FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Han, M Lee, C Park, S Baek, J AF Han, Minah Lee, Changwoo Park, Subok Baek, Jongduk TI Investigation on slice direction dependent detectability of volumetric cone beam CT images SO OPTICS EXPRESS LA English DT Article ID CHANNELIZED HOTELLING OBSERVER; DISTRIBUTED LUMPY BACKGROUNDS; COMPUTED-TOMOGRAPHY SYSTEM; SPECT MAP RECONSTRUCTION; NOISE POWER SPECTRUM; LESION SIZE; MODEL OBSERVERS; DETECTION TASKS; OBJECT VARIABILITY; GAUSSIAN SIGNAL AB We investigate the detection performance of transverse and longitudinal planes for various signal sizes (i.e., 1 mm to 8 mm diameter spheres) in cone beam computed tomography (CBCT) images. CBCT images are generated by computer simulation and images are reconstructed using an FDK algorithm. For each slice direction and signal size, a human observer study is conducted with a signal-known-exactly/background-known-exactly (SKE/BKE) binary detection task. The detection performance of human observers is compared with that of a channelized Hotelling observer (CHO). The detection performance of an ideal linear observer is also calculated using a CHO with Laguerre-Gauss (LG) channels. The detectability of high contrast small signals (i.e., up to 4-mm-diameter spheres) is higher in the longitudinal plane than the transverse plane. It is also shown that CHO performance correlates well with human observer performance in both transverse and longitudinal plane images. (C) 2016 Optical Society of America C1 [Han, Minah; Lee, Changwoo; Baek, Jongduk] Yonsei Univ, Sch Integrated Technol, Inchon, South Korea. [Han, Minah; Lee, Changwoo; Baek, Jongduk] Yonsei Univ, Yonsei Inst Convergence Technol, Inchon, South Korea. [Park, Subok] US FDA, Silver Spring, MD USA. RP Baek, J (reprint author), Yonsei Univ, Sch Integrated Technol, Inchon, South Korea.; Baek, J (reprint author), Yonsei Univ, Yonsei Inst Convergence Technol, Inchon, South Korea. EM jongdukbaek@yonsei.ac.kr FU MSIP (Ministry of Science, ICT and Future Planning), Korea, under the IT Consilience Creative Programs [IITP-2015-R0346-15-1008]; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning [2015R1C1A1A01052268]; National Research Foundation of Korea [NRF-2015K2A1A2067635] FX This research was supported by the MSIP (Ministry of Science, ICT and Future Planning), Korea, under the IT Consilience Creative Programs (IITP-2015-R0346-15-1008) supervised by the IITP (Institute for Information& Communications Technology Promotion), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2015R1C1A1A01052268) and the framework of international cooperation program managed by National Research Foundation of Korea (NRF-2015K2A1A2067635). NR 59 TC 1 Z9 1 U1 1 U2 1 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD FEB 22 PY 2016 VL 24 IS 4 BP 3749 EP 3764 DI 10.1364/OE.24.003749 PG 16 WC Optics SC Optics GA DF5ZQ UT WOS:000371433700054 PM 26907031 ER PT J AU Tolstorukov, MY Virnik, K Zhurkin, VB Adhya, S AF Tolstorukov, Michael Y. Virnik, Konstantin Zhurkin, Victor B. Adhya, Sankar TI Organization of DNA in a bacterial nucleoid SO BMC MICROBIOLOGY LA English DT Article DE Bacterial; Nucleoid; MNase; Digestion; Sequencing; Genomic; DNA; Packaging; Structural; Organization ID ESCHERICHIA-COLI CHROMOSOME; SEQUENCE-DIRECTED CURVATURE; PROKARYOTIC DNA; GENE-EXPRESSION; MICROCOCCAL NUCLEASE; ELECTRON-MICROSCOPY; FOLDED CHROMOSOMES; BINDING PROTEINS; CHIP-SEQ; H-NS AB Background: It is unclear how DNA is packaged in a bacterial cell in the absence of nucleosomes. To investigate the initial level of DNA condensation in bacterial nucleoid we used in vivo DNA digestion coupled with high-throughput sequencing of the digestion-resistant fragments. To this end, we transformed E. coli cells with a plasmid expressing micrococcal nuclease. The nuclease expression was under the control of AraC repressor, which enabled us to perform an inducible digestion of bacterial nucleoid inside a living cell. Results: Analysis of the genomic localization of the digestion-resistant fragments revealed their non-random distribution. The patterns observed in the distribution of the sequenced fragments indicate the presence of short DNA segments protected from the enzyme digestion, possibly because of interaction with DNA-binding proteins. The average length of such digestion-resistant segments is about 50 bp and the characteristic repeat in their distribution is about 90 bp. The gene starts are depleted of the digestion-resistant fragments, suggesting that these genomic regions are more exposed than genomic sequences on average. Sequence analysis of the digestion-resistant segments showed that while the GC-content of such sequences is close to the genome-wide value, they are depleted of A-tracts as compared to the bulk genomic DNA or to the randomized sequence of the same nucleotide composition. Conclusions: Our results suggest that DNA is packaged in the bacterial nucleoid in a non-random way that facilitates interaction of the DNA binding factors with regulatory regions of the genome. C1 [Tolstorukov, Michael Y.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Tolstorukov, Michael Y.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Virnik, Konstantin] FDA, Ctr Biol, Off Vaccines, Lab Immunoregulat,Div Viral Prod, Silver Spring, MD 20993 USA. [Zhurkin, Victor B.] NCI, Lab Cell Biol, NIH, Bethesda, MD 20892 USA. [Adhya, Sankar] NCI, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. EM adhyas@mail.nih.gov NR 77 TC 1 Z9 1 U1 4 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD FEB 20 PY 2016 VL 16 AR 22 DI 10.1186/s12866-016-0637-3 PG 11 WC Microbiology SC Microbiology GA DE2RK UT WOS:000370474300001 PM 26897370 ER PT J AU Trbojevich, RA Fernandez, A Watanabe, F Mustafa, T Bryant, MS AF Trbojevich, Raul A. Fernandez, Avelina Watanabe, Fumiya Mustafa, Thikra Bryant, Matthew S. TI Comparative study of silver nanoparticle permeation using Side-Bi-Side and Franz diffusion cells SO JOURNAL OF NANOPARTICLE RESEARCH LA English DT Article DE Membranes; Silver nanoparticles; Diffusion cells; Food packaging; Permeation; Environmental and health effects ID FOOD CONTAINERS; FILMS; NANOTECHNOLOGY; NANOCOMPOSITES; MIGRATION; RELEASE AB Better understanding the mechanisms of nanoparticle permeation through membranes and packaging polymers has important implications for the evaluation of drug transdermal uptake, in food safety and the environmental implications of nanotechnology. In this study, permeation of 21 nm diameter silver nanoparticles (AgNPs) was tested using Side-Bi-Side and Franz static diffusion cells through hydrophilic 0.1 and 0.05 lm pore diameter 125 mu m thick synthetic cellulose membranes, and 16 and 120 mu m thick low-density polyethylene (LDPE) films. Experiments performed with LDPE films discarded permeation of AgNPs or Ag ions over the investigated time-frame in both diffusion systems. But controlled release of AgNPs has been quantified using semipermeable hydrophilic membranes. The permeation followed a quasi-linear time-dependent model during the experimental time-frame, which represents surface reaction-limited permeation. Diffusive flux, diffusion coefficients, and membrane permeability were determined as a function of pore size and diffusion model. Concentration gradient and pore size were key to understand mass transfer phenomena in the diffusion systems. C1 [Trbojevich, Raul A.; Bryant, Matthew S.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Fernandez, Avelina] Univ Valencia, Consejo Super Invest Cient, Inst Fis Corpuscular, Parc Cient, Valencia 46980, Spain. [Watanabe, Fumiya; Mustafa, Thikra] Univ Arkansas Little Rock, Ctr Integrat Nanotechnol Sci, 2801 S Univ Ave, Little Rock, AR 72204 USA. [Mustafa, Thikra] Univ Baghdad, Coll Sci Women, Dept Biol, Baghdad, Iraq. RP Fernandez, A (reprint author), Univ Valencia, Consejo Super Invest Cient, Inst Fis Corpuscular, Parc Cient, Valencia 46980, Spain. EM velifdez@ific.uv.es FU Division of Biochemical Toxicology, from National Center for Toxicological Research [E073680]; U.S. Food and Drug Administration FX This study was supported through the project # E073680, Division of Biochemical Toxicology, from National Center for Toxicological Research, and U.S. Food and Drug Administration. We gratefully acknowledge assistance of the FDA NCTR/ORA Nanotechnology Core Facility, Jefferson, Arkansas, in which part of this study was conducted. The authors thank Dr. Frederick Beland and Dr. Paul Howard for assistance in the review of this manuscript. NR 25 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1388-0764 EI 1572-896X J9 J NANOPART RES JI J. Nanopart. Res. PD FEB 19 PY 2016 VL 18 IS 3 AR 55 DI 10.1007/s11051-016-3363-8 PG 12 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA EB0OV UT WOS:000387044400002 ER PT J AU Su, JR Miller, ER Duffy, J Baer, BM Cano, MV AF Su, John R. Miller, Elaine R. Duffy, Jonathan Baer, Bethany M. Cano, Maria V. TI Administration Error Involving a Meningococcal Conjugate Vaccine - United States, March 1, 2010-September 22, 2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Su, John R.; Miller, Elaine R.; Duffy, Jonathan; Cano, Maria V.] CDC, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Baer, Bethany M.] Food & Drug Adm, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, San Diego, CA USA. RP Su, JR (reprint author), CDC, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM ezu2@cdc.gov NR 5 TC 1 Z9 1 U1 1 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD FEB 19 PY 2016 VL 65 IS 6 BP 161 EP 162 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DF4TY UT WOS:000371345000006 PM 26890604 ER PT J AU Meseda, CA Atukorale, V Kuhn, J Schmeisser, F Weir, JP AF Meseda, Clement A. Atukorale, Vajini Kuhn, Jordan Schmeisser, Falko Weir, Jerry P. TI Percutaneous Vaccination as an Effective Method of Delivery of MVA and MVA-Vectored Vaccines SO PLOS ONE LA English DT Article ID PHASE-I TRIAL; VIRUS-ANKARA; SMALLPOX VACCINE; INFLUENZA-VIRUS; CLINICAL-TRIAL; HEALTHY-ADULTS; MICRONEEDLE ARRAYS; SKIN VACCINATION; ANTIGEN DELIVERY; IMMUNE-RESPONSES AB The robustness of immune responses to an antigen could be dictated by the route of vaccine inoculation. Traditional smallpox vaccines, essentially vaccinia virus strains, that were used in the eradication of smallpox were administered by percutaneous inoculation (skin scarification). The modified vaccinia virus Ankara is licensed as a smallpox vaccine in Europe and Canada and currently undergoing clinical development in the United States. MVA is also being investigated as a vector for the delivery of heterologous genes for prophylactic or therapeutic immunization. Since MVA is replication-deficient, MVA and MVA-vectored vaccines are often inoculated through the intramuscular, intradermal or subcutaneous routes. Vaccine inoculation via the intramuscular, intradermal or subcutaneous routes requires the use of injection needles, and an estimated 10 to 20% of the population of the United States has needle phobia. Following an observation in our laboratory that a replication-deficient recombinant vaccinia virus derived from the New York City Board of Health strain elicited protective immune responses in a mouse model upon inoculation by tail scarification, we investigated whether MVA and MVA recombinants can elicit protective responses following percutaneous administration in mouse models. Our data suggest that MVA administered by percutaneous inoculation, elicited vaccinia-specific antibody responses, and protected mice from lethal vaccinia virus challenge, at levels comparable to or better than subcutaneous or intramuscular inoculation. High titers of specific neutralizing antibodies were elicited in mice inoculated with a recombinant MVA expressing the herpes simplex type 2 glycoprotein D after scarification. Similarly, a recombinant MVA expressing the hemagglutinin of attenuated influenza virus rgA/Viet Nam/1203/2004 (H5N1) elicited protective immune responses when administered at low doses by scarification. Taken together, our data suggest that MVA and MVA-vectored vaccines inoculated by scarification can elicit protective immune responses that are comparable to subcutaneous vaccination, and may allow for antigen sparing when vaccine supply is limited. C1 [Meseda, Clement A.; Atukorale, Vajini; Kuhn, Jordan; Schmeisser, Falko; Weir, Jerry P.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Meseda, CA (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Clement.Meseda@fda.hhs.gov FU Center for Biologics Evaluation and Research, US Food and Drug Administration; CBER/FDA FX The work described in this manuscript was supported by intramural research fund provided by the Center for Biologics Evaluation and Research, US Food and Drug Administration.; The authors wish to thank Drs. Bernard Moss and Linda Wyatt, NIAID/NIH, for the MVA and VV-WR viruses. We also thank Dr. Maryna Eichelberger and Dr. Alonzo Garcia, CBER/FDA, for reviewing this manuscript. This work was supported by intramural research funds from CBER/FDA. NR 89 TC 0 Z9 0 U1 4 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 FEB 19 PY 2016 VL 11 IS 2 AR e0149364 DI 10.1371/journal.pone.0149364 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF3DG UT WOS:000371223400048 PM 26895072 ER PT J AU He, WW Jia, HM Cai, JH Han, XN Zheng, Z Warner, WG Yin, JJ AF He, Weiwei Jia, Huimin Cai, Junhui Han, Xiangna Zheng, Zhi Warner, Wayne G. Yin, Jun-Jie TI Production of Reactive Oxygen Species and Electrons from Photoexcited ZnO and ZnS Nanoparticles: A Comparative Study for Unraveling their Distinct Photocatalytic Activities SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID HYDROGEN-PEROXIDE; HYBRID NANOSTRUCTURES; OXIDE NANOPARTICLES; CHARGE-CARRIERS; SINGLET OXYGEN; ZINC-OXIDE; GENERATION; DEGRADATION; SUPEROXIDE; LIGHT AB The photoactivity of semiconductor rianostructures makes them potentially useful for environmental remediation and antibacterial applications. Understanding the mechanism underlying the photochemical and photobiological activities of photoexcited semiconductors is of great importance for developing applications and assessing associated risks. In the current work, using electron spin resonance spectroscopy coupled with spin trapping and spin labeling techniques, we comparatively and systematically investigate the abilities of ZnO and ZnS to generate hydroxyl radical, superoxide, singlet oxygen, photoinduced electrons, and oxygen consumption during irradiation. It was found that although ZnO and ZnS, when photoexcited, can produce hydroxyl radical, superoxide, and singlet oxygen, ZnO is more effective than ZnS in producing hydroxyl radical and singlet oxygen while ZnS is more effective than ZnO in generating superoxide. The characterization with ESR spin labeling and oxirnetry indicates ZnS is about 4 times more active than ZnO in production of photoinduced electrons and consumption of oxygen. We compared the photocatalytic and antibacterial activities of ZnO and ZnS and found that ZnO exhibits efficient and broad photo catalytic and antibacterial activity, conversely, ZnS is only effective in photodegradation of RhB and killing Staphylococcus aureus. The distinct photocatalytic activities of ZnO and ZnS nanoparticles were attributable to their unique capability to facilitate the generation of reactive oxygen species and charge carriers during photoirradiation. These results provide valuable information, for understanding the photocatalytic mechanism of metal oxide and metal sulfides and for predicting their photocatalytic activities. C1 [He, Weiwei; Jia, Huimin; Cai, Junhui; Han, Xiangna; Zheng, Zhi] Xuchang Univ, Inst Surface Micro & Nanomat, Key Lab Micronano Energy Storage & Convers Mat He, Xuchang 461000, Henan, Peoples R China. [Warner, Wayne G.; Yin, Jun-Jie] US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Warner, Wayne G.; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP He, WW (reprint author), Xuchang Univ, Inst Surface Micro & Nanomat, Key Lab Micronano Energy Storage & Convers Mat He, Xuchang 461000, Henan, Peoples R China.; Yin, JJ (reprint author), US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA.; Yin, JJ (reprint author), US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM heweiweixcu@gmail.com; junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014; Zheng, Zhi/J-3198-2016 FU National Natural Science Foundation of China [21303153]; Program for Science & Technology Innovation Talents in Universities of Henan Province [14HASTIT008]; Innovation Scientists and Technicians Troop Construction Projects of Henan Province [144200510014] FX This work was supported by National Natural Science Foundation of China (Grant No. 21303153), Program for Science & Technology Innovation Talents in Universities of Henan Province (14HASTIT008), and Innovation Scientists and Technicians Troop Construction Projects of Henan Province (Grant No. 144200510014). This article is not an official US Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the US FDA is intended or should be inferred. NR 34 TC 5 Z9 5 U1 12 U2 46 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1932-7447 J9 J PHYS CHEM C JI J. Phys. Chem. C PD FEB 18 PY 2016 VL 120 IS 6 BP 3187 EP 3195 DI 10.1021/acs.jpcc.5b11456 PG 9 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DE5NW UT WOS:000370678700010 ER PT J AU Geller, AI Mozersky, RP Budnitz, DS AF Geller, Andrew I. Mozersky, Robert P. Budnitz, Daniel S. TI Emergency Department Visits Related to Dietary Supplements Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Geller, Andrew I.; Budnitz, Daniel S.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Mozersky, Robert P.] Food & Drug Adm, College Pk, MD USA. RP Geller, AI (reprint author), Ctr Dis Control & Prevent, Atlanta, GA USA. EM ageller@cdc.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 18 PY 2016 VL 374 IS 7 BP 695 EP 695 DI 10.1056/NEJMc1514454 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DD9ER UT WOS:000370229000030 PM 26886539 ER PT J AU Horne, HN Sherman, ME Pfeiffer, RM Figueroa, JD Khodr, ZG Falk, RT Pollak, M Patel, DA Palakal, MM Linville, L Papathomas, D Geller, B Vacek, PM Weaver, DL Chicoine, R Shepherd, J Mahmoudzadeh, AP Wang, J Fan, B Malkov, S Herschorn, S Hewitt, SM Brinton, LA Gierach, GL AF Horne, Hisani N. Sherman, Mark E. Pfeiffer, Ruth M. Figueroa, Jonine D. Khodr, Zeina G. Falk, Roni T. Pollak, Michael Patel, Deesha A. Palakal, Maya M. Linville, Laura Papathomas, Daphne Geller, Berta Vacek, Pamela M. Weaver, Donald L. Chicoine, Rachael Shepherd, John Mahmoudzadeh, Amir Pasha Wang, Jeff Fan, Bo Malkov, Serghei Herschorn, Sally Hewitt, Stephen M. Brinton, Louise A. Gierach, Gretchen L. TI Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease SO BREAST CANCER RESEARCH LA English DT Article ID CANCER-RISK; MAMMOGRAPHIC DENSITY; IGF-I; POSTMENOPAUSAL WOMEN; RACIAL-DIFFERENCES; MENSTRUAL-CYCLE; NURSES HEALTH; SEX-HORMONES; ASSOCIATION; IGFBP-3 AB Background: Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. Methods: Serum IGF-I, IGFBP-3 and IGF-I: IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. Results: Higher IGF-I levels among postmenopausal women and an elevated IGF-I: IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. Conclusions: These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system. C1 [Horne, Hisani N.; Khodr, Zeina G.; Falk, Roni T.; Patel, Deesha A.; Palakal, Maya M.; Linville, Laura; Papathomas, Daphne; Gierach, Gretchen L.] NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Rm 7-E108, Bethesda, MD 20892 USA. [Horne, Hisani N.] US FDA, Silver Spring, MD USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Pollak, Michael] McGill Univ, Montreal, PQ, Canada. [Patel, Deesha A.] Northwestern Univ, Sch Med, Chicago, IL 60611 USA. [Geller, Berta; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael] Univ Vermont, Burlington, VT USA. [Shepherd, John; Mahmoudzadeh, Amir Pasha; Fan, Bo; Malkov, Serghei; Herschorn, Sally] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Wang, Jeff] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Brinton, Louise A.] NCI, Off Director, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Gierach, GL (reprint author), NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Rm 7-E108, Bethesda, MD 20892 USA. EM gierachg@mail.nih.gov RI Gierach, Gretchen/E-1817-2016; OI Gierach, Gretchen/0000-0002-0165-5522; Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the NIH, National Cancer Institute; National Cancer Institute [U01CA70013, 1R21CA157254]; National Center for Research Resources [M01 RR000109]; Breast Cancer Research Stamp Funds FX The authors are indebted to the participants in the BREAST Stamp Project for their outstanding cooperation and to the physicians, pathologists, nurses, technologists, and interviewers for their efforts in the field. The authors thank Claire Bove, Patricia Lutton, Ellen Young and Aileen Burke for research assistance. We also thank Janet Lawler-Heaver and Kerry Grace Morrissey from Westat for study management support and Jane Demuth at Information Management Services for data support and analysis. The authors would also like to thank Patricia Madigan for her editorial assistance. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute and Breast Cancer Research Stamp Funds. Cooperative agreement U01CA70013 (BM Geller, PM Vacek, DL Weaver, RE Chicoine, SD Herschorn) and 1R21CA157254 (JA Shepherd, B Fan, AP Mahmoudzadeh, S Malkov) from the National Cancer Institute funded some of the data collection and image analysis for this study. Grant number M01 RR000109 from the National Center for Research Resources funded the blood processing at the University of Vermont General Clinical Research Center. NR 49 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD FEB 18 PY 2016 VL 18 AR 24 DI 10.1186/s13058-016-0678-4 PG 12 WC Oncology SC Oncology GA DE0NL UT WOS:000370321500001 PM 26893016 ER PT J AU Fleming, IMC Paris, Z Gaston, KW Balakrishnan, R Fredrick, K Rubio, MAT Alfonzo, JD AF Fleming, Ian M. C. Paris, Zdenek Gaston, Kirk W. Balakrishnan, R. Fredrick, Kurt Rubio, Mary Anne T. Alfonzo, Juan D. TI A tRNA methyltransferase paralog is important for ribosome stability and cell division in Trypanosoma brucei SO SCIENTIFIC REPORTS LA English DT Article ID BOWEN-CONRADI SYNDROME; SACCHAROMYCES-CEREVISIAE; AFRICAN TRYPANOSOMES; PROTOZOAN PARASITES; BIOGENESIS REQUIRES; EUGLENA-GRACILIS; BINDING PROTEIN; ASSEMBLY FACTOR; SUBUNIT; INTERFERENCE AB Most eukaryotic ribosomes contain 26/28S, 5S, and 5.8S large subunit ribosomal RNAs (LSU rRNAs) in addition to the 18S rRNA of the small subunit (SSU rRNA). However, in kinetoplastids, a group of organisms that include medically important members of the genus Trypanosoma and Leishmania, the 26/28S large subunit ribosomal RNA is uniquely composed of 6 rRNA fragments. In addition, recent studies have shown the presence of expansion segments in the large ribosomal subunit (60S) of Trypanosoma brucei. Given these differences in structure, processing and assembly, T. brucei ribosomes may require biogenesis factors not found in other organisms. Here, we show that one of two putative 3-methylcytidine methyltransferases, TbMTase37 (a homolog of human methyltransferase- like 6, METTL6), is important for ribosome stability in T. brucei. TbMTase37 localizes to the nucleolus and depletion of the protein results in accumulation of ribosomal particles lacking srRNA 4 and reduced levels of polysome associated ribosomes. We also find that TbMTase37 plays a role in cytokinesis, as loss of the protein leads to multi-flagellated and multi-nucleated cells. C1 [Fleming, Ian M. C.; Paris, Zdenek; Balakrishnan, R.; Fredrick, Kurt; Rubio, Mary Anne T.; Alfonzo, Juan D.] Ohio State Univ, Dept Microbiol, 484 W 12th Ave, Columbus, OH 43210 USA. [Fleming, Ian M. C.; Paris, Zdenek; Balakrishnan, R.; Fredrick, Kurt; Rubio, Mary Anne T.; Alfonzo, Juan D.] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. [Gaston, Kirk W.; Balakrishnan, R.] Univ Cincinnati, Dept Chem, Rieveschl Labs Mass Spectrometry, Cincinnati, OH 45221 USA. [Fredrick, Kurt; Alfonzo, Juan D.] Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA. [Paris, Zdenek] Univ South Bohemia, Inst Parasitol, Ctr Biol, Ceske Budejovice 37005, Budweis, Czech Republic. [Paris, Zdenek] Univ South Bohemia, Fac Sci, Ceske Budejovice 37005, Budweis, Czech Republic. [Gaston, Kirk W.] US FDA, Cincinnati, OH USA. RP Alfonzo, JD (reprint author), Ohio State Univ, Dept Microbiol, 484 W 12th Ave, Columbus, OH 43210 USA.; Alfonzo, JD (reprint author), Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA.; Alfonzo, JD (reprint author), Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA. EM alfonzo.1@osu.edu RI Paris, Zdenek/G-7349-2014 FU Czech Grant Agency [15-21450Y]; NIH [R01 GM084065-07, R01 GM072528]; NIH-NIGMS [T32-GM086252] FX We wish to thank M. Parsons for anti-Nog1 and all members of the Alfonzo laboratory for valuable discussion and insights. This work was supported by a Czech Grant Agency 15-21450Y grant to Z.P., NIH Grant R01 GM084065-07 to J.D.A. NIH-NIGMS Grant T32-GM086252 to I.M.C.F. and NIH grant R01 GM072528 to K. F. NR 44 TC 3 Z9 3 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 18 PY 2016 VL 6 AR 21438 DI 10.1038/srep21438 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE0WX UT WOS:000370347400001 PM 26888608 ER PT J AU Zhang, L Luo, S Zhang, BL AF Zhang, Lei Luo, Shen Zhang, Baolin TI Glycan analysis of therapeutic glycoproteins SO MABS LA English DT Review DE lectin microarray; Analytics; glycosylation; biopharmaceuticals; monoclonal antibodies; therapeutic proteins; glycan profiling ID ELECTROPHORESIS-MASS SPECTROMETRY; PROTEIN GLYCOSYLATION ANALYSIS; ANION-EXCHANGE CHROMATOGRAPHY; N-LINKED GLYCANS; INDUCED FLUORESCENCE DETECTION; CAPILLARY GEL-ELECTROPHORESIS; PULSED AMPEROMETRIC DETECTION; ASSISTED LECTIN MICROARRAY; MONOCLONAL-ANTIBODY; LIQUID-CHROMATOGRAPHY AB Therapeutic monoclonal antibodies (mAbs) are glycoproteins produced by living cell systems. The glycan moieties attached to the proteins can directly affect protein stability, bioactivity, and immunogenicity. Therefore, glycan variants of a glycoprotein product must be adequately analyzed and controlled to ensure product quality. However, the inherent complexity of protein glycosylation poses a daunting analytical challenge. This review provides an update of recent advances in glycan analysis, including the potential utility of lectin-based microarray for high throughput glycan profiling. Emphasis is placed on comparison of the major types of analytics for use in determining unique glycan features such as glycosylation site, glycan structure, and content. C1 [Zhang, Lei; Luo, Shen; Zhang, Baolin] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Zhang, BL (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Baolin.zhang@fda.hhs.gov RI Zhang, Lei/F-5171-2010 FU Intramural FDA HHS [FD999999] NR 115 TC 1 Z9 2 U1 10 U2 24 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD FEB 17 PY 2016 VL 8 IS 2 BP 205 EP 215 DI 10.1080/19420862.2015.1117719 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DF4TZ UT WOS:000371345100002 PM 26599345 ER PT J AU Fu, X Wang, Z Bhirde, A Zhu, J Liao, HS Carvajal, N Niu, G Eden, H Chen, XY Jin, AJ AF Fu, Xiao Wang, Zhe Bhirde, Ashwin Zhu, Jenny Liao, Hsien-Shun Carvajal, Nicole Niu, Gang Eden, Henry Chen, Xiaoyuan Jin, Albert J. TI Bio-AFM of Cancer Cells and Multifunctional Theranostics SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Fu, Xiao; Wang, Zhe; Bhirde, Ashwin; Zhu, Jenny; Liao, Hsien-Shun; Carvajal, Nicole; Niu, Gang; Eden, Henry; Chen, Xiaoyuan; Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Fu, Xiao] Beijing Inst Technol, Beijing 100081, Peoples R China. [Bhirde, Ashwin] US FDA, Silver Spring, MD USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 854-Pos BP 171A EP 171A PG 1 WC Biophysics SC Biophysics GA DK7GS UT WOS:000375093800342 ER PT J AU Hategan, AP Karnaukhova, E Dimitriadis, EK Bianchet, MA Nath, A AF Hategan, Alina Popescu Karnaukhova, Elena Dimitriadis, Emilios K. Bianchet, Mario A. Nath, Avindra TI Molecular Study of HIV-Tat Aggregation SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 60th Annual Meeting of the Biophysical-Society CY FEB 27-MAR 02, 2016 CL Los Angeles, CA SP Biophys Soc C1 [Hategan, Alina Popescu; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Karnaukhova, Elena] US FDA, CBER, Silver Spring, MD USA. [Dimitriadis, Emilios K.] NIBIB, Scanning Probe Microscopy Unit, NIH, Bethesda, MD USA. [Bianchet, Mario A.] Johns Hopkins Sch Med, Dept Neurol & Struct Enzymol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 16 PY 2016 VL 110 IS 3 SU 1 MA 1976-Pos BP 400A EP 400A PG 1 WC Biophysics SC Biophysics GA DK7YE UT WOS:000375142200444 ER PT J AU Lee, JM Hwang, D Park, J Kim, KJ Ahn, C Koo, BK AF Lee, Joo Myung Hwang, Doyeon Park, Jonghanne Kim, Kyung-Jin Ahn, Chul Koo, Bon-Kwon TI Response to Letter Regarding Article, "Percutaneous Coronary Intervention at Centers With and Without On-Site Surgical Backup: An Updated Meta-Analysis of 23 Studies" SO CIRCULATION LA English DT Letter C1 [Lee, Joo Myung; Hwang, Doyeon; Park, Jonghanne; Kim, Kyung-Jin; Koo, Bon-Kwon] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. [Lee, Joo Myung; Hwang, Doyeon; Park, Jonghanne; Kim, Kyung-Jin; Koo, Bon-Kwon] Seoul Natl Univ Hosp, Cardiovasc Ctr, Seoul 110744, South Korea. [Ahn, Chul] Food & Drug Adm, Ctr Devices & Radiol Hlth, Div Biostat, Silver Spring, MD USA. [Koo, Bon-Kwon] Seoul Natl Univ, Inst Aging, Seoul, South Korea. RP Lee, JM (reprint author), Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD FEB 16 PY 2016 VL 133 IS 7 BP E407 EP E407 DI 10.1161/CIRCULATIONAHA.115.020201 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DF0DW UT WOS:000371010200008 PM 26884632 ER PT J AU Beaver, JA AF Beaver, J. A. TI Development of molecular and genomic biomarkers: A regulatory path forward SO CANCER RESEARCH LA English DT Meeting Abstract CT 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 08-12, 2015 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Beaver, J. A.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2016 VL 76 SU 4 MA ES5-3 DI 10.1158/1538-7445.SABCS15-ES5-3 PG 1 WC Oncology SC Oncology GA DL4QN UT WOS:000375622400068 ER PT J AU Hoffmann, M Luo, Y Monday, SR Gonzalez-Escalona, N Ottesen, AR Muruvanda, T Wang, C Kastanis, G Keys, C Janies, D Senturk, IF Catalyurek, UV Wang, H Hammack, TS Wolfgang, WJ Schoonmaker-Bopp, D Chu, A Myers, R Haendiges, J Evans, PS Meng, JH Strain, EA Allard, MW Brown, EW AF Hoffmann, Maria Luo, Yan Monday, Steven R. Gonzalez-Escalona, Narjol Ottesen, Andrea R. Muruvanda, Tim Wang, Charles Kastanis, George Keys, Christine Janies, Daniel Senturk, Izzet F. Catalyurek, Umit V. Wang, Hua Hammack, Thomas S. Wolfgang, William J. Schoonmaker-Bopp, Dianna Chu, Alvina Myers, Robert Haendiges, Julie Evans, Peter S. Meng, Jianghong Strain, Errol A. Allard, Marc W. Brown, Eric W. TI Tracing Origins of the Salmonella Bareilly Strain Causing a Food-borne Outbreak in the United States SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE salmonellosis; geographic information systems; next generation sequencing; single nucleotide polymorphism; traceback ID INFECTION; EVOLUTION AB Background. Using a novel combination of whole-genome sequencing (WGS) analysis and geographic metadata, we traced the origins of Salmonella Bareilly isolates collected in 2012 during a widespread food-borne outbreak in the United States associated with scraped tuna imported from India. Methods. Using next-generation sequencing, we sequenced the complete genome of 100 Salmonella Bareilly isolates obtained from patients who consumed contaminated product, from natural sources, and from unrelated historically and geographically disparate foods. Pathogen genomes were linked to geography by projecting the phylogeny on a virtual globe and produced a transmission network. Results. Phylogenetic analysis of WGS data revealed a common origin for outbreak strains, indicating that patients in Maryland and New York were infected from sources originating at a facility in India. Conclusions. These data represent the first report fully integrating WGS analysis with geographic mapping and a novel use of transmission networks. Results showed that WGS vastly improves our ability to delimit the scope and source of bacterial food-borne contamination events. Furthermore, these findings reinforce the extraordinary utility that WGS brings to global outbreak investigation as a greatly enhanced approach to protecting the human food supply chain as well as public health in general. C1 [Hoffmann, Maria; Monday, Steven R.; Gonzalez-Escalona, Narjol; Ottesen, Andrea R.; Muruvanda, Tim; Wang, Charles; Kastanis, George; Keys, Christine; Wang, Hua; Hammack, Thomas S.; Evans, Peter S.; Allard, Marc W.; Brown, Eric W.] US FDA, Div Microbiol, Off Regulatory Sci, Ctr Food Safety & Nutr, College Pk, MD USA. [Luo, Yan; Strain, Errol A.] US FDA, Div Publ Hlth & Biostat, Off Food Def Commun & Emergency Response, Ctr Food Safety & Nutr, College Pk, MD USA. [Hoffmann, Maria; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Hoffmann, Maria; Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Chu, Alvina; Myers, Robert; Haendiges, Julie] Maryland Dept Hlth & Mental Hyg, Baltimore, MD USA. [Janies, Daniel] Univ N Carolina, Dept Bioinformat & Genom, Charlotte, NC 28223 USA. [Senturk, Izzet F.; Catalyurek, Umit V.] Ohio State Univ, Dept Biomed Informat, Columbus, OH 43210 USA. [Wolfgang, William J.; Schoonmaker-Bopp, Dianna] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12237 USA. RP Hoffmann, M (reprint author), 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM maria.hoffman@fda.hhs.gov OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 FU Joint Institute for Food Safety and Applied Nutrition, University of Maryland, College Park; Centers for Disease Control and Prevention, National Center for Infectious Disease, Epidemiology and Laboratory Capacity for Infectious Diseases [U50/CCU223671]; Defense Threat Reduction Agency [HDTRA1-14-C-0007] FX This work was supported by an appointment of MH by the Joint Institute for Food Safety and Applied Nutrition, University of Maryland, College Park (appointment to M. H.) and the Centers for Disease Control and Prevention, National Center for Infectious Disease, Epidemiology and Laboratory Capacity for Infectious Diseases Cooperative Agreement (grant U50/CCU223671 to W. J. W. and D. S. B.). The efforts for the geographic mapping and the novel concept of transmission network were funded by the Defense Threat Reduction Agency (contract HDTRA1-14-C-0007). NR 29 TC 14 Z9 14 U1 5 U2 10 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 FEB 15 PY 2016 VL 213 IS 4 BP 502 EP 508 DI 10.1093/infdis/jiv297 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DG9XS UT WOS:000372437700002 PM 25995194 ER PT J AU Harrington, PR Fleischer, R Connelly, SM Lewis, LL Murray, J AF Harrington, Patrick R. Fleischer, Russell Connelly, Sarah M. Lewis, Linda L. Murray, Jeffrey TI Marked Decrease in Lymphocyte Count in HIV/Hepatitis C Virus (HCV)-Coinfected Patients With Advanced Liver Disease During Anti-HCV Treatment With Direct-Acting Antiviral Regimens Including Ribavirin Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID HEPATITIS-C C1 [Harrington, Patrick R.; Fleischer, Russell; Connelly, Sarah M.; Lewis, Linda L.; Murray, Jeffrey] US FDA, Div Antiviral Prod, Off Antimicrobial Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Harrington, PR (reprint author), US FDA, CDER, OAP, DAVP, 10903 New Hampshire Ave,Bldg 22,Rm 6336, Silver Spring, MD 20993 USA. EM patrick.harrington@fda.hhs.gov NR 5 TC 0 Z9 0 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 FEB 15 PY 2016 VL 62 IS 4 BP 528 EP 529 DI 10.1093/cid/civ905 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DD9VX UT WOS:000370274900029 PM 26508511 ER PT J AU Krais, AM Speksnijder, EN Melis, JPM Singh, R Caldwell, A da Costa, GG Luijten, M Phillips, DH Arlt, VM AF Krais, Annette M. Speksnijder, Ewoud N. Melis, Joost P. M. Singh, Rajinder Caldwell, Anna da Costa, Goncalo Gamboa Luijten, Mirjam Phillips, David H. Arlt, Volker M. TI Metabolic activation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine and DNA adduct formation depends on p53: Studies in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE tumor suppressor p53; heterocyclic aromatic hydrocarbon; PhIP; carcinogen metabolism; DNA adduct formation; cytochrome P450; sulfotransferases; mouse model; mass spectrometry ID SULFOTRANSFERASES 1A1; TISSUE DISTRIBUTION; NULL MICE; EXPRESSION; MOUSE; CARCINOGENS; DEFICIENCY; KNOCKOUT; ENZYMES; TP53 AB The expression of the tumor suppressor p53 can influence the bioactivation of, and DNA damage induced by, the environmental carcinogen benzo[a] pyrene, indicating a role for p53 in its cytochrome P450 (CYP)-mediated biotransformation. The carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which is formed during the cooking of food, is also metabolically activated by CYP enzymes, particularly CYP1A2. We investigated the potential role of p53 in PhIP metabolism in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with a single oral dose of 50 mg/kg body weight PhIP. N-(Deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP-C8-dG) levels in DNA, measured by liquid chromatography-tandem mass spectrometry, were significantly lower in liver, colon, forestomach and glandular stomach of Trp53(-/-) mice compared to Trp53(+/+) mice. Lower PhIP-DNA adduct levels in the livers of Trp53(-/-) mice correlated with lower Cyp1a2 enzyme activity (measured by methoxyresorufin-O-demethylase activity) in these animals. Interestingly, PhIP-DNA adduct levels were significantly higher in kidney and bladder of Trp53(-/-) mice compared to Trp53(+/+) mice, which was accompanied by higher sulfotransferase (Sult) 1a1 protein levels and increased Sult1a1 enzyme activity (measured by 2-naphthylsulfate formation from 2-naphthol) in kidneys of these animals. Our study demonstrates a role for p53 in the metabolism of PhIP in vivo, extending previous results on a novel role for p53 in xenobiotic metabolism. Our results also indicate that the impact of p53 on PhIP biotransformation is tissue-dependent and that in addition to Cyp1a enzymes, Sult1a1 can contribute to PhIP-DNA adduct formation. C1 [Krais, Annette M.; Phillips, David H.; Arlt, Volker M.] Kings Coll London, MRC PHE Ctr Environm & Hlth, Analyt & Environm Sci Div, 150 Stamford St, London SE1 9NH, England. [Speksnijder, Ewoud N.; Melis, Joost P. M.; Luijten, Mirjam] Natl Inst Publ Hlth & Environm RIVM, Ctr Hlth Protect, NL-3721 MA Bilthoven, Netherlands. [Speksnijder, Ewoud N.; Melis, Joost P. M.; Luijten, Mirjam] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Singh, Rajinder] Univ Leicester, Dept Canc Studies & Mol Med, Leicester LE2 7LX, Leics, England. [Caldwell, Anna] Kings Coll London, Mass Spectrometry Facil, London SE1 9NH, England. [da Costa, Goncalo Gamboa] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Arlt, VM (reprint author), Kings Coll London, MRC PHE Ctr Environm & Hlth, Analyt & Environm Sci Div, 150 Stamford St, London SE1 9NH, England. EM volker.arlt@kcl.ac.uk FU Cancer Research UK [C313/A14329]; Wellcome Trust [101126/Z/13/Z, 101126/B/13/Z]; German Research Foundation (DFG) FX Grant sponsor: Cancer Research UK; Grant number: C313/A14329; Grant sponsor: Wellcome Trust; Grant numbers: 101126/Z/13/Z and 101126/B/13/Z; Grant sponsor: German Research Foundation (DFG; A.K.) NR 24 TC 2 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2016 VL 138 IS 4 BP 976 EP 982 DI 10.1002/ijc.29836 PG 7 WC Oncology SC Oncology GA DC4BH UT WOS:000369164200019 PM 26335255 ER PT J AU Alvarado-Facundo, E Vassell, R Schmeisser, F Weir, JP Weiss, CD Wang, W AF Alvarado-Facundo, Esmeralda Vassell, Russell Schmeisser, Falko Weir, Jerry P. Weiss, Carol D. Wang, Wei TI Glycosylation of Residue 141 of Subtype H7 Influenza A Hemagglutinin (HA) Affects HA-Pseudovirus Infectivity and Sensitivity to Site A Neutralizing Antibodies SO PLOS ONE LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; RECEPTOR-BINDING; LENTIVIRAL VECTOR; IMMUNE-RESPONSE; GENE DELIVERY; CELL-CULTURE; IN-VIVO; VIRUS; VACCINE; PSEUDOTYPES AB Human infections with H7 subtype influenza virus have been reported, including an H7N7 outbreak in Netherlands in 2003 and H7N9 infections in China in 2013. Previously, we reported murine monoclonal antibodies (mAbs) that recognize the antigenic site A of H7 hemagglutinin (HA). To better understand protective immunity of H7 vaccines and vaccine candidate selection, we used these mAbs to assess the antigenic relatedness among two H7 HA isolated from past human infections and determine residues that affect susceptibility to neutralization. We found that these mAbs neutralize pseudoviruses bearing HA of A/Shanghai/02/2013(H7N9), but not A/Netherlands/219/2003(H7N7). Glycosylation of the asparagine residue at position 141 (N141) (N133, H3 HA numbering) in the HA of A/Netherlands/219/2003 HA is responsible for this resistance, and it affects the infectivity of HA-pseudoviruses. The presence of threonine at position 143 (T135, H3 HA numbering) in the HA of A/Netherlands/219/2003, rather than an alanine found in the HA of A/Shanghai/02/2013(H7N9), accounts for these differences. These results demonstrate a key role for glycosylation of residue N141 in affecting H7 influenza HA-mediated entry and sensitivity to neutralizing antibodies, which have implications for candidate vaccine design. C1 [Alvarado-Facundo, Esmeralda; Vassell, Russell; Weiss, Carol D.; Wang, Wei] US FDA, Immunoregulat Lab, Div Viral Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Schmeisser, Falko; Weir, Jerry P.] US FDA, Lab DNA Viruses, Div Viral Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Weiss, CD; Wang, W (reprint author), US FDA, Immunoregulat Lab, Div Viral Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM carol.weiss@fda.hhs.gov; wei.wang@fda.hhs.gov FU US Food and Drug Administration; Biomedical Advanced Research and Development Authority, Department of Health and Human Services FX This work was supported by the US Food and Drug Administration and the Biomedical Advanced Research and Development Authority, Department of Health and Human Services. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 10 PY 2016 VL 11 IS 2 AR e0149149 DI 10.1371/journal.pone.0149149 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6PR UT WOS:000370046600161 PM 26862918 ER PT J AU Asati, A Kachurina, O Karol, A Dhir, V Nguyen, M Parkhill, R Kouiavskaia, D Chumakov, K Warren, W Kachurin, A AF Asati, Atul Kachurina, Olga Karol, Alex Dhir, Vipra Nguyen, Michael Parkhill, Robert Kouiavskaia, Diana Chumakov, Konstantin Warren, William Kachurin, Anatoly TI Fluorescence Adherence Inhibition Assay: A Novel Functional Assessment of Blocking Virus Attachment by Vaccine-Induced Antibodies SO PLOS ONE LA English DT Article ID YELLOW-FEVER VACCINE; FLOW-CYTOMETRY; IMMUNOFLUORESCENCE ASSAY; NEUTRALIZATION TEST; INFLUENZA-VIRUS; IGG ANTIBODIES; PROTEIN; ELISA; 17D AB Neutralizing antibodies induced by vaccination or natural infection play a critically important role in protection against the viral diseases. In general, neutralization of the viral infection occurs via two major pathways: pre- and post-attachment modes, the first being the most important for such infections as influenza and polio, the latter being significant for filoviruses. Neutralizing capacity of antibodies is typically evaluated by virus neutralization assays that assess reduction of viral infectivity to the target cells in the presence of functional antibodies. Plaque reduction neutralization test, microneutralization and immunofluorescent assays are often used as gold standard virus neutralization assays. However, these methods are associated with several important prerequisites such as use of live virus requiring safety precautions, tedious evaluation procedure and long assessment time. Hence, there is a need for a robust, inexpensive high throughput functional assay that can be performed rapidly using inactivated virus, without extensive safety precautions. Herein, we report a novel high throughput Fluorescence Adherence Inhibition assay (fADI) using inactivated virus labeled with fluorescent secondary antibodies virus and Vero cells or erythrocytes as targets. It requires only few hours to assess pre-attachment neutralizing capacity of donor sera. fADI assay was tested successfully on donors immunized with polio, yellow fever and influenza vaccines. To further simplify and improve the throughput of the assay, we have developed a mathematical approach for calculating the 50% titers from a single sample dilution, without the need to analyze multi-point titration curves. Assessment of pre- and post-vaccination human sera from subjects immunized with IPOL (R), YF-VAX (R) and 2013-2014 Fluzone (R) vaccines demonstrated high efficiency of the assay. The results correlated very well with microneutralization assay performed independently by the FDA Center of Biologics Evaluation and Research, with plaque reduction neutralization test performed by Focus Diagnostics, and with hemaglutination inhibition assay performed in-house at Sanofi Pasteur. Taken together, fADI assay appears to be a useful high throughput functional immunoassay for assessment of antibody-related neutralization of the viral infections for which pre-attachment neutralization pathway is predominant, such as polio, influenza, yellow fever and dengue. C1 [Asati, Atul; Kachurina, Olga; Karol, Alex; Dhir, Vipra; Nguyen, Michael; Parkhill, Robert; Warren, William; Kachurin, Anatoly] Sanofi Pasteur VaxDesign Campus, 2501 Discovery Dr Suite 3000, Orlando, FL 32826 USA. [Kouiavskaia, Diana; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Kachurin, A (reprint author), Sanofi Pasteur VaxDesign Campus, 2501 Discovery Dr Suite 3000, Orlando, FL 32826 USA. EM anatoly.kachurin@sanofipasteur.com FU Defense Threat Reduction Agency (DTRA) [HDTRA1-13-C-00011]; Biomedical Advanced Research and Development Authority (BARDA), Department of Health and Human Services [HHSO100201000035C]; Sanofi Pasteur; CBER FDA FX This project has been funded in whole or in part with Federal funds from Defense Threat Reduction Agency (DTRA) and Biomedical Advanced Research and Development Authority (BARDA), Department of Health and Human Services, under Contract No. HDTRA1-13-C-00011 and HHSO100201000035C, respectively. The funders had no role in study design, data collection and analysis, or preparation of the manuscript. The authors Atul Asati, Olga Kachurina, Alex Karol, Vipra Dhir, Michael Nguyen, Robert Parkhill, William Warren and Anatoly Kachurin are employed by Sanofi Pasteur. The authors Diana Kouiavskaia and Konstantin Chumakov are employed by Center for Biologics Evaluation and Research within FDA (CBER FDA). Both Sanofi Pasteur and CBER FDA provided support in the form of salaries for authors AA, OK, A. Kachurin, VD, MN, RP, WW, A. Karol, DK, and KC respectively, but did not have any additional role in the study design, data collection and analysis or preparation of the manuscript. The specific roles of the authors are articulated in the 'author contributions' section. NR 29 TC 0 Z9 0 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 FEB 10 PY 2016 VL 11 IS 2 AR e0144261 DI 10.1371/journal.pone.0144261 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6PR UT WOS:000370046600003 PM 26863313 ER PT J AU Hu, J Juan, W Sahyoun, NR AF Hu, Jing Juan, WenYen Sahyoun, Nadine R. TI Intake and Biomarkers of Folate and Risk of Cancer Morbidity in Older Adults, NHANES 1999-2002 with Medicare Linkage SO PLOS ONE LA English DT Article ID PROSPECTIVE-PAYMENT SYSTEM; RANDOMIZED CLINICAL-TRIAL; FOLIC-ACID INTAKE; MULTIVITAMIN USE; UNITED-STATES; COLON-CANCER; CLAIMS DATA; FORTIFICATION; ACCURACY; WOMEN AB Background After the 1998 mandatory folic acid fortification of enriched cereal-grain products in the U.S., safety concerns were raised that excess consumption of folic acid and high blood folate biomarkers detected in adults may increase the risk of certain types of cancer. Methods Baseline data from about 1400 participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2002, aged >= 57 years were linked to Medicare and mortality files through December 31, 2007. Using cox proportional hazards regression models, we assessed associations between dietary folate equivalents, folate biomarkers, the presence of unmetabolized folic acid and, overall cancer incidence. Results With 8,114 person-years of follow-up (median follow-up, 6.3 years), about 125 cancer cases were identified. After adjusting for confounders, the hazard ratios of the highest quartile versus the second quartile of RBC folate and dietary folate equivalents were 0.54 (95% CI: 0.31-0.93) and 0.54 (95% CI: 0.30-0.95), respectively. Additionally, serum and RBC folate as continuous variables were inversely and significantly associated with cancer incidence (p<0.01). No significant associations were observed between the presence of unmetabolized folic acid, intake of naturally-occurring food folate or folic acid separately, and cancer incidence. Conclusions High total folate intake and biomarkers in older adults appear to be protective against cancer in post-folic acid fortification years. This study does not show a negative impact of current level of folic acid fortification on cancer risk. As this is one of the few studies to examine the association between unmetabolized folic acid and cancer outcome, a study including a larger nationwide representative sample of the U.S. population is needed. C1 [Hu, Jing; Sahyoun, Nadine R.] 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, College Pk, MD USA. RP Sahyoun, NR (reprint author), Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. EM nsahyoun@umd.edu FU Maryland Agricultural Experiment Station (MAES) [MD-HNFS-7307] FX This work was fully supported by a grant from the Maryland Agricultural Experiment Station (MAES), MD-HNFS-7307. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study. NR 34 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 10 PY 2016 VL 11 IS 2 AR e0148697 DI 10.1371/journal.pone.0148697 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DD6PR UT WOS:000370046600098 PM 26862893 ER PT J AU Garber, EAE Parker, CH Handy, SM Cho, CY Panda, R Samadpour, M Reynaud, DH Ziobro, GC AF Garber, Eric A. E. Parker, Christine H. Handy, Sara M. Cho, Chung Y. Panda, Rakhi Samadpour, Mansour Reynaud, Danica H. Ziobro, George C. TI Presence of Undeclared Food Allergens in Cumin: The Need for Multiplex Methods SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE cumin; peanut; food allergen detection ID PEANUT ALLERGENS; GLUTEN; ASSAY; KITS AB Beginning in the autumn of 2014, millions of dollars of food and over 675 products were recalled in the United States due to the presence of undeclared peanut, attributed to cumin used in the manufacture of the products. Initial analyses also indicated the presence of almond. Subsequent research showed that the presence of peanut and almond did not fully explain the analytical results for the cumin samples. Using a combination of mass spectrometry, DNA-based methods (i.e., PCR and Sanger DNA Sequencing), microscopy, and antibody-based technologies (i.e., ELISA, Western blot analysis, and a novel xMAP multiplex assay) the presence of peanut was confirmed. Screening for secondary sources of adulteration (e.g., tree nuts, mahieb, peach, and cherry) supported the assessment that the cumin contained multiple contaminants. These results demonstrate the limitations of single analyte-specific assays and the need for orthogonal multiplex methods to detect food allergens irrespective of varietal or other differences. C1 [Garber, Eric A. E.; Parker, Christine H.; Handy, Sara M.; Cho, Chung Y.; Panda, Rakhi] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Samadpour, Mansour] IEH Labs & Consulting Grp Inc, Lake Forest Pk, WA 98155 USA. [Reynaud, Danica H.] AuthenTechnologies LLC, Richmond, CA 94806 USA. [Ziobro, George C.] US FDA, Off Food Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Garber, EAE (reprint author), US FDA, CFSAN, HFS 716 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Eric.Garber@fda.hhs.gov RI Handy, Sara/C-6195-2008 NR 26 TC 2 Z9 2 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD FEB 10 PY 2016 VL 64 IS 5 BP 1202 EP 1211 DI 10.1021/acs.jafc.5b05497 PG 10 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA DD8ZO UT WOS:000370215600020 PM 26769163 ER PT J AU Shen, J Lee, K Choi, S Qu, W Wang, Y Burgess, DJ AF Shen, Jie Lee, Kyulim Choi, Stephanie Qu, Wen Wang, Yan Burgess, Diane J. TI A reproducible accelerated in vitro release testing method for PLGA microspheres SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE PLGA microspheres; Porous; Compositionally equivalent; Accelerated in vitro release; Risperidone; USP apparatus 4 ID POLY(LACTIC-CO-GLYCOLIC ACID) MICROSPHERES; DRUG-RELEASE; BIODEGRADABLE MICROSPHERES; POLYMERIC MICROSPHERES; VIVO CORRELATION; QUALITY-CONTROL; MICROPARTICLES; DEGRADATION; DELIVERY; PROTEIN AB The objective of the present study was to develop a discriminatory and reproducible accelerated in vitro release method for long-acting PLGA microspheres with inner structure/porosity differences. Risperidone was chosen as a model drug. Qualitatively and quantitatively equivalent PLGA microspheres with different inner structure/porosity were obtained using different manufacturing processes. Physicochemical properties as well as degradation profiles of the prepared microspheres were investigated. Furthermore, in vitro release testing of the prepared risperidone microspheres was performed using the most common in vitro release methods (i.e., sample-and-separate and flow through) for this type of product. The obtained compositionally equivalent risperidone microspheres had similar drug loading but different inner structure/porosity. When microsphere particle size appeared similar, porous risperidone microspheres showed faster microsphere degradation and drug release compared with less porous microspheres. Both in vitro release methods investigated were able to differentiate risperidone microsphere formulations with differences in porosity under real-time (37 degrees C) and accelerated (45 degrees C) testing conditions. Notably, only the accelerated USP apparatus 4 method showed good reproducibility for highly porous risperidone microspheres. These results indicated that the accelerated USP apparatus 4 method is an appropriate fast quality control tool for long-acting PLGA microspheres (even with porous structures). (C) 2015 Elsevier B.V. All rights reserved. C1 [Shen, Jie; Lee, Kyulim; Burgess, Diane J.] Univ Connecticut, Sch Pharm, Storrs, CT 06269 USA. [Choi, Stephanie; Qu, Wen; Wang, Yan] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Burgess, DJ (reprint author), Univ Connecticut, Sch Pharm, Dept Pharmaceut Sci, 69 North Eagleville Rd U3092, Storrs, CT 06269 USA. EM d.burgess@uconn.edu FU Office of Research and Standards, Office of Generic Drugs, CDER at the FDA [1U01FD004931-01]; Sotax Corporation FX This work was financially supported by the Office of Research and Standards, Office of Generic Drugs, CDER at the FDA (1U01FD004931-01). Support from Sotax Corporation is highly appreciated. NR 31 TC 4 Z9 4 U1 9 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD FEB 10 PY 2016 VL 498 IS 1-2 BP 274 EP 282 DI 10.1016/j.ijpharm.2015.12.031 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB1SW UT WOS:000368290200028 PM 26705156 ER PT J AU Hung, HMJ Wang, SJ Lawrence, J AF Hung, H. M. J. Wang, Sue-Jane Lawrence, John TI Comments on "Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls' SO STATISTICS IN MEDICINE LA English DT Editorial Material C1 [Hung, H. M. J.; Lawrence, John] FDA, OB OTS CDER, Div Biometr 1, Silver Spring, MD 20993 USA. [Wang, Sue-Jane] FDA, OTS CDER, Off Biostat, Silver Spring, MD 20993 USA. RP Hung, HMJ (reprint author), FDA, OB OTS CDER, Div Biometr 1, Silver Spring, MD 20993 USA. EM hmjames.hung@gmail.com 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 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD FEB 10 PY 2016 VL 35 IS 3 BP 348 EP 349 DI 10.1002/sim.6806 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 DA7GP UT WOS:000367972900002 PM 26757952 ER PT J AU Federhen, S Rossello-Mora, R Klenk, HP Tindall, BJ Konstantinidis, KT Whitman, WB Brown, D Labeda, D Ussery, D Garrity, GM Colwell, RR Hasan, N Graf, J Parte, A Yarza, P Goldberg, B Sichtig, H Karsch-Mizrachi, I Clark, K McVeigh, R Pruitt, KD Tatusova, T Falk, R Turner, S Madden, T Kitts, P Kimchi, A Klimke, W Agarwala, R DiCuccio, M Ostell, J AF Federhen, Scott Rossello-Mora, Ramon Klenk, Hans-Peter Tindall, Brian J. Konstantinidis, Konstantinos T. Whitman, William B. Brown, Daniel Labeda, David Ussery, David Garrity, George M. Colwell, Rita R. Hasan, Nur Graf, Joerg Parte, Aidan Yarza, Pablo Goldberg, Brittany Sichtig, Heike Karsch-Mizrachi, Ilene Clark, Karen McVeigh, Richard Pruitt, Kim D. Tatusova, Tatiana Falk, Robert Turner, Sean Madden, Thomas Kitts, Paul Kimchi, Avi Klimke, William Agarwala, Richa DiCuccio, Michael Ostell, James TI Meeting report: GenBank microbial genomic taxonomy workshop (12-13 May, 2015) SO STANDARDS IN GENOMIC SCIENCES LA English DT Article DE GenBank; Genomic taxonomy; Misidentified sequence entries ID SPECIES DEFINITION; PROKARYOTES; BACTERIA; ARCHAEA AB Many genomes are incorrectly identified at GenBank. We developed a plan to find and correct misidentified genomes using genomic comparison statistics together with a scaffold of reliably identified genomes from type. A workshop was organized with broad representation from the bacterial taxonomic community to review the proposal, the GenBank Microbial Genomic Taxonomy Workshop, Bethesda MD, May 12-13, 2015. C1 [Federhen, Scott; Karsch-Mizrachi, Ilene; Clark, Karen; McVeigh, Richard; Pruitt, Kim D.; Tatusova, Tatiana; Falk, Robert; Turner, Sean; Madden, Thomas; Kitts, Paul; Kimchi, Avi; Klimke, William; Agarwala, Richa; DiCuccio, Michael; Ostell, James] NCBI, Bethesda, MD USA. [Rossello-Mora, Ramon] IMEDEA CSIC UIB, Esporles, Spain. [Klenk, Hans-Peter] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Tindall, Brian J.] Deutsch Sammlung Mikroorganism Zellkultur GmbH, Braunschweig, Germany. [Konstantinidis, Konstantinos T.] Georgia Inst Technol, Atlanta, GA 30332 USA. [Whitman, William B.] Univ Georgia, Athens, GA 30602 USA. [Brown, Daniel] Univ Florida, Gainesville, FL USA. [Labeda, David] USDA, Washington, DC 20250 USA. [Ussery, David] Oak Ridge Natl Lab, Oak Ridge, TN USA. [Garrity, George M.] Michigan State Univ, E Lansing, MI 48824 USA. [Colwell, Rita R.] Univ Maryland, College Pk, MD 20742 USA. [Hasan, Nur] CosmosID, Rockville, MD USA. [Graf, Joerg] Univ Connecticut, Storrs, CT USA. [Parte, Aidan] LPSN, New York, NY USA. [Yarza, Pablo] Ribocon, Bremen, Germany. [Goldberg, Brittany; Sichtig, Heike] US FDA, Silver Spring, MD USA. RP Federhen, S (reprint author), NCBI, Bethesda, MD USA. EM federhen@ncbi.nlm.nih.gov OI Parte, Aidan/0000-0002-6304-4217; Ussery, David/0000-0003-3632-5512; Graf, Joerg/0000-0001-5320-2712 NR 17 TC 7 Z9 7 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1944-3277 J9 STAND GENOMIC SCI JI Stand. Genomic Sci. PD FEB 9 PY 2016 VL 11 AR 15 DI 10.1186/s40793-016-0134-1 PG 8 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA DO7FR UT WOS:000377948300002 ER PT J AU Lin, YC Winokur, P Blake, A Wu, TX Manischewitz, J King, LR Romm, E Golding, H Bielekova, B AF Lin, Yen Chih Winokur, Paige Blake, Andrew Wu, Tianxia Manischewitz, Jody King, Lisa R. Romm, Elena Golding, Hana Bielekova, Bibiana TI Patients with MS under daclizumab therapy mount normal immune responses to influenza vaccination SO NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION LA English DT Article ID HIGH-YIELD PROCESS; MULTIPLE-SCLEROSIS; DOUBLE-BLIND; ALPHA-CHAIN; T-CELLS; INTERLEUKIN-2; ANTIBODY; RECEPTOR; TRIAL; LYMPHOCYTES AB Objective: The purpose of this study was to assess the potential immunosuppressive role of daclizumab, a humanized monoclonal antibody against the a chain of the interleukin 2 receptor, in vivo, by comparing immune responses to the 2013 seasonal influenza vaccination between patients with multiple sclerosis (MS) on long-term daclizumab therapy and controls. Methods: Previously defined subpopulations of adaptive immune cells known to correlate with the immune response to the influenza vaccination were evaluated by 12-color flow cytometry in 23 daclizumab-treated patients with MS and 14 MS or healthy controls before (D0) and 1 day (D1) and 7 days (D7) after administration of the 2013 Afluria vaccine. Neutralizing antibody titers and CD4(+), CD8(+) T cell, B cell, and natural killer cell proliferation to 3 strains of virus contained in the Afluria vaccine were assessed at D0, D7, and 180 days postvaccination. Results: Daclizumab-treated patients and controls demonstrated comparable, statistically significant expansions of previously defined subpopulations of activated CD8(+) T cells and B cells that characterize the development of effective immune responses to the influenza vaccine, while proliferation of T cells to influenza and control antigens was diminished in the daclizumab cohort. All participants fulfilled FDA criteria for seroconversion or seroprotection in antibody assays. Conclusion: Despite the mild immunosuppressive effects of daclizumab in vivo demonstrated by an increased incidence of infectious complications in clinical trials, patients with MS under daclizumab therapy mount normal antibody responses to influenza vaccinations. Neurol Neuroimmunol Neuroinflamm 2016;3:e196; doi: 10.1212/NXI.0000000000000196 C1 [Lin, Yen Chih; Winokur, Paige; Blake, Andrew; Romm, Elena; Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Manischewitz, Jody; King, Lisa R.; Golding, Hana] US FDA, CBER, Rockville, MD 20857 USA. [Bielekova, Bibiana] NIH, Ctr Human Immunol, Bldg 10, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM bibi.bielekova@nih.gov NR 26 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2332-7812 J9 NEUROL-NEUROIMMUNOL JI Neurol.-Neuroimmunol. Neuroinflammation PD FEB PY 2016 VL 3 IS 1 AR e196 DI 10.1212/NXI.0000000000000196 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DX7MT UT WOS:000384572500014 PM 26848487 ER PT J AU Bai, JPF Burckart, GJ Mulberg, AE AF Bai, Jane P. F. Burckart, Gilbert J. Mulberg, Andrew E. TI Literature Review of Gastrointestinal Physiology in the Elderly, in Pediatric Patients, and in Patients with Gastrointestinal Diseases SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Review DE paracellular transport; passive transport disease effects; pediatric; gastrointestinal transit; permeabiltiy; elderly; CYP enzymes; transporters; metabolism; solubility ID IRRITABLE-BOWEL-SYNDROME; INTESTINAL TRANSIT-TIME; AGE-RELATED-CHANGES; MESSENGER-RNA EXPRESSION; CROHNS-DISEASE; ULCERATIVE-COLITIS; P-GLYCOPROTEIN; GASTROESOPHAGEAL-REFLUX; HEALTHY-VOLUNTEERS; DRUG ABSORPTION AB Oral bioavailability studies during the development of new medical entities or generic drugs are typically performed in healthy volunteers. Approved drug products are, however, used by patients with diverse disease backgrounds, and by pediatric and elderly patients. To provide the knowledge base for assessing the potential effects of age or co-morbidity on the in vivo performance of an orally absorbed, systemically active drug product, the literature regarding the gastrointestinal (GI) physiological characteristics (pH, permeability, and transit time) in children, in the elderly, and in patients with GI diseases (irritable bowel syndrome, ulcerative colitis, and Crohn's disease) is reviewed herein, with the knowledge gaps highlighted. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Bai, Jane P. F.; Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Mulberg, Andrew E.] US FDA, Div Gastroenterol & Inborn Error Prod, Off Drug Evaluat 3, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Bai, JPF (reprint author), US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM jane.bai@fda.hhs.gov NR 75 TC 3 Z9 3 U1 4 U2 4 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 FEB PY 2016 VL 105 IS 2 BP 476 EP 483 DI 10.1002/jps.24696 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TQ UT WOS:000381768500011 PM 26539698 ER PT J AU Yang, YS Mohammad, A Berendt, RT Carlin, A Khan, MA Faustino, PJ AF Yang, Yongsheng Mohammad, Adil Berendt, Robert T. Carlin, Alan Khan, Mansoor A. Faustino, Patrick J. TI Evaluation of the In Vitro Efficacy of Sevelamer Hydrochloride and Sevelamer Carbonate SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE sevelamer; inductively coupled plasma; phosphate binding; langmuir equation; bioequivalence; polymeric drugs; kinetics; absorption; drug interaction ID CHRONIC-RENAL-FAILURE; CHRONIC KIDNEY-DISEASE; LANTHANUM CARBONATE; PHOSPHATE BINDERS; CLINICAL-IMPLICATIONS; CALCIUM-CARBONATE; DIALYSIS; HYPERPHOSPHATEMIA; SAFETY; MEAL AB The objective of this project is to develop an in vitro approach that can be used to determine the phosphate binding capacity of sevelamer hydrochloride and carbonate for both drug products and active pharmaceutical ingredients (APIs). A simple and efficient inductively coupled plasma spectrometer method for analysis of phosphate at physiologically relevant pH conditions has been developed and validated. The method addresses each of the analytical validation characteristics such as linearity, accuracy, precision, stability, and selectivity, and meets the acceptance criteria defined in the United States Food and Drug Administration guidance (Food and Drug Administration, Center for Drug Evaluation and Research. 2001. Guidance for industry-Bioanalytical method validation, May). The in vitro phosphate binding efficacies were systematically evaluated and compared for two drug products and two APIs. The phosphate binding profiles appeared similar between the drug products. Under all conditions, the sevelamer-phosphate binding reached equilibrium at 6 h. The 90% confidence interval for the k(2) ratio (sevelamer carbonate vs. sevelamer hydrochloride) was well within 80%-125% under all pH conditions. However, the k(1) ratio varied, indicating that there exists difference in the binding affinity. Our findings will be useful in assisting with "in vivo" biowaiver for the approval of generic sevelamer drug products. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Yang, Yongsheng; Mohammad, Adil; Carlin, Alan; Khan, Mansoor A.; Faustino, Patrick J.] US FDA, Div Prod Qual Res, Off Pharmaceut Qual, Life Sci Bldg 64, Silver Spring, MD 20993 USA. [Berendt, Robert T.] US FDA, Off Lifecycle Drug Prod, Off Pharmaceut Qual, Life Sci Bldg 75, Silver Spring, MD 20993 USA. RP Yang, YS (reprint author), US FDA, Div Prod Qual Res, Off Pharmaceut Qual, Life Sci Bldg 64, Silver Spring, MD 20993 USA. EM yongsheng.yang@fda.hhs.gov NR 32 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD FEB PY 2016 VL 105 IS 2 BP 864 EP 875 DI 10.1002/jps.24572 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TQ UT WOS:000381768500053 PM 26219932 ER PT J AU Vaithianathan, S Haidar, SH Zhang, XY Jiang, WL Avon, C Dowling, TC Shao, CX Kane, M Hoag, SW Flasar, MH Ting, TY Polli, JE AF Vaithianathan, Soundarya Haidar, Sam H. Zhang, Xinyuan Jiang, Wenlei Avon, Christopher Dowling, Thomas C. Shao, Changxing Kane, Maureen Hoag, Stephen W. Flasar, Mark H. Ting, Tricia Y. Polli, James E. TI Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE Biopharmaceutics Classification System (BCS); bioequivalence; excipients; oral absorption; permeability; cimetidine; acyclovir ID IN-VIVO BIOAVAILABILITY; LOW-PERMEABILITY DRUGS; DOSAGE FORMS; LIQUID-CHROMATOGRAPHY; BIOWAIVER MONOGRAPHS; CAPSULE FORMULATIONS; CELL MONOLAYERS; WORKSHOP REPORT; RELEASE; BIOEQUIVALENCE AB The objective was to assess the impact of larger than conventional amounts of 14 commonly used excipients on Biopharmaceutics Classification System (BCS) class 3 drug absorption in humans. Cimetidine and acyclovir were used as model class 3 drugs across three separate four-way crossover bioequivalence (BE) studies (n = 24 each) in healthy human volunteers, denoted as study 1A, 1B, and 2. In study 1A and 1B, three capsule formulations of each drug were manufactured, collectively involving 14 common excipients. Capsule formulations that incorporated hydroxypropyl methylcellulose (HPMC) or magnesium stearate exhibited lower absorption. The cimetidine commercial solution contained sorbitol and also resulted in lower absorption. Hence, in study 2, two capsule formulations with lower amounts of HPMC and magnesium stearate, the sorbitol-containing commercial solution, and a sorbitol-free solution were assessed for BE. Overall, 12 common excipients were found in large amounts to not impact BCS class 3 drug absorption in humans, such that these excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather simply be not more than the quantities studied here. Meanwhile, for each HPMC and microcrystalline cellulose, BCS class 3 biowaivers require these two excipients to be qualitatively the same and quantitatively very similar to the reference. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Vaithianathan, Soundarya; Avon, Christopher; Shao, Changxing; Kane, Maureen; Hoag, Stephen W.; Polli, James E.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Haidar, Sam H.; Zhang, Xinyuan; Jiang, Wenlei] US FDA, Silver Spring, MD 20993 USA. [Dowling, Thomas C.] Ferris State Univ, Dept Pharm Practice, Grand Rapids, MI 49503 USA. [Flasar, Mark H.] Univ Maryland, Dept Gastroenterol & Hepatol, Baltimore, MD 21201 USA. [Ting, Tricia Y.] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. RP Polli, JE (reprint author), Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. EM jpolli@rx.umaryland.edu RI Dowling, Thomas/D-2147-2013 OI Dowling, Thomas/0000-0003-3214-9283 FU US FDA contracts [HHSF223200910020C, HHSF223200810041C]; University of Maryland Clinical Translational Science Institute; University of Maryland General Clinical Research Center; University of Maryland Mass Spectrometry Center [S0P1841-IQB2014] FX This work was supported by US FDA contracts HHSF223200910020C and HHSF223200810041C. This work was supported in part by the University of Maryland Clinical Translational Science Institute, the University of Maryland General Clinical Research Center, and the University of Maryland Mass Spectrometry Center (S0P1841-IQB2014). NR 44 TC 2 Z9 2 U1 6 U2 6 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 FEB PY 2016 VL 105 IS 2 BP 996 EP 1005 DI 10.1002/jps.24643 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TQ UT WOS:000381768500068 PM 26375604 ER PT J AU Chin, SJ Durmowicz, AG Chowdhury, BA AF Chin, Stacy J. Durmowicz, Anthony G. Chowdhury, Badrul A. TI Tiotropium Respimat Is Effective for the Treatment of Asthma at a Dose Lower Than That for Chronic Obstructive Pulmonary Disease SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article AB Anticholinergic drug products are not part of the current treatment paradigm for asthma, despite their widespread availability for chronic obstructive pulmonary disease (COPD) and interest in their use for asthma. Published study results, mostly of short duration and primarily with ipratropium and tiotropium, have revealed inconsistent efficacy results. Consequently, the role of inhaled anticholinergic drugs in the treatment of asthma has been unclear. This commentary discusses and comments on data from five clinical trials in adults that were submitted by Boehringer Ingelheim to the U.S. Food and Drug Administration to support approval of tiotropium delivered by the Respimat device (Spiriva Respimat) for the treatment of asthma. These trials provided substantial evidence that supported the approval of Spiriva Respimat at a recommended dose of 2.5 mu g once daily for asthma. Notably, in trials that evaluated two doses of tiotropium, 2.5 mu g and 5 mu g (the dose approved for COPD), pulmonary function measures for Spiriva Respimat 2.5 mu g once daily were better overall than those obtained for the 5-mu g once-daily dose, thus justifying selection of the lower dose for asthma. Spiriva Respimat represents the first new class of drug approved by the U.S. Food and Drug Administration for the treatment of asthma in more than a decade. The availability of Spiriva Respimat for asthma along with other novel therapies currently under development has the potential to impact asthma treatment guidelines. C1 [Chin, Stacy J.; Durmowicz, Anthony G.; Chowdhury, Badrul A.] US FDA, Div Pulm Allergy & Rheumatol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Chin, SJ (reprint author), US FDA, Div Pulm Allergy & Rheumatol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM stacy.chin@fda.hhs.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD FEB PY 2016 VL 13 IS 2 BP 173 EP 179 DI 10.1513/AnnalsATS.201510-712PS PG 7 WC Respiratory System SC Respiratory System GA DQ4HJ UT WOS:000379164400008 PM 26650145 ER PT J AU Tyson, GH Li, C Ayers, S McDermott, PF Zhao, SH AF Tyson, Gregory H. Li, Cong Ayers, Sherry McDermott, Patrick F. Zhao, Shaohua TI Using whole-genome sequencing to determine appropriate streptomycin epidemiological cutoffs for Salmonella and Escherichia coli SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE Salmonella; E. coli; whole-genome sequencing; streptomycin; resistance; genotyping ID ANTIMICROBIAL RESISTANCE; NUCLEOTIDE-SEQUENCE; SURVEILLANCE; ANIMALS; HUMANS; VALUES AB For Enterobacteriaceae such as Salmonella spp. and Escherichia coli, no unified interpretive resistance criteria exist for streptomycin, an epidemiologically important antibiotic. As part of the National Antimicrobial Resistance Monitoring System, we had previously used a minimum inhibitory concentration of >= 64 mu g mL(-1) as an epidemiological cutoff value (ECV) to define non-wild-type isolates. To identify whether this ECV correlated with genetic determinants of resistance, we performed whole-genome sequencing of 463 Salmonella and E. coli isolates to identify streptomycin resistance genotypes. From this analysis, we found that using a streptomycin resistance breakpoint of >= 64 mu g mL(-1)1 classified over 20% of strains possessing aadA or strA/strB resistance genes as wild-type. Therefore, to improve the concordance between genotypic and phenotypic data, we propose reducing the phenotypic cutoff values to >= 32 mu g mL(-1) for both Salmonella and E. coli, to be used widely as ECVs to categorize non-wild-type isolates. C1 [Tyson, Gregory H.; Li, Cong; Ayers, Sherry; McDermott, Patrick F.; Zhao, Shaohua] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. RP Tyson, GH (reprint author), US FDA, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM gregory.tyson@fda.hhs.gov NR 17 TC 3 Z9 3 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0378-1097 EI 1574-6968 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD FEB PY 2016 VL 363 IS 4 AR fnw009 DI 10.1093/femsle/fnw009 PG 5 WC Microbiology SC Microbiology GA DO7MI UT WOS:000377966300008 ER PT J AU Alrwisan, A Eworuke, E AF Alrwisan, Adel Eworuke, Efe TI ARE DISCREPANCIES IN WAITING TIME FOR CHEST PAIN AT EMERGENCY DEPARTMENTS BETWEEN AFRICAN AMERICANS AND WHITES IMPROVING OVER TIME? SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE African American; disparity; emergency department; race; waiting time ID UNITED-STATES; DISPARITIES; INSURANCE; CARE AB Background: One of the Healthy People 2010 goals was to eliminate racial disparities in the U.S health system. To date, we have limited knowledge about the impact of Healthy People on racial disparities at emergency departments (EDs). Objective: We sought to investigate whether there has been an improvement in ED waiting time to see a physician for African Americans (AAs) compared to whites with chest pain symptoms that suggest acute coronary syndrome (ACS). Methods: A retrospective analysis of the National Hospital and Ambulatory Care Survey data from 2004 to 2011 was conducted in adults with visits related to ACS. We compared covariate-adjusted odds ratios for race for each study year and 2011. In addition, adjusted average differences in waiting times (i.e., time to see a physician) for AAs and whites for each study year were compared. Results: A total of 15,438 visits related to ACS symptoms were made during the study period. The waiting time for AAs (median, 33 min) was statistically longer compared to whites (median, 21 min). In addition, the adjusted waiting time for AAs was 30% longer compared to whites (95% confidence interval, 24-36%). Pairwise comparison of adjusted odds ratios between the year 2011 and other years was not significantly different (all p values = 0.32), suggesting no change in the difference in waiting times during the study period. Conclusion: Among patients presenting to the ED with symptoms suggesting ACS, AA compared to whites waited longer to receive care. In addition, this difference in waiting time persisted during the study period, even after the implementation of the Healthy People 2010 initiative. Additional research is warranted to investigate the underlying reasons for unequal care offered to AAs at EDs and the implications on disease outcome. (C) 2016 Elsevier Inc. C1 [Alrwisan, Adel] Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, POB 100496, Gainesville, FL 32610 USA. [Alrwisan, Adel] Saudi Food & Drug Author Vigilance & Crisis Manag, Riyadh, Saudi Arabia. [Eworuke, Efe] US FDA, Div Epidemiol 2, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Washington, DC 20204 USA. RP Alrwisan, A (reprint author), Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, POB 100496, Gainesville, FL 32610 USA. NR 21 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD FEB PY 2016 VL 50 IS 2 BP 349 EP 354 DI 10.1016/j.jemermed.2015.07.033 PG 6 WC Emergency Medicine SC Emergency Medicine GA DI2BB UT WOS:000373299600041 PM 26371975 ER PT J AU Breslin, ME Hamilton, DK Guo, RS Ye, P Jiang, XT Stewart, P Chin, S Kim, EH Burks, AW AF Breslin, Moira E. Hamilton, Deanna K. Guo, Rishu Ye, Ping Jiang, Xiaotong Stewart, Paul Chin, Stacy Kim, Edwin H. Burks, A. Wesley TI Basophil Activation and Peanut-Specific IgE Are Not Predictors of Threshold Dose during a Double-Blind Placebo-Controlled Food Challenge (DBPCFC) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 04-07, 2016 CL Los Angeles, CA SP Amer Acad Allergy, Asthma & Immunol C1 [Breslin, Moira E.; Hamilton, Deanna K.; Guo, Rishu; Ye, Ping; Jiang, Xiaotong; Stewart, Paul; Kim, Edwin H.; Burks, A. Wesley] Univ N Carolina, Chapel Hill, NC USA. [Chin, Stacy] US FDA, CDER, Washington, DC 20204 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2016 VL 137 IS 2 SU S MA 414 BP AB125 EP AB125 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA DK6BI UT WOS:000375005402104 ER PT J AU Khurana, T Shartouny, JR David, NA Slater, JE AF Khurana, Taruna Shartouny, Jessica R. David, Natalie A. Slater, Jay E. TI Measurement of Major Allergen Mus m 1 in Commercial Mouse Allergen Extracts and Mouse Urine SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 04-07, 2016 CL Los Angeles, CA SP Amer Acad Allergy, Asthma & Immunol C1 [Khurana, Taruna; Shartouny, Jessica R.; David, Natalie A.; Slater, Jay E.] FDA, CBER, OVRR, DBPAP, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2016 VL 137 IS 2 SU S MA 595 BP AB182 EP AB182 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA DK6BI UT WOS:000375005403041 ER PT J AU Kwegyir-Afful, EK Westermann-Clark, E Zhang, YT Luccioli, S AF Kwegyir-Afful, Ernest K. Westermann-Clark, Emma Zhang, Yuanting Luccioli, Stefano TI Food Diversity, Breastfeeding Frequency, and the Incidence of Food Allergy and Eczema in the First Year of Life SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 04-07, 2016 CL Los Angeles, CA SP Amer Acad Allergy, Asthma & Immunol C1 [Kwegyir-Afful, Ernest K.; Zhang, Yuanting; Luccioli, Stefano] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Westermann-Clark, Emma] Univ S Florida, Dept Internal Med, Morsani Coll Med, Tampa, FL 33612 USA. NR 0 TC 0 Z9 0 U1 3 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2016 VL 137 IS 2 SU S MA 481 BP AB147 EP AB147 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA DK6BI UT WOS:000375005402172 ER PT J AU Mattison, CP Khurana, T Tarver, M Florane, C Grimm, CC Pakala, S Cottone, C Riegel, C Slater, JE AF Mattison, Christopher P. Khurana, Taruna Tarver, Matthew Florane, Christopher Grimm, Casey C. Pakala, Suman Cottone, Carrie Riegel, Claudia Slater, Jay E. TI Termite Proteins Cross-React with Cockroach Allergens SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 04-07, 2016 CL Los Angeles, CA SP Amer Acad Allergy, Asthma & Immunol C1 [Mattison, Christopher P.; Florane, Christopher; Grimm, Casey C.] USDA ARS, SRRC, New Orleans, LA USA. [Khurana, Taruna; Slater, Jay E.] US FDA, CBER, OVRR, DBPAP, Silver Spring, MD USA. [Tarver, Matthew] Bayer CropSci, West Sacramento, CA USA. [Pakala, Suman] Univ Georgia, Athens, GA 30602 USA. [Cottone, Carrie; Riegel, Claudia] New Orleans Mosquito Termite & Rodent Control Boa, New Orleans, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2016 VL 137 IS 2 SU S MA 872 BP AB266 EP AB266 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA DK6BI UT WOS:000375005404068 ER PT J AU Rabin, RL Novatt, H Theisen, TC Renn, LA AF Rabin, Ronald L. Novatt, Hilary Theisen, Terence C. Renn, Lynnsey A. TI Patterns of Interferon Regulatory Factor 1 (IRF1) Expression By Respiratory Epithelial Cells Reveal Non-Redundancy of Type I Versus Type III Interferons SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY MAR 04-07, 2016 CL Los Angeles, CA SP Amer Acad Allergy, Asthma & Immunol C1 [Rabin, Ronald L.] US FDA, CBER, Silver Spring, MD USA. [Novatt, Hilary] US FDA, Ctr Biol & Evaluat, Silver Spring, MD USA. [Novatt, Hilary; Theisen, Terence C.; Renn, Lynnsey A.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2016 VL 137 IS 2 SU S MA L50 BP AB405 EP AB405 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA DK6BI UT WOS:000375005405031 ER PT J AU Jarow, JP Ahmed, HU Choyke, PL Taneja, SS Scardino, PT AF Jarow, Jonathan P. Ahmed, Hashim U. Choyke, Peter L. Taneja, Samir S. Scardino, Peter T. TI Partial Gland Ablation for Prostate Cancer: Report of a Food and Drug Administration, American Urological Association, and Society of Urologic Oncology Public Workshop SO UROLOGY LA English DT Article ID FOCAL THERAPY; CONSENSUS PANEL; ULTRASOUND; PATHWAY; BIOPSY AB OBJECTIVE To summarize the discussion that took place at a public workshop, co-sponsored by the U.S. Food and Drug Administration, the American Urological Association, and Society of Urologic Oncology reviewing the current state of the art for partial gland ablation (PGA) for the management of patients with prostate cancer. The purpose of this workshop was to discuss potential indications, current available evidence, and designs for future trials to provide the evidence needed by patients and providers to decide how and when to use PGA. METHODS A workshop evaluating PGA for prostate cancer was held in New Orleans, Louisiana, in May 2015. Invited experts representing all stakeholders and attendees discussed the regulatory development of medical products, technology available, potential indications, and designs of trials to evaluate this modality of therapy. RESULTS The panel presented the current information on the technologies available to perform PGA, the potential indications, and results of prior consensus conferences. Use of magnetic resonance imaging for patient selection, guide therapy, and follow-up was discussed. Designs of trials to assess PGA outcomes were discussed. CONCLUSION The general consensus was that currently available technologies are capable of selective ablation with reasonable accuracy, but that criteria for patient selection remain debatable, and long-term cancer control remains to be established in properly designed and well-performed prospective clinical trials. Concerns include the potential for excessive, unnecessary use in patients with low-risk cancer and, conversely, that current diagnostic techniques may underestimate the extent and aggressiveness of some cancers, leading to inadequate treatment. Published by Elsevier Inc. C1 US FDA, CDER Off Med Policy, Silver Spring, MD USA. UCL, Div Surg & Intervent Sci, London, England. NCI, Ctr Canc Res, Reston, VA USA. NYU, Langone Med Ctr, Div Urol Oncol, New York, NY USA. Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA. RP Jarow, JP (reprint author), Off Med Policy, WO51 RM6338,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jonathan.jarow@fda.hhs.gov FU Sonacare Inc.; Trod Medical; Sophiris Biocorp; Biobot; Hitachi-Aloka FX Hashim U. Ahmed received clinical trial funding from Sonacare Inc., and also funding for conference travel and honoraria for lectures at courses organized by the said company. He is currently a paid proctor for HIFU. He also received current clinical trial funding from Trod Medical and Sophiris Biocorp. He is previous Consultant for protocol writing at Steba Biotech and is current Consultant for protocol writing for Exact Imaging. He previously received resources from Angiodynamics Inc. through free device and probe use within investigator-led clinical trial. At present, he received resources from Hitachi through free probe use within investigator led clinical trial. Samir S. Taneja is a paid consultant to Hitachi-Aloka and a study investigator for Steba-Biotech and Trod Medical. He received funding from Biobot and Hitachi-Aloka. The remaining authors declare that they have no relevant financial interests. NR 27 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD FEB PY 2016 VL 88 BP 8 EP 13 DI 10.1016/j.urology.2015.11.018 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DI4IW UT WOS:000373464600006 PM 26621480 ER PT J AU Anez, G Heisey, DAR Chancey, C Fares, RCG Espina, LM Souza, KPR Teixeira-Carvalho, A Krysztof, DE Foster, GA Stramer, SL Rios, M AF Anez, German Heisey, Daniel A. R. Chancey, Caren Fares, Rafaelle C. G. Espina, Luz M. Souza, Katia P. R. Teixeira-Carvalho, Andrea Krysztof, David E. Foster, Gregory A. Stramer, Susan L. Rios, Maria TI Distribution of Dengue Virus Types 1 and 4 in Blood Components from Infected Blood Donors from Puerto Rico SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TRANSFUSION-TRANSMITTED DENGUE; HEPATITIS-C VIRUS; TRANSPLANT RECIPIENTS; HEMORRHAGIC-FEVER; DISEASE SEVERITY; WEST; VIREMIA; RNA; TRANSMISSION; SEROTYPE AB Background Dengue is a mosquito-borne viral disease caused by the four dengue viruses (DENV-1 to 4) that can also be transmitted by blood transfusion and organ transplantation. The distribution of DENV in the components of blood from infected donors is poorly understood. Methods We used an in-house TaqMan qRT-PCR assay to test residual samples of plasma, cellular components of whole blood (CCWB), serum and clot specimens from the same collection from blood donors who were DENV-RNA-reactive in a parallel blood safety study. To assess whether DENV RNA detected by TaqMan was associated with infectious virus, DENV infectivity in available samples was determined by culture in mosquito cells. Results DENV RNA was detected by TaqMan in all tested blood components, albeit more consistently in the cellular components; 78.8% of CCWB, 73.3% of clots, 86.7% of sera and 41.8% of plasma samples. DENV-1 was detected in 48 plasma and 97 CCWB samples while DENV-4 was detected in 21 plasma and 31 CCWB samples. In mosquito cell cultures, 29/111 (26.1%) plasma and 32/97 (32.7%) CCWB samples were infectious. A subset of samples from 29 donors was separately analyzed to compare DENV viral loads in the available blood components. DENV viral loads did not differ significantly between components and ranged from 3-8 log(10) PCR-detectable units/ml. Conclusions DENV was present in all tested components from most donors, and viral RNA was not preferentially distributed in any of the tested components. Infectious DENV was also present in similar proportions in cultured plasma, clot and CCWB samples, indicating that these components may serve as a resource when sample sizes are limited. However, these results suggest that the sensitivity of the nucleic acid tests (NAT) for these viruses would not be improved by testing whole blood or components other than plasma. C1 [Anez, German; Heisey, Daniel A. R.; Chancey, Caren; Fares, Rafaelle C. G.; Espina, Luz M.; Souza, Katia P. R.; Teixeira-Carvalho, Andrea; Rios, Maria] US FDA, Silver Spring, MD USA. [Krysztof, David E.; Foster, Gregory A.; Stramer, Susan L.] Amer Red Cross, Gaithersburg, MD USA. [Anez, German] Sanofi Pasteur, Swiftwater, PA USA. [Heisey, Daniel A. R.] Virginia Commonwealth Univ, Richmond, VA USA. [Espina, Luz M.] Univ Zulia, Maracaibo 4011, Venezuela. [Souza, Katia P. R.] Fundacao Oswaldo Cruz FIOCRUZ, Rio De Janeiro, Brazil. [Teixeira-Carvalho, Andrea] Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil. RP Rios, M (reprint author), US FDA, Silver Spring, MD USA. EM maria.rios@fda.hhs.gov OI Anez, German/0000-0001-5361-3001 FU United States Food and Drug Administration, Center for Biologics Evaluation and Research; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) FX This study was internally funded by the United States Food and Drug Administration, Center for Biologics Evaluation and Research. This project was supported in part by appointments (DARH, CC, LME, KPRS, ATC) to the Research Participation Program at the Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and F.D.A. ATC thanks Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) for the fellowship (PQ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2016 VL 10 IS 2 AR e0004445 DI 10.1371/journal.pntd.0004445 PG 17 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DH1TH UT WOS:000372567300053 PM 26871560 ER PT J AU Kerlin, R Bolon, B Burkhardt, J Francke, S Greaves, P Meador, V Popp, J AF Kerlin, Roy Bolon, Brad Burkhardt, John Francke, Sabine Greaves, Peter Meador, Vince Popp, James TI Scientific and Regulatory Policy Committee: Recommended ("Best") Practices for Determining, Communicating, and Using Adverse Effect Data from Nonclinical Studies SO TOXICOLOGIC PATHOLOGY LA English DT Article DE adversity; NOAEL; nonclinical; risk assessment; toxicity study ID BENCHMARK DOSE APPROACH; BEAGLE DOGS; TOXICITY; NOAEL; TOXICOLOGY; CHEMICALS; ANIMALS; HUMANS; RATS AB Recommendations (best practices) are provided by the Society of Toxicologic Pathology's Adversity Working Group for making consistent interpretations of test article-related effects as adverse and assigning a no observed adverse effect level (NOAEL) in nonclinical toxicity studies. Adverse is a term indicating harm to the test animal, while nonadverse indicates lack of harm. Adverse findings in the study reports should be defined in relation to effects on the test species used and within the context of the given study. Test article-related effects should be described on their own merits, and decisions to consider them as adverse or nonadverse should be justified. Related effects may be discussed together; in particular, markers of toxicity that are not in and of themselves adverse ideally should be discussed in conjunction with the causal toxicity to determine adversity. Adverse findings should be identified in subreports (clinical data, pathology data, etc.) if sufficient information is available, and/or in the final study report as individual or grouped findings, but study NOAELs should be established at the level of the overall study report. Interpretations such as not biologically relevant or not toxicologically important should be avoided unless defined and supported by scientific rationale. Decisions defining adverse findings and the NOAEL in final study reports should combine the expertise of all contributing scientific disciplines. Where possible, use of NOAELs in data tables should be linked to explanatory text that places them in context. Ideally, in nonclinical summary documents, NOAELs from multiple studies are considered together in defining the most important adverse responses in the most sensitive species. These responses are then considered along with an understanding of their likely mechanisms, as well as other information such as variability in species sensitivity, comparative pathology, reversibility and progression, kinetics, and metabolism of the test substance to help assess human risk. C1 [Kerlin, Roy] Pfizer Worldwide Res & Dev, Drug Safety Res & Dev, Groton, CT 06340 USA. [Bolon, Brad] GEMpath Inc, Longmont, CO USA. [Burkhardt, John] AbbVie Res & Dev, Preclin Safety, N Chicago, IL USA. [Francke, Sabine] US FDA, CFSAN, College Pk, MD USA. [Greaves, Peter] Leicester Royal Infirm, Dept Canc Studies, Leicester, Leics, England. [Meador, Vince] Covance Labs Inc, Madison, WI USA. [Popp, James] Stratoxon LLC, Lancaster, PA USA. RP Kerlin, R (reprint author), Pfizer Worldwide Res & Dev, Drug Safety Res & Dev, Groton, CT 06340 USA. EM roy.l.kerlin@pfizer.com FU Society of Toxicologic Pathology FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This document was sponsored and is supported by the Society of Toxicologic Pathology and is endorsed by other professional organizations involved with toxicologic pathology, including The American College of Veterinary Pathologists, The American Society for Veterinary Clinical Pathology, Societe Francaise de Pathologie Toxicologique'' (French Society of Toxicologic Pathology), The British Society of Toxicologic Pathology, The European Society of Toxicologic Pathology, The Japanese Society of Toxicologic Pathology, and The American College of Toxicology). NR 40 TC 4 Z9 4 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2016 VL 44 IS 2 BP 147 EP 162 DI 10.1177/0192623315623265 PG 16 WC Pathology; Toxicology SC Pathology; Toxicology GA DH0KL UT WOS:000372473000002 PM 26704930 ER PT J AU Wang, W Alvarado-Facundo, E Chen, Q Anderson, CM Scott, D Vassell, R Weiss, CD AF Wang, Wei Alvarado-Facundo, Esmeralda Chen, Qiong Anderson, Christine M. Scott, Dorothy Vassell, Russell Weiss, Carol D. TI Serum Samples From Middle-aged Adults Vaccinated Annually with Seasonal Influenza Vaccines Cross-neutralize Some Potential Pandemic Influenza Viruses SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE cross-neutralization; influenza vaccines; neutralizing antibodies; pandemic influenza; stem antibodies ID REACTIVE ANTIBODY-RESPONSES; H2N2; H3; H1; H5 AB We examined serum samples from adults ages 48-64 who received multiple seasonal influenza vaccines from 2004 to 2009 for cross-neutralizing antibodies to potential pandemic strains. Using pseudoviruses bearing various hemagglutinins (HA-pseudoviruses), we found serum neutralization titers (>= 160) in 100% against A/Japan/305/1957 (H2N2), 53% against A/Hong Kong/1073/99 (H9N2), 56% against the H3N2 variant A/Indiana/08/11 (H3N2v), 11% against A/Hong Kong/G9/97 (H9N2), and 36% A/chicken/Hong Kong/SF4/01 (H6N1). None had titers >160 to A/Shanghai/2/13 (H7N9) or A/Netherlands/219/03 (H7N7). Thirty-six percent to 0% had neutralization titers to various H5N1 strains. Titers to H9, H6, and H5 HA-pseudoviruses correlated with each other, but not with H3N2v, suggesting group-specific cross-neutralization. C1 [Wang, Wei; Alvarado-Facundo, Esmeralda; Chen, Qiong; Vassell, Russell; Weiss, Carol D.] US FDA, Div Viral Prod, Lab Immunoregulat, Silver Spring, MD 20993 USA. [Anderson, Christine M.; Scott, Dorothy] US FDA, Ctr Biol Evaluat & Res, Div Hematol, Silver Spring, MD 20993 USA. RP Weiss, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,WO Bldg 72,Rm 1214, Silver Spring, MD 20993 USA. EM carol.weiss@fda.hhs.gov FU US Food and Drug Administration FX This work was supported by institutional funds from the US Food and Drug Administration. NR 15 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2016 VL 213 IS 3 BP 403 EP 406 DI 10.1093/infdis/jiv407 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DG9XB UT WOS:000372436000011 PM 26243315 ER PT J AU Lapteva, L Pariser, AR AF Lapteva, Larissa Pariser, Anne R. TI Investigational New Drug applications: a 1-year pilot study on rates and reasons for clinical hold SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Article DE Rare Diseases; Drugs; Investigational; Clinical Research AB Background The Food and Drug Administration (FDA)'s Center for Drug Evaluation and Research (CDER) receives about 1500 initial Investigational New Drug applications (INDs) per year. In the first 30days after initial IND submission, FDA conducts a review to determine whether the proposed investigation is safe to proceed, and if not, the IND may be placed on clinical hold. Methods A retrospective study of rates and reasons for clinical hold for all initial INDs submitted to CDER in fiscal year (FY) 2013 was performed. INDs were assessed for reasons that led to clinical hold, included chemistry, manufacturing and controls (CMC), animal toxicology or clinical issues. INDs were further categorized by commercial versus research sponsorship, and rare versus common disease indications. All INDs placed on hold were reassessed by whether they remained on hold within the first year following hold imposition. Results CDER received 1410 initial INDs in FY 2013, of which 125 (8.9%) were placed on hold during the first 30days after initial submission. Of the INDs placed on hold, more than half became active within the first year after first imposition of hold. CMC reasons were most commonly cited, followed by clinical, then toxicology reasons. There were no substantive differences in rates and reasons for hold between INDs for rare or common disease indications, or between commercial or research INDs. Conclusions The vast majority of initial INDs moved forward within 30days after submission, and for those applications placed on hold, most became active within 1year. The findings also suggest that many holds for new drug product programs can be avoided by following the available guidelines for investigational product development. C1 [Lapteva, Larissa] US FDA, Div Therapeut Performance, Off Res & Stand, Off Gener Drugs,CDER, Silver Spring, MD USA. [Pariser, Anne R.] US FDA, Off Translat Sci, CDER, 10903 New Hampshire Ave,WO21-4607, Silver Spring, MD 20993 USA. RP Pariser, AR (reprint author), US FDA, Off Translat Sci, CDER, 10903 New Hampshire Ave,WO21-4607, Silver Spring, MD 20993 USA. EM anne.pariser@fda.hhs.gov NR 9 TC 0 Z9 0 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 2016 VL 64 IS 2 BP 376 EP 382 DI 10.1136/jim-2015-000010 PG 7 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA DG6FX UT WOS:000372179700005 PM 26911627 ER PT J AU Kluetz, PG Pazdur, R AF Kluetz, Paul G. Pazdur, Richard TI Looking to the future in an unprecedented time for cancer drug development SO SEMINARS IN ONCOLOGY LA English DT Review DE Clinical trials; Regulation; Endpoints ID ONCOLOGY; TRIALS AB Basic research in cancer biology, genetics and immunology has resulted in improved insights into mechanisms that drive tumor initiation and growth. This improved biologic understanding of the diseases we treat has led to unprecedented therapeutic breakthroughs across multiple tumor types. In this article, we discuss opportunities and. challenges in contemporary cancer drug development, highlighting efficacy endpoints, clinical trial design and the thoughtful inclusion of the patient perspective. As the field re-examines old practices and explores new opportunities, we must continue to efficiently utilize the human and scientific resources at our disposal to foster the development and delivery of safe and effective therapies to cancer patients. Published by Elsevier Inc. C1 [Kluetz, Paul G.; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, FDA CDER OND, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Kluetz, PG (reprint author), US FDA, Off Hematol & Oncol Prod, FDA CDER OND, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Paul.Kluetz@fda.hhs.gov NR 9 TC 2 Z9 2 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2016 VL 43 IS 1 BP 2 EP 3 DI 10.1053/j.seminoncol.2016.01.001 PG 2 WC Oncology SC Oncology GA DH3KM UT WOS:000372685900002 PM 26970117 ER PT J AU Gierach, GL Patel, DA Pfeiffer, RM Figueroa, JD Linville, L Papathomas, D Johnson, JM Chicoine, RE Herschorn, SD Shepherd, JA Wang, J Malkov, S Vacek, PM Weaver, DL Fan, B Mahmoudzadeh, AP Palakal, M Xiang, J Oh, H Horne, HN Sprague, BL Hewitt, SM Brinton, LA Sherman, ME AF Gierach, Gretchen L. Patel, Deesha A. Pfeiffer, Ruth M. Figueroa, Jonine D. Linville, Laura Papathomas, Daphne Johnson, Jason M. Chicoine, Rachael E. Herschorn, Sally D. Shepherd, John A. Wang, Jeff Malkov, Serghei Vacek, Pamela M. Weaver, Donald L. Fan, Bo Mahmoudzadeh, Amir Pasha Palakal, Maya Xiang, Jackie Oh, Hannah Horne, Hisani N. Sprague, Brian L. Hewitt, Stephen M. Brinton, Louise A. Sherman, Mark E. TI Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities SO CANCER PREVENTION RESEARCH LA English DT Article ID CANCER RISK; TISSUE COMPOSITION; FIBROGLANDULAR TISSUE; ASSOCIATION; AGE; PATTERNS; BIOPSY; WOMEN AB Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLU), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (perilesional). Three measures inversely related to TDLU involution (TDLU count/mm(2), median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40-65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent perilesional MD (P trend = 0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P trend<0.05) and absolute perilesionalMD (P = 0.003). Acini count was directly associated with absolute perilesional MD (P = 0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P trend <= 0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in perilesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction. (C)2015 AACR. C1 [Gierach, Gretchen L.; Patel, Deesha A.; Figueroa, Jonine D.; Linville, Laura; Papathomas, Daphne; Palakal, Maya; Xiang, Jackie; Oh, Hannah; Horne, Hisani N.