripheral blood following dosing with safrole suggesting that, as far both safrole and estragole, oxidative damage may contribute to genotoxicity. Taken together, these results implicate multiple mechanisms of estragole genotoxicity. DNA damage arises from chemical-specific interaction and is also mediated by oxidative species. Environ. Mol. Mutagen. 56:356-365, 2015. (c) 2014 Crown copyright. C1 [Ding, Wei; Bishop, Michelle E.; Pearce, Mason G.; Lyn-Cook, Lascelles E.; Manjanatha, Mugimane G.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Levy, Dan D.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Davis, Kelly J.; White, Gene A.] US FDA, Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Jeffrey, Alan M.; Duan, Jian-Dong; Williams, Gary M.] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. RP Ding, W (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Wei.Ding@fda.hhs.gov FU US Food and Drug Administration FX Grant sponsor: US Food and Drug Administration. NR 49 TC 5 Z9 5 U1 3 U2 9 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 MAY PY 2015 VL 56 IS 4 BP 356 EP 365 DI 10.1002/em.21918 PG 10 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CG6IR UT WOS:000353403700002 PM 25361439 ER PT J AU Chang, LC Lin, CTJ AF Chang, LinChiat Lin, Chung-Tung Jordan TI Comparing Food Label Experiments Using Samples from Web Panels versus Mall Intercepts SO FIELD METHODS LA English DT Article DE web surveys; web panels; mall intercepts; sample recruitment mode comparison; food labeling experiment ID MECHANICAL TURK; TELEPHONE; INTERNET; EXPERIENCE; ACCURACY AB To regulate health messages on food labels, the U.S. Food and Drug Administration (FDA) traditionally relied on mall intercepts to collect consumer data. In recent years, web surveys have presented a viable alternative for presenting visual stimuli with more control and efficiency in data collection. However, there is a paucity of empirical data that compares mall intercept versus web panel samples to inform the relative merits and weaknesses of each sample source and their corresponding impact on study outcomes. We analyzed an FDA experiment deployed concurrently on a sample of consumers intercepted at shopping malls and a sample of consumers recruited by a web panel. Despite sample differences in demographics, topic knowledge, and time spent on survey, results from the core experiment were the same, that is, both samples yielded the same conclusions about the effects of the food label statements on consumer perceptions and intentions. C1 [Chang, LinChiat] LinChiat Chang Consulting LLC, San Francisco, CA 94110 USA. [Lin, Chung-Tung Jordan] US FDA, College Pk, MD USA. RP Chang, LC (reprint author), LinChiat Chang Consulting LLC, San Francisco, CA 94110 USA. EM contact@linchiat.com FU U.S. Food and Drug Administration [HHSF223201210784P] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Preparation of this manuscript was funded by research contract HHSF223201210784P from the U.S. Food and Drug Administration. NR 23 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1525-822X EI 1552-3969 J9 FIELD METHOD JI Field Methods PD MAY PY 2015 VL 27 IS 2 BP 182 EP 198 DI 10.1177/1525822X14548395 PG 17 WC Anthropology; Social Sciences, Interdisciplinary SC Anthropology; Social Sciences - Other Topics GA CG1MV UT WOS:000353037900005 ER PT J AU Pan, HM Xu, J Kweon, OG Zou, W Feng, JH He, GX Cerniglia, CE Chen, HZ AF Pan, Hongmiao Xu, Joshua Kweon, Oh-Gew Zou, Wen Feng, Jinhui He, Gui-Xin Cerniglia, Carl E. Chen, Huizhong TI Differential gene expression in Staphylococcus aureus exposed to Orange II and Sudan III azo dyes SO JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY LA English DT Article DE Staphylococcus aureus; Orange II; Sudan III; Microarray; Gene expression ID OXIDATIVE STRESS-RESPONSE; GCN5-RELATED N-ACETYLTRANSFERASES; METHIONINE SULFOXIDE REDUCTASES; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; REDUCED SUSCEPTIBILITY; MICROBIAL-DEGRADATION; SUBSTRATE-SPECIFICITY; GENOME SEQUENCE; HEPG2 CELLS AB We previously demonstrated the effects of azo dyes and their reduction metabolites on bacterial cell growth and cell viability. In this report, the effects of Orange II and Sudan III on gene expression profiling in Staphylococcus aureus ATCC BAA 1556 were analyzed using microarray and quantitative RT-PCR technology. Upon exposure to 6 mu g/ml Orange II for 18 h, 21 genes were found to be differently expressed. Among them, 8 and 13 genes were up- and down-regulated, respectively. Most proteins encoded by these differentially expressed genes involve stress response caused by drug metabolism, oxidation, and alkaline shock indicating that S. aureus could adapt to Orange II exposure through a balance between up and down regulated gene expression. Whereas, after exposure to 6 mu g/ml Sudan III for 18 h, 57 genes were differentially expressed. In which, 51 genes were up-regulated and 6 were down-regulated. Most proteins encoded by these differentially expressed genes involve in cell wall/membrane biogenesis and biosynthesis, nutrient uptake, transport and metabolite, and stress response, suggesting that Sudan III damages the bacterial cell wall or/and membrane due to binding of the dye. Further analysis indicated that all differentially expressed genes encoded membrane proteins were up-regulated and most of them serve as transporters. The result suggested that these genes might contribute to survival, persistence and growth in the presence of Sudan III. Only one gene msrA, which plays an important role in oxidative stress resistance, was found to be down-regulated after exposure to both Orange II and Sudan III. The present results suggested that both these two azo dyes can cause stress in S. aureus and the response of the bacterium to the stress is mainly related to characteristics of the azo dyes. C1 [Pan, Hongmiao; Kweon, Oh-Gew; Feng, Jinhui; Cerniglia, Carl E.; Chen, Huizhong] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Pan, Hongmiao] Chinese Acad Sci, Inst Oceanol, Key Lab Marine Ecol & Environm Sci, Qingdao 266071, Peoples R China. [Xu, Joshua; Zou, Wen] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [He, Gui-Xin] Univ Massachusetts, Dept Clin Lab & Nutr Sci, Lowell, MA 01854 USA. RP Chen, HZ (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM huizhong.chen@fda.hhs.gov FU National Center for Toxicological Research; United States Food and Drug Administration; Oak Ridge Institute for Science and Education FX We thank Drs. Steven L. Foley and Kidon Sung for their critical review of this manuscript. This study was funded by National Center for Toxicological Research, United States Food and Drug Administration, and supported in part by appointments (HP and JF) to the Postgraduate Research Fellowship Program by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. The views presented in this article do not necessarily reflect those of the Food and Drug Administration. NR 85 TC 1 Z9 1 U1 2 U2 24 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1367-5435 EI 1476-5535 J9 J IND MICROBIOL BIOT JI J. Ind. Microbiol. Biotechnol. PD MAY PY 2015 VL 42 IS 5 BP 745 EP 757 DI 10.1007/s10295-015-1599-4 PG 13 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CF9DA UT WOS:000352860600009 PM 25720844 ER PT J AU Coelho, SG Valencia, JC Yin, LL Smuda, C Mahns, A Kolbe, L Miller, SA Beer, JZ Zhang, GF Tuma, PL Hearing, VJ AF Coelho, Sergio G. Valencia, Julio C. Yin, Lanlan Smuda, Christoph Mahns, Andre Kolbe, Ludger Miller, Sharon A. Beer, Janusz Z. Zhang, Guofeng Tuma, Pamela L. Hearing, Vincent J. TI UV exposure modulates hemidesmosome plasticity, contributing to long-term pigmentation in human skin SO JOURNAL OF PATHOLOGY LA English DT Article DE hemidesmosome; skin; pigmentation; ultraviolet radiation; sunburn ID ULTRAVIOLET-RADIATION; HUMAN KERATINOCYTES; SOX PROTEINS; IN-SITU; MELANOMA; DIFFERENTIATION; ASSOCIATION; GENE; DNA; PROLIFERATION AB Human skin colour, ie pigmentation, differs widely among individuals, as do their responses to various types of ultraviolet radiation (UV) and their risks of skin cancer. In some individuals, UV-induced pigmentation persists for months to years in a phenomenon termed long-lasting pigmentation (LLP). It is unclear whether LLP is an indicator of potential risk for skin cancer. LLP seems to have similar features to other forms of hyperpigmentation, eg solar lentigines or age spots, which are clinical markers of photodamage and risk factors for precancerous lesions. To investigate what UV-induced molecular changes may persist in individuals with LLP, clinical specimens from non-sunburn-inducing repeated UV exposures (UVA, UVB or UVA + UVB) at 4 months post-exposure (short-term LLP) were evaluated by microarray analysis and dataset mining. Validated targets were further evaluated in clinical specimens from six healthy individuals (three LLP+ and three LLP-) followed for more than 9 months (long-term LLP) who initially received a single sunburn-inducing UVA + UVB exposure. The results support a UV-induced hyperpigmentation model in which basal keratinocytes have an impaired ability to remove melanin that leads to a compensatory mechanism by neighbouring keratinocytes with increased proliferative capacity to maintain skin homeostasis. The attenuated expression of SOX7 and other hemidesmosomal components (integrin 64 and plectin) leads to increased melanosome uptake by keratinocytes and points to a spatial regulation within the epidermis. The reduced density of hemidesmosomes provides supporting evidence for plasticity at the epidermal-dermal junction. Altered hemidesmosome plasticity, and the sustained nature of LLP, may be mediated by the role of SOX7 in basal keratinocytes. The long-term sustained subtle changes detected are modest, but sufficient to create dramatic visual differences in skin colour. These results suggest that the hyperpigmentation phenomenon leading to increased interdigitation develops in order to maintain normal skin homeostasis in individuals with LLP. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Coelho, Sergio G.; Valencia, Julio C.; Yin, Lanlan; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Smuda, Christoph; Mahns, Andre; Kolbe, Ludger] Beiersdorf AG, R&D Skin Res, Hamburg, Germany. [Miller, Sharon A.; Beer, Janusz Z.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Tuma, Pamela L.] Catholic Univ Amer, Dept Biol, Washington, DC 20064 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 FU Office of Science; Center for Devices and Radiological Health, Food and Drug Administration; National Cancer Institute, National Institutes of Health FX This research was supported in part by the Office of Science and the Center for Devices and Radiological Health, Food and Drug Administration, and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. We would like to acknowledge Professors Ito and Wakamatsu for completing the melanosome melanin analysis. NR 39 TC 4 Z9 4 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD MAY PY 2015 VL 236 IS 1 BP 17 EP 29 DI 10.1002/path.4497 PG 13 WC Oncology; Pathology SC Oncology; Pathology GA CG1OF UT WOS:000353041900003 PM 25488118 ER PT J AU Otsuka, K Wagner, C Selen, A Dressman, J AF Otsuka, Keiichi Wagner, Christian Selen, Arzu Dressman, Jennifer TI Prediction of in-vivo pharmacokinetic profile for immediate and modified release oral dosage forms of furosemide using an in-vitro-in-silico-in-vivo approach SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article DE biorelevant dissolution; furosemide; modified release; oral administration; physiologically based pharmacokinetic models ID POORLY SOLUBLE DRUG; BIORELEVANT DISSOLUTION; ABSOLUTE BIOAVAILABILITY; PERFORMANCE; ABSORPTION; MEDIA; FOOD; DANAZOL; TOOL AB ObjectivesTo develop a physiologically based pharmacokinetic (PBPK) model for furosemide immediate release (IR) tablets and modified release (MR) capsules by coupling biorelevant dissolution testing results with pharmacokinetic (PK) and physiologic parameters, and to investigate the key factors influencing furosemide absorption using simulation approaches and the PBPK model. MethodsUsing solubility, dissolution kinetics, gastrointestinal (GI) parameters and disposition parameters, a PBPK model for furosemide was developed with STELLA software. Solubility and dissolution profiles for both formulations were evaluated in biorelevant and compendial media. The simulated plasma profiles were compared with in-vivo profiles using point estimates of area under plasma concentration-time curve, maximal concentration after the dose and time to maximal concentration after the dose. Key findingsSimulated plasma profiles of both furosemide IR tablets and MR capsules were similar to the observed in-vivo profile in terms of PK parameters. Sensitivity analysis of the IR tablet model indicated that both the gastric emptying and absorption rate have an influence on the plasma profile. For the MR capsules, the sensitivity analysis suggested that the release rate in the small intestine, gastric emptying and the absorption rate all have an influence on the plasma profile. ConclusionsA predictive model to describe both IR and MR dosage forms containing furosemide was attained. Because sensitivity analysis of the model is able to identify key factors influencing the plasma profile, this in-vitro-in-silico-in-vivo approach could be a useful tool for facilitating formulation development of drug products. C1 [Otsuka, Keiichi; Wagner, Christian; Dressman, Jennifer] Goethe Univ Frankfurt, Inst Pharmaceut Technol, D-60438 Frankfurt, Germany. [Selen, Arzu] US FDA, Off New Drug Qual Assessment, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Dressman, J (reprint author), Goethe Univ Frankfurt, Inst Pharmaceut Technol, Max von Laue Str 9, D-60438 Frankfurt, Germany. EM dressman@em.uni-frankfurt.de RI Fachbereich14, Dekanat/C-8553-2015 NR 28 TC 0 Z9 0 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3573 EI 2042-7158 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD MAY PY 2015 VL 67 IS 5 BP 651 EP 665 DI 10.1111/jphp.12365 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CG5ND UT WOS:000353337800005 PM 25644429 ER PT J AU Calhoun, WR Ilev, IK AF Calhoun, William R., III Ilev, Ilko K. TI Effect of therapeutic femtosecond laser pulse energy, repetition rate, and numerical aperture on laser-induced second and third harmonic generation in corneal tissue SO LASERS IN MEDICAL SCIENCE LA English DT Article DE Cornea; Collagen; Harmonic generation; Femtosecond laser ID REFRACTIVE SURGERY; MICROSCOPY; MECHANISMS; COLLAGEN; RETINA; DAMAGE; PHOTOTOXICITY; KERATOCONUS; ABLATION; STROMA AB Clinical therapy incorporating femtosecond laser (FSL) devices is a quickly growing field in modern biomedical technology due to their precision and ability to generate therapeutic effects with substantially less laser pulse energy. FSLs have the potential to produce nonlinear optical effects such as harmonic generation (HG), especially in tissues with significant nonlinear susceptibilities such as the cornea. HG in corneal tissue has been demonstrated in nonlinear harmonic microscopy using low-power FSLs. Furthermore, the wavelength ranges of harmonic spectral emissions generated in corneal tissues are known to be phototoxic above certain intensities. We have investigated how the critical FSL parameters pulse energy, pulse repetition rate, and numerical aperture influence both second (SHG) and third harmonic generation (THG) in corneal tissue. Experimental results demonstrated corresponding increases in HG intensity with increasing repetition rate and numerical aperture. HG duration decreased with increasing repetition rate and pulse energy. The data also demonstrated a significant difference in HG between FSL parameters representing the two most common classes of FSL therapeutic devices. C1 [Calhoun, William R., III; Ilev, Ilko K.] US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Calhoun, William R., III] Virginia Commonwealth Univ, Dept Biomed Engn, Richmond, VA 23284 USA. RP Calhoun, WR (reprint author), Virginia Commonwealth Univ, Dept Biomed Engn, Med Coll Virginia Campus, Richmond, VA 23284 USA. EM william.calhoun@fda.hhs.gov NR 40 TC 0 Z9 0 U1 2 U2 8 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0268-8921 EI 1435-604X J9 LASER MED SCI JI Lasers Med. Sci. PD MAY PY 2015 VL 30 IS 4 BP 1341 EP 1346 DI 10.1007/s10103-015-1726-5 PG 6 WC Engineering, Biomedical; Surgery SC Engineering; Surgery GA CF9QC UT WOS:000352899400023 PM 25779115 ER PT J AU Knox, C Hampp, C Willy, M Winterstein, AG Dal Pan, G AF Knox, Caitlin Hampp, Christian Willy, Mary Winterstein, Almut G. Dal Pan, Gerald TI Patient understanding of drug risks: an evaluation of medication guide assessments SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE knowledge; medication guide; FDA; REMS; pharmacoepidemiology ID CONVEYING SAFETY INFORMATION; REMS ASSESSMENT SURVEY; CONSUMER; PHARMACIES; LITERACY AB PurposeWhen a Medication Guide (MG) is part of Risk Evaluation and Mitigation Strategy (REMS), manufacturers assess the effectiveness of MGs through patient surveys, which have not undergone systematic evaluation. We aimed to characterize knowledge rates from these patient surveys, describe their design and respondent characteristics, and explore predictors of acceptable knowledge rates. MethodsWe analyzed MG assessments submitted to the Food and Drug Administration from September 2008 through June 2012. We evaluated the prevalence of specific characteristics, and calculated knowledge rates, whereby we defined acceptable knowledge when 80% of respondents correctly answered questions about the primary drug risk. Univariate logistic models were used to investigate the predictors of acceptable knowledge rates. ResultsWe analyzed the first completed MG assessment for each drug with a patient survey, resulting in 66 unique MG assessments. The mean knowledge rate was 63.8%, with 20 MG assessments (30.3%) achieving the 80% threshold. Compared to assessments that did not reach acceptable knowledge rates, those that did were more likely associated with additional REMS elements (e.g. Elements to Assure Safe Use or Communication Plans). Other factors, including mean age, reading or understanding the MG, and being offered or accepting counseling were not associated with knowledge rates. There was considerable variation in the design of MG assessments. ConclusionsMost MG assessments did not reach the 80% knowledge threshold, but those associated with additional interventions were more likely to achieve it. Our study highlights the need to improve patient-directed information and the methods of assessing it. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Knox, Caitlin; Winterstein, Almut G.] Univ Florida, Coll Pharm, Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Hampp, Christian; Willy, Mary; Dal Pan, Gerald] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Winterstein, Almut G.] Univ Florida, Coll Publ Hlth & Hlth Profess, Epidemiol, Gainesville, FL USA. [Winterstein, Almut G.] Univ Florida, Coll Med, Gainesville, FL USA. RP Knox, C (reprint author), Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, Gainesville, FL 32611 USA. EM cknox@ufl.edu FU Mary Kay Owens (MKO) Fellowship FX Caitlin Knox is a recipient of the American Foundation for Pharmaceutical Educations (AFPE) 2012 Pre-Doctoral Fellow and the Mary Kay Owens (MKO) Fellowship. NR 22 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD MAY PY 2015 VL 24 IS 5 BP 518 EP 525 DI 10.1002/pds.3762 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA CG6KG UT WOS:000353408700009 PM 25808393 ER PT J AU Guthrie, J Mancino, L Lin, CTJ AF Guthrie, Joanne Mancino, Lisa Lin, Chung-Tung Jordan TI Nudging Consumers toward Better Food Choices: Policy Approaches to Changing Food Consumption Behaviors SO PSYCHOLOGY & MARKETING LA English DT Review ID HEALTH CLAIMS; LABEL USE; GUIDANCE-SYSTEM; PUBLIC-HEALTH; NUTRITION EDUCATION; OBESITY; INFORMATION; FRAMEWORK; FAT; COMMUNICATION AB The high prevalence of obesity and its associated illnesses, such as cancer, heart disease and diabetes, has sparked interest in finding ways to encourage consumers to make healthier food choices. At the public level, providing information about why and how to choose a healthy diet has been the typical approach to encouraging behavioral change. Information can also influence food producers and marketers to develop and promote more healthful products, creating an environment in which it is easier for consumers to make healthier dietary choices. Nevertheless, information may not always be effective in improving food choices. One explanation is that nutrition information is complex and difficult to convey in a clear, actionable manner. Also, knowledge, while necessary, may not be sufficient to motivate behavior change. Even when consumers understand nutrition information, competing preferences for tastier, less expensive, or more convenient foods may lead them to make other choices. Findings from psychology, marketing, and behavioral economics research suggest approaches that may enhance the effectiveness of informational approaches and complement informational efforts. More research is needed to further develop these strategies and evaluate their effectiveness. C1 [Guthrie, Joanne; Mancino, Lisa] USDA, Washington, DC USA. [Lin, Chung-Tung Jordan] US FDA, Rockville, MD 20857 USA. RP Guthrie, J (reprint author), ERS, Food Econ Div, USDA, 1400 Independence Ave SW,Mailstop 1800, Washington, DC 20250 USA. EM jguthrie@ers.usda.gov NR 105 TC 7 Z9 7 U1 36 U2 106 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-6046 EI 1520-6793 J9 PSYCHOL MARKET JI Psychol. Mark. PD MAY PY 2015 VL 32 IS 5 SI SI BP 501 EP 511 DI 10.1002/mar.20795 PG 11 WC Business; Psychology, Applied SC Business & Economics; Psychology GA CG4EH UT WOS:000353235600003 ER PT J AU Scully, CG Kramer, GC Strauss, DG AF Scully, Christopher G. Kramer, George C. Strauss, David G. TI EVALUATION OF HEART RATE AND BLOOD PRESSURE VARIABILITY AS INDICATORS OF PHYSIOLOGICAL COMPENSATION TO HEMORRHAGE BEFORE SHOCK SO SHOCK LA English DT Article DE Hemorrhage; compensation; heart rate variability; blood pressure variability ID SYMPATHETIC-NERVE ACTIVITY; TIME-FREQUENCY ANALYSIS; CENTRAL HYPOVOLEMIA; ARTERIAL-PRESSURE; PERIOD VARIABILITY; OXYGEN-SATURATION; CONSCIOUS DOGS; WAVE-FORM; OSCILLATIONS; HUMANS AB Individual responses to hemorrhage vary, with varying periods of compensation before the development of shock. We characterized heart rate and blood pressure variability measures during hemorrhage of 25 mL/kg(Body Weight) for 15 min in conscious sheep (N = 7, 14 total hemorrhages) as markers of the transition from compensated to decompensated shock using the continuous wavelet transform. Heart rate-low frequency (HR-LF) and systolic blood pressure-low frequency (SBP-LF) indices were developed to represent the change in spectral power during hemorrhage as low-frequency (0.06-0.15 Hz) power divided by the sum of high (0.15-1.0 Hz)- and very low (0.02 - 0.06 Hz) frequency power. Heart rate rose from 96.3 (22.2) beats/min (mean [SD] across all trials) to a peak of 176.0 (25.4) beats/min occurring at a minimum time of 5.3 min to a maximum of 22.1 min (11.7 [1.6] min), depending on the trial, after the start of hemorrhage. During the HR-compensated response to hemorrhage, there was elevated HR-LF and SBP-LF in five of the seven animals. In these animals, HR-LF and SBP-LF dropped to below baseline levels around the time of the peak HR. The results from this conscious-animal study suggest that HR and SBP low-frequency power rise during the compensation phase of the response to hemorrhage in conscious sheep. Use of variability monitoring could aid in describing an individual's current response to hemorrhage and anticipation of impending decompensation; however, individual differences in the response limit this potential. C1 [Scully, Christopher G.; Strauss, David G.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Kramer, George C.] Univ Texas Med Branch, Dept Anesthesiol, Galveston, TX 77555 USA. RP Scully, CG (reprint author), US FDA, 10903 New Hampshire Ave,WO62-1202C, Silver Spring, MD 20993 USA. EM christopher.scully@fda.hhs.gov FU US Food and Drug Administration's Medical Countermeasures Initiative FX This work was supported in part by the US Food and Drug Administration's Medical Countermeasures Initiative and an appointment to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. NR 27 TC 5 Z9 5 U1 1 U2 7 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 MAY PY 2015 VL 43 IS 5 BP 463 EP 469 DI 10.1097/SHK.0000000000000340 PG 7 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA CG2ZT UT WOS:000353146200007 PM 25692248 ER PT J AU Bonne, O Gill, J Lerner, A Nugent, AC Vythilingam, M Neumeister, A Drevets, WC AF Bonne, Omer Gill, Jessica Lerner, Alicja Nugent, Allison C. Vythilingam, Meena Neumeister, Alexander Drevets, Wayne C. TI Altered Cerebral gamma-Amniobutyric Acid Type A-Benzodiazapine Receptor Binding in PTSD Determined by [11C] Flumazenil Positron Emission Tomography SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 70th Annual Scientific Meeting of the Society-of-Biological-Psychiatry on Stress, Emotion, Neurodevelopment and Psychopathology CY MAY 14-16, 2015 CL Toronto, CANADA SP Soc Biol Psychiat DE PTSD; PET; GABA-A; DMN C1 [Bonne, Omer] Hadassah Univ Hosp, Psychiat, IL-91120 Jerusalem, Israel. [Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. [Lerner, Alicja] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Nugent, Allison C.] NIH, Branch Experiemental Therapeut, Bethesda, MD 20892 USA. [Vythilingam, Meena] Deployment Hlth Clin Ctr, Clin Sci & Translat, Chevy Chase, MD USA. [Neumeister, Alexander] NYU, Langone Med Ctr, Psychiat & Radiol, New York, NY USA. [Drevets, Wayne C.] Johnson & Johnson Inc, Janssen Res & Dev, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2015 VL 77 IS 9 SU S MA 258 BP 99S EP 99S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CF0BM UT WOS:000352207500251 ER PT J AU Woo, EJ AF Woo, Emily Jane TI Letter to the Editor: On Patient Safety: How Well Do We Police Ourselves? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Letter C1 US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Woo, EJ (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jane.woo@fda.hhs.gov NR 3 TC 0 Z9 0 U1 0 U2 3 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 MAY PY 2015 VL 473 IS 5 BP 1847 EP 1848 DI 10.1007/s11999-015-4221-1 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CF1CB UT WOS:000352280100052 PM 25716214 ER PT J AU Irwin, DC Baek, JH Hassell, K Nuss, R Eigenberger, P Lisk, C Loomis, Z Maltzahn, J Stenmark, KR Nozik-Grayck, E Buehler, PW AF Irwin, David C. Baek, Jin Hyen Hassell, Kathryn Nuss, Rachelle Eigenberger, Paul Lisk, Christina Loomis, Zoe Maltzahn, Joanne Stenmark, Kurt R. Nozik-Grayck, Eva Buehler, Paul W. TI Hemoglobin-induced lung vascular oxidation, inflammation, and remodeling contribute to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeated-dose haptoglobin administration SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Hemoglobin; Heme; Iron; Lipid peroxidation; Hemolysis; Sickle cell disease; Thalassemia; Free radicals ID SICKLE-CELL-DISEASE; INTRAVASCULAR HEMOLYSIS; ARTERIAL-HYPERTENSION; TRANSFUSION; THALASSEMIA; LESSONS; COMPLEX; MICE; IRON; WALL AB Haptoglobin (Hp) is an approved treatment in Japan for trauma, burns, and massive transfusion-related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia-mediated PH. Rats were simultaneously exposed to chronic Hb infusion (35 mg per day) and hypobaric hypoxia for 5 weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated nonheme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right-ventricular hypertrophy, which suggests a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia and (2) suggest a novel therapy for chronic hemolysis-associated PH. (C) 2015 Elsevier Inc. All rights reserved. C1 [Irwin, David C.; Eigenberger, Paul; Lisk, Christina; Maltzahn, Joanne; Buehler, Paul W.] Univ Colorado Denver, Sch Med, Div Cardiol, Cardiovasc Pulm Res Grp, Aurora, CO 80045 USA. [Baek, Jin Hyen; Buehler, Paul W.] US FDA, Lab Biochem & Vasc Biol, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Hassell, Kathryn; Nuss, Rachelle; Loomis, Zoe] Colorado Sickle Cell Treatment & Res Ctr, Aurora, CO 80045 USA. [Hassell, Kathryn; Nuss, Rachelle; Loomis, Zoe] Univ Colorado Denver, Aurora, CO 80045 USA. [Stenmark, Kurt R.; Nozik-Grayck, Eva] Univ Colorado Denver, Sch Med, Cardiovasc Pulm Res Grp, Pediat, Aurora, CO 80045 USA. RP Irwin, DC (reprint author), Univ Colorado Denver, Sch Med, Div Cardiol, Cardiovasc Pulm Res Grp, Anschutz Med Campus, Aurora, CO 80045 USA. EM David.Irwin@UCDenver.edu FU American Physiological Society; National Heart, Lung, and Blood Institute [5P01HL014985-38] FX We thank Julie Harral for her expertise in surgical pump implantation, acute and chronic rat catheterizations, and instrumentation to obtain pulmonary and systemic blood pressures and cardiac outputs. We thank Malcolm Anderson for performing the IHC staining of the lungs for 4-HNE. This study was supported in part by the Giles F. Filley Award from the American Physiological Society (D.C.I.) and by National Heart, Lung, and Blood Institute Grant 5P01HL014985-38 (K.R.S.). 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 38 TC 10 Z9 10 U1 1 U2 6 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 2015 VL 82 BP 50 EP 62 DI 10.1016/j.freeradbiomed.2015.01.012 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CF8PF UT WOS:000352823700006 PM 25656991 ER PT J AU Seidman, JD Woodburn, R AF Seidman, Jeffrey D. Woodburn, Renee TI Pseudoxanthomatous Salpingitis as an Ex Vivo Model of Fallopian Tube Serous Carcinogenesis: A Clinicopathologic Study of 49 Cases SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Salpingitis; Endometriosis; Iron; Lipofuscin; Hemosiderin; Pseudoxanthomatous inflammation; Carcinogenesis; Fallopian tube; Serous carcinoma; Ovarian carcinoma ID INCESSANT MENSTRUATION HYPOTHESIS; OVARIAN-CANCER; XANTHOGRANULOMATOUS SALPINGITIS; PIGMENTOSIS TUBAE; IRON; PATHOGENESIS; ENDOMETRIOSIS; INFLAMMATION; CARCINOMA; MUTATION AB Iron is a well-documented carcinogen based on both animal models and observational studies in humans. There are limited published data on pseudoxanthomatous salpingitis, an uncommon condition characterized by the accumulation of histiocytes containing iron and iron-related compounds-lipofuscin and hemosiderinin the lamina propria of the fallopian tube. The clinical and pathologic features of 49 consecutive cases were evaluated. The mean patient age was 53. A history of endometriosis was found in 20%, infertility in 17%, and tubal ligation in 7%. Thirteen (27%) had endometrial cancer and 2 patients had prior radiation therapy for cervical carcinoma. Histologic evidence of endometriosis other than tubal pigment deposition was identified in 65%, and in the fallopian tubes in 35%. Pigment deposition was unilateral in 65% and multifocal or diffuse in 80%. Plasma cells, eosinophils, and neutrophils were present in the tubal lamina propria in 57%, 18%, and 24%, respectively. Hydrosalpinx was present in 51%. An iron stain was positive in pseudoxanthoma cells lacking hemosiderin in 14 of 18 cases (78%). By immunohistochemistry, 2 of 22 cases displayed p53 signatures. The Ki67 proliferation index was elevated (>10%) in 11 of 22 cases, with a mean index of 32% in those cases. An elevated proliferation index did not correlate with inflammation. In summary, these findings characterize the clinical and pathologic features of pseudoxanthomatous salpingitis and confirm its close association with endometriosis, occasional association with radiation therapy, and the presence of iron in the histiocytes. In view of the evolving paradigm shift implicating the fallopian tubal epithelium as the site of origin of high-grade extrauterine serous carcinoma, the presence of iron and iron-related compounds in the fallopian tube provides an opportunity to study the early events in high-grade serous carcinogenesis in a setting characterized by a well-documented carcinogen in close anatomic proximity to the putative epithelium of origin. C1 [Seidman, Jeffrey D.] Washington Hosp Ctr, Dept Pathol & Lab Med, Washington, DC 20010 USA. [Woodburn, Renee] Washington Hosp Ctr, Dept Obstet & Gynecol, Washington, DC 20010 USA. RP Seidman, JD (reprint author), US FDA, Mol Pathol & Cytol Branch, Div Mol Genet & Pathol, Off In Vitro Diagnost & Radiol Hlth,Ctr Devices &, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jeffrey.seidman@fda.hhs.gov NR 37 TC 1 Z9 1 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD MAY PY 2015 VL 34 IS 3 BP 275 EP 280 DI 10.1097/PGP.0000000000000154 PG 6 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA CF6BG UT WOS:000352640800010 PM 25760905 ER PT J AU Ponnamperuma, RM Ha, L Reilly, D Jay, S Weinberg, WC AF Ponnamperuma, R. M. Ha, L. Reilly, D. Jay, S. Weinberg, W. C. TI Bmi-1 differentially regulates p16(ink4a) and p19(arf) in p63-overexpressing keratinocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 06-09, 2015 CL Atlanta, GA SP Soc Investigat Dermatol C1 [Ponnamperuma, R. M.; Ha, L.; Reilly, D.; Weinberg, W. C.] CDER FDA, Lab Mol Oncol OBP, Silver Spring, MD USA. [Jay, S.] SIAC Frederick Inc, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2015 VL 135 SU 1 MA 142 BP S24 EP S24 PG 1 WC Dermatology SC Dermatology GA CF8CO UT WOS:000352783200143 ER PT J AU Rahman, Z Bykadi, S Siddiqui, A Khan, MA AF Rahman, Ziyaur Bykadi, Srikant Siddiqui, Akhtar Khan, Mansoor A. TI Comparison of X-ray Powder Diffraction and Solid-State Nuclear Magnetic Resonance in Estimating Crystalline Fraction of Tacrolimus in Sustained-Release Amorphous Solid Dispersion and Development of Discriminating Dissolution Method SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE solid dispersion; dissolution; X-ray powder diffractometry; solid state NMR; principal component analysis; partial least squares ID SOLVENT EVAPORATION; CHEMOMETRIC METHODS; CROSS-POLARIZATION; PHYSICAL STABILITY; FLIP-BACK; CPMAS NMR; DRUG; QUANTIFICATION; FORMULATION; SOLUBILITY AB The focus of present investigation was to explore X-ray powder diffraction (XRPD) and solid-state nuclear magnetic resonance (ssNMR) techniques for amorphous and crystalline tacrolimus quantification in the sustained-release amorphous solid dispersion (ASD), and to propose discriminating dissolution method that can detect crystalline drug. The ASD and crystalline physical mixture was mixed in various proportions to make sample matrices containing 0%-100% crystalline-amorphous tacrolimus. Partial-least-square regression and principle component regression were applied to the spectral data. Dissolution of the ASD in the US FDA recommended dissolution medium with and without surfactant was performed. R-2 > 0.99 and slope was close to one for all the models. Root-mean-square of prediction, standard error of prediction, and bias were higher in ssNMR-based models when compared with XRPD data models. Dissolution of the ASD decreased with an increase in the crystalline tacrolimus in the formulations. Furthermore, detection of crystalline tacrolimus in the ASD was progressively masked with an increase in the surfactant level in the dissolution medium. XRPD and ssNMR can be used equally to quantitate the crystalline and amorphous fraction of tacrolimus in the ASD with good accuracy; however, ssNMR data collection time is excessively long, and minimum surfactant level in the dissolution medium maximizes detection of crystalline reversion in the formulation. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1777-1786, 2015 C1 [Rahman, Ziyaur; Bykadi, Srikant; Siddiqui, Akhtar; Khan, Mansoor A.] US FDA, Div Prod Qual & Res, Off Testing & Res, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual & Res, Off Testing & Res, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. EM Mansoor.Khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X NR 28 TC 4 Z9 4 U1 4 U2 18 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 MAY PY 2015 VL 104 IS 5 BP 1777 EP 1786 DI 10.1002/jps.24400 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CF5AW UT WOS:000352567900022 PM 25753829 ER PT J AU Bhattacharya, P Dey, R Dagur, P Kruhlak, M Debrabant, A Okeeffe, NI McCoy, J Nakhasi, H AF Bhattacharya, Parna Dey, Ranadhir Dagur, Pradeep Kruhlak, Michael Debrabant, Alain Okeeffe, Nevien Ismail McCoy, John Nakhasi, Hira TI Genetically modified live attenuated L. donovani parasite induces classical activation of macrophages (M1 phenotype) leading to generation of Th1 response in BALB/c mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (IMMUNOLOGY) CY MAY 08-12, 2015 CL New Orleans, LA SP Amer Assoc Immunologists C1 [Dagur, Pradeep; McCoy, John] NHLBI, NIH, Bethesda, MD 20892 USA. [Kruhlak, Michael] NCI, NIH, Bethesda, MD 20892 USA. [Bhattacharya, Parna; Dey, Ranadhir; Debrabant, Alain; Okeeffe, Nevien Ismail; Nakhasi, Hira] US FDA, DETTD, CBER, Silver Spring, MD 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 2015 VL 194 SU 1 MA VAC4P.1102 PG 1 WC Immunology SC Immunology GA DQ7RG UT WOS:000379404504121 ER PT J AU Golding, B Jiang, HY Sauna, Z Levin, D AF Golding, Basil Jiang, Haiyan Sauna, Zuben Levin, Ditza TI Immune responses to chimeric human-FIX-mouse-Fc fusion protein in a hemophilia B mouse model SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (IMMUNOLOGY) CY MAY 08-12, 2015 CL New Orleans, LA SP Amer Assoc Immunologists C1 [Golding, Basil; Sauna, Zuben; Levin, Ditza] FDA CBER, Rockville, MD USA. [Jiang, Haiyan] Biogen Idec Inc, Immunol, Cambridge, MA 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 2015 VL 194 SU 1 MA THER2P.963 PG 2 WC Immunology SC Immunology GA DQ7RG UT WOS:000379404500005 ER PT J AU Johnson, A Myers, M AF Johnson, Annie Myers, Michael TI NSAIDs inhibit NFk beta activation to prevent inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (IMMUNOLOGY) CY MAY 08-12, 2015 CL New Orleans, LA SP Amer Assoc Immunologists C1 [Johnson, Annie; Myers, Michael] US FDA, Upper Marlboro, MD 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 2015 VL 194 SU 1 MA IRC4P.602 PG 2 WC Immunology SC Immunology GA DQ7RG UT WOS:000379404501300 ER PT J AU Morozov, G Zhao, HY Mage, M Boyd, L Venna, R Norcross, M McMurtrey, C Hildebrand, W Schuck, P Jiang, JS Natarajan, K Margulies, D AF Morozov, Giora Zhao, Huaying Mage, Michael Boyd, Lisa Venna, Ramesh Norcross, Michael McMurtrey, Curtis Hildebrand, William Schuck, Peter Jiang, Jiansheng Natarajan, Kannan Margulies, David TI Direct interaction of recombinant TAPBPR with MHC-I molecules: stabilization of peptide-free MHC-I promotes high affinity peptide loading SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (IMMUNOLOGY) CY MAY 08-12, 2015 CL New Orleans, LA SP Amer Assoc Immunologists C1 [Morozov, Giora; Mage, Michael; Boyd, Lisa; Jiang, Jiansheng; Natarajan, Kannan; Margulies, David] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Huaying; Schuck, Peter] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. [Venna, Ramesh; Norcross, Michael] US FDA, Lab Immunol, Div Therapeut Prot, CDER, Bethesda, MD 20014 USA. [McMurtrey, Curtis; Hildebrand, William] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 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 2015 VL 194 SU 1 MA APP5P.102 PG 2 WC Immunology SC Immunology GA DQ7RG UT WOS:000379404500132 ER PT J AU Myers, M Deaver, C Peters, S Swaim, H Yancy, H AF Myers, Michael Deaver, Christine Peters, Sharla Swaim, Heidi Yancy, Haile TI Identifying biomarkers from an in vitro carrageenan model of inflammation in swine SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (IMMUNOLOGY) CY MAY 08-12, 2015 CL New Orleans, LA SP Amer Assoc Immunologists C1 [Myers, Michael; Deaver, Christine; Peters, Sharla; Swaim, Heidi; Yancy, Haile] US FDA, Laurel, MD 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 2015 VL 194 SU 1 MA INM8P.359 PG 1 WC Immunology SC Immunology GA DQ7RG UT WOS:000379404502103 ER PT J AU Rajawat, Y Berkson, J McFarland, H Morgan, R Zhao, YB Rosenberg, A AF Rajawat, Yogendra Berkson, Julia McFarland, Hugh Morgan, Richard Zhao, Yangbing Rosenberg, Amy TI Induction of antigen specific transplantation tolerance using chimeric antigen receptor type T cells engineered to kill allospecific T cells by a gene therapy immunotherapeutic approach SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (IMMUNOLOGY) CY MAY 08-12, 2015 CL New Orleans, LA SP Amer Assoc Immunologists C1 [Rajawat, Yogendra; Berkson, Julia; McFarland, Hugh; Rosenberg, Amy] US FDA, DBRR III OBP, CDER, Silver Spring, MD USA. [Morgan, Richard] Bluebird Bio, Immunotherapy, Cambridge, MA USA. [Zhao, Yangbing] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 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 2015 VL 194 SU 1 MA TRAN2P.968 PG 1 WC Immunology SC Immunology GA DQ7RG UT WOS:000379404502155 ER PT J AU Cortazar, P Geyer, CE AF Cortazar, Patricia Geyer, Charles E., Jr. TI Pathological Complete Response in Neoadjuvant Treatment of Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID SURGICAL ADJUVANT BREAST; PROJECT PROTOCOL B-27; PRIMARY CHEMOTHERAPY; OPEN-LABEL; PREOPERATIVE CHEMOTHERAPY; COMPLETE ERADICATION; PHASE-3 TRIAL; PRIMARY TUMOR; TRASTUZUMAB; THERAPY AB There has been recent interest in using pathological complete response (pCR) as a potential surrogate endpoint for long-term outcomes in the neoadjuvant treatment of high-risk, early-stage breast cancer. We review the clinical trials that have contributed to our understanding of the association between pCR and long-term outcomes, describe the various definitions of pCR, describe patient populations in which pCR may predict long-term benefit, and discuss the implications of pCR on drug development and accelerated approval for neoadjuvant treatment of breast cancer. Varying definitions of pCR across clinical trials conducted in heterogeneous patient populations make understanding the association of pCR with long-term outcomes challenging. The US Food and Drug Administration established the Collaborative Trials in Neoadjuvant Breast Cancer group to evaluate the potential use of pCR as a regulatory endpoint. The group demonstrated that pCR defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0) provided a better association with improved outcomes compared to eradication of invasive tumor from the breast alone (ypT0/is). Even though pCR was not validated as a surrogate endpoint for long-term outcomes, the promising data regarding the strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer supported the opening of an accelerated approval pathway for patients with high-risk, early-stage breast cancer. C1 [Cortazar, Patricia] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. RP Cortazar, P (reprint author), US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM patricia.cortazar@fda.hhs.gov FU Genentech, Inc. FX This educational review series, "Neoadjuvant Therapy in Breast Cancer" is supported by an educational grant from Genentech, Inc. The Society of Surgical Oncology offers CME/MOC for this educational review series. Visit www.moc.surgonc.org for additional information. NR 41 TC 9 Z9 9 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD MAY PY 2015 VL 22 IS 5 BP 1441 EP 1446 DI 10.1245/s10434-015-4404-8 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA CF0JN UT WOS:000352229800008 PM 25727556 ER PT J AU Bennett, SD Littrell, KW Hill, TA Mahovic, M Behravesh, CB AF Bennett, S. D. Littrell, K. W. Hill, T. A. Mahovic, M. Behravesh, C. Barton TI Multistate foodborne disease outbreaks associated with raw tomatoes, United States, 1990-2010: a recurring public health problem SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Food safety; foodborne infections; outbreaks; produce; Salmonella; tomatoes ID SALMONELLA-ENTERICA; FRESH PRODUCE; SURVIVAL; PLANTS; MONTEVIDEO; COLONIZATION; TEMPERATURE; RESTAURANTS; SURFACES; CONTACT AB We examined multistate outbreaks attributed to raw tomatoes in the United States from 1990 to 2010. We summarized the demographic and epidemiological characteristics of 15 outbreaks resulting in 1959 illnesses, 384 hospitalizations, and three deaths. Most (80%) outbreaks were reported during 2000-2010; 73% occurred May-September. Outbreaks commonly affected adult (median age 34 years) women (median 58% of outbreak cases). All outbreaks were caused by Salmonella [serotypes Newport (n = 6 outbreaks), Braenderup (n = 2), Baildon, Enteritidis, Javiana, Montevideo, Thompson, Typhimurium (n = 1 each); multiple serotypes (n = 1)]. Red, round (69% of outbreaks), Roma (23%), and grape (8%) tomatoes were implicated. Most (93%) outbreaks were associated with tomatoes served predominantly in restaurants. However, traceback investigations suggested that contamination occurred on farms, at packinghouses, or at fresh-cut processing facilities. Government agencies, academia, trade associations, and the fresh tomato industry should consider further efforts to identify interventions to reduce contamination of tomatoes during production and processing. C1 [Bennett, S. D.; Behravesh, C. Barton] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA 30333 USA. [Littrell, K. W.] Univ Minnesota, Sch Publ Hlth, St Paul, MN 55108 USA. [Hill, T. A.] Food & Drug Adm, Coordinated Outbreak Response & Evaluat Network, College Pk, MD USA. [Mahovic, M.] Food & Drug Adm, Ctr Food Safety & Appl Nutr, Produce Safety Staff, College Pk, MD USA. RP Bennett, SD (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,MS C 09, Atlanta, GA 30333 USA. EM iyk3@cdc.gov FU Centers for Disease Control and Prevention FX This work was supported by the Centers for Disease Control and Prevention. The findings of this study are based in part on contributions by state, local, tribal and territorial health departments. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. NR 35 TC 13 Z9 13 U1 2 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 EI 1469-4409 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD MAY PY 2015 VL 143 IS 7 BP 1352 EP 1359 DI 10.1017/S0950268814002167 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CF6ZW UT WOS:000352706700002 PM 25167220 ER PT J AU Ashley, EM Nardinelli, C Lavaty, RA AF Ashley, Elizabeth M. Nardinelli, Clark Lavaty, Rosemarie A. TI ESTIMATING THE BENEFITS OF PUBLIC HEALTH POLICIES THAT REDUCE HARMFUL CONSUMPTION SO HEALTH ECONOMICS LA English DT Article DE addiction; consumer welfare; cost-benefit analysis; internality; policy intervention; time inconsistency; D61; I18 ID SMOKING-CESSATION; RATIONAL ADDICTION; SELF-COMMAND AB For products such as tobacco and junk food, where policy interventions are often designed to decrease consumption, affected consumers gain utility from improvements in lifetime health and longevity but also lose utility associated with the activity of consuming the product. In the case of anti-smoking policies, even though published estimates of gross health and longevity benefits are up to 900 times higher than the net consumer benefits suggested by a more direct willingness-to-pay estimation approach, there is little recognition in the cost-benefit and cost-effectiveness literature that gross estimates will overstate intrapersonal welfare improvements when utility losses are not netted out. This paper presents a general framework for analyzing policies that are designed to reduce inefficiently high consumption and provides a rule of thumb for the relationship between net and gross consumer welfare effects: where there exists a plausible estimate of the tax that would allow consumers to fully internalize health costs, the ratio of the tax to the per-unit long-term cost can provide an upper bound on the ratio of net to gross benefits. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Ashley, Elizabeth M.; Nardinelli, Clark; Lavaty, Rosemarie A.] US FDA, Silver Spring, MD USA. RP Ashley, EM (reprint author), Off Management & Budget, 725 17th St NW, Washington, DC 20503 USA. EM Elizabeth_M_Ashley@omb.eop.gov NR 31 TC 2 Z9 2 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9230 EI 1099-1050 J9 HEALTH ECON JI Health Econ. PD MAY PY 2015 VL 24 IS 5 BP 617 EP 624 DI 10.1002/hec.3040 PG 8 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CF5XT UT WOS:000352631300009 PM 24615744 ER PT J AU Wiseman, FK Cancellotti, E Piccardo, P Iremonger, K Boyle, A Brown, D Ironside, JW Manson, JC Diack, AB AF Wiseman, Frances K. Cancellotti, Enrico Piccardo, Pedro Iremonger, Kayleigh Boyle, Aileen Brown, Deborah Ironside, James W. Manson, Jean C. Diack, Abigail B. TI The Glycosylation Status of PrPC Is a Key Factor in Determining Transmissible Spongiform Encephalopathy Transmission between Species SO JOURNAL OF VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; HUMAN PRION PROTEIN; STRAIN VARIATION; VARIANT CJD; MOLECULAR-BASIS; SCRAPIE AGENT; N-TERMINUS; IN-VITRO; MICE; BRAIN AB The risk of transmission of transmissible spongiform encephalopathies (TSE) between different species has been notoriously unpredictable because the mechanisms of transmission are not fully understood. A transmission barrier between species often prevents infection of a new host with a TSE agent. Nonetheless, some TSE agents are able to cross this barrier and infect new species, with devastating consequences. The host PrPC misfolds during disease pathogenesis and has a major role in controlling the transmission of agents between species, but sequence compatibility between host and agent PrPC does not fully explain host susceptibility. PrPC is posttranslationally modified by the addition of glycan moieties which have an important role in the infectious process. Here, we show in vivo that glycosylation of the host PrPC has a significant impact on the transmission of TSE between different host species. We infected mice carrying different glycosylated forms of PrPC with two human agents (sCJDMM2 and vCJD) and one hamster strain (263K). The absence of glycosylation at both or the first PrPC glycosylation site in the host results in almost complete resistance to disease. The absence of the second site of N-glycan has a dramatic effect on the barrier to transmission between host species, facilitating the transmission of sCJDMM2 to a host normally resistant to this agent. These results highlight glycosylation of PrPC as a key factor in determining the transmission efficiency of TSEs between different species. C1 [Wiseman, Frances K.; Cancellotti, Enrico; Piccardo, Pedro; Iremonger, Kayleigh; Boyle, Aileen; Brown, Deborah; Manson, Jean C.; Diack, Abigail B.] Univ Edinburgh, Div Neurobiol, Roslin Inst, Easter Bush, Midlothian, Scotland. [Wiseman, Frances K.; Cancellotti, Enrico; Piccardo, Pedro; Iremonger, Kayleigh; Boyle, Aileen; Brown, Deborah; Manson, Jean C.; Diack, Abigail B.] Univ Edinburgh, RDSVS, Easter Bush, Midlothian, Scotland. [Ironside, James W.] Univ Edinburgh, Natl Creutzfeldt Jakob Dis Res & Surveillance Uni, Edinburgh, Midlothian, Scotland. [Piccardo, Pedro] US FDA, Rockville, MD 20857 USA. RP Diack, AB (reprint author), Univ Edinburgh, Div Neurobiol, Roslin Inst, Easter Bush, Midlothian, Scotland. EM abigail.diack@roslin.ed.ac.uk OI Ironside, James/0000-0001-5869-2108 FU BBSRC; MRC; Wellcome Trust [069283]; Scottish Government; Department of Health, England FX This work was supported by the BBSRC and MRC. The NCJDRSU Brain Bank is part of the Edinburgh Brain Bank, which is funded by MRC. F.W. was funded by a Wellcome Trust Ph.D. studentship (069283). K.I. was funded by a BBSRC studentship.; NCJDRSU is supported by the Scottish Government and the Department of Health, England. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. 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 58 TC 6 Z9 7 U1 2 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAY PY 2015 VL 89 IS 9 BP 4738 EP 4747 DI 10.1128/JVI.02296-14 PG 10 WC Virology SC Virology GA CF0FX UT WOS:000352219600004 PM 25673720 ER PT J AU Tang, S Bosch-Marce, M Patel, A Margolis, TP Krause, PR AF Tang, Shuang Bosch-Marce, Marta Patel, Amita Margolis, Todd P. Krause, Philip R. TI Characterization of Herpes Simplex Virus 2 Primary MicroRNA Transcript Regulation SO JOURNAL OF VIROLOGY LA English DT Article ID LATENCY-ASSOCIATED TRANSCRIPT; READING FRAME P; EPINEPHRINE-INDUCED REACTIVATION; SARCOMA-ASSOCIATED HERPESVIRUS; GANGLIONIC ORGAN-CULTURES; RABBIT EYE MODEL; GENE-EXPRESSION; IN-VIVO; INFECTED NEURONS; MESSENGER-RNA AB In order to understand factors that may influence latency-associated transcription and latency-associated transcript (LAT) phenotypes, we studied the expression of the herpes simplex virus 2 (HSV-2) LAT-associated microRNAs (miRNAs). We mapped the transcription initiation sites of all three primary miRNA transcripts and identified the ICP4-binding sequences at the transcription initiation sites of both HSV-2 LAT (pri-miRNA for miR-I and miR-II, which target ICP34.5, and miR-III, which targets ICP0) and L/ST (a pri-miRNA for miR-I and miR-II) but not at that of the primary miR-H6 (for which the target is unknown). We confirmed activity of the putative HSV-2 L/ST promoter and found that ICP4 trans-activates the L/ST promoter when the ICP4-binding site at its transcription initiation site is mutated, suggesting that ICP4 may play a dual role in regulating transcription of L/ST and, consequently, of miR-I and miR-II. LAT exon 1 (containing LAT enhancer sequences), together with the LAT promoter region, comprises a bidirectional promoter required for the expression of both LAT-encoded miRNAs and miR-H6 in latently infected mouse ganglia. The ability of ICP4 to suppress ICP34.5-targeting miRNAs and to activate lytic viral genes suggests that ICP4 could play a key role in the switch between latency and reactivation. IMPORTANCE The HSV-2 LAT and viral miRNAs expressed in the LAT region are the most abundant viral transcripts during HSV latency. The balance between the expression of LAT and LAT-associated miRNAs and the expression of lytic viral transcripts from the opposite strand appears to influence whether individual HSV-infected neurons will be latently or productively infected. The outcome of neuronal infection may thus depend on regulation of gene expression of the corresponding primary miRNAs. In the present study, we characterize promoter sequences responsible for miRNA expression, including identification of the primary miRNA 5' ends and evaluation of ICP4 response. These findings provide further insight into the virus' strategy to tightly control expression of lytic cycle genes (especially the neurovirulence factor, ICP34.5) and suggest a mechanism (via ICP4) for the transition from latency to reactivated productive infection. C1 [Tang, Shuang; Bosch-Marce, Marta; Patel, Amita; Krause, Philip R.] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Margolis, Todd P.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. RP Krause, PR (reprint author), US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM shuang.tang@fda.hhs.gov; philip.krause@fda.hhs.gov FU intramural research programs of the Center for Biologics Evaluation and Research; Research To Prevent Blindness; [EY022697]; [EY002687] FX This study was supported by the intramural research programs of the Center for Biologics Evaluation and Research. This study was also supported by EY022697 (T.P.M.), EY002687 (Vision Core grant), and an unrestricted grant from Research To Prevent Blindness to the Department of Ophthalmology and Visual Sciences at Washington University. NR 59 TC 2 Z9 2 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAY PY 2015 VL 89 IS 9 BP 4837 EP 4848 DI 10.1128/JVI.03135-14 PG 12 WC Virology SC Virology GA CF0FX UT WOS:000352219600013 PM 25673716 ER PT J AU Kim, E Okada, K Beeler, JA Crim, RL Steitz, J Piedra, PA Gilbert, BE Gambotto, A AF Kim, Eun Okada, Kaori Beeler, Judy A. Crim, Roberta L. Steitz, Julia Piedra, Pedro A. Gilbert, Brian E. Gambotto, Andrea TI Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model (vol 88, pg 5100, 2014) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Kim, Eun; Okada, Kaori; Steitz, Julia; Gambotto, Andrea] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15260 USA. [Beeler, Judy A.; Crim, Roberta L.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Piedra, Pedro A.; Gilbert, Brian E.] Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. RP Beeler, JA (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15260 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAY PY 2015 VL 89 IS 9 BP 5193 EP 5193 DI 10.1128/JVI.03669 PG 1 WC Virology SC Virology GA CF0FX UT WOS:000352219600047 PM 25841050 ER PT J AU Jenkins, SV Qu, HO Mudalige, T Ingle, TM Wang, RR Wang, F Howard, PC Chen, JY Zhang, YB AF Jenkins, Samir V. Qu, Haiou Mudalige, Thilak Ingle, Taylor M. Wang, Rongrong Wang, Feng Howard, Paul C. Chen, Jingyi Zhang, Yongbin TI Rapid determination of plasmonic nanoparticle agglomeration status in blood SO BIOMATERIALS LA English DT Article DE Nanoparticles; Gold; Silver; Blood; Darkfield microscopy; Single particle ICP-MS ID ENHANCED RAMAN-SPECTROSCOPY; DARK-FIELD MICROSCOPY; GOLD NANOPARTICLES; SILVER NANOPARTICLES; MASS SPECTROMETRY; CARBON NANOTUBES; CELLULAR UPTAKE; PARTICLE-SIZE; CELLS; SERS AB Plasmonic nanomaterials as drug delivery or bio-imaging agents are typically introduced to biological systems through intravenous administration. However, the potential for agglomeration of nanoparticles in biological systems could dramatically affect their pharmacokinetic profile and toxic potential. Development of rapid screening methods to evaluate agglomeration is urgently needed to monitor the physical nature of nanoparticles as they are introduced into blood. Here, we establish novel methods using darkfield microscopy with hyperspectral detection (hsDFM), single particle inductively-coupled plasma mass spectrometry (spICP-MS), and confocal Raman microscopy (cRM) to discriminate gold nanoparticles (AuNPs) and their agglomerates in blood. Rich information about nanoparticle agglomeration in situ is provided by hsDFM monitoring of the plasmon resonance of primary nanoparticles and their agglomerates in whole blood; cRM is an effective complement to hsDFM to detect AuNP agglomerates in minimally manipulated samples. The AuNPs and the particle agglomerates were further distinguished in blood for the first time by quantification of particle mass using spICP-MS with excellent sensitivity and specificity. Furthermore, the agglomeration status of synthesized and commercial NPs incubated in blood was successfully assessed using the developed methods. Together, these complementary methods enable rapid determination of the agglomeration status of plasmonic nanomaterials in biological systems, specifically blood. Published by Elsevier Ltd. C1 [Jenkins, Samir V.; Qu, Haiou; Mudalige, Thilak; Ingle, Taylor M.; Wang, Rongrong; Howard, Paul C.; Zhang, Yongbin] US FDA, NCTR ORA Nanotechnol Core Facil, Jefferson, AR 72079 USA. [Jenkins, Samir V.; Wang, Feng; Chen, Jingyi] Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA. [Qu, Haiou; Mudalige, Thilak] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, Jefferson, AR 72079 USA. [Ingle, Taylor M.; Wang, Rongrong; Howard, Paul C.; Zhang, Yongbin] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wang, Rongrong] Hunan Prov Food & Drug Control, Changsha 410001, Hunan, Peoples R China. RP Zhang, YB (reprint author), US FDA, NCTR ORA Nanotechnol Core Facil, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Yongbin.Zhang@fda.hhs.gov RI Wang, Feng/J-8583-2014; Chen, Jingyi/E-7168-2010 OI Wang, Feng/0000-0002-2740-3534; Chen, Jingyi/0000-0003-0012-9640 FU U.S. Department of Energy; U.S. Food and Drug Administration; Arkansas Biosciences Institute; National Institutes of Health [NIH P30 GM103450]; University of Arkansas FX This research was supported in part by an appointment (S. Jenkins) to the Research Participation Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. We thank the pilot project funds from the Arkansas Biosciences Institute, the National Institutes of Health (NIH P30 GM103450), and startup funds from the University of Arkansas, to J. Chen. We appreciate the thorough review of this manuscript by. T. Eustaquio, P. Fu, S. Linder, and A. Patri. NR 72 TC 7 Z9 7 U1 7 U2 111 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 MAY PY 2015 VL 51 BP 226 EP 237 DI 10.1016/j.biomaterials.2015.01.072 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CE4JK UT WOS:000351796700022 PM 25771013 ER PT J AU Zhang, ZW Wang, CG Troendle, JF AF Zhang, Zhiwei Wang, Chenguang Troendle, James F. TI Optimizing the order of hypotheses in serial testing of multiple endpoints in clinical trials SO STATISTICS IN MEDICINE LA English DT Article DE chain procedure; fixed sequence; hierarchical testing; multiple comparisons; multiplicity; secondary endpoint ID BONFERRONI PROCEDURE; FIXED-SEQUENCE; GATEKEEPING STRATEGIES; ADJUSTMENT METHODS; SELECTION; EFFICACY; WEIGHTS AB Clinical trials usually collect information on a large number of variables or endpoints, including one or more primary endpoints as well as a number of secondary endpoints representing different aspects of treatment effectiveness and safety. In this article, we focus on serial testing procedures that test multiple endpoints in a pre-specified order, and consider how to optimize the order of endpoints subject to any clinical constraints, with respect to the expected number of successes (i.e., endpoints that reach statistical significance) or the expected gain (if endpoints are associated with numerical utilities). We consider some common approaches to this problem and propose two new approaches: a greedy algorithm based on conditional power and a simulated annealing algorithm that attempts to improve a given sequence in a random and iterative fashion. Simulation results indicate that the proposed algorithms are useful for finding a high-performing sequence, and that optimized fixed sequence procedures can be competitive against traditional multiple testing procedures such as Holm's. The methods and findings are illustrated with two examples concerning migraine and asthma. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Wang, Chenguang] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Div Biostat & Bioinformat, Baltimore, MD USA. [Troendle, James F.] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Zhang, ZW (reprint author), DBS OSB CDRH FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov NR 33 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD APR 30 PY 2015 VL 34 IS 9 BP 1467 EP 1482 DI 10.1002/sim.6425 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 CF4MV UT WOS:000352524100003 PM 25620627 ER PT J AU Serano, P Angelone, LM Katnani, H Eskandar, E Bonmassar, G AF Serano, Peter Angelone, Leonardo M. Katnani, Husam Eskandar, Emad Bonmassar, Giorgio TI A Novel Brain Stimulation Technology Provides Compatibility with MRI SO Scientific Reports LA English DT Article ID ABSORPTION RATE; HUMAN HEAD; 1.5 T; METALLIC IMPLANTS; OBLIQUE-INCIDENCE; SIMULTANEOUS EEG; IN-VITRO; DEEP; ELECTRODES; SYSTEMS AB Clinical electrical stimulation systems - such as pacemakers and deep brain stimulators (DBS) - are an increasingly common therapeutic option to treat a large range of medical conditions. Despite their remarkable success, one of the significant limitations of these medical devices is the limited compatibility with magnetic resonance imaging (MRI), a standard diagnostic tool in medicine. During an MRI exam, the leads used with these devices, implanted in the body of the patient, act as an electric antenna potentially causing a large amount of energy to be absorbed in the tissue, which can lead to serious heat-related injury. This study presents a novel lead design that reduces the antenna effect and allows for decreased tissue heating during MRI. The optimal parameters of the wire design were determined by a combination of computational modeling and experimental measurements. The results of these simulations were used to build a prototype, which was tested in a gel phantom during an MRI scan. Measurement results showed a three-fold decrease in heating when compared to a commercially available DBS lead. Accordingly, the proposed design may allow a significantly increased number of patients with medical implants to have safe access to the diagnostic benefits of MRI. C1 [Serano, Peter; Angelone, Leonardo M.; Bonmassar, Giorgio] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Serano, Peter] Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. [Serano, Peter; Angelone, Leonardo M.] US FDA, Ctr Devices & Radiol Hlth, Div Biomed Phys, Off Sci & Engn Labs, Silver Spring, MD USA. [Katnani, Husam; Eskandar, Emad] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. RP Bonmassar, G (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM giorgio.bonmassar@mgh.harvard.edu FU NIH/NINDS [U01-NS075026]; NIH/NIBIB [1R21EB016449-01A1]; National Center for Research Resources [P41-RR14075]; MIND institute FX The authors acknowledge Karen Lindell, Richard Gray, Sunder Rajan, Bruce Rosen, Brian Beard, and Devashish Shrivastava for scientific discussion, and John Kirsch for software support with the temperature measurements. This research was supported by the grants U01-NS075026 (NIH/NINDS), 1R21EB016449-01A1 (NIH/NIBIB), the National Center for Research Resources (P41-RR14075), and by the MIND institute. 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 61 TC 3 Z9 3 U1 1 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 APR 29 PY 2015 VL 5 AR 9805 DI 10.1038/srep09805 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG9GB UT WOS:000353621700001 PM 25924189 ER PT J AU Weinshenker, BG Barron, G Behne, JM Bennett, JL Chin, PS Cree, BAC de Seze, J Flor, A Fujihara, K Greenberg, B Higashi, S Holt, W Khan, O Knappertz, V Levy, M Melia, AT Palace, J Smith, TJ Sormani, MP Van Herle, K VanMeter, S Villoslada, P Walton, MK Wasiewski, W Wingerchuk, DM Yeaman, MR AF Weinshenker, Brian G. Barron, Gerard Behne, Jacinta M. Bennett, Jeffery L. Chin, Peter S. Cree, Bruce A. C. de Seze, Jerome Flor, Armando Fujihara, Kazuo Greenberg, Benjamin Higashi, Sayumi Holt, William Khan, Omar Knappertz, Volker Levy, Michael Melia, Angela T. Palace, Jacqueline Smith, Terry J. Sormani, Maria Pia Van Herle, Katja VanMeter, Susan Villoslada, Pablo Walton, Marc K. Wasiewski, Warren Wingerchuk, Dean M. Yeaman, Michael R. CA Guthy-Jackson Charitable Fdn Int TI Challenges and opportunities in designing clinical trials for neuromyelitis optica SO NEUROLOGY LA English DT Review ID MULTIPLE-SCLEROSIS; PLASMA-EXCHANGE; SPECTRUM DISORDER; POSITIVE PATIENTS; IMMUNOGLOBULIN-G; OPEN-LABEL; NMO-IGG; ANTIBODY; INTERLEUKIN-6; AQUAPORIN-4 AB Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end. C1 [Weinshenker, Brian G.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Barron, Gerard; Flor, Armando] MedImmune Ltd, Cambridge, England. [Behne, Jacinta M.; Van Herle, Katja] Guthy Jackson Fdn, San Diego, CA USA. [Bennett, Jeffery L.] Univ Colorado Denver, Dept Neurol, Aurora, CO USA. [Bennett, Jeffery L.] Univ Colorado Denver, Dept Ophthalmol, Aurora, CO USA. [Chin, Peter S.] Novartis Pharmaceut, E Hanover, NJ USA. [Cree, Bruce A. C.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [de Seze, Jerome] Univ Strasbourg, INSERM, CIC, Federat Med Translat Strasbourg, Strasbourg, France. [de Seze, Jerome] Univ Strasbourg, INSERM, UMR 1119, Federat Med Translat Strasbourg, Strasbourg, France. [Fujihara, Kazuo] Tohoku Univ, Dept Multiple Sclerosis Therapeut, Sendai, Miyagi 980, Japan. [Greenberg, Benjamin] Univ Texas Southwestern, Dept Neurol, Dallas, TX USA. [Higashi, Sayumi; Melia, Angela T.] Chugai Pharma USA, Berkeley Hts, NJ USA. [Holt, William] PPD Inc, Wilmington, NC USA. [Khan, Omar] Wayne State Univ, Dept Neurol, Detroit, MI USA. [Knappertz, Volker] Teva Pharmaceut, Frazer, PA USA. [Knappertz, Volker] Univ Dusseldorf, Dept Neurol, Dusseldorf, Germany. [Levy, Michael] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Palace, Jacqueline] Oxford Univ Hosp Trust, Dept Neurol, Oxford, England. [Smith, Terry J.] Univ Michigan, Kellogg Eye Ctr, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Internal Med, Div Metab Endocrine & Diabet, Ann Arbor, MI USA. [Sormani, Maria Pia] Univ Genoa, Dept Hlth Sci, I-16126 Genoa, Italy. [Van Herle, Katja] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [VanMeter, Susan] GlaxoSmithKline, Res Triangle Pk, NC USA. [Villoslada, Pablo] Hosp Clin Barcelona, Inst Biomed Res August Pi Sunyer IDIBAPS, Ctr Neuroimmunol, Villarroel, Spain. [Walton, Marc K.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wasiewski, Warren] Alex Pharmaceut Inc, Cheshire, CT USA. [Wingerchuk, Dean M.] Mayo Clin, Dept Neurol, Scottsdale, AZ USA. [Yeaman, Michael R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Mol Med, Los Angeles, CA 90095 USA. [Yeaman, Michael R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Infect Dis, Los Angeles, CA 90095 USA. [Yeaman, Michael R.] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Yeaman, Michael R.] Harbor UCLA Med Ctr, LABioMed, Torrance, CA 90509 USA. RP Weinshenker, BG (reprint author), Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. EM weinb@mayo.edu RI De Seze, Jerome/M-8316-2016 OI De Seze, Jerome/0000-0002-7197-7578 FU Guthy-Jackson Charitable Foundation FX Drs. Weinshenker, Van Herle, Smith, and Yeaman have received support for activities that led to this manuscript by the Guthy-Jackson Charitable Foundation. NR 56 TC 6 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD APR 28 PY 2015 VL 84 IS 17 BP 1805 EP 1815 DI 10.1212/WNL.0000000000001520 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA CH5GB UT WOS:000354062200020 PM 25841026 ER PT J AU Simhadri, VR Dimitrova, M Mariano, JL Zenarruzabeitia, O Zhong, WM Ozawa, T Muraguchi, A Kishi, H Eichelberger, MC Borrego, F AF Simhadri, Venkateswara R. Dimitrova, Milena Mariano, John L. Zenarruzabeitia, Olatz Zhong, Weimin Ozawa, Tatsuhiko Muraguchi, Atsushi Kishi, Hiroyuki Eichelberger, Maryna C. Borrego, Francisco TI A Human Anti-M2 Antibody Mediates Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Cytokine Secretion by Resting and Cytokine-Preactivated Natural Killer (NK) Cells SO PLOS ONE LA English DT Article ID INFLUENZA-A VIRUS; HUMAN MONOCLONAL-ANTIBODY; MATRIX PROTEIN-2; M2 PROTEIN; EXTRACELLULAR DOMAIN; SEASONAL INFLUENZA; ADAPTIVE IMMUNITY; UNIVERSAL VACCINE; INFECTION; PROTECTION AB The highly conserved matrix protein 2 (M2) is a good candidate for the development of a broadly protective influenza vaccine that induces long-lasting immunity. In animal models, natural killer (NK) cells have been proposed to play an important role in the protection provided by M2-based vaccines through a mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated the ability of the human anti-M2 Ab1-10 monoclonal antibody (mAb) to activate human NK cells. They mediated ADCC against M2-expressing cells in the presence of Ab1-10 mAb. Furthermore, NK cell pro-inflammatory cytokine and chemokine secretion is also enhanced when Ab1-10 mAb is present. We also generated cytokine-preactivated NK cells and showed that they still displayed increased effector functions in the presence of Ab1-10 mAb. Thus, our study has demonstrated that human resting and cytokine-preactivated NK cells may have a very important role in the protection provided by anti-M2 Abs. C1 [Simhadri, Venkateswara R.; Dimitrova, Milena; Mariano, John L.; Borrego, Francisco] US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod Review & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Zenarruzabeitia, Olatz] BioCruces Hlth Res Inst, Immunopathol Grp, Baracaldo, Basque Country, Spain. [Zenarruzabeitia, Olatz] Basque Ctr Transfus & Human Tissues, Cell Therapy & Stem Cell Grp, Galdakao, Basque Country, Spain. [Zhong, Weimin] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Ozawa, Tatsuhiko; Muraguchi, Atsushi; Kishi, Hiroyuki] Toyama Univ, Grad Sch Med & Pharmaceut Sci, Dept Immunol, Toyama, Japan. [Eichelberger, Maryna C.] Food & Drug Adm, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Borrego, Francisco] Basque Fdn Sci, Ikerbasque, Bilbao, Basque Country, Spain. RP Simhadri, VR (reprint author), US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod Review & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. EM venkateswara.simhadri@fda.hhs.gov; francisco.borregorabasco@osakidetza.net FU Medical Counter Measure Initiatives (MCMi), U.S. Food and Drug Administration (FDA) FX This work was funded by the Medical Counter Measure Initiatives (MCMi), U.S. Food and Drug Administration (FDA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 27 PY 2015 VL 10 IS 4 AR e0124677 DI 10.1371/journal.pone.0124677 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG9SB UT WOS:000353659100060 PM 25915748 ER PT J AU Rosati, M Alicea, C Kulkarni, V Virnik, K Hockenbury, M Sardesai, NY Pavlakis, GN Valentin, A Berkower, I Felber, BK AF Rosati, Margherita Alicea, Candido Kulkarni, Viraj Virnik, Konstantin Hockenbury, Max Sardesai, Niranjan Y. Pavlakis, George N. Valentin, Antonio Berkower, Ira Felber, Barbara K. TI Recombinant rubella vectors elicit SIV Gag-specific T cell responses with cytotoxic potential in rhesus macaques SO VACCINE LA English DT Article DE Live attenuated viral vector; Rubella vaccine strain RA27/3; Rhesus macaque; SIV Gag; De nova cellular responses; Recall cellular responses; Memory T cells; Cytotoxic T cells; DNA vaccine; CM9 tetramer response; IFN-gamma response; HIV vaccine; DNA prime rubella boost; Rubella prime boost ID IMMUNODEFICIENCY VIRUS CHALLENGE; HUMORAL IMMUNE-RESPONSES; MEASLES-VACCINE VECTOR; NEUTRALIZING ANTIBODIES; ANKARA RECOMBINANTS; SIVMAC251 CHALLENGE; VIRAL VECTORS; HIV; DNA; ANTIGENS AB Live-attenuated rubella vaccine strain RA27/3 has been demonstrated to be safe and immunogenic in millions of children. The vaccine strain was used to insert SIV gag sequences and the resulting rubella vectors were tested in rhesus macaques alone and together with SIV gag DNA in different vaccine prime-boost combinations. We previously reported that such rubella vectors induce robust and durable SIV-specific humoral immune responses in macaques. Here, we report that recombinant rubella vectors elicit robust de novo SIV-specific cellular immune responses detectable for >10 months even after a single vaccination. The antigen-specific responses induced by the rubella vector include central and effector memory CD4(+) and CD8(+) T cells with cytotoxic potential. Rubella vectors can be administered repeatedly even after vaccination with the rubella vaccine strain RA27/3. Vaccine regimens including rubella vector and Sly gag DNA in different prime-boost combinations resulted in robust long-lasting cellular responses with significant increase of cellular responses upon boost. Rubella vectors provide a potent platform for inducing HIV-specific immunity that can be combined with DNA in a prime-boost regimen to elicit durable cellular immunity. Published by Elsevier Ltd. C1 [Rosati, Margherita; Pavlakis, George N.; Valentin, Antonio] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Alicea, Candido; Kulkarni, Viraj; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Virnik, Konstantin; Hockenbury, Max; Berkower, Ira] US FDA, Immunoregulat Lab, Div Viral Prod, Off Vaccines,Ctr Biol, Silver Spring, MD USA. [Sardesai, Niranjan Y.] Inovio Pharmaceut, Plymouth Meeting, PA USA. RP Berkower, I (reprint author), NCI, Ctr Canc Res, 1050 Boyles St,Bldg 535,Room 209, Frederick, MD 21702 USA. EM ira.berkower@fda.hhs.gov; barbara.felber@nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) (BKF, GNP). NR 49 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD APR 27 PY 2015 VL 33 IS 18 BP 2167 EP 2174 DI 10.1016/j.vaccine.2015.02.067 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CH0XQ UT WOS:000353746100009 PM 25802183 ER PT J AU Chang, CM Corey, CG Rostron, BL Apelberg, BJ AF Chang, Cindy M. Corey, Catherine G. Rostron, Brian L. Apelberg, Benjamin J. TI Systematic review of cigar smoking and all cause and smoking related mortality SO BMC PUBLIC HEALTH LA English DT Review DE Cigars; Mortality; Systematic review ID UNITED-STATES VETERANS; CORONARY-HEART-DISEASE; PIPE SMOKING; FOLLOW-UP; CANCER MORTALITY; YOUNG-ADULTS; TOBACCO USE; MEN; RISK; DEATH AB Background: Cigars are a growing public health concern, given the changes in cigar use patterns in the US and elsewhere since the 1960s. We conducted a systematic review of published studies on current cigar smoking and all-cause and cause-specific mortality risks to inform potential regulatory approaches and future research that would strengthen the body of evidence. Methods: Using 3 different databases and handsearching, we identified epidemiological studies published prior to June 2014 that examined the association between cigar smoking and all-cause mortality and smoking-related mortality. Detailed study characteristics as well as association-level characteristics, including effect estimates and 95% confidence intervals, were abstracted or calculated from each selected study. Results: A total of 22 studies from 16 different prospective cohorts were identified. Primary cigar smoking (current, exclusive cigar smoking with no history of previous cigarette or pipe smoking) was associated with all cause-mortality, oral cancer, esophageal cancer, pancreatic cancer, laryngeal cancer, lung cancer, coronary heart disease (CHD), and aortic aneurysm. Strong dose trends by cigars per day and inhalation level for primary cigar smoking were observed for oral, esophageal, laryngeal, and lung cancers. Among primary cigar smokers reporting no inhalation, relative mortality risk was still highly elevated for oral, esophageal, and laryngeal cancers. Conclusions: In summary, cigar smoking carries many of the same health risks as cigarette smoking. Mortality risks from cigar smoking vary by level of exposure as measured by cigars per day and inhalation level and can be as high as or exceed those of cigarette smoking. The body of evidence would be strengthened by future studies that focus on the health effects of primary cigar smoking and incorporate more contemporary and diverse study populations to better reflect the current patterns of cigar use in the US. Ideally, these studies would also collect detailed information on cigar type, exposure level, and biomarkers of exposure and potential harm. C1 [Chang, Cindy M.; Corey, Catherine G.; Rostron, Brian L.; Apelberg, Benjamin J.] US FDA, Off Sci, Ctr Tobacco Prod, Document Control Ctr, Silver Spring, MD 20993 USA. RP Chang, CM (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, Document Control Ctr, Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Cindy.Chang@fda.hhs.gov NR 42 TC 0 Z9 0 U1 1 U2 9 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 APR 24 PY 2015 VL 15 DI 10.1186/s12889-015-1617-5 PG 20 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CG6AX UT WOS:000353378500001 ER PT J AU Brady, RA Bruno, VM Burns, DL AF Brady, Rebecca A. Bruno, Vincent M. Burns, Drusilla L. TI RNA-Seq Analysis of the Host Response to Staphylococcus aureus Skin and Soft Tissue Infection in a Mouse Model SO PLOS ONE LA English DT Article ID REGULATES INNATE IMMUNITY; UNITED-STATES; KERATIN 1; INFLAMMATION; EXPRESSION; NEUTROPHILS; ACTIVATION; MECHANISMS; GAMMA AB Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTI), which are primarily self-limiting. We conducted a comprehensive analysis of the host transcriptome during a S. aureus SSTI to provide insight on the protective mechanisms that thwart these infections. We utilized a murine SSTI model in which one ear is epicutaneously challenged while the other is not. We then harvested these infected and uninfected ears, as well as ears from naive mice, at one, four, and seven days post-challenge, and performed RNA sequencing (RNA-seq) using the Illumina platform. RNA-seq data demonstrated a robust response at the site of infection. Comparison of gene expression profiles between infected ears and the non-infected ears of challenged mice defined the local response to infection, while comparisons of expression profiles of non-infected ears from challenged mice to ears of naive mice revealed changes in gene expression levels away from the site indicative of a systemic response. Over 1000 genes exhibited increased expression locally at all tested time points. The local response was more robust than the systemic response. Through evaluation of the RNA-seq data using the Upstream Regulator Analytic as part of the Ingenuity Pathway Analysis software package, we found that changes in the activation and inhibition of regulatory pathways happen first locally, and lag behind systemically. The activated pathways are highly similar at all three time points during SSTI, suggesting a stable global response over time. Transcript increases and pathway activation involve pro- and anti-inflammatory mediators, chemotaxis, cell signaling, keratins, and TH1/TH17 cytokines. Transcript decreases and pathway inhibition demonstrate that metabolic genes and anti-inflammatory pathways are repressed. These data provide insight on the host responses that may aid in resolution of this self-limited S. aureus infection, and may shed light on potential immune correlates of protection for staphylococcal SSTI. C1 [Brady, Rebecca A.; Burns, Drusilla L.] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Bruno, Vincent M.] Univ Maryland, Inst Genome Sci, Baltimore, MD 21201 USA. RP Brady, RA (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Rebecca.Brady@fda.hhs.gov FU Intramural Research Program of the Center for Biologics Evaluation and Research, Food and Drug Administration; National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); Department of Health and Human Services [HHSN272200900009C] FX This work was supported by the Intramural Research Program of the Center for Biologics Evaluation and Research, Food and Drug Administration. The sequencing for this project was funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and Department of Health and Human Services under contract number HHSN272200900009C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 2 Z9 2 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 22 PY 2015 VL 10 IS 4 AR e0124877 DI 10.1371/journal.pone.0124877 PG 31 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG5KV UT WOS:000353331500103 PM 25901897 ER PT J AU Haile, LA Puig, M Kelley-Baker, L Verthelyi, D AF Haile, Lydia Asrat Puig, Montserrat Kelley-Baker, Logan Verthelyi, Daniela TI Detection of Innate Immune Response Modulating Impurities in Therapeutic Proteins SO PLOS ONE LA English DT Article ID AMEBOCYTE LYSATE ASSAY; VITRO PYROGEN TEST; WHOLE-BLOOD; MONONUCLEAR-CELLS; RABBIT PYROGEN; IMMUNOGENICITY; ENDOTOXIN; LIPOPOLYSACCHARIDE; ACTIVATION; INDICATORS AB Therapeutic proteins can contain multiple impurities, some of which are variants of the product, while others are derived from the cell substrate and the manufacturing process. Such impurities, even when present at trace levels, have the potential to activate innate immune cells in peripheral blood or embedded in tissues causing expression of cytokines and chemokines, increasing antigen uptake, facilitating processing and presentation by antigen presenting cells, and fostering product immunogenicity. Currently, while products are tested for host cell protein content, assays to control innate immune response modulating impurities (IIRMIs) in products are focused mainly on endotoxin and nucleic acids, however, depending on the cell substrate and the manufacturing process, numerous other IIRMI could be present. In these studies we assess two approaches that allow for the detection of a broader subset of IIRMIs. In the first, we use commercial cell lines transfected with Toll like receptors (TLR) to detect receptor-specific agonists. This method is sensitive to trace levels of IIRMI and provides information of the type of IIRMIs present but is limited by the availability of stably transfected cell lines and requires pre-existing knowledge of the IIRMIs likely to be present in the product. Alternatively, the use of a combination of macrophage cell lines of human and mouse origin allows for the detection of a broader spectrum of impurities, but does not identify the source of the activation. Importantly, for either system the lower limit of detection (LLOD) of impurities was similar to that of PBMC and it was not modified by the therapeutic protein tested, even in settings where the product had inherent immune modulatory properties. Together these data indicate that a cell-based assay approach could be used to screen products for the presence of IIRMIs and inform immunogenicity risk assessments, particularly in the context of comparability exercises. C1 [Haile, Lydia Asrat; Puig, Montserrat; Kelley-Baker, Logan; Verthelyi, Daniela] US FDA, Immunol Lab, Div Biotechnol Review & Res 3, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Verthelyi, D (reprint author), US FDA, Immunol Lab, Div Biotechnol Review & Res 3, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM daniela.verthelyi@fda.hhs.gov FU Food and Drug Administration FX The work was funded by the Food and Drug Administration. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 10 Z9 10 U1 2 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 APR 22 PY 2015 VL 10 IS 4 AR e0125078 DI 10.1371/journal.pone.0125078 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG5KV UT WOS:000353331500111 PM 25901912 ER PT J AU Iacono, MI Neufeld, E Akinnagbe, E Bower, K Wolf, J Oikonomidis, IV Sharma, D Lloyd, B Wilm, BJ Wyss, M Pruessmann, KP Jakab, A Makris, N Cohen, ED Kuster, N Kainz, W Angelone, LM AF Iacono, Maria Ida Neufeld, Esra Akinnagbe, Esther Bower, Kelsey Wolf, Johanna Oikonomidis, Ioannis Vogiatzis Sharma, Deepika Lloyd, Bryn Wilm, Bertram J. Wyss, Michael Pruessmann, Klaas P. Jakab, Andras Makris, Nikos Cohen, Ethan D. Kuster, Niels Kainz, Wolfgang Angelone, Leonardo M. TI MIDA: A Multimodal Imaging-Based Detailed Anatomical Model of the Human Head and Neck SO PLOS ONE LA English DT Article ID INDUCED CURRENT DENSITIES; MONTE-CARLO CALCULATIONS; REALISTIC ANTHROPOMORPHIC PHANTOM; RADIATION PROTECTION DOSIMETRY; EXTERNAL PHOTON IRRADIATION; VISIBLE HUMAN PROJECT; FEMALE VOXEL PHANTOM; CONVERSION COEFFICIENTS; INTERNAL DOSIMETRY; ABSORBED FRACTIONS AB Computational modeling and simulations are increasingly being used to complement experimental testing for analysis of safety and efficacy of medical devices. Multiple voxel- and surface-based whole-and partial-body models have been proposed in the literature, typically with spatial resolution in the range of 1-2 mm and with 10-50 different tissue types resolved. We have developed a multimodal imaging-based detailed anatomical model of the human head and neck, named "MIDA". The model was obtained by integrating three different magnetic resonance imaging (MRI) modalities, the parameters of which were tailored to enhance the signals of specific tissues: i) structural T1- and T2-weighted MRIs; a specific heavily T2-weighted MRI slab with high nerve contrast optimized to enhance the structures of the ear and eye; ii) magnetic resonance angiography (MRA) data to image the vasculature, and iii) diffusion tensor imaging (DTI) to obtain information on anisotropy and fiber orientation. The unique multimodal high-resolution approach allowed resolving 153 structures, including several distinct muscles, bones and skull layers, arteries and veins, nerves, as well as salivary glands. The model offers also a detailed characterization of eyes, ears, and deep brain structures. A special automatic atlas-based segmentation procedure was adopted to include a detailed map of the nuclei of the thalamus and midbrain into the head model. The suitability of the model to simulations involving different numerical methods, discretization approaches, as well as DTI-based tensorial electrical conductivity, was examined in a case-study, in which the electric field was generated by transcranial alternating current stimulation. The voxel- and the surface-based versions of the models are freely available to the scientific community. C1 [Iacono, Maria Ida; Akinnagbe, Esther; Bower, Kelsey; Cohen, Ethan D.; Kainz, Wolfgang; Angelone, Leonardo M.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Biomed Phys, Silver Spring, MD 20993 USA. [Neufeld, Esra; Wolf, Johanna; Oikonomidis, Ioannis Vogiatzis; Sharma, Deepika; Lloyd, Bryn; Kuster, Niels] ITIS Fdn Res Informat Technol Soc, Zurich, Switzerland. [Wolf, Johanna; Oikonomidis, Ioannis Vogiatzis; Sharma, Deepika; Kuster, Niels] Swiss Fed Inst Technol, CH-8092 Zurich, Switzerland. [Wilm, Bertram J.; Wyss, Michael; Pruessmann, Klaas P.] Univ Zurich, Inst Biomed Engn, Zurich, Switzerland. [Wilm, Bertram J.; Wyss, Michael; Pruessmann, Klaas P.] Swiss Fed Inst Technol, Zurich, Switzerland. [Jakab, Andras] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Computat Imaging Res Lab, Vienna, Austria. [Jakab, Andras] Swiss Fed Inst Technol, Comp Vision Lab, Zurich, Switzerland. [Makris, Nikos] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging,Dept Radiol, Charlestown, MA 02129 USA. [Makris, Nikos] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Morphometr Anal,Dept Psychiat & Neurol, Charlestown, MA 02129 USA. RP Angelone, LM (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Biomed Phys, Silver Spring, MD 20993 USA. EM Leonardo.angelone@fda.hhs.gov FU National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health [1R21EB016449-01A1]; U.S. Food and Drug Administration; CTI [14930.1 PFLS-LS]; Center for Devices and Radiological Health FX This research was supported in part by the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health (1R21EB016449-01A1), in part by the U.S. Food and Drug Administration's Critical Path Initiative, in part by CTI (14930.1 PFLS-LS), and in part by the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 97 TC 9 Z9 9 U1 3 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 APR 22 PY 2015 VL 10 IS 4 AR e0124126 DI 10.1371/journal.pone.0124126 PG 35 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG5KV UT WOS:000353331500078 PM 25901747 ER PT J AU Sharfstein, JM AF Sharfstein, Joshua M. TI Of Mouse and Measles SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT News Item C1 [Sharfstein, Joshua M.] Johns Hopkins Bloomberg Sch Publ Hlth, Publ Hlth Practice & Training, Baltimore, MD 21205 USA. [Sharfstein, Joshua M.] Maryland Dept Hlth & Mental Hyg, Baltimore, MD 21201 USA. [Sharfstein, Joshua M.] US FDA, Rockville, MD 20857 USA. RP Sharfstein, JM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Publ Hlth Practice & Training, Baltimore, MD 21205 USA. EM joshua.sharfstein@jhu.edu NR 0 TC 0 Z9 0 U1 0 U2 3 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 APR 21 PY 2015 VL 313 IS 15 BP 1504 EP 1505 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CG3SA UT WOS:000353198700003 PM 25898033 ER PT J AU Fordyce, CB Roe, MT Ahmad, T Libby, P Borer, JS Hiatt, WR Bristow, MR Packer, M Wasserman, SM Braunstein, N Pitt, B DeMets, DL Cooper-Arnold, K Armstrong, PW Berkowitz, SD Scott, R Prats, J Galis, ZS Stockbridge, N Peterson, ED Califf, RM AF Fordyce, Christopher B. Roe, Matthew T. Ahmad, Tariq Libby, Peter Borer, Jeffrey S. Hiatt, William R. Bristow, Michael R. Packer, Milton Wasserman, Scott M. Braunstein, Ned Pitt, Bertram DeMets, David L. Cooper-Arnold, Katharine Armstrong, Paul W. Berkowitz, Scott D. Scott, Rob Prats, Jayne Galis, Zorina S. Stockbridge, Norman Peterson, Eric D. Califf, Robert M. TI Cardiovascular Drug Development SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE biomarkers; cardiovascular; agents; clinical trials; drug costs; pharmacological; policy ID PROGRESSION-FREE SURVIVAL; DECOMPENSATED HEART-FAILURE; ACUTE CORONARY SYNDROMES; CLINICAL-RESEARCH; END-POINTS; SURROGATE MARKERS; RANDOMIZED-TRIALS; ARTERY-DISEASE; STATIN THERAPY; UNITED-STATES AB Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular end-points. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified. (C) 2015 by the American College of Cardiology Foundation. C1 [Fordyce, Christopher B.; Roe, Matthew T.; Ahmad, Tariq; Peterson, Eric D.; Califf, Robert M.] Duke Clin Res Inst, Durham, NC 27705 USA. [Libby, Peter] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Borer, Jeffrey S.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Hiatt, William R.; Bristow, Michael R.] Univ Colorado, Sch Med, Aurora, CO USA. [Packer, Milton; Scott, Rob] Univ Texas SW Med Ctr Dallas, Dept Clin Neurosci, Dallas, TX 75390 USA. [Wasserman, Scott M.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Braunstein, Ned] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. [Pitt, Bertram] Univ Michigan, Sch Med, Ann Arbor, MI USA. [DeMets, David L.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Cooper-Arnold, Katharine; Galis, Zorina S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Armstrong, Paul W.] Univ Alberta, Canadian VIGOUR Ctr, Edmonton, AB, Canada. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Whippany, NJ USA. [Prats, Jayne] Medicines Co, Parsippany, NJ USA. [Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Fordyce, CB (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM christopher.fordyce@duke.edu FU Boehringer Ingelheim; Merck Sharp Dohme; Duke Clinical Research Institute (DCRI); GlaxoSmithKiline; Amylin Pharmaceutical, Inc.; DCRI; Merck Co., Inc.; F. Hoffmann-La Roche Ltd.; American College of Cardiology; American Heart Association; Eli Lilly Co.; Janssen Pharmaceutical Products; Merck Co.; Sanofi-Aventis; Amylin; Bristol-Myers Squibb; Janssen Research and Development LLC; Merck; Novartis; Amgen; Bayer Healthcare; BMEB Services LLC; Medscape LLC/heart; Regado NJ; Roche FX Dr. Armstrong received research grants from Boehringer Ingelheim, Merck Sharp & Dohme in conjunction with Duke Clinical Research Institute (DCRI), GlaxoSmithKiline, Amylin Pharmaceutical, Inc. in conjunction with DCRI, Merck & Co., Inc., Sanofi-aventis Research and Development, and Regado Bioscience; and received consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck & Co., Inc., F. Hoffmann-La Roche Ltd., Axio/Orexigen, Merck, Eli Lilly, and Bayer. Dr. Berkowitz is an employee of Bayer HealthCare. Dr. Scott is an employee of and shareholder of Amgen, Inc. Dr. Prats is an employee of The Medicines Company. Dr. Stockbridge is an employee of the Food and Drug Administration. Dr. Peterson has received research grants from the American College of Cardiology, American Heart Association, Eli Lilly & Co., Janssen Pharmaceutical Products, and the Society of Thoracic Surgeons; and has received consulting fees from AstraZeneca, Bayer AG, Boehringer Ingelheim, Genentech, Janssen Pharmaceutical Products, Merck & Co., and Sanofi-Aventis. Dr. Califf has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly & Co., Janssen Research and Development LLC, Merck, and Novartis; and received consulting fees from Amgen, Bayer Healthcare, BMEB Services LLC, Medscape LLC/heart. org, Merck, Novartis, Regado NJ, and Roche; and has equity in N30 Pharma and Portola. The views expressed are those of the authors and do not necessarily reflect official National Heart, Lung, and Blood Institute positions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 100 TC 22 Z9 22 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 21 PY 2015 VL 65 IS 15 BP 1567 EP 1582 DI 10.1016/j.jacc.2015.03.016 PG 16 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CG0KW UT WOS:000352956500011 PM 25881939 ER PT J AU Chung, MH Wang, YP Tang, HL Zou, W Basinger, J Xu, XW Tong, WD AF Chung, Ming-Hua Wang, Yuping Tang, Hailin Zou, Wen Basinger, John Xu, Xiaowei Tong, Weida TI Asymmetric author-topic model for knowledge discovering of big data in toxicogenomics SO FRONTIERS IN PHARMACOLOGY LA English DT Article DE toxicogenomics; machine learning; probabilistic topic modeling; author-topic model; bioinformatics; TG-GATEs ID GENE-EXPRESSION PATTERNS; CDNA MICROARRAY; HEPATOTOXICITY; GLUTATHIONE; METABOLITE; TOXICITY; CANCER AB The advancement of high-throughput screening technologies facilitates the generation of massive amount of biological data, a big data phenomena in biomedical science. Yet, researchers still heavily rely on keyword search and/or literature review to navigate the databases and analyses are often done in rather small-scale. As a result, the rich information of a database has not been fully utilized, particularly for the information embedded in the interactive nature between data points that are largely ignored and buried. For the past 10 years, probabilistic topic modeling has been recognized as an effective machine learning algorithm to annotate the hidden thematic structure of massive collection of documents. The analogy between text corpus and large-scale genomic data enables the application of text mining tools, like probabilistic topic models, to explore hidden patterns of genomic data and to the extension of altered biological functions. In this paper, we developed a generalized probabilistic topic model to analyze a toxicogenomics dataset that consists of a large number of gene expression data from the rat livers treated with drugs in multiple dose and time-points. We discovered the hidden patterns in gene expression associated with the effect of doses and time-points of treatment. Finally, we illustrated the ability of our model to identify the evidence of potential reduction of animal use. C1 [Chung, Ming-Hua] Univ Arkansas, Dept Math Sci, Fayetteville, AR 72701 USA. [Wang, Yuping; Tang, Hailin; Zou, Wen; Basinger, John; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Xu, Xiaowei] Univ Arkansas, Dept Informat Sci, Little Rock, AR 72204 USA. RP Xu, XW (reprint author), Dept Informat Sci, 2801 Univ Ave EIT 550, Little Rock, AR 72204 USA. EM xwxu@ualr.edu; weida.tong@fda.hhs.gov NR 35 TC 0 Z9 0 U1 6 U2 10 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD APR 20 PY 2015 VL 6 AR 81 DI 10.3389/fphar.2015.00081 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CW5LB UT WOS:000365035800001 PM 25941488 ER PT J AU Dutta, DK Potnis, PA Rhodes, K Wood, SC AF Dutta, Debargh K. Potnis, Pushya A. Rhodes, Kelly Wood, Steven C. TI Wear Particles Derived from Metal Hip Implants Induce the Generation of Multinucleated Giant Cells in a 3-Dimensional Peripheral Tissue-Equivalent Model SO PLOS ONE LA English DT Article ID TOTAL JOINT ARTHROPLASTIES; COBALT-ALLOY PARTICLES; ACID-PHOSPHATASE TRAP; IN-VITRO; OSTEOCLAST DIFFERENTIATION; ORTHOPEDIC IMPLANTS; ENDOTHELIAL-CELLS; BONE; MACROPHAGES; EXPRESSION AB Multinucleate giant cells (MGCs) are formed by the fusion of 5 to 15 monocytes or macrophages. MGCs can be generated by hip implants at the site where the metal surface of the device is in close contact with tissue. MGCs play a critical role in the inflammatory processes associated with adverse events such as aseptic loosening of the prosthetic joints and bone degeneration process called osteolysis. Upon interaction with metal wear particles, endothelial cells upregulate pro-inflammatory cytokines and other factors that enhance a localized immune response. However, the role of endothelial cells in the generation of MGCs has not been completely investigated. We developed a three-dimensional peripheral tissue-equivalent model (PTE) consisting of collagen gel, supporting a monolayer of endothelial cells and human peripheral blood mononuclear cells (PBMCs) on top, which mimics peripheral tissue under normal physiological conditions. The cultures were incubated for 14 days with Cobalt chromium alloy (CoCr ASTM F75, 1-5 micron) wear particles. PBMC were allowed to transit the endothelium and harvested cells were analyzed for MGC generation via flow cytometry. An increase in forward scatter (cell size) and in the propidium iodide (PI) uptake (DNA intercalating dye) was used to identify MGCs. Our results show that endothelial cells induce the generation of MGCs to a level 4 fold higher in 3-dimentional PTE system as compared to traditional 2-dimensional culture plates. Further characterization of MGCs showed upregulated expression of tartrate resistant alkaline phosphatase (TRAP) and dendritic cell specific transmembrane protein, (DC-STAMP), which are markers of bone degrading cells called osteoclasts. In sum, we have established a robust and relevant model to examine MGC and osteoclast formation in a tissue like environment using flow cytometry and RT-PCR. With endothelial cells help, we observed a consistent generation of metal wear particle-induced MGCs, which heralds metal on metal hip failures. C1 [Dutta, Debargh K.; Potnis, Pushya A.; Rhodes, Kelly; Wood, Steven C.] FDA, CDRH, Dept Biol Chem & Mat Sci, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Dutta, Debargh K.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Rhodes, Kelly] Univ Maryland, College Pk, MD 20742 USA. RP Dutta, DK (reprint author), FDA, CDRH, Dept Biol Chem & Mat Sci, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM debargh.dutta@gmail.com RI Dutta, Debargh/J-6086-2015 OI Dutta, Debargh/0000-0003-1517-0670 FU Office of Women's Health [14-01-0009-SW]; Food and Drug Administration FX This work was supported by Office of Women's Health, grant number#14-01-0009-SW; intramural funding from the 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 38 TC 1 Z9 1 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 20 PY 2015 VL 10 IS 4 AR e0124389 DI 10.1371/journal.pone.0124389 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG3XA UT WOS:000353211700090 PM 25894745 ER PT J AU Arrozola, RA Singh, T Corey, CC Husten, CC Neff, LJ Apelberg, BJ Bunnell, RJ Choiniere, CJ King, BA Cox, S McAfee, T Carahallo, RS AF Arrozola, Rene A. Singh, Tushar Corey, Catherine C. Husten, Corinne C. Neff, Linda J. Apelberg, Benjamin J. Bunnell, Rebecca J. Choiniere, Conrad J. King, Brian A. Cox, Shanna McAfee, Tim Carahallo, Ralph S. TI Tobacco Use Among Middle and High School Students - United States, 2011-2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Arrozola, Rene A.; Singh, Tushar; Neff, Linda J.; Bunnell, Rebecca J.; King, Brian A.; Cox, Shanna; McAfee, Tim; Carahallo, Ralph S.] 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 C.; Husten, Corinne C.; Apelberg, Benjamin J.; Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Arrozola, RA (reprint author), CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM rarra/ola@cdc.gov NR 9 TC 97 Z9 97 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD APR 17 PY 2015 VL 64 IS 14 BP 381 EP 385 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CG5WS UT WOS:000353367200003 ER PT J AU Baker, MA Lieu, TA Li, LL Hua, W Qiang, YD Kawai, AT Fireman, BH Martin, DB Nguyen, MD AF Baker, Meghan A. Lieu, Tracy A. Li, Lingling Hua, Wei Qiang, Yandong Kawai, Alison Tse Fireman, Bruce H. Martin, David B. Nguyen, Michael D. TI A Vaccine Study Design Selection Framework for the Postlicensure Rapid Immunization Safety Monitoring Program SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE immunization; methods; Mini-Sentinel; PRISM; safety; surveillance; vaccine ID INACTIVATED INFLUENZA VACCINE; IMMUNE THROMBOCYTOPENIC PURPURA; CASE-SERIES METHOD; ROTAVIRUS VACCINE; FEBRILE SEIZURES; US INFANTS; RISK; CHILDREN; INTUSSUSCEPTION; IDENTIFICATION AB The Postlicensure Rapid Immunization Safety Monitoring Program, the vaccination safety monitoring component of the US Food and Drug Administration's Mini-Sentinel project, is currently the largest cohort in the US general population for vaccine safety surveillance. We developed a study design selection framework to provide a roadmap and description of methods that may be utilized to evaluate potential associations between vaccines and health outcomes of interest in the Postlicensure Rapid Immunization Safety Monitoring Program and other systems using administrative data. The strengths and weaknesses of designs for vaccine safety monitoring, including the cohort design, the case-centered design, the risk interval design, the case-control design, the self-controlled risk interval design, the self-controlled case series method, and the case-crossover design, are described and summarized in tabular form. A structured decision table is provided to aid in planning of future vaccine safety monitoring activities, and the data components comprising the structured decision table are delineated. The study design selection framework provides a starting point for planning vaccine safety evaluations using claims-based data sources. C1 [Baker, Meghan A.; Lieu, Tracy A.; Li, Lingling; Kawai, Alison Tse] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02215 USA. [Baker, Meghan A.; Lieu, Tracy A.; Li, Lingling; Kawai, Alison Tse] Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA. [Baker, Meghan A.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Lieu, Tracy A.; Fireman, Bruce H.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Hua, Wei; Qiang, Yandong; Martin, David B.; Nguyen, Michael D.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Baker, MA (reprint author), Harvard Pilgrim Hlth Care Inst, Dept Populat Med, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. EM meghan_baker@harvardpilgrim.org FU Food and Drug Administration through the Department of Health and Human Services [HHSF223200910006I] FX This work was supported by the Food and Drug Administration through the Department of Health and Human Services (contract HHSF223200910006I). NR 36 TC 7 Z9 7 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2015 VL 181 IS 8 BP 608 EP 618 DI 10.1093/aje/kwu322 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CH1XG UT WOS:000353815700008 PM 25769306 ER PT J AU Yang, X Salminen, WF Shi, Q Greenhaw, J Gill, PS Bhattacharyya, S Beger, RD Mendrick, DL Mattes, WB James, LP AF Yang, Xi Salminen, William F. Shi, Qiang Greenhaw, James Gill, Pritmohinder S. Bhattacharyya, Sudeepa Beger, Richard D. Mendrick, Donna L. Mattes, William B. James, Laura P. TI Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Acetaminophen; Pediatric; Urine; MicroRNA; DILI ID INDUCED LIVER-INJURY; CIRCULATING MICRORNAS; PROTEIN ADDUCTS; INDUCED HEPATOTOXICITY; OVERDOSE; SERUM; HEPATITIS; HUMANS; CANCER; INTERFERON AB Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n = 10), 2) hospitalized children receiving therapeutic doses of APAP (n = 10) and 3) children hospitalized for APAP overdose (n = 8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, -375, -423-5p, -30d-5p, -125b-5p, -4732-5p, -204-5p, and -574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, -940, -9-3p and -302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetyl-para-guinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R = 0.94; p < 0.01) followed by miR-375 (R = 0.70; p = 0.05). Conclusion: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity. Published by Elsevier Inc. C1 [Yang, Xi; Salminen, William F.; Shi, Qiang; Greenhaw, James; Beger, Richard D.; Mendrick, Donna L.; Mattes, William B.] Food & Drug Adm, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Gill, Pritmohinder S.; Bhattacharyya, Sudeepa; James, Laura P.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Gill, Pritmohinder S.; Bhattacharyya, Sudeepa; James, Laura P.] Arkansas Childrens Hosp, Clin Pharmacol & Toxicol Sect, Little Rock, AR 72205 USA. RP Yang, X (reprint author), Food & Drug Adm, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Xi.Yang@fda.hhs.gov; Willie.Salminen@parexel.com; Qiang.Shi@fda.hhs.gov; James.Greenhaw@fda.hhs.gov; PSGill@uams.edu; SBhattacharyya2@uams.edu; Richard.Beger@fda.hhs.gov; Donna.Mendrick@fda.hhs.gov; William.Mattes@fda.hhs.gov; jameslaurap@uams.edu FU National Institutes of Health, National Institutes of Diabetes, Digestive and Kidney Diseases [R01 DK75936] FX This study was funded in part by a grant (R01 DK75936 to LPJ) from the National Institutes of Health, National Institutes of Diabetes, Digestive and Kidney Diseases. James is part owner of Acetaminophen Toxicity Diagnostics, LLC and has a patent pending for the development of a commercial assay for measurement of acetaminophen protein adducts. 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 40 TC 18 Z9 20 U1 1 U2 6 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 APR 15 PY 2015 VL 284 IS 2 BP 180 EP 187 DI 10.1016/j.taap.2015.02.013 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CH2OH UT WOS:000353864000008 PM 25708609 ER PT J AU Pirone-Davies, C Hoffmann, M Roberts, RJ Muruvanda, T Timme, RE Strain, E Luo, Y Payne, J Luong, K Song, Y Tsai, YC Boitano, M Clark, TA Korlach, J Evans, PS Allard, MW AF Pirone-Davies, Cary Hoffmann, Maria Roberts, Richard J. Muruvanda, Tim Timme, Ruth E. Strain, Errol Luo, Yan Payne, Justin Luong, Khai Song, Yi Tsai, Yu-Chih Boitano, Matthew Clark, Tyson A. Korlach, Jonas Evans, Peter S. Allard, Marc W. TI Genome-Wide Methylation Patterns in Salmonella enterica Subsp enterica Serovars SO PLOS ONE LA English DT Article ID DNA ADENINE METHYLATION; ESCHERICHIA-COLI; SINGLE-MOLECULE; RESTRICTION ENZYMES; GENES; METHYLTRANSFERASE; SPECIFICITIES; DATABASE; TOOL AB The methylation of DNA bases plays an important role in numerous biological processes including development, gene expression, and DNA replication. Salmonella is an important foodborne pathogen, and methylation in Salmonella is implicated in virulence. Using single molecule real-time (SMRT) DNA-sequencing, we sequenced and assembled the complete genomes of eleven Salmonella enterica isolates from nine different serovars, and analysed the whole-genome methylation patterns of each genome. We describe 16 distinct N-6-methyladenine (m6A) methylated motifs, one N-4-methylcytosine (m4C) motif, and one combined m6A-m4C motif. Eight of these motifs are novel, i.e., they have not been previously described. We also identified the methyltransferases (MTases) associated with 13 of the motifs. Some motifs are conserved across all Salmonella serovars tested, while others were found only in a subset of serovars. Eight of the nine serovars contained a unique methylated motif that was not found in any other serovar (most of these motifs were part of Type I restriction modification systems), indicating the high diversity of methylation patterns present in Salmonella. C1 [Pirone-Davies, Cary; Hoffmann, Maria; Muruvanda, Tim; Timme, Ruth E.; Payne, Justin; Evans, Peter S.; Allard, Marc W.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Microbiol, College Pk, MD 20993 USA. [Roberts, Richard J.] New England Biolabs Inc, Ipswich, MA USA. [Strain, Errol; Luo, Yan] US FDA, Ctr Food Safety & Appl Nutr, Off Analyt & Outreach, College Pk, MD USA. [Luong, Khai; Song, Yi; Tsai, Yu-Chih; Boitano, Matthew; Clark, Tyson A.; Korlach, Jonas] Pacific Biosci, Menlo Pk, CA USA. RP Pirone-Davies, C (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Microbiol, College Pk, MD 20993 USA. EM cary.pirone@fda.hhs.gov OI Roberts, Richard/0000-0002-4348-0169 FU Center for Food Safety and Applied Nutrition at the US Food and Drug Administration; National Institutes of Health [1R44GM105125]; Research Fellowship Program for Center for Food Safety and Applied Nutrition; New England Biolabs; Pacific Biosciences FX This work was supported by the Center for Food Safety and Applied Nutrition at the US Food and Drug Administration, http://www.fda.gov/AboutFDA/CentersOffices/OfficeofFoods/CFSAN/; the National Institutes of Health (grant number 1R44GM105125 to RJR), www.nih.gov; and the Research Fellowship Program for Center for Food Safety and Applied Nutrition, administered by the Oak Ridge Associated Universities to CPD. New England Biolabs and Pacific Biosciences provided support in the form of salaries for authors RJR, KL, YS, YCT, MB, TAC, and JK, but did not have any additional role in the study design, data collection, decision to publish, or preparation of the manuscript. However, they did participate in analysis of some of the data; RJR identified methyltransferases in the genomes sequenced, and KL, YS, YCT, MB, TAC, and JK helped assemble several of the genomes. The specific roles of these authors are articulated in the 'author contributions' section. NR 40 TC 6 Z9 7 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 10 PY 2015 VL 10 IS 4 AR e0123639 DI 10.1371/journal.pone.0123639 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CF5II UT WOS:000352590300107 PM 25860355 ER PT J AU Lurie, P Chan-Tack, KM Woodcock, J AF Lurie, Peter Chan-Tack, Kirk M. Woodcock, Janet TI Expanded Access to Investigational Drugs SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Lurie, Peter; Chan-Tack, Kirk M.; Woodcock, Janet] US FDA, Silver Spring, MD 20993 USA. RP Lurie, P (reprint author), US FDA, Silver Spring, MD 20993 USA. EM peter.lurie@fda.hhs.gov NR 4 TC 1 Z9 1 U1 0 U2 7 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 9 PY 2015 VL 372 IS 15 BP 1473 EP 1473 DI 10.1056/NEJMc1501823 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CF2ZV UT WOS:000352417900024 PM 25853763 ER PT J AU Moore, TW Finley, PD Apelberg, BJ Ambrose, BK Brodsky, NS Brown, TJ Husten, C Glass, RJ AF Moore, Thomas W. Finley, Patrick D. Apelberg, Benjamin J. Ambrose, Bridget K. Brodsky, Nancy S. Brown, Theresa J. Husten, Corinne Glass, Robert J. TI An opinion-driven behavioral dynamics model for addictive behaviors SO EUROPEAN PHYSICAL JOURNAL B LA English DT Article ID LARGE SOCIAL NETWORK; UNITED-STATES; BOUNDED CONFIDENCE; CIGARETTE-SMOKING; TOBACCO USE; INTERVENTIONS; SOCIOPHYSICS; SMOKERS; SPREAD; ADULTS AB We present a model of behavioral dynamics that combines a social network-based opinion dynamics model with behavioral mapping. The behavioral component is discrete and history-dependent to represent situations in which an individual's behavior is initially driven by opinion and later constrained by physiological or psychological conditions that serve to maintain the behavior. Individuals are modeled as nodes in a social network connected by directed edges. Parameter sweeps illustrate model behavior and the effects of individual parameters and parameter interactions on model results. Mapping a continuous opinion variable into a discrete behavioral space induces clustering on directed networks. Clusters provide targets of opportunity for influencing the network state; however, the smaller the network the greater the stochasticity and potential variability in outcomes. This has implications both for behaviors that are influenced by close relationships verses those influenced by societal norms and for the effectiveness of strategies for influencing those behaviors. C1 [Moore, Thomas W.; Finley, Patrick D.; Brodsky, Nancy S.; Brown, Theresa J.; Glass, Robert J.] Sandia Natl Labs, Albuquerque, NM 87185 USA. [Apelberg, Benjamin J.; Ambrose, Bridget K.; Husten, Corinne] US FDA, Ctr Tobacco Prod, Rockville, MD 20850 USA. RP Moore, TW (reprint author), Sandia Natl Labs, PO 5800 MS1138, Albuquerque, NM 87185 USA. EM tmoore@sandia.gov FU U.S. Food and Drug Administration; U.S. Department of Energy/Sandia National Laboratories [224109011]; U.S. Department of Energy's National Nuclear Security Administration [DE-AC04-94AL85000] FX This work was funded by the U.S. Food and Drug Administration through a contract with the U.S. Department of Energy/Sandia National Laboratories (funding document 224109011). Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000. The funders, other than employees named as authors or described in the acknowledgments, had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This article represents the views of the authors, and should not be construed to represent FDA's views or policies. NR 39 TC 0 Z9 0 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1434-6028 EI 1434-6036 J9 EUR PHYS J B JI Eur. Phys. J. B PD APR 8 PY 2015 VL 88 IS 4 AR 95 DI 10.1140/epjb/e2015-40462-y PG 28 WC Physics, Condensed Matter SC Physics GA CF7AG UT WOS:000352707800001 ER PT J AU Liu, F Mahmood, M Xu, Y Watanabe, F Biris, AS Hansen, DK Inselman, A Casciano, D Patterson, TA Paule, MG Slikker, W Wang, C AF Liu, Fang Mahmood, Meena Xu, Yang Watanabe, Fumiya Biris, Alexandru S. Hansen, Deborah K. Inselman, Amy Casciano, Daniel Patterson, Tucker A. Paule, Merle G. Slikker, William, Jr. Wang, Cheng TI Effects of silver nanoparticles on human and rat embryonic neural stem cells SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE silver nanoparticles; neural stem cells; developmental neurotoxicity; reactive oxygen species; acetyl-l-carnitine ID ACETYL-L-CARNITINE; HUMAN SKIN KERATINOCYTES; D-ASPARTATE RECEPTOR; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; FOREBRAIN CULTURE; INDUCED APOPTOSIS; CARBON NANOTUBES; CORTICAL-NEURONS; SPINAL-CORD AB Silver nano-particles (Ag-NPs) are becoming increasingly prevalent in consumer products as antibacterial agents. The increased use of Ag NP-enhanced products will almost certainly increase environmental silver levels, resulting in increased exposures and the potential for increased adverse reactions including neurotoxic effects. In the present study, embryonic neural stem cells (NSCs) from human and rat fetuses (gestational day-16) were used to determine whether Ag-NPs are capable of causing developmental neurotoxicity. The NSCs were cultured in serum free medium supplemented with appropriate growth factors. On the eighth day in vitro (DIV 8), the cells were exposed to Ag-NPs at concentrations of 1, 5, 10, and 20 mu g/ml for 24h. The cultured cells then were characterized by NSC markers including nestin and SOX2 and a variety of assays were utilized to determine the effects of Ag-NPs on NSC proliferation and viability and the underlying mechanisms associated with these effects. The results indicate that mitochondrial viability (MTT metabolism) was substantially attenuated and LDH release was increased significantly in a dose-dependent manner. Ag-NPs-induced neurotoxicity was further confirmed by up-regulated Bax protein expression, an increased number of TUN EL-positively stained cells, and elevated reactive oxygen species (ROS). NSC proliferation was also significantly decreased by Ag-NPs. Co-administration of acetyl-L-carnitine, an antioxidant agent, effectively blocked the adverse effects associated with Ag-NP exposure. C1 [Liu, Fang; Patterson, Tucker A.; Paule, Merle G.; Slikker, William, Jr.; Wang, Cheng] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Food & Drug Adm, Jefferson, AR 72079 USA. [Mahmood, Meena; Xu, Yang; Watanabe, Fumiya; Biris, Alexandru S.; Casciano, Daniel] Univ Arkansas, Ctr Integrat Nanotechnol Sci, Little Rock, AR 72204 USA. [Hansen, Deborah K.; Inselman, Amy] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Food & Drug Adm, Jefferson, AR 72079 USA. RP Liu, F (reprint author), US FDA, Natl Ctr Toxicol Res, Food & Drug Adm HFT 132, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM fang.liu@fda.hhs.gov; asbiris@ualr.edu NR 44 TC 4 Z9 4 U1 0 U2 20 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD APR 8 PY 2015 VL 9 AR 115 DI 10.3389/fnins.2015.00115 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CG0RY UT WOS:000352976500001 PM 25904840 ER PT J AU Chuang-Stein, C Balakrishnan, N Berzofsky, M Herring, A Hulting, F McKenzie, J Price, D Stigler, S Williams, G Wasserstein, R AF Chuang-Stein, Christy Balakrishnan, Narayanaswamy Berzofsky, Marcus Herring, Amy Hulting, Fred McKenzie, John Price, Dionne Stigler, Stephen Williams, George Wasserstein, Ronald TI Celebrating the 175th Anniversary of ASA SO AMERICAN STATISTICIAN LA English DT Editorial Material C1 [Chuang-Stein, Christy] Pfizer, Kalamazoo, MI 49009 USA. [Balakrishnan, Narayanaswamy] McMaster Univ, Dept Math & Stat, Hamilton, ON L8S 4K1, Canada. [Berzofsky, Marcus] RTI Int, Res Triangle Pk, NC 27709 USA. [Herring, Amy] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Herring, Amy] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27599 USA. [Hulting, Fred] Gen Mills Inc, Minneapolis, MN 55427 USA. [McKenzie, John] Babson Coll, Math & Sci Div, Babson Pk, MA 02457 USA. [Price, Dionne] US Dept HHS, US FDA, Silver Spring, MD 20993 USA. [Stigler, Stephen] Univ Chicago, Dept Stat, Stat, Chicago, IL 60637 USA. [Williams, George] Amgen Inc, Thousand Oaks, CA USA. [Wasserstein, Ronald] Amer Stat Assoc, Alexandria, VA 22314 USA. RP Chuang-Stein, C (reprint author), Pfizer, 5857 Stoney Brook Rd, Kalamazoo, MI 49009 USA. EM christy.j.chuang-stein@pfizer.com; bala@univmail.cis.mcmaster.ca; berzofsky@rti.org; aherring@bios.unc.edu; fred.hulting@genmills.com; mckenzie@babson.edu; dionne.price@fda.hhs.gov; stigler@uchicago.edu; WilliamsGeoW@aol.com; ron@amstat.org NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0003-1305 EI 1537-2731 J9 AM STAT JI Am. Stat. PD APR 3 PY 2015 VL 69 IS 2 BP 64 EP 67 DI 10.1080/00031305.2015.1028765 PG 4 WC Statistics & Probability SC Mathematics GA CL5TK UT WOS:000357023700002 ER PT J AU Nelson, RM Roth-Cline, M Prohaska, K Cox, E Borio, L Temple, R AF Nelson, Robert M. Roth-Cline, Michelle Prohaska, Kevin Cox, Edward Borio, Luciana Temple, Robert TI Right Job, Wrong Tool: A Commentary on Designing Clinical Trials for Ebola Virus Disease SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID THERAPY C1 [Nelson, Robert M.; Roth-Cline, Michelle; Prohaska, Kevin; Cox, Edward; Borio, Luciana; Temple, Robert] US FDA, Silver Spring, MD 20993 USA. RP Nelson, RM (reprint author), US FDA, Off Pediat Therapeut, 10903 New Hampshire Ave,WO32,Room 5126, Silver Spring, MD 20993 USA. EM Robert.Nelson@fda.hhs.gov NR 9 TC 3 Z9 3 U1 2 U2 10 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD APR 3 PY 2015 VL 15 IS 4 BP 33 EP 36 DI 10.1080/15265161.2015.1010018 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA CF5RO UT WOS:000352614900007 PM 25856596 ER PT J AU Moran-Gilad, J Sintchenko, V Pedersen, SK Wolfgang, WJ Pettengill, J Strain, E Hendriksen, RS AF Moran-Gilad, Jacob Sintchenko, Vitali Pedersen, Susanne Karlsmose Wolfgang, William J. Pettengill, James Strain, Errol Hendriksen, Rene S. CA Global Microbial Identifier TI Proficiency testing for bacterial whole genome sequencing: an end-user survey of current capabilities, requirements and priorities SO BMC INFECTIOUS DISEASES LA English DT Article DE Proficiency; Bioinformatics; Next-generation sequencing; Survey; End-users; Public health; Microbiology; Standards ID CLINICAL MICROBIOLOGY; NEXT-GENERATION; ESCHERICHIA-COLI; OUTBREAK; EPIDEMIOLOGY AB The advent of next-generation sequencing (NGS) has revolutionised public health microbiology. Given the potential impact of NGS, it is paramount to ensure standardisation of 'wet' laboratory and bioinformatic protocols and promote comparability of methods employed by different laboratories and their outputs. Therefore, one of the ambitious goals of the Global Microbial Identifier (GMI) initiative (http://www.globalmicrobialidentifier.org/) has been to establish a mechanism for inter-laboratory NGS proficiency testing (PT). This report presents findings from the survey recently conducted by Working Group 4 among GMI members in order to ascertain NGS end-use requirements and attitudes towards NGS PT. The survey identified the high professional diversity of laboratories engaged in NGS-based public health projects and the wide range of capabilities within institutions, at a notable range of costs. The priority pathogens reported by respondents reflected the key drivers for NGS use (high burden disease and 'high profile' pathogens). The performance of and participation in PT was perceived as important by most respondents. The wide range of sequencing and bioinformatics practices reported by end-users highlights the importance of standardisation and harmonisation of NGS in public health and underpins the use of PT as a means to assuring quality. The findings of this survey will guide the design of the GMI PT program in relation to the spectrum of pathogens included, testing frequency and volume as well as technical requirements. The PT program for external quality assurance will evolve and inform the introduction of NGS into clinical and public health microbiology practice in the post-genomic era. C1 [Moran-Gilad, Jacob] Minist Hlth, Publ Hlth Serv, Jerusalem, Israel. [Moran-Gilad, Jacob] Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, Surveillance & Pathogen Israeli Ctr Excellence, IL-84105 Beer Sheva, Israel. [Sintchenko, Vitali] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Sintchenko, Vitali] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Sintchenko, Vitali] Westmead Hosp, Ctr Infect Dis & Microbiol Publ Hlth, Inst Clin Pathol & Med Res Pathol West, Sydney, NSW, Australia. [Pedersen, Susanne Karlsmose; Hendriksen, Rene S.] Tech Univ Denmark, Natl Food Inst, Res Grp Microbial Genom & Antimicrobial Resistanc, DK-2800 Lyngby, Denmark. [Wolfgang, William J.] New York State Dept Hlth, Bacteriol Lab, Wadsworth Ctr, Albany, NY USA. [Pettengill, James; Strain, Errol] US FDA, Biostat Branch, College Pk, MD USA. RP Hendriksen, RS (reprint author), Tech Univ Denmark, Natl Food Inst, Res Grp Microbial Genom & Antimicrobial Resistanc, Bldg 204,Ground Floor, DK-2800 Lyngby, Denmark. EM rshe@food.dtu.dk NR 21 TC 5 Z9 5 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD APR 3 PY 2015 VL 15 AR 174 DI 10.1186/s12879-015-0902-3 PG 10 WC Infectious Diseases SC Infectious Diseases GA CF5KL UT WOS:000352595900001 PM 25887164 ER PT J AU Petrochenko, PE Torgersen, J Gruber, P Hicks, LA Zheng, JW Kumar, G Narayan, RJ Goering, PL Liska, R Stampfl, J Ovsianikov, A AF Petrochenko, Peter E. Torgersen, Jan Gruber, Peter Hicks, Lucas A. Zheng, Jiwen Kumar, Girish Narayan, Roger J. Goering, Peter L. Liska, Robert Stampfl, Juergen Ovsianikov, Aleksandr TI Laser 3D Printing with Sub-Microscale Resolution of Porous Elastomeric Scaffolds for Supporting Human Bone Stem Cells SO ADVANCED HEALTHCARE MATERIALS LA English DT Article ID 2-PHOTON POLYMERIZATION; REACTIVE DILUENTS; PROLIFERATION; TOPOGRAPHY; STIFFNESS; SURFACES; OSSEOINTEGRATION; DIFFERENTIATION; BIOMATERIALS; HOMEOSTASIS AB A reproducible method is needed to fabricate 3D scaffold constructs that results in periodic and uniform structures with precise control at sub-micrometer and micrometer length scales. In this study, fabrication of scaffolds by two-photon polymerization (2PP) of a biodegradable urethane and acrylate-based photoelastomer is demonstrated. This material supports 2PP processing with sub-micrometer spatial resolution. The high photoreactivity of the biophotoelastomer permits 2PP processing at a scanning speed of 1000 mm s(-1), facilitating rapid fabrication of relatively large structures (>5 mm(3)). These structures are custom printed for in vitro assay screening in 96-well plates and are sufficiently flexible to enable facile handling and transplantation. These results indicate that stable scaffolds with porosities of greater than 60% can be produced using 2PP. Human bone marrow stromal cells grown on 3D scaffolds exhibit increased growth and proliferation compared to smooth 2D scaffold controls. 3D scaffolds adsorb larger amounts of protein than smooth 2D scaffolds due to their larger surface area; the scaffolds also allow cells to attach in multiple planes and to completely infiltrate the porous scaffolds. The flexible photoelastomer material is biocompatible in vitro and is associated with facile handling, making it a viable candidate for further study of complex 3D-printed scaffolds. C1 [Petrochenko, Peter E.; Zheng, Jiwen; Kumar, Girish; Goering, Peter L.] US FDA, Off Sci & Engn Labs, Silver Spring, MD USA. [Petrochenko, Peter E.; Hicks, Lucas A.; Narayan, Roger J.] Univ N Carolina, Joint Dept Biomed Engn, Chapel Hill, NC 27599 USA. [Torgersen, Jan; Gruber, Peter; Stampfl, Juergen; Ovsianikov, Aleksandr] Vienna Univ Technol, Inst Mat Sci & Technol, A-1040 Vienna, Austria. [Liska, Robert] Vienna Univ Technol, Inst Appl Synthet Chem, A-1040 Vienna, Austria. RP Narayan, RJ (reprint author), Univ N Carolina, Joint Dept Biomed Engn, Chapel Hill, NC 27599 USA. EM roger_narayan@msn.com; Aleksandr.Ovsianikov@tuwien.ac.at RI Liska, Robert/C-2814-2008; Ovsianikov, Aleksandr /K-8128-2015 OI Liska, Robert/0000-0001-7865-1936; Ovsianikov, Aleksandr /0000-0001-5846-0198 FU NSF [936110] FX P.E.P. and L.H. were supported in part by NSF Award #936110. The authors thank Carl Simon for valuable scientific discussions. SEM imaging of the scaffolds was carried out using facilities at the University Service Centre for Transmission Electron Microscopy at the Vienna University of Technology. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. The following adjusments were implemented on April 2, 2015: 1) author A. Ovsianikov became co-corresponding author; 2) technical details in Section 2.4 were corrected; 3) Reference 29 was replaced. NR 47 TC 5 Z9 7 U1 10 U2 86 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 EI 2192-2659 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD APR 2 PY 2015 VL 4 IS 5 BP 739 EP 747 DI 10.1002/adhm.201400442 PG 9 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA CF5TR UT WOS:000352620500013 PM 25522214 ER PT J AU Boynton, MH Portnoy, DB Noar, SM Flaherty, B Grana, R AF Boynton, Marcella H. Portnoy, David B. Noar, Seth M. Flaherty, Brian Grana, Rachel TI MIND THE GAPS: USING THEORY-BASED TOBACCO PREVENTION AND CONTROL RESEARCH TO INFORM REGULATORY SCIENCE SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Boynton, Marcella H.] Univ N Carolina, Chapel Hill, NC USA. [Portnoy, David B.] US FDA, Silver Spring, MD USA. [Noar, Seth M.] Univ N Carolina, Chapel Hill, NC USA. [Flaherty, Brian] Univ Washington, Seattle, WA 98195 USA. [Grana, Rachel] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD APR PY 2015 VL 49 SU 1 MA 48 BP S157 EP S157 PG 1 WC Psychology, Multidisciplinary SC Psychology GA DA5EH UT WOS:000367825002106 ER PT J AU Delfino, JG AF Delfino, Jana G. TI U.S. federal safety standards, guidelines and regulations for MRI systems: An overview SO APPLIED RADIOLOGY LA English DT Article C1 [Delfino, Jana G.] US FDA, Silver Spring, MD USA. RP Delfino, JG (reprint author), US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ANDERSON PUBLISHING, INC PI SCOTCH PLAINS PA 180 GLENSIDE AVE, SCOTCH PLAINS, NJ 07076 USA SN 0160-9963 EI 1879-2898 J9 APPL RADIOL JI Appl. Radiol. PD APR PY 2015 VL 44 IS 4 BP 20 EP 23 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DE4OF UT WOS:000370608500003 ER PT J AU Banda, M AF Banda, Malathi TI Detection of Mutant RAS Subpopulations in Colorectal Cancer Patients SO EBIOMEDICINE LA English DT Editorial Material ID ACQUIRED-RESISTANCE; MUTATIONS; TUMOR C1 [Banda, Malathi] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. RP Banda, M (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, HFT 130,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Malathi.Banda@fda.hhs.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD APR PY 2015 VL 2 IS 4 BP 280 EP 281 DI 10.1016/j.ebiom.2015.03.008 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CX8KL UT WOS:000365952100005 PM 26137569 ER PT J AU Cottman-Thomas, E Ming, S Tedaldi, L Wagner, G Chen, Y Chen, X Cai, C Linhardt, R Vann, W AF Cottman-Thomas, Ebony Ming, Shonoi Tedaldi, Lauren Wagner, Gerd Chen, Yi Chen, Xi Cai, Cao Linhardt, Robert Vann, Willie TI Inhibition of Neisseria meningitidis Group X N-Acetylglucosamine-1-Phosphotransferase by Donor Substrate Analogues SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting CY MAR 28-APR 01, 2015 CL Boston, MA SP Amer Assoc Anatomists, Amer Physiol Soc, Amer Soc Biochem & Mol Biol, ASIP, ASN, ASPET C1 [Cottman-Thomas, Ebony; Ming, Shonoi; Vann, Willie] US FDA, Lab Bacterial Polysaccharides, Silver Spring, MD USA. [Tedaldi, Lauren; Wagner, Gerd] Kings Coll London, Dept Chem, London WC2R 2LS, England. [Chen, Yi; Chen, Xi] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. [Cai, Cao; Linhardt, Robert] Rensselaer Polytech Inst, Dept Chem & Chem Biol, Troy, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD APR PY 2015 VL 29 SU 1 MA 721.26 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CS0BT UT WOS:000361722701256 ER PT J AU Dausch, J AF Dausch, Judith TI FDA's Evaluations of GRAS Food Ingredients SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting CY MAR 28-APR 01, 2015 CL Boston, MA SP Amer Assoc Anatomists, Amer Physiol Soc, Amer Soc Biochem & Mol Biol, ASIP, ASN, ASPET C1 [Dausch, Judith] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD APR PY 2015 VL 29 SU 1 MA 741.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CS0BT UT WOS:000361722702116 ER PT J AU Hu, J Juan, WY Sahyoun, N AF Hu, Jing Juan, Wenyen Sahyoun, Nadine TI Associations between Folate Biomarker Levels and Renal Function among Adults in the US SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting CY MAR 28-APR 01, 2015 CL Boston, MA SP Amer Assoc Anatomists, Amer Physiol Soc, Amer Soc Biochem & Mol Biol, ASIP, ASN, ASPET C1 [Hu, Jing; Sahyoun, Nadine] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Juan, Wenyen] US FDA, Off Nutr Labeling & Dietary Supplements, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD APR PY 2015 VL 29 SU 1 MA 906.30 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CS0BT UT WOS:000361722705453 ER PT J AU Ming, S Peterson, D Vann, W AF Ming, Shonoi Peterson, Dwight Vann, Willie TI Kinetic characterization of the alpha-2,9 polysialyltransferase of Neisseria meningitidis SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting CY MAR 28-APR 01, 2015 CL Boston, MA SP Amer Assoc Anatomists, Amer Physiol Soc, Amer Soc Biochem & Mol Biol, ASIP, ASN, ASPET C1 [Ming, Shonoi; Peterson, Dwight; Vann, Willie] US FDA, Lab Bacterial Polysaccharides, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD APR PY 2015 VL 29 SU 1 MA 722.8 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CS0BT UT WOS:000361722701286 ER PT J AU Thon, V Peterson, D Vionnet, J Vann, W AF Thon, Vireak Peterson, Dwight Vionnet, Justine Vann, Willie TI Function of KpsS, KpsC, and NeuE in Escherichia coli K1 Polysialic Acid Biosynthesis SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting CY MAR 28-APR 01, 2015 CL Boston, MA SP Amer Assoc Anatomists, Amer Physiol Soc, Amer Soc Biochem & Mol Biol, ASIP, ASN, ASPET C1 [Thon, Vireak; Peterson, Dwight; Vionnet, Justine; Vann, Willie] US FDA, Lab Bacterial Polysaccharides, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD APR PY 2015 VL 29 SU 1 MA 718.12 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CS0BT UT WOS:000361722701187 ER PT J AU Haley-Zitlin, V Peckham, J Kropp, J Granberg, E Anderson, A Mroz, T AF Haley-Zitlin, Vivian Peckham, Janet Kropp, Jaclyn Granberg, Ellen Anderson, Annie Mroz, Tom TI Factors Responsible for National School Lunch Program Participants' Entree Selections SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Haley-Zitlin, Vivian; Anderson, Annie] Clemson Univ, Food Nutr & Packaging Sci, Clemson, SC 29631 USA. [Peckham, Janet] US FDA, Econ, Rockville, MD 20857 USA. [Kropp, Jaclyn] Univ Florida, Food & Resource Econ, Gainesville, FL 32611 USA. [Granberg, Ellen] Clemson Univ, Dept Sociol & Anthropol, Clemson, SC 29631 USA. [Mroz, Tom] Univ Georgia, Dept Econ, Athens, GA 30602 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD APR PY 2015 VL 29 SU 1 MA 597.5 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CR6PV UT WOS:000361470505112 ER PT J AU Pai, A Meyer, D Bales, B Cotero, V Pai, M Zheng, N Jiang, W AF Pai, A. Meyer, D. Bales, B. Cotero, V. Pai, M. Zheng, N. Jiang, W. TI LABILE IRON RELEASE FROM INTRAVENOUS (IV) IRON FORMULATIONS: CONSIDERATIONS FOR BIOEQUIVALENCE SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Spring Clinical Meeting of National-Kidney-Foundation CY MAR 25-29, 2015 CL Grapevine, TX SP Natl Kidney Fdn C1 Albany Coll Pharm & Hlth Sci, Albany, NY USA. Gen Elect Global Res Ctr, Niskayuna, NY USA. US FDA, Off Gener Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2015 VL 65 IS 4 MA 194 BP A63 EP A63 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA CJ9BE UT WOS:000355796500197 ER PT J AU Mercer, CN Hofstra, AH Todorov, TI Roberge, J Burgisser, A Adams, DT Cosca, M AF Mercer, Celestine N. Hofstra, Albert H. Todorov, Todor I. Roberge, Julie Burgisser, Alain Adams, David T. Cosca, Michael TI Pre-Eruptive Conditions of the Hideaway Park Topaz Rhyolite: Insights into Metal Source and Evolution of Magma Parental to the Henderson Porphyry Molybdenum Deposit, Colorado SO JOURNAL OF PETROLOGY LA English DT Article DE rhyolite; crystallization; P-T conditions; melt inclusions; metals; degassing; Henderson porphyry molybdenum deposit; LA-ICP-MS ID WESTERN UNITED-STATES; TAUPO VOLCANIC ZONE; SILICATE MELT INCLUSIONS; TAYLOR CREEK RHYOLITE; RIO-GRANDE RIFT; BISHOP TUFF; NEW-MEXICO; NEW-ZEALAND; TRACE-ELEMENTS; PARTITION-COEFFICIENTS AB The Hideaway Park tuff is the only preserved extrusive volcanic unit related to the Red Mountain intrusive complex, which produced the world-class Henderson porphyry Mo deposit. Located within the Colorado Mineral Belt, USA, Henderson is the second largest Climax-type Mo deposit in the world, and is therefore an excellent location to investigate magmatic processes leading to Climax-type Mo mineralization. We combine an extensive dataset of major element, volatile, and trace element abundances in quartz-hosted melt inclusions and pumice matrix glass with major element geochemistry from phenocrysts to reconstruct the pre-eruptive conditions and the source and evolution of metals within the magma. Melt inclusions are slightly peraluminous topaz rhyolitic in composition and are volatile-charged (<= 6 wt % H2O, <= 600 ppm CO2, similar to 0.3-1.0 wt % F, similar to 2300-3500 ppm Cl) and metal-rich (similar to 7-24 ppm Mo, similar to 4-14 ppm W, similar to 21-52 ppm Pb, similar to 28-2700 ppm Zn, <0.1-29 ppm Cu, similar to 0.3-1.8 ppm Bi, similar to 40-760 ppb Ag, similar to 690-1400 ppm Mn). Melt inclusion and pumice matrix glass chemistry reveal that the Hideaway Park magma evolved by large degrees of fractional crystallization (<= 60-70%) during quartz crystallization and melt inclusion entrapment at pressures of <= 300 MPa (<= 8km depth), with little to no crystallization upon shallow ascent and eruption. Filter pressing, crystal settling, magma recharge and mixing of less evolved rhyolite melt, and volatile exsolution were important processes during magma evolution; the low estimated viscosities (similar to 10(5)-10(10) Pa s) of these H2O- and F-rich melts probably enhanced these processes. A noteworthy discrepancy between the metal contents in the pumice matrix glass and in the melt inclusions suggests that after quartz crystallization ceased upon shallow magma ascent and eruption, the Hideaway Park magma exsolved an aqueous fluid into which Mo, Bi, Ag, Zn, Mn, Cs, and Y strongly partitioned. Given that the Henderson deposit contains anomalous abundances of not only Mo, but also W, Pb, Zn, Cu, Bi, Ag, and Mn, we suggest that these metals were sourced from similar fluids exsolved from unerupted portions of the same magmatic system. Trace element ratios imply that Mo was sourced deep, from either the lower crust or metasomatized mantle. The origin of sulfur remains unresolved; however, given the extremely low S solubility of rhyolite melts in the shallow crust we favor the possibility that another source of S might supplement or account for that present in the ore deposit, probably the comagmatic, mantle-derived lamprophyres that occur in minor quantities with the voluminous topaz rhyolites in the area. To account for the 437 Mt of MoS2 (similar to 1.0 x 10(6) t Mo) present in the Henderson ore deposit, a volume of similar to 45 km(3) of Hideaway Park rhyolite magma would have been necessary to supply the Mo (a cylindrical pluton measuring 3.1 km x 6.0 km) along with sparging of similar to 6.8 x 10(5) t of S from similar to 0.05 km(3) of lamprophyre magma. Based on a weighted mean Ar-40/Ar-39 age of 27.58 +/- 0.24 Ma, similar melt geochemistry, and characteristically F-rich biotite phenocrysts, we conclude that the Hideaway Park tuff was cogenetic with the intrusions at Red Mountain that formed the Henderson deposit. C1 [Mercer, Celestine N.; Hofstra, Albert H.; Cosca, Michael] US Geol Survey, Denver Inclus Anal Lab, Denver, CO 80225 USA. [Todorov, Todor I.] US FDA, Ctr Food & Drug & Safety & Appl Nutr, College Pk, MD 20740 USA. [Roberge, Julie] Inst Politecn Nacl, ESIA Ticoman, Mexico City 07340, DF, Mexico. [Burgisser, Alain] Univ Savoie, ISTerre, F-73376 Le Bourget Du Lac, France. [Adams, David T.] Macquarie Univ, Dept Earth & Planetary Sci, Sydney, NSW 2109, Australia. RP Mercer, CN (reprint author), US Geol Survey, Denver Inclus Anal Lab, Box 25046, Denver, CO 80225 USA. EM cmercer@usgs.gov OI Adams, David/0000-0003-2679-2344 NR 157 TC 3 Z9 3 U1 2 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-3530 EI 1460-2415 J9 J PETROL JI J. Petrol. PD APR PY 2015 VL 56 IS 4 BP 645 EP 679 DI 10.1093/petrology/egv010 PG 35 WC Geochemistry & Geophysics SC Geochemistry & Geophysics GA CJ1GY UT WOS:000355233200001 ER PT J AU Singh, P Sha, Q Lacher, DW Del Valle, J Mosci, RE Moore, JA Scribner, KT Manning, SD AF Singh, Pallavi Sha, Qiong Lacher, David W. Del Valle, Jacquelyn Mosci, Rebekah E. Moore, Jennifer A. Scribner, Kim T. Manning, Shannon D. TI Characterization of enteropathogenic and Shiga toxin-producing Escherichia coil in cattle and deer in a shared agroecosystem SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Article DE STEC; EPEC; EHEC; cattle; deer; transmission; MLST; fingerprinting ID WHITE-TAILED DEER; FREE-RANGING DEER; COLI O157; UNITED-STATES; MICROSATELLITE LOCI; CONVERTING PHAGES; ANIMAL SOURCES; WILD DEER; PREVALENCE; STRAINS AB Shiga toxin-producing Escherichia coil (STEC) is an important foodborne pathogen. Cattle are suggested to be an important reservoir for STEC; however, these pathogens have also been isolated from other livestock and wildlife. In this study we sought to investigate transmission of STEC, enterohemorrhagic E. coli (EHEC) and enteropathogenic E coli (EPEC) between cattle and white-tailed deer in a shared agroecosystem. Cattle feces were collected from 100 animals in a Michigan dairy farm in July 2012, while 163 deer fecal samples were collected during two sampling periods (March and June). The locations of deer fecal pellets were recorded via geographic information system mapping and microsatellite multi-locus genotyping was used to link the fecal samples to individual deer at both time points. Following subculture to sorbitol MacConkey agar and STEC CHROMagar, the pathogens were characterized by serotyping, stx profiling, and PCR-based fingerprinting; multilocus sequence typing (MLST) was performed on a subset. STEC and EHEC were cultured from 12 to 16% of cattle, respectively, and EPEC was found in 36%. Deer were significantly less likely to have a pathogen in March vs. June where the frequency of STEC, EHEC, and EPEC was 1, 6, and 22%, respectively. PCR fingerprinting and MLST clustered the cattle- and deer-derived strains together in a phylogenetic tree. Two STEC strains recovered from both animal species shared MLST and fingerprinting profiles, thereby providing evidence of interspecies transmission and highlighting the importance of wildlife species in pathogen shedding dynamics and persistence in the environment and cattle herds. C1 [Singh, Pallavi; Sha, Qiong; Del Valle, Jacquelyn; Mosci, Rebekah E.; Manning, Shannon D.] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. [Lacher, David W.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Moore, Jennifer A.] Grand Valley State Univ, Dept Biol, Allendale, MI 49401 USA. [Scribner, Kim T.] Michigan State Univ, Dept Fisheries & Wildlife, E Lansing, MI 48824 USA. RP Manning, SD (reprint author), Michigan State Univ, Dept Microbiol & Mol Genet, 1129 Farm Lane, E Lansing, MI 48824 USA. EM mannin71@msu.edu FU USDA [2011-67005-30004]; W.K. Kellogg Foundation FX The authors thank USDA (2011-67005-30004; SM) and the W.K. Kellogg Foundation (KS, JM) for their financial support of this study as well as the Kellogg Biological Station, particularly Santiago Utsumi, for allowing us to sample the grounds and cattle. We thank Dr. Vilma Yuzbasiyan-Gurkan for supporting students working on this project through the Merial Veterinary Scholars Summer Research Program (NIH) and thank the many individuals who participated in the samplings including Drs. Daniel Grooms, Paul Bartlett, Steven Rust, and Cristina Venegas Vargas. We also thank Lindsey Ouellette, Scott Henderson, Akanksha Khare, Lisette Delgado, and Johnathan Lehnert for sample preparations and pathogen detection as well as Emily Cannell and Jeannette Kanefsky for white-tailed deer genotyping and sexing. NR 51 TC 5 Z9 5 U1 3 U2 22 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD APR 1 PY 2015 VL 5 AR 29 DI 10.3389/fcimb.2015.00029 PG 13 WC Immunology; Microbiology SC Immunology; Microbiology GA CI6UO UT WOS:000354898500001 PM 25883908 ER PT J AU Junod, S AF Junod, Suzanne TI Jogging the Institutional Memory: Writing the History of the Federal Government SO JOURNAL OF THE HISTORY OF MEDICINE AND ALLIED SCIENCES LA English DT Editorial Material C1 US FDA, Hist Off, Silver Spring, MD 20993 USA. RP Junod, S (reprint author), US FDA, Hist Off, White Oak 1,Room 1204, Silver Spring, MD 20993 USA. EM suzanne.junod@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-5045 EI 1468-4373 J9 J HIST MED ALL SCI JI J. Hist. Med. Allied Sci. PD APR PY 2015 VL 70 IS 2 BP 311 EP 314 DI 10.1093/jhmas/jrv003 PG 4 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA CI4CH UT WOS:000354693700006 PM 25862751 ER PT J AU Xia, QS Ma, L He, XB Cai, LN Fu, PP AF Xia, Qingsu Ma, Liang He, Xiaobo Cai, Lining Fu, Peter P. TI 7-Glutathione Pyrrole Adduct: A Potential DNA Reactive Metabolite of Pyrrolizidine Alkaloids SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID ALCOHOL GLUTATHIONE CONJUGATE; PERFUSED-RAT-LIVER; MICROSOMAL FORMATION; IN-VIVO; MONOCROTALINE; ACTIVATION; TRICHODESMINE; MECHANISMS; RETRORSINE; CLIVORINE AB Pyrrolizidine alkaloid (PA)-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. PAs require metabolic activation to form pyrrolic metabolites to exert cytotoxicity and tumorigenicity. We previously determined that metabolism of tumorigenic PAs produced four DNA adducts, designated as DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, that are responsible for liver tumor initiation. 