FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Parra, GI Sosnovtsev, SV Abente, EJ Sandoval-Jaime, C Bok, K Dolan, MA Green, KY AF Parra, Gabriel I. Sosnovtsev, Stanislav V. Abente, Eugenio J. Sandoval-Jaime, Carlos Bok, Karin Dolan, Michael A. Green, Kim Y. TI Mapping and modeling of a strain-specific epitope in the Norwalk virus capsid inner shell SO VIROLOGY LA English DT Article DE Noroviruses; Epitope-tagging; Caliciviruses ID BLOOD GROUP ANTIGENS; PROTEIN INTERACTIONS; HOT-SPOTS; NOROVIRUS; VACCINE; GASTROENTERITIS; BINDING; INFECTION; ANTIBODY; SYSTEM AB Noroviruses are diverse positive-strand RNA viruses associated with acute gastroenteritis. Cross-reactive epitopes have been mapped primarily to conserved sequences in the capsid VP1 Shell (S) domain, and strain-specific epitopes to the highly variable Protruding (P) domain. In this work, we investigated a strain-specific linear epitope defined by MAb NV10 that was raised against prototype (Genogroup 1.1) strain Norwalk virus (NV). Using peptide scanning and mutagenesis, the epitope was mapped to amino acids 21-32 (LVPEVNASDPLA) of the NV S domain, and its specificity was verified by epitope transfer and reactivity with a recombinant MAb NV10 single-chain variable fragment (scFv). Comparative structural modeling of the NV10 strain-specific and the broadly cross-reactive TV20 epitopes identified two internal non-overlapping sites in the NV shell, corresponding to variable and conserved amino acid sequences among strains, respectively. The S domain, like the P domain, contains strain-specific epitopes that contribute to the antigenic diversity among the noroviruses. Published by Elsevier Inc. C1 [Parra, Gabriel I.; Sosnovtsev, Stanislav V.; Abente, Eugenio J.; Sandoval-Jaime, Carlos; Bok, Karin; Green, Kim Y.] NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 50 South Dr,Bldg 50,Room 6318, Bethesda, MD 20892 USA. [Dolan, Michael A.] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Green, KY (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 50 South Dr,Bldg 50,Room 6318, Bethesda, MD 20892 USA. EM kgreen@niaid.nih.gov OI Abente, Eugenio/0000-0002-3390-2786; Parra, Gabriel/0000-0002-1102-4740 FU Division of Intramural Research, NIAID, NIH, of the Department of Health and Human Services, U.S FX This research was funded by the Division of Intramural Research, NIAID, NIH, of the Department of Health and Human Services, U.S. NR 52 TC 0 Z9 0 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY PY 2016 VL 492 BP 232 EP 241 DI 10.1016/j.virol.2016.02.019 PG 10 WC Virology SC Virology GA DJ4WX UT WOS:000374209900026 PM 26971245 ER PT J AU Elliott, JC Stohl, M Wall, MM Keyes, KM Skodol, AE Eaton, NR Shmulewitz, D Goodwin, RD Grant, BF Hasin, DS AF Elliott, Jennifer C. Stohl, Malka Wall, Melanie M. Keyes, Katherine M. Skodol, Andrew E. Eaton, Nicholas R. Shmulewitz, Dvora Goodwin, Renee D. Grant, Bridget F. Hasin, Deborah S. TI Childhood maltreatment, personality disorders and 3-year persistence of adult alcohol and nicotine dependence in a national sample SO ADDICTION LA English DT Article DE Alcohol; child abuse; child neglect; childhood maltreatment; chronic; mediation; nicotine; persistence; personality disorders; substance dependence ID GENERAL-POPULATION SAMPLE; PSYCHIATRIC DIAGNOSTIC MODULES; SUBSTANCE USE DISORDERS; DRUG-USE DISORDERS; IV AUDADIS-IV; UNITED-STATES; EPIDEMIOLOGIC SURVEY; DSM-IV; INTERVENING VARIABLES; MENTAL-DISORDERS AB Background and AimsPersistent cases of alcohol and nicotine dependence are associated with considerable morbidity and mortality, and are predicted by childhood maltreatment and personality disorders. Our aim was to test whether personality disorders (individually or conjointly) mediate the relationship between childhood maltreatment and the persistence of dependence. DesignPersonality disorders, modeled dimensionally, were tested as mediators of the relationship between childhood maltreatment and the 3-year persistence of alcohol and nicotine dependence in participants in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) who had current alcohol and nicotine dependence in their baseline interview. Individual personality disorders were assessed in separate models. Then, those that were significant were examined jointly in multiple mediator models to determine their total and unique effects. SettingA large, nationally representative US survey. ParticipantsParticipants 18years who completed baseline and 3-year follow-up NESARC interviews who had baseline alcohol dependence (n=1172; 68% male) or nicotine dependence (n=4017; 52.9% male). MeasurementsAlcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS-IV) measures of childhood maltreatment, personality disorders and alcohol/nicotine dependence. FindingsIndividual models indicated that many personality disorders mediated the relationship between childhood maltreatment and the 3-year persistence of alcohol and nicotine dependence (each explaining 6-46% of the total effect, Ps<0.05). In multiple mediator models, borderline and antisocial symptoms remained significant mediators, each explaining 20-37% of the total effect (Ps<0.01). ConclusionsPersonality disorder symptoms (especially borderline and antisocial) help explain the association between childhood maltreatment and persistent alcohol and nicotine dependence. C1 [Elliott, Jennifer C.; Keyes, Katherine M.; Goodwin, Renee D.; Hasin, Deborah S.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Elliott, Jennifer C.; Stohl, Malka; Wall, Melanie M.; Shmulewitz, Dvora; Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Elliott, Jennifer C.; Wall, Melanie M.; Skodol, Andrew E.; Shmulewitz, Dvora; Hasin, Deborah S.] Columbia Univ, Dept Psychiat, Med Ctr, New York, NY USA. [Wall, Melanie M.] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. [Skodol, Andrew E.] Univ Arizona, Coll Med, Dept Psychiat, Tucson, AZ USA. [Eaton, Nicholas R.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Goodwin, Renee D.] CUNY Queens Coll, Dept Psychol, Queens, NY USA. [Goodwin, Renee D.] CUNY, Grad Ctr, Queens, NY USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Rockville, MD 20852 USA. RP Hasin, DS (reprint author), Columbia Univ, New York State Psychiat Inst, 1051 Riverside Dr 123, New York, NY 10032 USA. EM dsh2@columbia.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U01AA018111, K05AA014223, K23AA023753]; National Institute on Drug Abuse (NIDA) [T32DA031099]; New York State Psychiatric Institute; NIAAA; NIAAA, National Institutes of Health; NIDA FX This study was funded by grants U01AA018111, K05AA014223, and K23AA023753 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Drs. Hasin and Elliott); T32DA031099 from the National Institute on Drug Abuse (NIDA) (Dr. Hasin); and the New York State Psychiatric Institute (Drs. Hasin and Wall). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the NIAAA and funded in part by the Intramural Program, NIAAA, National Institutes of Health, with additional support from NIDA. No conflict of interest is declared. NR 59 TC 1 Z9 1 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD MAY PY 2016 VL 111 IS 5 BP 913 EP 923 DI 10.1111/add.13292 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DJ3HO UT WOS:000374095600021 PM 26714255 ER PT J AU Shearrer, GE O'Reilly, GA Belcher, BR Daniels, MJ Goran, MI Spruijt-Metz, D Davis, JN AF Shearrer, Grace E. O'Reilly, Gillian A. Belcher, Britini R. Daniels, Michael J. Goran, Michael I. Spruijt-Metz, Donna Davis, Jaimie N. TI The impact of sugar sweetened beverage intake on hunger and satiety in minority adolescents (vol 97, pg 43, 2016) SO APPETITE LA English DT Correction C1 [Shearrer, Grace E.; Davis, Jaimie N.] Univ Texas Austin, Dept Nutr, Austin, TX 78712 USA. [O'Reilly, Gillian A.; Spruijt-Metz, Donna] Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA USA. [Belcher, Britini R.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Bethesda, MD 20892 USA. [Daniels, Michael J.] Univ Texas Austin, Dept Stat & Computat, Austin, TX 78712 USA. [Goran, Michael I.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Inst Prevent Res, Los Angeles, CA 90033 USA. RP Davis, JN (reprint author), Univ Texas Austin, Dept Nutr, Austin, TX 78712 USA. EM jaimie.davis@austin.utexas.edu NR 1 TC 0 Z9 0 U1 5 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD MAY 1 PY 2016 VL 100 BP 272 EP 272 DI 10.1016/j.appet.2016.02.036 PG 1 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA DJ0BK UT WOS:000373866200032 ER PT J AU Bortner, CD Scoltock, AB Cain, DW Cidlowski, JA AF Bortner, C. D. Scoltock, A. B. Cain, D. W. Cidlowski, J. A. TI T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID DRUG-RESISTANCE; CANCER-CELLS; MITOCHONDRIA; MECHANISMS; RECEPTORS; PROTEINS; PROLIFERATION; DETERMINANTS; NECROSIS; FAMILY AB We developed a model system to investigate apoptotic resistance in T cells using osmotic stress (OS) to drive selection of death-resistant cells. Exposure of S49 (Neo) T cells to multiple rounds of OS followed by recovery of surviving cells resulted in the selection of a population of T cells (S49 (OS 4-25)) that failed to die in response to a variety of intrinsic apoptotic stimuli including acute OS, but remained sensitive to extrinsic apoptotic initiators. Genome-wide microarray analysis comparing the S49 (OS 4-25) with the parent S49 (Neo) cells revealed over 8500 differentially regulated genes, with almost 90% of those identified being repressed. Surprisingly, our data revealed that apoptotic resistance is not associated with expected changes in pro-or antiapoptotic Bcl-2 family member genes. Rather, these cells lack several characteristics associated with the initial signaling or activation of the intrinsic apoptosis pathway, including failure to increase mitochondrial-derived reactive oxygen species, failure to increase intracellular calcium, failure to deplete glutathione, failure to release cytochrome c from the mitochondria, along with a lack of induced caspase activity. The S49 (OS 4-25) cells exhibit metabolic characteristics indicative of the Warburg effect, and, despite numerous changes in mitochondria gene expression, the mitochondria have a normal metabolic capacity. Interestingly, the S49 (OS 4-25) cells have developed a complete dependence on glucose for survival, and glucose withdrawal results in cell death with many of the essential characteristics of apoptosis. Furthermore, we show that other dietary sugars such as galactose support the viability of the S49 (OS 4-25) cells in the absence of glucose; however, this carbon source sensitizes these cells to die. Our findings suggest that carbon substrate reprogramming for energy production in the S49 (OS 4-25) cells results in stimulus-specific recognition defects in the activation of intrinsic apoptotic pathways. C1 [Bortner, C. D.; Scoltock, A. B.; Cain, D. W.; Cidlowski, J. A.] NIEHS, Signal Transduct Lab, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Signal Transduct Lab, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cidlowski@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX We thank Laura Wharey and Kevin Gerrish of the National Institute of Environmental Health Sciences microarray facility for the generation and initial analysis of the microarray data and Dr Karen Debalsi for her helpful discussion on the Seahorse Technology. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 46 TC 0 Z9 0 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAY PY 2016 VL 23 IS 5 BP 889 EP 902 DI 10.1038/cdd.2015.156 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DJ3SW UT WOS:000374127500014 PM 26658018 ER PT J AU Macalou, S Robey, RW Gozzi, GJ Shukla, S Grosjean, I Hegedus, T Ambudkar, SV Bates, SE Di Pietro, A AF Macalou, S. Robey, R. W. Gozzi, G. Jabor Shukla, S. Grosjean, I. Hegedus, T. Ambudkar, S. V. Bates, S. E. Di Pietro, A. TI The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE ABC transporter; Breast cancer resistance protein/ABCG2; ATP hydrolysis; C motif/ABC signature; Drug efflux coupling; Specific sequence ID CASSETTE SIGNATURE MOTIFS; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; BINDING; GENE; INHIBITION; HYDROLYSIS; PREDICTION; MUTATIONS; POTENT AB The ATP-binding cassette (ABC) transporters of class G display a different domain organisation than P-glycoprotein/ABCB1 and bacterial homologues with a nucleotide-binding domain preceding the transmembrane domain. The linker region connecting these domains is unique and its function and structure cannot be predicted. Sequence analysis revealed that the human ABCG2 linker contains a LSGGE sequence, homologous to the canonical C-motif/ABC signature present in all ABC nucleotide-binding domains. Predictions of disorder and of secondary structures indicated that this C2-sequence was highly mobile and located between an alpha-helix and a loop similarly to the C-motif. Point mutations of the two first residues of the C2-sequence fully abolished the transport-coupled ATPase activity, and led to the complete loss of cell resistance to mitoxantrone. The interaction with potent, selective and non-competitive, ABCG2 inhibitors was also significantly altered upon mutation. These results suggest an important mechanistic role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux. C1 [Macalou, S.; Gozzi, G. Jabor; Di Pietro, A.] Univ Lyon 1, Equipe Labellisee Ligue 2014, BMSSI, UMR 5086 CNRS,IBCP, F-69007 Lyon, France. [Robey, R. W.; Bates, S. E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shukla, S.; Ambudkar, S. V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Grosjean, I.] IBCP, CelluloNet Biobank BB 0033 00072, Facil SFR Biosci UMS3444 US8, F-69007 Lyon, France. [Hegedus, T.] Semmelweis Univ, Hungarian Acad Sci, MTA SE Mol Biophys Res Grp, H-1085 Budapest, Hungary. [Hegedus, T.] Semmelweis Univ, Dept Biophys & Radiat Biol, H-1085 Budapest, Hungary. RP Di Pietro, A (reprint author), Univ Lyon 1, Equipe Labellisee Ligue 2014, BMSSI, UMR 5086 CNRS,IBCP, F-69007 Lyon, France. EM a.dipietro@ibcp.fr FU CNRS; University Lyon 1 [UMR 5086]; Ligue Nationale contre le Cancer (Equipe Labellisee Ligue); Ligue de la Loire contre le Cancer; Association pour la Recherche sur le Cancer; Region Rhone-Alpes (Explora'Doc mobility program); Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [Z01 BC010030-17]; OTKA [K 111678]; Bolyai Fellowship of the Hungarian Academy of Sciences FX Drs. A. Ahmed-Belkacem and C. Gauthier are acknowledged for their help in initiating the studies and performing some experiments, respectively. This work was supported by the CNRS and University Lyon 1 (UMR 5086), and the Ligue Nationale contre le Cancer (Equipe Labellisee Ligue 2014) to A.D.P. S.M. was recipient of fellowships from the Ligue de la Loire contre le Cancer, the Association pour la Recherche sur le Cancer and the Region Rhone-Alpes (Explora'Doc mobility program with S.E.B.). R.W.R., S.S., S.V.A. and S.E.B. were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (Z01 BC010030-17). The authors also thank research funding from OTKA K 111678 and the Bolyai Fellowship of the Hungarian Academy of Sciences to T.H. NR 36 TC 0 Z9 0 U1 7 U2 16 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD MAY PY 2016 VL 73 IS 9 BP 1927 EP 1937 DI 10.1007/s00018-015-2118-5 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DJ3NH UT WOS:000374111800012 PM 26708291 ER PT J AU Liu, X Cao, YF Ran, RX Dong, PP Gonzalez, FJ XueWu Huang, T Chen, JX Fu, ZW Li, RS Liu, YZ Sun, HZ Fang, ZZ AF Liu, Xin Cao, Yun-Feng Ran, Rui-Xue Dong, Pei-Pei Gonzalez, Frank J. XueWu Huang, Ting Chen, Jian-Xin Fu, Zhi-Wei Li, Rong-Shan Liu, Yong-Zhe Sun, Hong-Zhi Fang, Zhong-Ze TI New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases (vol 144, pg 1966, 2015) SO CHEMOSPHERE LA English DT Correction C1 [Liu, Xin; Sun, Hong-Zhi] Liaoning Med Univ, Affiliated Hosp 1, Jinzhou, Liaoning, Peoples R China. [Cao, Yun-Feng; Chen, Jian-Xin] Shanghai Inst Planned Parenthood Res, Shanghai Engn & Technol Res Ctr Reprod Hlth Drug, Key Lab Contracept & Devices Res NPFPC, Shanghai, Peoples R China. [Ran, Rui-Xue; Li, Rong-Shan] Tianjin Med Univ, Tianjin Key Lab Technol Enabling Dev Clin Therape, Sch Pharm, Tianjin, Peoples R China. [Liu, Yong-Zhe; Fang, Zhong-Ze] Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, 22 Qixiangtai Rd, Tianjin 300070, Peoples R China. [Dong, Pei-Pei] Dalian Med Univ, Inst Integrat Med, Dalian, Peoples R China. [XueWu; Fu, Zhi-Wei] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian, Peoples R China. [XueWu; Fu, Zhi-Wei] Liaoning Med Univ, Affiliated Hosp 1, Dalian, Peoples R China. [XueWu; Fu, Zhi-Wei] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian, Peoples R China. [XueWu; Fu, Zhi-Wei] Dalian Univ, Affiliated Zhongshan Hosp, Dalian 116012, Peoples R China. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sun, HZ (reprint author), Liaoning Med Univ, Affiliated Hosp 1, Jinzhou, Liaoning, Peoples R China.; Fang, ZZ (reprint author), Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, 22 Qixiangtai Rd, Tianjin 300070, Peoples R China. EM fangzhongze@tmu.edu.cn NR 1 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 EI 1879-1298 J9 CHEMOSPHERE JI Chemosphere PD MAY PY 2016 VL 151 BP 357 EP 357 DI 10.1016/j.chemosphere.2016.03.049 PG 1 WC Environmental Sciences SC Environmental Sciences & Ecology GA DJ2YK UT WOS:000374071000045 ER PT J AU Yang, CS Pomerantz, H Mannava, KA Corwin, J Weinstock, MA Fleckman, P DiGiovanna, JJ Robinson-Bostom, L AF Yang, Catherine S. Pomerantz, Hyemin Mannava, Kathleen A. Corwin, Jessica Weinstock, Martin A. Fleckman, Philip DiGiovanna, John J. Robinson-Bostom, Leslie TI Comparing histopathology from patients with X-linked recessive ichthyosis and autosomal recessive congenital ichthyosis with transglutaminase 1 mutation: A report from the National Registry for Ichthyosis and Related Skin Disorders SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter ID HISTOLOGY; VULGARIS C1 [Yang, Catherine S.; Weinstock, Martin A.; Robinson-Bostom, Leslie] Brown Univ, Alpert Med Sch, Dept Dermatol, 593 Eddy St APC 1018, Providence, RI 02903 USA. [Pomerantz, Hyemin; Weinstock, Martin A.] VA Med Ctr, Dermatoepidemiol Unit, Providence, RI USA. [Mannava, Kathleen A.] Wake Forest Sch Med, Dept Pathol, Winston Salem, NC USA. [Corwin, Jessica] Vacaville Med Ctr, Dept Dermatol, Vacaville, CA USA. [Fleckman, Philip] Univ Washington, Div Dermatol, Seattle, WA 98195 USA. [DiGiovanna, John J.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Yang, CS (reprint author), Brown Univ, Alpert Med Sch, Dept Dermatol, 593 Eddy St APC 1018, Providence, RI 02903 USA. EM catherine_yang@brown.edu FU Intramural NIH HHS [Z99 CA999999]; NCATS NIH HHS [UL1TR000423, UL1 TR000423]; NCRR NIH HHS [M01 RR000037]; NIAMS NIH HHS [N01-AR-1-2252, N01 AR042216] NR 5 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2016 VL 74 IS 5 BP 1008 EP 1010 DI 10.1016/j.jaad.2015.12.027 PG 4 WC Dermatology SC Dermatology GA DJ3PF UT WOS:000374117100033 PM 27085231 ER PT J AU Miller, JG Li, M Mazilu, D Hunt, T Horvath, KA AF Miller, Justin G. Li, Ming Mazilu, Dumitru Hunt, Tim Horvath, Keith A. TI Real-time magnetic resonance imaging-guided transcatheter aortic valve replacement SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article DE transcatheter aortic valve replacement; real-time magnetic resonance image; swine animal model; Medtronic CoreValve ID 3-DIMENSIONAL TRANSESOPHAGEAL ECHOCARDIOGRAPHY; COMPUTED-TOMOGRAPHY; INTERACTIVE MRI; IN-VITRO; IMPLANTATION; DISEASE; STENOSIS; SURGERY; BIOPROSTHESIS; PROSTHESIS AB Objectives: To demonstrate the feasibility of Real-time magnetic resonance imaging (rtMRI) guided transcatheter aortic valve replacement (TAVR) with an active guidewire and anMRI compatible valve delivery catheter system in a swine model. Methods: The CoreValve system was minimally modified to be MRI-compatible by replacing the stainless steel components with fluoroplastic resin and high-density polyethylene components. Eight swine weighing 60-90 kg underwent rtMRI-guided TAVR with an active guidewire through a left subclavian approach. Results: Two imaging planes (long-axis view and short-axis view) were used simultaneously for real-time imaging during implantation. Successful deployment was performed without rapid ventricular pacing or cardiopulmonary bypass. Postdeployment images were acquired to evaluate the final valve position in addition to valvular and cardiac function. Conclusions: Our results show that the CoreValve can be easily and effectively deployed through a left subclavian approach using rtMRI guidance, a minimally modified valve delivery catheter system, and an active guidewire. This method allows superior visualization before deployment, thereby allowing placement of the valve with pinpoint accuracy. rtMRI has the added benefit of the ability to perform immediate postprocedural functional assessment, while eliminating the morbidity associated with radiation exposure, rapid ventricular pacing, contrast media renal toxicity, and a more invasive procedure. Use of a commercially available device brings this rtMRI-guided approach closer to clinical reality. C1 [Miller, Justin G.; Li, Ming; Mazilu, Dumitru; Hunt, Tim; Horvath, Keith A.] NHLBI, Cardiothorac Surg Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Horvath, KA (reprint author), 10 Ctr Dr,Bldg 10,Rm B1D47, Bethesda, MD 20892 USA. EM horvathka@mail.nih.gov FU National Heart, Lung and Blood Institute, Division of Intramural Research FX This research was funded by the National Heart, Lung and Blood Institute, Division of Intramural Research. NR 51 TC 1 Z9 1 U1 2 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD MAY PY 2016 VL 151 IS 5 BP 1269 EP 1277 DI 10.1016/j.jtcvs.2015.11.024 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DJ3PO UT WOS:000374118100013 PM 26725711 ER PT J AU Miller, JG Li, M Mazilu, D Hunt, T Horvath, KA AF Miller, Justin G. Li, Ming Mazilu, Dumitru Hunt, Tim Horvath, Keith A. TI Robot-assisted real-time magnetic resonance image-guided transcatheter aortic valve replacement SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article DE robot-assisted transcatheter aortic valve replacement; real-time magnetic resonance image; swine animal model ID 3-DIMENSIONAL TRANSESOPHAGEAL ECHOCARDIOGRAPHY; COMPUTED-TOMOGRAPHY; INTERACTIVE MRI; IMPLANTATION; BIOPROSTHESIS; STENOSIS; GUIDANCE; DISEASE; DEVICES; SURGERY AB Background: Real-time magnetic resonance imaging (rtMRI)-guided transcatheter aortic valve replacement (TAVR) offers improved visualization, real-time imaging, and pinpoint accuracy with device delivery. Unfortunately, performing a TAVR in a MRI scanner can be a difficult task owing to limited space and an awkward working environment. Our solution was to design a MRI-compatible robot-assisted device to insert and deploy a self-expanding valve from a remote computer console. We present our preliminary results in a swine model. Methods: We used an MRI-compatible robotic arm and developed a valve delivery module. A 12-mm trocar was inserted in the apex of the heart via a subxiphoid incision. The delivery device and nitinol stented prosthesis were mounted on the robot. Two continuous real-time imaging planes provided a virtual real-time 3-dimensional reconstruction. The valve was deployed remotely by the surgeon via a graphic user interface. Results: In this acute nonsurvival study, 8 swine underwent robot-assisted rtMRI TAVR for evaluation of feasibility. Device deployment took a mean of 61 +/- 5 seconds. Postdeployment necropsy was performed to confirm correlations between imaging and actual valve positions. Conclusions: These results demonstrate the feasibility of robotic-assisted TAVR using rtMRI guidance. This approach may eliminate some of the challenges of performing a procedure while working inside of an MRI scanner, and may improve the success of TAVR. It provides superior visualization during the insertion process, pinpoint accuracy of deployment, and, potentially, communication between the imaging device and the robotic module to prevent incorrect or misaligned deployment. C1 [Miller, Justin G.; Li, Ming; Mazilu, Dumitru; Hunt, Tim; Horvath, Keith A.] NHLBI, Cardiothorac Surg Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Horvath, KA (reprint author), 10 Ctr Dr,Bldg 10,Rm B1D47, Bethesda, MD 20892 USA. EM horvathka@mail.nih.gov FU National Heart, Lung and Blood Institute FX This research received intramural funding from the National Heart, Lung and Blood Institute. NR 40 TC 1 Z9 1 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD MAY PY 2016 VL 151 IS 5 BP 1407 EP 1412 DI 10.1016/j.jtcvs.2015.11.047 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DJ3PO UT WOS:000374118100041 PM 26778373 ER PT J AU Mok, KY Sheerin, U Simon-Sanchez, J Salaka, A Chester, L Escott-Price, V Mantripragada, K Doherty, KM Noyce, AJ Mencacci, NE Lubbe, SJ Williams-Gray, CH Barker, RA Van Dijk, KD Berendse, HW Heutink, P Corvol, JC Cormier, F Lesage, S Brice, A Brockmann, K Schulte, C Gasser, T Foltynie, T Limousin, P Morrison, KE Clarke, CE Sawcer, S Warner, TT Lees, AJ Morris, HR Nalls, MA Singleton, AB Hardy, J Abramov, AY Plagnol, V Williams, NM Wood, NW AF Mok, Kin Y. Sheerin, Una Simon-Sanchez, Javier Salaka, Afnan Chester, Lucy Escott-Price, Valentina Mantripragada, Kiran Doherty, Karen M. Noyce, Alastair J. Mencacci, Niccolo E. Lubbe, Steven J. Williams-Gray, Caroline H. Barker, Roger A. Van Dijk, Karin D. Berendse, Henk W. Heutink, Peter Corvol, Jean-Christophe Cormier, Florence Lesage, Suzanne Brice, Alexis Brockmann, Kathrin Schulte, Claudia Gasser, Thomas Foltynie, Thomas Limousin, Patricia Morrison, Karen E. Clarke, Carl E. Sawcer, Stephen Warner, Tom T. Lees, Andrew J. Morris, Huw R. Nalls, Mike A. Singleton, Andrew B. Hardy, John Abramov, Andrey Y. Plagnol, Vincent Williams, Nigel M. Wood, Nicholas W. CA Int Parkinson's Dis Genomics TI Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data SO LANCET NEUROLOGY LA English DT Article ID CLINICAL-FEATURES; SCHIZOPHRENIA; METAANALYSIS; DIAGNOSIS; IDENTIFICATION; COOCCURRENCE; GENETICS; RISK; LOCI AB Background Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. Methods We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. Findings We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0.00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0.001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32.0-55.5; mean 42.1 years [SD 11.9]) than in those who did not carry a deletion (median 61 years, 95% CI 60.5-61.0; mean 60.3 years [SD 12.8]). A 22q11.2 deletion was present in more patients with early-onset (p<0.0001) and late-onset Parkinson's disease (p=0.016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0.005). Interpretation Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. Copyright (C) Mok et al. Open Access article distributed under the terms of CC BY. C1 [Mok, Kin Y.; Sheerin, Una; Noyce, Alastair J.; Mencacci, Niccolo E.; Hardy, John; Abramov, Andrey Y.; Wood, Nicholas W.] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Doherty, Karen M.; Noyce, Alastair J.; Warner, Tom T.; Lees, Andrew J.; Hardy, John] UCL Inst Neurol, Reta Lila Weston Inst Neurol Studies, London WC1N 3BG, England. [Foltynie, Thomas; Limousin, Patricia] UCL Inst Neurol, Sobell Dept Motor Neurosci, London WC1N 3BG, England. [Lubbe, Steven J.; Morris, Huw R.] UCL Inst Neurol, Dept Clin Neurosci, London WC1N 3BG, England. [Mok, Kin Y.] Hong Kong Univ Sci & Technol, Div Life Sci, Hong Kong, Hong Kong, Peoples R China. [Simon-Sanchez, Javier] Hertie Inst Clin Brain Res HIH, Genet & Epigenet Neurodegenerat, Tubingen, Germany. [Brockmann, Kathrin; Schulte, Claudia; Gasser, Thomas] Hertie Inst Clin Brain Res HIH, Dept Neurodegenerat Dis, Tubingen, Germany. [Simon-Sanchez, Javier] German Ctr Neurodegenerat Dis DZNE, Genet & Epigenet Neurodegenerat, Tubingen, Germany. [Heutink, Peter] German Ctr Neurodegenerat Dis DZNE, Genome Biol Neurodegenerat Dis, Tubingen, Germany. [Brockmann, Kathrin; Schulte, Claudia; Gasser, Thomas] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Salaka, Afnan; Chester, Lucy; Escott-Price, Valentina; Mantripragada, Kiran; Williams, Nigel M.] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, Cardiff CF24 4HQ, S Glam, Wales. [Salaka, Afnan] Umm Al Qura Univ, Fac Appl Med Sci, Med Genet & Lab Med Dept, Mecca, Saudi Arabia. [Doherty, Karen M.] Royal Victoria Hosp, Dept Reg Neurosci, Belfast BT12 6BA, Antrim, North Ireland. [Williams-Gray, Caroline H.; Barker, Roger A.] Univ Cambridge, Dept Clin Neurosci, John van Geest Ctr Brain Repair, Forvie Site, Cambridge, England. [Sawcer, Stephen] Univ Cambridge, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge, England. [Van Dijk, Karin D.; Berendse, Henk W.] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Corvol, Jean-Christophe; Cormier, Florence; Lesage, Suzanne; Brice, Alexis] Univ Paris 06, Sorbonne Univ, French Natl Ctr Sci Res CNRS,Inst Cerveau, Res Unit U1127,INSERM,Res Unit UMR 7225, Paris, France. [Corvol, Jean-Christophe; Cormier, Florence; Lesage, Suzanne; Brice, Alexis] Univ Paris 06, Sorbonne Univ, Inst Cerveau, Res Unit UMR S 1127, Paris, France. [Corvol, Jean-Christophe; Cormier, Florence; Lesage, Suzanne; Brice, Alexis] Moelle Epiniere Brain & Spine Inst ICM, Paris, France. [Corvol, Jean-Christophe; Cormier, Florence; Lesage, Suzanne; Brice, Alexis] INSERM, Clin Invest Ctr, U1422, Paris, France. [Corvol, Jean-Christophe; Cormier, Florence; Lesage, Suzanne; Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Ctr Invest Clin Pitie Neurosci, Paris, France. [Brockmann, Kathrin; Schulte, Claudia; Gasser, Thomas] Univ Tubingen, Dept Neurodegenerat Dis, Tubingen, Germany. [Morrison, Karen E.] Univ Birmingham, Coll Med & Dent Sci, Inst Clin Sci, Birmingham, W Midlands, England. [Clarke, Carl E.] Univ Birmingham, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Nalls, Mike A.; Singleton, Andrew B.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Plagnol, Vincent] UCL Genet Inst, London, England. RP Wood, NW (reprint author), UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.; Williams, NM (reprint author), Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, Cardiff CF24 4HQ, S Glam, Wales. EM williamsnm@cf.ac.uk; n.wood@ucl.ac.uk RI Hardy, John/C-2451-2009; Mok, Kin/F-5860-2012; Lubbe, Steven/L-8261-2013; Singleton, Andrew/C-3010-2009; Morris, Huw/B-8527-2008; Abramov, Andrey/H-9053-2012; Warner, Thomas/A-1454-2013; Wood, Nicholas/C-2505-2009; corvol, jean-christophe/I-6387-2012; OI Morris, Huw/0000-0002-5473-3774; Abramov, Andrey/0000-0002-7646-7235; Warner, Thomas/0000-0001-6195-6995; Wood, Nicholas/0000-0002-9500-3348; corvol, jean-christophe/0000-0001-7325-0199; Escott-Price, Valentina/0000-0003-1784-5483 FU UK Medical Research Council; UK Wellcome Trust; Parkinson's UK; Patrick Berthoud Trust; National Institutes of Health; Investissements d'Avenir [ANR-10-IAIHU-06]; Dutch Parkinson Foundation (Parkinson Vereniging); Neuroscience Campus Amsterdam; National Institute for Health Research, National Institute on Aging, National Institutes of Health FX UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health. NR 47 TC 5 Z9 5 U1 9 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD MAY PY 2016 VL 15 IS 6 BP 585 EP 596 DI 10.1016/S1474-4422(16)00071-5 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA DI9PW UT WOS:000373835900017 PM 27017469 ER PT J AU Zou, T Jaladanki, SK Liu, L Xiao, L Chung, HK Wang, JY Xu, Y Gorospe, M Wang, JY AF Zou, Tongtong Jaladanki, Suraj K. Liu, Lan Xiao, Lan Chung, Hee Kyoung Wang, Jun-Yao Xu, Yan Gorospe, Myriam Wang, Jian-Ying TI y H19 Long Noncoding RNA Regulates Intestinal Epithelial Barrier Function via MicroRNA 675 by Interacting with RNA-Binding Protein HuR SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID IMPRINTED GENE NETWORK; MESSENGER-RNA; TIGHT JUNCTION; E-CADHERIN; CANCER METASTASIS; PROCESSING BODIES; TUMOR-SUPPRESSOR; CELL-MIGRATION; TRANSLATION; GROWTH AB The disruption of the intestinal epithelial barrier function occurs commonly in various pathologies, but the exact mechanisms responsible are unclear. The H19 long noncoding RNA (lncRNA) regulates the expression of different genes and has been implicated in human genetic disorders and cancer. Here, we report that H19 plays an important role in controlling the intestinal epithelial barrier function by serving as a precursor for microRNA 675 (miR-675). H19 overexpression increased the cellular abundance of miR-675, which in turn destabilized and repressed the translation of mRNAs encoding tight junction protein ZO-1 and adherens junction E-cadherin, resulting in the dysfunction of the epithelial barrier. Increasing the level of the RNA-binding protein HuR in cells overexpressing H19 prevented the stimulation of miR-675 processing from H19, promoted ZO-1 and E-cadherin expression, and restored the epithelial barrier function to a nearly normal level. In contrast, the targeted deletion of HuR in intestinal epithelial cells enhanced miR-675 production in the mucosa and delayed the recovery of the gut barrier function after exposure to mesenteric ischemia/reperfusion. These results indicate that H19 interacts with HuR and regulates the intestinal epithelial barrier function via the H19-encoded miR-675 by altering ZO-1 and E-cadherin expression posttranscriptionally. C1 [Zou, Tongtong; Jaladanki, Suraj K.; Liu, Lan; Xiao, Lan; Chung, Hee Kyoung; Wang, Jun-Yao; Xu, Yan; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Zou, Tongtong; Jaladanki, Suraj K.; Liu, Lan; Xiao, Lan; Chung, Hee Kyoung; Wang, Jun-Yao; Xu, Yan; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Gorospe, Myriam] NIA, Genet Lab, IRP, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA.; Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA.; Wang, JY (reprint author), Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. EM jwang@smail.umaryland.edu FU VA Merit Review Award; HHS \ National Institutes of Health (NIH) [DK57819, DK61972, DK68491] FX This work, including the efforts of Jian-Ying Wang, was funded by VA Merit Review Award. This work, including the efforts of Jian-Ying Wang, was funded by HHS vertical bar National Institutes of Health (NIH) (DK57819, DK61972, and DK68491). NR 64 TC 4 Z9 4 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY PY 2016 VL 36 IS 9 BP 1332 EP 1341 DI 10.1128/MCB.01030-15 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DJ3MZ UT WOS:000374110900002 PM 26884465 ER PT J AU Patial, S Stumpo, DJ Young, WS Ward, JM Flake, GP Blackshear, PJ AF Patial, Sonika Stumpo, Deborah J. Young, W. Scott, III Ward, James M. Flake, Gordon P. Blackshear, Perry J. TI Effects of Combined Tristetraprolin/Tumor Necrosis Factor Receptor Deficiency on the Splenic Transcriptome SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-BINDING PROTEINS; ZINC-FINGER DOMAIN; MESSENGER-RNA; IRON-DEFICIENCY; GENE-EXPRESSION; CHRONIC DISEASE; TNF-ALPHA; DEADENYLATION; DEGRADATION; HOMEOSTASIS AB Tristetraprolin (TTP) acts by binding to AU-rich elements in certain mRNAs, such as tumor necrosis factor (TNF) mRNA, and increasing their decay rates. TTP knockout mice exhibit a profound inflammatory syndrome that is largely due to increased TNF levels. Although TTP's effects on gene expression have been well studied in cultured cells, little is known about its functions in intact tissues. We performed deep RNA sequencing on spleens from TTP knockout mice that were also deficient in both TNF receptors ("triple knockout" mice) to remove the secondary effects of excess TNF activity. To help identify posttranscriptionally regulated transcripts, we also compared changes in mature mRNA levels to levels of transiently expressed pre-mRNA. In the triple knockout spleens, levels of 3,014 transcripts were significantly affected by 1.5-fold or more, but only a small fraction exhibited differential mRNA/pre-mRNA changes suggestive of increased mRNA stability. Transferrin receptor mRNA, which contains two highly conserved potential TTP binding sites, was significantly upregulated relative to its pre-mRNA. This was reflected in increased transferrin receptor expression and increased splenic iron/hemosiderin deposition. Our results suggest that TTP deficiency has profound effects on the splenic transcriptome, even in the absence of secondary increases in TNF activity. C1 [Patial, Sonika; Stumpo, Deborah J.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. [Ward, James M.] NIEHS, Integrat Bioinformat, POB 12233, Res Triangle Pk, NC 27709 USA. [Flake, Gordon P.] NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. [Young, W. Scott, III] NIMH, Sect Neural Gene Express, Bethesda, MD 20892 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA.; Blackshear, PJ (reprint author), Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA.; Blackshear, PJ (reprint author), Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. EM black009@niehs.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU NIH, National Institute of Environmental Health Sciences; National Institute of Mental Health FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and National Institute of Mental Health. NR 47 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY PY 2016 VL 36 IS 9 BP 1395 EP 1411 DI 10.1128/MCB.01068-15 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DJ3MZ UT WOS:000374110900007 PM 26976640 ER PT J AU Kiss, A Koppel, AC Anders, J Cataisson, C Yuspa, SH Blumenberg, M Efimova, T AF Kiss, Alexi Koppel, Aaron C. Anders, Joanna Cataisson, Christophe Yuspa, Stuart H. Blumenberg, Miroslav Efimova, Tatiana TI Keratinocyte p38 loss inhibits Ras-induced tumor formation, while systemic p38 loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin SO MOLECULAR CARCINOGENESIS LA English DT Article DE p38; knockout mice; orthotopic skin grafts; skin inflammation; p38 ID ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; CELL-TRANSFORMATION; CANCER DEVELOPMENT; P38-DELTA; DIFFERENTIATION; MICE; P38-GAMMA; MORPHOGENESIS; TUMORIGENESIS AB p38 expression and/or activity are increased in human cutaneous malignancies, including invasive squamous cell carcinoma (SCC) and head and neck SCC, but the role of p38 in cutaneous carcinogenesis has not been well-defined. We have reported that mice with germline loss of p38 exhibited a reduced susceptibility to skin tumor development compared with wild-type mice in the two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical skin carcinogenesis model. Here, we report that p38 gene ablation inhibited the growth of tumors generated from v-ras(Ha)-transformed keratinocytes in skin orthografts to nude mice, indicating that keratinocyte-intrinsic p38 is required for Ras-induced tumorigenesis. Gene expression profiling of v-ras(Ha)-transformed p38-null keratinocytes revealed transcriptional changes associated with cellular responses linked to tumor suppression, such as reduced proliferation and increased differentiation, cell adhesion, and cell communications. Notably, a short-term DMBA/TPA challenge, modeling the initial stages of chemical skin carcinogenesis treatment, elicited an enhanced inflammation in p38-null skin compared with skin of wild-type mice, as assessed by measuring the expression of pro-inflammatory cytokines, including IL-1, IL-6, IL-17, and TNF. Additionally, p38-null skin and p38-null keratinocytes exhibited increased p38 activation and signaling in response to acute inflammatory challenges, suggesting a role for p38 in stimulating the elevated inflammatory response in p38-null skin during the initial phases of the DMBA/TPA treatment compared with similarly treated p38(+/+) skin. Altogether, our results indicate that p38 signaling regulates skin carcinogenesis not only by keratinocyte cell-autonomous mechanisms, but also by influencing the interaction between between the epithelial compartment of the developing skin tumor and its stromal microenvironment. (c) 2015 Wiley Periodicals, Inc. C1 [Kiss, Alexi; Koppel, Aaron C.; Efimova, Tatiana] Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA. [Anders, Joanna; Cataisson, Christophe; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Blumenberg, Miroslav] NYU, Sch Med, RO Perelman Dept Dermatol, New York, NY USA. RP Efimova, T (reprint author), Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA.; Efimova, T (reprint author), Washington Univ, Sch Med, Div Dermatol, Dept Internal Med, Campus Box 8123,660 S Euclid Ave, St Louis, MO 63110 USA. FU National Institutes of Health [R01 CA133038]; Center for Cancer Research of the National Cancer Institute FX Grant sponsor: National Institutes of Health; Grant number: R01 CA133038; Grant sponsor: Center for Cancer Research of the National Cancer Institute NR 51 TC 0 Z9 0 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAY PY 2016 VL 55 IS 5 BP 563 EP 574 DI 10.1002/mc.22303 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA DJ3IA UT WOS:000374096800013 PM 25753147 ER PT J AU Poletto, M Malfatti, MC Dorjsuren, D Scognamiglio, PL Marasco, D Vascotto, C Jadhav, A Maloney, DJ Wilson, DM Simeonov, A Tell, G AF Poletto, Mattia Malfatti, Matilde C. Dorjsuren, Dorjbal Scognamiglio, Pasqualina L. Marasco, Daniela Vascotto, Carlo Jadhav, Ajit Maloney, David J. Wilson, David M., III Simeonov, Anton Tell, Gianluca TI Inhibitors of the apurinic/apyrimidinic endonuclease 1 (APE1)/nucleophosmin (NPM1) interaction that display anti-tumor properties SO MOLECULAR CARCINOGENESIS LA English DT Article DE APE1; NPM1; protein; protein interaction; small molecule; combination therapy ID BASE EXCISION-REPAIR; CRITICAL LYSINE RESIDUES; N-TERMINAL DOMAIN; HEPATOCELLULAR-CARCINOMA; DNA-REPAIR; PROGNOSTIC-SIGNIFICANCE; PROTEIN INTERACTIONS; PROXIMITY LIGATION; CELLS; APE1 AB The apurinic/apyrimidinic endonuclease 1 (APE1) is a protein central to the base excision DNA repair pathway and operates in the modulation of gene expression through redox-dependent and independent mechanisms. Aberrant expression and localization of APE1 in tumors are recurrent hallmarks of aggressiveness and resistance to therapy. We identified and characterized the molecular association between APE1 and nucleophosmin (NPM1), a multifunctional protein involved in the preservation of genome stability and rRNA maturation. This protein-protein interaction modulates subcellular localization and endonuclease activity of APE1. Moreover, we reported a correlation between APE1 and NPM1 expression levels in ovarian cancer, with NPM1 overexpression being a marker of poor prognosis. These observations suggest that tumors that display an augmented APE1/NPM1 association may exhibit increased aggressiveness and resistance. Therefore, targeting the APE1/NPM1 interaction might represent an innovative strategy for the development of anticancer drugs, as tumor cells relying on higher levels of APE1 and NPM1 for proliferation and survival may be more sensitive than untransformed cells. We set up a chemiluminescence-based high-throughput screening assay in order to find small molecules able to interfere with the APE1/NPM1 interaction. This screening led to the identification of a set of bioactive compounds that impair the APE1/NPM1 association in living cells. Interestingly, some of these molecules display anti-proliferative activity and sensitize cells to therapeutically relevant genotoxins. Given the prognostic significance of APE1 and NPM1, these compounds might prove effective in the treatment of tumors that show abundant levels of both proteins, such as ovarian or hepatic carcinomas. (c) 2015 Wiley Periodicals, Inc. C1 [Poletto, Mattia; Malfatti, Matilde C.; Vascotto, Carlo; Tell, Gianluca] Univ Udine, Dept Med & Biol Sci, Ple Kolbe 4, I-33100 Udine, Italy. [Dorjsuren, Dorjbal; Jadhav, Ajit; Maloney, David J.; Simeonov, Anton] Natl Ctr Adv Translat Sci, NIH Chem Genom Ctr, NIH, Bethesda, MD USA. [Scognamiglio, Pasqualina L.; Marasco, Daniela] Univ Naples Federico II, CIRPEB, Dept Pharm, Naples, Italy. [Scognamiglio, Pasqualina L.] IIT, Ctr Adv Biomat Healthcare CRIB, Naples, Italy. [Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Tell, G (reprint author), Univ Udine, Dept Med & Biol Sci, Ple Kolbe 4, I-33100 Udine, Italy.; Simeonov, A (reprint author), Natl Ctr Adv Translat Sci, NIH Chem Genom Ctr, NIH, Bethesda, MD USA. OI vascotto, carlo/0000-0003-4431-029X; Tell, Gianluca/0000-0001-8845-6448 FU Associazione Italiana per la Ricerca sul Cancro [IG10269, IG14038]; European Regional development Fund (ERDF); National Funds by the Autonomous Region Friuli Venezia Giulia, in quality of Managing Authority; Crossborder cooperation program Italy-Slovenia; Intramural Research Program at the NIH, National Institute on Aging; Intramural Research Program of the National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH08468] FX Grant sponsor: The Associazione Italiana per la Ricerca sul Cancro; Grant number: IG10269 and IG14038; Grant sponsor: The European Regional development Fund (ERDF) and the National Funds, implemented by the Autonomous Region Friuli Venezia Giulia, in quality of Managing Authority, Grant name: The Crossborder cooperation program Italy-Slovenia 2007-2013; Grant sponsor: The Intramural Research Program at the NIH, National Institute on Aging; Grant sponsor: The Intramural Research Program of the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Grant number: U54MH08468 NR 52 TC 9 Z9 9 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAY PY 2016 VL 55 IS 5 BP 688 EP 704 DI 10.1002/mc.22313 PG 17 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA DJ3IA UT WOS:000374096800023 PM 25865359 ER PT J AU Gunduz-Cinar, O Flynn, S Brockway, E Kaugars, K Baldi, R Ramikie, TS Cinar, R Kunos, G Patel, S Holmes, A AF Gunduz-Cinar, Ozge Flynn, Shaun Brockway, Emma Kaugars, Katherine Baldi, Rita Ramikie, Teniel S. Cinar, Resat Kunos, George Patel, Sachin Holmes, Andrew TI Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID ACID AMIDE HYDROLASE; POSTTRAUMATIC-STRESS-DISORDER; SEROTONIN REUPTAKE INHIBITORS; ANTIDEPRESSANT-LIKE ACTIVITY; CB1 CANNABINOID RECEPTORS; ELEVATED PLUS-MAZE; BASOLATERAL AMYGDALA; TRANSLATIONAL EVIDENCE; PREFRONTAL CORTEX; NEURONAL CIRCUITS AB Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitator), effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired I 29S1/Sv I mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB I receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. C1 [Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. [Baldi, Rita; Ramikie, Teniel S.; Patel, Sachin] Vanderbilt Univ, Med Ctr, Dept Psychiat & Mol Physiol & Biophys, Nashville, TN USA. [Cinar, Resat; Kunos, George] NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. RP Gunduz-Cinar, O; Holmes, A (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM ozge.gunduzcinar@nih.gov; holmesan@mail.nih.gov OI CINAR, RESAT/0000-0002-8597-7253 FU NIAAA Intramural Research Program; NIH [MH100096, MH09012]; Vanderbilt University FX This research was supported by the NIAAA Intramural Research Program and NIH Grants MH100096 and MH09012 (to SP). SP receives research contract support from Lundbeck Pharmaceuticals; however, the current work was supported entirely by the NIH and Vanderbilt University. The authors declare no conflict of interest. NR 80 TC 4 Z9 4 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2016 VL 41 IS 6 BP 1598 EP 1609 DI 10.1038/npp.2015.318 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DJ1MD UT WOS:000373966000018 PM 26514583 ER PT J AU Mezey, E AF Mezey, Eva TI On the origin of blood cells - hematopoiesis revisited SO ORAL DISEASES LA English DT Editorial Material ID STEM-CELLS; PROGENITORS; IDENTIFICATION; PROLIFERATION C1 [Mezey, Eva] NIDCR, Adult Stem Cell Sect, CSDB, NIH, Bethesda, MD USA. RP Mezey, E (reprint author), NIDCR, Adult Stem Cell Sect, CSDB, NIH, Bethesda, MD USA. FU Intramural NIH HHS [, Z01 DE000714-04] NR 16 TC 0 Z9 0 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD MAY PY 2016 VL 22 IS 4 BP 247 EP 248 DI 10.1111/odi.12445 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DJ2PH UT WOS:000374046600001 PM 26802784 ER PT J AU Gupta, R Dhyani, M Kendzerska, T Pandi-Perumal, SR BaHammam, AS Srivanitchapoom, P Pandey, S Hallett, M AF Gupta, R. Dhyani, M. Kendzerska, T. Pandi-Perumal, S. R. BaHammam, A. S. Srivanitchapoom, P. Pandey, S. Hallett, M. TI Restless legs syndrome and pregnancy: prevalence, possible pathophysiological mechanisms and treatment SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Review DE pregnancy; prevalence; restless legs syndrome; treatment ID WILLIS-EKBOM DISEASE; LIMB MOVEMENT-DISORDER; INTRAVENOUS IRON SUCROSE; OBSTRUCTIVE SLEEP-APNEA; VITAMIN-D DEFICIENCY; LOW SERUM FERRITIN; PARKINSONS-DISEASE; PRIMARY HYPERPARATHYROIDISM; DIAGNOSTIC-CRITERIA; CONTROLLED TRIAL AB Restless legs syndrome (RLS) is a common sleep disorder that may be associated with pregnancy. Studies have found that the prevalence of RLS among pregnant women ranged from 10 to 34%. Typically, there is complete remission of symptoms soon after parturition; however, in some patients, they may continue postpartum. RLS has been shown to be associated with a number of complications in pregnancy including preeclampsia and increased incidence of Cesarean sections. Although multiple hypotheses have been proposed to explain this association, each individual hypothesis cannot completely explain the whole pathogenesis. Present understanding suggests that a strong family history, low serum iron and ferritin level, and high estrogen level during pregnancy might play important roles. Vitamin D deficiency and calcium metabolism may also play a role. Medical treatment of RLS during pregnancy is difficult and challenging considering the risks to mother and fetus. However, in some cases, the disease may be severe enough to require treatment. C1 [Gupta, R.; Dhyani, M.] Himalayan Inst Med Sci, Dept Psychiat, Dehra Dun 248016, Uttar Pradesh, India. [Gupta, R.; Dhyani, M.] Himalayan Inst Med Sci, Sleep Clin, Dehra Dun 248016, Uttar Pradesh, India. [Kendzerska, T.] Sunnybrook Hlth Sci Ctr, Inst Clin Evaluat Sci, Toronto, ON M4N 3M5, Canada. [Pandi-Perumal, S. R.] Somnogen Canada Inc, Toronto, ON, Canada. [BaHammam, A. S.] King Saud Univ, Univ Sleep Disorders Ctr, Coll Med, Dept Med, Riyadh, Saudi Arabia. [BaHammam, A. S.] Natl Plan Sci Technol & Innovat Riyadh, Strateg Technol Program, Riyadh, Saudi Arabia. [Srivanitchapoom, P.; Hallett, M.] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Srivanitchapoom, P.] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med, Bangkok 10700, Thailand. [Pandey, S.] Govind Ballabh Pant Inst Postgrad Med Educ & Res, New Delhi, India. RP Gupta, R (reprint author), Himalayan Inst Med Sci, Dept Psychiat, Dehra Dun 248016, Uttar Pradesh, India.; Gupta, R (reprint author), Himalayan Inst Med Sci, Sleep Clin, Dehra Dun 248016, Uttar Pradesh, India. EM sleepdoc.ravi@gmail.com RI BaHammam, Ahmed/B-9037-2008; Seithikurippu R, Pandi-Perumal/Q-8281-2016; OI BaHammam, Ahmed/0000-0002-1706-6167; Seithikurippu R, Pandi-Perumal/0000-0002-8686-7259; Gupta, Ravi/0000-0003-2583-563X; Kendzerska, Tetyana/0000-0002-5301-1796 NR 98 TC 2 Z9 2 U1 6 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-6314 EI 1600-0404 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD MAY PY 2016 VL 133 IS 5 BP 320 EP 329 DI 10.1111/ane.12520 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA DI8TH UT WOS:000373774300001 PM 26482928 ER PT J AU McPherron, AC AF McPherron, A. C. TI The ups and downs of exercise and insulin sensitivity: a role for the myokine myostatin in glucose metabolism? SO ACTA PHYSIOLOGICA LA English DT Editorial Material ID EXPRESSION C1 [McPherron, A. C.] NIDDK, Bethesda, MD 20892 USA. [McPherron, A. C.] MyoTherapeutics, Silver Spring, MD USA. RP McPherron, AC (reprint author), NIDDK, Bethesda, MD 20892 USA.; McPherron, AC (reprint author), MyoTherapeutics, Silver Spring, MD USA. EM mcpherrona@niddk.nih.gov NR 11 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1748-1708 EI 1748-1716 J9 ACTA PHYSIOL JI Acta Physiol. PD MAY PY 2016 VL 217 IS 1 BP 6 EP 10 DI 10.1111/apha.12650 PG 5 WC Physiology SC Physiology GA DI4UM UT WOS:000373494900002 PM 26751052 ER PT J AU Schwartz, LP Silberberg, A Casey, AH Paukner, A Suomi, SJ AF Schwartz, Lindsay P. Silberberg, Alan Casey, Anna H. Paukner, Annika Suomi, Stephen J. TI Scaling reward value with demand curves versus preference tests SO ANIMAL COGNITION LA English DT Article DE Behavioral economics; Exponential model of demand; Choice; Monkeys ID MONKEYS CEBUS-APELLA; CAPUCHIN MONKEYS; INEQUITY AVERSION; REFLEX STRENGTH; FOOD; GRATIFICATION; ECONOMICS; CHOICE; DRIVE; DELAY AB In Experiment 1, six capuchins lifted a weight during a 10-min session to receive a food piece. Across conditions, the weight was increased across six different amounts for three different food types. The number of food pieces obtained as a function of the weight lifted was fitted by a demand equation that is hypothesized to quantify food value. For most subjects, this analysis showed that the three food types differed little in value. In Experiment 2, these monkeys were given pairwise choices among these food types. In 13 of 18 comparisons, preferences at least equaled a 3-to-1 ratio; in seven comparisons, preference was absolute. There was no relation between values based on degree of preference versus values based on the demand equation. When choices in the present report were compared to similar data with these subjects from another study, between-study lability in preference emerged. This outcome contrasts with the finding in demand analysis that test-retest reliability is high. We attribute the unreliability and extreme assignment of value based on preference tests to high substitutability between foods. We suggest use of demand analysis instead of preference tests for studies that compare the values of different foods. A better strategy might be to avoid manipulating value by using different foods. Where possible, value should be manipulated by varying amounts of a single food type because, over an appropriate range, more food is consistently more valuable than less. Such an approach would be immune to problems in between-food substitutability. C1 [Schwartz, Lindsay P.; Silberberg, Alan; Casey, Anna H.] Amer Univ, Dept Psychol, Washington, DC 20016 USA. [Paukner, Annika; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Poolesville, MD USA. RP Schwartz, LP (reprint author), Amer Univ, Dept Psychol, Washington, DC 20016 USA. EM lindsaypschwartz@gmail.com FU Intramural NIH HHS [Z99 HD999999] NR 25 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1435-9448 EI 1435-9456 J9 ANIM COGN JI Anim. Cogn. PD MAY PY 2016 VL 19 IS 3 BP 631 EP 641 DI 10.1007/s10071-016-0967-4 PG 11 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA DI8IE UT WOS:000373743900018 PM 26908005 ER PT J AU Kim, HK Isaacs-Trepanier, C Elmi, N Rapoport, SI Andreazza, AC AF Kim, Helena K. Isaacs-Trepanier, Cameron Elmi, Nika Rapoport, Stanley I. Andreazza, Ana C. TI Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE NMDA; Lipid peroxidation; Mitochondria; Excitotoxicity; Lithium ID ARACHIDONIC-ACID RELEASE; MAGNETIC-RESONANCE-SPECTROSCOPY; CEREBELLAR GRANULE CELLS; OXIDATIVE STRESS; BIPOLAR DISORDER; RECEPTOR ACTIVATION; COMPLEX-I; NEURODEGENERATIVE DISORDERS; HIPPOCAMPAL-NEURONS; PREFRONTAL CORTEX AB Chronic N-methyl-D-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kim, Helena K.; Isaacs-Trepanier, Cameron; Elmi, Nika; Andreazza, Ana C.] Univ Toronto, Dept Pharmacol, Med Sci Bldg, Toronto, ON M5S 1A8, Canada. [Kim, Helena K.; Isaacs-Trepanier, Cameron; Elmi, Nika; Andreazza, Ana C.] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada. [Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Neurosci Lab, NIH, Bethesda, MD 20892 USA. [Andreazza, Ana C.] Ctr Addict & Mental Hlth, Toronto, ON M5T 1R8, Canada. RP Andreazza, AC (reprint author), RM4204,1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada. EM helenakim0913@gmail.com; cameron.isaacs.trepanier@gmail.com; nikaelmi@gmail.com; sir@mail.nih.gov; ana.andreazza@utoronto.ca FU National Institute on Aging, NIH; Canadian Institute of Health Research [CIHR MOP 133439]; Brain and Behavior Research Foundation (NARSAD); Ontario Mental Health Foundation FX The work by SIR was entirely supported by the Intramural Program of the National Institute on Aging, NIH. ACA receives grant funding from Canadian Institute of Health Research (CIHR MOP 133439) and Brain and Behavior Research Foundation (NARSAD). HKK was supported by the Ontario Mental Health Foundation. Funding sources had no involvement in study design, collection, analysis and interpretation of data, and preparation of the manuscript. NR 62 TC 2 Z9 2 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD MAY PY 2016 VL 76 BP 59 EP 65 DI 10.1016/j.jpsychires.2016.02.001 PG 7 WC Psychiatry SC Psychiatry GA DI3QB UT WOS:000373412400008 PM 26894301 ER PT J AU Andrade, LR Salles, FT Grati, M Manor, U Kachar, B AF Andrade, Leonardo R. Salles, Felipe T. Grati, M'hamed Manor, Uri Kachar, Bechara TI Tectorins crosslink type II collagen fibrils and connect the tectorial membrane to the spiral limbus SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Extracellular matrix; Electron microscopy; Immunogold-labeling; Tectorial membrane; Tectorins ID INNER-EAR; TRAVELING-WAVES; ALPHA-TECTORIN; HEARING IMPAIRMENT; SENSORY EPITHELIA; DEAFNESS; MUTATIONS; MATRIX; MOUSE AB All inner ear organs possess extracellular matrix appendices over the sensory epithelia that are crucial for their proper function. The tectorial membrane (TM) is a gelatinous acellular membrane located above the hearing sensory epithelium and is composed mostly of type II collagen, and alpha and beta tectorins. TM molecules self-assemble in the endolymph fluid environment, interacting medially with the spiral limbus and distally with the outer hair cell stereocilia. Here, we used immunogold labeling in freeze-substituted mouse cochleae to assess the fine localization of both tectorins in distinct TM regions. We observed that the TM adheres to the spiral limbus through a dense thin matrix enriched in alpha- and beta-tectorin, both likely bound to the membranes of interdental cells. Freeze-etching images revealed that type II collagen fibrils were crosslinked by short thin filaments (4 +/- 1.5 nm, width), resembling another collagen type protein, or chains of globular elements (15 +/- 3.2 nm, diameter). Gold-particles for both tectorins also localized adjacent to the type II collagen fibrils, suggesting that these globules might be composed essentially of alpha- and beta-tectorins. Finally, the presence of gold-particles at the TM lower side suggests that the outer hair cell stereocilia membrane has a molecular partner to tectorins, probably stereocilin, allowing the physical connection between the TM and the organ of Corti. (C) 2016 Elsevier Inc. All rights reserved. C1 [Andrade, Leonardo R.; Salles, Felipe T.; Grati, M'hamed; Manor, Uri; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Andrade, Leonardo R.] Univ Fed Rio de Janeiro, Inst Biomed Sci, Lab Biomineralizat, BR-21941902 Rio De Janeiro, RJ, Brazil. [Salles, Felipe T.] Univ Florida, Coll Dent, Dept Community Dent & Behav Sci, Gainesville, FL 32610 USA. [Grati, M'hamed] Univ Miami, Miller Sch Med, Dept Otolaryngol, Mol Genet Lab, Miami, FL 33136 USA. [Manor, Uri] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Organelle Biol, NIH, Bethesda, MD 20892 USA. RP Andrade, LR (reprint author), Univ Fed Rio de Janeiro, Inst Biomed Sci, Lab Biomineralizat, ICB,CCS,Ilha Fundao, Av Carlos Chagas Filho 373,F2-30, BR-21941902 Rio De Janeiro, RJ, Brazil.; Kachar, B (reprint author), NIDCD, Lab Cell Struct & Dynam, NIH, 35A Convent Dr 3D-824, Bethesda, MD 20892 USA. EM andrade@histo.ufrj.br; kacharb@nidcd.nih.gov OI Grati, M'hamed/0000-0002-4490-1682; Manor, Uri/0000-0002-9802-1955 FU NIH [Z01-DC000002] FX We would like to Dr. Ronald Petralia (NIDCD, NIH) for the use of the TEM and critical reading of the manuscript, and Nicole Thompson (NIDCD) for the grammar review. Work was supported by NIH intramural research funds Z01-DC000002. We declare no conflict of interest. NR 29 TC 0 Z9 0 U1 5 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 EI 1095-8657 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAY PY 2016 VL 194 IS 2 BP 139 EP 146 DI 10.1016/j.jsb.2016.01.006 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DI3QS UT WOS:000373414200001 PM 26806019 ER PT J AU Marabini, R Ludtke, SJ Murray, SC Chiu, W de la Rosa-Trevin, JM Patwardhan, A Heymann, JB Carazo, JM AF Marabini, Roberto Ludtke, Steven J. Murray, Stephen C. Chiu, Wah de la Rosa-Trevin, Jose M. Patwardhan, Ardan Heymann, J. Bernard Carazo, Jose M. TI The Electron Microscopy eXchange (EMX) initiative SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Electron microscopy; Data sharing; Conventions; Standardization ID COMMUNITY STANDARD; SOFTWARE SUITE; REPRESENTATION; INFORMATION; BIOLOGY; FORMAT; MODEL AB Three-dimensional electron microscopy (3DEM) of ice-embedded samples allows the structural analysis of large biological macromolecules close to their native state. Different techniques have been developed during the last forty years to process cryo-electron microscopy (cryo-EM) data. Not surprisingly, success in analysis and interpretation is highly correlated with the continuous development of image processing packages. The field has matured to the point where further progress in data and methods sharing depends on an agreement between the packages on how to describe common image processing tasks. Such standardization will facilitate the use of software as well as seamless collaboration, allowing the sharing of rich information between different platforms. Our aim here is to describe the Electron Microscopy eXchange (EMX) initiative, launched at the 2012 Instruct Image Processing Center Developer Workshop, with the intention of developing a first set of standard conventions for the interchange of information for single-particle analysis (EMX version 1.0). These conventions cover the specification of the metadata for micrograph and particle images, including contrast transfer function (CTF) parameters and particle orientations. EMX v1.0 has already been implemented in the Bsoft, EMAN, Xmipp and Scipion image processing packages. It has been and will be used in the CTF and EMDataBank Validation Challenges respectively. It is also being used in EMPIAR, the Electron Microscopy Pilot Image Archive, which stores raw image data related to the 3DEM reconstructions in EMDB. (C) 2016 Elsevier Inc. All rights reserved. C1 [Marabini, Roberto] Univ Autonoma Madrid, Escuela Politecn Super, Campus Univ Autonoma, E-28049 Madrid, Spain. [Ludtke, Steven J.; Chiu, Wah] Baylor Coll Med, Natl Ctr Macromol Imaging, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [de la Rosa-Trevin, Jose M.; Carazo, Jose M.] Natl Ctr Biotechnol CSIC, Biocomp Unit, C Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain. [Patwardhan, Ardan] European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge, England. [Heymann, J. Bernard] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Murray, Stephen C.] Baylor Coll Med, Grad Program Struct & Computat Biol & Mol Biophys, Houston, TX 77030 USA. RP Marabini, R (reprint author), Univ Autonoma Madrid, Escuela Politecn Super, Campus Univ Autonoma, E-28049 Madrid, Spain. EM roberto@cnb.csic.es OI Patwardhan, Ardan/0000-0001-7663-9028; Marabini, Roberto/0000-0001-7876-1684 FU Spanish Ministry of Economy and Competitiveness [AIC-A-2011-0638, BIO2013-44647-R, BFU2013-41249-P]; Comunidad de Madrid through grant CAM [S2010/BMD-2305]; European Union (EU) and Horizon 2020 [EINFRA-2014-2, 654142, EINFRA-2015-1, 675858]; USA National Institutes of Health [R01GM079429, R01GM080139, P41GM103832]; Instruct, a component of the European Strategy Forum on Research Infrastructures (ESFRI); Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX The authors acknowledge financial support from the Spanish Ministry of Economy and Competitiveness through grants AIC-A-2011-0638, BIO2013-44647-R and BFU2013-41249-P; the Comunidad de Madrid through grant CAM (S2010/BMD-2305); the European Union (EU) and Horizon 2020 through grants: EINFRA-2014-2: EGI Engage (Proposal: 654142) and EINFRA-2015-1: West-Life (Proposal: 675858); and the USA National Institutes of Health through grants: R01GM079429, R01GM080139 and P41GM103832.; This work was partially funded by Instruct, a component of the European Strategy Forum on Research Infrastructures (ESFRI), and supported by national member subscriptions and by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 29 TC 3 Z9 3 U1 3 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 EI 1095-8657 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAY PY 2016 VL 194 IS 2 BP 156 EP 163 DI 10.1016/j.jsb.2016.02.008 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DI3QS UT WOS:000373414200003 PM 26873784 ER PT J AU Turkbey, B Choyke, PL Pinto, PA AF Turkbey, Baris Choyke, Peter L. Pinto, Peter A. TI Untitled SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Choyke, Peter L.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD MAY PY 2016 VL 195 IS 5 BP 1427 EP 1427 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DJ3ZI UT WOS:000374144800036 PM 26921011 ER PT J AU Muniz, JA Gomez, G Gonzalez, B Rivero-Echeto, MC Cadet, JL Garcia-Rill, E Urbano, FJ Bisagno, V AF Muniz, Javier A. Gomez, Gimena Gonzalez, Betina Celeste Rivero-Echeto, Maria Cadet, Jean Lud Garcia-Rill, Edgar Urbano, Francisco J. Bisagno, Veronica TI Combined Effects of Simultaneous Exposure to Caffeine and Cocaine in the Mouse Striatum SO NEUROTOXICITY RESEARCH LA English DT Article DE Cocaine; Caffeine; Striatum; Locomotor; sensitization; Dopamine; Astroglia ID ADENOSINE A(2A) RECEPTORS; FIBRILLARY ACIDIC PROTEIN; SUBSTANCE USE DISORDERS; GENE-EXPRESSION; ORAL CAFFEINE; SENSITIZATION; DOPAMINE; BRAIN; MECHANISMS; ADDICTION AB Caffeine is the world's most popular psychoactive drug and is also an active adulterant found in many drugs of abuse, including seized cocaine samples. Despite several studies which examine the effects of caffeine or cocaine administered as single agents, little data are available for these agents when given in combination. The purpose of the present study was to determine if combined intake of both psychostimulants can lead to maladaptive changes in striatal function. Mice were injected with a binge regimen (intermittent treatment for 13 days) of caffeine (3 x 5 mg/kg), cocaine (3 x 10 mg/kg), or combined administration. We found that chronic caffeine potentiated locomotion induced by cocaine and that both caffeine-treated groups showed sensitization. Striatal tissue was obtained 24 h and 7 days after last injection (withdrawal) for immunohistochemistry and mRNA expression. Our results show that combined intake of both psychostimulants can increase GFAP immunoreactivity in the striatum at both times post treatment. Gene expression analysis, targeted at dopamine, adenosine, and glutamate receptor subunit genes, revealed significant transcript down-regulation in the dorsal striatum of AMPA, NMDA, D1 and D2 receptor subunit mRNA expression in the group that received combined treatment, but not after individual administration. At withdrawal, we found increased D1 receptor mRNA expression along with increased A1, AMPA, NMDA, and metabotropic subunit expression. A2A mRNA showed decreased expression after both times in all experimental groups. Our study provides evidence that there are striatal alterations mediated by combined caffeine and cocaine administration, and highlights negative outcomes of chronic intake of both psychostimulants. C1 [Muniz, Javier A.; Gomez, Gimena; Gonzalez, Betina; Bisagno, Veronica] Univ Buenos Aires, CONICET, Inst Invest Farmacol, Buenos Aires, DF, Argentina. [Celeste Rivero-Echeto, Maria; Urbano, Francisco J.] Univ Buenos Aires, CONICET, Dept Fisiol Biol Mol & Celular Dr Hector Maldonad, Lab Fisiol & Biol Mol,Inst Fisiol Biol Mol & Neur, Junin 956,Piso 5,C1113, Buenos Aires, DF, Argentina. [Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, NIH, Intramural Res Program, Baltimore, MD USA. [Garcia-Rill, Edgar] Univ Arkansas Med Sci, Dept Neurobiol & Dev Sci, Ctr Translat Neurosci, Little Rock, AR 72205 USA. RP Bisagno, V (reprint author), Univ Buenos Aires, CONICET, Inst Invest Farmacol, Buenos Aires, DF, Argentina. EM vbisagno@ffyb.uba.ar FU FONCYT-Agencia Nacional de Promocion Cientifica y Tecnologica Argentina [BID 1728 OC.AR. T 2012-0924, BID 1728 OC.AR. PICT2012-1769]; UBACYT [2014-2017 #201201301013 05BA]; core facilities of Center for Translational Neuroscience; UAMS, USA; NIH award [P20 GM110702] FX Dr. Bisagno has been authorized to study drug abuse substances in animal models by A.N.M.A.T. (National Board of Medicine Food and Medical Technology, Ministerio de Salud, Argentina). This work was supported by FONCYT-Agencia Nacional de Promocion Cientifica y Tecnologica; BID 1728 OC.AR. T 2012-0924 Argentina (to Dr. Bisagno) and FONCYT-Agencia Nacional de Promocion Cientifica y Tecnologica; BID 1728 OC.AR. PICT2012-1769, Argentina, and UBACYT 2014-2017 #201201301013 05BA (to Dr. Urbano). In addition, this work was supported by core facilities of the Center for Translational Neuroscience, UAMS, USA, supported by NIH award P20 GM110702. NR 69 TC 1 Z9 1 U1 4 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 EI 1476-3524 J9 NEUROTOX RES JI Neurotox. Res. PD MAY PY 2016 VL 29 IS 4 BP 525 EP 538 DI 10.1007/s12640-016-9601-0 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DI6VM UT WOS:000373638300007 PM 26858178 ER PT J AU Hinkle, SN Mitchell, EM Grantz, KL Ye, AJ Schisterman, EF AF Hinkle, Stefanie N. Mitchell, Emily M. Grantz, Katherine L. Ye, Aijun Schisterman, Enrique F. TI Maternal Weight Gain During Pregnancy: Comparing Methods to Address Bias Due to Length of Gestation in Epidemiological Studies SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE Bias; Epidemiology; Weight gain; Pregnancy; Gestational age ID COLLIDER-STRATIFICATION BIAS; INFANT-MORTALITY; AGE; MODELS; ADJUST AB BackgroundStudies examining total gestational weight gain (GWG) and outcomes associated with gestational age (GA) are potentially biased. The z-score has been proposed to mitigate this bias. We evaluated a regression-based adjustment for GA to remove the correlation between GWG and GA, and compared it to published weight-gain-for-gestational-age z-scores when applied to a study sample with different underlying population characteristics. MethodsUsing 65 643 singleton deliveries to normal weight women at 12 US clinical sites, we simulated a null association between GWG and neonatal mortality. Logistic regression was used to estimate approximate relative risks (RR) of neonatal mortality associated with GWG, unadjusted and adjusted for GA, and the z-score, overall and within study sites. Average RRs across 5000 replicates were calculated with 95% coverage probability to indicate model bias and precision, where 95% is nominal. ResultsUnder a simulated null association, total GWG resulted in a biased mortality estimate (RR = 0.87; coverage = 0%); estimates adjusted for GA were unbiased (RR = 1.00; coverage = 94%). Quintile-specific RRs ranged from 0.97-1.03. Similar results were observed for site-specific analyses. The overall z-score RR was 0.97 (84% coverage) with quintile-specific RRs ranging from 0.64-0.90. Estimates were close to 1.0 at most sites, with coverage from 70-94%. Sites 1 and 6 were biased with RRs of 0.66 and 1.43, respectively, and coverage of 70% and 80%. ConclusionsAdjusting for GA achieves unbiased estimates of the association between total GWG and neonatal mortality, providing an accessible alternative to the weight-gain-for-gestational-age z-scores without requiring assumptions concerning underlying population characteristics. C1 [Hinkle, Stefanie N.; Mitchell, Emily M.; Grantz, Katherine L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Ye, Aijun] Glotech Inc, Rockville, MD USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Hinkle, Stefanie/0000-0003-4312-708X; Schisterman, Enrique/0000-0003-3757-641X; Grantz, Katherine/0000-0003-0276-8534 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN267200603425C] FX This research was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract number HHSN267200603425C). The authors would like to thank Drs. Nansi S. Boghossian, Jennifer A. Hutcheon, Robert W. Platt and Lindsey A. Sjaarda for their helpful suggestions to earlier versions of the manuscript. The authors have no conflicts of interest. NR 19 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAY PY 2016 VL 30 IS 3 BP 294 EP 304 DI 10.1111/ppe.12284 PG 11 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA DI6QD UT WOS:000373623800010 PM 26916673 ER PT J AU Tian, Q Resnick, SM Landman, BA Huo, YK Venkatraman, VK Gonzalez, CE Simonsick, EM Shardell, MD Ferrucci, L Studenski, SA AF Tian, Qu Resnick, Susan M. Landman, Bennett A. Huo, Yuankai Venkatraman, Vijay K. Gonzalez, Christopher E. Simonsick, Eleanor M. Shardell, Michelle D. Ferrucci, Luigi Studenski, Stephanie A. TI Lower gray matter integrity is associated with greater lap time variation in high-functioning older adults SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Gray matter integrity; Diffusion tensor imaging; Mean diffusivity; Lap time variation; High-functioning older adults ID GAIT VARIABILITY; ALZHEIMERS-DISEASE; EXECUTIVE FUNCTION; COGNITIVE DECLINE; BRAIN; RISK; VOLUME; WALKING; PEOPLE AB Background: Lower integrity of cerebral gray matter is associated with higher gait variability. It is not known whether gray matter integrity is associated with higher lap time variation (LTV), a clinically accessible measure of gait variability, high levels of which have been associated with mortality. This study examines the cross-sectional association between gray matter mean diffusivity (MD) and LTV in community-dwelling older adults. Methods: Study participants consisted of 449 high-functioning adults aged 50 and older (56.8% female) in the Baltimore Longitudinal Study of Aging, free of overt neurological disease. The magnitude of MD in the gray matter, a measure of impaired tissue integrity, was assessed by diffusion tensor imaging in 16 regions of interest (ROIs) involved with executive function, sensorimotor function, and memory. LTV was assessed as variability in lap time based on individual trajectories over ten 40-m laps. Age, sex, height, and weight were covariates. The model additionally adjusted for mean lap time and health conditions that may affect LTV. Results: Higher levels of average MD across 16 ROIs were significantly associated with higher LTV after adjustment for covariates. Specifically, higher MD in the precuneus and the anterior and middle cingulate cortices was strongly associated with higher LTV, as compared to other ROIs. The association persisted after adjustment for mean lap time, hypertension, and diabetes. Conclusions: Lower gray matter integrity in selected areas may underlie greater LTV in high-functioning community-dwelling older adults. Longitudinal studies are warranted to examine whether changes in gray matter integrity precede more variable gait. Published by Elsevier Inc. C1 [Tian, Qu; Simonsick, Eleanor M.; Shardell, Michelle D.; Ferrucci, Luigi; Studenski, Stephanie A.