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Chicoine, Rachael E.; Herschorn, Sally D.; Vacek, Pamela M.; Weaver, Donald L.; Sprague, Brian L.] Univ Vermont, Burlington, VT USA. [Johnson, Jason M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Shepherd, John A.; Wang, Jeff; Malkov, Serghei; Fan, Bo; Mahmoudzadeh, Amir Pasha] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Patel, Deesha A.] Northwestern Univ, Div Gen Internal Med, Feinberg Sch Med, Evanston, IL USA. [Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Inst Genet & Mol Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Linville, Laura] George Washington Sch Med & Hlth Studies, Washington, DC USA. [Wang, Jeff] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan. [Horne, Hisani N.] US FDA, Silver Spring, MD USA. RP Gierach, GL (reprint author), NCI, 9609 Med Ctr Dr,Rm 7-E108, Bethesda, MD 20892 USA. EM gierachg@mail.nih.gov RI Gierach, Gretchen/E-1817-2016; OI Gierach, Gretchen/0000-0002-0165-5522; Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the NCI; NCI [U01CA70013, U54CA163303, 1R21CA157254]; Breast Cancer Research Stamp Funds from the NCI [U01CA70013, U54CA163303, 1R21CA157254] FX This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the NCI. Breast Cancer Research Stamp Funds and cooperative agreement U01CA70013 and U54CA163303 (to B.M. Geller, P.M. Vacek, D.L. Weaver, R.E. Chicoine, S.D. Herschorn, and B. Sprague) and 1R21CA157254 (to J.A. Shepherd, S. Malkov, B. Fan, and A.P. Mahmoudzadeh) from the NCI funded some of the data collection and image analysis for this study. NR 39 TC 7 Z9 7 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2016 VL 9 IS 2 BP 149 EP 158 DI 10.1158/1940-6207.CAPR-15-0282 PG 10 WC Oncology SC Oncology GA DG3YC UT WOS:000372006100006 PM 26645278 ER PT J AU Campi-Azevedo, AC Costa-Pereira, C Antonelli, LR Fonseca, CT Teixeira-Carvalho, A Villela-Rezende, G Santos, RA Batista, MA Campos, FM Pacheco-Porto, L Melo, OA Hossell, DMSH Coelho-dos-Reis, JG Peruhype-Magalhaes, V Costa-Silva, MF de Oliveira, JG Farias, RH Noronha, TG Lemos, JA von Doellinger, VD Simoes, M de Souza, MM Malaquias, LC Persi, HR Pereira, JM Martins, JA Dornelas-Ribeiro, M Vinhas, AD Alves, TR Maia, MD Freire, MD Martins, RD Homma, A Romano, APM Domingues, CM Tauil, PL Vasconcelos, PF Rios, M Caldas, IR Camacho, LA Martins, OA AF Campi-Azevedo, Ana Carolina Costa-Pereira, Christiane Antonelli, Lis R. Fonseca, Cristina T. Teixeira-Carvalho, Andrea Villela-Rezende, Gabriela Santos, Raiany A. Batista, Mauricio A. Campos, Fernanda M. Pacheco-Porto, Luiza Melo Junior, Otoni A. Hossell, Debora M. S. H. Coelho-dos-Reis, Jordana G. Peruhype-Magalhaes, Vanessa Costa-Silva, Matheus F. de Oliveira, Jaquelline G. Farias, Roberto H. Noronha, Tatiana G. Lemos, Jandira A. von Doellinger, Vanessa dos R. Simoes, Marisol de Souza, Mirian M. Malaquias, Luiz C. Persi, Harold R. Pereira, Jorge M. Martins, Jose A. Dornelas-Ribeiro, Marcos Vinhas, Aline de A. Alves, Tatiane R. Maia, Maria de L. Freire, Marcos da S. Martins, Reinaldo de M. Homma, Akira Romano, Alessandro P. M. Domingues, Carla M. Tauil, Pedro L. Vasconcelos, Pedro F. Rios, Maria Caldas, Iramaya R. Camacho, Luiz A. Martins-Filho, Olindo Assis TI Booster dose after 10 years is recommended following 17DD-YF primary vaccination SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE yellow fever; vaccine; cytokine; flow cytometry; memory cells and vaccination; duration of immunity ID YELLOW-FEVER VIRUS; ANTIGEN PRESENTATION; IMMUNE ACTIVATION; CELLS; 17D; RESPONSES; VACCINES; IMMUNIZATION; ANTIBODIES; INFECTION AB A single vaccination of Yellow Fever vaccines is believed to confer life-long protection. In this study, results of vaccinees who received a single dose of 17DD-YF immunization followed over 10 y challenge this premise. YF-neutralizing antibodies, subsets of memory T and B cells as well as cytokine-producing lymphocytes were evaluated in groups of adults before (NVday0) and after (PVday30-45, PVyear1-4, PVyear5-9, PVyear10-11, PVyear12-13) 17DD-YF primary vaccination. YF-neutralizing antibodies decrease significantly from PVyear1-4 to PVyear12-13 as compared to PVday30-45, and the seropositivity rates (PRNT2.9Log(10)mIU/mL) become critical (lower than 90%) beyond PVyear5-9. YF-specific memory phenotypes (effector T-cells and classical B-cells) significantly increase at PVday30-45 as compared to naive baseline. Moreover, these phenotypes tend to decrease at PVyear10-11 as compared to PVday30-45. Decreasing levels of TNF-(+) and IFN-(+) produced by CD4(+) and CD8(+) T-cells along with increasing levels of IL-10(+)CD4(+)T-cells were characteristic of anti-YF response over time. Systems biology profiling represented by hierarchic networks revealed that while the naive baseline is characterized by independent micro-nets, primary vaccinees displayed an imbricate network with essential role of central and effector CD8(+) memory T-cell responses. Any putative limitations of this cross-sectional study will certainly be answered by the ongoing longitudinal population-based investigation. Overall, our data support the current Brazilian national immunization policy guidelines that recommend one booster dose 10 y after primary 17DD-YF vaccination. C1 [Campi-Azevedo, Ana Carolina; Costa-Pereira, Christiane; Antonelli, Lis R.; Fonseca, Cristina T.; Teixeira-Carvalho, Andrea; Villela-Rezende, Gabriela; Santos, Raiany A.; Batista, Mauricio A.; Campos, Fernanda M.; Pacheco-Porto, Luiza; Melo Junior, Otoni A.; Hossell, Debora M. S. H.; Coelho-dos-Reis, Jordana G.; Peruhype-Magalhaes, Vanessa; Costa-Silva, Matheus F.; de Oliveira, Jaquelline G.; Martins-Filho, Olindo Assis] Fiocruz MS, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil. [Farias, Roberto H.; Noronha, Tatiana G.; von Doellinger, Vanessa dos R.; Simoes, Marisol; de Souza, Mirian M.; Freire, Marcos da S.; Martins, Reinaldo de M.] Fiocruz MS, Inst Tecnol Imunobiol Biomanguinhos, Rio De Janeiro, Brazil. [Lemos, Jandira A.] Governo Estado Minas Gerais, Secretaria Estado Saude, Belo Horizonte, MG, Brazil. [Malaquias, Luiz C.] Univ Fed Alfenas, Alfenas, MG, Brazil. [Persi, Harold R.; Pereira, Jorge M.; Martins, Jose A.; Dornelas-Ribeiro, Marcos; Vinhas, Aline de A.; Alves, Tatiane R.] Inst Biol Exercito, Rio De Janeiro, Brazil. [Maia, Maria de L.; Homma, Akira] Fiocruz MS, Assessoria Clin Biomanguinhos, Rio De Janeiro, Brazil. [Romano, Alessandro P. M.; Domingues, Carla M.] Minist Saude, Secretaria Vigilancia Saude, Sao Paulo, Brazil. [Tauil, Pedro L.] Univ Brasilia, BR-70910900 Brasilia, DF, Brazil. [Vasconcelos, Pedro F.] IEC, Ananindeua, Para, Brazil. [Rios, Maria] US FDA, CBER, Silver Spring, MD USA. [Caldas, Iramaya R.] Fiocruz MS, Diretoria Reg Brasilia Direb, Brasilia, DF, Brazil. [Camacho, Luiz A.] Fiocruz MS, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. RP Martins, OA (reprint author), Fiocruz MS, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil. EM oamfilho@cpqrr.fiocruz.br RI Martins, Reinaldo/I-3413-2015 OI Martins, Reinaldo/0000-0002-0667-532X FU Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG); Bio-Manguinhos/FIOCRUZ; PROEP/CPqRR/FIOCRUZ; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Programa Nacional de Imunizacoes (PNI) - Ministerio da Saude Brazil; FIOTEC; PDTIS; CAPES; Secretaria de Vigilancia em Saude (SVS); CNPq MCTI/CNPQ/Universal [14/2014, 444417/2014-1, 458134/2014-7]; CNPq FX The authors thank Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Bio-Manguinhos/FIOCRUZ; PROEP/CPqRR/FIOCRUZ; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Programa Nacional de Imunizacoes (PNI) - Ministerio da Saude Brazil, FIOTEC, PDTIS, CAPES and Secretaria de Vigilancia em Saude (SVS) for financial support. ACCA and JGCdR received financial support from CNPq MCTI/CNPQ/Universal 14/2014 (ACCA - Grant # 444417/2014-1 and JGCdR - Grant # 458134/2014-7). OAMF and ATC thank the CNPq for the fellowships (PQ). NR 29 TC 3 Z9 3 U1 2 U2 2 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 FEB 1 PY 2016 VL 12 IS 2 BP 491 EP 502 DI 10.1080/21645515.2015.1082693 PG 12 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA DG0HK UT WOS:000371745700040 PM 26360663 ER PT J AU Silverstein, JS Casey, BJ Kofinas, P Dair, BJ AF Silverstein, Joshua S. Casey, Brendan J. Kofinas, Peter Dair, Benita J. TI Protein Adsorption on Chemically Modified Block Copolymer Nanodomains: Influence of Charge and Flow SO JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY LA English DT Article DE Quartz Crystal Microbalance; Atomic Force Microscopy; Block Copolymer; Protein Adsorption; Nanopattern ID QUARTZ-CRYSTAL MICROBALANCE; SELF-ASSEMBLED MONOLAYERS; HYDROPHOBIC SURFACES; CELL-ADHESION; CONFORMATIONAL-CHANGES; PLASMA-PROTEINS; SOLID-SURFACES; SERUM-ALBUMIN; ACRYLIC-ACID; IN-SITU AB Understanding the interactions of biomacromolecules with nanoengineered surfaces is vital for assessing material biocompatibility. This study focuses on the dynamics of protein adsorption on nanopatterned block copolymers (BCPs). Poly(styrene)-block-poly(1,2-butadiene) BCPs functionalized with an acid, amine, amide, or captopril moieties were processed to produce nanopatterned films. These films were characterized using water contact angle measurements and atomic force microscopy in air and liquid to determine how the modification process affected wettability and swelling. Protein adsorption experiments were conducted under static and dynamic conditions via a quartz crystal microbalance with dissipation. Proteins of various size, charge, and stability were investigated to determine whether their physical characteristics affected adsorption. Significantly decreased contact angles were caused by selective swelling of modified BCP domains. The results indicate that nanopatterned chemistry and experimental conditions strongly impact adsorption dynamics. Depending on the structural stability of the protein, polyelectrolyte surfaces significantly increased adsorption over controls. Further analysis suggested that protein stability may correlate with dissipation versus frequency plots. C1 [Silverstein, Joshua S.; Kofinas, Peter] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Silverstein, Joshua S.; Casey, Brendan J.; Dair, Benita J.] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Chem & Mat Sci, Silver Spring, MD 20993 USA. RP Dair, BJ (reprint author), US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Chem & Mat Sci, Silver Spring, MD 20993 USA. OI Kofinas, Peter/0000-0001-6657-3037 NR 51 TC 0 Z9 0 U1 5 U2 17 PU AMER SCIENTIFIC PUBLISHERS PI VALENCIA PA 26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA SN 1533-4880 EI 1533-4899 J9 J NANOSCI NANOTECHNO JI J. Nanosci. Nanotechnol. PD FEB PY 2016 VL 16 IS 2 BP 1460 EP 1470 DI 10.1166/jnn.2016.10895 PG 11 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DG8UJ UT WOS:000372358800033 PM 27433605 ER PT J AU Wang, X Tan, JY Biswas, S Zhao, JQ Devadas, K Ye, ZP Hewlett, I AF Wang, Xue Tan, Jiying Biswas, Santanu Zhao, Jiangqin Devadas, Krishnakumar Ye, Zhiping Hewlett, Indira TI Pandemic Influenza A (H1N1) Virus Infection Increases Apoptosis and HIV-1 Replication in HIV-1 Infected Jurkat Cells SO VIRUSES-BASEL LA English DT Article DE HIV-1; pandemic influenza A (H1N1) virus; apoptosis; CD4; replication ID RESPIRATORY-DISTRESS-SYNDROME; CRITICALLY-ILL PATIENTS; SYNCYTIUM FORMATION; A(H1N1) INFECTION; LIPID RAFTS; T-CELLS; H5N1; NEURAMINIDASE; ACTIVATION; CYTOKINES AB Influenza virus infection has a significant impact on public health, since it is a major cause of morbidity and mortality. It is not well-known whether influenza virus infection affects cell death and human immunodeficiency virus (HIV)-1 replication in HIV-1-infected patients. Using a lymphoma cell line, Jurkat, we examined the in vitro effects of pandemic influenza A (H1N1) virus (pH1N1) infection on cell death and HIV-1 RNA production in infected cells. We found that pH1N1 infection increased apoptotic cell death through Fas and Bax-mediated pathways in HIV-1-infected Jurkat cells. Infection with pH1N1 virus could promote HIV-1 RNA production by activating host transcription factors including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B), nuclear factor of activated T-cells (NFAT) and activator protein 1 (AP-1) through mitogen-activated protein kinases (MAPK) pathways and T-cell antigen receptor (TCR)-related pathways. The replication of HIV-1 latent infection could be reactivated by pH1N1 infection through TCR and apoptotic pathways. These data indicate that HIV-1 replication can be activated by pH1N1 virus in HIV-1-infected cells resulting in induction of cell death through apoptotic pathways. C1 [Wang, Xue; Tan, Jiying; Biswas, Santanu; Zhao, Jiangqin; Devadas, Krishnakumar; Hewlett, Indira] US FDA, CBER, Div Emerging & Transfus Transmitted Dis, Mol Virol Lab, Bldg 72,Rm 4322,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Ye, Zhiping] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Silver Spring, MD 20993 USA. [Tan, Jiying] Lanzhou Univ, Sch Basic Med Sci, Dept Immunol, Lanzhou 730000, Gansu, Peoples R China. RP Wang, X; Hewlett, I (reprint author), US FDA, CBER, Div Emerging & Transfus Transmitted Dis, Mol Virol Lab, Bldg 72,Rm 4322,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM xue.wang@fda.hhs.gov; tangjy@lzu.edu.cn; Santanu.biswas@fda.hhs.gov; Jiangqin.zhao@fda.hhs.gov; Krishnakumar.devada@fda.hhs.gov; zhiping.ye@fda.hhs.gov; indira.hewlett@fda.hhs.gov FU internal CBER modernizing science grant FX The authors wish to acknowledge of Mohan Haleyurgirisetty and Viswanath Ragupathy for critical review of this manuscript, and acknowledge of the NIH AIDS reagent repository for the reagents. This work was supported by an internal CBER modernizing science grant. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. NR 41 TC 0 Z9 0 U1 3 U2 3 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD FEB PY 2016 VL 8 IS 2 AR 33 DI 10.3390/v8020033 PG 11 WC Virology SC Virology GA DG1MI UT WOS:000371831800018 ER PT J AU Marrone, AK Tryndyak, V Beland, FA Pogribny, IP AF Marrone, April K. Tryndyak, Volodymyr Beland, Frederick A. Pogribny, Igor P. TI MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B-1 and Benzo[a]pyrene in Human HepaRG Cells SO TOXICOLOGICAL SCIENCES LA English DT Article DE HepaRG cells; aflatoxin B1; benzo[a]pyrene; microRNA ID GENE-EXPRESSION PROFILES; MIR-122 EXPRESSION; HUMAN HEPATOCYTES; CANCER HAZARDS; LIVER-DISEASE; IDENTIFICATION; CLUSTER; HEPATOCARCINOGENESIS; BIOASSAY; BINDING AB Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B-1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B-2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, particularly in a marked over-expression of miR-410. An additional novel finding is the dose-and time-dependent inhibition of miR-122 in AFB1-treated HepaRG cells. Mechanistically, the AFB1-induced down-regulation of miR-122 was attributed to inhibition of the HNF4A/miR-122 regulatory pathway. These results demonstrate that HepaRG cells can be used to investigate miRNA responses to xenobiotic exposure, and illustrate the existence of early non-genotoxic events, in addition to a well-established genotoxic mode of action changes, in the mechanismof AFB1 and B[a]P carcinogenicity. C1 [Marrone, April K.; Tryndyak, Volodymyr; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 44 TC 3 Z9 3 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2016 VL 149 IS 2 BP 496 EP 502 DI 10.1093/toxsci/kfv253 PG 7 WC Toxicology SC Toxicology GA DF8NF UT WOS:000371613900022 PM 26609139 ER PT J AU Xia, XJ Wieslander, B Strauss, DG Wagner, GS Zareba, W Moss, AJ Couderc, JP AF Xia, Xiaojuan Wieslander, Bjorn Strauss, David G. Wagner, Galen S. Zareba, Wojciech Moss, Arthur J. Couderc, Jean-Philippe TI Automatic QRS Selvester scoring system in patients with left bundle branch block SO EUROPACE LA English DT Article DE Selvester QRS scoring system; Left bundle branch block; Electrocardiography ID CARDIAC-RESYNCHRONIZATION THERAPY; MYOCARDIAL INFARCT SIZE; QUANTITATIVE ANATOMIC FINDINGS; SCAR; CONDUCTION; QUANTIFICATION; CARDIOMYOPATHY AB The Selvester QRS scoring system uses quantitative criteria from the standard 12-lead electrocardiogram (ECG) to estimate the myocardial scar size of patients, including those with left bundle branch block (LBBB). Automation of the scoring system could facilitate the clinical use of this technique which requires a set of multiple QRS patterns to be identified and measured. We developed a series of algorithms to automatically detect and measure the QRS parameters required for Selvester scoring. The 'QUantitative and Automatic REport of Selvester Score' was designed specifically for the analysis of ECGs from patients meeting new strict criteria for complete LBBB. The algorithms were designed using a training (n = 36) and a validation (n = 180) set of ECGs, consisting of signal-averaged 12-lead ECGs (1000 Hz sampling) recorded from 216 LBBB patients from the MADIT-CRT. We assessed the performance of the methods using expert manually adjudicated ECGs. The average of absolute differences between automatic and adjudicated Selvester scoring was 1.2 +/- 1.5 points. The range of average differences for continuous measurements of wave locations and interval durations varied between 0 and 6 ms. Erroneous detection of Q, R, S, R', and S' waves (oversensed or missed) were 3, 1, 1, 16, and 6%, respectively. Seven percent of notches detected in the first 40 ms were misdetected. We propose an efficient computerized method for the automatic measurement of the Selvester score in patients with the strict LBBB. C1 [Xia, Xiaojuan; Zareba, Wojciech; Moss, Arthur J.; Couderc, Jean-Philippe] Univ Rochester, Med Ctr, Div Cardiol, Heart Res Follow Up Program, 265 Crittenden Blvd,POB 653, Rochester, NY 14642 USA. [Wieslander, Bjorn] Karolinska Inst, Clin Physiol, Stockholm, Sweden. [Wieslander, Bjorn] Karolinska Univ Hosp, Stockholm, Sweden. [Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. [Wagner, Galen S.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. RP Xia, XJ (reprint author), Univ Rochester, Med Ctr, Div Cardiol, Heart Res Follow Up Program, 265 Crittenden Blvd,POB 653, Rochester, NY 14642 USA. EM heartjxx@heart.rochester.edu NR 20 TC 3 Z9 3 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1099-5129 EI 1532-2092 J9 EUROPACE JI Europace PD FEB 1 PY 2016 VL 18 IS 2 BP 308 EP 314 DI 10.1093/europace/euv040 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DF3LB UT WOS:000371244400023 PM 25805156 ER PT J AU Zaza, S Koonin, LM Ajao, A Nystrom, SV Branson, R Patel, A Bray, B Iademarco, MF AF Zaza, Stephanie Koonin, Lisa M. Ajao, Adebola Nystrom, Scott V. Branson, Richard Patel, Anita Bray, Bruce Iademarco, Michael F. TI A Conceptual Framework for Allocation of Federally Stockpiled Ventilators During Large-Scale Public Health Emergencies SO HEALTH SECURITY LA English DT Article ID MASS CRITICAL-CARE; MECHANICAL VENTILATORS; DEFINITIVE CARE; CRITICALLY-ILL; UNITED-STATES; JANUARY 26-27; TASK-FORCE; INFLUENZA; DISASTER; RESOURCES AB Some types of public health emergencies could result in large numbers of patients with respiratory failure who need mechanical ventilation. Federal public health planning has included needs assessment and stockpiling of ventilators. However, additional federal guidance is needed to assist states in further allocating federally supplied ventilators to individual hospitals to ensure that ventilators are shipped to facilities where they can best be used during an emergency. A major consideration in planning is a hospital's ability to absorb additional ventilators, based on available space and staff expertise. A simple pro rata plan that does not take these factors into account might result in suboptimal use or unused scarce resources. This article proposes a conceptual framework that identifies the steps in planning and an important gap in federal guidance regarding the distribution of stockpiled mechanical ventilators during an emergency. C1 [Zaza, Stephanie] CDC, Ctr Dis Control & Prevent, Natl Ctr HIV AIDS STD Viral Hepatitis & TB Preven, Div Adolescent & Sch Hlth, Atlanta, GA 30333 USA. [Zaza, Stephanie; Koonin, Lisa M.] CDC, Off Infect Dis, Influenza Coordinat Unit, Atlanta, GA 30333 USA. [Ajao, Adebola] US FDA, Off Med Policy Initiat, Div Clin Trials Qual, Silver Spring, MD USA. [Nystrom, Scott V.] Off Policy & Planning, Div Med Countermeasure Strategy & Requirements, Washington, DC USA. [Nystrom, Scott V.] Dept Hlth & Human Serv, Preparedness & Response, Washington, DC USA. [Branson, Richard] Univ Cincinnati, Surg, Cincinnati, OH USA. [Patel, Anita] CDC, Off Publ Hlth Preparedness & Response, Div Strateg Natl Stockpile, Atlanta, GA 30333 USA. [Bray, Bruce] Emory Univ Hosp, Dept Resp Care, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. [Bray, Bruce] Emory Univ Hosp, Dept EKG, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. [Bray, Bruce] Emory Univ Hosp, Dept Neurophysiol, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. [Bray, Bruce] Emory Univ Hosp, Dept Pulm Funct & Blood Gas Labs, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. [Iademarco, Michael F.] CDC, Ctr Surveillance Epidemiol & Lab Serv, Atlanta, GA 30333 USA. RP Koonin, LM (reprint author), Ctr Dis Control & Prevent, Influenza Coordinat Unit, 1600 Clifton Rd NE,Mailstop A28, Atlanta, GA 30329 USA. EM lmk1@cdc.gov NR 32 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 2326-5094 EI 2326-5108 J9 HEALTH SECUR JI Health Secur. PD FEB 1 PY 2016 VL 14 IS 1 BP 1 EP 6 DI 10.1089/hs.2015.0043 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DF4QN UT WOS:000371334800001 PM 26828799 ER PT J AU Zusterzeel, R Selzman, KA Sanders, WE O'Callaghan, KM Canos, DA Vernooy, K Prinzen, FW Gorgels, APM Strauss, DG AF Zusterzeel, Robbert Selzman, Kimberly A. Sanders, William E. O'Callaghan, Kathryn M. Canos, Daniel A. Vernooy, Kevin Prinzen, Frits W. Gorgels, Anton P. M. Strauss, David G. TI Toward Sex-Specific Guidelines for Cardiac Resynchronization Therapy? SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH LA English DT Article DE Cardiac resynchronization therapy; Women; Sex; Guidelines; Outcomes ID BUNDLE-BRANCH-BLOCK; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; DYSSYNCHRONOUS HEART-FAILURE; CARDIOVASCULAR DATA REGISTRY; RANDOMIZED-CONTROLLED-TRIALS; CLINICAL EVENT REDUCTION; QRS MORPHOLOGY; PR INTERVAL; IMPROVE HF; WOMEN AB An important treatment for patients with heart failure is cardiac resynchronization therapy (CRT). Even though only 20 % of women were included in clinical trials for CRT, a benefit has been shown in recent studies for subgroups of women compared to their male counterparts. Given this low inclusion rate of women in clinical studies, professional society guideline-based CRT recommendations, such as those by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS), may not truly represent the best treatment for women, especially since most of the reports that showed this greater benefit in women were published after the latest guidelines. Despite having research and multiple publications regarding sex-specific heart failure outcomes and response to CRT, the ACCF/AHA/HRS guidelines have not yet been updated to account for the recent information regarding the differences in benefit for women and men with similar patient characteristics. This review discusses the physiology behind CRT, sex-specific characteristics of heart failure, and cardiac electrophysiology and summarizes the current sex-specific literature to encourage consideration of CRT guidelines for women and men separately. C1 [Zusterzeel, Robbert; Selzman, Kimberly A.; Sanders, William E.; O'Callaghan, Kathryn M.; Canos, Daniel A.; Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Zusterzeel, Robbert; Vernooy, Kevin; Prinzen, Frits W.; Gorgels, Anton P. M.] Maastricht Univ, Med Ctr, Dept Cardiol, NL-6200 MD Maastricht, Netherlands. [Zusterzeel, Robbert] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Zusterzeel, R (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA.; Zusterzeel, R (reprint author), Maastricht Univ, Med Ctr, Dept Cardiol, NL-6200 MD Maastricht, Netherlands.; Zusterzeel, R (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. EM robbert.zusterzeel@fda.hhs.gov FU FDA Office of Women's Health; Oak Ridge Institute for Science and Education FX This project was supported in part by the FDA Office of Women's Health and by a research fellowship from the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. NR 58 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1937-5387 EI 1937-5395 J9 J CARDIOVASC TRANSL JI J. Cardiovasc. Transl. Res. PD FEB PY 2016 VL 9 IS 1 BP 12 EP 22 DI 10.1007/s12265-015-9663-z PG 11 WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental SC Cardiovascular System & Cardiology; Research & Experimental Medicine GA DF3OV UT WOS:000371255100003 PM 26659647 ER PT J AU Tryndyak, VP Marrone, AK Latendresse, JR Muskhelishvili, L Beland, FA Pogribny, IP AF Tryndyak, Volodymyr P. Marrone, April K. Latendresse, John R. Muskhelishvili, Levan Beland, Frederick A. Pogribny, Igor P. TI MicroRNA changes, activation of progenitor cells and severity of liver injury in mice induced by choline and folate deficiency SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Liver injury; Methyl-donor deficient diet; Mouse; MicroRNA; Progenitor cells ID HEPATOCYTE-LIKE CELLS; EMBRYONIC STEM-CELLS; NONALCOHOLIC STEATOHEPATITIS; INTERSTRAIN DIFFERENCES; DUCTULAR REACTION; NATURAL-HISTORY; DISEASE; EXPRESSION; FIBROSIS; DIET AB Dietary deficiency in methyl-group donors and cofactors induces liver injury that resembles many pathophysiological and histopathological features of human nonalcoholic fatty liver disease (NAFLD), including an altered expression of microRNAs (miRNAs). We evaluated the consequences of a choline- and folate-deficient (CFD) diet on the expression of miRNAs in the livers of male A/J and WSB/EiJ mice. The results demonstrate that NAFLD-like liver injury induced by the CFD diet in A/J and WSB/EiJ mice was associated with marked alterations in hepatic miRNAome profiles, with the magnitude of miRNA expression changes being greater in WSB/EiJ mice, the strain characterized by the greatest severity of liver injury. Specifically, WSB/EiJ mice exhibited more prominent changes in the expression of common miRNAs as compared to A/J mice and distinct miRNA alterations, including the overexpression of miR-134, miR-409-3p, miR-410 and miR-495 miRNAs that were accompanied by an activation of hepatic progenitor cells and fibrogenesis. This in vivo finding was further confirmed by in vitro experiments showing an overexpression of these miRNAs in undifferentiated progenitor hepatic HepaRG cells compared to in fully differentiated HepaRG cells. Additionally, a marked elevation of miR-134, miR-409-3p, miR-410 and miR-495 was found in plasma of WSB/EiJ mice fed the CFD diet, while none of the miRNAs was changed in plasma of A/J mice. These findings suggest that miRNAs may be crucial regulators responsible for the progression of NAFLD and may be useful as noninvasive diagnostic indicators of the severity and progression of NAFLD. Published by Elsevier Inc. C1 [Tryndyak, Volodymyr P.; Marrone, April K.; Beland, Frederick A.; Pogribny, Igor P.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Latendresse, John R.; Muskhelishvili, Levan] US FDA, Toxicol Pathol Associates, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 50 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD FEB PY 2016 VL 28 BP 83 EP 90 DI 10.1016/j.jnutbio.2015.10.001 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA DF4YS UT WOS:000371359100009 PM 26878785 ER PT J AU Everett, KD Conway, C Desany, GJ Baker, BL Choi, G Taylor, CA Edelman, ER AF Everett, Kay D. Conway, Claire Desany, Gerard J. Baker, Brian L. Choi, Gilwoo Taylor, Charles A. Edelman, Elazer R. TI Structural Mechanics Predictions Relating to Clinical Coronary Stent Fracture in a 5 Year Period in FDA MAUDE Database SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Stent fracture; Arterial deformation; Finite element analysis ID SIROLIMUS-ELUTING STENT; SUPERFICIAL FEMORAL-ARTERY; BALLOON-EXPANDABLE STENTS; FINITE-ELEMENT-ANALYSIS; FATIGUE LIFE; IMPLANTATION; IMPACT; STRESSES; DESIGN; SHAPE AB Endovascular stents are the mainstay of interventional cardiovascular medicine. Technological advances have reduced biological and clinical complications but not mechanical failure. Stent strut fracture is increasingly recognized as of paramount clinical importance. Though consensus reigns that fractures can result from material fatigue, how fracture is induced and the mechanisms underlying its clinical sequelae remain ill-defined. In this study, strut fractures were identified in the prospectively maintained Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience Database (MAUDE), covering years 2006-2011, and differentiated based on specific coronary artery implantation site and device configuration. These data, and knowledge of the extent of dynamic arterial deformations obtained from patient CT images and published data, were used to define boundary conditions for 3D finite element models incorporating multimodal, multi-cycle deformation. The structural response for a range of stent designs and configurations was predicted by computational models and included estimation of maximum principal, minimum principal and equivalent plastic strains. Fatigue assessment was performed with Goodman diagrams and safe/unsafe regions defined for different stent designs. Von Mises stress and maximum principal strain increased with multimodal, fully reversed deformation. Spatial maps of unsafe locations corresponded to the identified locations of fracture in different coronary arteries in the clinical database. These findings, for the first time, provide insight into a potential link between patient adverse events and computational modeling of stent deformation. Understanding of the mechanical forces imposed under different implantation conditions may assist in rational design and optimal placement of these devices. C1 [Everett, Kay D.; Conway, Claire; Edelman, Elazer R.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Desany, Gerard J.; Baker, Brian L.] US FDA, Winchester Engn & Analyt Ctr, Winchester, MA USA. [Choi, Gilwoo; Taylor, Charles A.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Edelman, Elazer R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Conway, C (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM kfurman@mit.edu; cconway@mit.edu; Gerard.Desany@fda.hhs.gov; Brian.Baker@fda.hhs.gov; giroo@heartflow.com; taylor@heartflow.com; ere@mit.edu OI /0000-0003-4236-2280 FU FDA Office of Regulatory Affairs; National Institute of Health [R01 GM49039] FX This work was funded in part by Grants from FDA Office of Regulatory Affairs, R01 GM49039 (ERE) from the National Institute of Health, and appointment to the Research Participation Program at FDA administered by Oak Ridge Institute for Science and Education (CC). NR 52 TC 3 Z9 3 U1 3 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD FEB PY 2016 VL 44 IS 2 BP 391 EP 403 DI 10.1007/s10439-015-1476-3 PG 13 WC Engineering, Biomedical SC Engineering GA DF0RJ UT WOS:000371046300011 PM 26467552 ER PT J AU Saylor, DM Forrey, C Kim, CS Warren, JA AF Saylor, David M. Forrey, Christopher Kim, Chang-Soo Warren, James A. TI Diffuse Interface Methods for Modeling Drug-Eluting Stent Coatings SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Microstructure; Thermodynamics; Diffusion; Simulation; Controlled release ID SOLVENT SYSTEMS; SELF-DIFFUSION; POLYMER; COEFFICIENTS; ARTERIAL; DELIVERY; RELEASE; TETRAHYDROFURAN; THERMODYNAMICS; SIMULATION AB An overview of diffuse interface models specific to drug-eluting stent coatings is presented. Microscale heterogeneities, both in the coating and use environment, dictate the performance of these coatings. Using diffuse interface methods, these heterogeneities can be explicitly incorporated into the model equations with relative ease. This enables one to predict the complex microstructures that evolve during coating fabrication and subsequent impact on drug release. Examples are provided that illustrate the wide range of phenomena that can be addressed with diffuse interface models including: crystallization, constrained phase separation, hydrolytic degradation, and heterogeneous binding. Challenges associated with the lack of material property data and numerical solution of the model equations are also highlighted. Finally, in light of these potential drawbacks, the potential to utilize diffuse interface models to help guide product and process development is discussed. C1 [Saylor, David M.; Forrey, Christopher] US FDA, Silver Spring, MD 20993 USA. [Kim, Chang-Soo] Univ Wisconsin, Milwaukee, WI 53211 USA. [Warren, James A.] NIST, Gaithersburg, MD 20899 USA. RP Saylor, DM (reprint author), US FDA, Silver Spring, MD 20993 USA. EM david.saylor@fda.hhs.gov NR 44 TC 1 Z9 1 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD FEB PY 2016 VL 44 IS 2 BP 548 EP 559 DI 10.1007/s10439-015-1375-7 PG 12 WC Engineering, Biomedical SC Engineering GA DF0RJ UT WOS:000371046300024 PM 26183961 ER PT J AU Kishnani, PS Dickson, PI Muldowney, L Lee, JJ Rosenberg, A Abichandani, R Bluestone, JA Burton, BK Dewey, M Freitas, A Gavin, D Griebel, D Hogan, M Holland, S Tanpaiboon, P Turka, LA Utz, JJ Wang, YM Whitley, CB Kazi, ZB Pariser, AR AF Kishnani, Priya S. Dickson, Patricia I. Muldowney, Laurie Lee, Jessica J. Rosenberg, Amy Abichandani, Rekha Bluestone, Jeffrey A. Burton, Barbara K. Dewey, Maureen Freitas, Alexandra Gavin, Derek Griebel, Donna Hogan, Melissa Holland, Stephen Tanpaiboon, Pranoot Turka, Laurence A. Utz, Jeanine J. Wang, Yow-Ming Whitley, Chester B. Kazi, Zoheb B. Pariser, Anne R. TI Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Immune tolerance; Lysosomal storage diseases; Enzyme replacement therapy; Inborn errors of metabolism; Neutralizing antibodies; Orphan drugs; Rare diseases ID INFANTILE POMPE DISEASE; FABRY-DISEASE; MUCOPOLYSACCHARIDOSIS-I; INTRAVENOUS IMMUNOGLOBULIN; NEUTRALIZING ANTIBODIES; CLINICAL-OUTCOMES; AGALSIDASE-ALPHA; DISORDERS; EFFICACY; SAFETY AB The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes. Published by Elsevier Inc. C1 [Kishnani, Priya S.; Kazi, Zoheb B.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Dickson, Patricia I.] Harbor UCLA Med Ctr, Div Med Genet, Los Angeles Biomed Res Inst, Torrance, CA 90505 USA. [Muldowney, Laurie; Lee, Jessica J.; Dewey, Maureen; Griebel, Donna] US FDA, Div Gastroenterol & Inborn Errors Metab Prod, Off New Drugs, CDER, Silver Spring, MD 20993 USA. [Rosenberg, Amy] US FDA, Div Therapeut Proteins, Off Biotechnol Prod, CDER, Silver Spring, MD 20993 USA. [Abichandani, Rekha] Shire, Lexington, MA 02421 USA. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Burton, Barbara K.] Northwestern Univ, Feinberg Sch Med, Ann & Robert H Lurie Childrens Hosp, Chicago, IL 60611 USA. [Freitas, Alexandra; Gavin, Derek] Natl Org Rare Disorders, Washington, DC 20036 USA. [Hogan, Melissa] Saving Case & Friends Inc, Thompsons Stn, TN 37179 USA. [Holland, Stephen] Natl MPS Soc, Durham, NC 27709 USA. [Tanpaiboon, Pranoot] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Turka, Laurence A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Transplantat Sci, Boston, MA 02129 USA. [Utz, Jeanine J.; Whitley, Chester B.] Univ Minnesota, Masonic Childrens Hosp, Minneapolis, MN 55455 USA. [Wang, Yow-Ming] US FDA, Div Clin Pharmacol 3, Off Clin Pharmacol, OTS,CDER, Silver Spring, MD 20993 USA. [Pariser, Anne R.] US FDA, OTS, CDER, 10903 New Hampshire Ave,W021-4607, Silver Spring, MD 20993 USA. RP Pariser, AR (reprint author), US FDA, OTS, CDER, 10903 New Hampshire Ave,W021-4607, Silver Spring, MD 20993 USA. EM priya.kishnani@duke.edu; pdickson@labiomed.org; laurie.muldowney@fda.hhs.gov; jessica.j.lee@fda.hhs.gov; amy.rosenberg@fda.hhs.gov; rabichan@shire.com; jeff.bluestone@ucsf.edu; bburton@luriechildrens.org; maureen.dewey@fda.hhs.gov; afreitas@rarediseases.org; dgavin@rarediseases.org; donna.griebel@fda.hhs.gov; melissa@savingcase.com; steve.holland@thomsonreuters.com; ptanpaib@childrensnational.org; lturka@partners.org; utz002@umn.edu; yowming.wang@fda.hhs.gov; whitley@umn.edu; zoheb.kazi@dm.duke.edu; anne.pariser@fda.hhs.gov OI Kazi, Zoheb/0000-0002-0447-2764 FU NIAID NIH HHS [R01 AI046643] NR 56 TC 2 Z9 2 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2016 VL 117 IS 2 BP 66 EP 83 DI 10.1016/j.ymgme.2015.11.001 PG 18 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DE8LS UT WOS:000370888100341 PM 26597321 ER PT J AU Li, CH Bies, RR Wang, Y Sharma, MR Karovic, S Werk, L Edelman, MJ Miller, AA Vokes, EE Oto, A Ratain, MJ Schwartz, LH Maitland, ML AF Li, C. H. Bies, R. R. Wang, Y. Sharma, M. R. Karovic, S. Werk, L. Edelman, M. J. Miller, A. A. Vokes, E. E. Oto, A. Ratain, M. J. Schwartz, L. H. Maitland, M. L. TI Comparative Effects of CT Imaging Measurement on RECIST End Points and Tumor Growth Kinetics Modeling SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE tomography; x-ray computed; humans; models; statistical; Response Evaluation Criteria in Solid Tumors; lung neoplasms; drug therapy; clinical trials; antineoplastic agents; pharmacology ID CELL-LUNG-CANCER; LEUKEMIA GROUP-B; PHASE-II; CLINICAL-TRIALS; DRUG DEVELOPMENT; DECISION-MAKING; SOLID TUMORS; SURVIVAL; ONCOLOGY; PREDICT AB Quantitative assessments of tumor burden and modeling of longitudinal growth could improve phase II oncology trials. To identify obstacles to wider use of quantitative measures we obtained recorded linear tumor measurements from three published lung cancer trials. Model-based parameters of tumor burden change were estimated and compared with similarly sized samples from separate trials. Time-to-tumor growth (TTG) was computed from measurements recorded on case report forms and a second radiologist blinded to the form data. Response Evaluation Criteria in Solid Tumors (RECIST)-based progression-free survival (PFS) measures were perfectly concordant between the original forms data and the blinded radiologist re-evaluation (intraclass correlation coefficient = 1), but these routine interrater differences in the identification and measurement of target lesions were associated with an average 18-week delay (range, -20 to 55 weeks) in TTG (intraclass correlation coefficient = 0.32). To exploit computational metrics for improving statistical power in small clinical trials will require increased precision of tumor burden assessments. C1 [Li, C. H.; Bies, R. R.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Li, C. H.; Bies, R. R.] Indiana Clin & Translat Sci Inst CTSI, Indianapolis, IN USA. [Bies, R. R.; Sharma, M. R.; Werk, L.; Edelman, M. J.; Miller, A. A.; Vokes, E. E.; Oto, A.; Ratain, M. J.; Schwartz, L. H.; Maitland, M. L.] Alliance Clin Trials Oncol, Boston, MA USA. [Wang, Y.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Sharma, M. R.; Karovic, S.; Vokes, E. E.; Oto, A.; Ratain, M. J.; Maitland, M. L.] Univ Chicago Med & Biol Sci, Chicago, IL USA. [Werk, L.] Duke Univ, Durham, NC USA. [Edelman, M. J.] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Miller, A. A.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Schwartz, L. H.] Columbia Univ, Coll Phys & Surg, New York, NY USA. RP Maitland, ML (reprint author), Alliance Clin Trials Oncol, Boston, MA USA.; Maitland, ML (reprint author), Univ Chicago Med & Biol Sci, Chicago, IL USA. EM mmaitlan@medicine.bsd.uchicago.edu FU NIH [K23CA124802, U10CA031946, R01CA194783]; Indiana CTSI from Eli Lilly and Company FX Support for this study was provided by NIH K23CA124802 (Career Development Award to M.L.M.), NIH U10CA031946 (Cancer and Leukemia Group B Chair's Development Project to M.L.M. and L.H.S.), NIH R01CA194783 (to M.L.M. and L.H.S.), and The Indiana CTSI through a gift from Eli Lilly and Company (C.H.L. and R.R.B.). The authors are grateful to Thomas Yaeger for technical assistance and Dr. Valerie Andre for expert guidance on tumor growth modeling. NR 39 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 EI 1752-8062 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2016 VL 9 IS 1 BP 43 EP 50 DI 10.1111/cts.12384 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DE5AD UT WOS:000370641400007 PM 26790562 ER PT J AU Luo, JJ Rasooly, A Wang, LQ Zeng, K Shen, CC Qian, P Yang, MH Qu, FL AF Luo, Junjun Rasooly, Avraham Wang, Liqiang Zeng, Ke Shen, Congcong Qian, Pin Yang, Minghui Qu, Fengli TI Fluorescent turn-on determination of the activity of peptidases using peptide templated gold nanoclusters SO MICROCHIMICA ACTA LA English DT Article DE beta-Secretases; APP cleaving enzyme; BACE1; beta-amyloid precursor protein; Transmission electron microscopy; Fluorometry ID AMYLOID PRECURSOR PROTEIN; HUMAN BETA-SECRETASE; BIOLOGICAL APPLICATIONS; SILVER NANOCLUSTERS; INHIBITORS; NANOPARTICLES; DISEASE; ENZYMES; SITE; CELL AB The fluorescence intensity of gold nanoclusters (AuNCs) is inversely related to the length of a peptide immobilized on its surface. This finding has been exploited to design a turn-on fluorescent method for the determination of the activity of peptidase. The beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) was chosen as a model peptidase. BACE1 cleaves the peptide substrates on AuNCs, and the fluorescence intensity of the AuNCs (at exCitation/emission wavelengths of 320/405 nm) carrying the rest of the cleaved peptide is significantly higher than that of the AuNCs with uncleaved peptide. Transmission electron microscopy revealed a decrease in the size of the AuNCs which is assumed cause fluorescence enhancement. The assay was applied to the determination of BACE1 activity in spiked cell lysates, and recoveries were between 96.9 and 104.0 %. C1 [Luo, Junjun; Wang, Liqiang; Zeng, Ke; Shen, Congcong; Qian, Pin; Yang, Minghui] Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China. [Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Qu, Fengli] Qufu Normal Univ, Coll Chem & Chem Engn, Qufu 273165, Shandong, Peoples R China. RP Yang, MH (reprint author), Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China.; Qu, FL (reprint author), Qufu Normal Univ, Coll Chem & Chem Engn, Qufu 273165, Shandong, Peoples R China. EM yangminghui@csu.edu.cn; fengliquhn@hotmail.com FU National Natural Science Foundation of China [21575165, 21375076]; Natural Science Foundation of Hunan province [2015JJ1019] FX The authors appreciate the support of this work by the National Natural Science Foundation of China (No. 21575165, 21375076) and Natural Science Foundation of Hunan province (No. 2015JJ1019). NR 31 TC 6 Z9 6 U1 12 U2 31 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0026-3672 EI 1436-5073 J9 MICROCHIM ACTA JI Microchim. Acta PD FEB PY 2016 VL 183 IS 2 BP 605 EP 610 DI 10.1007/s00604-015-1683-5 PG 6 WC Chemistry, Analytical SC Chemistry GA DD8KX UT WOS:000370176500011 ER PT J AU Wake, LM Ahn, I Farooqui, M Hahn, J Tian, X Steller-Stevenson, M Marti, G Wiestner, A Maric, I AF Wake, Laura M. Ahn, Inhye Farooqui, Mohammed Hahn, Jamie Tian, Xin Steller-Stevenson, Maryalice Marti, Gerald Wiestner, Adrian Maric, Irina TI Dual Antibody Immunohistochemistry: A Cost-Efficient and Sensitive New Tool for the Detection of Minimal Residual CLL SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NCI, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NIH, CC, DLM, Bldg 10, Bethesda, MD 20892 USA. US FDA, CDRH, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1507 BP 382A EP 382A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502513 ER PT J AU Gamalo, MA Wu, R Tiwari, RC AF Gamalo, M. Amper Wu, Rui Tiwari, Ram C. TI Bayesian approach to non-inferiority trials for normal means SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Non-inferiority; prior distribution; Jeffrey's prior; posterior distribution; fixed-margin approach ID ACTIVE-CONTROL TRIALS; STATISTICAL-METHODS; MEDICAL STATISTICS; CLINICAL-TRIALS; PLACEBO; ISSUES; CHOICE; DESIGN; DELTA AB Regulatory framework recommends that novel statistical methodology for analyzing trial results parallels the frequentist strategy, e.g. the new method must protect type-I error and arrive at a similar conclusion. Keeping these in mind, we construct a Bayesian approach for non-inferiority trials with normal response. A non-informative prior is assumed for the mean response of the experimental treatment and Jeffrey's prior for its corresponding variance when it is unknown. The posteriors of the mean response and variance of the treatment in historical trials are then assumed as priors for its corresponding parameters in the current trial, where that treatment serves as the active control. From these priors, a Bayesian decision criterion is derived to determine whether the experimental treatment is non-inferior to the active control. This criterion is evaluated and compared with the frequentist method using simulation studies. Results show that both Bayesian and frequentist approaches perform alike, but the Bayesian approach has a higher power when the variances are unknown. Both methods also arrive at the same conclusion of non-inferiority when applied on two real datasets. A major advantage of the proposed Bayesian approach lies in its ability to provide posterior probabilities for varying effect sizes of the experimental treatment over the active control. C1 [Gamalo, M. Amper] US FDA, Off Biostat, Rockville, MD 20993 USA. [Wu, Rui] Univ Connecticut, Dept Stat, Storrs, CT USA. [Tiwari, Ram C.] US FDA, Off Biostat, Stat Sci & Policy, Rockville, MD 20857 USA. RP Gamalo, MA (reprint author), US FDA, Off Biostat, Rockville, MD 20993 USA. EM Mark.Gamalo@fda.hhs.gov NR 28 TC 2 Z9 2 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2016 VL 25 IS 1 BP 221 EP 240 DI 10.1177/0962280212448723 PG 20 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DE5PZ UT WOS:000370685000013 PM 22619277 ER PT J AU Zhang, ZW Zhou, J Cao, WH Zhang, J AF Zhang, Zhiwei Zhou, Jie Cao, Weihua Zhang, Jun TI Causal inference with a quantitative exposure SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Dose-response relationship; double robustness; inverse probability weighting; outcome regression; propensity function; propensity score; stratification ID DOUBLY ROBUST ESTIMATION; PROPENSITY SCORE; PHYSICAL-ACTIVITY; BODY-COMPOSITION; INCOMPLETE DATA; MISSING DATA; MODELS; BIAS AB The current statistical literature on causal inference is mostly concerned with binary or categorical exposures, even though exposures of a quantitative nature are frequently encountered in epidemiologic research. In this article, we review the available methods for estimating the dose-response curve for a quantitative exposure, which include ordinary regression based on an outcome regression model, inverse propensity weighting and stratification based on a propensity function model, and an augmented inverse propensity weighting method that is doubly robust with respect to the two models. We note that an outcome regression model often imposes an implicit constraint on the dose-response curve, and propose a flexible modeling strategy that avoids constraining the dose-response curve. We also propose two new methods: a weighted regression method that combines ordinary regression with inverse propensity weighting and a stratified regression method that combines ordinary regression with stratification. The proposed methods are similar to the augmented inverse propensity weighting method in the sense of double robustness, but easier to implement and more generally applicable. The methods are illustrated with an obstetric example and compared in simulation studies. C1 [Zhang, Zhiwei; Zhou, Jie; Cao, Weihua] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, MOE, Shanghai 200030, Peoples R China. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Shanghai Key Lab Childrens Environm Hlth, Shanghai 200030, Peoples R China. RP Zhang, ZW (reprint author), US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM zhiwei_zhang@yahoo.com FU Intramural Research Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Zhiwei Zhang and Jun Zhang were supported in part by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 41 TC 2 Z9 2 U1 4 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2016 VL 25 IS 1 BP 314 EP 335 DI 10.1177/0962280212452333 PG 21 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DE5PZ UT WOS:000370685000018 PM 22729475 ER PT J AU Muthukumarana, S Tiwari, RC AF Muthukumarana, Saman Tiwari, Ram C. TI Meta-analysis using Dirichlet process SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Clustering; heterogeneity; log pseudo-marginal likelihood; Markov chain Monte Carlo; odds ratio ID DISTRIBUTIONS; TRIALS; MODELS; HETEROGENEITY; PRIORS AB This article develops a Bayesian approach for meta-analysis using the Dirichlet process. The key aspect of the Dirichlet process in meta-analysis is the ability to assess evidence of statistical heterogeneity or variation in the underlying effects across study while relaxing the distributional assumptions. We assume that the study effects are generated from a Dirichlet process. Under a Dirichlet process model, the study effects parameters have support on a discrete space and enable borrowing of information across studies while facilitating clustering among studies. We illustrate the proposed method by applying it to a dataset on the Program for International Student Assessment on 30 countries. Results from the data analysis, simulation studies, and the log pseudo-marginal likelihood model selection procedure indicate that the Dirichlet process model performs better than conventional alternative methods. C1 [Muthukumarana, Saman] Univ Manitoba, Dept Stat, Winnipeg, MB R3T 2N2, Canada. [Tiwari, Ram C.] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Muthukumarana, S (reprint author), Univ Manitoba, Dept Stat, Winnipeg, MB R3T 2N2, Canada. EM Saman.Muthukumarana@ad.umanitoba.ca FU Natural Sciences and Engineering Research Council of Canada FX Dr Muthukumarana's research has been partially supported by grant from the Natural Sciences and Engineering Research Council of Canada. NR 35 TC 0 Z9 0 U1 2 U2 8 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2016 VL 25 IS 1 BP 352 EP 365 DI 10.1177/0962280212453891 PG 14 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DE5PZ UT WOS:000370685000020 PM 22802045 ER PT J AU Proschan, MA Dodd, LE Price, D AF Proschan, Michael A. Dodd, Lori E. Price, Dionne TI Statistical considerations for a trial of Ebola virus disease therapeutics SO CLINICAL TRIALS LA English DT Article DE Barnard's test; Bayesian methods; beta-binomial distribution; conditional power; emerging infectious diseases; Fisher's exact test; group-sequential monitoring; non-informative prior ID CLINICAL-TRIALS; VACCINE TRIALS; TESTS AB The 2014 West African outbreak of Ebola virus ravaged Liberia, Sierra Leone, and Guinea, causing hemorrhagic fever and death. The need to identify effective therapeutics was acute. The usual drug development paradigm of phase I, followed by phase II, and then phase III trials would take too long. These and other factors led to the design of a clinical trial of Ebola virus disease therapeutics that differs from more conventional clinical trial designs. This article describes the Ebola virus disease medical countermeasures trial design and the thinking behind it. C1 [Proschan, Michael A.; Dodd, Lori E.] NIAID, 5601 Fishers Lane,Room 4C30,MSC 9820, Bethesda, MD 20892 USA. [Price, Dionne] US FDA, Silver Spring, MD USA. RP Proschan, MA (reprint author), NIAID, 5601 Fishers Lane,Room 4C30,MSC 9820, Bethesda, MD 20892 USA. EM ProschaM@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 13 TC 6 Z9 6 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2016 VL 13 IS 1 BP 39 EP 48 DI 10.1177/1740774515620145 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DD5UT UT WOS:000369990700007 PM 26768567 ER PT J AU Russek-Cohen, E Rubin, D Price, D Sun, W Cox, E Borio, L AF Russek-Cohen, Estelle Rubin, Daniel Price, Dionne Sun, Wellington Cox, Edward Borio, Luciana TI A US Food and Drug Administration perspective on evaluating medical products for Ebola SO CLINICAL TRIALS LA English DT Article DE Therapeutic clinical trials; vaccine clinical trials; Ebola ID SIERRA-LEONE; VACCINE; TRIALS C1 [Russek-Cohen, Estelle; Sun, Wellington] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Rubin, Daniel; Price, Dionne; Cox, Edward] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Borio, Luciana] US FDA, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Russek-Cohen, E (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM estelle.russek-cohen@fda.hhs.gov NR 13 TC 2 Z9 2 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2016 VL 13 IS 1 BP 105 EP 109 DI 10.1177/1740774515620613 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DD5UT UT WOS:000369990700018 PM 26768565 ER PT J AU Sanad, YM Johnson, K Park, SH Han, J Deck, J Foley, SL Kenney, B Ricke, S Nayak, R AF Sanad, Yasser M. Johnson, Kelly Park, Si Hong Han, Jing Deck, Joanna Foley, Steven L. Kenney, Brett Ricke, Steven Nayak, Rajesh TI Molecular Characterization of Salmonella enterica Serovars Isolated from a Turkey Production Facility in the Absence of Selective Antimicrobial Pressure SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID ANTIBIOTIC-RESISTANT SALMONELLA; ESCHERICHIA-COLI; UNITED-STATES; POULTRY FARMS; PREVALENCE; VIRULENCE; CHICKEN; SEROTYPES; PROFILES; PLASMID AB This study evaluated antimicrobial resistance and virulence factors in Salmonella enterica isolated from a turkey flock in which the birds were raised in an environment where antimicrobials were not administered to the birds, either through feed or water. Salmonella was isolated from turkeys and various environmental samples in the facility using conventional microbiological procedures. Isolates were serotyped and analyzed phenotypically by antimicrobial resistance profiling and genotypically by pulsed-field gel electrophoresis (PFGE) fingerprinting, integron analysis, plasmid profiling, replicon-based incompatibility (Inc) group typing, and virulence gene profiling. Ninety-five S. enterica isolates were isolated from cecal contents (n=29), feed (n=22), leftover feed (n=13), litter (n=12), drinkers (n=10), environment (n=8), and an insect. The following serotypes were identified: Montevideo (24%), Anatum (22%), Agona (17%), Kentucky and Worthington (12%), Senftenberg (11%), and rough phenotypes (3%). The majority of isolates (61/95; 64%) were susceptible to 12 antimicrobials tested; however, despite the absence of antimicrobials in the facility, approximately 36% of the isolates were resistant to two to five antimicrobials. Class 1 integrons were detected in 8% of the isolates. The integron sequence analysis revealed dihydrofolate reductase (dhfr) and aminoglycoside adenylyl transferase (aadA2) genes, which encode trimethoprim and streptomycin resistance, respectively. Furthermore, 71% of the isolates had at least one plasmid. There were five plasmid replicon types identified among the isolates, including IncI1, IncHI2, IncFIIA, IncB/O, and IncP, with variable prevalence among the serotypes. All 95 isolates tested polymerase chain reaction-positive for 19 virulence genes and negative for virD4 and virB4. The virulence gene profiles were similar within the isolates from the same serotype. Within particular serotypes, PFGE patterns revealed 100% similarity, even when the bacterial strains were isolated from different sources, indicating cross-colonization of sources within the turkey facility. On this antibiotic-free turkey farm, turkeys and feed appeared to be the major reservoirs of multidrug-resistant Salmonella, which harbored multiple virulence genes. C1 [Sanad, Yasser M.; Johnson, Kelly; Han, Jing; Deck, Joanna; Foley, Steven L.; Nayak, Rajesh] US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Park, Si Hong; Ricke, Steven] Univ Arkansas, Ctr Food Safety, Fayetteville, AR 72701 USA. [Park, Si Hong; Ricke, Steven] Univ Arkansas, Dept Food Sci, Fayetteville, AR 72703 USA. [Kenney, Brett] W Virginia Univ, Dept Anim & Nutr Sci, Morgantown, WV 26506 USA. RP Nayak, R (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Rajesh.Nayak@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX We thank Dr. Alessandra Carattoli for providing the positive controls for Incompatibility replicon typing and Dr. Bashar Shaheen for his technical expertise. We also thank Drs. Carl Cerniglia, Sangeeta Khare, and John Sutherland for reviewing the manuscript. Authors Yasser M. Sanad, Kelly Johnson, and Jing Han were supported through the Oak Ridge Institute for Science and Education. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 43 TC 0 Z9 0 U1 6 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD FEB 1 PY 2016 VL 13 IS 2 BP 80 EP 87 DI 10.1089/fpd.2015.2002 PG 8 WC Food Science & Technology SC Food Science & Technology GA DD2OJ UT WOS:000369761700005 PM 26653998 ER PT J AU Nyan, DC Swinson, KL AF Nyan, Dougbeh-Chris Swinson, Kevin L. TI A method for rapid detection and genotype identification of hepatitis C virus 1-6 by one-step reverse transcription loop-mediated isothermal amplification SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Hepatitis C virus; Detection; Isothermal amplification; Genotype identification; Plasma; Serum ID HEPATOCELLULAR-CARCINOMA; INFECTION; REGION; RNA; QUANTIFICATION; CIRRHOSIS; ASSAY AB Objective: Hepatitis C virus (HCV) is probably the leading cause of liver cirrhosis and hepatocellular carcinoma globally. Diagnostic tools conventionally used for the detection and identification of HCV infection are technically demanding, time-consuming, and costly for resource-limited environments. This study reports the development of the first rapid loop-mediated reverse transcription isothermal amplification assay that rapidly detects and identifies HCV genotypes in blood components. Methods: RNA extracted from donor plasma and serum specimens was applied to a one-step reverse transcription loop-mediated isothermal amplification reaction performed with HCV-specific oligonucleotides. Reactions were conducted at 63.5 degrees C for 30-60 min. The diagnostic characteristics of the assay were investigated and validated with clinical specimens. Results: Electrophoretic analysis of amplification revealed detection and identification of HCV genotypes 1-6. Positive amplification revealed unique ladder-like banding patterns that identified each HCV genotype. The assay demonstrated a sensitivity of 91.5% and specificity of 100%. Rapid naked-eye detection of HCV infection was facilitated by observation of an intense fluorescent glow of amplified targets under UV illumination. Conclusion: These diagnostic characteristics highlight the potential utility of this assay for the rapid detection and genotype identification of HCV infection in field and point-of-care settings in endemic regions and resource-limited environments. (C) 2015 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. C1 [Nyan, Dougbeh-Chris] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Swinson, Kevin L.] Morgan State Univ, Dept Biol, Baltimore, MD 21239 USA. RP Nyan, DC (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM dnyan@doctor.com NR 38 TC 2 Z9 2 U1 3 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD FEB PY 2016 VL 43 BP 30 EP 36 DI 10.1016/j.ijid.2015.12.002 PG 7 WC Infectious Diseases SC Infectious Diseases GA DD2ZE UT WOS:000369789900007 PM 26686938 ER PT J AU Reddy, NR Patazca, E Morrissey, TR Skinner, GE Loeza, V Schill, KM Larkin, JW AF Reddy, N. Rukma Patazca, Eduardo Morrissey, Travis R. Skinner, Guy E. Loeza, Viviana Schill, Kristin M. Larkin, John W. TI Thermal and Pressure-Assisted Thermal Destruction Kinetics for Spores of Type A Clostridium botulinum and Clostridium sporogenes PA3679 SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Clostridium botulinum; Clostridium sporogenes PA3679; High pressure processing; Resistance; Spores ID ELEVATED-TEMPERATURES; B SPORES; PA 3679; INACTIVATION; RESISTANCE; SPORULATION; ENDOSPORES; STRAIN; HEAT AB The purpose of this study was to determine the inactivation kinetics of the spores of the most resistant proteolytic Clostridium botulinum strains (Giorgio-A and 69-A, as determined from an earlier screening study) and of Clostridium sporogenes PA3679 and to compare the thermal and pressure-assisted thermal resistance of these spores. Spores of these strains were prepared using a biphasic medium method. C. sporogenes PA3679 spores were heat treated before spore preparation. Using laboratory-scale and pilot-scale pressure test systems, spores of Giorgio-A, 69-A, and PA3679 suspended in ACES [N-(2-acetamido)-2-aminoethanesulfonic acid] buffer (pH 7.0) were exposed to various combinations of temperature (93 to 121 degrees C) and pressure (0.1 to 750 MPa) to determine their resistance. More than a 5-log reduction occurred after 3 min at 113 degrees C for spores of Giorgio-A and 69-A and after 5 min at 117 degrees C for spores of PA3679. A combination of high temperatures (93 to 121 degrees C) and pressures yielded greater log reductions of spores of Giorgio-A, 69-A, and PA3679 compared with reduction obtained with high temperatures alone. No survivors from initial levels (>5.0 log CFU) of Giorgio-A and 69-A were detected when processed at a combination of high temperature (117 and 121 degrees C) and high pressure (600 and 750 MPa) for <1 min in a pilot-scale pressure test system. Increasing pressure from 600 to 750 MPa at 117 C decreased the time from 2.7 to 1 min for a >4.5-log reduction of PA3679 spores. Thermal D-values of Giorgio-A, 69-A, and PA3679 spores decreased (i.e., 29.1 to 0.33 min for Giorgio-A, 40.5 to 0.27 min for 69-A, and 335.2 to 2.16 min for PA3679) as the temperature increased from 97 to 117 degrees C. Pressure-assisted thermal D-values of Giorgio-A, 69-A, and PA3679 also decreased as temperature increased from 97 to 121 degrees C at both pressures (600 and 750 MPa) (i.e., 17.19 to 0.15 min for Giorgio-A, 9.58 to 0.15 min for 69-A, and 12.93 to 0.33 min for PA3679 at 600 MPa). At higher temperatures (117 or 121 degrees C), increasing pressure from 600 to 750 MPa had an effect on pressure-assisted thermal D-values of PA3679 (i.e., at 117 degrees C, pressure-assisted thermal D-value decreased from 0.55 to 0.28 min as pressure increased from 600 to 750 MPa), but pressure had no effect on pressure-assisted thermal D-values of Giorgio-A and 69-A. When compared with Giorgio-A and 69-A, PA3679 had higher thermal and pressure-assisted thermal D-values. C. sporogenes PA3679 spores were generally more resistant to combinations of high pressure and high temperature than were the spores of the C. botulinum strains tested in this study. C1 [Reddy, N. Rukma; Morrissey, Travis R.; Skinner, Guy E.; Schill, Kristin M.; Larkin, John W.] US FDA, Ctr Food Safety & Appl Nutr, Div Food Proc Sci & Technol, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. [Patazca, Eduardo; Loeza, Viviana] IIT, Inst Food Safety & Hlth, 6502 South Archer Rd, Bedford, IL 60501 USA. RP Reddy, NR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Food Proc Sci & Technol, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM rukma.reddy@fda.hhs.gov FU U.S. Food and Drug Administration; Illinois Institute of Technology FX We acknowledge the assistance of Lindsay Halik for performing some experiments and Hossein Daryaei for providing pressure-assisted thermal D-value data of C. sporogenes PA3679 for temperatures 113 to 121 degrees C. This work was supported by a grant from the U.S. Food and Drug Administration to the Institute for Food Safety and Health, Illinois Institute of Technology. NR 32 TC 1 Z9 1 U1 6 U2 14 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD FEB PY 2016 VL 79 IS 2 BP 253 EP 262 DI 10.4315/0362-028X.JFP-15-310 PG 10 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DD2TR UT WOS:000369775600009 PM 26818986 ER PT J AU Aikin, KJ Sullivan, HW Betts, KR AF Aikin, Kathryn J. Sullivan, Helen W. Betts, Kevin R. TI Disease Information in Direct-to-Consumer Prescription Drug Print Ads SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID ADVERTISEMENTS AB Direct-to-consumer (DTC) prescription drug advertisements sometimes include information about the disease condition in addition to information about the advertised product. Although the intent of such information is to educate about the disease condition, in some cases consumers may mistakenly assume that the drug will address all of the potential consequences of the condition mentioned in the ad. We investigated the effects of adding disease information to DTC prescription drug print ads on consumer product perceptions and understanding. Participants (4,064 adults) viewed 1 of 15 DTC print ads for fictitious prescription drugs indicated to treat chronic obstructive pulmonary disease, anemia, or lymphoma that varied in disease information presence, type, and format. Participants answered questions that assessed risk and benefit memory, perception, and behavioral intention. Results indicate that exposure to disease information as part of DTC prescription drug ads can promote the impression that the drug addresses consequences of the condition that are not part of the drug's indication. C1 [Aikin, Kathryn J.; Sullivan, Helen W.; Betts, Kevin R.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Aikin, KJ (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Kathryn.Aikin@fda.hhs.gov NR 25 TC 1 Z9 1 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD FEB 1 PY 2016 VL 21 IS 2 BP 228 EP 239 DI 10.1080/10810730.2015.1058440 PG 12 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA DD3TX UT WOS:000369847000010 PM 26717304 ER PT J AU Madak-Erdogan, Z Gong, P Zhao, YRC Xu, LW Wrobel, KU Hartman, JA Wang, M Cam, A Iwaniec, UT Turner, RT Twaddle, NC Doerge, DR Khan, IA Katzenellenbogen, JA Katzenellenbogen, BS Helferich, WG AF Madak-Erdogan, Zeynep Gong, Ping Zhao, Yiru Chen Xu, Liwen Wrobel, Kinga U. Hartman, James A. Wang, Michelle Cam, Anthony Iwaniec, Urszula T. Turner, Russell T. Twaddle, Nathan C. Doerge, Daniel R. Khan, Ikhlas A. Katzenellenbogen, John A. Katzenellenbogen, Benita S. Helferich, William G. TI Dietary licorice root supplementation reduces diet-induced weight gain, lipid deposition, and hepatic steatosis in ovariectomized mice without stimulating reproductive tissues and mammary gland SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE Botanical estrogens; Dietary supplements; Estrogen receptor; Licorice root; Menopause; Metabolism ID FATTY LIVER-DISEASE; HORMONE-THERAPY; POSTMENOPAUSAL WOMEN; INSULIN-RESISTANCE; METABOLIC SYNDROME; GLUCOSE-TOLERANCE; ADIPOSE-TISSUE; BREAST-CANCER; X RECEPTORS; MECHANISMS AB ScopeWe studied the impact of dietary supplementation with licorice root components on diet-induced obesity, fat accumulation, and hepatic steatosis in ovariectomized C57BL/6 mice as a menopause model. Materials and methodsWe evaluated the molecular and physiological effects of dietary licorice root administered to ovariectomized C57BL/6 mice as root powder (LRP), extracts (LRE), or isolated isoliquiritigenin (ILQ) on reproductive (uterus and mammary gland) and nonreproductive tissues important in regulating metabolism (liver, perigonadal, perirenal, mesenteric, and subcutaneous fat). Quantitative outcome measures including body weight, fat distribution (magnetic resonance imaging), food consumption, bone density and weight (Dual-energy X-ray absorptiometry), and gene expression were assessed by the degree of restoration to the preovariectomized health state. We characterized histological (H&E and oil red O staining) and molecular properties (expression of certain disease markers) of these tissues, and correlated these with metabolic phenotype as well as blood levels of bioactives. ConclusionAlthough LRE and ILQ provided some benefit, LRP was the most effective in reducing body weight gain, overall fat deposition, liver steatosis, and expression of hepatic lipid synthesis genes following ovariectomy. Our data demonstrate that licorice root provided improvement of multiple metabolic parameters under conditions of low estrogen and high-fat diets without stimulating reproductive tissues. C1 [Madak-Erdogan, Zeynep; Wrobel, Kinga U.; Hartman, James A.; Wang, Michelle; Cam, Anthony; Helferich, William G.] Univ Illinois, Bot Res Ctr, Dept Food Sci, Urbana, IL USA. [Madak-Erdogan, Zeynep; Wrobel, Kinga U.; Hartman, James A.; Wang, Michelle; Cam, Anthony; Helferich, William G.] Univ Illinois, Dept Human Nutr, Urbana, IL USA. [Gong, Ping; Zhao, Yiru Chen; Xu, Liwen; Katzenellenbogen, Benita S.] Univ Illinois, Mol & Integrat Physiol, Urbana, IL USA. [Katzenellenbogen, John A.] Univ Illinois, Chem, Urbana, IL USA. [Iwaniec, Urszula T.; Turner, Russell T.] Oregon State Univ, Skeletal Biol Lab, Sch Biol & Populat Hlth Sci, Corvallis, OR 97331 USA. [Twaddle, Nathan C.; Doerge, Daniel R.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Khan, Ikhlas A.] Univ Mississippi, Natl Ctr Nat Prod Res, Sch Pharm, University, MS 38677 USA. [Khan, Ikhlas A.] Univ Mississippi, Div Pharmacognosy, Dept BioMol Sci, Sch Pharm, University, MS 38677 USA. RP Madak-Erdogan, Z (reprint author), Univ Illinois, Bot Res Ctr, Dept Food Sci, Urbana, IL USA. EM zmadake2@illinois.edu OI Madak-Erdogan, Zeynep/0000-0003-2607-1643 FU NIH from the National Center for Complementary and Alternative Medicines (NCCAM) [P50AT006268]; Office of Dietary Supplements (ODS); National Cancer Institute (NCI); National Institute of Food and Agriculture, U.S. Department of Agriculture [ILLU-698-909] FX This work was supported by the NIH [P50AT006268] (W. G. H., B. S. K., J. A. K., D. R. D., I. A. K.) from the National Center for Complementary and Alternative Medicines (NCCAM), the Office of Dietary Supplements (ODS), and the National Cancer Institute (NCI) and National Institute of Food and Agriculture, U.S. Department of Agriculture, award ILLU-698-909 (Z. M. E.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, U.S. Food and Drug Administration, and U.S. Department of Agriculture. NR 50 TC 4 Z9 4 U1 2 U2 8 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 FEB PY 2016 VL 60 IS 2 BP 369 EP 380 DI 10.1002/mnfr.201500445 PG 12 WC Food Science & Technology SC Food Science & Technology GA DD5KO UT WOS:000369962800012 PM 26555669 ER PT J AU Heidor, R de Conti, A Ortega, JF Furtado, KS Silva, RC Tavares, PELM Purgatto, E Ract, JNR de Paiva, SAR Gioielli, LA Pogribny, IP Moreno, FS AF Heidor, Renato de Conti, Aline Ortega, Juliana F. Furtado, Kelly S. Silva, Roberta C. Tavares, Paulo E. L. M. Purgatto, Eduardo Ract, Juliana N. R. de Paiva, Sergio A. R. Gioielli, Luiz A. Pogribny, Igor P. Moreno, Fernando S. TI The chemopreventive activity of butyrate-containing structured lipids in experimental rat hepatocarcinogenesis SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE Chemoprevention; Liver carcinogenesis; Rat; Structured lipids; Tributyrin ID HEPATOCELLULAR-CARCINOMA; SIGNALING PATHWAY; SODIUM-BUTYRATE; DNA METHYLATION; ACID PRODRUG; FLAXSEED OIL; CYCLIN D1; CANCER; TRIBUTYRIN; CHROMATIN AB ScopeEmerging evidence indicates that the use of bioactive food components is a promising strategy to prevent the development of liver cancer. The goal of this study was to examine the chemopreventive effect of butyrate-containing structured lipids (STLs) produced by an enzymatic interesterification of tributyrin and flaxseed oil on rat hepatocarcinogenesis. Methods and resultsMale Wistar rats were subjected to a classic resistant hepatocyte model of liver carcinogenesis and treated with STLs, tributyrin or flaxseed oil during the initial phases of hepatocarcinogenesis. Treatment with STLs and tributyrin strongly inhibited the development of preneoplastic liver lesions. The chemopreventive activity of tributyrin was associated with the induction of apoptosis and reduction of the expression of major activated hepatocarcinogenesis-related oncogenes. Treatment with STLs caused substantially greater inhibitory effects than tributyrin on oncogene expression. ConclusionThese results demonstrate that the tumor-suppressing activity of butyrate-containing STLs is associated with its ability to prevent and inhibit activation of major hepatocarcinogenesis-related oncogenes. Enrichment of histone H3K9me3 and H3K27me3 at the promoter of Myc and Ccnd1 genes may be related to the inhibitory effect on oncogene expression in the livers of STL-treated rats. C1 [Heidor, Renato; Ortega, Juliana F.; Furtado, Kelly S.; Tavares, Paulo E. L. M.; Moreno, Fernando S.] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Food & Expt Nutr, Lab Diet Nutr & Canc, Sao Paulo, Brazil. [de Conti, Aline; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Silva, Roberta C.; Ract, Juliana N. R.; Gioielli, Luiz A.] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Biochem & Pharmaceut Technol, Sao Paulo, Brazil. [Purgatto, Eduardo] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Food & Expt Nutr, Lab Food Chem & Biochem, BR-05508 Sao Paulo, Brazil. [de Paiva, Sergio A. R.] Sao Paulo State Univ, Botucatu Med Sch, Dept Internal Med, Botucatu, SP, Brazil. [Heidor, Renato; Furtado, Kelly S.; Purgatto, Eduardo; Moreno, Fernando S.] Univ Sao Paulo, Fac Pharmaceut Sci, Adv Res Ctr Food Sci & Nutr NAPAN, BR-05508 Sao Paulo, Brazil. [Heidor, Renato; Purgatto, Eduardo; de Paiva, Sergio A. R.; Moreno, Fernando S.] Univ Sao Paulo, Fac Pharmaceut Sci, Food Res Ctr FORC, BR-05508 Sao Paulo, Brazil. RP Moreno, FS (reprint author), Univ Sao Paulo, Fac Pharmaceut Sci, Dept Food & Expt Nutr, Lab Diet Nutr & Canc, Sao Paulo, Brazil.; Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA.; Moreno, FS (reprint author), Univ Sao Paulo, Fac Pharmaceut Sci, Adv Res Ctr Food Sci & Nutr NAPAN, BR-05508 Sao Paulo, Brazil.; Moreno, FS (reprint author), Univ Sao Paulo, Fac Pharmaceut Sci, Food Res Ctr FORC, BR-05508 Sao Paulo, Brazil. EM igor.pogribny@fda.hhs.gov; rmoreno@usp.br RI Purgatto, Eduardo/C-7707-2009; Food Research Center, FoRC/J-7793-2015; Heidor, Renato/O-1125-2013; Ract, Juliana/D-2367-2011; Moreno, Fernando/I-1943-2013; Paiva, Sergio/A-5101-2008 OI Purgatto, Eduardo/0000-0002-7372-1197; Food Research Center, FoRC/0000-0003-0248-8911; Heidor, Renato/0000-0001-7427-6518; Ract, Juliana/0000-0001-5845-9445; Paiva, Sergio/0000-0003-4412-1990 NR 50 TC 1 Z9 1 U1 2 U2 14 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 FEB PY 2016 VL 60 IS 2 BP 420 EP 429 DI 10.1002/mnfr.201500643 PG 10 WC Food Science & Technology SC Food Science & Technology GA DD5KO UT WOS:000369962800017 PM 26548572 ER PT J AU Ghasriani, H Hodgson, DJ Brinson, RG McEwen, I Buhse, LF Kozlowski, S Marino, JP Aubin, Y Keire, DA AF Ghasriani, Houman Hodgson, Derek J. Brinson, Robert G. McEwen, Ian Buhse, Lucinda F. Kozlowski, Steven Marino, John P. Aubin, Yves Keire, David A. TI Precision and robustness of 2D-NMR for structure assessment of filgrastim biosimilars SO NATURE BIOTECHNOLOGY LA English DT Letter ID ORDER STRUCTURE; NMR C1 [Ghasriani, Houman; Buhse, Lucinda F.; Keire, David A.] US FDA, Ctr Drug Evaluat & Res, Div Pharmaceut Anal, St Louis, MO USA. [Hodgson, Derek J.; Aubin, Yves] Hlth Canada, Biol & Genet Therapies Directorate, Ctr Biol Evaluat, Ottawa, ON K1A 0L2, Canada. [Brinson, Robert G.; Marino, John P.] NIST, Inst Biosci & Biotechnol Res, Rockville, MD USA. [McEwen, Ian] Med Prod Agcy Sweden, Uppsala, Sweden. [Kozlowski, Steven] US FDA, Ctr Drug Evaluat & Res, Off Biotechnol Prod, Silver Spring, MD USA. RP Keire, DA (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Pharmaceut Anal, St Louis, MO USA.; Aubin, Y (reprint author), Hlth Canada, Biol & Genet Therapies Directorate, Ctr Biol Evaluat, Ottawa, ON K1A 0L2, Canada.; Marino, JP (reprint author), NIST, Inst Biosci & Biotechnol Res, Rockville, MD USA. EM john.marino@nist.gov; yves.aubin@hc-sc.gc.ca; david.keire@fda.hhs.gov FU Intramural NIST DOC [9999-NIST] NR 10 TC 4 Z9 4 U1 4 U2 10 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 FEB PY 2016 VL 34 IS 2 BP 139 EP 141 DI 10.1038/nbt.3474 PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DD0OK UT WOS:000369619100011 PM 26849514 ER PT J AU Hansen, C Andrade, SE Freiman, H Dublin, S Haffenreffer, K Cooper, WO Cheetham, TC Toh, S Li, DK Raebel, MA Kuntz, JL Perrin, N Rosales, AG Carter, S Pawloski, PA Maloney, EM Graham, DJ Sahin, L Scott, PE Yap, J Davis, R AF Hansen, Craig Andrade, Susan E. Freiman, Heather Dublin, Sascha Haffenreffer, Katie Cooper, William O. Cheetham, T. Craig Toh, Sengwee Li, De-Kun Raebel, Marsha A. Kuntz, Jennifer L. Perrin, Nancy Rosales, A. Gabriela Carter, Shelley Pawloski, Pamala A. Maloney, Elizabeth M. Graham, David J. Sahin, Leyla Scott, Pamela E. Yap, John Davis, Robert TI Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE medications; pregnancy; birth defects; sulfonamides; antibacterial agents; pharmacoepidemiology ID FOLIC-ACID ANTAGONISTS; URINARY-TRACT-INFECTIONS; BIRTH-DEFECTS-PREVENTION; DISEASES SOCIETY; MALFORMATIONS; ASSOCIATION; GUIDELINES; EXPOSURE; AMERICA; CLEFTS AB BackgroundSulfonamide antibacterials are widely used in pregnancy, but evidence about their safety is mixed. The objective of this study was to assess the association between first-trimester sulfonamide exposure and risk of specific congenital malformations. MethodsMother-infant pairs were selected from a cohort of 1.2 million live-born deliveries (2001-2008) at 11 US health plans comprising the Medication Exposure in Pregnancy Risk Evaluation Program. Mothers with first-trimester trimethoprim-sulfonamide (TMP-SUL) exposures were randomly matched 1:1 to (i) a primary comparison group (mothers exposed to penicillins and/or cephalosporins) and (ii) a secondary comparison group (mothers with no dispensing of an antibacterial, antiprotozoal, or antimalarial medication during the same time period). The outcomes were cardiovascular abnormalities, cleft palate/lip, clubfoot, and urinary tract abnormalities. ResultsWe first identified 7615 infants in the TMP-SUL exposure group, of which 7595 (99%) were exposed to a combination of TMP-SUL and the remaining 1% to sulfonamides alone. After matching (1:1) to the comparator groups and only including those with complete data on covariates, there were 20064 (n=6688 per group) in the primary analyses. Overall, cardiovascular defects (1.52%) were the most common and cleft lip/palate (0.10%) the least common that were evaluated. Compared with penicillin/cephalosporin exposure, and no antibacterial exposure, TMP-SUL exposure was not associated with statistically significant elevated risks for cardiovascular, cleft lip/palate, clubfoot, or urinary system defects. ConclusionsFirst-trimester TMP-SUL exposure was not associated with a higher risk of the congenital anomalies studied, compared with exposure to penicillins and/or cephalosporins, or no exposure to antibacterials. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Hansen, Craig; Freiman, Heather; Davis, Robert] Kaiser Permanente Georgia, Ctr Clin & Outcomes Res, Atlanta, GA USA. [Hansen, Craig] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Andrade, Susan E.] Univ Massachusetts, Med Sch Worcester, Meyers Primary Care Inst, Worcester, MA 01605 USA. [Freiman, Heather] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Dublin, Sascha] Grp Hlth Res Inst, Seattle, WA USA. [Haffenreffer, Katie; Toh, Sengwee] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Haffenreffer, Katie; Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Cooper, William O.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Cooper, William O.] Vanderbilt Univ, Sch Med, Dept Hlth Policy, Nashville, TN 37212 USA. [Cheetham, T. Craig] Kaiser Permanente So Calif, Pharm Analyt Serv, Downey, CA USA. [Li, De-Kun] Kaiser Permanente, Kaiser Fdn Res Inst, Div Res, Oakland, CA USA. [Raebel, Marsha A.] Kaiser Permanente, Colorado Inst Hlth Res, Denver, CO USA. [Kuntz, Jennifer L.; Perrin, Nancy; Rosales, A. Gabriela] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Carter, Shelley] LCF Res, Albuquerque, NM USA. [Pawloski, Pamala A.] Hlth Partners Inst Educ & Res, Minneapolis, MN USA. [Maloney, Elizabeth M.; Graham, David J.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Sahin, Leyla] US FDA, Off New Drugs, Silver Spring, MD USA. [Scott, Pamela E.] US FDA, Off Womens Hlth, Silver Spring, MD USA. [Yap, John] US FDA, Off Biostat, Silver Spring, MD USA. [Davis, Robert] Univ Tennessee, Ctr Biomed Informat, Memphis, TN USA. [Davis, Robert] Univ Tennessee, Dept Pediat, Memphis, TN USA. RP Andrade, SE (reprint author), Univ Massachusetts, Med Sch Worcester, Meyers Primary Care Inst, Worcester, MA 01605 USA. EM sandrade@meyersprimary.org RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU NIA NIH HHS [K23 AG028954]; PHS HHS [HHSF2232010000029I] NR 31 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD FEB PY 2016 VL 25 IS 2 BP 170 EP 178 DI 10.1002/pds.3919 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD6TA UT WOS:000370056200007 PM 26599424 ER PT J AU Pacanowski, M Huang, SM AF Pacanowski, M. Huang, S. M. TI Precision Medicine SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material C1 [Pacanowski, M.; Huang, S. M.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. RP Pacanowski, M (reprint author), US FDA, Off Clin Pharmacol, Silver Spring, MD USA. EM Michael.Pacanowski@fda.hhs.gov NR 15 TC 4 Z9 4 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 IS 2 BP 124 EP 129 DI 10.1002/cpt.296 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100001 PM 26800326 ER PT J AU Jang, SH Yan, Z Lazor, JA AF Jang, S. H. Yan, Z. Lazor, J. A. TI Therapeutic drug monitoring: A patient management tool for precision medicine SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID INVASIVE FUNGAL-INFECTIONS AB The precision medicine initiative is designed to better understand the causes of disease, to develop target therapies, and to identify patients that would benefit from treatment. Prescribing the right dose, which is not always the same to all patients, is needed for a successful outcome. The purpose of this commentary is to discuss the role of dose individualization based on therapeutic drug monitoring as a clinical patient management tool in the application of precision medicine. C1 [Jang, S. H.; Yan, Z.; Lazor, J. A.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Jang, SH (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM seong.jang@fda.hhs.gov NR 10 TC 5 Z9 5 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 IS 2 BP 148 EP 150 DI 10.1002/cpt.298 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100011 PM 26565378 ER PT J AU Woodcock, J AF Woodcock, J. TI "Precision" drug development? SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB The concept of precision medicine has entered broad public consciousness, spurred by a string of targeted drug approvals, highlighted by the availability of personal gene sequences, and accompanied by some remarkable claims about the future of medicine. It is likely that precision medicines will require precision drug development programs. What might such programs look like? C1 [Woodcock, J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Woodcock, J (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM janet.woodcock@fda.hhs.gov NR 1 TC 1 Z9 1 U1 1 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 FEB PY 2016 VL 99 IS 2 BP 152 EP 154 DI 10.1002/cpt.255 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100013 PM 26331240 ER PT J AU Woosley, RL Whyte, J Mohamadi, A Romero, K AF Woosley, R. L. Whyte, J. Mohamadi, A. Romero, K. TI Medical decision support systems and therapeutics: The role of autopilots SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID TORSADE-DE-POINTES; RISK AB For decades, medical practice has increasingly relied on prescription medicines to treat, cure, or prevent illness but their net benefit is reduced by prescribing errors that result in adverse drug reactions (ADRs) and tens of thousands of deaths each year. Optimal prescribing requires effective management of massive amounts of data. Clinical decision support systems (CDSS) can help manage information and support optimal therapeutic decisions before errors are made by operating as the prescribers' autopilot. C1 [Woosley, R. L.] AZCERT Inc, Oro Valley, AZ USA. [Woosley, R. L.] Univ Arizona, Coll Med, Phoenix, AZ USA. [Whyte, J.; Mohamadi, A.] US FDA, Safe Use Initiat, Silver Spring, MD USA. [Romero, K.] Crit Path Inst, Clin Pharmacol, Tucson, AZ USA. RP Woosley, RL (reprint author), AZCERT Inc, Oro Valley, AZ USA.; Woosley, RL (reprint author), Univ Arizona, Coll Med, Phoenix, AZ USA. EM rwoosley@azcert.org OI Woosley, Raymond L./0000-0002-2588-328X NR 10 TC 6 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 IS 2 BP 161 EP 164 DI 10.1002/cpt.259 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100016 PM 26352903 ER PT J AU Kalman, LV Agundez, JAG Appell, ML Black, JL Bell, GC Boukouvala, S Bruckner, C Bruford, E Caudle, K Coulthard, SA Daly, AK Del Tredici, AL den Dunnen, JT Drozda, K Everts, RE Flockhart, D Freimuth, RR Gaedigk, A Hachad, H Hartshorne, T Ingelman-Sundberg, M Klein, TE Lauschke, VM Maglott, DR McLeod, HL McMillin, GA Meyer, UA Muller, DJ Nickerson, DA Oetting, WS Pacanowski, M Pratt, VM Relling, MV Roberts, A Rubinstein, WS Sangkuhl, K Schwab, M Scott, SA Sim, SC Thirumaran, RK Toji, LH Tyndale, RF van Schaik, RHN Whirl-Carrillo, M Yeo, KTJ Zanger, UM AF Kalman, L. V. Agundez, J. A. G. Appell, M. Lindqvist Black, J. L. Bell, G. C. Boukouvala, S. Bruckner, C. Bruford, E. Caudle, K. Coulthard, S. A. Daly, A. K. Del Tredici, A. L. den Dunnen, J. T. Drozda, K. Everts, R. E. Flockhart, D. Freimuth, R. R. Gaedigk, A. Hachad, H. Hartshorne, T. Ingelman-Sundberg, M. Klein, T. E. Lauschke, V. M. Maglott, D. R. McLeod, H. L. McMillin, G. A. Meyer, U. A. Mueller, D. J. Nickerson, D. A. Oetting, W. S. Pacanowski, M. Pratt, V. M. Relling, M. V. Roberts, A. Rubinstein, W. S. Sangkuhl, K. Schwab, M. Scott, S. A. Sim, S. C. Thirumaran, R. K. Toji, L. H. Tyndale, R. F. van Schaik, R. H. N. Whirl-Carrillo, M. Yeo, K. T. J. Zanger, U. M. TI Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PERSONALIZED MEDICINE; IMPLEMENTATION CONSORTIUM; MOLECULAR-PATHOLOGY; VKORC1 HAPLOTYPES; CLINICAL-PRACTICE; DRUG DEVELOPMENT; INFORMATION; PERSPECTIVE; ASSOCIATION; TRANSPORTER AB This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward. C1 [Kalman, L. V.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Agundez, J. A. G.] Univ Extremadura, Dept Pharmacol, Caceres, Spain. [Appell, M. Lindqvist] Linkoping Univ, Fac Med & Hlth Sci, Dept Med & Hlth Sci, Div Drug Res, Linkoping, Sweden. [Black, J. L.; Freimuth, R. R.] Mayo Clin, Rochester, MN USA. [Bell, G. C.; McLeod, H. L.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Boukouvala, S.] Democritus Univ Thrace, Dept Mol Biol & Genet, Alexandroupolis, Greece. [Bruckner, C.] Affymetrix, Santa Clara, CA USA. [Bruford, E.] European Mol Biol Lab, EMBL EBI, HUGO Gene Nomenclature Comm, Wellcome Genome Campus, Hinxton, England. [Caudle, K.; Relling, M. V.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Coulthard, S. A.; Daly, A. K.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Del Tredici, A. L.] Millennium Hlth LLC, San Diego, CA USA. [den Dunnen, J. T.] Leiden Univ, Med Ctr, Dept Human Genet & Clin Genet, Leiden, Netherlands. [Drozda, K.; Pacanowski, M.] US FDA, Silver Spring, MD USA. [Everts, R. E.] Agena Biosci, San Diego, CA USA. [Flockhart, D.; Pratt, V. M.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Gaedigk, A.] Univ Missouri, Childrens Mercy Kansas City, Div Clin Pharmacol & Therapeut Innovat, Kansas City, MO 64110 USA. [Gaedigk, A.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA. [Hachad, H.] Translat Software, Bellevue, WA USA. [Hartshorne, T.] Thermo Fisher Sci, Dept Genet Anal, San Francisco, CA USA. [Ingelman-Sundberg, M.; Lauschke, V. M.; Sim, S. C.] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Klein, T. E.; Sangkuhl, K.; Whirl-Carrillo, M.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Maglott, D. R.; Rubinstein, W. S.] Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD USA. [McMillin, G. A.] Univ Utah, Salt Lake City, UT USA. [McMillin, G. A.] ARUP Labs, Salt Lake City, UT USA. [Meyer, U. A.] Univ Basel, Basel, Switzerland. [Mueller, D. J.] Univ Toronto, Dept Psychiat, CAMH, Toronto, ON, Canada. [Nickerson, D. A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Oetting, W. S.] Univ Minnesota, Dept Expt & Clin Pharmacol, Minneapolis, MN USA. [Roberts, A.] Aegis Sci Corp, Nashville, TN USA. [Schwab, M.; Zanger, U. M.] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany. [Schwab, M.; Zanger, U. M.] Univ Hosp, Dept Clin Pharmacol, Tubingen, Germany. [Scott, S. A.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Thirumaran, R. K.] Genelex Corp, Seattle, WA USA. [Toji, L. H.] Coriell Inst Med Res, Camden, NJ USA. [Tyndale, R. F.] Univ Toronto, CAMH, Toronto, ON, Canada. [Tyndale, R. F.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Tyndale, R. F.] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada. [van Schaik, R. H. N.] Erasmus MC, Dept Clin Chem, Int Federat Clin Chem IFCC Task Force Pharmacogen, Rotterdam, Netherlands. [Yeo, K. T. J.] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. RP Kalman, LV (reprint author), Ctr Dis Control & Prevent, Atlanta, GA USA. EM LKalman@cdc.gov RI Agundez, Jose/A-5503-2008; Mueller, Daniel/L-4159-2016; Zanger, Ulrich/A-9364-2012; Daly, Ann/H-3144-2011; OI Mueller, Daniel/0000-0003-4978-4400; Zanger, Ulrich/0000-0002-5276-2002; Daly, Ann/0000-0002-7321-0629; Agundez, Jose/0000-0001-6895-9160; Bruford, Elspeth/0000-0002-8380-5247; Lauschke, Volker/0000-0002-1140-6204 FU Intramural CDC HHS [CC999999]; NCI NIH HHS [P30 CA021765]; NHGRI NIH HHS [U01 HG007762, U01HG007762, U41 HG003345, U41HG003345]; NIDA NIH HHS [R01 DA035736]; NIGMS NIH HHS [R24GM115264, 2 R01 GM088076-05, K23 GM104401, R01 GM088076, R24 GM061374, R24 GM115264, R24 GM61374, U19 GM061388, U19 GM61388]; Wellcome Trust [099129/Z/12/Z] NR 54 TC 8 Z9 9 U1 6 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 IS 2 BP 172 EP 185 DI 10.1002/cpt.280 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100020 PM 26479518 ER PT J AU Vicini, P Fields, O Lai, E Litwack, ED Martin, AM Morgan, TM Pacanowski, MA Papaluca, M Perez, OD Ringel, MS Robson, M Sakul, H Vockley, J Zaks, T Dolsten, M Sogaard, M AF Vicini, P. Fields, O. Lai, E. Litwack, E. D. Martin, A-M Morgan, T. M. Pacanowski, M. A. Papaluca, M. Perez, O. D. Ringel, M. S. Robson, M. Sakul, H. Vockley, J. Zaks, T. Dolsten, M. Sogaard, M. TI Precision medicine in the age of big data: The present and future role of large-scale unbiased sequencing in drug discovery and development SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID PERSONALIZED MEDICINE; STRATIFIED MEDICINE; INCIDENTAL FINDINGS; COMPANION DIAGNOSTICS; CLINICAL GENOME; CANCER; CHALLENGES; PROJECT; EXOME; RECOMMENDATIONS AB High throughput molecular and functional profiling of patients is a key driver of precision medicine. DNA and RNA characterization has been enabled at unprecedented cost and scale through rapid, disruptive progress in sequencing technology, but challenges persist in data management and interpretation. We analyze the state-of-the-art of large-scale unbiased sequencing in drug discovery and development, including technology, application, ethical, regulatory, policy and commercial considerations, and discuss issues of LUS implementation in clinical and regulatory practice. C1 [Vicini, P.; Fields, O.; Perez, O. D.; Sakul, H.; Dolsten, M.; Sogaard, M.] Pfizer Worldwide Res & Dev, La Jolla, CA USA. [Vicini, P.; Fields, O.; Perez, O. D.; Sakul, H.; Dolsten, M.; Sogaard, M.] Pfizer Worldwide Res & Dev, Collegeville, PA USA. [Vicini, P.; Fields, O.; Perez, O. D.; Sakul, H.; Dolsten, M.; Sogaard, M.] Pfizer Worldwide Res & Dev, New York, NY USA. [Fields, O.] Takeda Pharmaceut Int, Deerfield, IL USA. [Litwack, E. D.; Pacanowski, M. A.] US FDA, Silver Spring, MD USA. [Martin, A-M] GlaxoSmithKline, Collegeville, PA USA. [Morgan, T. M.; Robson, M.] Novartis Inst Biomed Res, Cambridge, MA USA. [Morgan, T. M.; Robson, M.] Novartis Inst Biomed Res, E Hanover, NJ USA. [Papaluca, M.] European Med Agcy, London, England. [Ringel, M. S.] Boston Consulting Grp Inc, Boston, MA USA. [Vockley, J.] Inova Translat Med Inst, Falls Church, VA USA. [Zaks, T.] Sanofi, Cambridge, MA USA. RP Sogaard, M (reprint author), Pfizer Worldwide Res & Dev, La Jolla, CA USA.; Sogaard, M (reprint author), Pfizer Worldwide Res & Dev, Collegeville, PA USA. EM morten.sogaard@pfizer.com NR 74 TC 5 Z9 6 U1 9 U2 34 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 IS 2 BP 198 EP 207 DI 10.1002/cpt.293 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100022 PM 26536838 ER PT J AU Johannesen, L Vicente, J Mason, JW Erato, C Sanabria, C Waite-Labott, K Hong, M Lin, J Guo, P Mutlib, A Wang, J Crumb, WJ Blinova, K Chan, D Stohlman, J Florian, J Ugander, M Stockbridge, N Strauss, DG AF Johannesen, L. Vicente, J. Mason, J. W. Erato, C. Sanabria, C. Waite-Labott, K. Hong, M. Lin, J. Guo, P. Mutlib, A. Wang, J. Crumb, W. J. Blinova, K. Chan, D. Stohlman, J. Florian, J. Ugander, M. Stockbridge, N. Strauss, D. G. TI Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID TORSADE-DE-POINTES; VENTRICULAR-ARRHYTHMIAS; MULTICHANNEL BLOCK; POTASSIUM CHANNEL; MEXILETINE; LIDOCAINE; QUINIDINE; HERG; COMBINATION; INTERVAL AB Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-T-peak (J-T(peak)c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-T(peak)c may add value beyond only assessing QTc. C1 [Johannesen, L.; Vicente, J.; Blinova, K.; Chan, D.; Stohlman, J.; Ugander, M.; Strauss, D. G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Johannesen, L.; Ugander, M.; Strauss, D. G.] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Johannesen, L.; Ugander, M.; Strauss, D. G.] Karolinska Univ Hosp, Stockholm, Sweden. [Vicente, J.; Florian, J.; Stockbridge, N.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Vicente, J.] Univ Zaragoza, IIS Aragon, Aragon Inst Engn Res I3A, BSICoS Grp, Zaragoza, Spain. [Mason, J. W.; Erato, C.; Sanabria, C.; Waite-Labott, K.] Spaulding Clin, West Bend, WI USA. [Mason, J. W.] Univ Utah, Salt Lake City, UT USA. [Hong, M.; Lin, J.; Guo, P.; Mutlib, A.; Wang, J.] Frontage Labs, Exton, PA USA. [Crumb, W. J.] Zenas Technol, Metairie, LA USA. RP Strauss, DG (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA.; Strauss, DG (reprint author), Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden.; Strauss, DG (reprint author), Karolinska Univ Hosp, Stockholm, Sweden. EM David.Strauss@fda.hhs.gov OI Ugander, Martin/0000-0003-3665-2038; Vicente, Jose/0000-0001-9963-1205 NR 38 TC 14 Z9 14 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 IS 2 BP 214 EP 223 DI 10.1002/cpt.205 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100024 PM 26259627 ER PT J AU Coleman, BN Johnson, SE Tessrnan, GK Tworek, C Alexander, J Dickinson, DM Rath, J Green, KM AF Coleman, Blair N. Johnson, Sarah E. Tessrnan, Greta K. Tworek, Cindy Alexander, Jennifer Dickinson, Denise M. Rath, Jessica Green, Kerry M. TI "It's not smoke. It's not tar. It's not 4000 chemicals. Case closed": Exploring attitudes, beliefs, and perceived social norms of e-cigarette use among adult users SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Electronic cigarettes; Qualitative research; Tobacco use ID NICOTINE DELIVERY-SYSTEMS; ELECTRONIC CIGARETTES; HARM PERCEPTIONS; AWARENESS; BENEFITS; REASONS AB Background: Electronic cigarette (e-cigarette) use is rapidly increasing among adults in the U.S. The purpose of this qualitative study was to explore consumer perceptions about e-cigarettes, including knowledge, attitudes, beliefs and perceived social norms. Methods: A total of 14 focus groups (N=116) were conducted with current adult e-cigarette users in five U.S. cities from March through May, 2014. Focus groups were segmented by age (young adults aged 18-29 and older adults aged 30 and older) as well as by e-cigarette use status (exclusive e-cigarette users and non-exclusive e-cigarette users). Focus group discussions lasted approximately 60-min and were audio-recorded and transcribed; data were analyzed using a phenomenological approach. Results: Participants expressed many positive attitudes towards e-cigarettes and simultaneously reported a lack of information and knowledge about the products. Focus group participants overwhelmingly felt as though the ingredients of e-cigarettes were likely less harmful than conventional cigarettes. Additionally, many described positive reactions from family and friends, especially when e-cigarettes were used in place of conventional cigarettes. Conclusions: Findings from this qualitative study provide insight into consumer knowledge, attitudes and beliefs about e-cigarettes increasing our understanding of why and how they are being used. Such information will help provide insight into the potential public health impact of these emerging products. Published by Elsevier Ireland Ltd. C1 [Coleman, Blair N.; Johnson, Sarah E.; Tessrnan, Greta K.; Tworek, Cindy] US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Alexander, Jennifer; Dickinson, Denise M.] RTI Int, 3040 E Cornwallis Rd, Res Triangle Pk, NC 27709 USA. [Rath, Jessica] Truth Initiat Evaluat Sci & Res, 900 G St NW,Fourth Floor, Washington, DC 20001 USA. [Green, Kerry M.] Univ Maryland, Sch Publ Hlth, Dept Behav & Community Hlth, 2242 Valley Dr, College Pk, MD 20742 USA. RP Coleman, BN (reprint author), US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Blair.Coleman@fda.hhs.gov FU U.S. Food and Drug Administration (FDA) Center for Tobacco Products (CTP) FX Funding for data collection and analysis was provided by the U.S. Food and Drug Administration (FDA) Center for Tobacco Products (CTP). NR 22 TC 6 Z9 6 U1 11 U2 27 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 FEB 1 PY 2016 VL 159 BP 80 EP 85 DI 10.1016/j.drugalcdep.2015.11.028 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DC8LX UT WOS:000369472200011 PM 26708706 ER PT J AU McCormack, L Lefebvre, RC Bann, C Taylor, O Rausch, P AF McCormack, Lauren Lefebvre, R. Craig Bann, Carla Taylor, Olivia Rausch, Paula TI Consumer Understanding, Preferences, and Responses to Different Versions of Drug Safety Messages in the United States: A Randomized Controlled Trial SO DRUG SAFETY LA English DT Article ID RISK COMMUNICATION; HEALTH LITERACY; FDA; READABILITY; INSTRUMENT; FUTURE AB Introduction As part of its mission, the US Food and Drug Administration (FDA) communicates with the public regularly about the benefits and risks of prescription and over-the-counter (OTC) drugs. Effectively communicating risk, however, is a significant public health challenge. Objective To better understand how different populations understand information communicated by the FDA about drug safety, we conducted a randomized experiment to examine comprehension and other measures of effectiveness of drug safety messages that occurred in a post-market surveillance phase. Methods We used an Internet panel survey of 1244 consumers, of whom 58 % used prescription drugs in the past year. Half of the sample panel was randomized to read a previous FDA Drug Safety Communication (DSC) with the drug name changed, and the other half was randomized to read a revised version of the same DSC. We examined how making certain modifications to the way drug risk information is communicated has an impact on comprehension and behavioral intentions, including the user's likelihood of discontinuing the drug. We also studied how comprehension varied by respondent characteristics, health literacy skills, risk perceptions, and trust in the message. Results Based on a five-item comprehension index, the revised version of the message was associated with significantly greater comprehension of the information relative to the standard version (63 vs 52 % correct, p < 0.001). Significantly more respondents found the revised version to be clear (82 vs 73 %, p < 0.000), while fewer in that group reported learning something new (78 % vs 84 %, p = 0.015). No significant differences emerged between the two groups in terms of the message being informative, convincing, or helpful. We found no significant differences between the two groups in terms of behavioral intentions, risk perception, and trust. Conclusions We found that making plain language changes to the DSC significantly increased consumers' level of comprehension of its content, providing support for ongoing use and further exploration of these strategies in pharmacovigilance communication research. The study findings have important implications for future drug safety and other communication messages related to prescription drugs. C1 [McCormack, Lauren; Lefebvre, R. Craig; Taylor, Olivia] RTI Int, Ctr Commun Sci, 3040 East Cornwallis Rd, Res Triangle Pk, NC 27709 USA. [Bann, Carla] RTI Int, Div Stat & Data Sci, Res Triangle Pk, NC 27709 USA. [Rausch, Paula] US FDA, Ctr Drug Evaluat & Res, Off Commun, Silver Spring, MD USA. RP McCormack, L (reprint author), RTI Int, Ctr Commun Sci, 3040 East Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM lmac@rti.org FU US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Communications [1 U18 FD004608-01] FX The US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Communications funded and participated in all phases of this project through a cooperative agreement with RTI International, award #1 U18 FD004608-01. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the FDA, CDER, or the US Department of Health and Human Services. NR 36 TC 2 Z9 2 U1 3 U2 7 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD FEB PY 2016 VL 39 IS 2 BP 171 EP 184 DI 10.1007/s40264-015-0358-9 PG 14 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA DC5YB UT WOS:000369295500007 PM 26547718 ER PT J AU Choi, M Ghammraoui, B Badal, A Badano, A AF Choi, Mina Ghammraoui, Bahaa Badal, Andreu Badano, Aldo TI Monte Carlo X-ray transport simulation of small-angle X-ray scattering instruments using measured sample cross sections SO JOURNAL OF APPLIED CRYSTALLOGRAPHY LA English DT Article DE small-angle X-ray scattering; empirical cross sections; Monte Carlo simulations; molecular interactions AB Small-angle X-ray scattering (SAXS) has recently been proposed as a novel noninvasive in vivo molecular imaging technique to characterize molecular interactions deep within the body using high-contrast probes. This article describes a detailed Monte Carlo X-ray transport simulation technique that utilizes user-provided cross sections to describe X-ray interaction in virtual samples and explore SAXS instrument design choices. The accuracy of the simulation code is validated with sample material cross sections derived from analytical models and empirical measurements of a homogeneous spherical gold nanoparticle (GNP) monomer, a dimer and heterogeneous mixtures of the two in aqueous solution. Analytical and measured scattering profiles from these samples were converted to cross sections using an absolute water standard. Our Monte Carlo estimates of the fraction of dimers from analytically derived and empirically derived cross sections are strongly correlated, with less than 1.5 and 16% error, respectively, to the expected concentration of monomer and dimer species. In addition, a variety of monoenergetic X-ray beams were simulated to investigate coherent scattering versus radiation dose for a range of sample sizes. For GNP spheres in aqueous solution, the energy range that produces the most coherent scattering at the detector per deposited energy was between 31 and 49 keV for a sample thickness of 1 mm to 10 cm. The method described here for the detailed simulation of SAXS using measured and modeled cross sections will enable instrumentation optimization for in vivo molecular imaging applications. C1 [Choi, Mina; Ghammraoui, Bahaa; Badal, Andreu; Badano, Aldo] US FDA, Div Imaging Diagnost & Software Reliabil, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Choi, Mina; Badano, Aldo] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Badano, A (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA.; Badano, A (reprint author), Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 FU Fischell Fellowship in Biomedical Engineering; FDA Medical Countermeasures Initiative (MCMi) FX MC was supported by the Fischell Fellowship in Biomedical Engineering. This work was supported by the FDA Medical Countermeasures Initiative (MCMi). The mention of commercial products herein is not to be construed as either an actual or an implied endorsement of such products by the Department of Health and Human Services. This is a contribution of the US Food and Drug Administration and is not subject to copyright. NR 15 TC 0 Z9 0 U1 2 U2 2 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 1600-5767 J9 J APPL CRYSTALLOGR JI J. Appl. Crystallogr. PD FEB PY 2016 VL 49 BP 188 EP 194 DI 10.1107/S1600576715023924 PN 1 PG 7 WC Chemistry, Multidisciplinary; Crystallography SC Chemistry; Crystallography GA DC7HB UT WOS:000369389300022 ER PT J AU Morgan, SJ French, EL Thomson, JJ Seaborn, CP Shively, CA Krukonis, ES AF Morgan, Sarah J. French, Emily L. Thomson, Joshua J. Seaborn, Craig P. Shively, Christian A. Krukonis, Eric S. TI Formation of an Intramolecular Periplasmic Disulfide Bond in TcpP Protects TcpP and TcpH from Degradation in Vibrio cholerae SO JOURNAL OF BACTERIOLOGY LA English DT Article ID VIRULENCE GENE-EXPRESSION; REGULATED INTRAMEMBRANE PROTEOLYSIS; TRANSCRIPTIONAL ACTIVATION; SIGNAL-TRANSDUCTION; ESCHERICHIA-COLI; TOXR REGULON; DNA-BINDING; STRESS-RESPONSE; CELL-ENVELOPE; PROMOTER AB TcpP and ToxR coordinately regulate transcription of toxT, the master regulator of numerous virulence factors in Vibrio cholerae. TcpP and ToxR are membrane-localized transcription factors, each with a periplasmic domain containing two cysteines. In ToxR, these cysteines form an intramolecular disulfide bond and a cysteine-to-serine substitution affects activity. We determined that the two periplasmic cysteines of TcpP also form an intramolecular disulfide bond. Disruption of this intramolecular disulfide bond by mutation of either cysteine resulted in formation of intermolecular disulfide bonds. Furthermore, disruption of the intramolecular disulfide bond in TcpP decreased the stability of TcpP. While the decreased stability of TcpP-C207S resulted in a nearly complete loss of toxT activation and cholera toxin (CT) production, the second cysteine mutant, TcpP-C218S, was partially resistant to proteolytic degradation and maintained similar to 50% toxT activation capacity. TcpP-C218S was also TcpH independent, since deletion of tcpH did not affect the stability of TcpP-C218S, whereas wild-type TcpP was degraded in the absence of TcpH. Finally, TcpH was also unstable when intramolecular disulfides could not be formed in TcpP, suggesting that the single periplasmic cysteine in TcpH may assist with disulfide bond formation in TcpP by interacting with the periplasmic cysteines of TcpP. Consistent with this finding, a TcpH-C114S mutant was unable to stabilize TcpP and was itself unstable. Our findings demonstrate a periplasmic disulfide bond in TcpP is critical for TcpP stability and virulence gene expression. IMPORTANCE The Vibrio cholerae transcription factor TcpP, in conjunction with ToxR, regulates transcription of toxT, the master regulator of numerous virulence factors in Vibrio cholerae. TcpP is a membrane-localized transcription factor with a periplasmic domain containing two cysteines. We determined that the two periplasmic cysteines of TcpP form an intramolecular disulfide bond and disruption of the intramolecular disulfide bond in TcpP decreased the stability of TcpP and reduced virulence gene expression. Normally TcpH, another membrane-localized periplasmic protein, protects TcpP from degradation. However, we found that TcpH was also unstable when intramolecular disulfides could not be formed in TcpP, indicating that the periplasmic cysteines of TcpP are required for functional interaction with TcpH and that this interaction is required for both TcpP and TcpH stability. C1 [Morgan, Sarah J.; Seaborn, Craig P.; Krukonis, Eric S.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [French, Emily L.; Thomson, Joshua J.; Krukonis, Eric S.] Univ Detroit Mercy, Sch Dent, Dept Biomed & Diagnost Sci, Detroit, MI 48221 USA. [Shively, Christian A.] Univ Michigan, Sch Med, Program Cell & Mol Biol, Ann Arbor, MI USA. [Morgan, Sarah J.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Seaborn, Craig P.] Food & Drug Adm, Cincinnati, OH USA. RP Krukonis, ES (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. EM krukones@udmercy.edu FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI075087] FX HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Eric Krukonis under grant number AI075087. NR 48 TC 0 Z9 0 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD FEB PY 2016 VL 198 IS 3 BP 498 EP 509 DI 10.1128/JB.00338-15 PG 12 WC Microbiology SC Microbiology GA DC4AY UT WOS:000369163300015 ER PT J AU Wake, LM Ahn, I Farooqui, M Hahn, J Tian, X Stetler-Stevenson, M Marti, G Wiestner, A Maric, I AF Wake, Laura M. Ahn, Inhye Farooqui, Mohammed Hahn, Jamie Tian, Xin Stetler-Stevenson, Maryalice Marti, Gerald Wiestner, Adrian Maric, Irina TI Dual Antibody Immunohistochemistry: A Cost-Efficient and Sensitive New Tool for the Detection of Minimal Residual CLL SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NCI, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NIH, CC, DLM, Bldg 10, Bethesda, MD 20892 USA. US FDA, CDRH, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1507 BP 382A EP 382A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702246 ER PT J AU Song, Y Zemlyanoy, D Chen, X Nie, HC Su, ZY Fang, K Yang, XH Smith, D Byrn, S Lubach, JW AF Song, Yang Zemlyanoy, Dmitry Chen, Xin Nie, Haichen Su, Ziyang Fang, Ke Yang, Xinghao Smith, Daniel Byrn, Stephen Lubach, Joseph W. TI Acid-Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study SO MOLECULAR PHARMACEUTICS LA English DT Article DE lapatinib; gefitinib; amorphous; solid dispersion; physical stability; dissolution rate; XPS; solid-state NMR; ionic interaction; salt ID HOT-MELT EXTRUSION; ANGLE-SPINNING NMR; STATE NMR; INTERMOLECULAR INTERACTIONS; DIFFERENT POLYMERS; N-15 NMR; SPECTROSCOPY; STABILIZATION; INDOMETHACIN; CRYSTALLIZATION AB This study investigates the potential drug excipient interactions of polystyrene sulfonic acid (PSSA) and two weakly basic anticancer drugs, lapatinib (LB) and gefitinib (GB), in amorphous solid dispersions. Based on the strong acidity of the sulfonic acid functional group, PSSA was hypothesized to exhibit specific intermolecular acid base interactions with both model basic drugs. Ultraviolet (UV) spectroscopy identified red shifts, which correlated well with the color change observed in lapatinib PSSA solutions. Fourier transform infrared (FTIR) spectra suggest the protonation of the quinazoline nitrogen atom in both model compounds, which agrees well with data from the crystalline ditosylate salt of lapatinib. X-ray photoelectron spectroscopy (XPS) detected increases in binding energy of the basic nitrogen atoms in both lapatinib and gefitinib, strongly indicating protonation of these nitrogen atoms. N-15 solid-state NMR spectroscopy provided direct spectroscopic evidence for protonation of the quinazoline nitrogen atoms in both LB and GB, as well as the secondary amine nitrogen atom in LB and the tertiary amine nitrogen atom in GB. The observed chemical shifts in the LB PSSA N-15 spectrum also agree very well with the lapatinib ditosylate salt where proton transfer is known. Additionally, the dissolution and physical stability behaviors of both amorphous solid dispersions were examined. PSSA was found to significantly improve the dissolution of LB and GB and effectively inhibit the crystallization of LB and GB under accelerated storage conditions due to the beneficial strong intermolecular acid base interaction between the sulfonic acid groups and basic nitrogen centers. C1 [Song, Yang; Nie, Haichen; Fang, Ke; Smith, Daniel; Byrn, Stephen] Purdue Univ, Dept Ind & Phys Pharm, W Lafayette, IN 47907 USA. [Zemlyanoy, Dmitry] Purdue Univ, Birck Nanotechnol Ctr, W Lafayette, IN 47907 USA. [Chen, Xin] GlaxoSmithKline, Collegeville, PA 19426 USA. [Su, Ziyang] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Yang, Xinghao] Nanjing Normal Univ, Coll Life Sci, Nanjing 210046, Jiangsu, Peoples R China. [Lubach, Joseph W.] Genentech Inc, Small Mol Pharmaceut Sci, San Francisco, CA 94080 USA. RP Lubach, JW (reprint author), Genentech Inc, Small Mol Pharmaceut Sci, San Francisco, CA 94080 USA. EM lubach.joseph@gene.com NR 41 TC 3 Z9 3 U1 4 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD FEB PY 2016 VL 13 IS 2 BP 483 EP 492 DI 10.1021/acs.molpharmaceut.5b00708 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DC6VE UT WOS:000369356900016 PM 26716395 ER PT J AU Bairi, VG Lim, JH Quevedo, IR Mudalige, TK Linder, SW AF Bairi, Venu Gopal Lim, Jin-Hee Quevedo, Ivan R. Mudalige, Thilak K. Linder, Sean W. TI Portable X-ray fluorescence spectroscopy as a rapid screening technique for analysis of TiO2 and ZnO in sunscreens SO SPECTROCHIMICA ACTA PART B-ATOMIC SPECTROSCOPY LA English DT Article DE Sunscreens; Metals; Quantitation; Portable x-ray fluorescence spectroscopy analyzer; Inductively coupled plasma-mass spectrometry ID TITANIUM-DIOXIDE; ZINC-OXIDE; SPECTROMETRY; XRF; CONTROVERSIES; INGREDIENTS; ANALYZER AB This investigation reports a rapid and simple screening technique for the quantification of titanium and zinc in commercial sunscreens using portable X-ray fluorescence spectroscopy (pXRF). A highly evolved technique, inductively coupled plasma-mass spectroscopy (ICP-MS) was chosen as a comparative technique to pXRF, and a good correlation (r(2)> 0.995) with acceptable variations (525%) in results between both techniques was observed. Analytical figures of merit such as detection limit, quantitation limit, and linear range of the method are reported for the pXRF technique. This method has a good linearity (r(2) > 0.995) for the analysis of titanium (Ti) in the range of 0.4-14.23 wt%, and zinc (Zn) in the range of 1.0-23.90 wt%. However, most commercial sunscreens contain organic ingredients, and these ingredients are known to cause matrix effects. The development of appropriate matrix matched working standards to obtain the calibration curve was found to be a major challenge for the pXRF measurements. In this study, we have overcome the matrix effect by using metal-free commercial sunscreens as a dispersing media for the preparation of working standards. An easy extension of this unique methodology for preparing working standards in different matrices was also.reported. This method is simple, rapid, and cost-effective and, in comparison to conventional techniques (e.g., ICP-MS), did not generate toxic wastes during sample analysis. Published by Elsevier B.V. C1 [Bairi, Venu Gopal; Lim, Jin-Hee; Quevedo, Ivan R.; Mudalige, Thilak K.; Linder, Sean W.] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Lim, JH; Linder, SW (reprint author), US FDA, Arkansas Reg Lab, Off Regulatory Affairs, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Jin.Lim@fda.hhs.gov; Sean.Linder@fda.hhs.gov FU Nanotechnology CORES (Collaborative Opportunities for Research Excellence in Science) Program; U.S. Department of Energy; FDA FX This work was performed at the Nanotechnology Core Facility (NanoCore) located in the U.S. Food and Drug Administration's Jefferson Laboratories campus (Jefferson, Arkansas), which also houses the FDA National Center for Toxicological Research and the FDA Office of Regulatory Affairs, Arkansas Regional Laboratory. This project was graciously supported by Nanotechnology CORES (Collaborative Opportunities for Research Excellence in Science) Program administered by the FDA Office of Chief Scientist, and supported in part by an appointment to the Research Participation Program at the Office of Regulatory Affairs/Arkansas Regional Laboratory, U.S. FDA, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between U.S. Department of Energy and FDA. The views expressed in this manuscript are those of the authors and should not be interpreted as the official opinion or policy of the U.S. Food and Drug Administration, Department of Health and Human Services, or any other agency or component of the U.S. government. The mention of trades names, commercial products, or organizations is for clarification of the methods used and should not be interpreted as an endorsement of a product or manufacturer. We would like to thank Paul C. Howard, Lydia Velazquez, Germarie Sanchez-Pomales, Patrick Sisco, Haiou Qu, Yasith Nanayaldcara, and Nuwan Kothalawala for their support, valuable time, and comments. NR 32 TC 2 Z9 2 U1 9 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0584-8547 J9 SPECTROCHIM ACTA B JI Spectroc. Acta Pt. B-Atom. Spectr. PD FEB 1 PY 2016 VL 116 BP 21 EP 27 DI 10.1016/j.sab.2015.11.008 PG 7 WC Spectroscopy SC Spectroscopy GA DC8JE UT WOS:000369464900004 PM 27076699 ER PT J AU Xu, L Ziegelbauer, J Wang, R Wu, WW Shen, RF Juhl, H Zhang, YQ Rosenberg, A AF Xu, Lai Ziegelbauer, Joseph Wang, Rong Wu, Wells W. Shen, Rong-Fong Juhl, Hartmut Zhang, Yaqin Rosenberg, Amy TI Distinct Profiles for Mitochondrial t-RNAs and Small Nucleolar RNAs in Locally Invasive and Metastatic Colorectal Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER; RECTAL-CANCER; COLON-CANCER; EXPRESSION; HYPOXIA; GENES; MICRORNA; PROLIFERATION; METABOLISM; BIOMARKERS AB Purpose: To gain insight into factors involved in tumor progression and metastasis, we examined the role of noncoding RNAs in the biologic characteristics of colorectal carcinoma, in paired samples of tumor together with normal mucosa from the same colorectal carcinoma patient. The tumor and healthy tissue samples were collected and stored under stringent conditions, thereby minimizing warm ischemic time. Experimental Design: We focused particularly on distinctions among high-stage tumors and tumors with known metastases, performing RNA-Seq analysis that quantifies transcript abundance and identifies novel transcripts. Results: In comparing 35 colorectal carcinomas, including 9 metastatic tumors (metastases to lymph nodes and lymphatic vessels), with their matched healthy control mucosa, we found a distinct signature of mitochondrial transfer RNAs (MT-tRNA) and small nucleolar RNAs (snoRNA) for metastatic and high-stage colorectal carcinoma. We also found the following: (i) MT-TF (phenylalanine) and snord12B expression correlated with a substantial number of miRNAs and mRNAs in 14 colorectal carcinomas examined; (ii) an miRNA signature of oxidative stress, hypoxia, and a shift to glycolytic metabolism in 14 colorectal carcinomas, regardless of grade and stage; and (iii) heterogeneous MT-tRNA/snoRNA fingerprints for 35 pairs. Conclusions: These findings could potentially assist in more accurate and predictive staging of colorectal carcinoma, including identification of those colorectal carcinomas likely to metastasize. (C)2015 AACR. C1 [Xu, Lai; Wang, Rong; Zhang, Yaqin; Rosenberg, Amy] FDA, OBP DBRR 3, CDER, Silver Spring, MD USA. [Ziegelbauer, Joseph] NCI, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Wu, Wells W.; Shen, Rong-Fong] FDA, Facil Biotechnol Resources, CBER, Silver Spring, MD USA. [Juhl, Hartmut] Indivumed GMBH, Hamburg, Germany. RP Rosenberg, A (reprint author), FDA, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM amy.rosenberg@fda.hhs.gov OI Ziegelbauer, Joseph/0000-0001-6464-6941 FU Intramural NIH HHS [Z99 OD999999] NR 34 TC 2 Z9 2 U1 0 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 FEB 1 PY 2016 VL 22 IS 3 BP 773 EP 784 DI 10.1158/1078-0432.CCR-15-0737 PG 12 WC Oncology SC Oncology GA DC2XY UT WOS:000369083300027 PM 26384739 ER PT J AU Cartwright, EJ Nguyen, T Melluso, C Ayers, T Lane, C Hodges, A Li, X Quammen, J Yendell, SJ Adams, J Mitchell, J Rickert, R Klos, R Williams, IT Behravesh, CB Wright, J AF Cartwright, E. J. Nguyen, T. Melluso, C. Ayers, T. Lane, C. Hodges, A. Li, X. Quammen, J. Yendell, S. J. Adams, J. Mitchell, J. Rickert, R. Klos, R. Williams, I. T. Behravesh, C. Barton Wright, J. TI A Multistate Investigation of Antibiotic-Resistant Salmonella enterica Serotype I 4,[5],12:i:- Infections as Part of an International Outbreak Associated with Frozen Feeder Rodents SO ZOONOSES AND PUBLIC HEALTH LA English DT Article DE Salmonella; outbreak; reptiles; frozen feeder rodents; zoonoses; amphibians ID MAIL-ORDER HATCHERY; UNITED-STATES; LIVE POULTRY; TYPHIMURIUM; PREVALENCE; AMPHIBIANS; EXPOSURE; SURVIVAL; REPTILES; CONTACT AB While most human Salmonella infections result from exposure to contaminated foods, an estimated 11% of all Salmonella infections are attributed to animal exposures, including both direct animal handling and indirect exposures such as cleaning cages and handling contaminated pet food. This report describes the epidemiologic, environmental and laboratory investigations conducted in the United States as part of the response to an international outbreak of tetracycline-resistant Salmonella enterica serotype I 4,[5],12:i:- infections with over 500 illnesses occurring from 2008 to 2010. This investigation found that illness due to the outbreak strain was significantly associated with exposure to pet reptiles and frozen feeder rodents used as food for pet reptiles. Salmonella isolates indistinguishable from the outbreak strain were isolated from a frozen feeder mice-fed reptile owned by a case patient, as well as from frozen feeder mice and environmental samples collected from a rodent producing facility (Company A). An international voluntary recall of all Company A produced frozen feeder animals sold between May 2009 and July 2010 occurred. Only 13% of cases in our investigation were aware of the association between Salmonella infection and mice or rats. Consumers, the pet industry, healthcare providers and veterinarians need to be aware of the potential health risk posed by feeder rodents, whether live or frozen. Frozen feeder rodent producers, suppliers and distributors should follow the animal food labelling requirements as described in 21 CFR 501.5, and all packages of frozen feeder rodents should include safe handling instructions. Persons should wash their hands thoroughly with soap and water after handling live or frozen feeder rodents, as well as reptiles or anything in the area where the animals live. Continued opportunities exist for public health officials, the pet industry, veterinarians and consumers to work together to prevent salmonellosis associated with pet food, pets and other animals. C1 [Cartwright, E. J.] CDC, Epidem Intelligence Serv, Sci Educ & Profess Dev Program Off, OSELS, Atlanta, GA 30333 USA. [Cartwright, E. J.; Nguyen, T.; Ayers, T.; Quammen, J.; Yendell, S. J.; Mitchell, J.; Rickert, R.; Williams, I. T.; Behravesh, C. Barton; Wright, J.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging Zoonot & Infect Dis, Atlanta, GA USA. [Cartwright, E. J.] Emory Univ, Sch Med, Div Infect Dis, Atlanta, GA USA. [Melluso, C.; Hodges, A.; Li, X.] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. [Lane, C.] Publ Hlth England, Ctr Infect Dis Surveillance & Control, London, United Kingdom. [Yendell, S. J.] CDC, Epidemiol Elect Program, Sci Educ & Profess Dev Program Off, OSELS, Atlanta, GA 30333 USA. [Adams, J.] Assoc Publ Hlth Labs, Silver Spring, MD USA. [Klos, R.] Wisconsin Div Publ Hlth, Madison, WI USA. RP Cartwright, EJ (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,MS A-38, Atlanta, GA 30333 USA. EM ecartw2@emory.edu OI Ayers, Tracy/0000-0003-4140-3263 FU United States Centers for Disease Control and Prevention FX This work was supported by the United States Centers for Disease Control and Prevention. NR 40 TC 0 Z9 0 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1863-1959 EI 1863-2378 J9 ZOONOSES PUBLIC HLTH JI Zoonoses Public Health PD FEB PY 2016 VL 63 IS 1 BP 62 EP 71 DI 10.1111/zph.12205 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases; Veterinary Sciences SC Public, Environmental & Occupational Health; Infectious Diseases; Veterinary Sciences GA DB8YH UT WOS:000368802600007 PM 25996458 ER PT J AU Ahn, M Li, L Kim, M AF Ahn, M. Li, L. Kim, M. TI THE SURVEY OF FDA APPROVED NEW MOLECULAR ENTITIES THAT ARE TERATOGENIC AND THEIR DRUG INTERACTION POTENTIALS WITH HORMONAL CONTRACEPTIVES. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Ahn, M.; Li, L.; Kim, M.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-085 BP S98 EP S98 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600350 ER PT J AU Babiskin, A Fang, L Choi, S Zhao, L AF Babiskin, A. Fang, L. Choi, S. Zhao, L. TI PHARMACOKINETIC MODELING AND SIMULATION OF NALTREXONE FOR EXTENDED-RELEASE INTRAMUSCULAR INJECTABLE SUSPENSION TO DERIVE ALTERNATIVE BIOEQUIVALENCE METRICS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Babiskin, A.; Fang, L.; Choi, S.; Zhao, L.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-096 BP S56 EP S56 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600199 ER PT J AU Dong, Z Yang, X Arya, V Zhang, L AF Dong, Z. Yang, X. Arya, V. Zhang, L. TI COMPARING VARIOUS IN VITRO PREDICTION CRITERIA TO ASSESS THE POTENTIAL OF A NEW MOLECULAR ENTITY (NME) TO INHIBIT OCT2 AND MATE TRANSPORTERS IN VIVO. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Dong, Z.; Yang, X.; Arya, V.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-076 BP S94 EP S96 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600341 ER PT J AU Dong, Z Yang, X Arya, V Zhang, L AF Dong, Z. Yang, X. Arya, V. Zhang, L. TI COMPARING VARIOUS IN VITRO PREDICTION CRITERIA TO ASSESS THE POTENTIAL OF A NEW MOLECULAR ENTITY (NME) TO INHIBIT ORGANIC ANION TRANSPORTER 1 AND 3 (OAT1 AND OAT3) IN VIVO. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Dong, Z.; Yang, X.; Arya, V.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-075 BP S94 EP S94 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600340 ER PT J AU Gopalakrishnan, M Mehta, M Uppoor, R Mathis, M Farchione, T Kempf, L Zhang, J Younis, I AF Gopalakrishnan, M. Mehta, M. Uppoor, R. Mathis, M. Farchione, T. Kempf, L. Zhang, J. Younis, I. TI INCREASING PLACEBO RESPONSE AND DECREASING TREATMENT EFFECTS IN SCHIZOPHRENIA TRIALS - THE TREND CONTINUES: AN UPDATE FROM US FOOD AND DRUG ADMINISTRATION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Gopalakrishnan, M.; Mehta, M.; Uppoor, R.; Mathis, M.; Farchione, T.; Kempf, L.; Zhang, J.; Younis, I.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-107 BP S103 EP S103 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600371 ER PT J AU Grimstein, M Hsu, V Zhao, P AF Grimstein, M. Hsu, V. Zhao, P. TI PBPK MODELING OF CIPROFLOXACIN - KNOWLEDGE EXTENSION BY CONFIRMING THE EFFECT OF INTRINSIC AND EXTRINSIC PATIENT FACTORS ON RENAL OAT ACTIVITIES SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Grimstein, M.; Hsu, V.; Zhao, P.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-101 BP S57 EP S57 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600204 ER PT J AU Hsu, V Grimstein, M Zhao, P AF Hsu, V. Grimstein, M. Zhao, P. TI LEVERAGING POTENTIAL CHANGES IN RENAL TRANSPORTER ACTIVITY TO PREDICT DRUG PHARMACOKINETICS DURING PREGNANCY USING PBPK MODELING SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Hsu, V.; Grimstein, M.; Zhao, P.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-100 BP S57 EP S57 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600203 ER PT J AU Hsueh, C Yoshida, K Meyer, T Zhang, L Huang, S Giacomini, K AF Hsueh, C. Yoshida, K. Meyer, T. Zhang, L. Huang, S. Giacomini, K. TI THE ACTIVITIES OF ORGANIC ANION TRANSPORTERS, OATP1B1/1B3 AND OAT1/3 ARE MODULATED BY UREMIC TOXINS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Hsueh, C.; Giacomini, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Yoshida, K.; Zhang, L.; Huang, S.] US FDA, Silver Spring, MD USA. [Meyer, T.] Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PWII-1 BP S73 EP S73 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600259 ER PT J AU Hsueh, C Yoshida, K Meyer, T Zhang, L Huang, S Giacomini, K AF Hsueh, C. Yoshida, K. Meyer, T. Zhang, L. Huang, S. Giacomini, K. TI THE ACTIVITIES OF ORGANIC ANION TRANSPORTERS, OATP1B1/1B3 AND OAT1/3 AREMODULATED BY UREMIC TOXINS. C. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Hsueh, C.; Giacomini, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Yoshida, K.; Zhang, L.; Huang, S.] US FDA, Silver Spring, MD USA. [Meyer, T.] Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PT-08 BP S15 EP S15 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600040 ER PT J AU Lee, J Wang, J Florian, J Wang, Y Kettl, D Marcus, K Woitach, A AF Lee, J. Wang, J. Florian, J. Wang, Y. Kettl, D. Marcus, K. Woitach, A. TI EXPOSURE-RESPONSE ANALYSES IN THE RISK-BENEFIT EVALUATION OF SECUKINUMAB FOR PLAQUE PSORIASIS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Lee, J.; Wang, J.; Florian, J.; Wang, Y.; Kettl, D.; Marcus, K.; Woitach, A.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-140 BP S67 EP S68 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600243 ER PT J AU Liu, J Kim, G Xu, J McKee, A Hu, M Palmby, T Zhuang, L Zhao, L AF Liu, J. Kim, G. Xu, J. McKee, A. Hu, M. Palmby, T. Zhuang, L. Zhao, L. TI COMBINED POPULATION PK MODELING AND DISPROPORTIONALITY ANALYSES TO ASSESS THE ASSOCIATION BETWEEN KINASE INHIBITION AND ADVERSE EVENTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Liu, J.] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA. [Kim, G.; Xu, J.; McKee, A.; Palmby, T.] US FDA, Off Hematol & Oncol Prod, Off New Drugs, CDER, Silver Spring, MD USA. [Hu, M.; Zhao, L.] US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, Off Gener Drugs,CDER, Silver Spring, MD USA. [Zhuang, L.] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-044 BP S86 EP S86 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600309 ER PT J AU Liu, J Kim, G Xu, J McKee, A Hu, M Palmby, T Zhuang, L Zhao, L AF Liu, J. Kim, G. Xu, J. McKee, A. Hu, M. Palmby, T. Zhuang, L. Zhao, L. TI COMBINED POPULATION PK MODELING AND DISPROPORTIONALITY ANALYSES TO ASSESS THE ASSOCIATION BETWEEN KINASE INHIBITION AND ADVERSE EVENTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Liu, J.] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA. [Kim, G.; Xu, J.; McKee, A.; Palmby, T.] US FDA, Off Hematol & Oncol Prod, Off New Drugs, CDER, Silver Spring, MD USA. [Hu, M.; Zhao, L.] US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, Off Gener Drugs,CDER, Silver Spring, MD USA. [Zhuang, L.] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA OPC-4 BP S12 EP S13 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600032 ER PT J AU Ma, L Habtemariam, B Dinndorf, P Mercado, MS Lin, T Wang, Y AF Ma, L. Habtemariam, B. Dinndorf, P. Mercado, M. S. Lin, T. Wang, Y. TI OPTIMIZING THE DOSE OF PLERIXAFOR IN LOW BODY WEIGHT PATIENTS WITH NON-HODGKIN'S LYMPHOMA. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Ma, L.; Habtemariam, B.; Dinndorf, P.; Wang, Y.] US FDA, Silver Spring, MD USA. [Mercado, M. S.; Lin, T.] Sanofi, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-074 BP S50 EP S51 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600177 ER PT J AU Ma, L Williams, GM Ouyang, Y Dickerson, W Huang, L Melhem, M Chow, AT Yang, B Harrold, JM Laniyonu, A Zalkikar, J Gorovets, A Marzella, L Mehrotra, N AF Ma, L. Williams, G. M. Ouyang, Y. Dickerson, W. Huang, L. Melhem, M. Chow, A. T. Yang, B. Harrold, J. M. Laniyonu, A. Zalkikar, J. Gorovets, A. Marzella, L. Mehrotra, N. TI PATIENTS WITH HEMATOPOIETIC SYNDROME OF ACUTE RADIATION SYNDROME (HS-ARS): CONSIDERATIONS ON THE DOSE SELECTION FOR FILGRASTIM UNDER THE ANIMAL RULE. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Ma, L.; Williams, G. M.; Ouyang, Y.; Dickerson, W.; Huang, L.; Laniyonu, A.; Zalkikar, J.; Gorovets, A.; Marzella, L.; Mehrotra, N.] US FDA, Silver Spring, MD USA. [Melhem, M.; Chow, A. T.; Yang, B.; Harrold, J. M.] Amgen Inc, Thousand Oaks, CA 91320 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-073 BP S50 EP S50 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600176 ER PT J AU Madrasi, K Samant, S Kim, M Li, F Voss, S Kehoe, T Schmidt, S Li, L AF Madrasi, K. Samant, S. Kim, M. Li, F. Voss, S. Kehoe, T. Schmidt, S. Li, L. TI DEVELOPMENT OF A MECHANISM-BASED DRUG-DISEASE MODEL TO QUANTIFY POSTMENOPAUSAL OSTEOPOROSIS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Madrasi, K.; Kim, M.; Li, F.; Voss, S.; Kehoe, T.; Li, L.] US FDA, Silver Spring, MD USA. [Samant, S.; Schmidt, S.] Univ Florida, Orlando, FL 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA OII-2 BP S105 EP S105 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600378 ER PT J AU Meng, Z Trame, MN Schmidt, S Fang, L Lesko, L AF Meng, Z. Trame, M. N. Schmidt, S. Fang, L. Lesko, L. TI APPLICATION OF PHARMACOKINETIC/PHARMACODYNAMIC MODELING TO SIMULATE POTENTIAL DIFFERENCES IN BIOEQUIVALENCE BETWEEN GENERIC AND BRAND NAME GABAPENTIN PRODUCTS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Meng, Z.; Trame, M. N.; Schmidt, S.; Lesko, L.] Univ Florida, Orlando, FL USA. [Fang, L.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 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 FEB PY 2016 VL 99 SU 1 MA PI-117 BP S61 EP S62 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600220 ER PT J AU Mizuno, T Fukuda, T Emoto, C Christians, U Jiang, W Alloway, RR Vinks, AA AF Mizuno, T. Fukuda, T. Emoto, C. Christians, U. Jiang, W. Alloway, R. R. Vinks, A. A. TI POPULATION PHARMACOKINETIC-PHARMACOGENETIC ANALYSIS OF TACROLIMUS IN RENAL TRANSPLANT PATIENTS PARTICIPATING IN A PROSPECTIVE BIOEQUIVALENCE STUDY. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Mizuno, T.; Fukuda, T.; Emoto, C.; Vinks, A. A.] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, Cincinnati, OH 45229 USA. [Christians, U.] Univ Colorado, Clin Res & Dev iC42, Aurora, CO USA. [Jiang, W.] US FDA, Off Gener Drugs, Silver Spring, MD USA. [Alloway, R. R.] Univ Cincinnati, Coll Med, Dept Internal Med, Div Nephrol, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-039 BP S41 EP S41 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600142 ER PT J AU Pan, Y Cui, M Jiang, X Conner, D Zhao, L Stier, E AF Pan, Y. Cui, M. Jiang, X. Conner, D. Zhao, L. Stier, E. TI PBPK MODELING AND SIMULATION OF RECTAL/COLON ABSORPTION FOR SUPPOSITORY DRUGS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Pan, Y.; Cui, M.; Jiang, X.; Conner, D.; Zhao, L.; Stier, E.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-038 BP S41 EP S41 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600141 ER PT J AU Ramamoorthy, A Sadler, BM van Hasselt, J Elassaiss-Schaap, J Kasichayanula, S Edwards, Y van der Graaf, PH Zhang, L Wagner, JA AF Ramamoorthy, A. Sadler, B. M. van Hasselt, J. Elassaiss-Schaap, Jeroen Kasichayanula, S. Edwards, Y. van der Graaf, P. H. Zhang, L. Wagner, J. A. TI THE PROOF IS IN THE PEE: WHAT HAVE WE LEARNED ABOUT POPULATION ASPARAGUS URINARY ODOR KINETICS? SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Ramamoorthy, A.; Zhang, L.] US FDA, Silver Spring, MD USA. [Sadler, B. M.; Edwards, Y.] ICON, Raleigh, NC USA. [van Hasselt, J.; Elassaiss-Schaap, Jeroen; van der Graaf, P. H.] Leiden Univ, Leiden, Netherlands. [Kasichayanula, S.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Wagner, J. A.] Takeda Pharmaceut Int Co, Cambridge, MA USA. RI Elassaiss-Schaap , Jeroen/Q-5451-2016 NR 0 TC 0 Z9 0 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 FEB PY 2016 VL 99 SU 1 MA PI-083 BP S53 EP S53 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600186 ER PT J AU Wagner, C Pan, Y Hsu, V Sinha, V Zhao, P AF Wagner, C. Pan, Y. Hsu, V. Sinha, V. Zhao, P. TI PREDICTING THE EFFECT OF CYP3A INDUCERS ON THE PHARMACOKINETICS OF SUBSTRATE DRUGS USING PBPK MODELING - AN ANALYSIS OF PBPK SUBMISSIONS TO THE FDA SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Wagner, C.; Pan, Y.; Hsu, V.; Sinha, V.; Zhao, P.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA E-022 BP S26 EP S27 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600084 ER PT J AU Yoshida, K Sun, B Zhao, P Zhang, L Huang, S AF Yoshida, K. Sun, B. Zhao, P. Zhang, L. Huang, S. TI COMPARISON OF THE EFFECT OF CHRONIC KIDNEY DISEASE (CKD) ON PHARMACOKINETICS OF OATP, CYP2D6, AND CYP3A SUBSTRATES. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Yoshida, K.; Sun, B.; Zhao, P.; Zhang, L.; Huang, S.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-004 BP S76 EP S76 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600271 ER PT J AU Younis, IR Sinha, V AF Younis, I. R. Sinha, V. TI THE ROLE OF POPULATION PK IN INFORMING DOSING RECOMMENDATIONS FOR PATIENTS WITH HEPATIC AND RENAL IMPAIRMENT. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Younis, I. R.; Sinha, V.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-106 BP S103 EP S103 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600370 ER PT J AU Zaman, S Gao, C Abernethy, DR AF Zaman, S. Gao, C. Abernethy, D. R. TI A SYSTEMS BIOLOGY APPROACH TO PREDICTING CARDIOTOXICITY ASSOCIATED WITH TYROSINE KINASE INHIBITORS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Zaman, S.; Abernethy, D. R.] US FDA, Silver Spring, MD USA. [Gao, C.] Rutgers State Univ, New Brunswick, NJ 08903 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PWIII-4 BP S75 EP S75 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600266 ER PT J AU Zaman, S Gao, C Abernethy, DR AF Zaman, S. Gao, C. Abernethy, D. R. TI A SYSTEMS BIOLOGY APPROACH TO PREDICTING CARDIOTOXICITY ASSOCIATED WITH TYROSINE KINASE INHIBITORS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Zaman, S.; Abernethy, D. R.] US FDA, Silver Spring, MD USA. [Gao, C.] Rutgers State Univ, New Brunswick, NJ 08903 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PT-29 BP S20 EP S20 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600061 ER PT J AU Zaman, S Gao, C Abernethy, DR AF Zaman, S. Gao, C. Abernethy, D. R. TI A SYSTEMS BIOLOGY APPROACH TO PREDICTING CARDIOTOXICITY ASSOCIATED WITH TYROSINE KINASE INHIBITORS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Zaman, S.; Abernethy, D. R.] US FDA, Silver Spring, MD USA. [Gao, C.] Rutgers State Univ, New Brunswick, NJ 08903 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PC-12 BP S7 EP S8 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600013 ER PT J AU Zhang, N Shon, J Kim, M Li, L AF Zhang, N. Shon, J. Kim, M. Li, L. TI ROLE OF CYP3A4 IN ORAL CONTRACEPTIVE CLEARANCE. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Zhang, N.; Shon, J.; Kim, M.; Li, L.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-095 BP S56 EP S56 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600198 ER PT J AU Zhou, T Arya, V Zhang, L AF Zhou, T. Arya, V. Zhang, L. TI COMPARING VARIOUS IN VITRO PREDICTION CRITERIA TO ASSESS THE POTENTIAL OF A NEW MOLECULAR ENTITY (NME) TO INHIBIT P-GLYCOPROTEIN (P-GP) IN VIVO. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Zhou, T.; Arya, V.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-057 BP S89 EP S90 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600322 ER PT J AU Zhuang, L Wang, X Ma, L Bhattaram, A Mulugeta, Y Yu, J Mehrotra, N Wang, Y AF Zhuang, L. Wang, X. Ma, L. Bhattaram, A. Mulugeta, Y. Yu, J. Mehrotra, N. Wang, Y. TI APPLICATION OF PHARMACOMETRICS IN DOSE SELECTION OF DRUGS AND BIOLOGICS DEVELOPED UNDER THE ANIMAL RULE. L. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Zhuang, L.; Wang, X.; Ma, L.; Bhattaram, A.; Mulugeta, Y.; Yu, J.; Mehrotra, N.; Wang, Y.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-048 BP S43 EP S43 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600151 ER PT J AU Segars, K Simpson, S Kerdahi, K Sulaiman, IM AF Segars, Katharine Simpson, Steven Kerdahi, Khalil Sulaiman, Irshad M. TI Evaluation of Cronobacter Growth and Phenotypic Variation Under Modified Culture Conditions SO CURRENT MICROBIOLOGY LA English DT Article ID ENTEROBACTER-SAKAZAKII; INFANT FORMULA; PRODUCTS; MEDIA; MILK AB Cronobacter sakazakii is an opportunistic pathogen known to cause acute meningitis and necrotizing enterocolitis in neonates and immunocompromised individuals. It has been isolated from a wide range of food and environmental samples, and has been linked to outbreaks associated with powdered infant formula. This study was carried out to assess variations in growth conditions (temperature, pH, and sugar supplement) and to establish how these changes impact phenotypic characteristics for successful recovery and identification of Cronobacter, particularly for routine surveillance purposes. A total of six Cronobacter isolates were tested to evaluate the above growth conditions, including three ATCC Cronobacter reference and three environmental isolates obtained from regulatory sample screening. Although only slight changes in colony-forming units were observed across the pH range and the sugars tested, the morphology was significantly impacted by changes in these growth factors. Incubation between 30 and 50 A degrees C resulted in growth after 24 h, and the growth was slower at ambient temperature and colony formation was most robust at 30 A degrees C. Results of this study suggest that 30 A degrees C may be suitable for recovery of some Cronobacter strains, and minor variations in growth conditions can alter colony morphology and appearance. Expression of unique biological characteristics based on phenotypic observations may be beneficial for differentiating various Cronobacter strains. C1 [Segars, Katharine; Simpson, Steven; Kerdahi, Khalil; Sulaiman, Irshad M.] US FDA, Southeast Reg Lab, 60 Eighth St, Atlanta, GA 30309 USA. RP Sulaiman, IM (reprint author), US FDA, Southeast Reg Lab, 60 Eighth St, Atlanta, GA 30309 USA. EM Irshad.Sulaiman@fda.hhs.gov FU FDA Commissioner's Fellowship Program FX The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the views or official position of the U.S. Food and Drug Administration (FDA). The names of vendors or manufacturers are provided as examples of available product sources; inclusion does not imply endorsement of the vendors, manufacturers, or products by the FDA or the U.S. Department of Health and Human Services. This study was supported in part by funding from the FDA 2013 Commissioner's Fellowship Program. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 16 TC 0 Z9 0 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0343-8651 EI 1432-0991 J9 CURR MICROBIOL JI Curr. Microbiol. PD FEB PY 2016 VL 72 IS 2 BP 190 EP 197 DI 10.1007/s00284-015-0936-1 PG 8 WC Microbiology SC Microbiology GA DB6PO UT WOS:000368637300012 PM 26567034 ER PT J AU Srigley, CT Oles, CJ Kia, ARF Mossoba, MM AF Srigley, Cynthia T. Oles, Carolyn J. Kia, Ali Reza Fardin Mossoba, Magdi M. TI Authenticity Assessment of Extra Virgin Olive Oil: Evaluation of Desmethylsterols and Triterpene Dialcohols SO JOURNAL OF THE AMERICAN OIL CHEMISTS SOCIETY LA English DT Article DE Adulteration; Authenticity; Desmethylsterol; Erythrodiol; Extra virgin olive oil; Gas chromatography; Purity; Sterol; Triterpene dialcohol; Uvaol ID HAZELNUT OIL; ESTERIFIED STEROLS; ADULTERATION; PHYTOSTEROLS; ALCOHOLS; CULTIVAR; QUALITY; COLUMN; GC AB Extra virgin olive oil (EVOO) has a long history of economic adulteration, the detection of which presents significant challenges due to the diverse composition of cultivars grown around the world and the limitations of existing methods for detecting adulteration. In this study, using Method COI/T.20/Doc. No. 30/Rev. 1 of the International Olive Council, the authenticity of 88 market samples of EVOO was evaluated by comparing total sterol contents, desmethylsterol composition, and contents of triterpene dialcohols (erythrodiol and uvaol) with purity criteria specified in the United States Standards for grades of olive oil and olive-pomace oil. Three of the 88 samples labeled as EVOO failed to meet purity criteria, indicating possible adulteration with commodity oil and/or solvent-extracted olive oil. Detection of adulteration was also evaluated by spiking an EVOO sample with commodity oil at the 10 % level. As expected, eight of the spiked samples (canola, corn, hazelnut, peanut, safflower, soybean, and sunflower oils, and palm olein) failed to meet purity criteria. Two of the three samples spiked with 10 % hazelnut oil went undetected for adulteration. Overall, a low occurrence rate of adulteration (< 5 %), based on purity criteria for desmethylsterols and triterpene dialcohols, was detected for the 88 products labeled as EVOO. C1 [Srigley, Cynthia T.; Oles, Carolyn J.; Kia, Ali Reza Fardin; Mossoba, Magdi M.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 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 NR 30 TC 1 Z9 1 U1 5 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0003-021X EI 1558-9331 J9 J AM OIL CHEM SOC JI J. Am. Oil Chem. Soc. PD FEB PY 2016 VL 93 IS 2 BP 171 EP 181 DI 10.1007/s11746-015-2759-4 PG 11 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA DB7NH UT WOS:000368701800002 ER PT J AU Butler, KS Young, MYL Li, ZH Elespuru, RK Wood, SC AF Butler, Kimberly S. Young, Megan Y. L. Li, Zhihua Elespuru, Rosalie K. Wood, Steven C. TI Performance characteristics of the AmpliSeq Cancer Hotspot panel v2 in combination with the Ion Torrent Next Generation Sequencing Personal Genome Machine SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Next generation sequencing; Cancer Hotspot panel; Ion Torrent Personal Genome Machine; Mutation detection; Systematic error analysis; Performance analysis ID DIAGNOSTICS; GENES; MUTATIONS; PGM AB Next-Generation Sequencing is a rapidly advancing technology that has research and clinical applications. For many cancers, it is important to know the precise mutation(s) present, as specific mutations could indicate or contra-indicate certain treatments as well as be indicative of prognosis. Using the Ion Torrent Personal Genome Machine and the AmpliSeq Cancer Hotspot panel v2, we sequenced two pancreatic cancer cell lines, BxPC-3 and HPAF-II, alone or in mixtures, to determine the error rate, sensitivity, and reproducibility of this system. The system resulted in coverage averaging 2000x across the various amplicons and was able to reliably and reproducibly identify mutations present at a rate of 5%. Identification of mutations present at a lower rate was possible by altering the parameters by which calls were made, but with an increase in erroneous, low-level calls. The panel was able to identify known mutations in these cell lines that are present in the COSMIC database. In addition, other, novel mutations were also identified that may prove clinically useful. The system was assessed for systematic errors such as homopolymer effects, end of amplicon effects and patterns in NO CALL sequence. Overall, the system is adequate at identifying the known, targeted mutations in the panel. Published by Elsevier Inc. C1 [Butler, Kimberly S.; Young, Megan Y. L.; Elespuru, Rosalie K.; Wood, Steven C.] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Li, Zhihua] US FDA, Off Med Prod & Tobacco, Ctr Drug Evaluat & Res, Off Translat Sci,Off Clin Pharmacol,Div Appl Regu, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Wood, SC (reprint author), US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM steven.wood@fda.hhs.gov FU Medical Countermeasures Initiative; Critical Path Program; MCMi Program; National Cancer Institute Interagency Oncology Taskforce; Office of Science and Engineering Laboratories, CDRH, FDA; U.S. Department of Energy; U.S. Food and Drug Administration FX The authors thank the Medical Countermeasures Initiative for funding this work. The authors acknowledge E. Mansfield (CDRH/OIR) and P. Potnis (CDRH/ODE) for securing funds from the Critical Path and MCMi Programs to establish the Ion Torrent Gene Sequencing Core Laboratory at CDRH/OSEL, where this research was conducted. This study was supported by funds provided by the National Cancer Institute Interagency Oncology Taskforce and the Office of Science and Engineering Laboratories, CDRH, FDA. This project was supported in part by an appointment to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 24 TC 0 Z9 0 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 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD FEB PY 2016 VL 74 BP 178 EP 186 DI 10.1016/j.yrtph.2015.09.011 PG 9 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DB5LG UT WOS:000368555000020 PM 26387931 ER PT J AU Costa, AP Xu, XM Khan, MA Burgess, DJ AF Costa, Antonio P. Xu, Xiaoming Khan, Mansoor A. Burgess, Diane J. TI Liposome Formation Using a Coaxial Turbulent Jet in Co-Flow SO PHARMACEUTICAL RESEARCH LA English DT Article DE coaxial turbulent jet; continuous manufacturing; ethanol injection; liposome processing; monodispersed liposomes; unilamellar ID ETHANOL INJECTION METHOD; ROUND JET; NANOPARTICLES; SIZE AB Liposomes are robust drug delivery systems that have been developed into FDA-approved drug products for several pharmaceutical indications. Direct control in producing liposomes of a particular particle size and particle size distribution is extremely important since liposome size may impact cellular uptake and biodistribution. A device consisting of an injection-port was fabricated to form a coaxial turbulent jet in co-flow that produces liposomes via the ethanol injection method. By altering the injection-port dimensions and flow rates, a fluid flow profile (i.e., flow velocity ratio vs. Reynolds number) was plotted and associated with the polydispersity index of liposomes. Certain flow conditions produced unilamellar, monodispersed liposomes and the mean particle size was controllable from 25 up to > 465 nm. The mean liposome size is highly dependent on the Reynolds number of the mixed ethanol/aqueous phase and independent of the flow velocity ratio. The significance of this work is that the Reynolds number is predictive of the liposome particle size, independent of the injection-port dimensions. In addition, a new model describing liposome formation is outlined. The significance of the model is that it relates fluid dynamic properties and lipid-molecule physical properties to the final liposome size. C1 [Costa, Antonio P.; Burgess, Diane J.] Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA. [Xu, Xiaoming; Khan, Mansoor A.] FDA CDER DPQR, Silver Spring, MD 20993 USA. RP Burgess, DJ (reprint author), Univ Connecticut, Dept Pharmaceut Sci, 69 N Eagleville Rd U3092, Storrs, CT 06269 USA. EM d.burgess@uconn.edu FU U.S. FDA [HHSF223201310117C] FX This work was supported by the U.S. FDA (Grant#: HHSF223201310117C). We thank Dr. M. Cantino and Dr. X. Sun from the Biosciences Electron Microscope Laboratory of the Physiology and Neurobiology Department at the University of Connecticut for their work on the negative stain TEM micrographs. The authors would like to acknowledge Dr. Jiwen Zheng and Dr. Yong Wu at the FDA White Oak Nanotechnology Core Facility for instrument use, scientific and technical assistance. A. Costa was an AFPE fellow during the time period of this research. NR 26 TC 0 Z9 0 U1 6 U2 22 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD FEB PY 2016 VL 33 IS 2 BP 404 EP 416 DI 10.1007/s11095-015-1798-8 PG 13 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DA8RH UT WOS:000368073300013 PM 26428671 ER PT J AU Kryndushkin, D Rao, VA AF Kryndushkin, Dmitry Rao, V. Ashutosh TI Comparative Effects of Metal-Catalyzed Oxidizing Systems on Carbonylation and Integrity of Therapeutic Proteins SO PHARMACEUTICAL RESEARCH LA English DT Article DE aggregation; ascorbic acid; carbonylation; leachables; protein pharmaceuticals ID AMINO-ACID-RESIDUES; MONOCLONAL-ANTIBODIES; MEDIATED OXIDATION; FENTON CHEMISTRY; ASCORBIC-ACID; FREE-RADICALS; STABILITY; FORMULATION; BINDING; GROWTH AB Ascorbic acid has been considered as a potential radical scavenging excipient for pharmaceutical formulations. However, under certain circumstances, ascorbic acid can generate reactive oxygen species via redox cycling. The objective of this study was to investigate ascorbic acid-induced oxidative carbonylation of therapeutic proteins and correlate the increase in carbonylation with protein aggregation. An optimized ELISA for quantifying carbonyl levels was used to compare the oxidizing potentials of ascorbic acid and hydrogen peroxide by testing four pharmaceutically-relevant proteins (human serum albumin, immunoglobulin G, granulocyte-colony stimulating factor and calcitonin). Several transition metals at micromolar concentrations were evaluated for their ability to enhance ascorbic acid-induced protein carbonylation. Protein aggregation under oxidative conditions, with or without free radical scavengers, was measured by aggregate binding fluorescent dye and confirmed by microfluidic imaging. Addition of ascorbic acid alone resulted in higher increases in carbonylation than addition of hydrogen peroxide. The presence of trace amounts (> 75 ppb) of copper enhanced oxidative effects of ascorbic acid, whereas other tested metals did not comparably promote oxidation. During oxidation, protein destabilization indicated by loss of the full-length protein, positively correlated with the increase in protein aggregation. However, levels of aggregation did not always correlate with the levels of protein carbonylation. At comparable carbonylation levels, addition of copper produced greater protein destabilization and aggregation than addition of iron. The results strongly suggest that ascorbic acid with traces of metals, especially copper, can promote therapeutic protein carbonylation and potentially aggregation. At similar carbonylation levels, some oxidative conditions may lead to greater protein destabilization than others. C1 [Kryndushkin, Dmitry; Rao, V. Ashutosh] US FDA, Lab Appl Biochem, Div Biotechnol Prod Res & Review 3, Off Biotechnol Prod,Off Pharmaceut Qual,Ctr Drug, Silver Spring, MD 20993 USA. RP Rao, VA (reprint author), US FDA, Lab Appl Biochem, Div Biotechnol Prod Res & Review 3, Off Biotechnol Prod,Off Pharmaceut Qual,Ctr Drug, Silver Spring, MD 20993 USA. EM ashutosh.rao@fda.hhs.gov FU CDER Critical Path Initiative FX This research was supported by the CDER Critical Path Initiative. We thank Dr. Shen Luo for help with microfluidic imaging. We would like to thank Dr. Hiroshi Uehara and Elliot Rosen (FDA) for critical reading of the manuscript. The authors have no competing financial interests to disclose. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the U.S. Food and Drug Administration and the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 52 TC 1 Z9 1 U1 3 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD FEB PY 2016 VL 33 IS 2 BP 526 EP 539 DI 10.1007/s11095-015-1807-y PG 14 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DA8RH UT WOS:000368073300022 PM 26499343 ER PT J AU Brink, JA Miller, DL AF Brink, James A. Miller, Donald L. TI NCRP PROGRAM AREA COMMITTEE 4: RADIATION PROTECTION IN MEDICINE SO HEALTH PHYSICS LA English DT Article DE National Council on Radiation Protection and Measurements; fluoroscopy; radiation protection; radiation; medical AB Program Area Committee (PAC) 4 deals with issues in radiation protection in healthcare settings. NCRP Statement No. 11 was published at the end of 2014, and three active scientific committees (SC) are at workSC 4-5, SC 4-7, and SC 4-8. PAC 4 is also considering a number of topics that could be addressed by new scientific committees in the future. C1 [Brink, James A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Brink, JA (reprint author), Massachusetts Gen Hosp, 175 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM jabrink@partners.org NR 3 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2016 VL 110 IS 2 BP 106 EP 108 DI 10.1097/HP.0000000000000403 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DA5CC UT WOS:000367818700005 PM 26717159 ER PT J AU Harris, GR Church, CC Dalecki, D Ziskin, MC Bagley, JE AF Harris, Gerald R. Church, Charles C. Dalecki, Diane Ziskin, Marvin C. Bagley, Jennifer E. TI COMPARISON OF THERMAL SAFETY PRACTICE GUIDELINES FOR DIAGNOSTIC ULTRASOUND EXPOSURES SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Review DE Bio-effects; Fetal; Output display standard; Thermal index; Ultrasound ID AMERICAN-INSTITUTE; INDEX; HYPERTHERMIA; PREGNANCY; DEFECTS; RAT AB This article examines the historical evolution of various practice guidelines designed to minimize the possibility of thermal injury during a diagnostic ultrasound examination, including those published by the American Institute of Ultrasound in Medicine, British Medical Ultrasound Society and Health Canada. The guidelines for prenatal/neonatal examinations are in general agreement, but significant differences were found for postnatal exposures. We propose sets of thermal index versus exposure time for these examination categories below which there is reasonable assurance that an examination can be conducted without risk of producing an adverse thermal effect under any scanning conditions. If it is necessary to exceed these guidelines, the occurrence of an adverse thermal event is still unlikely in most situations because of mitigating factors such as transducer movement and perfusion, but the general principle of "as low as reasonably achievable'' should be followed. Some limitations of the biological effects studies underpinning the guidelines also are discussed briefly. (C) 2016 World Federation for Ultrasound in Medicine & Biology. C1 [Harris, Gerald R.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Church, Charles C.] Univ Mississippi, Natl Ctr Phys Acoust, University, MS 38677 USA. [Dalecki, Diane] Univ Rochester, Dept Biomed Engn, Rochester, NY USA. [Ziskin, Marvin C.] Temple Univ, Sch Med, Ctr Biomed Phys, Philadelphia, PA 19122 USA. [Bagley, Jennifer E.] Univ Oklahoma, Hlth Sci Ctr, Dept Med Imaging & Radiat Sci, Tulsa, OK USA. RP Harris, GR (reprint author), 132 South Van Buren St, Rockville, MD 20850 USA. EM gerald.harris13@gmail.com NR 33 TC 1 Z9 1 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-5629 EI 1879-291X J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD FEB PY 2016 VL 42 IS 2 BP 345 EP 357 DI 10.1016/j.ultrasmedbio.2015.09.016 PG 13 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DA3XX UT WOS:000367735800001 PM 26626492 ER PT J AU Chamkasem, N Lee, S Harmon, T AF Chamkasem, Narong Lee, Sookwang Harmon, Tiffany TI Analysis of 19 PCB congeners in catfish tissue using a modified QuEChERS method with GC-MS/MS SO FOOD CHEMISTRY LA English DT Article DE Triple quadrupole; Tandem mass spectrometry; Gas chromatography; PCB congeners residue analysis; Catfish; QuEChERS ID CAPILLARY GAS-CHROMATOGRAPHY; POLYCHLORINATED-BIPHENYLS; PESTICIDE-RESIDUES; EXTRACTION; PRODUCE AB A simple approach to determine 19 PCB congeners in catfish tissue was presented. A modified QuEChERS method employing high solvent to sample ratio 10:1 was used to improve the extraction recovery of 19 PCB congeners. After salting out by shaking with anhydrous magnesium sulfate and sodium chloride, 1 mL of acetonitrile extract was pipetted into a 2-mL centrifuge tube containing anhydrous magnesium sulfate, primary secondary amine sorbent, and C-18 sorbent. The tube was then shaken and centrifuged to absorb fat and fatty acid residue present in the acetonitrile extract. The acetonitrile extract was analyzed by GC-MS/MS. The excellent sensitivity of GC-MS/MS allows for the direct injection of the samples to detect the low level of the PCB congeners. The method therefore is high throughput, uses fewer consumable lab supplies, and provides excellent sensitivity with an LOQ below 1 ng/g. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Chamkasem, Narong; Lee, Sookwang; Harmon, Tiffany] US FDA, Southeast Reg Lab, Atlanta, GA 30309 USA. RP Chamkasem, N (reprint author), US FDA, Southeast Reg Lab, 60 Eighth St NE, Atlanta, GA 30309 USA. EM narong.chamkasem@fda.hhs.gov NR 16 TC 2 Z9 2 U1 8 U2 180 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0308-8146 EI 1873-7072 J9 FOOD CHEM JI Food Chem. PD FEB 1 PY 2016 VL 192 BP 900 EP 906 DI 10.1016/j.foodchem.2015.07.088 PG 7 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA CS7ZC UT WOS:000362304500115 PM 26304427 ER PT J AU Devadas, K Biswas, S Haleyurgirisetty, M Wood, O Ragupathy, V Lee, S Hewlett, I AF Devadas, Krishnakumar Biswas, Santanu Haleyurgirisetty, Mohan Wood, Owen Ragupathy, Viswanath Lee, Sherwin Hewlett, Indira TI Analysis of Host Gene Expression Profile in HIV-1 and HIV-2 Infected T-Cells SO PLOS ONE LA English DT Article ID VIRUS TYPE-1 INFECTION; CD4+T CELLS; VIRAL LOAD; JURKAT CELLS; IDENTIFICATION; CANCER; REPLICATION; METABOLISM; CD4(+); DIFFERENTIATION AB HIV replication is closely regulated by a complex pathway of host factors, many of them being determinants of cell tropism and host susceptibility to HIV infection. These host factors are known to exert a positive or negative influence on the replication of the two major types of HIV, HIV-1 and HIV-2, thereby modulating virus infectivity, host response to infection and ultimately disease progression profiles characteristic of these two types. Understanding the differential regulation of host cellular factors in response to HIV-1 and HIV-2 infections will help us to understand the apparent differences in rates of disease progression and pathogenesis. This knowledge would aid in the discovery of new biomarkers that may serve as novel targets for therapy and diagnosis. The objective of this study was to determine the differential expression of host genes in response to HIV-1/HIV-2 infection. To achieve this, we analyzed the effects of HIV-1 (MN) and HIV-2 (ROD) infection on the expression of host factors in PBMC at the RNA level using the Agilent Whole Human Genome Oligo Microarray. Differentially expressed genes were identified and their biological functions determined. Host gene expression profiles were significantly changed. Gene expression profiling analysis identified a subset of differentially expressed genes in HIV-1 and HIV-2 infected cells. Genes involved in cellular metabolism, apoptosis, immune cell proliferation and activation, cytokines, chemokines, and transcription factors were differentially expressed in HIV-1 infected cells. Relatively few genes were differentially expressed in cells infected with HIV-2. C1 [Devadas, Krishnakumar; Biswas, Santanu; Haleyurgirisetty, Mohan; Wood, Owen; Ragupathy, Viswanath; Lee, Sherwin; Hewlett, Indira] US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Devadas, K; Hewlett, I (reprint author), US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Krishnakumar.devadas@fda.hhs.gov; Indira.hewlett@fda.hhs.gov FU Intramural CBER Modernizing Grant; Food and Drug Administration FX This work was funded by an Intramural CBER Modernizing Grant and the Food and Drug Administration. NR 42 TC 1 Z9 1 U1 3 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 JAN 28 PY 2016 VL 11 IS 1 AR e0147421 DI 10.1371/journal.pone.0147421 PG 29 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9GF UT WOS:000369528400027 PM 26821323 ER PT J AU Gubrij, IB Pangle, AK Pang, L Johnson, LG AF Gubrij, Igor B. Pangle, Amanda K. Pang, Li Johnson, Larry G. TI Reversal of MicroRNA Dysregulation in an Animal Model of Pulmonary Hypertension SO PLOS ONE LA English DT Article ID SMOOTH-MUSCLE-CELLS; ARTERIAL-HYPERTENSION; MOLECULAR PATHOGENESIS; CHRONIC HYPOXIA; DISEASE; PROLIFERATION; MONOCROTALINE; GENE; SURVIVAL; INHIBITION AB Background Animals models have played an important role in enhancing our understanding of the pathogenesis of pulmonary arterial hypertension (PAH). Dysregulation of the profile of microRNAs (miRNAs) has been demonstrated in human tissues from PAH patients and in animal models. In this study, we measured miRNA levels in the monocrotaline (MCT) rat model of PAH and examined whether blocking a specific dysregulated miRNA not previously reported in this model, attenuated PAH. We also evaluated changes in miRNA expression in lung specimens from MCT PAH rats overexpressing human prostacyclin synthase, which has been shown to attenuate MCT PAH. Methods Expression levels of a panel of miRNAs were measured in MCT-PAH rats as compared to naive (saline) control rats. Subsequently, MCT PAH rats were injected with a specific inhibitor (antagomiR) for miR-223 (A223) or a nonspecific control oligonucleotide (A-control) 4 days after MCT administration, then weekly. Three weeks later, RV systolic pressure and RV mass were measured. Total RNA, isolated from the lungs, microdissected pulmonary arteries, and right ventricle, was reverse transcribed and real-time quantitative PCR was performed. MiRNA levels were also measured in RNA isolated from paraffin sections of MCT-PAH rats overexpressing prostacyclin synthase. Results MiRs 17, 21, and 223 were consistently upregulated, whereas miRs 126, 145, 150, 204, 424, and 503 were downregulated in MCT PAH as compared to vehicle control. A223 significantly reduced levels of miR-223 in PA and lungs of MCT PAH rats as compared to levels measured in A-control or control MCT PAH rats, but A223 did not attenuate MCT PAH. Right ventricular mass and right ventricular systolic pressure in rats treated with A223 were not different from values in A-control or MCT PAH rats. In contrast, analysis of total RNA from lung specimens of MCT PAH rats overexpressing human prostacyclin synthase (hPGIS) demonstrated reversal of MCT-induced upregulation of miRs 17, 21, and 223 and an increase in levels of miR-424 and miR-503. Reduction in bone morphogenetic receptor 2 (BMPR2) messenger (m) RNA expression was not altered by A223, whereas human prostacyclin synthase overexpression restored BMPR2 mRNA to levels in MCT PAH to levels measured in naive controls. Conclusions Inhibition of miR-223 did not attenuate MCT PAH, whereas human prostacyclin synthase overexpression restored miRNA levels in MCT PAH to levels detected in naive rats. These data may establish a paradigm linking attenuation of PAH to restoration of BMPR2 signaling. C1 [Gubrij, Igor B.; Pangle, Amanda K.; Johnson, Larry G.] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. [Gubrij, Igor B.; Pangle, Amanda K.; Johnson, Larry G.] Univ Arkansas Med Sci, Dept Internal Med, Div Pulm & Crit Med, Little Rock, AR 72205 USA. [Pang, Li] Univ Arkansas Med Sci, Dept Pharmacol, Little Rock, AR 72205 USA. [Pang, Li] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Johnson, LG (reprint author), Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA.; Johnson, LG (reprint author), Univ Arkansas Med Sci, Dept Internal Med, Div Pulm & Crit Med, Little Rock, AR 72205 USA. EM lgjohnson@uams.edu FU U.S. Dept. of Veterans Affairs; Arkansas Biosciences Institute; Canadian Heart Centre and Actelion Pharmaceuticals FX This manuscript was supported by a VA Merit Grant (LGJ) from the U.S. Dept. of Veterans Affairs and a grant from the Arkansas Biosciences Institute (LGJ). LGJ is an investigator on the PAHQueri trial sponsored by the Canadian Heart Centre and Actelion Pharmaceuticals. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 0 Z9 0 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 27 PY 2016 VL 11 IS 1 AR e0147827 DI 10.1371/journal.pone.0147827 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9GD UT WOS:000369528200057 PM 26815432 ER PT J AU Srivastava, HK Wolfgang, S Rodriguez, JD AF Srivastava, Hirsch K. Wolfgang, Steven Rodriguez, Jason D. TI Rapid screening of guar gum using portable Raman spectral identification methods SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Rapid screening; Economically-motivated adulteration; Raw ingredients; Spectroscopy; Identification tests ID SPECTROSCOPY AB Guar gum is a well-known inactive ingredient (excipient) used in a variety of oral pharmaceutical dosage forms as a thickener and stabilizer of suspensions and as a binder of powders. It is also widely used as a food ingredient in which case alternatives with similar properties, including chemically similar gums, are readily available. Recent supply shortages and price fluctuations have caused guar gum to come under increasing scrutiny for possible adulteration by substitution of cheaper alternatives. One way that the U.S. FDA is attempting to screen pharmaceutical ingredients at risk for adulteration or substitution is through field-deployable spectroscopic screening. Here we report a comprehensive approach to evaluate two field-deployable Raman methods-spectral correlation and principal component analysis-to differentiate guar gum from other gums. We report a comparison of the sensitivity of the spectroscopic screening methods with current compendial identification tests. The ability of the spectroscopic methods to perform unambiguous identification of guar gum compared to other gums makes them an enhanced surveillance alternative to the current compendial identification tests, which are largely subjective in nature. Our findings indicate that Raman spectral identification methods perform better than compendial identification methods and are able to distinguish guar gum from other gums with 100% accuracy for samples tested by spectral correlation and principal component analysis. Published by Elsevier B.V. C1 [Srivastava, Hirsch K.; Wolfgang, Steven; Rodriguez, Jason D.] US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. RP Rodriguez, JD (reprint author), US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. EM Jason.Rodriguez@fda.hhs.gov OI Rodriguez, Jason/0000-0002-8814-1144; Wolfgang, Steven/0000-0001-6512-3210 FU CDER Critical Path and Regulatory Science & Review Enhancement Programs FX This project was supported in part by the CDER Critical Path and Regulatory Science & Review Enhancement Programs. This project was supported in part by an appointment (H.K.S) to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 22 TC 0 Z9 0 U1 4 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 25 PY 2016 VL 118 BP 387 EP 392 DI 10.1016/j.jpba.2015.11.013 PG 6 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DA2NT UT WOS:000367633800046 PM 26609678 ER PT J AU Laux, P Tralau, T Tentschert, J Blume, A Al Dahouk, S Baumler, W Bernstein, E Bocca, B Alimonti, A Colebrook, H de Cuyper, C Dahne, L Hauri, U Howard, PC Janssen, P Katz, L Klitzman, B Kluger, N Krutak, L Platzek, T Scott-Lang, V Serup, J Teubner, W Schreiver, I Wilkniss, E Luch, A AF Laux, Peter Tralau, Tewes Tentschert, Jutta Blume, Annegret Al Dahouk, Sascha Baeumler, Wolfgang Bernstein, Eric Bocca, Beatrice Alimonti, Alessandro Colebrook, Helen de Cuyper, Christa Daehne, Lars Hauri, Urs Howard, Paul C. Janssen, Paul Katz, Linda Klitzman, Bruce Kluger, Nicolas Krutak, Lars Platzek, Thomas Scott-Lang, Victoria Serup, Jorgen Teubner, Wera Schreiver, Ines Wilkniss, Elena Luch, Andreas TI A medical-toxicological view of tattooing SO LANCET LA English DT Review ID RED TATTOO; SKIN INFECTIONS; PATCH-TEST; 1064 NM; LASER; INKS; PIGMENTS; REMOVAL; BLACK; MICE AB Long perceived as a form of exotic self-expression in some social fringe groups, tattoos have left their maverick image behind and become mainstream, particularly for young people. Historically, tattoo-related health and safety regulations have focused on rules of hygiene and prevention of infections. Meanwhile, the increasing popularity of tattooing has led to the development of many new colours, allowing tattoos to be more spectacular than ever before. However, little is known about the toxicological risks of the ingredients used. For risk assessment, safe intradermal application of these pigments needs data for toxicity and biokinetics and increased knowledge about the removal of tattoos. Other concerns are the potential for phototoxicity, substance migration, and the possible metabolic conversion of tattoo ink ingredients into toxic substances. Similar considerations apply to cleavage products that are formed during laser-assisted tattoo removal. In this Review, we summarise the issues of concern, putting them into context, and provide perspectives for the assessment of the acute and chronic health effects associated with tattooing. C1 [Laux, Peter; Tralau, Tewes; Tentschert, Jutta; Blume, Annegret; Al Dahouk, Sascha; Platzek, Thomas; Schreiver, Ines; Wilkniss, Elena; Luch, Andreas] German Fed Inst Risk Assessment BfR, Dept Prod Safety, Berlin, Germany. [Baeumler, Wolfgang] Univ Regensburg, Klin & Poliklin Dermatol, D-93053 Regensburg, Germany. [Bernstein, Eric] Main Line Ctr Laser Surg, Ardmore, PA USA. [Bocca, Beatrice; Alimonti, Alessandro] Ist Super Sanita, I-00161 Rome, Italy. [Colebrook, Helen] Minist Hlth New Zealand, Wellington, New Zealand. [de Cuyper, Christa] Acad Hosp St Jan, Brugge, Belgium. [Daehne, Lars] Surflay Nanotec, Berlin, Germany. [Hauri, Urs] Kantonales Lab Basel Stadt, Basel, Switzerland. [Howard, Paul C.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Janssen, Paul] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Katz, Linda] US FDA, College Pk, MD USA. [Klitzman, Bruce] Duke Univ, Med Ctr, Durham, NC USA. [Kluger, Nicolas] Univ Helsinki, Helsinki, Finland. [Kluger, Nicolas] Helsinki Univ Hosp, Helsinki, Finland. [Krutak, Lars] Smithsonian Inst, Washington, DC 20560 USA. [Scott-Lang, Victoria] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Serup, Jorgen] Bispebjerg Hosp, Dept Dermatol, Tattoo Clin, DK-2400 Copenhagen NV, Denmark. [Teubner, Wera] BASF Schweiz AG, Basel, Switzerland. RP Luch, A (reprint author), German Fed Inst Risk Assessment BfR, Dept Prod Safety, Berlin, Germany. EM andreas.luch@bfr.bund.de OI Al Dahouk, Sascha/0000-0003-3835-0818 FU BfR FX The writing of this Review and the realisation of the 1st International Conference on Tattoo Safety at the German Federal Institute for Risk Assessment (BfR) in 2013 has been financially supported by intramural grants of the BfR. This document does not reflect the official policy of the USA Food and Drug Administration and the mention of specific products does not constitute an endorsement. NR 86 TC 10 Z9 10 U1 13 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 23 PY 2016 VL 387 IS 10016 BP 395 EP 402 DI 10.1016/S0140-6736(15)60215-X PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DB4XI UT WOS:000368516500038 PM 26211826 ER PT J AU Agol, V Cello, J Chumakov, K Ehrenfeld, E Wimmer, E AF Agol, Vadim Cello, Jeronimo Chumakov, Konstantin Ehrenfeld, Ellie Wimmer, Eckard TI Eradicating polio: A balancing act SO SCIENCE LA English DT Letter C1 [Agol, Vadim; Chumakov, Konstantin] MP Chumakov Inst Poliomyelitis & Viral Encephalit, Moscow 142782, Russia. [Agol, Vadim] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physical Chem Biol, Moscow 119899, Russia. [Cello, Jeronimo; Wimmer, Eckard] SUNY Stony Brook, Dept Mol Genet & Microbiol, Sch Med, Stony Brook, NY 11794 USA. [Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. [Ehrenfeld, Ellie] NIAID, NIH, Bethesda, MD 20892 USA. RP Chumakov, K (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. EM Konstantin.Chumakov@fda.hhs.gov NR 4 TC 0 Z9 0 U1 2 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 22 PY 2016 VL 351 IS 6271 BP 348 EP 348 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB3VH UT WOS:000368440500028 PM 26798005 ER PT J AU Min, KW Liggett, JL Silva, G Wu, WW Wang, R Shen, RF Eling, TE Baek, SJ AF Min, K-W Liggett, J. L. Silva, G. Wu, W. W. Wang, R. Shen, R-F Eling, T. E. Baek, S. J. TI NAG-1/GDF15 accumulates in the nucleus and modulates transcriptional regulation of the Smad pathway SO ONCOGENE LA English DT Article ID DRUG-ACTIVATED GENE-1; BETA SUPERFAMILY MEMBER; GROWTH-FACTOR-BETA; COLORECTAL-CANCER CELLS; MORPHOGENETIC PROTEIN; PROSTATE CARCINOMA; SIGNALING PATHWAY; TRANSGENIC MICE; MOUSE MODEL; EXPRESSION AB Protein dynamics, modifications and trafficking are all processes that can modulate protein activity. Accumulating evidence strongly suggests that many proteins have distinctive roles dependent on cellular location. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a transforming growth factor-beta (TGF-beta) superfamily protein that has a role in cancer, obesity and inflammation. NAG-1 is synthesized and cleaved into a mature peptide, which is ultimately secreted into the extracellular matrix (ECM). In this study, we have found that full-length NAG-1 is expressed in not only the cytoplasm and ECM, but also in the nucleus. NAG-1 is dynamically moved to the nucleus, exported into cytoplasm and further transported into the ECM. We have also found that nuclear NAG-1 contributes to inhibition of the Smad pathway by interrupting the Smad complex. Overall, our study indicates that NAG-1 is localized in the nucleus and provides new evidence that NAG-1 controls transcriptional regulation in the Smad pathway. C1 [Min, K-W; Liggett, J. L.; Silva, G.; Baek, S. J.] Univ Tennessee, Coll Vet Med, Dept Biomed & Diagnost Sci, 2407 River Dr, Knoxville, TN 37996 USA. [Wu, W. W.; Wang, R.; Shen, R-F] US FDA, CBER, Facil Biotechnol Resources, Bethesda, MD 20014 USA. [Eling, T. E.] NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Min, K-W] Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA. RP Baek, SJ (reprint author), Univ Tennessee, Coll Vet Med, Dept Biomed & Diagnost Sci, 2407 River Dr, Knoxville, TN 37996 USA. EM sbaek2@utk.edu RI Silva, Gabriel/D-7731-2017; OI Silva, Gabriel/0000-0002-5660-9769; Min, Kyung-Won/0000-0002-8718-3588 FU National Institutes of Health [R01CA108975]; Center of Excellence in Livestock Diseases and Human Health, University of Tennessee; CAPES Foundation, Brazil [BEX 3159/14-0]; NIH, NIEHS Intramural Research Program [Z01-ES010016-14] FX We thank Dr Xingya Wang (College of Pharmaceutical Science, Zhejiang Chinese Medical University, China) and Ms Misty Bailey (University of Tennessee) for their critical reading of the manuscript. We also thank Dr John Dunlap (Advanced Microscopy and Imaging Center at The University of Tennessee) for providing technical help on confocal microscopy. This work was supported by the National Institutes of Health (R01CA108975), and the Center of Excellence in Livestock Diseases and Human Health, University of Tennessee, to SJB and a grant (BEX 3159/14-0) from the CAPES Foundation, Brazil (GS). This research was also supported, in part, by the NIH, NIEHS Intramural Research Program (TEE) Z01-ES010016-14. NR 68 TC 5 Z9 5 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JAN 21 PY 2016 VL 35 IS 3 BP 377 EP 388 DI 10.1038/onc.2015.95 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DC2OF UT WOS:000369055300011 PM 25893289 ER PT J AU Eichelberger, MC Couzens, L Gao, YH Levine, M Katz, J Wagner, R Thompson, CI Hoschler, K Laurie, K Bai, T Engelhardt, OG Wood, J AF Eichelberger, Maryna C. Couzens, Laura Gao, Yonghong Levine, Min Katz, Jacqueline Wagner, Ralf Thompson, Catherine I. Hoeschler, Katja Laurie, Karen Bai, Tian Engelhardt, Othmar G. Wood, John CA ELLA Study Participants TI Comparability of neuraminidase inhibition antibody titers measured by enzyme-linked lectin assay (ELLA) for the analysis of influenza vaccine immunogenicity SO VACCINE LA English DT Article DE Influenza; Neuraminidase; Assay; Variability; CONSISE; ELLA ID VIRUS; STANDARD; A(H3N2) AB Neuraminidase-inhibition (NI) antibody titers can be used to evaluate the immunogenicity of inactivated influenza vaccines and have provided evidence of serologic cross-reactivity between seasonal and pandemic H1N1 viruses. The traditional thiobarbituric acid assay is impractical for large serologic analyses, and therefore many laboratories use an enzyme-linked lectin assay (ELLA) to determine serum NI antibody titers. The comparability of ELLA NI antibody titers when measured in different laboratories was unknown. Here we report a study conducted through the Consortium for the Standardisation of Influenza SeroEpidemiology (CONSISE) to evaluate the variability of the ELLA. NI antibody titers of a set of 12 samples were measured against both N1 and N2 neuraminidase antigens in 3 independent assays by each of 23 laboratories. For a sample repeated in the same assay, >= 96% of N1 and N2 assays had less than a 4-fold difference in titer. Comparison of the titers measured in assays conducted on 3 different days in the same laboratory showed that a four-fold difference in titer was uncommon. Titers of the same sera measured in different laboratories spanned 3 to 6 two-fold dilutions (i.e., 8-64 fold difference in titer), with an average percent geometric coefficient of variation (%GCV) of 112 and 82% against N1 and N2 antigens, respectively. The difference in titer as indicated by fold range and %GCV was improved by normalizing the NI titers to a standard that was included in each assay. This study identified background signal and the amount of antigen in the assay as critical factors that influence titer, providing important information toward development of a consensus ELLA protocol. Published by Elsevier Ltd. C1 [Eichelberger, Maryna C.; Couzens, Laura] US FDA, Div Viral Prod, CBER, Silver Spring, MD USA. [Gao, Yonghong] US Dept HHS, BARDA, Washington, DC 20201 USA. [Levine, Min; Katz, Jacqueline] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Wagner, Ralf] Paul Ehrlich Inst, Langen, Germany. [Thompson, Catherine I.; Hoeschler, Katja] Publ Hlth England, London, England. [Laurie, Karen] WHO Collaborating Ctr, Melbourne, Vic, Australia. [Bai, Tian] Natl Inst Viral Dis Control & Prevent, WHO Collaborating Ctr, Beijing, Peoples R China. [Engelhardt, Othmar G.] Med & Healthcare Prod Regulatory Agcy, Natl Inst Biol Stand & Control, Potters Bar, Herts, England. [Wood, John] Natl Inst Biol Stand & Controls, New York, NY USA. RP Eichelberger, MC (reprint author), US FDA, Div Viral Prod, CBER, Silver Spring, MD USA. EM Maryna.Eichelberger@fda.hhs.gov FU Intramural Research Program of the NIH, NIAID; BARDA interagency agreement [224-14-1010] FX We are indebted to Maria van Kerkhove for providing leadership and advice throughout this study, and Mario Barro for suggestions and support. This research was supported in part by the Intramural Research Program of the NIH, NIAID and BARDA interagency agreement #224-14-1010. We thank Drs. David Evers, Sara Gagneten, and Steven Rubin for critical review of the manuscript. NR 18 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 JAN 20 PY 2016 VL 34 IS 4 BP 458 EP 465 DI 10.1016/j.vaccine.2015.12.022 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DB9WJ UT WOS:000368868100011 PM 26707221 ER PT J AU Ponnusamy, D Kozlova, EV Sha, J Erova, TE Azar, SR Fitts, EC Kirtley, ML Tiner, BL Andersson, JA Grim, CJ Isom, RP Hasan, NA Colwell, RR Chopra, AK AF Ponnusamy, Duraisamy Kozlova, Elena V. Sha, Jian Erova, Tatiana E. Azar, Sasha R. Fitts, Eric C. Kirtley, Michelle L. Tiner, Bethany L. Andersson, Jourdan A. Grim, Christopher J. Isom, Richard P. Hasan, Nur A. Colwell, Rita R. Chopra, Ashok K. TI Cross-talk among flesh-eating Aeromonas hydrophila strains in mixed infection leading to necrotizing fasciitis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Aeromonas hydrophila; necrotizing fasciitis; mixed infections; intramuscular mouse model; metagenomics ID PSEUDOMONAS-AERUGINOSA; VIRULENCE FACTORS; GAS-GANGRENE; EXOTOXIN; PATIENT; WATER; HOST AB Necrotizing fasciitis (NF) caused by flesh-eating bacteria is associated with high case fatality. In an earlier study, we reported infection of an immunocompetent individual with multiple strains of Aeromonas hydrophila (NF1-NF4), the latter three constituted a clonal group whereas NF1 was phylogenetically distinct. To understand the complex interactions of these strains in NF pathophysiology, a mouse model was used, whereby either single or mixed A. hydrophila strains were injected intramuscularly. NF2, which harbors exotoxin A (exoA) gene, was highly virulent when injected alone, but its virulence was attenuated in the presence of NF1 (exoA-minus). NF1 alone, although not lethal to animals, became highly virulent when combined with NF2, its virulence augmented by cis-exoA expression when injected alone in mice. Based on metagenomics and microbiological analyses, it was found that, in mixed infection, NF1 selectively disseminated to mouse peripheral organs, whereas the other strains (NF2, NF3, and NF4) were confined to the injection site and eventually cleared. In vitro studies showed NF2 to be more effectively phagocytized and killed by macrophages than NF1. NF1 inhibited growth of NF2 on solid media, but ExoA of NF2 augmented virulence of NF1 and the presence of NF1 facilitated clearance of NF2 from animals either by enhanced priming of host immune system or direct killing via a contact-dependent mechanism. C1 [Ponnusamy, Duraisamy; Kozlova, Elena V.; Sha, Jian; Erova, Tatiana E.; Azar, Sasha R.; Fitts, Eric C.; Kirtley, Michelle L.; Tiner, Bethany L.; Andersson, Jourdan A.; Chopra, Ashok K.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Grim, Christopher J.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. [Isom, Richard P.; Hasan, Nur A.; Colwell, Rita R.] CosmosID Inc, Rockville, MD 20850 USA. [Hasan, Nur A.; Colwell, Rita R.] Univ Maryland, Inst Adv Comp Studies, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Colwell, Rita R.