7-Glutathione-(+/-)-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine (7-GS-DHP), formed in vivo and in vitro, and 7,9-di-GS-DHP, formed in vitro, are both considered detoxified metabolites. However, in this study we determined that incubation of 7-GS-DHP with 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) yields DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts as well as the reactive metabolite DHP. Furthermore, reaction of 7-GS-DHP with calf thymus DNA in aqueous solution at 37 degrees C for 4, 8, 16, 24, 48, or 72 h, followed by enzymatic hydrolysis yielded DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts. Under our current experimental conditions, DHP-dA-3 and DHP-dA-4 adducts were formed in a trace amount from the reaction of 7,9-di-GS-DHP with dA. No DHP-dG-3 or DHP-dG-4 adducts were detected from the reaction of 7,9-di-GS-DHP with dG. This study represents the first report that the 7-GS-DHP adduct can be a potential reactive metabolite of PAs leading to DNA adduct formation. C1 [Xia, Qingsu; Ma, Liang; He, Xiaobo; Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Cai, Lining] Biotranex LLC, Monmouth Jct, NJ 08852 USA. RP Fu, PP (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov FU Postgraduate Research Program at the NCTR FX This research was supported in part by appointments (L.M. and X.H.) to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. NR 25 TC 11 Z9 11 U1 3 U2 12 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 APR PY 2015 VL 28 IS 4 BP 615 EP 620 DI 10.1021/tx500417q PG 6 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA CG6RK UT WOS:000353429700008 PM 25768656 ER PT J AU Liu, J Mansouri, K Judson, RS Martin, MT Hong, HX Chen, MJ Xu, XW Thomas, RS Shah, I AF Liu, Jie Mansouri, Kamel Judson, Richard S. Martin, Matthew T. Hong, Huixiao Chen, Minjun Xu, Xiaowei Thomas, Russell S. Shah, Imran TI Predicting Hepatotoxicity Using ToxCast in Vitro Bioactivity and Chemical Structure SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID DECISION-SUPPORT TOOLS; PROTEIN 18 KDA; TRANSLOCATOR PROTEIN; COMPUTATIONAL TOXICOLOGY; ENVIRONMENTAL CHEMICALS; REPRODUCTIVE TOXICITY; LIVER-DISEASE; CLASSIFICATION; MODELS; HAZARD AB The U.S. Tox21 and EPA ToxCast program screen thousands of environmental chemicals for bioactivity using hundreds of high-throughput in vitro assays to build predictive models of toxicity. We represented chemicals based on bioactivity and chemical structure descriptors, then used supervised machine learning to predict in vivo hepatotoxic effects. A set of 677 chemicals was represented by 711 in vitro bioactivity descriptors (from ToxCast assays), 4,376 chemical structure descriptors (from QikProp, OpenBabel, PaDEL, and PubChem), and three hepatotoxicity categories (from animal studies). Hepatotoxicants were defined by rat liver histopathology observed after chronic chemical testing and grouped into hypertrophy (161), injury (101) and proliferative lesions (99). Classifiers were built using six machine learning algorithms: linear discriminant analysis (LDA), Naive Bayes (NB), support vector machines (SVM), classification and regression trees (CART), k-nearest neighbors (KNN), and an ensemble of these classifiers (ENSMB). Classifiers of hepatotoxicity were built using chemical structure descriptors, ToxCast bioactivity descriptors, and hybrid descriptors. Predictive performance was evaluated using 10-fold cross-validation testing and in-loop, filter-based, feature subset selection. Hybrid classifiers had the best balanced accuracy for predicting hypertrophy (0.84 +/- 0.08), injury (0.80 +/- 0.09), and proliferative lesions (0.80 +/- 0.10). Though chemical and bioactivity classifiers had a similar balanced accuracy, the former were more sensitive, and the latter were more specific. CART, ENSMB, and SVM classifiers performed the best, and nuclear receptor activation and mitochondrial functions were frequently found in highly predictive classifiers of hepatotoxicity. ToxCast and ToxRefDB provide the largest and richest publicly available data sets for mining linkages between the in vitro bioactivity of environmental chemicals and their adverse histopathological outcomes. Our findings demonstrate the utility of high-throughput assays for characterizing rodent hepatotoxicants, the benefit of using hybrid representations that integrate bioactivity and chemical structure, and the need for objective evaluation of classification performance. C1 [Liu, Jie; Mansouri, Kamel; Judson, Richard S.; Martin, Matthew T.; Thomas, Russell S.; Shah, Imran] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Liu, Jie; Xu, Xiaowei] Univ Arkansas, Dept Informat Sci, Little Rock, AR 72204 USA. [Liu, Jie; Mansouri, Kamel] Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37831 USA. [Hong, Huixiao; Chen, Minjun; Xu, Xiaowei] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Shah, I (reprint author), US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. EM shah.imran@epa.gov OI Thomas, Russell/0000-0002-2340-0301; Judson, Richard/0000-0002-2348-9633; Mansouri, Kamel/0000-0002-6426-8036 FU Research Participation Program at the Office of Research and Development, U.S. Environmental Protection Agency FX This project was supported in part by an appointment to the Research Participation Program at the Office of Research and Development, U.S. Environmental Protection Agency, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S Department of Energy and EPA. NR 61 TC 14 Z9 14 U1 5 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD APR PY 2015 VL 28 IS 4 BP 738 EP 751 DI 10.1021/tx500501h PG 14 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA CG6RK UT WOS:000353429700021 PM 25697799 ER PT J AU Bender, JB Barlam, TF Glore, RP Gumley, N Grayzel, SE Hoang, C Murphy, MJ Papich, MG Sykes, JE Watts, JL Whichard, JM AF Bender, Jeff B. Barlam, Tamar F. Glore, Reilly P. Gumley, Nigel Grayzel, Sharon E. Hoang, Christine Murphy, Michael J. Papich, Mark G. Sykes, Jane E. Watts, Jeffrey L. Whichard, Jean M. TI The AVMA Task Force for Antimicrobial Stewardship in Companion Animal Practice responds SO JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION LA English DT Letter C1 [Bender, Jeff B.] Univ Minnesota, Coll Vet Med, Dept Vet Populat Med, St Paul, MN 55108 USA. [Barlam, Tamar F.] Boston Med Ctr, Infect Dis Sect, Boston, MA USA. [Glore, Reilly P.] Brady Vet Hosp, Montesano, WA USA. [Gumley, Nigel] Canadian Vet Med Assoc, Ottawa, ON, Canada. [Grayzel, Sharon E.] Columbia Vet Ctr, Vancouver, WA USA. [Hoang, Christine] AVMA, Schaumburg, IL USA. [Murphy, Michael J.] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. [Papich, Mark G.] N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC USA. [Sykes, Jane E.] Univ Calif Davis, Sch Vet Med, Dept Med & Epidemiol, Davis, CA 95616 USA. [Watts, Jeffrey L.] Zoetis, Antiinfect Res VMRD, Kalamazoo, MI USA. [Whichard, Jean M.] CDC, Atlanta, GA 30333 USA. RP Bender, JB (reprint author), Univ Minnesota, Coll Vet Med, Dept Vet Populat Med, St Paul, MN 55108 USA. NR 1 TC 1 Z9 1 U1 1 U2 4 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0003-1488 EI 1943-569X J9 JAVMA-J AM VET MED A JI JAVMA-J. Am. Vet. Med. Assoc. PD APR 1 PY 2015 VL 246 IS 7 BP 727 EP 728 PG 2 WC Veterinary Sciences SC Veterinary Sciences GA CH1KS UT WOS:000353780900022 PM 25958435 ER PT J AU Maruvada, S Liu, YB Soneson, JE Herman, BA Harris, GR AF Maruvada, Subha Liu, Yunbo Soneson, Joshua E. Herman, Bruce A. Harris, Gerald R. TI Comparison between experimental and computational methods for the acoustic and thermal characterization of therapeutic ultrasound fields SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID INTENSITY FOCUSED ULTRASOUND; TISSUE-MIMICKING MATERIAL; PROSTATE-CANCER; HIFU ABLATION; MUSCLE; TUMORS; SOUND; VIVO AB For high intensity therapeutic ultrasound (HITU) devices, pre-clinical testing can include measurement of power, pressure/intensity and temperature distribution, acoustic and thermal simulations, and assessment of targeting accuracy and treatment monitoring. Relevant International Electrotechnical Commission documents recently have been published. However, technical challenges remain because of the often focused, large amplitude pressure fields encountered. Measurement and modeling issues include using hydrophones and radiation force balances at HITU power levels, validation of simulation models, and tissue-mimicking material (TMM) development for temperature measurements. To better understand these issues, a comparison study was undertaken between simulations and measurements of the HITU acoustic field distribution in water and TMM and temperature rise in TMM. For the specific conditions of this study, the following results were obtained. In water, the simulated values for p+ and p- were 3% lower and 10% higher, respectively, than those measured by hydrophone. In TMM, the simulated values for p+ and p- were 2% and 10% higher than those measured by hydrophone, respectively. The simulated spatial-peak temporal-average intensity values in water and TMM were greater than those obtained by hydrophone by 3%. Simulated and measured end-of-sonication temperatures agreed to within their respective uncertainties (coefficients of variation of approximately 20% and 10%, respectively). C1 [Maruvada, Subha; Liu, Yunbo; Soneson, Joshua E.; Herman, Bruce A.; Harris, Gerald R.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Maruvada, S (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM subha.maruvada@fda.hhs.gov NR 35 TC 3 Z9 3 U1 0 U2 8 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 APR PY 2015 VL 137 IS 4 BP 1704 EP 1713 DI 10.1121/1.4916280 PG 10 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA CG9QV UT WOS:000353653500027 PM 25920823 ER PT J AU Parvizi, J Alijanipour, P Barberi, EF Hickok, NJ Phillips, KS Shapiro, IM Schwarz, EM Stevens, MH Wang, Y Shirtliff, ME AF Parvizi, Javad Alijanipour, Pouya Barberi, Elie F. Hickok, Noreen J. Phillips, K. Scott Shapiro, Irving M. Schwarz, Edward M. Stevens, Michelle H. Wang, Yi Shirtliff, Mark E. TI Novel Developments in the Prevention, Diagnosis, and Treatment of Periprosthetic Joint Infections SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Article ID STAPHYLOCOCCUS-EPIDERMIDIS BIOFILMS; BETA-N-ACETYLGLUCOSAMINIDASE; L-ALANINE AMIDASE; IN-VITRO; IMMUNE-RESPONSE; BACTERIAL-COLONIZATION; PSEUDOMONAS-AERUGINOSA; MICROBIAL BIOFILMS; PASSIVE-IMMUNIZATION; VANCOMYCIN ACTIVITY AB Periprosthetic joint infection (PJI) is one of the most challenging complications compromising the outcome of an otherwise successful operation. Considerable efforts have been invested in the recent years to address paradigm shifts in our understanding of the complex microbiological phenomena that contribute to the pathophysiology of PJI, such as microbial adherence, biofilm formation, and resistance to antibiotics. This article is an introduction to some of the recent advancements in the prevention, diagnosis, and treatment of PJI. It describes how industry, academic researchers, and government are increasing collaboration to address PJI through development of novel technologies, therapeutic strategies, and regulatory science that specifically target the unique biofilm-associated aspects of its pathogenesis. C1 [Parvizi, Javad; Alijanipour, Pouya] Thomas Jefferson Univ, Rothman Inst, Philadelphia, PA 19107 USA. [Hickok, Noreen J.; Shapiro, Irving M.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Barberi, Elie F.] Mayo Clin, Div Infect Dis, Dept Med, Rochester, MN USA. [Phillips, K. Scott] US FDA, Beltsville, MD USA. [Schwarz, Edward M.] Univ Rochester, Med Ctr, Ctr Musculoskeletal Res, Rochester, NY 14642 USA. [Stevens, Michelle H.] 3M Healthcare, Woodbury, MN USA. [Wang, Yi] US FDA, Silver Spring, MD USA. [Shirtliff, Mark E.] Univ Maryland, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA. RP Parvizi, J (reprint author), Thomas Jefferson Univ, Rothman Inst, Philadelphia, PA 19107 USA. RI phillips, kenneth/F-7560-2014; Phillips, Kenneth/A-2156-2013 OI phillips, kenneth/0000-0002-6552-0694; Phillips, Kenneth/0000-0002-6552-0694 NR 121 TC 9 Z9 9 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1067-151X EI 1940-5480 J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD APR PY 2015 VL 23 SU 1 BP S32 EP S43 DI 10.5435/JAAOS-D-14-00455 PG 12 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CH6ES UT WOS:000354129700006 PM 25808968 ER PT J AU Vicente, J Johannesen, L Mason, JW Crumb, WJ Pueyo, E Stockbridge, N Strauss, DG AF Vicente, Jose Johannesen, Lars Mason, Jay W. Crumb, William J. Pueyo, Esther Stockbridge, Norman Strauss, David G. TI Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE electrocardiography; ion channels; long-QT syndrome; pharmacology; torsade de pointes ID LONG QT SYNDROME; TORSADE-DE-POINTES; HOLTER RECORDINGS; HEART-RATE; REPOLARIZATION; DRUGS; RISK; ABNORMALITIES; INHIBITION; DISPERSION AB Background-Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology. Methods and Results-Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide). Conclusions-T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk. C1 [Vicente, Jose; Johannesen, Lars; Pueyo, Esther; Strauss, David G.] US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD 20993 USA. [Vicente, Jose; Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, CDER, Silver Spring, MD 20993 USA. [Vicente, Jose; Pueyo, Esther] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. [Johannesen, Lars; Strauss, David G.] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Johannesen, Lars; Strauss, David G.] Karolinska Univ Hosp, Stockholm, Sweden. [Pueyo, Esther] Biomed Res Networking Ctr Bioengn Biomat & Nanome, Zaragoza, Spain. [Mason, Jay W.] Spaulding Clin Res, West Bend, WI USA. [Crumb, William J.] Zenas Technol, New Orleans, LA USA. RP Strauss, DG (reprint author), US FDA, 10903 New Hampshire Ave,WO62-1126, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov OI Vicente, Jose/0000-0001-9963-1205 FU U.S. Food and Drug Administration's Critical Path Initiative, U.S. Food and Drug Administration's Office of Women's Health; Ministerio de Economia y Competitividad (MINECO), Spain [TIN2013-41998-R]; Grupo Consolidado BSICoS from DGA (Aragon) and European Social Fund (EU) FX This study was supported by U.S. Food and Drug Administration's Critical Path Initiative, U.S. Food and Drug Administration's Office of Women's Health, and appointments to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. Pueyo is funded by Ministerio de Economia y Competitividad (MINECO), Spain, under project TIN2013-41998-R and by Grupo Consolidado BSICoS from DGA (Aragon) and European Social Fund (EU). NR 40 TC 17 Z9 17 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD APR PY 2015 VL 4 IS 4 AR e001615 DI 10.1161/JAHA.114.001615 PG 24 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CH6HN UT WOS:000354137300016 ER PT J AU Liu, Y Liu, YJ Yin, JJ Nie, ZH AF Liu, Yi Liu, Yijing Yin, Jun-Jie Nie, Zhihong TI Self-Assembly of Amphiphilic Block Copolymer-Tethered Nanoparticles: a New Approach to Nanoscale Design of Functional Materials SO MACROMOLECULAR RAPID COMMUNICATIONS LA English DT Article DE vesicles; nanoparticles; self-assembly; biological applications ID TRANSFER RADICAL POLYMERIZATION; GOLD NANOPARTICLES; METAL NANOPARTICLES; INORGANIC NANOPARTICLES; TRIBLOCK COPOLYMERS; DIBLOCK COPOLYMERS; PLASMONIC VESICLES; SURFACE-CHEMISTRY; CARBON NANOTUBES; STERIC HINDRANCE AB Colloidal molecules constructed from polymers and nanoparticles (NPs) have recently emerged as a novel class of building blocks for assembling functional hybrid materials. Particularly, self-assembly of amphiphilic block copolymer (BCP)-tethered NPs (BNPs) has shown great promise in the nanoscale design of functional hybrid materials. On the one hand, structurally the BNPs can be considered as molecular equivalents that are capable of self-assembly at multiple hierarchical levels. On the other hand, the assembly of BNPs shows significant differences from molecular assembly due to their large dimension, complex geometry, and multiscale interactions involved in the assembly process. The manipulation of BCPs localized near the surface of the NPs offers an effective tool for engineering the interactions between NPs and hence the complexity of NP assembly. In this Feature Article, recent progresses on the self-assembly of BNPs into functional materials are summarized. First, major strategies for assembling amphiphilic BNPs are highlighted. Secondly, the application of hybrid nanostructures (e.g., vesicles) assembled from BNPs in the field of biomedical imaging and delivery is discussed. Finally, current challenges and perspectives at this frontier are outlined. C1 [Liu, Yi; Liu, Yijing; Nie, Zhihong] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Liu, Yi; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Nie, ZH (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. EM znie@umd.edu RI Yin, Jun Jie /E-5619-2014; Nie, Zhihong/D-7495-2011; Liu, Yijing/D-6666-2016 OI Nie, Zhihong/0000-0001-9639-905X; FU NSF career award [DMR-1255377]; ACS Petroleum Research Fund (PRF) [53461-DNI7]; 3M non-tenured faculty award; University of Maryland; Joint Institute for Food Safety and Nutrition, University of Maryland, College Park, MD through FDA [5U01FD001418] FX This work was supported by the NSF career award (DMR-1255377), ACS Petroleum Research Fund (PRF no. 53461-DNI7), 3M non-tenured faculty award, startup funds from the University of Maryland. The authors also gratefully acknowledge the support of the Joint Institute for Food Safety and Nutrition, University of Maryland, College Park, MD through a cooperative agreement funded by FDA, Grant No. 5U01FD001418 (Yi Liu). This article is not an official U.S. FDA guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 104 TC 8 Z9 8 U1 9 U2 96 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1022-1336 EI 1521-3927 J9 MACROMOL RAPID COMM JI Macromol. Rapid Commun. PD APR PY 2015 VL 36 IS 8 BP 711 EP 725 DI 10.1002/marc.201400661 PG 15 WC Polymer Science SC Polymer Science GA CH7MP UT WOS:000354221000001 PM 25684551 ER PT J AU Chango, A Pogribny, IP AF Chango, Abalo Pogribny, Igor P. TI Considering Maternal Dietary Modulators for Epigenetic Regulation and Programming of the Fetal Epigenome SO NUTRIENTS LA English DT Review ID METHYL-DEFICIENT DIET; EMBRYONIC STEM-CELLS; HIGH-FAT DIET; DNA METHYLATION; RETINOIC ACID; GENE-EXPRESSION; CANCER CHEMOPREVENTION; HISTONE MODIFICATIONS; PROSTATE-CANCER; HUMAN-DISEASE AB Fetal life is characterized by a tremendous plasticity and ability to respond to various environmental and lifestyle factors, including maternal nutrition. Identification of the role of dietary factors that can modulate and reshape the cellular epigenome during development, including methyl group donors (e.g., folate, choline) and bioactive compounds (e.g., polyphenols) is of great importance; however, there is insufficient knowledge of a particular effect of each type of modulator and/or their combination on fetal life. To enhance the quality and safety of food products for proper fetal health and disease prevention in later life, a better understanding of the underlying mechanisms of dietary epigenetic modulators during the critical prenatal period is necessary. This review focuses on the influence of maternal dietary components on DNA methylation, histone modification, and microRNAs, and summarizes current knowledge of the effect and importance of dietary components on epigenetic mechanisms that control the proper expression of genetic information. Evidence reveals that some components in the maternal diet can directly or indirectly affect epigenetic mechanisms. Understanding the underlying mechanisms of how early-life nutritional environment affects the epigenome during development is of great importance for the successful prevention of adult chronic diseases through optimal maternal nutrition. C1 [Chango, Abalo] Polytech Inst LaSalle Beauvais, Dept Nutr & Hlth Sci, EGEAL UP 2012 10 101, F-60026 Beauvais, France. [Pogribny, Igor P.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Chango, A (reprint author), Polytech Inst LaSalle Beauvais, Dept Nutr & Hlth Sci, EGEAL UP 2012 10 101, F-60026 Beauvais, France. EM abalo.chango@lasalle-beauvais.fr; igor.pogribny@fda.hhs.gov NR 144 TC 14 Z9 15 U1 5 U2 22 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD APR PY 2015 VL 7 IS 4 BP 2748 EP 2770 DI 10.3390/nu7042748 PG 23 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CH0KY UT WOS:000353709800040 PM 25875118 ER PT J AU Plant, EP Ye, ZP AF Plant, Ewan P. Ye, Zhiping TI Chimeric neuraminidase and mutant PB1 gene constellation improves growth and yield of H5N1 vaccine candidate virus SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID INFLUENZA-A-VIRUS; HEMAGGLUTININ CONTENT; REASSORTANTS; GLYCOSYLATION; REPLICATION; SEGMENTS; SYSTEM AB We previously showed that a mutated PB1 gene improved the growth kinetics of a H3N2 influenza reassortant. Here, we showed that the same mutations improved the growth kinetics of a virus containing the A/Vietnam/1203/2004 (H5N1) haemagglutinin and neuraminidase (NA). Total protein yield and NA activity were increased when a chimeric NA was included. These increases indicated that the synergistic effect was due to the gene constellation containing both the altered PB1 gene and the chimeric NA gene. C1 [Plant, Ewan P.; Ye, Zhiping] US FDA, Lab Resp Viral Dis, Div Viral Prod, Off Vaccine Res & Review, Silver Spring, MD 20993 USA. RP Plant, EP (reprint author), US FDA, Lab Resp Viral Dis, Div Viral Prod, Off Vaccine Res & Review, Silver Spring, MD 20993 USA. OI Plant, Ewan/0000-0003-0166-5939 FU Biomedical Advanced Research and Development Authority, Department of Health and Human Services FX We would like to thank ViroCyt personnel for providing technical assistance with the Virus Counter, and Laura Couzens and Maryna Eichelberger for assistance and reagents for the NA assay. This work was supported in part by the Biomedical Advanced Research and Development Authority, Department of Health and Human Services. NR 22 TC 2 Z9 2 U1 1 U2 4 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2015 VL 96 BP 752 EP 755 DI 10.1099/jgv.0.000025 PN 4 PG 4 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA CG9CE UT WOS:000353611200003 PM 25502649 ER PT J AU Materniak, M Kubis, P Rola-Luszczak, M Khan, AS Buseyne, F Lindemann, D Lochelt, M Kuzmak, J AF Materniak, Magdalena Kubis, Piotr Rola-Luszczak, Marzena Khan, Arifa S. Buseyne, Florence Lindemann, Dirk Loechelt, Martin Kuzmak, Jacek TI Tenth International Foamy Virus Conference 2014-Achievements and Perspectives SO VIRUSES-BASEL LA English DT Article ID IDENTIFICATION; RETROVIRUSES; HUMANS; TRANSMISSION; APOBEC3; VECTOR AB For the past two decades, scientists from around the world, working on different aspects of foamy virus (FV) research, have gathered in different research institutions almost every two years to present their recent results in formal talks, to discuss their ongoing studies informally, and to initiate fruitful collaborations. In this report we review the 2014 anniversary conference to share the meeting summary with the virology community and hope to arouse interest by other researchers to join this exciting field. The topics covered included epidemiology, virus molecular biology, and immunology of FV infection in non-human primates, cattle, and humans with zoonotic FV infections, as well as recent findings on endogenous FVs. Several topics focused on virus replication and interactions between viral and cellular proteins. Use of FV in biomedical research was highlighted with presentations on using FV vectors for gene therapy and FV proteins as scaffold for vaccine antigen presentation. On behalf of the FV community, this report also includes a short tribute to commemorate Prof. Axel Rethwilm, one of the leading experts in the field of retrovirology and foamy viruses, who passed away 29 July 2014. C1 [Materniak, Magdalena; Kubis, Piotr; Rola-Luszczak, Marzena; Kuzmak, Jacek] Natl Inst Vet Res, Dept Biochem, PL-24100 Pulawy, Poland. [Khan, Arifa S.] US FDA, Lab Retroviruses, Div Viral Prod, OVRR,CBER, Silver Spring, MD 20993 USA. [Buseyne, Florence] Inst Pasteur, Unite Epidemiol & Physiopathol Virus Oncogenes, F-75015 Paris, France. [Lindemann, Dirk] Tech Univ Dresden, Inst Virol, Med Fac Carl Gustav Carus, D-01307 Dresden, Germany. [Loechelt, Martin] German Canc Res Ctr, Dept Genome Modificat & Carcinogenesis, D-69121 Heidelberg, Germany. RP Materniak, M (reprint author), Natl Inst Vet Res, Dept Biochem, PL-24100 Pulawy, Poland. EM magdalena.materniak@piwet.pulawy.pl; kubip@piwet.pulawy.pl; mrolka@piwet.pulawy.pl; arifa.khan@fda.hhs.gov; florence.buseyne@pasteur.fr; Dirk.Lindemann@tu-dresden.de; m.loechelt@dkfz.de; jkuzmak@piwet.pulawy.pl NR 28 TC 3 Z9 3 U1 3 U2 5 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD APR PY 2015 VL 7 IS 4 BP 1651 EP 1666 DI 10.3390/v7041651 PG 16 WC Virology SC Virology GA CH0OH UT WOS:000353720400007 PM 25835535 ER PT J AU Juhlin, K Karimi, G Ander, M Camilli, S Dheda, M Har, TS Isahak, R Lee, SJ Vaughan, S Caduff, P Noren, GN AF Juhlin, Kristina Karimi, Ghazaleh Ander, Maria Camilli, Sara Dheda, Mukesh Har, Tan Siew Isahak, Rokiah Lee, Su-Jung Vaughan, Sarah Caduff, Pia Noren, G. Niklas TI Using VigiBase to Identify Substandard Medicines: Detection Capacity and Key Prerequisites SO DRUG SAFETY LA English DT Article ID CONTAMINATED HEPARIN AB Background Substandard medicines, whether the result of intentional manipulation or lack of compliance with good manufacturing practice (GMP) or good distribution practice (GDP), pose a significant potential threat to patient safety. Spontaneous adverse drug reaction reporting systems can contribute to identification of quality problems that cause unwanted and/or harmful effects, and to identification of clusters of lack of efficacy. In 2011, the Uppsala Monitoring Centre (UMC) constructed a novel algorithm to identify reporting patterns suggestive of substandard medicines in spontaneous reporting, and applied it to VigiBase (R), the World Health Organization's global individual case safety report database. The algorithm identified some historical clusters related to substandard products, which were later able to be confirmed in the literature or by contact with national centres (NCs). As relevant and detailed information is often lacking in the VigiBase reports but might be available at the reporting NC, further evaluation of the algorithm was undertaken with involvement from NCs. Objective To evaluate the effectiveness of an algorithm that identifies clusters of potentially substandard medicines, when these are assessed directly at the NC concerned. Methods The algorithm identifies countries and time periods with disproportionately high reporting of product inadequacy. NCs with at least 20 clusters were eligible to participate in the study, and six NCs-those in the Republic of Korea, Malaysia, Singapore, South Africa, the UK and the USA-were selected, taking into account the geographical spread and prevalence of recent clusters. The clusters were systematically assessed at the NCs, following a standardized protocol, and then compiled centrally at the UMC. The clusters were classified as 'confirmed', 'potential' or 'unlikely' substandard products; or as 'confirmed not substandard' when confirmed by an investigation; or as 'indecisive' when the information available did not allow a sound assessment even at the NC. Results The assessment of a total of 147 clusters resulted in 8 confirmed, 12 potential and 51 unlikely substandard products, and a further 19 clusters were confirmed as not substandard. Reflecting the difficulty of evaluating suspected substandard products retrospectively when additional information from the primary reporter, as well as samples, are no longer available, 57 clusters were classified as indecisive. Conclusion While application of the algorithm to VigiBase allowed identification of some substandard medicines, some key prerequisites have been identified that need to be fulfilled at the national level for the algorithm to be useful in practice. Such key factors are fast handling and transfer of incoming reports into VigiBase, detailed information on the product and its distribution channels, the possibility of contacting primary reporters for further information, availability of samples of suspected products and laboratory capacity to analyse suspected products. C1 [Juhlin, Kristina; Karimi, Ghazaleh; Ander, Maria; Caduff, Pia; Noren, G. Niklas] Uppsala Monitoring Ctr, S-75140 Uppsala, Sweden. [Camilli, Sara] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Dheda, Mukesh] Med Regulatory Author, Natl Dept Hlth, Pharmacovigilance Unit, Pretoria, South Africa. [Har, Tan Siew] Hlth Prod Regulat Grp, Vigilance & Compliance Branch, Singapore, Singapore. [Isahak, Rokiah] Minist Hlth, Natl Pharmaceut Control Bur, Petaling Jaya, Malaysia. [Lee, Su-Jung] Minist Food & Drug Safety, Pharmaceut Safety Informat, Cheongwon, South Korea. [Vaughan, Sarah] Med & Healthcare Prod Regulatory Agcy, London, England. [Noren, G. Niklas] Stockholm Univ, Dept Math, S-10691 Stockholm, Sweden. RP Juhlin, K (reprint author), Uppsala Monitoring Ctr, Box 1051, S-75140 Uppsala, Sweden. EM kristina.juhlin@who-umc.org FU Monitoring Medicines Project [223566]; US Food and Drug Administration [1U01FD005031-01] FX Financial support for the algorithm development was provided through the Monitoring Medicines Project (FP7 Grant No. 223566). The empirical evaluation was conducted with financial support from the US Food and Drug Administration (Collaboration and Capacity Building Ensuring Global Product Safety and Quality cooperative Agreement No. 1U01FD005031-01). NR 11 TC 3 Z9 3 U1 0 U2 5 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 APR PY 2015 VL 38 IS 4 BP 373 EP 382 DI 10.1007/s40264-015-0271-2 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA CG5NZ UT WOS:000353340100007 PM 25687792 ER PT J AU Smith, SM Hunsinger, M McKeown, A Parkhurst, M Allen, R Kopko, S Lu, Y Wilson, HD Burke, LB Desjardins, P McDermott, MP Rappaport, BA Turk, DC Dworkin, RH AF Smith, Shannon M. Hunsinger, Matthew McKeown, Andrew Parkhurst, Melissa Allen, Robert Kopko, Stephen Lu, Yun Wilson, Hilary D. Burke, Laurie B. Desjardins, Paul McDermott, Michael P. Rappaport, Bob A. Turk, Dennis C. Dworkin, Robert H. TI Quality of Pain Intensity Assessment Reporting: ACTTION Systematic Review and Recommendations SO JOURNAL OF PAIN LA English DT Review DE Pain intensity; pain measurement; pain research ID CLINICAL-TRIALS; IMMPACT RECOMMENDATIONS; SENSITIVITY; RESPONSES; RATINGS; COMPLEX; SINGLE; SCALES AB Pain intensity assessments are used widely in human pain research, and their transparent reporting is crucial to interpreting study results. In this systematic review, we examined reporting of human pain intensity assessments and related elements (eg, administration frequency, time period assessed, type of pain) in all empirical pain studies with adult participants in 3 major pain journals (ie, European Journal of Pain, Journal of Pain, and Pain) between January 2011 and July 2012. Of the 262 articles identified, close to one-quarter (24%) ambiguously reported the pain intensity assessment. Elements related to the pain intensity assessment were frequently not reported: 31% did not identify the time period participants were asked to rate, 43% failed to report the type of pain intensity rated, and 58% did not report the specific location or pain condition rated. No differences were observed between randomized clinical trials and experimental (eg, studies involving experimental manipulation without random group assignment and blinding) and observational studies in reporting quality. The ability to understand study results, and to compare results between studies, is compromised when pain intensity assessments are not fully reported. Recommendations are presented regarding key details for investigators to consider when conducting and reporting pain intensity assessments in human adults. Perspective: This systematic review demonstrates that publications of pain research often incompletely report pain intensity assessments and their details (eg, administration frequency, type of pain). Failure to fully report details of pain intensity assessments creates ambiguity in interpreting research results. Recommendations are proposed to increase transparent reporting. (C) 2015 by the American Pain Society C1 [Smith, Shannon M.; McKeown, Andrew; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14642 USA. [Parkhurst, Melissa] Univ Rochester, Sch Med & Dent, Dept Psychiat, Rochester, NY 14642 USA. [McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. [McDermott, Michael P.; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [McDermott, Michael P.; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Ctr Human Expt Therapeut, Rochester, NY 14642 USA. [Hunsinger, Matthew] Univ Pacific, Sch Profess Psychol, Hillsboro, OR USA. [Allen, Robert] Ctr Xion Corp, Baltimore, MD USA. [Kopko, Stephen] Clin Data Interchange Stand Consortium, Austin, TX USA. [Lu, Yun] KAI Res Inc, Rockville, MD USA. [Wilson, Hilary D.] Evidera, Seattle, WA USA. [Burke, Laurie B.] LORA Grp LLC, Royal Oak, MI USA. [Desjardins, Paul] Desjardins Associates, Maplewood, NJ USA. [Rappaport, Bob A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Smith, SM (reprint author), Univ Rochester, Sch Med & Dent, Dept Anesthesiol, 601 Elmwood Ave,Box 604, Rochester, NY 14642 USA. EM shannon1_smith@urmc.rochester.edu FU FDA; ACTTION public-private partnership FX Financial support for this project was provided by the ACTTION public-private partnership, which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. NR 22 TC 5 Z9 5 U1 2 U2 5 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2015 VL 16 IS 4 BP 299 EP 305 DI 10.1016/j.jpain.2015.01.004 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CF7PF UT WOS:000352748100001 PM 25637296 ER PT J AU Moro, PL Jankosky, C Menschik, D Lewis, P Duffy, J Stewart, B Shimabukuro, TT AF Moro, Pedro L. Jankosky, Christopher Menschik, David Lewis, Paige Duffy, Jonathan Stewart, Brock Shimabukuro, Tom T. TI Adverse Events following Haemophilus influenzae Type b Vaccines in the Vaccine Adverse Event Reporting System, 1990-2013 SO JOURNAL OF PEDIATRICS LA English DT Article ID INFANT-DEATH-SYNDROME; IMMUNIZATION SAFETY DATA; CONJUGATE VACCINE; UNITED-STATES; ACELLULAR PERTUSSIS; FEBRILE SEIZURES; CASE-DEFINITION; RISK; IMMUNOGENICITY; TETANUS AB Objective To characterize adverse events (AEs) after Haemophilus influenzae type b (Hib) vaccines reported to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system. Study design We searched VAERS for US reports after Hib vaccines among reports received from January 1, 1990, to December 1, 2013. We reviewed a random sample of reports and accompanying medical records for reports classified as serious. All reports of death were reviewed. Physicians assigned a primary clinical category to each reviewed report. We used empirical Bayesian data mining to identify AEs that were disproportionally reported after Hib vaccines. Results VAERS received 29 747 reports after Hib vaccines; 5179 (17%) were serious, including 896 reports of deaths. Median age was 6 months (range 0-1022 months). Sudden infant death syndrome was the stated cause of death in 384 (51%) of 749 death reports with autopsy/death certificate records. The most common nondeath serious AE categories were neurologic (80; 37%), other noninfectious (46; 22%) (comprising mainly constitutional signs and symptoms); and gastrointestinal (39; 18%) conditions. No new safety concerns were identified after clinical review of reports of AEs that exceeded the data mining statistical threshold. Conclusion Review of VAERS reports did not identify any new or unexpected safety concerns for Hib vaccines. C1 [Moro, Pedro L.; Lewis, Paige; Duffy, Jonathan; Stewart, Brock; Shimabukuro, Tom T.] Ctr Dis Control & Prevent, Immunizat Safety Off, Atlanta, GA 30333 USA. [Jankosky, Christopher; Menschik, David] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Moro, PL (reprint author), Ctr Dis Control & Prevent, Immunizat Safety Off, Div Healthcare Qual Promot, 1600 Clifton Rd,MS D26, Atlanta, GA 30333 USA. EM pmoro@cdc.gov FU Centers for Disease Control and Prevention (CDC); Food and Drug Administration (FDA) FX Funded by the Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC or the FDA. The authors declare no conflicts of interest. NR 34 TC 4 Z9 4 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2015 VL 166 IS 4 BP 992 EP 997 DI 10.1016/j.jpeds.2014.12.014 PG 6 WC Pediatrics SC Pediatrics GA CG6DL UT WOS:000353385700039 PM 25598306 ER PT J AU Halachmi, S Felten, R Silverman, PM Kosoglu, M Ogden, N Nipper, J Luke, MC AF Halachmi, Shlomit Felten, Richard Silverman, Phyllis M. Kosoglu, Mehmet Ogden, Neil Nipper, Joshua Luke, Markham C. TI MEDICAL DEVICES AND CLINICAL TRIAL DESIGN FOR THE TREATMENT OR IMPROVEMENT IN THE APPEARANCE OF FUNGALLY-INFECTED NAILS SO LASERS IN SURGERY AND MEDICINE LA English DT Meeting Abstract C1 [Halachmi, Shlomit; Felten, Richard; Silverman, Phyllis M.; Kosoglu, Mehmet; Ogden, Neil; Nipper, Joshua; Luke, Markham C.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD APR PY 2015 VL 47 IS 4 MA LB12 BP 377 EP 377 PG 1 WC Dermatology; Surgery SC Dermatology; Surgery GA CG4DN UT WOS:000353233100023 ER PT J AU de Conti, A Kobets, T Tryndyak, V Burnett, SD Han, T Fuscoe, JC Beland, FA Doerge, DR Pogribny, IP AF de Conti, Aline Kobets, Tetyana Tryndyak, Volodymyr Burnett, Sarah D. Han, Tao Fuscoe, James C. Beland, Frederick A. Doerge, Daniel R. Pogribny, Igor P. TI Persistence of Furan-Induced Epigenetic Aberrations in the Livers of F344 Rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE microarrays; gene expression profiling; genetic toxicology; liver carcinogenesis ID DIETARY METHYL DEFICIENCY; FEMALE B6C3F1 MICE; DNA-REPAIR GENES; CELL-PROLIFERATION; CARCINOGEN FURAN; HISTONE MODIFICATIONS; COLORECTAL-CANCER; GLOBAL DNA; IN-VIVO; EXPRESSION AB Furan is a heterocyclic organic compound produced in the chemical manufacturing industry and also found in a broad range of food products, including infant formulas and baby foods. Previous reports have indicated that the adverse biological effects of furan, including its liver tumorigenicity, may be associated with epigenetic abnormalities. In the present study, we investigated the persistence of epigenetic alterations in rat liver. Male F344 rats were treated by gavage 5 days per week with 8 mg furan/kg body weight (bw)/day for 90 days. After the last treatment, rats were divided randomly into 4 groups; 1 group of rats was sacrificed 24 h after the last treatment, whereas other groups were maintained without further furan treatment for an additional 90, 180, or 360 days. Treatment with furan for 90 days resulted in alterations in histone lysine methylation and acetylation, induction of base-excision DNA repair genes, suggesting oxidative damage to DNA, and changes in the gene expression in the livers. A majority of these furan-induced molecular changes was transient and disappeared after the cessation of furan treatment. In contrast, histone H3 lysine 9 and H3 lysine 56 showed a sustained and time-depended decrease in acetylation, which was associated with formation of heterochromatin and altered gene expression. These results indicate that furan-induced adverse effects may be mechanistically related to sustained changes in histone lysine acetylation that compromise the ability of cells to maintain and control properly the expression of genetic information. C1 [de Conti, Aline; Kobets, Tetyana; Tryndyak, Volodymyr; Burnett, Sarah D.; Beland, Frederick A.; Doerge, Daniel R.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Han, Tao; Fuscoe, James C.] Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov FU National Toxicology Program (NTP); FDA ((FDA IAG) [224-12-0003]; NIEHS (NIEHS IAG) [AES12013] FX This work was carried out under the auspices of the National Toxicology Program (NTP) and supported by an Interagency Agreement between FDA and NIEHS (FDA IAG No. 224-12-0003/NIEHS IAG No. AES12013). NR 48 TC 8 Z9 8 U1 1 U2 20 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 2015 VL 144 IS 2 BP 217 EP 226 DI 10.1093/toxsci/kfu313 PG 10 WC Toxicology SC Toxicology GA CG8FT UT WOS:000353543400003 PM 25539665 ER PT J AU Malinauskas, RA Saha, A Sheldon, MI AF Malinauskas, Richard A. Saha, Anindita Sheldon, Murray I. TI Working With the Food and Drug Administration's Center for Devices to Advance Regulatory Science and Medical Device Innovation SO ARTIFICIAL ORGANS LA English DT Editorial Material C1 [Malinauskas, Richard A.] US FDA, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Saha, Anindita; Sheldon, Murray I.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Malinauskas, RA (reprint author), US FDA, Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM richard.malinauskas@fda.hhs.gov; anindita.saha@fda.hhs.gov; murray.sheldon@fda.hhs.gov NR 14 TC 1 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-564X EI 1525-1594 J9 ARTIF ORGANS JI Artif. Organs PD APR PY 2015 VL 39 IS 4 BP 293 EP 299 DI 10.1111/aor.12505 PG 7 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA CF5EV UT WOS:000352580300001 PM 25850595 ER PT J AU Calvert, R Vohra, S Ferguson, M Wiesenfeld, P AF Calvert, Richard Vohra, Sanah Ferguson, Martine Wiesenfeld, Paddy TI A beating heart cell model to predict cardiotoxicity: Effects of the dietary supplement ingredients higenamine, phenylethylamine, ephedrine and caffeine SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE iCell cardiomyocytes; Ephedrine; Caffeine; Higenamine; Phenylethylamine; Cardiac effects ID BETA-PHENYLETHYLAMINE; DOUBLE-BLIND; CHRONOTROPIC RESPONSES; HEALTHY-VOLUNTEERS; ISOLATED ATRIA; RAT; PLACEBO; PHARMACOKINETICS; MECHANISMS; AMINES AB Some dietary supplements may contain cardiac stimulants and potential cardiotoxins. In vitro studies may identify ingredients of concern. A beating human cardiomyocyte cell line was used to evaluate cellular effects following phenylethylamine (PEA), higenamine, ephedrine or caffeine treatment. PEA and higenamine exposure levels simulated published blood levels in humans or animals after intravenous administration. Ephedrine and caffeine levels approximated published blood levels following human oral intake. At low or midrange levels, each chemical was examined plus or minus 501.mu M caffeine, simulating human blood levels reported after consumption of caffeine-enriched dietary supplements. To measure beats per minute (BPM), peak width, etc., rhythmic rise and fall in intracellular calcium levels following 30 min of treatment was examined. Higenamine 31.3 ng/ml or 313 ng/ml significantly increased BPM in an escalating manner. PEA increased BPM at 0.8 and 8 mu g/ml, while 80 mu g/mIPEA reduced BPM and widened peaks. Ephedrine produced a significant BPM dose response from 0.5 to 5.0 mu M. Caffeine increased BPM only at a toxic level of 250 mu M. Adding caffeine to PEA or higenamine but not ephedrine further increased BPM. These in vitro results suggest that additional testing may be warranted in vivo to further evaluate these effects. Published by Elsevier Ltd. C1 [Calvert, Richard; Vohra, Sanah; Wiesenfeld, Paddy] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol, Laurel, MD 20708 USA. [Ferguson, Martine] US FDA, Ctr Food Safety & Appl Nutr, Off Management, Div Math, College Pk, MD 20740 USA. RP Calvert, R (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM richard.calvert@fda.hhs.gov FU U.S. Food and Drug Administration FX The authors wish to thank Dr. Liang Guo (Frederick National Laboratory for Cancer Research) for his extremely valuable advice on optimal growth conditions for the iCell cardiomyocytes. This study was funded by the U.S. Food and Drug Administration. NR 38 TC 1 Z9 2 U1 1 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 APR PY 2015 VL 78 BP 207 EP 213 DI 10.1016/j.fct.2015.01.022 PG 7 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CF6JQ UT WOS:000352663400025 PM 25684415 ER PT J AU Tegenge, MA Mitkus, RJ AF Tegenge, Million A. Mitkus, Robert J. TI A first-generation physiologically based pharmacokinetic (PBPK) model of alpha-tocopherol in human influenza vaccine adjuvant SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Alpha-tocopherol; Emulsion; Vaccines; Adjuvants; AS03 (R) ID OMEGA-HYDROXYLASE PATHWAY; LOW-DENSITY-LIPOPROTEIN; HUMAN ADIPOSE-TISSUE; IN-WATER EMULSION; VITAMIN-E; INTRAMUSCULAR INJECTION; BLOOD-FLOW; INTESTINAL-ABSORPTION; PLASMA-LIPOPROTEINS; AFFERENT LYMPH AB Alpha (alpha)-tocopherol is a component of a new generation of squalene-containing oil-in-water (SQ/W) emulsion adjuvants that have been licensed for use in certain influenza vaccines. Since regulatory pharmacokinetic studies are not routinely required for influenza vaccines, the in vivo fate of this vaccine constituent is largely unknown. In this study, we constructed a physiologically based pharmacokinetic (PBPK) model for emulsified alpha-tocopherol in human adults and infants. An independent sheep PBPK model was also developed to inform the local preferential lymphatic transfer and for the purpose of model evaluation. The PBPK model predicts that alpha-tocopherol will be removed from the injection site within 24 h and rapidly transfer predominantly into draining lymph nodes. A much lower concentration of alpha-tocopherol was estimated to peak in plasma within 8 h. Any systemically absorbed alpha-tocopherol was predicted to accumulate slowly in adipose tissue, but not in other tissues. Model evaluation and uncertainty analyses indicated acceptable fit, with the fraction of dose taken up into the lymphatics as most influential on plasma concentration. In summary, this study estimates the in vivo fate of alpha-tocopherol in adjuvanted influenza vaccine, may be relevant in explaining its immunodynamics in humans, and informs current regulatory risk-benefit analyses. Published by Elsevier Inc. C1 [Tegenge, Million A.; Mitkus, Robert J.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Tegenge, MA (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM million.tegenge@fda.hhs.gov NR 71 TC 1 Z9 1 U1 2 U2 12 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 2015 VL 71 IS 3 BP 353 EP 364 DI 10.1016/j.yrtph.2015.02.005 PG 12 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CF8PG UT WOS:000352823800001 PM 25683773 ER PT J AU Saber, H Leighton, JK AF Saber, Haleh Leighton, John K. TI An FDA oncology analysis of antibody-drug conjugates SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Antibody-drug conjugates; First-in-human start dose selection; Oncology drug development ID ANTICANCER DRUGS; GEMTUZUMAB OZOGAMICIN; TRASTUZUMAB EMTANSINE; CANCER AB Antibody-drug conjugates (ADCs) are complex molecules composed of monoclonal antibodies conjugated to potent cytotoxic agents through chemical linkers. Because of this complexity, sponsors have used different approaches for the design of nonclinical studies to support the safety evaluation of ADCs and first-in-human (FIH) dose selection. We analyzed this data with the goal of describing the relationship between nonclinical study results and Phase 1 study outcomes. We summarized the following data from investigational new drug applications (INDs) for ADCs: plasma stability, animal study designs and toxicities, and algorithms used for FIH dose selection. Our review found that selecting a FIH dose that is 1/6th the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys or 1/10th the STD10 in rodents scaled according to body surface area (BSA) generally resulted in the acceptable balance of safety and efficient dose-escalation in a Phase 1 trial. Other approaches may also be acceptable, e.g. 1/10th the HNSTD in monkeys using BSA or 1/10th the NOAEL in monkeys or rodents using body weight for scaling. While the animal data for the vc-MMAE platform yielded variable range of HNSTDs in cynomolgus monkeys, MTDs were in a narrow range in patients, suggesting that for ADCs sharing the same small molecule drug, linker and drug:antibody ratio, prior clinical data can inform the design of a Phase 1 clinical trial. Published by Elsevier Inc. C1 [Saber, Haleh; Leighton, John K.] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Silver Spring, MD 20903 USA. RP Leighton, JK (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM john.leighton@fda.hhs.gov NR 16 TC 20 Z9 21 U1 1 U2 10 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 2015 VL 71 IS 3 BP 444 EP 452 DI 10.1016/j.yrtph.2015.01.014 PG 9 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CF8PG UT WOS:000352823800010 PM 25661711 ER PT J AU Scully, CG Forrest, S Galeotti, L Schwartz, SB Strauss, DG AF Scully, Christopher G. Forrest, Shawn Galeotti, Loriano Schwartz, Suzanne B. Strauss, David G. TI Advancing Regulatory Science to Bring Novel Medical Devices for Use in Emergency Care to Market: The Role of the Food and Drug Administration SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID BUNDLE-BRANCH BLOCK; CRITERIA; STRICT AB The Food and Drug Administration (FDA) performs regulatory science to provide science-based medical product regulatory decisions. This article describes the types of scientific research the FDA's Center for Devices and Radiological Health performs and highlights specific projects related to medical devices for emergency medicine. In addition, this article discusses how results from regulatory science are used by the FDA to support the regulatory process as well as how the results are communicated to the public. Regulatory science supports the FDA's mission to assure safe, effective, and high-quality medical products are available to patients. C1 [Scully, Christopher G.; Galeotti, Loriano; Strauss, David G.] Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Forrest, Shawn] Off Device Evaluat, Silver Spring, MD USA. [Schwartz, Suzanne B.] Food & Drug Adm, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Strauss, DG (reprint author), Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov FU Food and Drug Administration's Medical Countermeasures Initiative; Research Participation Program at the Center for Devices and Radiological Health 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 work was supported in part by the Food and Drug Administration's Medical Countermeasures Initiative and appointments to the Research Participation Program at the Center for Devices and Radiological Health, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the Food and Drug Administration. NR 18 TC 2 Z9 2 U1 1 U2 8 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 2015 VL 65 IS 4 BP 400 EP 403 DI 10.1016/j.annemergmed.2014.07.008 PG 4 WC Emergency Medicine SC Emergency Medicine GA CE9RN UT WOS:000352181200011 PM 25128009 ER PT J AU Herbst, RS Gandara, DR Hirsch, FR Redman, MW LeBlanc, M Mack, PC Schwartz, LH Vokes, E Ramalingam, SS Bradley, JD Sparks, D Zhou, Y Miwa, C Miller, VA Yelensky, R Li, YL Allen, JD Sigal, EV Wholley, D Sigman, CC Blumenthal, GM Malik, S Kelloff, GJ Abrams, JS Blanke, CD Papadimitrakopoulou, VA AF Herbst, Roy S. Gandara, David R. Hirsch, Fred R. Redman, Mary W. LeBlanc, Michael Mack, Philip C. Schwartz, Lawrence H. Vokes, Everett Ramalingam, Suresh S. Bradley, Jeffrey D. Sparks, Dana Zhou, Yang Miwa, Crystal Miller, Vincent A. Yelensky, Roman Li, Yali Allen, Jeff D. Sigal, Ellen V. Wholley, David Sigman, Caroline C. Blumenthal, Gideon M. Malik, Shakun Kelloff, Gary J. Abrams, Jeffrey S. Blanke, Charles D. Papadimitrakopoulou, Vassiliki A. TI Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400 SO CLINICAL CANCER RESEARCH LA English DT Article ID CLINICAL-TRIALS; SELECTIVE INHIBITOR; ANTITUMOR-ACTIVITY; BREAST-CANCER; IN-VIVO; ONCOLOGY; GENOMICS; ALECTINIB; AZD4547; DESIGN AB The Lung Master Protocol (Lung-MAP, S1400) is a ground-breaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of these changes is low (5%-20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here, we describe our approach to development of a biomarker-driven phase II/II multisubstudy "Master Protocol," using a common platform(next-generation DNA sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care. (C) 2015 AACR. C1 [Herbst, Roy S.; Zhou, Yang] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. [Gandara, David R.; Mack, Philip C.] Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. [Hirsch, Fred R.] Univ Colorado, Dept Med Oncol, Hlth Sci Ctr, Aurora, CO USA. [Redman, Mary W.; LeBlanc, Michael] SWOG Stat Ctr, Seattle, WA USA. [Redman, Mary W.; LeBlanc, Michael] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Schwartz, Lawrence H.] Columbia Univ, Dept Radiol, Coll Med, New York, NY USA. [Vokes, Everett] Univ Chicago Med & Biol Sci, Dept Med, Chicago, IL USA. [Ramalingam, Suresh S.] Emory Univ, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Bradley, Jeffrey D.] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO USA. [Sparks, Dana; Miwa, Crystal] SWOG Operat Off, San Antonio, TX USA. [Miller, Vincent A.; Yelensky, Roman; Li, Yali] Fdn Med, Cambridge, MA USA. [Allen, Jeff D.; Sigal, Ellen V.] Friends Canc Res, Washington, DC USA. [Wholley, David] Fdn Natl Inst Hlth, Bethesda, MD USA. [Sigman, Caroline C.] CCS Associates, Mountain View, CA USA. [Blumenthal, Gideon M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Malik, Shakun] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Kelloff, Gary J.] NCI, Canc Imaging Program, Bethesda, MD 20892 USA. [Abrams, Jeffrey S.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Blanke, Charles D.] SWOG Grp Chairs Office, Portland, OR USA. [Blanke, Charles D.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Papadimitrakopoulou, Vassiliki A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Herbst, RS (reprint author), Yale Univ, Sch Med, Yale Canc Ctr, POB 208028, New Haven, CT 06520 USA. EM roy.herbst@yale.edu FU NCI of the NIH [U10CA180888, U10CA180819, R01CA155196]; Amgen; AstraZeneca; Genentech; Pfizer, through the Foundation for the National Institutes of Health FX This work was supported in part by the NCI of the NIH under award numbers U10CA180888 (to SWOG), U10CA180819 (to SWOG), and R01CA155196 (to R.S. Herbst) and by Amgen, AstraZeneca, Genentech, and Pfizer, through the Foundation for the National Institutes of Health and in partnership with Friends of Cancer Research. NR 42 TC 41 Z9 42 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2015 VL 21 IS 7 BP 1514 EP 1524 DI 10.1158/1078-0432.CCR-13-3473 PG 11 WC Oncology SC Oncology GA CE8FI UT WOS:000352076700004 PM 25680375 ER PT J AU Miller, BW Przepiorka, D de Claro, RA Lee, K Nie, L Simpson, N Gudi, R Saber, H Shord, S Bullock, J Marathe, D Mehrotra, N Hsieh, LS Ghosh, D Brown, J Kane, RC Justice, R Kaminskas, E Farrell, AT Pazdur, R AF Miller, Barry W. Przepiorka, Donna de Claro, R. Angelo Lee, Kyung Nie, Lei Simpson, Natalie Gudi, Ramadevi Saber, Haleh Shord, Stacy Bullock, Julie Marathe, Dhananjay Mehrotra, Nitin Hsieh, Li Shan Ghosh, Debasis Brown, Janice Kane, Robert C. Justice, Robert Kaminskas, Edvardas Farrell, Ann T. Pazdur, Richard TI FDA Approval: Idelalisib Monotherapy for the Treatment of Patients with Follicular Lymphoma and Small Lymphocytic Lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article ID INDOLENT LYMPHOMA; THERAPY AB On July 23, 2014, the FDA granted accelerated approval to idelalisib (Zydelig tablets; Gilead Sciences, Inc.) for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies. In a multicenter, single-arm trial, 123 patients with relapsed indolent non-Hodgkin lymphomas received idelalisib, 150 mg orally twice daily. In patients with follicular lymphoma, the overall response rate (ORR) was 54%, and the median duration of response (DOR) was not evaluable; median follow-up was 8.1 months. In patients with SLL, the ORR was 58% and the median DOR was 11.9 months. One-half of patients experienced a serious adverse reaction of pneumonia, pyrexia, sepsis, febrile neutropenia, diarrhea, or pneumonitis. Other common adverse reactions were abdominal pain, nausea, fatigue, cough, dyspnea, and rash. Common treatment-emergent laboratory abnormalities were elevations in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, absolute lymphocytes, and triglycerides. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials. (C) 2015 AACR. C1 [Miller, Barry W.; Przepiorka, Donna; de Claro, R. Angelo; Simpson, Natalie; Gudi, Ramadevi; Saber, Haleh; Kane, Robert C.; Justice, Robert; Kaminskas, Edvardas; Farrell, Ann T.; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. [Lee, Kyung; Nie, Lei] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD 20993 USA. [Shord, Stacy; Bullock, Julie; Marathe, Dhananjay; Mehrotra, Nitin] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD 20993 USA. [Hsieh, Li Shan; Ghosh, Debasis; Brown, Janice] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Sci, Silver Spring, MD 20993 USA. RP Miller, BW (reprint author), US FDA, Div Hematol Prod, WO22-2114,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Barry.Millerr@fda.hhs.gov NR 16 TC 18 Z9 18 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 APR 1 PY 2015 VL 21 IS 7 BP 1525 EP 1529 DI 10.1158/1078-0432.CCR-14-2522 PG 5 WC Oncology SC Oncology GA CE8FI UT WOS:000352076700005 PM 25645861 ER PT J AU Wang, T Xiao, M Ge, YB Krepler, C Belser, E Lopez-Coral, A Xu, XW Zhang, G Azumas, R Liu, Q Liu, R Li, L Amaravadi, RK Xu, W Karakousis, G Gangadhar, TC Schuchter, LM Lieu, M Khare, S Halloran, MB Herlyn, M Kaufman, RE AF Wang, Tao Xiao, Min Ge, Yingbin Krepler, Clemens Belser, Eric Lopez-Coral, Alfonso Xu, Xiaowei Zhang, Gao Azumas, Rikka Liu, Qin Liu, Rui Li, Ling Amaravadi, Ravi K. Xu, Wei Karakousis, Giorgos Gangadhar, Tara C. Schuchter, Lynn M. Lieu, Melissa Khare, Sanika Halloran, Molly B. Herlyn, Meenhard Kaufman, Russel E. TI BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN-MALIGNANT MELANOMA; RAF INHIBITORS; IN-VIVO; MAPK PATHWAY; TNF-ALPHA; RESISTANCE; KINASE; CELLS; ANGIOGENESIS; RECEPTOR AB Purpose: To investigate the roles of melanoma-associated macrophages in melanoma resistance to BRAF inhibitors (BRAFi). Experimental Design: An in vitro macrophage and melanoma cell coculture system was used to investigate whether macrophages play a role in melanoma resistance to BRAFi. The effects of macrophages in tumor resistance were examined by proliferation assay, cell death assay, and Western blot analyses. Furthermore, two mouse preclinical models were used to validate whether targeting macrophages can increase the antitumor activity of BRAFi. Finally, the number of macrophages in melanoma tissues was examined by immunohistochemistry. Results: We demonstrate that in BRAF-mutant melanomas, BRAFi paradoxically activate the mitogen-activated protein kinase (MAPK) pathway in macrophages to produce VEGF, which reactivates the MAPK pathway and stimulates cell growth in melanoma cells. Blocking the MAPK pathway or VEGF signaling then reverses macrophage-mediated resistance. Targeting macrophages increases the antitumor activity of BRAFi in mouse and human tumor models. The presence of macrophages in melanomas predicts early relapse after therapy. Conclusions: Our findings demonstrate that macrophages play a critical role in melanoma resistance to BRAFi, suggesting that targeting macrophages will benefit patients with BRAF-mutant melanoma. (C)2015 AACR. C1 [Wang, Tao; Xiao, Min; Krepler, Clemens; Belser, Eric; Zhang, Gao; Liu, Qin; Li, Ling; Halloran, Molly B.; Herlyn, Meenhard; Kaufman, Russel E.] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, Philadelphia, PA 19104 USA. [Ge, Yingbin] Nanjing Med Univ, Dept Physiol, Nanjing, Jiangsu, Peoples R China. [Lopez-Coral, Alfonso] Catholic Univ Amer, Grad Program, Washington, DC 20064 USA. [Xu, Xiaowei] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Azumas, Rikka; Liu, Rui] Univ Penn, Undergrad Program, Philadelphia, PA 19104 USA. [Amaravadi, Ravi K.; Gangadhar, Tara C.; Schuchter, Lynn M.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Amaravadi, Ravi K.; Xu, Wei; Karakousis, Giorgos; Gangadhar, Tara C.; Schuchter, Lynn M.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Karakousis, Giorgos] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Lieu, Melissa] Univ Sci, Undergrad Program, Philadelphia, PA USA. [Khare, Sanika] Univ Penn, Biotechnol Sch Engn & Appl Sci, Philadelphia, PA 19104 USA. RP Wang, T (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 72-Room 2329, Silver Spring, MD 20903 USA. EM tao.wang@fda.hhs.gov; HerlynM@wistar.org; kaufman@wistar.org RI Zhang, Gao/D-3471-2017 FU National Institutes of Health [5P30CA 010815-42, CA047159, CA025874, CA114046, CA076674, CA098101]; Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health; Wistar Institute Intramural grants FX This work was supported by grants from the National Institutes of Health (5P30CA 010815-42) and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health (R.E. Kaufman and T. Wang), The Wistar Institute Intramural grants for R.E. Kaufman and T. Wang, and National Institutes of Health grants for M. Herlyn and T. Wang (CA047159, CA025874, CA114046, CA076674, and CA098101). NR 61 TC 17 Z9 18 U1 4 U2 14 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 2015 VL 21 IS 7 BP 1652 EP 1664 DI 10.1158/1078-0432.CCR-14-1554 PG 13 WC Oncology SC Oncology GA CE8FI UT WOS:000352076700020 PM 25617424 ER PT J AU Yang, XJ Belosay, A Hartman, JA Song, HX Zhang, YK Wang, WD Doerge, DR Helferich, WG AF Yang, Xujuan Belosay, Aashvini Hartman, James A. Song, Huaxin Zhang, Yukun Wang, Wendan Doerge, Daniel R. Helferich, William G. TI Dietary soy isoflavones increase metastasis to lungs in an experimental model of breast cancer with bone micro-tumors SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE Dietary soy isoflavones; Breast cancer; Bone micro-metastasis; Lung metastasis ID IN-VITRO; MCF-7 TUMORS; STAGE-I; GENISTEIN; CELLS; CARCINOMA; METABOLISM; LIGNANS; MARROW; HEALTH AB Bone is one of the most common sites for metastasis in breast cancer (BC). Micro-metastasis in bone marrow was detected in 30 % of patients with stage I, II, or III BC at primary surgery and is a strong indicator of poor prognosis. The role dietary soy isoflavones play in BC with bone micro-metastasis is unclear. In this study, we examined the effects of genistein, daidzein, (-)-equol or a mixture of soy isoflavones on BC with bone micro-metastasis using an experimental model of murine mammary cancer 4T1 cells engineered with luciferase. A small number (1000) of 4T1 cells were injected into the tibia of female Balb/c mice to establish micro-tumors in bone. Soy isoflavones were supplemented in the AIN-93G diet at 750 mg/kg and were provided to mice from 3 weeks before to 3 weeks after cell injection. Bioluminescent imaging was conducted on day 2 (D2), D6, D8, D16 and D20 post cell injection and the results indicated dietary soy isoflavones enhanced the growth of bone micro-tumors on D8. Furthermore, dietary soy isoflavones stimulated metastatic tumor formation in lungs and increased Ki-67 protein expression in these metastasized tumors. In vitro, soy isoflavones (< 10 mu M) had limited effects on the growth, motility or invasion of 4T1 cells. Thus, the in vivo stimulatory effect could be likely due to systemic effects between the host, 4T1 tumors and soy isoflavones. In conclusion, soy isoflavones stimulate BC with bone micro-metastasis in mice and further investigations are needed regarding their consumption by BC survivors. C1 [Yang, Xujuan; Belosay, Aashvini; Hartman, James A.; Zhang, Yukun; Wang, Wendan; Helferich, William G.] Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61801 USA. [Song, Huaxin] Texas Tech Univ, Sch Nursing, Hlth Sci Ctr, Lubbock, TX USA. [Doerge, Daniel R.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Helferich, WG (reprint author), Univ Illinois, Dept Food Sci & Human Nutr, 580 Bevier Hall,905 S Goodwin Ave, Urbana, IL 61801 USA. EM helferic@illinois.edu FU National Cancer Institute from the National Center for Complementary and Alternative Medicines (NCCAM) [CA77355, P50AT006268] FX This project was made possible by the National Cancer Institute Grant Number [CA77355] and [P50AT006268] to (WGH) from the National Center for Complementary and Alternative Medicines (NCCAM), 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 NCCAM, ODS, NCI or the National Institutes of Health. In addition, the views expressed in this paper do not necessarily reflect those of the U.S. Food and Drug Administration. NR 42 TC 10 Z9 13 U1 2 U2 14 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 APR PY 2015 VL 32 IS 4 BP 323 EP 333 DI 10.1007/s10585-015-9709-2 PG 11 WC Oncology SC Oncology GA CF6BR UT WOS:000352642000003 PM 25749878 ER PT J AU Sanyal, AJ Friedman, SL McCullough, AJ Dimick-Santos, L AF Sanyal, Arun J. Friedman, Scott L. McCullough, Arthur J. Dimick-Santos, Lara TI Challenges and Opportunities in Drug and Biomarker Development for Nonalcoholic Steatohepatitis: Findings and Recommendations From an American Association for the Study of Liver Diseases-US Food and Drug Administration Joint Workshop SO HEPATOLOGY LA English DT Article ID QUALITY-OF-LIFE; VENOUS-PRESSURE GRADIENT; FARNESOID-X-RECEPTOR; POPULATION-BASED COHORT; TERM-FOLLOW-UP; FATTY LIVER; NATURAL-HISTORY; HEPATOCELLULAR-CARCINOMA; HEPATIC-ENCEPHALOPATHY; COMPENSATED CIRRHOSIS AB Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) in North America. It is a growing contributor to the burden of CDL requiring liver transplantation. Cirrhosis is also associated with an increased risk of hepatocellular cancer, which may occur even in the absence of cirrhosis in subjects with nonalcoholic steatohepatitis (NASH), the histological form of NAFLD associated with increased liver-related mortality. The diagnosis of NASH currently requires a liver biopsy. There are also no U.S. Food and Drug Administration (FDA)-approved therapies for NASH. Therefore, there is a need to develop better diagnostic and therapeutic strategies for patients with NASH, targeting both those with early-stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. The long relatively asymptomatic time interval in the progression of NAFLD and NASH to cirrhosis and ultimately liver failure, along with gaps in knowledge regarding disease modifiers, combine to present significant challenges in trial design. Therefore, there is an urgent need to develop methods to identify the populations at particular risk of disease progression and validate endpoints that reflect meaningful changes in health status in this population. This article summarizes the discussion at a joint workshop held September 5 and 6, 2013 in Silver Spring, Maryland, sponsored by the FDA and the American Association for the Study of Liver Diseases to develop guidance on diagnostic and therapeutic modalities for NASH. (Hepatology 2015;61:1392-1405) C1 [Sanyal, Arun J.] Virginia Commonwealth Univ, Sch Med, Dept Internal Med, Div Gastroenterol Hepatol & Nutr, Richmond, VA 23298 USA. [Friedman, Scott L.] Icahn Sch Med Mt Sinai, Div Liver Dis, New York, NY 10029 USA. [McCullough, Arthur J.] Cleveland Clin, Lerner Coll Med, Dept Gastroenterol & Pathobiol, Cleveland, OH 44106 USA. [Dimick-Santos, Lara] US FDA, Silver Spring, MD USA. RP Sanyal, AJ (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Internal Med, Div Gastroenterol Hepatol & Nutr, MCV Box 980341, Richmond, VA 23298 USA. EM asanyal@mcvh-vcu.edu FU U.S. Food and Drug Administration by the American Association for the Study of Liver Diseases FX This work was supported by the U.S. Food and Drug Administration by the American Association for the Study of Liver Diseases. NR 76 TC 51 Z9 52 U1 3 U2 12 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 APR PY 2015 VL 61 IS 4 BP 1392 EP 1405 DI 10.1002/hep.27678 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CE8NM UT WOS:000352099700033 PM 25557690 ER PT J AU Liu, YT Santillo, MF Flynn, TJ Ferguson, MS AF Liu, Yitong Santillo, Michael F. Flynn, Thomas J. Ferguson, Martine S. TI Sex hormone modulation of both induction and inhibition of CYP1A by genistein in HepG2/C3A cells SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Article DE Genistein; CYP1A; Induction; Inhibition Sex hormones ID HEPATOCELLULAR-CARCINOMA; BETA-NAPHTHOFLAVONE; PROSTATE-CANCER; IN-VITRO; BREAST; MECHANISMS; GROWTH; RISK; CYTOCHROME-P450; ISOFLAVONES AB Genistein is a widely consumed phytoestrogen in dietary supplements and has been reported to play roles in both cancer prevention and promotion. These conflicting effects may be complicated by sex differences. Cytochrome P450 1A (CYP1A) participates in carcinogen activation and detoxification, and the enzyme may interact with genistein. Therefore, modulation of CYP1A by a combination of genistein and sex hormones could be responsible for sex differences related to cancer prevention and promotion. In the current study, a human liver cell line, HepG2/C3A, cultured in sex hormone-supplemented media was used to investigate the modulatory effect of genistein on CYP1A gene expression and activity. Genistein exerted both long-term (72 h) induction and short-term (immediate) inhibition of CYP1A activity in HepG2/C3A cells. In the long-term study, CYP1A gene expression and enzyme activity were induced to a greater extent in male hormone-supplemented cells than female ones. In the short-term study, CYP1A activity was inhibited more strongly by genistein in the male hormone-supplemented cells than in the female hormone-supplemented cells. These significant differences suggest that male hormones can modulate the effects of genistein on CYP1A gene expression and activity. C1 [Liu, Yitong; Santillo, Michael F.; Flynn, Thomas J.] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Ferguson, Martine S.] US FDA, Div Publ Hlth Informat & Analyt, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Liu, YT (reprint author), US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 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; Flynn, Thomas/0000-0002-7248-0643 NR 29 TC 0 Z9 0 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-2690 EI 1543-706X J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD APR PY 2015 VL 51 IS 4 BP 426 EP 431 DI 10.1007/s11626-014-9848-9 PG 6 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CF1DA UT WOS:000352282600012 PM 25479735 ER PT J AU Lim, JH Sisco, P Mudalige, TK Sanchez-Pomales, G Howard, PC Linder, SW AF Lim, Jin-Hee Sisco, Patrick Mudalige, Thilak K. Sanchez-Pomales, Germarie Howard, Paul C. Linder, Sean W. TI Detection and Characterization of SiO2 and TiO2 Nanostructures in Dietary Supplements SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE nanotechnology; nanomaterials; silicon dioxide; titanium dioxide; dietary supplements ID FIELD-FLOW-FRACTIONATION; TITANIUM-DIOXIDE NANOPARTICLES; FOOD; SIZE; PARTICLES; PRODUCTS; SILVER; ADULTS AB Nanomaterials are beginning to enter our daily lives through various consumer products as the result of technology commercialization. The development of methodologies to detect the presence of nanomaterials in consumer products is an essential element in understanding our exposure. In this study, we have developed methods for the separation and characterization of silicon dioxide (SiO2) and titanium dioxide (TiO2) nanostructures in dietary supplements marketed in products specifically targeted for women. A total of 12 commercial products claiming the inclusion of SiO2 and TiO2, but not making any claims regarding the particle size, were randomly selected for purchase through various retailers. To isolate nanostructures from these products, a simple methodology that combines acid digestion and centrifugation was utilized. Once isolated, the chemical composition, size, morphology, and crystal structure were characterized using mass spectroscopy, light scattering, electron microscopy, and X-ray diffraction techniques. SiO2 and TiO2 nanostructures were detected in 11 of 12 products using these methods. Many of the isolated nanoscale materials showed a high degree of aggregation; however, identified individual structures had at least one dimension below 100 nm. These robust methods can be used for routine monitoring of commercial products for nanoscale oxides of silica and titanium. C1 [Lim, Jin-Hee; Sisco, Patrick; Mudalige, Thilak K.; Sanchez-Pomales, Germarie; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. [Howard, Paul C.] US FDA, Natl Ctr Toxicol Res, Off Sci Coordinat, Jefferson, AR 72079 USA. RP Lim, JH (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Jin.Lim@fda.hhs.gov; Sean.Linder@fda.hhs.gov FU FDA Office of Women's Health; U.S. Department of Energy; FDA FX This work was graciously supported by the FDA Office of Women's Health. This project was supported in part by an appointment to the Research Participation Program at the Office of Regulatory Affairs/Arkansas Regional Laboratory, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. The views expressed in this paper are those of the authors and should not be interpreted as the official opinion or policy of the U.S. Food and Drug Administration, Department of Health and Human Services, or any other agency or component of the U.S. government. The mention of trade names, commercial products, or organizations is for clarification of the methods used and should not be interpreted as an endorsement of a product or manufacturer. NR 46 TC 6 Z9 6 U1 5 U2 40 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 APR 1 PY 2015 VL 63 IS 12 BP 3144 EP 3152 DI 10.1021/acs.jafc.5b00392 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CF0OX UT WOS:000352245200010 PM 25738207 ER PT J AU Qu, HO Mudalige, TK Linder, SW AF Qu, Haiou Mudalige, Thilak K. Linder, Sean W. TI Arsenic Speciation in Rice by Capillary Electrophoresis/Inductively Coupled Plasma Mass Spectrometry: Enzyme-Assisted Water-Phase Microwave Digestion SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE arsenic speciation; rice; capillary electrophoresis; inductively coupled plasma mass spectrometry; enzyme-assisted microwave digestion ID ICP-MS; EXTRACTION; SELENIUM; PRODUCTS; VERIFICATION; INTERFACE; FLOUR; WHEAT; GRAIN; SOIL AB We report an analytical methodology for the quantification of common arsenic species in rice and rice cereal using capillary electrophoresis coupled with inductively coupled plasma mass spectrometry (CE-ICPMS). An enzyme (i.e., a-amylase)-assisted water-phase microwave extraction procedure was used to extract four common arsenic species, including dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), arsenite [As(III)], and arsenate [As(V)] from the rice matrices. The addition of the enzyme a-amylase during the extraction process was necessary to reduce the sample viscosity, which subsequently increased the injection volume and enhanced the signal response. o-Arsanilic acid (o-ASA) was added to the sample solution as a mobility marker and internal standard. The obtained repeatability [i.e., relative standard deviation (RSD %)] of the four arsenic analytes of interest was less than 1.23% for elution time and 2.91% for peak area. The detection limits were determined to be 0.15-0.27 ng g(-1). Rice standard reference materials SRM 1568b and CRM 7503-a were used to validate this method. The quantitative concentrations of each organic arsenic and summed inorganic arsenic were found within 5% difference of the certified values of the two reference materials. C1 [Qu, Haiou; Mudalige, Thilak K.; Linder, Sean W.] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, Jefferson, AR 72079 USA. RP Mudalige, TK (reprint author), US FDA, Arkansas Reg Lab, Off Regulatory Affairs, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM thilak.mudalige@fda.hhs.gov; sean.linder@fda.hhs.gov FU U.S. Department of Energy; FDA FX This project was supported in part by an appointment to the Research Participation Program at the Office of Regulatory Affairs/Arkansas Regional Laboratory, FDA, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. The views expressed in this document are those of the authors and should not be interpreted as the official opinion or policy of the FDA, Department of Health and Human Services, or any other agency or component of the U.S. government. The mention of trades names, commercial products, or organizations is for clarification of the methods used and should not be interpreted as an endorsement of a product or manufacturer. NR 35 TC 13 Z9 13 U1 12 U2 82 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 APR 1 PY 2015 VL 63 IS 12 BP 3153 EP 3160 DI 10.1021/acs.jafc.5b00446 PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CF0OX UT WOS:000352245200011 PM 25751525 ER PT J AU Kouiavskaia, D Chen, ZC Dragunsky, E Mirochnitchenko, O Purcell, R Chumakov, K AF Kouiavskaia, Diana Chen, Zhaochun Dragunsky, Eugenia Mirochnitchenko, Olga Purcell, Robert Chumakov, Konstantin TI A single chimpanzee-human neutralizing monoclonal antibody provides post-exposure protection against type 1 and type 2 polioviruses SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE Polio eradication; Antiviral therapy; Drug-resistance; Chronic virus excretors; Emergency prophylaxis ID RESISTANCE; VACCINE; VARIANTS; ERADICATION; V-073; POLIO; MICE AB Background: Development of anti-poliovirus therapies to complement vaccination is an urgent priority. A number of antiviral drugs are in development. Recently we have developed human monoclonal antibodies that could be used for treatment of chronically infected individuals and emergency response to potential reappearance of polioviruses after eradication. Objective: The aim of this study was to characterize neutralizing activity of anti-poliovirus monoclonal antibody A12 against wild type, vaccine-derived, and drug-resistant poliovirus strains, evaluate in vivo pre- and post-exposure protective properties of the antibody against polioviruses of serotypes 1 and 2, and to determine whether it interferes with response to immunization with poliovirus vaccine. Study design: Immunogenicity studies were performed in CD1 mice. Poliovirus neutralizing titers were determined in poliovirus microneutralization assay. Poliovirus immunization-challenge experiments were performed in poliovirus-susceptible TgPVR21 mice. Results: We show that monoclonal antibody A12 effectively neutralizes in vitro a broad range of type 1 and type 2 wild and vaccine-derived polioviruses, provides effective pre- and post-exposure protection of TgPVR21 mice from challenge with a lethal dose of poliovirus. Treatment of animals with the antibody concurrent with IPV immunization does not prevent immune response to the vaccine. Conclusions: Anti-poliovirus antibody A12 effectively neutralizes a range of wild and VDPV strains and protectstransgenic mice susceptible to poliovirus against lethal challenge upon pre- and post-exposure administration. This suggests that the antibodies could be used in combination with drugs and/or vaccine to improve their efficacy and prevent emergence of resistant variants, and provides a justification for initiating their clinical evaluation. Published by Elsevier B.V. C1 [Kouiavskaia, Diana; Dragunsky, Eugenia; Mirochnitchenko, Olga; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Chen, Zhaochun; Purcell, Robert] NIAID, NIH, Bethesda, MD 20892 USA. RP Chumakov, K (reprint author), CBER FDA, 10903 New Hampshire Ave,Bldg 52,Room 1128, Silver Spring, MD 20993 USA. EM konstantin.chumakov@fda.hhs.gov FU intramural research programs at the Food and Drug Administration; National Institute of Allergy and Infectious Diseases FX This study was supported by the intramural research programs at the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases. NR 24 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD APR PY 2015 VL 65 BP 32 EP 37 DI 10.1016/j.jcv.2015.01.023 PG 6 WC Virology SC Virology GA CF6XZ UT WOS:000352701500007 PM 25766984 ER PT J AU Keller, SE Stam, CN Gradl, DR Chen, Z Larkin, EL Pickens, SR Chirtel, SJ AF Keller, Susanne E. Stam, Christina N. Gradl, Dana R. Chen, Zhengzai Larkin, Emily L. Pickens, Shannon R. Chirtel, Stuart J. TI Survival of Salmonella on Chamomile, Peppermint, and Green Tea during Storage and Subsequent Survival or Growth following Tea Brewing SO JOURNAL OF FOOD PROTECTION LA English DT Article ID THERMAL-RESISTANCE; UNITED-STATES; WATER ACTIVITY; BLACK PEPPER; DRY DOG; INFECTIONS; OUTBREAK; FOOD; GERMANY AB The survival of Salmonella on dried chamomile flowers, peppermint leaves, and green tea leaves stored under different conditions was examined Survival and growth of Salmonella was also assessed after subsequent brewing using dried inoculated teas. A Salmonella enterica serovar cocktail was inoculated onto different dried tea leaves or flowers to give starting populations of approximately 10 log CFU/g. The inoculum was allowed to dry (at ambient temperature for 24 h) onto the dried leaves or flowers prior to storage under 25 and 35 degrees C at low (<30% relative humidity [RH]) and high (>90% RH) humidity levels. Under the four storage conditions tested, survival followed the order 25 degrees C with low RH > 35 degrees C with low RH > 25 degrees C with high RH > 35 C with high RH. Salmonella losses at 25 degrees C with low RH occurred primarily during drying, after which populations showed little decline over 6 months. In contrast, Salmonella decreased below detection after 45 days at 35 degrees C and high RH in all teas tested. The thermal resistance of Salmonella was assessed at 55 degrees C immediately after inoculation of tea leaves or flowers, after drying (24 h) onto tea leaves or flowers, and after 28 days of storage at 25 degrees C with low RH. All conditions resulted in similar D-values (2.78 + 0.12, 3.04 + 0.07, and 2.78 + 0.56, at 0 h, 24 h, and 28 days, respectively), indicating thermal resistance of Salmonella in brewed tea did not change after desiccation and 28 days of storage. In addition, all brewed teas tested supported the growth of Salmonella. If Salmonella survives after storage, it may also survive and grow after a home brewing process. C1 [Keller, Susanne E.; Stam, Christina N.; Gradl, Dana R.; Larkin, Emily L.] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Chen, Zhengzai; Pickens, Shannon R.] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Chirtel, Stuart J.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Keller, SE (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. EM Susanne.keller@fda.hhs.gov FU U.S. Food and Drug Administration (FDA) [5U01FD003801] FX This work was supported by the U.S. Food and Drug Administration (FDA) collaborative grant 5U01FD003801 and by appointments to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. NR 32 TC 1 Z9 1 U1 2 U2 12 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD APR PY 2015 VL 78 IS 4 BP 661 EP 667 DI 10.4315/0362-028X.JFP-14-508 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CF3QM UT WOS:000352463600004 PM 25836389 ER PT J AU Kruger, N Hoffmann, M Drexler, JF Muller, MA Corman, VM Sauder, C Rubin, S He, B Orvell, C Drosten, C Herrler, G AF Krueger, Nadine Hoffmann, Markus Drexler, Jan Felix Mueller, Marcel Alexander Corman, Victor Max Sauder, Christian Rubin, Steven He, Biao Orvell, Claes Drosten, Christian Herrler, Georg TI Functional Properties and Genetic Relatedness of the Fusion and Hemagglutinin-Neuraminidase Proteins of a Mumps Virus-Like Bat Virus SO JOURNAL OF VIROLOGY LA English DT Article ID SARS-LIKE CORONAVIRUS; INFLUENZA-A VIRUS; SURFACE GLYCOPROTEINS; SH GENE; HENIPAVIRUS; PARAMYXOVIRUSES; SEQUENCE; STRAINS; ENTRY; ALIGNMENT AB A bat virus with high phylogenetic relatedness to human mumps virus (MuV) was identified recently at the nucleic acid level. We analyzed the functional activities of the hemagglutinin-neuraminidase (HN) and the fusion (F) proteins of the bat virus (batMuV) and compared them to the respective proteins of a human isolate. Transfected cells expressing the F and HN proteins of batMuV were recognized by antibodies directed against these proteins of human MuV, indicating that both viruses are serologically related. Fusion, hemadsorption, and neuraminidase activities were demonstrated for batMuV, and either bat-derived protein could substitute for its human MuV counterpart in inducing syncytium formation when coexpressed in different mammalian cell lines, including chiropteran cells. Cells expressing batMuV glycoproteins were shown to have lower neuraminidase activity. The syncytia were smaller, and they were present in lower numbers than those observed after coexpression of the corresponding glycoproteins of a clinical isolate of MuV (hMuV). The phenotypic differences in the neuraminidase and fusion activity between the glycoproteins of batMuV and hMuV are explained by differences in the expression level of the HN and F proteins of the two viruses. In the case of the F protein, analysis of chimeric proteins revealed that the signal peptide of the bat MuV fusion protein is responsible for the lower surface expression. These results indicate that the surface glycoproteins of batMuV are serologically and functionally related to those of hMuV, raising the possibility of bats as a reservoir for interspecies transmission. IMPORTANCE The recently described MuV-like bat virus is unique among other recently identified human-like bat-associated viruses because of its high sequence homology (approximately 90% in most genes) to its human counterpart. Although it is not known if humans can be infected by batMuV, the antigenic relatedness between the bat and human forms of the virus suggests that humans carrying neutralizing antibodies against MuV are protected from infection by batMuV. The close functional relationship between MuV and batMuV is demonstrated by cooperation of the respective HN and F proteins to induce syncytium formation in heterologous expression studies. An interesting feature of the glycoproteins of batMuV is the downregulation of the fusion activity by the signal peptide of F, which has not been reported for other paramyxoviruses. These results are important contributions for risk assessment and for a better understanding of the replication strategy of batMuV. C1 [Krueger, Nadine; Hoffmann, Markus; Herrler, Georg] Univ Vet Med Hannover, Inst Virol, Hannover, Germany. [Drexler, Jan Felix; Mueller, Marcel Alexander; Corman, Victor Max; Drosten, Christian] Univ Bonn, Med Ctr, Inst Virol, Bonn, Germany. [Sauder, Christian; Rubin, Steven] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [He, Biao] Univ Georgia, Dept Infect Dis, Athens, GA 30602 USA. [Orvell, Claes] Karolinska Inst, Div Lab Med, Stockholm, Sweden. RP Herrler, G (reprint author), Univ Vet Med Hannover, Inst Virol, Hannover, Germany. EM Georg.Herrler@tiho-hannover.de OI Mueller, Marcel/0000-0003-2242-5117; Corman, Victor Max/0000-0002-3605-0136 FU fellowship of the Hannover Graduate School for Veterinary Pathobiology, Neuroinfectiology, and Translational Medicine (HGNI); DFG [HE 1168/14-1, SFB621 TP B7]; Bundesministerium fur Bildung und Forschung (Ecology and Pathogenesis of SARS) [01KI1005B, 01KI1006D] FX N.K. was funded by a fellowship of the Hannover Graduate School for Veterinary Pathobiology, Neuroinfectiology, and Translational Medicine (HGNI). This work was supported by grants to G.H. from DFG (HE 1168/14-1 and SFB621 TP B7) and from Bundesministerium fur Bildung und Forschung (Ecology and Pathogenesis of SARS, project code 01KI1005B, and FluResearchNet, project code 01KI1006D). NR 47 TC 4 Z9 4 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD APR PY 2015 VL 89 IS 8 BP 4539 EP 4548 DI 10.1128/JVI.03693-14 PG 10 WC Virology SC Virology GA CF0FL UT WOS:000352218400042 PM 25741010 ER PT J AU Chen, A Itana, H Xia, GJ Pepe, S Pariser, A AF Chen, Alice Itana, Hawi Xia, Guanjun Pepe, Salvatore Pariser, Anne TI Sex Subgroup Analyses in Pivotal Clinical Trials of New Drug and Biologic Products Approved by FDA Center for Drug Evaluation and Research in 2014 SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Chen, Alice; Xia, Guanjun; Pariser, Anne] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Itana, Hawi] US FDA, Off Womens Hlth, Off Commissioner, Silver Spring, MD USA. [Pepe, Salvatore] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, 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 1 PY 2015 VL 24 IS 4 MA P27 BP 12 EP 12 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 CF5YE UT WOS:000352632500028 ER PT J AU Fadiran, E Itana, H Chen, A Pariser, A Soon, G AF Fadiran, Emmanuel Itana, Hawi Chen, Alice Pariser, Anne Soon, Greg TI Demographics by Sex and Race of Study Participants in Clinical Trials for Oncology Drugs Approved by the FDA in 2013 SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Fadiran, Emmanuel; Itana, Hawi] US FDA, Res & Dev, Off Womens Hlth, Silver Spring, MD USA. [Chen, Alice] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pariser, Anne] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Soon, Greg] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD APR 1 PY 2015 VL 24 IS 4 MA P33 BP 14 EP 15 PG 2 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 CF5YE UT WOS:000352632500034 ER PT J AU Xia, GJ Chen, A Itana, H Pepe, S Pariser, A AF Xia, Guanjun Chen, Alice Itana, Hawi Pepe, Salvatore Pariser, Anne TI Sex Subgroup Analysis from US and International Sites for Pivotal Clinical Trials of New Drugs and Biologic Products Approved by CDER/FDA in January-July 2014 SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Xia, Guanjun; Chen, Alice; Pariser, Anne] CDER, OTS, Marlboro, NJ USA. [Itana, Hawi] OC, OWH, Silver Spring, MD USA. [Pepe, Salvatore] CDER, OND, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD APR 1 PY 2015 VL 24 IS 4 MA P127 BP 48 EP 49 PG 2 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 CF5YE UT WOS:000352632500128 ER PT J AU Papoian, T Chiu, HJ Elayan, I Jagadeesh, G Khan, I Laniyonu, AA Li, CXG Saulnier, M Simpson, N Yang, BC AF Papoian, Thomas Chiu, Haw-Jyh Elayan, Ikram Jagadeesh, Gowraganahalli Khan, Imran Laniyonu, Adebayo A. Li, Cindy Xinguang Saulnier, Muriel Simpson, Natalie Yang, Baichun TI Secondary pharmacology data to assess potential off-target activity of new drugs: a regulatory perspective SO NATURE REVIEWS DRUG DISCOVERY LA English DT Letter ID SAFETY PHARMACOLOGY C1 [Papoian, Thomas; Jagadeesh, Gowraganahalli; Saulnier, Muriel; Yang, Baichun] US FDA, Div Cardiovasc & Renal Prod, Silver Spring, MD 20993 USA. [Chiu, Haw-Jyh; Simpson, Natalie] US FDA, Div Hematol Oncol Toxicol, Silver Spring, MD 20993 USA. [Elayan, Ikram; Khan, Imran] US FDA, Div Psychiat Prod, Silver Spring, MD 20993 USA. [Laniyonu, Adebayo A.] US FDA, Div Med Imaging Prod, Silver Spring, MD 20993 USA. [Li, Cindy Xinguang] US FDA, Div Nonprescript Drug Prod, Silver Spring, MD 20993 USA. RP Papoian, T (reprint author), US FDA, Div Cardiovasc & Renal Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Thomas.Papoian@fda.hhs.gov NR 10 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD APR PY 2015 VL 14 IS 4 DI 10.1038/nrd3845-c1 PG 3 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA CE9WW UT WOS:000352195200019 ER PT J AU Garra, BS AF Garra, Brian S. TI Elastography: history, principles, and technique comparison SO ABDOMINAL IMAGING LA English DT Article DE Elastography; Elasticity; Shear wave; Ultrasound; Breast; Thyroid; Lymph node ID REAL-TIME ELASTOGRAPHY; ULTRASOUND ELASTOGRAPHY; TRANSIENT ELASTOGRAPHY; EFSUMB GUIDELINES; THYROID-NODULES; US ELASTOGRAPHY; BREAST-LESIONS; CLINICAL-USE; LYMPH-NODES; BENIGN AB Elastography is a relatively new imaging technology that creates images of tissue stiffness. It can be thought of an extension of the ancient technique of palpation but it gives better spatial localization information and is less subjective. Two main types of elastography are currently in use, strain elastography where the tissue displacement in response to gentle pressure is used to compute and image tissue strain, and shear wave elastography where the speed of shear waves traversing tissue is measured and used to create an image of tissue stiffness. Each method has advantages and disadvantages but generally strain imaging is excellent for focal lesions and shear wave imaging, being more quantitative, is best for diffuse organ diseases. Strain imaging requires additional training in acquisition technique to obtain high quality images. Pitfalls to avoid and tips for good images are provided. Improvements in strain imaging are focused on better quality indicators and better methods for quantification. Improvements in shear wave imaging will be higher frame rates, greater accuracy in focal lesions, and making results more comparable between different ultrasound systems. Both methods will continue to improve and will provide ever more powerful new tools for diagnosis of diffuse and focal diseases. C1 [Garra, Brian S.] Washington DC VA Med Ctr, Washington, DC 20422 USA. [Garra, Brian S.] US FDA, Silver Spring, MD USA. RP Garra, BS (reprint author), Washington DC VA Med Ctr, Washington, DC 20422 USA. EM brian.garra@fda.hhs.gov NR 40 TC 9 Z9 10 U1 4 U2 22 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD APR PY 2015 VL 40 IS 4 BP 680 EP 697 DI 10.1007/s00261-014-0305-8 PG 18 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA CE3AS UT WOS:000351697000002 PM 25637125 ER PT J AU Sager, PT Seltzer, J Turner, JR Anderson, JL Hiatt, WR Kowey, P Prochaska, JJ Stockbridge, N White, WB AF Sager, Philip T. Seltzer, Jonathan Turner, J. Rick Anderson, Jeffrey L. Hiatt, William R. Kowey, Peter Prochaska, Judith J. Stockbridge, Norman White, William B. TI Cardiovascular Safety Outcome Trials: A meeting report from the Cardiac Safety Research Consortium SO AMERICAN HEART JOURNAL LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; DRUG DEVELOPMENT; RISK; METAANALYSIS; TIOTROPIUM; EVENTS; METHODOLOGY; VARENICLINE; INHALER; DEATH AB This White Paper provides a summary of presentations and discussions at a Cardiovascular Safety Outcome Trials Think Tank cosponsored by the Cardiac Safety Research Consortium, the US Food and Drug Administration, and the American College of Cardiology, held at American College of Cardiology's Heart House, Washington, DC, on February 19, 2014. Studies to assess cardiovascular (CV) risk of a new drug are sometimes requested by regulators to resolve ambiguous safety signals seen during its development or among other members of its class. Think Tank participants thought that important considerations in undertaking such studies were as follows: (1) plausibility-how likely it is that a possible signal indicating risk is real, based on strength of evidence, and/or whether a plausible mechanism of action for potential CV harm has been identified; (2) relevance-what relative and absolute CV risk would need to be excluded to determine that the drug had an acceptable benefit-to-risk balance for its use in the intended patient population; and (3) how plausibility and relevance influence the timing and approach to further safety assessment. C1 [Sager, Philip T.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Seltzer, Jonathan] ACI Clin, Bala Cynwyd, PA USA. [Turner, J. Rick] Quintiles Inc, Durham, NC USA. [Anderson, Jeffrey L.] Intermt Heart Inst, Salt Lake City, UT USA. [Hiatt, William R.] Univ Colorado, Sch Med, Div Cardiol CPC Clin Res, Aurora, CO USA. [Kowey, Peter] Lankenau Med Ctr, Philadelphia, PA USA. [Prochaska, Judith J.] Stanford Univ, Stanford Prevent Res Ctr, Palo Alto, CA 94304 USA. [Stockbridge, Norman] US FDA, Silver Spring, MD USA. [White, William B.] Univ Connecticut, Sch Med, Ctr Cardiol, Farmington, CT 06030 USA. RP White, WB (reprint author), Univ Connecticut, Sch Med, Calhoun Cardiol Ctr, Farmington, CT 06030 USA. EM wwhite@uchc.edu FU National Institutes of Health (NIH); Sanofi-Aventis; Medicines Company; NIH; AstraZeneca; Bayer; GSK; Merck; Pluristem; ReNeuron; Rigel; Kyushu University; State of California Tobacco Related Disease Research Program; Pfizer Inc.; National Institute of Aging (NIH) FX Philip T. Sager: safety consultant (member of DSMB, CV end point committee, consultant, or advisory board) to Shire Pharmaceuticals, Chemo, Helssin, Milestone, Medtronic, Aerpio, SK Science, Viamet, SNBL, Biomedical Systems, iCardiac, Celgene, and Genentech. He is a member of the FDA Cardiovascular and Renal Drugs Advisory Committee and the CSRC Executive Committee and serves on the Board of Directors of Anthera, Inc. Jonathan Seltzer: employee of ACI Clinical. J. Rick Turner: employee and shareholder of Quintiles, Inc. Jeffrey L Anderson: grant support from the National Institutes of Health (NIH), Sanofi-Aventis, Medicines Company. William R. Hiatt: research grant support to CPC Clinical Research (University clinical trials research center) from NIH, AstraZeneca, Bayer, GSK, Merck, Pluristem, ReNeuron, Rigel, and Kyushu University. Peter R Kowey: safety consultant (member of DSMB, CV end point committee, consultant, or advisory board) to Astra-Zeneca; Astellas, Inc; Forest Resarch Institute; and Roche, Inc. Judith J. Prochaska: research grant support from NIH, the State of California Tobacco Related Disease Research Program, and Pfizer Inc. Norman Stockbridge: nothing to disclose (employee of FDA). William B White: grant support from National Institute of Aging (NIH) and consultant (Safety Research only) to Astra-Zeneca, Celgene, Forest Research Institute, Roche, Inc, Teva Pharmaceuticals, and Takeda Development Center of North America. NR 28 TC 10 Z9 10 U1 1 U2 2 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 APR PY 2015 VL 169 IS 4 BP 486 EP 495 DI 10.1016/j.ahj.2015.01.007 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE6MC UT WOS:000351949500011 PM 25819855 ER PT J AU Savage, WJ Buchanan, GR Yawn, BP Afenyi-Annan, AN Ballas, SK Goldsmith, JC Hassell, KL James, AH John-Sowah, J Jordan, L Lottenberg, R Murad, MH Ortiz, E Tanabe, PJ Ware, RE Lanzkron, SM AF Savage, William J. Buchanan, George R. Yawn, Barbara P. Afenyi-Annan, Araba N. Ballas, Samir K. Goldsmith, Jonathan C. Hassell, Kathryn L. James, Andra H. John-Sowah, Joylene Jordan, Lanetta Lottenberg, Richard Murad, M. Hassan Ortiz, Eduardo Tanabe, Paula J. Ware, Russell E. Lanzkron, Sophie M. TI Evidence gaps in the management of sickle cell disease: A summary of needed research SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID HYDROXYUREA; ANEMIA C1 [Savage, William J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Buchanan, George R.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Yawn, Barbara P.] Olmsted Med Ctr, Rochester, MN USA. [Afenyi-Annan, Araba N.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Ballas, Samir K.] Thomas Jefferson Univ, Cardeza Fdn, Dept Med Hematol, Philadelphia, PA 19107 USA. [Goldsmith, Jonathan C.] US FDA, Rare Dis Program, Off New Drugs, Silver Spring, MD USA. [Hassell, Kathryn L.] Univ Colorado, Dept Med, Denver, CO USA. [James, Andra H.] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [John-Sowah, Joylene] NHLBI, Bethesda, MD 20892 USA. [Jordan, Lanetta] Univ Miami, Miller Sch Med, Fdn Sickle Cell Dis Res, Miami, FL 33136 USA. [Lottenberg, Richard] Univ Florida, Dept Med, Gainesville, FL USA. [Murad, M. Hassan] Mayo Clin, Coll Med, Dept Preventat Occupat & Aerosp Med, Rochester, MN USA. [Ortiz, Eduardo] Atlas Res, Washington, DC USA. [Tanabe, Paula J.] Duke Univ, Sch Nursing, Durham, NC USA. [Tanabe, Paula J.] Duke Univ, Sch Med, Durham, NC USA. [Ware, Russell E.] Cincinnati Childrens Hosp Med Ctr, Dept Hematol, Cincinnati, OH 45229 USA. [Lanzkron, Sophie M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Savage, WJ (reprint author), 75 Francis St,Amory 260, Boston, MA 02115 USA. EM wjsavage@partners.org NR 5 TC 8 Z9 8 U1 1 U2 9 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 APR PY 2015 VL 90 IS 4 BP 273 EP 275 DI 10.1002/ajh.23945 PG 3 WC Hematology SC Hematology GA CE2WE UT WOS:000351680800009 PM 25639238 ER PT J AU Zeiger, E Gollapudi, B Aardema, MJ Auerbach, S Boverhof, D Custer, L Dedon, P Honma, M Ishida, S Kasinski, AL Kim, JH Manjanatha, MG Marlowe, J Pfuhler, S Pogribny, I Slikker, W Stankowski, LF Tanir, JY Tice, R van Benthem, J White, P Witt, KL Thybaud, V AF Zeiger, Errol Gollapudi, Bhaskar Aardema, Marilyn J. Auerbach, Scott Boverhof, Darrell Custer, Laura Dedon, Peter Honma, Masamitsu Ishida, Seiichi Kasinski, Andrea L. Kim, James H. Manjanatha, Mugimane G. Marlowe, Jennifer Pfuhler, Stefan Pogribny, Igor Slikker, William Stankowski, Leon F., Jr. Tanir, Jennifer Y. Tice, Raymond van Benthem, Jan White, Paul Witt, Kristine L. Thybaud, Veronique TI Opportunities to Integrate New Approaches in Genetic Toxicology: An ILSI-HESI Workshop Report SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE genetic toxicity; mutation; epigenetics; genomics AB Genetic toxicity tests currently used to identify and characterize potential human mutagens and carcinogens rely on measurements of primary DNA damage, gene mutation, and chromosome damage in vitro and in rodents. The International Life Sciences Institute Health and Environmental Sciences Institute (ILSI-HESI) Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity Testing held an April 2012 Workshop in Washington, DC, to consider the impact of new understanding of biology and new technologies on the identification and characterization of genotoxic substances, and to identify new approaches to inform more accurate human risk assessment for genetic and carcinogenic effects. Workshop organizers and speakers were from industry, academe, and government. The Workshop focused on biological effects and technologies that would potentially yield the most useful information for evaluating human risk of genetic damage. Also addressed was the impact that improved understanding of biology and availability of new techniques might have on genetic toxicology practices. Workshop topics included (1) alternative experimental models to improve genetic toxicity testing, (2) Biomarkers of epigenetic changes and their applicability to genetic toxicology, and (3) new technologies and approaches. The ability of these new tests and technologies to be developed into tests to identify and characterize genotoxic agents; to serve as a bridge between in vitro and in vivo rodent, or preferably human, data; or to be used to provide dose response information for quantitative risk assessment was also addressed. A summary of the workshop and links to the scientific presentations are provided. Environ. Mol. Mutagen. 56:277-285, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Zeiger, Errol] Errol Zeiger Consulting, Chapel Hill, NC 27514 USA. [Gollapudi, Bhaskar; Boverhof, Darrell] Dow Chem Co USA, Midland, MI 48674 USA. [Aardema, Marilyn J.] BioReliance Corp, Marilyn Aardema Consulting LLC, Rockville, MD USA. [Auerbach, Scott; Tice, Raymond; Witt, Kristine L.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Custer, Laura] Bristol Myers Squibb Co, Dept Genet Toxicol, New York, NY 10154 USA. [Dedon, Peter] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Honma, Masamitsu] Natl Inst Hlth Sci, Div Genet & Mutagenesis, Tokyo, Japan. [Ishida, Seiichi] Natl Inst Hlth Sci, Div Pharmacol, Tokyo, Japan. [Kasinski, Andrea L.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. [Kim, James H.; Tanir, Jennifer Y.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. [Manjanatha, Mugimane G.; Pogribny, Igor; Slikker, William] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Marlowe, Jennifer] Novartis, Cambridge, MA USA. [Pfuhler, Stefan] Procter & Gamble Co, Cincinnati, OH USA. [Stankowski, Leon F., Jr.] BioReliance Corp, Rockville, MD USA. [van Benthem, Jan] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [White, Paul] Hlth Canada, Environm Hlth Sci & Res Div, Ottawa, ON K1A 0L2, Canada. [Thybaud, Veronique] Sanofi, Vitry Alfortville Res Ctr, Vitry Sur Seine, France. RP Zeiger, E (reprint author), Errol Zeiger Consulting, Chapel Hill, NC 27514 USA. EM zeiger@nc.rr.com RI Kasinski, Andrea/E-7951-2014; OI Dedon, Peter/0000-0003-0011-3067; white, paul/0000-0001-5853-4759 FU ILSI/HESI IVGT committee FX The organizing committee is grateful to the researchers who agreed to participate in this Workshop. In addition, the support of the ILSI/HESI staff, particularly Eric Moore, was invaluable for the organization, logistics, and day-to-day running of the Workshop. The authors also thank the ILSI/HESI IVGT committee for its financial and intellectual support. NR 3 TC 1 Z9 1 U1 0 U2 15 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 APR PY 2015 VL 56 IS 3 BP 277 EP 285 DI 10.1002/em.21923 PG 9 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CE4BZ UT WOS:000351777100001 PM 25482136 ER PT J AU Park, BS Rajan, SS Guag, JW Angelone, LM AF Park, Bu S. Rajan, Sunder S. Guag, Joshua W. Angelone, Leonardo M. TI A Novel Method to Decrease Electric Field and SAR Using an External High Dielectric Sleeve at 3 T Head MRI: Numerical and Experimental Results SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Barium titanate; birdcage coil; coil design; distilled water; finite-difference time domain (FDTD); specific absorption rate (SAR) ID MAGNETIC-RESONANCE; COIL; PERMITTIVITY; PADS; ENHANCEMENT; SIMULATIONS; STRENGTH; MODELS AB Materials with high dielectric constant (HDC) have been used in high field MRI to decrease specific absorption rate (SAR), increase magnetic field intensity, and increase signal-to-noise ratio. In previous studies, the HDC materials were placed inside the RF coil decreasing the space available. This study describes an alternative approach that considers an HDC-based sleeve placed outside the RF coil. The effects of an HDC on the electromagnetic (EM) field were studied using numerical simulations with a coil unloaded and loaded with a human head model. In addition, experimental EM measurements at 128 MHz were performed inside a custom-made head coil, fitted with a distilled water sleeve. The numerical simulations showed up to 40% decrease in maximum 10 g-avg. SAR on the surface of the head model with an HDC material of barium titanate. Experimental measurements also showed up to 20% decrease of maximum electric field using an HDC material of distilled water. The proposed method can be incorporated in the design of high field transmit RF coils. C1 [Park, Bu S.; Rajan, Sunder S.; Guag, Joshua W.; Angelone, Leonardo M.] US FDA, Div Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Park, BS (reprint author), US FDA, Div Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM bu.park@fda.hhs.gov; sunder.rajan@fda.hhs.gov; Joshua.Guag@fda.hhs.gov; leonardo.angelone@fda.hhs.gov OI Angelone, Leonardo/0000-0002-1105-021X FU FDA Center of Devices and Radiological Health Critical Path Program FX This work was supported by the FDA Center of Devices and Radiological Health Critical Path Program. NR 22 TC 2 Z9 2 U1 3 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD APR PY 2015 VL 62 IS 4 BP 1063 EP 1069 DI 10.1109/TBME.2014.2364512 PG 7 WC Engineering, Biomedical SC Engineering GA CE3ZR UT WOS:000351769700006 PM 25347873 ER PT J AU Dreher, ML Nagaraja, S Li, J AF Dreher, Maureen L. Nagaraja, Srinidhi Li, Jian TI Creep loading during degradation attenuates mechanical property loss in PLGA SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE PLGA; degradation; absorbable polymer; load ID IN-VITRO DEGRADATION; HYDROLYTIC DEGRADATION; BIODEGRADABLE POLYMERS; FIXATION DEVICES; SCAFFOLDS; VIVO; BEHAVIOR; SUTURES; PH AB While absorbable materials and medical devices primarily degrade through hydrolysis, their degradation kinetics are sensitive to environmental conditions, including temperature, pH, and mechanical loading. While there is some consistent information in the literature suggesting that strain controlled loading accelerates strength loss, there is much more limited information on the interaction between degradation and mechanical load applied under force control. Force control conditions impose a different stress state on the material and therefore, may exhibit different effects on degradation. In this study, the interaction between loading and degradation rate for an exemplary absorbable polymer, poly(l-lactide-co-glycolide), was investigated. The results indicated that load during degradation results in significant polymer creep, which is associated with increased force loss, but decreased strength loss (i.e., stress based parameters such as ultimate stress). This study further identified that changes to the degradation kinetics from exposure to loading were not associated with alterations to polymer crystallinity but were associated with delayed loss of molecular weight. Overall, these results demonstrate the importance of investigating the interaction between loading and degradation and that physical changes, such as those induced by creep, rather than chemical changes offer the strongest explanation for alteration of degradation kinetics. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 700-708, 2015. C1 [Dreher, Maureen L.; Nagaraja, Srinidhi] US FDA, Div Solid & Fluid Mech, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Li, Jian] US FDA, Div Chem & Mat Sci, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. RP Dreher, ML (reprint author), US FDA, Div Solid & Fluid Mech, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM maureen.dreher@fda.hhs.gov FU FDA's Office of the Critical Path Initiative FX The authors gratefully acknowledge FDA's Office of the Critical Path Initiative for funding this study. They also gratefully acknowledge Halpro Inc (Rockville, MD) for fabrication of custom grips used in the study. NR 29 TC 2 Z9 2 U1 5 U2 17 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 APR PY 2015 VL 103 IS 3 BP 700 EP 708 DI 10.1002/jbm.b.33248 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CE3WG UT WOS:000351760000023 PM 25052133 ER PT J AU Herz, ND Engeda, J Zusterzeel, R Sanders, WE O'Callaghan, KM Strauss, DG Jacobs, SB Selzman, KA Pina, IL Canos, DA AF Herz, Naomi D. Engeda, Joseph Zusterzeel, Robbert Sanders, William E. O'Callaghan, Kathryn M. Strauss, David G. Jacobs, Samantha B. Selzman, Kimberly A. Pina, Ileana L. Canos, Daniel A. TI Sex Differences in Device Therapy for Heart Failure: Utilization, Outcomes, and Adverse Events SO JOURNAL OF WOMENS HEALTH LA English DT Article ID CARDIAC-RESYNCHRONIZATION THERAPY; DEFIBRILLATOR IMPLANTATION TRIAL; VENTRICULAR SYSTOLIC FUNCTION; STROKE STATISTICS-2014 UPDATE; CLINICAL-EVALUATION MIRACLE; GENDER-RELATED DIFFERENCES; LONG-TERM SURVIVAL; CARE-HF TRIAL; CARDIOVERTER-DEFIBRILLATOR; DIASTOLIC FUNCTION AB Background: Multiple studies of heart failure patients demonstrated significant improvement in exercise capacity, quality of life, cardiac left ventricular function, and survival from cardiac resynchronization therapy (CRT), but the underenrollment of women in these studies is notable. Etiological and pathophysiological differences may result in different outcomes in response to this treatment by sex. The observed disproportionate representation of women suggests that many women with heart failure either do not meet current clinical criteria to receive CRT in trials or are not properly recruited and maintained in these studies. Methods: We performed a systematic literature review through May 2014 of clinical trials and registries of CRT use that stratified outcomes by sex or reported percent women included. One-hundred eighty-three studies contained sex-specific information. Results: Ninety percent of the studies evaluated included <= 35% women. Fifty-six articles included effectiveness data that reported response with regard to specific outcome parameters. When compared with men, women exhibited more dramatic improvement in specific parameters. In the studies reporting hazard ratios for hospitalization or death, women generally had greater benefit from CRT. Conclusions: Our review confirms women are markedly underrepresented in CRT trials, and when a CRT device is implanted, women have a therapeutic response that is equivalent to or better than in men, while there is no difference in adverse events reported by sex. C1 [Herz, Naomi D.; Engeda, Joseph; Zusterzeel, Robbert; Sanders, William E.; O'Callaghan, Kathryn M.; Strauss, David G.; Jacobs, Samantha B.; Selzman, Kimberly A.; Pina, Ileana L.; Canos, Daniel A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Canos, DA (reprint author), US FDA, 10903 New Hampshire Ave,WO66-4113, Silver Spring, MD 20993 USA. EM Daniel.Canos@fda.hhs.gov FU FDA's Office of Women's Health, Silver Spring, MD; Oak Ridge Institute for Science and Education FX The authors would like to thank Mitchell Shein for his insightful comments on this paper. Funding for this work was provided by the FDA's Office of Women's Health, Silver Spring, MD 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 129 TC 3 Z9 3 U1 1 U2 7 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 1 PY 2015 VL 24 IS 4 BP 261 EP 271 DI 10.1089/jwh.2014.4980 PG 11 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 CF5YG UT WOS:000352632700002 PM 25793483 ER PT J AU Kuchinsky, S Ascher, J AF Kuchinsky, Sarah Ascher, Jill TI Postoperative multimodal pain management SO LAB ANIMAL LA English DT Editorial Material ID BUPRENORPHINE; ANALGESIA; RATS; MICE C1 [Kuchinsky, Sarah; Ascher, Jill] US FDA, Silver Spring, MD 20993 USA. RP Kuchinsky, S (reprint author), US FDA, Silver Spring, MD 20993 USA. EM sarah.kuchinsky@fda.hhs.gov NR 9 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD APR PY 2015 VL 44 IS 4 BP 136 EP 138 PG 3 WC Veterinary Sciences SC Veterinary Sciences GA CE8WA UT WOS:000352123600018 ER PT J AU Huang, C Galons, JP Graff, CG Clarkson, EW Bilgin, A Kalb, B Martin, DR Altbach, MI AF Huang, Chuan Galons, Jean-Philippe Graff, Christian G. Clarkson, Eric W. Bilgin, Ali Kalb, Bobby Martin, Diego R. Altbach, Maria I. TI Correcting Partial Volume Effects in Biexponential T-2 Estimation of Small Lesions SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE T-2 estimation; MR parameter estimation; partial volume effect; lesion classification ID CONVENTIONAL SPIN-ECHO; FOCAL LIVER-LESIONS; T2 RELAXATION-TIMES; MR-IMAGES; RECONSTRUCTION; HEMANGIOMAS; RELAXOMETRY; EXCITATION; NOISE; DIFFERENTIATION AB PurposeT(2) mapping provides a quantitative approach for focal liver lesion characterization. For small lesions, a biexponential model should be used to account for partial volume effects (PVE). However, conventional biexponential fitting suffers from large uncertainty of the fitted parameters when noise is present. The purpose of this work is to develop a more robust method to correct for PVE affecting small lesions. MethodsWe developed a region of interest-based joint biexponential fitting (JBF) algorithm to estimate the T-2 of lesions affected by PVE. JBF takes advantage of the lesion fraction variation among voxels within a region of interest. JBF is compared to conventional approaches using Cramer-Rao lower bound analysis, numerical simulations, phantom, and in vivo data. ResultsJBF provides more accurate and precise T-2 estimates in the presence of PVE. Furthermore, JBF is less sensitive to region of interest drawing. Phantom and in vivo results show that JBF can be combined with a reconstruction method for highly undersampled data, enabling the characterization of small abdominal lesions from data acquired in a single breath hold. ConclusionThe JBF algorithm provides more accurate and stable T-2 estimates for small structures than conventional techniques when PVE is present. It should be particularly useful for the characterization of small abdominal lesions. Magn Reson Med 73:1632-1642, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Huang, Chuan] Univ Arizona, Dept Math, Tucson, AZ 85724 USA. [Huang, Chuan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Imaging,Ctr Adv Med Imaging Sci, Boston, MA USA. [Galons, Jean-Philippe; Kalb, Bobby; Martin, Diego R.; Altbach, Maria I.] Univ Arizona, Dept Med Imaging, Tucson, AZ 85724 USA. [Graff, Christian G.] US FDA, Div Imaging & Appl Math, Silver Spring, MD USA. [Clarkson, Eric W.] Univ Arizona, Coll Opt Sci, Tucson, AZ 85724 USA. [Bilgin, Ali] Univ Arizona, Dept Elect & Comp Engn, Tucson, AZ 85724 USA. [Bilgin, Ali] Univ Arizona, Dept Biomed Engn, Tucson, AZ 85724 USA. RP Altbach, MI (reprint author), Univ Arizona, Dept Med Imaging, Tucson, AZ 85724 USA. EM maltbach@email.arizona.edu FU NIH [HL085385] FX Grant sponsor: NIH; Grant number: HL085385. NR 35 TC 1 Z9 1 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD APR PY 2015 VL 73 IS 4 BP 1632 EP 1642 DI 10.1002/mrm.25250 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CE2XS UT WOS:000351685900030 PM 24753061 ER PT J AU Darpo, B Benson, C Dota, C Ferber, G Garnett, C Green, CL Jarugula, V Johannesen, L Keirns, J Krudys, K Liu, J Ortemann-Renon, C Riley, S Sarapa, N Smith, B Stoltz, RR Zhou, M Stockbridge, N AF Darpo, B. Benson, C. Dota, C. Ferber, G. Garnett, C. Green, C. L. Jarugula, V. Johannesen, L. Keirns, J. Krudys, K. Liu, J. Ortemann-Renon, C. Riley, S. Sarapa, N. Smith, B. Stoltz, R. R. Zhou, M. Stockbridge, N. TI Results From the IQ-CSRC Prospective Study Support Replacement of the Thorough QT Study by QT Assessment in the Early Clinical Phase SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID STATISTICAL ISSUES; PROLONGATION; QT/QTC; INTERVAL; DATABASE; DRUGS AB The QT effects of five QT-positive and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/QTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean QTcF effect was above 10 ms. For the negative drug, levocetirizine, a QTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study. C1 [Darpo, B.] Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Karolinska Inst, Stockholm, Sweden. [Darpo, B.; Smith, B.; Zhou, M.] iCardiac Technol, Rochester, NY USA. [Benson, C.] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Dota, C.] AstraZeneca R&D, Molndal, Sweden. [Ferber, G.] Stat Georg Ferber, Riehen, Switzerland. [Garnett, C.] Certara, St Louis, MO USA. [Green, C. L.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Jarugula, V.] Novartis Inst Biomed Res, Drug Metab & Pharmacokinet, E Hanover, NJ USA. [Johannesen, L.] US FDA, Div Pharmacometr, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Johannesen, L.] Karolinska Univ Hosp, Dept Clin Physiol, Karolinska Inst, Stockholm, Sweden. [Keirns, J.] Astellas Pharma Global Dev, Global Clin Pharmacol & Exploratory Dev, Northbrook, IL USA. [Krudys, K.; Liu, J.] US FDA, Div Pharmacometr, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Ortemann-Renon, C.] Sanofi Rech, Clin & Exploratory Pharmacol, Bridgewater, NJ USA. [Riley, S.] Pfizer, Clin Pharmacol, Global Innovat Pharma Business, Groton, CT USA. [Sarapa, N.] Bayer Healthcare, Clin Sci, Whippany, NJ USA. [Stoltz, R. R.] Covance Clin Res Unit, Evansville, IN USA. [Stockbridge, N.] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Darpo, B (reprint author), Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Karolinska Inst, Stockholm, Sweden. EM borje.darpo@telia.com NR 35 TC 36 Z9 36 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 APR PY 2015 VL 97 IS 4 BP 326 EP 335 DI 10.1002/cpt.60 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CD9QK UT WOS:000351432700019 PM 25670536 ER PT J AU Wang, Y Harigaya, Y Cavaille-Coll, M Colangelo, P Reynolds, KS AF Wang, Y. Harigaya, Y. Cavaille-Coll, M. Colangelo, P. Reynolds, K. S. TI Justification of Noninferiority Margin: Methodology Considerations in an Exposure-Response Analysis SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article AB The pivotal clinical trial to support the indication of liver transplantation for everolimus was based on a noninferiority trial design. The unique trial design made it impossible to estimate the noninferiority margin at the design stage. Even though the trial was conducted based on a noninferiority margin of 12% for the primary efficacy endpoint, the lack of consensus on this margin made the efficacy results difficult to interpret. A novel pharmacometric approach was applied to derive a new margin. Even though it was smaller than 12%, the new margin was large enough so that the observed efficacy results became interpretable. This novel analysis was an important contributor to the totality of evidence approach that led to the approval of everolimus for the new indication. This approval represents the approval of a new drug in more than 10 years for the indication of liver transplantation. C1 [Wang, Y.] US FDA, Div Pharmacometr, Off Clin Pharmacol, Silver Spring, MD 20993 USA. [Harigaya, Y.; Colangelo, P.; Reynolds, K. S.] US FDA, Div Clin Pharmacol 4, Off Clin Pharmacol, Silver Spring, MD USA. [Cavaille-Coll, M.] US FDA, Div Transplant & Ophthalmol Prod, Off Antimicrobial Prod, Off New Drug, Silver Spring, MD USA. RP Wang, Y (reprint author), US FDA, Div Pharmacometr, Off Clin Pharmacol, Silver Spring, MD 20993 USA. EM yaning.wang@fda.hhs.gov NR 4 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD APR PY 2015 VL 97 IS 4 BP 404 EP 410 DI 10.1002/cpt.44 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CD9QK UT WOS:000351432700026 PM 25670256 ER PT J AU Mahmood, I AF Mahmood, Iftekhar TI Prediction of drug clearance in children: a review of different methodologies SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE allometric models; children; drug clearance; physiological models; population-based pharmacometric models ID STEM-CELL TRANSPLANTATION; SINGLE-DOSE PHARMACOKINETICS; MORPHINE MATURATION MODEL; PEDIATRIC AGE RANGE; POPULATION PHARMACOKINETICS; INTRAVENOUS BUSULFAN; ALLOMETRIC EXPONENTS; PROPOFOL CLEARANCE; METABOLIC-RATES; BODY-WEIGHT AB Introduction: Children are not small adults because the differences between adults and children are not simply due to body weight, but also due to physiological and biochemical differences. Hence, dosing in children should not be a 'small adult dose'. During pediatric drug development, selection of a suitable dose for the first-in-children clinical study (Pharmacokinetic [PK], safety and efficacy) is of utmost importance. Considering the importance of clearance in dose selection, a lot of approaches have been suggested for the prediction of drug clearance in children. This review examines many proposed methods for the prediction of drug clearance in the pediatric population and highlights the application and limitations of these proposed methods. Areas covered: In this review, different methods for the prediction of drug clearance in the pediatric population are discussed. These methods include allometric models, population-based pharmacometric models and physiologically based PK models. Expert opinion: All models discussed here have uncertainties in their predictive power and should be only used as exploratory tools during pediatric drug development. Allometric models, if used with knowledge and understanding, is a powerful tool for the prediction of drug clearance in pediatric population. C1 US FDA, Ctr Biol Evaluat & Res, Off Blood Review & Res, Div Hematol, Silver Spring, MD 20993 USA. RP Mahmood, I (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Blood Review & Res, Div Hematol, Silver Spring, MD 20993 USA. EM Iftekhar.mahmood@fda.hhs.gov NR 92 TC 2 Z9 2 U1 0 U2 4 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 APR PY 2015 VL 11 IS 4 BP 573 EP 587 DI 10.1517/17425255.2015.1019463 PG 15 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA CD6WO UT WOS:000351231200008 PM 25740388 ER PT J AU Marrone, AK Beland, FA Pogribny, IP AF Marrone, April K. Beland, Frederick A. Pogribny, Igor P. TI The role for microRNAs in drug toxicity and in safety assessment SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE adverse drug reactions; drug toxicity; microRNAs; safety assessment ID INDUCED LIVER-INJURY; BLOOD MIRNA EXPRESSION; CIRCULATING MICRORNAS; INDUCED NEUROTOXICITY; NONCODING RNAS; RAT-LIVER; INDUCED CARDIOTOXICITY; MYOCARDIAL-INFARCTION; PROPOFOL ANESTHESIA; PLASMA MICRORNAS AB Introduction: Adverse drug reactions present significant challenges that impact pharmaceutical development and are major burdens to public health services worldwide. In response to this need, the field of toxicology is rapidly expanding to identify key pathways involved in drug toxicity. Areas covered: MicroRNAs (miRNAs) are a class of small evolutionary conserved endogenous non-coding RNAs that regulate the translation of protein-coding genes. A wide range of toxicants alter miRNA levels in target organs and these altered miRNAs can also be detected in easily accessible biological fluids. This, combined with an early miRNA response to toxic insults and miRNA stability, substantiates the potential for these small molecules to be useful biomarkers for drug safety assessment. Expert opinion: miRNAs are early indicators and useful tools to detect drug-induced toxicity. Incorporation of miRNA profiling into the drug safety testing process will complement currently used techniques and may substantially enhance drug safety. With the increasing interests in translational research, the field of miRNA biomarker research will continue to expand and become an important part of the investigation of human drug toxicity. C1 [Marrone, April K.; Beland, Frederick A.; Pogribny, Igor P.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 92 TC 4 Z9 4 U1 1 U2 17 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 APR PY 2015 VL 11 IS 4 BP 601 EP 611 DI 10.1517/17425255.2015.1021687 PG 11 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA CD6WO UT WOS:000351231200010 PM 25739314 ER PT J AU Tallent, SM Hait, JM Bennett, RW AF Tallent, S. M. Hait, J. M. Bennett, R. W. TI Analysis of Bacillus cereus toxicity using PCR, ELISA and a lateral flow device SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE Bacillus cereus; detection; enterotoxigenic; food poisoning; food-borne illness ID BROAD DISTRIBUTION; LIVER-FAILURE; STRAINS; THURINGIENSIS; TOXIN; GENES AB AimsThe aim of this study was to evaluate the performance of immunodetection methods and PCR analysis of enterotoxigenic Bacillus cereus strains. Methods and ResultsEighty-eight enterotoxigenic B.cereus group strains linked to food-borne outbreaks and illnesses were studied with 30 exclusivity nonenterotoxigenic strains including Bacillus amyoliquifaciens, Bacillus subtilis, Staphylococcus aureus, Salmonella and Escherichia coli for this assessment. The PCR results showed 80% agreement with immunoassays for the Nhe target and 84% for the Hbl product. All exclusivity strains were PCR and serologically negative. ConclusionsPCR has proven to be a valuable tool when used in conjunction with immunoassays to quickly identify enterotoxigenic B.cereus group strains. Significance and Impact of the StudyThis study assessed the utility of rapid methods to characterize enterotoxigenic profiles of B.cereus group strains. The identification of enterotoxigenic bacteria and any associated toxins detected from food products is essential in food defense programs as public health officials search for methods to rapidly and accurately screen a global food supply. C1 [Tallent, S. M.; Hait, J. M.; Bennett, R. W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Tallent, SM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Sandra.tallent@fda.hhs.gov NR 19 TC 2 Z9 2 U1 3 U2 19 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 2015 VL 118 IS 4 BP 1068 EP 1075 DI 10.1111/jam.12766 PG 8 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CD9BU UT WOS:000351392200027 PM 25627167 ER PT J AU Zerbe, CS Rosen, LB Browne, S Marciano, B Opal, S Holland, SM AF Zerbe, Christa S. Rosen, Lindsey B. Browne, Sarah Marciano, Betty Opal, Steven Holland, Steven M. TI BURKHOLDERIA CEPACIA COMPLEX INFECTION ASSOCIATED WITH DEFECTS IN IL-12 SIGNALING SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT North American Annual Conference of the Clinical-Immunology-Society (CIS) on Immune Deficiency and Dysregulation CY APR 09-12, 2015 CL Houston, TX SP Clin Immunol Soc C1 [Zerbe, Christa S.; Rosen, Lindsey B.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Browne, Sarah] Food & Drug Adm, Silver Spring, MD USA. [Browne, Sarah] NIAID, Bethesda, MD 20892 USA. [Opal, Steven] Brown Univ, Providence, RI 02912 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 2015 VL 35 IS 3 MA 3744 BP 325 EP 325 PG 1 WC Immunology SC Immunology GA CE0QT UT WOS:000351510200077 ER PT J AU Son, I Binet, R Lin, A Hammack, TS Kase, JA AF Son, Insook Binet, Rachel Lin, Andrew Hammack, Thomas S. Kase, Julie A. TI Identification of five Shiga toxin-producing Escherichia coli genes by Luminex microbead-based suspension array SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article ID PCR AB To rapidly identify the presence of potentially virulent O157:H7 and non-O157 Shiga toxin-producing Escherichia colt (STEC), a PCR-based Luminex suspension assay was developed to detect the genes coding for four virulence factors (stx1, stx2, eae, and ehxA) plus the O157:H7-specific +93 uidA single nucleotide polymorphism. Published by Elsevier B.V. C1 [Son, Insook; Binet, Rachel; Hammack, Thomas S.; Kase, Julie A.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [Lin, Andrew] US FDA, San Francisco Lab, Alameda, CA 94502 USA. RP Son, I (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy,Mailstop HFS-711, College Pk, MD 20740 USA. EM insook.son@fda.hhs.gov; rachel.binet@fda.hhs.gov; andrew.lin@fda.hhs.gov; thomas.hammack@fda.hhs.gov; julie.kase@fda.hhs.gov NR 14 TC 1 Z9 2 U1 1 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD APR PY 2015 VL 111 BP 108 EP 110 DI 10.1016/j.mimet.2015.02.008 PG 3 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CE4JN UT WOS:000351797000016 PM 25686714 ER PT J AU Takmakov, P Ruda, K Phillips, KS Isayeva, IS Krauthamer, V Welle, CG AF Takmakov, Pavel Ruda, Kiersten Phillips, K. Scott Isayeva, Irada S. Krauthamer, Victor Welle, Cristin G. TI Rapid evaluation of the durability of cortical neural implants using accelerated aging with reactive oxygen species SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE neural prosthetics; cortical neural implants; brain-machine interface; microelectrode arrays; accelerated aging; electrochemical impedance spectroscopy; electron microscopy ID SILICON MICROELECTRODE ARRAYS; CLINICAL ETHICAL CONCERNS; BRAIN-MACHINE INTERFACES; HYDROGEN-PEROXIDE; POLYURETHANE ELASTOMERS; BARRIER BREACH; TISSUE; DEVICES; ELECTRODES; CORTEX AB Objective. A challenge for implementing high bandwidth cortical brain-machine interface devices in patients is the limited functional lifespan of implanted recording electrodes. Development of implant technology currently requires extensive non-clinical testing to demonstrate device performance. However, testing the durability of the implants in vivo is time-consuming and expensive. Validated in vitro methodologies may reduce the need for extensive testing in animal models. Approach. Here we describe an in vitro platform for rapid evaluation of implant stability. We designed a reactive accelerated aging (RAA) protocol that employs elevated temperature and reactive oxygen species (ROS) to create a harsh aging environment. Commercially available microelectrode arrays (MEAs) were placed in a solution of hydrogen peroxide at 87 degrees C for a period of 7 days. We monitored changes to the implants with scanning electron microscopy and broad spectrum electrochemical impedance spectroscopy (1 Hz-1 MHz) and correlated the physical changes with impedance data to identify markers associated with implant failure. Main results. RAA produced a diverse range of effects on the structural integrity and electrochemical properties of electrodes. Temperature and ROS appeared to have different effects on structural elements, with increased temperature causing insulation loss from the electrode microwires, and ROS concentration correlating with tungsten metal dissolution. All array types experienced impedance declines, consistent with published literature showing chronic (>30 days) declines in array impedance in vivo. Impedance change was greatest at frequencies < 10 Hz, and smallest at frequencies 1 kHz and above. Though electrode performance is traditionally characterized by impedance at 1 kHz, our results indicate that an impedance change at 1 kHz is not a reliable predictive marker of implant degradation or failure. Significance. ROS, which are known to be present in vivo, can create structural damage and change electrical properties of MEAs. Broad-spectrum electrical impedance spectroscopy demonstrates increased sensitivity to electrode damage compared with single-frequency measurements. RAA can be a useful tool to simulate worst-case in vivo damage resulting from chronic electrode implantation, simplifying the device development lifecycle. C1 [Takmakov, Pavel; Phillips, K. Scott; Isayeva, Irada S.] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,White Oak Fed Res Ctr, Silver Spring, MD 20903 USA. [Ruda, Kiersten; Krauthamer, Victor; Welle, Cristin G.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,White Oak Fed Res Ctr, Silver Spring, MD USA. RP Takmakov, P (reprint author), US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,White Oak Fed Res Ctr, Silver Spring, MD 20903 USA. EM Cristin.Welle@fda.hhs.gov RI phillips, kenneth/F-7560-2014; Phillips, Kenneth/A-2156-2013; OI phillips, kenneth/0000-0002-6552-0694; Phillips, Kenneth/0000-0002-6552-0694; Takmakov, Pavel/0000-0001-6591-0257; Welle, Cristin/0000-0001-8735-0983 FU Defense Advanced Research Projects Agency Microsystems Technology Office (DARPA, MTO); US Food and Drug Administration [FDA-DARPA 224-10-6006] FX Authors would like to thank Dr Eugene Civillico, Dr Dinesh V Patwardhan and Dr Benita J Dair for their help with the project; Dr Katherine Vorvolakos and Dr Eric Sussman for providing the feedback on the manuscript; Defense Advanced Research Projects Agency Microsystems Technology Office (DARPA, MTO) for funding through an Interagency Agreement with the US Food and Drug Administration (FDA-DARPA 224-10-6006). NR 73 TC 10 Z9 10 U1 2 U2 14 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 2015 VL 12 IS 2 AR 026003 DI 10.1088/1741-2560/12/2/026003 PG 16 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA CD3NQ UT WOS:000350985900004 PM 25627426 ER PT J AU Perivilli, S Kakhi, M Stippler, E AF Perivilli, Satish Kakhi, Maziar Stippler, Erika TI Computational Fluid Dynamics Simulation of Hydrodynamics in USP Apparatus 3-The Influence of Dip Rate SO PHARMACEUTICAL RESEARCH LA English DT Article DE apparatus 3; computational fluid dynamics; dissolution testing; hydrodynamics; wall shear stress ID DRUG-RELEASE; DISSOLUTION; FLOW AB Purpose This study investigated the influence of dip rate on USP Apparatus 3 hydrodynamics in the presence of a solid dosage form (e g. tablet) using Computational Fluid Dynamics (CFD) simulations. The primary variables of interest were the liquid phase velocity in the computational domain and wall shear stresses on the tablet surfaces. Methods Geometry building and model setup were based on a number of simplifying assumptions. Computational grid-independent solutions were achieved for dip rates ranging from 5 to 10 dips per minute (dpm). Results For all cases studied, the hydrodynamics exhibited a periodicity dictated by the dip rate. Cycle-to-cycle variations were found to be negligible. Higher velocities were predicted in the wake of the tablet and they peaked at midway positions both during the up- and downstrokes of the cylinder. Three sub-regions of velocity were identified inside the reciprocating cylinder. Results also showed localized vortices/recirculations specific to the up- and downstroke, in addition to local stagnation zones. The wall shear stresses and velocity magnitudes scaled proportionately with increasing dip rates while exhibiting qualitatively similar behavior in their spatial and temporal distributions. Conclusions Based on the predictions of the 2D axisymmetric CFD model, the hydrodynamics in USP Apparatus 3 is characterized by complex and periodic flow structures. C1 [Perivilli, Satish; Stippler, Erika] US Pharmacopeial Convent Inc, Rockville, MD 20852 USA. [Kakhi, Maziar] US FDA, Off Testing & Res, Silver Spring, MD 20993 USA. RP Perivilli, S (reprint author), US Pharmacopeial Convent Inc, 12601 Twinbrook Pkwy, Rockville, MD 20852 USA. EM svp@usp.org NR 18 TC 1 Z9 1 U1 1 U2 5 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 APR PY 2015 VL 32 IS 4 BP 1304 EP 1315 DI 10.1007/s11095-014-1534-9 PG 12 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA CD6AG UT WOS:000351169800011 PM 25407541 ER PT J AU Menis, M Forshee, RA Anderson, SA McKean, S Gondalia, R Warnock, R Johnson, C Mintz, PD Worrall, CM Kelman, JA Izurieta, HS AF Menis, M. Forshee, R. A. Anderson, S. A. McKean, S. Gondalia, R. Warnock, R. Johnson, C. Mintz, P. D. Worrall, C. M. Kelman, J. A. Izurieta, H. S. TI Febrile non-haemolytic transfusion reaction occurrence and potential risk factors among the US elderly transfused in the inpatient setting, as recorded in Medicare databases during 2011-2012 SO VOX SANGUINIS LA English DT Article DE administrative databases; elderly; febrile non-haemolytic transfusion reaction; inpatient; Medicare; potential risk factors ID OUTCOMES FOLLOWING INSTITUTION; CELLULAR BLOOD COMPONENTS; UNIVERSAL LEUKOREDUCTION; ADMINISTRATIVE DATA; NONINFECTIOUS COMPLICATIONS; REDUCTION; PLATELETS; RATES; RBCS AB Background and ObjectivesFebrile non-haemolytic transfusion reaction (FNHTR) is an acute transfusion complication resulting in fever, chills and/or rigours. Study's objective was to assess FNHTR occurrence and potential risk factors among inpatient U.S. elderly Medicare beneficiaries, ages 65 and older, during 2011-2012. Materials and MethodsOur retrospective claims-based study utilized large Medicare administrative databases. FNHTR was ascertained via ICD-9-CM diagnosis code, and transfusions were identified by recorded procedure and revenue centre codes. The study ascertained FNHTR rates among the inpatient elderly overall and by age, gender, race, blood components and units transfused. Multivariate logistic regression analyses were used to assess potential risk factors. ResultsAmong 4336338 inpatient transfusion stays for elderly during 2011-2012, 2517 had FNHTR diagnosis recorded, an overall rate of 580 per 100000 stays. FNHTR rates (per 100000 stays) varied by age, gender, number of units and blood components transfused. FNHTR rates were substantially higher for RBCs- and platelets-containing transfusions as compared to plasma only. Significantly higher odds of FNHTR were identified with greater number of units transfused (P<001), for females vs. males (OR=115, 95% CI 104-127), and with 1-year histories of transfusion (OR=125, 95% CI 110-142), lymphoma (OR=122, 95% CI 102-146), leukaemia (OR=190, 95% CI 156-231) and other diseases. ConclusionsOur study shows increased FNHTR occurrence among elderly with greater number of units and with RBCs- and platelets-containing transfusions, suggesting need to evaluate effectiveness of prestorage leucoreduction in elderly. The study also suggests importance of prior recipient alloimmunization and underlying health conditions in the development of FNHTR. C1 [Menis, M.; Forshee, R. A.; Anderson, S. A.; Mintz, P. D.; Izurieta, H. S.] US FDA, Silver Spring, MD 20993 USA. [McKean, S.; Gondalia, R.; Warnock, R.; Johnson, C.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.; Kelman, J. A.] Ctr Medicare Serv, Baltimore, MD USA. [Worrall, C. M.; Kelman, J. A.] Ctr Medicaid Serv, Baltimore, MD USA. RP Menis, M (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, 10903 New Hampshire Ave,White Oak Bldg 71, Silver Spring, MD 20993 USA. EM mikhail.menis@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Biologics Evaluation and Research FX This study was funded by the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. NR 45 TC 3 Z9 3 U1 0 U2 2 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 APR PY 2015 VL 108 IS 3 BP 251 EP 261 DI 10.1111/vox.12215 PG 11 WC Hematology SC Hematology GA CE0CW UT WOS:000351473000006 PM 25470076 ER PT J AU Anderson, HA Roche, PA AF Anderson, Howard A. Roche, Paul A. TI MHC class II association with lipid rafts on the antigen presenting cell surface SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Review DE MHC class II; Lipid raft; T lymphocyte; Antigen presenting cell ID PEPTIDE COMPLEXES; MEMBRANE MICRODOMAINS; PLASMA-MEMBRANE; DENDRITIC CELLS; IMMUNOLOGICAL SYNAPSE; CHOLESTEROL-RICH; INVARIANT CHAIN; T-CELLS; HLA-DR; MOLECULES AB MHC class II (MHC-II) molecules function by binding peptides derived from either self or foreign proteins and expressing these peptides on the surface of antigen presenting cells (APCs) for recognition by CD4T cells. MHC-II is known to exist on clusters on the surface of APCs, and a variety of biochemical and functional studies have suggested that these clusters represent lipid raft microdomain-associated MHC-II. This review will summarize data exploring the biosynthesis of raft-associated MHC-II and the role that lipid raft association plays in regulating T cell activation by APCs. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling. Published by Elsevier B.V. C1 [Anderson, Howard A.] Ctr Drug Evaluat & Res, Div Therapeut Prot, Food & Drug Adm, Silver Spring, MD 20993 USA. [Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov FU National Cancer Institute; U.S. Food and Drug Administration FX The work from the Roche laboratory cited in this review was supported by the Intramural Research Program of the National Cancer Institute. H.A.A. is supported by the U.S. Food and Drug Administration. NR 71 TC 8 Z9 8 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD APR PY 2015 VL 1853 IS 4 SI SI BP 775 EP 780 DI 10.1016/j.bbamcr.2014.09.019 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CD2UX UT WOS:000350935600003 PM 25261705 ER PT J AU Vallelian, F Deuel, JW Opitz, L Schaer, CA Puglia, M Lonn, M Engelsberger, W Schauer, S Karnaukhova, E Spahn, DR Stocker, R Buehler, PW Schaer, DJ AF Vallelian, F. Deuel, J. W. Opitz, L. Schaer, C. A. Puglia, M. Loenn, M. Engelsberger, W. Schauer, S. Karnaukhova, E. Spahn, D. R. Stocker, R. Buehler, P. W. Schaer, D. J. TI Proteasome inhibition and oxidative reactions disrupt cellular homeostasis during heme stress SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID GUINEA-PIGS; HEMOGLOBIN; HAPTOGLOBIN; PROTEINS; DEGRADATION; COMPLEX; PEROXIDATION; MECHANISMS; EXPRESSION; INDUCTION AB Dual control of cellular heme levels by extracellular scavenger proteins and degradation by heme oxygenases is essential in diseases associated with increased heme release. During severe hemolysis or rhabdomyolysis, uncontrolled heme exposure can cause acute kidney injury and endothelial cell damage. The toxicity of heme was primarily attributed to its pro-oxidant effects; however additional mechanisms of heme toxicity have not been studied systematically. In addition to redox reactivity, heme may adversely alter cellular functions by binding to essential proteins and impairing their function. We studied inducible heme oxygenase (Hmox1)-deficient mouse embryo fibroblast cell lines as a model to systematically explore adaptive and disruptive responses that were triggered by intracellular heme levels exceeding the homeostatic range. We extensively characterized the proteome phenotype of the cellular heme stress responses by quantitative mass spectrometry of stable isotope-labeled cells that covered more than 2000 individual proteins. The most significant signals specific to heme toxicity were consistent with oxidative stress and impaired protein degradation by the proteasome. This ultimately led to an activation of the response to unfolded proteins. These observations were explained mechanistically by demonstrating binding of heme to the proteasome that was linked to impaired proteasome function. Oxidative heme reactions and proteasome inhibition could be differentiated as synergistic activities of the porphyrin. Based on the present data a novel model of cellular heme toxicity is proposed, whereby proteasome inhibition by heme sustains a cycle of oxidative stress, protein modification, accumulation of damaged proteins and cell death. C1 [Vallelian, F.; Deuel, J. W.; Schaer, C. A.; Puglia, M.; Engelsberger, W.; Schaer, D. J.] Univ Zurich Hosp, Div Internal Med, CH-8091 Zurich, Switzerland. [Opitz, L.; Puglia, M.; Schauer, S.] Univ Zurich, Swiss Fed Inst Technol Zurich, Funct Genom Ctr Zurich, Zurich, Switzerland. [Schaer, C. A.; Spahn, D. R.] Univ Zurich, Inst Anesthesiol, Zurich, Switzerland. [Loenn, M.; Stocker, R.] Univ Sydney, Sch Med Sci, Discipline Pathol, Sydney, NSW 2006, Australia. [Loenn, M.; Stocker, R.] Univ Sydney, Bosch Inst, Sydney, NSW 2006, Australia. [Karnaukhova, E.; Buehler, P. W.] FDA, CBER, Lab Biochem & Vasc Biol, Bethesda, MD USA. [Stocker, R.] Victor Chang Cardiac Res Inst, Sydney, NSW, Australia. [Stocker, R.] Univ New S Wales, Sydney, NSW, Australia. [Schaer, D. J.] Univ Zurich, Ctr Evolutionary Med, Zurich, Switzerland. RP Schaer, DJ (reprint author), Univ Zurich Hosp, Div Internal Med, Ramistr 100, CH-8091 Zurich, Switzerland. EM dominik.schaer@usz.ch OI Deuel, Jeremy/0000-0002-5409-7712 FU Swiss National Science Foundation [310030/120658, 31003A/138500]; University of Zurich Research Priority Program 'Integrative Human Physiology'; Swiss Federal Commission for Technology and Innovation (CTI); 'Patient Blood Management' Program of the Department of Health of the Canton of Zurich, Switzerland; National Health & Medical Research Council (NHMRC) of Australia FX This work was supported by the Swiss National Science Foundation (Grants 310030/120658 and 31003A/138500 to DJS); the University of Zurich Research Priority Program 'Integrative Human Physiology'; the Swiss Federal Commission for Technology and Innovation (CTI); the 'Patient Blood Management' Program of the Department of Health of the Canton of Zurich, Switzerland; and the National Health & Medical Research Council (NHMRC) of Australia to RS. ML was also supported by a short-term visiting fellowship from the Swiss National Science Foundation. NR 34 TC 6 Z9 6 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD APR PY 2015 VL 22 IS 4 BP 597 EP 611 DI 10.1038/cdd.2014.154 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CD1TM UT WOS:000350857200010 PM 25301065 ER PT J AU Gupta, S Pelton, AR Weaver, JD Gong, XY Nagaraja, S AF Gupta, Shikha Pelton, Alan R. Weaver, Jason D. Gong, Xiao-Yan Nagaraja, Srinidhi TI High compressive pre-strains reduce the bending fatigue life of nitinol wire SO JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS LA English DT Article DE Nitinol; Pseudoelastic; Shape memory; Fatigue; Bending; Crimp; Pre-strain; Endovascular ID SHAPE-MEMORY ALLOYS; NI SINGLE-CRYSTALS; MARTENSITIC-TRANSFORMATION; POLYCRYSTALLINE NITI; SUPERELASTIC NITINOL; MEDICAL APPLICATIONS; PHYSICAL METALLURGY; SEPTAL OCCLUDER; VALVE STENT; FRACTURE AB Prior to implantation, Nitinol-based transcatheter endovascular devices are subject to a complex thermo-mechanical pre-strain associated with constraint onto a delivery catheter, device sterilization, and final deployment. Though such large thermo-mechanical excursions are known to impact the microstructural and mechanical properties of Nitinol, their effect on fatigue properties is still not well understood. The present study investigated the effects of large thermo-mechanical pre-strains on the fatigue of pseudoelastic Nitinol wire using fully reversed rotary bend fatigue (RBF) experiments. Electropolished Nitinol wires were subjected to a 0%, 8% or 10% bending pre-strain and RBF testing at 0.3-1.5% strain amplitudes for up to 10(8) cycles. The imposition of 8% or 10% bending pre-strain resulted in residual set in the wire. Large pre-strains also significantly reduced the fatigue life of Nitinol wires below 0.8% strain amplitude. While 0% and 8% pre-strain wires exhibited distinct low-cycle and high-cycle fatigue regions, reaching run out at 108 cycles at 0.6% and 0.4% strain amplitude, respectively, 10% pre-strain wires continued to fracture at less than 10(5) cycles, even at 0.3% strain amplitude. Furthermore, over 70% fatigue cracks were found to initiate on the compressive pre-strain surface in pre-strained wires. In light of the texture-dependent tension-compression asymmetry in Nitinol, this reduction in fatigue life and preferential crack initiation in pre-strained wires is thought to be attributed to compressive pre-strain-induced plasticity and tensile residual stresses as well as the formation of martensite variants. Despite differences in fatigue life, SEM revealed that the size, shape and morphology of the fatigue fracture surfaces were comparable across the pre-strain levels. Further, the mechanisms underlying fatigue were found to be similar; despite large differences in cycles to failure across strain amplitudes and pre-strain levels, cracks initiated from surface inclusions in nearly all wires. Compressive pre-strain-induced damage may accelerate such crack initiation, thereby reducing fatigue life. The results of the present study indicate that large compressive pre-strains are detrimental to the fatigue properties of Nitinol, and, taken together, the findings underscore the importance of accounting for thermo-mechanical history in the design and testing of wire-based percutaneous implants. Published by Elsevier Ltd. C1 [Gupta, Shikha; Weaver, Jason D.; Nagaraja, Srinidhi] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Appl Mech, Silver Spring, MD 20993 USA. [Pelton, Alan R.] G RAU Inc, Fremont, CA USA. [Gong, Xiao-Yan] Med Implant Mech, Irvine, CA USA. RP Nagaraja, S (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 2210, Silver Spring, MD 20993 USA. EM srinidhi.nagaraja@fda.hhs.gov OI NAGARAJA, SRINIDHI/0000-0001-7394-7164 FU FDA Commissioner's Fellowship Program FX The authors would like to acknowledge support from the FDA Commissioner's Fellowship Program. Nitinol wires were provided by Nitinol Devices and Components through a materials transfer agreement. We would like to thank Lot Vien for assistance with electropolished wire fabrication, Jason Galginaitis and Timothy Murphy for their assistance with fatigue testing and SEM analysis, Hamed Ghods and Glenn Link for modifying RBT systems. We also acknowledge stimulating conversations with Professor Aaron Stebner (Colorado School of Mines). NR 64 TC 2 Z9 2 U1 3 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1751-6161 EI 1878-0180 J9 J MECH BEHAV BIOMED JI J. Mech. Behav. Biomed. Mater. PD APR PY 2015 VL 44 BP 96 EP 108 DI 10.1016/j.jmbbm.2014.12.007 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CD1LK UT WOS:000350836200011 PM 25625888 ER PT J AU Wong, JM Jones, JW Jiang, WL Polli, JE Kane, MA AF Wong, Jessica M. Jones, Jace W. Jiang, Wenlei Polli, James E. Kane, Maureen A. TI Quantification of Lamotrigine in Patient Plasma Using a Fast Liquid Chromatography-Tandem Mass Spectrometry Method With Backflush Technology SO THERAPEUTIC DRUG MONITORING LA English DT Article DE lamotrigine; high performance liquid chromatography; tandem mass spectrometry; human plasma; quantification; backflush; fast LC; bioequivalence; pharmacokinetics ID 10 ANTIEPILEPTIC DRUGS; HUMAN SERUM; LC-MS/MS; FAST GRADIENT; PERFORMANCE; CARBAMAZEPINE; PHENYTOIN; HPLC; ASSAY; METABOLITES AB Background: Recent concerns have been raised by neurologists and patients with epilepsy regarding the bioequivalence of generic lamotrigine to the brand Lamictal. Bioequivalence studies require the quantification of lamotrigine in human plasma, including in the presence of other drugs, for studies that will use patients with epilepsy rather than healthy volunteers. Methods: Lamotrigine was extracted from plasma through a simple protein precipitation and analyzed by fast liquid chromatography coupled to heated electrospray ionization with tandem mass spectrometric detection. A backflush step to remove interferent accumulation on column was included, and a stable isotope-labeled lamotrigine was used as an internal standard. The method was validated for accuracy, precision, interday and intraday coefficient of variation, specificity, lower limit of detection, lower limit of quantification, linearity, range, instrument precision, freeze-thaw, dilution integrity, and sample stability. Specificity evaluation included consideration of the impact of other antiepileptic drugs. Results: The described method has a linear range of 8-10,000 ng/mL of lamotrigine (r(2) = 0.9999) and a lower limit of detection of 1 ng/mL and a lower limit of quantification of 8 ng/mL. Intraday and interday reproducibility were less than 10.0% relative SD and 10.4% relative SD, respectively, and the percent recovery varied from 96.6% to 109.3% at various lamotrigine concentrations. A backflush step reduced matrix effects and no interference peak from plasma or other antiepileptic drugs were observed. Conclusions: A liquid chromatography-heated electrospray ionization-tandem mass spectrometry method including a backflush step was developed and validated to measure lamotrigine concentration in patient plasma. The method will be applied to bioequivalence studies that compare brand versus generic lamotrigine. C1 [Wong, Jessica M.; Jones, Jace W.; Polli, James E.; Kane, Maureen A.