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Resnick, Susan M.; Venkatraman, Vijay K.; Gonzalez, Christopher E.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Landman, Bennett A.; Huo, Yuankai] Vanderbilt Univ, Sch Engn, Nashville, TN 37212 USA. RP Tian, Q (reprint author), NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA.; Tian, Q (reprint author), 251 Bayview Blvd,Suite 100,Rm 04B316, Baltimore, MD 21224 USA. EM qu.tian@nih.gov RI Tian, Qu/E-5266-2015 OI Tian, Qu/0000-0003-2706-1439 FU National Institute on Aging [03-AG-0325] FX This research was supported by the Intramural Research Program of the National Institute on Aging (grant number: 03-AG-0325). The authors would like to acknowledge the editorial assistance from the National Institutes of Health Fellows Editorial Board. NR 35 TC 1 Z9 1 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD MAY PY 2016 VL 77 BP 46 EP 51 DI 10.1016/j.exger.2016.02.009 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DH5GZ UT WOS:000372815800007 PM 26899565 ER PT J AU O'Suoji, C Welch, JJG Perkins, SL Smith, LM Weitzman, S Simko, SJ Galardy, PJ Bollard, CM Gross, TG Termuhlen, AM AF O'Suoji, Chibuzo Welch, Jennifer J. G. Perkins, Sherrie L. Smith, Lynette M. Weitzman, Sheila Simko, Stephen J. Galardy, Paul J. Bollard, Catherine M. Gross, Thomas G. Termuhlen, Amanda M. TI Rare Pediatric Non-Hodgkin Lymphomas: A Report From Children's Oncology Group Study ANHL 04B1 SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cutaneous lymphoma; follicular lymphoma; Non-Hodgkin lymphoma ID T-CELL LYMPHOMA; FOLLICULAR-LYMPHOMA; CLINICOPATHOLOGICAL FEATURES; CUTANEOUS LYMPHOMA; MYCOSIS-FUNGOIDES; YOUNG-ADULTS; EXPERIENCE; CHILDHOOD; TRANSPLANTATION; THERAPY AB BackgroundNon-Hodgkin lymphoma (NHL) is a relatively common malignancy in pediatric patients; however, a small subgroup have unusual lymphoma subtypes for the pediatric population. ProcedureThe Children's Oncology Group Rare and Cutaneous NHL registry's (protocol ANHL 04B1) main objectives were to determine the pathologic, biologic, and clinical features of rare and cutaneous pediatric NHL and establish a bank of centrally reviewed tissue specimens. We report the clinical data, treatment data, and outcome for rare pediatric NHL. ResultsIn 101 lymphomas, there is a 97.8% concordance between the reviewing study pathologists and an 87.6% concordance between the central and institutional pathology review. Samples in the specimen bank include primary tumor tissue that is snap frozen, in paraffin blocks, or H&E-stained and unstained paraffin slides as well as blood, serum, and bone marrow. This descriptive analysis shows that children with pediatric follicular lymphoma, mucosa-associated lymphoid tissue, nodal marginal zone lymphoma, primary cutaneous, primary central nervous system lymphoma, and subcutaneous panniculitis-like T-cell lymphomas have 100% survival at a median of 2 years from enrollment. There are early deaths, mostly from progressive disease, in subjects with peripheral T-cell (not otherwise specified), NKT, and hepatosplenic T-cell lymphomas. ConclusionsThis registry provides high-quality biologic specimens with clinical data to investigators working on the biology of these unusual pediatric diseases. C1 [O'Suoji, Chibuzo] W Virginia Univ, Div Pediat Hematol Oncol, Charleston, WV 25304 USA. [Welch, Jennifer J. G.] Brown Univ, Hasbro Childrens Hosp, Alpert Med Sch, Div Pediat Hematol Oncol, Providence, RI 02912 USA. [Perkins, Sherrie L.] Univ Utah Hlth Sci, Dept Pathol, Salt Lake City, UT USA. [Smith, Lynette M.] Univ Nebraska Med Ctr, Dept Biostat, Omaha, NE USA. [Weitzman, Sheila] Hosp Sick Children, Div Pediat Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Simko, Stephen J.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Galardy, Paul J.] Mayo Clin, Div Pediat Hematol Oncol, Rochester, MN USA. [Bollard, Catherine M.] George Washington Univ, Childrens Natl Hlth Syst, Washington, DC USA. [Gross, Thomas G.] NCI, Rockville, MD USA. [Termuhlen, Amanda M.] Univ So Calif, Keck Sch Med, Dept Pediat, Los Angeles, CA 90033 USA. RP Termuhlen, AM (reprint author), Childrens Hosp Los Angeles, Div Pediat Hematol Oncol BMT, 4650 Sunset Blvd,Mailstop 54, Los Angeles, CA 90027 USA. EM atermuhlen@chla.usc.edu FU COG [U10CA098543]; Human Specimen Banking in NCI [U24CA114766]; Statistics Data Center [U10CA098413] FX Grant sponsor: COG Chair's; Grant number: U10CA098543; Grant sponsor: Human Specimen Banking in NCI-Sponsored Clinical Trials; Grant number: U24CA114766; Grant sponsor: Statistics & Data Center; Grant number: U10CA098413. NR 38 TC 4 Z9 4 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAY PY 2016 VL 63 IS 5 BP 794 EP 800 DI 10.1002/pbc.25881 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DH7CD UT WOS:000372947900005 PM 26728447 ER PT J AU Smarr, MM Grantz, KL Zhang, CL Sundaram, R Maisog, JM Barr, DB Louis, GMB AF Smarr, Melissa M. Grantz, Katherine L. Zhang, Cuilin Sundaram, Rajeshwari Maisog, Jose M. Barr, Dana Boyd Louis, Germaine M. Buck TI Persistent organic pollutants and pregnancy complications SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Gestational diabetes mellitus; Hypertension; Organochlorine pesticides; Polybrominated diphenyl ethers; Preconception ID GESTATIONAL DIABETES-MELLITUS; POLYBROMINATED DIPHENYL ETHERS; SERUM CONCENTRATIONS; HYPERTENSIVE DISORDERS; GLUCOSE-METABOLISM; DETECTION LIMITS; EXPOSURE; HEALTH; ASSOCIATION; POPULATION AB We sought to investigate the relationship between maternal preconception exposures to persistent organic pollutants (POPs) and pregnancy complications, gestational diabetes (GDM) and gestational hypertension. Data from 258 (51%) women with human chorionic gonadotropin (hCG) confirmed pregnancies reaching >= 24 weeks gestation, from a prospective cohort of 501 couples who discontinued contraception to attempt pregnancy, were analyzed. Preconception concentrations of 9 organochlorine pesticides (OCPs) and 10 polybrominated diphenyl ethers (PBDEs) were quantified in serum. In separate multiple logistic regression models of self-reported physician diagnosed outcomes: GDM (11%) and gestational hypertension (10%), chemicals were natural log-transformed and rescaled by their standard deviation (SD). Models were adjusted for serum lipids, and then adjusted for age, body mass index, race, and smoking. Models were additionally adjusted for the sum of the remaining POPs in each chemical class. Women's serum concentration of PBDE congener 153 (PBDE-153) was positively associated with an increased odds of GDM per SD increase in log-transformed concentration, for unadjusted (OR = 1.36, 95% CI: 1.02-1.81), a priori adjusted (OR = 1.38, 95% CI: 1.03-1.86) and with the sum of remaining PBDEs (OR = 1.79, 95% CI: 1.18, 2.74) models. Our findings suggest that at environmentally relevant concentrations, maternal exposure to POPs prior to conception may contribute to increased chance of developing GDM. Published by Elsevier B.V. C1 [Smarr, Melissa M.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Director, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. [Grantz, Katherine L.; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. [Maisog, Jose M.] Glotech Inc, Rockville, MD 20852 USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, 1518 Clifton Rd, Atlanta, GA 30322 USA. RP Smarr, MM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. EM melissa.smarr@mail.nih.gov; katherine.grantz@nih.gov; zhangcu@mail.nih.gov; sundaramr2@mail.nih.gov; bravas02@gmail.com; dbbarr@emory.edu; louisg@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490; Sundaram, Rajeshwari/0000-0002-6918-5002; Grantz, Katherine/0000-0003-0276-8534 FU NICHD [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358] FX This research was supported by the Intramural Research Program of the NICHD (contracts N01-HD-3-3355, N01-HD-3-3356, and NOH-HD-3-3358). NR 46 TC 5 Z9 5 U1 6 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD MAY 1 PY 2016 VL 551 BP 285 EP 291 DI 10.1016/j.scitotenv.2016.02.030 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA DH2BT UT WOS:000372589800031 PM 26878640 ER PT J AU Poniewierska-Baran, A Schneider, G Sun, WY Abdelbaset-Ismail, A Barr, FG Ratajczak, MZ AF Poniewierska-Baran, Agata Schneider, Gabriela Sun, Wenyue Abdelbaset-Ismail, Ahmed Barr, Frederic G. Ratajczak, Mariusz Z. TI Human rhabdomyosarcoma cells express functional pituitary and gonadal sex hormone receptors: therapeutic implications SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE rhabdomyosarcoma; follicle-stimulating hormone; luteinizing hormone; androgen; proliferation; metastasis ID TISSUE-LEVELS INCREASE; ALVEOLAR RHABDOMYOSARCOMA; HEPATOCELLULAR-CARCINOMA; PROMETASTATIC FACTORS; ESTROGEN-RECEPTORS; INHIBITORY FACTOR; BIOACTIVE LIPIDS; TUMOR-METASTASIS; GASTRIC-CANCER; LUNG-CANCER AB Evidence has accumulated that sex hormones play an important role in several types of cancer. Because they are also involved in skeletal muscle development and regeneration, we were therefore interested in their potential involvement in the pathogenesis of human rhabdomyosarcoma (RMS), a skeletal muscle tumor. In the present study, we employed eight RMS cell lines (three fusion positive and five fusion negative RMS cell lines) and mRNA samples obtained from RMS patients. The expression of sex hormone receptors was evaluated by RT-PCR and their functionality by chemotaxis, adhesion and direct cell proliferation assays. We report here for the first time that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) receptors are expressed in established human RMS cell lines as well as in primary tumor samples isolated from RMS patients. We also report that human RMS cell lines responded both to pituitary and gonadal sex hormone stimulation by enhanced proliferation, chemotaxis, cell adhesion and phosphorylation of MAPKp42/44 and AKT. In summary, our results indicate that sex hormones are involved in the pathogenesis and progression of RMS, and therefore, their therapeutic application should be avoided in patients that have been diagnosed with RMS. C1 [Poniewierska-Baran, Agata; Schneider, Gabriela; Abdelbaset-Ismail, Ahmed; Ratajczak, Mariusz Z.] Univ Louisville, James Graham Brown Canc Ctr, Stem Cell Inst, 500 S Floyd St,Room 107, Louisville, KY 40202 USA. [Poniewierska-Baran, Agata] Pomeranian Med Univ, Dept Physiol, Szczecin, Poland. [Sun, Wenyue; Ratajczak, Mariusz Z.] Med Univ Warsaw, Dept Regenerat Med, Warsaw, Poland. [Barr, Frederic G.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. RP Ratajczak, MZ (reprint author), Univ Louisville, James Graham Brown Canc Ctr, Stem Cell Inst, 500 S Floyd St,Room 107, Louisville, KY 40202 USA. EM mzrata01@louisville.edu RI Abdelbaset Ismail , Ahmed/P-4700-2015 OI Abdelbaset Ismail , Ahmed/0000-0002-2135-1753 FU NIH [2R01 DK074720, R01HL112788]; Stella and Henry Endowment; Maestro grant [2011/02/A/NZ4/00035]; NCN Harmonia Grant [UMO-2014/14/M/NZ3/00475]; Intramural Research Program of the National Cancer Institute FX We would like to thank Dr Sylwia Rzeszotek from Pomeranian Medical University for her help with immunofluorescence staining. The present study was supported by the NIH grants 2R01 DK074720 and R01HL112788, the Stella and Henry Endowment, the Maestro grant 2011/02/A/NZ4/00035 and the NCN Harmonia Grant UMO-2014/14/M/NZ3/00475 to M.Z.R. The work by F.G.B. and W.S. was supported by the Intramural Research Program of the National Cancer Institute. NR 55 TC 1 Z9 1 U1 0 U2 5 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD MAY PY 2016 VL 48 IS 5 BP 1815 EP 1824 DI 10.3892/ijo.2016.3439 PG 10 WC Oncology SC Oncology GA DH1TU UT WOS:000372568600006 PM 26983595 ER PT J AU Al-Dimasi, S Saloum, G Saykali, B Khoury, O Liu, SH Lepla, SH Abi-Habib, R El-Sibai, M AF Al-Dimasi, Saleh Saloum, Gilbert Saykali, Bechara Khoury, Oula Liu, Shihui Lepla, Stephen H. Abi-Habib, Ralph El-Sibai, Mirvat TI Targeting the MAP kinase pathway in astrocytoma cells using a recombinant anthrax lethal toxin as a way to inhibit cell motility and invasion SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE anthrax toxin; astrocytomas; motility; invasion; MAPK; RhoA ID RHO-GTPASES; SIGNALING PATHWAYS; IN-VIVO; CANCER; MIGRATION; RECEPTOR; TUMORS; ROLES; INACTIVATION; ACTIVATION AB Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Understanding and targeting cancer cell invasion is an important therapeutic approach. Cell invasion is a complex process that replies on many signaling pathways including the mitogen-activated protein (MAP) kinase (MAPK). In many cell lines, the use of MAPK-targeted drugs proved to be a potential method to inhibit cancer cell motility. In the present study, we use a recombinant anthrax lethal toxin (LeTx), which selectively inhibits the MAPK pathway, in order to target invasion. LeTx proved ineffective on cell survival in astrocytoma (as well as normal cells). However, astrocytoma cells that were treated with LeTx showed a significant decrease in cell motility as seen by wound healing as well as random 2D motility in serum. The cells also showed a decrease in invasion across a collagen matrix. The effect of LeTx on cell migration was mediated though the deregulation of Rho GTPases, which play a role in cell motility. Finally, the effect of LeTx on cell migration and Rho GTPases was mimicked by the inhibition of the MAPK pathway. In this study, we describe for the first time the effect of the LeTx on cancer cell motility and invasion not cell survival making it a potentially selective brain tumor invasion inhibitor. C1 [Al-Dimasi, Saleh; Saloum, Gilbert; Saykali, Bechara; Khoury, Oula; Abi-Habib, Ralph; El-Sibai, Mirvat] Lebanese Amer Univ, Dept Nat Sci, POB 13-5053, Beirut 11022801, Lebanon. [Liu, Shihui; Lepla, Stephen H.] NIH, Microbial Pathogenesis Sect, Parasit Dis Lab, Bldg 10, Bethesda, MD 20892 USA. RP El-Sibai, M (reprint author), Lebanese Amer Univ, Dept Nat Sci, POB 13-5053, Beirut 11022801, Lebanon. EM mirvat.elsibai@lau.edu.lb FU Natural Science Department at Lebanese American University; [CA100324]; [GM064346] FX The ROI_Tracker software was supplied by David Entenberg and John Condeelis as supported by CA100324 and GM064346. The present study was supported by the Natural Science Department at the Lebanese American University. NR 37 TC 0 Z9 0 U1 1 U2 7 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD MAY PY 2016 VL 48 IS 5 BP 1913 EP 1920 DI 10.3892/ijo.2016.3431 PG 8 WC Oncology SC Oncology GA DH1TU UT WOS:000372568600016 PM 26984023 ER PT J AU Ruan, XB AF Ruan, Xiangbo TI Long Non-Coding RNA Central of Glucose Homeostasis SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE LncRNA; GLUCOSE METABOLISM; DIABETES; CANCER METABOLISM ID BETA-CELL TRANSCRIPTOME; PROSTATE-SPECIFIC GENE; CANCER METASTASIS; BLADDER-CARCINOMA; METABOLISM; EXPRESSION; DIFFERENTIATION; PROLIFERATION; UCA1; SRA AB Glucose metabolism is one of the fundamental biochemical processes in mammals. Metabolism of glucose is subjected to tissue and cell specific regulation involving many transporters, enzymes, and transcriptional factors. Dysregulation of glucose metabolism has been linked to many human diseases such as diabetes and cancer. Long non-coding RNAs (lncRNAs) are a novel class of functional RNAs that regulate multiple biological functions through diverse mechanisms including recruitment of epigenetic modifier proteins, control of mRNA decay and translation, and DNA sequestration of transcription factors. Recent studies have demonstrated that lncRNAs play an important role in regulating differentiation and homeostasis of metabolic tissues. This review will discuss lncRNA biology with a focus on their role in regulating glucose metabolism in cancer cells and metabolic tissues. (C) 2015 Wiley Periodicals, Inc. C1 [Ruan, Xiangbo] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Ruan, XB (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM xiangbo.ruan@nih.gov RI Ruan, Xiangbo/P-9265-2016 NR 57 TC 4 Z9 4 U1 2 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD MAY PY 2016 VL 117 IS 5 BP 1061 EP 1065 DI 10.1002/jcb.25427 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG7QE UT WOS:000372278000001 PM 26530464 ER PT J AU Winchester, DA Gurel, B Till, C Goodman, PJ Tangen, CM Santella, RM Johnson-Pais, TL Leach, RJ Thompson, IM Xu, JF Zheng, SL Lucia, MS Lippman, SM Parnes, HL Isaacs, WB Drake, CG De Marzo, AM Platz, EA AF Winchester, Danyelle A. Gurel, Bora Till, Cathee Goodman, Phyllis J. Tangen, Catherine M. Santella, Regina M. Johnson-Pais, Teresa L. Leach, Robin J. Thompson, Ian M. Xu, Jianfeng Zheng, S. Lilly Lucia, M. Scott Lippman, Scott M. Parnes, Howard L. Isaacs, William B. Drake, Charles G. De Marzo, Angelo M. Platz, Elizabeth A. TI Key genes involved in the immune response are generally not associated with intraprostatic inflammation in men without a prostate cancer diagnosis: Results from the prostate cancer prevention trial SO PROSTATE LA English DT Article DE genes; inflammation; prostate cancer ID PLACEBO ARM; RISK; POLYMORPHISM AB BACKGROUNDWe previously reported that both intraprostatic inflammation and SNPs in genes involved in the immune response are associated with prostate cancer risk and disease grade. In the present study, we evaluated the association between these SNPs and intraprostatic inflammation in men without a prostate cancer diagnosis. METHODSIncluded in this cross-sectional study were 205 white controls from a case-control study nested in the placebo arm of the Prostate Cancer Prevention Trial. We analyzed inflammation data from the review of H&E-stained prostate tissue sections from biopsies performed per protocol at the end of the trial irrespective of clinical indication, and data for 16 SNPs in key genes involved in the immune response (IL1, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, TNFA; 7 tagSNPs in IL10). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between carrying at least one minor allele and having at least one biopsy core (of a mean of three reviewed) with inflammation. RESULTSNone of the SNPs evaluated was statistically significantly associated with having at least one core with inflammation. However, possible inverse associations were present for carrying the minor allele of rs2069762 (G) in IL2 (OR=0.51, 95%CI 0.25-1.02); carrying two copies of the minor allele of rs1800871 (T) of IL10 (OR=0.29, 95%CI 0.08-1.00); and carrying the minor allele of rs486907 (A) in RNASEL (OR=0.52, 95%CI 0.26-1.06). After creating a genetic risk score from the three SNPs possibly associated with inflammation, the odds of inflammation increased with increasing number of risk alleles (P-trend=0.008). CONCLUSIONWhile our findings do not generally support a cross-sectional link between individual SNPs in key genes involved in the immune response and intraprostatic inflammation in men without a prostate cancer diagnosis, they do suggest that some of these variants when in combination may be associated with intraprostatic inflammation in benign tissue. Prostate 76:565-574, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Winchester, Danyelle A.; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. [Gurel, Bora; De Marzo, Angelo M.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Gurel, Bora] Kocaeli Univ, Sch Med, Dept Pathol, Kocaeli, Turkey. [Till, Cathee; Goodman, Phyllis J.; Tangen, Catherine M.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY USA. [Johnson-Pais, Teresa L.; Leach, Robin J.; Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Xu, Jianfeng; Zheng, S. Lilly] NorthShore Univ Hlth Syst, Program Personalized Canc Care, Evanston, IL USA. [Xu, Jianfeng; Zheng, S. Lilly] NorthShore Univ Hlth Syst, Dept Surg, Evanston, IL USA. [Zheng, S. Lilly] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Lucia, M. Scott] Univ Colorado, Dept Pathol, Anschutz Med Campus, Aurora, CO USA. [Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Parnes, Howard L.] NCI, Div Canc Prevent, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Isaacs, William B.; Drake, Charles G.; De Marzo, Angelo M.; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD USA. [Isaacs, William B.; Drake, Charles G.; De Marzo, Angelo M.; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [Isaacs, William B.; Drake, Charles G.; De Marzo, Angelo M.; Platz, Elizabeth A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Drake, Charles G.] Johns Hopkins Univ, Sch Med, Dept Immunol, Baltimore, MD USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM eplatz1@jhu.edu FU National Cancer Institute, National Institutes of Health [P01 CA108964, P30 CA54174, U10 CA37429, UM1 CA182883, T32 CA009314] FX Grant sponsor: National Cancer Institute, National Institutes of Health; Grant numbers: P01 CA108964; P30 CA54174; U10 CA37429; UM1 CA182883; T32 CA009314. NR 18 TC 1 Z9 1 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD MAY 1 PY 2016 VL 76 IS 6 BP 565 EP 574 DI 10.1002/pros.23147 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA DH2UW UT WOS:000372643200005 PM 26771888 ER PT J AU Caruso, V Sreedharan, S Carlini, VP Jacobsson, JA Haitina, T Hammer, J Stephansson, O Crona, F Sommer, WH Riserus, U Lannfelt, L Marcus, C Heilig, M de Barioglio, SR Fredriksson, R Schioth, HB AF Caruso, Vanni Sreedharan, Smitha Carlini, Valeria P. Jacobsson, Josefin A. Haitina, Tatjana Hammer, Joanna Stephansson, Olga Crona, Filip Sommer, Wolfgang H. Riserus, Ulf Lannfelt, Lars Marcus, Claude Heilig, Markus de Barioglio, Susana R. Fredriksson, Robert Schioth, Helgi B. TI mRNA GPR162 changes are associated with decreased food intake in rat, and its human genetic variants with impairments in glucose homeostasis in two Swedish cohorts SO GENE LA English DT Article DE GPCRs; GPR162; Food intake; Obesity; Glucose homeostasis ID PROTEIN-COUPLED RECEPTORS; ARCUATE NUCLEUS; EVOLUTIONARY HISTORY; POMC NEURONS; HUMAN GENOME; BODY-WEIGHT; LEPTIN; BRAIN; EXPRESSION; RESISTANCE AB G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating intercellular interactions of fundamental physiological importance for survival including regulation of food intake, blood pressure, and hormonal sensing signaling, among other roles. Homeostatic alterations in the physiological status of GPCRs are often associated with underlying causes of disease, and to date, several orphan GPCRs are still uncharacterized. Findings from our previous study demonstrate that the Rhodopsin family protein GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in hypothalamus, amygdala, and ventral tegmental area, regions strictly interconnected and involved in the regulation of energy homeostasis and hedonic feeding. In this study, we provide a further anatomical characterization of GPR162 in mouse brain via in situ hybridization as well as detailed mRNA expression in a panel of rat tissues complementing a specie-specific mapping of the receptor. We also provide an attempt to demonstrate a functional implication of GPR162 in food intake-related behavior via antisense knockdown studies. Furthermore, we performed human genetic studies in which for the first time, variants of the GPR162 gene were associated with impairments in glucose homeostasis. (C) 2016 Published by Elsevier B.V. C1 [Caruso, Vanni; Sreedharan, Smitha; Carlini, Valeria P.; Jacobsson, Josefin A.; Haitina, Tatjana; Hammer, Joanna; Stephansson, Olga; Crona, Filip; Fredriksson, Robert; Schioth, Helgi B.] Uppsala Univ BMC, Unit Funct Pharmacol, Dept Neurosci, SE-75124 Uppsala, Sweden. [Caruso, Vanni] Univ Tasmania UTAS, Fac Pharm, Hobart, Tas 7001, Australia. [Carlini, Valeria P.; de Barioglio, Susana R.] Univ Nacl Cordoba, Fac Ciencias Quim Haya Torre & Medina Allende, Dept Farmacol, Ciudad Univ, RA-5016 Cordoba, Argentina. [Sommer, Wolfgang H.] Cent Inst Mental Hlth, Dept Psychopharmacol, Mannheim, Germany. [Riserus, Ulf] Uppsala Univ, Dept Publ Hlth & Caring Sci Clin Nutr & Metab, Uppsala, Sweden. [Lannfelt, Lars] Uppsala Univ, Dept Publ Hlth & Caring Sci, Geriatr, Uppsala, Sweden. [Marcus, Claude] Karolinska Inst, Dept Clin Sci Intervent & Technol, Natl Childhood Obes Ctr, Div Pediat, Stockholm, Sweden. [Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Caruso, V (reprint author), Biomed Ctr, Dept Neurosci, Unit Funct Pharmacol, Box 593, SE-75124 Uppsala, Sweden. EM vanni.caruso@neuro.uu.se FU Swedish Research Council; Ahlens Foundation; Swedish Brain Research Foundation; Novo Nordisk Foundation; Engkvist Foundation; Magnus Bergvall Foundation FX This study was supported by the Swedish Research Council, Ahlens Foundation, The Swedish Brain Research Foundation, The Novo Nordisk Foundation, Engkvist Foundation, and Magnus Bergvall Foundation. NR 42 TC 0 Z9 0 