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Colwell, RR (reprint author), CosmosID Inc, Rockville, MD 20850 USA. EM rcolwell@umiacs.umd.edu; achopra@utmb.edu FU Leon Bromberg and Robert E. Shope endowment, University of Texas Medical Branch; Robert E. Shope and John S. Dunn Distinguished Chair in Global Health endowment, University of Texas Medical Branch; NIH [2RO1A1039129]; James W. McLaughlin Postdoctoral Fellowship; WHO Collaborating Center for Vaccine Development, UTMB; T32 Biodefense Training Grant [AI060549] FX Financial support was provided to A.K.C. through Leon Bromberg and Robert E. Shope and John S. Dunn Distinguished Chair in Global Health endowments, University of Texas Medical Branch, and NIH Grant 2RO1A1039129 was awarded to R.R.C. D.P. was supported in part by the James W. McLaughlin Postdoctoral Fellowship. B.L.T. and J.A.A. were supported in part by the WHO Collaborating Center for Vaccine Development, UTMB. E.C.F. was supported in part by T32 Biodefense Training Grant AI060549. NR 23 TC 4 Z9 4 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 19 PY 2016 VL 113 IS 3 BP 722 EP 727 DI 10.1073/pnas.1523817113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB4BX UT WOS:000368458800068 PM 26733683 ER PT J AU Pettengill, EA Pettengill, JB Binet, R AF Pettengill, Emily A. Pettengill, James B. Binet, Rachel TI Phylogenetic Analyses of Shigella and Enteroinvasive Escherichia coli for the Identification of Molecular Epidemiological Markers: Whole-Genome Comparative Analysis Does Not Support Distinct Genera Designation SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Shigella; enteroinvasive E. coli (EIEC); phylogeny; whole genome sequencing; classification; epidemiological markers ID MULTILOCUS GENOTYPE DATA; POPULATION-STRUCTURE; RAPID DETECTION; DIARRHEA; EVOLUTION; PATHOGENS; INFERENCE; GENETICS; STRAINS; ORIGINS AB As a leading cause of bacterial dysentery, Shigella represents a significant threat to public health and food safety. Related, but often overlooked, enteroinvasive Escherichia coli (EIEC) can also cause dysentery. Current typing methods have limited ability to identify and differentiate between these pathogens despite the need for rapid and accurate identification of pathogens for clinical treatment and outbreak response. We present a comprehensive phylogeny of Shigella and EIEC using whole genome sequencing of 169 samples, constituting unparalleled strain diversity, and observe a lack of monophyly between Shigella and EIEC and among Shigella taxonomic groups. The evolutionary relationships in the phylogeny are supported by analyses of population structure and hierarchical clustering patterns of translated gene homolog abundance. Lastly, we identified a panel of 404 single nucleotide polymorphism (SNP) markers specific to each phylogenetic cluster for more accurate identification of Shigella and EIEC. Our findings show that Shigella and EIEC are not distinct evolutionary groups within the E. coli genus and, thus, EIEC as a group is not the ancestor to Shigella. The multiple analyses presented provide evidence for reconsidering the taxonomic placement of Shigella. The SNP markers offer more discriminatory power to molecular epidemiological typing methods involving these bacterial pathogens. C1 [Pettengill, Emily A.; Binet, Rachel] US FDA, Div Microbiol, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Pettengill, James B.] US FDA, Div Publ Hlth Informat & Analyt, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Binet, R (reprint author), US FDA, Div Microbiol, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM rachel.binet@fda.hhs.gov FU Research Participation Program at the Center for Food Safety and Applied Nutrition; U.S. Department of Energy; U.S. Food and Drug Administration FX EP was 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 58 TC 3 Z9 3 U1 2 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD JAN 19 PY 2016 VL 6 AR 1573 DI 10.3389/fmicb.2015.01573 PG 11 WC Microbiology SC Microbiology GA DB3BW UT WOS:000368386000001 ER PT J AU Qu, HO Mudalige, TK Linder, SW AF Qu, Haiou Mudalige, Thilak K. Linder, Sean W. TI Capillary electrophoresis coupled with inductively coupled mass spectrometry as an alternative to cloud point extraction based methods for rapid quantification of silver ions and surface coated silver nanoparticles SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Silver nanoparticles; Ionic silver; Speciation and quantification; Capillary electrophoresis; Inductively coupled mass spectrometry ID FIELD FLOW FRACTIONATION; ANTIBACTERIAL PRODUCTS; ENVIRONMENTAL WATERS; DIETARY-SUPPLEMENTS; GOLD NANOPARTICLES; ICP-MS; SEPARATION; SPECIATION; TRANSFORMATION; CYTOTOXICITY AB Speciation and accurate quantification of ionic silver and metallic silver nanoparticles are critical to investigate silver toxicity and to determine the shelf-life of products that contain nano silver under various storage conditions. We developed a rapid method for quantification of silver ions and silver nanoparticles using capillary electrophoresis (CE) interfaced with inductively-coupled plasma mass spectrometry (ICPMS). The addition of 2-mercaptopropionylglycine (tiopronin) to the background electrolyte was used to facilitate the chromatographic separation of ionic silver and maintain the oxidation state of silver. The obtained limits of detection were 0.05 mu g kg(-1) of silver nanoparticles and 0.03 mu g kg(-1) of ionic silver. Nanoparticles of varied sizes (10-110 nm) with different surface coating, including citrate acid, lipoic acid, polyvinylpyrrolidone and bovine serum albumin (BSA) were successfully analyzed. Particularly good recoveries (>93%) were obtained for both ionic silver and silver nanoparticle in the presence of excess amount of BSA. The method was further tested with six commercially available dietary supplements which varied in concentration and matrix components. The summed values of silver ions and silver nanoparticles correlated well with the total silver concentration determined by ICPMS after acid digestion. This method can serve as an alternative to cloud point extraction technique when the extraction efficiency for protein coated nanoparticles is low. (C) 2015 Elsevier B.V. All rights reserved. C1 [Qu, Haiou; Mudalige, Thilak K.; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Mudalige, TK; Linder, SW (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Thilak.Mudalige@fda.hhs.gov; Sean.Linder@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 26 TC 5 Z9 5 U1 24 U2 61 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JAN 15 PY 2016 VL 1429 BP 348 EP 353 DI 10.1016/j.chroma.2015.12.033 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DC9RQ UT WOS:000369559100038 PM 26724893 ER PT J AU Marks, NS AF Marks, Norman S. TI Dietary Supplements: How Family Physicians Can Address Safety Concerns by Working with the FDA SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material ID CAFFEINE C1 [Marks, Norman S.] US FDA, Silver Spring, MD USA. EM normarks@gmail.com NR 22 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X EI 1532-0650 J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD JAN 15 PY 2016 VL 93 IS 2 BP 97 EP 98 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA DB2ZR UT WOS:000368379700003 PM 26926404 ER PT J AU Huque, MF AF Huque, Mohammad F. TI Validity of the Hochberg procedure revisited for clinical trial applications SO STATISTICS IN MEDICINE LA English DT Article DE Hochberg procedure; correlated tests; type I error rate control; primary endpoints; truncated Hochberg procedure ID IMPROVED BONFERRONI PROCEDURE; MULTIPLE TESTS; INEQUALITIES; VARIABLES AB There is much interest in using the Hochberg procedure (HP) for statistical tests on primary endpoints of confirmatory clinical trials. The procedure is simple to use and enjoys more power than the Bonferroni and the Holm procedures. However, the HP is not assumption free like the other two procedures. It controls the familywise type I error rate when test statistics (used for statistical tests) are independent or if dependent satisfy a conditionally independent formulation. Otherwise, its properties for dependent tests at present are not fully understood. Consequently, its use for confirmatory trials, especially for their primary endpoints, remains worrisome. Confirmatory trials are typically designed with 1-2 primary endpoints. Therefore, a question was raised at the Food and Drug Administration as to whether the HP is a valid test for the simple case of performing treatment-to-control comparisons on two primary endpoints when their test statistics are not independent. Confirmatory trials for statistical tests normally use simple test statistics, such as the normal Z, student's t, and chi-square. The literature does include some work on the HP for dependent cases covering these test statistics, but concerns remain regarding its use for confirmatory trials for which endpoint tests are mostly of the dependent kind. The purpose of this paper is therefore to revisit this procedure and provide sufficient details for better understanding of its performance for dependent cases related to the aforementioned question. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Huque, Mohammad F.] CDER, FDA, OTS, Off Biostat, Silver Spring, MD 20993 USA. RP Huque, MF (reprint author), US FDA, Div Biometr 4, Silver Spring, MD 20993 USA. EM Mohammad.Huque@fda.hhs.gov NR 21 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JAN 15 PY 2016 VL 35 IS 1 BP 5 EP 20 DI 10.1002/sim.6617 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 DA7GF UT WOS:000367971900001 PM 26278421 ER PT J AU Ammann, EM Jones, MP Link, BK Carnahan, RM Winiecki, SK Torner, JC McDowell, BD Fireman, BH Chrischilles, EA AF Ammann, Eric M. Jones, Michael P. Link, Brian K. Carnahan, Ryan M. Winiecki, Scott K. Torner, James C. McDowell, Bradley D. Fireman, Bruce H. Chrischilles, Elizabeth A. TI Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; PROPENSITY SCORE METHODS; HEALTH-CARE DATABASE; VENOUS THROMBOEMBOLISM; IMMUNOGLOBULIN THERAPY; ADMINISTRATIVE DATA; THROMBOTIC EVENTS; MULTIPLE-MYELOMA; PREDICTIVE-VALUE; UNITED-STATES AB In patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia (CLL) or multiple myeloma(MM), intravenous immune globulin (IVIg) may be administered to reduce the risk of infection. Since 2013, IVIg products have carried a boxed safety warning about the risk of thromboembolic events (TEEs), with TEEs reported in 0.5% to 15% of patients treated with IVIg. In this retrospective cohort study of older patients with CLL or MM identified from the Surveillance, Epidemiology, and End Results-Medicare Linked Database, we assessed rates of clinically serious TEEs in 2724 new users of IVIg and a propensity-matched comparison group of 8035 nonusers. For the primary end point, arterial TEE, we observed a transient increased risk of TEE during the day of an IVIg infusion and the day afterward (hazard ration = 3.40; 95% confidence interval [CI]: 1.25, 9.25); this risk declined over the remainder of the 30-day treatment cycle. When considered in terms of absolute risk averaged over a 1-year treatment period, the increase in risk attributable to IVIg was estimated to be 0.7% (95% CI: -0.2%, 2.0%) compared with a baseline risk of 1.8% for the arterial TEE end point. A statistically nonsignificant risk increase of 0.3% (95% CI: -0.4%, 1.5%) compared with a baseline risk of 1.1% was observed for the venous TEE end point. Further research is needed to establish the generalizability of these results to patients receiving higher doses of IVIg for other indications. C1 [Ammann, Eric M.; Carnahan, Ryan M.; Torner, James C.; Chrischilles, Elizabeth A.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Jones, Michael P.] Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA USA. [Link, Brian K.] Univ Iowa, Dept Internal Med, Div Hematol Oncol & Blood & Marrow Transplantat, Carver Coll Med, Iowa City, IA 52242 USA. [Winiecki, Scott K.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [McDowell, Bradley D.; Chrischilles, Elizabeth A.] Univ Iowa Hosp & Clin, Populat Res Core, Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. [Fireman, Bruce H.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. RP Ammann, EM (reprint author), Dept Epidemiol 400 CPHB, 145 N Riverside Dr, Iowa City, IA 52242 USA. EM eric-ammann@uiowa.edu FU NCCDPHP CDC HHS [U58 DP003862, U58DP003862-01]; NCI NIH HHS [HHSN261201000034C, HHSN261201000035I, HHSN261201000140C, P30 CA086862]; None [HHSN261201000035C]; PHS HHS [HHSF22301006T, HHSF223200910006I, HHSN261201000035C, HHSN2612010000CRC, HHSN261201000140C] NR 49 TC 4 Z9 4 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 14 PY 2016 VL 127 IS 2 BP 200 EP 207 DI 10.1182/blood-2015-05-647552 PG 8 WC Hematology SC Hematology GA DC5UG UT WOS:000369285400009 PM 26443622 ER PT J AU Joffe, HV Chang, C Sewell, C Easley, O Nguyen, C Dunn, S Lehrfeld, K Lee, LM Kim, MJ Slagle, AF Beitz, J AF Joffe, Hylton V. Chang, Christina Sewell, Catherine Easley, Olivia Nguyen, Christine Dunn, Somya Lehrfeld, Kimberly Lee, LaiMing Kim, Myong-Jin Slagle, Ashley F. Beitz, Julie TI FDA Approval of Flibanserin - Treating Hypoactive Sexual Desire Disorder SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Joffe, Hylton V.; Chang, Christina; Sewell, Catherine; Easley, Olivia; Nguyen, Christine; Dunn, Somya; Lehrfeld, Kimberly; Lee, LaiMing; Kim, Myong-Jin; Slagle, Ashley F.; Beitz, Julie] Food & Drug Adm, Silver Spring, MD 20993 USA. RP Joffe, HV (reprint author), Food & Drug Adm, Silver Spring, MD 20993 USA. NR 5 TC 7 Z9 7 U1 2 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 JAN 14 PY 2016 VL 374 IS 2 BP 101 EP 104 DI 10.1056/NEJMp1513686 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DA7PQ UT WOS:000367996700002 PM 26649985 ER PT J AU Compton, WM Jones, CM Baldwin, GT AF Compton, Wilson M. Jones, Christopher M. Baldwin, Grant T. TI Relationship between Nonmedical Prescription-Opioid Use and Heroin Use SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID NEW-YORK-CITY; INJECTION-DRUG USERS; UNITED-STATES; OVERDOSE DEATHS; RISK BEHAVIORS; YOUNG-ADULTS; ABUSE; EPIDEMIC; MISUSE; DEPENDENCE C1 [Compton, Wilson M.] NIDA, NIH, Silver Spring, MD USA. [Jones, Christopher M.] US FDA, Silver Spring, MD USA. [Baldwin, Grant T.] Ctr Dis Control & Prevent, Div Unintent Injury Prevent, Atlanta, GA USA. RP Compton, WM (reprint author), NIDA, NIH, 6001 Execut Blvd,MSC 9581, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov NR 65 TC 74 Z9 74 U1 9 U2 38 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 14 PY 2016 VL 374 IS 2 BP 154 EP 163 DI 10.1056/NEJMra1508490 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DA7PQ UT WOS:000367996700010 PM 26760086 ER PT J AU Hakk, H Shappell, NW Lupton, SJ Shelver, WL Fanaselle, W Oryang, D Yeung, CY Hoelzer, K Ma, YQ Gaalswyk, D Pouillot, R Van Doren, JM AF Hakk, Heldur Shappell, Nancy W. Lupton, Sara J. Shelver, Weilin L. Fanaselle, Wendy Oryang, David Yeung, Chi Yuen Hoelzer, Karin Ma, Yinqing Gaalswyk, Dennis Pouillot, Regis Van Doren, Jane M. TI Distribution of Animal Drugs between Skim Milk and Milk Fat Fractions in Spiked Whole Milk: Understanding the Potential Impact on Commercial Milk Products SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE veterinary drug residues; cream; antibiotics; anthelmintics; NSAID; partitioning distribution; milk ID IVERMECTIN RESIDUES; DAIRY SHEEP; CHEESE; ANTIBIOTICS; STABILITY; STORAGE; EPRINOMECTIN; INACTIVATION; ERYTHROMYCIN; ALBENDAZOLE AB Seven animal drugs [penicillin G (PENG), sulfadimethomine (SDMX), oxytetracycline (OTET), erythromycin (ERY), ketoprofen (KETO), thiabendazole (THIA), and ivermectin (IVR)] were used to evaluate the drug distribution between milk fat and skim milk fractions of cow milk. More than 90% of the radioactivity was distributed into the skim milk fraction for ERY, KETO, OTET, PENG, and SDMX, approximately 80% for THIA, and 13% for IVR. The distribution of drug between milk fat and skim milk fractions was significantly correlated to the drug's lipophilicity (partition coefficient, log P, or distribution coefficient, log D, which includes ionization). Data were fit with linear mixed effects models; the best fit was obtained within this data set with log D versus observed drug distribution ratios. These candidate empirical models serve for assisting to predict the distribution and concentration of these drugs in a variety of milk and milk products. C1 [Hakk, Heldur; Shappell, Nancy W.; Lupton, Sara J.; Shelver, Weilin L.] ARS, Biosci Res Lab, USDA, Fargo, ND 58102 USA. [Fanaselle, Wendy; Oryang, David; Yeung, Chi Yuen; Hoelzer, Karin; Ma, Yinqing; Gaalswyk, Dennis; Pouillot, Regis; Van Doren, Jane M.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hakk, H (reprint author), ARS, Biosci Res Lab, USDA, 1605 Albrecht Blvd, Fargo, ND 58102 USA. EM Heldur.Hakk@ars.usda.gov RI Pouillot, Regis/E-8103-2010; OI Pouillot, Regis/0000-0002-6107-5212; Lupton, Sara/0000-0002-4566-595X FU FDA; USDA ARS [224-14-2006] FX This study was collaboratively funded by an interagency agreement with the FDA and USDA ARS (Interagency Agreement 224-14-2006) and, in part, by an appointment (K.H.) 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. This work was completed while K.H. was an ORISE Fellow for the FDA. NR 34 TC 1 Z9 1 U1 2 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD JAN 13 PY 2016 VL 64 IS 1 BP 326 EP 335 DI 10.1021/acs.jafc.5b04726 PG 10 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA DB2FE UT WOS:000368322900042 PM 26652058 ER PT J AU Kindrat, I Tryndyak, V de Conti, A Shpyleva, S Mudalige, TK Kobets, T Erstenyuk, AM Beland, FA Pogribny, IP AF Kindrat, Iryna Tryndyak, Volodymyr de Conti, Aline Shpyleva, Svitlana Mudalige, Thilak K. Kobets, Tetyana Erstenyuk, Anna M. Beland, Frederick A. Pogribny, Igor P. TI MicroRNA-152-mediated dysregulation of hepatic transferrin receptor 1 in liver carcinogenesis SO ONCOTARGET LA English DT Article DE hepatocellular carcinoma; iron metabolism; transferrin receptor 1; microRNA-152; dysregulation ID IRON REGULATORY PROTEINS; HEPATOCELLULAR-CARCINOMA; EXPRESSION; RAT; CELLS; CANCER; GROWTH; 2-ACETYLAMINOFLUORENE; METABOLISM; ACTIVATION AB Over-expression of transferrin receptor 1 (TFRC) is observed in hepatocellular carcinoma (HCC); however, there is a lack of conclusive information regarding the mechanisms of this dysregulation. In the present study, we demonstrated a significant increase in the levels of TFRC mRNA and protein in preneoplastic livers from relevant experimental models of human hepatocarcinogenesis and in human HCC cells. Additionally, using the TCGA database, we demonstrated an over-expression of TFRC in human HCC tissue samples and a markedly decreased level of microRNA-152 (miR-152) when compared to non-tumor liver tissue. The results indicated that the increase in levels of TFRC in human HCC cells and human HCC tissue samples may be attributed, in part, to a post-transcriptional mechanism mediated by a downregulation of miR-152. This was evidenced by a strong inverse correlation between the level of TFRC and the expression of miR-152 in human HCC cells (r = -0.99, p = 4. 7 x 10(-9)), and was confirmed by in vitro experiments showing that transfection of human HCC cell lines with miR-152 effectively suppressed TFRC expression. This suggests that miR-152-specific targeting of TFRC may provide a selective anticancer therapeutic approach for the treatment of HCC. C1 [Kindrat, Iryna; Tryndyak, Volodymyr; de Conti, Aline; Shpyleva, Svitlana; Kobets, Tetyana; Beland, Frederick A.; Pogribny, Igor P.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Mudalige, Thilak K.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR USA. [Kindrat, Iryna; Erstenyuk, Anna M.] Ivano Frankivsk Natl Med Univ, Dept Biol & Med Chem, Ivano Frankivsk, Ukraine. RP Pogribny, IP (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov FU NCTR FX This work was supported in part by appointment (I.K., A.d.C., and T.K.) to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education (ORISE). The views expressed in this manuscript do not necessarily represent those of the U.S. Food and Drug Administration. NR 49 TC 1 Z9 2 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JAN 12 PY 2016 VL 7 IS 2 BP 1276 EP 1287 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DD5GP UT WOS:000369951100016 PM 26657500 ER PT J AU Duff, MR Chopra, S Strader, MB Agarwal, PK Howell, EE AF Duff, Michael R., Jr. Chopra, Shaileja Strader, Michael Brad Agarwal, Pratul K. Howell, Elizabeth E. TI Tales of Dihydrofolate Binding to R67 Dihydrofolate Reductase SO BIOCHEMISTRY LA English DT Article ID ACTIVE-SITE PORE; TERNARY COMPLEX; LIGAND-BINDING; ENZYME CATALYSIS; PROTEIN; MUTATIONS; RESIDUES; PURIFICATION; DYNAMICS; FOLATE AB Homotetrameric R67 dihydrofolate reductase possesses 222 symmetry and a single active site pore. This situation results in a promiscuous binding site that accommodates either the substrate, dihydrofolate (DHF), or the cofactor, NADPH. NADPH interacts more directly with the protein as it is larger than the substrate. In contrast, the p-aminobenzoyl-glutamate tail of DHF, as monitored by nuclear magnetic resonance and crystallography, is disordered when bound. To explore whether smaller active site volumes (which should decrease the level of tail disorder by confinement effects) alter steady state rates, asymmetric mutations that decreased the half-pore volume by similar to 35% were constructed. Only minor effects on k(cat) were observed. To continue exploring the role of tail disorder in catalysis, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide-mediated cross-linking between R67 DHFR and folate was performed. A two-folate, one-tetramer complex results in the loss of enzyme activity where two symmetry-related K32 residues in the protein are cross-linked to the carboxylates of two bound folates. The tethered folate could be reduced, although with a <= 30-fold decreased rate, suggesting decreased dynamics and/or suboptimal positioning of the cross-linked folate for catalysis. Computer simulations that restrain the dihydrofolate tail near 1(32 indicate that cross-linking still allows movement of the p-aminobenzoyl ring, which allows the reaction to occur. Finally, a bis-ethylene-diamine-alpha,gamma-amide folate adduct was synthesized; both negatively charged carboxylates in the glutamate tail were replaced with positively charged amines. The K-i for this adduct was similar to 9-fold higher than for folate. These various results indicate a balance between folate tail disorder, which helps the enzyme bind substrate while dynamics facilitates catalysis. C1 [Duff, Michael R., Jr.; Chopra, Shaileja; Agarwal, Pratul K.; Howell, Elizabeth E.] Univ Tennessee, Dept Biochem & Cellular & Mol Biol, Knoxville, TN 37996 USA. [Strader, Michael Brad] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Agarwal, Pratul K.] Oak Ridge Natl Lab, Comp Sci & Math Div, Oak Ridge, TN 37831 USA. RP Howell, EE (reprint author), Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN 37996 USA. EM lzh@utk.edu FU National Science Foundation [MCB-0817827]; National Institutes of Health [GM 110669, GM105978] FX This work was supported by National Science Foundation Grant MCB-0817827 to E.E.H. and in part by National Institutes of Health Grants GM 110669 (to E.E.H.) and GM105978 (to P.K.A.). NR 65 TC 1 Z9 1 U1 2 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 12 PY 2016 VL 55 IS 1 BP 133 EP 145 DI 10.1021/acs.biochem.5b00981 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DB2FF UT WOS:000368323000014 PM 26637016 ER PT J AU Karzai, F Madan, RA Ning, YM Theoret, MR Arlen, PM Parnes, HL Ojemuyiwa, MA Strauss, J Dawson, NA McLeod, DG Harold, N Couvillon, A Cordes, LM Chen, C Steinberg, SM Sissung, TM Price, DK Gulley, JL Figg, WD Dahut, WL AF Karzai, Fatima Madan, Ravi Amrit Ning, Yang-Min Theoret, Marc Robert Arlen, Philip M. Parnes, Howard L. Ojemuyiwa, Michelle A. Strauss, Julius Dawson, Nancy Ann McLeod, David G. Harold, Nancy Couvillon, Anna Cordes, Lisa M. Chen, Clara Steinberg, Seth M. Sissung, Tristan M. Price, Douglas K. Gulley, James L. Figg, William Douglas Dahut, William L. TI Comparison of survival of African-American (AA) patients (pts) in docetaxel (D)-based combination therapies in metastatic castrate-resistant prostate cancer (mCRPC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 07-09, 2016 CL San Francisco, CA C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Genitourinary Malignancies Branch, CCR, NIH, Bethesda, MD 20892 USA. US FDA, Silver Spring, MD USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. Walter Reed Natl Mil Med Ctr, Rockville, MD USA. Lombardi Comprehens Canc Ctr, Washington, DC USA. Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NIH, Bldg 10, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Program, NIH, Bethesda, MD 20892 USA. NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; 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 JAN 10 PY 2016 VL 34 IS 2 SU S MA 272 PG 2 WC Oncology SC Oncology GA DO9LW UT WOS:000378109100271 ER PT J AU Ning, YMM Chen, C Maher, VE Xu, JX Kim, G Pazdur, R AF Ning, Yangmin M. Chen, Clara Maher, Virginia Ellen Xu, James Xunhai Kim, Geoffrey Pazdur, Richard TI Tumor progression versus bone scan "flare" in new lesions detected on early bone scans in patients with chemo-naive metastatic castration resistant prostate cancer (mCRPC) treated with placebo or enzalutamide SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Genitourinary Cancers Symposium CY JAN 07-09, 2016 CL San Francisco, CA C1 US FDA, Silver Spring, MD USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. US FDA, Washington, DC 20204 USA. US FDA, Ellicott City, 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 JAN 10 PY 2016 VL 34 IS 2 SU S MA 305 PG 1 WC Oncology SC Oncology GA DO9LW UT WOS:000378109100303 ER PT J AU Knolhoff, AM Croley, TR AF Knolhoff, Ann M. Croley, Timothy R. TI Non-targeted screening approaches for contaminants and adulterants in food using liquid chromatography hyphenated to high resolution mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Review DE Non-targeted screening; Food safety; LC/MS; HR-MS; Unknown analysis ID ISOTOPIC ABUNDANCE MEASUREMENTS; COLLISION-INDUCED DISSOCIATION; QUECHERS SAMPLE PREPARATION; DENSITY-FUNCTIONAL THEORY; ACCURATE-MASS; METABOLITE IDENTIFICATION; PESTICIDE-RESIDUES; CHEMICAL CONTAMINANTS; METABOLOMICS ANALYSIS; SMALL MOLECULES AB The majority of analytical methods for food safety monitor the presence of a specific compound or defined set of compounds. Non-targeted screening methods are complementary to these approaches by detecting and identifying unexpected compounds present in food matrices that may be harmful to public health. However, the development and implementation of generalized non-targeted screening workflows are particularly challenging, especially for food matrices due to inherent sample complexity and diversity and a large analyte concentration range. One approach that can be implemented is liquid chromatography coupled to high-resolution mass spectrometry, which serves to reduce this complexity and is capable of generating Molecular formulae for compounds of interest. Current capabilities, strategies, and challenges will be reviewed for sample preparation, mass spectrometry, chromatography, and data processing workflows. Considerations to increase the accuracy and speed of identifying unknown molecular species will also be addressed, including suggestions for achieving sufficient data quality for non-targeted screening applications. Published by Elsevier B.V. C1 [Knolhoff, Ann M.; Croley, Timothy R.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Knolhoff, AM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Ann.Knolhoff@fda.hhs.gov NR 111 TC 4 Z9 6 U1 24 U2 101 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JAN 8 PY 2016 VL 1428 BP 86 EP 96 DI 10.1016/j.chroma.2015.08.059 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DB5OR UT WOS:000368564000007 PM 26372444 ER PT J AU Ulitzky, L Lafer, MM KuKuruga, MA Silberstein, E Cehan, N Taylor, DR AF Ulitzky, Laura Lafer, Manuel M. KuKuruga, Mark A. Silberstein, Erica Cehan, Nicoleta Taylor, Deborah R. TI A New Signaling Pathway for HCV Inhibition by Estrogen: GPR30 Activation Leads to Cleavage of Occludin by MMP-9 SO PLOS ONE LA English DT Article ID HEPATITIS-C VIRUS; TIGHT JUNCTIONAL RESISTANCE; PROTEIN-COUPLED RECEPTOR; HEPATOMA-CELLS; BREAST-CANCER; ENTRY; POLARIZATION; INFECTION; DISEASE; PROGRESSION AB Poor outcome in response to hepatitis C virus, including higher viral load, hepatocellular carcinoma and cirrhosis, is more associated with men and postmenopausal women than with premenopausal women and women receiving hormone replacement therapy, suggesting that a-estradiol plays an innate role in preventing viral infection and liver disease. Consequently, most research in the field has concluded that estrogen affects HCV replication through viral interactions with estrogen receptor-a. Previously, estrogen-like antagonists, including Tamoxifen, were shown to reduce HCV RNA production and prevent viral entry, although the authors did not identify host factors involved. Estrogen can act alternatively through the membrane-bound G-protein-coupled estrogen receptor, GPR30. Here, human hepatoma Huh7.5 cells were infected with HCV J6/JFH-1 and treated with estrogen or Tamoxifen, resulting in a marked decrease in detectable virus. The effect was mimicked by G1, a GPR30-specific agonist, and was reversed by the GPR30-specific antagonist, G15. While previous studies have demonstrated that estrogen down-regulated occludin in cervical cancer cells, its action on liver cells was unknown. Occludin is a tight junction protein and HCV receptor and here we report that activation and cellular export of MMP-9 led to the cleavage of occludin upon estrogen treatment of liver cells. This is the first report of the cleavage of an HCV receptor in response to estrogen. We also identify the occludin cleavage site in extracellular Domain D; the motif required for HCV entry and spread. This pathway gives new insight into a novel innate antiviral pathway and the suboptimal environment that estrogen provides for the proliferation of the virus. It may also explain the disparate host-virus responses to HCV demonstrated by the two sexes. Moreover, these data suggest that hormone replacement therapy may have beneficial antiviral enhancement properties for HCV-infected postmenopausal women and show promise for new antiviral treatments for both men and women. C1 [Ulitzky, Laura; Lafer, Manuel M.; KuKuruga, Mark A.; Silberstein, Erica; Cehan, Nicoleta; Taylor, Deborah R.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Taylor, DR (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Deborah.Taylor@fda.hhs.gov FU Office of Women's Health, U.S. Food and Drug Administration FX This work was funded by the Office of Women's Health, U.S. Food and Drug Administration.; We gratefully acknowledge funding by the Office of Women's Health, U.S. Food and Drug Administration. We thank C.M. Rice for virus and cells and special thanks to German Anez for helpful discussions and invaluable input. 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 48 TC 3 Z9 3 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 5 PY 2016 VL 11 IS 1 AR e0145212 DI 10.1371/journal.pone.0145212 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DA4VZ UT WOS:000367801400027 PM 26731262 ER PT J AU Yang, MB Ruan, JQ Fu, PP Lin, G AF Yang, Mengbi Ruan, Jianqing Fu, Peter P. Lin, Ge TI Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Pyrrolizidine alkaloids; Hepatotoxicity; Metabolic activation; Reactive metabolites; Hepatic sinusoidal endothelial cell damage; Pyrrole-protein adducts ID OBSTRUCTION SYNDROME; VENOOCCLUSIVE DISEASE; HUMAN HEPATOCYTES; RAT HEPATOCYTES; LIVER-DISEASE; MONOCROTALINE; DEHYDRORETRONECINE; GLUTATHIONE; TOXICITY; ACTIVATION AB Pyrrolizidine alkaloids (PAs) widely distribute in plants and can cause hepatic sinusoidal obstruction syndrome (HSOS), which typically presents as a primary sinusoidal endothelial cell damage. It is well-recognized that after ingestion, PAs undergo hepatic cytochromes P450 (CYPs)-mediated metabolic activation to generate dehydropyrrolizidine alkaloids (DHPAs), which are hydrolyzed to dehydroretronecine (DHR). DHPAs and DHR are reactive metabolites having same core pyrrole moiety, and can bind proteins to form pyrrole-protein adducts, which are believed as the primary cause for PA-induced HSOS. However, to date, the direct evidences supporting the toxicity of DHPAs and DHR in the liver, in particular in the sinusoidal endothelial cells, are lacking. Using human hepatic sinusoidal endothelial cells (HSEC) and HepG2 (representing hepatic parenchymal cells), cells that lack CYPs activity, this study determined the direct cytotoxicity of dehydromonocrotaline, a representative DHPA, and DHR, but no cytotoxicity of the intact PA (monocrotaline) in both cell lines, confirming that reactive metabolites mediate PA intoxication. Comparing with HepG2, HSEC had significantly lower basal glutathione (GSH) level, and was significantly more susceptible to the reactive metabolites with severer GSH depletion and pyrrole-protein adducts formation. The toxic potency of two reactive metabolites was also compared. DHPA was more reactive than DHR, leading to severer toxicity. In conclusion, our results unambiguously provided the first direct evidence for the critical role of DHPA and DHR in the reactive metabolites-mediated PA-induced hepatotoxicity, which occurs predominantly in HSEC due to severe GSH depletion and the significant formation of pyrrole-protein adducts in HSEC. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Yang, Mengbi; Ruan, Jianqing; Lin, Ge] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. [Yang, Mengbi; Ruan, Jianqing; Lin, Ge] Chinese Acad Sci, Joint Res Lab Promoting Globalizat Tradit Chinese, Beijing 100864, Peoples R China. [Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Lin, G (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. EM linge@cuhk.edu.hk FU Research Grant Council of Hong Kong SAR [469712, 471013, 2140898]; Chinese University of Hong Kong [4054134, 4054215]; CUHK School of Biomedical Sciencese-Seed Fund for Joint Establishments FX The present studies were supported by Research Grant Council of Hong Kong SAR (GRF Grants, Project No.: 469712, 471013 and 2140898), The Chinese University of Hong Kong (Direct Grants: 4054134 and 4054215), and CUHK School of Biomedical Sciencese-Seed Fund for Joint Establishments. This article is not an official U.S. Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. The authors declare no competing financial interest. NR 53 TC 1 Z9 2 U1 6 U2 21 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 JAN 5 PY 2016 VL 243 BP 119 EP 126 DI 10.1016/j.cbi.2015.09.011 PG 8 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA CZ8QP UT WOS:000367364500013 PM 26365561 ER PT J AU Lambertini, E Buchanan, RL Narrod, C Ford, RM Baker, RC Pradhan, AK AF Lambertini, Elisabetta Buchanan, Robert L. Narrod, Clare Ford, Randall M. Baker, Robert C. Pradhan, Abani K. TI Quantitative assessment of human and pet exposure to Salmonella associated with dry pet foods SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE Dry pet food; Low moisture; Zoonotic pathogens; Risk assessment; Household handling ID UNITED-STATES; CROSS-CONTAMINATION; LISTERIA-MONOCYTOGENES; DOG FOOD; ANTIMICROBIAL SUSCEPTIBILITY; FOODBORNE ILLNESS; HUMAN HEALTH; CAT FOOD; OUTBREAK; INFECTIONS AB Recent Salmonella outbreaks associated with dry pet foods and treats highlight the importance of these foods as previously overlooked exposure vehicles for both pets and humans. In the last decade efforts have been made to raise the safety of this class of products, for instance by upgrading production equipment, cleaning protocols, and finished product testing. However, no comprehensive or quantitative risk profile is available for pet foods, thus limiting the ability to establish safety standards and assess the effectiveness of current and proposed Salmonella control measures. This study sought to develop an ingredients-to-consumer quantitative microbial exposure assessment model to: 1) estimate pet and human exposure to Salmonella via dry pet food, and 2) assess the impact of industry and household-level mitigation strategies on exposure. Data on prevalence and concentration of Salmonella in pet food ingredients, production process parameters, bacterial ecology, and contact transfer in the household were obtained through literature review, industry data, and targeted research. A probabilistic Monte Carlo modeling framework was developed to simulate the production process and basic household exposure routes. Under the range of assumptions adopted in this model, human exposure due to handling pet food is null to minimal if contamination occurs exclusively before extrusion. Exposure increases considerably if recontamination occurs post-extrusion during coating with fat, although mean ingested doses remain modest even at high fat contamination levels, due to the low percent of fat in the finished product. Exposure is highly variable, with the distribution of doses ingested by adult pet owners spanning 3 Log CFU per exposure event. Child exposure due to ingestion of 1 g of pet food leads to significantly higher doses than adult doses associated with handling the food. Recontamination after extrusion and coating, e.g., via dust or equipment surfaces, may also lead to exposure due to the absence of pathogen reduction steps after extrusion or at consumer households. Exposure is potentially highest when Salmonella is transferred to human food that is left at growth-promoting conditions. This model can be applied to evaluate the impact of alternative Salmonella control measures during production, risk communication to consumers, and regulatory standards. (C) 2015 Elsevier B.V. All rights reserved. C1 [Lambertini, Elisabetta; Buchanan, Robert L.; Pradhan, Abani K.] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Lambertini, Elisabetta; Buchanan, Robert L.; Pradhan, Abani K.] Univ Maryland, Ctr Food Safety & Secur Syst, College Pk, MD 20742 USA. [Narrod, Clare] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Ford, Randall M.] Mars Petcare US, Franklin, TN 37067 USA. [Baker, Robert C.] Mars Global Food Safety Ctr, Beijing 101407, Peoples R China. RP Pradhan, AK (reprint author), Univ Maryland, Dept Nutr & Food Sci, 0112 Skinner Bldg, College Pk, MD 20742 USA. EM akp@umd.edu FU MARS Petcare FX This study was funded by MARS Petcare. The authors wish to thank the team of students who assisted in the laboratory experiments on Salmonella decline and growth on pet food, in particular Ruth Oni, Huilin Cao, Miao Guo, Abhinav Mishra, Lind Wang, Xinyue Wang, Kathy Lou, Dan Li, and Yu Wang. NR 63 TC 1 Z9 1 U1 10 U2 55 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1605 EI 1879-3460 J9 INT J FOOD MICROBIOL JI Int. J. Food Microbiol. PD JAN 4 PY 2016 VL 216 BP 79 EP 90 DI 10.1016/j.ijfoodmicro.2015.09.005 PG 12 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA CW3LM UT WOS:000364893800010 PM 26414858 ER PT J AU Koti, KM AF Koti, Kallappa M. TI New Generalized p-Value Approach for Noninferiority Analysis SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Sample size.; Probability value; Beta distribution; Behrens-Fisher problem; Noncentrality parameter ID NON-INFERIORITY; TRIALS; CURVES AB The underlying statistical exercise in some noninferiority studies is to test a composite null hypothesis of a nonzero difference in the means of two normally distributed populations. These noninferiority studies are often analyzed under equal variances assumption. Unequal variances frequently occur in practice. In this article, we propose a noncentral t-distribution-based generalized test for proving noninferiority in the presence of unequal variances. We provide a simple SAS IML code to calculate the new generalized p-value. We compare the new generalized p-value with that of the Student's central t-distribution-based Tsui-Weerahandi generalized test. We conclude that Tsui-Weerahandi generalized test is conservative. C1 [Koti, Kallappa M.] US FDA, Div Biometr 5, 10903 New Hampshire Ave,HFD 711,Bldg 21, Silver Spring, MD 20993 USA. RP Koti, KM (reprint author), US FDA, Div Biometr 5, 10903 New Hampshire Ave,HFD 711,Bldg 21, Silver Spring, MD 20993 USA. EM Kallappa.Koti@fda.hhs.gov NR 14 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 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD JAN 2 PY 2016 VL 8 IS 1 BP 35 EP 39 DI 10.1080/19466315.2015.1093958 PG 5 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DH5QY UT WOS:000372848100004 ER PT J AU Weaver, J Ohlssen, D Li, JX AF Weaver, Jerry Ohlssen, David Li, Judy X. TI Strategies on Using Prior Information When Assessing Adverse Events SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Conjugate prior; Prior-data conflict; Bayesian methods; Meta-analytic-predictive prior; Robust mixture prior. ID CLINICAL-TRIALS; HISTORICAL INFORMATION; DRUG SAFETY; MODELS AB Assessing safety in drug development naturally incorporates an accumulation of knowledge as we progress from one study to another in a clinical development program. Ideally, it is the early clinical trial data that give us the greatest opportunity to leverage relevant historical information into the design and analysis of later phase clinical trials. While Bayesian methods would appear to provide an ideal framework for assessing safety in this context, concerns regarding the formulation and prespecification of a prior have limited their use in practice. More specifically, when information from previous studies is used to form a prior, an implicit assumption of exchangeability is made. However, the possibility of nonexchangeability, which could lead to conflict between prior and the data, cannot be ruled out. Based on these challenges, in this article we outline a number of strategies based on using simple Bayesian methods to assess safety concerns related to a prespecified adverse event. Three approaches to forming a prior distribution will be examined: (i) a single informative conjugate prior; (ii) a meta-analytic-predictive prior (MAP), which comprises of a mixture of conjugate priors; and (iii) a robust mixture prior, involving a combination of either the single conjugate prior or MAP with a noninformative prior. In the final case, when prior-data conflict arises between the historical informative prior and the data collected from the concurrent study, the addition of a noninformative prior serves as an automatic corrective feature. These methods will be illustrated with a motivating example involving the development of a new drug/delivery device for the treatment of agitation in schizophrenia. In addition, a simulation study will examine the performance of each approach to prior specification. C1 [Weaver, Jerry; Ohlssen, David] Novartis Pharmaceut, E Hanover, NJ 07936 USA. [Li, Judy X.] US FDA, Silver Spring, MD 20993 USA. RP Weaver, J; Ohlssen, D (reprint author), Novartis Pharmaceut, E Hanover, NJ 07936 USA.; Li, JX (reprint author), US FDA, Silver Spring, MD 20993 USA. EM jerry.weaver@novartis.com; david.ohlssen@novartis.com; judy.li@fda.hhs.gov NR 13 TC 2 Z9 2 U1 1 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD JAN 2 PY 2016 VL 8 IS 1 BP 106 EP 115 DI 10.1080/19466315.2015.1067252 PG 10 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DH5QY UT WOS:000372848100010 ER PT J AU Bot, A Bailey, C Brumeanu, T Casares, S Kuppuswamy, K Zaghouani, H AF Bot, Adrian Bailey, Celeste Brumeanu, Teodor Casares, Sofia Kuppuswamy, Kasturi Zaghouani, Habib TI Constantin A. Bona, M.D., Ph.D. OBITUARY SO INTERNATIONAL REVIEWS OF IMMUNOLOGY LA English DT Biographical-Item C1 [Bot, Adrian] Kite Pharma Inc, Int Reviews Immunol, 2225 Colorado Ave, Santa Monica, CA 90404 USA. [Bot, Adrian] Kite Pharma Inc, Translat Sci, 2225 Colorado Ave, Santa Monica, CA 90404 USA. [Bailey, Celeste] AMCR Inst, Escondido, CA USA. [Bailey, Celeste] Natl Univ, San Diego, CA USA. [Brumeanu, Teodor] Uniformed Serv Univ Hlth Sci, Dept Med Mol & Cell Biol, Bethesda, MD 20814 USA. [Casares, Sofia] Walter Reed Army Inst Res, US Mil Malaria Vaccine Program, Preclin Res, Naval Med Res Center, Silver Spring, MD USA. [Kuppuswamy, Kasturi] US FDA, US Dept HHS, Washington, DC 20204 USA. [Zaghouani, Habib] Univ Missouri, Mol Microbiol & Immunol, Columbia, MO USA. RP Bot, A (reprint author), Kite Pharma Inc, Int Reviews Immunol, 2225 Colorado Ave, Santa Monica, CA 90404 USA.; Bot, A (reprint author), Kite Pharma Inc, Translat Sci, 2225 Colorado Ave, Santa Monica, CA 90404 USA. EM abot@kitepharma.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0883-0185 EI 1563-5244 J9 INT REV IMMUNOL JI Int. Rev. Immunol. PD JAN 2 PY 2016 VL 35 IS 1 BP 1 EP 3 DI 10.3109/08830185.2016.1139991 PG 3 WC Immunology SC Immunology GA DG5EN UT WOS:000372098300001 PM 26959800 ER PT J AU He, XB Xia, QS Ma, L Fu, PP AF He, Xiaobo Xia, Qingsu Ma, Liang Fu, Peter P. TI 7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids SO JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART C-ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS LA English DT Review DE DNA adduct formation; metabolic activation; Pyrrolizidine alkaloid; 7-cysteine-DHP adducts ID ALCOHOL GLUTATHIONE CONJUGATE; FORMATION IN-VIVO; ADDUCT FORMATION; MICROSOMAL FORMATION; DIETARY-SUPPLEMENTS; N-OXIDES; ACTIVATION; LIVER; MONOCROTALINE; TUMORIGENICITY AB Pyrrolizidine alkaloids (PAs) require metabolic activation to exert cytotoxicity, genotoxicity, and tumorigenicity. We previously reported that (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts are responsible for PA-induced liver tumor formation in rats. In this study, we determined that metabolism of riddelliine and monocrotaline by human or rat liver microsomes produced 7-cysteine-DHP and DHP. The metabolism of 7-glutathionyl-DHP by human and rat liver microsomes also generated 7-cysteine-DHP. Further, reaction of 7-cysteine-DHP with calf thymus DNA in aqueous solution yielded the described DHP-derived DNA adducts. This study represents the first report that 7-cysteine-DHP is a new PA metabolite that can lead to DNA adduct formation. C1 [He, Xiaobo; Xia, Qingsu; Ma, Liang; Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Fu, PP (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov NR 33 TC 2 Z9 2 U1 2 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1059-0501 EI 1532-4095 J9 J ENVIRON SCI HEAL C JI J. Environ. Sci. Health Pt. C-Environ. Carcinog. Ecotoxicol. Rev. PD JAN 2 PY 2016 VL 34 IS 1 BP 57 EP 76 DI 10.1080/10590501.2015.1135593 PG 20 WC Oncology; Environmental Sciences; Toxicology SC Oncology; Environmental Sciences & Ecology; Toxicology GA DG0HZ UT WOS:000371747200003 PM 26761716 ER PT J AU Campbell, G Yue, LQ AF Campbell, Gregory Yue, Lilly Q. TI Statistical innovations in the medical device world sparked by the FDA SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Adaptive designs; Bayesian statistics; clinical trials; diagnostic test evaluation; missing data; propensity score; quantitative benefit-risk ID PROPENSITY SCORE; REGULATORY ISSUES; CLINICAL-TRIALS; MISSING DATA; DESIGN; PREFERENCES; CHALLENGES; EXPERIENCE; ACCURACY; RISKS AB The world of medical devices while highly diverse is extremely innovative, and this facilitates the adoption of innovative statistical techniques. Statisticians in the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration (FDA) have provided leadership in implementing statistical innovations. The innovations discussed include: the incorporation of Bayesian methods in clinical trials, adaptive designs, the use and development of propensity score methodology in the design and analysis of non-randomized observational studies, the use of tipping-point analysis for missing data, techniques for diagnostic test evaluation, bridging studies for companion diagnostic tests, quantitative benefit-risk decisions, and patient preference studies. C1 [Campbell, Gregory; Yue, Lilly Q.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Yue, LQ (reprint author), US FDA, CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM lilly.yue@fda.hhs.gov NR 49 TC 1 Z9 1 U1 1 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 JAN 2 PY 2016 VL 26 IS 1 SI SI BP 3 EP 16 DI 10.1080/10543406.2015.1092037 PG 14 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DB7VR UT WOS:000368725300002 PM 26372890 ER PT J AU Chakravarty, AG Izem, R Keeton, S Kim, CY Levenson, MS Soukup, M AF Chakravarty, Aloka G. Izem, Rima Keeton, Stephine Kim, Clara Y. Levenson, Mark S. Soukup, Mat TI The role of quantitative safety evaluation in regulatory decision making of drugs SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Evaluation of risk from extended; long-acting opioids; large safety outcome trials; meta-analysis for safety evaluation; post-marketing requirements; quantitative safety evaluation; the sentinel initiative ID RANDOMIZED CONTROLLED-TRIALS; MORTALITY RISKS; MYOCARDIAL-INFARCTION; PROPENSITY SCORE; US FOOD; ANTIDEPRESSANTS; METAANALYSIS; SUICIDALITY; DABIGATRAN; DISEASE AB Evaluation of safety is a critical component of drug review at the US Food and Drug Administration (FDA). Statisticians are playing an increasingly visible role in quantitative safety evaluation and regulatory decision-making. This article reviews the history and the recent events relating to quantitative drug safety evaluation at the FDA. The article then focuses on five active areas of quantitative drug safety evaluation and the role Division of Biometrics VII (DBVII) plays in these areas, namely meta-analysis for safety evaluation, large safety outcome trials, post-marketing requirements (PMRs), the Sentinel Initiative, and the evaluation of risk from extended/long-acting opioids. This article will focus chiefly on developments related to quantitative drug safety evaluation and not on the many additional developments in drug safety in general. C1 [Chakravarty, Aloka G.; Izem, Rima; Keeton, Stephine; Kim, Clara Y.; Levenson, Mark S.; Soukup, Mat] US FDA, Ctr Drug Evaluat & Res, Div Biometr 7, Off Biostat, 10903 New Hampshire Ave,Bldg 21 Room 3514, Silver Spring, MD 20993 USA. RP Chakravarty, AG (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Biometr 7, Off Biostat, 10903 New Hampshire Ave,Bldg 21 Room 3514, Silver Spring, MD 20993 USA. EM aloka.chakravarty@fda.hhs.gov NR 42 TC 0 Z9 0 U1 0 U2 2 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 JAN 2 PY 2016 VL 26 IS 1 SI SI BP 17 EP 29 DI 10.1080/10543406.2015.1092026 PG 13 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DB7VR UT WOS:000368725300003 PM 26372792 ER PT J AU McEvoy, BW AF McEvoy, Bradley W. TI Missing data in clinical trials for weight management SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Estimands; missing data; sensitivity analyses AB In 2014, the US FDA approved liraglutide for weight management. The statistical review of the application presented various challenges related to the handling of missing data. The ability of the drug to cause weight loss was not in question. The challenge centered on obtaining a reliable estimate of the intention-to-treat effect to support the risk-benefit evaluation. Subjects in the trials that stopped treatment prior to the endpoint were encouraged to attend the primary endpoint visit. Data from the subjects that returned for a primary efficacy assessment played a significant role in the statistical review. They were used to illustrate shortcomings of the applicant's primary efficacy analysis and sensitivity analyses. They were also used in the FDA analyses to address missing data. The goal of this article is to illustrate challenges and considerations associated with the handling of missing data in clinical trials. C1 [McEvoy, Bradley W.] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Div Biometr 2, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP McEvoy, BW (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Biostat, Div Biometr 2, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM bradley.mcevoy@fda.hhs.gov NR 14 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 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD JAN 2 PY 2016 VL 26 IS 1 SI SI BP 30 EP 36 DI 10.1080/10543406.2015.1094814 PG 7 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DB7VR UT WOS:000368725300004 PM 26418188 ER PT J AU Hung, HMJ Wang, SJ Yang, PL Jin, K Lawrence, J Kordzakhia, G Massie, T AF Hung, H. M. James Wang, Sue-Jane Yang, Peiling Jin, Kun Lawrence, John Kordzakhia, George Massie, Tristan TI Statistical challenges in a regulatory review of cardiovascular and CNS clinical trials SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Adaptive design; adaptive selection; adaptive statistical information; branching decision rule; multiplicity; type I error ID MULTIPLE END-POINTS; CONFIDENCE-INTERVALS; SAMPLE-SIZE; SEQUENTIAL DESIGN AB There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article. C1 [Hung, H. M. James; Yang, Peiling; Jin, Kun; Lawrence, John; Kordzakhia, George; Massie, Tristan] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Off Biostat,Div Biometr 1, Silver Spring, MD USA. [Wang, Sue-Jane] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Off Translat Sci, Silver Spring, MD USA. RP Hung, HMJ (reprint author), US FDA, OB OTS CDER, Div Biometr 1, 10903 New Hampshire Ave,Bldg 21,Room 4616, Silver Spring, MD 20993 USA. EM hsienming.hung@fda.hhs.gov NR 24 TC 0 Z9 0 U1 0 U2 2 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 JAN 2 PY 2016 VL 26 IS 1 SI SI BP 37 EP 43 DI 10.1080/10543406.2015.1092025 PG 7 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DB7VR UT WOS:000368725300005 PM 26366624 ER PT J AU Wu, PS Lin, M Chow, SC AF Wu, Pei-Shien Lin, Min Chow, Shein-Chung TI On sample size estimation and re-estimation adjusting for variability in confirmatory trials SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Achieving conditional power; controlling variability; maintaining effect size; reproducibility probability ID CLINICAL-TRIALS; INTERNAL PILOT; T-TEST AB Sample size estimation (SSE) is an important issue in the planning of clinical studies. While larger studies are likely to have sufficient power, it may be unethical to expose more patients than necessary to answer a scientific question. Budget considerations may also cause one to limit the study to an adequate size to answer the question at hand. Typically at the planning stage, a statistically based justification for sample size is provided. An effective sample size is usually planned under a pre-specified type I error rate, a desired power under a particular alternative and variability associated with the observations recorded. The nuisance parameter such as the variance is unknown in practice. Thus, information from a preliminary pilot study is often used to estimate the variance. However, calculating the sample size based on the estimated nuisance parameter may not be stable. Sample size re-estimation (SSR) at the interim analysis may provide an opportunity to re-evaluate the uncertainties using accrued data and continue the trial with an updated sample size. This article evaluates a proposed SSR method based on controlling the variability of nuisance parameter. A numerical study is used to assess the performance of proposed method with respect to the control of type I error. The proposed method and concepts could be extended to SSR approaches with respect to other criteria, such as maintaining effect size, achieving conditional power, and reaching a desired reproducibility probability. C1 [Wu, Pei-Shien; Chow, Shein-Chung] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Wu, Pei-Shien; Lin, Min] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Lin, M (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM min.lin@fda.hhs.gov NR 14 TC 0 Z9 0 U1 1 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 JAN 2 PY 2016 VL 26 IS 1 SI SI BP 44 EP 54 DI 10.1080/10543406.2015.1092031 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DB7VR UT WOS:000368725300006 PM 26378970 ER PT J AU Ivanova, A Zhang, ZW Thompson, L Yang, Y Kotz, RM Fang, X AF Ivanova, Anastasia Zhang, Zhiwei Thompson, Laura Yang, Ying Kotz, Richard M. Fang, Xin TI Can sequential parallel comparison design and two-way enriched design be useful in medical device clinical trials? SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Medical device; placebo response; sequential parallel comparison design; SPCD; TED; two-way enriched design ID PLACEBO-RESPONSE; DOUBLE-BLIND; MAJOR DEPRESSION; STIMULATION; STATISTICS AB Sequential parallel comparison design (SPCD) was proposed for trials with high placebo response. In the first stage of SPCD subjects are randomized between placebo and active treatment. In the second stage placebo nonresponders are re-randomized between placebo and active treatment. Data from the population of all comers and the subpopulations of placebo nonresponders then combined to yield a single p-value for treatment comparison. Two-way enriched design (TED) is an extension of SPCD where active treatment responders are also re-randomized between placebo and active treatment in Stage 2. This article investigates the potential uses of SPCD and TED in medical device trials. C1 [Ivanova, Anastasia] Univ N Carolina, Dept Biostat, CB 7420, Chapel Hill, NC 27599 USA. [Zhang, Zhiwei; Thompson, Laura; Yang, Ying; Kotz, Richard M.; Fang, Xin] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Ivanova, A (reprint author), Univ N Carolina, Dept Biostat, CB 7420, Chapel Hill, NC 27599 USA. EM aivanova@bios.unc.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD JAN 2 PY 2016 VL 26 IS 1 SI SI BP 167 EP 177 DI 10.1080/10543406.2015.1092028 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DB7VR UT WOS:000368725300013 PM 26368863 ER PT J AU Duncan, R Kourout, M Grigorenko, E Fisher, C Dong, M AF Duncan, Robert Kourout, Moussa Grigorenko, Elena Fisher, Carolyn Dong, Ming TI Advances in multiplex nucleic acid diagnostics for blood-borne pathogens: promises and pitfalls SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE multiplex diagnostics; nucleic acid tests; blood-borne; pathogen ID MEDIATED ISOTHERMAL AMPLIFICATION; POLYMERASE-CHAIN-REACTION; RESPIRATORY-TRACT INFECTIONS; IONIZATION MASS-SPECTROMETRY; T2 MAGNETIC-RESONANCE; REAL-TIME; RAPID DIAGNOSIS; DENGUE VIRUS; ANTIMICROBIAL THERAPY; HOSPITALIZED-PATIENTS AB The large number of blood-borne viruses, bacteria and parasites currently of concern, as well as many newly emerging pathogens, presents a daunting challenge to protection of the safety of blood for transfusion and diagnosing infectious diseases. Focusing on nucleic acid diagnostic tests, multiplex devices are coming into use with many more in various developmental stages that promise to offer solutions to the clinical need. The characteristics, advantages and disadvantages of platforms in clinical use and at the research and development stage are examined here. The presence of multiple assays and associated reagents operating simultaneously on one platform, implementation in traditional clinical laboratories and regulatory review will present special challenges. Fortunately, clinical laboratories have made dramatic technical progress in the last two decades and regulatory agencies have publicly expressed support for development of multiplex devices. C1 [Duncan, Robert; Kourout, Moussa; Fisher, Carolyn; Dong, Ming] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Grigorenko, Elena] Diatherix Labs LLC, Huntsville, AL 35806 USA. RP Duncan, R (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Robert.duncan@fda.hhs.gov NR 102 TC 0 Z9 0 U1 2 U2 12 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 JAN 2 PY 2016 VL 16 IS 1 BP 83 EP 95 DI 10.1586/14737159.2016.1112272 PG 13 WC Pathology SC Pathology GA DB3XG UT WOS:000368446200001 PM 26581018 ER PT J AU Volpe, DA AF Volpe, Donna A. TI Transporter assays as useful in vitro tools in drug discoveryand development SO EXPERT OPINION ON DRUG DISCOVERY LA English DT Review DE Drug transporters; efflux; in vitro; uptake ID SANDWICH-CULTURED HEPATOCYTES; CANCER RESISTANCE PROTEIN; P-GP INHIBITION; SUPPORT REGULATORY SUBMISSIONS; ORGANIC CATION TRANSPORTER; HUMAN INTESTINAL-MUCOSA; PROXIMAL TUBULAR CELLS; SPECIES-DIFFERENCES; EFFLUX TRANSPORTERS; CACO-2 CELLS AB Introduction: Drug transporters are transmembrane proteins that facilitate the transfer of substances in and out of cells and play a substantial role in drug absorption, distribution and elimination. During the drug discovery and development phases, in vitro assays are important tools to identify substrates and inhibitors of transporters.Areas covered: This article provides an overview of in vitro transporter assays, discussing their advantages, limitations, and sources of variability. Membrane-based assays take advantage of the location of efflux transporters for measurements of drug interactions. Cell-based systems are functional transporter assays that measure the passage of drugs across cell membranes and transporter proteins.Expert opinion: Use of optimized and validated in vitro transporter assays during drug discovery and development leads to a greater confidence in their results in determining whether a new compound is a substrate or inhibitor. The concept of transporter method suitability provides a general scheme to improve predictability and reduce variability of the in vitro assays by incorporating assay validation, acceptance criteria, and probe substrates and inhibitors. Such a scheme can potentially improve assay reproducibility and allow in vitro transporter assays to aid in defining a test compound as a substrate or inhibitor of efflux and uptake transporters. C1 [Volpe, Donna A.] US FDA, Silver Spring, MD 20903 USA. RP Volpe, DA (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM donna.volpe@fda.hhs.gov NR 113 TC 0 Z9 0 U1 7 U2 17 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1746-0441 EI 1746-045X J9 EXPERT OPIN DRUG DIS JI Expert. Opin. Drug Discov. PD JAN 2 PY 2016 VL 11 IS 1 BP 91 EP 103 DI 10.1517/17460441.2016.1101064 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DA7ZQ UT WOS:000368024500002 PM 26512742 ER PT J AU Sy, SKB Zhuang, LN Derendorf, H AF Sy, Sherwin K. B. Zhuang, Luning Derendorf, Hartmut TI Pharmacokinetics and pharmacodynamics in antibiotic dose optimization SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE antibiotics; in vitro models; PK-PD modeling; translational research ID CRITICALLY-ILL PATIENTS; LUNG INFECTION MODELS; COMMUNITY-ACQUIRED PNEUMONIA; SKIN-STRUCTURE INFECTIONS; PARA-AMINOSALICYLIC ACID; MUTANT SELECTION WINDOW; STAGE RENAL-DISEASE; IN-VITRO MODEL; PSEUDOMONAS-AERUGINOSA; BETA-LACTAMASE AB Introduction: Identifying the optimized dosing regimen and algorithm is critical in the development of antibiotics. Suboptimal regimens and inappropriate choice of drug give rise to drug-resistant bacteria which have limited the therapeutic utility of many commercially available antimicrobial agents. Strategies to optimize therapy of antimicrobial candidates to speed up the development process are urgently needed.Areas covered: We examined pharmacokinetics and pharmacodynamics of antimicrobial agents with modeling and simulation approaches. The approach that is based on minimum inhibitory concentration to evaluate antimicrobial dosing strategy is widely utilized in drug development. The modeling approach utilizing information from time-kill kinetic studies is a tool that can provide more information on the time-course of bacterial response to a particular dosing regimen. Animal studies of dosing regimens that mimic human pharmacokinetics are another option to evaluate antimicrobial efficacy. Empirical, semi-mechanistic and mechanistic models of bacterial dynamics and development of drug resistance in response to drug therapy are discussed.Expert opinion: Both theories and applications of these approaches provide an overall understanding of how the tools can streamline drug development process and help make crucial decisions. Many opportunities and potentials are presented to incorporate more rigorous integration of PK-PD modeling approaches even at preclinical stage to extrapolate to clinical settings, thus enabling successful trials and optimizing dosing strategies in relevant populations where the drug is mostly used. C1 [Sy, Sherwin K. B.; Zhuang, Luning; Derendorf, Hartmut] Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA. [Sy, Sherwin K. B.] Univ Estadual Maringa, Postgrad Program Biostat, Maringa, Parana, Brazil. [Zhuang, Luning] US FDA, Div Pharmacometr, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Derendorf, H (reprint author), Univ Florida, Coll Pharm, Dept Pharmaceut, POB 100494, Gainesville, FL 32610 USA. EM hartmut@ufl.edu OI Sy, Sherwin/0000-0001-6405-9130 NR 138 TC 4 Z9 4 U1 4 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 JAN 2 PY 2016 VL 12 IS 1 BP 93 EP 114 DI 10.1517/17425255.2016.1123250 PG 22 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA DA5HK UT WOS:000367833700002 PM 26652832 ER PT J AU Gray, PJ Conklin, SD Todorov, TI Kasko, SM AF Gray, Patrick J. Conklin, Sean D. Todorov, Todor I. Kasko, Sasha M. TI Cooking rice in excess water reduces both arsenic and enriched vitamins in the cooked grain SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Rice; arsenic; inorganic arsenic; iron; cadmium; washing; cooking; folate; niacin; thiamin ID RISK ASSESSMENTS; UNITED-STATES; ICP-MS; ACCUMULATION; SPECIATION AB This paper reports the effects of rinsing rice and cooking it in variable amounts of water on total arsenic, inorganic arsenic, iron, cadmium, manganese, folate, thiamin and niacin in the cooked grain. We prepared multiple rice varietals both rinsed and unrinsed and with varying amounts of cooking water. Rinsing rice before cooking has a minimal effect on the arsenic (As) content of the cooked grain, but washes enriched iron, folate, thiamin and niacin from polished and parboiled rice. Cooking rice in excess water efficiently reduces the amount of As in the cooked grain. Excess water cooking reduces average inorganic As by 40% from long grain polished, 60% from parboiled and 50% from brown rice. Iron, folate, niacin and thiamin are reduced by 50-70% for enriched polished and parboiled rice, but significantly less so for brown rice, which is not enriched. C1 [Gray, Patrick J.; Conklin, Sean D.; Todorov, Todor I.; Kasko, Sasha M.] US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20742 USA. RP Gray, PJ (reprint author), US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20742 USA. EM Patrick.Gray@fda.hhs.gov OI Gray, Patrick/0000-0002-8248-2749 NR 36 TC 1 Z9 1 U1 10 U2 29 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 JAN 2 PY 2016 VL 33 IS 1 BP 78 EP 85 DI 10.1080/19440049.2015.1103906 PG 8 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA CY6NM UT WOS:000366526000009 PM 26515534 ER PT J AU Naeger, LK Harrington, P Komatsu, T Deming, D AF Naeger, Lisa K. Harrington, Patrick Komatsu, Takashi Deming, Damon TI Effect of dolutegravir functional monotherapy on HIV-1 virological response in integrase strand transfer inhibitor resistant patients SO ANTIVIRAL THERAPY LA English DT Article AB Background: VIKING-4 assessed the safety and efficacy of dolutegravir in heavily antiretroviral treatment-experienced patients who had documented integrase strand transfer inhibitor (INSTI) resistance-associated substitutions in their HIV. VIKING-4 had a placebo-controlled 7-day dolutegravir functional monotherapy phase followed by dolutegravir plus an optimized background regimen for 48 weeks. Methods: Independent resistance analyses evaluated week 48 virological responses in the VIKING-4 trial based on the presence of baseline INSTI resistance-associated substitutions and baseline dolutegravir phenotypic susceptibility. Response rates at week 48 based on baseline dolutegravir resistance subgroups were compared for the 7-day dolutegravir functional monotherapy arm and placebo-control arm. Additionally, genotypic and phenotypic resistance at day 8 and time of failure was analysed for the virological failures from both arms. Results: Week 48 response rates for VIKING-4 were 23% (3/13) in the 7-day dolutegravir functional monotherapy arm compared with 60% (9/15) in the 7-day placebo arm. Response rates were consistently lower in the dolutegravir functional monotherapy arm across baseline INSTI genotypic and phenotypic subgroups. There was a higher proportion of virological failures in the 7-day dolutegravir functional monotherapy arm (n= 6/13; 46%) compared with the 7-day placebo arm (n= 3/15; 20%). Additionally, five virological failures in the dolutegravir arm had virus expressing emergent INSTI resistance-associated substitutions compared with two in the placebo arm. Conclusions: Analysis of response rates and resistance emergence in VIKING-4 suggests careful consideration should be given to the duration of functional monotherapy in future studies of highly treatment-experienced patients to reduce the risk of resistance and virological failure. C1 [Naeger, Lisa K.; Harrington, Patrick; Komatsu, Takashi; Deming, Damon] US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Naeger, LK (reprint author), US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM lisa.naeger@fda.hhs.gov NR 4 TC 1 Z9 1 U1 1 U2 1 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2016 VL 21 IS 6 BP 481 EP 488 DI 10.3851/IMP3033 PG 8 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA EN6BN UT WOS:000396089600002 PM 26866979 ER PT S AU Sakellaropoulos, T Hur, J Melas, IN Guo, EY Alexopoulos, L Bohlooly, M Bai, JPF AF Sakellaropoulos, Theodore Hur, Junguk Melas, Ioannis N. Guo, Ellen Y. Alexopoulos, Leonidas Bohlooly, Mohammad Bai, Jane P. F. BE Donev, R TI Computational Approaches to Accelerating Novel Medicine and Better Patient Care from Bedside to Benchtop SO ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY, VOL 102: PERSONALIZED MEDICINE SE Advances in Protein Chemistry and Structural Biology LA English DT Review; Book Chapter ID PROTEIN-PROTEIN INTERACTIONS; PRIMARY BREAST-CANCER; CELL LUNG-CANCER; COLORECTAL-CANCER; MISSENSE MUTATIONS; BIOMEDICAL TEXT; TYROSINE KINASE; GENE-EXPRESSION; EOSINOPHILIC LEUKEMIA; ENRICHMENT ANALYSIS AB Some successes have been achieved in the war on cancer over the past 30 years with recent efforts on protein kinase inhibitors. Nonetheless, we are still facing challenges due to cancer evolution. Cancers are complex and heterogeneous due to primary and secondary mutations, with phenotypic and molecular heterogeneity manifested among patients of a cancer, and within an individual patient throughout the disease course. Our understanding of cancer genomes has been facilitated by advances in omics and in bioinformatics technologies; major areas in cancer research are advancing in parallel on many fronts. Computational methods have been developed to decipher the molecular complexity of cancer and to identify driver mutations in cancers. Utilizing the identified driver mutations to develop effective therapy would require biological linkages from cellular context to clinical implication; for this purpose, computational mining of biomedical literature facilitates utilization of a huge volume of biomedical research data and knowledge. In addition, frontier technologies, such as genome editing technologies, are facilitating investigation of cancer mutations, and opening the door for developing novel treatments to treat diseases. We will review and highlight the challenges of treating cancers, which behave like moving targets due to mutation and evolution, and the current state-of-the-art research in the areas mentioned above. C1 [Sakellaropoulos, Theodore; Bai, Jane P. F.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Hur, Junguk] Univ North Dakota, Sch Med & Hlth Sci, Dept Biomed Sci, Grand Forks, ND USA. [Melas, Ioannis N.] Astrazeneca, Discovery Sci, Grp Quantitat Biol, Molndal, Sweden. [Guo, Ellen Y.] Univ Illinois, Mol & Cellular Biol Liberal Arts & Sci, Urbana, IL USA. [Alexopoulos, Leonidas] Natl Tech Univ Athens, Sch Mech Engn, Athens, Greece. [Alexopoulos, Leonidas] ProtAtonce Ltd, Athens, Greece. [Bohlooly, Mohammad] Astrazeneca, Discovery Sci Reagents & Assay Dev, Transgen Grp, Molndal, Sweden. RP Bai, JPF (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM jane.bai@fda.hhs.gov OI Hur, Junguk/0000-0002-0736-2149 NR 146 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 1876-1623 BN 978-0-12-804795-8 J9 ADV PROTEIN CHEM STR JI Adv. Protein Chem. Struct. Biol. PY 2016 VL 102 BP 147 EP 179 DI 10.1016/bs.apcsb.2015.09.005 PG 33 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BG9NQ UT WOS:000393455000007 PM 26827605 ER PT J AU Huang, Y Havert, M Gavin, D Serabian, M Ong, LL McIntyre, MC Ferry, N Kume, A Petrin, D Fu, YH Marti, A Oliveira, F Pavittranon, S Shin, W AF Huang, Ying Havert, Mike Gavin, Denise Serabian, Mercedes Ong, Lee Lee McIntyre, Maritza C. Ferry, Nicolas Kume, Akihiro Petrin, Dino Fu, Ying-Hsien Marti, Andreas Oliveira, Fabricio Pavittranon, Sumol Shin, Won TI Biodistribution studies: understanding international expectations SO MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT LA English DT Editorial Material C1 [Huang, Ying; Havert, Mike; Gavin, Denise; Serabian, Mercedes] US FDA, Silver Spring, MD 20993 USA. [Ong, Lee Lee] Singapore Hlth Sci Author, Singapore, Singapore. [McIntyre, Maritza C.] Bamboo Therapeut Inc Chapel Hill, Chapel Hill, NC USA. [Ferry, Nicolas] European Med Agcy, London, England. [Kume, Akihiro] Pharmaceut & Med Device Agcy Japan, Tokyo, Japan. [Petrin, Dino] Hlth Canada, Ottawa, ON, Canada. [Fu, Ying-Hsien] Taiwan Food & Drug Adm Chinese Taipei, Taipei, Taiwan. [Marti, Andreas] Swissmed Berne, Bern, Switzerland. [Oliveira, Fabricio] Natl Hlth Surveillance Agcy Brazil, Setor Ind, Brasilia, DF, Brazil. [Pavittranon, Sumol] Thailand Ctr Excellence Life Sci, Phayathai Bangkok, Thailand. [Shin, Won] South Korea Minist Food & Drug Safety, Chungcheongbuk Do, South Korea. RP Huang, Y; Gavin, D (reprint author), US FDA, Silver Spring, MD 20993 USA. EM ying.huang@fda.hhs.gov; denise.gavin@fda.hhs.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2329-0501 J9 MOL THER-METH CLIN D JI Mol.Ther.-Methods Clin. Dev. PY 2016 VL 3 AR UNSP 16022 DI 10.1038/mtm.2016.22 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EJ8DM UT WOS:000393455200033 ER PT S AU Akogwu, I Wang, N Zhang, CY Hong, HX Choi, H Gong, P AF Akogwu, Isaac Wang, Nan Zhang, Chaoyang Hong, Huixiao Choi, Hwanseok Gong, Ping BE Tian, T Jiang, Q Liu, Y Burrage, K Song, J Wang, Y Hu, X Morishita, S Zhu, Q Wang, G TI Factorial Analysis of Error Correction Performance Using Simulated Next-Generation Sequencing Data SO 2016 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE (BIBM) SE IEEE International Conference on Bioinformatics and Biomedicine-BIBM LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine (IEEE BIBM) CY DEC 15-18, 2016 CL Shenzhen, PEOPLES R CHINA SP IEEE, IEEE Comp Soc, Natl Sci Fdn, Harbin Inst Technol DE next-generation sequencing; performance metrics; error correction; multi-way ANOVA; k-mer spectrum; genome size; read length; coverage depth; simulation study; precision; F-score ID SINGLE-NUCLEOTIDE VARIANTS; READS; BIAS AB Error correction is a critical initial step in next-generation sequencing (NGS) data analysis. Although more than 60 tools have been developed, there is no systematic evidence-based comparison with regard to their strength and weakness, especially in terms of correction accuracy. Here we report a full factorial simulation study to examine how NGS dataset characteristics (genome size, coverage depth and read length in particular) affect error correction performance (precision and F-score), as well as to compare performance sensitivity/resistance of six k-mer spectrum-based methods to variations in dataset characteristics. Multi-way ANOVA tests indicate that choice of correction method and dataset characteristics had significant effects on performance metrics. Overall, BFC, Bless, Bloocoo and Musket performed better than Lighter and Trowel on 27 synthetic datasets. For each chosen method, read length and coverage depth showed more pronounced impact on performance than genome size. This study shed insights to the performance behavior of error correction methods in response to the common variables one would encounter in real-world NGS datasets. It also warrants further studies of wet lab-generated experimental NGS data to validate findings obtained from this simulation study. C1 [Akogwu, Isaac; Wang, Nan; Zhang, Chaoyang] Univ Southern Mississippi, Sch Comp, Hattiesburg, MS 39406 USA. [Hong, Huixiao] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. [Choi, Hwanseok] Univ Southern Mississippi, Dept Publ Hlth, Hattiesburg, MS 39406 USA. [Gong, Ping] US Army Engn Res & Dev Ctr, Environm Lab, Vicksburg, MS USA. RP Zhang, CY (reprint author), Univ Southern Mississippi, Sch Comp, Hattiesburg, MS 39406 USA. EM Chaoyang.zhang@usm.edu; Ping.Gong@usace.army.mil FU U.S. Army Environmental Quality/Installation (EQI) Basic Research Program; National Science Foundation [EPS 0903787] FX This work was supported by an intramural grant from the U.S. Army Environmental Quality/Installation (EQI) Basic Research Program to PG and a sub-award of National Science Foundation award EPS 0903787 to CZ and NW. Permission was granted by the Chief of Engineer to publish this paper. NR 24 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 2156-1125 BN 978-1-5090-1610-5 J9 IEEE INT C BIOINFORM PY 2016 BP 1164 EP 1169 PG 6 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA BG9GY UT WOS:000393191700200 ER PT S AU Islam, MA Lim, H Paoletti, N Abbas, H Jiang, ZH Cyranka, J Cleaveland, R Gao, SC Clarke, E Grosu, R Mangharam, R Cherry, E Fenton, F Gray, RA Glimm, J Lin, S Wang, QS Smolka, SA AF Islam, Md. Ariful Lim, Hyunkyung Paoletti, Nicola Abbas, Houssam Jiang, Zhihao Cyranka, Jacek Cleaveland, Rance Gao, Sicun Clarke, Edmund Grosu, Radu Mangharam, Rahul Cherry, Elizabeth Fenton, Flavio Gray, Richard A. Glimm, James Lin, Shan Wang, Qinsi Smolka, Scott A. BE Tian, T Jiang, Q Liu, Y Burrage, K Song, J Wang, Y Hu, X Morishita, S Zhu, Q Wang, G TI CyberCardia Project: Modeling, Verification and Validation of Implantable Cardiac Devices SO 2016 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE (BIBM) SE IEEE International Conference on Bioinformatics and Biomedicine-BIBM LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine (IEEE BIBM) CY DEC 15-18, 2016 CL Shenzhen, PEOPLES R CHINA SP IEEE, IEEE Comp Soc, Natl Sci Fdn, Harbin Inst Technol DE Cardiac electrophysiology; Implantable cardiac Devices; Formal Methods; Verification and Validation; Closed-loop control ID PERIOD-DOUBLING BIFURCATIONS; ACTION-POTENTIAL PROPAGATION; COMPUTATIONAL MODELS; VIRTUAL ELECTRODES; SPIRAL BREAKUP; FIBRILLATION; DEFIBRILLATION; DYNAMICS; TISSUE; STIMULATION AB In this paper, we survey recent progress in CyberCardia project, a CPS Frontier project funded by the National Science Foundation. The CyberCardia project will lead to significant advances in the state of the art for system verification and cardiac therapies based on the use of formal methods and closed-loop control and verification. The animating vision for the work is to enable the development of a true in silico design methodology for medical devices that can be used to speed the development of new devices and to provide greater assurance that their behavior matches designer intentions, and to pass regulatory muster more quickly so that they can be used on patients needing their care. The acceleration in medical-device innovation achievable as a result of the CyberCardia research will also have long-term and sustained societal benefits, as better diagnostic and therapeutic technologies enter into the practice of medicine more quickly. C1 [Islam, Md. Ariful; Clarke, Edmund; Wang, Qinsi] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Cyranka, Jacek] Rutgers State Univ, New Brunswick, NJ USA. [Lim, Hyunkyung; Paoletti, Nicola; Glimm, James; Lin, Shan; Smolka, Scott A.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Cleaveland, Rance] Univ Maryland, College Pk, MD 20742 USA. [Gao, Sicun] MIT, Cambridge, MA 02139 USA. [Grosu, Radu] Vienna Univ Technol, Vienna, Austria. [Abbas, Houssam; Jiang, Zhihao; Mangharam, Rahul] Univ Penn, Philadelphia, PA 19104 USA. [Cherry, Elizabeth] Rochester Inst Technol, Rochester, MN USA. [Fenton, Flavio] Georgia Inst Technol, Atlanta, GA 30332 USA. [Gray, Richard A.] US FDA, Rockville, MD 20857 USA. RP Islam, MA (reprint author), Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. FU NSF [IIS-1447549, CPS-1446832, CPS-1446725, CAR 1054247]; AFOSR [FA9550-14-1-0261, YIP FA9550-12-1-0336, CCF-0926190]; ONR [N00014-13-1-0090]; NASA [NNX12AN15H] FX Research supported in part by the following grants: NSF IIS-1447549, NSF CPS-1446832, NSF CPS-1446725, NSF CAR 1054247, AFOSR FA9550-14-1-0261, AFOSR YIP FA9550-12-1-0336, CCF-0926190, ONR N00014-13-1-0090, and NASA NNX12AN15H. NR 51 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 2156-1125 BN 978-1-5090-1610-5 J9 IEEE INT C BIOINFORM PY 2016 BP 1445 EP 1452 PG 8 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA BG9GY UT WOS:000393191700252 ER PT J AU Brannen, KC Chapin, RE Jacobs, AC Green, ML AF Brannen, Kimberly C. Chapin, Robert E. Jacobs, Abigail C. Green, Maia L. TI Alternative Models of Developmental and Reproductive Toxicity in Pharmaceutical Risk Assessment and the 3Rs SO ILAR JOURNAL LA English DT Review DE alternative; developmental toxicity; embryonic stem cells; reproductive toxicity; whole embryo culture; zebrafish; testis; ovary ID WHOLE-EMBRYO CULTURE; ZEBRAFISH DANIO-RERIO; METABOLIC-ACTIVATION SYSTEM; VITRO EMBRYOTOXICITY TESTS; STEM-CELL TEST; IN-VITRO; TOXICOLOGY ASSAY; PHASE-I; TESTICULAR TOXICITY; BRACHYDANIO-RERIO AB In the pharmaceutical industry, preclinical developmental and reproductive toxicity studies are conducted in laboratory animals in order to predict and prevent adverse effects of drugs on human reproductive health and development. However, these studies require a relatively large number of animals and are usually conducted late in the drug development process. Early, simple, and inexpensive screening assays could facilitate smarter decisions, reductions in animal use, and development of safe drugs. The current state and future needs for alternative models of developmental and reproductive toxicity are reviewed here. The most popular predictive developmental toxicity assays are embryonic stem cells, rodent whole embryo culture, and zebrafish, each of which involves fairly well-developed techniques with demonstrated utility in drug discovery and development. In vitro or ex vivo methods for male and female reproductive toxicity are less established, but there are promising assays available or being developed that may be useful in drug development, especially for elucidating mechanisms or screening backup compounds. While a number of challenges remain, much progress has been made in alternative developmental and reproductive toxicity models to date, and there is a strong collective enthusiasm in the industry to continue moving them forward. Therefore, it appears that these approaches may be widely used in the near future. C1 [Brannen, Kimberly C.; Green, Maia L.] Merck & Co Inc, Safety Assessment & Lab Anim Resources, West Point, PA USA. [Chapin, Robert E.] Pfizer Inc, Dev & Reprod Toxicol Ctr, Groton, CT 06340 USA. [Jacobs, Abigail C.] US FDA, Pharmacol Toxicol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Brannen, KC (reprint author), Merck & Co Inc, MRL, West Point, PA 19486 USA. EM kimberly.brannen@merck.com NR 101 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1084-2020 EI 1930-6180 J9 ILAR J JI ILAR J. PY 2016 VL 57 IS 2 BP 144 EP 156 DI 10.1093/ilar/ilw026 PG 13 WC Veterinary Sciences SC Veterinary Sciences GA EJ3HI UT WOS:000393102800005 PM 28053068 ER PT J AU Sistare, FD Mattes, WB LeCluyse, EL AF Sistare, Frank D. Mattes, William B. LeCluyse, Edward L. TI The Promise of New Technologies to Reduce, Refine, or Replace Animal Use while Reducing Risks of Drug Induced Liver Injury in Pharmaceutical Development SO ILAR JOURNAL LA English DT Review DE drug induced liver injury; hepatocyte; in vitro; predictive toxicology; liver biomarkers; high-content screening; computational model ID SALT EXPORT PUMP; PLURIPOTENT STEM-CELLS; ACETAMINOPHEN-INDUCED HEPATOTOXICITY; PRIMARY HUMAN HEPATOCYTES; PRIMARY RAT HEPATOCYTES; IN-VITRO TOXICITY; MITOCHONDRIAL TOXICITY; MICROPATTERNED COCULTURES; MATHEMATICAL-MODEL; GENE-EXPRESSION AB Drug induced liver injury (DILI) has contributed more to marketed pharmaceutical withdrawals and clinical development failures than any other human organ toxicity. DILI seen in animal studies also frequently leads to the discontinuation of promising drug candidates very early in the pipeline. This manuscript reviews and critically assesses the current regulatory expectations; the current drug development approaches, strategies, and gaps; and the numerous exciting opportunities becoming available to address these gaps through technological advances. Emerging integrated pharmaceutical development strategies, while far from uniform, have generally evolved to currently inform early DILI risk potential using supplemental assays for reactive metabolite formation, mitochondrial toxicity, inhibition of bile salt transport, and cellular imaging endpoints including cytotoxicity. Despite these approaches and robust animal testing, significant gaps in addressing human DILI remain. Increasingly sophisticated in vitro humanized test systems, new animal models, emerging computational models, and novel translational biomarkers are being introduced to improve our ability to more accurately predict DILI. Expectations are high for a future state with more predictive tools and problem solving strategies that will improve pharmaceutical discovery and development in relation to understanding human DILI risk potential and make it less dependent on animal studies for successfully developing safer drug candidates. C1 [Sistare, Frank D.] Merck & Co Inc, Safety Assessment & Lab Anim Resources, West Point, PA USA. [Mattes, William B.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. [LeCluyse, Edward L.] LifeNet Hlth, Res Triangle Pk, NC USA. RP Sistare, FD (reprint author), Merck & Co Inc, WP 45-205,770 Sumneytown Pike, West Point, PA 19486 USA. EM frank.sistare@merck.com NR 198 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1084-2020 EI 1930-6180 J9 ILAR J JI ILAR J. PY 2016 VL 57 IS 2 BP 186 EP 211 DI 10.1093/ilar/ilw025 PG 26 WC Veterinary Sciences SC Veterinary Sciences GA EJ3HI UT WOS:000393102800009 PM 28053072 ER PT J AU Centeno, JA Forcada, EG Bua, PP AF Antonio Centeno, Jose Gimenez Forcada, Elena Pena Bua, Pilar TI Medical Geology: An Emerging Discipline SO REVISTA DE SALUD AMBIENTAL LA Spanish DT Editorial Material C1 [Antonio Centeno, Jose] IMGA, Asociac Int Geol Med, Int Med Geol Assoc, Lausanne, Switzerland. [Antonio Centeno, Jose] US FDA, Comis Geociencias Gest Medioambiental UGS, Conferencias Int MedGeo Delegado USA, Rockville, MD 20857 USA. [Gimenez Forcada, Elena] IGME, Asociac Int Geol Med, Int Med Geol Assoc, IMGA, Madrid, Spain. [Pena Bua, Pilar] Univ Salamanca, Capitulo Espanol Asociac Int Geol Med, Int Med Geol Assoc, IMGA,UPSA, E-37008 Salamanca, Spain. RP Centeno, JA (reprint author), IMGA, Asociac Int Geol Med, Int Med Geol Assoc, Lausanne, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC ESPANOLA SANIDAD AMBIENTAL PI MADRID PA C LONDRES 17, MADRID, 28028, SPAIN SN 1577-9572 EI 1697-2791 J9 REV SALUD AMBIENT JI Rev. Salud Ambient. PY 2016 VL 16 IS 2 BP 164 EP 168 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI2CK UT WOS:000392293900009 ER PT J AU Holland, TL Mikita, S Bloom, D Roberts, J McCall, J Collyar, D Santiago, J Tiernan, R Toerner, J AF Holland, Thomas L. Mikita, Stephen Bloom, Diane Roberts, Jamie McCall, Jonathan Collyar, Deborah Santiago, Jonas Tiernan, Rosemary Toerner, Joseph TI Patient and physician attitudes regarding risk and benefit in streamlined development programmes for antibacterial drugs: a qualitative analysis SO BMJ OPEN LA English DT Article ID CHALLENGES; FUTURE AB Objectives: To explore patient, caregiver and physician perceptions and attitudes regarding the balance of benefit and risk in using antibacterial drugs developed through streamlined development processes. Design: Semistructured focus groups and in-depth interviews were conducted to elicit perceptions and attitudes about the use of antibacterial drugs to treat multidrug-resistant infections. Participants were given background information about antibiotic resistance, streamlined drug development programmes and FDA drug approval processes. Audio recordings of focus groups/interviews were reviewed and quotes excerpted and categorised to identify key themes. Participants: Two primary stakeholder groups were engaged: one comprising caregivers, healthy persons and patients who had recovered from or were at risk of resistant infection (N=67; 11 focus groups); and one comprising physicians who treat resistant infections (N=23). Results: Responses from focus groups/interviews indicated widespread awareness among patients/caregivers and physicians of the seriousness of the problem of antibacterial resistance. Both groups were willing to accept a degree of uncertainty regarding the balance of risk and benefit in a new therapy where a serious unmet need exists, but also expressed a desire for rigorous monitoring and rapid, transparent reporting of safety/effectiveness data. Both groups wanted to ensure that >1 physician had input on whether to treat patients with antibiotics developed through a streamlined process. Some patients/ caregivers unfamiliar with exigencies of critical care suggested a relatively large multidisciplinary team, while physicians believed individual expert consultations would be preferable. Both groups agreed that careful oversight and stewardship of antibacterial drugs are needed to ensure patient safety, preserve efficacy and prevent abuse. Conclusions: Groups comprising patients/caregivers and physicians were aware of serious issues posed by resistant infections and the lack of effective antibacterial drug therapies and shared a consensus that streamlined development programmes represent a necessary response to the resistance crisis, but one that requires enhanced safeguards and risk communication. C1 [Holland, Thomas L.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Holland, Thomas L.; Roberts, Jamie; McCall, Jonathan] Duke Clin Res Inst, Durham, NC 27705 USA. [Mikita, Stephen; Collyar, Deborah] Patient Advocates Res, Danville, CA USA. [Bloom, Diane] InFocus Res, Chapel Hill, NC USA. [Santiago, Jonas; Tiernan, Rosemary; Toerner, Joseph] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Holland, TL (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA.; Holland, TL (reprint author), Duke Clin Res Inst, Durham, NC 27705 USA. EM thomas.holland@duke.edu FU US Food and Drug Administration [R18FD005292, U19FD003800]; Clinical Trials Transformation Initiative's member organisations FX This work was made possible in part by the US Food and Drug Administration through grant R18FD005292 and cooperative agreement U19FD003800. Partial funding was also provided by pooled membership fees from the Clinical Trials Transformation Initiative's member organisations. NR 20 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-6055 J9 BMJ OPEN JI BMJ Open PY 2016 VL 6 IS 11 AR e013561 DI 10.1136/bmjopen-2016-013561 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EG8JQ UT WOS:000391303400081 PM 28186948 ER PT J AU Mahmood, I AF Mahmood, Iftekhar TI Prediction of Plasma Concentration-time Profiles of Drugs in Humans from Animals Following Oral Administration: An Allometric Approach SO CURRENT DRUG METABOLISM LA English DT Article DE Absorption; allometry; clearance; concentration-time; oral drugs; pharmacokinetics ID HUMAN PHARMACOKINETICS; DOSE PHARMACOKINETICS; HEALTHY-VOLUNTEERS; PRECLINICAL DATA; SCALE-UP; METABOLISM; CLEARANCE; VENLAFAXINE; EXCRETION; LEVOVIRIN AB Background: Allometric scaling is regularly used for the prediction of human pharmacokinetic (PK) parameters from animal PK studies. The predicted human PK parameters can also be used for the prediction of plasma concentration-time profiles in humans. Objectives: The main objective of this work is to predict human concentration-time profiles of drugs (one-compartment model) following oral administration using animal oral pharmacokinetic parameters. Methods: Six drugs from the literature were chosen that were described by one-compartment model in both humans and animals following oral administration. Pharmacokinetic parameters such as oral clearance, oral volume of distribution of the central compartment, time to reach maximum plasma concentration, absorption rate constant, and half-life in humans were predicted from animals using allometric scaling. These predicted human pharmacokinetic parameters were then used to predict human plasma concentrations-time profiles of drugs. Results: The results of this study indicate that the proposed method can be used to predict human plasma concentrations-time profiles of drugs with reasonable accuracy (<= 50% prediction error). Conclusions: Given the complexity in the pharmacokinetics of oral drugs there remains some uncertainty in this entire exercise. One can minimize the prediction error by experience in allometric scaling, scientific judgment, and unconventional or innovative thinking. C1 [Mahmood, Iftekhar] 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 har.mahmood@fda.hhs.gov NR 36 TC 0 Z9 0 U1 1 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2002 EI 1875-5453 J9 CURR DRUG METAB JI Curr. Drug Metab. PY 2016 VL 17 IS 10 BP 1006 EP 1013 DI 10.2174/13892002186661611211202 PG 8 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA EH9HV UT WOS:000392083300007 PM 27903219 ER PT J AU Holland, T Mikita, S Corneli, A Roberts, J McCall, J Collyar, D Santiago, J Tiernan, R AF Holland, T. Mikita, S. Corneli, A. Roberts, J. McCall, J. Collyar, D. Santiago, J. Tiernan, R. TI Streamlining Antibacterial Drug Development Programs To Address Unmet Medical Need: Patient And Provider Attitudes On A Modified Benefit-Risk Calculus SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 13-18, 2016 CL San Francisco, CA SP Amer Thorac Soc C1 [Holland, T.] Duke Univ, Sch Med, Durham, NC USA. [Mikita, S.; Collyar, D.] Clin Trials Transformat Initiat, Durham, NC USA. [Corneli, A.; McCall, J.] Duke Clin Res Inst, Durham, NC USA. [Roberts, J.] Duke Univ, Durham, NC USA. [Santiago, J.; Tiernan, R.] US FDA, Silver Spring, MD USA. EM jamie.roberts@duke.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2016 VL 193 MA A2112 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EG0VE UT WOS:000390749601252 ER PT J AU Pilon, AL Winn, ME Clayton, RS Hariprakasha, H AF Pilon, A. L. Winn, M. E. Clayton, R. S. Hariprakasha, H. TI Modification Of Cc10 Protein By Reactive Oxygen Species: A Novel Anti-Inflammatory Mechanism SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 13-18, 2016 CL San Francisco, CA SP Amer Thorac Soc C1 [Pilon, A. L.; Winn, M. E.; Clayton, R. S.] Therabron Therapeut Inc, Rockville, MD USA. [Hariprakasha, H.] US FDA, Silver Spring, MD USA. EM aprile.pilon@therabron.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2016 VL 193 MA A5907 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EG0VE UT WOS:000390749605568 ER PT J AU Irony, T Ho, M Christopher, S Levitan, B AF Irony, Telba Ho, Martin Christopher, Stephanie Levitan, Bennett TI Incorporating Patient Preferences into Medical Device Benefit-Risk Assessments SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Benefit-risk tradeoff; Food and Drug Administration (FDA); Minimum clinically meaningful benefit (MCMB); Patient-centered regulatory decision-making; Patient-preference elicitation; Preference-sensitive decision AB Patients play a unique role in medical device evaluation because they live with their conditions and consequences of the treatments they choose. They may weigh the benefits, risks, and other attributes of treatments differently than physicians and regulators. They may even be heterogenous among themselves when trading-off benefits and risks. Therefore, industry, regulators, and patient groups have a growing interest in exploring how to assess and incorporate patient preferences when conducting benefit-risk assessments of medical devices. This article discusses remarkable developments in this area: a proof-of-concept study on preferences of obese patients conducted by the Center for Devices and Radiological Health at the FDA (CDRH), the guidance documents on factors for benefit-risk determinations and on patient preference information issued recently by CDRH, and the Patient-Centered Benefit-Risk project developed by the Medical Device Innovation Consortium. We will also discuss important concepts related to patient preferences and use the CDRH study results to illustrate them. C1 [Irony, Telba] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Ho, Martin] US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Christopher, Stephanie] Med Device Innovat Consortium, Minneapolis, MN USA. [Levitan, Bennett] Janssen Res & Dev, Dept Epidemiol, Titusville, NJ USA. RP Irony, T (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Telba.irony@fda.hhs.gov FU Broad Agency Agreement from the U.S. Food and Drug Administration [BAA HHSF223201400011C] FX Funding for the MDIC Framework and Catalog came from a Broad Agency Agreement from the U.S. Food and Drug Administration (BAA HHSF223201400011C "Patient Centeredness: Integrating Patient Preference into Regulatory Submission.") NR 12 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2016 VL 8 IS 3 BP 230 EP 236 DI 10.1080/19466315.2015.1135820 PG 7 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EF5XM UT WOS:000390403100002 ER PT J AU Li, H Mukhi, V Lu, N Xu, YL Yue, LQ AF Li, Heng Mukhi, Vandana Lu, Nelson Xu, Yun-Ling Yue, Lilly Q. TI A Note on Good Practice of Objective Propensity Score Design for Premarket Nonrandomized Medical Device Studies with an Example SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Balance assessment; Regulatory submission; Stratification ID BIAS; SUBCLASSIFICATION AB In this short note, we highlight some key elements of the process of submitting an investigational device exemption of a nonrandomized clinical study that involves the use of propensity score methodology. Focus is given to the assessment of balance for propensity score stratification. C1 [Li, Heng; Mukhi, Vandana; Lu, Nelson; Xu, Yun-Ling; Yue, Lilly Q.] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Av,WO 66, Silver Spring, MD 20993 USA. RP Mukhi, V (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Av,WO 66, Silver Spring, MD 20993 USA. EM vandana.mukhi@fda.hhs.