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Jiang, Wenlei] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, Rockville, MD 20857 USA. RP Kane, MA (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Room 723N,Pharm Hall,20 N Pine St, Baltimore, MD 21201 USA. EM mkane@rx.umaryland.edu FU FDA [HHSF223201010144A]; University of Maryland School of Pharmacy Mass Spectrometry Center [SOP1841-IQB2014] FX Supported by FDA (contract no. HHSF223201010144A). Also supported by the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014). NR 54 TC 3 Z9 3 U1 2 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0163-4356 EI 1536-3694 J9 THER DRUG MONIT JI Ther. Drug Monit. PD APR PY 2015 VL 37 IS 2 BP 188 EP 197 PG 10 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA CD3SW UT WOS:000351002200007 PM 25162213 ER PT J AU Liu, W Zhang, B Zhang, ZW Chen, BJ Zhou, XH AF Liu, Wei Zhang, Bo Zhang, Zhiwei Chen, Baojiang Zhou, Xiao-Hua TI A pseudo-likelihood approach for estimating diagnostic accuracy of multiple binary medical tests SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article DE Sensitivity and specificity; Random effects; Latent class models; Composite likelihood; Imperfect reference standards ID GENERALIZED LINEAR-MODELS; LATENT CLASS ANALYSIS; GOLD STANDARD; MIXED MODELS; EM ALGORITHM; SPECIFICITY; SENSITIVITY; RATERS; CANCER; ERROR AB Latent class models with crossed subject-specific and test(rater)-specific random effects have been proposed to estimate the diagnostic accuracy (sensitivity and specificity) of a group of binary tests or binary ratings. However, the computation of these models are hindered by their complicated Monte Carlo Expectation-Maximization (MCEM) algorithm. In this article, a class of pseudo-likelihood functions is developed for conducting statistical inference with crossed random-effects latent class models in diagnostic medicine. Theoretically, the maximum pseudo-likelihood estimation is still consistent and has asymptotic normality. Numerically, our results show that not only the pseudo-likelihood approach significantly reduces the computational time, but it has comparable efficiency relative to the MCEM algorithm. In addition, dimension-wise likelihood, one of the proposed pseudo-likelihoods, demonstrates its superior performance in estimating sensitivity and specificity. Published by Elsevier B.V. C1 [Liu, Wei] Harbin Inst Technol, Dept Math, Harbin 150001, Peoples R China. [Zhang, Bo; Zhang, Zhiwei] Food & Drug Adm, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Div Biostat, Silver Spring, MD 20993 USA. [Chen, Baojiang] Univ Nebraska, Coll Publ Hlth, Med Ctr, Dept Biostat, Omaha, NE 68198 USA. [Zhou, Xiao-Hua] Univ Washington, HSR&D Ctr Excellence, Sch Publ Hlth & Community Med, US Dept Vet Affairs Puget Sound Hlth Care Syst,De, Seattle, WA 98198 USA. RP Zhang, B (reprint author), Food & Drug Adm, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Div Biostat, Silver Spring, MD 20993 USA. EM Bo.Zhang@fda.hhs.gov NR 40 TC 0 Z9 0 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 EI 1872-7352 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD APR PY 2015 VL 84 BP 85 EP 98 DI 10.1016/j.csda.2014.11.006 PG 14 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA AZ5LT UT WOS:000348263200007 ER PT J AU Wang, H Gill, VS Cheng, CM Gonzalez-Escalona, N Irvin, KA Zheng, J Bell, RL Jacobson, AP Hammack, TS AF Wang, Hua Gill, Vikas S. Cheng, Chorng-Ming Gonzalez-Escalona, Narjol Irvin, Kari A. Zheng, Jie Bell, Rebecca L. Jacobson, Andrew P. Hammack, Thomas S. TI Evaluation and comparison of rapid methods for the detection of Salmonella in naturally contaminated pine nuts using different pre enrichment media SO FOOD MICROBIOLOGY LA English DT Article DE Salmonella; Pre enrichment media; qPCR; Pathatrix (R) Auto; VIDAS (R) Easy; DNA extraction; PrepSEQ (TM); Pine nuts ID REAL-TIME PCR; UNIVERSAL PREENRICHMENT BROTH; IMMUNOMAGNETIC-SEPARATION; FOOD-PRODUCTS; COLI O157H7; RECOVERY; VALIDATION; SPP.; SYSTEM; CANTALOUPES AB Foodborne outbreaks, involving pine nuts and peanut butter, illustrate the need to rapidly detect Salmonella in low moisture foods. However, the current Bacteriological Analytical Manual (BAM) culture method for Salmonella, using lactose broth (LB) as a pre enrichment medium, has not reliably supported real-time quantitative PCR (qPCR) assays for certain foods. We evaluated two qPCR assays in LB and four other pre enrichment media: buffered peptone water (BPW), modified BPW (mBPW), Universal Pre enrichment broth (UPB), and BAX(R) MP media to detect Salmonella in naturally-contaminated pine nuts (2011 outbreak). A four-way comparison among culture method, Pathatrix(R) Auto, VIDAS(R) Easy SLM, and qPCR was conducted. Automated DNA extraction techniques were compared with manual extraction methods (boiling or InstaGene(TM)). There were no significant differences (P > 0.05) among the five pre enrichment media for pine nuts using the culture method. While both qPCR assays produced significantly (P <= 0.05) higher false negatives in 24 h pre enriched LB than in the other four media, they were as sensitive as the culture method in BPW, mBPW, UPB, and BAX media. The VIDAS Easy and qPCR were equivalent; Pathatrix was the least effective method. The Automatic PrepSEQ(TM) DNA extraction, using 1000 mu L of pre enrichment, was as effective as manual extraction methods. Published by Elsevier Ltd. C1 [Wang, Hua; Gill, Vikas S.; Gonzalez-Escalona, Narjol; Zheng, Jie; Bell, Rebecca L.; Jacobson, Andrew P.; Hammack, Thomas S.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Cheng, Chorng-Ming] US FDA, Pacific Reg Lab Southwest, Irvine, CA 92612 USA. [Irvin, Kari A.] US FDA, Coordinated Outbreak Response & Evaluat Network, College Pk, MD 20740 USA. RP Wang, H (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Microbial Methods Dev Branch,Div Microbiol, 5100 Paint Branch Pkwy,HFS-711, College Pk, MD 20740 USA. EM hua.wang@fda.hhs.gov OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 NR 42 TC 7 Z9 7 U1 9 U2 70 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD APR PY 2015 VL 46 BP 58 EP 65 DI 10.1016/j.fm.2014.06.028 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AW0OM UT WOS:000345992200008 PM 25475267 ER PT J AU Grasso, EM Grove, SF Halik, LA Arritt, F Keller, SE AF Grasso, Elizabeth M. Grove, Stephen F. Halik, Lindsay A. Arritt, Fletcher Keller, Susanne E. TI Cleaning and sanitation of Salmonella-contaminated peanut butter processing equipment SO FOOD MICROBIOLOGY LA English DT Article DE Peanut butter; Salmonella; Sanitation ID LOW-WATER ACTIVITY; FOODBORNE PATHOGENS; HEAT TOLERANCE; SURVIVAL; FOODS; TYPHIMURIUM; RESISTANCE; TENNESSEE; OUTBREAK; SEROVARS AB Microbial contamination of peanut butter by Salmonella poses a significant health risk as Salmonella may remain viable throughout the product shelf life. Effective cleaning and sanitation of processing lines are essential for preventing cross-contamination. The objective of this study was to evaluate the efficacy of a cleaning and sanitation procedure involving hot oil and 60% isopropanol, +/- quaternary ammonium compounds, to decontaminate pilot-scale processing equipment harboring Salmonella. Peanut butter inoculated with a cocktail of four Salmonella serovars (similar to 7 log CFU/g) was used to contaminate the equipment (similar to 75 L). The system was then emptied of peanut butter and treated with hot oil (90 degrees C) for 2 h followed by sanitizer for 1 h. Microbial analysis of food-contact surfaces (7 locations), peanut butter, and oil were conducted. Oil contained similar to 3.2 log CFU/mL on both trypticase soy agar with yeast extract (TSAYE) and xylose lysine deoxycholate (XLD), indicating hot oil alone was not sufficient to inactivate Salmonella. Environmental sampling found 0.25-1.12 log CFU/cm(2) remaining on processing equipment. After the isopropanol sanitation (+/- quaternary ammonium compounds), no Salmonella was detected in environmental samples on XLD (< 0.16 log CFU/cm(2)). These data suggest that a two-step hot oil clean and isopropanol sanitization treatment may eliminate pathogenic Salmonella from contaminated equipment. (C) 2014 The Authors. Published by Elsevier Ltd. C1 [Grasso, Elizabeth M.] US FDA, Off Commissioner, Bedford Pk, IL 60501 USA. [Grove, Stephen F.] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Halik, Lindsay A.; Keller, Susanne E.] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Arritt, Fletcher] N Carolina State Univ, Dept Food Bioproc & Nutr Sci, Raleigh, NC 27695 USA. RP Grasso, EM (reprint author), IIT, Inst Food Safety & Hlth, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. EM egrasso@iit.edu; sgrove@iit.edu; lhalik@iit.edu; fmarritt@ncsu.edu; Susanne.Keller@fda.hhs.gov FU U.S. Food and Drug Administration; U.S. Food and Drug Administration, Office of the Commissioner, Commissioner's Fellowship Program (CFP); International Life Sciences Institute (ILSI) North America FX This work was supported by the U.S. Food and Drug Administration and by appointments to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U. S. Department of Energy and the U. S. Food and Drug Administration. This project was also supported by the U.S. Food and Drug Administration, Office of the Commissioner, Commissioner's Fellowship Program (CFP). This project was also supported by the International Life Sciences Institute (ILSI) North America. NR 34 TC 1 Z9 1 U1 2 U2 70 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD APR PY 2015 VL 46 BP 100 EP 106 DI 10.1016/j.fm.2014.03.003 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AW0OM UT WOS:000345992200013 PM 25475272 ER PT J AU Kase, JA Maounounen-Laasri, A Son, I Lin, A Hammack, TS AF Kase, Julie A. Maounounen-Laasri, Anna Son, Insook Lin, Andrew Hammack, Thomas S. TI Comparison of eight different agars for the recovery of clinically relevant non-O157 Shiga toxin-producing Escherichia coli from baby spinach, cilantro, alfalfa sprouts and raw milk SO FOOD MICROBIOLOGY LA English DT Article DE Bacteriological agar; STEC; Fresh produce; Raw milk ID HEALTHY DOMESTIC-ANIMALS; WASHED BLOOD AGAR; SEROGROUPS O26; CATTLE; PREVALENCE; STEC; BEEF; O145; O111; O103 AB The FDA Bacteriological Analytical Manual (BAM) Chapter 4a recommends several agars for isolating non-O157 Shiga toxin-producing Escherichia coli (STEC); not all have been thoroughly tested for recovering STECs from food. Using E. coli strains representing ten clinically relevant O serogroups (O26, O45, O91, O103, O104, O111, O113, O121, O128, O145) in artificially-contaminated fresh produce - bagged baby spinach, alfalfa sprouts, cilantro, and raw milk - we evaluated the performance of 8 different agars. Performance was highly dependent upon strain used and the presence of inhibitors, but not necessarily dependent on food matrix. Tellurite resistant-negative strains, O91:-, O103:H6, O104:H21, O113:H21, and O128, grew poorly on CHROMagar STEC, Rainbow agar O157, and a modified Rainbow O157 (mRB) agar. Although adding washed sheep's blood to CHROMagar STEC and mRB agars improved overall performance; however, this also reversed the inhibition of non-target bacteria provided by original formulations. Variable colony coloration made selecting colonies from Rainbow agar O157 and mRB agars difficult. Study results support a strategy using inclusive agars (e.g. L-EMB, SHIBAM) in combination with selective agars (R & F E. coli O157:H7, CHROMagar STEC) to allow for recovery of the most STECs while increasing the probability of recovering STEC in high bacterial count matrices. Published by Elsevier Ltd. C1 [Kase, Julie A.; Son, Insook; Hammack, Thomas S.] US FDA, Div Microbiol, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Maounounen-Laasri, Anna] Oak Ridge Res Inst Sci & Educ, Oak Ridge, TN 37830 USA. [Lin, Andrew] US FDA, Off Regulatory Affairs San Francisco Lab, Alameda, CA 94502 USA. RP Kase, JA (reprint author), US FDA, Microbial Methods Dev Branch, Div Microbiol, Off Regulatory Sci,Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,Rm 3E-023,HFS 711, College Pk, MD 20740 USA. EM julie.kase@fda.hhs.gov; Anna.Laasri@fda.hhs.gov; Insook.Son@fda.hhs.gov; Andrew.Lin@fda.hhs.gov; Thomas.Hammack@fda.hhs.gov FU Center for Food Safety and Applied Nutrition FX This project was supported in part by an appointment to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education (AM-L). We thank Dr. Lili Fox Velez (FDA CFSAN) for her critical review of the manuscript and subsequent suggestions. NR 27 TC 10 Z9 10 U1 5 U2 56 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD APR PY 2015 VL 46 BP 280 EP 287 DI 10.1016/j.fm.2014.08.020 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AW0OM UT WOS:000345992200038 PM 25475297 ER PT J AU Yang, QR Wang, F Jones, KL Meng, JH Prinyawiwatkul, W Ge, BL AF Yang, Qianru Wang, Fei Jones, Kelly L. Meng, Jianghong Prinyawiwatkul, Witoon Ge, Beilei TI Evaluation of loop-mediated isothermal amplification for the rapid, reliable, and robust detection of Salmonella in produce SO FOOD MICROBIOLOGY LA English DT Article DE Detection; LAMP; Produce; qPCR; Salmonella ID REAL-TIME PCR; ESCHERICHIA-COLI; UNITED-STATES; LISTERIA-MONOCYTOGENES; FOOD; ENTERICA; LAMP; EGGS; SPP.; SURVEILLANCE AB Rapid, reliable, and robust detection of Salmonella in produce remains a challenge. In this study, loop-mediated isothermal amplification (LAMP) was comprehensively evaluated against real-time quantitative PCR (qPCR) for detecting diverse Salmonella serovars in various produce items (cantaloupe, pepper, and several varieties of lettuce, sprouts, and tomato). To mimic real-world contamination events, produce samples were surface-inoculated with low concentrations (1.1-2.9 CFU/25 g) of individual Salmonella strains representing ten serovars and tested after aging at 4 degrees C for 48 h. Four DNA extraction methods were also compared using produce enrichment broths. False-positive or false-negative results were not observed among 178 strains (151 Salmonella and 27 non-Salmonella) used to evaluate assay specificity. The detection limits for LAMP were 1.8-4 CFU per reaction in pure culture and 10(4)-10(6) CFU per 25 g (i.e., 10(2)-10(4) CFU per g) in produce without enrichment, comparable to those obtained by qPCR. After 6-8 h of enrichment, both LAMP and qPCR consistently detected these low concentrations of Salmonella of diverse serovars in all produce items except sprouts. The PrepMan Ultra sample preparation reagent yielded the best results among the four DNA extraction methods. Upon further validation, LAMP may be a valuable tool for routine Salmonella testing in produce. The difficulty of detecting Salmonella in sprouts, whether using LAMP or qPCR, warrants further study. Published by Elsevier Ltd. C1 [Yang, Qianru; Wang, Fei; Jones, Kelly L.; Ge, Beilei] US FDA, Div Anim & Food Microbiol, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. [Yang, Qianru; Prinyawiwatkul, Witoon] Louisiana State Univ, Ctr Agr, Dept Food Sci, Baton Rouge, LA 70803 USA. [Wang, Fei; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. RP Ge, BL (reprint author), US FDA, Div Anim & Food Microbiol, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM beilei.ge@fda.hhs.gov FU Center for Produce Safety at the University of California, Davis [SCB11064] FX This work was supported in part by a research grant (SCB11064) from the Center for Produce Safety at the University of California, Davis. NR 36 TC 3 Z9 5 U1 2 U2 84 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD APR PY 2015 VL 46 BP 485 EP 493 DI 10.1016/j.fm.2014.09.011 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AW0OM UT WOS:000345992200060 PM 25475319 ER PT J AU Dailey, RC Welch, LJ Hitchins, AD Smiley, RD AF Dailey, Rachel C. Welch, Lacinda J. Hitchins, Anthony D. Smiley, R. Derike TI Effect of Listeria seeligeri or Listeria welshimeri on Listeria monocytogenes detection in and recovery from buffered Listeria enrichment broth SO FOOD MICROBIOLOGY LA English DT Article DE Regulatory microbiology; Foodborne pathogen; Microbial competition; Real-time PCR; Immunofluorescence assay; Lateral flow device; Analytical microbiology; Selective enrichment; Listeria ID INNOCUA; FOOD; SAMPLES; COMPETITION; BACTERIA; GROWTH AB The presence of multiple species of Listeria in regulated food products is not uncommon and can complicate the recovery of Listeria monocytogenes particularly on a non-differentiating medium. The potential complications of Listeria seeligeri and Listeria welshimeri on the recovery of L. monocytogenes from inoculated food test samples using the U. S. Food and Drug Administration's (FDA) selective enrichment procedure was investigated. Post-enrichment enumeration, in the absence of food product, indicates that some L. seeligeri and L. monocytogenes pairings may have population differentials as great as 2.7 +/- 0.1 logs with L. seeligeri being the predominant species. A similar observation was noted for L. welshimeri and L. monocytogenes pairings which resulted in population differentials as large as 3.7 +/- 0.2 logs with L. welshimeri being the predominant species. Select strain pairings were used to inoculate guacamole, crab meat, broccoli, and cheese with subsequent recovery by the FDA Bacteriological Analytical Manual (BAM) method with 10 colonies per sample selected for confirmation. The presence of L. seeligeri had little effect on the recovery of L. monocytogenes. The presence of L. welshimeri resulted in the failure to recover L. monocytogenes in three out of the four food matrices. This work extends the observation that non-pathogenic species of Listeria can complicate the recovery of L. monocytogenes and that competition during selective enrichment is not limited to the presence of just Listeria innocua. Published by Elsevier Ltd. C1 [Dailey, Rachel C.; Welch, Lacinda J.; Smiley, R. Derike] US FDA, Arkansas Reg Lab, Jefferson, AR 72079 USA. [Hitchins, Anthony D.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20705 USA. RP Smiley, RD (reprint author), US FDA, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Ronald.Smiley@fda.hhs.gov FU U.S. FDA's Office of Regulatory Affairs; Arkansas Regional Laboratory FX The authors thank the U.S. FDA's Office of Regulatory Affairs and the Arkansas Regional Laboratory for their support of this research. The authors would like to thank Christina Stam from FDA/CFSAN and Brooke Whitney from FDA/CVM for critically reviewing the manuscript. NR 16 TC 3 Z9 3 U1 8 U2 58 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD APR PY 2015 VL 46 BP 528 EP 534 DI 10.1016/j.fm.2014.09.008 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AW0OM UT WOS:000345992200066 PM 25475325 ER PT J AU Day, JB Basavanna, U AF Day, J. B. Basavanna, U. TI Magnetic bead based immuno-detection of Listeria monocytogenes and Listeria ivanovii from infant formula and leafy green vegetables using the Bio-Plex suspension array system SO FOOD MICROBIOLOGY LA English DT Article DE Listeria; Detection; Foods; Macrophage; Bio-Plex ID REAL-TIME PCR; ESCHERICHIA-COLI O157-H7; CELL-CULTURE METHOD; TO-EAT FOODS; UNITED-STATES; EPIDEMIC LISTERIOSIS; SUBSEQUENT DETECTION; OUTBREAK; SALMONELLA; VIRULENCE AB Listeriosis, a disease contracted via the consumption of foods contaminated with pathogenic Listeria species, can produce severe symptoms and high mortality in susceptible people and animals. The development of molecular methods and immuno-based techniques for detection of pathogenic Listeria in foods has been challenging due to the presence of assay inhibiting food components. In this study, we utilize a macrophage cell culture system for the isolation and enrichment of Listeria monocytogenes and Listeria ivanovii from infant formula and leafy green vegetables for subsequent identification using the Luminex xMAP technique. Macrophage monolayers were exposed to infant formula, lettuce and celery contaminated with L. monocytogenes or L. ivanovii. Magnetic microspheres conjugated to Listeria specific antibody were used to capture Listeria from infected macrophages and then analyzed using the Bio-Plex 200 analyzer. As few as 10 CFU/mL or g of L. monocytogenes was detected in all foods tested. The detection limit for L. ivanovii was 10 CFU/mL in infant formula and 100 CFU/g in leafy greens. Microsphere bound Listeria obtained from infected macrophage lysates could also be isolated on selective media for subsequent confirmatory identification. This method presumptively identifies L. monocytogenes and L. ivanovii from infant formula, lettuce and celery in less than 28 h with confirmatory identifications completed in less than 48 h. Published by Elsevier Ltd. C1 [Day, J. B.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Basavanna, U.] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Day, JB (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM james.day@fda.hhs.gov NR 56 TC 6 Z9 6 U1 4 U2 57 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD APR PY 2015 VL 46 BP 564 EP 572 DI 10.1016/j.fm.2014.09.020 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AW0OM UT WOS:000345992200070 PM 25475329 ER PT J AU Blaylock, M Blackwell, R Merid, S Jackson, S Kotewicz, M Gopinath, G Ayers, SL Abbott, J Sabo, J Ewing, L Gangiredla, J Gebru, S Patel, I Jones, B Dudley, K Jarvis, K Hanes, DE Diallo, AA Beaubrun, JJG AF Blaylock, Morris Blackwell, Reginald Merid, Sosina Jackson, Scott Kotewicz, Michael Gopinath, Gopal Ayers, Sherry L. Abbott, Jason Sabo, Jonathan Ewing, Laura Gangiredla, Jayanthi Gebru, Solomon Patel, Isha Jones, Brooke Dudley, Kim Jarvis, Karen Hanes, Darcy E. Diallo, Alpha A. Beaubrun, Junia Jean-Gilles TI Comparison of Salmonella enterica serovar Bovismorbificans 2011 hummus outbreak strains with non-outbreak strains SO FOOD MICROBIOLOGY LA English DT Article DE Salmonella; Bovismorbificans; Hummus ID PCR-BASED METHOD; IDENTIFICATION; SEROTYPES; ORIGIN AB Eleven Salmonella enterica serovar Bovismorbificans isolates obtained from the U. S. District of Columbia during a 2011 hummus-associated foodborne outbreak were compared to 12 non-outbreak isolates. All isolates from the outbreak demonstrated a single PFGE pattern that was distinctly different from other isolates of S. Bovismorbificans as recorded in the PulseNet Database. Results from molecular analyses of the hummus-associated S. Bovismorbificans isolates indicate that the isolates from the outbreak were unique and have acquired an 80-90 kb plasmid. The impact of this study is that the information gained will add and expand our knowledge of diversity of the S. Bovismorbificans serovar. Published by Elsevier Ltd. C1 [Blaylock, Morris; Blackwell, Reginald; Merid, Sosina; Diallo, Alpha A.] Dept Forens Sci, Dist Columbia Publ Hlth Lab, Washington, DC 20024 USA. [Jackson, Scott; Kotewicz, Michael; Gopinath, Gopal; Ewing, Laura; Gangiredla, Jayanthi; Gebru, Solomon; Patel, Isha; Jones, Brooke; Dudley, Kim; Jarvis, Karen; Hanes, Darcy E.; Beaubrun, Junia Jean-Gilles] US FDA, Laurel, MD 20708 USA. [Ayers, Sherry L.; Abbott, Jason; Sabo, Jonathan] US FDA, Ctr Vet Med, Laurel, MD 20708 USA. RP Beaubrun, JJG (reprint author), FDA CFSAN OARSA DVA, 8301 Muirkirk Rd,Rm 3404, Laurel, MD 20708 USA. EM junia.jean-gillesbeaubrun@fda.hhs.gov NR 17 TC 0 Z9 0 U1 2 U2 13 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD APR PY 2015 VL 46 BP 627 EP 634 DI 10.1016/j.fm.2014.02.016 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AW0OM UT WOS:000345992200078 PM 25475337 ER PT J AU Moore, T Finley, P Brodsky, N Brown, T Apelberg, B Ambrose, B Glass, R AF Moore, Thomas Finley, Patrick Brodsky, Nancy Brown, Theresa Apelberg, Benjamin Ambrose, Bridget Glass, Robert TI Modeling Education and Advertising with Opinion Dynamics SO JASSS-THE JOURNAL OF ARTIFICIAL SOCIETIES AND SOCIAL SIMULATION LA English DT Article DE Opinion Dynamics; Social Networks; Media; Advertising ID ADOLESCENT SMOKING; MOVIES AB We present a modified Deffuant-Weisbuch opinion dynamics model that integrates the influence of media campaigns on opinion. Media campaigns promote messages intended to inform and influence the opinions of the targeted audiences through factual and emotional appeals. Media campaigns take many forms: brand-specific advertisements, promotions, and sponsorships, political, religious, or social messages, and public health and educational communications. We illustrate model-based analysis of campaigns using tobacco advertising and public health education as examples. In this example, "opinion" is not just an individual's attitude towards smoking, but the integration of a wide range of factors that influence the likelihood that an individual will decide to smoke, such as knowledge, perceived risk, perceived utility and affective evaluations of smoking. This model captures the ability of a media campaign to cause a shift in network-level average opinion, and the inability of a media message to do so if it promotes too extreme a viewpoint for a given target audience. Multiple runs displayed strong heterogeneity in response to media campaigns as the difference between network average initial opinion and broadcasted media opinion increased, with some networks responding ideally and others being largely unaffected. In addition, we show that networks that display community structure can be made more susceptible to be influenced by a media campaign by a complementary campaign focused on increasing tolerance to other opinions in targeted nodes with high betweenness centrality. Similarly, networks can be "inoculated" against advertising campaigns by a media campaign that decreases tolerance. C1 [Moore, Thomas; Finley, Patrick; Brodsky, Nancy; Brown, Theresa; Glass, Robert] Sandia Natl Labs, Albuquerque, NM 87185 USA. [Apelberg, Benjamin; Ambrose, Bridget] US FDA, Ctr Tobacco Prod, Rockville, MD 20850 USA. RP Moore, T (reprint author), Sandia Natl Labs, POB 5800,MS 1138, Albuquerque, NM 87185 USA. EM tmoore@sandia.gov; pdfinle@sandia.gov; nsbrods@sandia.gov; tjbrown@sandia.gov; benjamin.apelberg@fda.hhs.gov; bridget.ambrose@fda.hhs.gov; rjglass@sandia.gov FU U.S. Food and Drug Administration; U.S. Department of Energy/Sandia National Laboratories [224109011]; U.S. Department of Energy's National Nuclear Security Administration [DE-AC04-94AL85000] FX This work was funded by the U.S. Food and Drug Administration through a contract with the U.S. Department of Energy/Sandia National Laboratories (funding document 224109011). Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000. The funders, other than employees named as authors or described in the acknowledgments, had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 0 Z9 0 U1 0 U2 3 PU J A S S S PI GUILDFORD PA UNIV SURREY, DEPT SOCIOLOGY, GUILDFORD GU2 7XH, SURREY, ENGLAND SN 1460-7425 J9 JASSS-J ARTIF SOC S JI JASSS PD MAR 31 PY 2015 VL 18 IS 2 AR 7 PG 11 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA CH9RL UT WOS:000354373800011 ER PT J AU Chen, G Yu, DK Chen, JW Cao, RF Yang, J Wang, H Ji, XJ Ning, BT Shi, TL AF Chen, Geng Yu, Dianke Chen, Jiwei Cao, Ruifang Yang, Juan Wang, Huan Ji, Xiangjun Ning, Baitang Shi, Tieliu TI Re-annotation of presumed noncoding disease/trait-associated genetic variants by integrative analyses SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; RNA-SEQ; FUNCTIONAL ANNOTATION; SUSCEPTIBILITY LOCI; SEQUENCE VARIANTS; COMPLEX TRAITS; ELEMENTS; QUANTIFICATION; TRANSCRIPTS; POPULATION AB Using RefSeq annotations, most disease/trait-associated genetic variants identified by genome-wide association studies (GWAS) appear to be located within intronic or intergenic regions, which makes it difficult to interpret their functions. We reassessed GWAS-Associated single-nucleotide polymorphisms (herein termed as GASs) for their potential functionalities using integrative approaches. 8834 of 9184 RefSeq "noncoding'' GASs were reassessed to have potential regulatory functionalities. As examples, 3 variants (rs3130320, rs3806932 and rs6890853) were shown to have regulatory properties in HepG2, A549 and 293T cells. Except rs3130320 as a known expression quantitative trait loci (eQTL), rs3806932 and rs6890853 were not reported as eQTLs in previous reports. 1999 of 9184 "noncoding'' GASs were re-annotated to the promoters or intragenic regions using Ensembl, UCSC and AceView gene annotations but they were not annotated into corresponding regions in RefSeq database. Moreover, these GAS-harboring genes were broadly expressed across different tissues and a portion of them was expressed in a tissue-specific manner, suggesting that they could be functional. Collectively, our study demonstrates the benefits of using integrative analyses to interpret genetic variants and may help to predict or explain disease susceptibility more accurately and comprehensively. C1 [Chen, Geng; Chen, Jiwei; Cao, Ruifang; Yang, Juan; Wang, Huan; Ji, Xiangjun; Shi, Tieliu] E China Normal Univ, Shanghai Key Lab Regulatory Biol, Ctr Bioinformat & Computat Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China. [Chen, Geng; Chen, Jiwei; Cao, Ruifang; Yang, Juan; Wang, Huan; Ji, Xiangjun; Shi, Tieliu] E China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China. [Yu, Dianke; Ning, Baitang] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chen, Geng] Fudan Univ, Sch Pharm, Ctr Pharmacogen, Shanghai 201203, Peoples R China. RP Ning, BT (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Baitang.Ning@fda.hhs.gov; tieliushi01@gmail.com FU China Human Proteome Project [2014DFB30010]; National 973 Key Basic Research Program [2010CB945401]; National Natural Science Foundation of China [31240038]; Research Fund for the Doctoral Program of Higher Education of China [20120076110006]; Graduate School and Supercomputer Center of East China Normal University; MegaSci Inc.; FDA/NCTR's SEQC (Sequencing Quality Control) project [E0731901] FX We would like to thank Zhongchao Shen, Jianmin Yang, Qi Lv and Peng Li for their helpful discussions. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. This work was supported by grants from the China Human Proteome Project (2014DFB30010), the National 973 Key Basic Research Program (Grant No. 2010CB945401); the National Natural Science Foundation of China (31240038); Research Fund for the Doctoral Program of Higher Education of China (20120076110006); the Graduate School and Supercomputer Center of East China Normal University and MegaSci Inc. This study was also partially supported by the FDA/NCTR's SEQC (Sequencing Quality Control) project E0731901. NR 57 TC 6 Z9 6 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 30 PY 2015 VL 5 AR 9453 DI 10.1038/srep09453 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE6HV UT WOS:000351938400001 PM 25819875 ER PT J AU Ottesen, AR Gorham, S Pettengill, JB Rideout, S Evans, P Brown, E AF Ottesen, Andrea R. Gorham, Sasha Pettengill, James B. Rideout, Steven Evans, Peter Brown, Eric TI The impact of systemic and copper pesticide applications on the phyllosphere microflora of tomatoes SO JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE LA English DT Article DE tomatoes; phyllosphere; 16S 18S; metagenomic; phytobiome AB BACKGROUNDContamination of tomatoes by Salmonella can occur in agricultural settings. Little is currently understood about how agricultural inputs such as pesticide applications may impact epiphytic crop microflora and potentially play a role in contamination events. We examined the impact of two materials commonly used in Virginia tomato agriculture: acibenzolar-S-methyl (crop protectant) and copper oxychloride (pesticide) to identify the effects these materials may exert on baseline tomato microflora and on the incidence of three specific genera; Salmonella, Xanthomonas and Paenibacillus. RESULTSApproximately 186 441 16S rRNA gene and 39 381 18S rRNA gene sequences per independent replicate were used to analyze the impact of the pesticide applications on tomato microflora. An average of 3 346 677 (634 892 974 bases) shotgun sequences per replicate were used for metagenomic analyses. CONCLUSIONA significant decrease in the presence of Gammaproteobacteria was observed between controls and copper-treated plants, suggesting that copper is effective at suppressing growth of certain taxa in this class. A higher mean abundance of Salmonella and Paenibacillus in control samples compared to treatments may suggest that both systemic and copper applications diminish the presence of these genera in the phyllosphere; however, owing to the lack of statistical significance, this could also be due to other factors. The most distinctive separation of shared membership was observed in shotgun data between the two different sampling time-points (not between treatments), potentially supporting the hypothesis that environmental pressures may exert more selective pressures on epiphytic microflora than do certain agricultural management practices. (c) 2014 The Authors. Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. C1 [Ottesen, Andrea R.; Gorham, Sasha; Pettengill, James B.; Evans, Peter; Brown, Eric] US FDA, Mol Methods & Subtyping Branch, Div Microbiol, Off Regulatory Sci,Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Rideout, Steven] Virginia Tech, Virginia Agr Expt Stn, Painter, VA 23420 USA. RP Ottesen, AR (reprint author), 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. EM Andrea.Ottesen@fda.hhs.gov NR 16 TC 7 Z9 8 U1 5 U2 33 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-5142 EI 1097-0010 J9 J SCI FOOD AGR JI J. Sci. Food Agric. PD MAR 30 PY 2015 VL 95 IS 5 BP 1116 EP 1125 DI 10.1002/jsfa.7010 PG 10 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CD5ZQ UT WOS:000351168100030 PM 25410588 ER PT J AU Vugrin, ED Rostron, BL Verzi, SJ Brodsky, NS Brown, TJ Choiniere, CJ Coleman, BN Paredes, A Apelberg, BJ AF Vugrin, Eric D. Rostron, Brian L. Verzi, Stephen J. Brodsky, Nancy S. Brown, Theresa J. Choiniere, Conrad J. Coleman, Blair N. Paredes, Antonio Apelberg, Benjamin J. TI Modeling the Potential Effects of New Tobacco Products and Policies: A Dynamic Population Model for Multiple Product Use and Harm SO PLOS ONE LA English DT Article ID SMOKING-ATTRIBUTABLE MORTALITY; SIMSMOKE SIMULATION-MODEL; UNITED-STATES; REDUCING SMOKING; PUBLIC-POLICIES; PREVALENCE; DEATHS; CESSATION; IMPACT; PREVENTION AB Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use for the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability. C1 [Vugrin, Eric D.; Brodsky, Nancy S.] Sandia Natl Labs, Resilience & Regulatory Effects, Albuquerque, NM 87185 USA. [Rostron, Brian L.; Choiniere, Conrad J.; Coleman, Blair N.; Paredes, Antonio; Apelberg, Benjamin J.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. [Verzi, Stephen J.] Sandia Natl Labs, Syst Res Anal & Applicat, Albuquerque, NM 87185 USA. [Brown, Theresa J.] Sandia Natl Labs, Policy & Decis Analyt, Albuquerque, NM 87185 USA. RP Vugrin, ED (reprint author), Sandia Natl Labs, Resilience & Regulatory Effects, POB 5800, Albuquerque, NM 87185 USA. EM edvugri@sandia.gov FU U.S. Food and Drug Administration through U.S. Department of Energy/Sandia National Laboratories [224109011]; U.S. Department of Energy's National Nuclear Security Administration [DE-AC04-94AL85000] FX This work was funded by the U.S. Food and Drug Administration through a contract with the U.S. Department of Energy/Sandia National Laboratories (funding document 224109011). Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000. The funders, other than employees named as authors or described in the acknowledgments, had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This article represents the views of the authors, and should not be construed to represent U.S. Food and Drug Administration's views or policies. NR 59 TC 6 Z9 6 U1 2 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 27 PY 2015 VL 10 IS 3 AR e0121008 DI 10.1371/journal.pone.0121008 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CE8ZT UT WOS:000352133600058 PM 25815840 ER PT J AU Karimi-Shah, BA Chowdhury, BA AF Karimi-Shah, Banu A. Chowdhury, Badrul A. TI Forced Vital Capacity in Idiopathic Pulmonary Fibrosis - FDA Review of Pirfenidone and Nintedanib SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Karimi-Shah, Banu A.; Chowdhury, Badrul A.] US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Karimi-Shah, BA (reprint author), US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 4 TC 47 Z9 47 U1 4 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 26 PY 2015 VL 372 IS 13 BP 1189 EP 1191 DI 10.1056/NEJMp1500526 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CE1QD UT WOS:000351585900004 PM 25806913 ER PT J AU Blumenthal, GM Karuri, SW Zhang, H Zhang, LJ Khozin, S Kazandjian, D Tang, S Sridhara, R Keegan, P Pazdur, R AF Blumenthal, Gideon M. Karuri, Stella W. Zhang, Hui Zhang, Lijun Khozin, Sean Kazandjian, Dickran Tang, Shenghui Sridhara, Rajeshwari Keegan, Patricia Pazdur, Richard TI Overall Response Rate, Progression-Free Survival, and Overall Survival With Targeted and Standard Therapies in Advanced Non-Small-Cell Lung Cancer: US Food and Drug Administration Trial-Level and Patient-Level Analyses SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-III TRIAL; RANDOMIZED CLINICAL-TRIALS; 1ST-LINE TREATMENT; TUMOR RESPONSE; END-POINTS; OPEN-LABEL; APPROVAL; CHEMOTHERAPY; MULTICENTER; MUTATIONS AB Purpose To conduct analyses exploring trial-level and patient-level associations between overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) trials. Methods We identified 14 trials (N = 12,567) submitted to US Food and Drug Administration since 2003 of treatments for advanced NSCLC. Only randomized, active-controlled trials with more than 150 patients were included. Associations between trial-level PFS hazard ratio (HR), OS HR, and ORR odds ratio were analyzed using a weighted linear regression model. Patient-level responder analyses comparing PFS and OS between patients with and without an objective response were performed using pooled data from all studies. Results In the trial-level analysis, the association between PFS and ORR was strong (R-2 = 0.89; 95% CI, 0.80 to 0.98). There was no association between OS and ORR (R-2 = 0.09; 95% CI, 0 to 0.33) and OS and PFS (R-2 = 0.08; 95% CI, 0 to 0.31). In the patient-level responder analyses, patients who achieved a response had better PFS and OS compared with nonresponders (PFS: HR, 0.40; 95% CI, 0.38 to 0.42; OS: HR, 0.40; 95% CI, 0.38 to 0.43). Conclusion On a trial level, there is a strong association between ORR and PFS. An association between ORR and OS and between PFS and OS was not established, possibly because of cross-over and longer survival after progression in the targeted therapy and first-line trials. The patient-level analysis showed that responders have a better PFS and OS compared with nonresponders. A therapy in advanced NSCLC with a large magnitude of effect on ORR may have a large PFS effect. (C) 2015 by American Society of Clinical Oncology C1 [Blumenthal, Gideon M.; Karuri, Stella W.; Zhang, Hui; Zhang, Lijun; Khozin, Sean; Kazandjian, Dickran; Tang, Shenghui; Sridhara, Rajeshwari; Keegan, Patricia; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, White Oak, MD USA. RP Blumenthal, GM (reprint author), US FDA, WO22-2341,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Gideon.Blumenthal@fda.hhs.gov NR 45 TC 28 Z9 28 U1 2 U2 5 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 MAR 20 PY 2015 VL 33 IS 9 BP 1008 EP + DI 10.1200/JCO.2014.59.0489 PG 8 WC Oncology SC Oncology GA CK2QP UT WOS:000356056400010 PM 25667291 ER PT J AU Jackson, BR Salter, M Tarr, C Conrad, A Harvey, E Steinbock, L Saupe, A Sorenson, A Katz, L Stroika, S Jackson, KA Carleton, H Kucerova, Z Melka, D Strain, E Parish, M Mody, RK AF Jackson, Brendan R. Salter, Monique Tarr, Cheryl Conrad, Amanda Harvey, Emily Steinbock, Lisa Saupe, Amy Sorenson, Alida Katz, Lee Stroika, Steven Jackson, Kelly A. Carleton, Heather Kucerova, Zuzana Melka, David Strain, Errol Parish, Mickey Mody, Rajal K. TI Listeriosis Associated with Stone Fruit - United States, 2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Jackson, Brendan R.; Tarr, Cheryl; Conrad, Amanda; Katz, Lee; Stroika, Steven; Jackson, Kelly A.; Carleton, Heather; Kucerova, Zuzana; Mody, Rajal K.] CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Salter, Monique; Melka, David; Strain, Errol; Parish, Mickey] US FDA, Rockville, MD 20857 USA. [Conrad, Amanda] Atlanta Res & Educ Fdn, Atlanta, GA USA. [Harvey, Emily] Massachusetts Dept Publ Hlth, Boston, MA 02111 USA. [Steinbock, Lisa] City Northampton Hlth Dept, Northampton, MA USA. [Saupe, Amy] Minnesota Dept Hlth, Minneapolis, MN 55414 USA. [Sorenson, Alida] Minnesota Dept Agr, St Paul, MN USA. RP Jackson, BR (reprint author), CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM brjackson1@cdc.gov NR 1 TC 15 Z9 15 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD MAR 20 PY 2015 VL 64 IS 10 BP 282 EP 283 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CE2HG UT WOS:000351635500006 PM 25789745 ER PT J AU Tam, J Day, HR Rostron, BL Apelberg, BJ AF Tam, Jamie Day, Hannah R. Rostron, Brian L. Apelberg, Benjamin J. TI A systematic review of transitions between cigarette and smokeless tobacco product use in the United States SO BMC PUBLIC HEALTH LA English DT Article DE Smokeless tobacco; Smoking; Tobacco; Longitudinal; Transitions ID HIGH-SCHOOL-STUDENTS; RISK-FACTOR; SNUS; SMOKING; HEALTH; CANCER AB Background: Smokeless tobacco use is becoming an increasingly important public health issue in the US and may influence cigarette smoking behavior. Systematic information on transitions between smokeless tobacco and cigarette use in the US is limited. Methods: We conducted a systematic review of published literature on transitions between smokeless tobacco and cigarette use in the US. We searched PubMed, Web of Science and EbscoHost databases for all published articles from January 2000 to March 2014 that presented estimates of transitions in US youth and adult study populations over time between at least one of the following tobacco use states: exclusive cigarette smoking, exclusive smokeless tobacco use, dual use of both products, and use of neither product. We excluded non-English language studies, studies published before 2000, clinical trials, controlled cessation programs, and clinical studies or evaluations of smokeless tobacco cessation programs. Results: The review identified six studies on US populations published since 2000 with longitudinal data on some or all of the transitions that users can undergo between smokeless tobacco and cigarette use. There was considerable heterogeneity across studies in design and tobacco use definitions. Despite these differences, the existing data indicate that switching behaviors from exclusive smoking to exclusive smokeless tobacco use are limited (adults: 0%-1.4%, adolescents: 0.8%-3.8%) but may be more common from exclusive smokeless tobacco use to exclusive smoking (adults: 0.9%-26.6%, adolescents: 16.6%-25.5%). Among adults, exclusive cigarette smoking was generally stable and consistent (79.7% to 87.6%) over follow-up across studies but less stable in adolescents (46.8%-78.7%). Exclusive smokeless tobacco use was less stable than exclusive cigarette smoking over time (adults: 59.4%-76.6%, adolescents: 26.2%-44.8%). Conclusion: This review provides published estimates of the proportions of adults and adolescents transitioning between tobacco use categories from the most recently available studies on longitudinal transitions between smokeless tobacco and cigarettes in the US. These data can be used to track tobacco use behaviors and evaluate their effect on public health; however, the data for these studies were generally collected more than a decade ago. Additional research including nationally representative longitudinal estimates using consistent definitions and designs, would improve understanding of current tobacco transition behaviors. C1 [Tam, Jamie] Univ Michigan, Sch Publ Hlth, Dept Hlth Management & Policy, Ann Arbor, MI 48109 USA. [Day, Hannah R.; Rostron, Brian L.; Apelberg, Benjamin J.] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. RP Rostron, BL (reprint author), US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. EM brian.rostron@fda.hhs.gov FU NICHD NIH HHS [P01 HD031921] NR 22 TC 4 Z9 4 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAR 18 PY 2015 VL 15 AR 258 DI 10.1186/s12889-015-1594-8 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CE3MS UT WOS:000351731200003 PM 25849604 ER PT J AU Srinivasan, C Siddiqui, A Korang-Yeboah, M Khan, MA AF Srinivasan, Charudharshini Siddiqui, Akhtar Korang-Yeboah, Maxwell Khan, Mansoor A. TI Stability characterization and appearance of particulates in a lyophilized formulation of a model peptide hormone-human secretin SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Peptide; Lyophilization; Secretin; Mannitol; Stability; Particulates; Formulation ID PROTEIN FORMULATIONS; D-MANNITOL; MONOCLONAL-ANTIBODY; QUALITY ATTRIBUTES; RATIONAL DESIGN; HYDRATE; IMPACT; CRYSTALLIZATION; DIFFERENTIATION; SPECTROSCOPY AB Drug shortages and recalls are often caused due to particulate growth in parenteral products and can have serious clinical implications. Root cause analysis of such recalls and shortages may arise due to insufficient understanding of process, formulations issues and environmental effects than often reported filtration and inadequate personnel training. Therefore, the goal of this study was to use a model peptide hormone, secretin that is currently under drug shortage, and investigate the effect of excipients on the lyophilized secretin formulation and evaluate the effect of storage and excursion temperatures. Lyophilized formulation was assayed for secretin by reverse phase HPLC. Solid state characteristics of lyophilized formulation were determined by X-ray powder diffraction (XRPD), thermal and spectroscopic methods. Dynamic light scattering (DLS) was used to detect particulates in the formulation after reconstitution. To assess the environmental impact, the lyophilized samples were stored at -20 degrees C, 4 degrees C, 25 degrees C and 25 degrees C/60% RH and analyzed at time 0, 1, 4, and 8 weeks. HPLC analyses exhibited a decrease in secretin concentration by 8 week (20-27% fold decrease). Visual observation and DLS showed particulates and increased reconstitution time (e.g., at 25 degrees C/60% RH, particle size of similar to 390 nm at day 0 to >2 mu m as early as week 1; reconstitution time of similar to 20 s at day 0 to similar to 67 s at week 8). XRPD, thermal and spectroscopic methods demonstrated polymorphic transitions of mannitol and increased crystallinity in the lyophilized formulations with time. These studies potentially address the effect of product excursions outside the proposed label storage conditions which is -20 degrees C for secretin formulation and this is the first time it has been investigated. These observations indicate that both environmental factor and excipient may have an impact on the stability of secretin formulation and appearance of particles in the product. Published by Elsevier B.V. C1 [Srinivasan, Charudharshini; Siddiqui, Akhtar; Korang-Yeboah, Maxwell; Khan, Mansoor A.] US FDA, Div Product Qual Res, Off Testing & Res, OPQ,CDER, Silver Spring, MD USA. RP Khan, MA (reprint author), US FDA, CDER, DPQR, White Oak, LS Bldg 64,Room 1070,New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov FU FDA's Medical Counter-measures Initiative (MCMi) FX This project was supported in part by FDA's Medical Counter-measures Initiative (MCMi) for critical infrastructure development. NR 43 TC 1 Z9 1 U1 3 U2 15 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 15 PY 2015 VL 481 IS 1-2 BP 104 EP 113 DI 10.1016/j.ijpharm.2015.01.044 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC6CZ UT WOS:000350453600014 PM 25636302 ER PT J AU Norman, KN Clawson, ML Strockbine, NA Mandrell, RE Johnson, R Ziebell, K Zhao, SH Fratamico, PM Stones, R Allard, MW Bono, JL AF Norman, Keri N. Clawson, Michael L. Strockbine, Nancy A. Mandrell, Robert E. Johnson, Roger Ziebell, Kim Zhao, Shaohua Fratamico, Pina M. Stones, Robert Allard, Marc W. Bono, James L. TI Comparison of whole genome sequences from human and non-human Escherichia coil 026 strains SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Article DE Escherichia coli; O26; Shiga toxins; polymorphisms; phylogenetic ID COLI SEROGROUPS O26; ANTIMICROBIAL RESISTANCE; PHYLOGENETIC ANALYSIS; UNITED-STATES; MINCED BEEF; CATTLE; O111; INFECTIONS; OUTBREAK; O157 AB Shiga toxin-producing Escherichia coil (STEC) O26 is the second leading E co/i serogroup responsible for human illness outbreaks behind E coli O157:H7. Recent outbreaks have been linked to emerging pathogenic O26:H11 strains harboring stx2 only. Cattle have been recognized as an important reservoir of O26 strains harboring stx(1); however the reservoir of these emerging stx(2) strains is unknown. The objective of this study was to identify nucleotide polymorphisms in human and cattle-derived strains in order to compare differences in polymorphism derived genotypes and virulence gene profiles between the two host species. Whole genome sequencing was performed on 182 epidemiologically unrelated O26 strains, including 109 human-derived strains and 73 non-human-derived strains. A panel of 289 O26 strains (241 STEC and 48 non-STEC) was subsequently genotyped using a set of 283 polymorphisms identified by whole genome sequencing, resulting in 64 unique genotypes. Phylogenetic analyses identified seven clusters within the O26 strains. The seven clusters did not distinguish between isolates originating from humans or cattle; however, clusters did correspond with particular virulence gene profiles. Human and non-human-derived strains harboring stx(1) clustered separately from strains harboring stx2, strains harboring eae, and non-STEC strains. Strains harboring stx(2)were more closely related to non-STEC strains and strains harboring eae than to strains harboring stx(1). The finding of human and cattle-derived strains with the same polymorphism derived genotypes and similar virulence gene profiles, provides evidence that similar strains are found in cattle and humans and transmission between the two species may occur. C1 [Norman, Keri N.; Clawson, Michael L.; Bono, James L.] ARS, US Meat Anim Res Ctr, USDA, Clay Ctr, NE 68933 USA. [Strockbine, Nancy A.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. [Mandrell, Robert E.] ARS, Western Reg Res Ctr, USDA, Albany, CA USA. [Johnson, Roger; Ziebell, Kim] Publ Hlth Agcy Canada, Lab Foodborne Zoonoses, Guelph, ON, Canada. [Zhao, Shaohua] US FDA, Div Anim & Food Microbiol, Ctr Vet Med, Laurel, MD USA. [Fratamico, Pina M.] ARS, Eastern Reg Res Ctr, USDA, Wyndmoor, PA USA. [Stones, Robert] Food & Environm Res Agcy, York, N Yorkshire, England. [Allard, Marc W.] US FDA, Div Microbiol, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD USA. RP Bono, JL (reprint author), ARS, US Meat Anim Res Ctr, USDA, State Spur 18D,POB 166, Clay Ctr, NE 68933 USA. EM jim.bono@ars.usda.gov FU USDA CSREES NRI FX We would like to thank Sandy Fryda-Bradley, Linda Flathman, and Chris Zimmerman for outstanding technical support. The .sff files for both human and non-human DNA pools have been deposited into the short read archives under BioProject accession PRJNA274335. Some strains used were collected as part of a USDA CSREES NRI grant awarded to Dr. James Keen. The use of product and company names is necessary to accurately report the methods and results; however, the USDA neither guarantees nor warrants the standard of the products, and the use of the names by the USDA implies no approval of the products to the exclusion of others that may also be suitable. USDA is an equal opportunity provider and employer. NR 44 TC 2 Z9 2 U1 1 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD MAR 11 PY 2015 VL 5 AR 21 DI 10.3389/fcimb.2015.00021 PG 10 WC Immunology; Microbiology SC Immunology; Microbiology GA CF3MW UT WOS:000352454000001 PM 25815275 ER PT J AU Serratos, IN Castellanos, P Pastor, N Millan-Pacheco, C Rembao, D Perez-Montfort, R Cabrera, N Reyes-Espinosa, F Diaz-Garrido, P Lopez-Macay, A Martinez-Flores, K Lopez-Reyes, A Sanchez-Garcia, A Cuevas, E Santamaria, A AF Serratos, Iris N. Castellanos, Pilar Pastor, Nina Millan-Pacheco, Cesar Rembao, Daniel Perez-Montfort, Ruy Cabrera, Nallely Reyes-Espinosa, Francisco Diaz-Garrido, Paulina Lopez-Macay, Ambar Martinez-Flores, Karina Lopez-Reyes, Alberto Sanchez-Garcia, Aurora Cuevas, Elvis Santamaria, Abel TI Modeling the Interaction between Quinolinate and the Receptor for Advanced Glycation End Products (RAGE): Relevance for Early Neuropathological Processes SO PLOS ONE LA English DT Article ID ACID-INDUCED NEUROTOXICITY; NEURODEGENERATIVE DISORDERS; ENDPRODUCTS RAGE; SIGNAL-TRANSDUCTION; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; OXIDATIVE STRESS; RAT-BRAIN; ACTIVATION; RECOGNITION AB The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor involved in neurodegenerative and inflammatory disorders. RAGE induces cellular signaling upon binding to a variety of ligands. Evidence suggests that RAGE up-regulation is involved in quinolinate (QUIN)-induced toxicity. We investigated the QUIN-induced toxic events associated with early noxious responses, which might be linked to signaling cascades leading to cell death. The extent of early cellular damage caused by this receptor in the rat striatum was characterized by image processing methods. To document the direct interaction between QUIN and RAGE, we determined the binding constant (K-b) of RAGE (VC1 domain) with QUIN through a fluorescence assay. We modeled possible binding sites of QUIN to the VC1 domain for both rat and human RAGE. QUIN was found to bind at multiple sites to the VC1 dimer, each leading to particular mechanistic scenarios for the signaling evoked by QUIN binding, some of which directly alter RAGE oligomerization. This work contributes to the understanding of the phenomenon of RAGE-QUIN recognition, leading to the modulation of RAGE function. C1 [Serratos, Iris N.; Reyes-Espinosa, Francisco] Univ Autonoma Metropolitana Iztapalapa, Dept Quim, Mexico City 09340, DF, Mexico. [Serratos, Iris N.; Diaz-Garrido, Paulina; Santamaria, Abel] SSA, Manuel Velasco Suarez, Inst Nacl Neurol & Neurocirugia, Lab Aminocidos Excitadores, Mexico City, DF, Mexico. [Castellanos, Pilar] Univ Autonoma Metropolitana Iztapalapa, Dept Ingn Elect, Mexico City 09340, DF, Mexico. [Pastor, Nina] Univ Autonoma Estado Morelos, Fac Ciencias, Cuernavaca, Morelos, Mexico. [Millan-Pacheco, Cesar] Univ Nacl Autonoma Mexico, Inst Ciencias Fis, Cuernavaca 62191, Morelos, Mexico. [Rembao, Daniel; Sanchez-Garcia, Aurora] Inst Nacl Neurol & Neurocirug, Neuropatol, Manuel Velasco Suarez, Mexico City 09340, DF, Mexico. [Perez-Montfort, Ruy; Cabrera, Nallely] Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Bioquim & Biol Estruct, Mexico City 04510, DF, Mexico. [Lopez-Macay, Ambar; Martinez-Flores, Karina; Lopez-Reyes, Alberto] SSA, Inst Nacl Rehabil, Lab Liquido Sinovial, Mexico City, DF, Mexico. [Cuevas, Elvis] Natl Ctr Toxicol Research, FDA, Div Neurotoxicol, Neurochem Lab, Jefferson, AR USA. RP Serratos, IN (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Quim, Mexico City 09340, DF, Mexico. EM natzielly@gmail.com; absada@yahoo.com RI Millan-Pacheco, Cesar/I-4030-2016 OI Millan-Pacheco, Cesar/0000-0001-5180-6504 FU Consejo Nacional de Ciencia y Tecnologia [168692]; Secretaria de Educacion Publica [12412137]; No code Committe for Aid and Education in Neurochemistry FX The work was supported by the following: 168692 Consejo Nacional de Ciencia y Tecnologia http://www.conacyt.gob.mx/pci/index.php/component/users/?task = user.login INS; 12412137 Secretaria de Educacion Publica http://promep.sep.gob.mx/solicitudesv3 INS; and No code Committe for Aid and Education in Neurochemistry http://neurochemistry.org/funding/committee-for-aid-and-education-in-neu rochemistry-caen.html INS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 3 Z9 3 U1 3 U2 14 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 10 PY 2015 VL 10 IS 3 AR UNSP e0120221 DI 10.1371/journal.pone.0120221 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CD7MX UT WOS:000351275700062 PM 25757085 ER PT J AU Graff, CG Sidky, EY AF Graff, Christian G. Sidky, Emil Y. TI Compressive sensing in medical imaging SO APPLIED OPTICS LA English DT Editorial Material ID X-RAY CT; ITERATIVE RECONSTRUCTION ALGORITHM; FLAT-PANEL-DETECTOR; CARDIAC MICRO-CT; CONE-BEAM CT; COMPUTED-TOMOGRAPHY; PERFORMANCE EVALUATION; CONVEX-OPTIMIZATION; SCATTER CORRECTION; MRI AB The promise of compressive sensing, exploitation of compressibility to achieve high quality image reconstructions with less data, has attracted a great deal of attention in the medical imaging community. At the Compressed Sensing Incubator meeting held in April 2014 at OSA Headquarters inWashington, DC, presentations were given summarizing some of the research efforts ongoing in compressive sensing for x-ray computed tomography and magnetic resonance imaging systems. This article provides an expanded version of these presentations. Sparsity-exploiting reconstruction algorithms that have gained popularity in the medical imaging community are studied, and examples of clinical applications that could benefit from compressive sensing ideas are provided. The current and potential future impact of compressive sensing on the medical imaging field is discussed. (C) 2015 Optical Society of America C1 [Graff, Christian G.] US FDA, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. [Sidky, Emil Y.] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. RP Graff, CG (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM christian.graff@fda.hhs.gov FU NIH [CA158446, CA182264, EB018102, EB000225] FX This work was supported in part by NIH R01 grants CA158446, CA182264, EB018102, and EB000225. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 114 TC 9 Z9 9 U1 3 U2 31 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD MAR 10 PY 2015 VL 54 IS 8 BP C23 EP C44 DI 10.1364/AO.54.000C23 PG 22 WC Optics SC Optics GA CC9AE UT WOS:000350658900003 PM 25968400 ER PT J AU Jones, CM Lurie, P Woodcock, J AF Jones, Christopher M. Lurie, Peter Woodcock, Janet TI Preventing Prescription Opioid Abuse Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Jones, Christopher M.; Lurie, Peter] US FDA, Off Commissioner, Silver Spring, MD 20993 USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Jones, CM (reprint author), US FDA, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM christopher.m.jones@fda.hhs.gov NR 6 TC 0 Z9 0 U1 2 U2 3 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 10 PY 2015 VL 313 IS 10 BP 1060 EP 1061 DI 10.1001/jama.2015.0524 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CC8UE UT WOS:000350643100030 PM 25756451 ER PT J AU Banerjee, R Khandelwal, S Kozakai, Y Sahu, B Kumar, S AF Banerjee, Rajdeep Khandelwal, Sanjay Kozakai, Yukiko Sahu, Bikash Kumar, Sanjai TI CD47 regulates the phagocytic clearance and replication of the Plasmodium yoelii malaria parasite SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE malaria; Plasmodium yoelii; RBC; CD47; F4/80 ID BLOOD-STAGE DYNAMICS; MONOCLONAL-ANTIBODY; ERYTHROCYTE; CELLS; SURVIVAL; INVASION; PATHWAY; ANTIGEN; SWITCH AB Several Plasmodium species exhibit a strong age-based preference for the red blood cells (RBC) they infect, which in turn is a major determinant of disease severity and pathogenesis. The molecular basis underlying this age constraint on the use of RBC and its influence on parasite burden is poorly understood. CD47 is a marker of self on most cells, including RBC, which, in conjunction with signal regulatory protein alpha (expressed on macrophages), prevents the clearance of cells by the immune system. In this report, we have investigated the role of CD47 on the growth and survival of nonlethal Plasmodium yoelii 17XNL (PyNL) malaria in C57BL/6 mice. By using a quantitative biotin-labeling procedure and a GFP-expressing parasite, we demonstrate that PyNL parasites preferentially infect high levels of CD47 (CD47(hi))-expressing young RBC. Importantly, C57BL/6 CD47(-/-) mice were highly resistant to PyNL infection and developed a 9.3-fold lower peak parasitemia than their wild-type (WT) counterparts. The enhanced resistance to malaria observed in CD47(-/-) mice was associated with a higher percentage of splenic F4/80(+) cells, and these cells had a higher percentage of phagocytized parasitized RBC than infected WT mice during the acute phase of infection, when parasitemia was rapidly rising. Furthermore, injection of CD47-neutralizing anti-body caused a significant reduction in parasite burden in WT C57BL/6 mice. Together, these results strongly suggest that CD47hi young RBC may provide a shield to the malaria parasite from clearance by the phagocytic cells, which may be an immune escape mechanism used by Plasmodium parasites that preferentially infect young RBC. C1 [Banerjee, Rajdeep; Kozakai, Yukiko; Sahu, Bikash; Kumar, Sanjai] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Khandelwal, Sanjay] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Kumar, S (reprint author), US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM sanjai.kumar@fda.hhs.gov FU Food and Drug Administration FX We thank Bryan Grabias for critically reading this manuscript. This research was supported by intramural funding from the Food and Drug Administration. NR 25 TC 8 Z9 8 U1 2 U2 4 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 10 PY 2015 VL 112 IS 10 BP 3062 EP 3067 DI 10.1073/pnas.1418144112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC8VK UT WOS:000350646500048 PM 25713361 ER PT J AU Jiang, LL Eichelberge, MC AF Jiang, Lianlian Eichelberge, Maryna C. TI Evaluation of Epic((R)) label-free technology to quantify functional recombinant hemagglutinin SO BIOLOGICAL PROCEDURES ONLINE LA English DT Article DE Influenza; Hemagglutinin; Label free technology; Potency; Fetuin; Corning; Epic; Enspire; Recombinant ID SURFACE-PLASMON RESONANCE; SINGLE-RADIAL-IMMUNODIFFUSION; INFLUENZA-VIRUS HEMAGGLUTININ; POTENCY; IMMUNOASSAY; KINETICS; VACCINES AB Background: Alternative methods are being sought to measure the potency of influenza vaccines. Label free technologies that do not require the use of hemagglutinin (HA)-specific antisera are particularly attractive as the preparation of antiserum delays availability of potency reagents. The objective of these experiments was to evaluate the use of a Corning Epic((R)) label free method to quantify functional influenza hemagglutinin in rHA preparations. The method was optimized to quantify recombinant HA (rHA) of B/Brisbane/60/2008 (B/BR/08). Fetuin was immobilized onto plates and the change in wavelength of refracted light measured using an Enspire (Perkin Elmer) instrument. Results: The change in wavelength measured in response to addition of rHA of B/BR/08 was proportional to its concentration and was optimal in the presence of native rHA conformations. However, the assay was strain dependent and did not correlate with HAL) measured using turkey red blood cells. Conclusions: The Corning Epic((R)) label free method is suitable for quantifying the native forms of rHA for B/BR/08 and A/Brisbane/59/2007 (H1N1) and A/Hangxhou/3/2013 (H7N9). This method is a useful tool for research purposes but further investigation is needed to identify suitable glycoproteins to use as ligands that allow quantification of HAs from a broader range of virus strains. C1 [Jiang, Lianlian; Eichelberge, Maryna C.] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Eichelberge, MC (reprint author), US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Maryna.Eichelberger@fda.hhs.gov FU BARDA FX We thank Hana Golding and Surender Khurana for helpful discussion and are indebted to Can Apgar, Paige Derr, Heidi Morgan and Frauke Haenel for guidance in assay design and interpretation of results. This project was funded by BARDA. NR 20 TC 0 Z9 0 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1480-9222 J9 BIOL PROCED ONLINE JI Biol. Proced. Online PD MAR 9 PY 2015 VL 17 AR 7 DI 10.1186/s12575-015-0019-5 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CD3BD UT WOS:000350951900001 PM 25774096 ER PT J AU Genualdi, S Ntim, SA Begley, T AF Genualdi, Susan Ntim, Susana Addo Begley, Timothy TI Suitability of polystyrene as a functional barrier layer in coloured food contact materials SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE polystyrene; functional barrier; migration ID MIGRATION; PLASTICS; OILS AB Functional barriers in food contact materials (FCMs) are used to prevent or reduce migration from inner layers in multilayer structures to food. The effectiveness of functional barrier layers was investigated in coloured polystyrene (PS) bowls due to their intended condition of use with hot liquids such as soups or stew. Migration experiments were performed over a 10-day period using USFDA-recommended food simulants (10% ethanol, 50% ethanol, corn oil and Miglyol) along with several other food oils. At the end of the 10days, solvent dyes had migrated from the PS bowls at 12, 1 and 31000ngcm(-)(2) into coconut oil, palm kernel oil and Miglyol respectively, and in coconut oil and Miglyol the colour change was visible to the human eye. Scanning electron microscope (SEM) images revealed that the functional barrier was no longer intact for the bowls exposed to coconut oil, palm kernel oil, Miglyol, 10% ethanol, 50% ethanol and goat's milk. Additional tests showed that 1-dodecanol, a lauryl alcohol derived from palm kernel oil and coconut oil, was present in the PS bowls at an average concentration of 11mgkg(-1). This compound is likely to have been used as a dispersing agent for the solvent dye and aided the migration of the solvent dye from the PS bowl into the food simulant. The solvent dye was not found in the 10% ethanol, 50% ethanol and goat's milk food simulants above their respective limits of detection, which is likely to be due to its insolubility in aqueous solutions. A disrupted barrier layer is of concern because if there are unregulated materials in the inner layers of the laminate, they may migrate to food, and therefore be considered unapproved food additives resulting in the food being deemed adulterated under the Federal Food Drug and Cosmetic Act. C1 [Genualdi, Susan; Ntim, Susana Addo; Begley, Timothy] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Genualdi, S (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM susan.genualdi@fda.hhs.gov NR 15 TC 1 Z9 1 U1 1 U2 6 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 4 PY 2015 VL 32 IS 3 BP 395 EP 402 DI 10.1080/19440049.2014.1002116 PG 8 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA CF9BI UT WOS:000352856200012 PM 25569333 ER PT J AU Tsong, Y Yang, H AF Tsong, Yi Yang, Harry TI Guest Editors' Note: Special Issue on Recent Developments in Statistical Approaches for Chemistry and Manufacturing Control (CMC) and Quality-by-Design(QbD) SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Editorial Material C1 [Tsong, Yi] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Yang, Harry] MedImmune LLC, Gaithersburg, MD USA. RP Tsong, Y (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 0 TC 0 Z9 1 U1 1 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD MAR 4 PY 2015 VL 25 IS 2 SI SI BP 233 EP 233 DI 10.1080/10543406.2015.992661 PG 1 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CB8TN UT WOS:000349904200001 PM 25437635 ER PT J AU Shen, MY Dong, XY Tsong, Y AF Shen, Meiyu Dong, Xiaoyu Tsong, Yi TI Statistical Evaluation of Several Methods for Cut-Point Determination of Immunogenicity Screening Assay SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Immunogenicity screening assay; Cut point; Percentile; Confidence limit of a percentile AB The cut point of the immunogenicity screening assay is the level of response of the immunogenicity screening assay at or above which a sample is defined to be positive and below which it is defined to be negative. The Food and Drug Administration Guidance for Industry on Assay Development for Immunogenicity Testing of Therapeutic recommends the cut point to be an upper 95 percentile of the negative control patients. In this article, we assume that the assay data are a random sample from a normal distribution. The sample normal percentile is a point estimate with a variability that decreases with the increase of sample size. Therefore, the sample percentile does not assure at least 5% false-positive rate (FPR) with a high confidence level (e.g., 90%) when the sample size is not sufficiently enough. With this concern, we propose to use a lower confidence limit for a percentile as the cut point instead. We have conducted an extensive literature review on the estimation of the statistical cut point and compare several selected methods for the immunogenicity screening assay cut-point determination in terms of bias, the coverage probability, and FPR. The selected methods evaluated for the immunogenicity screening assay cut-point determination are sample normal percentile, the exact lower confidence limit of a normal percentile (Chakraborti and Li, 2007) and the approximate lower confidence limit of a normal percentile. It is shown that the actual coverage probability for the lower confidence limit of a normal percentile using approximate normal method is much larger than the required confidence level with a small number of assays conducted in practice. We recommend using the exact lower confidence limit of a normal percentile for cut-point determination. C1 [Shen, Meiyu; Dong, Xiaoyu; Tsong, Yi] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Shen, MY (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM meiyu.shen@fda.hhs.gov NR 5 TC 2 Z9 2 U1 3 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD MAR 4 PY 2015 VL 25 IS 2 SI SI BP 269 EP 279 DI 10.1080/10543406.2014.979196 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CB8TN UT WOS:000349904200005 PM 25356783 ER PT J AU Dong, XY Tsong, Y Shen, MY AF Dong, Xiaoyu Tsong, Yi Shen, Meiyu TI Statistical Considerations in Setting Product Specifications SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Quality control; Tolerance interval; Confidence limit; Percentile; Specification ID TOLERANCE LIMITS AB According to ICH Q6A (1999), a specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. For drug products, specifications usually consist of test methods and acceptance criteria for assay, impurities, pH, dissolution, moisture, and microbial limits, depending on the dosage forms. They are usually proposed by the manufacturers and subject to the regulatory approval for use. When the acceptance criteria in product specifications cannot be pre-defined based on prior knowledge, the conventional approach is to use data from a limited number of clinical batches during the clinical development phases. Often in time, such acceptance criterion is set as an interval bounded by the sample mean plus and minus two to four standard deviations. This interval may be revised with the accumulated data collected from released batches after drug approval. In this article, we describe and discuss the statistical issues of commonly used approaches in setting or revising specifications (usually tighten the limits), including reference interval, (Min, Max) method, tolerance interval, and confidence limit of percentiles. We also compare their performance in terms of the interval width and the intended coverage. Based on our study results and review experiences, we make some recommendations on how to select the appropriate statistical methods in setting product specifications to better ensure the product quality. C1 [Dong, Xiaoyu; Tsong, Yi; Shen, Meiyu] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Dong, XY (reprint author), US FDA, Div Biometr 6, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM xiaoyu.dong@fda.hhs.gov NR 16 TC 1 Z9 1 U1 3 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD MAR 4 PY 2015 VL 25 IS 2 SI SI BP 280 EP 294 DI 10.1080/10543406.2014.972511 PG 15 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CB8TN UT WOS:000349904200006 PM 25358110 ER PT J AU Dong, XY Tsong, Y Shen, MY Zhong, JL AF Dong, Xiaoyu Tsong, Yi Shen, Meiyu Zhong, Jinglin TI Using Tolerance Intervals for Assessment of Pharmaceutical Quality SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Two-sided tolerance interval; One-sided tolerance interval; Coverage hypothesis; Two one-sided test; Acceptance criteria ID DOSE UNIFORMITY; ASSURANCE TEST; TESTS; LIMITS; TRIALS; QT AB In quality control of drug products, tolerance intervals are commonly used methods to assure a certain proportion of the products covered within a pre-specified acceptance interval. Depending on the nature of the quality attributes, the corresponding acceptance interval could be one-sided or two-sided. Thus, the tolerance intervals can also be one-sided or two-sided. To better utilize tolerance intervals for quality assurance, we reviewed the computation method and studied their statistical properties in terms of batch acceptance probability in this article. We also illustrate the application of one-sided and two-sided tolerance, as well as two one-sided tests through the examples of dose content uniformity test, delivered dose uniformity test, and dissolution test. C1 [Dong, Xiaoyu; Tsong, Yi; Shen, Meiyu; Zhong, Jinglin] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Dong, XY (reprint author), US FDA, Div Biometr 6, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM xiaoyu.dong@fda.hhs.gov FU FDA CDER Regulatory Science Research Project fund [RSR-2010-18] FX The project was supported by the FDA CDER Regulatory Science Research Project fund # RSR-2010-18. NR 18 TC 1 Z9 1 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD MAR 4 PY 2015 VL 25 IS 2 SI SI BP 317 EP 327 DI 10.1080/10543406.2014.972512 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CB8TN UT WOS:000349904200009 PM 25356617 ER PT J AU Tsong, Y Dong, XY Shen, MY Lostritto, RT AF Tsong, Yi Dong, Xiaoyu Shen, Meiyu Lostritto, Richard T. TI Quality Assurance Test of Delivered Dose Uniformity of Multiple-Dose Inhaler and Dry Powder Inhaler Drug Products SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Two one-sided tests; Delivered dose uniformity; Two-tier group sequential; Tolerance interval; FDA Draft Guidance method AB The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium, the FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals (TOSTIs) for a small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters. C1 [Tsong, Yi; Dong, Xiaoyu; Shen, Meiyu] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Lostritto, Richard T.] US FDA, Off New Drug Qual Assurance, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Tsong, Y (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Room 4628,Bldg 21,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM yi.tsong@fda.hhs.gov NR 15 TC 2 Z9 2 U1 2 U2 22 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 4 PY 2015 VL 25 IS 2 SI SI BP 328 EP 338 DI 10.1080/10543406.2014.972510 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CB8TN UT WOS:000349904200010 PM 25357132 ER PT J AU Voronin, Y Zinszner, H Karg, C Brooks, K Coombs, R Hural, J Holt, R Fast, P Allen, M Busch, M Fruth, U Golding, H Khurana, S Mulenga, J Peel, S Schito, M Voronin, Y Barnabas, N Bentsen, C Graham, B Gray, G Levin, A McCluskey, M O'Connell, R Snow, B Ware, M AF Voronin, Yegor Zinszner, Helene Karg, Carissa Brooks, Katie Coombs, Robert Hural, John Holt, Renee Fast, Pat Allen, Mary Busch, Michael Fruth, Ulrich Golding, Hana Khurana, Surender Mulenga, Joseph Peel, Sheila Schito, Marco Voronin, Yegor Barnabas, Nomampondo Bentsen, Christopher Graham, Barney Gray, Glenda Levin, Andrew McCluskey, Margaret O'Connell, Robert Snow, Bill Ware, Mark CA VISR Working Grp Global HIV Vaccin TI HIV vaccine-induced sero-reactivity: A challenge for trial participants, researchers, and physicians SO VACCINE LA English DT Review DE HIV; Vaccine; Vaccine-induced sero-positivity; Vaccine-induced sero-reactivity; VISR; VISP ID DIFFERENTIAL-DIAGNOSIS; GENERATED ANTIBODIES; SEROPOSITIVITY; INFECTIONS; RECIPIENTS; ASSAY; FACE AB Antibody-inducing vaccines are a major focus in the preventive HIV vaccine field. Because the most common tests for HIV infection rely on detecting antibodies to HIV, they may also detect antibodies induced by a candidate HIV vaccine. The detection of vaccine-induced antibodies to HIV by serological tests is most commonly referred to as vaccine-induced sero-reactivity (VISR). VISR can be misinterpreted as a sign of HIV infection in a healthy study participant. In a participant who has developed vaccine-induced antibodies, accurate diagnosis of HIV infection (or lack thereof) may require specialized tests and algorithms (differential testing) that are usually not available in community settings. Organizations sponsoring clinical testing of preventive HIV vaccine candidates have an ethical obligation not only to inform healthy volunteers about the potential problems associated with participating in a clinical trial but also to help manage any resulting issues. This article explores the scope of VISR-related issues that become increasingly prevalent as the search for an effective HIV vaccine continues and will be paramount once a preventive vaccine is deployed. We also describe ways in which organizations conducting HIV vaccine trials have addressed these issues and outline areas where more work is needed. (C) 2014 The Authors. Published by Elsevier Ltd. C1 [Voronin, Yegor; Zinszner, Helene; Voronin, Yegor; Snow, Bill] Global HIV Vaccine Enterprise, New York, NY 10003 USA. [Karg, Carissa; Brooks, Katie; Hural, John; Holt, Renee] HIV Vaccine Trials Network, Seattle, WA USA. [Coombs, Robert] Univ Washington, Seattle, WA 98195 USA. [Fast, Pat] Int AIDS Vaccine Initiat, New York, NY USA. [Allen, Mary] NIAID, NIH, Bethesda, MD 20892 USA. [Busch, Michael] Blood Syst Res Inst, San Francisco, CA USA. [Fruth, Ulrich] WHO, CH-1211 Geneva, Switzerland. [Golding, Hana] Food & Drug Adm, Bethesda, MD USA. [Mulenga, Joseph] Zambia Natl Blood Transfus Serv, Lusaka, Zambia. [Peel, Sheila; O'Connell, Robert] Mil HIV Res Program, Silver Spring, MD USA. [Schito, Marco] Mil Med Inc, Div Henry M Jackson Fdn Adv, HJF DAIDS, Bethesda, MD USA. [Barnabas, Nomampondo; Gray, Glenda] Perinatal HIV Res Unit, Johannesburg, South Africa. [Bentsen, Christopher] Biorad Labs, Redmond, WA USA. [Graham, Barney] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Levin, Andrew] Immunetics Inc, Boston, MA USA. [McCluskey, Margaret] US Agcy Int Dev, Washington, DC 20523 USA. [O'Connell, Robert] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Ware, Mark] Clinton Hlth Access Initiat, Edinburgh, Midlothian, Scotland. RP Voronin, Y (reprint author), Global HIV Vaccine Enterprise, New York, NY 10003 USA. FU Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C]; United States Agency for International Development (USAID) FX We would like to thank all participants of the March 2013 meeting "Vaccine-Induced Sero-Reactivity/Sero-Positivity", whose opinions greatly influenced the content of this article. For a complete list of participants and the meeting report, visit http://www.vaccineenterprise.org/content/timely-topic-VISP. This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C. IAVI's work is made possible by generous support from many donors, including the United States Agency for International Development (USAID). A full list of IAVI donors is available at www.iavi.org. NR 30 TC 2 Z9 2 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD MAR 3 PY 2015 VL 33 IS 10 BP 1243 EP 1249 DI 10.1016/j.vaccine.2014.10.040 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CC1EI UT WOS:000350083600005 ER PT J AU Schmid, I Burcu, M Zito, JM AF Schmid, Ian Burcu, Mehmet Zito, Julie M. TI Medicaid Prior Authorization Policies for Pediatric Use of Antipsychotic Medications SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ADOLESCENTS; CHILDREN C1 [Schmid, Ian] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Burcu, Mehmet; Zito, Julie M.] Univ Maryland, Dept Pharmaceut Hlth Serv Res, Baltimore, MD 21201 USA. RP Zito, JM (reprint author), Univ Maryland, Dept Pharmaceut Hlth Serv Res, 220 Arch St, Baltimore, MD 21201 USA. EM jzito@rx.umaryland.edu NR 6 TC 6 Z9 6 U1 0 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 MAR 3 PY 2015 VL 313 IS 9 BP 966 EP 968 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CC3FN UT WOS:000350231800021 PM 25734740 ER PT J AU Joseph, S Nicolson, TJ Hammons, G Word, B Green-Knox, B Lyn-Cook, B AF Joseph, Stancy Nicolson, Tamara J. Hammons, George Word, Beverly Green-Knox, Bridgett Lyn-Cook, Beverly TI Expression of drug transporters in human kidney: impact of sex, age, and ethnicity SO BIOLOGY OF SEX DIFFERENCES LA English DT Article DE Kidney; Sex difference; Gene expression; Drug transporters; Age; Ethnicity; ATP-binding cassettes (ABCs); Solute carriers (SLCs) ID GENDER-RELATED DIFFERENCES; POLYMERASE-CHAIN-REACTION; GENE-EXPRESSION; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; INTERNAL CONTROL; RENAL-DISEASE; LIFE-CYCLE; VARIABILITY; VALIDATION; NORMALIZATION AB Background: Differences in expression of drug transporters in human kidney contribute to changes in pharmacokinetics and toxicokinetics of a variety of drug compounds. The basal expression levels of genes involved in drug transport processes in the kidney introduces differences in bioavailability, distribution, and clearance of drugs, possibly influencing drug efficacy and adverse reactions. Sex differences in gene expression of transporters are a key cause of differences in sex-dependent pharmacokinetics, which may characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Therefore, evaluating the expression of drug transporters in normal human kidneys is important to better understand differences in drug bioavailability, distribution, and clearance of drugs in humans. Other factors such as age and ethnicity may also contribute to individual differences in gene expression of drug transporters in the human kidney. Methods: Quantitative real-time PCR (QRT-PCR) was performed to determine the gene expression of 30 drug transporters in 95 age-matched normal human kidney tissues. Multiple Student's t-tests (Sidak-Bonferroni correction) and two-way ANOVA (Bonferroni correction) analyses were used to determine statistically significant differences. Results: In the 30 transporter genes examined, sex, ethnicity, and age differences in gene expression were exhibited in normal human kidney tissue. These changes in expression were not found to be differentially significant. However, sex-age and sex-ethnicity interactions were found to be statistically significant. For sex-age interactions, SCL22A12 was found to be significantly higher expressed in females <50 years compared to males <50 years. Expression levels of SLC22A2, SLC22A12, SLC6A16, and ABCB6 were significantly higher in females <50 years compared to females >= 50 years. In sex-ethnicity interactions, expression levels of ATP7B and KCNJ8 were found to be significantly higher in African American females compared to European American females. Also, the expression of SLC31A2 was significantly higher in European American males compared to European American females. Conclusions: Sex, age, and ethnic differences impacted the expression of drug transporters in normal human kidneys, which suggests that the analysis of gene expression of drug transporters will aid in improving the usage/dosage of drug therapies influencing personalized medicine and susceptibility to adverse drug reactions. C1 [Joseph, Stancy; Hammons, George; Word, Beverly; Lyn-Cook, Beverly] Natl Ctr Toxicol Res Food & Drug Adm, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Nicolson, Tamara J.] Drug Discovery & Dev, London, England. [Green-Knox, Bridgett] Natl Ctr Toxicol Res Food & Drug Adm, Div Syst Biol, Jefferson, AR 72079 USA. RP Lyn-Cook, B (reprint author), Natl Ctr Toxicol Res Food & Drug Adm, Div Biochem Toxicol, Bldg 50,Room 630,HFT 100,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Beverly.lyn-cook@fda.hhs.gov FU FDA Office of Women Health (OWH) FX The initial study was funded by a grant from the FDA Office of Women Health (OWH). NR 50 TC 6 Z9 6 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2042-6410 J9 BIOL SEX DIFFER JI Biol. Sex Differ. PD MAR 2 PY 2015 VL 6 AR 4 DI 10.1186/s13293-015-0020-3 PG 15 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA CC8LR UT WOS:000350620700001 PM 25750709 ER PT J AU Rafii, F AF Rafii, Fatemeh TI The Role of Colonic Bacteria in the Metabolism of the Natural Isoflavone Daidzin to Equol SO METABOLITES LA English DT Review DE metabolites; metabolism; intestinal bacteria; phytoestrogen; isoflavone; daidzin; daidzein; equol ID ESTROGEN-RECEPTOR-ALPHA; HUMAN INTESTINAL BACTERIUM; LACTOCOCCUS STRAIN 20-92; S-EQUOL; SOY ISOFLAVONES; IN-VITRO; HUMAN FECES; POSTMENOPAUSAL WOMEN; GUT MICROFLORA; SLACKIA-ISOFLAVONICONVERTENS AB Isoflavones are found in leguminous plants, especially soybeans. They have a structural similarity to natural estrogens, which enables them to bind to estrogen receptors and elicit biological activities similar to natural estrogens. They have been suggested to be beneficial for the prevention and therapy of hormone-dependent diseases. After soy products are consumed, the bacteria of the intestinal microflora metabolize isoflavones to metabolites with altered absorption, bioavailability, and estrogenic characteristics. Variations in the effect of soy products have been correlated with the isoflavone metabolites found in plasma and urine samples of the individuals consuming soy products. The beneficial effects of the soy isoflavone daidzin, the glycoside of daidzein, have been reported in individuals producing equol, a reduction product of daidzein produced by specific colonic bacteria in individuals called equol producers. These individuals comprise 30% and 60% of populations consuming Western and soy-rich Asian diets, respectively. Since the higher percentage of equol producers in populations consuming soy-rich diets is correlated with a lower incidence of hormone-dependent diseases, considerable efforts have been made to detect the specific colonic bacteria involved in the metabolism of daidzein to the more estrogenic compound, equol, which should facilitate the investigation of the metabolic activities related to this compound. C1 US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 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 122 TC 12 Z9 12 U1 3 U2 19 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2218-1989 J9 METABOLITES JI Metabolites PD MAR PY 2015 VL 5 IS 1 BP 56 EP 73 DI 10.3390/metabo5010056 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU0KZ UT WOS:000363206600002 PM 25594250 ER PT J AU Jarow, JP Baxley, JH AF Jarow, Jonathan P. Baxley, John H. TI Medical devices: US medical device regulation SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Medical devices; Regulations; Investigational device exemption AB Medical devices are regulated by the US Food and Drug Administration (FDA) within the Center for Devices and Radiological Health. Center for Devices and Radiological Health is responsible for protecting and promoting the public health by ensuring the safety, effectiveness, and quality of medical devices, ensuring the safety of radiation-emitting products, fostering innovation, and providing the public with accurate, science-based information about the products we oversee, throughout the total product life cycle. The FDA was granted the authority to regulate the manufacturing and marketing of medical devices in 1976. It does not regulate the practice of medicine. Devices are classified based on complexity and level of risk, and "pre-1976" devices were allowed to remain on the market after being classified without FDA review. Post-1976 devices of lower complexity and risk that are substantially equivalent to a marketed "predicate" device may be cleared through the 510(k) premarket notification process. Clinical data are typically not needed for 510(k) clearance. In contrast, higher-risk devices typically require premarket approval. Premarket approval applications must contain data demonstrating reasonable assurance of safety and efficacy, and this information typically includes clinical data. For novel devices that are not high risk, the de novo process allows FDA to simultaneously review and classify new devices. Devices that are not legally marketed are permitted to be used for clinical investigation purposes in the United States under the Investigational Device Exemptions regulation. Published by Elsevier Inc. C1 [Jarow, Jonathan P.; Baxley, John H.] US FDA, Silver Spring, MD 20993 USA. RP Jarow, JP (reprint author), US FDA, Silver Spring, MD 20993 USA. EM jonathan.jarow@fda.hhs.gov NR 2 TC 5 Z9 5 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD MAR PY 2015 VL 33 IS 3 BP 128 EP 132 DI 10.1016/j.urolonc.2014.10.004 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CU1IS UT WOS:000363275000025 PM 25458071 ER PT J AU Bross, PF Fan, CH George, B Shannon, K Joshi, BH Puri, RK AF Bross, Peter F. Fan, Chaohong George, Bindu Shannon, Kevin Joshi, Bharat H. Puri, Raj K. TI Regulation of biologic oncology products in the FDA's Center for Biologics Evaluation and Research SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Cancer vaccines; Oncology; Immunotherapy; Bladder cancer; Prostate cancer; FDA regulation; Gene therapy; Cell therapy ID BLADDER-CANCER; IMMUNOTHERAPY AB In the United States, cancer vaccines and immunotherapies, including cell and gene therapies and peptides and proteins used as therapeutic vaccines, are regulated by the Food and Drug Administration's Center for Biologics Evaluation and Research in the Office of Cellular. Tissue, and Gene Therapies (OCTGT). Center for Biologics Evaluation and Research has licensed two immunotherapy products for urologic indications: bacillus Calmette-Guerin for superficial bladder cancer and sipuleucel-T for advanced prostate cancer. OCTGT places a high priority on scientific and regulatory activities that promote the development of safe and effective cancer therapy products. OCTGT has published guidance documents and developed innovative tools that are designed to aid the rapid development of biologic products for patient use. The success of immunotherapeutic products for urologic malignancies stands as an example for ongoing and future therapeutic research and discovery. Published by Elsevier Inc. C1 [Bross, Peter F.; Fan, Chaohong; George, Bindu; Shannon, Kevin; Joshi, Bharat H.; Puri, Raj K.] US FDA, OCTGT, CBER, Silver Spring, MD 20993 USA. RP Puri, RK (reprint author), US FDA, OCTGT, CBER, Silver Spring, MD 20993 USA. EM raj.puri@fda.hhs.gov NR 17 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD MAR PY 2015 VL 33 IS 3 BP 133 EP 136 DI 10.1016/j.urolonc.2014.10.016 PG 4 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CU1IS UT WOS:000363275000026 PM 25441459 ER PT J AU Ning, YM Maher, VE AF Ning, Yang-Min Maher, V. Ellen TI Food and Drug Administration process for development and approval of drugs and radiopharmaceuticals: Treatments in urologic oncology SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Treatments in urologic oncology; FDA approval; Oncologic Drug Advisory Committee; Prostate cancer; Renal cancer; Bladder cancer ID CANCER; THERAPY AB Regulatory advice and assessment play an important role in the successful development of new drugs and radiopharmaceuticals for the treatment of urologic malignancies. Cooperation between the US Food and Drug Administration (FDA) and the pharmaceutical industry has led to the approval of more than 20 new urologic oncology products in the last 2 decades. Despite these advances, more effective treatments need to be developed and approved for the treatment of urologic malignancies. This review provides general information about the FDA's role in the development of investigational new drugs, with an emphasis on the regulatory process and the requirements for marketing approval. In addition, this review summarizes the products for the treatment of urologic malignancies that were approved by the FDA in the last 30 years and the key issues concerning urologic oncology products that were discussed publicly at Oncologic Drug Advisory Committee meetings in the past 10 years. Published by Elsevier Inc. C1 [Ning, Yang-Min; Maher, V. Ellen] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Ning, YM (reprint author), US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM ningy@cder.fda.gov NR 18 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 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD MAR PY 2015 VL 33 IS 3 BP 137 EP 142 DI 10.1016/j.urolonc.2014.12.008 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CU1IS UT WOS:000363275000027 PM 25613202 ER PT J AU Renn, LA Theisen, TC Navarro, MB Mane, VP Schramm, LM Kirschman, KD Fabozzi, G Hillyer, P Puig, M Verthelyi, D Rabin, RL AF Renn, Lynnsey A. Theisen, Terence C. Navarro, Maria B. Mane, Viraj P. Schramm, Lynnsie M. Kirschman, Kevin D. Fabozzi, Giulia Hillyer, Philippa Puig, Montserrat Verthelyi, Daniela Rabin, Ronald L. TI High-throughput Quantitative Real-time RT-PCR Assay for Determining Expression Profiles of Types I and III Interferon Subtypes SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 97; Interferon; Innate Immunity; qRT-PCR Assay; Probes; Primers; Automated Pipetting ID HEPATITIS-C; IFN; LAMBDA; VIRUS; ALPHA; CELLS; COMPLEX; AUTOIMMUNITY; GENES AB Described in this report is a qRT-PCR assay for the analysis of seventeen human IFN subtypes in a 384-well plate format that incorporates highly specific locked nucleic acid (LNA) and molecular beacon (MB) probes, transcript standards, automated multichannel pipetting, and plate drying. Determining expression among the type I interferons (IFN), especially the twelve IFN-a subtypes, is limited by their shared sequence identity; likewise, the sequences of the type III IFN, especially IFN-lambda 2 and -lambda 3, are highly similar. This assay provides a reliable, reproducible, and relatively inexpensive means to analyze the expression of the seventeen interferon subtype transcripts. C1 [Renn, Lynnsey A.; Theisen, Terence C.; Navarro, Maria B.; Mane, Viraj P.; Schramm, Lynnsie M.; Kirschman, Kevin D.; Fabozzi, Giulia; Hillyer, Philippa; Rabin, Ronald L.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Puig, Montserrat; Verthelyi, Daniela] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Rabin, RL (reprint author), US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. EM Ronald.Rabin@fda.hhs.gov FU CBER/FDA-NIAID/NIH [YI-AI-6153-01]; FDA/CBER intramural funds; FDA Medical Countermeasures Initiative FX This work was supported by CBER/FDA-NIAID/NIH Interagency Agreement YI-AI-6153-01, FDA/CBER intramural funds, and the FDA Medical Countermeasures Initiative. TCT, MNB, VPM, LMS, and KDK were supported by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science Education through an Interagency agreement between the U.S. Departmen of Energy and the U.S. Food and Drug Administration. NR 30 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2015 IS 97 AR e52650 DI 10.3791/52650 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MM UT WOS:000361534300066 ER PT J AU Twomey, JD Kim, SR Zhao, LQ Bozza, WP Zhang, BL AF Twomey, Julianne D. Kim, Su-Ryun Zhao, Liqun Bozza, William P. Zhang, Baolin TI Spatial dynamics of TRAIL death receptors in cancer cells SO DRUG RESISTANCE UPDATES LA English DT Review DE TRAIL; Death receptors; Surface expression; Targeted cancer therapy; Drug resistance ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; LIGAND (TRAIL)-INDUCED APOPTOSIS; PROTEIN-COUPLED RECEPTORS; MEDIATED APOPTOSIS; UP-REGULATION; LUNG-CANCER; LIPID RAFTS; ONCOGENIC RAS; FACTOR-ALPHA AB TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in cancer cells without harming most normal cells. Currently, multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL (rhTRAIL) and agonistic antibodies that target death receptors (DRs) 4 or 5. It is encouraging that these products have shown a tolerated safety profile in early phase studies. However, their therapeutic potential is likely limited by the emergence of tumor drug resistance phenomena. Increasing evidence indicates that TRAIL DRs are deficient on the plasma membrane of some cancer cells despite their total protein expression. Notably, the lack of surface DR4/DR5 is sufficient to render cancers resistant to TRAIL-induced apoptosis, regardless of the status of other apoptosis signaling components. The current review highlights recent findings on the dynamic expression of TRAIL death receptors, including the regulatory roles of endocytosis, autophagy, and Ras GTPase-mediated signaling events. This information could aid in the identification of novel predictive biomarkers of tumor response as well as the development of combinational drugs to overcome or bypass tumor drug resistance to TRAIL receptor-targeted therapies. Published by Elsevier Ltd. C1 [Twomey, Julianne D.; Kim, Su-Ryun; Zhao, Liqun; Bozza, William P.; Zhang, Baolin] US FDA, Div Biotechnol Review & Res 4, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhang, BL (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 52,Room 2128, Silver Spring, MD 20993 USA. EM Baolin.Zhang@fda.hhs.gov NR 130 TC 12 Z9 14 U1 1 U2 17 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 EI 1532-2084 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD MAR PY 2015 VL 19 BP 13 EP 21 DI 10.1016/j.drup.2015.02.001 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CI8ME UT WOS:000355025600002 PM 25840763 ER PT J AU Andrews, JC Choiniere, CJ Portnoy, DB AF Andrews, J. Craig Choiniere, Conrad J. Portnoy, David B. TI Opportunities for Consumer Research from the Food and Drug Administration's Center for Tobacco Products SO JOURNAL OF PUBLIC POLICY & MARKETING LA English DT Article DE Food and Drug Administration; tobacco; consumer research; warnings; new and emerging products ID CIGARETTE WARNING LABELS; UNITED-STATES; HEALTH WARNINGS; ANTISMOKING ADVERTISEMENTS; PERCEIVED EFFECTIVENESS; SMOKING PREVENTION; MEDIA CAMPAIGN; CONTROL ACT; SMOKERS; IMPACT AB The first purpose of this Policy Watch article is to discuss the Food and Drug Administration regulatory authority over the manufacture, marketing, and distribution of tobacco products. In doing so, the authors describe the public health goals and priorities from the Food and Drug Administration's Center for Tobacco Products. Then, the authors present current consumer and marketing research in important areas of reducing the death and disability resulting from tobacco use, such as the impacts of health warnings, modified risk tobacco products, new tobacco products, and public education campaigns. Finally, the authors identify important research gaps and offer specific opportunities for consumer researchers to consider. C1 [Andrews, J. Craig] Marquette Univ, Mkt, Milwaukee, WI 53233 USA. [Choiniere, Conrad J.] Ctr Tobacco Prod Food & Drug Adm, Div Populat Hlth Sci, Off Sci, Rockville, MD 20857 USA. Ctr Tobacco Prod Food & Drug Adm, Off Sci, Rockville, MD 20857 USA. RP Andrews, JC (reprint author), Marquette Univ, Mkt, Milwaukee, WI 53233 USA. EM craig.andrews@marquette.edu; conrad.choiniere@fda.hhs.gov; david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 NR 86 TC 3 Z9 3 U1 8 U2 13 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 2015 VL 34 IS 1 BP 119 EP 130 PG 12 WC Business SC Business & Economics GA CI2OI UT WOS:000354586500009 ER PT J AU Gleich, SJ Flick, R Hu, DQ Zaccariello, MJ Colligan, RC Katusic, SK Schroeder, DR Hanson, A Buenvenida, S Wilder, RT Sprung, J Voigt, RG Paule, MG Chelonis, JJ Warner, DO AF Gleich, Stephen J. Flick, Randall Hu, Danqing Zaccariello, Michael J. Colligan, Robert C. Katusic, Slavica K. Schroeder, Darrell R. Hanson, Andrew Buenvenida, Shonie Wilder, Robert T. Sprung, Juraj Voigt, Robert G. Paule, Merle G. Chelonis, John J. Warner, David O. TI Neurodevelopment of children exposed to anesthesia: Design of the Mayo Anesthesia Safety in Kids (MASK) study SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Anesthesia; Neurotoxicity; Population study; Propensity-match design; Operant Test Battery ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; INDUCED APOPTOTIC NEURODEGENERATION; OPERANT TEST BATTERY; DEVELOPING BRAIN; BIRTH COHORT; DEVELOPMENTAL ASPECTS; CHILDHOOD EXPOSURE; NEONATAL EXPOSURE; PERFORMANCE; METHYLPHENIDATE AB There is increasing evidence that exposure of developing brains in animals, including nonhuman primates, to commonly-utilized anesthetic agents may cause adverse effects on cognition and behavior. In this paper, we summarize our methodology for a population-based, propensity-matched study to evaluate possible anesthesia-related sequelae in preschool children when evaluated in elementary or high school. A cohort of all children born in Olmsted County, Minnesota between the years 1994 and 2007 who are currently local residents has been identified. Existing medical records are being used to identify all episodes of exposure to general anesthesia prior to the age of 3 years (i.e., prior to their 3rd birthday). Children with multiple, single, and no anesthesia exposure are sampled for testing between the ages of 8 and 12 years or 15 and 19 years during the period 2012-2016. To match children in different exposure groups as closely as possible, sampling is guided by propensity-matching for the likelihood of receiving anesthesia. Selected children are invited to participate in a single 4-hour session of neuropsychological testing, including the National Center for Toxicological Research-Operant Test Battery, which has been used to study anesthetic neurotoxicity in nonhuman primates. The results of this testing will be compared among children with different anesthetic exposure histories. The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks. (C) 2014 Elsevier Inc All rights reserved. C1 [Gleich, Stephen J.; Flick, Randall; Buenvenida, Shonie; Wilder, Robert T.; Sprung, Juraj; Warner, David O.] Mayo Clin, Dept Anesthesiol, Rochester, MN 55905 USA. [Hu, Danqing] Mayo Clin, Mayo Grad Sch, Rochester, MN 55905 USA. [Zaccariello, Michael J.; Colligan, Robert C.] Mayo Clin, Dept Psychol, Rochester, MN 55905 USA. [Katusic, Slavica K.; Schroeder, Darrell R.; Hanson, Andrew] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Voigt, Robert G.] Baylor Coll Med, Dept Pediat Med, Houston, TX 77030 USA. [Paule, Merle G.; Chelonis, John J.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Warner, DO (reprint author), Mayo Clin, Dept Anesthesiol, 200 1st St SW, Rochester, MN 55905 USA. EM warner.david@mayo.edu RI hu, dq/K-9722-2016 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD071907]; National Institute on Aging [R01-AG034676] FX This project is supported by grant HD071907 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and utilizes the resources of the Rochester Epidemiology Project, supported by grant R01-AG034676 from the National Institute on Aging. NR 52 TC 16 Z9 16 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2015 VL 41 BP 45 EP 54 DI 10.1016/j.cct.2014.12.020 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA CG0YQ UT WOS:000353000500006 PM 25555440 ER PT J AU Wang, HG Word, B Lyn-Cook, L Yang, MC Hammons, G Lyn-Cook, B AF Wang, Honggang Word, Beverly Lyn-Cook, Lascelles, Jr. Yang, Maocheng Hammons, George Lyn-Cook, Beverly TI Cytotoxicity of Chronic Exposure to 4 Cigarette Smoke Condensates in 2 Cell Lines SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE cigarette smoke condensate; chronic exposure; in vitro cytotoxicity assay; cell-specific responses; PSAE cells; hTERT cells ID IN-VITRO ASSAYS; BRONCHIAL EPITHELIAL-CELLS; LUNG-CANCER; MESENCHYMAL TRANSITION; OXIDATIVE STRESS; MAINSTREAM SMOKE; TEST SYSTEMS; TOBACCO; TOXICITY; TRANSCRIPTOME AB Tobacco use is the leading preventable cause of death. The cytotoxicity of cigarette smoke condensate (CSC), the particulate fraction of cigarette smoke without the vapor phase, has mostly been tested in short-term in vitro studies lasting from a few hours to a few days. Here, we assessed the toxicity of CSCs from 2 reference cigarettes, 3R4F and CM6, using a primary human small airway epithelial (PSAE) cell line by quantifying adenosine 5-triphosphate (ATP), 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), total glutathione (reduced glutathione [GSH] + oxidized glutathione [GSSG]), and lactate dehydrogenase (LDH) release over the course of 28 days. The CSCs, 0.3 to 10 g/mL, promoted cell proliferation at 120 hours of exposure, but demonstrated cytotoxicity at days 14 and 28. Interestingly, CSCs, 0.3 to 3 g/mL, showed a cell death effect at day 14 but induced cell proliferation at day 28. Consistently, transformation associated with morphological changes began by day 14 and the transformed cells grew dramatically at day 28. The LDH assay appeared to be sensitive for assessing early cell damage, whereas the ATP, MTS, and GSH assays were more suitable for determining later stage CSCs-induced cytotoxicity. The ATP assay showed greater sensitivity than the MTS and GSH assays. We also assessed the toxicity of CSCs in an human Telomerase Reverse Transcriptase (hTERT)-immortalized Barrett esophagus cell line (CP-C). The CP-C cells demonstrated dose- and time-dependent cytotoxicity over the course of 28 days but displayed higher resistance to CSCs than PSAE cells. This study demonstrates that CSCs cause cytotoxicity and induce transformation related to cell resistance and cell invasion properties. C1 [Wang, Honggang; Word, Beverly; Lyn-Cook, Lascelles, Jr.; Hammons, George; Lyn-Cook, Beverly] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Yang, Maocheng] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Lyn-Cook, B (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT-100, Jefferson, AR 72079 USA. EM beverly.lyn-cook@fda.hhs.gov NR 41 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD MAR-APR PY 2015 VL 34 IS 2 BP 182 EP 194 DI 10.1177/1091581815574349 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CG7CA UT WOS:000353458600006 PM 25800266 ER PT J AU Chen, Y Reddy, RM Li, WJ Yettlla, RR Lopez, S Woodman, M AF Chen, Yang Reddy, Ravinder M. Li, Wenjing Yettlla, Ramesh R. Lopez, Salvador Woodman, Michael TI Development and Validation of a High Performance Liquid Chromatographic Method for Simultaneous Determination of Vitamins A and D-3 in Fluid Milk Products SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID FAT-SOLUBLE VITAMINS; MASS-SPECTROMETRY; CHOLECALCIFEROL VITAMIN-D-3; INFANT; FOODS; FORMULAS; SUPPLEMENTS; EXTRACTION; CANCER; DAIRY AB An HPLC method for simultaneous determination of vitamins A and D-3 in fluid milk was developed and validated. Saponification and extraction conditions were studied for optimum recovery and simplicity. An RP HPLC system equipped with a C-18 column and diode array detector was used for quantitation. The method was subjected to a single-laboratory validation using skim, 2% fat, and whole milk samples at concentrations of 50, 100, and 200% of the recommended fortification levels for vitamins A and D-3 for Grade "A" fluid milk. The method quantitation limits for vitamins A and D-3 were 0.0072 and 0.0026 mu g/mL, respectively, Average recoveries between 94 and 110% and SD values ranging from 2.7 to 6.9% were obtained for both vitamins A and D-3. The accuracy of the method was evaluated using a National Institute of Standards and Technology standard reference material (1849a) and proficiency test samples. C1 [Chen, Yang; Reddy, Ravinder M.] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Li, Wenjing; Yettlla, Ramesh R.; Lopez, Salvador] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Woodman, Michael] Agilent Technol, Wilmington, DE 19808 USA. RP Chen, Y (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM yang.chen@fda.hhs.gov FU U.S. Department of Energy; FDA FX This project was supported in part by a Research Program appointment at the Center for Food Safety and Applied Nutrition administrated by the Oak Ridge Institute for Science and Education via an interagency agreement between the U.S. Department of Energy and the FDA. NR 27 TC 0 Z9 0 U1 4 U2 22 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 MAR-APR PY 2015 VL 98 IS 2 BP 390 EP 396 DI 10.5740/jaoacint.14-137 PG 7 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CG5EE UT WOS:000353313100022 PM 25905745 ER PT J AU Hubinger, JC AF Hubinger, Jean C. TI Determination of estriol, estradiol, estrone, and progesterone in cosmetic products SO JOURNAL OF COSMETIC SCIENCE LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; HORMONE REPLACEMENT THERAPY; TANDEM MASS-SPECTROMETRY; BREAST-CANCER; POSTMENOPAUSAL WOMEN; SEX-HORMONES; DIODE ARRAY; SKIN; ESTROGENS; EXTRACTION AB This report describes the development and validation of a reverse phase high-performance liquid chromatography (HPLC) method with UV detection for the determination of the hormones estriol, estradiol, estrone, and progesterone in topically applied products. The developed method was then used to conduct a postmarket survey of consumer products for these hormones. Each product was first mixed with Celite and then extracted with methanol. Extracts were cleaned on a Waters Oasis HLB solid phase extraction cartridge, and then analyzed using reversed phase HPLC. The analytes were separated using an Agilent Zorbax Eclipse XDB C8 (5 mu m, 250 mm by 4.6 mm) analytical column and detected by their absorbance at 230 nm. Chromatographic separation was achieved by a 1.0-ml/min linear gradient from 30% acetonitrile and 70% water to 80% acetonitrile and 20% water over 30 min. A final 5 min hold time and a re-equilibration time of 10 min were used to prepare the column for subsequent analysis. Recovery from two different brand lotions spiked with three different levels of estriol, estradiol, estrone, and progesterone ranged from 81.8% to 101%. In this study, a total of 70 cosmetic products were surveyed. Twenty two (63%) of the 35 products were labeled as containing an estrogen and/or progesterone and also provided quantitative label information about the hormone ingredient. The most frequently labeled hormones were progesterone (66%), estriol (46%), estradiol (11%), and estrone (6%). Six products labeled as containing estriol were found to contain estradiol. An estrogen and/or progesterone were found in 34 products at concentrations ranging from 86.0 to 26,800 mu g/g. Progesterone was not found in one product labeled as containing this hormone. An additional 35 products, which did not list hormones on their labels, were analyzed and estrogen or progesterone was not detected in these products. C1 US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hubinger, JC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Jean.Hubinger@fda.hhs.gov NR 31 TC 0 Z9 0 U1 4 U2 15 PU SOC COSMETIC CHEMISTS PI NEW YORK PA 120 WALL STREET, SUITE 2400, NEW YORK, NY 10005-4088 USA SN 1525-7886 J9 J COSMET SCI JI J. Cosmet. Sci. PD MAR-APR PY 2015 VL 66 IS 2 BP 113 EP 128 PG 16 WC Chemistry, Applied; Dermatology SC Chemistry; Dermatology GA CG3KO UT WOS:000353179300004 PM 26454975 ER PT J AU Genter, MB Brock, WJ Mattes, WB AF Genter, Mary Beth Brock, William J. Mattes, William B. TI Scientific Conduct ... and Misconduct SO TOXICOLOGICAL SCIENCES LA English DT Letter C1 [Genter, Mary Beth] Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Brock, William J.] Brock Sci Consulting LLC, Montgomery Village, MD 20886 USA. [Mattes, William B.] Natl Ctr Toxicol Res, Div Syst Biol Food & Drug Adm, Jefferson, AR 72079 USA. RP Genter, MB (reprint author), Univ Cincinnati, Dept Environm Hlth, 160 Panzeca Way,Kettering 144, Cincinnati, OH 45267 USA. EM Marybeth.genter@uc.edu NR 6 TC 0 Z9 0 U1 0 U2 3 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 2015 VL 144 IS 1 BP 3 EP 4 DI 10.1093/toxsci/kfu261 PG 2 WC Toxicology SC Toxicology GA CG8FP UT WOS:000353543000003 PM 25901331 ER PT J AU Woo, EJ AF Woo, Emily Jane TI Letter to the Editor: Fatal varicella due to the vaccine-strain varicella-zoster virus SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Letter DE adverse event; immunodeficiency; live viral vaccine; varicella zoster virus C1 US FDA, Silver Spring, MD 20993 USA. RP Woo, EJ (reprint author), US FDA, Silver Spring, MD 20993 USA. EM jane.woo@fda.hhs.gov NR 3 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD MAR PY 2015 VL 11 IS 3 BP 679 EP 679 DI 10.1080/21645515.2014.1004034 PG 1 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA CF5SA UT WOS:000352616100026 PM 25839218 ER PT J AU Ignatieva, AV Timofeeva, TA Rudneva, IA Shilov, AA Masalova, OV Klimova, RR Kushch, AA Ilyushina, NA Kaverin, NV AF Ignatieva, A. V. Timofeeva, T. A. Rudneva, I. A. Shilov, A. A. Masalova, O. V. Klimova, R. R. Kushch, A. A. Ilyushina, N. A. Kaverin, N. V. TI Effect of amino acid substitutions in the small subunit of the avian H5N2 influenza virus hemagglutinin on selection of the mutants, resistant to neutralizing monoclonal antibodies SO MOLECULAR BIOLOGY LA English DT Article DE influenza A virus; hemagglutinin H5; escape mutants; monoclonal antibodies; phenotypic properties ID ESCAPE MUTANTS; PROTEIN; PH; PATHOGENICITY; GLYCOPROTEIN; SPECIFICITY; ACTIVATION; INFECTION; VARIANTS; EPITOPES AB Mutations in the hemagglutinin (HA) protein molecule of influenza A viruses associated with the virus's resistance to physical and chemical factors can play important roles in the selection of influenza variants during circulation in nature. In this study, we examined escape mutants of the A/mallard/Pennsylvania/10218/84 (H5N2) influenza virus, which were selected with a monoclonal antibody specific to an epitope in the large HA subunit (HA1). We obtained escape mutant m4F11(4), which carries a single amino acid substitution S145P(1) in the HA1 subunit and two other mutants, m4G10(10) and m4G10(6), which accumulated additional mutations in the small subunit (HA2), i.e., L124F(2) and L124F(2)+N79D(2), respectively. We demonstrate that amino acid substitutions in HA2 of m4G10(10) and m4G10(6) viruses can compensate for the negative effect of the S145P(1) mutation, which manifested in a significant increase in the capacity for viral replication at the early stages of infection in chicken embryos, as well as in growth in the HA thermostability compared with the m4F11(4) escape mutant. We propose that these variations in phenotypic properties, which provide advantages during viral replication, play a role in the positive selection factor and are retained in the viral population. C1 [Ignatieva, A. V.; Timofeeva, T. A.; Rudneva, I. A.; Shilov, A. A.; Masalova, O. V.; Klimova, R. R.; Kushch, A. A.; Kaverin, N. V.] Minist Hlth Russian Federat, Ivanovsky Inst Virol, Moscow 123098, Russia. [Ilyushina, N. A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Ignatieva, AV (reprint author), Minist Hlth Russian Federat, Ivanovsky Inst Virol, Moscow 123098, Russia. EM valgella@yandex.ru OI Klimova, Regina/0000-0002-4147-8444; masalova, olga/0000-0001-5571-5669 FU Russian Foundation for Basic Research [12-04-00257] FX This work was supported by the Russian Foundation for Basic Research project no. 12-04-00257. NR 27 TC 1 Z9 1 U1 1 U2 6 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0026-8933 EI 1608-3245 J9 MOL BIOL+ JI Mol. Biol. PD MAR PY 2015 VL 49 IS 2 BP 303 EP 311 DI 10.1134/S002689331502003X PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CF9RC UT WOS:000352902500014 ER PT J AU Deisseroth, A Ko, CW Nie, L Zirkelbach, JF Zhao, L Bullock, J Mehrotra, N Del Valle, P Saber, H Sheth, C Gehrke, B Justice, R Farrell, A Pazdur, R AF Deisseroth, Albert Ko, Chia-Wen Nie, Lei Zirkelbach, Jeanne F. Zhao, Liang Bullock, Julie Mehrotra, Nitin Del Valle, Pedro Saber, Haleh Sheth, Christopher Gehrke, Brenda Justice, Robert Farrell, Ann Pazdur, Richard TI FDA Approval: Siltuximab for the Treatment of Patients with Multicentric Castleman Disease SO CLINICAL CANCER RESEARCH LA English DT Article ID KAPOSIS-SARCOMA; DNA-SEQUENCES; ANTIBODY; LYMPHOMA AB On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric humanmouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2: 1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC. The primary efficacy endpoint was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Tumor response was based on independent review of CT scans using the revised Response Criteria for Malignant Lymphoma, and symptomatic response was defined as complete resolution or stabilization of 34 MCD-related signs and symptoms as reported by the investigator. Thirty-four percent of patients in the siltuximab arm and no patients in the placebo arm met the primary endpoint (P = 0.0012). The most common adverse reactions (>10% compared with placebo) during treatment with siltuximab were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection. (C) 2015 AACR. C1 [Deisseroth, Albert; Del Valle, Pedro; Saber, Haleh; Sheth, Christopher; Gehrke, Brenda; Justice, Robert; Farrell, Ann; Pazdur, Richard] US FDA, Off Hematol & Oncol Drug Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Ko, Chia-Wen; Nie, Lei] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Zirkelbach, Jeanne F.; Zhao, Liang; Bullock, Julie; Mehrotra, Nitin] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Deisseroth, A (reprint author), US FDA, CDER, 10903 New Hampshire Ave,WO22-2334, Silver Spring, MD 20993 USA. EM Albert.Deisseroth@fda.hhs.gov NR 12 TC 14 Z9 16 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR PY 2015 VL 21 IS 5 BP 950 EP 954 DI 10.1158/1078-0432.CCR-14-1678 PG 5 WC Oncology SC Oncology GA CE6XZ UT WOS:000351982800005 PM 25601959 ER PT J AU Marino, MP Panigaj, M Ou, W Manirarora, J Wei, CH Reiser, J AF Marino, M. P. Panigaj, M. Ou, W. Manirarora, J. Wei, C-H Reiser, J. TI A scalable method to concentrate lentiviral vectors pseudotyped with measles virus glycoproteins SO GENE THERAPY LA English DT Article ID MEMBRANE CHROMATOGRAPHY; ENDOTHELIAL-CELLS; GENE-TRANSFER; PURIFICATION; TRANSDUCTION; TROPISM AB Lentiviral (LV) vectors have emerged as powerful tools for basic research and clinical applications because of their ability to stably transduce both dividing and nondividing cells. A wide range of viral envelope (Env) glycoproteins have the ability to associate with the membrane of LV vectors, a process that is referred to as pseudotyping. Pseudotyped vectors have the capacity to transduce specific cell types for specific applications. For example, LV vectors pseudotyped with the measles virus (MV)-derived hemagglutinin (H) and fusion (F) proteins have the ability to transduce quiescent lymphocytes. In addition, the MV H glycoprotein can be engineered allowing cell-specific targeting of LV vectors. One problem with MV glycoprotein-pseudotyped LV vectors is low titer during vector production. This results in the need to manufacture large volumes of the vectors and to concentrate them to appropriate titers. The commonly used centrifugation-based concentration techniques for LV vectors are not practical for large-scale vector manufacturing. Thus, there is a need for improved methods to concentrate LV vectors. In this study, we adapted an anion-exchange membrane chromatography method that we previously used in the context of LV vectors pseudotyped with the vesicular stomatitis virus glycoprotein to concentate MV glycoprotein-pseudotyped LV vectors. Up to 60% of the input vectors with an up to 5300-fold reduction in volume was achieved using this anion-exchange chromatography method in conjunction with a desalting/concentration step involving centrifugal filter units. This technique provides a rapid and scalable approach for concentrating MV-pseudotyped LV vectors that does not require an elaborate setup. C1 [Marino, M. P.; Panigaj, M.; Ou, W.; Manirarora, J.; Wei, C-H; Reiser, J.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Reiser, J (reprint author), US FDA, Div Cellular & Gene Therapies, CBER, 10903 New Hampshire Ave,Bldg 52-72,Room 3106, Silver Spring, MD 20993 USA. EM Jakob.Reiser@fda.hhs.gov RI Panigaj, Martin/G-6492-2013 FU Research Participation Program at the Center for Biologics Evaluation and Research FX This project was supported in part by an appointment of MP and JM 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 Food and Drug Administration. We are grateful to Linyi Zhang for help with the cell viability assay. We thank Robert Aksamit (FDA/CBER) and Zhili Xu (FDA/CBER) for helpful comments on the manuscript. NR 30 TC 0 Z9 0 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD MAR PY 2015 VL 22 IS 3 BP 280 EP 285 DI 10.1038/gt.2014.125 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CE9QX UT WOS:000352179600007 PM 25608718 ER PT J AU Bourcier, T McGovern, T Stavitskaya, L Kruhlak, N Jacobson-Kram, D AF Bourcier, Todd McGovern, Tim Stavitskaya, Lidiya Kruhlak, Naomi Jacobson-Kram, David TI Improving Prediction of Carcinogenicity to Reduce, Refine, and Replace the Use of Experimental Animals SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID ALTERNATIVE MODELS; AROMATIC-AMINES; PHARMACEUTICALS; TOXICOLOGY; FRAMEWORK; MUTAGENS; RODENTS; WEIGHT; RISK; RAT AB Cancer risk assessment of new pharmaceuticals is crucial to protect public health. However, clinical trials lack the duration needed to clearly detect drug-related tumor emergence, and biomarkers suggestive of increased cancer risk from a drug typically are not measured in clinical trials. Therefore, the carcinogenic potential of a new pharmaceutical is extrapolated predominately based on 2-y bioassays in rats and mice. A key drawback to this practice is that the results are frequently positive for tumors and can be irrelevant to human cancer risk for reasons such as dose, mode of action, and species specificity Alternative approaches typically strive to reduce, refine, and replace rodents in carcinogenicity assessments by leveraging findings in short-term studies, both in silico and in vivo, to predict the likely tumor outcome in rodents or, more broadly, to identify a cancer risk to patients. Given the complexities of carcinogenesis and the perceived impracticality of assessing risk in the course of clinical trials, studies conducted in animals will likely remain the standard by which potential cancer risks are characterized for new pharmaceuticals in the immediate foreseeable future. However, a weight-of-evidence evaluation based on short-term toxicologic, in silico, and pharmacologic data is a promising approach to identify with reasonable certainty those pharmaceuticals that present a likely cancer risk in humans and, conversely, those that do not present a human cancer risk. C1 [Bourcier, Todd; McGovern, Tim; Stavitskaya, Lidiya; Kruhlak, Naomi] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Jacobson-Kram, David] ToxRox Consulting, Mclean, VA 22101 USA. RP Bourcier, T (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM todd.bourcier@fda.hhs.gov NR 34 TC 3 Z9 3 U1 1 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAR PY 2015 VL 54 IS 2 BP 163 EP 169 PG 7 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CE8UJ UT WOS:000352119300007 PM 25836962 ER PT J AU Casey, W Jacobs, A Maull, E Matheson, J Clarke, C Lowit, A AF Casey, Warren Jacobs, Abigail Maull, Elizabeth Matheson, Joanna Clarke, Carol Lowit, Anna TI A New Path Forward: The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article AB In 2000, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was congressionally established, with representatives from Federal regulatory and research agencies that require, use, generate, or disseminate toxicologic and safety testing information. For over 15 y, ICCVAM and the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) have worked together to promote the development, validation, and regulatory acceptance of test methods that replace, reduce, or refine the use of animals in regulatory testing. In 2013, both NICEATM and ICCVAM underwent major changes to their operating paradigms, to increase the speed and efficiency of regulatory approval and industry adoption of 3Rs testing methods within the United States and internationally. Accordingly, increased emphasis has been placed on international activities, primarily through interaction with the Organization for Economic Cooperation and Development and participation in the International Cooperation on Alternative Test Methods. In addition, ICCVAM has committed to increasing public awareness of and transparency about federal agencies' 3R activities and to fostering interactions with stakeholders. Finally, although it continues to support ICCVAM, NICEATM's work now includes validation support for Tox21, a collaboration aimed at identifying in vitro methods and computational approaches for testing chemicals to better understand and predict hazards to humans and the environment. The combination of more efficient operating paradigms, increased international collaboration, improved communication and interaction with stakeholders, and active participation in Tox21 likely will substantially increase the number of 3Rs methods developed and used in the United States and internationally. C1 [Casey, Warren; Maull, Elizabeth] NIEHS, NIH, DNTP, NICEATM, Res Triangle Pk, NC 27709 USA. [Jacobs, Abigail] FDA, CDER, Silver Spring, MD USA. [Matheson, Joanna; Lowit, Anna] US Consumer Prod Safety Commiss, Bethesda, MD USA. [Clarke, Carol] USDA, Riverdale, MD USA. US EPA, Washington, DC 20460 USA. RP Casey, W (reprint author), NIEHS, NIH, DNTP, NICEATM, POB 12233, Res Triangle Pk, NC 27709 USA. EM warren.casey@nih.gov NR 3 TC 4 Z9 4 U1 0 U2 5 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAR PY 2015 VL 54 IS 2 BP 170 EP 173 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CE8UJ UT WOS:000352119300008 PM 25836963 ER PT J AU Rutkow, L Turner, L Lucas, E Hwang, C Alexander, GC AF Rutkow, Lainie Turner, Lydia Lucas, Eleanor Hwang, Catherine Alexander, G. Caleb TI Most Primary Care Physicians Are Aware Of Prescription Drug Monitoring Programs, But Many Find The Data Difficult To Access SO HEALTH AFFAIRS LA English DT Article ID CONTROLLED SUBSTANCES; DIVERSION; OPIOIDS; GUIDELINES; DEATHS; HEALTH; ABUSE; RATES; PAIN AB State prescription drug monitoring programs are common tools intended to reduce prescription drug abuse and diversion, or the nonmedical use of a prescribed drug. The success of these programs depends largely upon physicians' awareness and use of them. We conducted a nationally representative mail survey of 1,000 practicing primary care physicians in 2014 to characterize their attitudes toward and awareness and use of prescription drug monitoring programs. A total of 420 eligible physicians (adjusted response rate: 58 percent) returned completed surveys. Among all physicians surveyed, 72 percent were aware of their state's prescription drug monitoring program, and 53 percent reported using one of the programs. We identified several barriers that may prevent greater use of the programs, including the time-consuming nature of information retrieval and the lack of an intuitive format for data provided by the programs. These results suggest that the majority of US primary care physicians are aware of and use prescription drug monitoring programs at least on occasion, although many did not access these programs routinely. To increase the use of the programs in clinical practice, states should consider implementing legal mandates, investing in prescriber education and outreach, and taking measures to enhance ease of access to and use of the programs. C1 [Rutkow, Lainie] Johns Hopkins Bloomberg Sch Publ Hlth, Hlth Policy & Management, Baltimore, MD 21205 USA. [Turner, Lydia; Lucas, Eleanor; Hwang, Catherine; Alexander, G. Caleb] Johns Hopkins Bloomberg Sch Publ Hlth, Epidemiol, Baltimore, MD USA. [Hwang, Catherine] US FDA, ORISE, Silver Spring, MD USA. RP Rutkow, L (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Hlth Policy & Management, Baltimore, MD 21205 USA. EM galexand@jhsph.edu FU Robert Wood Johnson Foundation Public Health Law Research Program [71520]; Lipitz Public Health Policy Award from Johns Hopkins Bloomberg School of Public Health; Peripheral and Central Nervous System Advisory Committee at the Food and Drug Administration (FDA) FX Caleb Alexander and Lainie Rutkow are supported by the Robert Wood Johnson Foundation Public Health Law Research Program (Grant No. 71520). Alexander is also supported by the Lipitz Public Health Policy Award from the Johns Hopkins Bloomberg School of Public Health. The funding sources had no role in the design or conduct of the study, analysis or interpretation of the data, and preparation or final approval of the manuscript prior to publication. Alexander is chair of the Peripheral and Central Nervous System Advisory Committee at the Food and Drug Administration (FDA), serves as a paid consultant to IMS Health, and serves on an IMS Health scientific advisory board. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies. Catherine Hwang is an Oak Ridge Institute for Science and Education (ORISE) fellow at the FDA. NR 45 TC 19 Z9 20 U1 1 U2 3 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 2015 VL 34 IS 3 BP 484 EP 492 DI 10.1377/hlthaff.2014.1085 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CE3HB UT WOS:000351716200017 PM 25732500 ER PT J AU Yang, CH Tarkhov, A Marusczyk, J Bienfait, B Gasteiger, J Kleinoeder, T Magdziarz, T Sacher, O Schwab, CH Schwoebel, J Terfloth, L Arvidson, K Richard, A Worth, A Rothman, J AF Yang, Chihae Tarkhov, Aleksey Marusczyk, Joerg Bienfait, Bruno Gasteiger, Johann Kleinoeder, Thomas Magdziarz, Tomasz Sacher, Oliver Schwab, Christof H. Schwoebel, Johannes Terfloth, Lothar Arvidson, Kirk Richard, Ann Worth, Andrew Rothman, James TI New Publicly Available Chemical Query Language, CSRML, To Support Chemotype Representations for Application to Data Mining and Modeling SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID LINE NOTATION SLN; PREDICTIVE MODELS; SCREENING DATA; SYSTEM; CARCINOGENICITY; TOXICITY; ALERTS; DESIGN; UPDATE AB In designing an Electronic Lab Notebook (ELN), there is a balance to be struck between keeping it as general and multidisciplinary as possible for simplicity of use and maintenance and introducing more domain-specific functionality to increase its appeal to target research areas. Here, we describe the results of a collaboration between the Royal Society of Chemistry (RSC) and the University of Southampton, guided by the aims of the Dial-a-Molecule Grand Challenge, intended to achieve the best of both worlds and augment a discipline-agnostic ELN, LabTrove, with chemistry-specific functionality and using data provided by the ChemSpider platform. This has been done using plug-in technology to ensure maximum transferability with minimal effort of the chemistry functionality to other ELNs and equally other subject-specific functionality to LabTrove. The resulting product, ChemTrove, has undergone a usability trial by selected academics, and the resulting feedback will guide the future development of the underlying ELN technology. C1 [Yang, Chihae; Tarkhov, Aleksey; Marusczyk, Joerg; Bienfait, Bruno; Gasteiger, Johann; Kleinoeder, Thomas; Magdziarz, Tomasz; Sacher, Oliver; Schwab, Christof H.; Schwoebel, Johannes; Terfloth, Lothar] Mol Networks GmbH, D-91052 Erlangen, Germany. [Yang, Chihae; Rothman, James] Altamira LLC, Columbus, OH 43235 USA. [Rothman, James] Ohio State Univ, Dept Chem & Biomol Engn, Columbus, OH 43210 USA. [Yang, Chihae; Arvidson, Kirk] US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety FDA CFSAN OFAS, College Pk, MD 20740 USA. [Richard, Ann] US EPA, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA. [Worth, Andrew] EC Joint Res Ctr JRC, I-21027 Ispra, Italy. RP Yang, CH (reprint author), Mol Networks GmbH, D-91052 Erlangen, Germany. EM chihae.yang@molecular-networks.com NR 38 TC 11 Z9 11 U1 4 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD MAR PY 2015 VL 55 IS 3 BP 510 EP 528 DI 10.1021/ci500667v PG 19 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA CE2NS UT WOS:000351652900005 PM 25647539 ER PT J AU Turner, AD Higgins, C Davidson, K Veszelovszki, A Payne, D Hungerford, J Higman, W AF Turner, Andrew D. Higgins, Cowan Davidson, Keith Veszelovszki, Andrea Payne, Daniel Hungerford, James Higman, Wendy TI Potential Threats Posed by New or Emerging Marine Biotoxins in UK Waters and Examination of Detection Methodology Used in Their Control: Brevetoxins SO MARINE DRUGS LA English DT Review ID OYSTER CRASSOSTREA-VIRGINICA; HARMFUL ALGAL BLOOMS; DINOFLAGELLATE KARENIA-BREVISULCATA; IONIZATION MASS-SPECTROMETRY; IN-SITU HYBRIDIZATION; RED TIDE ALGAE; NEW-ZEALAND; FLOW-CYTOMETRY; AUSTROVENUS-STUTCHBURYI; CONTROLLED EXPOSURES AB Regular occurrence of brevetoxin-producing toxic phytoplankton in commercial shellfishery areas poses a significant risk to shellfish consumer health. Brevetoxins and their causative toxic phytoplankton are more limited in their global distribution than most marine toxins impacting commercial shellfisheries. On the other hand, trends in climate change could conceivably lead to increased risk posed by these toxins in UK waters. A request was made by UK food safety authorities to examine these toxins more closely to aid possible management strategies, should they pose a threat in the future. At the time of writing, brevetoxins have been detected in the Gulf of Mexico, the Southeast US coast and in New Zealand waters, where regulatory levels for brevetoxins in shellfish have existed for some time. This paper reviews evidence concerning the prevalence of brevetoxins and brevetoxin-producing phytoplankton in the UK, together with testing methodologies. Chemical, biological and biomolecular methods are reviewed, including recommendations for further work to enable effective testing. Although the focus here is on the UK, from a strategic standpoint many of the topics discussed will also be of interest in other parts of the world since new and emerging marine biotoxins are of global concern. C1 [Turner, Andrew D.; Payne, Daniel; Higman, Wendy] Cefas, Weymouth DT4 8UB, Dorset, England. [Higgins, Cowan] AFBI, Belfast BT9 5PX, Antrim, North Ireland. [Davidson, Keith; Veszelovszki, Andrea] SAMS, Oban PA37 1QA, Argyll, Scotland. [Payne, Daniel] Univ Surrey, Sch Biosci & Med, Guildford GU2 7TE, Surrey, England. [Hungerford, James] US FDA, Bothell, WA 98021 USA. RP Turner, AD (reprint author), Cefas, Barrack Rd, Weymouth DT4 8UB, Dorset, England. EM andrew.turner@cefas.co.uk; cowan.higgins@afbini.gov.uk; keith.davidson@sams.ac.uk; Andrea.veszelovszki@sams.ac.uk; Daniel.payne@cefas.co.uk; James.hungerford@fda.hhs.gov; Wendy.higman@cefas.co.uk RI Turner, Andrew/J-5658-2015 OI Turner, Andrew/0000-0003-1390-0924 FU Food Standards Agency Scotland [FS513005] FX The authors thank the Food Standards Agency Scotland who funded this review (contract code FS513005). NR 128 TC 1 Z9 2 U1 15 U2 32 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1660-3397 J9 MAR DRUGS JI Mar. Drugs PD MAR PY 2015 VL 13 IS 3 BP 1224 EP 1254 DI 10.3390/md13031224 PG 31 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CE6EW UT WOS:000351930500008 PM 25775421 ER PT J AU Booth, B Arnold, ME DeSilva, B Amaravadi, L Dudal, S Fluhler, E Gorovits, B Haidar, SH Kadavil, J Lowes, S Nicholson, R Rock, M Skelly, M Stevenson, L Subramaniam, S Weiner, R Woolf, E AF Booth, Brian Arnold, Mark E. DeSilva, Binodh Amaravadi, Lakshmi Dudal, Sherri Fluhler, Eric Gorovits, Boris Haidar, Sam H. Kadavil, John Lowes, Steve Nicholson, Robert Rock, Marie Skelly, Michael Stevenson, Lauren Subramaniam, Sriram Weiner, Russell Woolf, Eric TI Workshop Report: Crystal City V-Quantitative Bioanalytical Method Validation and Implementation: The 2013 Revised FDA Guidance SO AAPS JOURNAL LA English DT Article DE bioanalytical method validation; Crystal City V; FDA guidance ID LIGAND-BINDING ASSAYS; MASS-SPECTROMETRY; LINKER STABILITY; IN-VIVO; DRUG; IMMUNOCONJUGATE; MACROMOLECULES AB In September 2013, the FDA released a draft revision of the Bioanalytical Method Validation (BMV) Guidance, which included a number of changes to the expectations for bioanalysis, most notably the inclusion of biomarker assays and data. To provide a forum for an open, inclusive discussion of the revised draft BMV Guidance, the AAPS and FDA once again collaborated to convene a two-and-a-half day workshop during early December 2013 in Baltimore, MD, USA. The resulting format embodied extensive open discussion and each thematic session included only brief, concise descriptions by Agency and industry representatives prior to opening the floor discussion. The Workshop was built around four thematic sessions (Common Topics, Chromatographic, Ligand-Binding Assays, and Biomarkers) and a final session with international regulators, concluding with a review of the outcomes and recommendations from the thematic sessions. This Workshop report summarizes the outcomes and includes topics of agreement, those where the FDA will consider the Industry's perspective, and those where the workshop provided a first open dialogue. This article will be available to the bioanalytical community at http://www.aaps.org/BMV13. C1 [Booth, Brian; Haidar, Sam H.; Kadavil, John; Skelly, Michael; Subramaniam, Sriram] US FDA, Silver Spring, MD USA. [Arnold, Mark E.; DeSilva, Binodh] Bristol Myers Squibb Co, Princeton, NJ 08648 USA. [Amaravadi, Lakshmi; Stevenson, Lauren] Biogen Idec Inc, Cambridge, MA USA. [Dudal, Sherri] Roche Innovat Ctr, Basel, Switzerland. [Fluhler, Eric] Pfizer Inc, Pearl River, NY USA. [Gorovits, Boris] Pfizer Inc, Andover, MA USA. [Lowes, Steve] Quintiles Bioanalyt & ADME Labs, Ithaca, NY USA. [Nicholson, Robert] PPD, Richmond, VA USA. [Rock, Marie] WIL Res, Skokie, IL USA. [Weiner, Russell] Merck Res Labs, Rahway, NJ USA. [Woolf, Eric] Merck Res Labs, West Point, PA USA. RP Arnold, ME (reprint author), Bristol Myers Squibb Co, Princeton, NJ 08648 USA. EM mark.arnold@bms.com NR 22 TC 21 Z9 21 U1 1 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 MAR PY 2015 VL 17 IS 2 BP 277 EP 288 DI 10.1208/s12248-014-9696-2 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CE0WM UT WOS:000351530500001 PM 25549614 ER PT J AU Stevens, RE Gray, V Dorantes, A Gold, L Pham, L AF Stevens, Ruth E. Gray, Vivian Dorantes, Angelica Gold, Lynn Pham, Loan TI Scientific and Regulatory Standards for Assessing Product Performance Using the Similarity Factor, f2 SO AAPS JOURNAL LA English DT Editorial Material DE f2; similarity factor; 505(b)(2); dissolution; bootstrap ID DISSOLUTION PROFILES; STATISTICS; F(2) AB The similarity factor, f2, measures the sameness of dissolution profiles. The following commentary is an overview of discussions and presentations from a group of industry and US regulatory experts that have integrated the science and regulatory research and practice for assessing product performance, particularly for modified-release (MR) dosage forms, using f2. For a drug development sponsor or applicant with an orally complex dosage formulation, it is critical to understand dissolution methods and the similarity factor and how and/or when to apply it in their NDA, ANDA, or PMA submission. As part of any regulatory submission, it is critical to justify that the product performance has not been impacted by any change in the manufacturing process and/or the delayed and/or prolonged drug release characteristics compared to a similar conventional or another orally complex dosage form. The purposes of this document are (1) to provide a description of appropriate dissolution methods, how is the f2 calculated and how it can be used to justify product performance similarity, or not; (2) to provide an overview of alternative methods available for dissolution profile comparisons, and (3) to illustrate how applying these concepts in a focused way supports approval of submissions and regulatory dossiers and aligns them with on-going science and regulatory initiatives. A case study will be used as an example to demonstrate how dissolution testing and the f2 calculation results can impact regulatory outcomes from an NDA (505(b)(1)), NDA (505(b)(2)), ANDA (505(j)), supplemental NDAs/ANDAs, or PMA perspective. C1 [Stevens, Ruth E.; Gold, Lynn; Pham, Loan] Camargo Pharmaceut Serv, Cincinnati, OH 45242 USA. [Gray, Vivian] VA Gray Consulting, Hockessin, DE 19707 USA. [Dorantes, Angelica] US FDA, Silver Spring, MD 20993 USA. RP Stevens, RE (reprint author), Camargo Pharmaceut Serv, 9825 Kenwood Rd, Cincinnati, OH 45242 USA. EM rstevens@camargopharma.com NR 15 TC 6 Z9 6 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 MAR PY 2015 VL 17 IS 2 BP 301 EP 306 DI 10.1208/s12248-015-9723-y PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CE0WM UT WOS:000351530500004 PM 25669756 ER PT J AU Weber, B Lee, SL Delvadia, R Lionberger, R Li, BV Tsong, Y Hochhaus, G AF Weber, Benjamin Lee, Sau L. Delvadia, Renishkumar Lionberger, Robert Li, Bing V. Tsong, Yi Hochhaus, Guenther TI Application of the Modified Chi-Square Ratio Statistic in a Stepwise Procedure for Cascade Impactor Equivalence Testing SO AAPS JOURNAL LA English DT Article DE aerodynamic particle size distribution; bioequivalence; cascade impactor; chi-square ratio statistic; orally inhaled drug products ID PARTICLE-SIZE DISTRIBUTION AB Equivalence testing of aerodynamic particle size distribution (APSD) through multi-stage cascade impactors (CIs) is important for establishing bioequivalence of orally inhaled drug products. Recent work demonstrated that the median of the modified chi-square ratio statistic (MmCSRS) is a promising metric for APSD equivalence testing of test (T) and reference (R) products as it can be applied to a reduced number of CI sites that are more relevant for lung deposition. This metric is also less sensitive to the increased variability often observed for low-deposition sites. A method to establish critical values for the MmCSRS is described here. This method considers the variability of the R product by employing a reference variance scaling approach that allows definition of critical values as a function of the observed variability of the R product. A stepwise CI equivalence test is proposed that integrates the MmCSRS as a method for comparing the relative shapes of CI profiles and incorporates statistical tests for assessing equivalence of single actuation content and impactor sized mass. This stepwise CI equivalence test was applied to 55 published CI profile scenarios, which were classified as equivalent or inequivalent by members of the Product Quality Research Institute working group (PQRI WG). The results of the stepwise CI equivalence test using a 25% difference in MmCSRS as an acceptance criterion provided the best matching with those of the PQRI WG as decisions of both methods agreed in 75% of the 55 CI profile scenarios. C1 [Weber, Benjamin; Hochhaus, Guenther] Univ Florida, Coll Pharm, Dept Pharmaceut, Ctr Pharmacometr & Syst Pharmacol, Gainesville, FL 32610 USA. [Lee, Sau L.] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Delvadia, Renishkumar; Lionberger, Robert; Li, Bing V.] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Tsong, Yi] US FDA, Div Biometr 6, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Lee, SL (reprint author), US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, White Oak Bldg 51,Room 4144, Silver Spring, MD 20993 USA. EM Sau.Lee@fda.hhs.gov NR 14 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAR PY 2015 VL 17 IS 2 BP 370 EP 379 DI 10.1208/s12248-014-9698-0 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CE0WM UT WOS:000351530500011 PM 25515206 ER PT J AU Ye, HP Hill, J Gucinski, AC Boyne, MT Buhse, LF AF Ye, Hongping Hill, John Gucinski, Ashley C. Boyne, Michael T., II Buhse, Lucinda F. TI Direct Site-Specific Glycoform Identification and Quantitative Comparison of Glycoprotein Therapeutics: Imiglucerase and Velaglucerase Alfa SO AAPS JOURNAL LA English DT Article DE imiglucerase; quantitative comparison; site-specific glycoforms; velaglucerase alfa ID ACID-BETA-GLUCOSIDASE; MASS-SPECTROMETRY; GAUCHER-DISEASE; PROTEIN THERAPEUTICS; X-RAY; GLYCOSYLATION; GLUCOCEREBROSIDASE; BIOPHARMACEUTICALS; DISSOCIATION; THERAPY AB Gaucher disease, the most common lysosomal metabolic disorder, can be treated with enzyme replacement therapy (ERT). Recombinant human glucocerebrosidase imiglucerase (Cerezyme(A (R))), produced in Chinese hamster ovary cells, has been used for ERT of Gaucher disease for 20 years. Another recombinant glucocerebrosidase velaglucerase alfa (VPRIV), expressed in a human fibroblast cell line, was approved by the US Food and Drug Administration in 2010. The amino acid sequence difference at residue 495 of these two products is well documented. The overall N-linked qualitative glycan composition of these two products has also been reported previously. Herein, employing our recently developed approach utilizing isobaric tandem mass tag (TMT) labeling and an LTQ Orbitrap XL electron transfer dissociation (ETD) hybrid mass spectrometer, the site-specific glycoforms of these products were identified with ETD and collision-induced dissociation (CID) spectra. The quantitative comparison of site-specific glycans was achieved utilizing higher-energy collisional dissociation (HCD) spectra with a NanoMate used as both a fraction collector and a sample introduction device. From the trypsin-digested mixture of these two products, over 90 glycopeptides were identified by accurate mass matching. In addition to those previously reported, additional glycopeptides were detected with moderate abundance. The relative amount of each glycoform at a specific glycosylation site was determined based on reporter signal intensities of the TMT labeling reagents. This is the first report of site-specific simultaneous qualitative and quantitative comparison of glycoforms for Cerezyme(A (R)) and VPRIV. The results demonstrate that this method could be utilized for biosimilarity determination and counterfeit identification of glycoproteins. C1 [Ye, Hongping; Gucinski, Ashley C.; Boyne, Michael T., II; Buhse, Lucinda F.] US FDA, Div Pharmaceut Anal, CDER, St Louis, MO 63110 USA. RP Ye, HP (reprint author), US FDA, Div Pharmaceut Anal, CDER, 645 South Newstead Ave, St Louis, MO 63110 USA. EM hongping.ye@fda.hhs.gov FU FDA Critical Path grant program FX The authors gratefully acknowledge receipt of materials from Genzyme Corporation (Cerezyme (R)) and Shire Human Genetic Therapies, Inc. (VPRIV) which were used in this work. The work performed in the study was supported in part by the FDA Critical Path grant program awarded to H. Ye. NR 33 TC 1 Z9 1 U1 1 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 MAR PY 2015 VL 17 IS 2 BP 405 EP 415 DI 10.1208/s12248-014-9706-4 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CE0WM UT WOS:000351530500015 PM 25501675 ER PT J AU Butler, J Fonarow, GC O'Connor, C Adams, K Bonow, RO Cody, RJ Collins, SP Dunnmon, P Dinh, W Fiuzat, M Georgiopoulou, VV Grant, S Kim, SY Kupfer, S Lefkowitz, M Mentz, RJ Misselwitz, F Pitt, B Roessig, L Schelbert, E Shah, M Solomon, S Stockbridge, N Yancy, C Gheorghiade, M AF Butler, Javed Fonarow, Gregg C. O'Connor, Christopher Adams, Kirkwood Bonow, Robert O. Cody, Robert J. Collins, Sean P. Dunnmon, Preston Dinh, Wiffried Fiuzat, Mona Georgiopoulou, Vasiliki V. Grant, Stephen Kim, So-Young Kupfer, Stuart Lefkowitz, Martin Mentz, Robert J. Misselwitz, Frank Pitt, Bertram Roessig, Lothar Schelbert, Erik Shah, Monica Solomon, Scott Stockbridge, Norman Yancy, Clyde Gheorghiade, Mihai TI Improving cardiovascular clinical trials conduct in the United States: Recommendation from clinicians, researchers, sponsors, and regulators SO AMERICAN HEART JOURNAL LA English DT Article ID HEART-FAILURE; BLOOD INSTITUTE; NATIONAL HEART; OUTCOMES; GUIDELINES; TOLVAPTAN; BARRIERS; REGION; LUNG AB Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States. C1 [Butler, Javed] SUNY Stony Brook, Div Cardiol, Stony Brook, NY 11794 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. [O'Connor, Christopher; Fiuzat, Mona; Mentz, Robert J.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Adams, Kirkwood] Univ N Carolina, Chapel Hill, NC USA. [Bonow, Robert O.; Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Cody, Robert J.] Janssen Pharmaceut, Cardiovasc & Metab, Raritan, NJ USA. [Collins, Sean P.] Vanderbilt Univ, Nashville, TN 37235 USA. [Dunnmon, Preston; Grant, Stephen; Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Dinh, Wiffried] Witten Univ, Dept Cardiol, Witten, Germany. [Dinh, Wiffried] Bayer Pharma AG, Clin Sci, Global Drug Discovery, Berlin, Germany. [Georgiopoulou, Vasiliki V.] Emory Univ, Emory Cardiovasc Clin Res Inst, Atlanta, GA 30322 USA. [Kim, So-Young; Misselwitz, Frank; Roessig, Lothar] Bayer HealthCare, Global Clin Dev, Wuppertal, Germany. [Kupfer, Stuart] Takeda Pharmaceut Int, Deerfield, IL USA. [Lefkowitz, Martin] Novartis Pharmaceut Inc, E Hanover, NJ USA. [Pitt, Bertram] Univ Michigan, Div Cardiol, Sch Med, Ann Arbor, MI USA. [Schelbert, Erik] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA USA. [Shah, Monica] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Solomon, Scott] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Yancy, Clyde] Northwestern Univ, Dept Med, Div Cardiol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Butler, J (reprint author), SUNY Stony Brook, Div Cardiol, Hlth Sci Ctr, T-16,Room 080, Stony Brook, NY 11794 USA. EM javed.butler@stonybrookmedicine.edu OI Schelbert, Erik/0000-0003-0356-4437 FU National Institutes of Health; European Union; Health Resources Service Administration; Agency for Healthcare research and Quality; ResMed corporation; Otsuka; Roche Diagnostics; Amgen; Novartis Critical Diagnostics; Cardiorentis; Cardioxyl; Sorbent; Covis Pharmaceuticals; Res Med corporation; Gilead Sciences; Bayer; Novartis FX Authors' Conflict of Interest: Javed Butler reports research support from National Institutes of Health, European Union, and Health Resources Service Administration and is consultant to Amgen, Bayer, BG Medicine, Cardiocell, Celladon, GE Healthcare, Medtronic, Novartis, Ono Phrama, Otsuka, Takeda, Trevena, and Zensun. Gregg C. Fonarow has received research funding by the National Institutes of Health, Agency for Healthcare research and Quality, and has served as a consultant for Amgen, Bayer, Gambro, Janssen, Novartis, Medtronic, and Medicines Company. Christopher O'Connor has received researcg funding by ResMed corporation, Otsuka, and Roche Diagnostics and has served as a consultant for ResMed corporation. Kirkwood Adams has received research funding by Amgen, Roche Diagnostics, Novartis Critical Diagnostics, Otsuka, Cardiorentis, Cardioxyl, Sorbent, and Covis Pharmaceuticals and has served as consultant for Covis Pharmaceuticals. Robert O. Bonow has no relevant relationships. Robert J. Cody is an employee of Janssen R&D. Sean P. Collins has served as a consultant for Novartis, Radiometer, Medtronic, The Medicines Company, Trevena, and Thermo-Fisher Scientific. Preston Dunnmon has no relationships elevant to the contents of this manuscript. Wilfried Dinh is an employee of Bayer HealthCare. Mona Firuzat has received research funding by Res Med corporation, Otsuka, and Roche Diagnostics and has served as a consultant for Res Med corporation, Novartis, and Roche Diagnostics. Vasiliki V. Georgiopoulou has no relationships relevant to the contents of this manuscript to disclose. Stephen Grant has no relationships relevant to this manuscript. So-Young Kim is an employee of Bayer HealthCare. Stuart Kupfer is an employee of Takeda. Martin Lefkowitz is an employee of Novartis. Robert J. Mentz has received honoraria from ResMed, Thoratec, Novartis, and BristolMyers Squibb and research support from Gilead Sciences. Frank Misselwitz is an employee of and owns stock for Bayer HealthCare. Bertram Pitt has served as a consultant for Pfizer, Bayer, Relypsa, Stealth Peptides, and Mesoblast. Lothar Roessig is an employee of Bayer HealthCare. Erik Schelbert has received a Prohance contrast as a gift from Bracco for research. Monica Shah has no relationships relevant to the contents of this manuscript. Scott Solomon has received research support from and has served as a consultant for Novartis and Bayer. Norman Stockbridge has no relationships relevant to this manuscript. Clyde Yancy has no relationships relevant to this manuscript. Mihai Gheorghiade reports relationships with Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S.A., Errekappa. Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical Inc, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc and Trevena Therapeutics. NR 39 TC 10 Z9 10 U1 0 U2 2 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 MAR PY 2015 VL 169 IS 3 BP 305 EP 314 DI 10.1016/j.ahj.2014.12.001 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE0ID UT WOS:000351486800001 PM 25728719 ER PT J AU Sundh, F Simlund, J Harrison, JK Hughes, GC Vavalle, J Maynard, C Strauss, DG Wagner, GS Ugander, M AF Sundh, Frida Simlund, Jacob Harrison, John Kevin Hughes, G. Chad Vavalle, John Maynard, Charles Strauss, David G. Wagner, Galen S. Ugander, Martin TI Incidence of strict versus nonstrict left bundle branch block after transcatheter aortic valve replacement SO AMERICAN HEART JOURNAL LA English DT Article ID CARDIAC RESYNCHRONIZATION THERAPY; LEFT-VENTRICULAR HYPERTROPHY; CONDUCTION DISORDERS; PRESSURE-OVERLOAD; IMPLANTATION; ACTIVATION; STENOSIS; PREDICTORS; CRITERIA; IMPACT AB Background Up to one-third of patients diagnosed with left bundle branch block (LBBB) by conventional electrocardiographic (ECG) criteria are misdiagnosed. Strict LBBB shows decreased left ventricular pumping efficiency compared with nonstrict LBBB. However, no previous study has evaluated the frequency of strict LBBB after transcatheter aortic valve replacement (TAVR). The aim of this study was to determine the incidence of developing strict versus nonstrict LBBB after TAVR and test the hypothesis that preprocedure QRS duration does not predict strict LBBB but predicts development of nonstrict LBBB. Methods All patients receiving TAVR between 4/2011 and 2/2013 (n = 71) with no preexisting bundle branch block or permanent pacemaker were included. Twelve-lead ECGs were acquired preprocedure and both 1-day and 1-month postprocedure. All ECGs were classified as strict LBBB, nonstrict LBBB, or no LBBB. Results Sixty-eight patients had ECGs eligible for final analysis. On postprocedure day 1, 25 (37%) of 68 patients developed strict LBBB, and 2 patients (3%) developed nonstrict LBBB. At 1-month follow-up, the 2 patients diagnosed with nonstrict LBBB had resolved to normal, and 5 (20%) of 25 patients with strict LBBB had resolved to normal. Preprocedure QRS duration did not predict strict LBBB (P = .51). Because of the low incidence of nonstrict LBBB, QRS duration as a predictor of nonstrict LBBB could not be tested. Conclusions Almost all patients who developed evidence of LBBB after TAVR met the new strict criteria, indicating probable procedural injury to the left bundle branch. Preprocedural QRS duration did not predict the development of strict LBBB. C1 [Sundh, Frida; Simlund, Jacob; Ugander, Martin] Karolinska Inst, Dept Clin Physiol, SE-17176 Stockholm, Sweden. [Sundh, Frida; Simlund, Jacob; Ugander, Martin] Karolinska Univ Hosp, SE-17176 Stockholm, Sweden. [Sundh, Frida; Simlund, Jacob; Wagner, Galen S.] Duke Clin Res Inst, Durham, NC USA. [Harrison, John Kevin; Vavalle, John] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Hughes, G. Chad] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Vavalle, John] Univ N Carolina, Dept Cardiol, Chapel Hill, NC USA. [Maynard, Charles] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Strauss, David G.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Ugander, M (reprint author), Karolinska Inst, Dept Clin Physiol, N2 01, SE-17176 Stockholm, Sweden. EM martin.ugander@gmail.com RI Maynard, Charles/N-3906-2015; OI Maynard, Charles/0000-0002-1644-7814; Ugander, Martin/0000-0003-3665-2038 NR 26 TC 5 Z9 5 U1 0 U2 2 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 MAR PY 2015 VL 169 IS 3 BP 438 EP 444 DI 10.1016/j.ahj.2014.12.011 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE0ID UT WOS:000351486800017 PM 25728735 ER PT J AU Mahmood, I Goteti, K AF Mahmood, Iftekhar Goteti, Kosalaram TI Prediction of Drug Concentration-Time Profiles in Children From Adults: An Allometric Approach SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Article DE pharmacokinetics; allometry; concentration-time profile; children; adults ID TOTAL IV ANESTHESIA; ALFENTANIL PHARMACOKINETICS; CIMETIDINE; MIDAZOLAM; MORPHINE; KINETICS; AMIKACIN AB The main objective of this work was to evaluate 2 methods to predict concentration-time profiles of drugs in children (aged 5 years or older) from adult pharmacokinetic (PK) parameters. Five drugs from the literature were chosen for this study, and all these 5 drugs were described by a 2-compartment model in both adults and children. PK parameters (CL, V-c, V-ss, and V) were allometrically predicted in children from adults. PK constants such as A, B, , and were also predicted in children from adults as described in Appendix 1. Using predicted PK parameters and constants, concentration-time profiles of 5 drugs were predicted in children and compared with the observed profiles. Both methods of predictions provided fairly good prediction of concentration-time profiles in children. The predicted concentration-time profiles in children were comparable with the observed profiles and can be used to design first-in-children clinical trials. C1 [Mahmood, Iftekhar] US FDA, Dept Hematol, OBRR, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Goteti, Kosalaram] MedImmune LLC, Clin Pharmacol, Gaithersburg, MD USA. [Goteti, Kosalaram] MedImmune LLC, DMPK, Gaithersburg, MD USA. RP Mahmood, I (reprint author), US FDA, OBRR, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20852 USA. EM iftekhar.mahmood@fda.hhs.gov NR 19 TC 1 Z9 1 U1 1 U2 4 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 MAR-APR PY 2015 VL 22 IS 2 BP 132 EP 140 DI 10.1097/MJT.0b013e318274df57 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CE1CP UT WOS:000351549800017 PM 23676343 ER PT J AU Herbertson, LH Olia, SE Daly, A Noatch, CP Smith, WA Kameneva, MV Malinauskas, RA AF Herbertson, Luke H. Olia, Salim E. Daly, Amanda Noatch, Christopher P. Smith, William A. Kameneva, Marina V. Malinauskas, Richard A. TI Multilaboratory Study of Flow-Induced Hemolysis Using the FDA Benchmark Nozzle Model SO ARTIFICIAL ORGANS LA English DT Article DE Hemolysis; Red blood cell damage; Nozzle model; Fluid dynamics; In vitro hemolysis testing; Computational fluid dynamics ID RED-BLOOD-CELLS; CENTRIFUGAL PUMPS; SHEAR-STRESS; MECHANICAL FRAGILITY; SURFACE-ROUGHNESS; PLASMA HEMOGLOBIN; HEART-VALVES; DAMAGE; PREDICTION; IMPELLER AB Multilaboratory in vitro blood damage testing was performed on a simple nozzle model to determine how different flow parameters and blood properties affect device-induced hemolysis and to generate data for comparison with computational fluid dynamics-based predictions of blood damage as part of an FDA initiative for assessing medical device safety. Three independent laboratories evaluated hemolysis as a function of nozzle entrance geometry, flow rate, and blood properties. Bovine blood anticoagulated with acid citrate dextrose solution (2-80 h post-draw) was recirculated through nozzle-containing and paired nozzle-free control loops for 2 h. Controlled parameters included hematocrit (36 +/- 1.5%), temperature (25 degrees C), blood volume, flow rate, and pressure. Three nozzle test conditions were evaluated (n = 26-36 trials each): (i) sudden contraction at the entrance with a blood flow rate of 5 L/min, (ii) gradual cone at the entrance with a 6-L/min blood flow rate, and (iii) sudden-contraction inlet at 6 L/min. The blood damage caused only by the nozzle model was calculated by subtracting the hemolysis generated by the paired control loop test. Despite high intralaboratory variability, significant differences among the three test conditions were observed, with the sharp nozzle entrance causing the most hemolysis. Modified index of hemolysis (MIHnozzle) values were 0.292 +/- 0.249, 0.021 +/- 0.128, and 1.239 +/- 0.667 for conditions i-iii, respectively. Porcine blood generated hemolysis results similar to those obtained with bovine blood. Although the interlaboratory hemolysis results are only applicable for the specific blood parameters and nozzle model used here, these empirical data may help to advance computational fluid dynamics models for predicting blood damage. C1 [Herbertson, Luke H.; Malinauskas, Richard A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Olia, Salim E.; Daly, Amanda; Kameneva, Marina V.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Kameneva, Marina V.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Noatch, Christopher P.; Smith, William A.] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA. [Smith, William A.] Perfus Solut Inc, Dept Engn, Cleveland, OH USA. RP Herbertson, LH (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, 10903 New Hampshire Ave,WO 62,Room 2120, Silver Spring, MD 20993 USA. EM luke.herbertson@fda.hhs.gov FU US Food and Drug Administration's Critical Path Initiative FX This study was supported by the US Food and Drug Administration's Critical Path Initiative. From the FDA, we would like to thank Dr. Meijuan Li for providing invaluable statistical analyses, Dr. Prasanna Hariharan and Gavin D'Souza for performing computational simulations and error propagation analyses, Jean Rinaldi for reviewing the manuscript, and Drs. Sandy Stewart and Qijin Lu for technical support. We recognize and appreciate the support of Brittany Arcuri, Christine Flick, and Elizabeth Endrizzi for assisting with experiments at the Cleveland Clinic, and Andrew Wearden and Charles Lutzow for helping with experimental data collection at the University of Pittsburgh. We would also like to acknowledge the efforts of Dr. Steven Day, Matthew Giarra, and Alex Ship at the Rochester Institute of Technology in fabricating the nozzle models. Lastly, the authors would also like to thank Dr. Kurt Dasse, Farzad Parsaie, and the team at Levitronix LLC for providing centrifugal blood pumps for this study through a Material Transfer Agreement. Any mention of commercial products and/or manufacturers does not imply endorsement by the US Department of Health and Human Services. NR 43 TC 6 Z9 6 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-564X EI 1525-1594 J9 ARTIF ORGANS JI Artif. Organs PD MAR PY 2015 VL 39 IS 3 BP 237 EP U148 DI 10.1111/aor.12368 PG 12 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA CE1ZW UT WOS:000351612900007 PM 25180887 ER PT J AU Varma, MV Pang, KS Isoherranen, N Zhao, P AF Varma, Manthena V. Pang, K. Sandy Isoherranen, Nina Zhao, Ping TI Dealing with the complex drug-drug interactions: Towards mechanistic models SO BIOPHARMACEUTICS & DRUG DISPOSITION LA English DT Review DE physiologically based pharmacokinetic model; CYP; transporters; drug-drug interactions; metabolites ID IN-VITRO DATA; INTESTINAL 1ST-PASS METABOLISM; RAT SMALL-INTESTINE; TRANSPORTING POLYPEPTIDES OATPS; TIME-DEPENDENT INHIBITOR; SEGREGATED-FLOW MODEL; P-GLYCOPROTEIN; QUANTITATIVE PREDICTION; HEPATIC-UPTAKE; CYP3A4 INHIBITION AB Unmanageable severe adverse events caused by drug-drug interactions (DDIs), leading to market withdrawals or restrictions in the clinical usage, are increasingly avoided with the improvement in our ability to predict such DDIs quantitatively early in drug development. However, significant challenges arise in the evaluation and/or prediction of complex DDIs caused by inhibitor drugs and/or metabolites that affect not one but multiple pathways of drug clearance. This review summarizes the discussion topics at the 2013 AAPS symposium on Dealing with the complex drug-drug interactions: towards mechanistic models. Physiologically based pharmacokinetic (PBPK) models, in combination with the established in vitro-to-in vivo extrapolations of intestinal and hepatic disposition, have been successfully applied to predict clinical pharmacokinetics and DDIs, especially for drugs with CYP-mediated metabolism, and to explain transporter-mediated and complex DDIs. Although continuous developments are being made towards improved mechanistic prediction of the transporter-enzyme interplay in the hepatic and intestinal disposition and characterizing the metabolites contribution to DDIs, the prediction of DDIs involving them remains difficult. Regulatory guidelines also recommended use of PBPK modeling for the quantitative prediction and evaluation of DDIs involving multiple perpetrators and metabolites. Such mechanistic modeling approaches culminate to the consensus that modeling is helpful in predicting DDIs or quantitatively rationalizing the clinical findings in complex situations. Furthermore, they provide basis for the prediction and/or understanding the pharmacokinetics in populations like patients with renal impairment, pediatrics, or various ethnic groups where the conduct of clinical studies might not be feasible in early drug development stages and yet some guidance on management of dosage is necessary. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Varma, Manthena V.] Pfizer Inc, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA. [Pang, K. Sandy] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 3M2, Canada. [Isoherranen, Nina] Univ Washington, Sch Pharm, Dept Pharmaceut, Seattle, WA 98195 USA. [Zhao, Ping] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Varma, MV (reprint author), Pfizer Inc, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA. EM manthena.v.varma@pfizer.com NR 131 TC 11 Z9 13 U1 2 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0142-2782 EI 1099-081X J9 BIOPHARM DRUG DISPOS JI Biopharm. Drug Dispos. PD MAR PY 2015 VL 36 IS 2 BP 71 EP 92 DI 10.1002/bdd.1934 PG 22 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CD7YK UT WOS:000351311700002 PM 25545151 ER PT J AU Kraeling, MEK Zhou, WL Wang, P Ogunsola, OA AF Kraeling, Margaret E. K. Zhou, Wanlong Wang, Perry Ogunsola, Oluwatosin A. TI In vitro skin penetration of acetyl hexapeptide-8 from a cosmetic formulation SO CUTANEOUS AND OCULAR TOXICOLOGY LA English DT Article DE Acetyl hexapeptide-8; peptide; skin penetration ID INVITRO PERCUTANEOUS-ABSORPTION; CHROMAFFIN CELLS; PEPTIDES; EXOCYTOSIS; MIMICS; DOMAIN AB There is a concern that peptides in cosmetic creams marketed as anti-aging/anti-wrinkle may penetrate into the deep layers of the skin and potentially stimulate biological activity. Claims for one cosmetic peptide, acetyl hexapeptide-8 (Ac-EEMQRR-amide), suggest interference with neuromuscular signaling as its anti-wrinkle mechanism of action. Therefore, the skin penetration of commercially available Ac-EEMQRR-amide from a cosmetic formulation (oil-in-water (O/W) emulsion) was determined in hairless guinea pig (HGP) and human cadaver skin assembled into in vitro diffusion cells. An O/W emulsion containing 10% Ac-EEMQRR-amide was applied to skin at a dose of 2 mg/cm(2). After a 24-h exposure, the skin surface was washed to remove unabsorbed peptide. Skin disks were tape stripped to determine the amount of peptide in the stratum corneum. Removal of the stratum corneum layers was verified by confocal microscopy. The epidermis was heat separated from the dermis and each skin fraction was homogenized. Skin penetration of Ac-EEMQRR-amide was measured in skin layers by hydrophilic interaction liquid chromatography with tandem mass spectrometry using electrospray ionization (ESI) in the positive mode. Stable isotopically labeled hexapeptides were used as internal standards for the quantitation of native hexapeptides to correct for matrix effects associated with ESI. The results (percent of applied dose) showed that the majority of the Ac-EEMQRR-amide was washed from the surface of both HGP and human skin. Ac-EEMQRR-amide that penetrated skin remained mostly in the stratum corneum of HGP (0.54%) and human (0.22%) with the peptide levels decreasing as each layer was removed by tape stripping. Total Ac-EEMQRR-amide found in the epidermis of HGP and human skin was similar at 0.01%. No peptide was detected in the dermis or buffer collected underneath the skin for both human and HGP. There was no hexapeptide metabolite (H2N-EEMQRR-amide) detected in any layers of HGP skin, human skin or buffer collected underneath the skin. This skin penetration data will be useful for evaluating the safety of cosmetic products containing small peptide cosmetic ingredients. C1 [Kraeling, Margaret E. K.; Ogunsola, Oluwatosin A.] US FDA, Div Toxicol, CFSAN Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. [Zhou, Wanlong; Wang, Perry] US FDA, CFSAN Off Regulatory Sci, College Pk, MD USA. RP Kraeling, MEK (reprint author), US FDA, Div Toxicol, CFSAN Off Appl Res & Safety Assessment, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM margaret.kraeling@fda.hhs.gov FU Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors FX Conduct of these studies was performed under the guidance of the Institutional Animal Care and Use Committee and the Research Involving Human Subjects Committee (RIHSC) Protocol # 12-004F and with support from the Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors. Authors wish to thank Jeffrey J. Yourick, Robert L. Sprando, Alexander J. Krynitsky and Jeanne I. Rader (U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition) in support of this research. NR 22 TC 0 Z9 0 U1 6 U2 18 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1556-9527 EI 1556-9535 J9 CUTAN OCUL TOXICOL JI Cutan. Ocul. Toxicol. PD MAR PY 2015 VL 34 IS 1 BP 46 EP 52 DI 10.3109/15569527.2014.894521 PG 7 WC Ophthalmology; Toxicology SC Ophthalmology; Toxicology GA CD7XV UT WOS:000351309900010 PM 24754410 ER PT J AU Haley, BJ Allard, M Brown, E Hovingh, E Karns, JS van Kessel, JS AF Haley, B. J. Allard, M. Brown, E. Hovingh, E. Karns, J. S. van Kessel, J. S. TI Molecular detection of the index case of a subclinical Salmonella Kentucky epidemic on a dairy farm SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Food safety; genomics; Salmonella ID RESISTANT SALMONELLA; ENTERICA; HERD; DISSEMINATION; PREVALENCE; SEROTYPES; CATTLE AB Salmonella enterica commonly colonizes the intestinal tract of cattle and is a leading cause of foodborne illness. A previously described investigation into the prevalence of S. enterica on a dairy farm revealed an 8-year-long asymptomatic S. enterica epidemic caused by serotypes Cerro and Kentucky in the lactating herd. To investigate the source of the S. Kentucky strains, the genomes of two S. Kentucky isolates were sequenced; one collected prior to the epidemic (2004) and one collected during the epidemic (2010). Comparative genomic analysis demonstrated significant polymorphisms between the two strains. PCR primers targeting unique and strain-specific regions were developed, and screening of the archived isolates identified the index case of the asymptomatic S. Kentucky epidemic as a heifer that was raised off-site and transported onto the study farm in 2005. Analysis of isolates collected from all heifers brought onto the farm demonstrated frequent re-introduction of clones of the epidemic strain suggesting transmission of pathogens between farms might occur repeatedly. C1 [Haley, B. J.; Karns, J. S.] USDA ARS, Environm Microbial & Food Safety Lab, Beltsville Agr Res Ctr, Beltsville, MD USA. [Allard, M.; Brown, E.; van Kessel, J. S.] US FDA, Div Microbiol, Ctr Food Safety & Nutr, College Pk, MD USA. [Hovingh, E.] Penn State Univ, Anim Diagnost Lab, University Pk, PA USA. RP van Kessel, JS (reprint author), ARS, Environm Microbial & Food Safety Lab, USDA, BARC East, Serv,Room 202,Bldg 173, Beltsville, MD 20705 USA. EM joann.vankessel@ars.usda.gov NR 18 TC 1 Z9 1 U1 0 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 MAR PY 2015 VL 143 IS 4 BP 682 EP 686 DI 10.1017/S0950268814001289 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CD4NB UT WOS:000351058600002 PM 25703396 ER PT J AU Mahmood, I AF Mahmood, Iftekhar TI Prediction of glucuronidated drug clearance in pediatrics (<= 5 years): An allometric approach SO EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS LA English DT Article DE Glucuronidation; Clearance; Allometric exponents; Children ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTRAVENOUS CHLORAMPHENICOL SUCCINATE; PREMATURE-INFANTS; MORPHINE CLEARANCE; NEWBORN-INFANTS; PRETERM INFANTS; BODY-WEIGHT; PHARMACOKINETICS; CHILDREN; EXPONENT AB Children are not small adults. The differences between children of different age groups and adults are not merely due to body weight, but also due to physiological and biochemical differences resulting in different rates of drug metabolism or renal clearance. Glucuronidation is an important pathway of drug metabolism. Therefore, the objective of this study is to evaluate the predictive performance of several allometric exponents in children of a parts per thousand currency sign5 years for the total clearance of drugs which are mainly metabolized by glucuronidation. Four exponents (0.75, 1.0, 1.2, or 1.4) on the body weights and an allometric model developed from adults were evaluated. The four exponents and the allometric model were examined to determine the suitability of the method(s) to predict the clearances of drugs which are glucuronidated in children a parts per thousand currency sign5 years of age. Based on the analysis of ten drugs, it was noted that the combination of two allometric exponents 1.2 (for children a parts per thousand currency sign3 months) and 1.0 (for children a parts per thousand yen3 months a parts per thousand currency sign5 years) can be used to predict mean clearances of drugs which are mainly metabolized by glucuronidation. The suggested approach may be used to estimate a first-in-pediatric dose to initiate a pediatric clinical trial. C1 US FDA, Div Hematol, Ctr Biol Evaluat & Res, OBRR, Rockville, MD 20852 USA. RP Mahmood, I (reprint author), US FDA, Div Hematol, Ctr Biol Evaluat & Res, OBRR, 1401 Rockville Pike, Rockville, MD 20852 USA. EM iftekhar.mahmood@fda.hhs.gov NR 56 TC 0 Z9 0 U1 0 U2 4 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 MAR PY 2015 VL 40 IS 1 BP 53 EP 59 DI 10.1007/s13318-014-0178-9 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CD7XH UT WOS:000351308200007 PM 24519316 ER PT J AU Stephen, EA Walsh, DL Duraiswamy, N Vesnovsky, O Topoleski, LDT AF Stephen, Elizabeth A. Walsh, Donna L. Duraiswamy, Nandini Vesnovsky, Oleg Topoleski, L. D. Timmie TI Design of an Experimental Test System to Investigate Parameters Affecting Distal Tip Loads of Pacemaker and Defibrillator Leads SO JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME LA English DT Article DE pacemakers; defibrillators; leads; perforation ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; PERFORATION; ECHOCARDIOGRAPHY; ASSOCIATION; SOCIETY; HEART AB The purpose of this study was to design and evaluate a system to test the mechanical behavior of pacemaker and defibrillator leads. Over 300,000 pacemaker and implantable cardioverter defibrillator (ICD) procedures are performed every year in the U.S. for the treatment of cardiac arrhythmias, ventricular dysrhythmias, and congestive heart failure. These procedures require implanting transvenous leads into the interior wall of the heart. A serious and sometimes fatal complication that may occur during or after lead implantation is perforation of the lead tip through the heart wall. The factors that lead to perforation are not fully understood. This illustrates that the mechanical interactions between the lead tip and the cardiac tissue need to be further investigated to improve the outcome for pacemaker and ICD patients. To improve the performance of lead tips, the testing protocols must reproduce physiological and clinically relevant tip-tissue interactions. As a first step toward this goal, testing parameters that influence those interactions must be identified. We investigated the effect of test system parameters, which reproduce potentially critical physiological constraints, on the load experienced at the distal tip of thirteen pacemaker and defibrillator active-fixation leads. We evaluated the use of a constraint to simulate the effect of the right ventricle (RV constraint) in vivo, how and where the lead was fixed in the test configuration, location of the load cell in the test system, rotation and frequency of the test protocol, and the effect of stylets. Results showed the RV constraint and load cell placement had the largest impact on lead tip load, while rotation of the test setup and test frequency had a minimal impact. Recommendations are made for a test system and protocol for in vitro testing of leads that take into consideration in vivo conditions. Better approximations of the in vivo environment may lead to improved product development. The potential of this system to more effectively evaluate new pacemaker and defibrillator lead designs will require further study. C1 [Stephen, Elizabeth A.; Walsh, Donna L.; Duraiswamy, Nandini; Vesnovsky, Oleg; Topoleski, L. D. Timmie] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Topoleski, L. D. Timmie] Univ Maryland Baltimore Cty, Dept Mech Engn, Baltimore, MD 21250 USA. RP Walsh, DL (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM donna.walsh@fda.hhs.gov NR 19 TC 0 Z9 0 U1 2 U2 4 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 1932-6181 EI 1932-619X J9 J MED DEVICES JI J. Med. Devices PD MAR PY 2015 VL 9 IS 1 AR 011001 DI 10.1115/1.4028517 PG 8 WC Engineering, Biomedical SC Engineering GA CE2JS UT WOS:000351642500002 ER PT J AU Jerome, SM Inn, KGW Watjen, U Lin, ZC AF Jerome, Simon M. Inn, Kenneth G. W. Watjen, Uwe Lin, Zhichao TI Certified reference, intercomparison, performance evaluation and emergency preparedness exercise materials for radionuclides in food SO JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY LA English DT Article DE Global security; Food supply; Reference materials; Proficiency testing; Radioactive contamination AB The threat to global security from terrorist attack does not solely arise from illicit use of firearms, explosives or weapons of mass destruction. Terrorist threats will inevitably become more subtle as information and expertise is acquired by terrorist groups, and one vulnerable area is food and the food supply chain. Many laboratories, especially in countries with nuclear programmes, are involved in the routine monitoring of foodstuffs, and will be required to respond with increased food monitoring necessary for ensuring food safety and protecting public health after real (or perceived) contamination of food by either accidental or illicit means. This paper examines the needs for reference and performance testing materials that were identified at an international workshop to discuss this matter held at NIST in 2008, and further refined at a follow-up workshop in 2009. C1 [Jerome, Simon M.] Natl Phys Lab, Acoust & Ionising Radiat Div, Teddington TW11 0LW, Middx, England. [Inn, Kenneth G. W.] K&E Innovat Inc, Ewa Beach, HI 96706 USA. [Watjen, Uwe] Commiss European Communities, Inst Reference Mat & Measurements, Joint Res Ctr, B-2440 Geel, Belgium. [Lin, Zhichao] US FDA, Winchester Engn & Analyt Ctr, Winchester, MA 01890 USA. RP Jerome, SM (reprint author), Natl Phys Lab, Acoust & Ionising Radiat Div, Teddington TW11 0LW, Middx, England. EM simon.jerome@npl.co.uk FU National Measurement Office of the United Kingdom Department for Business, Innovation and Skills FX The authors wish to thank the participants in the workshops for their input into preparing this paper. The NPL author acknowledges the support funding provided by the National Measurement Office of the United Kingdom Department for Business, Innovation and Skills. NR 22 TC 2 Z9 2 U1 2 U2 6 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 2015 VL 303 IS 3 BP 1771 EP 1777 DI 10.1007/s10967-014-3724-7 PG 7 WC Chemistry, Analytical; Chemistry, Inorganic & Nuclear; Nuclear Science & Technology SC Chemistry; Nuclear Science & Technology GA CD2CL UT WOS:000350881300018 ER PT J AU Wear, KA AF Wear, Keith A. TI Nonlinear attenuation and dispersion in human calcaneus in vitro: Statistical validation and relationships to microarchitecture SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID BOVINE CANCELLOUS BONE; FREQUENCY-DEPENDENT ATTENUATION; ULTRASONIC WAVE-PROPAGATION; BIOT-ATTENBOROUGH MODEL; HUMAN TRABECULAR BONE; PHASE-VELOCITY; NEGATIVE DISPERSION; STRATIFIED MODEL; MECHANICAL-PROPERTIES; LONGITUDINAL-WAVES AB Through-transmission measurements were performed on 30 human calcaneus samples in vitro. Nonlinear attenuation and dispersion measurements were investigated by estimating 95% confidence intervals of coefficients of polynomial expansions of log magnitude and phase of transmission coefficients. Bone mineral density (BMD) was measured with dual x-ray absorptiometry. Microarchitecture was measured with microcomputed tomography. Statistically significant nonlinear attenuation and nonzero dispersion were confirmed for a clinical bandwidth of 300-750 kHz in 40%-43% of bone samples. The mean linear coefficient for attenuation was 10.3 dB/cm MHz [95% confidence interval (CI): 9.0-11.6 dB/cm MHz]. The mean quadratic coefficient for attenuation was 1.6 dB/cm MHz 2 (95% CI: 0.4-2.8 dB/cm MHz(2)). Nonlinear attenuation provided little information regarding BMD or microarchitecture. The quadratic coefficient for phase (which is related to dispersion) showed moderate correlations with BMD (r = -0.65; 95% CI: - 0.82 to -0.36), bone surface-to-volume ratio (r = 0.47; 95% CI: 0.12-0.72) and trabecular thickness (r = -0.40; 95% CI: -0.67 to -0.03). Dispersion was proportional to bone volume fraction raised to an exponent of 2.1 +/- 0.2, which is similar to the value for parallel nylon-wire phantoms (2.4 +/- 0.2) and supports a multiple-scattering model for dispersion. C1 US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Wear, KA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM keith.wear@fda.hhs.gov FU FDA Office of Women's Health FX The authors are grateful to (1) the FDA Office of Women's Health for funding, (2) Dr. James Reynolds and Angela Stuber, NIH Clinical Center, who helped with DXA measurements, and (3) Srinidhi Nagaraja and Maureen Dreher, FDA, who helped with preparing bone samples for microCT. 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 62 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2015 VL 137 IS 3 BP 1126 EP 1133 DI 10.1121/1.4908310 PG 8 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA CE1OR UT WOS:000351581800009 PM 25786928 ER PT J AU Miller, DL Vano, E Rehani, MM AF Miller, Donald L. Vano, Eliseo Rehani, Madan M. TI Reducing Radiation, Revising Reference Levels SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Vano, Eliseo] Complutense Univ Med Sch, Dept Radiol, Madrid, Spain. [Rehani, Madan M.] IAEA, A-1400 Vienna, Austria. RP Miller, DL (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM donald.miller@fda.hhs.gov NR 14 TC 2 Z9 2 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 MAR PY 2015 VL 12 IS 3 BP 214 EP 216 DI 10.1016/j.jacr.2014.07.012 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CD3ZD UT WOS:000351021500003 PM 25130134 ER PT J AU Kazi, ZB Prater, SN Rosenburg, AS Kishnani, PS AF Kazi, Zoheb B. Prater, Sean N. Rosenburg, Amy S. Kishnani, Priya S. TI CRIM-positive infantile Pompe disease: Characterization of immune responses in patients treated with ERT SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 28-31, 2015 CL Salt Lake City, UT SP Soc Inherited Metab Disorders C1 [Kazi, Zoheb B.; Prater, Sean N.; Kishnani, Priya S.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Rosenburg, Amy S.] US FDA, Div Therapeut Proteins, Silver Spring, MD USA. NR 0 TC 0 Z9 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2015 VL 114 IS 3 MA 41 BP 345 EP 345 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CD6IC UT WOS:000351191800070 ER PT J AU Wiley, JL Marusich, JA Thomas, BF Jackson, KJ AF Wiley, Jenny L. Marusich, Julie A. Thomas, Brian F. Jackson, Kia J. TI Determination of Behaviorally Effective Tobacco Constituent Doses in Rats SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE-INDUCED HYPERACTIVITY; DISCRIMINATIVE STIMULUS; COTININE LEVELS; NORNICOTINE; ALKALOIDS; METABOLITES; CIGARETTES; ANABASINE; SMOKING; MONKEYS AB Introduction: While nicotine has been established as the primary addictive drug that promotes tobacco use, recent peer-reviewed studies suggest that tobacco smoke contains additional chemical constituents that may have addictive potential. Additional research is necessary to determine the addictive potential of these tobacco constituents individually and in combination with tobacco smoke condensate; however, the behaviorally effective constituent doses necessary to conduct such studies are unclear. The primary objective of this study was to conduct behavioral studies in adult rats to determine the relevant behaviorally effective doses of the tobacco constituents, cotinine, myosmine, and anatabine to be used in future studies assessing the addictive potential of these compounds. Methods: Separate groups of adult male Sprague Dawley rats were treated with vehicle, nicotine, or various doses of cotinine, mysomine, or anatabine. Effects on locomotor activity were measured in 10-min bins for 60 min. Results: Nicotine (0.8 mg/kg) produced a biphasic effect on locomotor activity, with hypoactivity during the first 10 min and hyperactivity at 40-50 min. In contrast, cotinine (0.1 mg/kg) and myosmine (10-50 mg/kg) decreased activity without a later increase. Anatabine significantly increased locomotor activity at 1 mg/kg, but decreased it at 10 mg/kg. Prominent effects on overt behavior were observed at anatabine doses of 10 mg/kg and above. Conclusion: Nicotine, cotinine, myosmine, and anatabine produced distinct time-and dose-dependent patterns of effects on locomotor activity. Results from the study will aid in the selection of relevant doses for future studies assessing the addictive potential of these non-nicotine tobacco constituents. C1 [Wiley, Jenny L.; Marusich, Julie A.; Thomas, Brian F.] RTI Int, Res Triangle Pk, NC USA. [Jackson, Kia J.] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. RP Jackson, KJ (reprint author), US FDA, Ctr Tobacco Prod, Document Control Ctr Bldg 71,Room G335, Silver Spring, MD 20993 USA. EM kia.jackson@fda.hhs.gov FU Food and Drug Administration (Center for Tobacco Products) FX Research supported by a contract awarded to RTI by the Food and Drug Administration (Center for Tobacco Products). NR 20 TC 2 Z9 2 U1 1 U2 3 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 MAR PY 2015 VL 17 IS 3 BP 368 EP 371 DI 10.1093/ntr/ntu194 PG 4 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CD3AH UT WOS:000350949600015 PM 25271188 ER PT J AU Shen, MY Russek-Cohen, E Slud, EV AF Shen, Meiyu Russek-Cohen, Estelle Slud, Eric V. TI Exact calculation of power and sample size in bioequivalence studies using two one-sided tests SO PHARMACEUTICAL STATISTICS LA English DT Article DE bioequivalence; single endpoint; sample size; power; crossover; pharmacokinetic study ID BIOAVAILABILITY; EQUIVALENCE; GERMANY; TRIALS AB The number of subjects in a pharmacokinetic two-period two-treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one-sided tests procedure. No explicit mathematical formula for the power function in the context of the two one-sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t-distribution has been tabulated and graphed.Several approximations have previously been published for the probability of rejection in the two one-sided tests procedure for crossover bioequivalence studies. These approximations and associated sample size formulas are reviewed in this article and compared for various parameter combinations with exact power formulas derived here, which are computed analytically as univariate integrals and which have been validated by Monte Carlo simulations. The exact formulas for power and sample size are shown to improve markedly in realistic parameter settings over the previous approximations. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Shen, Meiyu] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Russek-Cohen, Estelle] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Slud, Eric V.] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Slud, Eric V.] US Bur Census, Ctr Stat Res & Methodol, Suitland, MD USA. RP Shen, MY (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM meiyu.shen@fda.hhs.gov NR 14 TC 1 Z9 1 U1 1 U2 6 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 MAR-APR PY 2015 VL 14 IS 2 BP 95 EP 101 DI 10.1002/pst.1666 PG 7 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CE0VO UT WOS:000351527100003 PM 25477145 ER PT J AU Rubio, T AF Rubio, Teresa TI Summaries of Safety Labeling Changes Approved By FDA-Boxed Warnings Highlights October-December 2014 SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT News Item C1 US FDA, Off Hlth & Constituent Affairs, Rockville, MD 20857 USA. RP Rubio, T (reprint author), US FDA, Off Hlth & Constituent Affairs, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD MAR 1 PY 2015 VL 72 IS 5 BP 343 EP 343 DI 10.2146/news150018 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC9QZ UT WOS:000350707000005 PM 25694404 ER PT J AU Chintagari, NR Nguyen, J Belcher, JD Vercellotti, GM Alayash, AI AF Chintagari, Narendranath Reddy Julia Nguyen Belcher, John D. Vercellotti, Gregory M. Alayash, Abdu I. TI Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Sickle cell disease; Kidney damage; Haptoglobin; Hemeoxygenase-1; Kidney proximal tubules ID GUINEA-PIGS; PROTEIN; MICE; VASOOCCLUSION; INFLAMMATION; DECREASES; PEROXIDE; COMPLEX; DRIVEN; IRON AB Sickle cell disease (SCD), a hereditary hemolytic disorder is characterized by chronic hemolysis, oxidative stress, vaso-occlusion and end-organ damage. Hemolysis releases toxic cell-free hemoglobin (Hb) into circulation. Under physiologic conditions, plasma Hb binds to haptoglobin (Hp) and forms Hb-Hp dimers. The dimers bind to CD163 receptors on macrophages for further internalization and degradation. However, in SCD patients plasma Hp is depleted and free Hb is cleared primarily by proximal tubules of kidneys. Excess free Hb in plasma predisposes patients to renal damage. We hypothesized that administration of exogenous Hp reduces Hb-mediated renal damage. To test this hypothesis, human renal proximal tubular cells (HK-2) were exposed to HbA (50 mu M heme) for 24 h. HbA increased the expression of heme oxygenase-1 (HO-1), an enzyme which degrades heme, reduces heme-mediated oxidative toxicity, and confers cytoprotection. Similarly, infusion of HbA (32 mu M heme/kg) induced HO-1 expression in kidneys of SCD mice. Immunohistochemistry confirmed the increased HO-1 expression in the proximal tubules of the kidney. Exogenous Hp attenuated the HbA-induced HO-1 expression in vitro and in SCD mice. Our results suggest that Hb-mediated oxidative toxicity may contribute to renal damage in SCD and that Hp treatment reduces heme/iron toxicity in the kidneys following hemolysis. Published by Elsevier Inc. C1 [Chintagari, Narendranath Reddy; Alayash, Abdu I.] US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Silver Spring, MD 20993 USA. [Julia Nguyen; Belcher, John D.; Vercellotti, Gregory M.] Univ Minnesota, Dept Med, Vasc Biol Ctr, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. RP Alayash, AI (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Bldg 52-72,Room 4106,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM abdu.alayash@fda.hhs.gov FU National Institutes of Health (NIH) [HL110900, HL115467-01]; U.S. Food and Drug Administration (MODSCI Grants) FX The authors acknowledge Dr. Dominador J. Manalo and Janvi Raichiura for help with the preliminary experiments. We acknowledge Francine Wood for providing catalase-reduced and stroma free adult human hemoglobin. We also acknowledge Bio Products Laboratory (BPL; Hertfordshire, UK) for generously providing the human haptoglobin. AIA acknowledges the support from the National Institutes of Health (NIH) under grant HL110900 and the U.S. Food and Drug Administration (MODSCI Grants). GMV and JDB were supported by a grant from NIH HL115467-01. NR 33 TC 10 Z9 11 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 EI 1096-0961 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR PY 2015 VL 54 IS 3 BP 302 EP 306 DI 10.1016/j.bcmd.2014.12.001 PG 5 WC Hematology SC Hematology GA CD3ZX UT WOS:000351023500018 PM 25582460 ER PT J AU Zusterzeel, R Spatz, ES Curtis, JP Sanders, WE Selzman, KA Pina, IL Bao, HK Ponirakis, A Varosy, PD Masoudi, FA Canos, DA Strauss, DG AF Zusterzeel, Robbert Spatz, Erica S. Curtis, Jeptha P. Sanders, William E. Selzman, Kimberly A. Pina, Ileana L. Bao, Haikun Ponirakis, Angelo Varosy, Paul D. Masoudi, Frederick A. Canos, Daniel A. Strauss, David G. TI Cardiac Resynchronization Therapy in Women Versus Men Observational Comparative Effectiveness Study From the National Cardiovascular Data Registry SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE bundle-branch block; cardiac resynchronization therapy; sex ID BUNDLE-BRANCH-BLOCK; DEFIBRILLATOR IMPLANTATION TRIAL; LEFT-VENTRICULAR DYSFUNCTION; SYMPTOMATIC HEART-FAILURE; QRS DURATION; MADIT-CRT; MORPHOLOGY; PREDICTORS; MORTALITY; SURVIVAL AB Background-Women have been under-represented in trials of cardiac resynchronization therapy-defibrillators (CRT-D). Previous studies suggest that women benefit from CRT-D at shorter QRS duration than men and that there may be no benefit of CRT-D in patients without left bundle branch block (LBBB) regardless of patient sex. Methods and Results-We compared sex-specific death risk in 75 079 patients with New York Heart Association class III or IV heart failure, reduced left ventricular ejection fraction, and prolonged QRS duration (>= 120 ms) receiving either CRT-D or implantable cardioverter defibrillator in subgroups according to QRS morphology and 10-ms increments in QRS duration. We applied propensity score weighting to control for differences between treatments. Among patients with LBBB, women receiving CRT-D had a lower relative death risk than those receiving an implantable cardioverter-defibrillator (absolute difference, 11%; hazard ratio=0.74 [95% confidence interval, 0.68-0.81]). In men, the lower mortality with CRT-D versus implantable cardioverter defibrillator was less pronounced (absolute difference, 9%; hazard ratio=0.84 [0.79-0.89]; sexxdevice interaction P=0.025). In those without LBBB, the mortality difference was modest and did not differ between women and men (absolute difference, 3%; hazard ratio=0.88 [0.79-0.97] in women and absolute difference, 2%; hazard ratio=0.95 [0.91-0.998] in men; interaction P=0.17). In subgroups according to QRS duration, CRT-D was associated with better survival in both sexes with LBBB and QRS >= 130 ms, whereas there was no clear relation between QRS duration and survival in patients without LBBB regardless of patient sex. Conclusions-In a large real-world population CRT-D was associated with a lower mortality risk in both sexes with LBBB, although more pronounced among women. Only among those with LBBB, both sexes had better survival with longer QRS duration. The mortality differences in patients without LBBB were attenuated in both sexes. C1 [Zusterzeel, Robbert; Sanders, William E.; Selzman, Kimberly A.; Pina, Ileana L.; Canos, Daniel A.; Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Spatz, Erica S.; Curtis, Jeptha P.; Bao, Haikun] Yale Univ, Sch Med, New Haven, CT USA. [Ponirakis, Angelo] Amer Coll Cardiol Fdn, Washington, DC USA. [Varosy, Paul D.] Univ Colorado, VA Eastern Colorado Hlth Care Syst, Denver, CO 80202 USA. [Varosy, Paul D.] Colorado Cardiovasc Outcomes Res Grp, Denver, CO USA. [Masoudi, Frederick A.] Univ Colorado, Aurora, CO USA. RP Strauss, DG (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave 62-1126, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov FU Food and Drug Administration (FDA) Office of Women's Health; Oak Ridge Institute for Science and Education FX This study was funded by the Food and Drug Administration (FDA) Office of Women's Health through a contract awarded to the American College of Cardiology. In addition, this study was supported by a research fellowship from the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. The implantable cardioverter defibrillator Registry is an initiative of the American College of Cardiology Foundation with partnering support from the Heart Rhythm Society. NR 36 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-7705 EI 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD MAR PY 2015 VL 8 IS 2 SU 1 BP S4 EP U31 DI 10.1161/CIRCOUTCOMES.114.001548 PG 23 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CD0MK UT WOS:000350767800002 PM 25714821 ER PT J AU Schick, A Steckel, RH AF Schick, Andreas Steckel, Richard H. TI Height, Human Capital, and Earnings: The Contributions of Cognitive and Noncognitive Ability SO JOURNAL OF HUMAN CAPITAL LA English DT Article ID LABOR-MARKET OUTCOMES; NEURAL DEVELOPMENT; CHILD-DEVELOPMENT; CAREER SUCCESS; GROWTH; MALNUTRITION; PERSONALITY; BEHAVIOR; HORMONE; STATURE AB Taller workers receive a substantial premium in earnings or wages, which some studies attribute to noncognitive abilities or social skills that are correlated with stature and rewarded in the labor market. Recent research argues that cognitive abilities explain the relationship. This paper reconciles the competing views by recognizing that net nutrition, a major determinant of adult height, fosters both cognitive and noncognitive abilities. Using data from Britain's National Childhood Development Study, we show that taller children have higher average cognitive and noncognitive test scores and that each aptitude accounts for a substantial and roughly equal portion of the stature-earnings premium. Together, cognitive and noncognitive abilities explain the height premium. C1 [Schick, Andreas] US FDA, Rockville, MD 20857 USA. [Steckel, Richard H.] Ohio State Univ, Columbus, OH 43210 USA. RP Schick, A (reprint author), US FDA, Rockville, MD 20857 USA. NR 57 TC 0 Z9 0 U1 1 U2 6 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1932-8575 EI 1932-8664 J9 J HUM CAPITAL JI J. Hum. Cap. PD SPR PY 2015 VL 9 IS 1 BP 94 EP 115 DI 10.1086/679675 PG 22 WC Economics SC Business & Economics GA CD1IK UT WOS:000350828100004 ER PT J AU McKeown, A Gewandter, JS McDermott, MP Pawlowski, JR Poli, JJ Rothstein, D Farrar, JT Gilron, I Katz, NP Lin, AH Rappaport, BA Rowbotham, MC Turk, DC Dworkin, RH Smith, SM AF McKeown, Andrew Gewandter, Jennifer S. McDermott, Michael P. Pawlowski, Joseph R. Poli, Joseph J. Rothstein, Daniel Farrar, John T. Gilron, Ian Katz, Nathaniel P. Lin, Allison H. Rappaport, Bob A. Rowbotham, Michael C. Turk, Dennis C. Dworkin, Robert H. Smith, Shannon M. TI Reporting of Sample Size Calculations in Analgesic Clinical Trials: ACTTION Systematic Review SO JOURNAL OF PAIN LA English DT Review DE Sample size; power; pain research ID RANDOMIZED CONTROLLED-TRIALS; IMMPACT RECOMMENDATIONS; UPDATED GUIDELINES; STATISTICAL POWER; ETHICS; STATEMENT AB Sample size calculations determine the number of participants required to have sufficiently high power to detect a given treatment effect. In this review, we examined the reporting quality of sample size calculations in 172 publications of double-blind randomized controlled trials of noninvasive pharmacologic or interventional (ie, invasive) pain treatments published in European Journal of Pain, Journal of Pain, and Pain from January 2006 through June 2013. Sixty-five percent of publications reported a sample size calculation but only 38% provided all elements required to replicate the calculated sample size. In publications reporting at least 1 element, 54% provided a justification for the treatment effect used to calculate sample size, and 24% of studies with continuous outcome variables justified the variability estimate. Publications of clinical pain condition trials reported a sample size calculation more frequently than experimental pain model trials (77% vs 33%, P < .001) but did not differ in the frequency of reporting all required elements. No significant differences in reporting of any or all elements were detected between publications of trials with industry and nonindustry sponsorship. Twenty-eight percent included a discrepancy between the reported number of planned and randomized participants. This study suggests that sample size calculation reporting in analgesic trial publications is usually incomplete. Investigators should provide detailed accounts of sample size calculations in publications of clinical trials of pain treatments, which is necessary for reporting transparency and communication of pre-trial design decisions. Perspective: In this systematic review of analgesic clinical trials, sample size calculations and the required elements (eg, treatment effect to be detected; power level) were incompletely reported. A lack of transparency regarding sample size calculations may raise questions about the appropriateness of the calculated sample size. (C) 2015 by the American Pain Society C1 [McKeown, Andrew; Gewandter, Jennifer S.; Pawlowski, Joseph R.; Poli, Joseph J.; Rothstein, Daniel; Dworkin, Robert H.; Smith, Shannon M.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14642 USA. [McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. [McDermott, Michael P.; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [McDermott, Michael P.; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Ctr Human Expt Therapeut, Rochester, NY 14642 USA. [Farrar, John T.] Univ Penn, Philadelphia, PA 19104 USA. [Gilron, Ian] Queens Univ, Kingston, ON, Canada. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.] Tufts Univ, Dept Anesthesiol, Boston, MA 02111 USA. [Lin, Allison H.; Rappaport, Bob A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Rowbotham, Michael C.] Calif Pacific Med Ctr, San Francisco, CA USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Smith, SM (reprint author), Univ Rochester, Sch Med & Dent, Dept Anesthesiol, 601 Elmwood Ave,Box 604, Rochester, NY 14642 USA. EM shannon1_smith@urmc.rochester.edu FU Food and Drug Administration (FDA); ACTTION public-private partnership from the FDA [U01 FD004187] FX The views expressed in this article are those of the authors and no official endorsement by the Food and Drug Administration (FDA) or the pharmaceutical and device companies that provided unrestricted grants to support the activities of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership should be inferred. Financial support for this project was provided by the ACTTION public-private partnership which has received research contracts, grants, or other revenue from the FDA (grant no. U01 FD004187), multiple pharmaceutical and device companies, and other sources. NR 23 TC 4 Z9 6 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD MAR PY 2015 VL 16 IS 3 BP 199 EP 206 DI 10.1016/j.jpain.2014.11.010 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CD4BJ UT WOS:000351027300001 PM 25481494 ER PT J AU Kontson, K Jennings, RJ AF Kontson, Kimberly Jennings, Robert J. TI Bowtie filters for dedicated breast CT: Theory and computational implementation SO MEDICAL PHYSICS LA English DT Article DE dedicated breast CT; bowtie filters; dose reduction; image quality ID X-RAY SCATTER; BEAM COMPUTED-TOMOGRAPHY; IMAGE QUALITY; SPECTRAL OPTIMIZATION; NOISE; RECONSTRUCTION; DESIGN; FEASIBILITY; FILTRATION; GEOMETRY AB Purpose: To design bowtie filters with improved properties for dedicated breast CT to improve image quality and reduce dose to the patient. Methods: The authors present three different bowtie filters designed for a cylindrical 14-cm diameter phantom with a uniform composition of 40/60 breast tissue, which vary in their design objectives and performance improvements. Bowtie design #1 is based on single material spectral matching and produces nearly uniform spectral shape for radiation incident upon the detector. Bowtie design #2 uses the idea of basis material decomposition to produce the same spectral shape and intensity at the detector, using two different materials. Bowtie design #3 eliminates the beam hardening effect in the reconstructed image by adjusting the bowtie filter thickness so that the effective attenuation coefficient for every ray is the same. All three designs are obtained using analytical computational methods and linear attenuation coefficients. Thus, the designs do not take into account the effects of scatter. The authors considered this to be a reasonable approach to the filter design problem since the use of Monte Carlo methods would have been computationally intensive. The filter profiles for a cone-angle of 0 degrees. were used for the entire length of each filter because the differences between those profiles and the correct cone-beam profiles for the cone angles in our system are very small, and the constant profiles allowed construction of the filters with the facilities available to us. For evaluation of the filters, we used Monte Carlo simulation techniques and the full cone-beam geometry. Images were generated with and without each bowtie filter to analyze the effect on dose distribution, noise uniformity, and contrast-to-noise ratio (CNR) homogeneity. Line profiles through the reconstructed images generated from the simulated projection images were also used as validation for the filter designs. Results: Examples of the three designs are presented. Initial verification of performance of the designs was done using analytical computations of HVL, intensity, and effective attenuation coefficient behind the phantom as a function of fan-angle with a cone-angle of 0 degrees. The performance of the designs depends only weakly on incident spectrum and tissue composition. For all designs, the dynamic range requirement on the detector was reduced compared to the no-bowtie-filter case. Further verification of the filter designs was achieved through analysis of reconstructed images from simulations. Simulation data also showed that the use of our bowtie filters can reduce peripheral dose to the breast by 61% and provide uniform noise and CNR distributions. The bowtie filter design concepts validated in this work were then used to create a computational realization of a 3D anthropomorphic bowtie filter capable of achieving a constant effective attenuation coefficient behind the entire field-of-view of an anthropomorphic breast phantom. Conclusions: Three different bowtie filter designs that vary in performance improvements were described and evaluated using computational and simulation techniques. Results indicate that the designs are robust against variations in breast diameter, breast composition, and tube voltage, and that the use of these filters can reduce patient dose and improve image quality compared to the no-bowtie-filter case. (C) 2015 American Association of Physicists in Medicine. C1 [Kontson, Kimberly] Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Imaging & Appl Math, Silver Spring, MD 20993 USA. RP Kontson, K (reprint author), Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. EM Kimberly.Kontson@fda.hhs.gov OI KONTSON, KIMBERLY/0000-0002-4978-6011 FU U.S. Food and Drug Administration's Office of Women's Health; U.S. Food and Drug Administration FX The authors would like to acknowledge Andreu Badal for his instruction on the effective use of the Monte Carlo simulation program PENELOPE, Lucretiu Popescu for his helpful discussions leading to a better understanding of beam hardening correction, and Rongping Zeng for her guidance with reconstruction methods and calculation of relevant parameters. The authors would also like to acknowledge funding from the U.S. Food and Drug Administration's Office of Women's Health and by appointments to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 33 TC 4 Z9 4 U1 0 U2 5 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAR PY 2015 VL 42 IS 3 BP 1453 EP 1462 DI 10.1118/1.4908002 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CC9BC UT WOS:000350661500029 PM 25735298 ER PT J AU Sharfstein, JM AF Sharfstein, Joshua M. TI Dear Health Care Lobbyists ... SO MILBANK QUARTERLY LA English DT Editorial Material C1 [Sharfstein, Joshua M.] Johns Hopkins Bloomberg Sch Publ Hlth, Publ Hlth Practice & Training, Baltimore, MD 21205 USA. [Sharfstein, Joshua M.] Maryland Dept Hlth & Mental Hyg, Baltimore, MD 21201 USA. [Sharfstein, Joshua M.] US FDA, Rockville, MD 20857 USA. [Sharfstein, Joshua M.] Health, Baltimore, MD USA. RP Sharfstein, JM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 615 North Wolfe St,Ste W1033D, Baltimore, MD 21205 USA. EM Joshua.Sharfstein@jhu.edu NR 0 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-378X EI 1468-0009 J9 MILBANK Q JI Milbank Q. PD MAR PY 2015 VL 93 IS 1 BP 15 EP 18 DI 10.1111/1468-0009.12099 PG 4 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CD0HZ UT WOS:000350752800004 PM 25752344 ER PT J AU Andrade, JE Ju, YH Baker, C Doerge, DR Helferich, WG AF Andrade, Juan E. Ju, Young H. Baker, Chandra Doerge, Daniel R. Helferich, William G. TI Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (MCF-7) xenograft model SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE Athymic mice; Breast cancer progression; Genistein; MCF-7; Soy protein isolate ID OVARIECTOMIZED ATHYMIC MICE; IN-VIVO; PHYSIOLOGICAL CONCENTRATIONS; ANTIESTROGEN THERAPY; POSTMENOPAUSAL WOMEN; STIMULATE GROWTH; SOY ISOFLAVONES; BALB/C MICE; NUDE-MICE; TAMOXIFEN AB Scope: The long-term effect of exposure to relevant dietary levels of genistein (GEN) on estrogen receptor-positive (ER+) human breast cancer (MCF-7) progression after GEN withdrawal in athymic mice xenograft model was studied. Materials and methods: Feeding studies were conducted to determine the estrogenic effect of diets on MCF-7 tumor growth: (1) implantation (19 weeks) and withdrawal (6 weeks) of 17 beta-estradiol (E2); (2) dietary GEN 500 and 750 ppm during treatment/withdrawal for 23/10 and 15/9 weeks, respectively; and, (3) dietary soy protein isolate (SPI) containing GEN 180 ppm for 31/9 weeks of treatment/withdrawal. MCF-7 tumors grew fast in the presence of E2 implantation and abruptly regressed completely after E2 withdrawal. At different rates, dietary GEN alone (500 and 750 ppm) and GEN (180 ppm)-containing SPI stimulated MCF-7 tumor growth. After removal of the stimulus diet, tumors induced by 750 ppm GEN, but not 500 ppm GEN or SPI, regressed completely. The protein expression of epidermal growth factor receptor 2 (HER2) was higher in the GEN- and SPI-induced nonregressing (GINR) tumors compared to MCF-7 and E2 controls. Conclusion: Long-term consumption of low GEN doses (<= 500 ppm) promotes MCF-7 tumor growth and results in GINR tumors with more aggressive and advanced growth phenotypes. C1 [Andrade, Juan E.; Helferich, William G.] Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61801 USA. [Ju, Young H.; Baker, Chandra] Virginia Polytech Inst & State Univ, Dept Human Nutr Foods & Exercise, Blacksburg, VA 24061 USA. [Doerge, Daniel R.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Helferich, WG (reprint author), Univ Illinois, Dept Food Sci & Human Nutr, 905 S Goodwin, Urbana, IL 61801 USA. EM helferic@illinois.edu OI Andrade, Juan/0000-0003-2349-9169 FU National Institute On Aging [P01AG024387]; National Center for Complementary and Alternative Medicines (NCCAM) [P50AT006268]; Office of Dietary Supplements (ODS); National Cancer Institute (NCI) FX This work was supported by Grant Number P01AG024387 from the National Institute On Aging [W.G.H. and Y.H.J.]; and Grant Number P50AT006268 from the National Center for Complementary and Alternative Medicines (NCCAM), the Office of Dietary Supplements (ODS) and the National Cancer Institute (NCI) [W.G.H. and D.D.] Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, ODS, NCI, or the National Institutes of Health. NR 54 TC 9 Z9 10 U1 4 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1613-4125 EI 1613-4133 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD MAR PY 2015 VL 59 IS 3 BP 413 EP 423 DI 10.1002/mnfr.201300780 PG 11 WC Food Science & Technology SC Food Science & Technology GA CD0LF UT WOS:000350763500004 PM 24668689 ER PT J AU Abraham, A El Said, KR Wang, YS Jester, ELE Plakas, SM Flewelling, LJ Henry, MS Pierce, RH AF Abraham, Ann El Said, Kathleen R. Wang, Yuesong Jester, Edward L. E. Plakas, Steven M. Flewelling, Leanne J. Henry, Michael S. Pierce, Richard H. TI Biomarkers of brevetoxin exposure and composite toxin levels in hard clam (Mercenaria sp.) exposed to Karenia brevis blooms SO TOXICON LA English DT Article DE Karenia brevis; Brevetoxins; Hard clams; Biomarkers ID OYSTER CRASSOSTREA-VIRGINICA; GYMNODINIUM-BREVE; SHELLFISH; METABOLITES; BIOASSAY; ASSAY AB Brevetoxins in clams (Mercenaria sp.) exposed to recurring blooms of Karenia brevis in Sarasota Bay, FL, were studied over a three-year period. Brevetoxin profiles in toxic clams were generated by ELISA and LC-MS. Several brevetoxin metabolites, as identified by LC-MS, were major contributors to the composite brevetoxin response of ELISA. These were S-desoxyBTX-B2 (m/z 1018), BTX-B2 (m/z 1034), BTX-B5 (m/z 911), open A-ring BTX-B5 (m/z 929), and BTX-B1 (m/z 1018). Summed values of these metabolites were highly correlated (R-2 = 0.9) with composite B-type brevetoxin measurements by ELISA. S-desoxyBTX-B2, BTX-B2, and BTX-B1 were the most persistent and detectable in shellfish for several months after dissipation of blooms. These metabolites were selected as LC-MS biomarkers of brevetoxin exposure and reflective of composite B-type brevetoxins in hard clam. ELISA and LC-MS values were moderately correlated with toxicity of the shellfish by mouse bioassay. ELISA and LC-MS methods offer rapid screening and confirmatory determination of brevetoxins, respectively, as well as toxicity assessment in clams exposed to K. brevis blooms. Published by Elsevier Ltd. C1 [Abraham, Ann; El Said, Kathleen R.; Wang, Yuesong; Jester, Edward L. E.; Plakas, Steven M.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. [Flewelling, Leanne J.] Fish & Wildlife Res Inst, St Petersburg, FL 33701 USA. [Henry, Michael S.; Pierce, Richard H.] Mote Marine Lab, Sarasota, FL 34236 USA. RP Abraham, A (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM ann.abraham@fda.hhs.gov FU NOAA-ECOHAB Award [NA03NOS4780197]; Florida Fish and Wildlife Conservation Commission [99013] FX We greatly appreciate the technical assistance by Paula Scott (Fish and Wildlife Research Institute) with the mouse bioassay. This project was funded by NOAA-ECOHAB Award No. NA03NOS4780197, and in part by the Florida Fish and Wildlife Conservation Commission Contract #99013, with in-kind support from the U.S. FDA, Gulf Coast Seafood Laboratory. NR 19 TC 0 Z9 0 U1 3 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD MAR PY 2015 VL 96 BP 82 EP 88 DI 10.1016/j.toxicon.2015.01.014 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CD2PY UT WOS:000350922700010 PM 25620222 ER PT J AU Arguello, DF Tomashek, KM Quinones, L Beltran, M Acosta, L Santiago, LM Biggerstaff, BJ Garcia-Rivera, EJ Sun, W Pollissard-Gadroy, L Luxemburger, C Hunsperger, E AF Argueello, D. Fermin Tomashek, Kay M. Quinones, Luz Beltran, Manuela Acosta, Luz Santiago, Luis M. Biggerstaff, Brad J. Garcia-Rivera, Enid J. Sun, Wellington Pollissard-Gadroy, Laurence Luxemburger, Christine Hunsperger, Elizabeth TI Incidence of Dengue Virus Infection in School-Aged Children in Puerto Rico: A Prospective Seroepidemiologic Study SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; RISK-FACTORS; PROSPECTIVE COHORT; HEMORRHAGIC-FEVER; SHOCK SYNDROME; OUTBREAK; THAILAND; SCHOOLCHILDREN; SURVEILLANCE; ANTIBODIES AB Dengue is a potentially fatal acute febrile illness caused by the mosquito-borne dengue viruses (DENV-1 to -4). To estimate DENV seroincidence in school-aged children, a 1-year prospective cohort study was conducted in Patillas, Puerto Rico; 10- to 18-year-olds (N = 345) were randomly selected from 13 public schools. At enrollment, 49.8% of the entire cohort had DENV immunoglobulin G (IgG) anti-DENV antibodies, and there were individuals with neutralizing antibodies specific to each of the four DENV. The mean age of participants with incident DENV infection was 13.4 years. The 1-year seroincidence rate was 5.6%, and 61.1% of infections were inapparent. Having IgG anti-DENV at enrollment was associated with seroincidence (risk ratio = 6.8). Acute febrile illnesses during the study period were captured by a fever diary and an enhanced and passive surveillance system in the municipios of Patillas and Guayama. In summary, at enrollment, nearly one-half of the participants had a prior DENV infection, with the highest incidence in the 10- to 11-year-olds, of which most were inapparent infections, and symptomatic infections were considered mild. C1 [Argueello, D. Fermin; Tomashek, Kay M.; Quinones, Luz; Beltran, Manuela; Acosta, Luz; Santiago, Luis M.; Hunsperger, Elizabeth] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Div Vector Borne Dis, Dengue Branch, San Juan, PR USA. [Biggerstaff, Brad J.] Ctr Dis Control & Prevent, Off Director, Natl Ctr Emerging & Zoonot Dis, Div Vector Borne Dis, Ft Collins, CO USA. [Garcia-Rivera, Enid J.] Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA. [Sun, Wellington] US FDA, Silver Spring, MD USA. [Pollissard-Gadroy, Laurence] Sanofi Aventis, Paris, France. [Luxemburger, Christine] Sanofi Pasteur, Lyon, France. RP Hunsperger, E (reprint author), CDC Dengue Branch, 1324 Calle Canada, San Juan, PR 00920 USA. EM dfmanito@gmail.com; kay.tomashek@nih.gov; luzquinones@hotmail.com; mvb6@cdc.gov; lda9@cdc.gov; bkb5@cdc.gov; enid.garcia3@upr.edu; Wellington.Sun@fda.hhs.gov; laurencehmp@gmail.com; Christine.Luxemburger@sanofipasteur.com; enh4@cdc.gov FU Cooperative Research and Development Agreement (CRDA) [CID-01-138-02]; Sanofi Pasteur, Inc. FX This work was supported, in part, under Cooperative Research and Development Agreement (CRDA) CID-01-138-02 with Sanofi Pasteur, Inc. NR 34 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAR PY 2015 VL 92 IS 3 BP 486 EP 491 DI 10.4269/ajtmh.14-0231 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CC7EB UT WOS:000350529400007 PM 25646256 ER PT J AU Kavanaugh, A Cush, JJ Ahmed, MS Bermas, BL Chakravarty, E Chambers, C Clowse, M Curtis, JR Dao, K Hankins, GDV Koren, G Kim, SC Lapteva, L Mahadevan, U Moore, T Nolan, M Ren, ZX Sammaritano, LR Seymour, S Weisman, MH AF Kavanaugh, Arthur Cush, John J. Ahmed, Mahmoud S. Bermas, Bonnie L. Chakravarty, Eliza Chambers, Christina Clowse, Megan Curtis, Jeffrey R. Dao, Kathryn Hankins, Gary D. V. Koren, Gideon Kim, Seoyoung C. Lapteva, Larissa Mahadevan, Uma Moore, Thomas Nolan, Martha Ren, Zhaoxia Sammaritano, Lisa R. Seymour, Sally Weisman, Michael H. TI Proceedings From the American College of Rheumatology Reproductive Health Summit: The Management of Fertility, Pregnancy, and Lactation in Women With Autoimmune and Systemic Inflammatory Diseases SO ARTHRITIS CARE & RESEARCH LA English DT Article ID LATE-PRETERM INFANTS; BREAST-MILK; LUPUS-ERYTHEMATOSUS; BOWEL-DISEASE; NURSING MOTHERS; BIRTH OUTCOMES; MATERNAL SERUM; CROHNS-DISEASE; CHILDREN BORN; UNITED-STATES C1 [Kavanaugh, Arthur; Chambers, Christina] Univ Calif San Diego, La Jolla, CA 92093 USA. [Cush, John J.; Dao, Kathryn] Baylor Res Inst, Dallas, TX USA. [Ahmed, Mahmoud S.; Hankins, Gary D. V.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Bermas, Bonnie L.; Kim, Seoyoung C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chakravarty, Eliza] Oklahoma Med Res Fdn, Edmond, OK USA. [Clowse, Megan] Duke Univ, Med Ctr, Durham, NC USA. [Curtis, Jeffrey R.] Univ Alabama Birmingham, Birmingham, AL USA. [Koren, Gideon] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Lapteva, Larissa; Seymour, Sally] US FDA, Silver Spring, MD USA. [Mahadevan, Uma] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Moore, Thomas] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Nolan, Martha] Soc Womens Hlth Res, Washington, DC USA. [Ren, Zhaoxia] NICHHD, NIH, Bethesda, MD 20892 USA. [Sammaritano, Lisa R.] Cornell Univ, Hosp Special Surg, Weill Med Coll, New York, NY 10021 USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Weisman, MH (reprint author), Cedars Sinai Med Ctr, Div Rheumatol, 8700 Beverly Blvd,B131, Los Angeles, CA 90048 USA. EM weisman@cshs.org OI Kim, Seoyoung/0000-0002-2517-3579 FU American College of Rheumatology FX The Reproductive Health Summit and preparation of this manuscript were supported by funding from the American College of Rheumatology. NR 106 TC 13 Z9 13 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD MAR PY 2015 VL 67 IS 3 BP 313 EP 325 DI 10.1002/acr.22516 PG 13 WC Rheumatology SC Rheumatology GA CC4BK UT WOS:000350295500001 PM 25385050 ER PT J AU Smith, B Huang, SM AF Smith, B. P. Huang, S-M TI Novel Approaches to Address Challenges in Global Drug Development SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material C1 [Smith, B. P.] Novartis Pharmaceut, E Hanover, NJ 07936 USA. [Huang, S-M] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Smith, B (reprint author), Novartis Pharmaceut, E Hanover, NJ 07936 USA. EM Brain_P.Smith@Novartis.com; ShiewMei.Huang@fda.hhs.gov NR 12 TC 4 Z9 4 U1 0 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 MAR PY 2015 VL 97 IS 3 BP 196 EP 199 DI 10.1002/cpt.62 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC3WK UT WOS:000350281500001 PM 25669768 ER PT J AU Romero, K Ito, K Rogers, JA Polhamus, D Qiu, R Stephenson, D Mohs, R Lalonde, R Sinha, V Wang, Y Brown, D Isaac, M Vamvakas, S Hemmings, R Pani, L Bain, LJ Corrigan, B AF Romero, K. Ito, K. Rogers, J. A. Polhamus, D. Qiu, R. Stephenson, D. Mohs, R. Lalonde, R. Sinha, V. Wang, Y. Brown, D. Isaac, M. Vamvakas, S. Hemmings, R. Pani, L. Bain, L. J. Corrigan, B. CA Alzheimer's Dis Neuroimaging Coalition Against Major Dis TI The Future Is Now: Model-Based Clinical Trial Design for Alzheimer's Disease SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease.(1) CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). C1 [Romero, K.; Stephenson, D.; Bain, L. J.] Crit Path Inst, Tucson, AZ 85718 USA. [Ito, K.; Qiu, R.; Lalonde, R.; Corrigan, B.] Pfizer Inc, Groton, CT 06340 USA. [Rogers, J. A.; Polhamus, D.] Metrum Res Grp, Tariffville, CT USA. [Mohs, R.] Eli Lilly, Lilly Corp Ctr, Indianapolis, IN USA. [Sinha, V.; Wang, Y.] US FDA, Silver Spring, MD USA. [Brown, D.; Isaac, M.; Vamvakas, S.; Hemmings, R.; Pani, L.] European Med Agcy, London, England. RP Stephenson, D (reprint author), Crit Path Inst, Tucson, AZ 85718 USA. EM dstephenson@c-path.org RI Kowall, Neil/G-6364-2012; OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438 NR 7 TC 7 Z9 7 U1 0 U2 17 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 2015 VL 97 IS 3 BP 210 EP 214 DI 10.1002/cpt.16 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC3WK UT WOS:000350281500021 PM 25669145 ER PT J AU Schuck, RN Florian, J Charlab, R Pacanowski, M AF Schuck, R. N. Florian, J. Charlab, R. Pacanowski, M. TI Trial Geography, Pharmacogenetics, and Global Drug Development SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID GENETIC-VARIATION; CLEARANCE; IL28B AB Drug development is increasingly global. The benefits of multiregional trials include worldwide evaluation of safety and efficacy. However, clinical practice, environmental, and genetic factors can vary across geographic regions, significantly influencing trial outcomes within a specific geographic region or the global population relative to the United States (US). Genomic technologies and research discoveries continue to advance at a remarkable pace, offering opportunities to explore intrinsic factors that could account for regional variability in drug pharmacokinetics or response. C1 [Schuck, R. N.; Florian, J.; Charlab, R.; Pacanowski, M.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Pacanowski, M (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Michael.Pacanowski@fda.hhs.gov NR 5 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2015 VL 97 IS 3 BP 218 EP 220 DI 10.1002/cpt.27 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC3WK UT WOS:000350281500023 PM 25669642 ER PT J AU Parekh, A Buckman-Garner, S McCune, S ONeill, R Geanacopoulos, M Amur, S Clingman, C Barratt, R Rocca, M Hills, I Woodcock, J AF Parekh, A. Buckman-Garner, S. McCune, S. ONeill, R. Geanacopoulos, M. Amur, S. Clingman, C. Barratt, R. Rocca, M. Hills, I. Woodcock, J. TI Catalyzing the Critical Path Initiative: FDA's Progress in Drug Development Activities SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID SIGNAL-DETECTION; CLINICAL-TRIALS; SUBMISSIONS; SIMULATION; UTILITY; SAFETY; IMPACT AB The US Food and Drug Administration (FDA) has directed considerable effort towards modernizing its regulatory processes over the past decade to address the challenges in the drug development sector. Through partnerships and input from stakeholders, multiple initiatives are under way, many projects have been launched, several have resulted in tangible results, and many are ongoing and under discussion. We are learning that collaborative efforts can better inform and leverage existing knowledge, that the challenges of data sharing and intellectual property can be overcome, and that there is wide interest in partnering to address key public health regulatory science issues. It is crucial that we continue to build on these initial efforts to facilitate drug development. C1 [Parekh, A.; Buckman-Garner, S.; McCune, S.; ONeill, R.; Geanacopoulos, M.; Amur, S.; Clingman, C.; Barratt, R.; Rocca, M.; Hills, I.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Woodcock, J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Parekh, A (reprint author), US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM ameeta.parekh@fda.hhs.gov NR 28 TC 10 Z9 10 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2015 VL 97 IS 3 BP 221 EP 233 DI 10.1002/cpt.42 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC3WK UT WOS:000350281500024 PM 25670629 ER PT J AU Ramamoorthy, A Pacanowski, MA Bull, J Zhang, L AF Ramamoorthy, A. Pacanowski, M. A. Bull, J. Zhang, L. TI Racial/Ethnic Differences in Drug Disposition and Response: Review of Recently Approved Drugs SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID CONVERTING-ENZYME-INHIBITOR; ETHNIC-DIFFERENCES; HEPATITIS-C; GENETIC-VARIATION; CLINICAL-TRIALS; WHITE PATIENTS; UNITED-STATES; LUNG-CANCER; JAPAN; PHARMACOKINETICS AB Race and ethnicity can contribute to interindividual differences in drug exposure and/or response, which may alter risk-benefit in certain populations. Approximately one-fifth of new drugs approved in the past 6 years demonstrated differences in exposure and/or response across racial/ethnic groups, translating to population-specific prescribing recommendations in a few cases. When data from diverse populations were lacking, additional postmarketing studies were recommended. In this review we highlight several cases where race/ethnicity was central to regulatory decision-making. C1 [Ramamoorthy, A.; Pacanowski, M. A.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Bull, J.] US FDA, Off Minor Hlth, Off Commissioner, Silver Spring, MD 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 58 TC 14 Z9 14 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2015 VL 97 IS 3 BP 263 EP 273 DI 10.1002/cpt.61 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC3WK UT WOS:000350281500027 PM 25669658 ER PT J AU Yu, LX Jiang, W Zhang, X Lionberger, R Makhlouf, F Schuirmann, DJ Muldowney, L Chen, ML Davit, B Conner, D Woodcock, J AF Yu, L. X. Jiang, W. Zhang, X. Lionberger, R. Makhlouf, F. Schuirmann, D. J. Muldowney, L. Chen, M-L Davit, B. Conner, D. Woodcock, J. TI Novel Bioequivalence Approach for Narrow Therapeutic Index Drugs SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PRODUCTS AB Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products. C1 [Yu, L. X.; Jiang, W.; Zhang, X.; Lionberger, R.; Makhlouf, F.; Schuirmann, D. J.; Muldowney, L.; Chen, M-L; Davit, B.; Conner, D.; Woodcock, J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Davit, B.] Merck Res Labs, Whitehouse Stn, NJ USA. RP Yu, LX (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM lawrence.yu@fda.hhs.gov NR 19 TC 11 Z9 12 U1 3 U2 12 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 2015 VL 97 IS 3 BP 286 EP 291 DI 10.1002/cpt.28 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC3WK UT WOS:000350281500029 PM 25669762 ER PT J AU Felter, SP Daston, GP Euling, SY Piersma, AH Tassinari, MS AF Felter, Susan P. Daston, George P. Euling, Susan Y. Piersma, Aldert H. Tassinari, Melissa S. TI Assessment of health risks resulting from early-life exposures: Are current chemical toxicity testing protocols and risk assessment methods adequate? SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE children; development; infants; life stage; quantitative risk assessment; susceptibility; sensitivity; subpopulations; uncertainty factor; variability; vulnerability ID DEFAULT UNCERTAINTY FACTOR; DRUG-METABOLIZING-ENZYMES; REFERENCE DOSE RFD; HUMAN VARIABILITY; DEVELOPMENTAL NEUROTOXICITY; IMMUNE-SYSTEM; PHARMACOKINETIC DIFFERENCES; REPRODUCTIVE-SYSTEM; ENVIRONMENTAL CONTAMINANTS; DIFFERENTIAL SENSITIVITY AB Over the last couple of decades, the awareness of the potential health impacts associated with early-life exposures has increased. Global regulatory approaches to chemical risk assessment are intended to be protective for the diverse human population including all life stages. However, questions persist as to whether the current testing approaches and risk assessment methodologies are adequately protective for infants and children. Here, we review physiological and developmental differences that may result in differential sensitivity associated with early-life exposures. It is clear that sensitivity to chemical exposures during early-life can be similar, higher, or lower than that of adults, and can change quickly within a short developmental time-frame. Moreover, age-related exposure differences provide an important consideration for overall susceptibility. Differential sensitivity associated with a life stage can reflect the toxicokinetic handling of a xenobiotic exposure, the toxicodynamic response, or both. Each of these is illustrated with chemical-specific examples. The adequacy of current testing protocols, proposed new tools, and risk assessment methods for systemic noncancer endpoints are reviewed in light of the potential for differential risk to infants and young children. C1 [Felter, Susan P.; Daston, George P.] Procter & Gamble Co, Cincinnati, OH 45217 USA. [Euling, Susan Y.] US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [Piersma, Aldert H.] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Tassinari, Melissa S.] US FDA, Ctr Drug Evaluat & Res, Washington, DC 20204 USA. RP Felter, SP (reprint author), Procter & Gamble Co, Cincinnati, OH 45217 USA. EM felter.sp@pg.com FU RIVM FX The authors' affiliations are as shown on the cover page. Susan Felter and George Daston are employees of Procter & Gamble, a corporation producing and marketing many products used with infants and children. Aldert Piersma is affiliated to the National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. RIVM is a government agency under the Dutch Ministry of Health, Welfare and Sports. RIVM has sponsored his contribution to the present piece of work. Susan Euling and Melissa Tassinari are employees of the US EPA and US FDA, respectively, which have regulatory authority related to a wide range of products/exposures that may impact the health of infants and children. This project was initiated by the Procter & Gamble scientists who asked the other authors to independently participate as professionals. The authors have sole responsibility for the writing and content of the article. The paper was reviewed internally at each author's home institution as is customary, however, those reviews did not influence the conclusions drawn nor the recommendations made by the authors. The design of the appraisal, the conduct of the appraisal, and the conclusions drawn in the paper are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency, the U.S. Food and Drug Administration, or RIVM. NR 166 TC 7 Z9 7 U1 5 U2 20 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD MAR PY 2015 VL 45 IS 3 BP 219 EP 244 DI 10.3109/10408444.2014.993919 PG 26 WC Toxicology SC Toxicology GA CC7UZ UT WOS:000350575200003 PM 25687245 ER PT J AU Herbold, NM Clotilde, LM Anderson, KM Kase, J Hartman, GL Himathongkham, S Lin, A Lauzon, CR AF Herbold, N. M. Clotilde, L. M. Anderson, K. M. Kase, J. Hartman, G. L. Himathongkham, S. Lin, A. Lauzon, C. R. TI Clustering of Clinical and Environmental Escherichia coli O104 Isolates Using the DiversiLab (TM) Repetitive Sequence-Based PCR System SO CURRENT MICROBIOLOGY LA English DT Article ID VANCOMYCIN-RESISTANT ENTEROCOCCI; HEMOLYTIC-UREMIC SYNDROME; POLYMERASE-CHAIN-REACTION; DNA-SEQUENCES; HOSPITALS; STRAINS; CARE AB The DiversiLab (TM) rep-PCR system was used to amplify DNA regions of 28 well-characterized Escherichia coli O104 strains to generate a digital DNA fingerprint profile for strain differentiation. E. coli O104 strains from human stools and other sources were examined. The results indicate that this system can cluster similar O104 strains rapidly. C1 [Herbold, N. M.; Lauzon, C. R.] Calif State Univ Hayward, Dept Biol Sci, Hayward, CA 94542 USA. [Clotilde, L. M.] MagArray Inc, Sunnyvale, CA 94089 USA. [Anderson, K. M.; Hartman, G. L.; Lin, A.] US FDA, Off Regulatory Affairs, San Francisco Dist Lab, Alameda, CA 94502 USA. [Kase, J.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [Himathongkham, S.] US FDA, Div Field Sci, Off Regulatory Affairs, Rockville, MD 20850 USA. RP Lauzon, CR (reprint author), Calif State Univ Hayward, Dept Biol Sci, 25800 Carlos Bee Blvd, Hayward, CA 94542 USA. EM carol.lauzon@csueastbay.edu NR 24 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0343-8651 EI 1432-0991 J9 CURR MICROBIOL JI Curr. Microbiol. PD MAR PY 2015 VL 70 IS 3 BP 436 EP 440 DI 10.1007/s00284-014-0728-z PG 5 WC Microbiology SC Microbiology GA CC3IO UT WOS:000350240600020 PM 25447271 ER PT J AU Zhao, JQ Ragupathy, V Liu, JK Wang, X Vemula, SV El Mubarak, HS Ye, ZP Landry, ML Hewlett, I AF Zhao, Jiangqin Ragupathy, Viswanath Liu, Jikun Wang, Xue Vemula, Sai Vikram El Mubarak, Haja Sittana Ye, Zhiping Landry, Marie L. Hewlett, Indira TI Nanomicroarray and Multiplex Next-Generation Sequencing for Simultaneous Identification and Characterization of Influenza Viruses SO EMERGING INFECTIOUS DISEASES LA English DT Article ID A H7N9 VIRUS; HUMAN INFECTIONS; RAPID DETECTION; MOLECULAR-BASIS; SWINE; HUMANS; PATHOGENICITY; OUTBREAK; HEMAGGLUTININ; AMPLIFICATION AB Conventional methods for detection and discrimination of influenza viruses are time consuming and labor intensive. We developed a diagnostic platform for simultaneous identification and characterization of influenza viruses that uses a combination of nanomicroarray for screening and multiplex next-generation sequencing (NGS) assays for laboratory confirmation. The nanomicroarray was developed to target hemagglutinin, neuraminidase, and matrix genes to identify influenza A and B viruses. PCR amplicons synthesized by using an adapted universal primer for all 8 gene segments of 9 influenza A subtypes were detected in the nanomicroarray and confirmed by the NGS assays. This platform can simultaneously detect and differentiate multiple influenza A subtypes in a single sample. Use of these methods as part of a new diagnostic algorithm for detection and confirmation of influenza infections may provide ongoing public health benefits by assisting with future epidemiologic studies and improving preparedness for potential influenza pandemics. C1 [Zhao, Jiangqin; Ragupathy, Viswanath; Liu, Jikun; Wang, Xue; Vemula, Sai Vikram; El Mubarak, Haja Sittana; Ye, Zhiping; Hewlett, Indira] US FDA, Silver Spring, MD USA. [Landry, Marie L.] Yale Univ, Sch Med, New Haven, CT USA. RP Zhao, JQ (reprint author), CBER FDA, Mol Virol Lab, Bldg 52-72,Rm 4308,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jiangqin.zhao@fda.hhs.gov; indira.hewlett@fda.hhs.gov FU FDA Center for Biologics Evaluation and Research intramural and Medical Countermeasures Initiative funds FX This work was funded through the FDA Center for Biologics Evaluation and Research intramural and Medical Countermeasures Initiative funds. NR 39 TC 7 Z9 7 U1 0 U2 9 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2015 VL 21 IS 3 BP 400 EP 408 DI 10.3201/eid2103.141169 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CC3SI UT WOS:000350269300002 PM 25694248 ER PT J AU Perry, D Sperling, R Katz, R Berry, D Dilts, D Hanna, D Salloway, S Trojanowski, JQ Bountra, C Krams, M Luthman, J Potkin, S Gribkoff, V Temple, R Wang, Y Carrillo, MC Stephenson, D Snyder, H Liu, E Ware, T McKew, J Fields, FO Bain, LJ Bens, C AF Perry, Daniel Sperling, Reisa Katz, Russell Berry, Donald Dilts, David Hanna, Debra Salloway, Stephen Trojanowski, John Q. Bountra, Chas Krams, Michael Luthman, Johan Potkin, Steven Gribkoff, Val Temple, Robert Wang, Yaning Carrillo, Maria C. Stephenson, Diane Snyder, Heather Liu, Enchi Ware, Tony McKew, John Fields, F. Owen Bain, Lisa J. Bens, Cynthia TI Building a roadmap for developing combination therapies for Alzheimer's disease SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE Alzheimer' disease; combination therapy; collaboration; co-development; novel therapy ID HYPOTHETICAL MODEL; DYNAMIC BIOMARKERS AB Combination therapy has proven to be an effective strategy for treating many of the world's most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer's disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition, the Critical Path Institute and the Alzheimer's Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality. C1 [Sperling, Reisa] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Katz, Russell] US FDA, San Diego, CA USA. [Berry, Donald] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Dilts, David] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Hanna, Debra; Stephenson, Diane] Crit Path Inst, Tucson, AZ USA. [Salloway, Stephen] Brown Univ, Butler Hosp, Providence, RI 02912 USA. [Trojanowski, John Q.] Univ Penn, Sch Med, Dept Pathol & Lab Med,Inst Ageing, Alzheimers Dis Core Ctr,Ctr Neurodegenerat Dis Re, Philadelphia, PA 19104 USA. [Bountra, Chas] Univ Oxford, Oxford, England. [Krams, Michael] Janssen Pharmaceut, Philadelphia, PA USA. [Luthman, Johan] Eisai & Co Ltd, Philadelphia, PA USA. [Potkin, Steven] Univ Calif Irvine, Irvine, CA USA. [Gribkoff, Val] Elan, San Francisco, CA USA. [Temple, Robert; Wang, Yaning] US FDA, Silver Spring, MD USA. [Carrillo, Maria C.; Snyder, Heather] Alzheimers Assoc, Chicago, IL USA. [Liu, Enchi] Janssen Pharmaceut, San Francisco, CA USA. [Ware, Tony] Eli Lilly & Co, Indianapolis, IN 46285 USA. [McKew, John] NIH, Bethesda, MD 20892 USA. [Fields, F. Owen] Pfizer, Philadelphia, PA USA. [Perry, Daniel; Bens, Cynthia] Alliance Aging Res, Washington, DC 20006 USA. RP Bens, C (reprint author), Alliance Aging Res, Washington, DC 20006 USA. EM cbens@agingresearch.org FU Eli Lilly; Eisai; Avid; Janssen; Biogen Idec; Merck Lilly; Roche; Genentech; Alkermes; Forest; FORUM Pharmaceuticals; Lundbeck; Merck; Novartis; Otsuka; Sunovion; Takeda; Toyama; Vanda; Wellcome Trust; IMI; Abbvie; Bayer Healthcare; Boehringer Ingelheim; GSK; Pfizer FX JQ Trojanowski may accrue revenue on patents submitted by the University of Pennsylvania on methods and diagnostics that he invented. F Owen Fields is employed by Pfizer and has stock options in Pfizer. R Sperling has served as a consultant to Roche, Isis, Genentech, Janssen and has received research support from Eli Lilly, Eisai, Avid and Janssen. J Luthman is an employee of Eisai and owns shares in AstraZeneca and Merck. S Salloway has received research support from Biogen Idec, Merck Lilly, Roche and Genentech. J McKew was an employee of aTyr pharma at the time of publication. V Gribkoff was an employee of Elan at the time of the meeting. S Potkin has received grant support, funding, honoraria, consultancy fees from the following companies; Alkermes, Eli Lilly, Forest, FORUM Pharmaceuticals, Genentech, Janssen, Lundbeck, Merck, Novartis, Otsuka, Roche, Sunovion, Takeda, Toyama and Vanda. E Liu is an employee of Janssen. C Bountra is funded by the Wellcome Trust, IMI, Abbvie, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novartis, Pfizer and Takeda. M Krams is employed by J&J. D Berry is co-owner of Berry Consultants, LLC. JA Ware is a full time employee of Eli Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 12 TC 6 Z9 6 U1 2 U2 12 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD MAR PY 2015 VL 15 IS 3 BP 327 EP 333 DI 10.1586/14737175.2015.996551 PG 7 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CC3KD UT WOS:000350245800010 PM 25708309 ER PT J AU Salazar, JK Wang, Y Yu, SJ Wang, H Zhang, W AF Salazar, Joelle K. Wang, Yun Yu, Shuijing Wang, Hui Zhang, Wei TI Polymerase chain reaction-based serotyping of pathogenic bacteria in food SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Review DE E. coli; Food contamination; Listeria; PCR; Salmonella; Serotyping ID RESISTANT STAPHYLOCOCCUS-AUREUS; ANTIGEN GENE-CLUSTER; REAL-TIME PCR; ACTIVE SURVEILLANCE NETWORK; 10 US SITES; FIELD GEL-ELECTROPHORESIS; ENTERICA SUBSP ENTERICA; ESCHERICHIA-COLI; LISTERIA-MONOCYTOGENES; MULTIPLEX PCR AB Serotyping analysis of bacterial pathogens in food products is important for foodborne disease surveillance and outbreak investigations. Traditional immunological techniques are labor-intensive and time-consuming, whereas polymerase chain reaction (PCR)-based techniques are more robust, consistent and rapid. PCR-based methods also provide easier standardization and better reproducibility. Here, we summarize some recent developments and applications of PCR-based serotyping for common foodborne pathogens, and provide a list of available bioinformatics tools for developing PCR-based serotyping assays. Published by Elsevier B.V. C1 [Salazar, Joelle K.; Wang, Yun] US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. [Yu, Shuijing] Jiangxi Univ Sci & Technol, Jiangxi Key Lab Min & Met Environm Pollut Control, Fac Resource & Environm Engn, Ganzhou, Jiangxi, Peoples R China. [Wang, Hui] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Food Safety Res, Shanghai, Peoples R China. [Zhang, Wei] IIT, Dept Food Sci & Nutr, Bedford Pk, IL USA. RP Salazar, JK (reprint author), US FDA, Div Food Proc Sci & Technol, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM Joelle.Salazar@fda.hhs.gov RI Wang, Yun/G-8899-2016 FU Agriculture and Food Research Initiative Grant from the U. S. Department of Agriculture National Institute of Food and Agriculture [2014-67017-21707]; Chu-Tian Lecturing Professorship from the Department of Education of Hubei Province; National Natural Science Foundation of China [31360388, 81328022]; Department of Education of Jiangxi Province [132[2012]]; U. S. Food and Drug Administration [U19FD005322]; Oak Ridge Institute for Science and Education Research Participation Program FX This work was supported in part by an Agriculture and Food Research Initiative Grant (No. 2014-67017-21707) from the U. S. Department of Agriculture National Institute of Food and Agriculture, a collaborative research grant (No. 81328022) from the National Natural Science Foundation of China, and the Chu-Tian Lecturing Professorship from the Department of Education of Hubei Province to WZ. This work was also supported in part by a grant (No. 31360388) from the National Natural Science Foundation of China, a grant from the Young Teacher of Ordinary Undergraduate Colleges and Universities for Visiting Abroad from the Department of Education of Jiangxi Province (No. 132[2012]) to SJY, and by grant number U19FD005322 from the U. S. Food and Drug Administration to the Illinois Institute of Technology. JKS and YW were supported by the Oak Ridge Institute for Science and Education Research Participation Program 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 149 TC 2 Z9 2 U1 0 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD MAR PY 2015 VL 110 BP 18 EP 26 DI 10.1016/j.mimet.2015.01.009 PG 9 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CC2RE UT WOS:000350191500004 PM 25596519 ER PT J AU Nagaraja, S Awada, HK Dreher, ML Bouck, JT Gupta, S AF Nagaraja, Srinidhi Awada, Hassan K. Dreher, Maureen L. Bouck, John T. Gupta, Shikha TI Effects of vertebroplasty on endplate subsidence in elderly female spines SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE vertebroplasty; biomechanics; trabecular bone; endplate; subsidence; micro-CT; lumbar ID PERCUTANEOUS VERTEBROPLASTY; COMPRESSION FRACTURES; VERTEBRAL BODY; CEMENT AUGMENTATION; OSTEOPOROTIC PATIENTS; RANDOMIZED-TRIAL; FINITE-ELEMENT; RISK-FACTORS; BONE-CEMENT; FOLLOW-UP AB OBJECT The aim in this study was to quantify the effects of vertebroplasty on endplate subsidence in treated and adjacent vertebrae and their relationship to endplate thickness and underlying trabecular bone in elderly female spines. METHODS Vertebral compression fractures were created in female cadaveric (age range 51-88 years) thoracolumbar spine segments. Specimens were placed into either the control or vertebroplasty group (n = 9/group) such that bone mineral density, trabecular microarchitecture, and age were statistically similar between groups. For the vertebroplasty group, polymethylmethacrylate bone cement was injected into the fractured vertebral body under fluoroscopy. Cyclic compression (685-1370 N sinusoid) was performed on all spine segments for 115,000 cycles. Micro-CT scans were obtained before and after cyclic loading to quantify endplate subsidence. Maximum subsidence was compared between groups in the caudal endplate of the superior adjacent vertebra (SVcau); cranial (TVcra) and caudal (TVcau) endplates of the treated vertebra; and the cranial endplate of the inferior adjacent vertebra (IVcra). In addition, micro-CT images were used to quantify average endplate thickness and trabecular bone volume fraction. These parameters were then correlated with maximum endplate subsidence for each endplate. RESULTS The maximum subsidence in SVcau endplate for the vertebroplasty group (0.34 +/- 0.58 mm) was significantly (p < 0.05) greater than for the control group (-0.13 +/- 0.27 mm). Maximum subsidence in the TVcra, TVcau, and IVcra endplates were greater in the vertebroplasty group, but these differences were not significant (p > 0.16). Increased subsidence in the vertebroplasty group manifested locally in the anterior region of the SVcau endplate and in the posterior region of the TVcra and TVcau endplates (p <0.10). Increased subsidence Was observed in thinner endplates with lower trabecular bone volume fraction for both vertebroplasty and control groups (R-2 correlation up to 62%). In the SVcau a endplate specifically, these 2 covariates aided in understanding subsidence differences between vertebroplasty and control groups. CONCLUSIONS Bone cement injected during vertebroplasty alters local biomechanics in elderly female spines, resulting in increased endplate disruption in treated and superior adjacent vertebrae. More specifically, bone cement increases subsidence in the posterior regions of the treated endplates and the anterior region of the superior caudal endplate. This increased subsidence may be the initial mechanism leading to subsequent compression fractures after vertebroplasty, particularly in vertebrae superior to the treated level. C1 [Nagaraja, Srinidhi; Awada, Hassan K.; Dreher, Maureen L.; Bouck, John T.; Gupta, Shikha] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Solid & Fluid Mech, Silver Spring, MD 20993 USA. RP Nagaraja, S (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Rm 2210, Silver Spring, MD 20993 USA. EM srinidhi.nagaraja@fda.hhs.gov FU FDA's Office of Women's Health FX This research study was funded by a grant through the FDA's Office of Women's Health. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. NR 46 TC 2 Z9 2 U1 1 U2 11 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 EI 1547-5646 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD MAR PY 2015 VL 22 IS 3 BP 273 EP 282 DI 10.3171/2014.10.SPINE14195 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA CC3RG UT WOS:000350266300008 PM 25525963 ER PT J AU Zaitseva, M McCullough, KT Cruz, S Thomas, A Diaz, CG Keilholz, L Grossi, IM Trost, LC Golding, H AF Zaitseva, Marina McCullough, Kevin Tyler Cruz, Stephanie Thomas, Antonia Diaz, Claudia G. Keilholz, Laurie Grossi, Irma M. Trost, Lawrence C. Golding, Hana TI Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus SO JOURNAL OF VIROLOGY LA English DT Article ID REPLICATION IN-VITRO; SMALLPOX VACCINATION; IMMUNODEFICIENT MICE; ALKOXYALKYL ESTERS; RESPIRATORY-TRACT; ECTROMELIA VIRUS; CYCLIC CIDOFOVIR; EFFICACY; INFECTIONS; MONKEYPOX AB Protection from lethality by postchallenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (nude, nu/nu) BALB/c mice infected with vaccinia virus (VACV). Whole-body bioluminescence imaging was used to record total fluxes in the nasal cavity, lungs, spleen, and liver and to enumerate pox lesions on tails of mice infected via the intranasal route with 10(5) PFU of recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve (AUCs) were calculated for individual mice to assess viral loads. A three-dose regimen of 20 mg/kg BCV administered every 48 h starting either on day 1 or day 2 postchallenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in providing protection from pox lesion development. All BCV-treated mice that survived challenge were also protected from rechallenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while animals were on the drug. Viral recrudescence occurred within 4 to 9 days, and mice succumbed similar to 10 to 20 days after treatment termination. Nude mice reconstituted with 10(5) T cells prior to challenge with 10(4) PFU of IHD-J-Luc and treated with BCV postchallenge survived the infection, cleared the virus from all organs, and survived rechallenge with 105 PFU of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immunocompetent and partially T cell-reconstituted immune-deficient mice from lethality, reduces viral dissemination in organs, prevents pox lesion development, and permits generation of VACV-specific memory. IMPORTANCE Mass vaccination is the primary element of the public health response to a smallpox outbreak. In addition to vaccination, however, antiviral drugs are required for individuals with uncertain exposure status to smallpox or for whom vaccination is contraindicated. Whole-body bioluminescence imaging was used to study the effect of brincidofovir (BCV) in normal and immune-deficient (nu/nu) mice infected with vaccinia virus, a model of smallpox. Postchallenge administration of 20 mg/kg BCV rescued normal and immune-deficient mice partially reconstituted with T cells from lethality and significantly reduced viral loads in organs. All BCV-treated mice that survived infection were protected from rechallenge without additional treatment. In immune-deficient mice, BCV extended survival. The data show that BCV controls viral replication at the site of challenge and reduces viral dissemination to internal organs, thus providing a shield for the developing adaptive immunity that clears the host of virus and builds virus-specific immunological memory. C1 [Zaitseva, Marina; McCullough, Kevin Tyler; Cruz, Stephanie; Thomas, Antonia; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Diaz, Claudia G.] US FDA, Vet Serv, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Keilholz, Laurie; Grossi, Irma M.; Trost, Lawrence C.] Chimerix Inc, Durham, NC USA. RP Zaitseva, M (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM marina.zaitseva@fda.hhs.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [IAA 224-06-1322]; FDA's Medical Countermeasure Initiative fund FX This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under IAA 224-06-1322 and by FDA's Medical Countermeasure Initiative fund. NR 42 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 6 BP 3295 EP 3307 DI 10.1128/JVI.03340-14 PG 13 WC Virology SC Virology GA CC2XQ UT WOS:000350208900025 PM 25589648 ER PT J AU Qiu, Q Xu, ZL Tian, J Moitra, R Gunti, S Notkins, AL Byrnes, AP AF Qiu, Qi Xu, Zhili Tian, Jie Moitra, Rituparna Gunti, Sreenivasulu Notkins, Abner L. Byrnes, Andrew P. TI Impact of Natural IgM Concentration on Gene Therapy with Adenovirus Type 5 Vectors SO JOURNAL OF VIROLOGY LA English DT Article ID IN-VIVO; POLYREACTIVE ANTIBODIES; CELL-DEVELOPMENT; KUPFFER CELLS; B-CELLS; MICE; COMPLEMENT; HEXON; LIVER; MACROPHAGES AB Natural IgM inhibits gene transfer by adenovirus type 5 (Ad5) vectors. We show that polyreactive natural IgM antibodies bind to Ad5 and that inhibition of liver transduction by IgM depends on Kupffer cells. By manipulating IgM concentration in vivo, we demonstrate that IgM inhibits liver transduction in a concentration-dependent manner. We further show that differences in natural IgM between BALB/c and C57BL/6 mice contribute to lower efficiency of Ad5 gene transfer in BALB/c mice. C1 [Qiu, Qi; Xu, Zhili; Tian, Jie; Moitra, Rituparna; Byrnes, Andrew P.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Gunti, Sreenivasulu; Notkins, Abner L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. RP Byrnes, AP (reprint author), US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Andrew.Byrnes@FDA.HHS.gov OI Byrnes, Andrew/0000-0003-1135-2629 FU U.S. Food and Drug Administration (FDA); FDA's Critical Path program; Oak Ridge Institute for Science and Education FX Funding was provided by the U.S. Food and Drug Administration (FDA), including the FDA's Critical Path program. This project was supported in part by fellowships administered by the Oak Ridge Institute for Science and Education. NR 28 TC 2 Z9 3 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2015 VL 89 IS 6 BP 3412 EP 3416 DI 10.1128/JVI.03217-14 PG 5 WC Virology SC Virology GA CC2XQ UT WOS:000350208900034 PM 25552715 ER PT J AU Izurieta, HS Thadani, N Shay, DK Lu, Y Maurer, A Foppa, IM Franks, R Pratt, D Forshee, RA MaCurdy, T Worrall, C Howery, AE Kelman, J AF Izurieta, Hector S. Thadani, Nicole Shay, David K. Lu, Yun Maurer, Aaron Foppa, Ivo M. Franks, Riley Pratt, Douglas Forshee, Richard A. MaCurdy, Thomas Worrall, Chris Howery, Andrew E. Kelman, Jeffrey TI Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis SO LANCET INFECTIOUS DISEASES LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; PLACEBO-CONTROLLED TRIAL; ELDERLY-PEOPLE; UNITED-STATES; MORTALITY BENEFITS; SEASONAL INFLUENZA; VACCINATION; SURVEILLANCE; ADULTS; RISK AB Background A high-dose trivalent inactivated influenza vaccine was licensed in 2009 by the US Food and Drug Administration (FDA) on the basis of serological criteria. We sought to establish whether high-dose inactivated influenza vaccine was more effective for prevention of influenza-related visits and hospital admissions in US Medicare beneficiaries than was standard-dose inactivated influenza vaccine. Methods In this retrospective cohort study, we identified Medicare beneficiaries aged 65 years and older who received high-dose or standard-dose inactivated influenza vaccines from community pharmacies that offered both vaccines during the 2012-13 influenza season. Outcomes were defined with billing codes on Medicare claims. The primary outcome was probable influenza infection, defined by receipt of a rapid influenza test followed by dispensing of the neuraminidase inhibitor oseltamivir. The secondary outcome was a hospital or emergency department visit, listing a Medicare billing code for influenza. We estimated relative vaccine effectiveness by comparing outcome rates in Medicare beneficiaries during periods of high influenza circulation. Univariate and multivariate Poisson regression models were used for analyses. Findings Between Aug 1, 2012 and Jan 31, 2013, we studied 929 730 recipients of high-dose vaccine and 1 615 545 recipients of standard-dose vaccine. Participants enrolled in each cohort were well balanced with respect to age and presence of underlying medical disorders. The high-dose vaccine (1.30 outcomes per 10 000 person-weeks) was 22% (95% CI 15-29) more effective than the standard-dose vaccine (1.01 outcomes per 10 000 person-weeks) for prevention of probable influenza infections (rapid influenza test followed by oseltamivir treatment) and 22% (95% CI 16-27%) more effective for prevention of influenza hospital admissions (0.86 outcomes per 10 000 person-weeks in the high-dose cohort vs 1.10 outcomes per 10 000 person-weeks in the standard-dose cohort). Interpretation Our retrospective cohort study in US Medicare beneficiaries shows that, in people 65 years of age and older, high-dose inactivated influenza vaccine was significantly more effective than standard-dose vaccine in prevention of influenza-related medical encounters. Additionally, the large population in our study enabled us to show, for the first time, a significant reduction in influenza-related hospital admissions in high-dose compared to standard-dose vaccine recipients, an outcome not shown in randomised studies. These results provide important new information to be considered by policy makers recommending influenza vaccinations for elderly people. C1 [Izurieta, Hector S.; Lu, Yun; Pratt, Douglas; Forshee, Richard A.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Thadani, Nicole; Maurer, Aaron; Franks, Riley; MaCurdy, Thomas; Howery, Andrew E.] Acumen LLC, Burlingame, CA USA. [Shay, David K.; Foppa, Ivo M.] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Foppa, Ivo M.] Battelle Mem Inst, Atlanta, GA USA. [Worrall, Chris; Kelman, Jeffrey] Ctr Medicare & Medicaid Serv, Washington, DC USA. RP Forshee, RA (reprint author), US FDA, Silver Spring, MD 20993 USA. EM richard.forshee@fda.hhs.gov OI Shay, David/0000-0001-9619-4820 FU FDA; office of the Assistant Secretary of Planning and Evaluation FX FDA and the office of the Assistant Secretary of Planning and Evaluation. NR 36 TC 31 Z9 31 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD MAR PY 2015 VL 15 IS 3 BP 293 EP 300 DI 10.1016/S1473-3099(14)71087-4 PG 8 WC Infectious Diseases SC Infectious Diseases GA CC3SA UT WOS:000350268500027 PM 25672568 ER PT J AU Woods, CM Applebaum, B Green, Y Kallgren, DL Kappeler, E AF Woods, Caira M. Applebaum, Bethany Green, Yvonne Kallgren, Deborah L. Kappeler, Evelyn CA US Dept Hlth Human Serv TI Women's Health: 30 Years of Progress in the US Department of Health and Human Services SO PUBLIC HEALTH REPORTS LA English DT Editorial Material C1 [Woods, Caira M.] US Dept HHS, Off Womens Hlth, Washington, DC 20201 USA. [Applebaum, Bethany] US Dept HHS, Hlth Resources & Serv Adm, Off Womens Hlth, Rockville, MD USA. [Green, Yvonne] Ctr Dis Control & Prevent, US Dept HHS, Off Womens Hlth, Atlanta, GA USA. [Kallgren, Deborah L.] US Dept HHS, US FDA, Off Womens Hlth, Silver Spring, MD USA. [Kappeler, Evelyn] US Dept HHS, Off Adolescent Hlth, Rockville, MD USA. RP Woods, CM (reprint author), US Dept HHS, Off Womens Hlth, 200 Independence Ave SW, Washington, DC 20201 USA. EM caira.woods@hhs.gov NR 54 TC 1 Z9 1 U1 0 U2 0 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 2015 VL 130 IS 2 BP 123 EP 127 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC7FR UT WOS:000350533600004 PM 25729100 ER PT J AU Powley, MW AF Powley, Mark W. TI (Q)SAR assessments of potentially mutagenic impurities: A regulatory perspective on the utility of expert knowledge and data submission SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Drug impurities; Mutagenicity; (Q)SAR; ICH M7 ID APPLICABILITY DOMAIN; CHEMICAL-STRUCTURE; CARCINOGENICITY; SALMONELLA; GENOTOXICITY; PREDICTION; QUINOLINE; PROGRAM AB (Quantitative) structure activity relationship [(Q)SAR] modeling is the primary tool used to evaluate the mutagenic potential associated with drug impurities. General recommendations regarding the use of (Q)SAR in regulatory decision making have recently been provided in the ICH M7 guideline. Although (Q)SAR alone is capable of achieving reasonable sensitivity and specificity, reliance on a simple positive or negative prediction can be problematic. The key to improving (Q)SAR performance is to integrate supporting information, also referred to as expert knowledge, into the final conclusion. In the regulatory context, expert knowledge is intended to (1) maximize confidence in a (Q)SAR prediction, (2) provide rationale to supersede a positive or negative (Q)SAR prediction, or (3) provide a basis for assessing mutagenicity in absence of a (Q)SAR prediction. Expert knowledge is subjective and is associated with great variability in regards to content and quality. However, it is still a critical component of impurity evaluations and its utility is acknowledged in the ICH M7 guideline. The current paper discusses the use of expert knowledge to support regulatory decision making, describes case studies, and provides recommendations for reporting data from (Q)SAR evaluations. Published by Elsevier Inc. C1 US FDA, Div Antiviral Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Powley, MW (reprint author), US FDA, Div Antiviral Prod, Off New Drugs, Ctr Drug Evaluat & Res, WO 22-RM 6389,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM mark.powley@fda.hhs.gov NR 22 TC 10 Z9 10 U1 1 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 2015 VL 71 IS 2 BP 295 EP 300 DI 10.1016/j.yrtph.2014.12.012 PG 6 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CC7FH UT WOS:000350532600022 PM 25545315 ER PT J AU Verma, RP Matthews, EJ AF Verma, Rajeshwar P. Matthews, Edwin J. TI Estimation of the chemical-induced eye injury using a weight-of-evidence (WoE) battery of 21 artificial neural network (ANN) c-QSAR models (QSAR-21): Part I: Irritation potential SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Artificial neural network; c-QSAR; Eye irritation; QSAR-21; Weight of evidence ID RABBIT EYE; VITRO ALTERNATIVES; ORGANIC-CHEMICALS; DRAIZE; VALIDATION; TESTS; DATABASE; ACCEPTANCE; PREDICTION; DESCRIPTOR AB Evaluation of potential chemical-induced eye injury through irritation and corrosion is required to ensure occupational and consumer safety for industrial, household and cosmetic ingredient chemicals. The historical method for evaluating eye irritant and corrosion potential of chemicals is the rabbit Draize test. However, the Draize test is controversial and its use is diminishing - the EU 7th Amendment to the Cosmetic Directive (76/768/EEC) and recast Regulation now bans marketing of new cosmetics having animal testing of their ingredients and requires non-animal alternative tests for safety assessments. Thus, in silica and/or in vitro tests are advocated. QSAR models for eye irritation have been reported for several small (congeneric) data sets; however, large global models have not been described. This report describes FDA/CFSAN's development of 21 ANN c-QSAR models (QSAR-21) to predict eye irritation using the ADMET Predictor (TM) program and a diverse training data set of 2928 chemicals. The 21 models had external (20% test set) and internal validation and average training/verification/test set statistics were: 88/88/ 85(%) sensitivity and 82/82/82(%) specificity, respectively. The new method utilized multiple artificial neural network (ANN) molecular descriptor selection functionalities to maximize the applicability domain of the battery. The eye irritation models will be used to provide information to fill the critical data gaps for the safety assessment of cosmetic ingredient chemicals. (C) 2014 Elsevier Inc. All rights reserved. C1 [Verma, Rajeshwar P.] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Verma, Rajeshwar P.; Matthews, Edwin J.] US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Verma, RP (reprint author), US FDA, OCAC OFAS, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Rajeshwar.Verma@fda.hhs.gov FU Office of Cosmetics and Colors (OCAC) at CFSAN of U.S. Food and Drug Administration (FDA) through the Oak Ridge Institute for Science and Education (ORISE); Office of Cosmetics and Colors (OCAC) at CFSAN of U.S. Food and Drug Administration (FDA) through the Goldbelt Falcon FX One of the authors (Dr. Rajeshwar P. Verma) is grateful to the Office of Cosmetics and Colors (OCAC) at CFSAN of U.S. Food and Drug Administration (FDA) for financial support through the Oak Ridge Institute for Science and Education (ORISE) and Goldbelt Falcon. NR 66 TC 3 Z9 3 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD MAR PY 2015 VL 71 IS 2 BP 318 EP 330 DI 10.1016/j.yrtph.2014.11.011 PG 13 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CC7FH UT WOS:000350532600024 PM 25497990 ER PT J AU Verma, RP Matthews, EJ AF Verma, Rajeshwar P. Matthews, Edwin J. TI Estimation of the chemical-induced eye injury using a Weight-of-Evidence (WoE) battery of 21 artificial neural network (ANN) c-QSAR models (QSAR-21): Part II: Corrosion potential SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Artificial neural network; c-QSAR; Eye corrosion; QSAR-21; Weight of evidence AB This is part II of an in silica investigation of chemical-induced eye injury that was conducted at FDA's CFSAN. Serious eye damage caused by chemical (eye corrosion) is assessed using the rabbit Draize test, and this endpoint is an essential part of hazard identification and labeling of industrial and consumer products to ensure occupational and consumer safety. There is an urgent need to develop an alternative to the Draize test because EU's 7th amendment to the Cosmetic Directive (EC, 2003; 76/768/EEC) and recast Regulation now bans animal testing on all cosmetic product ingredients and EU's REACH Program limits animal testing for chemicals in commerce. Although in silico methods have been reported for eye irritation (reversible damage), QSARs specific for eye corrosion (irreversible damage) have not been published. This report describes the development of 21 ANN c-QSAR models (QSAR-21) for assessing eye corrosion potential of chemicals using a large and diverse CFSAN data set of 504 chemicals, ADMET Predictor's three sensitivity analyses and ANNE classification functionalities with 20% test set selection from seven different methods. QSAR-21 models were internally and externally validated and exhibited high predictive performance: average statistics for the training, verification, and external test sets of these models were 96/96/94% sensitivity and 91/91/90% specificity. (C) 2014 Elsevier Inc. All rights reserved. C1 [Verma, Rajeshwar P.] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Verma, Rajeshwar P.; Matthews, Edwin J.] US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Verma, RP (reprint author), US FDA, OCAC OFAS, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Rajeshwar.Verma@fda.hhs.gov FU Office of Cosmetics and Colors (OCAC) at CFSAN of U.S. Food and Drug Administration (FDA) through the Oak Ridge Institute for Science and Education (ORISE); Office of Cosmetics and Colors (OCAC) at CFSAN of U.S. Food and Drug Administration (FDA) through the Goldbelt Falcon FX One of the authors (Dr. Rajeshwar P. Verma) is grateful to the Office of Cosmetics and Colors (OCAC) at CFSAN of U.S. Food and Drug Administration (FDA) for financial support through the Oak Ridge Institute for Science and Education (ORISE) and Goldbelt Falcon. NR 23 TC 3 Z9 3 U1 0 U2 7 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 2015 VL 71 IS 2 BP 331 EP 336 DI 10.1016/j.yrtph.2014.12.004 PG 6 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CC7FH UT WOS:000350532600025 PM 25510831 ER PT J AU Momper, JD Chang, Y Jackson, M Schuette, P Seo, S Younis, I Abernethy, DR Yao, L Capparelli, EV Burckart, GJ AF Momper, Jeremiah D. Chang, Yang Jackson, Matthew Schuette, Paul Seo, Shirley Younis, Islam Abernethy, Darrell R. Yao, Lynne Capparelli, Edmund V. Burckart, Gilbert J. TI Adverse Event Detection and Labeling in Pediatric Drug Development: Antiretroviral Drugs SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE drug safety; pediatrics; HIV; clinical trials; drug development ID HAART ERA; SAFETY; CHILDREN; RATES AB Background: Pediatric safety studies are conducted for drugs undergoing development for use in pediatric patients. The objective of this study was to describe safety studies and compare adverse events of antiretroviral drugs between pediatric patients and adult subjects. Methods: Pediatric and adult adverse event data were obtained from US Food and Drug Administration (FDA)-approved drug labels for 9 antiretroviral drugs with pediatric indications approved by the FDA prior to 2013. For adverse events (AEs) reported in both pediatric patients and adult subjects, the risk difference (RD) and associated confidence interval (CI) were calculated. Results: Of 35 drug-AE combinations, 10 AEs were reported at statistically significantly (P < .05) higher incidence rates in the pediatric population than in the adult population, and 3 AEs were reported at statistically significantly higher rates in the adult population than in the pediatric population. The largest differences where the risk of an AE was greater in pediatric patients than in adult subjects were for rash with efavirenz (RD = 36.24% [95% CI, 21.1 to 50.53]), diarrhea with efavirenz (RD = 24.53% [95% CI, 9.06 to 39.57]), and rash with nevirapine (RD = 16.14% [95% CI, 9.7 to 24.27]). The largest differences where the risk of an adverse event was lower in pediatric patients than in adult subjects were for headache with abacavir (RD = -12% [95% CI, -16.81 to -6.89]), diarrhea with tipranavir (RD = -11.32% [95% CI, -15.02 to -5.6]), and diarrhea with lamivudine (RD = -9.88% [95% CI, -15.91 to -3.98]). Conclusions: The adult adverse event experience provides preliminary data for pediatric drug safety, yet the specific types of adverse effects and frequencies may not be predicted in children based exclusively on adults. As adult safety data do not fully inform the pediatric safety profile, pediatric safety studies should continue to be conducted separately for drugs undergoing testing in pediatric patients. C1 [Momper, Jeremiah D.; Capparelli, Edmund V.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Chang, Yang] US FDA, Div Bioequivalence, Off Gener Drugs, Silver Spring, MD 20903 USA. [Jackson, Matthew; Schuette, Paul] US FDA, Off Biostat, Off Translat Sci, Silver Spring, MD 20903 USA. [Seo, Shirley; Younis, Islam; Abernethy, Darrell R.; Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD 20903 USA. [Yao, Lynne] US FDA, Div Pediat & Maternal Hlth, Off New Drugs, Silver Spring, MD 20903 USA. RP Burckart, GJ (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, CDER, White Oak Bldg 51,Room 3184, Silver Spring, MD 20903 USA. EM gilbert.burckart@fda.hhs.gov NR 22 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD MAR PY 2015 VL 49 IS 2 BP 302 EP 309 DI 10.1177/2168479014565471 PG 8 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CC6RF UT WOS:000350494000015 ER PT J AU Stebbings, R Wang, L Sutherland, J Kammel, M Gaigalas, AK John, M Roemer, B Kuhne, M Schneider, RJ Braun, M Engel, A Dikshit, DK Abbasi, F Marti, GE Paola Sassi, M Revel, L Kim, SK Baradez, MO Lekishvili, T Marshall, D Whitby, L Jing, W Ost, V Vonsky, M Neukammer, J AF Stebbings, Richard Wang, Lili Sutherland, Janet Kammel, Martin Gaigalas, Adolfas K. John, Manuela Roemer, Bodo Kuhne, Maren Schneider, Rudolf J. Braun, Michael Engel, Andrea Dikshit, Dinesh K. Abbasi, Fatima Marti, Gerald E. Paola Sassi, Maria Revel, Laura Kim, Sook-Kyung Baradez, Marc-Olivier Lekishvili, Tamara Marshall, Damian Whitby, Liam Jing, Wang Ost, Volker Vonsky, Maxim Neukammer, Joerg TI Quantification of Cells with Specific Phenotypes I: Determination of CD4+Cell Count Per Microliter in Reconstituted Lyophilized Human PBMC Prelabeled with Anti-CD4 FITC Antibody SO CYTOMETRY PART A LA English DT Article DE CD4+cell counting; relative concentration measurement; lyophilized cells; flow cytometry; standard measurement procedure; measurement of uncertainty; human immunodeficiency virus-1; acquired immunodeficiency syndrome; reference material ID HUMAN-IMMUNODEFICIENCY-VIRUS; FLOW-CYTOMETRY; ANTIRETROVIRAL THERAPY; QUALITY ASSESSMENT; HIV-INFECTION; ENUMERATION; LYMPHOCYTE; STANDARDIZATION; GUIDELINES; ACCURATE AB A surface-labeled lyophilized lymphocyte (sLL) preparation has been developed using human peripheral blood mononuclear cells prelabeled with a fluorescein isothiocyanate conjugated anti-CD4 monoclonal antibody. The sLL preparation is intended to be used as a reference material for CD4+ cell counting including the development of higher order reference measurement procedures and has been evaluated in the pilot study CCQM-P102. This study was conducted across 16 laboratories from eight countries to assess the ability of participants to quantify the CD4+ cell count of this reference material and to document cross-laboratory variability plus associated measurement uncertainties. Twelve different flow cytometer platforms were evaluated using a standard protocol that included calibration beads used to obtain quantitative measurements of CD4+ T cell counts. There was good overall cross-platform and counting method agreement with a grand mean of the laboratory calculated means of (301.7 +/- 4.9) L-1 CD4+ cells. Excluding outliers, greater than 90% of participant data agreed within +/- 15%. A major contribution to variation of sLL CD4+ cell counts was tube to tube variation of the calibration beads, amounting to an uncertainty of 3.6%. Variation due to preparative steps equated to an uncertainty of 2.6%. There was no reduction in variability when data files were centrally reanalyzed. Remaining variation was attributed to instrument specific differences. CD4+ cell counts obtained in CCQM-P102 are in excellent agreement and show the robustness of both the measurements and the data analysis and hence the suitability of sLL as a reference material for interlaboratory comparisons and external quality assessment. (c) 2015 The Authors. Published by Wiley Periodicals, Inc. C1 [Stebbings, Richard; Sutherland, Janet] NIBSC, Biotherapeut Grp, Potters Bar EN6 3QG, Herts, England. [Wang, Lili; Gaigalas, Adolfas K.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Kammel, Martin; John, Manuela; Neukammer, Joerg] PTB, Div Med Phys & Metrol Informat Technol, D-10587 Berlin, Germany. [Roemer, Bodo] Abbott GmbH & Co KG, D-65205 Wiesbaden, Germany. [Kuhne, Maren; Schneider, Rudolf J.] BAM Fed Inst Mat Res & Testing, Dept Analyt Chem, D-12489 Berlin, Germany. [Braun, Michael] Beckman Coulter GmbH, D-47807 Krefeld, Germany. [Engel, Andrea] Becton Dickinson GmbH, D-69126 Heidelberg, Germany. [Dikshit, Dinesh K.] CSIR Cent Drug Res Inst CDRI, Med & Proc Chem Div, Lucknow 226001, Uttar Pradesh, India. [Abbasi, Fatima; Marti, Gerald E.] US FDA, CDRH, Bethesda, MD 20993 USA. [Paola Sassi, Maria; Revel, Laura] Ist Nazl Ric Metrol INRIM, I-10135 Turin, Italy. [Kim, Sook-Kyung] Korea Res Inst Stand & Sci KRISS, Taejon 305340, South Korea. [Baradez, Marc-Olivier; Lekishvili, Tamara; Marshall, Damian] LGC Ltd, Sci & Innovat, Teddington TW11 0LY, Middx, England. [Whitby, Liam] UK Natl External Qual Assessment Serv UK NEQAS Le, Sheffield S10 2QD, S Yorkshire, England. [Jing, Wang] NIM, Div Med & Biol Measurement, Beijing, Peoples R China. [Ost, Volker] Partec GmbH, D-48161 Munster, Germany. [Vonsky, Maxim] DI Mendeleev Inst Metrol VNIIM, Dept State Stand Field Phys Chem Measurements, St Petersburg 190005, Russia. [Vonsky, Maxim] Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. RP Stebbings, R (reprint author), MedImmune Ltd, Aaron Klug Bldg,Granta Pk, Cambridge CB21 6GH, England. EM Stebbingsr@medimmune.com RI Schneider, Rudolf J./A-3771-2009; Stebbings, Richard/E-2117-2013; OI Schneider, Rudolf J./0000-0003-2228-1248; Stebbings, Richard/0000-0001-9628-2708; Vonsky, Maxim/0000-0003-4061-7411 NR 36 TC 2 Z9 2 U1 2 U2 6 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 MAR PY 2015 VL 87A IS 3 BP 244 EP 253 DI 10.1002/cyto.a.22614 PG 10 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CB9WJ UT WOS:000349984200007 PM 25655255 ER PT J AU Wang, L Stebbings, R Gaigalas, AK Sutherland, J Kammel, M John, M Roemer, B Kuhne, M Schneider, RJ Braun, M Engel, A Dikshit, D Abbasi, F Marti, GE Sassi, M Revel, L Kim, SK Baradez, M Lekishvili, T Marshall, D Whitby, L Jing, W Ost, V Vonsky, M Neukammer, J AF Wang, L. Stebbings, R. Gaigalas, A. K. Sutherland, J. Kammel, M. John, M. Roemer, B. Kuhne, M. Schneider, R. J. Braun, M. Engel, A. Dikshit, D. Abbasi, F. Marti, G. E. Sassi, M. Revel, L. Kim, S. K. Baradez, M. Lekishvili, T. Marshall, D. Whitby, L. Jing, W. Ost, V. Vonsky, M. Neukammer, J. TI Quantification of Cells with Specific Phenotypes II: Determination of CD4 Expression Level on Reconstituted Lyophilized Human PBMC Labelled with Anti-CD4 FITC Antibody SO CYTOMETRY PART A LA English DT Article DE surface labelled lyophilized PBMC; CD4 expression level; FITC; equivalent fluorescein fluorophore (EFF); quantitative flow cytometry; calibration; standard measurement procedure; measurement uncertainty; reference cell material ID ASSAYS PRACTICE GUIDELINES; MULTICOLOR FLOW-CYTOMETRY; LYMPHOCYTES; DENSITY; IMMUNODEFICIENCY; STANDARDIZATION; FLUOROPHORES; VARIABILITY; CALIBRATION; VALIDATION AB This report focuses on the characterization of CD4 expression level in terms of equivalent number of reference fluorophores (ERF). Twelve different flow cytometer platforms across sixteen laboratories were utilized in this study. As a first step the participants were asked to calibrate the fluorescein isothiocyanate (FITC) channel of each flow cytometer using commercially available calibration standard consisting of five populations of microspheres. Each population had an assigned value of equivalent fluorescein fluorophores (EFF denotes a special case of the generic term ERF with FITC as the reference fluorophore). The EFF values were assigned at the National Institute of Standards and Technology (NIST). A surface-labelled lyophilized cell preparation was provided by the National Institute of Biological Standards and Control (NIBSC), using human peripheral blood mononuclear cells (PBMC) pre-labeled with a FITC conjugated anti-CD4 monoclonal antibody. Three PBMC sample vials, provided to each participant, were used for the CD4 expression analysis. The PBMC are purported to have a fixed number of surface CD4 receptors. On the basis of the microsphere calibration, the EFF value of the PBMC samples was measured to characterize the population average CD4 expression level of the PBMC preparations. Both the results of data analysis performed by each participant and the results of centralized analysis of all participants' raw data are reported. Centralized analysis gave a mean EFF value of 22,300 and an uncertainty of 750, corresponding to 3.3% (level of confidence 68%) of the mean EFF value. The next step will entail the measurement of the ERF values of the lyophilized PBMC stained with labels for other fluorescence channels. The ultimate goal is to show that lyophilized PBMC is a suitable biological reference cell material for multicolor flow cytometry and that it can be used to present multicolor flow cytometry measurements in terms of ABC (antibodies bound per cell) units. (c) 2015 International Society for Advancement of Cytometry C1 [Wang, L.; Gaigalas, A. K.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Stebbings, R.; Sutherland, J.] NIBSC, Biotherapeut Grp, Potters Bar EN6 3QG, Herts, England. [Kammel, M.; John, M.; Neukammer, J.] PTB, Div Med Phys & Metrol Informat Technol, D-10587 Berlin, Germany. [Roemer, B.] Abbott GmbH & Co KG, Ludwigshafen, Germany. [Kuhne, M.; Schneider, R. J.] BAM Fed Inst Mat Res & Testing, Dept Analyt Chem, D-12489 Berlin, Germany. [Braun, M.] Beckman Coulter GmbH, D-47807 Krefeld, Germany. [Engel, A.] Becton Dickinson, D-69126 Heidelberg, Germany. [Dikshit, D.] CDRI, Med & Proc Chem Div, Lucknow 226001, Uttar Pradesh, India. [Abbasi, F.; Marti, G. E.] US FDA, CDRH, Bethesda, MD 20892 USA. [Sassi, M.; Revel, L.] INRIM Ist Nazl Ric Metrol, I-10135 Turin, Italy. [Kim, S. K.] KRISS, Taejon 305340, South Korea. [Baradez, M.; Lekishvili, T.; Marshall, D.] LGC Ltd, Sci & Innovat, Teddington TW11 0LY, Middx, England. [Whitby, L.] UK NEQAS UK Natl External Qual Assessment Serv, Sheffield S10 2QD, S Yorkshire, England. [Jing, W.] NIM, Div Med & Biol Measurement, Beijing, Peoples R China. [Ost, V.] Partec GmbH, D-48161 Munster, Germany. [Vonsky, M.] VNIIM DI Mendeleev Inst Metrol, Dept State Stand Field Phys Chem Measurements, St Petersburg 190005, Russia. [Vonsky, M.] Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. RP Wang, L (reprint author), NIST, 100 Bur Dr,Stop 8312, Gaithersburg, MD 20899 USA. EM lili.wang@nist.gov RI Schneider, Rudolf J./A-3771-2009; Stebbings, Richard/E-2117-2013; OI Schneider, Rudolf J./0000-0003-2228-1248; Stebbings, Richard/0000-0001-9628-2708; Vonsky, Maxim/0000-0003-4061-7411 NR 29 TC 2 Z9 2 U1 2 U2 5 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 MAR PY 2015 VL 87A IS 3 BP 254 EP 261 DI 10.1002/cyto.a.22634 PG 8 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CB9WJ UT WOS:000349984200008 PM 25655377 ER PT J AU Saini, S Hamasaki-Katagiri, N Pandey, GS Yanover, C Guelcher, C Simhadri, VL Dandekar, S Guerrera, MF Kimchi-Sarfaty, C Sauna, ZE AF Saini, S. Hamasaki-Katagiri, N. Pandey, G. S. Yanover, C. Guelcher, C. Simhadri, V. L. Dandekar, S. Guerrera, M. F. Kimchi-Sarfaty, C. Sauna, Z. E. TI Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B SO HAEMOPHILIA LA English DT Article DE F9 gene; factor IX; haemophilia B; immunogenicity; inhibitor antibodies ID PREVIOUSLY UNTREATED PATIENTS; FACTOR-BINDING SITES; INHIBITOR DEVELOPMENT; FACTOR-VIII; IMMUNE TOLERANCE; CLASS-II; MUTATIONS; POLYMORPHISMS; PREDICTION; RISK AB Inhibitors are an impediment to the effective management of haemophilia B (HB), but there is limited understanding of the underlying genetic risk factors. In this study we aim to understand the role of F9 gene mutations on inhibitor development in patients with HB. Mutations in the F9 gene were identified and HLA typing performed for five boys with severe HB. Data from the CDC Haemophilia B Mutation Project (CHBMP) database were used to assess association between F9 gene mutation type and inhibitor development. Analysis of the CHBMP database showed that larger disruptions in the F9 gene are associated with a higher life-time prevalence of inhibitors. We detected the following mutations in the five subjects, including four novel mutations: Nonsense in three patients (c.223 C>T; p.Arg75* in two siblings, c.553 C>T; p.Glu185*); Splice site in two patients (c.723+1G>A, c.278-27 A>G); Missense in one patient (c.580 A>G, p.Thr194Ala; c.723G>T; p.Gln241His). Of the two siblings only one responded to immune tolerance induction (ITI). These siblings have identical F9 gene mutations but differ with respect to the HLA alleles. Interestingly, an analysis of peptide-MHC binding affinities shows a significantly higher (one-sided unpaired t-test, P=0.0018) median affinity for FIX-derived peptides in the sibling that responded to ITI. We conclude that the nature of the F9 gene mutation may be an important risk factor for the development of inhibitors. In addition, the HLA alleles of the individual patients, in conjunction with the mutation type, could be a predictor for the development of inhibitors as well as the response to ITI. C1 [Saini, S.; Hamasaki-Katagiri, N.; Pandey, G. S.; Simhadri, V. L.; Kimchi-Sarfaty, C.; Sauna, Z. E.] US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Saini, S.; Guelcher, C.; Guerrera, M. F.] Ctr Canc & Blood Disorders, Childrens Natl Hlth Syst, Washington, DC USA. [Yanover, C.] IBM Res Lab, Haifa, Israel. [Dandekar, S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Guerrera, M. F.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. RP Kimchi-Sarfaty, C (reprint author), US FDA, Room 4118,Bldg 52,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM chava.kimchi-sarfaty@fda.hhs.gov; zuben.sauna@fda.hhs.gov RI Yanover, Chen/A-3754-2012 OI Yanover, Chen/0000-0003-3663-4286 NR 43 TC 3 Z9 4 U1 0 U2 4 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 MAR PY 2015 VL 21 IS 2 BP 210 EP 218 DI 10.1111/hae.12553 PG 9 WC Hematology SC Hematology GA CC0YC UT WOS:000350065000019 PM 25470321 ER PT J AU Seidman, JD AF Seidman, Jeffrey D. TI Serous Tubal Intraepithelial Carcinoma Localizes to the Tubal-peritoneal Junction: A Pivotal Clue to the Site of Origin of Extrauterine High-grade Serous Carcinoma (Ovarian Cancer) SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Fallopian tube; Intraepithelial carcinoma; Serous carcinoma; Peritoneum; Tubal-peritoneal junction; Ovarian carcinoma; Fallopian tube carcinoma; Epithelial junction; Carcinogenesis; BRCA ID FALLOPIAN-TUBE; CONTRALATERAL OVARY; MUTATION CARRIERS; CELL-TYPE; PATHOGENESIS; WOMEN; EPITHELIUM; SURFACE; LESIONS; CARCINOGENESIS AB Recent data suggest that intraepithelial carcinoma of the fallopian tube [serous tubal intraepithelial carcinoma (STIC)] is the precursor of high-grade extrauterine serous carcinoma. A more specific location for the origin of this lesion is suggested by the recently described junction between the fallopian tubal epithelium and the peritoneum [tubal-peritoneal junction (TPJ)]. Fallopian tubes from 202 patients with advanced-stage high-grade extrauterine serous carcinoma or carcinosarcoma were evaluated histologically as were 124 prophylactic salpingo-oophorectomy specimens. These included 54 patients with BRCA or other high-risk mutation or a family history of BRCA mutation and 70 with a personal or family history of breast carcinoma. STIC was found in 81 of 202 patients with serous carcinoma (40.1%). STIC was present in 73 of 141 (52%) cases in which the fimbriae were present and in 62 of 100 (62%) cases in which the TPJ was present (P not significant). In comparison with these groups, when fimbriae and TPJ were absent, STIC was found in 8 of 61 (13%) cases (P<0.0001). None of the prophylactic specimens contained STIC. The mean size of STIC was 1.7 mm. In 32 cases (39.5%), the lesion was flat and in 49 (60.5%), papillary. The mean size of flat STICs was 0.8 mm as compared with 2.3 mm for papillary STICs (P = 0.00005). STIC was identified in the same tissue fragment as the junction in 48 cases. The mean distance of STIC to the junction was 1.8 mm. In 11 cases, STIC was flanked by peritoneal mesothelium on one side and tubal epithelium on the opposite side. In 51 patients, the mean distance of invasive carcinoma from the TPJ was 1.8 mm. This distance was 1.9 mm when STIC was present (37 cases) in comparison with 1.5 mm when STIC was absent (14 cases) (P not significant). In 27 of 42 cases (64%), STIC was contiguous with invasive carcinoma. Lamina propria invasion was present in 71% of cases in which STIC was present as compared with 26% of cases in which STIC was absent (P<0.0001). Myosalpingeal invasion was present in 40% of cases in which STIC was present as compared with 26% of cases in which STIC was absent (P not significant). It is concluded that serous tubal intraepithelial carcinoma occurs at and in the immediate vicinity of the TPJ. In combination with the findings that STICs are present in a majority of cases when the TPJ is present, that flat STICs are smaller than papillary STICs, and that lamina propria invasion is more frequent in the presence of STIC, these data support STIC as the precursor of extrauterine high-grade serous carcinoma, they provide important clues to the site of origin of high-grade serous carcinoma (ovarian cancer), and can guide further research. C1 [Seidman, Jeffrey D.] Washington Hosp Ctr, Dept Pathol & Lab Med, Washington, DC 20010 USA. RP Seidman, JD (reprint author), US FDA, Pathol & Cytol Branch, Div Immunol & Hematol Devices, Off In Vitro Diagnost & Radiol Hlth,Ctr Devices &, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jdseidman@hotmail.com NR 50 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD MAR PY 2015 VL 34 IS 2 BP 112 EP 120 DI 10.1097/PGP.0000000000000123 PG 9 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA CB7AP UT WOS:000349778600002 PM 25675178 ER PT J AU Allison, G Cain, YT Cooney, C Garcia, T Bizjak, TG Holte, O Jagota, N Komas, B Korakianiti, E Kourti, D Madurawe, R Morefield, E Montgomery, F Nasr, M Randolph, W Robert, JL Rudd, D Zezza, D AF Allison, Gretchen Cain, Yanxi Tan Cooney, Charles Garcia, Tom Bizjak, Tara Gooen Holte, Oyvind Jagota, Nirdosh Komas, Bekki Korakianiti, Evdokia Kourti, Dora Madurawe, Rapti Morefield, Elaine Montgomery, Frank Nasr, Moheb Randolph, William Robert, Jean-Louis Rudd, Dave Zezza, Diane TI Regulatory and Quality Considerations for Continuous Manufacturing May 20-21, 2014 Continuous Manufacturing Symposium SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Editorial Material DE continuous manufacturing; GMP; ICH; regulatory considerations; validation; control strategy; unit operations; stability; processing; bioequivalence AB This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufacturing. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufacturing process description and control strategy in regulatory files, process validation, and key Good Manufacturing Practice (GMP) requirements. In addition, the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:803-812, 2015 C1 [Allison, Gretchen] Pfizer, Kalamazoo, MI USA. [Cain, Yanxi Tan] Novartis Pharma AG, Basel, Switzerland. [Cooney, Charles] MIT, Cambridge, MA 02139 USA. [Garcia, Tom] Pfizer, Groton, CT USA. [Bizjak, Tara Gooen; Madurawe, Rapti] US FDA, Silver Spring, MD USA. [Holte, Oyvind] Norwegian Med Agcy, Oslo, Norway. [Jagota, Nirdosh] Roche Pharma, Basel, Switzerland. [Komas, Bekki] GlaxoSmithKline, Res & Dev, Res Triangle Pk, NC USA. [Korakianiti, Evdokia; Rudd, Dave] EMA, London, England. [Kourti, Dora] GSK, Global Mfg & Supply, Ware, Herts, England. [Morefield, Elaine] Vertex Pharmaceut Inc, Pharmaceut Dev, Boston, MA USA. [Montgomery, Frank] Astrazeneca, Global Med Dev, Macclesfield SK10 2NA, Cheshire, England. [Nasr, Moheb] GlaxoSmithKline, Res & Dev, Collegeville, PA 19426 USA. [Randolph, William] J&J, Janssen, Janssen Supply Grp, New Brunswick, NJ USA. [Robert, Jean-Louis] Natl Hlth Lab, Luxembourg, Luxembourg. [Zezza, Diane] Novartis Pharmaceut, E Hanover, NJ USA. RP Nasr, M (reprint author), GlaxoSmithKline, Res & Dev, Collegeville, PA 19426 USA. EM moheb.m.nasr@gsk.com NR 0 TC 12 Z9 12 U1 2 U2 15 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 2015 VL 104 IS 3 BP 803 EP 812 DI 10.1002/jps.24324 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CB7BS UT WOS:000349781700007 PM 25830179 ER PT J AU Woo, EJ AF Woo, Emily Jane TI Allergic Reactions After Egg-Free Recombinant Influenza Vaccine: Reports to the US Vaccine Adverse Event Reporting System SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE influenza; vaccine; allergy; hypersensitivity; egg ID SAFETY; ANAPHYLAXIS AB The Vaccine Adverse Event Reporting System has received reports of allergic reactions following immunization with egg-free recombinant influenza vaccine, among patients with a self-reported egg allergy or previous allergic reaction to inactivated influenza vaccine. These results suggest that allergic reactions following influenza vaccination are not necessarily related to egg proteins. C1 [Woo, Emily Jane] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Woo, EJ (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 71,Rm 1028, Silver Spring, MD 20993 USA. EM jane.woo@fda.hhs.gov NR 14 TC 7 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 1 PY 2015 VL 60 IS 5 BP 777 EP 780 DI 10.1093/cid/ciu948 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CB6VY UT WOS:000349766100017 PM 25428412 ER EF