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD MAY 1 PY 2016 VL 581 IS 2 BP 139 EP 145 DI 10.1016/j.gene.2016.01.044 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DG3DG UT WOS:000371949100005 PM 26827797 ER PT J AU Chandrasekaran, AR Pushpanathan, M Halvorsen, K AF Chandrasekaran, Arun Richard Pushpanathan, Muthuirulan Halvorsen, Ken TI Evolution of DNA origami scaffolds SO MATERIALS LETTERS LA English DT Article DE DNA origami; DNA scaffolds; DNA self-assembly; DNA-based nanomaterials; Genome tailoring; DNA nanostructures ID POLYMERASE-CHAIN-REACTION; FOLDING DNA; PARANEMIC COHESION; NANOSCALE SHAPES; CRYSTALS; NANOSTRUCTURES; LINKAGE; DESIGN; ARRAYS; TILES AB Nanoscale materials made using DNA have been increasingly used for applications ranging from bio-sensors to nanoelectronics. Specifically, DNA origami - where one long single-stranded DNA scaffold is folded into nanoscale shapes and structures using short 'staple' oligonucleotides - typically relies on a single-stranded DNA scaffold derived from a viral genome. The sizes of structures that are made rely on the length of the scaffold strand; the most frequently used DNA scaffold is the single-stranded 7249-nucleotide circular M13mp18 genome. Modern techniques used in genome tailoring are now widely exploited for the creation of DNA scaffolds of various lengths for use in DNA origami. DNA scaffolds of lengths ranging from similar to 700-nucleotides to similar to 51,000 nucleotides have been prepared using biotechniques such as polymerase chain reaction, a combination of site-directed mutagenesis and site- and ligation independent cloning, and using the molecular toolbox of restriction and ligation enzymes. Such tailor-made DNA scaffolds allow the creation of origami nanostructures of desired sizes. (C) 2016 Elsevier B.V. All rights reserved. C1 [Chandrasekaran, Arun Richard; Halvorsen, Ken] SUNY Albany, RNA Inst, Albany, NY 12222 USA. [Pushpanathan, Muthuirulan] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Chandrasekaran, AR; Halvorsen, K (reprint author), SUNY Albany, RNA Inst, Albany, NY 12222 USA. EM arunrichard@nyu.edu; khalvorsen@albany.edu OI Pushpanathan, Muthuirulan/0000-0001-6240-3073 NR 46 TC 5 Z9 5 U1 22 U2 73 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-577X EI 1873-4979 J9 MATER LETT JI Mater. Lett. PD MAY 1 PY 2016 VL 170 BP 221 EP 224 DI 10.1016/j.matlet.2016.01.161 PG 4 WC Materials Science, Multidisciplinary; Physics, Applied SC Materials Science; Physics GA DG0TG UT WOS:000371778000054 ER PT J AU McGlynn, KA Hagberg, K Chen, J Braunlin, M Graubard, BI Suneja, N Jick, S Sahasrabuddhe, VV AF McGlynn, Katherine A. Hagberg, Katrina Chen, Jie Braunlin, Megan Graubard, Barry I. Suneja, Neha Jick, Susan Sahasrabuddhe, Vikrant V. TI Menopausal hormone therapy use and risk of primary liver cancer in the clinical practice research datalink SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE liver cancer; menopausal hormone therapy ID PRACTICE RESEARCH DATABASE; PLACEBO-CONTROLLED TRIAL; HEPATOCELLULAR-CARCINOMA; REPRODUCTIVE FACTORS; REPLACEMENT THERAPY; METAANALYSIS; WOMEN; HEPATOCARCINOGENESIS; DISEASE; MICE AB Primary liver cancer occurs less commonly among women than men in almost all countries. This discrepancy has suggested that hormone levels and/or exogenous hormone use could have an effect on risk, although prior studies have reached inconsistent conclusions. Thus, the current study was conducted to examine the relationship between menopausal hormone therapy (MHT) use and development of liver cancer. A nested case-control study was conducted within the United Kingdom's Clinical Practice Research Datalink (CPRD). Controls were matched, at a 4-to-1 ratio, to women diagnosed with primary liver cancer between 1988 and 2011. A second match, based on whether the cases and controls had diabetes, was also conducted. Odds ratios (OR) and 95% confidence intervals (95%CI) for associations of MHT with liver cancer were estimated using conditional logistic regression adjusted for known risk factors. In the overall match, 339 women with liver cancer were matched to 1318 controls. MHT use was associated with a significantly lower risk of liver cancer (ORadj=0.58, 95%CI=0.37-0.90) especially among users of estrogen-only MHT (ORadj=0.44, 95%CI=0.22-0.88) and among past users (ORadj=0.53, 95%CI=0.32-0.88). Among the matched cases (n=58) and controls (n=232) with diabetes, the odds ratios were similar to the overall analysis (ORadj=0.57, 95%CI=0.09-3.53), but did not attain statistical significance. In the current study, MHT use, especially estrogen-only MHT use, was associated with a significantly lower risk of liver cancer. These results support the need of further investigation into whether hormonal etiologies can explain the variation in liver cancer incidence between men and women. What's new? Pronounced gender discrepancy in the risk of primary liver cancer suggests that steroid hormone levels or exogenous hormone use are related to risk. In this analysis of data from the Clinical Practice Research Datalink in the United Kingdom, risk of liver cancer was found to be significantly reduced among women on menopausal hormone therapy (MHT). The association was evident particularly among users of estrogen-only MHT. The findings suggest that exogenous hormones protect against liver cancer, a phenomenon inviting further investigation. C1 [McGlynn, Katherine A.; Chen, Jie; Braunlin, Megan; Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hagberg, Katrina; Suneja, Neha; Jick, Susan] Boston Collaborat Drug Surveillance Program, Lexington, MA USA. [Hagberg, Katrina; Suneja, Neha; Jick, Susan] Boston Univ, Sch Publ Hlth, Lexington, MA USA. [Sahasrabuddhe, Vikrant V.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP McGlynn, KA (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM mcglynnk@mail.nih.gov RI CPRD, CPRD/B-9594-2017 FU National Institutes of Health FX Grant sponsor: National Institutes of Health NR 33 TC 1 Z9 1 U1 2 U2 28 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 MAY 1 PY 2016 VL 138 IS 9 BP 2146 EP 2153 DI 10.1002/ijc.29960 PG 8 WC Oncology SC Oncology GA DF2GY UT WOS:000371161800010 PM 26662112 ER PT J AU Taunk, P Hecht, E Stolzenberg-Solomon, R AF Taunk, Pulkit Hecht, Eric Stolzenberg-Solomon, Rachael TI Are meat and heme iron intake associated with pancreatic cancer? Results from the NIH-AARP diet and health cohort SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; heme iron; meat ID HETEROCYCLIC AMINE CONTENT; GLYCATION END-PRODUCTS; NUTRITIONAL FACTORS; PROCESSED MEAT; OXIDATIVE STRESS; VARYING DEGREES; FOOD GROUPS; RISK; POPULATION; RED AB Several studies on pancreatic cancer have reported significant positive associations for intake of red meat but null associations for heme iron. We assessed total, red, white and processed meat intake, meat cooking methods and doneness and heme iron and mutagen intake in relation to pancreatic cancer in the NIH-AARP Diet and Health Study cohort. A total of 322,846 participants (187,265 men and 135,581 women) successfully completed and returned the food frequency questionnaire between 1995 and 1996. After a mean follow-up of 9.2 years (up to 10.17 years), 1,417 individuals (895 men and 522 women) developed exocrine pancreatic cancer. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), and trends were calculated using the median value of each quantile. Models incorporated age as the time metric and were adjusted for smoking history, body mass index, self-reported diabetes and energy-adjusted saturated fat. Pancreatic cancer risk significantly increased with intake of total meat (Q5 vs. Q1: HR=1.20, 95% CI 1.02-1.42, p-trend=0.03), red meat (HR=1.22, 95% CI 1.01-1.48, p-trend=0.02), high-temperature cooked meat (HR=1.21, 95% CI 1.00-1.45, p-trend=0.02), grilled/barbequed meat (HR=1.24, 95% CI 1.03-1.50, p-trend=0.007), well/very well done meat (HR=1.32, 95% CI 1.10-1.58, p-trend=0.005) and heme iron from red meat (Q4 vs. Q1: HR=1.21, 95% CI 1.01-1.45, p-trend=0.04). When stratified by sex, these associations remained significant in men but not women except for white meat intake in women (HR=1.33, 95% CI 1.02-1.74, p-trend=0.04). Additional studies should confirm our findings that consuming heme iron from red meat increases pancreatic cancer risk. What's new? How would you like your steak? A new study examines whether meat cooking techniques boost pancreatic cancer risk. The comprehensive investigation also looked at total meat intake; meat intake by type; as well as heme iron and meat mutagen intake, using data from a questionnaire given to more than 567,000 persons. Of these, 1417 developed pancreatic cancer. Analysis showed that higher risk of pancreatic cancer accompanies total meat consumption, high temperature cooking, grilled meat, well done meat, red meat, and heme iron intake. This is the largest study yet to evaluate the link between meat cooking methods, heme iron, and pancreatic cancer. C1 [Taunk, Pulkit; Hecht, Eric] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA. [Taunk, Pulkit; Stolzenberg-Solomon, Rachael] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD USA. RP Stolzenberg-Solomon, R (reprint author), 9609 Med Ctr Dr,Room 6E420, Rockville, MD 20850 USA.; Taunk, P (reprint author), 4050 Presidential Dr, Palm Harbor, FL 34685 USA. EM pt44@med.miami.edu; rs221z@nih.gov FU National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry; from Georgia by the Georgia Center for Cancer Statistics; from California by the California Department of Health Services, Cancer Surveillance Section; from Michigan by the Michigan Cancer Surveillance Program; from Florida by the Florida Cancer Data System under contract to the Department of Health; from Louisiana by the Louisiana Tumor Registry; from New Jersey by the New Jersey State Cancer Registry; from North Carolina by the North Carolina Central Cancer Registry; from Pennsylvania by the Division of Health Statistics and Research, Pennsylvania Department of Health; from Texas by the Texas Cancer Registry and from Nevada by the Nevada Central Cancer Registry of the Division of Public and Behavioral Health for the State of Nevada. The views expressed herein are solely those of the authors and do not necessarily reflect those of the cancer registries or contractors. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. The authors are indebted to the participants of the NIH-AARP Diet and Health Study for their outstanding cooperation. NR 40 TC 3 Z9 3 U1 4 U2 27 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 MAY 1 PY 2016 VL 138 IS 9 BP 2172 EP 2189 DI 10.1002/ijc.29964 PG 18 WC Oncology SC Oncology GA DF2GY UT WOS:000371161800013 PM 26666579 ER PT J AU Minic, D Pajevic, S AF Minic, Djordje Pajevic, Sinisa TI Emergent "quantum" theory in complex adaptive systems SO MODERN PHYSICS LETTERS B LA English DT Article DE Emergent quantum theory; complex adaptive systems; system stability; Lotka-Volterra model ID LOTKA-VOLTERRA EQUATIONS; HAMILTONIAN STRUCTURES; STATISTICAL DISTANCE; MECHANICS; MULTISTABILITY; QUANTIZATION; MODELS; STATES; WAVE AB Motivated by the question of stability, in this paper we argue that an effective quantum-like theory can emerge in complex adaptive systems. In the concrete example of stochastic Lotka-Volterra dynamics, the relevant effective "Planck constant" associated with such emergent "quantum" theory has the dimensions of the square of the unit of time. Such an emergent quantum-like theory has inherently nonclassical stability as well as coherent properties that are not, in principle, endangered by thermal fluctuations and therefore might be of crucial importance in complex adaptive systems. C1 [Minic, Djordje] Virginia Tech, Dept Phys, Blacksburg, VA 24061 USA. [Pajevic, Sinisa] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Minic, D (reprint author), Virginia Tech, Dept Phys, Blacksburg, VA 24061 USA.; Pajevic, S (reprint author), NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. EM dminic@vt.edu; pajevic@nih.gov FU US Department of Energy [DE-FG02-13ER41917]; Intramural Research Program of the Center for Information Technology, National Institutes of Health FX We thank V. Balasubramanim N. Goldenfeld, W. Mather, I. Nemenman, M. Pleimling, ling V. Scarola, U. Tauber arrd J. Xing for illuminating discussions and comments. D. M. thanks the Aspen Center for Physics for providing a stimulating environment, for work. DM is supported in part by the US Department of Energy under contract DE-FG02-13ER41917, task A. S. Pajevic was supported by the Intramural Research Program of the Center for Information Technology, National Institutes of Health. NR 59 TC 0 Z9 0 U1 1 U2 1 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 0217-9849 EI 1793-6640 J9 MOD PHYS LETT B JI Mod. Phys. Lett. B PD APR 30 PY 2016 VL 30 IS 11 AR 1650201 DI 10.1142/S0217984916502018 PG 12 WC Physics, Applied; Physics, Condensed Matter; Physics, Mathematical SC Physics GA DM1QD UT WOS:000376120400012 ER PT J AU Zatzick, DF Russo, J Darnell, D Chambers, DA Palinkas, L Van Eaton, E Wang, J Ingraham, LM Guiney, R Heagerty, P Comstock, B Whiteside, LK Jurkovich, G AF Zatzick, Douglas F. Russo, Joan Darnell, Doyanne Chambers, David A. Palinkas, Lawrence Van Eaton, Erik Wang, Jin Ingraham, Leah M. Guiney, Roxanne Heagerty, Patrick Comstock, Bryan Whiteside, Lauren K. Jurkovich, Gregory TI An effectiveness-implementation hybrid trial study protocol targeting posttraumatic stress disorder and comorbidity SO IMPLEMENTATION SCIENCE LA English DT Article DE Traumatic injury; Multiple chronic conditions; Posttraumatic stress disorder; Depression; Suicidal ideation; Substance abuse; Effectiveness-implementation hybrid; Pragmatic clinical trial; American College of Surgeons; Policy ID RANDOMIZED CONTROLLED-TRIAL; STEPPED COLLABORATIVE CARE; INJURED TRAUMA SURVIVORS; POLYTRAUMA-CLINICAL-TRIAD; TIME TRADE-OFF; BRIEF INTERVENTION; SUBSTANCE USE; PREVENTIVE INTERVENTIONS; FUNCTIONAL OUTCOMES; DEPRESSIVE SYMPTOMS AB Background: Each year in the USA, 1.5-2.5 million Americans are so severely injured that they require inpatient hospitalization. Multiple conditions including posttraumatic stress disorder (PTSD), alcohol and drug use problems, depression, and chronic medical conditions are endemic among physical trauma survivors with and without traumatic brain injuries. Methods/design: The trauma survivors outcomes and support (TSOS) effectiveness-implementation hybrid trial is designed to test the delivery of high-quality screening and intervention for PTSD and comorbidities across 24 US level I trauma center sites. The pragmatic trial aims to recruit 960 patients. The TSOS investigation employs a stepped wedge cluster randomized design in which sites are randomized sequentially to initiate the intervention. Patients identified by a 10-domain electronic health record screen as high risk for PTSD are formally assessed with the PTSD Checklist for study entry. Patients randomized to the intervention condition will receive stepped collaborative care, while patients randomized to the control condition will receive enhanced usual care. The intervention training begins with a 1-day on-site workshop in the collaborative care intervention core elements that include care management, medication, cognitive behavioral therapy, and motivational-interviewing elements targeting PTSD and comorbidity. The training is followed by site supervision from the study team. The investigation aims to determine if intervention patients demonstrate significant reductions in PTSD and depressive symptoms, suicidal ideation, alcohol consumption, and improvements in physical function when compared to control patients. The study uses implementation science conceptual frameworks to evaluate the uptake of the intervention model. At the completion of the pragmatic trial, results will be presented at an American College of Surgeons' policy summit. Twenty-four representative US level I trauma centers have been selected for the study, and the protocol is being rolled out nationally. Discussion: The TSOS pragmatic trial simultaneously aims to establish the effectiveness of the collaborative care intervention targeting PTSD and comorbidity while also addressing sustainable implementation through American College of Surgeons' regulatory policy. The TSOS effectiveness-implementation hybrid design highlights the importance of partnerships with professional societies that can provide regulatory mandates targeting enhanced health care system sustainability of pragmatic trial results. C1 [Zatzick, Douglas F.; Russo, Joan; Darnell, Doyanne; Ingraham, Leah M.; Guiney, Roxanne] Univ Washington, Dept Psychiat & Behav Sci, 325 Ninth Ave,Box 359911, Seattle, WA 98104 USA. [Chambers, David A.] NCI, Div Canc Control & Populat Sci, BG 9609 MSC 9760,9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Palinkas, Lawrence] Univ So Calif, Sch Social Work, Montgomery Ross Fisher Bldg,Room 339, Los Angeles, CA 90089 USA. [Van Eaton, Erik] Univ Washington, Dept Surg, 325 Ninth Ave,Box 359796, Seattle, WA 98104 USA. [Zatzick, Douglas F.; Wang, Jin] Univ Washington, Harborview Injury Prevent Res Ctr, 325 Ninth Ave,Box 359960, Seattle, WA 98104 USA. [Heagerty, Patrick; Comstock, Bryan] Univ Washington, Dept Biostat, 1705 NE Pacific St,Box 357232, Seattle, WA 98195 USA. [Whiteside, Lauren K.] Univ Washington, Div Emergency Med, 25 Ninth Ave,Box 359702, Seattle, WA 98104 USA. [Jurkovich, Gregory] Univ Calif Davis, Dept Surg, 2221 Stockton Blvd,Cypress 3111, Sacramento, CA 95817 USA. RP Zatzick, DF (reprint author), Univ Washington, Dept Psychiat & Behav Sci, 325 Ninth Ave,Box 359911, Seattle, WA 98104 USA.; Zatzick, DF (reprint author), Univ Washington, Harborview Injury Prevent Res Ctr, 325 Ninth Ave,Box 359960, Seattle, WA 98104 USA. EM dzatzick@uw.edu FU National Institutes of Health (NIH) Common Fund, through Office of Strategic Coordination within the Office of the NIH Director [U54 AT007748, 1UH2MH106338-01/4UH3MH106338-02]; National Institute of Mental Health [1 K24MH086814-01A1] FX This work is supported by the National Institutes of Health (NIH) Common Fund, through cooperative agreements (U54 AT007748, 1UH2MH106338-01/4UH3MH106338-02) from the Office of Strategic Coordination within the Office of the NIH Director, and the National Institute of Mental Health (1 K24MH086814-01A1). The views presented here are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 152 TC 0 Z9 0 U1 4 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD APR 30 PY 2016 VL 11 AR 58 DI 10.1186/s13012-016-0424-4 PG 16 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DK7MO UT WOS:000375110000001 PM 27130272 ER PT J AU Smallwood, RF Potter, JS Robin, DA AF Smallwood, Rachel F. Potter, Jennifer S. Robin, Donald A. TI Neurophysiological mechanisms in acceptance and commitment therapy in opioid-addicted patients with chronic pain SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Chronic pain; Opioid addiction; Acceptance and Commitment Therapy ID INTRINSIC BRAIN CONNECTIVITY; FIBROMYALGIA; METAANALYSIS; MINDFULNESS AB Acceptance and Commitment Therapy (ACT) has been effectively utilized to treat both chronic pain and substance use disorder independently. Given these results and the vital need to treat the comorbidity of the two disorders, a pilot ACT treatment was implemented in individuals with comorbid chronic pain and opioid addiction. This pilot study supported using neurophysiology to characterize treatment effects and revealed that, following ACT, participants with this comorbidity exhibited reductions in brain activation due to painful stimulus and in connectivity at rest. (c) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Smallwood, Rachel F.; Robin, Donald A.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. [Smallwood, Rachel F.; Potter, Jennifer S.; Robin, Donald A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. RP Smallwood, RF (reprint author), Natl Inst Neurol Disorders & Stroke, 10 Ctr Dr MSC 1404, Bethesda, MD 20892 USA. EM rachel.smallwood@nih.gov FU NIH NIDA [K23DA022297-04] FX This study was supported by NIH NIDA Grant K23DA022297-04 (Potter). The authors thank Harvir Virk for his contributions. NR 18 TC 0 Z9 0 U1 8 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD APR 30 PY 2016 VL 250 BP 12 EP 14 DI 10.1016/j.pscychresns.2016.03.001 PG 3 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DK8EO UT WOS:000375160200002 PM 27107155 ER PT J AU Danaher, MR Albert, PS Roy, A Schisterman, EF AF Danaher, Michelle R. Albert, Paul S. Roy, Aninyda Schisterman, Enrique F. TI Estimation of interaction effects using pooled biospecimens in a case-control study SO STATISTICS IN MEDICINE LA English DT Article DE cytokines; expectation maximization; logistic regression; pooling designs; skewed biomarkers ID EM ALGORITHM; MISCARRIAGE; EXPOSURE; RISK AB Pooling, or physically mixing biospecimens, prior to evaluating biomarkers dramatically reduces biomarker evaluation cost, reduces the quantity of biospecimens required of each individual, and may reduce the percentage of laboratory measurements below the lower limit of detection. Motivated by a case-control study on miscarriage (binary outcome) and cytokines (continuous exposures), we are interested in estimating parameters in a logistic regression, where individuals with the same disease status (with or without a miscarriage) are paired and their pooled cytokine concentrations are assessed. Previous research has proposed a set-based logistic model to evaluate the relationship between a disease and pooled exposures. While the set-based logistic model is very useful for estimating main effects, it cannot estimate interactions of continuous exposures when both are measured in pools. Therefore, we propose using the expectation maximization (EM) algorithm to obtain estimators of all parameters in logistic regression model, including interactions effects. Using a simulation study, we present comparisons of efficiency under different scenarios where exposures have been measured in pools and individually. Our simulations show that randomly sampling half of the available biospecimens has less efficiency than pooling pairs of biospecimens stratified by disease status. The EM algorithm provides a method for estimating interaction effects when biospecimens have already been pooled for other reasons such as the gain in efficiency for estimating main effects demonstrated by previous research. This manuscript demonstrates that the EM algorithm offers a promising approach to estimate interaction effects of pooled biospecimens. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Danaher, Michelle R.; Albert, Paul S.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut BLVD Room 7B03H,MSC 7510, Bethesda, MD 20892 USA. [Danaher, Michelle R.; Roy, Aninyda] Univ Maryland, Dept Math & Stat, Baltimore, MD 21201 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut BLVD Room 7B03H,MSC 7510, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Long-Range Research Initiative of the American Chemistry Council; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD [HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001] FX This research was supported by the Long-Range Research Initiative of the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). This work utilized the computational resources of the NIH HPC Biowulf cluster. (http://hpc.nih.gov) NR 19 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 APR 30 PY 2016 VL 35 IS 9 BP 1502 EP 1513 DI 10.1002/sim.6798 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DI8GQ UT WOS:000373739900007 PM 26553532 ER PT J AU Andersson, M Diao, XX Wohlfarth, A Scheidweiler, KB Huestis, MA AF Andersson, Maria Diao, Xingxing Wohlfarth, Ariane Scheidweiler, Karl B. Huestis, Marilyn A. TI Metabolic profiling of new synthetic cannabinoids AMB and 5F-AMB by human hepatocyte and liver microsome incubations and high-resolution mass spectrometry SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID IN-VITRO; 3-N-BUTYLPHTHALIDE NBP; ACYL GLUCURONIDES; 5-FLUORO ANALOG; DRUG DISCOVERY; IDENTIFICATION; PHARMACOKINETICS; URINE; DERIVATIVES; STABILITY AB RationaleAMB (methyl (1-pentyl-1H-indazole-3-carbonyl)-L-valinate)) and its fluoro analog 5F-AMB (methyl (1-(5-fluoropentyl)-1H-indazole-3-carbonyl)-L-valinate) are two new synthetic cannabinoids that are structural analogs of AB-PINACA and 5F-AB-PINACA, respectively. 