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2016 VL 8 IS 3 BP 282 EP 286 DI 10.1080/19466315.2016.1148071 PG 5 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EF5XM UT WOS:000390403100008 ER PT J AU Cui, SQ Zhao, YQ Tiwari, RC AF Cui, Shiqi Zhao, Yueqin Tiwari, Ram C. TI Bayesian Approach to Personalized Benefit-Risk Assessment SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Benefit-risk measures; Dirichlet process; Generalized linear model; Gibbs sampling; Metropolis-Hastings algorithm; Model selection ID GIBBS SAMPLING APPROACH; REGRESSION-MODELS; POSTERIOR SIMULATION; QUANTITATIVE METHODS; CLINICAL-TRIALS; DISTRIBUTIONS; INFERENCE; MIXTURES; PRODUCTS; PROPOSAL AB Benefit-risk assessment is criticalin evaluating the effectiveness of a new drug before and after the approval Some benefit-risk measures depend on the probabilities of benefit-risk categories in which the subject-level benefit and risk outcomes are characterized. The existing benefit-risk methods for analyzing the categorical data depend only on the frequencies of mutually exclusive and collectively exhaustive categories that the subjects fall in, and thus ignore the subject-level differences. We propose a Bayesian method for analyzing he subject-level data with multiple visits. A generalized linear model is used to model the subject-level esporise probability, with respect to a "reference' category, assuming a loft model with subject-level category effects arid multiple visit effects. The random longitudinal visit effects are modeled by a multivariate normal distribution with zero means and first-order autoregressive structured variance-covariance matt' ces. In the proposed Bayesian setup, a Dirichlet process is used as a prior for the subject-level category effect to catch the similarity among the subject responses. We develoP r an efficient Ma kov chain Monte C lo algorithm for implementing the proposed method, and illustrate the estimation of individual benefit risk profiles through simulation. The performance of the proposed model fit is evaluated using two mode election approaches, namely, the deviance information criterion;{DIG) arid the log-pseudo marginal like hood (LPML). We analyze a clinical trial data using the proposed method to assess the subject-level or personalized benefit-risk in each arm, and to evaluate the aggregated benefit-risk difference between the treatments at different visits. C1 [Cui, Shiqi] Univ Missouri, Dept Stat, Columbia, MO 65211 USA. [Zhao, Yueqin; Tiwari, Ram C.] US FDA, Off Biostat, Silver Spring, MD 20993 USA. RP Zhao, YQ (reprint author), US FDA, Div Biometr 7, Off Biostat, OTS,CDER, Silver Spring, MD 20993 USA. EM Yueqin.Zhao@fda.hhs.gov NR 39 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2016 VL 8 IS 3 BP 316 EP 324 DI 10.1080/19466315.2016.1193045 PG 9 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EF5XM UT WOS:000390403100012 ER PT J AU Sun, WJ Zhou, LJ Grosser, S Kim, C AF Sun, Wanjie Zhou, Lingjie Grosser, Stella Kim, Carol TI A Meta-Analysis of Missing Data and Non-Compliance Data in Clinical Endpoint Bioequivalence Studies SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Bioequivalence; Meta-analysis; Missing data; Non-compliance data ID TRIALS AB Missing data and noncompliance data questions are especially important in evaluating locally acting generic drugs because primary equivalence analyses in clinical endpoint bioequivalence (BE) studies are based on the per-protocol (PP) population (generally, completers and compliers). A meta-analysis using six clinical endpoint BE studies for topical drugs reveals the following: (1) An average of 22% (95% CI: 15-29%) of randomized subjects are excluded from the PP population. (2) Of these excluded subjects, half (10.6%, 95% CI: 8.3-12.8%) dropped out. Most who dropped out (6.9%, 95% CI: 5.0-8.8%) did not specify reasons. (3) Noncompliance categories include out-of-window visits (7.7%, 95% CI: 5.5%-9.8%), dosing noncompliance (<75% or >125% of dose) (5%, 95% CI: 2.7%-7.4%), and restricted medication use (3.2%, 95% CI: 1.8%-4.7%). (4) Drop out and noncompliance are not completely at random: a better treatment effect is associated with less drop out and less noncompliance. (5) Drop out and noncompliance are correlated: noncompliers are more likely to drop out, and vice versa. These results will help regulators better understand the extent and pattern of drop out and noncompliance and shed light on designing appropriate analysis population, endpoints, estimands, and investigating primary and sensitivity methods for equivalence in clinical endpoint BE studies in presence of missing and noncompliance data. C1 [Sun, Wanjie; Grosser, Stella] US FDA, CDER, Off Biostat, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Zhou, Lingjie] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Kim, Carol] US FDA, CDER, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Sun, WJ (reprint author), US FDA, CDER, Off Biostat, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM wanjie.sun@fda.hhs.gov FU FDA CDLR Regulatory Science and Review (RSR) grant FX Supported by a FDA CDLR Regulatory Science and Review (RSR) grant. NR 18 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2016 VL 8 IS 3 BP 334 EP 344 DI 10.1080/19466315.2016.1201000 PG 11 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EF5XM UT WOS:000390403100014 ER PT J AU Li, MJ AF Li, Meijuan TI Statistical Methods for Clinical Validation of Follow-On Companion Diagnostic Devices via an External Concordance Study SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Comparator companion diagnostic device; Devices intended use population; Device-drug clinical trial; Drug efficacy; Follow-on companion diagnostic device; Personalized medicine ID PERSONALIZED MEDICINE; PREDICTIVE VALUES; DESIGNS; TESTS AB To date there are a number of FDA-approved companion diagnostics for use with specific corresponding therapeutic products. Hence, opportunities exist for device manufacturers to develop follow-on companion diagnostic devices. A follow-on companion diagnostic is intended to be used with the therapeutic product in the indicated patient population, as in the labeling of the comparator companion diagnostic. Thus, information provided by a follow-on companion diagnostic device is essential for the safe and effective use of the corresponding therapeutic product in the comparator companion diagnostic. However, the manufacturer of a follow-on companion diagnostic device may not have a therapeutic partner to conduct a new clinical trial, or there may lack the patient samples from the original clinical trial, where the comparator and therapeutic product were evaluated. As such, an external concordance study is conducted to assess the concordance between the comparator and the follow-on device. Difficulty and challenges arise on how to evaluate the follow-on devices clinical performance based the agreements from an external concordance study. In this article, we will discuss the challenges and issues for the clinical validation of follow-on devices and we aim to provide some statistical methods on how to support clinical validation of follow-on companion diagnostic devices for its proposed indications for use via an external concordance study. C1 [Li, Meijuan] US FDA, Div Biostat, 10903 New Hampshire Ave, 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 9 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2016 VL 8 IS 3 BP 355 EP 363 DI 10.1080/19466315.2016.1202859 PG 9 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EF5XM UT WOS:000390403100016 ER PT J AU Wang, YP Mai, YB He, WL AF Wang, Yaping Mai, Yabing He, Weili TI A Quantitative Approach for Benefit-Risk Assessment Using Stochastic Multi-Criteria Discriminatory Method SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Decision making; Partial information; Pharmaceutical ID ACCEPTABILITY ANALYSIS AB Benefit-risk (BR) assessment is important to ensure safety and effectiveness of medical projects in clinical development and post marketing surveillance. The evaluation of the balance between benefits and risks of a drug is fundamental to all stakeholders involved in the development, registration, and use of drugs. Many quantitative approaches have been developed that may draw together data from different sources to present them in ways that can aid decision-making. Among these quantitative approaches, multicriteria decision analysis (MCDA) is one of the most useful approaches, since it provides a framework for systematic and replicable analyses of complex decision problems involving value tradeoffs. In most real-life situations, decision makers are not able to get exact preference information (weights). To overcome this limitation of MCDA, a method called stochastic multicriteria acceptability analysis (SMAA) was proposed as a quantitative approach to BR assessment in drug development. The chief advantage of SMAA over most other MCDA methodologies is that it can be used with limited or no preference information and a data-driven approach can be used to obtain the inherent weighting among multicriteria. In this article, we propose the stochastic multicriteria discriminatory method (SMDM) that is based on the SMAA method with a focus on providing straightforward and informative assistance to decision making. We use SMDM to derive probability of better treatment, probability of significantly better treatment and the expected p-values of the evaluation results, on the basis of limited partial weight information or no weight information at all. C1 [Wang, Yaping] US FDA, Div Biometr 5, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Mai, Yabing; He, Weili] Merck Res Labs, Rahway, NJ USA. RP Wang, YP (reprint author), US FDA, Div Biometr 5, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Yaping.Wang@fda.hhs.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2016 VL 8 IS 4 BP 373 EP 378 DI 10.1080/19466315.2016.1202135 PG 6 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EF5XN UT WOS:000390403300003 ER PT J AU Ma, HJ Jiang, Q Chuang-Stein, C Evans, SR He, WL Quartey, G Scott, J Wen, SH Arani, R AF Ma, Haijun Jiang, Qi Chuang-Stein, Christy Evans, Scott R. He, Weili Quartey, George Scott, John Wen, Shihua Arani, Ramin TI Considerations on Endpoint Selection, Weighting Determination, and Uncertainty Evaluation in the Benefit-Risk Assessment of Medical Product SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Benefit-risk assessment; Benefit-risk endpoint selection; Uncertainty; Weighting ID MULTICRITERIA DECISION-ANALYSIS; CLINICAL-TRIALS; STATISTICAL CONSIDERATIONS; TASK-FORCE; DISCRETE; METHODOLOGIES; PREFERENCES; REGRESSION; MEDICINES; FRAMEWORK AB A structured benefit-risk assessment (BRA) is critical for drug development and lifecycle management. How to select B-R endpoints, determine weighting for these endpoints, and evaluate uncertainties are key aspects of the B-R decision-making process. In this article, we discuss key considerations on endpoint selection, challenges of double counting and correlated endpoints, and methods that can be used to address these challenges. In addition, we discuss the use of qualitative and quantitative weighting in BRA, techniques useful for weight construction, and weights based on empirical preferences. Potential sources for uncertainties in BRA, the approaches to illustrate and to address these uncertainties are described. Finally, we emphasize that benefit-risk assessment is a continuous process and requires cross-functional efforts. C1 [Ma, Haijun; Jiang, Qi] Amgen Inc, Global Biostat & Epidemiol, Thousand Oaks, CA 91320 USA. [Chuang-Stein, Christy] Chuang Stein Consulting, Kalamazoo, MI USA. [Evans, Scott R.] Harvard Sch Publ Hlth, Biostat, Boston, MA USA. [He, Weili] Merck & Co Inc, Kenilworth, NJ USA. [Quartey, George] Genentech Inc, 460 Point San Bruno Blvd, San Francisco, CA 94080 USA. [Scott, John] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Wen, Shihua] Novartis Pharmaceut, E Hanover, NJ USA. [Arani, Ramin] AstraZeneca Pharmaceut LP, Gaithersburg, MD USA. RP Ma, HJ (reprint author), Amgen Inc, Global Biostat & Epidemiol, Thousand Oaks, CA 91320 USA. EM hma@amgen.com NR 42 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2016 VL 8 IS 4 BP 417 EP 425 DI 10.1080/19466315.2016.1234974 PG 9 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EF5XN UT WOS:000390403300009 ER PT J AU Scott, J AF Scott, John TI Comment: Statisticians Staying Involved in Benefit-Risk Assessment SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Editorial Material C1 [Scott, John] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Scott, J (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PY 2016 VL 8 IS 4 BP 426 EP 427 DI 10.1080/19466315.2016.1213658 PG 2 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EF5XN UT WOS:000390403300010 ER PT J AU Lee, CT Boeshore, KL Wu, C Becker, KG Errico, SL Mash, DC Freed, WJ AF Lee, Chun-Ting Boeshore, Kristen L. Wu, Chun Becker, Kevin G. Errico, Stacie L. Mash, Deborah C. Freed, William J. TI Cocaine promotes primary human astrocyte proliferation via JNK-dependent up-regulation of cyclin A2 SO RESTORATIVE NEUROLOGY AND NEUROSCIENCE LA English DT Article DE Astrocytes; cocaine; reactive astrogliosis; addiction; JNK; cyclin A ID CELL-PROLIFERATION; NUCLEUS-ACCUMBENS; STRUCTURAL PLASTICITY; SIGNALING PATHWAYS; DENDRITIC SPINES; REACTIVE GLIOSIS; GENE ONTOLOGY; IN-VIVO; EXPRESSION; ACTIVATION AB Purpose: Astrocytes perform a plethora of important functions in the central nervous system (CNS) and are involved in cocaine-evoked synaptic plasticity. Previously, we showed that while cocaine decreased cyclin A2 expression in primary human neural progenitor cells, it increased cyclin A2 expression in human astrocytes. Since cyclin A2 is an essential regulator of the cell cycle, the aim of the present study is to clarify the effect of cocaine on proliferation of human astrocytes and elucidate the underlying molecular mechanisms. Methods: Primary human astrocytes were treated with either 1, 10, or 100 mu M cocaine for 48 hr, and cell proliferation was measured using the CyQUANT cell proliferation assay. To elucidate the molecular mechanisms through which cocaine affects the proliferation of astrocytes, we analyzed gene expression profiles in cocaine-treated primary human astrocytes using a human focused cDNA array. Gene ontology/pathway enrichment analysis, STRING protein-protein interaction analysis, RT-qPCR, and western blotting were used to identify signal transduction pathways that are involved in cocaine-induced astrocyte dysfunction. Results: Cocaine at 10 and 100 mu M significantly increased human astrocyte proliferation. Gene expression profiling revealed the JNK MAP kinase pathway as a driver of cell proliferation affected by cocaine in human astrocytes. Further experiments showed that cocaine-induced JNK activation induced up-regulation of cyclin A2, leading to enhanced proliferation of human astrocytes. Conclusion: Cocaine-induced abnormal increases in the number of astrocytes may cause disruption in neuron-glia signaling and contribute to synaptic impairment in the CNS. Understanding the mechanisms of cocaine's effects on human astrocytes may help to reveal the involvement of glial cells in addictive behaviors. C1 [Lee, Chun-Ting; Errico, Stacie L.; Freed, William J.] NIDA, Sect Dev & Plast, Cellular Neurobiol Res Branch, Intramural Res Program,NIH, Baltimore, MD USA. [Lee, Chun-Ting; Mash, Deborah C.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Boeshore, Kristen L.; Freed, William J.] Lebanon Valley Coll, Dept Biol, Annville, PA USA. [Wu, Chun; Mash, Deborah C.] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA. [Becker, Kevin G.] NIA, Gene Express & Genom Unit, Res Resources Branch, IRP,NIH, Baltimore, MD 21224 USA. RP Lee, CT (reprint author), US FDA, Ctr Biol Evaluat & Res, Bldg 52,Rm 1121,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Chun-Ting.Lee@fda.hhs.gov FU Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Aging FX This work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Aging. NR 77 TC 0 Z9 0 U1 3 U2 3 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0922-6028 EI 1878-3627 J9 RESTOR NEUROL NEUROS JI Restor. Neurol. Neurosci. PY 2016 VL 34 IS 6 BP 965 EP 976 DI 10.3233/RNN-160676 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EE0DG UT WOS:000389243100008 PM 27834787 ER PT S AU Kalaa, MO Butron, G Balid, W Refai, HH LaSorte, NJ AF Al Kalaa, Mohamad Omar Butron, Gregory Balid, Walid Refai, Hazem H. LaSorte, Nickolas J. GP IEEE TI Long Term Spectrum Survey of the 2.4 GHz ISM Band in Multiple Hospital Environments SO 2016 IEEE WIRELESS COMMUNICATIONS AND NETWORKING CONFERENCE SE IEEE Wireless Communications and Networking Conference LA English DT Proceedings Paper CT IEEE Wireless Communications and Networking Conference (WCNC) CY APR 03-07, 2016 CL Doha, QATAR SP IEEE, IEEE Commun Soc AB Wireless technology has become an invaluable facilitator in many aspects of daily life. Healthcare environments in particular have gained noticeable agility and flexibility by integrating wireless functionality into various medical equipment. As of late, chipsets designed to implement communication standards in the Industrial, Scientific and Medical (ISM) band have become inexpensive and widely available, making wireless-enabled medical devices reach increased number of users. However, the sharp increase in the number of operating nodes now occupying the ISM band has resulted in a cluttered spectrum with limited resources in many environments. In this paper, we report on a long term spectrum survey of the ISM band in both an intensive care unit (ICU) and a post-surgery recovery room (RR). Both spaces were concurrently surveyed for 28 consecutive days capturing spectrum occupancy on every weekday four times. Results indicate that spectrum occupancy patterns are location dependent. Examined sub-channels with significant correlation in activity pattern corresponded mainly to IEEE 802.11 channels 1, 6, and 11. Low daily duty cycle is indicated at a maximum of 5.17% at RR and 3.11% at ICU. C1 [Al Kalaa, Mohamad Omar; Butron, Gregory; Balid, Walid; Refai, Hazem H.] Univ Oklahoma, Dept Elect & Comp Engn, Norman, OK 73019 USA. [LaSorte, Nickolas J.] US FDA, Rockville, MD 20857 USA. RP Kalaa, MO (reprint author), Univ Oklahoma, Dept Elect & Comp Engn, Norman, OK 73019 USA. EM omarqal@ou.edu; gregorybutron@ou.edu; walid@ou.edu; hazem@ou.edu; Nickolas.Lasorte@fda.hhs.gov NR 26 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1525-3511 BN 978-1-4673-9814-5 J9 IEEE WCNC PY 2016 PG 6 WC Telecommunications SC Telecommunications GA BG4CR UT WOS:000388603100042 ER PT J AU Theunissen, PT Beken, S Beyer, BK Breslin, WJ Cappon, GD Chen, CL Chmielewski, G De Schaepdrijver, L Enright, B Foreman, JE Harrouk, W Hew, KW Hoberman, AM Hui, JY Knudsen, TB Laffan, SB Makris, SL Martin, M McNerney, ME Siezen, CL Stanislaus, DJ Stewart, J Thompson, KE Tornesi, B Van der Laan, JW Weinbauer, GF Wood, S Piersma, AH AF Theunissen, Peter T. Beken, Sonja Beyer, Bruce K. Breslin, William J. Cappon, Gregg D. Chen, Connie L. Chmielewski, Gary De Schaepdrijver, Luc Enright, Brian Foreman, Jennifer E. Harrouk, Wafa Hew, Kok-Wah Hoberman, Alan M. Hui, Julia Y. Knudsen, Thomas B. Laffan, Susan B. Makris, Susan L. Martin, Matt McNerney, Mary Ellen Siezen, Christine L. Stanislaus, Dinesh J. Stewart, Jane Thompson, Kary E. Tornesi, Belen Van der Laan, Jan Willem Weinbauer, Gerhard F. Wood, Sandra Piersma, Aldert H. TI Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE Pharmaceutical testing; embryo-fetal developmental toxicity; cross-species evaluation; non-clinical ID IN-VITRO; THALIDOMIDE; ABNORMALITIES; ANIMALS AB Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo-fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone. C1 [Theunissen, Peter T.; Van der Laan, Jan Willem; Piersma, Aldert H.] Natl Inst Publ Hlth & Environm RIVM, Ctr Hlth Protect, Bilthoven, Netherlands. [Theunissen, Peter T.; Siezen, Christine L.; Van der Laan, Jan Willem] Med Evaluat Board, Graadt van Roggenweg 500, NL-3531 AH Utrecht, Netherlands. [Theunissen, Peter T.] Univ Appl Sci Utrecht HU, Innovat Testing Life Sci & Chem, Utrecht, Netherlands. [Beken, Sonja] Fed Agcy Med & Hlth Prod, Brussels, Belgium. [Beyer, Bruce K.] Sanofi US Inc, Bridgewater, NJ USA. [Breslin, William J.] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN USA. [Cappon, Gregg D.] Pfizer Worldwide Res & Dev, Groton, CT USA. [Chen, Connie L.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. [Chmielewski, Gary] Covance Labs Inc, Greenfield, IN USA. [De Schaepdrijver, Luc] Janssen R&D, Preclin Dev & Safety Beerse, Beerse, Belgium. [Enright, Brian; Tornesi, Belen] AbbVie Inc, N Chicago, IL USA. [Foreman, Jennifer E.] ExxonMobil Biomed Sci Inc, Annandale, NJ USA. [Harrouk, Wafa] US FDA, Silver Spring, MD USA. [Hew, Kok-Wah] Takeda Pharmaceut Co, Deerfield, IL USA. [Hoberman, Alan M.] Charles River Labs, Preclin Serv, Horsham, PA USA. [Hui, Julia Y.] Celgene Corp, Summit, NJ USA. [Knudsen, Thomas B.; Martin, Matt] US EPA, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA. [Laffan, Susan B.; Stanislaus, Dinesh J.] GlaxoSmithKline, Safety Assessment, King Of Prussia, PA USA. [Makris, Susan L.] US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [McNerney, Mary Ellen; Thompson, Kary E.] Bristol Myers Squibb, Drug Safety Evaluat, New Brunswick, NJ USA. [Stewart, Jane] AstraZeneca, Drug Safety & Metab, Macclesfield, Cheshire, England. [Weinbauer, Gerhard F.] Covance Preclin Serv GmbH, Munster, Germany. [Wood, Sandra] Merck Res Labs, Upper Gwynedd, PA USA. [Piersma, Aldert H.] Univ Utrecht, Inst Risk Assessment Sci, Fac Vet Sci, Utrecht, Netherlands. RP Theunissen, PT (reprint author), Med Evaluat Board, Graadt van Roggenweg 500, NL-3531 AH Utrecht, Netherlands. EM P.Theunissen@cbg-meb.nl FU SLIM project; Dutch Government, Dept. Econimical Affairs; Utrecht Province; Utrecht City Administration [PID101063] FX SLIM project, by the Dutch Government, Dept. Econimical Affairs; The Utrecht Province and The Utrecht City Administration [PID101063]. ILSI HESI, 10.13039/100008663 NR 22 TC 0 Z9 0 U1 5 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PY 2016 VL 46 IS 10 BP 900 EP 910 DI 10.1080/10408444.2016.1224807 PG 11 WC Toxicology SC Toxicology GA ED3CF UT WOS:000388726200004 PM 27848393 ER PT J AU Blumenthal, GM Mansfield, E Pazdur, R AF Blumenthal, Gideon M. Mansfield, Elizabeth Pazdur, Richard TI Next-Generation Sequencing in Oncology in the Era of Precision Medicine SO JAMA ONCOLOGY LA English DT Editorial Material ID FDA C1 [Blumenthal, Gideon M.; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. [Mansfield, Elizabeth] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Blumenthal, GM (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM gideon.blumenthal@fda.hhs.gov NR 6 TC 7 Z9 7 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JAN PY 2016 VL 2 IS 1 BP 13 EP 14 DI 10.1001/jamaoncol.2015.4503 PG 2 WC Oncology SC Oncology GA DW5JE UT WOS:000383679300002 PM 26540172 ER PT J AU Kazandjian, D Khozin, S Blumenthal, G Zhang, LJ Tang, SH Libeg, M Kluetz, P Sridhara, R Keegan, P Pazdur, R AF Kazandjian, Dickran Khozin, Sean Blumenthal, Gideon Zhang, Lijun Tang, Shenghui Libeg, Meredith Kluetz, Paul Sridhara, Rajeshwari Keegan, Patricia Pazdur, Richard TI Benefit-Risk Summary of Nivolumab for Patients With Metastatic Squamous Cell Lung Cancer After Platinum-Based Chemotherapy A Report From the US Food and Drug Administration SO JAMA ONCOLOGY LA English DT Article ID TRIAL; GUIDELINE; MUTATIONS; THERAPIES; DOCETAXEL; ERLOTINIB; ALK AB IMPORTANCE Metastatic squamous non-small-cell lung cancer (SQ NSCLC) is a serious and life-threatening malignant condition with unmet medical need. In late December 2014, the US Food and Drug Administration (FDA) obtained the data monitoring committee report of a planned interim analysis of a trial in second-line SQ NSCLC (CM017) that demonstrated an overall survival benefit for patients treated with nivolumab compared with docetaxel. OBSERVATIONS In that trial, 272 patients with metastatic SQ NSCLC patients had been randomized to receive nivolumab (n = 135) or docetaxel (n = 137). Median overall survival was 9.2 months for patients randomized to nivolumab and 6.0 months for those randomized to docetaxel (hazard ratio, 0.59; 95% CI, 0.44-0.79; P <.001). The safety of nivolumab was evaluated in a single-arm trial of 117 patients in previously treated metastatic SQ NSCLC and was consistent with the safety profile in melanoma, with rare but serious immune-mediated adverse events managed with corticosteroids and dose interruption. CONCLUSIONS AND RELEVANCE The FDA granted nivolumab traditional approval on March 4, 2015, for treatment of metastatic SQ NSCLC with progression during or after platinum-based chemotherapy. The approval provides an important treatment option for these patients, affecting routine care and clinical trials. C1 [Kazandjian, Dickran; Khozin, Sean; Blumenthal, Gideon; Libeg, Meredith; Kluetz, Paul; Keegan, Patricia; Pazdur, Richard] USDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zhang, Lijun; Tang, Shenghui; Sridhara, Rajeshwari] USDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Kazandjian, D (reprint author), USDA, Off Hematol Oncol Prod, 10903 New Hampshire Ave NE,WO22 2320, Silver Spring, MD 20993 USA. EM Dickran.kazandjian@fda.hhs.gov NR 21 TC 9 Z9 10 U1 2 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JAN PY 2016 VL 2 IS 1 BP 118 EP 122 DI 10.1001/jamaoncol.2015.3934 PG 5 WC Oncology SC Oncology GA DW5JE UT WOS:000383679300024 PM 26470053 ER PT J AU Liu, AY Yue, LQ AF Liu, Aiyi Yue, Lilly Q. TI A conversation with Dr. Greg Campbell SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Editorial Material C1 [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Yue, Lilly Q.] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire, Silver Spring, MD 20993 USA. RP Yue, LQ (reprint author), US FDA, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire, Silver Spring, MD 20993 USA. EM lilly.yue@fda.hhs.gov OI Liu, Aiyi/0000-0002-6618-5082 NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2016 VL 26 IS 6 SI SI BP 1007 EP 1019 DI 10.1080/10543406.2016.1226331 PG 13 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA ED1HS UT WOS:000388596600001 PM 27548092 ER PT J AU Gamalo-Siebers, M Tiwari, R LaVange, L AF Gamalo-Siebers, Margaret Tiwari, Ram LaVange, Lisa TI Flexible shrinkage estimation of subgroup effects through Dirichlet process priors SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Dirichlet process prior; exchangeability; heterogeneity; model selection; shrinkage; subgroups ID CLINICAL-TRIAL DESIGNS; NONPARAMETRIC PROBLEMS; BAYESIAN-ANALYSIS; MODEL; DISTRIBUTIONS AB The paradigm shift towards precision medicine reignited interest in determining whether there are differential treatment effects in subgroups of trial participants. Intrinsic to this problem is that any assessment of a differential treatment effect is predicated on being able to estimate the treatment response accurately while satisfying constraints of balancing the risk of overlooking an important subgroup with the potential to make a decision based on a false discovery. While shrinkage models have been widely used to improve accuracy of subgroup parameter estimates by leveraging the relationship between them, there is still a possibility that it can lead to excessively conservative or anti-conservative results. This can possibly be due to the use of the normal distribution as prior, which forces outlying subjects to have their means over-shrunk towards the population mean, and the data from such subjects may be excessively influential in estimation of both the overall mean response and the mean response for each subgroup, or a model misspecification due to unaccounted variation or clustering. To address this issue, we investigate the use of nonparametric Bayes, particularly Dirichlet process priors, to create a flexible shrinkage model. This model represents uncertainty in the prior distribution for the overall response while accommodating heterogeneity among individual subgroups. We simulated data to compare estimates when there is no differential subgroup effect and when there is a differential subgroup effect. In either of these scenarios, the flexible shrinkage model does not force estimates to shrink excessively when similarity of treatment effects is not supported but still retains the attractiveness of improved precision given by the narrower credible intervals. We also applied the same method to a dataset based on trials conducted for an antimicrobial therapy on several related indications. C1 [Gamalo-Siebers, Margaret] Eli Lilly & Co, 893 S Delaware St, Indianapolis, IN 46285 USA. [Tiwari, Ram; LaVange, Lisa] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. RP Gamalo-Siebers, M (reprint author), Eli Lilly & Co, 893 S Delaware St, Indianapolis, IN 46285 USA. EM gamalo_margaret@lilly.com NR 35 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2016 VL 26 IS 6 SI SI BP 1040 EP 1055 DI 10.1080/10543406.2016.1226327 PG 16 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA ED1HS UT WOS:000388596600004 PM 27548701 ER PT J AU Li, JX Chen, WC Scott, JA AF Li, Judy X. Chen, Wei-Chen Scott, John A. TI Addressing prior-data conflict with empirical meta-analytic-predictive priors in clinical studies with historical information SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Bayesian method; historical information; prior-data conflict; safety study ID SEVERE HEMOPHILIA-A; FACTOR-VIII PRODUCTS; EFFECTIVE SAMPLE-SIZE; INHIBITOR DEVELOPMENT; TRIALS; MODELS; RECOMBINANT AB A common question in clinical studies is how to use historical data from earlier studies, leveraging relevant information into the design and analysis of a new study. Bayesian approaches are particularly well-suited to this task, with their natural ability to borrow strength across data sources. In this paper, we propose an eMAP approach for incorporating historical data into the analysis of clinical studies, and we discuss an application of this method to the analysis of observational safety studies for a class of products for patients with hemophilia A. The eMAP prior approach is flexible and robust to prior-data conflict. We conducted simulations to compare the frequentist operating characteristics of three approaches under different prior-data conflict assumptions and sample size scenarios. C1 [Li, Judy X.] OBE, FDA CBER, 10903 New Hampshire Ave,Bldg 71, Silver Spring, MD 20993 USA. [Chen, Wei-Chen] OBE DB, FDA CBER, Silver Spring, MD USA. [Scott, John A.] CBER, FDA, Rockville, MD USA. RP Li, JX (reprint author), OBE, FDA CBER, 10903 New Hampshire Ave,Bldg 71, Silver Spring, MD 20993 USA. EM judy.li@fda.hhs.gov FU FDA Office of Women's Health; U.S. Department of Energy; FDA/CBER FX This work was supported by the FDA Office of Women's Health. This project was supported in part by an appointment to the ORISE Research Participation Program at the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA/CBER. This work used the computational resources of the HPC clusters at the U.S. Food and Drug Administration, Center for Devices and Radiological Health (CDRH). NR 30 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2016 VL 26 IS 6 SI SI BP 1056 EP 1066 DI 10.1080/10543406.2016.1226324 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA ED1HS UT WOS:000388596600005 PM 27541990 ER PT J AU Yu, TH Li, Q Gray, G Yue, LQ AF Yu, Tinghui Li, Qin Gray, Gerry Yue, Lilly Q. TI Statistical innovations in diagnostic device evaluation SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Biomarker; bootstrap; companion diagnostics; missing data; MRMC studies; ROC ID COMPUTER-AIDED DETECTION; CLINICAL-TRIAL DESIGNS; VALIDATION; BIOMARKER; MEDICINE; READERS; FDA AB Due to rapid technological development, innovations in diagnostic devices are proceeding at an extremely fast pace. Accordingly, the needs for adopting innovative statistical methods have emerged in the evaluation of diagnostic devices. Statisticians in the Center for Devices and Radiological Health at the Food and Drug Administration have provided leadership in implementing statistical innovations. The innovations discussed in this article include: the adoption of bootstrap and Jackknife methods, the implementation of appropriate multiple reader multiple case study design, the application of robustness analyses for missing data, and the development of study designs and data analyses for companion diagnostics. C1 [Yu, Tinghui; Li, Qin; Gray, Gerry; Yue, Lilly Q.] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Yue, LQ (reprint author), US FDA, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM lilly.yue@fda.hhs.gov NR 42 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2016 VL 26 IS 6 SI SI BP 1067 EP 1077 DI 10.1080/10543406.2016.1226332 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA ED1HS UT WOS:000388596600006 PM 27541859 ER PT J AU Pennello, G Pantoja-Galicia, N Evans, S AF Pennello, Gene Pantoja-Galicia, Norberto Evans, Scott TI Comparing diagnostic tests on benefit-risk SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Clinical utility; cost; benefit ratio; decision theory; diagnostic yield; relative net benefit; risk threshold; weighted accuracy ID RELATIVE UTILITY CURVES; CLINICAL-TRIAL DESIGNS; PREDICTION; BIOMARKERS; MODELS; MARKER; PHASE AB Comparing diagnostic tests on accuracy alone can be inconclusive. For example, a test may have better sensitivity than another test yet worse specificity. Comparing tests on benefit risk may be more conclusive because clinical consequences of diagnostic error are considered. For benefit-risk evaluation, we propose diagnostic yield, the expected distribution of subjects with true positive, false positive, true negative, and false negative test results in a hypothetical population. We construct a table of diagnostic yield that includes the number of false positive subjects experiencing adverse consequences from unnecessary work-up. We then develop a decision theory for evaluating tests. The theory provides additional interpretation to quantities in the diagnostic yield table. It also indicates that the expected utility of a test relative to a perfect test is a weighted accuracy measure, the average of sensitivity and specificity weighted for prevalence and relative importance of false positive and false negative testing errors, also interpretable as the cost-benefit ratio of treating non-diseased and diseased subjects. We propose plots of diagnostic yield, weighted accuracy, and relative net benefit of tests as functions of prevalence or cost-benefit ratio. Concepts are illustrated with hypothetical screening tests for colorectal cancer with test positive subjects being referred to colonoscopy. C1 [Pennello, Gene; Pantoja-Galicia, Norberto] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Evans, Scott] Harvard T H Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Evans, Scott] Harvard T H Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Pennello, G (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM gene.pennello@fda.hhs.gov FU National Institute of Allergy And Infectious Diseases of the National Institutes of Health [UM1AI104681] FX Research reported in this publication was supported by the National Institute of Allergy And Infectious Diseases of the National Institutes of Health under Award Number UM1AI104681. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 22 TC 1 Z9 1 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2016 VL 26 IS 6 SI SI BP 1083 EP 1097 DI 10.1080/10543406.2016.1226335 PG 15 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA ED1HS UT WOS:000388596600008 PM 27548805 ER PT J AU Zhang, ZW Chu, JX Rahardja, D Zhang, H Tang, L AF Zhang, Zhiwei Chu, Jianxiong Rahardja, Dewi Zhang, Hui Tang, Li TI Responder analysis without dichotomization SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Clinical trial; delta method; efficiency; information bound; missing data; robustness AB In clinical trials, it is common practice to categorize subjects as responders and non-responders on the basis of one or more clinical measurements under pre-specified rules. Such a responder analysis is often criticized for the loss of information in dichotomizing one or more continuous or ordinal variables. It is worth noting that a responder analysis can be performed without dichotomization, because the proportion of responders for each treatment can be derived from a model for the original clinical variables (used to define a responder) and estimated by substituting maximum likelihood estimators of model parameters. This model-based approach can be considerably more efficient and more effective for dealing with missing data than the usual approach based on dichotomization. For parameter estimation, the model-based approach generally requires correct specification of the model for the original variables. However, under the sharp null hypothesis, the model-based approach remains unbiased for estimating the treatment difference even if the model is misspecified. We elaborate on these points and illustrate them with a series of simulation studies mimicking a study of Parkinson's disease, which involves longitudinal continuous data in the definition of a responder. C1 [Zhang, Zhiwei] Univ Calif Riverside, Dept Stat, Riverside, CA 92521 USA. [Chu, Jianxiong] US FDA, Ctr Devices & Radiol Hlth, Div Biostat, Off Surveillance & Biomet, Silver Spring, MD USA. [Rahardja, Dewi] US Dept Def, Ft George G Meade, MD USA. [Zhang, Hui; Tang, Li] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN USA. RP Zhang, ZW (reprint author), Univ Calif Riverside, Dept Stat, Riverside, CA 92521 USA. EM zhiwei.zhang@ucr.edu NR 15 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2016 VL 26 IS 6 SI SI BP 1125 EP 1135 DI 10.1080/10543406.2016.1226325 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA ED1HS UT WOS:000388596600012 PM 27540771 ER PT J AU Yue, LQ Campbell, G Lu, N Xu, YL Zuckerman, B AF Yue, Lilly Q. Campbell, Gregory Lu, Nelson Xu, Yunling Zuckerman, Bram TI Utilizing national and international registries to enhance pre-market medical device regulatory evaluation SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Data quality; observational comparative studies; propensity score; registry; study design ID PROPENSITY SCORE; CAUSAL INFERENCE; DESIGN; BIAS AB Regulatory decisions are made based on the assessment of risk and benefit of medical devices at the time of pre-market approval and subsequently, when post-market risk-benefit balance needs reevaluation. Such assessments depend on scientific evidence obtained from pre-market studies, post-approval studies, post-market surveillance studies, patient perspective information, as well as other real world data such as national and international registries. Such registries provide real world evidence and are playing a more and more important role in enhancing the safety and effectiveness evaluation of medical devices. While these registries provide large quantities of data reflecting real world practice and can potentially reduce the cost of clinical trials, challenges arise concerning (1) data quality adequate for regulatory decision-making, (2) bias introduced at every stage and aspect of study, (3) scientific validity of study designs, and (4) reliability and interpretability of study results. This article will discuss related statistical and regulatory challenges and opportunities with examples encountered in medical device regulatory reviews. C1 [Yue, Lilly Q.; Campbell, Gregory; Lu, Nelson; Xu, Yunling] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Zuckerman, Bram] US FDA, Div Cardiovasc Devices, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Yue, LQ (reprint author), US FDA, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM lilly.yue@fda.hhs.gov NR 17 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2016 VL 26 IS 6 SI SI BP 1136 EP 1145 DI 10.1080/10543406.2016.1226336 PG 10 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA ED1HS UT WOS:000388596600013 PM 27540636 ER PT J AU Megget, K AF Megget, Katrina TI cleaner hands SO CHEMISTRY & INDUSTRY LA English DT Article C1 [Megget, Katrina] US FDA, Rockville, MD 20857 USA. RP Megget, K (reprint author), US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 0009-3068 EI 2047-6329 J9 CHEM IND-LONDON JI Chem. Ind. PY 2016 VL 80 IS 9 BP 30 EP 32 PG 3 WC Chemistry, Applied SC Chemistry GA EC8WP UT WOS:000388424100020 ER PT B AU Sharma, M Ingram, D Graham, L AF Sharma, Manan Ingram, David Graham, Lorna BE Soon, JM Manning, L Wallace, CA TI Foodborne Outbreaks and Potential Routes of Contamination in Fresh and Fresh-Cut Fruits and Vegetables SO FOODBORNE DISEASES: CASE STUDIES OF OUTBREAKS IN THE AGRI-FOOD INDUSTRIES LA English DT Article; Book Chapter ID ESCHERICHIA-COLI O157-H7; UNPASTEURIZED ORANGE JUICE; UNITED-STATES; TYPHOID-FEVER; MULTISTATE OUTBREAK; SALMONELLA-POONA; CANTALOUPE RIND; SURVIVAL; WATERMELON; INFECTION C1 [Sharma, Manan] ARS, USDA, Beltsville, MD 20705 USA. [Ingram, David] US FDA, Div Produce Safety, College Pk, MD USA. [Graham, Lorna] Univ Maryland Eastern Shore, Dept Agr, Princess Anne, MD USA. RP Sharma, M (reprint author), ARS, USDA, Beltsville, MD 20705 USA. NR 68 TC 0 Z9 0 U1 0 U2 0 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4822-0828-3; 978-1-4822-0827-6 PY 2016 BP 19 EP 36 D2 10.1201/b19463 PG 18 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA BG3WN UT WOS:000388323700004 ER PT S AU Ghassemi, P Wang, QZ Pfefer, TJ AF Ghassemi, Pejhman Wang, Quanzeng Pfefer, T. Joshua BE Raghavachari, R Liang, R TI Dynamic thermal effects of epidermal melanin and plasmonic nanoparticles during photoacoustic breast imaging SO DESIGN AND QUALITY FOR BIOMEDICAL TECHNOLOGIES IX SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies IX CY FEB 13-14, 2016 CL San Francisco, CA SP SPIE DE melanin; plasmonic nanoparticles; photothermal safety; photoacoustic tomography; thermal imaging ID PORT-WINE STAINS; OPTICAL-PROPERTIES; LASER TREATMENT; GOLD NANORODS; HUMAN SKIN; TISSUE; SPECTROSCOPY; MICE AB Photoacoustic Tomography (PAT) employs high-power near-infrared (near-IR) laser pulses to generate structural and functional information on tissue chromophores up to several centimeters below the surface. Such insights may facilitate detection of breast cancer - the most common cancer in women. PAT mammography has been the subject of extensive research, including techniques based on exogenous agents for PAT contrast enhancement and molecular specificity. However, photothermal safety risks of PAT due to strong chromophores such as epidermal melanin and plasmonic nanoparticles have not been rigorously studied. We have used computational and experimental approaches to elucidate highly dynamic optical-thermal processes during PAT. A Monte Carlo model was used to simulate light propagation at 800 and 1064 nm in a multi-layer breast tissue geometry with different epidermal pigmentation levels and a tumor-simulating inclusion incorporating nanoparticles. Energy deposition results were then used in a bioheat transfer model to simulate temperature transients. Experimental measurements involved multi-layer hydrogel phantoms with inclusions incorporating gold nanoparticles. Phantom optical properties were measured using the inverse adding-doubling technique. Thermal imaging was performed as phantoms were irradiated with 5 ns near-IR pulses. Scenarios using 10 Hz laser irradiation of breast tissue containing various nanoparticle concentrations were implemented experimentally and computationally. Laser exposure levels were based on ANSI/IEC limits. Surface temperature measurements were compared to corresponding simulation data. In general, the effect of highly pigmented skin on temperature rise was significant, whereas unexpectedly small levels of temperature rise during nanoparticle irradiation were attributed to rapid photodegradation. Results provide key initial insights into light-tissue interactions impacting the safety and effectiveness of PAT. C1 [Ghassemi, Pejhman; Wang, Quanzeng; Pfefer, T. Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Pfefer, TJ (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM Joshua.Pfefer@fda.hhs.gov NR 31 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-934-4 J9 PROC SPIE PY 2016 VL 9700 AR 97000F DI 10.1117/12.2214870 PG 9 WC Physics, Applied; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Physics; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BF6RL UT WOS:000383614900014 ER PT S AU Wang, BH Ghassemi, P Wang, JT Wang, QZ Chen, Y Pfefer, J AF Wang, Bohan Ghassemi, Pejhman Wang, Jianting Wang, Quanzeng Chen, Yu Pfefer, Joshua BE Raghavachari, R Liang, R TI Performance Evaluation of CCD- and Mobile-Phone-Based Near-Infrared Fluorescence Imaging Systems with Molded and 3D-Printed Phantoms SO DESIGN AND QUALITY FOR BIOMEDICAL TECHNOLOGIES IX SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies IX CY FEB 13-14, 2016 CL San Francisco, CA SP SPIE DE Near infrared fluorescence; Performance testing; Mobile phone; 3D printing; Tissue phantoms AB Increasing numbers of devices are emerging which involve biophotonic imaging on a mobile platform. Therefore, effective test methods are needed to ensure that these devices provide a high level of image quality. We have developed novel phantoms for performance assessment of near infrared fluorescence (NIRF) imaging devices. Resin molding and 3D printing techniques were applied for phantom fabrication. Comparisons between two imaging approaches - a CCD-based scientific camera and an NIR-enabled mobile phone - were made based on evaluation of the contrast transfer function and penetration depth. Optical properties of the phantoms were evaluated, including absorption and scattering spectra and fluorescence excitation-emission matrices. The potential viability of contrast-enhanced biological NIRF imaging with a mobile phone is demonstrated, and color-channel-specific variations in image quality are documented. Our results provide evidence of the utility of novel phantom-based test methods for quantifying image quality in emerging NIRF devices. C1 [Wang, Bohan; Chen, Yu] Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. [Wang, Bohan; Ghassemi, Pejhman; Wang, Jianting; Wang, Quanzeng; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Wang, BH (reprint author), Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA.; Wang, BH (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-934-4 J9 PROC SPIE PY 2016 VL 9700 AR 970006 DI 10.1117/12.2220412 PG 8 WC Physics, Applied; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Physics; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BF6RL UT WOS:000383614900005 ER PT S AU Wang, JT Chen, Y Pfefer, J AF Wang, Jianting Chen, Yu Pfefer, Joshua BE Raghavachari, R Liang, R TI Quantitative Assessment Of Hyperspectral Imaging In Detection Of Plasmonic Nanoparticles - A Modified Contrast-detail Analysis Approach SO DESIGN AND QUALITY FOR BIOMEDICAL TECHNOLOGIES IX SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies IX CY FEB 13-14, 2016 CL San Francisco, CA SP SPIE DE Hyperspectral imaging; contrast-detail analysis; standardized test method; tissue phantom ID OPTICAL-PROPERTIES; TURBID MEDIA; GOLD NANORODS; TOMOGRAPHY; REFLECTANCE; TISSUES AB Hyperspectral reflectance imaging (HRI) is an emerging imaging modality being applied for clinical indications such as tissue oximetry, and cancer detection based on endogenous biological constituents including plasmonic nanoparticles. However, there is currently a lack of standardized test methods for objective, quantitative evaluation of HRI system performance. Contrast-detail analysis (CDA) is a phantom-based test method commonly used to evaluate medical imaging devices (e.g., mammography systems) in terms of their lower detection limit. We investigated a modified CDA (mCDA) method to quantify the detectability of gold nanoparticles by HRI systems. Silicone-based turbid phantoms containing micro-fluidic channels were developed for the mCDA tests. Polydimethylsiloxane (PDMS) phantom materials were doped with chromophores and scatterers to achieve biologically relevant optical properties (OPs). Molds were used to produce cylindrical channels of diameters 0.3 to 1.65 mm and depths of 0.2 mm inside the phantoms. Channels were filled with a mixture of hemoglobin and concentrations of gold nanorods (GNR) and measured with our HRI system. The contrast of GNRs was solved with a spectral unmixing algorithm from the reflectance spectra. The lowest detectable concentration was determined as a function of inclusion size and depth and plotted as modified contrast detail curve (mCDC). mCDCs were used to compare the detectabilities of the HRI system with different data processing algorithms. It is demonstrated that our mCDA test method involving turbid microchannel phantoms can help to elucidate the combined performance of imaging devices and plasmonic nanoparticle contrast agents. This approach may be useful for performing clinical trial standardization and device re-calibration, thus ensuring quality control and clinical performance. C1 [Wang, Jianting; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20093 USA. [Chen, Yu] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Pfefer, J (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20093 USA. EM Joshua.Pfefer@fda.hhs.gov NR 30 TC 0 Z9 0 U1 1 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-934-4 J9 PROC SPIE PY 2016 VL 9700 AR 97000D DI 10.1117/12.2214750 PG 8 WC Physics, Applied; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Physics; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BF6RL UT WOS:000383614900012 ER PT S AU Hong, HX Chen, MJ Ng, HW Tong, WD AF Hong, Huixiao Chen, Minjun Ng, Hui Wen Tong, Weida BE Benfenati, E TI QSAR Models at the US FDA/NCTR SO IN SILICO METHODS FOR PREDICTING DRUG TOXICITY SE Methods in Molecular Biology LA English DT Article; Book Chapter DE FDA; Databases; Liver toxicity; Endocrine disruptors ID INDUCED LIVER-INJURY; ENDOCRINE DISRUPTING CHEMICALS; HIV-1 INTEGRASE INHIBITORS; ESTROGEN-RECEPTOR BINDING; DENSITY-FUNCTIONAL THEORY; DECISION FOREST; MOLECULAR DOCKING; STRUCTURAL DESCRIPTORS; ENVIRONMENTAL CHEMICALS; CYTOCHROME-P450 CYP3A4 AB Quantitative structure-activity relationship (QSAR) has been used in the scientific research community for many decades and applied to drug discovery and development in the industry. QSAR technologies are advancing fast and attracting possible applications in regulatory science. To facilitate the development of reliable QSAR models, the FDA had invested a lot of efforts in constructing chemical databases with a variety of efficacy and safety endpoint data, as well as in the development of computational algorithms. In this chapter, we briefly describe some of the often used databases developed at the FDA such as EDKB (Endocrine Disruptor Knowledge Base), EADB (Estrogenic Activity Database), LTKB (Liver Toxicity Knowledge Base), and CERES (Chemical Evaluation and Risk Estimation System) and the technologies adopted by the agency such as Mold2 program for calculation of a large and diverse set of molecular descriptors and decision forest algorithm for QSAR model development. We also summarize some QSAR models that have been developed for safety evaluation of the FDA-regulated products. C1 [Hong, Huixiao; Chen, Minjun; Ng, Hui Wen; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Hong, HX (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 67 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1064-3745 BN 978-1-4939-3609-0; 978-1-4939-3607-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1425 BP 431 EP 459 DI 10.1007/978-1-4939-3609-0_18 D2 10.1007/978-1-4939-3609-0 PG 29 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA BG2YT UT WOS:000387782000019 PM 27311476 ER PT J AU Zhao, XQ Alexander, TN Hoffman, L Jones, C Delahanty, J Walker, M Berger, AT Talbert, E AF Zhao, Xiaoquan Alexander, Tesfa N. Hoffman, Leah Jones, Chaunetta Delahanty, Janine Walker, Matthew Berger, Amanda T. Talbert, Emily TI Youth Receptivity to FDA's The Real Cost Tobacco Prevention Campaign: Evidence From Message Pretesting SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID CESSATION MEDIA MESSAGES; PLANNED BEHAVIOR; SMOKING-CESSATION; EXTENDED VERSION; ADOLESCENTS; SMOKERS; IMPACT AB In February 2014, the Food and Drug Administration launched The Real Cost, a national youth tobacco prevention campaign. This article examines youth receptivity to potential campaign ads using data from 3 message pretesting studies featuring the same design and consistent instrumentation. A total of 3,258 adolescents ages 13-17 were randomized to either an ad-viewing condition or a no-exposure control condition. Perceived ad effectiveness, smoking-related beliefs, and attitudes were measured as outcome variables. The sample consisted of both experimental smokers (58%) and current nonsmokers at risk for cigarette initiation (42%). A total of 14 ads were tested across the three studies. Participants who viewed the ads generally considered them to be effective (with a mean perceived ad effectiveness score of 3.66 on a scale from 1 to 5). Compared to those in the control condition, participants in the ad-viewing condition reported stronger beliefs about the health risks of smoking (p<.001), a greater likelihood that smoking would lead to loss of control in life (p<.001), and more negative attitudes toward smoking (p<.001). Responses to campaign ads were largely consistent between experimenters and at-risk nonsmokers. Implications of the findings for the campaign are discussed. C1 [Zhao, Xiaoquan; Alexander, Tesfa N.; Hoffman, Leah; Jones, Chaunetta; Delahanty, Janine; Talbert, Emily] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. [Zhao, Xiaoquan] George Mason Univ, Dept Commun, MS3D6,4400 Univ Dr, Fairfax, VA 22030 USA. [Walker, Matthew; Berger, Amanda T.] Natl Acad Med, FDA Tobacco Regulatory Sci Fellowship, Washington, DC USA. RP Zhao, XQ (reprint author), George Mason Univ, Dept Commun, MS3D6,4400 Univ Dr, Fairfax, VA 22030 USA. EM xzhao3@gmu.edu FU Intramural FDA HHS [FD999999] NR 32 TC 0 Z9 0 U1 4 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PY 2016 VL 21 IS 11 BP 1153 EP 1160 DI 10.1080/10810730.2016.1233307 PG 8 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA EC3LW UT WOS:000388028600004 PM 27736365 ER PT J AU Rupert, DJ Read, JG Amoozegar, JB Moultrie, RR Taylor, OM O'Donoghue, AC Sullivan, HW AF Rupert, Douglas J. Read, Jennifer Gard Amoozegar, Jacqueline B. Moultrie, Rebecca R. Taylor, Olivia M. O'Donoghue, Amie C. Sullivan, Helen W. TI Peer-Generated Health Information: The Role of Online Communities in Patient and Caregiver Health Decisions SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID SOCIAL NETWORKS; INTERNET USE; NATIONAL-SURVEY; CANCER; CARE; SUPPORT; CREDIBILITY; IMPACT; WEB; BENEFITS AB Individuals increasingly access peer-generated health information (PGHI) through social media, especially online health communities (OHCs). Previous research has documented PGHI topics, credibility assessment strategies, and PGHI's connection with well-being. However, there is limited evidence on where, when, and why individuals seek PGHI and how they use PGHI in health decisions. We conducted in-person and online focus groups with verified OHC members (N=89)representing 50 different medical conditions and 77 OHCsto explore these topics. Two researchers independently coded transcripts with NVivo 9.2 and thematically analyzed responses. Most individuals accidentally discovered PGHI during Web searches rather than intentionally seeking it. Individuals valued PGHI primarily as an alternative information source about treatment options, self-care activities, and health care provider questions rather than a source of emotional support, and they acknowledged PGHI's limitation as anecdotal evidence. Individuals used PGHI as a springboard for additional research and patient-provider discussions, ultimately making treatment decisions alongside providers. These findings suggest that individuals use PGHI in much the same way they use traditional online health information and that PGHI facilitates, rather than obstructs, shared decision making with health care providers. C1 [Rupert, Douglas J.; Read, Jennifer Gard; Moultrie, Rebecca R.; Taylor, Olivia M.] RTI Int, Ctr Commun Sci, 3040 Cornwallis Rd, Res Triangle Pk, NC 27709 USA. [Amoozegar, Jacqueline B.] RTI Int, Social & Hlth Org Res & Evaluat Program, Res Triangle Pk, NC USA. [O'Donoghue, Amie C.; Sullivan, Helen W.] US FDA, Ctr Drug Evaluat & Res, Off Prescript Drug Promot, Silver Spring, MD USA. RP Rupert, DJ (reprint author), RTI Int, Ctr Commun Sci, 3040 Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM drupert@rti.org FU U.S. Food and Drug Administration, Office of Prescription Drug Promotion FX This research was funded by a contract from the U.S. Food and Drug Administration, Office of Prescription Drug Promotion. The findings and conclusions in this article are our own and do not necessarily reflect the opinions of the U.S. Food and Drug Administration. NR 63 TC 0 Z9 0 U1 4 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PY 2016 VL 21 IS 11 BP 1187 EP 1197 DI 10.1080/10810730.2016.1237592 PG 11 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA EC3LW UT WOS:000388028600008 PM 27805496 ER PT J AU Sullivan, HW O'Donoghue, AC Rupert, DJ Willoughby, JF Amoozegar, JB Aikin, KJ AF Sullivan, Helen W. O'Donoghue, Amie C. Rupert, Douglas J. Willoughby, Jessica Fitts Amoozegar, Jacqueline B. Aikin, Kathryn J. TI Are Disease Awareness Links on Prescription Drug Websites Misleading? A Randomized Study SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID HEALTH INFORMATION; ADVERTISING EXPOSURE; CONSUMER; PHYSICIANS; ADVERTISEMENTS; CREDIBILITY; PERCEPTIONS; DISCLOSURES; EXPERIENCE; CAPACITY AB We sought to determine whether links from branded prescription drug websites to websites containing disease information mislead participants about drug benefits and whether nonsponsorship disclosures diminish this potential effect. We randomly assigned online panelists with depression (N=1,071) to view a fictitious prescription drug website that had (a) no link to a disease information website (control), (b) a link with no disclosure, (c) a link with a simple nonsponsorship disclosure, or (d) a link with a detailed nonsponsorship disclosure. If participants in the link conditions did not click the link, they were returned to the drug website and encouraged to click it. All participants then completed an online questionnaire assessing recall, perceptions, and intentions. Few participants (12%) clicked the link without prompting; 67% did so when prompted. Compared with control participants, participants in link conditions were more likely to confuse disease information with drug benefits and to recall fewer true drug benefits. Disclosures did not diminish these effects, and exposure to disease information did not affect other perceptions or intentions. Consumers seem to confuse information on disease websites with information on branded prescription drug websites. Disclosures may not adequately help consumers to distinguish between the 2 types of information. C1 [Sullivan, Helen W.; O'Donoghue, Amie C.; Aikin, Kathryn J.] US FDA, Ctr Drug Evaluat & Res, Off Prescript Drug Promot, 10903 New Hampshire Ave,Bldg 51,Room 3238, Silver Spring, MD 20993 USA. [Rupert, Douglas J.; Amoozegar, Jacqueline B.] RTI Int, Res Triangle Pk, NC USA. [Willoughby, Jessica Fitts] Washington State Univ, Edward R Murrow Coll Commun, Pullman, WA 99164 USA. RP Sullivan, HW (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Prescript Drug Promot, 10903 New Hampshire Ave,Bldg 51,Room 3238, Silver Spring, MD 20993 USA. EM Helen.Sullivan@fda.hhs.gov OI Willoughby, Jessica/0000-0002-1118-9502 FU Office of Prescription Drug Promotion, U.S. Food and Drug Administration; RTI International FX Funding was provided by the Office of Prescription Drug Promotion, U.S. Food and Drug Administration, and data were collected through a contract with RTI International. Jessica Fitts Willoughby was a contractor with RTI International at the time this study was conducted. NR 47 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PY 2016 VL 21 IS 11 BP 1198 EP 1207 DI 10.1080/10810730.2016.1237594 PG 10 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA EC3LW UT WOS:000388028600009 PM 27805473 ER PT B AU Kweon, O Kim, SJ Sutherland, JB Cerniglia, CE AF Kweon, Ohgew Kim, Seong-Jae Sutherland, John B. Cerniglia, Carl E. BE Dlugonski, J TI Novel Insights into Polycyclic Aromatic Hydrocarbon Biodegradation Pathways Using Systems Biology and Bioinformatics Approaches SO MICROBIAL BIODEGRADATION: FROM OMICS TO FUNCTION AND APPLICATION LA English DT Article; Book Chapter ID MYCOBACTERIUM-VANBAALENII PYR-1; SP STRAIN PYR-1; PYRENE DEGRADATION; METABOLIC NETWORK; MOLECULAR CHARACTERIZATION; FLUORANTHENE METABOLISM; DEGRADING MYCOBACTERIA; CLASSIFICATION-SYSTEM; CATALASE-PEROXIDASE; DIOXYGENASE GENES AB Biodegradation of polycyclic aromatic hydrocarbons (PAHs) entails a complex and diverse set of biological reactions. Although there has been a massive effort over the years, understanding of the mechanism of PAH biodegradation has been limited when using the traditional approaches of genetics and biochemistry. The application of systems biology approaches, with advanced high-throughput analytical technologies, provides new global insights into not only the direct molecular mechanisms but also the genome-wide cellular ecophysiological responses involved in PAH degradation. This review describes research accomplishments from earlier traditional genetic and biochemical studies as well as the recent achievements of a combination of genomic, proteomic, and bioinformatics approaches to elucidate pathways for the degradation of high-molecular weight (HMW) PAHs. C1 [Kweon, Ohgew; Kim, Seong-Jae; Sutherland, John B.; Cerniglia, Carl E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Kweon, O (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM oh-gew.kweon@fda.hhs.gov; seong-jae.kim@fda.hhs.gov; john.sutherland@fda.hhs.gov; carl.cemiglia@hhs.fda.gov NR 87 TC 0 Z9 0 U1 2 U2 2 PU CAISTER ACADEMIC PRESS PI WYMONDHAM PA 32 HEWITTS LANE, WYMONDHAM NR 18 0JA, ENGLAND BN 978-1-910190-45-6 PY 2016 BP 143 EP 166 PG 24 WC Biotechnology & Applied Microbiology; Engineering, Environmental; Microbiology SC Biotechnology & Applied Microbiology; Engineering; Microbiology GA BG3AW UT WOS:000387832200009 ER PT S AU Zheng, JF Li, DW Chen, J Kainz, W AF Zheng, Jianfeng Li, Dawei Chen, Ji Kainz, Wolfgang GP IEEE TI Numerical Study of SAR for Multi-Component Orthopaedic Hip Replacement System During MRI SO 2016 IEEE INTERNATIONAL SYMPOSIUM ON ELECTROMAGNETIC COMPATIBILITY (EMC) SE IEEE International Symposium on Electromagnetic Compatibility LA English DT Proceedings Paper CT IEEE International Symposium on Electromagnetic Compatibility (EMC) CY JUL 25-29, 2016 CL Ottawa, CANADA SP IEEE Electromagnet Compatibil Soc DE RF heating; MRI; FDTD; Computational modeling ID HUMAN HEAD; DEVICES AB In this study we present numerical simulations of the Specific Absorption Rate (SAR) for multi-component orthopaedic hip replacement systems. The SAR is used to evaluate the radio frequency (RF)-induced heating of the devices during magnetic resonance imaging (MRI). Because multicomponent orthopaedic hip replacement systems have many combinations of components with various designs and sizes, it is computationally intensive, and almost impossible, to evaluate the SAR and the corresponding temperature rise for each possible combination and configuration. In this study, an effective searching strategy and a computational simulation model are developed to evaluate the factors associated with induced SAR in the tissue near an orthopaedic hip replacement system, and to find the "worst case" peak SAR for all possible combinations. The finite-difference time-domain (FDTD) was used to calculate the peak SAR for a typical hip replacement system inside the American Society for Testing and Materials (ASTM) phantom for both 1.5 Tesla (T) and 3T MRI systems. The results indicate that the stem and screw lengths are the most important factors influencing the peak SAR for both field strengths, 1.5T/64 MHz and 3T/128 MHz, respectively. The peak 1 gram averaged SAR reaches 216 W/kg and 103 W/kg for 64 MHz and 128 MHz, respectively. We also found that shortest stems, and the longest screws, typically induce higher peak SAR. C1 [Zheng, Jianfeng; Li, Dawei; Chen, Ji] Univ Houston, Dept Elect & Comp Engn, Houston, TX 77004 USA. [Kainz, Wolfgang] US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD USA. RP Zheng, JF (reprint author), Univ Houston, Dept Elect & Comp Engn, Houston, TX 77004 USA. EM jzheng4@central.uh.edu; wolfgang.kainz@fda.hhs.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2158-110X BN 978-1-5090-1441-5 J9 IEEE INT SYMP ELEC PY 2016 BP 116 EP 120 PG 5 WC Engineering, Electrical & Electronic; Physics, Applied SC Engineering; Physics GA BG1WI UT WOS:000387117700044 ER PT S AU Guo, R Zheng, JF Chen, J Kainz, W AF Guo, Ran Zheng, Jianfeng Chen, Ji Kainz, Wolfgang GP IEEE TI RF-Induced Heating Comparison Between in-vivo and in-phantom for 1.5T MRI SO 2016 IEEE INTERNATIONAL SYMPOSIUM ON ELECTROMAGNETIC COMPATIBILITY (EMC) SE IEEE International Symposium on Electromagnetic Compatibility LA English DT Proceedings Paper CT IEEE International Symposium on Electromagnetic Compatibility (EMC) CY JUL 25-29, 2016 CL Ottawa, CANADA SP IEEE Electromagnet Compatibil Soc DE RF-induced heating; MRI; orthopedic plate ID NUMERICAL-SIMULATION; IMPLANTS; DEVICES; COILS; SAR AB The RF-induced heating is one of the main problems in diagnostic MRI. The standard way to assess the RF-induced heating is to perform experimental or computational phantom studies. Due to the inherent differences in geometry and electrical parameters between the phantom and the human body, the induced RF-induced heating assessed in the phantom is typically not be the same as in human body. In this study, we investigate the difference in RF-induced heating between in-vivo and in-phantom assessment for an orthopedic femur and a humerus plate systems at 1.5T (64 MHz). We found that for this particular device the RF-induced heating for the in-phantom simulations is always higher than for the in-vivo simulations. However, to accurately predict the maximum in-vivo heating it is necessary to perform computational modeling using anatomically correct computer models and accurate computer models of the implant. C1 [Guo, Ran; Zheng, Jianfeng; Chen, Ji] Univ Houston, Dept Elect & Comp Engn, Houston, TX 77004 USA. [Kainz, Wolfgang] US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD USA. RP Guo, R (reprint author), Univ Houston, Dept Elect & Comp Engn, Houston, TX 77004 USA. EM rguo3@uh.edu; wolfgang.kainz@fda.hhs.gov NR 18 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2158-110X BN 978-1-5090-1441-5 J9 IEEE INT SYMP ELEC PY 2016 BP 121 EP 125 PG 5 WC Engineering, Electrical & Electronic; Physics, Applied SC Engineering; Physics GA BG1WI UT WOS:000387117700045 ER PT J AU Planchart, A Mattingly, CJ Allen, D Ceger, P Casey, W Hinton, D Kanungo, J Kullman, SW Tal, T Bondesson, M Burgess, SM Sullivan, C Kim, C Behl, M Padilla, S Reif, DM Tanguay, RL Hamm, J AF Planchart, Antonio Mattingly, Carolyn J. Allen, David Ceger, Patricia Casey, Warren Hinton, David Kanungo, Jyotshna Kullman, Seth W. Tal, Tamara Bondesson, Maria Burgess, Shawn M. Sullivan, Con Kim, Carol Behl, Mamta Padilla, Stephanie Reif, David M. Tanguay, Robert L. Hamm, Jon TI Advancing Toxicology Research Using In Vivo High Throughput Toxicology with Small Fish Models SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Article DE aquatic models; 21st century toxicology; alternatives ID ZEBRAFISH DANIO-RERIO; TRANSMEMBRANE CONDUCTANCE REGULATOR; ENDOCRINE-DISRUPTING CHEMICALS; MATERNAL STILBESTROL THERAPY; ARYL-HYDROCARBON RECEPTOR; INNATE IMMUNE-RESPONSE; ZINC-FINGER NUCLEASES; CYPRINUS-CARPIO L.; ENVIRONMENTAL CHEMICALS; TRANSGENIC ZEBRAFISH AB Small freshwater fish models, especially zebrafish, offer advantages over traditional rodent models, including low maintenance and husbandry costs, high fecundity, genetic diversity, physiology similar to that of traditional biomedical models, and reduced animal welfare concerns. The Collaborative Workshop on Aquatic Models and 21st Century Toxicology was held at North Carolina State University on May 5-6, 2014, in Raleigh, North Carolina, USA. Participants discussed the ways in which small fish are being used as models to screen toxicants and understand mechanisms of toxicity. Workshop participants agreed that the lack of standardized protocols is an impediment to broader acceptance of these models, whereas development of standardized protocols, validation, and subsequent regulatory acceptance would facilitate greater usage. Given the advantages and increasing application of small fish models, there was widespread interest in follow-up workshops to review and discuss developments in their use. In this article, we summarize the recommendations formulated by workshop participants to enhance the utility of small fish species in toxicology studies, as well as many of the advances in the field of toxicology that resulted from using small fish species, including advances in developmental toxicology, cardiovascular toxicology, neurotoxicology, and immunotoxicology. We also review many emerging issues that will benefit from using small fish species, especially zebrafish, and new technologies that will enable using these organisms to yield results unprecedented in their information content to better understand how toxicants affect development and health. C1 [Planchart, Antonio; Mattingly, Carolyn J.; Kullman, Seth W.; Reif, David M.] North Carolina State Univ, Dept Biol Sci, Campus Box 7633, Raleigh, NC 27695 USA. [Planchart, Antonio; Mattingly, Carolyn J.; Kullman, Seth W.; Reif, David M.] North Carolina State Univ, Ctr Human Hlth & Environm, Raleigh, NC USA. [Allen, David; Ceger, Patricia; Hamm, Jon] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Casey, Warren] NIEHS, Natl Toxicol Program, Interagency Ctr Evaluat Alternat Toxicol Methods, POB 12233, Res Triangle Pk, NC 27709 USA. [Hinton, David] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA. [Kanungo, Jyotshna] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Tal, Tamara; Padilla, Stephanie] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Bondesson, Maria] Univ Houston, Dept Pharmacol & Pharmaceut Sci, Houston, TX USA. [Burgess, Shawn M.] NHGRI, Bethesda, MD 20892 USA. [Sullivan, Con; Kim, Carol] Univ Maine, Dept Mol & Biomed Sci, Orono, ME USA. [Sullivan, Con; Kim, Carol] Univ Maine, Grad Sch Biomed Sci & Engn, Orono, ME USA. [Behl, Mamta] NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Tanguay, Robert L.] Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA. RP Planchart, A (reprint author), North Carolina State Univ, Dept Biol Sci, Campus Box 7633, Raleigh, NC 27695 USA. EM ajplanch@ncsu.edu FU North Carolina State University Center for Human Health and the Environment (NIH/NIEHS) [P30ES025128] FX The authors would like to thank Ms. Catherine Sprankle of Integrated Laboratory Systems, Inc., for editorial assistance. Financial support for the workshop was provided by the North Carolina State University Center for Human Health and the Environment (NIH/NIEHS P30ES025128). NR 202 TC 1 Z9 1 U1 8 U2 8 PU SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH PI HEILDEBERG PA TIERGARTENSTRASSE 17, HEILDEBERG, 69121, GERMANY SN 1868-596X EI 1868-8551 J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2016 VL 33 IS 4 BP 435 EP 452 DI 10.14573/altex.1601281 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB5RY UT WOS:000387439200007 PM 27328013 ER PT J AU Luo, H Mattes, W Mendrick, DL Hong, HX AF Luo, Heng Mattes, William Mendrick, Donna L. Hong, Huixiao TI Molecular Docking for Identification of Potential Targets for Drug Repurposing SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE Docking; Drug; Target; Target identification; Drug repurposing ID CHEMICAL-PROTEIN INTERACTOME; HIV-1 INTEGRASE INHIBITORS; HUMAN-LEUKOCYTE ANTIGENS; STRUCTURE ELUCIDATION; DECISION FOREST; EXPERT-SYSTEM; BINDING AFFINITIES; ALPHA-FETOPROTEIN; ESTROGENIC ACTIVITY; CRYSTAL-STRUCTURES AB Using existing drugs for new indications (drug repurposing) is an effective method not only to reduce drug development time and costs but also to develop treatments for new disease including those that are rare. In order to discover novel indications, potential target identification is a necessary step. One widely used method to identify potential targets is through molecule docking. It requires no prior information except structure inputs from both the drug and the target, and can identify potential targets for a given drug, or identify potential drugs for a specific target. Though molecular docking is popular for drug development and repurposing, challenges remain for the method. In order to improve the prediction accuracy, optimizing the target conformation, considering the solvents and adding cobinders to the system are possible solutions. C1 [Luo, Heng; Mattes, William; Mendrick, Donna L.; Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov FU Research Participation Program at the National Center for Toxicological Research FX The research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research (Heng Luo) 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 95 TC 0 Z9 0 U1 3 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 EI 1873-5294 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PY 2016 VL 16 IS 30 BP 3636 EP 3645 DI 10.2174/1568026616666160530181149 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EB0ZI UT WOS:000387075200008 PM 27334201 ER PT J AU Ye, H Wei, J Tang, KL Feuers, R Hong, HX AF Ye, Hao Wei, Jia Tang, Kailin Feuers, Ritchie Hong, Huixiao TI Drug Repositioning Through Network Pharmacology SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE Drug repositioning; Network pharmacology; Pathway analysis ID SACCHAROMYCES-CEREVISIAE GENOME; TARGET INTERACTION PREDICTION; DOCKING APPROACH; WEB SERVER; PATHWAY ANALYSIS; DATABASE; DISEASE; BIOMARKERS; DISCOVERY; BIOLOGY AB Low drug productivity has been a significant problem of the pharmaceutical industry for several decades even though numerous novel technologies were introduced during this period. Currently pharmacologic dogma, "single drug, single target, single disease", is at the root of the lack of drug productivity. From a systems biology viewpoint, network pharmacology has been proposed to complement the established guiding pharmacologic approaches. The rationale for network pharmacology as a major component of drug discovery and development is that a disease can be caused by perturbation of the disease-causing network and a drug may be designed to interact with multiple targets for modulation of such a network from the disease status toward normal status. Therefore, network pharmacology has been applied to guide and assist in drug repositioning. Drugs exerting their therapeutic effects may directly target disease-associated proteins, but they may also modulate the pathways involved in the pathological process. In this review, we discuss the progresses and prospects in network pharmacology, focusing on drug off-targets discovery, disease-associated protein identification, and pathway analysis for elucidating relationships between drug targets and disease-associated proteins. C1 [Ye, Hao; Hong, Huixiao] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wei, Jia] AstraZeneca, R&D Informat, Shanghai, Peoples R China. [Tang, Kailin] Tongji Univ, Sch Life Sci & Technol, Shanghai, Peoples R China. [Feuers, Ritchie] US FDA, Off Res, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Hong, HX (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov FU Research Participation Program at the National Center for Toxicological Research FX This research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research (Hao Ye) 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 content is solely the responsibility of the authors and does not necessarily represent the official views of the Food and Drugs Administration. NR 96 TC 0 Z9 0 U1 8 U2 8 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 EI 1873-5294 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PY 2016 VL 16 IS 30 BP 3646 EP 3656 DI 10.2174/1568026616666160530181328 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EB0ZI UT WOS:000387075200009 PM 27334200 ER PT J AU Lefebvre, RC McCormack, L Taylor, O Bann, C Rausch, P AF Lefebvre, R. Craig McCormack, Lauren Taylor, Olivia Bann, Carla Rausch, Paula TI A quantitative approach to segmentation for prescription drug safety programs SO JOURNAL OF SOCIAL MARKETING LA English DT Article DE Social marketing; Consumer attitudes; Audience research; Segmentation; Pharmacovigilance; Drug safety ID HEALTH LITERACY; INFORMATION-SEEKING; PUBLIC-HEALTH; RISK; COMMUNICATION; PHARMACEUTICALS; INSTRUMENT; STRATEGIES; CONSUMERS; OUTCOMES AB Purpose - The aim of this paper is to enhance the effectiveness of pharmacovigilance programs that provide information about medical products to benefit consumers, aid health care professional's decision-making and improve community health. This research sought to determine whether distinct segments of consumers can be identified for prescription drug safety social marketing and communication activities and if these segments would respond differently to information about prescription drug products. Design/methodology/approach - Theories of risk information-seeking behavior were used to develop questions for respondents in an online survey panel. Latent class analyses identified clusters that were similar in their ability to accurately interpret risks and benefits, preferred sources of health information, medication use and other related factors. Multinomial logistic regression models identified demographic and psychographic differences across the segments. Logistic and linear regression models were then used to compare each segment's responses to a specific drug safety information product. Findings - The 1,244 respondents were clustered into four segments: not engaged (12 per cent), low-involvement users (29 per cent), careful users (50 per cent) and social information seekers (9 per cent). These segments were distinguished by perceived seeking control, self-appraisal of skill, information insufficiency, self-efficacy, information competency and health literacy. Sources of health information and health-seeking behaviors were also different across the four segments. Significant differences were found among the segments in their comprehension and perceived utility of the content and their intentions to take relevant actions. Practical implications - From an array of potential behavioral influences, adults can be segmented by risk information-seeking constructs and related behaviors. These segments respond differently to drug safety information. Use of the personas developed in this work can help pharmacovigilance programs around the world develop more relevant and tailored social marketing products, services and content. Originality/value - A social marketing approach using empirically tested theoretical constructs can be useful for drug safety or pharmacovigilance programs. The results were used to create personas that quickly convey relevant information to drug safety program managers and staff. C1 [Lefebvre, R. Craig; McCormack, Lauren; Taylor, Olivia] RTI Int, Ctr Commun Sci, Res Triangle Pk, NC 27709 USA. [Bann, Carla] RTI Int, Social Stat & Environm Sci Dept, Res Triangle Pk, NC USA. [Rausch, Paula] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Lefebvre, RC (reprint author), RTI Int, Ctr Commun Sci, Res Triangle Pk, NC 27709 USA. EM clefebvre@rti.org NR 42 TC 0 Z9 0 U1 2 U2 2 PU EMERALD GROUP PUBLISHING LTD PI BINGLEY PA HOWARD HOUSE, WAGON LANE, BINGLEY BD16 1WA, W YORKSHIRE, ENGLAND SN 2042-6763 EI 2042-6771 J9 J SOC MARKET JI J. Soc. Market. PY 2016 VL 6 IS 4 BP 335 EP 360 DI 10.1108/JSOCM-06-2014-0037 PG 26 WC Business SC Business & Economics GA EB3HI UT WOS:000387254300002 ER PT J AU Tcheuko, L Gallas, B Samuelson, F AF Tcheuko, Lucas Gallas, Brandon Samuelson, Frank TI Using ANOVA/random-effects variance estimates to compute a two-sample U-statistic of order (1,1) estimate of variance SO JOURNAL OF STATISTICAL THEORY AND PRACTICE LA English DT Article DE AUC; ROC; variance components; rank statistic; ANOVA ID NONPARAMETRIC APPROACH AB The classical empirical, area under the receiver operating characteristic (ROC) curve (AUC) is a two-sample U-statistic of order (1,1). Its variance can be written out as a sum of three tractable covariances. It is then possible to consider each of these covariances as U-statistics themselves and follow the U-statistics formalism to derive their unbiased estimates. Over the years, alternative methods have been proposed to estimate the variance of AUC. For example, Delong et al. have proposed a straightforward estimate that has attractive asymptotic properties. At small sample sizes, however, the DeLong method will be biased. In the early stage of investigation, researchers don't always have enough data; therefore, those asymptotic variance estimates such as DeLong's can be unreliable. In this article we propose a two-way random effects analysis of variance (ANOVA) method to compute an unbiased variance estimate of a two-sample U-statistic of order (1,1) in general, and of the AUC in particular. We prove that this variance estimate is equal to the fully U-statistic result. In the particular case of the AUC variance estimate we compare our result to DeLong's AUC variance estimate. We extend the result to obtain an unbiased estimate of variance for a linear combination of possibly correlated AUCs. A natural consequence of this extension is the estimate of variance of the difference of the areas under two correlated ROC curves. This difference is of interest in many diagnostic studies, namely, the comparison of two different modalities used to diagnose the same disease. C1 [Tcheuko, Lucas; Gallas, Brandon; Samuelson, Frank] US FDA, Silver Spring, MD USA. RP Tcheuko, L (reprint author), US FDA, CDRH OSB DBS, 10903 New Hampshire Ave, Silver Spring, MD 20943 USA. EM lucast@math.umd.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA KARL JOHANS GATE 5, NO-0154 OSLO, NORWAY SN 1559-8608 EI 1559-8616 J9 J STAT THEORY PRACT JI J. Stat. Theory Pract. PY 2016 VL 10 IS 1 BP 87 EP 99 DI 10.1080/15598608.2015.1077759 PG 13 WC Statistics & Probability SC Mathematics GA EA7GG UT WOS:000386797800007 ER PT J AU Huang, X Wang, QY Zheng, J Chen, J Ghosn, M Shah, DJ Kainz, W AF Huang, Xin Wang, Qingyan Zheng, Jason Chen, Ji Ghosn, Mohamad Shah, Dipan J. Kainz, Wolfgang GP IEEE TI Using Transfer Function Approach To Develop MRI Visible and Low RF Heating Sleeve for Cardiac Applicaion SO 2016 IEEE/ACES INTERNATIONAL CONFERENCE ON WIRELESS INFORMATION TECHNOLOGY AND SYSTEMS (ICWITS) AND APPLIED COMPUTATIONAL ELECTROMAGNETICS (ACES) LA English DT Proceedings Paper CT IEEE/ACES International Conference on Wireless Information Technology (ICWITS) and System and Applied Computational Electromagnetics (ACES) CY MAR 13-17, 2016 CL Honolulu, HI SP IEEE Antennas & Propagat Soc, Appl Computat Electromagnet Soc, IEEE DE MRI RF Heating; MRI Visible Catheter ID IMPLANTED PACEMAKERS; APPARATUS AB A method is developed to evaluate the design of MRI visible and low heating catheter coating layer for cardiac and neuromodulation applications. The procedure consists of both experimental characterization of the coating layer as well as detailed electromagnetic simulation of human subject models during MRI procedure. Practical examples are used to demonstrate the effectiveness of this procedure. C1 [Huang, Xin; Wang, Qingyan; Zheng, Jason; Chen, Ji] Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. [Ghosn, Mohamad; Shah, Dipan J.] Houston Methodist DeBakey Heart & Vasc Ctr, 6550 Fannin St,Smith Tower,Suite 677, Houston, TX 77030 USA. [Kainz, Wolfgang] US FDA, Ctr Device & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Huang, X (reprint author), Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. NR 2 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-5090-1259-6 PY 2016 PG 2 WC Computer Science, Theory & Methods; Engineering, Electrical & Electronic; Telecommunications SC Computer Science; Engineering; Telecommunications GA BG0WM UT WOS:000386537100143 ER PT J AU Wang, W Zhang, B AF Wang, Wei Zhang, Bo TI Assessing natural direct and indirect effects for a continuous exposure and a dichotomous outcome SO JOURNAL OF STATISTICAL THEORY AND PRACTICE LA English DT Article DE Continuous exposure; mediation formula; natural direct effect; natural indirect effect; potential outcomes framework; sensitivity analysis ID MEDIATION ANALYSIS; MODELS; DISEASE; REGRESSION; INFERENCE; OBESITY AB Recent advances in the literature on mediation have extended from a traditional linear structural equation modeling approach to causal mediation analysis using potential outcomes framework. Pearl proposed a mediation formula to calculate expected potential outcomes used in the natural direct and indirect effects definition under the key sequential ignorability assumptions. Current methods mainly focused on binary exposure variables, and in this article, this approach is further extended to settings in which continuous exposures may be of interest. Focusing on a dichotomous outcome, we give precise definitions of the natural direct and indirect effects on both the risk difference and odds ratio scales utilizing the empirical joint distribution of the exposure and baseline covariates from the whole sample analysis population. A mediation-formula-based approach is proposed to estimate the corresponding causal quantities. Simulation study is conducted to assess the statistical properties of the proposed method, and we illustrate our approach by applying it to the Jackson Heart Study to estimate the mediation effects of diabetes on the relation between obesity and chronic kidney disease. Sensitivity analysis is performed to assess the impact of violation of no unmeasured mediator-outcome confounder assumption. C1 [Wang, Wei] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, New Guyton Res Bldg G562,2500 North State St, Jackson, MS 39216 USA. [Zhang, Bo] US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Wang, W (reprint author), Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, New Guyton Res Bldg G562,2500 North State St, Jackson, MS 39216 USA. EM wwang@umc.edu NR 27 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS AS PI OSLO PA KARL JOHANS GATE 5, NO-0154 OSLO, NORWAY SN 1559-8608 EI 1559-8616 J9 J STAT THEORY PRACT JI J. Stat. Theory Pract. PY 2016 VL 10 IS 3 BP 574 EP 587 DI 10.1080/15598608.2016.1203843 PG 14 WC Statistics & Probability SC Mathematics GA EA7GT UT WOS:000386799300007 PM 28255292 ER PT S AU Bakic, PR Myers, KJ Glick, SJ Maidment, ADA AF Bakic, Predrag R. Myers, Kyle J. Glick, Stephen J. Maidment, Andrew D. A. CA AAPM Task Grp 234 BE Tingberg, A Lang, K Timberg, P TI Virtual Tools for the Evaluation of Breast Imaging: State-of-the Science and Future Directions SO BREAST IMAGING, IWDM 2016 SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 13th International Workshop on Breast Imaging (IWDM) CY JUN 19-22, 2016 CL Malmo, SWEDEN DE Mammography; Digital breast tomosynthesis; Breast imaging simulation; Anthropomorphic phantoms; Virtual clinical trials; Model observers AB The beginning of this century saw the development of simulation methods for the evaluation of breast imaging, motivated by the limitations of conventional clinical trials. This has led to the formation of AAPM Task Group on Virtual Tools for the Validation of 3D/4D X-ray Breast Imaging Systems (TG234), gathering researchers from academia, industry, and government, interested in the development, testing, and adoption of these tools. TG234 is currently finalizing its report. The report has been designed as an experiential guide through the steps of simulating breast anatomy, image acquisition, image interpretation, and analysis. TG234 activities include disseminating the idea of virtual clinical trials through numerous focused conference sessions and AAPM annual meeting symposia. This paper reflects our desire to initiate wider discussion about the future directions in the development of virtual tools for the design and evaluation of novel breast imaging systems. C1 [Bakic, Predrag R.; Maidment, Andrew D. A.] Univ Penn, Dept Radiol, Philadelphia, PA USA. [Myers, Kyle J.; Glick, Stephen J.; AAPM Task Grp 234] US FDA, Silver Spring, MD USA. RP Bakic, PR (reprint author), Univ Penn, Dept Radiol, Philadelphia, PA USA. EM Predrag.Bakic@uphs.upenn.edu NR 9 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0302-9743 BN 978-3-319-41546-8; 978-3-319-41545-1 J9 LECT NOTES COMPUT SC PY 2016 VL 9699 BP 518 EP 524 DI 10.1007/978-3-319-41546-8_65 PG 7 WC Computer Science, Software Engineering; Computer Science, Theory & Methods; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BG0LB UT WOS:000386324200065 ER PT S AU Ikejimba, L Graff, C Glick, S AF Ikejimba, Lynda Graff, Christian Glick, Stephen BE Tingberg, A Lang, K Timberg, P TI Rapid Generation of Structured Physical Phantoms for Mammography and Digital Breast Tomosynthesis SO BREAST IMAGING, IWDM 2016 SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 13th International Workshop on Breast Imaging (IWDM) CY JUN 19-22, 2016 CL Malmo, SWEDEN DE Breast phantom; Anthropomorphic; Iodine; Linear attenuation AB Nonuniform phantoms are needed in order to fully characterize the impact of anatomical structures on system performance in mammography and digital breast tomosynthesis (DBT). In this work, a new type of textured physical phantom is presented, compatible for use in both 2D and 3D applications. The breast phantom was first modeled analytically, and then fabricated using inkjet printing onto parchment paper and slide transparencies. A radiographic ink solution was synthesized with 350 mg/mL iohexol and pigmented ink. The effective linear attenuation coefficient (mu(eff)) of the parchment paper alone (0.078 +/- 0.003 mm(-1)) was found to be very close to that of a 70 % adipose, 30 % fibroglandular tissue mixture (0.078 +/- 0.004 mm(-1)). The mu(eff) of the parchment paper with iodine (0.010 +/- 0.005 mm(-1)) was close to that of 100 % fibroglandular tissue (0.11 +/- 0.004 mm(-1)). This new parchment and iodine phantom has strong potential for use in imaging studies. C1 [Ikejimba, Lynda; Graff, Christian; Glick, Stephen] US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD 20993 USA. RP Ikejimba, L (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD 20993 USA. EM Lynda.Ikejimba@fda.hhs.gov; Christian.Graff@fda.hhs.gov; Stephen.Glick@fda.hhs.gov NR 7 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0302-9743 BN 978-3-319-41546-8; 978-3-319-41545-1 J9 LECT NOTES COMPUT SC PY 2016 VL 9699 BP 654 EP 659 DI 10.1007/978-3-319-41546-8_81 PG 6 WC Computer Science, Software Engineering; Computer Science, Theory & Methods; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BG0LB UT WOS:000386324200081 ER PT J AU Zhu, H Bouhifd, M Donley, E Egnash, L Kleinstreuer, N Kroese, ED Liu, ZC Luechtefeld, T Palmer, J Pamies, D Shen, J Strauss, V Wu, SD Hartung, T AF Zhu, Hao Bouhifd, Mounir Donley, Elizabeth Egnash, Laura Kleinstreuer, Nicole Kroese, E. Dinant Liu, Zhichao Luechtefeld, Thomas Palmer, Jessica Pamies, David Shen, Jie Strauss, Volker Wu, Shengde Hartung, Thomas TI Supporting Read-Across Using Biological Data SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Article DE read-across; biological similarity; safety assessment; big data ID COMPARATIVE TOXICOGENOMICS DATABASE; COMPUTATIONAL TOXICOLOGY RESOURCE; DETECTING REPRODUCTIVE TOXICANTS; ADVERSE OUTCOME PATHWAY; VITRO TEST BATTERY; IN-VITRO; RISK-ASSESSMENT; ENVIRONMENTAL CHEMICALS; DEVELOPMENTAL TOXICITY; SCREENING ASSAYS AB Read-across, i.e., filling toxicological data gaps by relating to similar chemicals for which test data are available, is usually done based on chemical similarity. Besides structure and physico-chemical properties, biological similarity based on biological data adds extra strength to this process. In the simplest case, chemically similar substances also show similar test results in relevant in vitro assays. This is a well-established method for the read-across of, e.g., genotoxicity assays. Larger datasets of biological and toxicological properties of hundreds and thousands of substances are becoming available, enabling big data approaches in read-across studies. In the context of developing Good Read-Across Practice guidance, a number of case studies using various big data sources were evaluated to assess the contribution of biological data to enriching read-across. An example is given for the US EPA's ToxCast dataset which allows read-across for high quality uterotrophic assays for estrogenic endocrine disruption. Similarly, an example is given for REACH registration data that enhances read-across for acute toxicity studies. A different approach is taken using omics data to establish biological similarity: Examples are given for in vitro stem cell models and short-term in vivo repeated dose studies in rats used to support read-across and category formation. These preliminary biological data-driven read-across studies show the way towards the generation of new read-across approaches that can inform chemical safety assessment. C1 [Zhu, Hao] Rutgers State Univ, Dept Chem, Camden, NJ USA. [Zhu, Hao] Rutgers State Univ, Ctr Computat & Integrat Biol, Camden, NJ USA. [Bouhifd, Mounir; Luechtefeld, Thomas; Pamies, David; Hartung, Thomas] Johns Hopkins Bloomberg Sch Publ Hlth, CAAT, Baltimore, MD USA. [Donley, Elizabeth; Egnash, Laura; Palmer, Jessica] Stemina Biomarker Discovery Inc, Madison, WI USA. [Kleinstreuer, Nicole] NIEHS, Natl Toxicol Program, Interagency Ctr Evaluat Alternat Toxicol Methods, POB 12233, Res Triangle Pk, NC 27709 USA. [Kroese, E. Dinant] TNO, Risk Anal Prod Dev, Zeist, Netherlands. [Liu, Zhichao] US FDA, NCTR, Little Rock, AR USA. [Shen, Jie] Res Inst Fragrance Mat Inc, Woodcliff Lake, NJ USA. [Strauss, Volker] BASF Aktiengesellsch Expt Toxicol & Ecol, Ludwigshafen, Germany. [Wu, Shengde] Procter & Gamble, Cincinnati, OH USA. [Hartung, Thomas] Univ Konstanz, CAAT Europe, Constance, Germany. RP Hartung, T (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Alternat Anim Testing, 615 North Wolfe St, Baltimore, MD 21205 USA. EM thartun1@jhu.edu OI Kleinstreuer, Nicole/0000-0002-7914-3682 FU NIEHS training grant [T32 ES007141]; EU Horizon 2020 project EUToxRisk FX T.L. was supported by NIEHS training grant (T32 ES007141). Support from the EU Horizon 2020 project EUToxRisk is gratefully appreciated. NR 110 TC 7 Z9 7 U1 8 U2 9 PU SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH PI HEILDEBERG PA TIERGARTENSTRASSE 17, HEILDEBERG, 69121, GERMANY SN 1868-596X EI 1868-8551 J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2016 VL 33 IS 2 BP 167 EP 182 DI 10.14573/altex.1601252 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DZ0FI UT WOS:000385512500008 PM 26863516 ER PT J AU Marx, U Andersson, TB Bahinski, A Beilmann, M Beken, S Cassee, FR Cirit, M Daneshian, M Fitzpatrick, S Frey, O Gaertner, C Giese, C Griffith, L Hartung, T Heringa, MB Hoeng, J de Jong, WH Kojima, H Kuehnl, J Leist, M Luch, A Maschmeyer, I Sakharov, D Sips, AJAM Steger-Hartmann, T Tagle, DA Tonevitsky, A Tralau, T Tsyb, S van de Stolpe, A Vandebriel, R Vulto, P Wang, JF Wiest, J Rodenburg, M Roth, A AF Marx, Uwe Andersson, Tommy B. Bahinski, Anthony Beilmann, Mario Beken, Sonja Cassee, Flemming R. Cirit, Murat Daneshian, Mardas Fitzpatrick, Susan Frey, Olivier Gaertner, Claudia Giese, Christoph Griffith, Linda Hartung, Thomas Heringa, Minne B. Hoeng, Julia de Jong, Wim H. Kojima, Hajime Kuehnl, Jochen Leist, Marcel Luch, Andreas Maschmeyer, Ilka Sakharov, Dmitry Sips, Adrienne J. A. M. Steger-Hartmann, Thomas Tagle, Danilo A. Tonevitsky, Alexander Tralau, Tewes Tsyb, Sergej van de Stolpe, Anja Vandebriel, Rob Vulto, Paul Wang, Jufeng Wiest, Joachim Rodenburg, Marleen Roth, Adrian TI Biology-Inspired Microphysiological System Approaches to Solve the Prediction Dilemma of Substance Testing SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Editorial Material DE microphysiological systems; organ-on-a-chip; in vitro models; predictive toxicology; drug testing ID ON-A-CHIP; PLURIPOTENT STEM-CELLS; SKIN SENSITIZATION POTENCY; NEURAL-NETWORK ANALYSIS; LYMPH-NODE ASSAY; MULTI-ORGAN-CHIP; IN-VITRO MODELS; SCREENING CONTACT ALLERGENS; OF-THE-ART; MICROFLUIDIC DEVICE AB The recent advent of microphysiological systems-microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro-promises to enable a global paradigm shift in drug development. An extraordinary US government initiative and various dedicated research programs in Europe and Asia recently have led to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis will model various disease stages and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agriculture, food, ecosystems or cosmetics, thus replacing the use of laboratory animal models. Here, thirty-six experts from academia, industry and regulatory bodies present the results of an intensive workshop (held in June 2015, Berlin, Germany). They review the status quo of microphysiological systems available today against industry needs, and assess the broad variety of approaches with fit-for-purpose potential in the drug development cycle. Feasible technical solutions to reach the next levels of human biology in vitro are proposed. Furthermore, key organ-on-a-chip case studies as well as various national and international programs are highlighted. Finally, a roadmap into the future towards more predictive and regulatory-accepted substance testing on a global scale is outlined. C1 [Marx, Uwe; Maschmeyer, Ilka] TissUse GmbH, Berlin, Germany. [Andersson, Tommy B.] AstraZeneca, Cardiovasc & Metab Dis Innovat Med & Early Dev Bi, Molndal, Sweden. [Andersson, Tommy B.] Karolinska Inst, Dept Physiol & Pharmacol, Pharmacogenet Sect, Stockholm, Sweden. [Bahinski, Anthony] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Beilmann, Mario] Boehringer Ingelheim Pharma GmbH & Co KG, Nonclin Drug Safety, Biberach, Germany. [Beken, Sonja] Fed Agcy Med & Hlth Prod, Brussels, Belgium. [Cassee, Flemming R.; Heringa, Minne B.; de Jong, Wim H.; Sips, Adrienne J. A. M.; Vandebriel, Rob; Rodenburg, Marleen] Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. [Cassee, Flemming R.] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Cirit, Murat; Griffith, Linda] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Daneshian, Mardas; Hartung, Thomas; Leist, Marcel] Univ Konstanz, Ctr Alternat Anim Testing Europe, Constance, Germany. [Fitzpatrick, Susan] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Frey, Olivier] Swiss Fed Inst Technol, Bio Engn Lab, Dept Biosyst Sci & Engn, Basel, Switzerland. [Gaertner, Claudia] Microfluid ChipShop GmbH, Jena, Germany. [Giese, Christoph] ProBioGen AG, Berlin, Germany. [Hartung, Thomas] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Alternat Anim Testing, Baltimore, MD USA. [Hoeng, Julia] Philip Morris Int R&D, Neuchatel, Switzerland. [Kojima, Hajime] Japanese Ctr Validat Anim Methods, Tokyo, Japan. [Kuehnl, Jochen] Beiersdorf, Hamburg, Germany. [Luch, Andreas; Tralau, Tewes] German Fed Inst Risk Assessment, Dept Chem & Prod Safety, Berlin, Germany. [Sakharov, Dmitry] Sci Res Ctr Bioclinicum, Moscow, Russia. [Steger-Hartmann, Thomas] Bayer, Invest Toxicol, Berlin, Germany. [Tagle, Danilo A.] Natl Ctr Adv Translat Sci, NIH, Bethesda, MD USA. [Tonevitsky, Alexander] Natl Ctr Med Radiol Res, Moscow, Russia. [Tsyb, Sergej] Russian Minist Prod & Trade, Moscow, Russia. [van de Stolpe, Anja] Inst Human Organ & Dis Model Technol, Leiden, Netherlands. [Vulto, Paul] MIMETAS BV, Leiden, Netherlands. [Wang, Jufeng] Chinese Natl Ctr Safety Evaluat Drugs, Beijing, Peoples R China. [Wiest, Joachim] Cellasys GmbH, Kronburg, Germany. [Roth, Adrian] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Basel, Switzerland. RP Marx, U (reprint author), TissUse GmbH, Berlin, Germany. EM Uwe.marx@tissuse.com RI Frey, Olivier/G-7065-2011; Leist, Marcel/D-2133-2010; OI Frey, Olivier/0000-0002-4259-3751; Leist, Marcel/0000-0002-3778-8693; Wiest, Joachim/0000-0003-4372-9523; Tonevitsky, Alexander/0000-0002-7079-7145 NR 374 TC 6 Z9 6 U1 15 U2 15 PU SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH PI HEILDEBERG PA TIERGARTENSTRASSE 17, HEILDEBERG, 69121, GERMANY SN 1868-596X EI 1868-8551 J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2016 VL 33 IS 3 BP 272 EP 321 DI 10.14573/altex.1603161 PG 50 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DZ0FW UT WOS:000385513900008 PM 27180100 ER PT J AU Biglan, KM Shoulson, I Kieburtz, K Oakes, D Kayson, E Shinaman, MA Zhao, HW Romer, M Young, A Hersch, S Penney, J Marder, K Paulsen, J Quaid, K Siemers, E Tanner, C Mallonee, W Suter, G Dubinsky, R Gray, C Nance, M Bundlie, S Radtke, D Kostyk, S Baic, C Caress, J Walker, F Hunt, V O'Neill, C Chouinard, S Factor, S Greenamyre, T Wood-Siverio, C Corey-Bloom, J Song, D Peavy, G Moskowitz, C Wesson, M Samii, A Bird, T Lipe, H Blindauer, K Marshall, F Zimmerman, C Goldstein, J Rosas, D Novak, P Caviness, J Adler, C Duffy, A Wheelock, V Tempkin, T Richman, D Seeberger, L Albin, R Chou, KL Racette, B Perlmutter, JS Perlman, S Bordelon, Y Martin, W Wieler, M Leavitt, B Raymond, L Decolongon, J Clarke, L Jankovic, J Hunter, C Hauser, RA Sanchez-Ramos, J Furtado, S Suchowersky, O Klimek, ML Guttman, M Sethna, R Feigin, A Cox, M Shannon, B Percy, A Dure, L Harrison, M Johnson, W Higgins, D Molho, E Nickerson, C Evans, S Hobson, D Singer, C Galvez-Jimenez, N Shannon, K Comella, C Ross, C Saint-Hilaire, MH Testa, C Rosenblatt, A Hogarth, P Weiner, W Como, P Kumar, R Cotto, C Stout, J Brocht, A Watts, A Eberly, S Weaver, C Foroud, T Gusella, J MacDonald, M Myers, R Fahn, S Shults, C AF Biglan, Kevin Michael Shoulson, Ira Kieburtz, Karl Oakes, David Kayson, Elise Shinaman, M. Aileen Zhao, Hongwei Romer, Megan Young, Anne Hersch, Steven Penney, Jack Marder, Karen Paulsen, Jane Quaid, Kimberly Siemers, Eric Tanner, Caroline Mallonee, William Suter, Greg Dubinsky, Richard Gray, Carolyn Nance, Martha Bundlie, Scott Radtke, Dawn Kostyk, Sandra Baic, Corrine Caress, James Walker, Francis Hunt, Victoria O'Neill, Christine Chouinard, Sylvain Factor, Stewart Greenamyre, Timothy Wood-Siverio, Cathy Corey-Bloom, Jody Song, David Peavy, Guerry Moskowitz, Carol Wesson, Melissa Samii, Ali Bird, Thomas Lipe, Hillary Blindauer, Karen Marshall, Frederick Zimmerman, Carol Goldstein, Jody Rosas, Diana Novak, Peter Caviness, John Adler, Charles Duffy, Amy Wheelock, Vicki Tempkin, Teresa Richman, David Seeberger, Lauren Albin, Roger Chou, Kelvin L. Racette, Brad Perlmutter, Joel S. Perlman, Susan Bordelon, Yvette Martin, Wayne Wieler, Marguerite Leavitt, Blair Raymond, Lynn Decolongon, Joji Clarke, Lorne Jankovic, Joseph Hunter, Christine Hauser, Robert A. Sanchez-Ramos, Juan Furtado, Sarah Suchowersky, Oksana Klimek, Mary Lou Guttman, Mark Sethna, Rustom Feigin, Andrew Cox, Marie Shannon, Barbara Percy, Alan Dure, Leon Harrison, Madaline Johnson, William Higgins, Donald Molho, Eric Nickerson, Constance Evans, Sharon Hobson, Douglas Singer, Carlos Galvez-Jimenez, Nestor Shannon, Kathleen Comella, Cynthia Ross, Christopher Saint-Hilaire, Marie H. Testa, Claudia Rosenblatt, Adam Hogarth, Penelope Weiner, William Como, Peter Kumar, Rajeev Cotto, Candace Stout, Julie Brocht, Alicia Watts, Arthur Eberly, Shirley Weaver, Christine Foroud, Tatiana Gusella, James MacDonald, Marcy Myers, Richard Fahn, Stanley Shults, Clifford CA Huntington Study Grp PHAROS Invest TI Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS) Implications for Clinical Trials SO JAMA NEUROLOGY LA English DT Article ID CAG REPEAT LENGTH; PREDICT-HD; COGNITIVE DECLINE; FLUENCY DEFICITS; TRACK-HD; DISEASE; PREMANIFEST; PROGRESSION; DIAGNOSIS; CARRIERS AB IMPORTANCE Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (>= 37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion. C1 [Biglan, Kevin Michael; Kieburtz, Karl; Kayson, Elise; Shinaman, M. Aileen; Marshall, Frederick; Zimmerman, Carol; Goldstein, Jody; Brocht, Alicia; Watts, Arthur; Weaver, Christine] Univ Rochester, Dept Neurol, Rochester, NY 14642 USA. [Shoulson, Ira] Georgetown Univ, Dept Neurol, Washington, DC USA. [Oakes, David; Eberly, Shirley] Univ Rochester, Dept Biostat, Rochester, NY USA. [Zhao, Hongwei] Texas A&M, Dept Epidemiol & Biostat, College Stn, TX USA. [Romer, Megan] Penn State Univ, Dept Stat, University Pk, PA 16802 USA. [Young, Anne; Hersch, Steven; Penney, Jack; Rosas, Diana; Novak, Peter; Gusella, James; MacDonald, Marcy] Massachusetts Gen Hosp, Charleston, SC USA. [Marder, Karen; Fahn, Stanley] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA. [Paulsen, Jane] Univ Iowa, Dept Psychiat & Neurol, Iowa City, IA USA. [Quaid, Kimberly; Wesson, Melissa; Foroud, Tatiana] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Siemers, Eric] Lilly Corp Ctr, Indianapolis, IN USA. [Tanner, Caroline] Parkinsons Inst, Sunnyvale, CA USA. [Mallonee, William] Hereditary Neurol Dis Ctr, Wichita, KS USA. [Suter, Greg; Dubinsky, Richard; Gray, Carolyn] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA. [Nance, Martha; Bundlie, Scott; Radtke, Dawn] Hennepin Cty Med Ctr, Dept Neurol, Minneapolis, MN 55415 USA. [Kostyk, Sandra; Baic, Corrine] Ohio State Univ, Dept Neurol, Columbus, OH 43210 USA. [Caress, James; Walker, Francis; Hunt, Victoria; O'Neill, Christine] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Chouinard, Sylvain] Hotel Dieu Hosp CHUM, Montreal, PQ, Canada. [Factor, Stewart; Greenamyre, Timothy; Wood-Siverio, Cathy] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Corey-Bloom, Jody; Song, David; Peavy, Guerry; Shults, Clifford] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Samii, Ali; Bird, Thomas; Lipe, Hillary] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Samii, Ali; Bird, Thomas; Lipe, Hillary] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Blindauer, Karen] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Caviness, John; Adler, Charles; Duffy, Amy] Mayo Clin Scottsdale, Dept Neurol, Scottsdale, AZ USA. [Wheelock, Vicki; Tempkin, Teresa; Richman, David] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [Seeberger, Lauren] Idaho Elks Rehabil Hosp, Boise, ID USA. [Albin, Roger; Chou, Kelvin L.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Racette, Brad; Perlmutter, Joel S.] Washington Univ, Dept Neurol, St Louis, MO USA. [Perlman, Susan; Bordelon, Yvette] Univ Calif Los Angeles, Med Ctr, Dept Neurol, Los Angeles, CA 90024 USA. [Martin, Wayne; Wieler, Marguerite] Univ Alberta, Dept Neurol, Edmonton, AB, Canada. [Leavitt, Blair; Raymond, Lynn; Decolongon, Joji; Clarke, Lorne] Univ British Columbia, Dept Neurol, Vancouver, BC, Canada. [Jankovic, Joseph; Hunter, Christine; Klimek, Mary Lou] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Hauser, Robert A.; Sanchez-Ramos, Juan] Univ S Florida, Dept Neurol, Tampa, FL USA. [Furtado, Sarah; Suchowersky, Oksana] Univ Calgary, Dept Neurol, Calgary, AB, Canada. [Guttman, Mark; Sethna, Rustom] Ctr Addict & Mental Hlth, Markham, ON, Canada. [Feigin, Andrew; Cox, Marie; Shannon, Barbara] North Shore LIJ Univ Hosp, Dept Neurol, Manhasset, NY USA. [Percy, Alan; Dure, Leon] Univ Alabama Birmingham, Dept Neurobiol, Birmingham, AL USA. [Harrison, Madaline] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Johnson, William] Univ Med & Dent New Jersey, Dept Neurol, Robert Wood Johnson Med Ctr, Stratford, NJ USA. [Higgins, Donald; Molho, Eric; Nickerson, Constance; Evans, Sharon] Albany Med Coll, Dept Neurol, Albany, NY 12208 USA. [Hobson, Douglas] Winnipeg Clin, Winnipeg, MB, Canada. [Singer, Carlos; Galvez-Jimenez, Nestor] Univ Miami, Dept Neurol, Miami, FL USA. [Shannon, Kathleen; Comella, Cynthia] Rush Univ, Dept Neurol Sci, Chicago, IL 60612 USA. [Ross, Christopher] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Saint-Hilaire, Marie H.; Myers, Richard] Boston Univ, Dept Neurol, Boston, MA USA. [Testa, Claudia; Rosenblatt, Adam] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA 23284 USA. [Hogarth, Penelope] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Weiner, William] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Como, Peter] US FDA, Rockville, MD 20857 USA. [Kumar, Rajeev] Rocky Mt Movement Disorders Ctr, Dept Neurol, Denver, CO USA. [Cotto, Candace] Inst Neurodegenerat Disorders, Dept Neurol, New Haven, CT USA. [Stout, Julie] Monash Univ, Clin & Cognit Neurosci Lab, Melbourne, Vic, Australia. RP Biglan, KM (reprint author), Univ Rochester, Dept Neurol, Rochester, NY 14642 USA. OI Raymond, Lynn/0000-0002-8610-1042 FU National Human Genome Research Institute; National Institutes of Health NINDS [5RO1-HG-02449]; High Q Foundation/CHDI Foundation, Inc; Huntington's Disease Society of America; Hereditary Disease Foundation; Huntington Society of Canada; Fox Family Foundation FX This research was supported by grants and awards from the National Human Genome Research Institute and grant 5RO1-HG-02449 from the National Institutes of Health NINDS (Dr Shoulson), the High Q Foundation/CHDI Foundation, Inc, the Huntington's Disease Society of America, the Hereditary Disease Foundation, the Huntington Society of Canada, and the Fox Family Foundation. NR 35 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD JAN PY 2016 VL 73 IS 1 BP 102 EP 110 DI 10.1001/jamaneurol.2015.2736 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DZ4RZ UT WOS:000385848500015 ER PT S AU Kaneko, KJ AF Kaneko, K. J. BE DePamphilis, ML TI Metabolism of Preimplantation Embryo Development: A Bystander or an Active Participant? SO MAMMALIAN PREIMPLANTATION DEVELOPMENT SE Current Topics in Developmental Biology LA English DT Review; Book Chapter ID PENTOSE-PHOSPHATE PATHWAY; EARLY MOUSE EMBRYO; INNER CELL MASS; YEAST SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL QUALITY-CONTROL; PROTEIN-COUPLED RECEPTOR; SIMPLEX OPTIMIZED MEDIUM; FATTY-ACID OXIDATION; CANDIDA-ALBICANS; AMINO-ACIDS AB Unicellular organisms are exquisitely sensitive to nutrient availability in the environment and have evolved elaborate mechanisms to sense the levels and types of nutrients, altering gene expression patterns accordingly to adjust the metabolic activities required to survive. Thus, environmental cues induce adaptive metabolic differentiation through transcriptional and posttranscriptional changes. Similarly, preimplantation embryos are exposed to various environmental cues within the maternal reproductive tract prior to implantation. Because only "simple" culture conditions are required, it is assumed that these embryos are genetically preprogrammed to develop with little influence from the environment, with the exception of few "necessities" provided by the environment. However, a wealth of literature now suggests that the developing embryos are greatly influenced by the maternal environment. Even though the developing embryos have the capacity and plasticity to deal with nutritional imbalance posed by an altered maternal environment, there is often a trade-off to the overall fitness of those embryos later in life. Despite these studies that underline the general importance of the reproductive environment during development, it is thought that the primary driver of mammalian development is strictly genetic and that metabolic adaptation by the preimplantation embryo is secondary to genetic control. In this review, I propose that not only does the maternal environment of developing preimplantation embryos influence developmental potential, pregnancy outcomes, and postnatal disease states, but that it has an active role in induction and potentiation of the first differentiation event, the production of trophectoderm and inner cell mass lineages. C1 [Kaneko, K. J.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Kaneko, KJ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM kotaro.kaneko@fda.hhs.gov NR 232 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0070-2153 BN 978-0-12-801617-6; 978-0-12-801428-8 J9 CURR TOP DEV BIOL JI Curr. Top. Dev. Biol. PY 2016 VL 120 BP 259 EP 310 DI 10.1016/bs.ctdb.2016.04.010 PG 52 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA BF6UG UT WOS:000383713000009 PM 27475855 ER PT J AU Wright, N Walters, P Strang, J AF Wright, Nat Walters, Pamela Strang, John TI Dual diagnosis in prisons: management of co-existing substance use and mental health disorders Prevalence of mental ill health in prisons SO ADVANCES IN DUAL DIAGNOSIS LA English DT Editorial Material ID PSYCHIATRIC-DISORDERS; OUTCOMES; SUICIDE; ENGLAND; COHORT; WALES; RISK; TC C1 [Walters, Pamela] SWL & St Georges Mental Hlth Trust, London, England. [Walters, Pamela] South London & Maudsley Mental Hlth NHS Trust, London, England. [Strang, John] Kings Coll London, IoPPN, Dept Addict Acad Act, London WC2R 2LS, England. [Strang, John] KHP AHSC Kings Hlth Partners Acad Hlth Sci Ctr, CAG, London, England. [Strang, John] South London & Maudsley SLaM NHS Fdn Trust, London, England. [Strang, John] Kings Coll London, London WC2R 2LS, England. [Strang, John] WHO, Geneva, Switzerland. [Strang, John] UNODC, Vienna, Austria. [Strang, John] US FDA, EMCDDA, Rockville, MD 20857 USA. [Strang, John] NIDA, Bethesda, MD USA. RP Walters, P (reprint author), SWL & St Georges Mental Hlth Trust, London, England.; Walters, P (reprint author), South London & Maudsley Mental Hlth NHS Trust, London, England. EM nat.wright@spectrum-cic.nhs.uk NR 32 TC 0 Z9 0 U1 1 U2 1 PU EMERALD GROUP PUBLISHING LTD PI BINGLEY PA HOWARD HOUSE, WAGON LANE, BINGLEY BD16 1WA, W YORKSHIRE, ENGLAND SN 1757-0972 EI 2042-8324 J9 ADV DUAL DIAGN JI Adv. Dual Diagn. PY 2016 VL 9 IS 1 BP 1 EP 6 DI 10.1108/ADD-12-2015-0025 PG 6 WC Psychology, Clinical SC Psychology GA DY0NW UT WOS:000384794500001 ER PT J AU Cai, CZ Nedosekin, DA Menyaev, YA Sarimollaoglu, M Proskurnin, MA Zharov, VP AF Cai, Chengzhong Nedosekin, Dmitry A. Menyaev, Yulian A. Sarimollaoglu, Mustafa Proskurnin, Mikhail A. Zharov, Vladimir P. TI Photoacoustic Flow Cytometry for Single Sickle Cell Detection In Vitro and In Vivo SO ANALYTICAL CELLULAR PATHOLOGY LA English DT Article ID DIAGNOSIS; HEMOGLOBINOPATHIES; DISEASE; BLOOD; MICE AB Control of sickle cell disease (SCD) stage and treatment efficiency are still time-consuming which makes well-timed prevention of SCD crisis difficult. We show here that in vivo photoacoustic (PA) flow cytometry (PAFC) has a potential for real-time monitoring of circulating sickled cells in mouse model. In vivo data were verified by in vitro PAFC and photothermal (PT) and PA spectral imaging of sickle red blood cells (sRBCs) expressing SCD-associated hemoglobin (HbS) compared to normal red blood cells (nRBCs). We discovered that PT and PA signal amplitudes from sRBCs in linear mode were 2-4-fold lower than those from nRBCs. PT and PA imaging revealed more profound spatial hemoglobin heterogeneity in sRBCs than in nRBCs, which can be associated with the presence of HbS clusters with high local absorption. This hypothesis was confirmed in nonlinear mode through nanobubble formation around overheated HbS clusters accompanied by spatially selective signal amplification. More profound differences in absorption of sRBCs than in nRBCs led to notable increase in PA signal fluctuation (fluctuation PAFC mode) as an indicator of SCD. The obtained data suggest that noninvasive label-free fluctuation PAFC has a potential for real-time enumeration of sRBCs both in vitro and in vivo. C1 [Cai, Chengzhong; Nedosekin, Dmitry A.; Menyaev, Yulian A.; Sarimollaoglu, Mustafa; Zharov, Vladimir P.] Univ Arkansas Med Sci, Arkansas Nanomed Ctr, Little Rock, AR 72205 USA. [Cai, Chengzhong] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Proskurnin, Mikhail A.] Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119991, Russia. RP Zharov, VP (reprint author), Univ Arkansas Med Sci, Arkansas Nanomed Ctr, Little Rock, AR 72205 USA. EM zharovvladimirp@uams.edu RI Proskurnin, Mikhail/E-9704-2011; OI Proskurnin, Mikhail/0000-0001-5577-6883; Menyaev, Yulian/0000-0001-5861-3641 FU National Institute of Health [R01CA131164, R01EB009230]; National Science Foundation [DB-155606085, OIA-1457888]; Russian Foundation for Basic Research [14-04-01361a, 16-03-01089a] FX This work was supported in part by the National Institute of Health (Grants R01CA131164 and R01EB009230), by the National Science Foundation (Grants DB-155606085 and OIA-1457888), and by the Russian Foundation for Basic Research (Grants 14-04-01361a and 16-03-01089a), The authors are thankful to Mr. Kai Carey (Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, Little Rock, USA) for the proofreading. NR 31 TC 1 Z9 1 U1 4 U2 4 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 315 MADISON AVE 3RD FLR, STE 3070, NEW YORK, NY 10017 USA SN 2210-7177 EI 2210-7185 J9 ANAL CELL PATHOL JI Anal. Cell. Pathol. PY 2016 AR 2642361 DI 10.1155/2016/2642361 PG 11 WC Oncology; Cell Biology; Pathology SC Oncology; Cell Biology; Pathology GA DY5KW UT WOS:000385139500001 ER PT J AU Hursh, DA Stultz, BG Park, SY AF Hursh, Deborah A. Stultz, Brian G. Park, Sung Yeon TI Jun N-terminal kinase signaling makes a face SO FLY LA English DT Article DE Bone Morphogenetic Protein (BMP); decapentaplegic (dpp); Drosophila; head morphogenesis; Jun N-terminal Kinase (JNK) ID DROSOPHILA WING DISC; CIS-REGULATORY REGION; DECAPENTAPLEGIC GENE; IMAGINAL DISCS; GROWTH-CONTROL; ADULT HEAD; DEVELOPMENTAL ANALYSIS; EPITHELIAL-CELLS; THORAX CLOSURE; VENTRAL HEAD AB decapentaplegic (dpp), the Drosophila ortholog of BMP 2/4, directs ventral adult head morphogenesis through expression in the peripodial epithelium of the eye-antennal disc. This dpp expressing domain exerts effects both on the peripodial epithelium, and the underlying disc proper epithelium. We have uncovered a role for the Jun N-terminal kinase (JNK) pathway in dpp-mediated ventral head development. JNK activity is required for dpp's action on the disc proper, but in the absence of dpp expression, excessive JNK activity is produced, leading to specific loss of maxillary palps. In this review we outline our hypotheses on how dpp acts by both short range and longer range mechanisms to direct head morphogenesis and speculate on the dual role of JNK signaling in this process. Finally, we describe the regulatory control of dpp expression in the eye-antennal disc, and pose the problem of how the various expression domains of a secreted protein can be targeted to their specific functions. C1 [Hursh, Deborah A.; Stultz, Brian G.] US FDA, Div Cell & Gene Therapies, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52-72,Rm 3216, Silver Spring, MD 20993 USA. [Park, Sung Yeon] Seoul Natl Univ, Coll Med, Dept Physiol, Ischem Hypox Dis Inst, Seoul, South Korea. RP Hursh, DA (reprint author), US FDA, Div Cell & Gene Therapies, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52-72,Rm 3216, Silver Spring, MD 20993 USA. EM deborah.hursh@fda.hhs.gov NR 56 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1933-6934 EI 1933-6942 J9 FLY JI Fly PY 2016 VL 10 IS 4 BP 195 EP 203 DI 10.1080/19336934.2016.1207012 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DX8XY UT WOS:000384676400006 PM 27384866 ER PT J AU Gamalo-Siebers, M Gao, AJ Lakshminarayanan, M Liu, GH Natanegara, F Railkar, R Schmidli, H Song, GC AF Gamalo-Siebers, Margaret Gao, Aijun Lakshminarayanan, Mani Liu, Guanghan Natanegara, Fanni Railkar, Radha Schmidli, Heinz Song, Guochen TI Bayesian methods for the design and analysis of noninferiority trials SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Bayesian inference; clinical trial; meta-analysis; noninferiority ID NON-INFERIORITY TRIALS; ACTIVE-CONTROL TRIALS; HISTORICAL CONTROL INFORMATION; SAMPLE-SIZE CALCULATIONS; CLINICAL-TRIALS; STATISTICAL-METHODS; BINARY OUTCOMES; END-POINTS; PLACEBO; PROPORTIONS AB The gold standard for evaluating treatment efficacy of a medical product is a placebo-controlled trial. However, when the use of placebo is considered to be unethical or impractical, a viable alternative for evaluating treatment efficacy is through a noninferiority (NI) study where a test treatment is compared to an active control treatment. The minimal objective of such a study is to determine whether the test treatment is superior to placebo. An assumption is made that if the active control treatment remains efficacious, as was observed when it was compared against placebo, then a test treatment that has comparable efficacy with the active control, within a certain range, must also be superior to placebo. Because of this assumption, the design, implementation, and analysis of NI trials present challenges for sponsors and regulators. In designing and analyzing NI trials, substantial historical data are often required on the active control treatment and placebo. Bayesian approaches provide a natural framework for synthesizing the historical data in the form of prior distributions that can effectively be used in design and analysis of a NI clinical trial. Despite a flurry of recent research activities in the area of Bayesian approaches in medical product development, there are still substantial gaps in recognition and acceptance of Bayesian approaches in NI trial design and analysis. The Bayesian Scientific Working Group of the Drug Information Association provides a coordinated effort to target the education and implementation issues on Bayesian approaches for NI trials. In this article, we provide a review of both frequentist and Bayesian approaches in NI trials, and elaborate on the implementation for two common Bayesian methods including hierarchical prior method and meta-analytic-predictive approach. Simulations are conducted to investigate the properties of the Bayesian methods, and some real clinical trial examples are presented for illustration. C1 [Gamalo-Siebers, Margaret] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Gao, Aijun] InVent Hlth Clin, Princeton, NJ USA. [Lakshminarayanan, Mani; Railkar, Radha] Pfizer Inc, Biotechnol Clin Dev Stat, Collegeville, PA 19426 USA. [Liu, Guanghan] Merck Sharp & Dohme Corp, N Wales, PA USA. [Natanegara, Fanni] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Schmidli, Heinz] Novartis Pharma AG, Basel, Switzerland. [Song, Guochen] Quintiles, Durham, NC USA. RP Lakshminarayanan, M (reprint author), Pfizer Inc, Biotechnol Clin Dev Stat, Collegeville, PA 19426 USA. EM Mani.Lakshminarayan@pfizer.com NR 52 TC 1 Z9 1 U1 3 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. PY 2016 VL 26 IS 5 BP 823 EP 841 DI 10.1080/10543406.2015.1074920 PG 19 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DX5SQ UT WOS:000384442400003 PM 26247350 ER PT J AU Liu, Y Upadhyaya, B Fardin-Kia, AR Juenemann, RM Dey, M AF Liu, Yi Upadhyaya, Bijaya Fardin-Kia, Ali Reza Juenemann, Robert M. Dey, Moul TI Dietary resistant starch type 4-derived butyrate attenuates nuclear factor-kappa-B1 through modulation of histone H3 trimethylation at lysine 27 SO FOOD & FUNCTION LA English DT Article ID CHAIN FATTY-ACIDS; NF-KAPPA-B; INTESTINAL EPITHELIAL-CELLS; REGULATORY T-CELLS; GUT MICROBIOTA; ENERGY-METABOLISM; SODIUM-BUTYRATE; GENE-EXPRESSION; UP-REGULATION; IL-10 AB Indigestible resistant starches (RS) are substrates for gut-microbial metabolism and have been shown to attenuate intestinal inflammation but the supporting evidence is inconsistent and lacks mechanistic explanation. We have recently reported dietary RS type 4 (RS4) induced improvements in immunometabolic functions in humans and a concomitant increase in butyrogenic gut-bacteria. Since inflammation is a key component in metabolic diseases, here we investigated the effects of RS4-derived butyrate on the epigenetic repression of pro-inflammatory genes in vivo and in vitro. RS4-fed mice, compared to the controldiet group, had higher cecal butyrate and increased tri-methylation of lysine 27 on histone 3 (H3K27me3) in the promoter of nuclear factor-kappa-B1 (NF kappa B1) in the colon tissue. The H3K27me3-enrichment inversely correlated with the concentration dependent down-regulation of NF kappa B1 in sodium butyrate treated human colon epithelial cells. Two additional inflammatory genes were attenuated by sodium butyrate, but were not linked with H3K27me3 changes. This exploratory study presents a new opportunity for studying underlying H3K27me3 and other methylation modifying mechanisms linked to RS4 biological activity. C1 [Liu, Yi; Upadhyaya, Bijaya; Juenemann, Robert M.; Dey, Moul] South Dakota State Univ, Dept Hlth & Nutr Sci, Box 2203, Brookings, SD 57007 USA. [Fardin-Kia, Ali Reza] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, HFS 717, College Pk, MD 20740 USA. RP Dey, M (reprint author), South Dakota State Univ, Dept Hlth & Nutr Sci, Box 2203, Brookings, SD 57007 USA. EM Moul.Dey@sdstate.edu FU MGP Ingredients Inc., Atchison KS [3P2662]; USDA National Institute of Food and Agriculture [Hatch] [1004817]; National Institutes of Health [R00AT4245] FX This work was supported by MGP Ingredients Inc., Atchison KS [3P2662], the USDA National Institute of Food and Agriculture [Hatch 1004817], and the National Institutes of Health [R00AT4245] to M.D. NR 49 TC 0 Z9 0 U1 2 U2 2 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2042-6496 EI 2042-650X J9 FOOD FUNCT JI Food Funct. PY 2016 VL 7 IS 9 BP 3772 EP 3781 DI 10.1039/c6fo00856a PG 10 WC Biochemistry & Molecular Biology; Food Science & Technology SC Biochemistry & Molecular Biology; Food Science & Technology GA DX3DS UT WOS:000384254100012 PM 27713965 ER PT J AU Yu, H Zeng, J Li, YH Thon, V Shi, BJ Chen, X AF Yu, Hai Zeng, Jie Li, Yanhong Thon, Vireak Shi, Baojun Chen, Xi TI Effective one-pot multienzyme (OPME) synthesis of monotreme milk oligosaccharides and other sialosides containing 4-O-acetyl sialic acid SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID EFFICIENT CHEMOENZYMATIC SYNTHESIS; INFLUENZA-VIRUS INFECTION; SUBSTRATE-SPECIFICITY; SIALYLTRANSFERASE; BETA-1-4-GALACTOSYLTRANSFERASES; PROMISCUITY; FLEXIBILITY; DERIVATIVES; DIVERSITY; LIBRARIES AB A facile one-pot two-enzyme chemoenzymatic approach has been established for the gram (Neu4,5Ac(2)alpha 3Lac, 1.33 g) and preparative scale (Neu4,5Ac(2)alpha 3LNnT) synthesis of monotreme milk oligosaccharides. Other O-acetyl-5-N-acetylneuraminic acid (Neu4,5Ac(2))-or 4-O-acetyl-5-N-glycolylneuraminic acid (Neu4Ac5Gc) -containing alpha 2-3-sialosides have also been synthesized in the preparative scale. Used as an effective probe, Neu4,5Ac(2 alpha)3Gal beta rho NP was found to be a suitable substrate by human influenza A viruses but not bacterial sialidases. C1 [Yu, Hai; Zeng, Jie; Li, Yanhong; Thon, Vireak; Shi, Baojun; Chen, Xi] Univ Calif Davis, Dept Chem, One Shields Ave, Davis, CA 95616 USA. [Zeng, Jie] Henan Inst Sci & Technol, Sch Food Sci, Xinxiang 453003, Henan, Peoples R China. [Shi, Baojun] Northwest A&F Univ, Coll Plant Protect, Yangling 712100, Shaanxi, Peoples R China. [Thon, Vireak] US FDA, Lab Bacterial Polysaccharides, Bethesda, MD 20892 USA. RP Chen, X (reprint author), Univ Calif Davis, Dept Chem, One Shields Ave, Davis, CA 95616 USA. EM xiichen@ucdavis.edu FU US NIH [R01HD065122, R01GM076360- 04S1, U01CA199792]; China Scholarship Council; NSF [DBIO-722538] FX This work was supported by US NIH grants R01HD065122, R01GM076360- 04S1 (to X. C.), and U01CA199792 (to A. V.) as well as scholarships from the China Scholarship Council (to J. Z. and B. S.). A Bruker Avance-800 NMR spectrometer was funded by NSF grant DBIO-722538. We would like to thank Professor Nicole Baumgarth at the University of California-Davis for providing purified human influenza viruses as kind gifts. H. Y., Y. L., and X. C. are co-founders of Glycohub, Inc., a company focused on the development of carbohydrate-based reagents, diagnostics, and therapeutics. Glycohub, Inc. played no role in the design, execution, interpretation, or publication of this study. NR 51 TC 1 Z9 1 U1 3 U2 3 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 EI 1477-0539 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PY 2016 VL 14 IS 36 BP 8586 EP 8597 DI 10.1039/c6ob01706a PG 12 WC Chemistry, Organic SC Chemistry GA DX3YF UT WOS:000384313100022 PM 27548611 ER PT S AU Hammer, DX Lozzi, A Boretsky, A Agrawal, A Welle, CG AF Hammer, Daniel X. Lozzi, Andrea Boretsky, Adam Agrawal, Anant Welle, Cristin G. BE Madsen, SJ Yang, VXD Jansen, ED Luo, Q Ding, J Roe, AW Mohanty, SK Thakor, NV TI Acute changes associated with electrode insertion measured with optical coherence microscopy SO CLINICAL AND TRANSLATIONAL NEUROPHOTONICS; NEURAL IMAGING AND SENSING; AND OPTOGENETICS AND OPTICAL MANIPULATION SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Clinical and Translational Neurophotonics; Neural Imaging and Sensing; and Optogenetics and Optical Manipulation CY FEB 13-16, 2016 CL San Francisco, CA SP SPIE DE Optical coherence microscopy; angiography; neurophotonics; capillary velocimetry; brain-computer interface; penetrating neural electrodes; neuroinflammatory response; cortical window model ID DOPPLER; ANGIOGRAPHY; TOMOGRAPHY; CONTRAST; TISSUE; BRAIN; OCT AB Despite advances in functional neural imaging, penetrating microelectrodes provide the most direct interface for the extraction of neural signals from the nervous system and are a critical component of many high degree-of-freedom brain-computer interface devices. Electrode insertion is a traumatic event that elicits a complex neuroinflammatory response. In this investigation we applied optical coherence microscopy (OCM), particularly optical coherence angiography (OCA), to characterize the immediate tissue response during microelectrode insertion. Microelectrodes of varying dimension and footprint (one-, two-, and four-shank) were inserted into mouse motor cortex beneath a window after craniotomy surgery. The microelectrodes were inserted in 3-4 steps at 15-20 degrees, with approximately 250 mu m linear insertion distance for each step. Before insertion and between each step, OCM datasets were collected, including for quantitative capillary velocimetry. A cohort of control animals without microelectrode insertion was also imaged over a similar time period (2-3 hours). Mechanical tissue deformation was observed in all the experimental animals. The quantitative angiography results varied across animals, and were not correlated with device dimensions. In some cases, localized flow drop-out was observed in a small region surrounding the electrode, while in other instances a global disruption in flow occurred, perhaps as a result of large vessel compression caused by mechanical pressure. OCM is a tool that can be used in various neurophotonics applications, including quantification of the neuroinflammatory response to penetrating electrode insertion. C1 [Hammer, Daniel X.; Lozzi, Andrea; Boretsky, Adam; Agrawal, Anant; Welle, Cristin G.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10913 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Hammer, DX (reprint author), US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10913 New Hampshire Ave, Silver Spring, MD 20993 USA. EM daniel.hammer@fda.hhs.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-960-3 J9 PROC SPIE PY 2016 VL 9690 AR UNSP 96901B DI 10.1117/12.2213073 PG 8 WC Neuroimaging; Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BF6KU UT WOS:000383224700017 ER PT S AU Vasudevan, S Kumsa, D Takmakov, P Welle, CG Hammer, DX AF Vasudevan, Srikanth Kumsa, Doe Takmakov, Pavel Welle, Cristin G. Hammer, Daniel X. BE Madsen, SJ Yang, VXD Jansen, ED Luo, Q Ding, J Roe, AW Mohanty, SK Thakor, NV TI Real Time Imaging of Peripheral Nerve Vasculature Using Optical Coherence Angiography SO CLINICAL AND TRANSLATIONAL NEUROPHOTONICS; NEURAL IMAGING AND SENSING; AND OPTOGENETICS AND OPTICAL MANIPULATION SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Clinical and Translational Neurophotonics; Neural Imaging and Sensing; and Optogenetics and Optical Manipulation CY FEB 13-16, 2016 CL San Francisco, CA SP SPIE DE Peripheral nerves; OCT; angiography; electrical stimulation; neuromodulation ID ELECTRICAL-STIMULATION; FUNCTIONAL-EVALUATION; RAT; VASOCONSTRICTION; MODEL AB The peripheral nervous system (PNS) carries bidirectional information between the central nervous system and distal organs. PNS stimulation has been widely used in medical devices for therapeutic indications, such as bladder control and seizure cessation. Investigational uses of PNS stimulation include providing sensory feedback for improved control of prosthetic limbs. While nerve safety has been well documented for stimulation parameters used in marketed devices, novel PNS stimulation devices may require alternative stimulation paradigms to achieve maximum therapeutic benefit. Improved testing paradigms to assess the safety of stimulation will expedite the development process for novel PNS stimulation devices. The objective of this research is to assess peripheral nerve vascular changes in real-time with optical coherence angiography (OCA). A 1300-nm OCA system was used to image vasculature changes in the rat sciatic nerve in the region around a surface contacting single electrode. Nerves and vasculature were imaged without stimulation for 180 minutes to quantify resting blood vessel diameter. Walking track analysis was used to assess motor function before and 6 days following experiments. There was no significant change in vessel diameter between baseline and other time points in all animals. Motor function tests indicated the experiments did not impair functionality. We also evaluated the capabilities to image the nerve during electrical stimulation in a pilot study. Combining OCA with established nerve assessment methods can be used to study the effects of electrical stimulation safety on neural and vascular tissue in the periphery. C1 [Vasudevan, Srikanth; Kumsa, Doe; Takmakov, Pavel; Welle, Cristin G.; Hammer, Daniel X.] US FDA, CDRH, OSEL, Silver Spring, MD 20993 USA. [Welle, Cristin G.] Univ Colorado Denver, Dept Neurosurg, Aurora, CO USA. [Kumsa, Doe] Med Device Innovat Consortium, St Louis Pk, MN USA. RP Vasudevan, S (reprint author), US FDA, CDRH, OSEL, Silver Spring, MD 20993 USA. OI Takmakov, Pavel/0000-0001-6591-0257 NR 14 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-960-3 J9 PROC SPIE PY 2016 VL 9690 AR UNSP 96901D DI 10.1117/12.2213160 PG 7 WC Neuroimaging; Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BF6KU UT WOS:000383224700018 ER PT S AU Wang, JT Huang, S Myers, M Chen, Y Welle, C Pfefer, J AF Wang, Jianting Huang, Stanley Myers, Matthew Chen, Yu Welle, Cristin Pfefer, Joshua BE Madsen, SJ Yang, VXD Jansen, ED Luo, Q Ding, J Roe, AW Mohanty, SK Thakor, NV TI Elucidation of the role of biological factors and device design in cerebral NIRS using an in vivo hematoma model based on highintensity focused ultrasound SO CLINICAL AND TRANSLATIONAL NEUROPHOTONICS; NEURAL IMAGING AND SENSING; AND OPTOGENETICS AND OPTICAL MANIPULATION SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Clinical and Translational Neurophotonics; Neural Imaging and Sensing; and Optogenetics and Optical Manipulation CY FEB 13-16, 2016 CL San Francisco, CA SP SPIE DE Near-infrared spectroscopy (NIRS); high-intensity focused ultrasound (HIFU); hematoma detection; traumatic brain injury (TBI); murine TBI model ID TRAUMATIC BRAIN-INJURY; NEAR-INFRARED SPECTROSCOPY; HEMORRHAGE AB Near-Infrared Spectroscopy (NIRS) is an emerging medical countermeasure for rapid, field detection of hematomas caused by traumatic brain injury (TBI). Bench and animal tests to determine NIRS sensitivity and specificity are needed. However, current animal models involving non-invasively induced, localized neural damage are limited. We investigated an in vivo murine hematoma model in which cerebral hemorrhage was induced noninvasively by high-intensity focused ultrasound (HIFU) with calibrated positioning and parameters. To characterize the morphology of induced hematomas, we used skull-intact histological evaluation. A multi-wavelength fiberoptic NIRS system with three source-detector separation distances was used to detect hematoma A 1.1 MHz transducer produced consistent small-to-medium hematoma localized to a single hemisphere, along with bruising of the scalp, with a low mortality rate. A 220 kHz transducer produced larger, more diffuse hematomas, with higher variability in size and a correspondingly higher mortality rate. No skin bruising or blood accumulation between the skin and skull was observed following injury application with the 220 kHz transducer. Histological analysis showed higher sensitivity for larger hematomas (>4x4 mm(2)). NIRS optical density change after HIFU was able to detect all hematomas, with sensitivity dependent on wavelength and separation distance. While improvements in methods for validating cerebral blood distribution are needed, the HIFU hematoma model provided useful insights that will inform development of biologically relevant, performance test methods for cerebral NIRS systems. C1 [Wang, Jianting; Huang, Stanley; Myers, Matthew; Welle, Cristin; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20093 USA. [Chen, Yu] Univ Maryland, Fischell Dept Bioengn, Jeong H Kim Engn Bldg 2330, College Pk, MD 20742 USA. RP Pfefer, J (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20093 USA. EM Joshua.Pfefer@fda.hhs.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-960-3 J9 PROC SPIE PY 2016 VL 9690 AR UNSP 96900U DI 10.1117/12.2217771 PG 8 WC Neuroimaging; Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BF6KU UT WOS:000383224700011 ER PT J AU Mossoba, ME Flynn, TJ Vohra, S Wiesenfeld, P Sprando, RL AF Mossoba, Miriam E. Flynn, Thomas J. Vohra, Sanah Wiesenfeld, Paddy Sprando, Robert L. TI Evaluation of "Dream Herb," Calea zacatechichi, for Nephrotoxicity Using Human Kidney Proximal Tubule Cells SO JOURNAL OF TOXICOLOGY LA English DT Article ID NF-KAPPA-B; SESQUITERPENE LACTONES; DIABETIC-NEPHROPATHY; MOLECULAR-STRUCTURE; PLANTS; BIOMARKERS; HK-2; FLAVONOIDS; TOXICITY; INJURY AB A recent surge in the use of dietary supplements, including herbal remedies, necessitates investigations into their safety profiles. "Dream herb," Calea zacatechichi, has long been used in traditional folk medicine for a variety of purposes and is currently being marketed in the US for medicinal purposes, including diabetes treatment. Despite the inherent vulnerability of the renal system to xenobiotic toxicity, there is a lack of safety studies on the nephrotoxic potential of this herb. Additionally, the high frequency of diabetes-associated kidney disease makes safety screening of C. zacatechichi for safety especially important. We exposed human proximal tubuleHK-2 cells to increasing doses of this herb alongside known toxicant and protectant control compounds to examine potential toxicity effects of C. zacatechichi relative to control compounds. We evaluated both cellular and mitochondrial functional changes related to toxicity of this dietary supplement and found that even at low doses evidence of cellular toxicity was significant. Moreover, these findings correlated with significantly elevated levels of nephrotoxicity biomarkers, lending further support for the need to further scrutinize the safety of this herbal dietary supplement. C1 [Mossoba, Miriam E.; Flynn, Thomas J.; Vohra, Sanah; Wiesenfeld, Paddy; Sprando, Robert L.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol,NIVTB, 8301 Muirkirk Rd, Laurel, MD 20708 USA. RP Mossoba, ME (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol,NIVTB, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM miriam.mossoba@fda.hhs.gov NR 52 TC 1 Z9 1 U1 2 U2 2 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 315 MADISON AVE 3RD FLR, STE 3070, NEW YORK, NY 10017 USA SN 1687-8191 EI 1687-8205 J9 J TOXICOL JI J. Toxicol. PY 2016 AR 9794570 DI 10.1155/2016/9794570 PG 7 WC Toxicology SC Toxicology GA DX1LX UT WOS:000384130000001 ER PT J AU Atienzar, FA Blomme, EA Chen, MJ Hewitt, P Kenna, JG Labbe, G Moulin, F Pognan, F Roth, AB Suter-Dick, L Ukairo, O Weaver, RJ Will, Y Dambach, DM AF Atienzar, Franck A. Blomme, Eric A. Chen, Minjun Hewitt, Philip Kenna, J. Gerry Labbe, Gilles Moulin, Frederic Pognan, Francois Roth, Adrian B. Suter-Dick, Laura Ukairo, Okechukwu Weaver, Richard J. Will, Yvonne Dambach, Donna M. TI Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans SO BIOMED RESEARCH INTERNATIONAL LA English DT Review ID INDUCED LIVER-INJURY; DRUG-INDUCED HEPATOTOXICITY; PRIMARY HUMAN HEPATOCYTES; SALT EXPORT PUMP; INDUCED MITOCHONDRIAL DYSFUNCTION; MICROARRAY EXPERIMENT MIAME; HEPATOMA HEPARG CELLS; HEPG2 CELLS; ORAL MEDICATIONS; RAT HEPATOCYTES AB Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. Well-defined clinical diagnostic criteria and risk factors are also missing. This paper summarizes key data interpretation challenges, practical considerations, model limitations, and the need for an integrated risk assessment. As demonstrated through selected initiatives to address other types of toxicities, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical DILI models across the pharmaceutical industry. Perspectives on the incorporation of newer technologies and the value of precompetitive consortia to identify useful practices are also discussed. C1 [Atienzar, Franck A.] UCB BioPharma SPRL, Chemin Foriest,R9 Bldg, B-1420 Braine Lalleud, Belgium. [Blomme, Eric A.] AbbVie, 1 North Waukegan Rd, N Chicago, IL 60064 USA. [Chen, Minjun] US Food & Drug Adm FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Hewitt, Philip] Merck KGaA, Frankfurter Str 250, D-64293 Darmstadt, Germany. [Kenna, J. Gerry] Drug Safety Consultant, Macclesfield SK11, Cheshire, England. [Labbe, Gilles] Sanofi, Batiment C Bernard,13 Quai Jules Guesdes,Zone B, F-94403 Vitry Sur Seine 94403, France. [Moulin, Frederic] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Pognan, Francois] Novartis Pharma AG, Klybeckstr 141, CH-4057 Basel, Switzerland. [Roth, Adrian B.] Hoffmann La Roche AG, CH-4000 Basel, Switzerland. [Suter-Dick, Laura] Univ Appl Sci Northwestern Switzerland, Sch Life Sci, Grundenstr 40, CH-4132 Muttenz, Switzerland. [Ukairo, Okechukwu] Ipsen Biosci Inc, 650 E Kendall St, Cambridge, MA 02142 USA. [Weaver, Richard J.] IRIS, 50 Rue Carnot, F-92284 Suresnes, France. [Will, Yvonne] Pfizer R&D, Drug Safety Res & Dev, Eastern Point Rd, Groton, CT 06340 USA. [Dambach, Donna M.] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA. RP Atienzar, FA (reprint author), UCB BioPharma SPRL, Chemin Foriest,R9 Bldg, B-1420 Braine Lalleud, Belgium. EM franck.atienzar@ucb.com NR 168 TC 0 Z9 0 U1 2 U2 2 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 315 MADISON AVE 3RD FLR, STE 3070, NEW YORK, NY 10017 USA SN 2314-6133 EI 2314-6141 J9 BIOMED RES INT JI Biomed Res. Int. PY 2016 AR 9737920 DI 10.1155/2016/9737920 PG 20 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA DW3AI UT WOS:000383513800001 ER PT J AU Weininger, S Jaffe, MB Robkin, M Rausch, T Arney, D Goldman, JM AF Weininger, Sandy Jaffe, Michael B. Robkin, Michael Rausch, Tracy Arney, David Goldman, Julian M. TI The Importance of State and Context in Safe Interoperable Medical Systems SO IEEE JOURNAL OF TRANSLATIONAL ENGINEERING IN HEALTH AND MEDICINE-JTEHM LA English DT Article DE Safety; interoperability; state; context AB This paper describes why "device state" and "patient context" information are necessary components of device models for safe interoperability. This paper includes a discussion of the importance of describing the roles of devices with respect to interactions (including human user workflows involving devices, and device to device communication) within a system, particularly those intended for use at the point-of-care, and how this role information is communicated. In addition, it describes the importance of clinical scenarios in creating device models for interoperable devices. C1 [Weininger, Sandy] FDA CDRH, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Jaffe, Michael B.; Arney, David; Goldman, Julian M.] Massachusetts Gen Hosp, Dept Anesthesia, MDPnP Program, Boston, MA 02114 USA. [Robkin, Michael] Anakena Solut Inc, Woodland Hills, CA 91367 USA. [Rausch, Tracy] DocBox Inc, Newton, MA 02460 USA. RP Weininger, S (reprint author), FDA CDRH, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM sandy.weininger@fda.hhs.gov NR 24 TC 1 Z9 1 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2372 J9 IEEE J TRANSL ENG HE JI IEEE J. Transl. Eng. Health Med.-JTEHM PY 2016 VL 4 AR 2800110 DI 10.1109/JTEHM.2016.2596283 PG 10 WC Engineering, Biomedical SC Engineering GA DV2TZ UT WOS:000382775900001 PM 27730013 ER PT J AU O'Donoghue, AC Sullivan, HW Williams, PA Squire, C Betts, KR Willoughby, JF Parvanta, S AF O'Donoghue, Amie C. Sullivan, Helen W. Williams, Pamela A. Squire, Claudia Betts, Kevin R. Willoughby, Jessica Fitts Parvanta, Sarah TI Consumers' Understanding of FDA Approval Requirements and Composite Scores in Direct-to-Consumer Prescription Drug Print Ads SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID EFFICACY INFORMATION; RANDOMIZED-TRIAL; BENEFITS; ADVERTISEMENTS; HARMS AB In 2 studies, we investigated how laypersons perceive the Food and Drug Administration (FDA) approval process, FDA authority, and the presentation of composite scores in direct-to-consumer (DTC) prescription drug print ads. The 1st study consisted of 4 focus groups (N=38) in 2 cities. Using a semi-structured guide, a moderator led participants through the viewing of 3 existing DTC print ads that differed in the presence or absence of composite score information, and participants discussed their views of the ads and their understanding of composite scores. The 2nd study surveyed a nationally representative sample of 1,629 individuals from the general population who saw a fictitious DTC print ad and answered closed-ended questions about the same topics. Results showed that knowledge of FDA approval and authority was mixed, with several misconceptions apparent. Many consumers were not familiar with the use of composite scores in a medical context or in advertising and, in the 1st study, expressed distrust of the product and the ad after learning about how composite scores are used. In the 2nd study, receiving composite score information changed the perceived clarity of the ad but not the perceived risk or benefits. Implications for the presentation of complex medical information are discussed. C1 [O'Donoghue, Amie C.; Sullivan, Helen W.; Betts, Kevin R.] US FDA, 10903 New Hampshire Ave,Bldg 51,Room 3236, Silver Spring, MD 10993 USA. [Williams, Pamela A.; Squire, Claudia; Willoughby, Jessica Fitts; Parvanta, Sarah] RTI Int Inc, Res Triangle Pk, NC USA. RP O'Donoghue, AC (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 51,Room 3236, Silver Spring, MD 10993 USA. EM amie.odonoghue@fda.hhs.gov OI Willoughby, Jessica/0000-0002-1118-9502 NR 24 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PY 2016 VL 21 IS 8 BP 927 EP 934 DI 10.1080/10810730.2016.1179367 PG 8 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA DU6LD UT WOS:000382325300006 PM 27414000 ER PT J AU Zhao, P AF Zhao, Ping TI Strategies, techniques, applications of combining top-down and bottom-up approaches in PBPK models SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 20th North American Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY OCT 18-22, 2015 CL Orlando, FL SP Int Soc Study Xenobiot C1 [Zhao, Ping] US FDA, Off Clin Pharmacol, CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2016 VL 48 SU 1 MA SC1.1 BP 6 EP 6 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DS4IO UT WOS:000380744900002 ER PT J AU Wang, YN AF Wang, Yaning TI Dose justification for special population: regulatory perspective SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 20th North American Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY OCT 18-22, 2015 CL Orlando, FL SP Int Soc Study Xenobiot C1 [Wang, Yaning] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2016 VL 48 SU 1 MA SC2.3 BP 7 EP 7 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DS4IO UT WOS:000380744900005 ER PT J AU Blank, M AF Blank, Melanie TI Renal biomarkers SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 20th North American Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY OCT 18-22, 2015 CL Orlando, FL SP Int Soc Study Xenobiot C1 [Blank, Melanie] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2016 VL 48 SU 1 MA S21 BP 15 EP 15 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DS4IO UT WOS:000380744900027 ER PT J AU Zhang, L AF Zhang, Lei TI A scientific perspective on drug interaction evaluation during drug development SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 20th North American Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY OCT 18-22, 2015 CL Orlando, FL SP Int Soc Study Xenobiot C1 [Zhang, Lei] US FDA, Off Clin Pharmacol, CDER, Silver Spring, MD USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2016 VL 48 SU 1 MA S26 BP 16 EP 16 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DS4IO UT WOS:000380744900031 ER PT J AU Sato, M Liu, Q Yoshida, K Li, L Rekic, D Reynolds, K Zhang, L Huang, SM Sinha, V Zhao, P AF Sato, Masanobu Liu, Qi Yoshida, Kenta Li, Li Rekic, Dinko Reynolds, Kellie Zhang, Lei Huang, Shiew Mei Sinha, Vikram Zhao, Ping TI Evaluation of drug interaction potential of CYP3A substrates - a tailored approach based on FM,CYP3A SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 20th North American Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY OCT 18-22, 2015 CL Orlando, FL SP Int Soc Study Xenobiot C1 [Sato, Masanobu; Liu, Qi; Yoshida, Kenta; Rekic, Dinko; Reynolds, Kellie; Zhang, Lei; Huang, Shiew Mei; Sinha, Vikram; Zhao, Ping] US FDA, Off Clin Pharmacol, CDER, Silver Spring, MD USA. [Sato, Masanobu] Pharmaceut & Med Devices Agcy PMDA, Silver Spring, MD USA. [Li, Li] CFDA, Ctr Drug Evaluat, Off Gener Drug Pharmaceut Sci, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2016 VL 48 SU 1 MA P91 BP 70 EP 71 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DS4IO UT WOS:000380744900147 ER PT J AU Volpe, DA Avaritt, BR AF Volpe, Donna A. Avaritt, Brittany R. TI Correlation of in vitro inhibition of midazolam CYP3A4-mediated metabolism to in vivo drug interactions SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 20th North American Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY OCT 18-22, 2015 CL Orlando, FL SP Int Soc Study Xenobiot C1 [Volpe, Donna A.; Avaritt, Brittany R.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2016 VL 48 SU 1 MA P127 BP 88 EP 88 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DS4IO UT WOS:000380744900181 ER PT J AU Myers, MB AF Myers, Meagan B. TI Targeted therapies with companion diagnostics in the management of breast cancer: current perspectives SO PHARMACOGENOMICS & PERSONALIZED MEDICINE LA English DT Review DE HER2; precision medicine; in vitro diagnostics; estrogen receptor; multigene assay ID ADJUVANT ENDOCRINE THERAPY; PRACTICE GUIDELINE UPDATE; INTERNATIONAL EXPERT CONSENSUS; 21-GENE RECURRENCE SCORE; LATE DISTANT RECURRENCE; ESTROGEN-RECEPTOR; CLINICAL-PRACTICE; AMERICAN SOCIETY; GENE-EXPRESSION; PAM50 RISK AB Breast cancer is a multifaceted disease exhibiting both intertumoral and intratumoral heterogeneity as well as variable disease course. Over 2 decades of research has advanced the understanding of the molecular substructure of breast cancer, directing the development of new therapeutic strategies against these actionable targets. In vitro diagnostics, and specifically companion diagnostics, have been integral in the successful development and implementation of these targeted therapies, such as those directed against the human epidermal growth factor receptor 2. Lately, there has been a surge in the development, commercialization, and marketing of diagnostic assays to assist in breast cancer patient care. More recently, multigene signature assays, such as Oncotype DX, MammaPrint, and Prosigna, have been integrated in the clinical setting in order to tailor decisions on adjuvant endocrine and chemotherapy treatment. This review provides an overview of the current state of breast cancer management and the use of companion diagnostics to direct personalized approaches in the treatment of breast cancer. C1 [Myers, Meagan B.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Myers, MB (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM meagan.myers@fda.hhs.gov NR 78 TC 3 Z9 3 U1 0 U2 4 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1178-7066 J9 PHARMACOGN PERS MED JI Pharmacogn. Pers. Med. PY 2016 VL 9 BP 7 EP 16 DI 10.2147/PGPM.S56055 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DU0IL UT WOS:000381886300002 PM 26858530 ER PT S AU Munos, B Baker, PC Bot, BM Crouthamel, M de Vries, G Ferguson, I Hixson, JD Malek, LA Mastrototaro, JJ Misra, V Ozcan, A Sacks, L Wang, P AF Munos, Bernard Baker, Pamela C. Bot, Brian M. Crouthamel, Michelle de Vries, Glen Ferguson, Ian Hixson, John D. Malek, Linda A. Mastrototaro, John J. Misra, Veena Ozcan, Aydogan Sacks, Leonard Wang, Pei GP Annals New York Acad Sci TI Mobile health: the power of wearables, sensors, and apps to transform clinical trials SO SPECIAL ISSUE: ANNALS REPORTS, VOL 1375 SE Annals of the New York Academy of Sciences LA English DT Article; Book Chapter DE biosensors; mobile technology; wireless; medical device; health care; data; clinical study ID ON-CHIP MICROSCOPY AB Mobile technology has become a ubiquitous part of everyday life, and the practical utility of mobile devices for improving human health is only now being realized. Wireless medical sensors, or mobile biosensors, are one such technology that is allowing the accumulation of real-time biometric data that may hold valuable clues for treating even some of the most devastating human diseases. From wearable gadgets to sophisticated implantable medical devices, the information retrieved from mobile technology has the potential to revolutionize how clinical research is conducted and how disease therapies are delivered in the coming years. Encompassing the fields of science and engineering, analytics, health care, business, and government, this report explores the promise that wearable biosensors, along with integrated mobile apps, hold for improving the quality of patient care and clinical outcomes. The discussion focuses on groundbreaking device innovation, data optimization and validation, commercial platform integration, clinical implementation and regulation, and the broad societal implications of using mobile health technologies. C1 [Munos, Bernard] Milken Inst, FasterCures, Washington, DC 20005 USA. [Baker, Pamela C.] Questex Media Grp LLC, FierceBigData, Newton, MA USA. [Bot, Brian M.] Sage Bionetworks, Seattle, WA USA. [Crouthamel, Michelle] GlaxoSmithKline, Collegeville, PA USA. [de Vries, Glen] Medidata Solut, New York, NY USA. [Ferguson, Ian] ARM, San Francisco, CA USA. [Hixson, John D.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Hixson, John D.] San Francisco VA Med Ctr, San Francisco, CA USA. [Malek, Linda A.] Moses & Singer LLP, Healthcare & Privacy & Cybersecur Practices, New York, NY USA. [Mastrototaro, John J.] Medtronic PLC, Los Angeles, CA USA. [Misra, Veena] North Carolina State Univ, NSF Nanosyst Engn Res Ctr NERC Adv Self Powered S, Raleigh, NC USA. [Ozcan, Aydogan] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA USA. [Ozcan, Aydogan] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA USA. [Ozcan, Aydogan] Univ Calif Los Angeles, Dept Elect Engn, Los Angeles, CA 90024 USA. [Sacks, Leonard] US FDA, Silver Spring, MD USA. [Wang, Pei] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Munos, B (reprint author), Milken Inst, FasterCures, Washington, DC 20005 USA. EM annals@nyas.org RI Emchi, Karma/Q-1952-2016 NR 40 TC 1 Z9 1 U1 14 U2 14 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2016 VL 1375 BP 3 EP 18 DI 10.1111/nyas.13117 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA BF5HR UT WOS:000382005200001 PM 27384501 ER PT S AU Bozza, WP Twomey, JD Kim, SR Zhang, BL AF Bozza, William P. Twomey, Julianne D. Kim, Su-Ryun Zhang, Baolin BE Muganda, PM TI Detection of Apoptosis: From Bench Side to Clinical Practice SO APOPTOSIS METHODS IN TOXICOLOGY SE Methods in Pharmacology and Toxicology LA English DT Article; Book Chapter DE Apoptosis; Apoptosis detection; In vitro apoptosis detection; In vivo apoptosis detection; Clinical apoptosis detection; DNA fragmentation; TUNEL; Caspase activation detection; Phosphatidylserine externalization ID PROGRAMMED CELL-DEATH; FLUOROCHROME-LABELED INHIBITORS; RADIOLABELED ANNEXIN-V; IN-VIVO EVALUATION; IMAGING CASPASE-3 ACTIVATION; TC-99M-LABELED C2A DOMAIN; FLOW-CYTOMETRIC DETECTION; PROTON MR SPECTROSCOPY; LARGE DNA-MOLECULES; PHOSPHATIDYLSERINE EXPRESSION AB Apoptosis or programmed cell death is implicated in several pathological conditions, such as cancer and neurodegenerative diseases. An increasing number of therapies are developed by targeting apoptosis signaling components to either induce or inhibit apoptosis in target cells. For these reasons, it is critical to develop appropriate analytical methods for the detection of apoptotic cell death in the context of monitoring relevant disease progression and therapeutic effects of clinical treatments (e.g., chemotherapy in cancer patients). This review provides an overview of the currently used methods for detection of apoptosis and their applications in research and clinical practice. C1 [Bozza, William P.; Twomey, Julianne D.; Kim, Su-Ryun; Zhang, Baolin] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Bozza, WP (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 124 TC 0 Z9 0 U1 3 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1557-2153 BN 978-1-4939-3588-8; 978-1-4939-3586-4 J9 METHOD PHARMACOL TOX JI Methods Pharmacol. Toxicol. PY 2016 BP 13 EP 29 DI 10.1007/978-1-4939-3588-8_2 D2 10.1007/978-1-4939-3588-8 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BF4TD UT WOS:000381683500003 ER PT S AU Seng, WL Zhang, DW McGrath, P AF Seng, Wen Lin Zhang, Dawei McGrath, Patricia BE Muganda, PM TI Microplate-Based Whole Zebrafish Caspase 3/7 Assay for Screening Small Molecule Compounds SO APOPTOSIS METHODS IN TOXICOLOGY SE Methods in Pharmacology and Toxicology LA English DT Article; Book Chapter DE Acridine orange; Assay; Apoptosis; Caspase; Chemiluminescence; ELISA; Methods; Microplate; Whole zebrafish ID PHYLOGENETIC ANALYSIS; KINETIC-ANALYSIS; IN-VIVO; APOPTOSIS; INHIBITOR; CELLS; SPECIFICITY; VALIDATION; INDUCTION AB In this research, using a commercially available human specific caspase 3/7 chemiluminescent test kit (Caspase 3/7 Glo, Promega, Madison, WI), developed for cell based assays, we describe a microplate-based whole zebrafish assay format to identify potential small molecule caspase inhibitors and activators. Based on the high degree of evolutionary conservation among species, we show that human specific 3/7 substrate cross reacts with zebrafish. Using untreated zebrafish, optimum assay conditions (including substrate concentration, number of zebrafish per microwell, and incubation time to generate a linear reaction) are determined. Robustness and reproducibility of the assay are established using a characterized caspase 3/7 inhibitor (z-VAD-fmk) and an activator (staurosporine). Next, the whole zebrafish microplate assay format is validated using three additional characterized caspase 3/7 inhibitors, two additional caspase 3/7 activators, and one control compound that has no effect on zebrafish apoptosis. Compared to other whole animal assay formats, chemiluminescence provides high sensitivity and low background. Next, results are compared with published results in mammalian cell based assays and animal models and show that the overall predictive success rate is 100 %. Compound effects on apoptosis are further confirmed visually by whole mount staining with acridine orange (AO), a live dye. Results support the high degree of conservation of key pathways in zebrafish and humans. The microplate-based whole zebrafish caspase 3/7 assay format represents a rapid, reproducible, predictive animal model for identifying potential inhibitors and activators. Use of zebrafish as an alternative animal model to identify potential apoptosis modulators can accelerate the drug discovery process and reduce costs. C1 [Seng, Wen Lin; McGrath, Patricia] Phylonix, Cambridge, MA 02139 USA. [Zhang, Dawei] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Seng, WL (reprint author), Phylonix, Cambridge, MA 02139 USA. NR 33 TC 0 Z9 0 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1557-2153 BN 978-1-4939-3588-8; 978-1-4939-3586-4 J9 METHOD PHARMACOL TOX JI Methods Pharmacol. Toxicol. PY 2016 BP 193 EP 209 DI 10.1007/978-1-4939-3588-8_11 D2 10.1007/978-1-4939-3588-8 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BF4TD UT WOS:000381683500012 ER PT J AU Li, XJ Zhang, L Zhou, RF Yu, CY Shi, CL Shao, C Li, Y Xu, DQ AF Li, Xiaojie Zhang, Ling Zhou, Ruifang Yu, Chunyu Shi, Chaoling Shao, Chen Li, Yang Xu, Deqi TI Effects of a human plasma membrane-associated sialidase siRNA on prostate cancer SO INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY LA English DT Article DE Neu3; siRNA; tunnel; apoptosis; Attenuated Salmonella ID PROTEIN EXPRESSION THERAPY; SALMONELLA-TYPHIMURIUM; APOPTOSIS SUPPRESSION; TUMOR; VOLUNTEERS; VECTOR; NEU3 AB Human plasma membrane-associated sialidase (Neu3) mainly localized in plasma membranes and plays crucial roles in the regulation of cell surface functions. We investigated the effects and molecular mechanisms of Neu3 on cell growth and apoptosis in vivo and in vitro in this study. Initially, we found the levels of Neu3 expression were higher in prostate cancer tissues and cell lines than in normal prostate tissues. We then applied a Neu3 siRNA approach to block Neu3 signaling using PC-3M cells as model cells. PC-3M cells transfected with Neu3-specific short hairpin RNA plasmid inhibited cell proliferation and induced apoptosis significantly. Knocking down neu3 decreased the expression of Bcl-2 and increased the expression of Bax, Caspase-3 in PC-3M cells. The experiments suggest that Neu3 is a promising molecular target for prostate cancer therapy. C1 [Li, Xiaojie; Zhou, Ruifang] Taizhou Polytech Coll, Taizhou, Peoples R China. [Li, Xiaojie; Zhang, Ling; Yu, Chunyu; Shi, Chaoling; Shao, Chen; Li, Yang] Jilin Univ, Coll Basic Med Sci, Prostate Dis Prevent & Treatment Res Ctr, Dept Pathophysiol, Changchun, Peoples R China. [Xu, Deqi] US FDA, Lab Enter & Sexually Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Li, Y (reprint author), Jilin Univ, Norman Bethune Med Sch, Prostate Dis Prevent & Treatment Res Ctr, Dept Pathophysiol, Xinmin St, Changchun 130021, Peoples R China. EM lyang@jlu.edu.cn NR 18 TC 0 Z9 0 U1 1 U2 1 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 1936-2625 J9 INT J CLIN EXP PATHO JI Int. J. Clin. Exp. Pathol. PY 2016 VL 9 IS 3 BP 4101 EP 4109 PG 9 WC Oncology; Pathology SC Oncology; Pathology GA DO2FA UT WOS:000377594100175 ER PT J AU Korang-Yeboah, M Rahman, Z Shah, DA Khan, MA AF Korang-Yeboah, Maxwell Rahman, Ziyaur Shah, Dhaval A. Khan, Mansoor A. TI Spectroscopic-Based Chemometric Models for Quantifying Low Levels of Solid-State Transitions in Extended Release Theophylline Formulations SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE chemometrics; controlled release; partial least squares; formulation; near-infrared spectroscopy; Raman spectroscopy; pseudopolymorph; solid state stability ID PHARMACEUTICAL SOLIDS; REFLECTANCE SPECTRA; HYDRATE FORMATION; DRUG-RELEASE; TABLETS; CRYSTALLIZATION; QUANTIFICATION; MOISTURE; POWDER; RAMAN AB Variations in the solid state form of a pharmaceutical solid have profound impact on the product quality and clinical performance. Quantitative models that allow rapid and accurate determination of polymorphic changes in pharmaceutical products are essential in ensuring product quality throughout its lifecycle. This study reports the development and validation of chemometric models of Raman and near infrared spectroscopy (NIR) for quantifying the extent of pseudopolymorphic transitions of theophylline in extended release formulations. The chemometric models were developed using sample matrices consisting of the commonly used excipients and at the ratios in commercially available products. A combination of scatter removal (multiplicative signal correction and standard normal variate) and derivatization (Savitzky-Golay second derivative) algorithm were used for data pretreatment. Partial least squares and principal component regression models were developed and their performance assessed. Diagnostic statistics such as the root mean square error, correlation coefficient, bias and Q(2) were used as parameters to test the model fit and performance. The models developed had a good fit and performance as shown by the values of the diagnostic statistics. The model diagnostic statistics were similar for MSC-SG and SNV-SG treated spectra. Similarly, PLSR and PCR models had comparable performance. Raman chemometric models were slightly better than their corresponding NIR model. The Raman and NIR chemometric models developed had good accuracy and precision as demonstrated by closeness of the predicted values for the independent observations to the actual TMO content hence the developed models can serve as useful tools in quantifying and controlling solid state transitions in extended release theophylline products. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Korang-Yeboah, Maxwell; Rahman, Ziyaur; Shah, Dhaval A.] US FDA, Div Prod Qual & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Khan, Mansoor A.] Texas A&M Hlth Sci Ctr, Irma Lerma Rangel Coll Pharm, College Stn, TX 77843 USA. RP Khan, MA (reprint author), Texas A&M Hlth Sci Ctr, Irma Lerma Rangel Coll Pharm, College Stn, TX 77843 USA. EM mkhan@pharmacy.tamhsc.edu OI Rahman, Ziyaur/0000-0002-0402-825X NR 32 TC 1 Z9 1 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD JAN PY 2016 VL 105 IS 1 BP 97 EP 105 DI 10.1016/j.xphs.2015.11.007 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TN UT WOS:000381768000014 PM 26852844 ER PT J AU Moreno, FS Heidor, R Pogribny, IP AF Moreno, Fernando Salvador Heidor, Renato Pogribny, Igor P. TI Nutritional Epigenetics and the Prevention of Hepatocellular Carcinoma with Bioactive Food Constituents SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Review ID RAT-LIVER CARCINOGENESIS; ADENOSYL-L-METHIONINE; LONG NONCODING RNA; NONALCOHOLIC FATTY LIVER; TUMOR-SUPPRESSOR GENE; PERICENTROMERIC SATELLITE REGIONS; HISTONE LYSINE METHYLTRANSFERASE; CANCER CHEMOPREVENTIVE AGENT; GLYCINE N-METHYLTRANSFERASE; DIETARY METHYL DEFICIENCY AB Hepatocellular carcinoma (HCC) is an aggressive and life-threatening disease often diagnosed at intermediate or advanced stages, which substantially limits therapeutic approaches to its successful treatment. This indicates that the prevention of HCC may be the most promising strategy in reducing its incidence and mortality. Emerging evidence indicates that numerous nutrients and nonnutrient dietary bioactive components can reduce the occurrence and/or delay the development of HCC through modifications of deregulated epigenetic mechanisms. This review examines the existing knowledge on the epigenetic mechanism-based studies in in vitro and in vivo models of HCC on the chemopreventive potential of epigenetic food components, including dietary methyl-group donors, epigallocatechin-3-gallate, sodium butyrate, resveratrol, curcumin, and sulforaphane, on liver carcinogenesis. Future direction and potential challenges in the effective use of bioactive food constituents in the prevention of HCC are highlighted and discussed. C1 [Moreno, Fernando Salvador; Heidor, Renato] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Food & Expt Nutr, Lab Diet Nutr & Canc, Sao Paulo, Brazil. [Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov RI Moreno, Fernando/I-1943-2013 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP] [2013/20477-6]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq] [455663/2014-9] FX Financial support was received from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP] projeto 2013/20477-6 and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq] projeto 455663/2014-9. NR 198 TC 0 Z9 0 U1 2 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0163-5581 EI 1532-7914 J9 NUTR CANCER JI Nutr. Cancer PY 2016 VL 68 IS 5 BP 719 EP 733 DI 10.1080/01635581.2016.1180410 PG 15 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA DS6HP UT WOS:000380883200001 PM 27266713 ER PT J AU Karunathilaka, SR Farris, S Mossoba, MM Moore, JC Yakes, BJ AF Karunathilaka, Sanjeewa R. Farris, Samantha Mossoba, Magdi M. Moore, Jeffrey C. Yakes, Betsy Jean TI Characterising variances of milk powder and instrumentation for the development of a non-targeted, Raman spectroscopy and chemometrics detection method for the evaluation of authenticity SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Skim milk powder (SMP); non-fat dry milk (NFDM); authentication; Raman spectroscopy; chemometrics; PCA; variance ID NEAR-INFRARED SPECTROSCOPY; ECONOMICALLY MOTIVATED ADULTERATION; NUTRITIONAL PARAMETERS; OLIVE OIL; FT-RAMAN; SPECTRA; SKIM; MELAMINE; LACTOSE AB There is a need to develop rapid tools to screen milk products for economically motivated adulteration. An understanding of the physiochemical variability within skim milk powder (SMP) and non-fat dry milk (NFDM) is the key to establishing the natural differences of these commodities prior to the development of non-targeted detection methods. This study explored the sources of variance in 71 commercial SMP and NFDM samples using Raman spectroscopy and principal component analysis (PCA) and characterised the largest number of commercial milk powders acquired from a broad number of international manufacturers. Spectral pre-processing using a gap-segment derivative transformation (gap size = 5, segment width = 9, fourth derivative) in combination with sample normalisation was necessary to reduce the fluorescence background of the milk powder samples. PC scores plots revealed no clear trends for various parameters, including day of analysis, powder type, supplier and processing temperatures, while the largest variance was due to irreproducibility in sample positioning. Significant chemical sources of variances were explained by using the spectral features in the PC loadings plots where four samples from the same manufacturer were determined to likely contain an additional component or lactose anomers, and one additional sample was identified as an outlier and likely containing an adulterant or differing quality components. The variance study discussed herein with this large, diverse set of milk powders holds promise for future use as a non-targeted screening method that could be applied to commercial milk powders. C1 [Karunathilaka, Sanjeewa R.; Farris, Samantha; Mossoba, Magdi M.; Yakes, Betsy Jean] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Moore, Jeffrey C.] US Pharmacopeial Convent Inc, Rockville, MD USA. RP Yakes, BJ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Betsy.Yakes@fda.hhs.gov FU Research Participation Program at the Center for Food Safety and the Applied Nutrition FX S.R.K. acknowledges the support provided by an appointment to the Research Participation Program at the Center for Food Safety and the Applied Nutrition, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration (US FDA). NR 38 TC 1 Z9 1 U1 4 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2016 VL 33 IS 6 BP 921 EP 932 DI 10.1080/19440049.2016.1188437 PG 12 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DR8GX UT WOS:000380137500001 PM 27167451 ER PT J AU White, J Wrzesinski, C Green, M Johnson, GT McCluskey, JD Abritis, A Harbison, RD AF White, Jennifer Wrzesinski, Claudia Green, Martin Johnson, Giffe T. McCluskey, James D. Abritis, Alison Harbison, Raymond D. TI A novel method for deriving thresholds of toxicological concern for vaccine constituents SO TOXICOLOGY MECHANISMS AND METHODS LA English DT Article DE Biologics; QSAR; TTCs; vaccine safety AB Safety assessment evaluating the presence of impurities, residual materials, and contaminants in vaccines is a focus of current research. Thresholds of toxicological concern (TTCs) are mathematically modeled levels used for assessing the safety of many food and medication constituents. In this study, six algorithms are selected from the open-access ToxTree software program to derive a method for calculating TTCs for vaccine constituents: In Vivo Rodent Micronucleus assay/LD50, Benigni-Bossa/LD50, Cramer Extended/LD50, In Vivo Rodent Micronucleus assay/TDLo, Benigni-Bossa/TDLo, and the Cramer Extended/TDLo. Using an initial dataset (n = 197) taken from INCHEM, RepDose, RTECS, and TOXNET, the chemicals were divided into two families: "positive" - based on the presence of structures associated with adverse outcomes, or "negative" - no such structures or having structures that appear to be protective of health. The final validation indicated that the Benigni-Bossa/LD50 method is the most appropriate for calculating TTCs for vaccine constituents. Final TTCs were designated as 18.06 mu g/person and 20.61 mu g/person for the Benigni-Bossa/LD50 positive and negative structural families, respectively. C1 [White, Jennifer; Johnson, Giffe T.; McCluskey, James D.; Abritis, Alison; Harbison, Raymond D.] Univ S Florida, Coll Publ Hlth, Ctr Environm & Occupat Risk Anal & Management, Tampa, FL 33612 USA. [Wrzesinski, Claudia; Green, Martin] US FDA, Rockville, MD USA. RP Harbison, RD (reprint author), Univ S Florida, Coll Publ Hlth, Ctr Environm & Occupat Risk Anal & Management, Tampa, FL 33612 USA. EM rharbison@ix.netcom.com NR 13 TC 1 Z9 1 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1537-6516 EI 1537-6524 J9 TOXICOL MECH METHOD JI Toxicol. Mech. Methods PY 2016 VL 26 IS 4 BP 270 EP 275 DI 10.3109/15376516.2016.1170250 PG 6 WC Toxicology SC Toxicology GA DR7AP UT WOS:000380052700006 PM 27098016 ER PT J AU Alayash, AI AF Alayash, Abdu I. TI Memorial - Dr. Joseph C. Fratantoni SO ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY LA English DT Biographical-Item C1 [Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave Bldg 52-72,Room 4106, Silver Spring, MD 20993 USA. RP Alayash, AI (reprint author), US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave Bldg 52-72,Room 4106, Silver Spring, MD 20993 USA. EM abdu.alayash@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 2169-1401 EI 2169-141X J9 ARTIF CELL NANOMED B JI Artif. Cell. Nanomed. Biotechnol. PY 2016 VL 44 IS 4 BP 1049 EP 1049 DI 10.3109/21691401.2016.1154278 PG 1 WC Biotechnology & Applied Microbiology; Engineering, Biomedical; Materials Science, Biomaterials SC Biotechnology & Applied Microbiology; Engineering; Materials Science GA DQ9PL UT WOS:000379541700001 PM 26950293 ER PT J AU Doell, DL Folmer, DE Lee, HS Butts, KM Carberry, SE AF Doell, Diana L. Folmer, Daniel E. Lee, Hyoung S. Butts, Kyla M. Carberry, Susan E. TI Exposure estimate for FD&C colour additives for the US population SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Dietary exposure; food consumption; FD&C Blue No. 1; FD&C Blue No. 2; FD&C Green No. 3; FD&C Red No. 3; FD&C Red No. 40; FD&C Yellow No. 5; FD&C Yellow No. 6 ID ARTIFICIAL FOOD COLORS; POTENTIAL BEHAVIORAL-IMPLICATIONS; COMMONLY CONSUMED BEVERAGES; USAGE PATTERN; CHILDREN; CONSUMPTION; INDIA; KUWAIT AB Dietary exposures to the seven food, drug, and cosmetic (FD&C) colour additives that are approved for general use in food in the United States were estimated for the US population (aged 2 years and older), children (aged 2-5 years) and teenage boys (aged 13-18 years) based on analytical levels of the FD&C colour additives in foods. Approximately 600 foods were chosen for analysis, based on a survey of product labels, for the levels of FD&C colour additives. Dietary exposure was estimated using both 2-day food consumption data from the combined 2007-10 National Health and Nutrition Examination Survey (NHANES) and 10-14-day food consumption data from the 2007-10 NPD Group, Inc. National Eating Trends - Nutrient Intake Database (NPD NET-NID). Dietary exposure was estimated at the mean and 90th percentile using three different exposure scenarios: low exposure, average exposure and high exposure, to account for the range in the amount of each FD&C colour additive for a given food. For all populations and all exposure scenarios, the highest cumulative eaters-only exposures in food were determined for FD&C Red No. 40, FD&C Yellow No. 5 and FD&C Yellow No. 6. In addition, the eaters-only exposure was estimated for individual food categories in order to determine which food categories contributed the most to the exposure for each FD&C colour additive. Breakfast Cereal, Juice Drinks, Soft Drinks, and Frozen Dairy Desserts/Sherbet (also referred to as Ice Cream, Frozen Yogurt, Sherbet (including Bars, Sticks, Sandwiches)) were the major contributing food categories to exposure for multiple FD&C colour additives for all three populations. C1 [Doell, Diana L.; Folmer, Daniel E.; Lee, Hyoung S.; Butts, Kyla M.; Carberry, Susan E.] US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, HFS 265,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Doell, DL (reprint author), US FDA, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, HFS 265,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Diana.Doell@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 28 TC 1 Z9 1 U1 7 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2016 VL 33 IS 5 BP 782 EP 797 DI 10.1080/19440049.2016.1179536 PG 16 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DR0KJ UT WOS:000379596100005 PM 27092991 ER PT J AU Paseiro-Cerrato, R Tongchat, C Franz, R AF Paseiro-Cerrato, Rafael Tongchat, Chinawat Franz, Roland TI Study of the partition coefficients K-p/f of seven model migrants from LDPE polymer in contact with food simulants SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Food-contact materials; low-density polyethylene (LDPE); migration modelling; partition coefficients; temperature; food simulants ID PACKAGING MATERIALS; TIME-TEMPERATURE; MIGRATION; FOODSTUFFS; PLASTICS; ADDITIVES; PRODUCTS; KINETICS; SUPPORT; FILMS AB This study evaluated the influence of parameters such as temperature and type of low-density polyethylene (LDPE) film on the log K-p/f values of seven model migrants in food simulants. Two different types of LDPE films contaminated by extrusion and immersion were placed in contact with three food simulants including 20% ethanol, 50% ethanol and olive oil under several time-temperature conditions. Results suggest that most log K-p/f values are little affected by these parameters in this study. In addition, the relation between log K-p/f and log P-o/w was established for each food simulant and regression lines, as well as correlation coefficients, were calculated. Correlations were compared with data from real foodstuffs. Data presented in this study could be valuable in assigning certain foods to particular food simulants as well as predicting the mass transfer of potential migrants into different types of food or food simulants, avoiding tedious and expensive laboratory analysis. The results could be especially useful for regulatory agencies as well as for the food industry. C1 [Paseiro-Cerrato, Rafael] Univ Santiago de Compostela, Fac Pharm, Dept Analyt Chem Nutr & Food Sci, Santiago De Compostela, Spain. [Tongchat, Chinawat; Franz, Roland] Fraunhofer Inst Proc Engn & Packaging IVV, Freising Weihenstephan, Germany. [Paseiro-Cerrato, Rafael] USFDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Tongchat, Chinawat] Ctr ASEAN Food Contact Mat Testing, Dept Sci Serv, Bangkok 10400, Thailand. RP Paseiro-Cerrato, R (reprint author), Univ Santiago de Compostela, Fac Pharm, Dept Analyt Chem Nutr & Food Sci, Santiago De Compostela, Spain.; Paseiro-Cerrato, R (reprint author), USFDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Rafael.Cerrato@fda.hhs.gov FU Ministerio de Ciencia e Innovacion [BES-2009-023016] FX The authors are grateful to the Ministerio de Ciencia e Innovacion for a Predoctoral Fellowship FPI [reference BES-2009-023016] awarded to Rafael Paseiro-Cerrato. NR 16 TC 0 Z9 0 U1 7 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2016 VL 33 IS 5 BP 885 EP 892 DI 10.1080/19440049.2016.1166873 PG 8 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DR0KJ UT WOS:000379596100015 PM 26998811 ER PT J AU Ntim, SA Thomas, TA Noonan, GO AF Ntim, Susana Addo Thomas, Treye A. Noonan, Gregory O. TI Influence of aqueous food simulants on potential nanoparticle detection in migration studies involving nanoenabled food-contact substances SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Silver nanoparticles; food simulant; stability; AF4; sp-ICP-MS ID PLASMA-MASS SPECTROMETRY; SILVER NANOPARTICLES; CONTAINERS; NANOSILVER; SIZE; PH; NANOCOMPOSITE; DISSOLUTION; SEPARATION; KINETICS AB Research focused on assessing potential consumer exposure to nanoparticles released from nano-enabled food-contact materials (FCMs) has often reached conflicting conclusions regarding the detection of migrating nanoparticles. These conflicting conclusions, coupled with the potential for nanoparticles to be unstable in certain food simulants, has necessitated a closer look at the role played by food simulants recommended for use in nanoparticle migration evaluation. The influence of aqueous food simulants on nanoparticles under migration evaluation conditions is reported herein. The stability of silver nanoparticles (AgNP) spiked into three food simulants (water, 10% ethanol and 3% acetic acid) was investigated using asymmetric flow field-flow fractionation (AF4), ultrafiltration, electron microscopy (EM), and single-particle inductively coupled plasma mass spectrometry (sp-ICP-MS). While 3% acetic acid induced significant oxidative dissolution of AgNP to silver ions, there were very minor to no changes in the physicochemical properties of AgNP in water and 10% ethanol. C1 [Ntim, Susana Addo; Noonan, Gregory O.] USFDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, 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), USFDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, 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 (CPSC) and the US Food and Drug Administration (USFDA). NR 27 TC 1 Z9 1 U1 4 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2016 VL 33 IS 5 BP 905 EP 912 DI 10.1080/19440049.2016.1174506 PG 8 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DR0KJ UT WOS:000379596100017 ER PT J AU Guo, XQ Mei, N AF Guo, Xiaoqing Mei, Nan TI Aloe vera: A review of toxicity and adverse clinical effects SO JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART C-ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS LA English DT Review DE Aloe gel; aloe latex; Aloe vera; carcinogenicity; genotoxicity; toxicological effects ID PERFORMANCE LIQUID-CHROMATOGRAPHY; VAR. NATALENSIS BERGER; INNER LEAF FILLET; BARBADENSIS MILLER; IN-VITRO; PHENOLIC-COMPOUNDS; SAFETY EVALUATION; TOPOISOMERASE-II; MAMMALIAN-CELLS; HERBAL PRODUCTS AB The Aloe plant is employed as a dietary supplement in a variety of foods and as an ingredient in cosmetic products. The widespread human exposure and its potential toxic and carcinogenic activities raise safety concerns. Chemical analysis reveals that the Aloe plant contains various polysaccharides and phenolic chemicals, notably anthraquinones. Ingestion of Aloe preparations is associated with diarrhea, hypokalemia, pseudomelanosis coli, kidney failure, as well as phototoxicity and hypersensitive reactions. Recently, Aloe vera whole leaf extract showed clear evidence of carcinogenic activity in rats, and was classified by the International Agency for Research on Cancer as a possible human carcinogen (Group 2B). This review presents updated information on the toxicological effects, including the cytotoxicity, genotoxicity, carcinogenicity, and adverse clinical effects of Aloe vera whole leaf extract, gel, and latex. C1 [Guo, Xiaoqing; Mei, Nan] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Mei, N (reprint author), Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Nan.Mei@fda.hhs.gov NR 99 TC 2 Z9 3 U1 12 U2 16 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1059-0501 EI 1532-4095 J9 J ENVIRON SCI HEAL C JI J. Environ. Sci. Health Pt. C-Environ. Carcinog. Ecotoxicol. Rev. PY 2016 VL 34 IS 2 BP 77 EP 96 DI 10.1080/10590501.2016.1166826 PG 20 WC Oncology; Environmental Sciences; Toxicology SC Oncology; Environmental Sciences & Ecology; Toxicology GA DR0RL UT WOS:000379614500001 PM 26986231 ER PT J AU Rahman, MA Lin, KK Tiwari, RC Jackson, M AF Rahman, Mohammad A. Lin, Karl K. Tiwari, Ram C. Jackson, Matthew TI Exact Poly-K Test SO COMMUNICATIONS IN STATISTICS-SIMULATION AND COMPUTATION LA English DT Article; Proceedings Paper CT 1st Meeting of y-BIS / 1st Meeting of jSPE CY JUL 23-26, 2012 CL Caparica, PORTUGAL DE Carcinogenicity studies; Dose response; Exact test; Poly-K test ID CARCINOGENICITY AB For animal carcinogenicity study with multiple dose groups, positive trend test and pairwise comparisons of treated groups with control are generally performed using the Cochran-Armitage, Peto test, or Poly-K test. These tests are asymptotically normal. The exact version of Cochran-Armitage and Peto tests are available based on the permutation test assuming fixed column and row totals. For Poly-K test column totals depend on the mortality pattern of the animals and can not be kept fixed over the permutations of the animals. In this work a modification of the permutation test is suggested that can be applied on exact Poly-K test. C1 [Rahman, Mohammad A.; Lin, Karl K.; Jackson, Matthew] US FDA, Div Biometr 6, Off Biostat, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tiwari, Ram C.] US FDA, Off Biostat, CDER, Silver Spring, MD 20993 USA. RP Rahman, MA (reprint author), US FDA, Div Biometr 6, Off Biostat, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM mohammad.rahman@fda.hhs.gov NR 6 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0361-0918 EI 1532-4141 J9 COMMUN STAT-SIMUL C JI Commun. Stat.-Simul. Comput. PY 2016 VL 45 IS 7 BP 2257 EP 2266 DI 10.1080/03610918.2014.901351 PG 10 WC Statistics & Probability SC Mathematics GA DQ2PK UT WOS:000379044600003 ER PT J AU Austin, CA Hinkley, GK Mishra, AR Zhang, Q Umbreit, TH Betz, MW Wildt, BE Casey, BJ Francke-Carroll, S Hussain, SM Roberts, SM Brown, KM Goering, PL AF Austin, Carlye A. Hinkley, Georgia K. Mishra, Anurag R. Zhang, Qin Umbreit, Thomas H. Betz, Martha W. Wildt, Bridget E. Casey, Brendan J. Francke-Carroll, Sabine Hussain, Saber M. Roberts, Stephen M. Brown, Ken M. Goering, Peter L. TI Distribution and accumulation of 10 nm silver nanoparticles in maternal tissues and visceral yolk sac of pregnant mice, and a potential effect on embryo growth SO NANOTOXICOLOGY LA English DT Article DE Development; fetus; nanoparticles; nanosilver; pregnancy; toxicity ID ORAL-EXPOSURE; PLACENTA; TOXICITY; TRANSFERRIN; TRANSPORT; STORAGE; IONS; RATS AB We examined the distribution of silver in pregnant mice and embryos/fetuses following intravenous injections of 10 nm silver nanoparticles (AgNPs) or soluble silver nitrate (AgNO3) at dose levels of 0 (citrate buffer control) or 66 mg Ag/mouse to pregnant mice on gestation days (GDs) 7, 8 and 9. Selected maternal tissues and all embryos/fetuses from control, AgNP- and AgNO3-treated groups on GD10 and control and AgNP-treated groups on GD16 were processed for the measurement of silver concentrations, intracellular AgNP localization, histopathology and gross examination of tissue morphology. Inductively-coupled plasma mass spectrometry revealed silver in all examined tissues following either AgNP or AgNO3 treatment, with highest concentrations of silver in maternal liver, spleen and visceral yolk sac (VYS), and lowest concentrations in embryos/fetuses. For VYS, mean silver concentration following AgNO3 treatment (4.87 ng Ag/mg tissue) was approximately two-fold that following AgNP treatment (2.31 ng Ag/mg tissue); for all other tissues examined, mean silver concentrations following either AgNP or AgNO3 treatment were not significantly different from each other (e.g. 2.57 or 2.84 ng Ag/mg tissue in maternal liver and 1.61 or 2.50 ng Ag/mg tissue in maternal spleen following AgNP or AgNO3 treatment, respectively). Hyperspectral imaging revealed AgNP aggregates in maternal liver, kidney, spleen and VYS from AgNP-treated mice, but not AgNO3-treated mice. Additionally, one or more embryos collected on GD10 from eight of ten AgNP-treated mice appeared small for their age (i.e. Theiler stage 13 [GD8.5] or younger). In the control group (N = 11), this effect was seen in embryos from only one mouse. In conclusion, intravenous injection of 10 nm AgNPs to pregnant mice resulted in notable silver accumulation in maternal liver, spleen and VYS, and may have affected embryonic growth. Silver accumulation in embryos/fetuses was negligible. C1 [Austin, Carlye A.; Brown, Ken M.] George Washington Univ, Dept Biol Sci, Washington, DC 20052 USA. [Hinkley, Georgia K.; Roberts, Stephen M.] Univ Florida, Ctr Environm & Human Toxicol, Gainesville, FL USA. [Mishra, Anurag R.; Zhang, Qin; Umbreit, Thomas H.; Betz, Martha W.; Wildt, Bridget E.; Casey, Brendan J.; Goering, Peter L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Francke-Carroll, Sabine] US FDA, Ctr Food Safety & Nutr, College Pk, MD USA. [Hussain, Saber M.] Air Force Res Lab, Dayton, OH USA. RP Goering, PL (reprint author), US FDA, Ctr Devices & Radiol Hlth, White Oak Life Sci Lab, WO64-4064,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM peter.goering@fda.hhs.gov NR 31 TC 1 Z9 1 U1 2 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1743-5390 EI 1743-5404 J9 NANOTOXICOLOGY JI Nanotoxicology PY 2016 VL 10 IS 6 BP 654 EP 661 DI 10.3109/17435390.2015.1107143 PG 8 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA DQ5MA UT WOS:000379248300002 PM 26593872 ER PT J AU Wildt, BE Celedon, A Maurer, EI Casey, BJ Nagy, AM Hussain, SM Goering, PL AF Wildt, Bridget E. Celedon, Alfredo Maurer, Elizabeth I. Casey, Brendan J. Nagy, Amber M. Hussain, Saber M. Goering, Peter L. TI Intracellular accumulation and dissolution of silver nanoparticles in L-929 fibroblast cells using live cell time-lapse microscopy SO NANOTOXICOLOGY LA English DT Article DE Cellular uptake; confocal microscopy; ICP-MS; image analysis; nanosilver; transmission electron microscopy; silver ions; silver nanoparticles ID IN-VITRO; ORAL-EXPOSURE; CYTOTOXICITY; TOXICITY; RESPONSES; GENOTOXICITY; INFLAMMATION; BURNS; RATS AB Cytotoxicity assessments of nanomaterials, such as silver nanoparticles, are challenging due to interferences with test reagents and indicators as well uncertainties in dosing as a result of the complex nature of nanoparticle intracellular accumulation. Furthermore, current theories suggest that silver nanoparticle cytotoxicity is a result of silver nanoparticle dissolution and subsequent ion release. This study introduces a novel technique, nanoparticle associated cytotoxicity microscopy analysis (NACMA), which combines fluorescence microscopy detection using ethidium homodimer-1, a cell permeability marker that binds to DNA after a cell membrane is compromised (a classical dead-cell indicator dye), with live cell time-lapse microscopy and image analysis to simultaneously investigate silver nanoparticle accumulation and cytotoxicity in L-929 fibroblast cells. Results of this method are consistent with traditional methods of assessing cytotoxicity and nanoparticle accumulation. Studies conducted on 10, 50, 100 and 200nm silver nanoparticles reveal size dependent cytotoxicity with particularly high cytotoxicity from 10nm particles. In addition, NACMA results, when combined with transmission electron microscopy imaging, reveal direct evidence of intracellular silver ion dissolution and possible nanoparticle reformation within cells for all silver nanoparticle sizes. C1 [Wildt, Bridget E.; Casey, Brendan J.; Nagy, Amber M.; Goering, Peter L.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Celedon, Alfredo] Pontificia Univ Catolica Chile, Santiago, Chile. [Celedon, Alfredo] Scanogen Inc, Baltimore, MD USA. [Maurer, Elizabeth I.; Hussain, Saber M.] 711th Human Performance Wing, Appl Biotechnol Branch, Dayton, OH USA. RP Goering, PL (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 64,Rm 4064, Silver Spring, MD 20993 USA. EM peter.goering@fda.hhs.gov FU U.S. Food and Drug Administration nanotechnology research funds FX This work was supported by U.S. Food and Drug Administration nanotechnology research funds. We acknowledge the Research Fellowship Program support administered by the Oak Ridge Associated University through a contract with the U.S. Food and Drug Administration. NR 38 TC 0 Z9 0 U1 9 U2 21 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1743-5390 EI 1743-5404 J9 NANOTOXICOLOGY JI Nanotoxicology PY 2016 VL 10 IS 6 BP 710 EP 719 DI 10.3109/17435390.2015.1113321 PG 10 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA DQ5MA UT WOS:000379248300008 PM 26643278 ER PT J AU Grabias, B Kumar, S AF Grabias, Bryan Kumar, Sanjai TI Adverse neuropsychiatric effects of antimalarial drugs SO EXPERT OPINION ON DRUG SAFETY LA English DT Review DE Antimalarials; neurotoxicity; psychiatric adverse events ID PLASMODIUM-FALCIPARUM MALARIA; SUB-SAHARAN AFRICA; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; RANDOMIZED CONTROLLED-TRIAL; DOUBLE-BLIND; ATOVAQUONE-PROGUANIL; DOXYCYCLINE PROPHYLAXIS; CHLOROQUINE RESISTANCE; ARTEMISININ RESISTANCE; MEFLOQUINE TREATMENT AB Introduction: Antimalarial drugs are the primary weapon to treat parasite infection, save lives, and curtail further transmission. Accumulating data have indicated that at least some antimalarial drugs may contribute to severe neurological and/or psychiatric side effects which further complicates their use and limits the pool of available medications. Areas covered: In this review article, we summarize published scientific studies in search of evidence of the neuropsychiatric effects that may be attributed to the commonly used antimalarial drugs administered alone or in combination. Each individual drug was used as a search term in addition to keywords such as neuropsychiatric, adverse events, and neurotoxicity. Expert opinion: Accumulating data based on published reports over several decades have suggested that among the major commonly used antimalarial drugs, only mefloquine exhibited clear indications of serious neurological and/or psychiatric side effects. A more systematic approach to assess the neuropsychiatric adverse effects of new or repurposed antimalarial drugs on their safety, tolerability and efficacy phases of clinical studies and in post-marketing surveillance, is needed to ensure that these life-saving tools remain available and can be prescribed with appropriate caution and medical judgment. C1 [Grabias, Bryan; Kumar, Sanjai] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Kumar, S (reprint author), US FDA, Lab Emerging Pathogens, Dept Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, 10903 New Hampshire,Ave Bldg 52-72 Rm 5304, Silver Spring, MD 20993 USA. EM Sanjai.Kumar@fda.hhs.gov NR 104 TC 2 Z9 2 U1 7 U2 9 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1474-0338 EI 1744-764X J9 EXPERT OPIN DRUG SAF JI Expert Opin. Drug Saf. PY 2016 VL 15 IS 7 BP 903 EP 910 DI 10.1080/14740338.2016.1175428 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DP9XA UT WOS:000378850000004 PM 27077782 ER PT J AU Huang, L Tang, L Zhang, B Zhang, ZW Zhang, H AF Huang, Lu Tang, Li Zhang, Bo Zhang, Zhiwei Zhang, Hui TI Comparison of different computational implementations on fitting generalized linear mixed-effects models for repeated count measures SO JOURNAL OF STATISTICAL COMPUTATION AND SIMULATION LA English DT Article DE Repeated count data; overdispersion; integral approximation; linearization; R; SAS ID ALGORITHMS; INFERENCE AB In modelling repeated count outcomes, generalized linear mixed-effects models are commonly used to account for within-cluster correlations. However, inconsistent results are frequently generated by various statistical R packages and SAS procedures, especially in case of a moderate or strong within-cluster correlation or overdispersion. We investigated the underlying numerical approaches and statistical theories on which these packages and procedures are built. We then compared the performance of these statistical packages and procedures by simulating both Poisson-distributed and overdispersed count data. The SAS NLMIXED procedure outperformed the others procedures in all settings. C1 [Huang, Lu; Tang, Li; Zhang, Hui] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA. [Zhang, Bo; Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Zhang, H (reprint author), St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA. EM hui.zhang@stjude.org RI Zhang, Hui/E-8112-2010 FU ALSAC FX LH, LT, and HZ receive support from the ALSAC. NR 31 TC 1 Z9 1 U1 0 U2 1 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. PY 2016 VL 86 IS 12 BP 2392 EP 2404 DI 10.1080/00949655.2015.1111376 PG 13 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA DP7ZM UT WOS:000378717700008 ER PT S AU Abbey, CK Wu, YR Burnside, ES Wunderlich, A Samuelson, FW Boone, JM AF Abbey, Craig K. Wu, Yirong Burnside, Elizabeth S. Wunderlich, Adam Samuelson, Frank W. Boone, John M. BE Abbey, CK Kupinski, MA TI A Utility/Cost Analysis of Breast Cancer Risk Prediction Algorithms SO MEDICAL IMAGING 2016: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY MAR 02-03, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD DE Risk prediction; breast cancer screening; expected cost; diagnostic utility ID SCREENING MAMMOGRAPHY; RELATIVE UTILITY; PERFORMANCE; RADIOLOGISTS; WOMEN AB Breast cancer risk prediction algorithms are used to identify subpopulations that are at increased risk for developing breast cancer. They can be based on many different sources of data such as demographics, relatives with cancer, gene expression, and various phenotypic features such as breast density. Women who are identified as high risk may undergo a more extensive (and expensive) screening process that includes MRI or ultrasound imaging in addition to the standard full-field digital mammography (FFDM) exam. Given that there are many ways that risk prediction may be accomplished, it is of interest to evaluate them in terms of expected cost, which includes the costs of diagnostic outcomes. In this work we perform an expected-cost analysis of risk prediction algorithms that is based on a published model that includes the costs associated with diagnostic outcomes (true-positive, false-positive, etc.). We assume the existence of a standard screening method and an enhanced screening method with higher scan cost, higher sensitivity, and lower specificity. We then assess expected cost of using a risk prediction algorithm to determine who gets the enhanced screening method under the strong assumption that risk and diagnostic performance are independent. We find that if risk prediction leads to a high enough positive predictive value, it will be cost-effective regardless of the size of the subpopulation. Furthermore, in terms of the hit-rate and false-alarm rate of the of the risk-prediction algorithm, iso-cost contours are lines with slope determined by properties of the available diagnostic systems for screening. C1 [Abbey, Craig K.] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. [Wu, Yirong; Burnside, Elizabeth S.] Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. [Wunderlich, Adam; Samuelson, Frank W.] US FDA, Div Imaging & Appl Math, OSEL, CDRH, Silver Spring, MD 20993 USA. [Boone, John M.] Univ Calif Davis, Med Ctr, Dept Radiol, Sacramento, CA 95817 USA. RP Abbey, CK (reprint author), Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0022-5 J9 PROC SPIE PY 2016 VL 9787 AR 97871J DI 10.1117/12.2217850 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BF0CK UT WOS:000378534200053 ER PT S AU Chen, WJ Hu, N AF Chen, Weijie Hu, Nan BE Abbey, CK Kupinski, MA TI Proper bibeta ROC model: algorithm, software, and performance evaluation SO MEDICAL IMAGING 2016: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY MAR 02-03, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD DE Proper ROC model; ROC curve fitting; maximum likelihood estimation; ROC software ID MAXIMUM-LIKELIHOOD-ESTIMATION; CURVES AB Semi-parametric models are often used to fit data collected in receiver operating characteristic (ROC) experiments to obtain a smooth ROC curve and ROC parameters for statistical inference purposes. The proper bibeta model as recently proposed by Mossman and Peng enjoys several theoretical properties. In addition to having explicit density functions for the latent decision variable and an explicit functional form of the ROC curve, the two-parameter bibeta model also has simple closed-form expressions for true-positive fraction (TPF), false-positive fraction (FPF), and the area under the ROC curve (AUC). In this work, we developed a computational algorithm and R package implementing this model for ROC curve fitting. Our algorithm can deal with any ordinal data (categorical or continuous). To improve accuracy, efficiency, and reliability of our software, we adopted several strategies in our computational algorithm including: (1) the LABROC4 categorization to obtain the true maximum likelihood estimation of the ROC parameters; (2) a principled approach to initializing parameters; (3) analytical first-order and second-order derivatives of the likelihood function; (4) an efficient optimization procedure (the L-BFGS algorithm in the R package "nlopt"); and (5) an analytical delta method to estimate the variance of the AUC. We evaluated the performance of our software with intensive simulation studies and compared with the conventional binormal and the proper binormal-likelihood-ratio models developed at the University of Chicago. Our simulation results indicate that our software is highly accurate, efficient, and reliable. C1 [Chen, Weijie] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Hu, Nan] Univ Iowa, Dept Math, Iowa City, IA 52242 USA. RP Chen, WJ (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM weijie.chen@fda.hhs.gov NR 16 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0022-5 J9 PROC SPIE PY 2016 VL 9787 AR 97870E DI 10.1117/12.2216777 PG 8 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BF0CK UT WOS:000378534200013 ER PT S AU Han, M Park, S Baek, J AF Han, Minah Park, Subok Baek, Jongduk BE Abbey, CK Kupinski, MA TI Effect of anatomical backgrounds on detectability in volumetric cone beam CT images SO MEDICAL IMAGING 2016: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY MAR 02-03, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD ID OBSERVER; CHANNELS; NOISE AB As anatomical noise is often a dominating factor affecting signal detection in medical imaging, we investigate the effects of anatomical backgrounds on signal detection in volumetric cone beam CT images. Signal detection performances are compared between transverse and longitudinal planes with either uniform or anatomical backgrounds. Sphere objects with diameters of 1mm, 5mm, 8mm, and 11mm are used as the signals. Three-dimensional (3D) anatomical backgrounds are generated using an anatomical noise power spectrum, 1/f(beta), with beta=3, equivalent to mammographic background [1]. The mean voxel value of the 3D anatomical backgrounds is used as an attenuation coefficient of the uniform background. Noisy projection data are acquired by the forward projection of the uniform and anatomical 3D backgrounds with/without sphere lesions and by the addition of quantum noise. Then, images are reconstructed by an FDK algorithm [2]. For each signal size, signal detection performances in transverse and longitudinal planes are measured by calculating the task SNR of a channelized Hotelling observer with Laguerre-Gauss channels. In the uniform background case, transverse planes yield higher task SNR values for all sphere diameters but 1mm. In the anatomical background case, longitudinal planes yield higher task SNR values for all signal diameters. The results indicate that it is beneficial to use longitudinal planes to detect spherical signals in anatomical backgrounds. C1 [Han, Minah; Baek, Jongduk] Yonsei Univ, Sch Integrated Technol, Seoul 120749, South Korea. [Han, Minah; Baek, Jongduk] Yonsei Univ, Yonsei Inst Convergence Technol, Seoul 120749, South Korea. [Park, Subok] US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD USA. RP Han, M (reprint author), Yonsei Univ, Sch Integrated Technol, Seoul 120749, South Korea.; Han, M (reprint author), Yonsei Univ, Yonsei Inst Convergence Technol, Seoul 120749, South Korea. NR 12 TC 1 Z9 1 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0022-5 J9 PROC SPIE PY 2016 VL 9787 AR 978717 DI 10.1117/12.2214689 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BF0CK UT WOS:000378534200041 ER PT S AU Lee, C Baek, J Park, S AF Lee, Changwoo Baek, Jongduk Park, Subok BE Abbey, CK Kupinski, MA TI Investigation on location-dependent detectability of a small mass for digital breast tomosynthesis evaluation SO MEDICAL IMAGING 2016: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY MAR 02-03, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD DE Model observers; Laguerre-Gauss channels; anatomical background statistics; location-dependent detectability; digital breast tomosynthesis ID CONE-BEAM CT; OF-THE-ART; ALGORITHM; MICROCALCIFICATION; MAMMOGRAPHY; SIMULATION; PROJECTION; SYSTEM AB Digital breast tomosynthesis (DBT) is an emerging imaging modality for improved breast cancer detection and diagnosis [1-5]. Numerous efforts have been made to find quantitative metrics associated with mammographic image quality assessment, such as the exponent beta of anatomical noise power spectrum, glandularity, contrast noise ratio, etc. [6-8]. In addition, with the use of Fourier-domain detectability for a task-based assessment of DBT, a stationarity assumption on reconstructed image statistics was often made [9-11], resulting in the use of multiple regions-of-interest (ROIs) from different locations in order to increase sample size. While all these metrics provide some information on mammographic image characteristics and signal detection, the relationship between these metrics and detectability in DBT evaluation has not been fully understood. In this work, we investigated spatial-domain detectability trends and levels as a function of the number of slices N-s at three different ROI locations on the same image slice, where background statistics differ in terms of the aforementioned metrics. Detectabilities for the three ROI locations were calculated using multi-slice channelized Hotelling observers with 2D/3D Laguerre-Gauss channels. Our simulation results show that detectability levels and trends as a function of N-s vary across these three ROI locations. They also show that the exponent beta, mean glandularity, and mean attenuation coefficient vary across the three ROI locations but they do not necessarily predict the ranking of detectability levels and trends across these ROI locations. C1 [Lee, Changwoo; Baek, Jongduk] Yonsei Univ, Sch Integrated Technol, Seoul 120749, South Korea. [Lee, Changwoo; Baek, Jongduk] Yonsei Univ, Yonsei Inst Convergence Technol, Seoul 120749, South Korea. [Park, Subok] US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD USA. RP Park, S (reprint author), 10903 New Hampshire Ave,WO62-31092,Room 3109, Silver Spring, MD 20993 USA. EM subok.park@fda.hhs.gov NR 21 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0022-5 J9 PROC SPIE PY 2016 VL 9787 AR 97870V DI 10.1117/12.2216579 PG 9 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BF0CK UT WOS:000378534200029 ER PT S AU Sahiner, B Chen, WJ Pezeshk, A Petrick, N AF Sahiner, Berkman Chen, Weijie Pezeshk, Aria Petrick, Nicholas BE Abbey, CK Kupinski, MA TI Semi-parametric Estimation of the Area Under the Precision-Recall Curve SO MEDICAL IMAGING 2016: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY MAR 02-03, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD DE Precision-recall curve; receiver operating characteristic curve; area under curve; information retrieval AB Precision and recall are two common metrics used in the evaluation of information retrieval systems. By changing the number of retrieved documents, one can obtain a precision-recall curve. The area under the precision-recall curve (AUCPR) has been suggested as a performance measure for information retrieval systems, in a manner similar to the use of the area under the receiver operating characteristic curve in binary classification. Limited work has been performed in the literature to investigate the bias and variance of AUCPR estimators. The goal of our study was to investigate the bias and variability of a semi-parametric binormal method for estimating the AUCPR, and to compare it to other techniques, such as average precision (AP) and lower trapezoid (LT) approximation. We show how AUCPR can be obtained given the binormal model parameters, and how its variance can be estimated using the delta method. We performed simulation experiments with normal and non-normal data, and investigated the effect of sample size and prevalence. Our results indicated that the semi-parametric binormal approach provided AUCPR estimates with small bias and confidence intervals with acceptable coverage when the sample size was large, and the performance of the binormal model was comparable to or better than alternative methods evaluated in this study when the sample size was small. We conclude that the semi-parametric binormal model can be used to accurately estimate the AUCPR, and that the confidence intervals derived from the model can be at least as accurate as from other alternatives, even for non-normal decision variable distributions. C1 [Sahiner, Berkman; Chen, Weijie; Pezeshk, Aria; Petrick, Nicholas] US FDA, CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Sahiner, B (reprint author), US FDA, CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Berkman.sahiner@fda.hhs.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0022-5 J9 PROC SPIE PY 2016 VL 9787 AR 97870D DI 10.1117/12.2216434 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BF0CK UT WOS:000378534200012 ER PT S AU Wen, GZ Markey, MK Park, S AF Wen, Gezheng Markey, Mia K. Park, Subok BE Abbey, CK Kupinski, MA TI Model observer design for detecting multiple abnormalities in anatomical background images SO MEDICAL IMAGING 2016: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY MAR 02-03, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD DE Multiple signal detection; channelized Hotelling observer; multifocal and multicentric cancer; mammographic image evaluation; partial least squares; Laguerre-Gauss function ID CLUSTERED LUMPY BACKGROUNDS; BREAST TOMOSYNTHESIS; TEXTURE SYNTHESIS; GAZE-TRACKING; ACQUISITION; CANCERS; PERCEPTION; SIMULATION; LOCATIONS; ALGORITHM AB As psychophysical studies are resource-intensive to conduct, model observers are commonly used to assess and optimize medical imaging quality. Existing model observers were typically designed to detect at most one signal. However, in clinical practice, there may be multiple abnormalities in a single image set (e.g., multifocal and multicentric breast cancers (MMBC)), which can impact treatment planning. Prevalence of signals can be different across anatomical regions, and human observers do not know the number or location of signals a priori. As new imaging techniques have the potential to improve multiple-signal detection (e.g., digital breast tomosynthesis may be more effective for diagnosis of MMBC than planar mammography), image quality assessment approaches addressing such tasks are needed. In this study, we present a model-observer mechanism to detect multiple signals in the same image dataset. To handle the high dimensionality of images, a novel implementation of partial least squares (PLS) was developed to estimate different sets of efficient channels directly from the images. Without any prior knowledge of the background or the signals, the PLS channels capture interactions between signals and the background which provide discriminant image information. Corresponding linear decision templates are employed to generate both image-level and location-specific scores on the presence of signals. Our preliminary results show that the model observer using PLS channels, compared to our first attempts with Laguerre-Gauss channels, can achieve high performance with a reasonably small number of channels, and the optimal design of the model observer may vary as the tasks of clinical interest change. C1 [Wen, Gezheng] Univ Texas Austin, Dept Elect & Comp Engn, Austin, TX 78712 USA. [Wen, Gezheng] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Markey, Mia K.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Markey, Mia K.] Univ Texas MD Anderson Canc Ctr, Dept Imaging Phys, Houston, TX 77030 USA. [Park, Subok] US FDA, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. RP Wen, GZ (reprint author), Univ Texas Austin, Dept Elect & Comp Engn, Austin, TX 78712 USA.; Wen, GZ (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. EM wen.gezheng@utexas.edu; mia.markey@utexas.edu; subok.Park@fda.hhs.gov NR 34 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0022-5 J9 PROC SPIE PY 2016 VL 9787 AR 97870S DI 10.1117/12.2217665 PG 11 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BF0CK UT WOS:000378534200026 ER PT S AU Yngvesson, SK Karellas, A Glick, S Khan, A Siqueira, PR Kelly, PA Peter, BS AF Yngvesson, Sigfrid K. Karellas, Andrew Glick, Stephen Khan, Ashraf Siqueira, Paul R. Kelly, Patrick A. Peter, Benjamin St. BE Jansen, ED TI Breast cancer margin detection with a single frequency terahertz imaging system SO OPTICAL INTERACTIONS WITH TISSUE AND CELLS XXVII SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Optical Interactions with Tissue and Cells XXVII CY FEB 14-17, 2016 CL San Francisco, CA SP SPIE DE Breast cancer; medical imaging; reflectivity; refractive index; single frequency THz imaging (SFTI); THz ID CONSERVATION SURGERY; SPECTROSCOPY; TECHNOLOGY; CARCINOMA; THERAPY; DOMAIN; TIME AB The ability to discern malignant from benign tissue in excised human breast specimens in Breast Conservation Surgery (BCS) was evaluated using a prototype single frequency terahertz radiation. Terahertz (THz) images of the specimens in reflection mode were obtained by employing a gas laser source and mechanical scanning. The images were correlated with optical histological micrographs of the same specimens, and a mean discrimination of 73% was found for five out of six samples using Receiver Operating Characteristic (ROC) analysis. This result is similar to what has previously been obtained using Terahertz pulsed imaging (TPI) techniques. We will discuss the specific advantages of Single frequency THz imaging (SFTI) compared with TPI for potentially allowing the development of much faster, more compact and less expensive cancer imaging systems that could be adapted for employment in the operating room. The system design and characterization of the prototype SFTI system are discussed in detail. The initial results are encouraging but further development of the technology and clinical evaluation is needed to evaluate its feasibility in the clinical environment. C1 [Yngvesson, Sigfrid K.; Siqueira, Paul R.; Kelly, Patrick A.] Univ Massachusetts, Dept Elect & Comp Engn, Amherst, MA 01003 USA. [Karellas, Andrew; Khan, Ashraf] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [Glick, Stephen] US FDA, US Dept HHS, Silver Spring, MD 20993 USA. [Peter, Benjamin St.] Spectral Sci Inc, Burlington, MA 01803 USA. RP Yngvesson, SK (reprint author), Univ Massachusetts, Dept Elect & Comp Engn, Amherst, MA 01003 USA. NR 45 TC 0 Z9 0 U1 5 U2 7 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-940-5 J9 PROC SPIE PY 2016 VL 9706 AR 970603 DI 10.1117/12.2216385 PG 16 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA BF0HH UT WOS:000378852400002 ER PT S AU Vogt, WC Jia, CX Wear, KA Garra, BS Pfefer, TJ AF Vogt, William C. Jia, Congxian Wear, Keith A. Garra, Brian S. Pfefer, T. Joshua BE Oraevsky, AA Wang, LV TI Nanoparticle-Enhanced Spectral Photoacoustic Tomography: Effect of Oxygen Saturation and Tissue Heterogeneity SO PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2016 SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Photons Plus Ultrasound - Imaging and Sensing CY FEB 14-17, 2016 CL San Francisco, CA SP SPIE, Seno Med Instruments Inc DE Gold nanorods; tissue phantoms; blood oxygenation; oximetry ID MEDIA AB Molecular imaging for breast cancer detection, infectious disease diagnostics and preclinical animal research may be achievable through combined use of targeted exogenous agents such as nanoparticles and spectral Photoacoustic Tomography (PAT). However, tissue heterogeneity can alter fluence distributions and acoustic propagation, corrupting measured PAT absorption spectra and complicating in vivo nanoparticle detection and quantitation Highly absorptive vascular structures represent a common confounding factor, and variations in vessel hemoglobin saturation (SO2) may alter spectral content of signals from adjacent/deeper regions. To evaluate the impact of this effect on PAT nanoparticle detectability, we constructed heterogeneous phantoms with well-characterized channel-inclusion geometries and biologically relevant optical and acoustic properties. Phantoms contained an array of tubes at several depths filled with hemoglobin solutions doped with varying concentrations of gold nanorods with an absorption peak at 780 nm. Both overlying and target network SO2 was tuned using sodium dithionite. Phantoms were imaged from 700 to 900 nm using a custom PAT system comprised of a tunable pulsed laser and a research-grade ultrasound system. Recovered nanoparticle spectra were analyzed and compared with results from both spectrophotometry and PAT data from water immersed tubes containing blood and nanoparticle solutions. Results suggested that nanoparticle selection for a given PAT application should take into account expected oxygenation states of both target blood vessel and background tissue oxygenation to achieve optimal performance. C1 [Vogt, William C.; Jia, Congxian; Wear, Keith A.; Garra, Brian S.; Pfefer, T. Joshua] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20093 USA. RP Pfefer, TJ (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20093 USA. EM Joshua.Pfefer@fda.hhs.gov NR 11 TC 0 Z9 0 U1 4 U2 4 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-942-9 J9 PROC SPIE PY 2016 VL 9708 AR 97081H DI 10.1117/12.2213468 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BF0AZ UT WOS:000378437000050 ER PT J AU Nnaji, CN Mach, PM Acheampong, JS Falconer, TM Verbeck, GF AF Nnaji, Chinyere N. Mach, Phillip M. Acheampong, Jason S. Falconer, Travis M. Verbeck, Guido F. TI Analysis of trace amounts of adulterants found in powders/supplements utilizing Raman spectroscopy coupled to direct analyte-probed nanoextraction-nanospray ionization-mass spectrometry SO ANALYTICAL METHODS LA English DT Article ID DIETARY-SUPPLEMENTS; SYNTHETIC ADULTERANTS; LIQUID-CHROMATOGRAPHY; IMAGING METHODS; INFANT FORMULA; POWDERED MILK; MELAMINE; MS; SIBUTRAMINE; EXTRACTION AB In the United States, all food products have to be regulated to inform the consumers of the ingredients contained within. Some ingredients are not included on the label and yet are still found in the products. Presented is a Raman imaging technique for rapid, nondestructive, and spatially relevant localization of adulterants in powders. Raman spectroscopy followed by direct analyte-probed nanoextraction coupled to nanospray ionization-mass spectrometry allows rapid determination of the presence of each adulterant, leading to positive identifications such as melamine. The location and identification of these trace particles can then be extracted using a nanomanipulator. The nanomanipulation technique uses a solvent filled capillary tip which can be positioned on the particle of interest. Direct mass spectrometric analysis via nanospray of the particulate of interest eliminates time consuming chromatographic techniques prior to mass spectrometry analysis. This coupled technique combines rapid Raman spectroscopy techniques with direct mass spectrometry to confirm the presence of an adulterant. This technique was applied to an FDA supplied test sample, in which sibutramine, phenolphthalein, and melamine were confirmed to be present. C1 [Nnaji, Chinyere N.; Mach, Phillip M.; Acheampong, Jason S.; Verbeck, Guido F.] Univ N Texas, Dept Chem, Denton, TX 76203 USA. [Falconer, Travis M.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Verbeck, GF (reprint author), Univ N Texas, Dept Chem, Denton, TX 76203 USA. EM gverbeck@unt.edu FU Intramural FDA HHS [FD999999] NR 53 TC 0 Z9 0 U1 5 U2 6 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1759-9660 EI 1759-9679 J9 ANAL METHODS-UK JI Anal. Methods PY 2016 VL 8 IS 24 BP 4798 EP 4807 DI 10.1039/c6ay00828c PG 10 WC Chemistry, Analytical; Food Science & Technology; Spectroscopy SC Chemistry; Food Science & Technology; Spectroscopy GA DP1DV UT WOS:000378231600003 PM 27482293 ER PT J AU Pillai, KV Gray, PJ Tien, CC Bleher, R Sung, LP Duncan, TV AF Pillai, Karthik V. Gray, Patrick J. Tien, Chun-Chieh Bleher, Reiner Sung, Li-Piin Duncan, Timothy V. TI Environmental release of core-shell semiconductor nanocrystals from free-standing polymer nanocomposite films SO ENVIRONMENTAL SCIENCE-NANO LA English DT Article ID FOOD-CONTACT MATERIALS; EXPOSURE ASSESSMENT; PACKAGING APPLICATIONS; SILVER NANOPARTICLES; CONSUMER PRODUCTS; MIGRATION; POLYETHYLENE; NANOSILVER; COMPOSITES; NANOCLAY AB Concomitant with the development of polymer nanocomposite (PNC) technologies across numerous industries is an expanding awareness of the uncertainty with which engineered nanoparticles embedded within these materials may be released into the external environment, particularly liquid media. Recently there has been an interest in evaluating potential exposure to nanoscale fillers from PNCs, but existing studies often rely upon uncharacterized, poor quality, or proprietary materials, creating a barrier to making general mechanistic conclusions about release phenomena. In this study we employed semiconductor nanoparticles (quantum dots, QDs) as model nanofillers to quantify potential release into liquid media under specific environmental conditions. QDs of two sizes were incorporated into low-density polyethylene by melt compounding and the mixtures were extruded as free-standing fluorescent films. These films were subjected to tests under conditions intended to accelerate potential release of embedded particles or dissolved residuals into liquid environments. Using inductively-coupled plasma mass spectrometry and laser scanning confocal microscopy, it was found that the acidity of the external medium, exposure time, and small differences in particle size (on the order of a few nm) all play pivotal roles in release kinetics. Particle dissolution was found to play a major if not dominant role in the release process. This paper also presents the first evidence that internally embedded nanoparticles contribute to the mass transfer, an observation made possible via the use of a model system that was deliberately designed to probe the complex relationships between nanoparticle-enabled plastics and the environment. C1 [Pillai, Karthik V.; Gray, Patrick J.; Duncan, Timothy V.] US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. [Tien, Chun-Chieh; Sung, Li-Piin] NIST, Polymer Mat Grp, 100 Bur Dr, Gaithersburg, MD 20899 USA. [Bleher, Reiner] Northwestern Univ, Northwestern Univ Atom & Nanoscale Characterizat, Evanston, IL 60208 USA. [Bleher, Reiner] Northwestern Univ, Dept Mat Sci & Engn, Evanston, IL 60208 USA. RP Duncan, TV (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM timothy.duncan@fda.hhs.gov OI Gray, Patrick/0000-0002-8248-2749 FU FDA/CFSAN; MRSEC program at the Materials Research Center [NSF DMR-1121262]; International Institute for Nanotechnology (IIN); State of Illinois, through the IIN FX The authors gratefully acknowledge Glenn J. Bastiaans, Ph. D., President of NanoOptical Materials, for helpful discussions related to QD performance and composition. The authors also thank FDA/CFSAN for financial support of this work. This work made use of the EPIC facility (NUANCE Center-Northwestern University), which has received support from the MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); and the State of Illinois, through the IIN. NR 48 TC 2 Z9 2 U1 6 U2 12 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2051-8153 EI 2051-8161 J9 ENVIRON SCI-NANO JI Environ.-Sci. Nano PY 2016 VL 3 IS 3 BP 657 EP 669 DI 10.1039/c6en00064a PG 13 WC Chemistry, Multidisciplinary; Environmental Sciences; Nanoscience & Nanotechnology SC Chemistry; Environmental Sciences & Ecology; Science & Technology - Other Topics GA DP1IZ UT WOS:000378245000016 PM 27529026 ER PT S AU Choi, M Alam, N Dahal, E Ghammraoui, B Badano, A AF Choi, Mina Alam, Nadia Dahal, Eshan Ghammraoui, Bahaa Badano, Aldo BE Gimi, B Krol, A TI Alzheimer's disease imaging biomarkers using small-angle x-ray scattering SO MEDICAL IMAGING 2016-BIOMEDICAL APPLICATIONS IN MOLECULAR, STRUCTURAL, AND FUNCTIONAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT SPIE Biomedical Applications in Molecular, Structural and Functional Imaging Conference CY MAR 01-03, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, imXPAD DE Alzheimer's disease; Small angle x-ray scattering; cross sections; Monte Carlo simulations; biomarkers; amyloid beta AB There is a need for novel imaging, techniques for the earlier detection of Alzheimer's disease (All). Two hallmarks of AD are amyloid beta (A beta) plaques and tau tangles that are formed in the brain. Well-characterized x-ray cross sections of A beta and tau proteins in a variety of structural states could potentially be used as AD biomarkers for small-angle x-ray scattering (SANS) imaging without the need for injectable probes or contrast agents. First, however, the protein structures must be controlled and measured to determine accurate biomarkers for SAXS imaging. Here we report SAXS measurements of A beta(42) and tau(352) in a 50% dimethyl sulfoxide (DMSO) solution in which these proteins are believed to remain monomeric because of the stabilizing interaction of DMSO solution. Our SANS analysis showed the aggregation of both proteins. in particular, we found that the aggregation of A beta(42) slowly progresses with time in comparison to tau(352) that aggregates at a faster rate and reaches a steady-state. Furthermore, the measured signals were compared to the theoretical SANS profiles of A beta(42) monomer, A beta(42) fibril, and tau(352) that were computed from their respective protein data bank structures. We have begun the work to systematically control the structural states of these proteins in vitro using various solvent conditions. Our future work is to utilize the distinct SAXS profiles of various structural states of A beta and tau to build a library of signals of interest for SAXS imaging in brain tissue. C1 [Choi, Mina; Dahal, Eshan; Badano, Aldo] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Choi, Mina; Alam, Nadia; Dahal, Eshan; Ghammraoui, Bahaa; Badano, Aldo] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Badano, A (reprint author), Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA.; Badano, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 16 TC 0 Z9 0 U1 1 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0023-2 J9 PROC SPIE PY 2016 VL 9788 AR 978802 DI 10.1117/12.2217408 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BE9WB UT WOS:000378223800002 ER PT S AU Badal, A AF Badal, Andreu BE Kontos, D Flohr, TG Lo, JY TI Prototype adaptive bow-tie filter based on spatial exposure time modulation SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE bow-tie filter; dynamic filter; x-ray beam shaping; adaptive imaging ID CT AB In recent years, there has been an increased interest in the development of dynamic bow -tie filters that are able to provide patient-specific x-ray beam shaping. We introduce the first physical prototype of a new adaptive bow-tie filter design based on the concept of "spatial exposure time modulation." While most existing bow -tie filters operate by attenuating the radiation beam differently in different locations using partially attenuating objects, the presented filter shapes the radiation field using two movable completely radio-opaque collimators. The aperture and speed of the collimators is modulated in synchrony with the x-ray exposure to selectively block the radiation emitted to different parts of the object. This mode of operation does not allow the reproduction of every possible attenuation profile, but it can reproduce the profile of any object with an attenuation profile monotonically decreasing from the center to the periphery, such as an object with an elliptical cross section. Therefore, the new adaptive filter provides the same advantages as the currently existing static bow -tie filters, which are typically designed to work for a pre-determined cylindrical object at a fixed distance from the source, and provides the additional capability to adapt its performance at image acquisition time to better compensate for the actual diameter and location of the imaged object. A detailed description of the prototype filter, the implemented control methods, and a preliminary experimental validation of its performance are presented. C1 [Badal, Andreu] US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD 20993 USA. RP Badal, A (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD 20993 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 DI 10.1117/12.2217235 PG 7 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900113 ER PT S AU Choi, M Ghammraoui, B Badal, A Badano, A AF Choi, Mina Ghammraoui, Bahaa Badal, Andreu Badano, Aldo BE Kontos, D Flohr, TG Lo, JY TI Method to study sample object size limit of small-angle x-ray scattering computed tomography SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Small angle x-ray scattering imaging; Monte Carlo simulations; x-ray phantoms; dose estimation; small animal imaging systems AB Small-angle x-ray scattering (SAXS) imaging is an emerging medical tool that can be used for in vivo detailed tissue characterization and has the potential to provide added contrast to conventional x-ray projection and CT imaging. We used a publicly available MC-GPU code to simulate x-ray trajectories in a SAXS-CT geometry for a target material embedded in a water background material with varying sample sizes (1, 3, 5, and 10 mm). Our target materials were water solution of gold nanoparticle (GNP) spheres with a radius of 6 nm and a water solution with dissolved serum albumin (BSA) proteins due to their well-characterized scatter profiles at small angles and highly scattering properties. The background material was water. Our objective is to study how the reconstructed scatter profile degrades at larger target imaging depths and increasing sample sizes. We have found that scatter profiles of the GNP in water can still be reconstructed at depths up to 5 mm embedded at the center of a 10 mm sample. Scatter profiles of BSA in water were also reconstructed at depths up to 5 mm in a 10 mm sample but with noticeable signal degradation as compared to the GNP sample. This work presents a method to study the sample size limits for future SAXS-CT imaging systems. C1 [Choi, Mina; Badano, Aldo] Univ Maryland, College Pk, MD 20742 USA. [Ghammraoui, Bahaa; Badal, Andreu; Badano, Aldo] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Choi, M (reprint author), Univ Maryland, College Pk, MD 20742 USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 11 TC 0 Z9 0 U1 1 U2 2 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 97831Z DI 10.1117/12.2216325 PG 6 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900068 ER PT S AU Clark, M Ghammraoui, B Badal, A AF Clark, Matthew Ghammraoui, Bahaa Badal, Andreu BE Kontos, D Flohr, TG Lo, JY TI Reproducing 2D Breast Mammography Images with 3D Printed Phantoms SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE mammography; breast phantoms; 3D printing AB Mammography is currently the standard imaging modality used to screen women for breast abnormalities and, as a result, it is a tool of great importance for the early detection of breast cancer. Physical phantoms are commonly used as surrogates of breast tissue to evaluate some aspects of the performance of mammography systems. However, most phantoms do not reproduce the anatomic heterogeneity of real breasts. New fabrication technologies, such as 3D printing, have created the opportunity to build more complex, anatomically realistic breast phantoms that could potentially assist in the evaluation of mammography systems. The primary objective of this work is to present a simple, easily reproducible methodology to design and print 3D objects that replicate the attenuation profile observed in real 2D mammograms. The secondary objective is to evaluate the capabilities and limitations of the competing 3D printing technologies, and characterize the x-ray properties of the different materials they use. Printable phantoms can be created using the open-source code introduced in this work, which processes a raw mammography image to estimate the amount of x-ray attenuation at each pixel, and outputs a triangle mesh object that encodes the observed attenuation map. The conversion from the observed pixel gray value to a column of printed material with equivalent attenuation requires certain assumptions and knowledge of multiple imaging system parameters, such as x-ray energy spectrum, source-to-object distance, compressed breast thickness, and average breast material attenuation. A detailed description of the new software, a characterization of the printed materials using x-ray spectroscopy, and an evaluation of the realism of the sample printed phantoms are presented. C1 [Ghammraoui, Bahaa; Badal, Andreu] US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD USA. [Clark, Matthew] Univ Maryland, Mech Engn, College Pk, MD 20742 USA. RP Clark, M (reprint author), Univ Maryland, Mech Engn, College Pk, MD 20742 USA. NR 7 TC 0 Z9 0 U1 3 U2 3 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 97830B DI 10.1117/12.2217215 PG 9 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900010 ER PT S AU Fang, Y Badano, A AF Fang, Yuan Badano, Aldo BE Kontos, D Flohr, TG Lo, JY TI DQE simulation of a-Se x-ray detectors using ARTEMIS SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Monte Carlo simulation; amorphous selenium; ARTEMIS; detective quantum efficiency ID AMORPHOUS SELENIUM; QUANTUM EFFICIENCY; DIGITAL RADIOLOGY; SCREENS; ABSORPTION; ENERGY; NOISE AB Detective Quantum Efficiency (DQE) is one of the most important image quality metrics for evaluating the spatial resolution performance of flat-panel x-ray detectors. In this work, we simulate the DQE of amorphous selenium (a-Se) x-ray detectors with a detailed Monte Carlo transport code (ARTEMIS) for modeling semiconductor-based direct x-ray detectors. The transport of electron-hole pairs is achieved with a spatiotemporal model that accounts for recombination and trapping of carriers and Coulombic effects of space charge and external applied electric field. A range of x-ray energies has been simulated from 10 to 100 keV. The DQE results can be used to study the spatial resolution characteristics of detectors at different energies. C1 [Fang, Yuan] US FDA, Off Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Diagnost Xray Syst Branch,Div Radiol Hlth, Silver Spring, MD 20993 USA. [Badano, Aldo] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD USA. RP Fang, Y (reprint author), US FDA, Off Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Diagnost Xray Syst Branch,Div Radiol Hlth, Silver Spring, MD 20993 USA. EM yuan.fang@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 21 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 978314 DI 10.1117/12.2214805 PG 6 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900038 ER PT S AU Gavrielides, MA Li, Q Zeng, RP Gong, Q Myers, K Sahiner, B Petrick, N AF Gavrielides, Marios A. Li, Qin Zeng, Rongping Gong, Qi Myers, Kyle Sahiner, Berkman Petrick, Nicholas BE Kontos, D Flohr, TG Lo, JY TI Detectable change of lung nodule volume with CT in a phantom study with high and low signal to background contrast SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE lung nodule; volumetric computed tomography; change analysis; minimum detectable change; protocol; quantitative imaging biomarkers ID GROUND-GLASS OPACITY; PULMONARY NODULES; RECONSTRUCTION AB In previous work we developed a method for predicting the minimum detectable change (MDC) in nodule volume based on volumetric CT measurements. MDC was defined as the minimum increase/decrease in a nodule volume distinguishable from the baseline measurement at a specified level of detection performance, assessed using the area under the ROC curve (AUC). In this work we derived volume estimates of a set of synthetic nodules and calculated the detection performance for distinguishing them from baseline measurements. Eight spherical objects of 100HU radiodensity ranging in diameter from 5.0mm to 5.75mm and 8.0mm to 8.75mm with 0.25mm increments were placed in an anthropomorphic phantom with either no background (high-contrast task) or gelatin background (low-contrast task). The baseline was defined as 5.0mm for the first set of nodules and 8.0mm for the second set. The phantom was scanned using varying exposures, and reconstructed with slice thickness of 0.75, 1.5, and 3.0mm and two reconstruction kernels (standard and smooth). Volume measurements were derived using a previously developed matched- filter approach. Results showed that nodule size, slice thickness, and nodule-to-background contrast affected detectable change in nodule volume when using our volume estimator and the acquisition settings from our study. We also compared our experimental results to the values estimated by our previously-developed MDC prediction method. We found that experimental data for the 8mm baseline nodules matched very well with our predicted values of MDC. These results support considering the use of this metric when standardizing imaging protocols for lung nodule size change assessment. C1 [Gavrielides, Marios A.; Li, Qin; Zeng, Rongping; Gong, Qi; Myers, Kyle; Sahiner, Berkman; Petrick, Nicholas] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Gavrielides, MA (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 19 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 978329 DI 10.1117/12.2217887 PG 8 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900076 ER PT S AU Glick, SJ Makeev, A AF Glick, Stephen J. Makeev, Andrey BE Kontos, D Flohr, TG Lo, JY TI Optimal Exposure Techniques for Iodinated Contrast Enhanced Breast CT SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Breast CT; X-ray Filters; Iodinated Contrast Imaging ID SYSTEMS; MAMMOGRAMS; RADIATION; NOISE AB Screening for breast cancer using mammography has been very successful in the effort to reduce breast cancer mortality, and its use has largely resulted in the 30% reduction in breast cancer mortality observed since 1990 [1]. However, diagnostic mammography remains an area of breast imaging that is in great need for improvement. One imaging modality proposed for improving the accuracy of diagnostic workup is iodinated contrast-enhanced breast CT [2]. In this study, a mathematical framework is used to evaluate optimal exposure techniques for contrast-enhanced breast CT. The ideal observer signal-to-noise ratio (i.e., d') figure-of-merit is used to provide a task perfoimance based assessment of optimal acquisition parameters under the assumptions of a linear, shift-invariant imaging system. A parallel-cascade model was used to estimate signal and noise propagation through the detector, and a realistic lesion model with iodine uptake was embedded into a structured breast background. Ideal observer perfoimance was investigated across kVp settings, filter materials, and filter thickness. Results indicated many kVp spectra/filter combinations can improve perfoimance over currently used x-ray spectra. C1 [Glick, Stephen J.; Makeev, Andrey] US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD 20993 USA. RP Glick, SJ (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Silver Spring, MD 20993 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 97832N DI 10.1117/12.2216806 PG 6 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900089 ER PT S AU Graff, CG AF Graff, Christian G. BE Kontos, D Flohr, TG Lo, JY TI A New, Open-Source, Multi-Modality Digital Breast Phantom SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE breast; x-ray; MRI; phantom ID SOFTWARE PHANTOM; NOISE AB Art anthropomorphic digital breast phantom has been developed with the goal of generating random voxelized breast models that capture the anatomic variability observed in vivo. This is a new phantom and is not based OR existing digital breast phantoms or segmentation of patient images. It has been designed at the outset to be modality agnostic (i.e., suitable for use in modeling x-ray based imaging systems, magnetic resonance imaging, and potentially other imaging systems) and open source so that users may freely modify the phantom to suit a particular study. In this work we describe the modeling techniques that have been developed, the capabilities and novel features of this phantom, and study simulated images produced from it. Starting from a base quadric, a series of deformations are performed to create a breast with a particular volume and shape. Initial glandular compartments are generated using a. Voronoi technique and a. ductal tree structure with terminal duct lobular units is grown from the nipple into each compartment. An additional step involving the creation of fat and glandular lobules using a Perlin noise function is performed to create more realistic glandular/fat tissue interfaces and generate a Cooper's ligament network. A vascular tree is grown front the chest muscle into the breast tissue. Breast compression is performed using a neo-Hookean elasticity model. We show simulated rnammographic and T-1-weightexl MRI images and study properties of these images. C1 [Graff, Christian G.] US FDA, Div Imaging Diagnost & Software Reliabil, 10903 New Hampshire Ave, Silver Spring, MD 20993 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 NR 16 TC 3 Z9 3 U1 1 U2 2 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 978309 DI 10.1117/12.2216312 PG 10 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900008 ER PT S AU Ikejimba, L Glick, SJ Samei, E Lo, JY AF Ikejimba, Lynda Glick, Stephen J. Samei, Ehsan Lo, Joseph Y. BE Kontos, D Flohr, TG Lo, JY TI Comparison of model and human observer performance in FFDM, DBT, and synthetic mammography SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Anthropomorphic phantom; Digital breast tomosynthesis; Contrast detail; Model observer; Synthetic mammography ID BREAST TOMOSYNTHESIS; IMAGE QUALITY; OPTIMIZATION; ACQUISITION; NOISE AB Reader studies are important in assessing breast imaging systems. The purpose of this work was to assess task-based perfounance of full field digital mammography (FFDM), digital breast tomosynthesis (DBT), and synthetic mammography (SM) using different phantom types, and to determine an accurate observer model for human readers. Images were acquired on a Hologic Selenia Dimensions system with a unifoun and anthropomorphic phantom. A contrast detail insert of small, low-contrast disks was created using an inkjet printer with iodine-doped ink and inserted in the phantoms. The disks varied in diameter from 210 to 630 mu m, and in contrast from 1.1% contrast to 2.2% in regular increments. Human and model observers performed a 4-alternative forced choice experiment. The models were a non-prewhitening matched filter with eye model (NPWE) and a channelized Hotelling observer with either Gabor channels (Gabor-CHO) or Laguerre-Gauss channels (LG-CHO). With the given phantoms, reader scores were higher in FFDM and DBT than SM. The structure in the phantom background had a bigger impact on outcome for DBT than for FFDM or SM. All three model observers showed good correlation with humans in the unifoun background, with p between 0.89 and 0.93. However, in the structured background, only the CHOs had high correlation, with p=0.92 for Gabor-CHO, 0.90 for LG-CHO, and 0.77 for NPWE. Because results of any analysis can depend on the phantom structure, conclusions of modality perfounance may need to be taken in the context of an appropriate model observer and a realistic phantom. C1 [Ikejimba, Lynda; Samei, Ehsan; Lo, Joseph Y.] Duke Univ, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Dept Radiol, Durham, NC 27708 USA. [Ikejimba, Lynda; Glick, Stephen J.] US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Rockville, MD 20857 USA. [Samei, Ehsan; Lo, Joseph Y.] Duke Univ, Dept Elect & Comp Engn, Dept Biomed Engn, Durham, NC USA. [Samei, Ehsan] Duke Univ, Dept Phys, Durham, NC USA. RP Ikejimba, L (reprint author), Duke Univ, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Dept Radiol, Durham, NC 27708 USA.; Ikejimba, L (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Rockville, MD 20857 USA. EM lci@duke.edu NR 22 TC 1 Z9 1 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 978325 DI 10.1117/12.2216858 PG 10 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900072 ER PT S AU Li, Q Liu, ST Myers, K Gavrielides, MA Zeng, RP Sahiner, B Petrick, N AF Li, Qin Liu, Songtao Myers, Kyle Gavrielides, Marios A. Zeng, Rongping Sahiner, Berkman Petrick, Nicholas BE Kontos, D Flohr, TG Lo, JY TI Calcium scoring with dual-energy CT in men and women: an anthropomorphic phantom study SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Coronary calcium scoring; dual-energy computed tomography; phantom study; gender differences; quantitative imaging; coronary imaging ID CORONARY-ARTERY CALCIUM; INITIAL-EXPERIENCE; QUANTIFICATION; ANGIOGRAPHY; PRINCIPLES AB This work aimed to quantify and compare the potential impact of gender differences on coronary artery calcium scoring with dual-energy CT. An anthropomorphic thorax phantom with four synthetic heart vessels (diameter 3-4.5 mm: female/male left main and left circumflex artery) were scanned with and without female breast plates. Ten repeat scans were acquired in both single- and dual-energy modes and reconstructed at six reconstruction settings: two slice thicknesses (3 mm, 0.6 mm) and three reconstruction algorithms (FBP, IR3, IRS). Agatston and calcium volume scores were estimated from the reconstructed data using a segmentation-based approach. Total calcium score (summation of four vessels), and male/female calcium scores (summation of male/female vessels scanned in phantom without/with breast plates) were calculated accordingly. Both Agatston and calcium volume scores were found comparable between single- and dual-energy scans (Pearson r= 0.99, p<0.05). The total calcium scores were larger for the thinner slice thickness. Among the scores obtained from the three reconstruction algorithms, FBP yielded the highest and IRS yielded the lowest scores. The total calcium scores from the phantom without breast plates were significantly larger than those from the phantom with breast plates, and the difference increased with the stronger denoising in iterative algorithm and with thicker slices. Both gender-based anatomical differences and vessel size impacted the calcium scores. The calcium volume scores tended to be underestimated when the vessels were smaller. These findings are valuable for understanding inconsistencies between women and men in calcium scoring, and for standardizing imaging protocols for improved gender-specific calcium scoring. C1 [Li, Qin; Myers, Kyle; Gavrielides, Marios A.; Zeng, Rongping; Sahiner, Berkman; Petrick, Nicholas] US FDA, CDRH OSEL DIDSR, Silver Spring, MD 20993 USA. [Liu, Songtao] US FDA, CDRH OIR DRH DXRS, Silver Spring, MD USA. RP Li, Q (reprint author), US FDA, CDRH OSEL DIDSR, Silver Spring, MD 20993 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 978346 DI 10.1117/12.2216105 PG 7 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900142 ER PT S AU Makeev, A Ikejimba, L Lo, JY Glick, SJ AF Makeev, Andrey Ikejimba, Lynda Lo, Joseph Y. Glick, Stephen J. BE Kontos, D Flohr, TG Lo, JY TI Investigation of Optimal Parameters for Penalized Maximum-Likelihood Reconstruction Applied to Iodinated Contrast-Enhanced Breast CT SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Penalized maximum likelihood; breast CT; iodine-doped ink printed phantom; Hotelling observer AB Although digital mammography has reduced breast cancer mortality by approximately 30%, sensitivity and specificity are still far from perfect. In particular, the performance of mammography is especially limited for women with dense breast tissue. Two out of every three biopsies performed in the U.S. are unnecessary, thereby resulting in increased patient anxiety, pain, and possible complications. One promising tomographic breast imaging method that has recently been approved by the FDA is dedicated breast computed tomography (BCT). However, visualizing lesions with BCT can still be challenging for women with dense breast tissue due to the minimal contrast for lesions surrounded by fibroglandular tissue. In recent years there has been renewed interest in improving lesion conspicuity in x-ray breast imaging by administration of an iodinated contrast agent. Due to the fully 3-D imaging nature of BCT, as well as sub-optimal contrast enhancement while the breast is under compression with mammography and breast tomosynthesis, dedicated BCT of the uncompressed breast is likely to offer the best solution for injected contrast-enhanced x-ray breast imaging. It is well known that use of statistically-based iterative reconstruction in CT results in improved image quality at lower radiation dose. Here we investigate possible improvements in image reconstruction for BCT, by optimizing free regularization parameter in method of maximum likelihood and comparing its performance with clinical cone-beam filtered backprojection (FBP) algorithm. C1 [Makeev, Andrey; Glick, Stephen J.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. [Ikejimba, Lynda; Lo, Joseph Y.] Duke Univ, Dept Radiol, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Durham, NC 27708 USA. [Lo, Joseph Y.] Duke Univ, Dept Biomed Engn, Dept Elect & Comp Engn, Durham, NC 27708 USA. RP Makeev, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. EM andrey.makeev@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 978327 DI 10.1117/12.2217438 PG 7 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900074 ER PT S AU Maurino, SL Badano, A Cunningham, IA Karim, KS AF Maurino, Sebastian Lopez Badano, Aldo Cunningham, Ian A. Karim, Karim S. BE Kontos, D Flohr, TG Lo, JY TI Theoretical and Monte Carlo optimization of a stacked three-layer flat-panel x-ray imager for applications in multi-spectral diagnostic medical imaging SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Dual Energy; X-ray; Diagnosis; Multilayer; Flat-Panel Detector ID ENERGY CHEST RADIOGRAPHY; SANDWICH DETECTOR; SCINTILLATORS; SYSTEMS; NOISE; PERFORMANCE; NODULES AB We propose a new design of a stacked three-layer flat-panel x-ray detector for dual-energy (DE) imaging. Each layer consists of its own scintillator of individual thickness and an underlying thin-film-transistor-based flat-panel. Three images are obtained simultaneously in the detector during the same x-ray exposure, thereby eliminating any motion artifacts. The detector operation is two-fold: a conventional radiography image can be obtained by combining all three layers' images, while a DE subtraction image can be obtained from the front and back layers' images, where the middle layer acts as a mid-filter that helps achieve spectral separation. We proceed to optimize the detector parameters for two sample imaging tasks that could particularly benefit from this new detector by obtaining the best possible signal to noise ratio per root entrance exposure using well-established theoretical models adapted to fit our new design. These results are compared to a conventional DE temporal subtraction detector and a single-shot DE subtraction detector with a copper mid-filter, both of which underwent the same theoretical optimization. The findings are then validated using advanced Monte Carlo simulations for all optimized detector setups. Given the performance expected from initial results and the recent decrease in price for digital x-ray detectors, the simplicity of the three-layer stacked imager approach appears promising to usher in a new generation of multi-spectral digital x-ray diagnostics. C1 [Maurino, Sebastian Lopez; Karim, Karim S.] Univ Waterloo, Elect & Comp Engn, Waterloo, ON N2L 3G1, Canada. [Badano, Aldo] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Cunningham, Ian A.] Univ Western Ontario, Robarts Res Inst, Imaging Res Labs, London, ON N6A 5B7, Canada. [Cunningham, Ian A.] Univ Western Ontario, Dept Med Biophys, London, ON N6A 5B7, Canada. [Karim, Karim S.] Univ Waterloo, Ctr Bioengn & Biotechnol, Waterloo, ON N2L 3G1, Canada. RP Maurino, SL; Karim, KS (reprint author), Univ Waterloo, Elect & Comp Engn, Waterloo, ON N2L 3G1, Canada.; Karim, KS (reprint author), Univ Waterloo, Ctr Bioengn & Biotechnol, Waterloo, ON N2L 3G1, Canada. EM slopezma@uwaterloo.ca; kkarim@uwaterloo.ca OI badano, aldo/0000-0003-3712-6670 NR 42 TC 0 Z9 0 U1 1 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 97833Z DI 10.1117/12.2217085 PG 14 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900137 ER PT S AU Popescu, LM AF Popescu, Lucretiu M. BE Kontos, D Flohr, TG Lo, JY TI Hybrid deterministic and stochastic X-ray transport simulation for transmission computed tomography with advanced detector noise model SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare ID PULSE-HEIGHT SPECTROSCOPY; SYSTEM AB We present a model for simulation of noisy X-ray computed tomography data sets. The model is made of two main components, a photon transport simulation component that generates the noiseless photon field incident on the detector, and a detector response model that takes as input the incident photon field parameters and given the X-ray source intensity and exposure time can generate noisy data sets, accordingly. The photon transport simulation component combines direct ray-tracing of polychromatic X-rays for calculation of transmitted data, with Monte Carlo simulation for calculation of the scattered-photon data. The Monte Carlo scatter simulation is accelerated by implementing particle splitting and importance sampling variance reduction techniques. The detector-incident photon field data are stored as energy expansion coefficients on a refined grid that covers the detector area. From these data the detector response model is able to generate noisy detector data realizations, by reconstituting the main parameters that describe each detector element response in statistical terms, including spatial correlations. The model is able to generate very fast, on the fly, CT data sets corresponding to different radiation doses, as well as detector response characteristics, facilitating data management in extensive optimization studies by reducing the computation time and storage space demands. C1 [Popescu, Lucretiu M.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Popescu, LM (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM lucretiu.popescu@fda.hhs.gov NR 13 TC 0 Z9 0 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 97833H DI 10.1117/12.2217281 PG 10 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900119 ER PT S AU Sikaria, D Musinksy, S Sturgeon, GM Solomon, J Diao, A Gehm, ME Samei, E Glick, SJ Lo, JY AF Sikaria, Dhiraj Musinksy, Stephanie Sturgeon, Gregory M. Solomon, Justin Diao, Andrew Gehm, Michael E. Samei, Ehsan Glick, Stephen J. Lo, Joseph Y. BE Kontos, D Flohr, TG Lo, JY TI Second generation anthropomorphic physical phantom for mammography and DBT: Incorporating voxelized 3D printing and inkjet printing of iodinated lesion inserts SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Mammography; digital breast tomosynthesis; phantom design; phantom evaluation; 3D printing; image quality; x-ray imaging; quality control ID BREAST PHANTOM AB Physical phantoms are needed for the evaluation and optimization of new digital breast tomosynthesis (DBT) systems. Previously, we developed an anthropomorphic phantom based on human subject breast CT data and fabricated using commercial 3D printing. We now present three key advancements: voxelized 3D printing, photopolymer material doping, and 2D inkjet printing of lesion inserts. First, we bypassed the printer's control software in order to print in voxelized form instead of conventional STL surfaces, thus improving resolution and allowing dithering to mix the two photopolymer materials into arbitrary proportions. We demonstrated ability to print details as small as 150 mu m, and dithering to combine VeroWhitePlus and TangoPlus in 10% increments. Second, to address the limited attenuation difference among commercial photopolymers, we evaluated a beta sample from Stratasys with increased TiO2 doping concentration up to 2.5%, which corresponded to 98% breast density. By spanning 36% to 98% breast density, this doubles our previous contrast. Third, using inkjet printers modified to print with iopamidol, we created 2D lesion patterns on paper that can be sandwiched into the phantom. Inkjet printing has advantages of being inexpensive and easy, and more contrast can be delivered through overprinting. Printing resolution was maintained at 210 lam horizontally and 330 lam vertically even after 10 overprints. Contrast increased linearly with overprinting at 0.7% per overprint. Together, these three new features provide the basis for creating a new anthropomorphic physical breast phantom with improved resolution and contrast, as well as the ability to insert 2D lesions for task-based assessment of performance. C1 [Sikaria, Dhiraj; Musinksy, Stephanie; Samei, Ehsan; Lo, Joseph Y.] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. [Diao, Andrew; Gehm, Michael E.; Samei, Ehsan; Lo, Joseph Y.] Duke Univ, Dept Elect & Comp Engn, Durham, NC USA. [Sikaria, Dhiraj; Musinksy, Stephanie; Sturgeon, Gregory M.; Solomon, Justin; Samei, Ehsan; Lo, Joseph Y.] Duke Univ, Sch Med, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC USA. [Solomon, Justin; Samei, Ehsan; Lo, Joseph Y.] Duke Univ, Med Phys Grad Program, Durham, NC 27706 USA. [Glick, Stephen J.] US FDA, Div Imaging Diagnost & Software Reliabil, OSEL, CDRH, Rockville, MD 20857 USA. [Samei, Ehsan] Duke Univ, Dept Phys, Durham, NC 27706 USA. RP Sikaria, D (reprint author), Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA.; Sikaria, D (reprint author), Duke Univ, Sch Med, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC USA. NR 6 TC 1 Z9 1 U1 3 U2 3 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 978360 DI 10.1117/12.2217667 PG 10 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900202 ER PT S AU Sturgeon, GM Tward, DJ Ketcha, M Ratnanather, JT Miller, MI Park, S Segars, WP Lo, JY AF Sturgeon, Gregory M. Tward, Daniel J. Ketcha, M. Ratnanather, J. T. Miller, M. I. Park, Subok Segars, W. P. Lo, Joseph Y. BE Kontos, D Flohr, TG Lo, JY TI Eigenbreasts for Statistical Breast Phantoms SO MEDICAL IMAGING 2016: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD, Carestream Hlth Inc, GE Healthcare DE Eigenbreasts; statistical breast phantoms; computational phantom; virtual clinical trials; model observer; breast imaging AB To facilitate rigorous virtual clinical trials using model observers for breast imaging optimization and evaluation, we demonstrated a method of defining statistical models, based on 177 sets of breast CT patient data, in order to generate tens of thousands of unique digital breast phantoms. In order to separate anatomical texture from variation in breast shape, each training set of breast phantoms were deformed to a consistent atlas compressed geometry. Principal component analysis (PCA) was then performed on the shape-matched breast CT volumes to capture the variation of patient breast textures. PCA decomposes the training set of N breast CT volumes into an N-1-dimensional space of eigenvectors, which we call eigenbreasts. By summing weighted combinations of eigenbreasts, a large ensemble of different breast phantoms can be newly created. Different training sets can be used in eigenbreast analysis for designing basis models to target sub-populations defined by breast characteristics, such as size or density. In this work, we plan to generate ensembles of 30,000 new phantoms based on glandularity for an upcoming virtual trial of lesion detectability in digital breast tomosynthesis. Our method extends our series of digital and physical breast phantoms based on human subject anatomy, providing the capability to generate new, unique ensembles consisting of tens of thousands or more virtual subjects. This work represents an important step towards conducting future virtual trials for tasks-based assessment of breast imaging, where it is vital to have a large ensemble of realistic phantoms for statistical power as well as clinical relevance. C1 [Sturgeon, Gregory M.; Segars, W. P.; Lo, Joseph Y.] Duke Univ, Med Ctr, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC 27710 USA. [Tward, Daniel J.; Ketcha, M.; Ratnanather, J. T.; Miller, M. I.] Johns Hopkins Univ, Ctr Imaging Sci, Baltimore, MD USA. [Park, Subok] OSEL CDRH FDA, Div Imaging Diagnost & Software Reliabil, White Oak, MD USA. RP Sturgeon, GM (reprint author), Duke Univ, Med Ctr, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC 27710 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0018-8 J9 PROC SPIE PY 2016 VL 9783 AR 97832B DI 10.1117/12.2216398 PG 9 WC Optics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BE9YS UT WOS:000378352900078 ER PT S AU Hassan, M Ilev, IK AF Hassan, Moinuddin Ilev, Ilko K. BE Gannot, I TI Fiber-optic Fourier transform infrared (FO-FTIR) spectroscopy for detecting endotoxin contamination in ophthalmic viscosurgical devices (OVDS) (Conference Presentation) SO OPTICAL FIBERS AND SENSORS FOR MEDICAL DIAGNOSTICS AND TREATMENT APPLICATIONS XVI SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Optical Fibers and Sensors for Medical Diagnostics and Treatment Applications XVI CY FEB 13-14, 2016 CL San Francisco, CA SP SPIE C1 [Hassan, Moinuddin; Ilev, Ilko K.] US FDA, Rockville, MD 20857 USA. RP Hassan, M (reprint author), US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-936-8 J9 PROC SPIE PY 2016 VL 9702 AR 970204 DI 10.1117/12.2219746 PG 1 WC Remote Sensing; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Remote Sensing; Optics; Radiology, Nuclear Medicine & Medical Imaging GA BE9RZ UT WOS:000378117400003 ER PT S AU Ilev, IK Walker, B Calhoun, W Hassan, M AF Ilev, Ilko K. Walker, Bennett Calhoun, William Hassan, Moinuddin BE Gannot, I TI Advanced biosensing methodologies developed for evaluating performance quality and safety of emerging biophotonics technologies and medical devices (Conference Presentation) SO OPTICAL FIBERS AND SENSORS FOR MEDICAL DIAGNOSTICS AND TREATMENT APPLICATIONS XVI SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Optical Fibers and Sensors for Medical Diagnostics and Treatment Applications XVI CY FEB 13-14, 2016 CL San Francisco, CA SP SPIE C1 [Ilev, Ilko K.; Walker, Bennett; Calhoun, William; Hassan, Moinuddin] US FDA, Rockville, MD 20857 USA. RP Ilev, IK (reprint author), US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-936-8 J9 PROC SPIE PY 2016 VL 9702 AR 97020O DI 10.1117/12.2220083 PG 1 WC Remote Sensing; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Remote Sensing; Optics; Radiology, Nuclear Medicine & Medical Imaging GA BE9RZ UT WOS:000378117400020 ER PT J AU Dmitrienko, A Kordzakhia, G Brechenmacher, T AF Dmitrienko, Alex Kordzakhia, George Brechenmacher, Thomas TI Mixture-based gatekeeping procedures for multiplicity problems with multiple sequences of hypotheses SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Clinical trials; closed testing; gatekeeping procedure; mixture method; multiple testing ID CLINICAL-TRIAL APPLICATIONS; ADJUSTMENT METHODS; TESTING PROCEDURES; MULTISTAGE AB Complex multiplicity problems arise in drug development programs with several sets of clinical objectives. This article considers a common setting with two sources of multiplicity induced by the analysis of multiple dose levels based on ordered endpoints. This results in multiplicity problems with multiple sequences of null hypotheses of no effect. Type I error rate inflation in problems of this type is typically addressed by using gatekeeping procedures that account for the hierarchical structure of the trial objectives. A general method for building gatekeeping procedures, known as the mixture method, tends to be conservative in problems with several sequences of hypotheses. This article defines a modified mixture method and shows that this method provides a power advantage over the standard mixture method. In addition, it is demonstrated that in special cases the modified mixture method allows for a stepwise testing algorithm, which facilities the implementation of gatekeeping procedures and general decision making. The new methodology is illustrated using two clinical trial examples. C1 [Dmitrienko, Alex] Ctr Stat Drug Dev, Quintiles Innovat, 12121 Beverly St, Overland Pk, KS 66209 USA. [Kordzakhia, George] US FDA, Silver Spring, MD USA. [Brechenmacher, Thomas] Novartis, Paris, France. RP Dmitrienko, A (reprint author), Ctr Stat Drug Dev, Quintiles Innovat, 12121 Beverly St, Overland Pk, KS 66209 USA. EM Alex.Dmitrienko@gmail.com NR 20 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2016 VL 26 IS 4 BP 758 EP 780 DI 10.1080/10543406.2015.1074917 PG 23 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DN5GY UT WOS:000377095800012 PM 26247744 ER PT S AU Chumakov, KM AF Chumakov, Konstantin M. BE Martin, J TI Methods to Monitor Molecular Consistency of Oral Polio Vaccine SO POLIOVIRUS: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Reversion to virulence; Quality control of Oral Polio Vaccine; Quantitative analysis of mutations; PCR; Deep-sequencing ID NONCODING REGION; NEUROVIRULENCE; PCR; QUANTITATION; TEMPERATURE; MUTATIONS; REVERSION; MUTANTS; ASSAY AB Replication of viruses leads to emergence of mutations and their content in viral populations can increase by selection depending on growth conditions. Some of these mutations have deleterious effect on vaccine safety, such as neurovirulent reversions in the 5'-UTR of attenuated Sabin strains of poliovirus. Their content in vaccine batches must be tightly controlled during vaccine manufacture to ensure safety of the product. This chapter describes a quantitative molecular procedure called mutant analysis by PCR and restriction enzyme cleavage (MAPREC) that is used to monitor content of neurovirulent revertants in Oral Polio Vaccine (OPV). The method can be used for quantitative analysis of any other mutation in a viral population. C1 [Chumakov, Konstantin M.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Chumakov, KM (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 14 TC 0 Z9 0 U1 1 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-3292-4; 978-1-4939-3291-7 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2016 VL 1387 BP 263 EP 277 DI 10.1007/978-1-4939-3292-4_14 D2 10.1007/978-1-4939-3292-4 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Infectious Diseases; Medical Laboratory Technology; Virology SC Biochemistry & Molecular Biology; Infectious Diseases; Medical Laboratory Technology; Virology GA BE8LQ UT WOS:000376577800015 PM 26983740 ER PT J AU Rahardja, D Wu, H Huang, SG Chu, JX AF Rahardja, Dewi Wu, Han Huang, Shuguang Chu, Jianxiong TI Confidence intervals for the odds ratio of two independent binomial proportions using data with one type of misclassification SO JOURNAL OF STATISTICS & MANAGEMENT SYSTEMS LA English DT Article DE Odds ratio; Identifiability; Binary data; False positive misclassification ID FALSE-POSITIVE MISCLASSIFICATION; DOUBLE SAMPLING SCHEME; BINARY DATA; BAYESIAN-APPROACH; SUBJECT AB We derive a confidence interval for the odd ratio of two independent binomial proportion parameters with one type of misclassification using an easy-to-implement closed-form algorithm based on the Maximum Likelihood Estimator (MLE) and its asymptotic variance. The model identifiability is obtained via doubly sampled data. For illustration, we apply our methods to a sudden infant death syndrome (SIDS) dataset. C1 [Rahardja, Dewi] US Dept Def, Ft George G Meade, MD 20755 USA. [Wu, Han] Mankato State Univ, Dept Math & Stat, Mankato, MN 56001 USA. [Huang, Shuguang] Precis Therapeut Inc, Dept Biostat, Pittsburgh, PA 15203 USA. [Chu, Jianxiong] US FDA, Silver Spring, MD 20993 USA. RP Rahardja, D (reprint author), US Dept Def, Ft George G Meade, MD 20755 USA. EM rahardja@gmail.com NR 14 TC 0 Z9 0 U1 1 U2 1 PU TARU PUBLICATIONS PI NEW DELHI PA G-159, PUSHKAR ENCLAVE, PASHCHIM VIHAR, NEW DELHI, 110 063, INDIA SN 0972-0510 EI 2169-0014 J9 J STAT MANAG SYST JI J. Stat. Manag. Syst. PY 2016 VL 19 IS 2 BP 259 EP 268 DI 10.1080/09720510.2015.1047572 PG 10 WC Statistics & Probability SC Mathematics GA DM7JP UT WOS:000376536800006 ER PT J AU Skorski, MR Esenther, JM Ahmed, Z Miller, AE Hartings, MR AF Skorski, Matthew R. Esenther, Jake M. Ahmed, Zeeshan Miller, Abigail E. Hartings, Matthew R. TI The chemical, mechanical, and physical properties of 3D printed materials composed of TiO2-ABS nanocomposites SO SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS LA English DT Article DE 3D printing; nanocomposite; TiO2 nanoparticle; ABS; photocatalysis ID NANOPARTICLES; REACTIONWARE; WATER; PHOTOCATALYSIS; PURIFICATION; DEPENDENCE; STABILITY; SHAPE AB To expand the chemical capabilities of 3D printed structures generated from commercial thermoplastic printers, we have produced and printed polymer filaments that contain inorganic nanoparticles. TiO2 was dispersed into acrylonitrile butadiene styrene (ABS) and extruded into filaments with 1.75 mm diameters. We produced filaments with TiO2 compositions of 1, 5, and 10% (kg/kg) and printed structures using a commercial 3D printer. Our experiments suggest that ABS undergoes minor degradation in the presence of TiO2 during the different processing steps. The measured mechanical properties (strain and Young's modulus) for all of the composites are similar to those of structures printed from the pure polymer. TiO2 incorporation at 1% negatively affects the stress at breaking point and the flexural stress. Structures produced from the 5 and 10% nanocomposites display a higher breaking point stress than those printed from the pure polymer. TiO2 within the printed matrix was able to quench the intrinsic fluorescence of the polymer. TiO2 was also able to photocatalyze the degradation of a rhodamine 6G in solution. These experiments display chemical reactivity in nanocomposites that are printed using commercial 3D printers, and we expect that our methodology will help to inform others who seek to incorporate catalytic nanoparticles in 3D printed structures. C1 [Skorski, Matthew R.; Esenther, Jake M.; Miller, Abigail E.; Hartings, Matthew R.] Amer Univ, Dept Chem, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. [Ahmed, Zeeshan] NIST, Thermodynam Metrol Grp, Sensor Sci Div, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Miller, Abigail E.] US FDA, Washington, DC 20204 USA. RP Skorski, MR (reprint author), Amer Univ, Dept Chem, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. EM hartings@american.edu FU Intramural NIST DOC [9999-NIST] NR 33 TC 1 Z9 1 U1 26 U2 43 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1468-6996 EI 1878-5514 J9 SCI TECHNOL ADV MAT JI Sci. Technol. Adv. Mater. PY 2016 VL 17 IS 1 BP 89 EP 97 DI 10.1080/14686996.2016.1152879 PG 9 WC Materials Science, Multidisciplinary SC Materials Science GA DM7AD UT WOS:000376503300012 PM 27375367 ER PT J AU Chockalingam, AK Hamed, S Goodwin, DG Rosenzweig, BA Pang, E Boyne, MT Patel, V AF Chockalingam, Ashok K. Hamed, Salaheldin Goodwin, David G. Rosenzweig, Barry A. Pang, Eric Boyne, Michael T., II Patel, Vikram TI The Effect of Oseltamivir on the Disease Progression of Lethal Influenza A Virus Infection: Plasma Cytokine and miRNA Responses in a Mouse Model SO DISEASE MARKERS LA English DT Article ID NEURAMINIDASE INHIBITOR OSELTAMIVIR; HIGHLY PATHOGENIC H5N1; MICRORNA EXPRESSION; MICE; MORTALITY; VIRULENCE; SERUM; LUNG; H1N1 AB Lethal influenza A virus infection leads to acute lung injury and possibly lethal complications. There has been a continuous effort to identify the possible predictors of disease severity. Unlike earlier studies, where biomarkers were analyzed on certain time points or days after infection, in this study biomarkers were evaluated over the entire course of infection. Circulating proinflammatory cytokines and/or miRNAs that track with the onset and progression of lethal A/Puerto Rico/8/34 (PR8) influenza A virus infection and their response to oseltamivir treatment were investigated up to 10 days after infection. Changes in plasma cytokines (IL-1 beta., IL-10, IL-12p70, IL-6, KC, TNF-alpha, and IFN-gamma) and several candidate miRNAs were profiled. Among the cytokines analyzed, IL-6 and KC/GRO cytokines appeared to correlate with peak viral titer. Over the selected 48 miRNAs profiled, certain miRNAs were up-or downregulated in a manner that was dependent on the oseltamivir treatment and disease severity. Our findings suggest that IL-6 and KC/GRO cytokines can be a potential disease severity biomarker and/or marker for the progression/remission of infection. Further studies to explore other cytokines, miRNAs, and lung injury proteins in serum with different subtypes of influenza A viruses with varying disease severity may provide new insight into other unique biomarkers. C1 [Chockalingam, Ashok K.; Rosenzweig, Barry A.; Patel, Vikram] US FDA, DARS, OCP, OTS,CDER, Silver Spring, MD 20993 USA. [Hamed, Salaheldin] US FDA, OCP, OTS, CDER, Silver Spring, MD 20993 USA. [Goodwin, David G.] US FDA, DMD, OIR, CDRH, Silver Spring, MD 20993 USA. [Pang, Eric] US FDA, OPQ, OLDP, CDER, Silver Spring, MD 20993 USA. [Boyne, Michael T., II] US FDA, DPA, OTR, OPS,CDER, Silver Spring, MD 20993 USA. RP Patel, V (reprint author), US FDA, DARS, OCP, OTS,CDER, Silver Spring, MD 20993 USA. EM vikram.patel@fda.hhs.gov FU Medical Countermeasures Initiative (MCMi), Center for Drug Evaluation and Research (CDER), US Food and Drug Administration FX This project received funding from Medical Countermeasures Initiative (MCMi), Center for Drug Evaluation and Research (CDER), US Food and Drug Administration. The authors thank Dr. Karol Thompson, Division of Applied Regulatory Science (CDER), US FDA, for her valuable input for the miRNA arrays and for critically reading the paper. NR 34 TC 0 Z9 0 U1 2 U2 4 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 0278-0240 EI 1875-8630 J9 DIS MARKERS JI Dis. Markers PY 2016 AR 9296457 DI 10.1155/2016/9296457 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental; Pathology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine; Pathology GA DJ7VC UT WOS:000374420200001 ER PT J AU Todorov, TI Gray, PJ AF Todorov, Todor I. Gray, Patrick J. TI Analysis of iodine in food samples by inductively coupled plasma-mass spectrometry SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Iodine; ICP-MS; alkaline extraction; carbon addition; validation; reference materials ID VALIDATION; COMBUSTION; PRODUCTS; SYSTEM; MILK AB This work shows a method for the determination of iodine in a variety of food samples and reference materials using inductively coupled plasma-mass spectrometry (ICP-MS) following alkaline extraction. Optimisation of the addition of organic carbon showed that a minimum of 3% 2-propanol was necessary for a constant ratio of iodine to internal standard. The limit of quantification (LOQ), calculated as 30 sigma for the method, was 36 ng g(-1) in solid food samples. For method validation, seven standard reference materials (SRM) and 21 fortified food samples were used. The precision (%RSD) of the measurements was in the 2-7% range. Accuracies for the SRMs were 85-105%, while the fortified food samples showed 81-119% recoveries, including a number of samples fortified at 50% of the LOQ. C1 [Todorov, Todor I.; Gray, Patrick J.] US Food & Drug Adm, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Todorov, TI (reprint author), US Food & Drug Adm, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM todor.todorov@fda.hhs.gov OI Gray, Patrick/0000-0002-8248-2749 NR 32 TC 1 Z9 1 U1 5 U2 10 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. PY 2016 VL 33 IS 2 BP 282 EP 290 DI 10.1080/19440049.2015.1131337 PG 9 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DK0HS UT WOS:000374594200012 PM 26730958 ER PT J AU Vaclavikova, M Paseiro-Cerrato, R Vaclavik, L Noonan, GO DeVries, J Begley, TH AF Vaclavikova, Marta Paseiro-Cerrato, Rafael Vaclavik, Lukas Noonan, Gregory O. DeVries, Jonathan Begley, Timothy H. TI Target and non-target analysis of migrants from PVC-coated cans using UHPLC-Q-Orbitrap MS: evaluation of long-term migration testing SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE PVC; food cans; plasticisers; cross linking agent; benzoguanamine; migration; UHPLC-HRMS ID EPOXIDIZED SOYBEAN OIL; CHROMATOGRAPHY-MASS SPECTROMETRY; RAPID IDENTIFICATION; PLANT TOXINS; LID GASKETS; FOOD; PLASTICIZERS; ADDITIVES AB A simple, rapid and sensitive method for analyzing multi-target and non-target additives in polyvinyl chloride (PVC) food can coatings using ultra-high-performance liquid chromatography coupled to quadrupole-orbital ion-trap mass spectrometry was developed. This procedure was used to study the behaviour of a cross-linking agent, benzoguanamine (BGA), two slip agents, oleamide and erucamide, and 18 other commonly used plasticisers including phthalates, adipates, sebacates, acetyl tributyl citrate and epoxidised soybean or linseed oils. This optimised method was used to detect these analytes in food simulants (water and 3% acetic acid) in a long-term migration test of PVC-coated food cans for a period ranging from 1 day to 1.5 years at 40 degrees C. Although very low detection limits (5 ng ml(-1)) were obtained for the majority of compounds, none of the monitored plasticisers and slip agents was detected in simulants extracted from cans over the period of the test. However, the presence of BGA in both aqueous food simulants was confirmed based on high-resolution mass spectrometry, product ion spectra and analysis of a reference standard. The BGA concentration in both simulants continued to increase with storage time: after 1.5 years storage in aqueous food simulants at 40 degrees C, BGA was detected at concentrations up to 84 mu g dm(-2). We believe this is the first study describing the long-term migration capacity of BGA from any vinyl coating material intended for use in PVC-coated food cans. Our results may have implications for migration test protocols for food cans that will be stored for extended time periods. C1 [Vaclavikova, Marta; Paseiro-Cerrato, Rafael; Vaclavik, Lukas; Noonan, Gregory O.; Begley, Timothy H.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [DeVries, Jonathan] DeVries Associates, Coon Rapids, MN USA. RP Vaclavikova, M (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM marta.vaclavikova1@gmail.com NR 26 TC 1 Z9 1 U1 5 U2 16 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PY 2016 VL 33 IS 2 BP 352 EP 363 DI 10.1080/19440049.2015.1128564 PG 12 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DK0HS UT WOS:000374594200019 PM 26744815 ER PT J AU Genualdi, S MacMahon, S Robbins, K Farris, S Shyong, N DeJager, L AF Genualdi, Susie MacMahon, Shaun Robbins, Katherine Farris, Samantha Shyong, Nicole DeJager, Lowri TI Method development and survey of Sudan I-IV in palm oil and chilli spices in the Washington, DC, area SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Sudan dyes; palm oil; colour additive; LC-MS/MS; LC-DAD ID CONTAINING FOODSTUFFS; ARRAY DETECTION; DYES AB Sudan I, II, III and IV dyes are banned for use as food colorants in the United States and European Union because they are toxic and carcinogenic. These dyes have been illegally used as food additives in products such as chilli spices and palm oil to enhance their red colour. From 2003 to 2005, the European Union made a series of decisions requiring chilli spices and palm oil imported to the European Union to contain analytical reports declaring them free of Sudan I-IV. In order for the USFDA to investigate the adulteration of palm oil and chilli spices with unapproved colour additives in the United States, a method was developed for the extraction and analysis of Sudan dyes in palm oil, and previous methods were validated for Sudan dyes in chilli spices. Both LC-DAD and LC-MS/MS methods were examined for their limitations and effectiveness in identifying adulterated samples. Method validation was performed for both chilli spices and palm oil by spiking samples known to be free of Sudan dyes at concentrations close to the limit of detection. Reproducibility, matrix effects, and selectivity of the method were also investigated. Additionally, for the first time a survey of palm oil and chilli spices was performed in the United States, specifically in the Washington, DC, area. Illegal dyes, primarily Sudan IV, were detected in palm oil at concentrations from 150 to 24 000 ng ml(-1). Low concentrations (< 21 mu g kg(-1)) of Sudan dyes were found in 11 out of 57 spices and are most likely a result of cross-contamination during preparation and storage and not intentional adulteration. C1 [Genualdi, Susie; MacMahon, Shaun; Robbins, Katherine; Farris, Samantha; Shyong, Nicole; DeJager, Lowri] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Genualdi, S (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM susan.genualdi@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 20 TC 0 Z9 0 U1 4 U2 7 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. PY 2016 VL 33 IS 4 BP 583 EP 591 DI 10.1080/19440049.2016.1147986 PG 9 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DK0HT UT WOS:000374594400001 PM 26824489 ER PT J AU Peddareddygari, LR Hanna, PA Igo, RP Luo, YQA Won, S Hirano, M Grewal, RP AF Peddareddygari, Leema Reddy Hanna, Philip A. Igo, Robert P., Jr. Luo, Yuqun A. Won, Sungho Hirano, Michio Grewal, Raji P. TI Autosomal dominant hereditary spastic paraplegia with axonal sensory motor polyneuropathy maps to chromosome 21q 22.3 SO INTERNATIONAL JOURNAL OF NEUROSCIENCE LA English DT Article DE hereditary spastic paraplegia; clinical and genetic analysis; autosomal dominant; family-based linkage analysis; fine mapping; candidate gene analysis AB Aim: Hereditary spastic paraplegia (HSP) are a genetically and clinically heterogeneous group of disorders. At present, 19 autosomal dominant loci for HSP have been mapped. We ascertained an American family of European descent segregating an autosomal dominant HSP associated with peripheral neuropathy. Methods: A genome wide scan was performed with 410 microsatellite repeat marker (Weber lab screening set 16) and following linkage and haplotype analysis, fine mapping was performed. Established genes or loci for HSP were excluded by direct sequencing or haplotype analysis. Results: All established loci for HSP were excluded. Fine mapping suggested a locus on chromosome 21q22.3 flanked by markers D21S1411 and D21S1446 with a maximum logarithm of odds score of 2.05 and was supported by haplotype analysis. A number of candidate genes in this region were analyzed and no disease-producing mutations were detected. Conclusion: We present the clinical and genetic analysis of an American family with autosomal dominant HSP with axonal sensory motor polyneuropathy mapping to a novel locus on chromosome 21q22.3 designated SPG56. C1 [Peddareddygari, Leema Reddy] Neurogenet Inst, Sharon Hill, PA USA. [Hanna, Philip A.] JFK Med Ctr, New Jersey Neurosci Inst, Edison, NJ USA. [Igo, Robert P., Jr.; Luo, Yuqun A.; Won, Sungho] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Luo, Yuqun A.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MA USA. [Won, Sungho] Seoul Natl Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Hirano, Michio] Columbia Univ, Dept Neurol, New York, NY USA. [Grewal, Raji P.] St Francis Med Ctr, Inst Neurosci, Trenton, NJ USA. RP Grewal, RP (reprint author), Seton Hall Univ, St Francis Med Ctr, Neurosci, 601 Hamilton Ave, Trenton, NJ USA. EM RGrewal@stfrancismedical.org FU Neurogenetics Foundation, Cranbury, NJ, USA; Neurogenetics Institute, Sharon Hill, PA, USA FX The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. We acknowledge support from the Neurogenetics Foundation, Cranbury, NJ, USA and the Neurogenetics Institute, Sharon Hill, PA, USA. NR 6 TC 0 Z9 0 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0020-7454 EI 1563-5279 J9 INT J NEUROSCI JI Int. J. Neurosci. PY 2016 VL 126 IS 7 BP 600 EP 606 DI 10.3109/00207454.2015.1048805 PG 7 WC Neurosciences SC Neurosciences & Neurology GA DL4QY UT WOS:000375623500005 PM 26000935 ER PT J AU Tegegn, TZ De Paoli, SH Orecna, M Elhelu, OK Woodle, SA Tarandovskiy, ID Ovanesov, MV Simak, J AF Tegegn, Tseday Z. De Paoli, Silvia H. Orecna, Martina Elhelu, Oumsalama K. Woodle, Samuel A. Tarandovskiy, Ivan D. Ovanesov, Mikhail V. Simak, Jan TI Characterization of procoagulant extracellular vesicles and platelet membrane disintegration in DMSO-cryopreserved platelets SO JOURNAL OF EXTRACELLULAR VESICLES LA English DT Article DE extracellular vesicles; microparticles; platelet physiology; blood products; thrombin; transfusion medicine; nanoparticle tracking analysis; flow cytometry; atomic force microscopy; electron microscopy ID NANOPARTICLE TRACKING ANALYSIS; PERCENT DIMETHYL-SULFOXIDE; MULTICOLOR FLOW-CYTOMETRY; FREEZING HUMAN PLATELETS; FROZEN HUMAN PLATELETS; HUMAN BLOOD-PLATELETS; CARBON NANOTUBES; HEMOSTATIC EFFECTIVENESS; CALCIUM-ENTRY; TISSUE FACTOR AB Background: Freezing is promising for extended platelet (PLT) storage for transfusion. 6% DMSO cryopreserved PLTs (CPPs) are currently in clinical development. CPPs contain significant amount of platelet membrane vesicles (PMVs). PLT-membrane changes and PMV release in CPP are poorly understood, and haemostatic effects of CPP PMVs are not fully elucidated. This study aims to investigate PLT-membrane alterations in CPPs and provide comprehensive characterization of CPP PMVs, and their contribution to procoagulant activity (PCA) of CPPs. Methods: CPPs and corresponding liquid-stored PLTs (LSPs) were characterized by flow cytometry (FC), fluorescence polarization (FP), nanoparticle tracking analysis (NTA), electron microscopy (SEM, TEM), atomic force microscopy (AFM) and thrombin-generation (TG) test. Results: SEM and TEM revealed disintegration and vesiculation of the PLT-plasma membrane and loss of intracellular organization in 60% PLTs in CPPs. FP demonstrated that 6% DMSO alone and with freezing-thawing caused marked increase in PLT-membrane fluidity. The FC counts of annexin V-binding PMVs and CD41a(+) PMVs were 68-and 56-folds higher, respectively, in CPPs than in LSPs. The AFM and NTA size distribution of PMVs in CPPs indicated a peak diameter of 100 nm, corresponding to exosome-size vesicles. TG-based PCA of CPPs was 2- and 9-folds higher per PLT and per volume, respectively, compared to LSPs. Differential centrifugation showed that CPP supernatant contributed 26% to CPP TG-PCA, mostly by the exosome-size PMVs and their TG-PCA was phosphatidylserine dependent. Conclusions: Major portion of CPPs does not show activation phenotype but exhibits grape-like membrane disintegration with significant increase of membrane fluidity induced by 6% DMSO alone and further aggravated by freezing-thawing process. DMSO cryopreservation of PLTs is associated with the release of PMVs and marked increase of TG-PCA, as compared to LSPs. Exosome-size PMVs have significant contribution to PCA of CPPs. C1 [Tegegn, Tseday Z.; De Paoli, Silvia H.; Orecna, Martina; Elhelu, Oumsalama K.; Woodle, Samuel A.; Tarandovskiy, Ivan D.; Ovanesov, Mikhail V.; Simak, Jan] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Simak, J (reprint author), US FDA, Lab Cellular Hematol, DHRR OBRR, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,WO Bldg 52-72,Rm 4210, Silver Spring, MD 20993 USA. EM jan.simak@fda.hhs.gov NR 51 TC 1 Z9 1 U1 6 U2 9 PU CO-ACTION PUBLISHING PI JARFALLA PA RIPVAGEN 7, JARFALLA, SE-175 64, SWEDEN SN 2001-3078 J9 J EXTRACELL VESICLES JI J. Extracell. Vesicles PY 2016 VL 5 AR 30422 DI 10.3402/jev.v5.30422 PG 13 WC Cell Biology SC Cell Biology GA DL8WE UT WOS:000375921900001 PM 27151397 ER PT J AU Gavrielides, MA Li, Q Zeng, RP Myers, KJ Sahiner, B Petrick, N AF Gavrielides, Marios A. Li, Qin Zeng, Rongping Myers, Kyle J. Sahiner, Berkman Petrick, Nicholas TI Volume estimation of multidensity nodules with thoracic computed tomography SO JOURNAL OF MEDICAL IMAGING LA English DT Article DE volume estimation; multidensity nodules; thoracic computed tomography; phantom study ID GROUND-GLASS OPACITY; PULMONARY NODULES; SIZE ESTIMATION; CT; PHANTOM; RECONSTRUCTION AB This work focuses on volume estimation of "multidensity" lung nodules in a phantom computed tomography study. Eight objects were manufactured by enclosing spherical cores within larger spheres of double the diameter but with a different density. Different combinations of outer-shell/inner-core diameters and densities were created. The nodules were placed within an anthropomorphic phantom and scanned with various acquisition and reconstruction parameters. The volumes of the entire multidensity object as well as the inner core of the object were estimated using a model-based volume estimator. Results showed percent volume bias across all nodules and imaging protocols with slice thicknesses <5 mm ranging from -5.1% to 6.6% for the entire object (standard deviation ranged from 1.5% to 7.6%), and within -12.6% to 5.7% for the inner-core measurement (standard deviation ranged from 2.0% to 17.7%). Overall, the estimation error was larger for the inner-core measurements, which was expected due to the smaller size of the core. Reconstructed slice thickness was found to substantially affect volumetric error for both tasks; exposure and reconstruction kernel were not. These findings provide information for understanding uncertainty in volumetry of nodules that include multiple densities such as ground glass opacities with a solid component. (C) 2016 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Gavrielides, Marios A.; Li, Qin; Zeng, Rongping; Myers, Kyle J.; Sahiner, Berkman; Petrick, Nicholas] US FDA, DIDSR, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 4126, Silver Spring, MD 20993 USA. RP Gavrielides, MA (reprint author), US FDA, DIDSR, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 4126, Silver Spring, MD 20993 USA. EM marios.gavrielides@fda.hhs.gov NR 18 TC 0 Z9 0 U1 1 U2 3 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-4302 EI 2329-4310 J9 J MED IMAGING JI J. Med. Imaging PD JAN-MAR PY 2016 VL 3 IS 1 AR 013504 DI 10.1117/1.JMI.3.1.013504 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DJ5HA UT WOS:000374236300015 PM 26844235 ER PT J AU Asher, DM Gregori, L Serer, A McDowell, KL AF Asher, David M. Gregori, Luisa Serer, Arthur McDowell, Kristy L. TI Rapid testing for Creutzfeldt-Jakob disease in donors of human tissues SO PRION LA English DT Meeting Abstract C1 [Asher, David M.; Gregori, Luisa; Serer, Arthur; McDowell, Kristy L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1933-6896 EI 1933-690X J9 PRION JI Prion PY 2016 VL 10 SU 1 MA P-123 BP S99 EP S100 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK1EW UT WOS:000374656300141 ER PT J AU Yang, H Huang, Y Bui-Klimke, T Gregori, L Asher, DM Forshee, RA Anderson, SA AF Yang, Hong Huang, Yin Bui-Klimke, Travis Gregori, Luisa Asher, David M. Forshee, Richard A. Anderson, Steven A. TI Geographic risk of variant Creutzfeldt-Jakob disease: A risk ranking model to evaluate options for blood donor deferral policies in the US SO PRION LA English DT Meeting Abstract C1 [Yang, Hong; Huang, Yin; Gregori, Luisa; Forshee, Richard A.; Anderson, Steven A.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1933-6896 EI 1933-690X J9 PRION JI Prion PY 2016 VL 10 SU 1 MA P-126 BP S101 EP S102 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK1EW UT WOS:000374656300144 ER PT J AU Goktas, H Wang, XX Boscher, ND Torosian, S Gleason, KK AF Goktas, Hilal Wang, Xiaoxue Boscher, Nicolas D. Torosian, Stephen Gleason, Karen K. TI Functionalizable and electrically conductive thin films formed by oxidative chemical vapor deposition (oCVD) from mixtures of 3-thiopheneethanol (3TE) and ethylene dioxythiophene (EDOT) SO JOURNAL OF MATERIALS CHEMISTRY C LA English DT Article ID POLYMER-COVERED ELECTRODES; POLY(3,4-ETHYLENEDIOXYTHIOPHENE) FILMS; CONJUGATED POLYMERS; REACTIVE GROUPS; SOLAR-CELLS; DERIVATIVES; ELECTROPOLYMERIZATION; TRANSPARENT; SIGNATURES; BIOSENSOR AB Mixtures of 3-thiopheneethanol (3TE) and 3,4-ethylenedioxythiophene (EDOT) were used as the reactants for oxidative chemical vapor deposition (oCVD). Monomer (3TE : EDOT) feed ratios of (3 : 1), (3 : 2), (3 : 3), (2 : 3), and (1 : 3) were employed to obtain conductive polymer thin films with varying densities of hydroxyl pendant groups. The incorporation of both 3TE and EDOT units into the deposited films was confirmed by a combination of high resolution mass spectrometry, UV-visible-Near Infrared (UV-vis-NIR), and Fourier transform infrared (FTIR) spectroscopy, yielding conductive and -OH functionalized thin films. Theoretical analysis of the initial formation of dimers was studied by using density functional theory (DFT). The calculation predicts that the reaction of 3TE and EDOT is kinetically favored over the combination of two 3TE monomers. The pi-pi* transition observed at 425 nm in the UV-vis-NIR spectra of the 3TE polymerized film red shifts with increasing EDOT incorporation. This transition is observed at 523 nm in the film prepared using (1 : 3) a monomer feed ratio. C1 [Goktas, Hilal; Wang, Xiaoxue; Boscher, Nicolas D.; Gleason, Karen K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Goktas, Hilal; Torosian, Stephen] US FDA, Winchester Engn & Analyt Ctr, 109 Holton St, Winchester, MA 01890 USA. [Boscher, Nicolas D.] Luxembourg Inst Sci & Technol, Mat Res & Technol Dept, 5 Ave Hauts Fourneaux, L-4362 Luxembourg, Luxembourg. RP Gleason, KK (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM kkg@mit.edu RI Gleason, Karen/G-1471-2013 OI Gleason, Karen/0000-0001-6127-1056 FU FDA ORISE Fellowship FX Hilal Goktas, on-leave from Physics Department of Canakkale Onsekiz Mart University, was supported by the FDA ORISE Fellowship. N. D. B. is particularly grateful to the Fonds National de la Recherche (FNR) of Luxembourg for supporting his visiting scientist position within the Gleason group (SENSi project). N. Desbenoit and G. Frache from LIST are acknowledged for acquisition of the mass-spectrometry measurements. NR 45 TC 1 Z9 1 U1 5 U2 7 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2050-7526 EI 2050-7534 J9 J MATER CHEM C JI J. Mater. Chem. C PY 2016 VL 4 IS 16 BP 3403 EP 3414 DI 10.1039/c6tc00567e PG 12 WC Materials Science, Multidisciplinary; Physics, Applied SC Materials Science; Physics GA DK2ZU UT WOS:000374785300006 ER PT J AU Ma, XM Zhang, XT Yang, L Wang, G Jiang, K Wu, G Cui, WG Wei, ZP AF Ma, Xiaoming Zhang, Xiaoting Yang, Lin Wang, Ge Jiang, Kai Wu, Geoffrey Cui, Weigang Wei, Zipeng TI Tunable construction of multi-shelled hollow carbonate nanospheres and their potential applications SO NANOSCALE LA English DT Article ID LITHIUM-ION BATTERIES; HEAVY-METAL IONS; MESOPOROUS SILICA NANOSPHERES; AMORPHOUS CALCIUM-CARBONATE; TEMPLATE-FREE SYNTHESIS; SENSITIZED SOLAR-CELLS; DRUG-DELIVERY; FUNCTIONALIZED CELL; ACCURATE CONTROL; MICROSPHERES AB The development of multi-shelled hollow carbonate nanospheres (MHCN) for biomedical applications is challenging, and has not been reported. In this study, a facile approach is firstly reported to synthesize hierarchically porous MHCN with controllable shell numbers using a novel strategy called layer-by-layer thermal decomposition of organic acid salts and templates. The choice of organic acid salts as the reactants is innovative and crucial. The shell numbers of porous MHCN can be easily controlled and tuned through adjusting the adsorption temperature of organic acid salts and/or the adsorption ability of the template. The synthetic method can not only open a window to prepare the multi-shelled carbonates but also provide a new strategy to synthesise other multi-shelled inorganic salts. Notably, the hierarchically porous multi-shelled hollow structures empower the carbonates with not only a large specific surface area but also good porosity and permeability, showing great potential for future applications. Herein, our in vitro/vivo evaluations show that CaCO3 MHCN possess a high drug loading capacity and a sustained-release drug profile. It is highly expected that this novel synthetic strategy for MHCN and novel MHCN platform have the potential for biomedical applications in the near future. C1 [Ma, Xiaoming; Zhang, Xiaoting; Yang, Lin; Wang, Ge; Jiang, Kai; Wei, Zipeng] Henan Normal Univ, Collaborat Innovat Ctr Henan Prov Green Mfg Fine, Key Lab Green Chem Media & React, Minist Educ,Sch Chem & Chem Engn, Xinxiang 453007, Henan, Peoples R China. [Wu, Geoffrey] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Cui, Weigang] Xinxiang Med Univ, Dept Human Anat, Xinxiang 453003, Henan, Peoples R China. RP Ma, XM (reprint author), Henan Normal Univ, Collaborat Innovat Ctr Henan Prov Green Mfg Fine, Key Lab Green Chem Media & React, Minist Educ,Sch Chem & Chem Engn, Xinxiang 453007, Henan, Peoples R China. EM sunshinyma@hotmail.com FU National Science Foundation of China [21271065, 21171051]; NFSC-Henan Talent Training United Fund [U1204519] FX We thank Professor Xinming Liu (Department of Pharmaceutical Sciences, College of Pharmacy, the University of Nebraska Medical Center) for assistance in the characterization studies and the biomedical applications of the multi-shelled CaCO3. This work was financially supported by the National Science Foundation of China (Grant No. 21271065 and No. 21171051) and the NFSC-Henan Talent Training United Fund (Grant No. U1204519). NR 46 TC 1 Z9 1 U1 23 U2 51 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2016 VL 8 IS 16 BP 8687 EP 8695 DI 10.1039/c6nr00866f PG 9 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DK3BA UT WOS:000374788800034 PM 27049523 ER PT J AU Klionsky, DJ Abdelmohsen, K Abe, A Abedin, MJ Abeliovich, H Arozena, AA Adachi, H Adams, CM Adams, PD Adeli, K Adhihetty, PJ Adler, SG Agam, G Agarwal, R Aghi, MK Agnello, M Agostinis, P Aguilar, PV Aguirre-Ghiso, J Airoldi, EM Ait-Si-Ali, S Akematsu, T Akporiaye, ET Al-Rubeai, M Albaiceta, GM Albanese, C Albani, D Albert, ML Aldudo, J Algul, H Alirezaei, M Alloza, I Almasan, A Almonte-Beceril, M Alnemri, ES Alonso, C Altan-Bonnet, N Altieri, DC Alvarez, S Alvarez-Erviti, L Alves, S Amadoro, G Amano, A Amantini, C Ambrosio, S Amelio, I Amer, AO Amessou, M Amon, A An, ZY Anania, FA Andersen, SU Andley, UP Andreadi, CK Andrieu-Abadie, N Anel, A Ann, DK Anoopkumar-Dukie, S Antonioli, M Aoki, H Apostolova, N Aquila, S Aquilano, K Araki, K Arama, E Aranda, A Araya, J Arcaro, A Arias, E Arimoto, H Ariosa, AR Armstrong, JL Arnould, T Arsov, I Asanuma, K Askanas, V Asselin, E Atarashi, R Atherton, SS Atkin, JD Attardi, LD Auberger, P Auburger, G Aurelian, L Autelli, R Avagliano, L Avantaggiati, ML Avrahami, L Awale, S Azad, N Bachetti, T Backer, JM Bae, DH Bae, JS Bae, ON Bae, SH Baehrecke, EH Baek, SH Baghdiguian, S Bagniewska-Zadworna, A Bai, H Bai, J Bai, XY Bailly, Y Balaji, KN Balduini, W Ballabio, A Balzan, R Banerjee, R Banhegyi, G Bao, HJ Barbeau, B Barrachina, MD Barreiro, E Bartel, B Bartolome, A Bassham, DC Bassi, MT Bast, RC Basu, A Batista, MT Batoko, H Battino, M Bauckman, K Baumgarner, BL Bayer, KU Beale, R Beaulieu, JF Beck, GR Becker, C Beckham, JD Bedard, PA Bednarski, PJ Begley, TJ Behl, C Behrends, C Behrens, GMN Behrns, KE Bejarano, E Belaid, A Belleudi, F Benard, G Berchem, G Bergamaschi, D Bergami, M Berkhout, B Berliocchi, L Bernard, A Bernard, M Bernassola, F Bertolotti, A Bess, AS Besteiro, S Bettuzzi, S Bhalla, S Bhattacharyya, S Bhutia, SK Biagosch, C Bianchi, MW Biard-Piechaczyk, M Billes, V Bincoletto, C Bingol, B Bird, SW Bitoun, M Bjedov, I Blackstone, C Blanc, L Blanco, GA Blomhoff, HK Boada-Romero, E Bockler, S Boes, M Boesze-Battaglia, K Boise, LH Bolino, A Boman, A Bonaldo, P Bordi, M Bosch, J Botana, LM Botti, J Bou, G Bouche, M Bouchecareilh, M Boucher, MJ Boulton, ME Bouret, SG Boya, P Boyer-Guittaut, M Bozhkov, PV Brady, N Braga, VMM Brancolini, C Braus, GH Bravo-San Pedro, JM Brennan, LA Bresnick, EH Brest, P Bridges, D Bringer, MA Brini, M Brito, GC Brodin, B Brookes, PS Brown, EJ Brown, K Broxmeyer, HE Bruhat, A Brum, PC Brumell, JH Brunetti-Pierri, N Bryson-Richardson, RJ Buch, S Buchan, AM Budak, H Bulavin, DV Bultman, SJ Bultman, SJ Bumbasirevic, V Burelle, Y Burke, RE Burmeister, M Butikofer, P Caberlotto, L Cadwell, K Cahova, M Cai, DS Cai, JJ Cai, Q Calatayud, S Camougrand, N Campanella, M Campbell, GR Campbell, M Campello, S Candau, R Caniggia, I Cantoni, L Cao, LZ Caplan, AB Caraglia, M Cardinali, C Cardoso, SM Carew, JS Carleton, LA Carlin, CR Carloni, S Carlsson, SR Carmona-Gutierrez, D Carneiro, LAM Carnevali, O Carra, S Carrier, A Carroll, B Casas, C Casas, J Cassinelli, G Castets, P Castro-Obregon, S Cavallini, G Ceccherini, I Cecconi, F Cederbaum, AI Cena, V Cenci, S Cerella, C Cervia, D Cetrullo, S Chaachouay, H Chae, HJ Chagin, AS Chai, CY Chakrabarti, G Chamilos, G Chan, EYW Chan, MTV Chandra, D Chandra, P Chang, CP Chang, RCC Chang, TY Chatham, JC Chatterjee, S Chauhan, S Che, YS Cheetham, ME Cheluvappa, R Chen, CJ Chen, G Chen, GC Chen, GQ Chen, HZ Chen, JW Chen, JK Chen, M Chen, MZ Chen, PW Chen, Q Chen, Q Chen, SD Chen, S Chen, SSL Chen, W Chen, WJ Chen, WQ 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Filippi-Chiela, Eduardo C. Filomeni, Giuseppe Fimia, Gian Maria Fingert, John H. Finkbeiner, Steven Finkel, Toren Fiorito, Filomena Fisher, Paul B. Flajolet, Marc Flamigni, Flavio Florey, Oliver Florio, Salvatore Floto, R. Andres Folini, Marco Follo, Carlo Fon, Edward A. Fornai, Francesco Fortunato, Franco Fraldi, Alessandro Franco, Rodrigo Francois, Arnaud Francois, Aurelie Frankel, Lisa B. Fraser, Iain D. C. Frey, Norbert Freyssenet, Damien G. Frezza, Christian Friedman, Scott L. Frigo, Daniel E. Fu, Dongxu Fuentes, Jose M. Fueyo, Juan Fujitani, Yoshio Fujiwara, Yuuki Fujiya, Mikihiro Fukuda, Mitsunori Fulda, Simone Fusco, Carmela Gabryel, Bozena Gaestel, Matthias Gailly, Philippe Gajewska, Malgorzata Galadari, Sehamuddin Galili, Gad Galindo, Inmaculada Galindo, Maria F. Galliciotti, Giovanna Galluzzi, Lorenzo Galluzzi, Luca Galy, Vincent Gammoh, Noor Gandy, Sam Ganesan, Anand K. Ganesan, Swamynathan Ganley, Ian G. Gannage, Monique Gao, Fen-Biao Gao, Feng Gao, Jian-Xin Garcia Nannig, Lorena Vescovi, Eleonora Garcia Garcia-Macia, Marina Garcia-Ruiz, Carmen Garg, Abhishek D. Garg, Pramod Kumar Gargini, Ricardo Gassen, Nils Christian Gatica, Damian Gatti, Evelina Gavard, Julie Gavathiotis, Evripidis Ge, Liang Ge, Pengfei Ge, Shengfang Gean, Po-Wu Gelmetti, Vania Genazzani, Armando A. Geng, Jiefei Genschik, Pascal Gerner, Lisa Gestwicki, Jason E. Gewirtz, David A. Ghavami, Saeid Ghigo, Eric Ghosh, Debabrata Giammarioli, Anna Maria Giampieri, Francesca Giampietri, Claudia Giatromanolaki, Alexandra Gibbings, Derrick J. Gibellini, Lara Gibson, Spencer B. Ginet, Vanessa Giordano, Antonio Giorgini, Flaviano Giovannetti, Elisa Girardin, Stephen E. Gispert, Suzana Giuliano, Sandy Gladson, Candece L. Glavic, Alvaro Gleave, Martin Godefroy, Nelly Gogal, Robert M., Jr. Gokulan, Kuppan Goldman, Gustavo H. Goletti, Delia Goligorsky, Michael S. Gomes, Aldrin V. Gomes, Ligia C. Gomez, Hernando Gomez-Manzano, Candelaria Gomez-Sanchez, Ruben Goncalves, Dawit A. P. Goncu, Ebru Gong, Qingqiu Gongora, Celine Gonzalez, Carlos B. Gonzalez-Alegre, Pedro Gonzalez-Cabo, Pilar Ana Gonzalez-Polo, Rosa Goping, Ing Swie Gorbea, Carlos Gorbunov, Nikolai V. Goring, Daphne R. Gorman, Adrienne M. Gorski, Sharon M. Goruppi, Sandro Goto-Yamada, Shino Gotor, Cecilia Gottlieb, Roberta A. Gozes, Illana Gozuacik, Devrim Graba, Yacine Graef, Martin Granato, Giovanna E. Grant, Gary Dean Grant, Steven Gravina, Giovanni Luca Green, Douglas R. Greenhough, Alexander Greenwood, Michael T. Grimaldi, Benedetto Gros, Frederic Grose, Charles Groulx, Jean-Francois Gruber, Florian Grumati, Paolo Grune, Tilman Guan, Jun-Lin Guan, Kun-Liang Guerra, Barbara Guillen, Carlos Gulshan, Kailash Gunst, Jan Guo, Chuanyong Guo, Lei Guo, Ming Guo, Wenjie Guo, Xu-Guang Gust, Andrea A. Gustafsson, Asa B. Gutierrez, Elaine Gutierrez, Maximiliano G. Gwak, Ho-Shin Haas, Albert Haber, James E. Hadano, Shinji Hagedorn, Monica Hahn, David R. Halayko, Andrew J. Hamacher-Brady, Anne Hamada, Kozo Hamai, Ahmed Hamann, Andrea Hamasaki, Maho Hamer, Isabelle Hamid, Qutayba Hammond, Ester M. Han, Feng Han, Weidong Handa, James T. Hanover, John A. Hansen, Malene Harada, Masaru Harhaji-Trajkovic, Ljubica Harper, J. Wade Harrath, Abdel Halim Harris, Adrian L. Harris, James Hasler, Udo Hasselblatt, Peter Hasui, Kazuhisa Hawley, Robert G. Hawley, Teresa S. He, Congcong He, Cynthia Y. He, Fengtian He, Gu He, Rong-Rong He, Xian-Hui He, You-Wen He, Yu-Ying Heath, Joan K. Hebert, Marie-Josee Heinzen, Robert A. Helgason, Gudmundur Vignir Hensel, Michael Henske, Elizabeth P. Her, Chengtao Herman, Paul K. Hernandez, Agustin Hernandez, Carlos Hernandez-Tiedra, Sonia Hetz, Claudio Hiesinger, P. Robin Higaki, Katsumi Hilfiker, Sabine Hill, Bradford G. Hill, Joseph A. Hill, William D. Hino, Keisuke Hofius, Daniel Hofman, Paul Hoeglinger, Guenter U. Hoehfeld, Joerg Holz, Marina K. Hong, Yonggeun Hood, David A. Hoozemans, Jeroen J. M. Hoppe, Thorsten Hsu, Chin Hsu, Chin-Yuan Hsu, Li-Chung Hu, Dong Hu, Guochang Hu, Hong-Ming Hu, Hongbo Hu, Ming Chang Hu, Yu-Chen Hu, Zhuo-Wei Hua, Fang Hua, Ya Huang, Canhua Huang, Huey-Lan Huang, Kuo-How Huang, Kuo-Yang Huang, Shile Huang, Shiqian Huang, Wei-Pang Huang, Yi-Ran Huang, Yong Huang, Yunfei Huber, Tobias B. Huebbe, Patricia Huh, Won-Ki Hulmi, Juha J. Hur, Gang Min Hurley, James H. Husak, Zvenyslava Hussain, Sabah N. A. Hussain, Salik Hwang, Jung Jin Hwang, Seungmin Hwang, Thomas I. S. Ichihara, Atsuhiro Imai, Yuzuru Imbriano, Carol Inomata, Megumi Into, Takeshi Iovane, Valentina Iovanna, Juan L. Iozzo, Renato V. Ip, Nancy Y. Irazoqui, Javier E. Iribarren, Pablo Isaka, Yoshitaka Isakovic, Aleksandra J. Ischiropoulos, Harry Isenberg, Jeffrey S. Ishaq, Mohammad Ishida, Hiroyuki Ishii, Isao Ishmael, Jane E. Isidoro, Ciro Isobe, Ken-ichi Isono, Erika Issazadeh-Navikas, Shohreh Itahana, Koji Itakura, Eisuke Ivanov, Andrei I. Iyer, Anand Krishnan V. Izquierdo, Jose M. Izumi, Yotaro Izzo, Valentina Jaeaettelae, Marja Jaber, Nadia Jackson, Daniel John Jackson, William T. Jacob, Tony George Jacques, Thomas S. Jagannath, Chinnaswamy Jain, Ashish Jana, Nihar Ranjan Jang, Byoung Kuk Jani, Alkesh Janji, Bassam Jannig, Paulo Roberto Jansson, Patric J. Jean, Steve Jendrach, Marina Jeon, Ju-Hong Jessen, Niels Jeung, Eui-Bae Jia, Kailiang Jia, Lijun Jiang, Hong Jiang, Hongchi Jiang, Liwen Jiang, Teng Jiang, Xiaoyan Jiang, Xuejun Jiang, Xuejun Jiang, Ying Jiang, Yongjun Jimenez, Alberto Jin, Cheng Jin, Hongchuan Jin, Lei Jin, Meiyan Jin, Shengkan Jinwal, Umesh Kumar Jo, Eun-Kyeong Johansen, Terje Johnson, Daniel E. Johnson, Gail V. W. Johnson, James D. Jonasch, Eric Jones, Chris Joosten, Leo A. B. Jordan, Joaquin Joseph, Anna-Maria Joseph, Bertrand Joubert, Annie M. Ju, Dianwen Ju, Jingfang Juan, Hsueh-Fen Juenemann, Katrin Juhasz, Gabor Jung, Hye Seung Jung, Jae U. Jung, Yong-Keun Jungbluth, Heinz Justice, Matthew J. Jutten, Barry Kaakoush, Nadeem O. Kaarniranta, Kai Kaasik, Allen Kabuta, Tomohiro Kaeffer, Bertrand Kagedal, Katarina Kahana, Alon Kajimura, Shingo Kakhlon, Or Kalia, Manjula Kalvakolanu, Dhan V. Kamada, Yoshiaki Kambas, Konstantinos Kaminskyy, Vitaliy O. Kampinga, Harm H. Kandouz, Mustapha Kang, Chanhee Kang, Rui Kang, Tae-Cheon Kanki, Tomotake Kanneganti, Thirumala-Devi Kanno, Haruo Kanthasamy, Anumantha G. Kantorow, Marc Kaparakis-Liaskos, Maria Kapuy, Orsolya Karantza, Vassiliki Karim, Md Razaul Karmakar, Parimal Kaser, Arthur Kaushik, Susmita Kawula, Thomas Kaynar, A. Murat Ke, Po-Yuan Ke, Zun-Ji Kehrl, John H. Keller, Kate E. Kemper, Jongsook Kim Kenworthy, Anne K. Kepp, Oliver Kern, Andreas Kesari, Santosh Kessel, David Ketteler, Robin Kettelhut, Isis do Carmo Khambu, Bilon Khan, Muzamil Majid Khandelwal, Vinoth K. M. Khare, Sangeeta Kiang, Juliann G. Kiger, Amy A. Kihara, Akio Kim, Arianna L. Kim, Cheol Hyeon Kim, Deok Ryong Kim, Do-Hyung Kim, Eung Kweon Kim, Hye Young Kim, Hyung-Ryong Kim, Jae-Sung Kim, Jeong Hun Kim, Jin Cheon Kim, Jin Hyoung Kim, Kwang Woon Kim, Michael D. Kim, Moon-Moo Kim, Peter K. Kim, Seong Who Kim, Soo-Youl Kim, Yong-Sun Kim, Yonghyun Kimchi, Adi Kimmelman, Alec C. Kimura, Tomonori King, Jason S. Kirkegaard, Karla Kirkin, Vladimir Kirshenbaum, Lorrie A. Kishi, Shuji Kitajima, Yasuo Kitamoto, Katsuhiko Kitaoka, Yasushi Kitazato, Kaio Kley, Rudolf A. Klimecki, Walter T. Klinkenberg, Michael Klucken, Jochen Knaevelsrud, Helene Knecht, Erwin Knuppertz, Laura Ko, Jiunn-Liang Kobayashi, Satoru Koch, Jan C. Koechlin-Ramonatxo, Christelle Koenig, Ulrich Ko, Young Ho Koehler, Katja Kohlwein, Sepp D. Koike, Masato Komatsu, Masaaki Kominami, Eiki Kong, Dexin Kong, Hee Jeong Konstantakou, Eumorphia G. Kopp, Benjamin T. Korcsmaros, Tamas Korhonen, Laura Korolchuk, Viktor I. Koshkina, Nadya V. Kou, Yanjun Koukourakis, Michael I. Koumenis, Constantinos Kovacs, Attila L. Kovacs, Tibor Kovacs, Werner J. Koya, Daisuke Kraft, Claudine Krainc, Dimitri Kramer, Helmut Kravic-Stevovic, Tamara Krek, Wilhelm Kretz-Remy, Carole Krick, Roswitha Krishnamurthy, Malathi Kriston-Vizi, Janos Kroemer, Guido Kruer, Michael C. Kruger, Rejko Ktistakis, Nicholas T. Kuchitsu, Kazuyuki Kuhn, Christian Kumar, Addanki Pratap Kumar, Anuj Kumar, Ashok Kumar, Deepak Kumar, Dhiraj Kumar, Rakesh Kumar, Sharad Kundu, Mondira Kung, Hsing-Jien Kuno, Atsushi Kuo, Sheng-Han Kuret, Jeff Kurz, Tino Kwok, Terry Kwon, Taeg Kyu Kwon, Yong Tae Kyrmizi, Irene La Spada, Albert R. Lafont, Frank Lahm, Tim Lakkaraju, Aparna Lam, Truong Lamark, Trond Lancel, Steve Landowski, Terry H. Lane, Darius J. R. Lane, Jon D. Lanzi, Cinzia Lapaquette, Pierre Lapierre, Louis R. Laporte, Jocelyn Laukkarinen, Johanna Laurie, Gordon W. Lavandero, Sergio Lavie, Lena LaVoie, Matthew J. Law, Betty Yuen Kwan Law, Helen Ka-wai Law, Kelsey B. Layfield, Robert Lazo, Pedro A. Le Cam, Laurent Le Roch, Karine G. Le Stunff, Herve Leardkamolkarn, Vijittra Lecuit, Marc Lee, Byung-Hoon Lee, Che-Hsin Lee, Erinna F. Lee, Gyun Min Lee, He-Jin Lee, Hsinyu Lee, Jae Keun Lee, Jongdae Lee, Ju-Hyun Lee, Jun Hee Lee, Michael Lee, Myung-Shik Lee, Patty J. Lee, Sam W. Lee, Seung-Jae Lee, Shiow-Ju Lee, Stella Y. Lee, Sug Hyung Lee, Sung Sik Lee, Sung-Joon Lee, Sunhee Lee, Ying-Ray Lee, Yong J. Lee, Young H. Leeuwenburgh, Christiaan Lefort, Sylvain Legouis, Renaud Lei, Jinzhi Lei, Qun-Ying Leib, David A. Leibowitz, Gil Lekli, Istvan Lemaire, Stephane D. Lemasters, John J. Lemberg, Marius K. Lemoine, Antoinette Leng, Shuilong Lenz, Guido Lenzi, Paola Lerman, Lilach O. Barbato, Daniele Lettieri Leu, Julia I-Ju Leung, Hing Y. Levine, Beth Lewis, Patrick A. Lezoualc'h, Frank Li, Chi Li, Faqiang Li, Feng-Jun Li, Jun Li, Ke Li, Lian Li, Min Li, Min Li, Qiang Li, Rui Li, Sheng Li, Wei Li, Wei Li, Xiaotao Li, Yumin Lian, Jiqin Liang, Chengyu Liang, Qiangrong Liao, Yulin Liberal, Joana Liberski, Pawel P. Lie, Pearl Lieberman, Andrew P. Lim, Hyunjung Jade Lim, Kah-Leong Lim, Kyu Lima, Raquel T. Lin, Chang-Shen Lin, Chiou-Feng Lin, Fang Lin, Fangming Lin, Fu-Cheng Lin, Kui Lin, Kwang-Huei Lin, Pei-Hui Lin, Tianwei Lin, Wan-Wan Lin, Yee-Shin Lin, Yong Linden, Rafael Lindholm, Dan Lindqvist, Lisa M. Lingor, Paul Linkermann, Andreas Liotta, Lance A. Lipinski, Marta M. Lira, Vitor A. Lisanti, Michael P. Liton, Paloma B. Liu, Bo Liu, Chong Liu, Chun-Feng Liu, Fei Liu, Hung-Jen Liu, Jianxun Liu, Jing-Jing Liu, Jing-Lan Liu, Ke Liu, Leyuan Liu, Liang Liu, Quentin Liu, Rong-Yu Liu, Shiming Liu, Shuwen Liu, Wei Liu, Xian-De Liu, Xiangguo Liu, Xiao-Hong Liu, Xinfeng Liu, Xu Liu, Xueqin Liu, Yang Liu, Yule Liu, Zexian Liu, Zhe Liuzzi, Juan P. Lizard, Gerard Ljujic, Mila Lodhi, Irfan J. Logue, Susan E. Lokeshwar, Bal L. Long, Yun Chau Lonial, Sagar Loos, Benjamin Lopez-Otin, Carlos Lopez-Vicario, Cristina Lorente, Mar Lorenzi, Philip L. Lorincz, Peter Los, Marek Lotze, Michael T. Lovat, Penny E. Lu, Binfeng Lu, Bo Lu, Jiahong Lu, Qing Lu, She-Min Lu, Shuyan Lu, Yingying Luciano, Federic Luckhart, Shirley Lucocq, John Milton Ludovico, Paula Lugea, Aurelia Lukacs, Nicholas W. Lum, Julian J. Lund, Anders H. Luo, Honglin Luo, Jia Luo, Shouqing Luparello, Claudio Lyons, Timothy Ma, Jianjie Ma, Yi Ma, Yong Ma, Zhenyi Machado, Juliano Machado-Santelli, Glaucia M. Macian, Fernando MacIntosh, Gustavo C. MacKeigan, Jeffrey P. Macleod, Kay F. MacMicking, John D. MacMillan-Crow, Lee Ann Madeo, Frank Madesh, Muniswamy Madrigal-Matute, Julio Maeda, Akiko Maeda, Tatsuya Maegawa, Gustavo Maellaro, Emilia Maes, Hannelore Magarinos, Marta Maiese, Kenneth Maiti, Tapas K. Maiuri, Luigi Maiuri, Maria Chiara Maki, Carl G. Malli, Roland Malorni, Walter Maloyan, Alina Mami-Chouaib, Fathia Man, Na Mancias, Joseph D. Mandelkow, Eva-Maria Mandell, Michael A. Manfredi, Angelo A. Manie, Serge N. Manzoni, Claudia Mao, Kai Mao, Zixu Mao, Zong-Wan Marambaud, Philippe Marconi, Anna Maria Marelja, Zvonimir Marfe, Gabriella Margeta, Marta Margittai, Eva Mari, Muriel Mariani, Francesca V. Marin, Concepcio Marinelli, Sara Marino, Guillermo Markovic, Ivanka Marquez, Rebecca Martelli, Alberto M. Martens, Sascha Martin, Katie R. Martin, Seamus J. Martin, Shaun Martin-Acebes, Miguel A. Martin-Sanz, Paloma Martinand-Mari, Camille Martinet, Wim Martinez, Jennifer Martinez-Lopez, Nuria Martinez-Outschoorn, Ubaldo Martinez-Velazquez, Moises Martinez-Vicente, Marta Martins, Waleska Kerllen Mashima, Hirosato Mastrianni, James A. Matarese, Giuseppe Matarrese, Paola Mateo, Roberto Matoba, Satoaki Matsumoto, Naomichi Matsushita, Takehiko Matsuura, Akira Matsuzawa, Takeshi Mattson, Mark P. Matus, Soledad Maugeri, Norma Mauvezin, Caroline Mayer, Andreas Maysinger, Dusica Mazzolini, Guillermo D. McBrayer, Mary Kate McCall, Kimberly McCormick, Craig McInerney, Gerald M. McIver, Skye C. McKenna, Sharon McMahon, John J. McNeish, Iain A. Mechta-Grigoriou, Fatima Medema, Jan Paul Medina, Diego L. Megyeri, Klara Mehrpour, Maryam Mehta, Jawahar L. Mei, Yide Meier, Ute-Christiane Meijer, Alfred J. Melendez, Alicia Melino, Gerry Melino, Sonia Tenorio de Melo, Edesio Jose Mena, Maria A. Meneghini, Marc D. Menendez, Javier A. Menezes, Regina Meng, Liesu Meng, Ling-hua Meng, Songshu Menghini, Rossella Menko, A. Sue Menna-Barreto, Rubem F. S. Menon, Manoj B. Meraz-Rios, Marco A. Merla, Giuseppe Merlini, Luciano Merlot, Angelica M. Meryk, Andreas Meschini, Stefania Meyer, Joel N. Mi, Man-Tian Miao, Chao-Yu Micale, Lucia Michaeli, Simon Michiels, Carine Migliaccio, Anna Rita Mihailidou, Anastasia Susie Mijaljica, Dalibor Mikoshiba, Katsuhiko Milan, Enrico Miller-Fleming, Leonor Mills, Gordon B. Mills, Ian G. Minakaki, Georgia Minassian, Berge A. Ming, Xiu-Fen Minibayeva, Farida Minina, Elena A. Mintern, Justine D. Minucci, Saverio Miranda-Vizuete, Antonio Mitchell, Claire H. Miyamoto, Shigeki Miyazawa, Keisuke Mizushima, Noboru Mnich, Katarzyna Mograbi, Baharia Mohseni, Simin Moita, Luis Ferreira Molinari, Marco Molinari, Maurizio Moller, Andreas Buch Mollereau, Bertrand Mollinedo, Faustino Monick, Martha M. Monick, Martha M. Montagnaro, Serena Montell, Craig Moore, Darren J. Moore, Michael N. Mora-Rodriguez, Rodrigo Moreira, Paula I. Morel, Etienne Morelli, Maria Beatrice Moreno, Sandra Morgan, Michael J. Moris, Arnaud Moriyasu, Yuji Morrison, Janna L. Morrison, Lynda A. Morselli, Eugenia Moscat, Jorge Moseley, Pope L. Mostowy, Serge Motori, Elisa Mottet, Denis Mottram, Jeremy C. Moussa, Charbel E-H Mpakou, Vassiliki E. Mukhtar, Hasan Levy, Jean M. Mulcahy Muller, Sylviane Munoz-Moreno, Raquel Munoz-Pinedo, Cristina Muenz, Christian Murphy, Maureen E. Murray, James T. Murthy, Aditya Mysorekar, Indira U. Nabi, Ivan R. Nabissi, Massimo Nader, Gustavo A. Nagahara, Yukitoshi Nagai, Yoshitaka Nagata, Kazuhiro Nagelkerke, Anika Nagy, Peter Naidu, Samisubbu R. Nair, Sreejayan Nakano, Hiroyasu Nakatogawa, Hitoshi Nanjundan, Meera Napolitano, Gennaro Naqvi, Naweed I. Nardacci, Roberta Narendra, Derek P. Narita, Masashi Nascimbeni, Anna Chiara Natarajan, Ramesh Navegantes, Luiz C. Nawrocki, Steffan T. Nazarko, Taras Y. Nazarko, Volodymyr Y. Neill, Thomas Neri, Luca M. Netea, Mihai G. Netea-Maier, Romana T. Neves, Bruno M. Ney, Paul A. Nezis, Ioannis P. Nguyen, Hang T. T. Huu Phuc Nguyen Nicot, Anne-Sophie Nilsen, Hilde Nilsson, Per Nishimura, Mikio Nishino, Ichizo Niso-Santano, Mireia Niu, Hua Nixon, Ralph A. Njar, Vincent C. O. Noda, Takeshi Noegel, Angelika A. Nolte, Elsie Magdalena Norberg, Erik Norga, Koenraad K. Noureini, Sakineh Kazemi Notomi, Shoji Notterpek, Lucia Nowikovsky, Karin Nukina, Nobuyuki Nuernberger, Thorsten O'Donnell, Valerie B. O'Donovan, Tracey O'Dwyer, Peter J. Oehme, Ina Oeste, Clara L. Ogawa, Michinaga Ogretmen, Besim Ogura, Yuji Oh, Young J. Ohmuraya, Masaki Ohshima, Takayuki Ojha, Rani Okamoto, Koji Okazaki, Toshiro Oliver, F. Javier Ollinger, Karin Olsson, Stefan Orban, Daniel P. Ordonez, Paulina Orhon, Idil Orosz, Laszlo O'Rourke, Eyleen J. Orozco, Helena Ortega, Angel L. Ortona, Elena Osellame, Laura D. Oshima, Junko Oshima, Shigeru Osiewacz, Heinz D. Otomo, Takanobu Otsu, Kinya Ou, Jing-hsiung James Outeiro, Tiago F. Ouyang, Dong-yun Ouyang, Hongjiao Overholtzer, Michael Ozbun, Michelle A. Ozdinler, P. Hande Ozpolat, Bulent Pacelli, Consiglia Paganetti, Paolo Page, Guylene Pages, Gilles Pagnini, Ugo Pajak, Beata Pak, Stephen C. Pakos-Zebrucka, Karolina Pakpour, Nazzy Palkova, Zdena Palladino, Francesca Pallauf, Kathrin Pallet, Nicolas Palmieri, Marta Paludan, Soren R. Palumbo, Camilla Palumbo, Silvia Pampliega, Olatz Pan, Hongming Pan, Wei Panaretakis, Theocharis Pandey, Aseem Pantazopoulou, Areti Papackova, Zuzana Papademetrio, Daniela L. Papassideri, Issidora Papini, Alessio Parajuli, Nirmala Pardo, Julian Parekh, Vrajesh V. Parenti, Giancarlo Park, Jong-In Park, Junsoo Park, Ohkmae K. Parker, Roy Parlato, Rosanna Parys, Jan B. Parzych, Katherine R. Pasquet, Jean-Max Pasquier, Benoit Pasumarthi, Kishore B. S. Patschan, Daniel Patterson, Cam Pattingre, Sophie Pattison, Scott Pause, Arnim Pavenstaedt, Hermann Pavone, Flaminia Pedrozo, Zully Pena, Fernando J. Penalva, Miguel A. Pende, Mario Peng, Jianxin Penna, Fabio Penninger, Josef M. Pensalfini, Anna Pepe, Salvatore Pereira, Gustavo J. S. Pereira, Paulo C. Perez-de la Cruz, Veronica Esther Perez-Perez, Maria Perez-Rodriguez, Diego Perez-Sala, Dolores Perier, Celine Perl, Andras Perlmutter, David H. Perrotta, Ida Pervaiz, Shazib Pesonen, Maija Pessin, Jeffrey E. Peters, Godefridus J. Petersen, Morten Petrache, Irina Petrof, Basil J. Petrovski, Goran Phang, James M. Piacentini, Mauro Pierdominici, Marina Pierre, Philippe Pierrefite-Carle, Valerie Pietrocola, Federico Pimentel-Muinos, Felipe X. Pinar, Mario Pineda, Benjamin Pinkas-Kramarski, Ronit Pinti, Marcello Pinton, Paolo Piperdi, Bilal Piret, James M. Platanias, Leonidas C. Platta, Harald W. Plowey, Edward D. Poggeler, Stefanie Poirot, Marc Polcic, Peter Poletti, Angelo Poon, Audrey H. Popelka, Hana Popova, Blagovesta Poprawa, Izabela Poulose, Shibu M. Poulton, Joanna Powers, Scott K. Powers, Ted Pozuelo-Rubio, Mercedes Prak, Krisna Prange, Reinhild Prescott, Mark Priault, Muriel Prince, Sharon Proia, Richard L. Proikas-Cezanne, Tassula Prokisch, Holger Promponas, Vasilis J. Przyklenk, Karin Puertollano, Rosa Pugazhenthi, Subbiah Puglielli, Luigi Pujol, Aurora Puyal, Julien Pyeon, Dohun Qi, Xin Qian, Wen-bin Qin, Zheng-Hong Qiu, Yu Qu, Ziwei Quadrilatero, Joe Quinn, Frederick Raben, Nina Rabinowich, Hannah Radogna, Flavia Ragusa, Michael J. Rahmani, Mohamed Raina, Komal Ramanadham, Sasanka Ramesh, Rajagopal Rami, Abdelhaq Randall-Demllo, Sarron Randow, Felix Rao, Hai Rao, V. Ashutosh Rasmussen, Blake B. Rasse, Tobias M. Ratovitski, Edward A. Rautou, Pierre-Emmanuel Ray, Swapan K. Razani, Babak Reed, Bruce H. Reggiori, Fulvio Rehm, Markus Reichert, Andreas S. Rein, Theo Reiner, David J. Reits, Eric Ren, Jun Ren, Xingcong Renna, Maurizio Reusch, Jane E. B. Revuelta, Jose L. Reyes, Leticia Rezaie, Alireza R. Richards, Robert I. Richardson, Des R. Richetta, Clemence Riehle, Michael A. Rihn, Bertrand H. Rikihisa, Yasuko Riley, Brigit E. Rimbach, Gerald Rippo, Maria Rita Ritis, Konstantinos Rizzi, Federica Rizzo, Elizete Roach, Peter J. Robbins, Jeffrey Roberge, Michel Roca, Gabriela Roccheri, Maria Carmela Rocha, Sonia Rodrigues, Cecilia M. P. Rodriguez, Clara I. Rodriguez de Cordoba, Santiago Rodriguez-Muela, Natalia Roelofs, Jeroen Rogov, Vladimir V. Rohn, Troy T. Rohrer, Baerbel Romanelli, Davide Romani, Luigina Silvia Romano, Patricia Roncero, M. Isabel G. Luis Rosa, Jose Rosello, Alicia Rosen, Kirill V. Rosenstiel, Philip Rost-Roszkowska, Magdalena Roth, Kevin A. Roue, Gael Rouis, Mustapha Rouschop, Kasper M. Ruan, Daniel T. Ruano, Diego Rubinsztein, David C. Rucker, Edmund B., III Rudich, Assaf Rudolf, Emil Rudolf, Ruediger Ruegg, Markus A. Ruiz-Roldan, Carmen Ruparelia, Avnika Ashok Rusmini, Paola Russ, David W. Russo, Gian Luigi Russo, Giuseppe Russo, Rossella Rusten, Tor Erik Ryabovol, Victoria Ryan, Kevin M. Ryter, Stefan W. Sabatini, David M. Sacher, Michael Sachse, Carsten Sack, Michael N. 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[Schwarten, Melanie; Willbold, Dieter] Forschungszentrum Juelich, Struct Biochem ICS 6, Julich, Germany. [Kumar, Rakesh] George Washington Univ, Dept Biochem & Mol Med, Washington, DC USA. [Tavernarakis, Nektarios] Fdn Res & Technol Hellas, Iraklion, Greece. [Ye, Mingxiang; Zhang, Jian] Fourth Mil Med Univ, Dept Biochem & Mol Biol, Xian 710032, Peoples R China. [Wang, Mei-Qing] Fourth Mil Med Univ, Dept Oral Anat & Physiol & TMD, Coll Stomatol, Xian 710032, Peoples R China. [Zhang, Jian] Fourth Mil Med Univ, Dept Pulm Med, Xijing Hosp, Xian 710032, Shaanxi, Peoples R China. [Gutierrez, Maximiliano G.] Francis Crick Inst, Mill Hill Lab, London, England. [Dumit, Veronica I.] Univ Freiburg, Ctr Biol Syst Anal ZBSA, Core Facil Prote, Hugstetter Str 55, D-79106 Freiburg, Germany. [Weindl, Guenther] Free Univ Berlin, Inst Pharm Pharmacol & Toxicol, Berlin, Germany. [Jiang, Yongjun; Liu, Xueqin] Freshwater Aquaculture Collaborat Innovat Ctr Hub, Wuhan, Peoples R China. [Becker, Christoph] Univ Erlangen Nurnberg, Dept Med 1, D-91054 Erlangen, Germany. [Lei, Qun-Ying] Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Sch Basic Med Sci,Inst Biomed Sci, Shanghai 200433, Peoples R China. [Wu, Jian] Fudan Univ, Shanghai Med Coll, Key Lab Mol Virol, Shanghai 200433, Peoples R China. [Chen, Zhen; Wang, Peng; Zhang, Xiangnan] Fudan Univ, Ctr Canc, Dept Integrat Oncol, Shanghai 200433, Peoples R China. [Jia, Lijun] Fudan Univ, Canc Inst, Shanghai Canc Ctr,Shanghai Med Coll, Collaborat Innovat Ctr Canc Med,Dept Oncol, Shanghai 200433, Peoples R China. [Ju, Dianwen] Fudan Univ, Dept Biosynth, Key Lab Smart Drug Delivery, Minist Educ,Sch Pharm, Shanghai 200433, Peoples R China. [Xu, Feng] Fudan Univ, Dept Neurosug, Shanghai 200433, Peoples R China. [Du, Lihuan] Fujian Prov Hosp, Dept Urol, Fuzhou, Peoples R China. [Skwarska, Anna] Gdansk Univ Technol, Dept Pharmaceut Technol & Biochem, Gdansk, Poland. [Chang, Ta Yuan] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH USA. [Leib, David A.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Lebanon, NH USA. [Yang, Wannian] Weis Ctr Res, Geisinger Clin, Danville, PA 17822 USA. [Murthy, Aditya] Genentech Inc, Dept Canc Immunol, San Francisco, CA 94080 USA. [Campagne, Menno van Lookeren] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA. [Bingol, Baris] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA. [Lin, Kui] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA. [Brown, Eric J.] Genentech Inc, Immunol & Infect Dis, San Francisco, CA 94080 USA. [Braus, Gerhard H.; Popova, Blagovesta] Univ Gottingen, Dept Mol Microbiol & Genet, Inst Microbiol & Genet, D-37073 Gottingen, Germany. [Poggeler, Stefanie] Univ Gottingen, Inst Microbiol & Genet, Dept Genet Eukaryot Microorganisms, D-37073 Gottingen, Germany. [Vasko, Radovan] Univ Gottingen, Dept Nephrol & Rheumatol, D-37073 Gottingen, Germany. [Krick, Roswitha; Thumm, Michael] Univ Gottingen, Inst Cellular Biochem, D-37073 Gottingen, Germany. [Liotta, Lance A.] George Mason Univ, Manassas, VA USA. [Hawley, Robert G.] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC USA. [Hawley, Teresa S.] George Washington Univ, Flow Cytometry Core Facil, Washington, DC USA. [Moussa, Charbel E-H] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. [Clarke, Robert] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Suzuki, Yuichiro J.] Georgetown Univ, Dept Physiol & Pharmacol, Washington, DC USA. [Albanese, Chris] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC USA. [Albanese, Chris] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Pathol, Washington, DC USA. [Avantaggiati, Maria Laura] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Lokeshwar, Bal L.] Georgia Regents Univ, Ctr Canc, Dept Med, Augusta, GA USA. [Hill, William D.] Georgia Regents Univ, Dept Neurol, Augusta, GA USA. [Hill, William D.] Georgia Regents Univ, Dept Orthopaed Surg, Augusta, GA USA. [Hill, William D.] Georgia Regents Univ, Inst Regenerat & Reparat Med, Augusta, GA USA. [Atherton, Sally S.] Georgia Regents Univ, Med Coll Georgia, Augusta, GA USA. [Chen, Jian-Kang; Dong, Zheng; Hill, William D.; Xu, Jinxian] Georgia Regents Univ, Med Coll Georgia, Dept Cellular Biol & Anat, Augusta, GA USA. [Chen, Jian-Kang; Xu, Jinxian] Georgia Regents Univ, Med Coll Georgia, Dept Med, Augusta, GA USA. [Oehme, Ina] German Canc Res Ctr, Clin Cooperat Unit CCU Pediat Oncol, Heidelberg, Germany. [Hamacher-Brady, Anne] German Canc Res Ctr, Lysosomal Syst Biol, Heidelberg, Germany. [Brady, Nathan] German Canc Res Ctr, Syst Biol Cell Death Mech, Heidelberg, Germany. [Hoeglinger, Guenter U.] German Ctr Neurodegenerat Dis DZNE, Munich, Germany. [Grune, Tilman] German Inst Human Nutr, Dept Mol Toxicol, Nuthetal, Germany. [Vandenabeele, Peter] Univ Ghent, Dept Biomed Mol Biol, Inflammat Res Ctr, VIB,Methusalem Program, B-9000 Ghent, Belgium. [Menendez, Javier A.] ICO, Girona Biomed Res Inst IDIBGI, Catalonia, Spain. [Auburger, Georg; Gispert, Suzana; Klinkenberg, Michael] Goethe Univ, Sch Med, Expt Neurol, Frankfurt, Germany. [Doetsch, Volker; Rogov, Vladimir V.] Goethe Univ Frankfurt, Inst Biophys Chem, D-60054 Frankfurt, Germany. [Dikic, Ivan; Grumati, Paolo] Goethe Univ, Sch Med, Inst Biochem 2, Frankfurt, Germany. [Dikic, Ivan; Grumati, Paolo] Buchmann Inst Mol Life, Frankfurt, Germany. [Schaefer, Liliana] Goethe Univ, Inst Pharmacol & Toxicol, Frankfurt, Germany. [Fulda, Simone] Goethe Univ, Inst Expt Canc Res Pediat, Frankfurt, Germany. [Hamann, Andrea; Knuppertz, Laura; Osiewacz, Heinz D.] Goethe Univ, Inst Mol Biosci, Mol Dev Biol, Frankfurt, Hesse, Germany. [Veras, Patricia S. T.] Fundacao Oswaldo Cruz, FIOCRUZ BA, Goncalo Moniz Res Ctr, Lab Pathol & Biointervent, Salvador, BA, Brazil. [Gwak, Ho-Shin] Grad Sch Canc Sci & Policy, Dept Syst Canc Sci, Goyang, South Korea. [Choi, Eun-Kyoung] Hallym Univ, Grad Sch, Chunchon, Kangwon Do, South Korea. [Anoopkumar-Dukie, Shailendra; Grant, Gary Dean] Griffith Univ, Menzies Hlth Inst Queensland, Nathan, Qld 4111, Australia. [Leng, Shuilong] Guangzhou Med Univ, Dept Human Anat, Sch Basic Sci, Guangzhou, Guangdong, Peoples R China. [Sakakura, Koichi] Gunma Univ, Grad Sch Med, Dept Otolaryngol Head & Neck Surg, Gunma, Japan. [Sato, Miyuki] Gunma Univ, Lab Mol Membrane Biol, Inst Mol & Cellular Regulat, Gunma, Japan. [Sato, Ken] Gunma Univ, Lab Mol Traff, Inst Mol & Cellular Regulat, Gunma, Japan. [Bravo-San Pedro, Jose M.; Galluzzi, Lorenzo; Izzo, Valentina; Pietrocola, Federico; Sica, Valentina] Gustave Roussy Canc Campus, Villejuif, France. [Kroemer, Guido] Gustave Roussy Comprehens Canc Ctr, Villejuif, France. [Chouaib, Salem; Mami-Chouaib, Fathia] Inst Gustave Roussy, Villejuif, France. [Kim, Deok Ryong] Gyeongsang Natl Univ, Sch Med, Dept Biochem & Convergence Med Sci, JinJu, Gyeongsang, South Korea. [Kim, Deok Ryong] Inst Hlth Sci, JinJu, South Korea. [Leibowitz, Gil] Hadassah Hebrew Univ, Med Ctr, Endocrinol & Metab Serv, Dept Med, Jerusalem, Israel. [Kakhlon, Or] Hadassah Hebrew Univ, Med Ctr, Dept Neurol, Jerusalem, Israel. [Kang, Tae-Cheon] Hallym Univ, Dept Anat & Neurobiol, Coll Med, Kangwon Do, South Korea. [Choi, Eun-Kyoung] Hallym Univ, Dept Biomed Gerontol, Chunchon, Kangwon Do, South Korea. [Kim, Yong-Sun] Hallym Univ, Dept Microbiol, Coll Med, Chunchon, Gangwon, South Korea. [Ko, Young Ho] Hallym Univ, Ilsong Inst Life Sci, Chunchon, South Korea. [Suh, Sang Won] Hallym Univ, Sch Med, Dept Physiol, Chunchon, South Korea. [Azad, Neelam; Iyer, Anand Krishnan V.] Hampton Univ, Dept Pharmaceut Sci, Sch Pharm, Hampton, VA 23668 USA. [Yang, Yi] Hangzhou Normal Univ, Dept Pharmacol, Sch Med, Hangzhou, Zhejiang, Peoples R China. [Behrens, Georg M. N.] Hannover Med Sch, Dept Clin Immunol & Rheumotol, Hannover, Germany. [Gaestel, Matthias; Menon, Manoj B.] Hannover Med Sch, Dept Biochem, Hannover, Germany. [Thum, Thomas] Hannover Med Sch, Inst Mol & Translat Therapeut Strategies IMTTS, Hannover, Germany. [Bae, Ok-Nam] Hanyang Univ, Coll Pharm, Ansan, South Korea. [Wang, Dong] Harbin Med Univ, Coll Bioinformat Sci & Technol, Harbin, Heilongjiang, Peoples R China. [Xu, Hongwei] Harbin Med Univ, Dept Immunol, Heilongjiang Prov Key Lab Infect & Immun, Harbin, Peoples R China. [Chou, Tsui-Fen] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Chou, Tsui-Fen] Los Angeles Biomed Res Inst, Div Med Genet, Dept Pediat, Torrance, CA USA. [Geng, Jiefei; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Xavier, Ramnik J.] Broad Inst, Boston, MA USA. [Kang, Chanhee] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Genet,Div Genet, Boston, MA 02115 USA. [Kimmelman, Alec C.; Mancias, Joseph D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mancias, Joseph D.] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Harper, J. Wade; Yuan, Junying] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Irazoqui, Javier E.] Harvard Univ, Sch Med, Lab Comparat Immunol,Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis,Res Inst, Boston, MA 02115 USA. [Narendra, Derek P.] Harvard Univ, Sch Med, Neurol Residency Program, Brigham & Womens Hosp, Boston, MA 02115 USA. [Narendra, Derek P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Notomi, Shoji; Vavvas, Demetrios G.] Harvard Univ, Sch Med, Ophthalmol, Boston, MA 02115 USA. [Airoldi, Edoardo M.] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Yuan, Zhi-Min] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Sarrias, Maria Rosa] Hlth Res Inst Germans Trias Pujol, Badalona, Spain. [Abeliovich, Hagai] Hebrew Univ Jerusalem, Fac Agr Food & Environm Biochem & Food Sci, IL-76100 Rehovot, Israel. [Rasse, Tobias M.] Heidelberg Univ, Deutsch Krebsforschungszentrum, Proteostasis Neurodegenerat Dis B180, CHS Res Grp CellNetworks, Heidelberg, Germany. [Schuck, Sebastian] Heidelberg Univ, Zentrum Mol Biol Univ Heidelberg ZMBH, Heidelberg, Germany. [Ventura, Natascia] Univ Dusseldorf, Inst Clin Chem, Dusseldorf, Germany. [Ventura, Natascia] Diagnost Lab, Fac Med, Dusseldorf, Germany. [Willbold, Dieter] Univ Dusseldorf, Inst Phys Biol, Dusseldorf, Germany. [Stork, Bjoern] Univ Dusseldorf, Inst Mol Med, Dusseldorf, Germany. [Schmitz, Ingo] Helmholtz Ctr Infect Res, Syst Oriented Immunol & Inflammat Res, Braunschweig, Germany. [Korhonen, Laura] Univ Helsinki, Cent Hosp, Fac Med, Div Child Psychiat, Helsinki, Finland. [Screen, Mark] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Zhou, Guang-Zhou] Henan Univ Technol, Coll Bioengn, Zhengzhou 450000, Henan Province, Peoples R China. [Tanji, Kunikazu] Hirosaki Univ, Grad Sch Med, Hirosaki, Aomori, Japan. [Yamada, Takahiro] Hokkaido Univ, Grad Sch Med, Dept Obstet & Gynecol, Sapporo, Hokkaido, Japan. [Kihara, Akio] Hokkaido Univ, Fac Pharmaceut Sci, Kita 12, Sapporo, Hokkaido 060, Japan. [Ubukata, Makoto] Hokkaido Univ, Res Fac Agr, Sapporo, Hokkaido, Japan. [Li, Min; Song, Ju-Xian] Hong Kong Baptist Univ, Sch Chinese Med, Kowloon, Hong Kong, Peoples R China. [Law, Helen Ka-wai; Siu, Parco M.] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Fac Hlth & Social Sci, Kowloon, Hong Kong, Peoples R China. [Ip, Nancy Y.] Hong Kong Univ Sci & Technol, Kowloon, Hong Kong, Peoples R China. [Rautou, Pierre-Emmanuel] Hop Beaujon, Paris, France. [Kroemer, Guido] Hop Europeen Georges Pompidou, AP HP, Paris, France. [Cerella, Claudia; Radogna, Flavia] Hop Kirchberg, Lab Biol Mol & Cellulaire Canc, Luxembourg, Luxembourg. [Lemoine, Antoinette] Hop Univ Paris Sud Biochim & Oncogenet, Hop Paul Brousse, Villejuif, France. [Brumell, John H.] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Mena, Maria A.] Hosp Univ Ramon Cajal, CIBERNED, Dept Neurobiol, Madrid, Spain. [Frigo, Daniel E.] Houston Methodist Res Inst, Genom Med Program, Houston, TX USA. [Kang, Chanhee] Howard Hughes Med Inst, Boston, MA 02115 USA. [Levine, Beth] Howard Hughes Med Inst, Dallas, TX USA. [Yan, Xianghua] Huazhong Agr Univ, Coll Anim Sci & Technol, Wuhan, Hubei, Peoples R China. [Jiang, Yongjun; Liu, Xueqin] Huazhong Agr Univ, Dept Aquat Anim Med, Coll Fisheries, Wuhan, Peoples R China. [Liu, Zexian; Xue, Yu] Huazhong Univ Sci & Technol, Dept Biomed Engn, Coll Life Sci & Technol, Wuhan 430074, Hubei, Peoples R China. [Kaparakis-Liaskos, Maria] Ctr Innate Immun & Infect Dis, Hudson Inst Med Res, Melbourne, Vic, Australia. [Shen, Chiung-Chyi] Hungkuang Univ, Dept Phys Therapy, Taichung, Taiwan. [Aranda, Agustin] Inst Agrochem & Food Technol, IATA CSIC, Paterna, Valencia, Spain. [Menezes, Regina; dos Santos, Claudia Nunes] Inst Biol Expt & Tecnol, iBET, Oeiras, Portugal. [Huang, Yong] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Cederbaum, Arthur I.] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Gandy, Sam] Icahn Sch Med Mt Sinai, Dept Neurol, Ctr Cognit Hlth, Mt Sinai Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Gandy, Sam] Icahn Sch Med Mt Sinai, Dept Psychiat, Ctr Cognit Hlth, Mt Sinai Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Yue, Zhenyu] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Wu, Defeng] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Le Cam, Laurent] Inst Rech Cancerol Montpellier, ICM, Montpellier, France. [Pujol, Aurora] ICREA Catalan Inst Res & Adv Studies, Catalonia, Spain. [Vaccari, Thomas] FIRC Inst Mol Oncol, IFOM, Milan, Italy. [Sonawane, Avinash] IIT Univ, Sch Biotechnol, Bhubaneswar, Orissa, India. [Barreiro, Esther] Pompeu Fabra Univ, Barcelona Biomed Res Pk, Dept Resp Med, Lung Canc & Muscle Res Grp,IMIM Hosp Mar CIBERES, Barcelona, Spain. [Thurston, Teresa L. M.] Univ London Imperial Coll Sci Technol & Med, MRC Ctr Mol Bacteriol & Infect, London, England. [Braga, Vania M. M.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [de Belleroche, Jackie] Univ London Imperial Coll Sci Technol & Med, Neurogenet Grp, Div Brain Sci, London, England. [Mostowy, Serge] Univ London Imperial Coll Sci Technol & Med, Microbiol Sect, MRC Ctr Mol Bacteriol & Infect, London, England. [Lee, Michael] Incheon Natl Univ, Div Life Siences, Inchon, South Korea. [Balaji, Kithiganahalli Narayanaswamy] Indian Inst Sci, Dept Microbiol & Cell Biol, Bangalore 560012, Karnataka, India. [Somasundaram, Kumaravel] Indian Inst Sci Microbiol & Cell Biol, Bangalore, Karnataka, India. [Dubey, Vikash Kumar] Indian Inst Technol, Dept Biosci & Bioengn, Gauhati, Assam, India. [Maiti, Tapas K.] Indian Inst Technol, Dept Biotechnol, Kharagpur 721302, W Bengal, India. [Justice, Matthew J.] Indiana Univ Sch Med, Biochem & Mol Biol, Denver, CO USA. [Dong, X. Charlie; Roach, Peter J.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Naidu, Samisubbu R.] Indiana Univ Sch Med, Dept Dermatol, Indianapolis, IN 46202 USA. [Broxmeyer, Hal E.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Boulton, Michael E.] Indiana Univ Sch Med, Dept Ophthalmol, Indianapolis, IN 46202 USA. [Khambu, Bilon; Yin, Xiao-Ming] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Lahm, Tim] Indiana Univ Sch Med, Richard L Roudebush VA Med Ctr, Div Pulm, Crit Care Sleep & Occupat Med, Indianapolis, IN 46202 USA. [Hong, Yonggeun] Inje Univ, Dept Rehabil Sci, Coll Biomed Sci & Engn, u HARC, Gimhae, South Korea. [Corazzari, Marco] INMI IRCCS L Spallanzani, Rome, Italy. [Bruhat, Alain] Ctr Clermont Theix, INRA, Nutr Humaine UMR 1019, St Genes Champanelle, France. [Favier, Francois B.] INRA, Dynam Musculaire & Metab UMR866, F-34060 Montpellier, France. [Seiliez, Iban] INRA, UR1067, Nutr Metab Aquaculture, St Pee Sur Nivelle, France. [Luciano, Federic] INSERM, U1065, C3M, Team 2, Nice, France. [Belaid, Amine; Brest, Patrick; Mograbi, Baharia] IRCAN, INSERM, U1081, CNRS UMR7284, Nice, France. [Giuliano, Sandy] Ctr Sci Monaco, Biomed Dept, Monaco, Monaco. [Giuliano, Sandy; Pages, Gilles] Univ Nice Sophia Antipolis, Inst Res Canc & Ageing Nice, CNRS UMR 7284, INSERM U1081, F-06189 Nice, France. [Dupuis, Luc] INSERM, U1118, Mecanismes Cent & Periphet Neurodegenerescence, Strasbourg, France. [Kepp, Oliver; Torriglia, Alicia] INSERM, U1138, Paris, France. [Pallet, Nicolas] INSERM, U1147, Paris, France. [Mechta-Grigoriou, Fatima] Inst Curie, INSERM U830, Stress & Canc Lab, Paris, France. [Benard, Giovanni] INSERM U862, Neuroctr Magendie, Bordeaux, France. [Le Cam, Laurent] INSERM U896, Montpellier, France. [Duran, Raul V.; Villar, Victor H.] Univ Bordeaux, INSERM U916, Inst Europeen Chim & Biol, Pessac, France. [Teixeira-Clerc, Fatima] INSERM U955, Fac Med Creteil, UMR S955, Creteil, France. [Laporte, Jocelyn; Nicot, Anne-Sophie] Univ Strasbourg, INSERM U964, CNRS UMR7104, Dept Translat Med,IGBMC, Illkirch Graffenstaden, France. [Andrieu-Abadie, Nathalie] Ctr Rech Cancerol Toulouse, INSERM UMR1037, Toulouse, France. [Dugail, Isabelle] INSERM UMRS 1166, Unite Rech Malad Cardiovasc Metab & Nutr, Paris, France. [Kroemer, Guido] INSERM, Cordeliers Res Canc, Paris, France. [Bulavin, Dmitry V.] INSERM, UMR CNRS 7284 U1081, Nice, France. [Gatti, Evelina; Pierre, Philippe] INSERM, U1104, Marseille, France. [Corti, Olga] INSERM, U1127, CNRS, UMR 7225, Paris, France. [Bravo-San Pedro, Jose M.; Galluzzi, Lorenzo; Izzo, Valentina; Pietrocola, Federico; Sica, Valentina] INSERM, U1138, Paris, France. [Rautou, Pierre-Emmanuel] INSERM, U970, Paris, France. [Roue, Gael] IDIBAPS, Hemato Oncol Dept, Barcelona, Spain. [Francois, Aurelie] Inst Cancerol Lorraine, Vandoeuvre Les Nancy, France. [Le Cam, Laurent] Inst Canc Montpellier, Montpellier, France. [Fiorito, Filomena] Ist Zooprofilattico Sperimentale Mezzogio, Dept Chem, Naples, Italy. [Echard, Arnaud] Inst Pasteur, CNRS URA2582, Cell Biol & Infect Dept, Membrane Traff & Cell Div Lab, Paris, France. [Lafont, Frank] Univ Lille, Ctr Infect & Immun Lille, Inst Pasteur Lille, CNRS,INSERM,Lille Reg Univ Hosp Ctr, Lille, France. [Colucci-Guyon, Emma] Inst Pasteur, CNRS, URA2578, Unite Macrophages & Dev Immunite,Dept Biol Dev &, Paris, France. [Albert, Matthew L.] Inst Pasteur, Dept Immunol, Paris, France. [Lecuit, Marc] Inst Pasteur, INSERM, Biol Infect Unit, Paris, France. [Papackova, Zuzana] Inst Clin & Expt Med, Ctr Med Expt, Dept Metab & Diabet, Prague, Czech Republic. [Bianchi, Michele Wolfe] Univ Paris Saclay, Inst Integrat Biol Cell, Gif Sur Yvette, France. [Zorzano, Antonio] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona, Spain. [Triola, Gemma] Spanish Res Council IQAC CSIC, Inst Adv Chem Catalonia, Dept Biomed Chem, Barcelona, Spain. [Ryabovol, Victoria] Inst Biochem & Biophys, Kazan, Russia. [Almonte-Beceril, Maylin] Inst Biomed Invest INIBIC, Inflamat & Regenerat Med, Coruna, Spain. [Jones, Chris] Inst Canc Res, Div Mol Pathol & Canc Therapeut, London SW3 6JB, England. [Zhivotovsky, Boris] Karolinska Inst, Inst Environm Med, Div Toxicol, Stockholm, Sweden. [Chauhan, Santosh] Inst Life Sci, Bhubaneswar, Odisa, India. [Ishaq, Mohammad] Inst Microbial Technol IMTECH, Cell Biol & Immunol Div, Chandigarh, India. [Vachova, Libuse] Inst Microbiol ASCR, Vvi, Prague, Czech Republic. [Penninger, Josef M.] Austrian Acad Sci, IMBA, Inst Mol Biotechnol, A-1010 Vienna, Austria. [Scovassi, A. Ivana] CNR, Inst Mol Genet, Pavia, Italy. [Stulik, Jiri] FMHS UO, Inst Mol Pathol & Biol, Hradec Kralove, Czech Republic. [Stepkowski, Tomasz M.] Ctr Radiobiol & Biol Dosimetry, Inst Nucl Chem & Technol, Dorodna, Poland. [Vescovi, Eleonora Garcia] Inst Biol Mol & Celular Rosario IBR CONICET, Rosario, Argentina. [Lazo, Pedro A.] Hosp Univ Salamanca, Inst Invest Biomed Salamanca IBSAL, Salamanca, Spain. [Martin-Sanz, Paloma] Ctr Invest Biomed Red Enfermedade Hepat & Digest, Inst Invest Biomed Albert Sols, CSIC UAM, Madrid, Spain. [Valverde, Angela M.] CSIC UAM, Inst Invest Biomed Albert Sols, Madrid, Spain. [Fernandez-Checa, Jose C.] CSIC IDI BAPS, Inst Invest Biomed Barcelona, Barcelona, Spain. [Fernandez-Checa, Jose C.] CIBEREHD, ISCIII, Ctr Invest Red Enfermedades Hepat & Digest, Barcelona, Spain. [Oliver, F. Javier] CSIC, IPBLN, Granada, Spain. [Menezes, Regina; dos Santos, Claudia Nunes] Univ Nova Lisboa, Inst Tecnol Quim & Biol Antonio Xavier, P-2780156 Oeiras, Portugal. [Moita, Luis Ferreira] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Garcia-Ruiz, Carmen] Hosp Clin Barcelona IDIBAPS, Inst Invest Biomed Barcelona IIBB CSIC, Liver Unit, Barcelona, Spain. [Garcia-Ruiz, Carmen] CIBEREHD, Barcelona, Spain. [Wappner, Pablo] Inst Leloir, Buenos Aires, DF, Argentina. [Alonso, Covadonga; Galindo, Inmaculada; Munoz-Moreno, Raquel] Inst Nacl Invest & Tecnol Agr & Alimentaria INIA, Dept Biotecnol, Madrid, Spain. [Perez-de la Cruz, Veronica] Inst Nacl Neurol & Neurocirug, Neurochem Unit, Mexico City, DF, Mexico. [Pineda, Benjamin] Inst Nacl Neurol & Neurocirug, Neuroimmunol & Neuro Oncol Unit, Mexico City, DF, Mexico. [Menna-Barreto, Rubem F. S.] Fiocruz MS, Inst Oswaldo Cruz, Lab Biol Celular, BR-21045900 Rio De Janeiro, Brazil. [Chandra, Pallavi; Kumar, Dhiraj] Int Ctr Genet Engn & Biotechnol, Immunol Grp, New Delhi, India. [Kanthasamy, Anumantha G.] Iowa State Univ, Dept Biomed Sci, Iowa Ctr Adv Neurotoxicl, Ames, IA USA. [Bassham, Diane C.] Iowa State Univ, Dept Genet Dev & Cell Biol, Ames, IA USA. [MacIntosh, Gustavo C.] Iowa State Univ, Roy J Carver Dept Biochem Biophys & Mol Biol, Ames, IA USA. [Fusco, Carmela; Merla, Giuseppe; Micale, Lucia] IRCCS Casa Sollievo Sofferenza, Med Genet Unit, San Giovanni Rotondo, FG, Italy. [Fornai, Francesco; Sciarretta, Sebastiano] IRCCS Neuromed, Pozzilli, IS, Italy. [Ferraro, Elisabetta] IRCCS San Raffaele Pisana, Lab Skeletal Muscle Dev & Metab, Rome, Italy. [Cecconi, Francesco; D'Amelio, Marcello; Molinari, Marco; Viscomi, Maria Teresa] IRCCS Santa Lucia Fdn, Rome, Italy. [Campello, Silvia] IRCCS Santa Lucia Fdn, Dept Expt Neurosci, Rome, Italy. [Crippa, Valeria] IRCCS C Mondino Natl Neurol Inst, Expt Neurobiol Lab, Pavia, Italy. [Facchiano, Antonio] IRCCS, Ist Dermopatico Immacolata, Rome, Italy. [Cantoni, Lavinia] IRCCS Ist Ric Farmacol Mario Negri, Dept Mol Biochem & Pharmacol, Milan, Italy. [Albani, Diego] IRCCS Ist Ric Farmacol Mario Negri, Dept Neurosci, Milan, Italy. [Matarese, Giuseppe] IRCCS MultiMed, Milan, Italy. [Marin, Concepcio] Inst Invest Biomed August Pi & Sunyer IDIBAPS, IRCE, Barcelona, Spain. [Gongora, Celine] INSERM, IRCM, Inst Rech Cancerol Montpellier, U896, Montpellier, France. [Pattingre, Sophie] IRCM, Inst Rech Cancerol Montpellier, Montpellier, France. [Cottet, Sandra; Schorderet, Daniel F.] IRO, Inst Res Ophthalmol, Sion, Switzerland. [Chiariello, Mario; Colecchia, David] Ist Fisiol Clin, Siena, Italy. [Bachetti, Tiziana; Ceccherini, Isabella] UOC Med Genet, Ist Giannina Gaslini, Genoa, Italy. [Grimaldi, Benedetto] Ist Italiano Tecnol, Dept Drug Discovery & Dev, Lab Mol Med, Genoa, Italy. [Giovannetti, Elisa] Univ Pisa, AIRC Start UP Unit, Canc Pharmacol Lab, Pisa, Italy. 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[Shintani, Michiko] Kobe Univ, Grad Sch Hlth Sci, Pathol Lab, Div Med Biophys, Kobe, Hyogo, Japan. [Matsushita, Takehiko] Kobe Univ, Grad Sch Med, Dept Orthopaed Surg, Kobe, Hyogo, Japan. [Voitsekhovskaja, Olga V.] Komarov Bot Inst RAS, Plant Ecol Physiol Lab, St Petersburg, Russia. [Cho, Ssang-Goo] Konkuk Univ, Dept Anim Biotechnol, Seoul, South Korea. [Lim, Hyunjung Jade] Konkuk Univ, Dept Vet Med, Seoul, South Korea. [Chung, Hyewon] Konkuk Univ, Sch Med, Dept Ophthalmol, Seoul, South Korea. [Lee, He-Jin] Konkuk Univ, Sch Med, Dept Anat, Seoul, South Korea. [Kim, Cheol Hyeon] Korea Canc Ctr Hosp, Dept Internal Med, Seoul, South Korea. [Lee, Sung-Joon] Korea Univ, Dept Biotechnol, PLUS Grad Sch Life Sci & Biotechnol BK21, Seoul, South Korea. [Chi, Sung-Gil; Choi, Eui-Ju; Lee, Jae Keun; Wright, Karen L.] Korea Univ, Dept Life Sci & Biotechnol, Seoul, South Korea. [Chun, Taehoon] Korea Univ, Dept Biotechnol, Coll Life Sci & Biotechnol, Seoul, South Korea. [Park, Ohkmae K.; Song, Hyun Kyu] Korea Univ, Div Life Sci, Seoul, South Korea. [Van Den Bosch, Ludo] Katholieke Univ Leuven, Leuven, Belgium. [Van Den Bosch, Ludo] VIB, Vesalius Res Ctr, Neurobiol Lab, Leuven, Belgium. [Gunst, Jan; Van den Berghe, Greet; Vanhorebeek, Ilse] Katholieke Univ Leuven, Clin Div, Leuven, Belgium. [Gunst, Jan; Van den Berghe, Greet; Vanhorebeek, Ilse] Lab Intens Care Med, Dept Cellular & Mol Med, Leuven, Belgium. [Decuypere, Jean-Paul] Katholieke Univ Leuven, Dept Abdominal Transplant Surg, Leuven, Belgium. [Martin, Shaun] Katholieke Univ Leuven, Dept Cellular & Mol Med, Leuven, Belgium. [Soenen, Stefaan J.] Katholieke Univ Leuven, Dept Imaging & Pathol, Leuven, Belgium. [Agostinis, Patrizia; Maes, Hannelore] Katholieke Univ Leuven, Lab Cell Death Res & Therapy, Dept Cellular & Mol Med, Campus Gasthuisberg, Leuven, Belgium. [Bultynck, Geert; Parys, Jan B.] Katholieke Univ Leuven, Lab Mol & Cellular Signaling, Dept Cellular & Mol Med, Leuven, Belgium. [Ohmuraya, Masaki] Kumamoto Univ, Inst Resource Dev & Anal, Kumamoto, Japan. [Agam, Galila] Kunming Univ Sci & Technol, Sch Med, Kunmimg, Yunnan, Peoples R China. [Tanaka, Masaki; Watanabe, Yoshihisa] Kyoto Prefectural Univ Med, Dept Basic Geriatr, Kyoto, Japan. [Matoba, Satoaki] Kyoto Prefectural Univ Med, Dept Cardiovasc Med, Grad Sch Med Sci, Kyoto, Japan. [Nagata, Kazuhiro] Kyoto Sangyo Univ, Dept Life Sci, Kyoto 603, Japan. [Ushioda, Ryo] Kyoto Sangyo Univ, Dept Mol Biosci, Fac Life Sci, Kyoto 603, Japan. [Goto-Yamada, Shino] Kyoto Univ, Dept Bot, Kyoto, Japan. [Shioi, Tetsuo] Kyoto Univ, Dept Cardiovasc Med, Kyoto, Japan. [Asanuma, Katsuhiko] Kyoto Univ, Grad Sch Med, Med Innocat Ctr TMK Project, Kyoto, Japan. [Cho, Dong-Hyung] Kyung Hee Univ, Grad Sch East Wast Med Sci, Seoul, South Korea. [Bae, Jae-Sung] Kyungpook Natl Univ, Dept Physiol, Sch Med, Daegu, South Korea. [Shirabe, Ken] Kyushu Univ, Dept Surg & Sci, Fukuoka 812, Japan. [Fairlie, W. Douglas; Lee, Erinna F.] Olivia Newton John Canc Res Inst, Melbourne, Vic, Australia. [Soo, Kai Y.] La Trobe Univ, Dept Biochem & Genet, La Trobe Inst Mol Sci, Melbourne, Vic, Australia. [Fairlie, W. Douglas; Lee, Erinna F.] La Trobe Univ, Dept Chem & Phys, Melbourne, Vic, Australia. [Fairlie, W. Douglas; Lee, Erinna F.] La Trobe Univ, Sch Canc Med, Melbourne, Vic, Australia. [Paganetti, Paolo] Neurodegenerat Grp, Lab Biomed Neurosci NSI EOC, Torricella Taverne, Switzerland. [Nilsson, Per] RIKEN, Brain Sci Inst, Lab Proteolyt Neurosci, Wako, Saitama, Japan. [Choi, Eun-Kyoung] Ilsong Inst Life Sci, Lab Cellular Aging & Neurodegenerat, Anyang, Gyeonggi Do, South Korea. [Mayer, Andreas] Univ Lancaster, Fac Hlth & Med, Div Biomed & Life Sci, Lancaster, England. [Erenpreisa, Jekaterina] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Spaink, Herman P.] Leiden Univ, Inst Biol, Leiden, Netherlands. [Stern, Stephan T.] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick, MD USA. [Los, Marek] Med Univ Silesia, ENT Dept, Sch Med, Katowice, Poland. [Kagedal, Katarina; Mohseni, Simin; Ollinger, Karin] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Kurz, Tino] Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden. [Boman, Andrea] Linkoping Univ, Expt Pathol, Dept Clin & Expt Med, Fac Hlth Sci, Linkoping, Sweden. [Taylor, Mark J.] Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England. [Shajahan-Haq, Ayesha N.] Georgetown Univ, Med Ctr, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Zhivotovsky, Boris] Lomonosov Moscow State Univ, Fac Basic Med, Moscow, Russia. [Tooze, Sharon A.] Canc Res UK, London Res Inst, London, England. [Swanton, Charles] UCL, Inst Canc, London, England. 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[Tan, Mei Lan] Malaysian Inst Pharmaceut & Nutraceuticals, George Town, Malaysia. [Rudolf, Ruediger; Wild, Franziska] Mannheim Univ Appl Sci, Inst Mol & Cell Biol, Mannheim, Germany. [Slaninova, Iva] Masaryk Univ, Dept Biol, Fac Med, Brno, Czech Republic. [Costes, Safia; Mao, Kai] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Costes, Safia] Harvard Univ, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Costes, Safia] Dept Neurol, Boston, MA USA. [Goruppi, Sandro; Lee, Sam W.; Tannous, Bakhos A.] Massachusetts Gen Hosp, Charlestown, MA USA. [Goruppi, Sandro; Lee, Sam W.] Harvard Univ, Sch Med, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Mao, Kai] Harvard Univ, Sch Med, Dept Mol Biol, Dept Genet, Boston, MA 02115 USA. [Tannous, Bakhos A.] Harvard Univ, Sch Med, Expt Therapeut & Mol Imaging Lab, Neurosci Ctr, Charlestown, MA USA. [Vyas, Jatin M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Amon, Angelika; Santaguida, Stefano] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Graef, Martin; Motori, Elisa] Max Planck Inst Biol Ageing, Cologne, Germany. [Storchova, Zuzana] Max Planck Inst Biochem, Grp Maintenance Genome Stabil, Klopferspitz 18A, D-82152 Martinsried, Germany. [Wollert, Thomas] Max Planck Inst Biochem, Mol Membrane & Organelle Biol, Klopferspitz 18A, D-82152 Martinsried, Germany. [Chowdhury, Kamal] Max Planck Inst Biophys Chem, Dept Mol Cell Biol, D-37077 Gottingen, Germany. [Gassen, Nils Christian; Rein, Theo] Max Planck Inst Psychiat, Translat Res Psychiat, Munich, Germany. [Schulze, Ryan J.] Mayo Clin, Dept Biochem, Rochester, MN USA. [Fiesel, Fabienne C.; Springer, Wolfdieter] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Lerman, Lilach O.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Sinicrope, Frank A.; Xu, Xiaolei] Mayo Clin, Rochester, MN USA. 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[Ichihara, Atsuhiro] Tokyo Womens Med Univ, Dept Endocrinol & Hypertens, Tokyo, Japan. [Guo, Chuanyong] Tongji Univ, Sch Med, Dept Gastroenterol, Shanghai Peoples Hosp 10, Shanghai 200092, Peoples R China. [Sun, Fang-Lin] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China. [Zacksenhaus, Eldad] Univ Hlth Network, Div Adv Diagnost, Toronto Gen Res Inst, Toronto, ON, Canada. [Higaki, Katsumi] Tottori Univ, Res Ctr Biosci & Technol, Yonago, Tottori, Japan. [Kalia, Manjula] Translat Hlth Sci & Technol Inst, Vaccine & Infect Dis Res Ctr, Faridabad, India. [Lum, Julian J.] Trev & Joyce Deeley Res Ctr, Victoria, BC, Canada. [Lum, Julian J.] Univ Victoria, BC Canc Agcy, Victoria, BC, Canada. [Lum, Julian J.] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC, Canada. [Martin, Seamus J.] Trinity Coll Dublin, Dept Genet, Smurfit Inst, Dublin, Ireland. [Murray, James T.] Trinity Coll Dublin, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin, Ireland. [Campbell, Matthew] Trinity Coll Dublin, Smurfit Inst Genet, Dublin, Ireland. [Chen, Ye-Guang; Liu, Yule; Wang, Yan] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. [Yu, Li] Tsinghua Univ, State Key Lab Biomembrane & Membrane Biotechnol, Tsing Hua Univ, Peking Univ,Joint Ctr Life Sci,Sch Life Sci, Beijing 100084, Peoples R China. [Lei, Jinzhi] Tsinghua Univ, Zhou Pei Yuan Ctr Appl Math, Beijing 100084, Peoples R China. [Taylor, Allen] Tufts Univ, USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Dash, Srikanta] Tulane Univ, Hlth Sci Ctr, Dept Pathol & Lab Med, New Orleans, LA 70118 USA. [Simak, Jan] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Rao, V. Ashutosh] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Galadari, Sehamuddin] UAE Univ, Cell Signaling Lab, Dept Biochem, Coll Med & Hlth Sci, Abu Dhabi, U Arab Emirates. [Bjedov, Ivana] UCL Canc Inst, London, England. [Salomoni, Paolo] UCL Canc Inst, Samantha Dickson Brain Canc Unit, London, England. [Jacques, Thomas S.] UCL Inst Child Hlth, London, England. [Jacques, Thomas S.] Great Ormond St Hosp Children NHS Fdn Trust, London, England. [Lewis, Patrick A.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Manzoni, Claudia] UCL Inst Neurol, London, England. [Cheetham, Michael E.] UCL Inst Ophthalmol, London, England. [Guo, Ming] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. [Linden, Rafael] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Rio de Janeiro, Brazil. [Simmet, Thomas] Univ Ulm, Inst Pharmacol Nat Cpds & Clin Pharmacol, D-89069 Ulm, Germany. [Carlsson, Sven R.] Umea Univ, Dept Med Biochem & Biophys, Umea, Sweden. [Kaeffer, Bertrand] UMR 1280, Nantes, France. [Manie, Serge N.] CNRS, INSERM 1052, UMR 5286, Canc Res Ctr Lyon, Lyon, France. [Maiuri, Maria Chiara] Ctr Rech Cordeliers, UMRS 1138, Paris, France. [Gorbunov, Nikolai V.] Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. [Kiang, Juliann G.] Uniformed Serv Univ Hlth Sci, Radiat Combined Injury Program, Armed Forces Radiobiol Res Inst, Bethesda, MD 20814 USA. [Ozpolat, Bulent; Scovassi, A. Ivana; Stellrecht, Christine M.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Gonzalez, Carlos B.] Univ Austral Chile, Dept Physiol, Valdivia, Chile. [Diaz-Nido, Javier] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, CIBERER, Madrid, Spain. [Gargini, Ricardo] Univ Autonoma Madrid, CNB CSIC, Ctr Biol Mol Severo Ochoa, Dept Biol Mol, Madrid, Spain. [Cuezva, Jose M.] Univ Autonoma Madrid, Dept Biol Mol, Madrid, Spain. [Magarinos, Marta] Univ Autonoma Madrid, Dept Biol, Madrid, Spain. [Guillen, Carlos] Univ Complutense, Sch Pharm, E-28040 Madrid, Spain. [Guillen, Carlos] Inst Salud Carlos III, CIBER Diabet & Enfermedades Metab Olicas Asociada, Madrid, Spain. [Papademetrio, Daniela L.] Univ Buenos Aires, Inmunol, Fac Farm & Bioquim, Buenos Aires, DF, Argentina. [Cena, Valentin] Univ Castilla La Mancha, Albacete, Spain. [Jordan, Joaquin] Univ Castilla La Mancha, Fac Med, Dept Ciencias Med, Albacete, Spain. [Sanchez-Prieto, Ricardo] Univ Castilla La Mancha, Lab Oncol Mol, Ctr Reg Invest Biomed, Albacete, Spain. [Troncoso, Rodrigo] Univ Chile, Adv Ctr Chron Dis ACCDiS, Fac Ciencias Quim & Farmaceut, Santiago, Chile. [Chiong, Mario; Criollo, Alfredo; Lavandero, Sergio] Univ Chile, Adv Ctr Chron Dis ACCDiS, Santiago, Chile. [Diaz-Araya, Guillermo] Univ Chile, Fac Ciencias Quim & Farmaceut, Santiago, Chile. [Glavic, Alvaro] Univ Chile, Fac Ciencias, Dept Biol, Ctr Regulac Genoma, Santiago, Chile. [Troncoso, Rodrigo] Univ Chile, INTA, Santiago, Chile. [Corral-Ramos, Cristina; Di Pietro, Antonio; Roncero, M. Isabel G.; Ruiz-Roldan, Carmen] Univ Cordoba, Campus Excelencia Agroalimentario CeiA3, Dept Genet, Cordoba, Spain. [Mora-Rodriguez, Rodrigo] Univ Costa Rica, CIET, San Jose, Costa Rica. [Fuentes, Jose M.; Gomez-Sanchez, Ruben; Ana Gonzalez-Polo, Rosa; Niso-Santano, Mireia] Univ Extremadura, CIBERNED, Dept Bioquim & Biol Mol & Genent, Fac Enfermeria & Terapia Ocupac, Caceres, Spain. [Fernandez-Lopez, Arsenio; Perez-Rodriguez, Diego] Univ Leon, Area Biol Celular, Inst Biomed, E-24071 Leon, Spain. [Fernandez-Barrena, Maite G.] Univ Navarra, Ctr Invest Med Aplicada, E-31080 Pamplona, Spain. [Albaiceta, Guillermo M.] Univ Oviedo, Dept Biol Func, Oviedo, Spain. [Fernandez, Alvaro F.; Lopez-Otin, Carlos] Univ Oviedo, Inst Univ Oncol, Dept Bioquim & Biol Mol, Oviedo, Spain. [Jimenez, Alberto] Univ Salamanca, Dept Microbiol & Genet, Campus Miguel Unamuno, E-37008 Salamanca, Spain. [Boada-Romero, Emilio; Pimentel-Muinos, Felipe X.] Univ Salamanca, IBMCC, Ctr Invest Canc, Campus Unamuno, Salamanca, Spain. [Miranda-Vizuete, Antonio] Univ Seville, Inst Biomed Sevilla, Hosp Univ Virgen Rocio, Consejo Super Invest Cient, Seville, Spain. [Ruano, Diego] Univ Seville, Inst Biomed Sevilla, Seville, Spain. [Crespo, Jose L.; Esther Perez-Perez, Maria] Univ Seville, CSIC, Inst Bioquim Vegetal & Fotosintesis, Seville, Spain. [Couve, Eduardo] Univ Valparaiso, Inst Biol, Fac Ciencias, Valparaiso, Chile. [Pardo, Julian] Univ Zaragoza Araid, IIS Aragon, Ctr Invest Biomed Aragon, Zaragoza, Spain. [Filippi-Chiela, Eduardo C.; Lenz, Guido; Thome, Marcos P.] Univ Fed Rio Grande do Sul, Dept Biophys, Porto Alegre, RS, Brazil. [Filippi-Chiela, Eduardo C.; Lenz, Guido; Thome, Marcos P.] Ctr Biotechnol, Porto Alegre, RS, Brazil. [Silvia Romano, Patricia] Univ Nacl Cuyo FCM UNCUYO, Inst Histol & Embriol IHEM CONICET, Fac Ciencias Med, Mendoza, Argentina. [Sanchez-Alcazar, Jose A.] Univ Pablo Olavide, CABD, Consejo Super Invest Cient Junta Andalucia, Seville, Spain. [Weis, Simone Nardin] Univ Brasilia, Dept Biol Celular, Brasilia, DF, Brazil. [Rodrigues, Cecilia M. P.] Univ Lisbon, Res Inst Med iMed ULisboa, Fac Pharm, Lisbon, Portugal. [Botana, Luis M.] Univ Santiago Compostela, Dept Farmacol, Fac Vet, Lugo, Spain. [Goldman, Gustavo H.] Univ Sao Paulo, FCFRP, USP, Sao Paulo, Brazil. [Hernandez, Agustin] Univ Sao Paulo, Dept Parasitol, Inst Ciencias Biomed, Sao Paulo, Brazil. [Brito, Glauber C.] Univ Sao Paulo, Inst Canc Estado Sao Paulo, Fac Med, Sao Paulo, SP, Brazil. [Tenorio de Melo, Edesio Jose] Univ Estadual Norte Fluminense, Ctr Biociencias Biotecnol, Lab Biol Celular & Tecidual, Setor Toxicol Celular, Campos Goytacazes, Rio De Janeiro, Brazil. [Rizzo, Elizete] Univ Fed Minas Gerais, Dept Morfol, Inst Ciencias Biol, Belo Horizonte, MG, Brazil. [Bincoletto, Claudia] Univ Fed Sao Paulo UNIFESP, Dept Farmacol, Escola Paulista Med, Sao Paulo, SP, Brazil. [Vieira, Helena L. A.] Univ Nova Lisboa, CEDOC, NOVA Med Sch, Lisbon, Portugal. [Revuelta, Jose L.] Univ Salamanca, Dept Microbiol & Genet, Campus Miguel Unamuno, E-37008 Salamanca, Spain. [Poletti, Angelo; Rusmini, Paola] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy. [Carra, Serena] Univ Modena & Reggio Emilia, Dipartimento Sci Biomed Metab & Neurosci, Modena, Italy. [Follo, Carlo; Isidoro, Ciro] Univ Piemonte Orientale, Dipartimento Sci Salute, Novara, Italy. [Genazzani, Armando A.] Univ Piemonte Orientale, Novara, Italy. [Matarese, Giuseppe] Univ Salerno, Dipartimento Med & Chirurg, I-84100 Salerno, Italy. [Rippo, Maria Rita] Univ Politecn Marche, Dept Clin & Mol Sci, Ancona, Italy. [Cenci, Simone; Milan, Enrico] Univ Vita Salute San Raffaele, Milan, Italy. [Casas, Caty] Univ Autonoma Barcelona, Dept Cell Biol Physiol & Immunol, Inst Neurociencies, E-08193 Barcelona, Spain. [Ventura, Salvador] Autonomous Univ Barcelona, Inst Biotecnol & Biomed, Bellaterra, Barcelona, Spain. [Ventura, Salvador] Dept Bioquim & Biol Mol, Bellaterra, Barcelona, Spain. [Zorzano, Antonio] Univ Barcelona, Dept Bioquim & Biol Mol, Fac Biol, Barcelona, Spain. [Luis Rosa, Jose] Univ Barcelona, Hosp Llobregat, Dept Ciencies Fisiol Giques 2, Inst Invest Biomed Bellvitge IDI BELL, Campus Bellvitge, Barcelona, Spain. [Segui-Simarro, Jose M.] Univ Politecn Valencia, COMAV Inst, E-46022 Valencia, Spain. [Reichert, Andreas S.] Univ Klinikum Dusseldorf, Inst Biochem & Mol Biol 1, Dusseldorf, Germany. [Bouchecareilh, Marion; Priault, Muriel] Univ Bordeaux Segalen, Inst Biochim & Genet Cellulaires, CNRS, UMR 5095, Bordeaux, France. [Pasquet, Jean-Max] Univ Bordeaux Segalen, INSERM U1035, Hematopoiese Leucem & Cibles Therapeut, Bordeaux, France. [Duvezin-Caubet, Stephane] Univ Bordeaux, Inst Biochim & Genet Cellulaires, CNRS, UMR 5095, Bordeaux, France. [Lapaquette, Pierre] Univ Bourgogne Franche Comte, Agrosup Dijon, UMR PAM, Equipe Vin Aliment Microbiol, Dijon, France. [Feron, Olivier] Catholic Univ Louvain, IREC, B-1200 Brussels, Belgium. [Batoko, Henri] Catholic Univ Louvain, Inst Sci Vie, Louvain La Neuve, Belgium. [Deldicque, Louise] Catholic Univ Louvain, Inst Neurosci, Louvain La Neuve, Belgium. [Gailly, Philippe] Catholic Univ Louvain, Lab Cell Physiol, B-1200 Brussels, Belgium. [Bruhat, Alain] Univ Clermont 1, UFR Med, Nutr Humaine UMR1019, Clermont Ferrand, France. [Dalmasso, Guillaume; Darfeuille-Michaud, Arlette; Nguyen, Hang T. T.] Univ Auvergne, M2iSH, INSERM UMR 1071, Ctr Biomed Rech & Valorisat,Fac Med, Clermont Ferrand, France. [Djavaheri-Mergny, Mojgan] Univ Bordeaux, INSERM U916, Inst Bergonie, Bordeaux, France. [Dehay, Benjamin] Univ Bordeaux, Inst Malad Neurodegenerat, CNRS UMR 5293, Bordeaux, France. [Camougrand, Nadine] Univ Bordeaux, CNRS, Inst Biochim & Genet Cellulaires, UMR 5095, Bordeaux, France. [Delage-Mourroux, Regis] Univ Franche Comte, UFR Sci & Tech EA3922, SFR IBCT FED 4234, Estrogenes Express Genique & Pathol Syst Nerveux, Besancon, France. [Boyer-Guittaut, Michaeel] Univ Franche Comte, UFR Sci & Tech, Lab Biochim, Besancon, France. [Verdier, Mireille] Univ Limoges, EA 3842, LHCP, Fac Med, Limoges, France. [Kretz-Remy, Carole] Univ Lyon, Lyon, France. [Kretz-Remy, Carole] Univ Lyon 1, Ctr Genet & Physiol Mol & Cellulaire, F-69622 Villeurbanne, France. [Freyssenet, Damien G.] Univ Lyon, Fac Med, Saint Etienne, France. [Faure, Mathias] Univ Lyon, INSERM, CIRI, Ecole Normale Super Lyon,CNRS,UMR 5308,U 111, Lyon, France. [Mollereau, Bertrand] Univ Lyon, CNRS UMR 5239, Mol Cell Biol Lab, Ecole Normale Super Lyon, Lyon, France. [Besteiro, Sebastien] Univ Montpellier, DIMNP, CNRS, UMR 5235, F-34059 Montpellier, France. [Pattingre, Sophie] Univ Montpellier, Inst Reg Canc Montpellier, INSERM, U 1194, F-34059 Montpellier, France. [Favier, Francois B.] Univ Montpellier, F-34059 Montpellier, France. [Bernard, Monique; Hebert, Marie-Josee] Univ Montreal, Dept Med, Montreal, PQ, Canada. [Pacelli, Consiglia] Univ Montreal, Dept Pharmacol, Fac Med, Montreal, PQ H3C 3J7, Canada. [Burelle, Yan] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada. [Knaevelsrud, Helene] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. [Vallette, Francois] Univ Nantes, CRCNA, UMRINSERM 892, CNRS 6299, Nantes, France. [Chevet, Eric] Univ Rennes 1, OSS, ERL INSERM 440, Ctr Lutte Canc Eugene Marquis, Rennes, France. [Beaulieu, Jean-Francois; Jean, Steve] Univ Sherbrooke, Dept Anat & Cell Biol, Fac Med & Hlth Sci, Sherbrooke, PQ J1K 2R1, Canada. [Dupuis, Luc] Univ Strasbourg, Fac Med, UMRS 1118, Strasbourg, France. [Gros, Frederic] Univ Strasbourg, CNRS UPR3572, Immunopathol & Chim Therapeut, IBMC, Strasbourg, France. [Barbeau, Benoit] Univ Quebec, Dept Sci Biol, Montreal, PQ H3C 3P8, Canada. [Barbeau, Benoit] Ctr Rech BioMed, Montreal, PQ, Canada. [Taillebourg, Emmanuel] Univ Grenoble Alpes, CEA DSV iRTSV BGE GenandChem, INSERM, U1038, Grenoble, France. [Francois, Arnaud] Univ Laval, Neurosci Axis, Quebec City, PQ, Canada. [Cnop, Miriam] Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium. [Palladino, Francesca] Univ Lyon, Ecole Normale Super Lyon, Lyon, France. [Baghdiguian, Stephen] Univ Montpellier 2, Inst Sci Evolut, CNRS, UMR 5554, Montpellier, Languedoc Rouss, France. [Pierrefite-Carle, Valerie] Univ Nice Sophia Antipolis, UMR MATOs CEA iBEB E 4320TIRO, Fac Med, Nice, France. [Kroemer, Guido] Univ Paris 05, Apoptosis Canc & Immun Lab, Team 11, Equipe Labellisee Ligue Canc & Cell Biol & Met Pl, Paris, France. [Tamburini, Jerome] Univ Paris 05, Inst Cochin, Sorbonne Paris Cite, Fac Med, Paris, France. [Pende, Mario] Univ Paris 05, Inst Necker Enfants Malades, INSERM, U1151, Paris, France. [Rautou, Pierre-Emmanuel] Univ Paris 05, Paris, France. [Bravo-San Pedro, Jose M.; Galluzzi, Lorenzo; Izzo, Valentina; Pietrocola, Federico; Sica, Valentina] Univ Paris Descartes Paris V, Paris, France. [Botti, Joelle; Codogno, Patrice; Dupont, Nicolas; Hamai, Ahmed; Mehrpour, Maryam; Morel, Etienne; Nascimbeni, Anna Chiara; Orhon, Idil] Univ Paris 05, Sorbonne Paris Cite, INEM, INSERM U1151,CNRS UMR 5253, Paris, France. [Ait-Si-Ali, Slimane] Univ Paris 05, Sorbonne Paris Cite, Ctr Epigenet & Destin Cellulaire, CNRS,UMR 7216, Paris, France. [Le Stunff, Herve] Univ Paris 05, Unite Biol Fonctionnelle & Adaptat, CNRS UMR 8251, Paris, France. [Bianchi, Michele Wolfe] Univ Paris Est Creteil, Creteil, France. [Teixeira-Clerc, Fatima] Univ Paris Est, Inst Mondor Rech Biomed, Paris, France. [Le Stunff, Herve; Legouis, Renaud] Univ Paris Sud, CEA, CNRS, Inst Integrat Biol Cell, Gif Sur Yvette, France. [Bianchi, Michele Wolfe] Univ Paris Sud, CEA, CNRS, Paris, France. [Deutsch, Eric] Univ Paris Sud, INSERM 1030, Gustave Roussy Canc Campus, Paris, France. [Dokudovskaya, Svetlana] Univ Paris Sud, Inst Gustave Roussy, CNRS UMR 8126, Villejuif, France. [Wiels, Joelle] Univ Paris Sud, Univ Paris Saclay, CNRS UMR 8126, Inst Gustave Roussy, Villejuif, France. [Tan, Mei Lan] Univ Sains Malaysia, Adv Med & Dent Inst, Minist Sci Technol & Innovat, George Town, Malaysia. [D'Orazi, Gabriella] Univ G dAnnunzio, Dept Med Oral & Biotechnol Sci, Chieti, Italy. [Corasaniti, Maria Tiziana] Magna Graecia Univ Catanzaro, Dept Hlth Sci, Catanzaro, Italy. [Isakovic, Aleksandra J.] Univ Belgrade, Sch Med, Belgrade, Serbia. [Lizard, Gerard] Univ Bourgogne Franche Comte, EA 7270, INSERM, Dijon, France. [Fortunato, Franco] Univ Clin Heidelberg, Dept Expt Surg, Heidelberg, Germany. [Rami, Abdelhaq] Univ Clin, Inst Cellular & Mol Anat Anat 3, Frankfurt, Germany. [McKenna, Sharon; O'Donovan, Tracey] Natl Univ Ireland Univ Coll Cork, BioSci Inst Co, Cork Canc Res Ctr, Cork, Ireland. [Waeber, Christian] Natl Univ Ireland Univ Coll Cork, Sch Pharm, Dept Pharmacol & Therapeut, Cork, Ireland. [Al-Rubeai, Mohamed] Univ Coll Dublin, Sch Chem & Bioproc Engn, Dublin 2, Ireland. [Alvarez-Erviti, Lydia; Cooper, J. Mark] UCL, Dept Clin Neurosci, London, England. [Ketteler, Robin; Kriston-Vizi, Janos; Prak, Krisna] UCL, MRC Lab Mol Cell Biol, London, England. [Duchen, Michael R.] UCL, UCL Consortium Mitochondrial Res, London, England. [Duchen, Michael R.] Dept Cell & Dev Biol, London, England. [Clementi, Emilio] Univ Milan, Univ Hosp Luigi Sacco, Clin Pharmacol Unit, Natl Res Council,Inst Neurosci,Dept Biomed & Clin, Milan, Italy. [Strnad, Pavel] Univ Hosp Aachen, IZKF, Aachen, Germany. [Strnad, Pavel] Dept Internal Med III, Aachen, Germany. [Puyal, Julien; Truttmann, Anita C.] Univ Lausanne, Univ Hosp Ctr, Clin Neonatol, Dept Pediat & Pediat Surg, Lausanne, Switzerland. [Bergami, Matteo] Univ Hosp Cologne, CECAD Res Ctr, Cologne, Germany. [Klucken, Jochen; Minakaki, Georgia] Univ Erlangen Nurnberg, Univ Hosp Erlangen, D-91054 Erlangen, Germany. [Hasselblatt, Peter] Univ Hosp Freiburg, Dept Med 2, Freiburg, Germany. [Dahmen, Uta] Univ Hosp Jena, Dept Gen Visceral & Vasc Surg, Expt Transplantat Surg, Jena, Germany. [Bou, German] Univ Hosp La Coruna, Dept Microbiol, La Coruna, Spain. [Pavenstaedt, Hermann] Univ Hosp Muenster, Internal Med D, Dept Nephrol Hypertens & Rheumatol, Albert Schweitzer Campus, Munster, Germany. [Patschan, Daniel] Univ Hosp Gottingen, Dept Nephrol & Rheumatol, Gottingen, Germany. [Duchosal, Michel A.] Univ Hosp Lausanne, Serv & Cent Lab Hematol, Lausanne, Switzerland. [Weide, Thomas] Univ Hosp Muenster, Dept Internal Med D, Mol Nephrol, Munster, Germany. [Schneider, E. Marion] Univ Hosp Ulm, Sekt Expt Anaestesiol, Ulm, Germany. [Scharl, Michael] Univ Hosp Zurich, Div Gastroenterol & Hepatolog, Zurich, Switzerland. [Decuypere, Jean-Paul] Univ Hosp Leuven, Dept Microbiol & Immunol, Lab Abdominal Transplantat, Leuven, Belgium. [Vandenberghe, Wim] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium. [Martinez, Jennifer] Natl Inst Environm Hlth Sci, Immun Inflammat & Dis Lab, Res Triangle Pk, NC USA. [Duez, Helene; Lancel, Steve] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,U1011,EGID, Lille, France. [Huber, Tobias B.] Univ Med Ctr Freiburg, Freiburg, Germany. [Vellenga, Edo] Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands. [Galliciotti, Giovanna] Univ Hamburg, Med Ctr, Inst Neuropathol, Hamburg, Germany. [Behl, Christian] Johannes Gutenberg Univ Mainz, Med Ctr, Inst Pathobiochemi, D-55122 Mainz, Germany. [Mari, Muriel; Reggiori, Fulvio] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands. [Schmidt, Jens] Univ Gottingen, Med Ctr, Clin Neurol, D-37073 Gottingen, Germany. [Schmidt, Jens] Dept Neuroimmunol, Gottingen, Germany. [Outeiro, Tiago F.] Univ Gottingen, Med Ctr, Dept Neurodegenerat & Restorat Res, D-37073 Gottingen, Germany. [Boes, Marianne] Univ Utrecht, Med Ctr, Lab Translat Immunol, Utrecht, Netherlands. [Boes, Marianne] Univ Hosp Children & Youth, Dept Pediat Immunol, Utrecht, Netherlands. [Koch, Jan C.] Univ Med Gottingen, Dept Neurol, Gottingen, Germany. [Wang, Jing] Univ Montpellier I, INSERM U1051, Montpellier, France. [Vidal, Michel] Univ Montpellier, UMR5235, F-34059 Montpellier, France. [Coxon, Fraser P.] Univ Aberdeen, Div Appl Med, Aberdeen, Scotland. [Ganesan, Swamynathan] Univ Adelaide, Alzheimers Dis Genet Lab, Adelaide, SA, Australia. [Richards, Robert I.] Univ Adelaide, Dept Genet & Evolut, Sch Biol Sci, Adelaide, SA, Australia. [Ramanadham, Sasanka] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol CDIB, Comprehens Diabet Ctr UCDC, Birmingham, AL USA. [Xu, Zhi-Xiang] Univ Alabama Birmingham, Dept Med, Div Hematol & Oncol, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Roth, Kevin A.; Shacka, John J.; Zhang, Jianhua] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Darley-Usmar, Victor M.] Univ Alabama Birmingham, Dept Pathol, Ctr Free Radical Biol, Birmingham, AL 35294 USA. [Chatham, John C.] Univ Alabama Birmingham, Div Mol & Cellular Pathol, Dept Pathol, Birmingham, AL USA. [Kim, Yonghyun] Univ Alabama, Dept Chem & Biol Engn, Tuscaloosa, AL USA. [Goping, Ing Swie] Univ Alberta, Dept Biochem, Edmonton, AB, Canada. [Diaz-Laviada, Ines] Univ Alcala De Henares, Dept Syst Biol, Biochem & Mol Biol Unit, Sch Med, Madrid, Spain. [Medema, Jan Paul] Univ Amsterdam, Acad Med Ctr, Lab Expt Oncol & Radiobiol, Meibergdreef 9, NL-1105 AZ Amsterdam, North Holland, Netherlands. [Juenemann, Katrin] Univ Amsterdam, Acad Med Ctr, Dept Cellbiol & Histol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Meijer, Alfred J.] Univ Amsterdam, Acad Med Ctr, Dept Med Biochem, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Berkhout, Ben] Univ Amsterdam, Acad Med Ctr, Lab Expt Virol, Ctr Infect & Immun Amsterdam CINIMA, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Norga, Koenraad K.] Univ Antwerp, Dept Paediat Oncol, B-2020 Antwerp, Belgium. [De Meyer, Guido R. Y.; Martinet, Wim] Univ Antwerp, Lab Physiopharmacol, B-2020 Antwerp, Belgium. [Landowski, Terry H.] Univ Arizona, Ctr Canc, Dept Med, Tucson, AZ USA. [Kruer, Michael C.] Univ Arizona, Coll Med, Barrow Neurol Inst, Phoenix Childrens Hosp,Dept Child Hlth, Phoenix, AZ USA. [Riehle, Michael A.] Univ Arizona, Dept Entomol, Tucson, AZ USA. [Chen, Yin; Klimecki, Walter T.; Zhang, Donna D.] Univ Arizona, Dept Pharmacol & Toxicol, Coll Pharm, Tucson, AZ 85721 USA. [Ding, Zufeng; Mehta, Jawahar L.] Univ Arkansas Med Sci, Dept Cardiol, Little Rock, AR 72205 USA. [Voth, Daniel E.] Univ Arkansas Med Sci, Dept Microbiol & Immunol, Little Rock, AR 72205 USA. [MacMillan-Crow, Lee Ann; Parajuli, Nirmala] Univ Arkansas Med Sci, Dept Pharmacol Toxicol, Little Rock, AR 72205 USA. [Dridi, Sami] Univ Arkansas, Ctr Excellence Poultry Sci, Fayetteville, AR 72701 USA. [Konstantakou, Eumorphia G.; Stravopodis, Dimitrios J.; Trougakos, Ioannis P.; Velentzas, Athanassios D.] Univ Athens, Dept Cell Biol & Biophys, Fac Biol, Athens, Greece. [Mpakou, Vassiliki E.] Univ Athens, Sch Med, Dept Internal Med 2, Athens, Greece. [Mpakou, Vassiliki E.] Attikon Univ, Gen Hosp, Res Inst, Athens, Greece. [Kampinga, Harm H.] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands. [Pierre, Philippe] Univ Aveiro, Inst Res Biomed iBiMED, Aveiro Hlth Sci Program, Aveiro, Portugal. [Neves, Bruno M.] Univ Aveiro QOPNA, Dept Chem, Aveiro, Portugal. [Claria, Joan; Lopez-Vicario, Cristina] Univ Barcelona, Dept Biochem & Mol Genet, Hosp Clin, IDIBAPS CIBERehd, Barcelona, Spain. [Ambrosio, Santiago] Univ Barcelona, Sch Med, Campus Bellvitge, Lhospitalet De Llobregat, Spain. [Cocco, Tiziana] Univ Bari Aldo Moro, Dept Basic Med Sci Neurosci & Organs Senses, Bari, Italy. [Tucci, Marco] Univ Bari Aldo Moro, Dept Biomed Sci & Clin Oncol, Bari, Italy. [Simone, Cristiano] Univ Bari Aldo Moro, Div Med Genet, DIMO, Sch Med, Bari, Italy. [Castets, Perrine; Ruegg, Markus A.; Spang, Anne] Univ Basel, Biozentrum, Basel, BS, Switzerland. [Boeckler, Stefan; Westermann, Benedikt] Univ Bayreuth, Cell Biol, Bayreuth, Germany. [Steegborn, Clemens] Univ Bayreuth, Dept Biochem, Bayreuth, Germany. [Harhaji-Trajkovic, Ljubica] Univ Belgrade, Inst Biol Res Sinisa Stankov, Belgrade, Serbia. [Kravic-Stevovic, Tamara] Univ Belgrade, Inst Histol & Embryol, Sch Med, Belgrade, Serbia. [Markovic, Ivanka] Univ Belgrade, Inst Med & Clin Biochem, Fac Med, Belgrade, Serbia. [Trajkovic, Vladimir] Univ Belgrade, Sch Med, Belgrade, Serbia. [Bumbasirevic, Vladimir] Univ Belgrade, Sch Med, Inst Histol & Embryol, Belgrade, Serbia. [Tschan, Mario P.] Univ Bern, Div Expt Pathol, Inst Pathol, Bern, Switzerland. [Arcaro, Alexandre] Univ Bern, Div Pediat Hematol Oncol, Dept Clin Res, Bern, Switzerland. [Buetikofer, Peter] Univ Bern, Inst Biochem & Mol Med, Bern, Switzerland. [Simon, Hans-Uwe] Univ Bern, Inst Pharmacol, Bern, Switzerland. [Sarkar, Sovan; Ward, Carl] Univ Birmingham, Inst Biomed Res, Inst Canc & Genom Sci, Coll Med & Dent Sci, Birmingham, W Midlands, England. [Taylor, Graham S.] Univ Birmingham, Inst Immunol & Immunotherapy, Birmingham, W Midlands, England. [Martelli, Alberto M.] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy. [Cetrullo, Silvia; Flamigni, Flavio] Univ Bologna, Dipartimento Sci Biomed & Neuromotorie, Bologna, Italy. [Walter, Jochen] Univ Bonn, Dept Neurol, Bonn, Germany. [Haas, Albert; Hoehfeld, Joerg] Univ Bonn, Inst Cell Biol, Bonn, Germany. [Till, Andreas] Univ Bonn, Inst Reconstruct Neurobiol, Bonn, Germany. [Fanzani, Alessandro] Univ Brescia, Dept Mol & Translat Med, Brescia, Italy. [Lane, Jon D.] Univ Bristol, Sch Biochem, Bristol, Avon, England. [Greenhough, Alexander] Univ Bristol, Sch Cellular & Mol Med, Bristol, Avon, England. [Roberge, Michel; Yip, Calvin K.] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V5Z 1M9, Canada. [Johnson, James D.; Nabi, Ivan R.] Univ British Columbia, Dept Cellular & Physiol Sci, Vancouver, BC V5Z 1M9, Canada. [Wang, Yu Tian] Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada. [Wang, Yu Tian] Brain Res Ctr, Vancouver, BC, Canada. [Luo, Honglin] Univ British Columbia, Dept Pathol & Lab Med, James Hogg Res Ctr, Vancouver, BC V5Z 1M9, Canada. [Shi, Junyan] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Toker, Lilach] Univ British Columbia, Dept Psychiat, Vancouver, BC V5Z 1M9, Canada. [Gleave, Martin] Univ British Columbia, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada. [Jiang, Xiaoyan] Univ British Columbia, Med Genet & BC Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1M9, Canada. [Piret, James M.] Univ British Columbia, Michael Smith Labs, Dept Chem & Biol Engn, Vancouver, BC V5Z 1M9, Canada. [Turner, Robin F. B.] Univ British Columbia, Michael Smith Labs, Vancouver, BC V5Z 1M9, Canada. [Blanco, Guillermo A.] Univ Buenos Aires, IDEHU CONICET, Fac Pharm & Biochem, Buenos Aires, DF, Argentina. [Alvarez, Silvia] Univ Buenos Aires, Inst Biochem & Biophys, Sch Pharm & Biochem, Buenos Aires, DF, Argentina. [Vaccaro, Maria I.] Univ Buenos Aires, Natl Council Sci & Tech Res CONICET, Inst Biochem & Mol Med, Dept Pathophysiol,Sch Pharm & Biochem, Buenos Aires, DF, Argentina. [Perrotta, Ida] Univ Calabria, Dept Biol Ecol & Earth Sci, Lab Electron Microscopy, I-87036 Cosenza, Italy. [Aquila, Saveria] Univ Calabria, Dept Pharm Hlth & Nutrit Sci, I-87036 Cosenza, Italy. [Russo, Rossella] Univ Calabria, Dept Pharm Hlth & Nutrit Sci, Sect Preclin & Translat Pharmacol, I-87036 Cosenza, Italy. [Chakrabarti, Gopal] Univ Calcutta, Dept Biotechnol, Dr BC Guha Ctr Genet Engn & Biotechnol, Kolkata, WB, India. [Zheng, Xi-Long] Univ Calgary, Dept Biochem & Mol Biol, Libin Cardiovasc Inst Alberta, Calgary, AB, Canada. [Schatzl, Hermann M.] Univ Calgary, Fac Vet Med, Calgary, AB, Canada. [Hurley, James H.; Thorner, Jeremy] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Ge, Liang; Schekman, Randy] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Kung, Hsing-Jien] Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA. [Luckhart, Shirley; Pakpour, Nazzy] Univ Calif Davis, Dept Med Microbiol & Immunol, Sch Med, Davis, CA 95616 USA. [Powers, Ted] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. [Gomes, Aldrin V.] Univ Calif Davis, Dept Neurobiol Physiol & Behav, Davis, CA 95616 USA. [Dinesh-Kumar, Savithrama P.] Univ Calif Davis, Dept Plant Biol, Davis, CA 95616 USA. [Dinesh-Kumar, Savithrama P.] Coll Biol Sci, Genome Ctr, Davis, CA USA. [van Doorn, Wouter G.] Univ Calif Davis, Mann Lab, Dept Plant Sci, Davis, CA 95616 USA. [Edinger, Aimee L.] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92717 USA. [Chen, Jeff W.] Univ Calif Irvine, Dept Neurosurg, Irvine, CA USA. [Steffan, Joan] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Ganesan, Anand K.] Univ Calif Irvine, Irvine, CA USA. [Xia, Tian] Univ Calif Los Angeles, Dept Med, Los Angeles, CA USA. [Costes, Safia] Univ Calif Los Angeles, David Geffen Sch Med, Larry Hillblom Islet Res Ctr, Los Angeles, CA 90095 USA. [Le Roch, Karine G.] Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. [Steele, John W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Lee, Jongdae; Satriano, Joseph] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Sigurdson, Christina J.] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Spector, Stephen A.] Univ Calif San Diego, Dept Pediat Div Infect Dis, La Jolla, CA 92093 USA. [Campbell, Grant R.; Ordonez, Paulina] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Guan, Kun-Liang] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Guan, Kun-Liang] Moores Canc Ctr, La Jolla, CA USA. [Miyamoto, Shigeki] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [La Spada, Albert R.] Univ Calif San Diego, Dept Cellular & Mol Med, Div Biol Sci, Inst Genom Med, La Jolla, CA 92093 USA. [La Spada, Albert R.] Univ Calif San Diego, Dept Neurosci, Div Biol Sci, Inst Genom Med, La Jolla, CA 92093 USA. [La Spada, Albert R.] Univ Calif San Diego, Dept Pediat, Div Biol Sci, Inst Genom Med, La Jolla, CA 92093 USA. [Kiger, Amy A.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Liu, Jing-Jing; Nazarko, Taras Y.] Univ Calif San Diego, Div Biol Sci, Mol Biol Sect, La Jolla, CA 92093 USA. [Till, Andreas] Univ Calif San Diego, San Diego Ctr Syst Biol, La Jolla, CA 92093 USA. [Cohen, Ezra E. W.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Soontornniyomkij, Virawudh] Univ Calif San Diego, Sch Med, Dept Psychiat, La Jolla, CA 92093 USA. [Gustafsson, Asa B.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Cox, Jeffery S.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Aghi, Manish K.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [An, Zhenyi] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Hetz, Claudio; Matus, Soledad] FONDAP Ctr Gerosci Brain Hlth & Metab, Santiago, Chile. [Gestwicki, Jason E.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Sarwal, Minnie M.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Finkbeiner, Steven] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Finkbeiner, Steven] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. [Finkbeiner, Steven] Gladstone Inst Neurol Dis, San Francisco, CA USA. [Debnath, Jayanta; Margeta, Marta] Univ Calif San Francisco, Sch Med, Dept Pathol, San Francisco, CA 94143 USA. [Kajimura, Shingo] Univ Calif San Francisco, UCSF Diabet Ctr, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA. [Montell, Craig] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA. [Kaser, Arthur] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England. [Rubinsztein, David C.] Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 2QQ, England. [Floto, R. Andres] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Narita, Masashi] Univ Cambridge, Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Cambridge, England. [Miller-Fleming, Leonor] Univ Cambridge, Dept Biochem, Cambridge, England. [Renna, Maurizio] Univ Cambridge, Dept Med Genet, Cambridge Inst Med Res, Cambridge, England. [Randow, Felix] Univ Cambridge, Dept Med, Addenbrookes Hosp, Cambridge CB2 2QQ, England. [Beale, Rupert] Univ Cambridge, Dept Pathol, Div Virol, Tennis Court Rd, Cambridge CB2 1QP, England. [Amantini, Consuelo] Univ Camerino, Sch Biosci & Vet Med, I-62032 Camerino, Italy. [Nabissi, Massimo] Univ Camerino, Sch Pharm, I-62032 Camerino, Italy. [Santoni, Giorgio] Univ Camerino, Sch Pharm, Sect Expt Med, I-62032 Camerino, MC, Italy. [Ferreira-Halder, Carmen Verissima] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Campinas, SP, Brazil. [Dobson, Renwick C. J.] Univ Canterbury, Biomol Interact Ctr, Sch Biol Sci, Christchurch 1, New Zealand. [Prince, Sharon] Univ Cape Town, Dept Human Biol, ZA-7925 Cape Town, Western Provinc, South Africa. [Davids, Lester M.] Univ Cape Town, Redox Lab, Dept Human Biol, ZA-7925 Cape Town, South Africa. [Zervos, Antonis S.] Univ Cent Florida, Coll Med, Burnett Sch Biomed Sci, Orlando, FL 32816 USA. [He, Yu-Ying] Univ Chicago, Dept Med, Dermatol Sect, Chicago, IL 60637 USA. [Choi, Jayoung; Hwang, Seungmin] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Mastrianni, James A.] Univ Chicago, Pritzker Sch Med, Dept Neurol, Chicago, IL 60637 USA. [Macleod, Kay F.] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. [Corbalan, Ramon; Garcia Nannig, Lorena] Univ Chile, Adv Ctr Chron Dis ACCDiS, Div Cardiovasc Dis, Fac Med, Santiago, Chile. [Pedrozo, Zully] P Catholic Univ Chile, Adv Ctr Chron Dis ACCDiS, Fac Med, Santiago, Chile. [Matus, Soledad] Univ Chile, Biomed Neurosci Inst, Santiago, Chile. [Segura-Aguilar, Juan] Univ Chile, Fac Med, ICBM Mol & Clin Pharmacol, Santiago 7, Chile. [Hetz, Claudio] Univ Chile, Fac Med, Inst Biomed Sci, Ctr Mol Studies Cell,Program Cellular,Mol Biol &, Santiago 7, Chile. [Weaver, Timothy E.] Univ Cincinnati, Coll Med, Cincinnati Childrens Res Fdn, Cincinnati, OH USA. [Weaver, Timothy E.] Dept Pediat, Cincinnati, OH USA. [Czyzyk-Krzeska, Maria F.; Guan, Jun-Lin; Wang, Chenran] Dept Pediat, Coll Med, Dept Canc Biol, Cincinnati, OH USA. [Robbins, Jeffrey] Univ Cincinnati, Cincinnati Childrens Hosp, Cincinnati, OH USA. [Choubey, Divaker] Univ Cincinnati, Cincinnati, OH USA. [Moreira, Paula I.] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Moreira, Paula I.] Fac Med, Coimbra, Portugal. [Cruz, Maria Teresa; Liberal, Joana] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Cruz, Maria Teresa; Liberal, Joana] Fac Pharm, Coimbra, Portugal. [Vega-Naredo, Ignacio] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, Cantanhede, Portugal. [Batista, Maria Teresa] Univ Coimbra, Coimbra, Portugal. [Cardoso, Sandra Morais] Univ Coimbra, Fac Med, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Pereira, Paulo C.] Univ Coimbra, IBILI, Fac Med, Coimbra, Portugal. [Fabri, Mario] Univ Cologne, Dept Dermatol, D-50931 Cologne, Germany. [Hoppe, Thorsten] Univ Cologne, Inst Genet, CECAD Res Ctr, D-50931 Cologne, Germany. [Noegel, Angelika A.] Univ Cologne, Inst Biochem 1, Fac Med, Cologne, Germany. [Eichinger, Ludwig] Univ Cologne, Fac Med, Ctr Biochem, D-50931 Cologne, Germany. [Edelstein, Charles L.] Univ Colorado, Boulder, CO 80309 USA. [Weekes, Colin D.] Univ Colorado, Div Med Oncol, Dept Med, Aurora, CO USA. [Agarwal, Rajesh; Raina, Komal] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Aurora, CO USA. [Jani, Alkesh] Univ Colorado, Denver, CO USA. [Jani, Alkesh] Denver VAMC, Denver, CO USA. [Levy, Jean M. Mulcahy] Univ Colorado, Dept Pediat, Ctr Canc & Blood Disorders, Aurora, CO USA. [Parker, Roy] Univ Colorado, HHMI, Dept Chem & Biochem, Aurora, CO USA. [Pugazhenthi, Subbiah] Univ Colorado, Sch Med, Anschutz Med Campus, Aurora, CO USA. [Reusch, Jane E. B.] Univ Colorado, Sch Med, Aurora, CO USA. [Pyeon, Dohun] Univ Colorado, Sch Med, Dept Immunol & Microbiol, Aurora, CO USA. [Bayer, K. Ulrich; Morgan, Michael J.; Thorburn, Andrew] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO USA. [Beckham, J. David] Univ Colorado, Sch Med, Div Infect Dis, Aurora, CO USA. [Frankel, Lisa B.; Issazadeh-Navikas, Shohreh; Lund, Anders H.] Univ Copenhagen, BRIC, Copenhagen, Denmark. [Petersen, Morten] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. [Olsson, Stefan] Univ Copenhagen, Dept Plant & Environm Sci, Sect Genet & Microbiol, Copenhagen, Denmark. [Tavernarakis, Nektarios] Univ Crete, Dept Basic Sci, Fac Med, Iraklion, Greece. [Tavernarakis, Nektarios] Univ Crete, Inst Mol Biol & Biotechnol, Iraklion, Greece. [Chamilos, Georgios; Kyrmizi, Irene] Univ Crete, Sch Med, Dept Infect Dis, Iraklion, Greece. [Promponas, Vasilis J.] Univ Cyprus, Dept Biol Sci, Bioinformat Res Lab, CY-1678 Nicosia, Cyprus. [Fesus, Laszlo] Univ Debrecen, Debrecen, Hungary. [Lekli, Istvan] Univ Debrecen, Fac Pharm, Dept Pharmacol, Debrecen, Hungary. [van Golen, Kenneth L.] Univ Delaware, Dept Biol Sci, Newark, DE USA. [van Golen, Kenneth L.] Univ Delaware, Ctr Translat Canc Res, Newark, DE USA. [Rocha, Sonia] Univ Dundee, Ctr Gene Regulat & Express, Coll Life Sci, Dundee DD1 4HN, Scotland. [Ganley, Ian G.] Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Sch Life Sci, Dundee, Scotland. [Wileman, Tom] Univ E Anglia, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England. [Pesonen, Maija] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm Toxicol, Kuopio, Finland. [Kaarniranta, Kai] Univ Eastern Finland, Kuopio Univ Hosp, Dept Ophthalmol, Kuopio, Finland. [Digard, Paul] Univ Edinburgh, Easter Bush, Roslin Insitute, Edinburgh EH8 9YL, Midlothian, Scotland. [Gammoh, Noor] Univ Edinburgh, Edinburgh Canc Res Ctr, Edinburgh, Midlothian, Scotland. [Wilkinson, Simon] Univ Edinburgh, Edinburgh Canc Res UK Ctr, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Distler, Joerg H. W.] Univ Erlangen Nurnberg, Dept Internal Med 3, D-91054 Erlangen, Germany. [Moore, Michael N.] Univ Exeter, Sch Med, ECEHH, Truro, Cornwall, England. [Talbot, Nicholas J.] Univ Exeter, Sch Biosci, Exeter, Devon, England. [Pena, Fernando J.; Tapia, Jose A.] Univ Extremadura, Dept Med, Fac Vet Med, Caceres, Spain. [Neri, Luca M.; Pinton, Paolo] Univ Ferrara, Dept Morphol Surg & Expt Med, I-44100 Ferrara, Italy. [Papini, Alessio] Univ Florence, Dept Biol, Florence, Italy. [Dunn, William A., Jr.] Univ Florida, Coll Med, Dept Anat & Cell Biol, Gainesville, FL USA. [Notterpek, Lucia] Univ Florida, Coll Med, Dept Neurosci, Gainesville, FL USA. [Joseph, Anna-Maria] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Wohlgemuth, Stephanie E.] Univ Florida, Dept Anim Sci, IFAS Coll Agr & Life Sci, Gainesville, FL 32611 USA. [Adhihetty, Peter J.; Powers, Scott K.] Univ Florida, Dept Appl Physiol & Kinesiol, Gainesville, FL USA. [Maegawa, Gustavo] Univ Flo