5F-AMB is scheduled as an illicit drug in China, Germany, Singapore and Japan, and no metabolism data are currently available for either drug. The aim of the present work was to investigate the metabolism of AMB and 5F-AMB and propose appropriate markers to identify their intake in clinical or forensic cases. MethodsAMB and 5F-AMB were incubated in human hepatocytes (10 mol/L) to generate phase I and II metabolites, which were identified with a TripleTOF 5600(+) high-resolution mass spectrometer. AMB and 5F-AMB metabolic stability studies also were performed with human liver microsomes (HLM) to evaluate metabolic clearances, and to adequately design the human hepatocyte experiment. ResultsAMB and 5F-AMB were quickly metabolized in HLM with a 1.1 0.1 and 1.0 +/- 0.2min T-1/2, respectively. The predominant metabolic pathway for AMB and 5F-AMB in hepatocytes was ester hydrolysis, and further oxidation and/or glucuronidation. In total, 19 metabolites were identified for AMB and 17 for 5F-AMB. We describe metabolites to differentiate AMB from 5F-AMB, and metabolites that are common to both analytes due to oxidative defluorination of 5F-AMB. ConclusionsFor the first time, AMB and 5F-AMB metabolism profiles were characterized, providing valuable data for identifying these two novel psychoactive substances. The difficulties of differentiating AMB and 5F-AMB from AB-PINACA/5F-AB-PINACA metabolites also were examined. These data improve the interpretation of urinary markers after AMB and 5F-AMB intake. Published in 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Andersson, Maria; Diao, Xingxing; Wohlfarth, Ariane; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, IRP, NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. [Wohlfarth, Ariane] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, S-58758 Linkoping, Sweden. [Wohlfarth, Ariane] Linkoping Univ, Dept Drug Res, S-58185 Linkoping, Sweden. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, IRP, NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. EM marilyn.huestis@gmail.com FU Intramural Research Program (IRP) of the National Institute on Drug Abuse, National Institutes of Health FX This research was funded by the Intramural Research Program (IRP) of the National Institute on Drug Abuse, National Institutes of Health. We would also like to acknowledge the Molecular Discovery Company for providing the MetaSite software. NR 36 TC 8 Z9 8 U1 6 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-4198 EI 1097-0231 J9 RAPID COMMUN MASS SP JI Rapid Commun. Mass Spectrom. PD APR 30 PY 2016 VL 30 IS 8 BP 1067 EP 1078 DI 10.1002/rcm.7538 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA DH8US UT WOS:000373073000007 PM 27003044 ER PT J AU Bandrowski, A Brinkman, R Brochhausen, M Brush, MH Bug, B Chibucos, MC Clancy, K Courtot, M Derom, D Dumontier, M Fan, LJ Fostel, J Fragoso, G Gibson, F Gonzalez-Beltran, A Haendel, MA He, YQ Heiskanen, M Hernandez-Boussard, T Jensen, M Lin, Y Lister, AL Lord, P Malone, J Manduchi, E Mcgee, M Morrison, N Overton, JA Parkinson, H Peters, B Rocca-Serra, P Ruttenberg, A Sansone, SA Scheuermann, RH Schober, D Smith, B Soldatova, LN Stoeckert, CJ Taylor, CF Torniai, C Turner, JA Vita, R Whetzel, PL Zheng, J AF Bandrowski, Anita Brinkman, Ryan Brochhausen, Mathias Brush, Matthew H. Bug, Bill Chibucos, Marcus C. Clancy, Kevin Courtot, Melanie Derom, Dirk Dumontier, Michel Fan, Liju Fostel, Jennifer Fragoso, Gilberto Gibson, Frank Gonzalez-Beltran, Alejandra Haendel, Melissa A. He, Yongqun Heiskanen, Mervi Hernandez-Boussard, Tina Jensen, Mark Lin, Yu Lister, Allyson L. Lord, Phillip Malone, James Manduchi, Elisabetta McGee, Monnie Morrison, Norman Overton, James A. Parkinson, Helen Peters, Bjoern Rocca-Serra, Philippe Ruttenberg, Alan Sansone, Susanna-Assunta Scheuermann, Richard H. Schober, Daniel Smith, Barry Soldatova, Larisa N. Stoeckert, Christian J., Jr. Taylor, Chris F. Torniai, Carlo Turner, Jessica A. Vita, Randi Whetzel, Patricia L. Zheng, Jie TI The Ontology for Biomedical Investigations SO PLOS ONE LA English DT Article ID FUNCTIONAL GENOMICS; MINIMUM INFORMATION; MICROARRAY DATA; OBO FOUNDRY; STANDARDS; DATABASE; FORMAT; TAB; SPECIFICATION; FRAMEWORK AB The Ontology for Biomedical Investigations (OBI) is an ontology that provides terms with precisely defined meanings to describe all aspects of how investigations in the biological and medical domains are conducted. OBI re-uses ontologies that provide a representation of biomedical knowledge from the Open Biological and Biomedical Ontologies (OBO) project and adds the ability to describe how this knowledge was derived. We here describe the state of OBI and several applications that are using it, such as adding semantic expressivity to existing databases, building data entry forms, and enabling interoperability between knowledge resources. OBI covers all phases of the investigation process, such as planning, execution and reporting. It represents information and material entities that participate in these processes, as well as roles and functions. Prior to OBI, it was not possible to use a single internally consistent resource that could be applied to multiple types of experiments for these applications. OBI has made this possible by creating terms for entities involved in biological and medical investigations and by importing parts of other biomedical ontologies such as GO, Chemical Entities of Biological Interest (ChEBI) and Phenotype Attribute and Trait Ontology (PATO) without altering their meaning. OBI is being used in a wide range of projects covering genomics, multi-omics, immunology, and catalogs of services. OBI has also spawned other ontologies (Information Artifact Ontology) and methods for importing parts of ontologies (Minimum information to reference an external ontology term (MIREOT)). The OBI project is an open cross-disciplinary collaborative effort, encompassing multiple research communities from around the globe. To date, OBI has created 2366 classes and 40 relations along with textual and formal definitions. The OBI Consortium maintains a web resource (http://obi-ontology. org) providing details on the people, policies, and issues being addressed in association with OBI. The current release of OBI is available at http://purl.obolibrary.org/obo/obi. owl. C1 [Bandrowski, Anita; Whetzel, Patricia L.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Brinkman, Ryan] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada. [Brochhausen, Mathias] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Brush, Matthew H.; Haendel, Melissa A.; Torniai, Carlo] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Bug, Bill] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Chibucos, Marcus C.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Clancy, Kevin] Thermo Fisher Sci, Carlsbad, CA USA. [Courtot, Melanie] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Derom, Dirk] Vrije Univ Brussel, Brussels, Belgium. [Dumontier, Michel; Hernandez-Boussard, Tina] Stanford Univ, Stanford, CA 94305 USA. [Fan, Liju] Ontol Workshop LLC, Columbia, MD USA. [Fostel, Jennifer] NIEHS, Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Fragoso, Gilberto] NIH, Ctr Biomed Informat & Informat Technol, Rockville, MD USA. [Gibson, Frank] Royal Soc Chem, Cambridge, England. [Gonzalez-Beltran, Alejandra; Lister, Allyson L.; Rocca-Serra, Philippe; Sansone, Susanna-Assunta] Univ Oxford, Oxford, England. [He, Yongqun; Lin, Yu] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Heiskanen, Mervi] NCI, Rockville, MD USA. [Jensen, Mark; Ruttenberg, Alan; Smith, Barry] Univ Buffalo, Buffalo, NY USA. [Lord, Phillip] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Malone, James; Parkinson, Helen; Taylor, Chris F.] European Bioinformat Inst, European Mol Biol Lab, Hinxton, Cambs, England. [Manduchi, Elisabetta; Stoeckert, Christian J., Jr.; Zheng, Jie] Univ Penn, Philadelphia, PA 19104 USA. [McGee, Monnie] So Methodist Univ, Dallas, TX 75275 USA. [Morrison, Norman] Univ Manchester, Manchester, England. [Overton, James A.; Peters, Bjoern; Vita, Randi] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. [Scheuermann, Richard H.] J Craig Venter Inst, La Jolla, CA USA. [Schober, Daniel] Leibniz Inst Plant Biochem, Halle, Saxony Anhalt, Germany. [Soldatova, Larisa N.] Brunel Univ London, Uxbridge, Middx, England. [Turner, Jessica A.] Georgia State Univ, Atlanta, GA 30303 USA. RP Bandrowski, A (reprint author), Univ Calif San Diego, La Jolla, CA 92093 USA. RI Brinkman, Ryan/B-1108-2008; OI Brinkman, Ryan/0000-0002-9765-2990; Parkinson, Helen/0000-0003-3035-4195; Gibson, Frank/0000-0003-3382-1748; Courtot, Melanie/0000-0002-9551-6370; Bandrowski, Anita/0000-0002-5497-0243; Chibucos, Marcus/0000-0001-9586-0780 FU National Institute of Allergy and Infectious Diseases [R01AI081062]; National Institutes of Health [R01GM093132, U01 DK 072473, P41 HG003619, HHSN272201400030C, HHSN272201400028C, HHSN272201200010C, 1U19AI118626]; California Institute for Regenerative Medicine [GC1R-06673-B]; National Science Foundation Division of Biological Infrastructure [1458400]; Engineering and Physical Sciences Research Council UK [EP/M015661/1, EP/K030582/1]; European Network of Excellence (NoE) [503630]; Biotechnology and Biological Sciences Research Council [BB/E025080/1, BB/G000638/1, BB/C008200/1, BB/I000917/1, BB/L024101/1]; European Commission [H2020-EU.1.4.1.3 654241, H2020-EU.3.1634107] FX This work was supported by the National Institute of Allergy and Infectious Diseases (https://www.niaid.nih.gov/Pages/default.aspx) R01AI081062 to YH, the National Institutes of Health (http://www.nih.gov/) R01GM093132, U01 DK 072473, P41 HG003619 and HHSN272201400030C to CJS, HHSN272201400028C to RHS, HHSN272201200010C and 1U19AI118626 to BP, the California Institute for Regenerative Medicine (https://www.cirm.ca.gov) GC1R-06673-B to RHS, the National Science Foundation Division of Biological Infrastructure (http://www.nsf.gov) 1458400 to MCC and the Engineering and Physical Sciences Research Council UK (https://www.epsrc.ac.uk/) EP/M015661/1 and EP/K030582/1 to LNS. This work was also supported by the European Network of Excellence (NoE) (http://www.enfin.org) 503630 to DS, the Biotechnology and Biological Sciences Research Council (http://www.bbsrc.ac.uk) BB/E025080/1 and BB/G000638/1 to DS, BB/C008200/1 to ALL, BB/I000917/1, BB/G000638/1, BB/E025080/1, BB/L024101/1 to PRS, SAS, AGB and ALL and the European Commission (https://ec.europa.eu/programmes/horizon2020) H2020-EU.1.4.1.3 654241 and H2020-EU.3.1634107 to PRS, SAS and AGB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 5 Z9 5 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 29 PY 2016 VL 11 IS 4 AR e0154556 DI 10.1371/journal.pone.0154556 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK8XM UT WOS:000375212600038 PM 27128319 ER PT J AU Yun, KJ Han, K Kim, MK Park, YM Baek, KH Song, KH Kwon, HS AF Yun, Kyung-Jin Han, Kyungdo Kim, Mee Kyoung Park, Yong-Moon Baek, Ki-Hyun Song, Ki-Ho Kwon, Hyuk-Sang TI Insulin Resistance Distribution and Cut-Off Value in Koreans from the 2008-2010 Korean National Health and Nutrition Examination Survey SO PLOS ONE LA English DT Article ID HOMEOSTASIS MODEL ASSESSMENT; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; POPULATION; GLUCOSE; INDEX; SENSITIVITY; SECRETION; MENOPAUSE; NONOBESE AB Background We sought to identify the distribution and cut-off value of the 'homeostasis model assessment of insulin resistance' (HOMA-IR) according to gender and menopausal status for metabolic syndrome in Koreans. Methods Data were from the Korean National Health and Nutrition Examination Survey in 20082010. The subjects included adults aged 20 years or older. We excluded participants who had diabetes or fasting serum glucose >= 7 mmol/L. Finally, 11,121 subjects (4,911 men, 3,597 premenopausal women, 2,613 postmenopausal women) were enrolled. The modified Adult Treatment Panel III criteria were used to define metabolic syndrome. Results The mean HOMA-IR was 2.11 (2.07-2.15) for men, 2.0 (1.97-2.04) for premenopausal women, and 2.14 (2.2-2.19) for postmenopausal women. The first cut-off values in men, premenopausal women, and postmenopausal women were 2.23 (sensitivity 70.6%, specificity 66.9%), 2.39 (sensitivity 72.3%, specificity 76.4%), and 2.48 (sensitivity 51.9%, specificity 80.2%), respectively. Based on the first HOMA-IR cut-off value, the prevalence of metabolic syndrome was 22.9% in men, 13.7% in premenopausal women, and 51.6% in postmenopausal women. The second cut-off value was around 3.2 in all three groups. Based on the second HOMA-IR cut-off value, the prevalence of metabolic syndrome was 50.8% in men, 42.5% in premenopausal women, and 71.6% in postmenopausal women. Conclusion In conclusion, the first cut-off values for HOMA-IR were 2.2-2.5 and the second cut-off value was 3.2 in Korea. The distribution of HOMA-IR showed differences according to gender and menopausal status. When we apply HOMA-IR, we should consider gender, menopausal status, and the prevalence of metabolic syndrome. C1 [Yun, Kyung-Jin; Kim, Mee Kyoung; Baek, Ki-Hyun; Song, Ki-Ho; Kwon, Hyuk-Sang] Yeouido St Marys Hosp, Div Endocrinol & Metab, Dept Internal Med, Seoul, South Korea. [Han, Kyungdo] Catholic Univ Korea, Dept Med Stat, Coll Med, Seoul, South Korea. [Park, Yong-Moon] NIEHS, Dept Epidemiol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Kwon, HS (reprint author), Yeouido St Marys Hosp, Div Endocrinol & Metab, Dept Internal Med, Seoul, South Korea. EM drkwon@catholic.ac.kr OI PARK, YONG-MOON/0000-0002-5879-6879 NR 29 TC 2 Z9 2 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 29 PY 2016 VL 11 IS 4 AR e0154593 DI 10.1371/journal.pone.0154593 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK8XM UT WOS:000375212600044 PM 27128847 ER PT J AU Terajima, M Taga, Y Chen, YL Cabral, WA Hou-Fu, G Srisawasdi, S Nagasawa, M Sumida, N Hattori, S Kurie, JM Marini, JC Yamauchi, M AF Terajima, Masahiko Taga, Yuki Chen, Yulong Cabral, Wayne A. Hou-Fu, Guo Srisawasdi, Sirivimol Nagasawa, Masako Sumida, Noriko Hattori, Shunji Kurie, Jonathan M. Marini, Joan C. Yamauchi, Mitsuo TI Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LYSYL HYDROXYLASE; OSTEOGENESIS IMPERFECTA; BRUCK-SYNDROME; NULL MICE; MUTATIONS; BONE; DEFICIENCY; PROTEIN; CELLS; EXPRESSION AB Covalent intermolecular cross-linking provides collagen fibrils with stability. The cross-linking chemistry is tissue-specific and determined primarily by the state of lysine hydroxylation at specific sites. A recent study on cyclophilin B (CypB) null mice, a model of recessive osteogenesis imperfecta, demonstrated that lysine hydroxylation at the helical cross-linking site of bone type I collagen was diminished in these animals (Cabral, W. A., Perdivara, I., Weis, M., Terajima, M., Blissett, A. R., Chang, W., Perosky, J. E., Makareeva, E. N., Mertz, E. L., Leikin, S., Tomer, K. B., Kozloff, K. M., Eyre, D. R., Yamauchi, M., and Marini, J. C. (2014) PLoS Genet. 10, e1004465). However, the extent of decrease appears to be tissue-and molecular site-specific, the mechanism of which is unknown. Here we report that although CypB deficiency resulted in lower lysine hydroxylation in the helical cross-linking sites, it was increased in the telopeptide cross-linking sites in tendon type I collagen. This resulted in a decrease in the lysine aldehyde-derived cross-links but generation of hydroxylysine aldehyde-derived cross-links. The latter were absent from the wild type and heterozygous mice. Glycosylation of hydroxylysine residues was moderately increased in the CypB null tendon. Wefound that CypB interacted with all lysyl hydroxylase isoforms (isoforms 1-3) and a putative lysyl hydroxylase-2 chaperone, 65-kDa FK506-binding protein. Tendon collagen in CypB null mice showed severe size and organizational abnormalities. The data indicate that CypB modulates collagen cross-linking by differentially affecting lysine hydroxylation in a site-specific manner, possibly via its interaction with lysyl hydroxylases and associated molecules. This study underscores the critical importance of collagen post-translational modifications in connective tissue formation. C1 [Terajima, Masahiko; Sumida, Noriko; Yamauchi, Mitsuo] Univ N Carolina, Sch Dent, North Carolina Oral Hlth Inst, Chapel Hill, NC 27599 USA. [Taga, Yuki; Hattori, Shunji] Nippi Res Inst Biomatrix, Ibaraki 3020017, Japan. [Chen, Yulong; Hou-Fu, Guo; Kurie, Jonathan M.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Cabral, Wayne A.; Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. [Srisawasdi, Sirivimol] Chulalongkorn Univ, Dept Operat Dent, Bangkok 10330, Thailand. [Nagasawa, Masako] Niigata Univ, Grad Sch Med & Dent Sci, Div Bioprosthodont, Niigata 9518514, Japan. RP Yamauchi, M (reprint author), Univ N Carolina, Sch Dent, North Carolina Oral Hlth Inst, Chapel Hill, NC 27599 USA. EM mitsuo_yamauchi@unc.edu OI Taga, Yuki/0000-0001-9100-758X FU National Institute of Health Grants, National Institutes of Health-NIAMS [R21AR060978]; National Institute of Health Grants, National Institutes of Health-NCI [R01CA105155] FX This work was supported in part by National Institute of Health Grants, National Institutes of Health-NIAMS R21AR060978, NCI R01CA105155. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 50 TC 4 Z9 4 U1 4 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 29 PY 2016 VL 291 IS 18 BP 9501 EP 9512 DI 10.1074/jbc.M115.699470 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL4JY UT WOS:000375602300011 PM 26934917 ER PT J AU Knight, DK Belenko, S Wiley, T Robertson, AA Arrigona, N Dennis, M Bartkowski, JP McReynolds, LS Becan, JE Knudsen, HK Wasserman, GA Rose, E DiClemente, R Leukefeld, C AF Knight, Danica K. Belenko, Steven Wiley, Tisha Robertson, Angela A. Arrigona, Nancy Dennis, Michael Bartkowski, John P. McReynolds, Larkin S. Becan, Jennifer E. Knudsen, Hannah K. Wasserman, Gail A. Rose, Eve DiClemente, Ralph Leukefeld, Carl CA JJ-TRIALS Cooperative TI Juvenile Justice-Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS): a cluster randomized trial targeting system-wide improvement in substance use services SO IMPLEMENTATION SCIENCE LA English DT Article DE Evidence-based practice implementation; System change; Interagency collaboration; Substance use; Treatment services; Data-driven decision-making; Juvenile justice; Adolescent; Justice-involved youth; Cluster randomized trial ID TIME-SERIES ANALYSIS; ABUSE TREATMENT; IMPLEMENTATION-RESEARCH; INFORMATION-TECHNOLOGY; USE DISORDERS; DRUG COURT; HIV CARE; HEALTH; ENGAGEMENT; PREVENTION AB Background: The purpose of this paper is to describe the Juvenile Justice-Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS) study, a cooperative implementation science initiative involving the National Institute on Drug Abuse, six research centers, a coordinating center, and Juvenile Justice Partners representing seven US states. While the pooling of resources across centers enables a robust implementation study design involving 36 juvenile justice agencies and their behavioral health partner agencies, co-producing a study protocol that has potential to advance implementation science, meets the needs of all constituencies (funding agency, researchers, partners, study sites), and can be implemented with fidelity across the cooperative can be challenging. This paper describes (a) the study background and rationale, including the juvenile justice context and best practices for substance use disorders, (b) the selection and use of an implementation science framework to guide study design and inform selection of implementation components, and (c) the specific study design elements, including research questions, implementation interventions, measurement, and analytic plan. Methods/design: The JJ-TRIALS primary study uses a head-to-head cluster randomized trial with a phased rollout to evaluate the differential effectiveness of two conditions (Core and Enhanced) in 36 sites located in seven states. A Core strategy for promoting change is compared to an Enhanced strategy that incorporates all core strategies plus active facilitation. Target outcomes include improvements in evidence-based screening, assessment, and linkage to substance use treatment. Discussion: Contributions to implementation science are discussed as well as challenges associated with designing and deploying a complex, collaborative project. C1 [Knight, Danica K.; Becan, Jennifer E.] Texas Christian Univ, Inst Behav Res, POB 32880, Ft Worth, TX 76129 USA. [Belenko, Steven] Temple Univ, Dept Criminal Justice, Philadelphia, PA 19122 USA. [Wiley, Tisha] NIDA, Bethseda, MD USA. [Robertson, Angela A.] Mississippi State Univ, Social Sci Res Ctr, Starkville, MS USA. [Arrigona, Nancy] Council State Govt Justice Ctr, Austin, TX USA. [Dennis, Michael] Chestnut Hlth Syst, Normal, IL USA. [Bartkowski, John P.] Univ Texas San Antonio, Dept Sociol, San Antonio, TX USA. [McReynolds, Larkin S.; Wasserman, Gail A.] Columbia Univ NYSPI, Ctr Promot Mental Hlth Juvenile Justice, New York, NY USA. [Knudsen, Hannah K.; Leukefeld, Carl] Univ Kentucky, Behav Sci, Lexington, KY USA. [Rose, Eve; DiClemente, Ralph] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Knight, DK (reprint author), Texas Christian Univ, Inst Behav Res, POB 32880, Ft Worth, TX 76129 USA. EM d.knight@tcu.edu FU JJ-TRIALS cooperative agreement, at the National Institute on Drug Abuse (NIDA) by the National Institutes of Health (NIH); Chestnut Health Systems [U01DA036221]; Columbia University [U01DA036226]; Emory University [U01DA036233]; Mississippi State University [U01DA036176]; Temple University [U01DA036225]; Texas Christian University [U01DA036224]; University of Kentucky [U01DA036158] FX This study was funded under the JJ-TRIALS cooperative agreement, funded at the National Institute on Drug Abuse (NIDA) by the National Institutes of Health (NIH). The authors gratefully acknowledge the collaborative contributions of NIDA and support from the following grant awards: Chestnut Health Systems (U01DA036221); Columbia University (U01DA036226); Emory University (U01DA036233); Mississippi State University (U01DA036176); Temple University (U01DA036225); Texas Christian University (U01DA036224); and University of Kentucky (U01DA036158). NIDA Science Officer on this project is Tisha Wiley. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIDA, NIH, or the participating universities or JJ systems. NR 80 TC 2 Z9 2 U1 6 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD APR 29 PY 2016 VL 11 AR 57 DI 10.1186/s13012-016-0423-5 PG 18 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DK7MN UT WOS:000375109900001 PM 27130175 ER PT J AU Park, JY An, YR An, CM Kang, JH Kim, EM Kim, H Cho, S Kim, J AF Park, Jung Youn An, Yong-Rock An, Chul-Min Kang, Jung-Ha Kim, Eun Mi Kim, Heebal Cho, Seoae Kim, Jaemin TI Evolutionary constraints over microsatellite abundance in larger mammals as a potential mechanism against carcinogenic burden SO SCIENTIFIC REPORTS LA English DT Article ID METABOLIC-RATE; SIMPLE SEQUENCES; MOLECULAR CLOCK; BODY-SIZE; CANCER; GENOME; TEMPERATURE; DNA; GENERATION; MUTATIONS AB Larger organisms tend to live longer, have more potentially carcinogenic cells, and undergo more cell divisions. While one might intuitively expect cancer incidence to scale with body size, this assertion does not hold over the range of different mammals. Explaining this lack of correlation, so-called 'Peto's paradox' can likely increase our understanding of how cancer defense mechanisms are shaped by natural selection. Here, we study the occurrence of microsatellite in mammal genomes and observe that animals with expanded body size restrain the number of microsatellite. To take into account of higher mutation rate in the microsatellite region compared to that of genome, limiting the abundance of somatic mutations might explain how larger organisms could overcome the burden of cancer. These observations may serve as the basis to better understand how evolution has modeled protective mechanisms against cancer development. C1 [Park, Jung Youn; An, Chul-Min; Kang, Jung-Ha; Kim, Eun Mi] Natl Fisheries Res & Dev Inst, Biotechnol Res Div, Busan 619705, South Korea. [An, Yong-Rock] Natl Fisheries Res & Dev Inst, Cetacean Res Inst, Ulsan 680050, South Korea. [Kim, Heebal] Seoul Natl Univ, Dept Agr Biotechnol, Seoul 151921, South Korea. [Kim, Heebal] Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea. [Kim, Heebal; Cho, Seoae] Seoul Natl Univ, C&K Genom, Res Pk, Seoul 151919, South Korea. [Kim, Jaemin] NHGRI, NIH, Bethesda, MD 20892 USA. RP Cho, S (reprint author), Seoul Natl Univ, C&K Genom, Res Pk, Seoul 151919, South Korea.; Kim, J (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM seoae@cnkgenomics.com; jmkim85@snu.ac.kr OI Kim, Heebal/0000-0003-3064-1303 FU National Fisheries Research and Development Institute (NFRDI) [RP-2015-BT-009]; Marine Biotechnology Program (Genome Analysis of Marine Organisms and Development of Functional Applications) - Ministry of Oceans and Fisheries, Korea [PJT200620] FX This work was funded by a grant from the National Fisheries Research and Development Institute (NFRDI), contribution number RP-2015-BT-009. This research was also supported by a grant from Marine Biotechnology Program (PJT200620, Genome Analysis of Marine Organisms and Development of Functional Applications) funded by Ministry of Oceans and Fisheries, Korea. NR 40 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 29 PY 2016 VL 6 AR 25246 DI 10.1038/srep25246 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK8NO UT WOS:000375183800001 PM 27125812 ER PT J AU Van Boeckel, TP Takahashi, S Liao, QH Xing, WJ Lai, SJ Hsiao, V Liu, FF Zheng, YM Chang, ZR Yuan, C Metcalf, CJE Yu, HJ Grenfell, BT AF Van Boeckel, Thomas P. Takahashi, Saki Liao, Qiaohong Xing, Weijia Lai, Shengjie Hsiao, Victor Liu, Fengfeng Zheng, Yaming Chang, Zhaorui Yuan, Chen Metcalf, C. Jessica E. Yu, Hongjie Grenfell, Bryan T. TI Hand, Foot, and Mouth Disease in China: Critical Community Size and Spatial Vaccination Strategies SO SCIENTIFIC REPORTS LA English DT Article ID ENTEROVIRUS 71 VACCINE; MEASLES EPIDEMICS; DYNAMICS; OUTBREAK; MODEL; TRANSMISSION; CHILDREN; SEASONALITY; INFECTIONS; SINGAPORE AB Hand Foot and Mouth Disease (HFMD) constitutes a considerable burden for health care systems across China. Yet this burden displays important geographic heterogeneity that directly affects the local persistence and the dynamics of the disease, and thus the ability to control it through vaccination campaigns. Here, we use detailed geographic surveillance data and epidemic models to estimate the critical community size (CCS) of HFMD associated enterovirus serotypes CV-A16 and EV-A71 and we explore what spatial vaccination strategies may best reduce the burden of HFMD. We found CCS ranging from 336,979 (+/- 225,866) to 722,372 (+/- 150,562) with the lowest estimates associated with EV-A71 in the southern region of China where multiple transmission seasons have previously been identified. Our results suggest the existence of a regional immigration-recolonization dynamic driven by urban centers. If EV-A71 vaccines doses are limited, these would be optimally deployed in highly populated urban centers and in high-prevalence areas. If HFMD vaccines are included in China's National Immunization Program in order to achieve high coverage rates (> 85%), routine vaccination of newborns largely outperforms strategies in which the equivalent number of doses is equally divided between routine vaccination of newborns and pulse vaccination of the community at large. C1 [Van Boeckel, Thomas P.; Takahashi, Saki; Hsiao, Victor; Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Van Boeckel, Thomas P.] ETH, Inst Integrat Biol, Zurich, Switzerland. [Liao, Qiaohong; Xing, Weijia; Lai, Shengjie; Liu, Fengfeng; Zheng, Yaming; Chang, Zhaorui; Yuan, Chen; Yu, Hongjie] Chinese Ctr Dis Control & Prevent, Div Infect Dis, Key Lab Surveillance & Earlywarning Infect Dis, Beijing, Peoples R China. [Xing, Weijia] Taishan Med Coll, Sch Publ Hlth, Jinan, Shandong, Peoples R China. [Lai, Shengjie] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Metcalf, C. Jessica E.] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Van Boeckel, TP (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA.; Van Boeckel, TP (reprint author), ETH, Inst Integrat Biol, Zurich, Switzerland.; Yu, HJ (reprint author), Chinese Ctr Dis Control & Prevent, Div Infect Dis, Key Lab Surveillance & Earlywarning Infect Dis, Beijing, Peoples R China. EM thomas.vanboeckel@env.ethz.ch; yuhj@chinacdc.cn FU National Science Fund for Distinguished Young Scholars [81525023]; National Natural Science Foundation of China [81473031]; Li Ka Shing Oxford Global Health Programme [B9RST00-B900.57]; Science and Technology Directorate, Department of Homeland Security contract [HSHQDC-12-C-00058]; Bill and Melinda Gates Foundation; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, national Institutes of Health; ETH Zurich postdoctoral fellowship program; program for Adaptation to a Changing Environment of ETH Zurich; Ministry of Science and Technology of China [2012 ZX10004-201, 2014BAI13B05]; Flowminder Foundation, Stockholm, Sweden FX This work is funded by the National Science Fund for Distinguished Young Scholars (No. 81525023) (Hongjie Yu), the National Natural Science Foundation of China (No. 81473031) (Hongjie Yu), the Li Ka Shing Oxford Global Health Programme (No. B9RST00-B900.57) (Hongjie Yu) the Science and Technology Directorate, Department of Homeland Security contract HSHQDC-12-C-00058 (B.T.G. and T.P.V.B.), the Bill and Melinda Gates Foundation (B.T.G.), and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, national Institutes of Health (B.T.G. and C.J.E.M.). The ETH Zurich postdoctoral fellowship program (T.P.V.B), the program for Adaptation to a Changing Environment of ETH Zurich (T.P.V.B.), the National Natural Science Foundation of China (No. 81473031) (Hongjie Yu), the Ministry of Science and Technology of China (2012 ZX10004-201 and 2014BAI13B05) (Hongjie Yu), National Science Fund for Distinguished Young Scholars of China (No. 81525023) (Hongjie Yu) and Flowminder Foundation, Stockholm, Sweden (Shengjie Lai). The funding sources played no role in developing this paper and preparing it for submission. NR 47 TC 1 Z9 1 U1 12 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 29 PY 2016 VL 6 AR 25248 DI 10.1038/srep25248 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK8NR UT WOS:000375184100001 PM 27125917 ER PT J AU Beck, DE Reddy, PVN Lv, W Abdelmalak, M Tender, GS Lopez, S Agama, K Marchand, C Pommier, Y Cushman, M AF Beck, Daniel E. Reddy, P. V. Narasimha Lv, Wei Abdelmalak, Monica Tender, Gabrielle S. Lopez, Sophia Agama, Keli Marchand, Christophe Pommier, Yves Cushman, Mark TI Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DNA PHOSPHODIESTERASE I; POTENTIAL ANTICANCER AGENTS; LACTAM SIDE-CHAIN; BIOLOGICAL EVALUATION; CLEAVAGE COMPLEXES; MJ-III-65 NSC-706744; INHIBITORS; CAMPTOTHECIN; MECHANISM; DRUG AB Several indenoisoquinolines have shown promise as anticancer agents in clinical trials. Incorporation of a nitrogen atom modulating ligand-binding site interactions, physicochemical proper ties, and biological activities. Four series of aza-A-ring indenoisoquinolines were synthesized in which the nitrogen atom was systematically rotated through positions 1, 2, 3, and 4. The resulting compounds were tested to establish the optimal nitrogen position for topoisomerase IB (Topl) enzyme poisoning activity and cytotoxicity to human cancer cells. The 4-aza compounds were the most likely to yield derivatives with high Topl inhibitory activity. However, the relationship between structure and cytotoxicity was more complicated since the potency was influenced strongly by the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines 45 and 46 had nitrogen in the 2- or 3 positions and a 3'-dimethylaminopropyl side chain, and they had MGM GI(50) values that were slightly better than the corresponding indenoisoquinoline 64. C1 [Beck, Daniel E.; Reddy, P. V. Narasimha; Lv, Wei; Cushman, Mark] Purdue Univ, Dept Med Chem & Mol Pharmacol, Coll Pharm, W Lafayette, IN 47907 USA. [Beck, Daniel E.; Reddy, P. V. Narasimha; Lv, Wei; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Abdelmalak, Monica; Tender, Gabrielle S.; Lopez, Sophia; Agama, Keli; Marchand, Christophe; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Abdelmalak, Monica; Tender, Gabrielle S.; Lopez, Sophia; Agama, Keli; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Dept Med Chem & Mol Pharmacol, Coll Pharm, W Lafayette, IN 47907 USA.; Cushman, M (reprint author), Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. EM cushman@purdue.edu FU National Institutes of Health (NIH) [U01CA089566, P30CACA023168]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Developmental Therapeutics Program at the National Cancer Institute [NO1-CO-56000] FX This work was made possible by the National Institutes of Health (NIH) through support with Research Grants U01CA089566 and P30CACA023168. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. In vitro cytotoxicity testing was performed by the Developmental Therapeutics Program at the National Cancer Institute, under contract NO1-CO-56000. NR 49 TC 3 Z9 3 U1 3 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD APR 28 PY 2016 VL 59 IS 8 BP 3840 EP 3853 DI 10.1021/acs.jmedchem.6b00003 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DL3FP UT WOS:000375519900017 PM 27070999 ER PT J AU Shah, R Tanriverdi, K Levy, D Larson, M Gerstein, M Mick, E Rozowsky, J Kitchen, R Murthy, V Mikalev, E Freedman, JE AF Shah, Ravi Tanriverdi, Kahraman Levy, Daniel Larson, Martin Gerstein, Mark Mick, Eric Rozowsky, Joel Kitchen, Robert Murthy, Venkatesh Mikalev, Ekaterina Freedman, Jane E. TI Discordant Expression of Circulating microRNA from Cellular and Extracellular Sources SO PLOS ONE LA English DT Article ID PLATELET; TRANSCRIPTOME; BLOOD AB MicroRNA (miRNA) expression has rapidly grown into one of the largest fields for disease characterization and development of clinical biomarkers. Consensus is lacking in regards to the optimal sample source or if different circulating sources are concordant. Here, using miRNA measurements from contemporaneously obtained whole blood-and plasma-derived RNA from 2391 individuals, we demonstrate that plasma and blood miRNA levels are divergent and may reflect different biological processes and disease associations. C1 [Shah, Ravi] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [Tanriverdi, Kahraman; Mikalev, Ekaterina; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA 01605 USA. [Levy, Daniel; Larson, Martin] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Levy, Daniel; Larson, Martin] NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gerstein, Mark; Rozowsky, Joel; Kitchen, Robert] Yale Univ, Sch Med, Computat Biol & Bioinformat Program, 333 Cedar St, New Haven, CT 06520 USA. [Mick, Eric] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA 01605 USA. [Murthy, Venkatesh] Univ Michigan, Dept Cardiol, 1500 E Med Ctr Dr SPC 5873, Ann Arbor, MI 48109 USA. RP Freedman, JE (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA 01605 USA. EM jane.freedman@umassmed.edu OI Murthy, Venkatesh/0000-0002-7901-1321; Rozowsky, Joel/0000-0002-3565-0762 FU National Institutes of Health (NIH) as part of the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director [N01-HC 25195, P01-HL085381, UH2TR000921, U01HL126495] FX This work was supported by National Institutes of Health (NIH) grants N01-HC 25195, P01-HL085381 (to J.E.F.); UH2TR000921 and U01HL126495 (to J.E.F.; www.nih.gov), as part of the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. NR 19 TC 4 Z9 4 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 28 PY 2016 VL 11 IS 4 AR e0153691 DI 10.1371/journal.pone.0153691 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK8XE UT WOS:000375211700023 PM 27123852 ER PT J AU Ewer, K Rampling, T Venkatraman, N Bowyer, G Wright, D Lambe, T Imoukhuede, EB Payne, R Fehling, SK Strecker, T Biedenkopf, N Krahling, V Tully, CM Edwards, NJ Bentley, EM Samuel, D Labbe, G Jin, J Gibani, M Minhinnick, A Wilkie, M Poulton, I Lella, N Roberts, R Hartnell, F Bliss, C Sierra-Davidson, K Powlson, J Berrie, E Tedder, R Roman, F De Ryck, I Nicosia, A Sullivan, NJ Stanley, DA Mbaya, OT Ledgerwood, JE Schwartz, RM Siani, L Colloca, S Folgori, A Di Marco, S Cortese, R Wright, E Becker, S Graham, BS Koup, RA Levine, MM Volkmann, A Chaplin, P Pollard, AJ Draper, SJ Ballou, WR Lawrie, A Gilbert, SC Hill, AVS AF Ewer, K. Rampling, T. Venkatraman, N. Bowyer, G. Wright, D. Lambe, T. Imoukhuede, E. B. Payne, R. Fehling, S. K. Strecker, T. Biedenkopf, N. Kraehling, V. Tully, C. M. Edwards, N. J. Bentley, E. M. Samuel, D. Labbe, G. Jin, J. Gibani, M. Minhinnick, A. Wilkie, M. Poulton, I. Lella, N. Roberts, R. Hartnell, F. Bliss, C. Sierra-Davidson, K. Powlson, J. Berrie, E. Tedder, R. Roman, F. De Ryck, I. Nicosia, A. Sullivan, N. J. Stanley, D. A. Mbaya, O. T. Ledgerwood, J. E. Schwartz, R. M. Siani, L. Colloca, S. Folgori, A. Di Marco, S. Cortese, R. Wright, E. Becker, S. Graham, B. S. Koup, R. A. Levine, M. M. Volkmann, A. Chaplin, P. Pollard, A. J. Draper, S. J. Ballou, W. R. Lawrie, A. Gilbert, S. C. Hill, A. V. S. TI A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PROTECTS NONHUMAN-PRIMATES; IMMUNITY; VIRUS; CHALLENGE; INFECTION; HUMANS AB BACKGROUND The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak. METHODS In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels - 1x10(10) viral particles, 2.5x10(10) viral particles, and 5x10(10) viral particles - with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime-boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability. RESULTS No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001). CONCLUSIONS The ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. C1 [Ewer, K.; Rampling, T.; Venkatraman, N.; Bowyer, G.; Wright, D.; Lambe, T.; Imoukhuede, E. B.; Payne, R.; Tully, C. M.; Edwards, N. J.; Labbe, G.; Jin, J.; Gibani, M.; Minhinnick, A.; Wilkie, M.; Poulton, I.; Lella, N.; Roberts, R.; Hartnell, F.; Bliss, C.; Sierra-Davidson, K.; Powlson, J.; Berrie, E.; Pollard, A. J.; Draper, S. J.; Lawrie, A.; Gilbert, S. C.; Hill, A. V. S.] Univ Oxford, Jenner Inst, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England. [Ewer, K.; Rampling, T.; Venkatraman, N.; Bowyer, G.; Wright, D.; Lambe, T.; Imoukhuede, E. B.; Payne, R.; Tully, C. M.; Edwards, N. J.; Labbe, G.; Jin, J.; Gibani, M.; Minhinnick, A.; Wilkie, M.; Poulton, I.; Lella, N.; Roberts, R.; Hartnell, F.; Bliss, C.; Sierra-Davidson, K.; Powlson, J.; Berrie, E.; Pollard, A. J.; Draper, S. J.; Lawrie, A.; Gilbert, S. C.; Hill, A. V. S.] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford OX3 7DQ, England. [Ewer, K.; Rampling, T.; Venkatraman, N.; Bowyer, G.; Wright, D.; Lambe, T.; Imoukhuede, E. B.; Payne, R.; Tully, C. M.; Edwards, N. J.; Labbe, G.; Jin, J.; Gibani, M.; Minhinnick, A.; Wilkie, M.; Poulton, I.; Lella, N.; Roberts, R.; Hartnell, F.; Bliss, C.; Sierra-Davidson, K.; Powlson, J.; Berrie, E.; Pollard, A. J.; Draper, S. J.; Lawrie, A.; Gilbert, S. C.; Hill, A. V. S.] Oxford Biomed Res Ctr, Natl Inst Hlth Res, Oxford, England. [Bentley, E. M.; Wright, E.] Univ Westminster, Fac Sci & Technol, Viral Pseudotype Unit, London W1R 8AL, England. [Samuel, D.; Tedder, R.] Publ Hlth Agcy, Virus Reference Dept, London, England. [Fehling, S. K.; Strecker, T.; Biedenkopf, N.; Kraehling, V.; Becker, S.] Univ Marburg, Inst Virol, D-35032 Marburg, Germany. [Becker, S.] German Ctr Infect Res, Partner Site Giessen Marburg Langen, Marburg, Germany. [Volkmann, A.; Chaplin, P.] Bavarian Nord, Martinsried, Germany. [Roman, F.; De Ryck, I.; Ballou, W. R.] GlaxoSmithKline Biol, Rixensart, Belgium. [Nicosia, A.; Siani, L.; Colloca, S.; Folgori, A.; Di Marco, S.] ReiThera, Rome, Italy. [Nicosia, A.] Univ Naples Federico II, CEINGE, Naples, Italy. [Nicosia, A.] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy. [Sullivan, N. J.; Stanley, D. A.; Mbaya, O. T.; Ledgerwood, J. E.; Schwartz, R. M.; Graham, B. S.; Koup, R. A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Levine, M. M.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Cortese, R.] Keires, Basel, Switzerland. RP Hill, AVS (reprint author), Univ Oxford, Jenner Inst, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England. EM adrian.hill@ndm.ox.ac.uk OI Wright, Edward/0000-0001-7041-5138; Bentley, Emma M./0000-0001-6109-2840 FU Wellcome Trust FX Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875. NR 30 TC 24 Z9 24 U1 4 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 28 PY 2016 VL 374 IS 17 BP 1635 EP 1646 DI 10.1056/NEJMoa1411627 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DK3UR UT WOS:000374843400007 PM 25629663 ER PT J AU Porter, JR Fisher, BE Batchelor, E AF Porter, Joshua R. Fisher, Brian E. Batchelor, Eric TI p53 Pulses Diversify Target Gene Expression Dynamics in an mRNA Half-Life-Dependent Manner and Delineate Co-regulated Target Gene Subnetworks SO CELL SYSTEMS LA English DT Article ID P53-MDM2 FEEDBACK LOOP; DNA-DAMAGE; CELLS; NOISE; TRANSCRIPTION; TRANSMISSION; OSCILLATIONS; ACTIVATION; INDUCTION; NETWORKS AB The transcription factor p53 responds to DNA double-strand breaks by increasing in concentration in a series of pulses of fixed amplitude, duration, and period. How p53 pulses influence the dynamics of p53 target gene expression is not understood. Here, we show that, in bulk cell populations, patterns of p53 target gene expression cluster into groups with stereotyped temporal behaviors, including pulsing and rising dynamics. These behaviors correlate statistically with the mRNA decay rates of target genes: short mRNA half-lives produce pulses of gene expression. This relationship can be recapitulated by mathematical models of p53-dependent gene expression in single cells and cell populations. Single-cell transcriptional profiling demonstrates that expression of a subset of p53 target genes is coordinated across time within single cells; p53 pulsing attenuates this coordination. These results help delineate how p53 orchestrates the complex DNA damage response and give insight into the function of pulsatile signaling pathways. C1 [Porter, Joshua R.; Fisher, Brian E.; Batchelor, Eric] NCI, Pathol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. RP Batchelor, E (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. EM batchelore@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, CCR FX We thank W. Telford and V. Kapoor in the Center for Cancer Research (CCR) ETIB Flow Cytometry Core for aid in single-cell sorting as well as M. Raffeld and the CCR Molecular Diagnostics Unit and J. Zhu and the National Heart, Lung, and Blood Institute DNA Sequencing and Genomics Core for help with single cell transcriptional profiling. We also thank D. Levens, the Levens lab, A. Moody, A. Sun, T. Przytycka, C. Parent, J. Oberholtzer, A. Loewer, L. Goentoro, J. Hansen, J. Stommel, and J. Luo for helpful discussions. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, CCR. NR 32 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD APR 27 PY 2016 VL 2 IS 4 BP 272 EP 282 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EL1CY UT WOS:000394359300010 PM 27135539 ER PT J AU Kohn, EC Ivy, SP AF Kohn, Elise C. Ivy, S. Percy TI Confronting the Care Delivery Challenges Arising from Precision Medicine SO FRONTIERS IN ONCOLOGY LA English DT Article DE precision medicine; biomarkers; targets; genetic testing; opportunities; obstacles ID CELL LUNG-CANCER; ENDOMETRIAL CANCER; OVARIAN-CANCER; METHOD VALIDATION; DRUG DEVELOPMENT; CLINICAL-TRIALS; BIOMARKERS; MANAGEMENT; CARCINOMA; TUMOR AB Understanding the biology of cancer at the cellular and molecular levels, and the application of such knowledge to the patient, has opened new opportunities and uncovered new obstacles to quality cancer care delivery. Benefits include our ability to now understand that many, if not most, cancers are not one-size-fits-all. Cancers are a variety of diseases for which intervention may be very different. This approach is beginning to bear fruit in gynecologic cancers where we are investigating therapeutic optimization at a more focused level, that while not yet precision care, is perhaps much improved. Obstacles to quality care for patients come from many directions. These include incomplete understanding of the role of the mutant proteins in the cancers, the narrow spectrum of agents, broader mutational profiles in solid tumors, and sometimes overzealous application of the findings of genetic testing. This has been further compromised by the unbridled use of social media by all stakeholders in cancer care often without scientific qualification, where anecdote sometimes masquerades as a fact. The only current remedy is to wave the flag of caution, encourage all patients who undergo genetic testing, either germline or somatic, to do so with the oversight of genetic counselors and physician scientists knowledgeable in the pathways involved. This aspiration is accomplished with well-designed clinical trials that inform next steps in this complex and ever evolving process. C1 [Kohn, Elise C.; Ivy, S. Percy] NCI, Canc Therapy Evaluat Program, Div Canc Therapy & Diag, Rockville, MD USA. RP Kohn, EC (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Therapy & Diag, Rockville, MD USA. EM kohne@mail.nih.gov NR 40 TC 1 Z9 1 U1 1 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD APR 27 PY 2016 VL 6 AR 106 DI 10.3389/fonc.2016.00106 PG 7 WC Oncology SC Oncology GA DK3OZ UT WOS:000374828200001 PM 27200294 ER PT J AU Roseland, JM Patterson, KY Andrews, KW Phillips, KM Phillips, MM Pehrsson, PR Dufresne, GL Jakobsen, J Gusev, PA Savarala, S Nguyen, QV Makowski, AJ Scheuerell, CR Larouche, GP Wise, SA Harnly, JM Williams, JR Betz, JM Taylor, CL AF Roseland, Janet Maxwell Patterson, Kristine Y. Andrews, Karen W. Phillips, Katherine M. Phillips, Melissa M. Pehrsson, Pamela R. Dufresne, Guy L. Jakobsen, Jette Gusev, Pavel A. Savarala, Sushma Nguyen, Quynhanh V. Makowski, Andrew J. Scheuerell, Chad R. Larouche, Guillaume P. Wise, Stephen A. Harnly, James M. Williams, Juhi R. Betz, Joseph M. Taylor, Christine L. TI Interlaboratory Trial for Measurement of Vitamin D and 25-Hydroxyvitamin D [25(OH)D] in Foods and a Dietary Supplement Using Liquid Chromatography-Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE reference material; food; dietary supplement; vitamin D-3 (cholecalciferol); 25-hydroxyvitamin D-3 (25-hydroxycholcalciferol) ID NUTRIENT ANALYSIS PROGRAM; CARDIOVASCULAR-DISEASE; BIOLOGICAL-ACTIVITY; NATIONAL FOOD; D-3; SERUM; EGGS; MEAT; HEALTH; FISH AB Assessment of total vitamin D intake from foods and dietary supplements (DSs) may be incomplete if 25-hydroxyvitamin D [25(OH)D] intake is not included. However, 25(OH)D data for such intake assessments are lacking, no food or DS reference materials (RMs) are available, and comparison of laboratory performance has been needed. The primary goal of this study was to evaluate whether vitamin D-3 and 25(OH)D-3 concentrations in food and DS materials could be measured with acceptable reproducibility. Five experienced laboratories from the United States and other countries participated, all using liquid chromatography tandem mass spectrometry but no common analytical protocol; however, various methods were used for determining vitamin D-3 in the DS. Five animal-based materials (including three commercially available RMs) and one DS were analyzed. Reproducibility results for the materials were acceptable. Thus, it is possible to obtain consistent results among experienced laboratories for vitamin D-3 and 25(OH)D-3, in foods and a DS. C1 [Roseland, Janet Maxwell; Patterson, Kristine Y.; Andrews, Karen W.; Pehrsson, Pamela R.; Gusev, Pavel A.; Savarala, Sushma; Nguyen, Quynhanh V.; Williams, Juhi R.] USDA ARS, Nutrient Data Lab, BARC West, 10300 Baltimore Ave,Bldg 005, Beltsville, MD 20705 USA. [Phillips, Katherine M.] Virginia Tech, Biochem Dept 0308, 304 Engel Hall, Blacksburg, VA 24061 USA. [Phillips, Melissa M.; Wise, Stephen A.] NIST, Div Chem Sci, MS 8392,100 Bur Dr, Gaithersburg, MD 20899 USA. [Dufresne, Guy L.] Hlth Canada, Food & Nutr Lab, 1001 St Laurent Ouest, Longueuil, PQ J4K 1C7, Canada. [Jakobsen, Jette] Tech Univ Denmark, Natl Food Inst, Div Food Chem, Soborg, Denmark. [Makowski, Andrew J.] Heartland Assays LLC, Suite 4400,2711 South Loop Dr, Ames, IA 50010 USA. [Scheuerell, Chad R.] Covance Labs, 3301 Kinsman Blvd, Madison, WI 53704 USA. [Betz, Joseph M.; Taylor, Christine L.] NIH, Off Dietary Supplements, 3B01,MSC 7517,6100 Execut Blvd, Bethesda, MD 20892 USA. [Harnly, James M.] USDA ARS, Food Composit & Method Dev Lab, BARC East, Bldg 161,10300 Baltimore Ave, Beltsville, MD 20705 USA. RP Roseland, JM (reprint author), USDA ARS, Nutrient Data Lab, BARC West, 10300 Baltimore Ave,Bldg 005, Beltsville, MD 20705 USA. EM janet.roseland@ars.usda.gov FU Office of Dietary Supplements of the National Institutes of Health [60 1235 3012] FX Partial funding for this work was provided under Agreement 60 1235 3012 from Office of Dietary Supplements of the National Institutes of Health. NR 47 TC 0 Z9 0 U1 5 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD APR 27 PY 2016 VL 64 IS 16 BP 3167 EP 3175 DI 10.1021/acs.jafc.5b05016 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA DK9IO UT WOS:000375244300008 PM 27045951 ER PT J AU Thrane, S Janitzek, CM Matondo, S Resende, M Gustavsson, T de Jongh, WA Clemmensen, S Roeffen, W van de Vegte-Bolmer, M van Gemert, GJ Sauerwein, R Schiller, JT Nielsen, MA Theander, TG Salanti, A Sander, AF AF Thrane, Susan Janitzek, Christoph M. Matondo, Sungwa Resende, Mafalda Gustavsson, Tobias de Jongh, Willem Adriaan Clemmensen, Stine Roeffen, Will van de Vegte-Bolmer, Marga van Gemert, Geert Jan Sauerwein, Robert Schiller, John T. Nielsen, Morten A. Theander, Thor G. Salanti, Ali Sander, Adam F. TI Bacterial superglue enables easy development of efficient virus-like particle based vaccines SO JOURNAL OF NANOBIOTECHNOLOGY LA English DT Article ID PLASMODIUM-FALCIPARUM PARASITES; TRANSMISSION-BLOCKING ACTIVITY; PREGNANCY-ASSOCIATED MALARIA; ANTIBODY-RESPONSES; IMMUNODEFICIENCY VIRUS; IMMUNE-RESPONSE; CORE PARTICLES; PROTEIN; ANTIGEN; PFS25 AB Background: Virus-like particles (VLPs) represent a significant advance in the development of subunit vaccines, combining high safety and efficacy. Their particulate nature and dense repetitive subunit organization makes them ideal scaffolds for display of vaccine antigens. Traditional approaches for VLP-based antigen display require labor-intensive trial-and-error optimization, and often fail to generate dense antigen display. Here we utilize the split-intein (SpyTag/SpyCatcher) conjugation system to generate stable isopeptide bound antigen-VLP complexes by simply mixing of the antigen and VLP components. Results: Genetic fusion of SpyTag or SpyCatcher to the N-terminus and/or C-terminus of the Acinetobacter phage AP205 capsid protein resulted in formation of stable, nonaggregated VLPs expressing one SpyCatcher, one SpyTag or two SpyTags per capsid protein. Mixing of spy-VLPs with eleven different vaccine antigens fused to SpyCatcher or SpyTag resulted in formation of antigen-VLP complexes with coupling efficiencies (% occupancy of total VLP binding sites) ranging from 22-88 %. In mice, spy-VLP vaccines presenting the malaria proteins Pfs25 or VAR2CSA markedly increased antibody titer, affinity, longevity and functional efficacy compared to corresponding vaccines employing monomeric proteins. The spy-VLP vaccines also effectively broke B cell self-tolerance and induced potent and durable antibody responses upon vaccination with cancer or allergy-associated self-antigens (PD-L1, CTLA-4 and IL-5). Conclusions: The spy-VLP system constitutes a versatile and rapid method to develop highly immunogenic VLP-based vaccines. Our data provide proof-of-concept for the technology's ability to present complex vaccine antigens to the immune system and elicit robust functional antibody responses as well as to efficiently break B cell self-tolerance. The spy-VLP-system may serve as a generic tool for the cost-effective development of effective VLP-vaccines against both infectious-and non-communicable diseases and could facilitate rapid and unbiased screening of vaccine candidate antigens. C1 [Thrane, Susan; Janitzek, Christoph M.; Resende, Mafalda; Gustavsson, Tobias; Clemmensen, Stine; Nielsen, Morten A.; Theander, Thor G.; Salanti, Ali; Sander, Adam F.] Univ Copenhagen, Dept Immunol & Microbiol, Ctr Med Parasitol, Copenhagen, Denmark. [Thrane, Susan; Janitzek, Christoph M.; Resende, Mafalda; Gustavsson, Tobias; Clemmensen, Stine; Nielsen, Morten A.; Theander, Thor G.; Salanti, Ali; Sander, Adam F.] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen, Denmark. [Matondo, Sungwa] KCMC, Kilimanjaro Clin Res Inst, Moshi, Tanzania. [de Jongh, Willem Adriaan; Clemmensen, Stine] ExpreS2 Biotechnol, SCION DTU Sci Pk, Horsholm, Denmark. [Roeffen, Will; van de Vegte-Bolmer, Marga; van Gemert, Geert Jan; Sauerwein, Robert] Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Salanti, A; Sander, AF (reprint author), Univ Copenhagen, Dept Immunol & Microbiol, Ctr Med Parasitol, Copenhagen, Denmark. EM salanti@sund.ku.dk; adamsander@gmail.com OI Theander, Thor G./0000-0002-3509-7514 FU PATH Malaria Vaccine Initiative; Danish Research Council [13127]; European Union [304815]; Bill and Melinda Gates Foundation [APP178218] FX The authors would like to thank Jens Hedelund Madsen, Anne Corfitz, Elham Marjan Mohammad Alijazaeri and Nahla Chehabi for technical assistance. We would like to thank Susheel Kumar Sinhg for the kind donation of mAb 4B7 and The Biophysics Facility-Protein Structure and Function Program from Center for Protein Research, Copenhagen, for assisting us with DLS measurements. We would like to thank Dr. Carole Long and Dr. Kazutoyo Miura, NIH, for assisting with SMFA analysis, and the PATH Malaria Vaccine Initiative for their funding support to the NIH for this effort. This study was supported by DANIDA, IdMalVac from the Danish Research Councils (Grant 13127), PlacMalVac under the European Union Seventh Framework Programme, FP7-HEALTH-2012-INNOVATION under grant agreement no. 304815 and through a grant from Bill and Melinda Gates Foundation Grant ID APP178218. NR 61 TC 6 Z9 6 U1 9 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-3155 J9 J NANOBIOTECHNOL JI J. Nanobiotechnol. PD APR 27 PY 2016 VL 14 AR 30 DI 10.1186/s12951-016-0181-1 PG 16 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA DK5EP UT WOS:000374942800001 PM 27117585 ER PT J AU Jasmin, KM McGettigan, C Agnew, ZK Lavan, N Josephs, O Cummins, F Scott, SK AF Jasmin, Kyle M. McGettigan, Carolyn Agnew, Zarinah K. Lavan, Nadine Josephs, Oliver Cummins, Fred Scott, Sophie K. TI Cohesion and Joint Speech: Right Hemisphere Contributions to Synchronized Vocal Production SO JOURNAL OF NEUROSCIENCE LA English DT Article DE coordinated action; fMRI; joint speech; right hemisphere; social cohesion; speech control ID SENSORIMOTOR SYNCHRONIZATION; AUDITORY-CORTEX; NONHUMAN-PRIMATES; FEEDBACK-CONTROL; NEURAL BASIS; SELF-FACE; CONVERSATION; COORDINATION; BRAIN; COMMUNICATION AB Synchronized behavior (chanting, singing, praying, dancing) is found in all human cultures and is central to religious, military, and political activities, which require people to act collaboratively and cohesively; however, we know little about the neural underpinnings of many kinds of synchronous behavior (e.g., vocal behavior) or its role in establishing and maintaining group cohesion. In the present study, we measured neural activity using fMRI while participants spoke simultaneously with another person. We manipulated whether the couple spoke the same sentence (allowing synchrony) or different sentences (preventing synchrony), and also whether the voice the participant heard was "live" (allowing rich reciprocal interaction) or prerecorded (with no such mutual influence). Synchronous speech was associated with increased activity in posterior and anterior auditory fields. When, and only when, participants spoke with a partner who was both synchronous and "live," we observed a lack of the suppression of auditory cortex, which is commonly seen as a neural correlate of speech production. Instead, auditory cortex responded as though it were processing another talker's speech. Our results suggest that detecting synchrony leads to a change in the perceptual consequences of one'sownactions: they are processed as though they were other-, rather than self-produced. This may contribute to our understanding of synchronized behavior as a group-bonding tool. C1 [Jasmin, Kyle M.; McGettigan, Carolyn; Scott, Sophie K.] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Jasmin, Kyle M.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20492 USA. [McGettigan, Carolyn; Lavan, Nadine] Univ London, Dept Psychol, London TW20 0EX, England. [Agnew, Zarinah K.] Univ Calif San Francisco, Dept Otolaryngol, San Francisco, CA 94143 USA. [Josephs, Oliver] UCL, Inst Neurol, London WC1N 3BG, England. [Cummins, Fred] Univ Coll Dublin, Sch Comp Sci, Dublin 4, Ireland. RP Scott, SK (reprint author), 17 Queen Sq, London WC1N 3AR, England. EM sophie.scott@ucl.ac.uk RI Scott, Sophie/A-1843-2010; McGettigan, Carolyn/A-3660-2010 OI Scott, Sophie/0000-0001-7510-6297; McGettigan, Carolyn/0000-0001-6293-3795 FU University College London National Institute of Mental Health; Wellcome Trust [WT090961MA] FX This work was supported by a University College London National Institute of Mental Health Joint Doctoral Training Program in Neuroscience Award to K.M.J., and a Wellcome Trust Senior Research Fellowship in Biomedical (no. WT090961MA) Science to S.K.S. NR 63 TC 1 Z9 1 U1 4 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 27 PY 2016 VL 36 IS 17 BP 4669 EP 4680 DI 10.1523/JNEUROSCI.4075-15.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DK7UF UT WOS:000375130500003 PM 27122026 ER PT J AU Papaleo, F Yang, F Paterson, C Palumbo, S Carr, GV Wang, YH Floyd, K Huang, WW Thomas, CJ Chen, JS Weinberger, DR Law, AJ AF Papaleo, Francesco Yang, Feng Paterson, Clare Palumbo, Sara Carr, Gregory V. Wang, Yanhong Floyd, Kirsten Huang, Wenwei Thomas, Craig J. Chen, Jingshan Weinberger, Daniel R. Law, Amanda J. TI Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model SO JOURNAL OF NEUROSCIENCE LA English DT Article DE AKT; ErbB; IC87114; neuregulin; PIK3CD; schizophrenia ID LONG-TERM POTENTIATION; PARVALBUMIN-POSITIVE INTERNEURONS; CORTICAL PYRAMIDAL NEURONS; WORKING-MEMORY; COGNITIVE IMPAIRMENT; RECOGNITION MEMORY; PREFRONTAL CORTEX; SOCIAL COGNITION; BIPOLAR DISORDER; CANDIDATE GENES AB Schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110 delta, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110 delta reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110 delta as a target for antipsychotic drug development. C1 [Papaleo, Francesco; Yang, Feng; Palumbo, Sara; Carr, Gregory V.; Wang, Yanhong; Chen, Jingshan; Weinberger, Daniel R.; Law, Amanda J.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Papaleo, Francesco] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, Via Morego 30, I-16163 Genoa, Italy. [Yang, Feng; Wang, Yanhong; Weinberger, Daniel R.] Lieber Inst Brain Dev, Johns Hopkins Univ Med Campus, Baltimore, MD 21205 USA. [Paterson, Clare; Floyd, Kirsten; Law, Amanda J.] Univ Colorado, Sch Med, Dept Psychiat, 12700 East 19th Ave,Mailstop 8619,RC2,Rm 4100C, Aurora, CO 80045 USA. [Palumbo, Sara; Carr, Gregory V.] Univ Pisa, Dept Surg Med & Mol Pathol, Lab Mol Biol, I-56126 Pisa, Italy. [Palumbo, Sara; Carr, Gregory V.] Univ Pisa, Crit Care, I-56126 Pisa, Italy. [Huang, Wenwei; Thomas, Craig J.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Law, Amanda J.] Univ Colorado, Sch Med, Dept Cell & Dev Biol, 12700 East 19th Ave,Mailstop 8619,RC2,Rm 4100C, Aurora, CO 80045 USA. RP Law, AJ (reprint author), Univ Colorado, Sch Med, Dept Psychiat, 12700 East 19th Ave,Mailstop 8619,RC2,Rm 4100C, Aurora, CO 80045 USA.; Law, AJ (reprint author), Univ Colorado, Sch Med, Dept Cell & Dev Biol, 12700 East 19th Ave,Mailstop 8619,RC2,Rm 4100C, Aurora, CO 80045 USA. EM amanda.law@ucdenver.edu RI palumbo, sara/B-1603-2013; Carr, Gregory/M-8821-2016; OI palumbo, sara/0000-0002-3809-6058; Carr, Gregory/0000-0002-6091-6729; Papaleo, Francesco/0000-0002-6326-0657; Law, Amanda/0000-0002-2574-1564 FU National Institute of Mental Health (NIMH) Intramural Research Program, National Institutes of Health (NIH); NIH, NIMH [P50 MH-086383-06, R01 MH103716-02]; Brain and Behavior Research Foundation/NARSAD; Dr. Nancy Gary Endowed Chair in Children's Mental Health Disorders FX This work was supported by funding from the National Institute of Mental Health (NIMH) Intramural Research Program, National Institutes of Health (NIH) to A.J.L and D.R.W., and by extramural funding from the NIH, NIMH to A.J.L (P50 MH-086383-06 and R01 MH103716-02). Support was also provided by the Sidney R. Baer, Jr. Award. Outstanding Research Achievement Prize for Schizophrenia Research from the Brain and Behavior Research Foundation/NARSAD and the Dr. Nancy Gary Endowed Chair in Children's Mental Health Disorders, both held by A.J.L. We thank Dr. James Pickel and the NIMH Division of Intramural Programs, Transgenic Core Facility for mouse oocyte injections, Mr. Qingjun Tian of NIMH, NIH for genotyping and mouse brain dissections and Dr. Wei Tan of NCI, NIH for original EF372273 construct synthesis. NR 98 TC 3 Z9 3 U1 6 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 27 PY 2016 VL 36 IS 17 BP 4859 EP 4875 DI 10.1523/JNEUROSCI.4632-15.2016 PG 17 WC Neurosciences SC Neurosciences & Neurology GA DK7UF UT WOS:000375130500018 PM 27122041 ER PT J AU Avella, MA Baibakov, BA Jimenez-Movilla, M Sadusky, AB Dean, J AF Avella, Matteo A. Baibakov, Boris A. Jimenez-Movilla, Maria Sadusky, Anna Burkart Dean, Jurrien TI ZP2 peptide beads select human sperm in vitro, decoy mouse sperm in vivo, and provide reversible contraception SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ZONA-PELLUCIDA PROTEIN; ACROSOME REACTION; TRANSGENIC MICE; SULFATED GLYCOPROTEIN; GAMETE RECOGNITION; SPERMATOZOA; SPERMATOGENESIS; FERTILIZATION; INHIBITION; MORPHOLOGY AB Gamete recognition in the female reproductive tract occurs at the surface of the zona pellucida surrounding ovulated eggs. The acellular zona matrix is composed of three (mouse) or four (human) proteins (ZP1 to ZP4), and the amino terminus of ZP2 is the primary sperm-binding ligand. Mouse and human sperm bind, respectively, to recombinant moZP2(35-149) and huZP2(39-154) peptides attached to agarose beads. Mouse ZP2 peptide beads markedly inhibited fertilization of ovulated mouse eggs inseminated in vitro and incubated overnight. Similarly, human ZP2 peptide beads prevented sperm binding and penetration of transgenic ZP2(Rescue) zonae pellucidae, in which human ZP2 replaced mouse ZP2. When mouse ZP2 peptide beads were transcervically deposited into the uterus, there was no change in mating behavior and copulatory plugs were present, but bound sperm did not progress into the oviduct and female mice were infertile. On average, contraception lasted > 10 estrus cycles but was reversible with no detectable pathology in the reproductive tract. Despite the long-term contraceptive effect, initial sperm binding to the peptide beads was reversible in vitro. We exploited this observation to select human sperm that were better able to penetrate the zonae of human ZP2(Rescue) eggs, and the approach holds promise for identifying superior sperm for human assisted reproductive technologies (ART). We conclude that the amino-terminal ZP2 peptide supports sperm binding, which is initially reversible but, with time, becomes irreversible. Short-term, reversible binding may be useful in selecting sperm for ART, and long-term binding decoys sperm and results in effective contraception in mice. C1 [Avella, Matteo A.; Baibakov, Boris A.; Sadusky, Anna Burkart; Dean, Jurrien] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Jimenez-Movilla, Maria] Univ Murcia, Sch Med, Dept Cell Biol & Histol, IMIB, E-30100 Murcia, Spain. RP Dean, J (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM jurriend@helix.nih.gov RI Jimenez-Movilla, Maria/I-1004-2015 OI Jimenez-Movilla, Maria/0000-0002-1572-8219 FU Intramural Research Program of NIDDK, NIH; Fundacion Seneca-Agencia y Tecnologia de la Region de Murcia (Jovenes Lideres en Investigacion) FX The research was supported by the Intramural Research Program of NIDDK, NIH. The contributions of M.J.-M. were supported by the Fundacion Seneca-Agencia y Tecnologia de la Region de Murcia (Jovenes Lideres en Investigacion). NR 38 TC 3 Z9 3 U1 5 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD APR 27 PY 2016 VL 8 IS 336 AR 336ra60 DI 10.1126/scitranslmed.aad9946 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DK3QW UT WOS:000374833500005 PM 27122613 ER PT J AU Liput, DJ Lu, V Davis, MI Puhl, HL Ikeda, SR AF Liput, Daniel J. Lu, Van B. Davis, Margaret I. Puhl, Henry L. Ikeda, Stephen R. TI Rem2, a member of the RGK family of small GTPases, is enriched in nuclei of the basal ganglia SO SCIENTIFIC REPORTS LA English DT Article ID DEPENDENT CALCIUM-CHANNELS; CENTRAL-NERVOUS-SYSTEM; GTP-BINDING PROTEINS; DENDRITIC COMPLEXITY; CELL-SHAPE; NEURONS; EXPRESSION; NEOSTRIATUM; STRIATUM; PHOSPHORYLATION AB Rem2 is a member of the RGK subfamily of RAS small GTPases. Rem2 inhibits high voltage activated calcium channels, is involved in synaptogenesis, and regulates dendritic morphology. Rem2 is the primary RGK protein expressed in the nervous system, but to date, the precise expression patterns of this protein are unknown. In this study, we characterized Rem2 expression in the mouse nervous system. In the CNS, Rem2 mRNA was detected in all regions examined, but was enriched in the striatum. An antibody specific for Rem2 was validated using a Rem2 knockout mouse model and used to show abundant expression in striatonigral and striatopallidal medium spiny neurons but not in several interneuron populations. In the PNS, Rem2 was abundant in a subpopulation of neurons in the trigeminal and dorsal root ganglia, but was absent in sympathetic neurons of superior cervical ganglia. Under basal conditions, Rem2 was subject to post-translational phosphorylation, likely at multiple residues. Further, Rem2 mRNA and protein expression peaked at postnatal week two, which corresponds to the period of robust neuronal maturation in rodents. This study will be useful for elucidating the functions of Rem2 in basal ganglia physiology. C1 [Liput, Daniel J.; Lu, Van B.; Puhl, Henry L.; Ikeda, Stephen R.] NIAAA, Labs Mol Physiol, NIH, Bethesda, MD 20892 USA. [Davis, Margaret I.] NIAAA, Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Ikeda, SR (reprint author), NIAAA, Labs Mol Physiol, NIH, Bethesda, MD 20892 USA. EM sikeda@mail.nih.gov FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research (DICBR) FX This work was supported by the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research (DICBR). NR 42 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 27 PY 2016 VL 6 AR 25137 DI 10.1038/srep25137 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK4AP UT WOS:000374858900002 PM 27118437 ER PT J AU Nagaya, T Nakamura, Y Sato, K Zhang, YF Ni, M Choyke, PL Ho, M Kobayashi, H AF Nagaya, Tadanobu Nakamura, Yuko Sato, Kazuhide Zhang, Yi-Fan Ni, Min Choyke, Peter L. Ho, Mitchell Kobayashi, Hisataka TI Near infrared photoimmunotherapy with an anti-mesothelin antibody SO ONCOTARGET LA English DT Article DE near infrared photoimmunotherapy; mesothelin; hYP218; humanized monoclonal antibodies; molecular imaging ID FLUORESCENCE-GUIDED SURGERY; PANCREATIC-CANCER; ENHANCED PERMEABILITY; PLEURAL MESOTHELIOMA; POTENTIATING FACTOR; SERUM MESOTHELIN; OVARIAN-CANCER; TUMOR-MODEL; THERAPY; ADENOCARCINOMAS AB Near Infrared-Photoimmunotherapy (NIR-PIT) is a new, highly selective tumor treatment that employs an antibody-photon absorber conjugate (APC). When the APC attaches to its target cell and is exposed to NIR light, highly selective cell killing is observed. NIR-PIT has been demonstrated with a limited number of antibodies. Mesothelin is overexpressed in several malignancies and is emerging as a therapeutic target. A recently humanized antibody (hYP218) has been generated against mesothelin that demonstrates high affinity binding. Here, we describe the efficacy of NIR-PIT, using hYP218 as the antibody within the APC to target a mesothelin expressing A431/H9 cell. The hYP218 antibody was conjugated to a photo-absorber, IR700 and incubated with the cells. The hYP218-IR700 showed specific binding to cells and cell-specific killing was observed in vitro. After implanting A431/H9 cells in an athymic nude mouse, tumor-bearing mice were treated with the following regimen of NIR-PIT; 100 mu g of hYP218-IR700 i.v., NIR light was administered at 50 J/cm(2) on day 1 after injection and 100 J/cm(2) of light on day 2 after injection. The hYP218-IR700 showed high tumor accumulation and a high tumor-background ratio (TBR). Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups (p < 0.001), and significantly prolonged survival (p < 0.0001 vs other groups). Thus, the new anti-mesothelin antibody, hYP218, is suitable as an antibody-drug conjugate for NIR-PIT. Furthermore, NIR-PIT with hYP218-IR700 is a promising candidate for the treatment of mesothelin-expressing tumors that could be readily translated to humans. C1 [Nagaya, Tadanobu; Nakamura, Yuko; Sato, Kazuhide; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhang, Yi-Fan; Ni, Min; Ho, Mitchell] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov OI Zhang, Yifan/0000-0002-0629-0200 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research [ZIA BC011513, Z01 BC010891, ZIA BC010891]; JSPS; (China) Jiangsu Government Scholarship for Overseas Studies FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (ZIA BC011513, Z01 BC010891, ZIA BC010891). Kazuhide Sato is supported with JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH. Min Ni is supported with the (China) Jiangsu Government Scholarship for Overseas Studies. We thank Dr. Bryan Fleming (NCI) for editorial assistance. NR 38 TC 5 Z9 5 U1 9 U2 10 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 26 PY 2016 VL 7 IS 17 BP 23361 EP 23369 DI 10.18632/oncotarget.8025 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO3UB UT WOS:000377706200030 PM 26981775 ER PT J AU Kwilas, AR Ardiani, A Gameiro, SR Richards, J Hall, AB Hodge, JW AF Kwilas, Anna R. Ardiani, Andressa Gameiro, Sofia R. Richards, Jacob Hall, Ashley B. Hodge, James W. TI Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin SO ONCOTARGET LA English DT Article DE enzalutamide; abiraterone; androgen deprivation therapy; TNBC; immunogenic modulation ID TRAIL-INDUCED APOPTOSIS; PROSTATE-CANCER; TUMOR-CELLS; COMBINATION THERAPY; IMPROVES SURVIVAL; LIGAND TRAIL; IN-VITRO; EXPRESSION; OPG; PATHWAY AB Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of enzalutamide on breast cancer cells, both enzalutamide and abiraterone improved the sensitivity of breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression as well as a significant reduction in the expression of osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR-TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition therapy for the treatment of AR-TNBC, especially in combination with cancer immunotherapy, providing a potential novel therapeutic option for select patients. C1 [Kwilas, Anna R.; Ardiani, Andressa; Gameiro, Sofia R.; Richards, Jacob; Hall, Ashley B.; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 55 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 26 PY 2016 VL 7 IS 17 BP 23498 EP 23511 DI 10.18632/oncotarget.8274 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO3UB UT WOS:000377706200040 PM 27015557 ER PT J AU Tanigawa, S Taguchi, A Sharma, N Perantoni, AO Nishinakamura, R AF Tanigawa, Shunsuke Taguchi, Atsuhiro Sharma, Nirmala Perantoni, Alan O. Nishinakamura, Ryuichi TI Selective In Vitro Propagation of Nephron Progenitors Derived from Embryos and Pluripotent Stem Cells SO CELL REPORTS LA English DT Article ID SELF-RENEWAL; MOUSE KIDNEY; NEPHROGENESIS; MAINTAIN; SIX2; DIFFERENTIATION; ORGANOGENESIS; MESENCHYME; INDUCTION; ORGANOIDS AB Nephron progenitors in the embryonic kidney propagate while generating differentiated nephrons. However, in mice, the progenitors terminally differentiate shortly after birth. Here, we report a method for selectively expanding nephron progenitors in vitro in an undifferentiated state. Combinatorial and concentration-dependent stimulation with LIF, FGF2/9, BMP7, and a WNT agonist is critical for expansion. The purified progenitors proliferated beyond the physiological limits observed in vivo, both for cell numbers and lifespan. Neonatal progenitors were maintained for a week, while progenitors from embryonic day 11.5 expanded 1,800-fold for nearly 20 days and still reconstituted 3D nephrons containing glomeruli and renal tubules. Furthermore, progenitors generated from mouse embryonic stem cells and human induced pluripotent cells could be expanded with retained nephron-forming potential. Thus, we have established in vitro conditions for promoting the propagation of nephron progenitors, which will be essential for dissecting the mechanisms of kidney organogenesis and for regenerative medicine. C1 [Tanigawa, Shunsuke; Taguchi, Atsuhiro; Nishinakamura, Ryuichi] Kumamoto Univ, Inst Mol Embryol & Genet, Dept Kidney Dev, Kumamoto 8600811, Japan. [Sharma, Nirmala; Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, NIH, Ft Detrick, MD 21702 USA. RP Nishinakamura, R (reprint author), Kumamoto Univ, Inst Mol Embryol & Genet, Dept Kidney Dev, Kumamoto 8600811, Japan. EM ryuichi@kumamoto-u.ac.jp OI Taguchi, Atsuhiro/0000-0003-1741-2987 FU Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [26860640, 26253051]; program for leading graduate schools, HIGO program, Kumamoto University FX We thank Tomoko Ohmori and Sayoko Fujimura for their technical assistance. This study was supported, in part, by grants KAKENHI 26860640 to S.T. and 26253051 to R.N. from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. This work was also supported, in part, by the program for leading graduate schools, HIGO program, Kumamoto University. NR 41 TC 4 Z9 4 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD APR 26 PY 2016 VL 15 IS 4 BP 801 EP 813 DI 10.1016/j.celrep.2016.03.076 PG 13 WC Cell Biology SC Cell Biology GA DK2FS UT WOS:000374730600013 ER PT J AU Wang, XT Campbell, MR Lacher, SE Cho, HY Wan, M Crowl, CL Chorley, BN Bond, GL Kleeberger, SR Slattery, M Bell, DA AF Wang, Xuting Campbell, Michelle R. Lacher, Sarah E. Cho, Hye-Youn Wan, Ma Crowl, Christopher L. Chorley, Brian N. Bond, Gareth L. Kleeberger, Steven R. Slattery, Matthew Bell, Douglas A. TI A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders SO CELL REPORTS LA English DT Article ID GENE-EXPRESSION; HUMAN GENOME; NEURODEGENERATIVE DISEASES; ALZHEIMERS-DISEASE; CONSENSUS SEQUENCE; COMMON VARIANTS; IDENTIFICATION; NRF2; DNA; TAU AB The NRF2/sMAF protein complex regulates the oxidative stress response by occupying cis-acting enhancers containing an antioxidant response element (ARE). Integrating genome-wide maps of NRF2/sMAF occupancy with disease-susceptibility loci, we discovered eight polymorphic AREs linked to 14 highly ranked disease-risk SNPs in individuals of European ancestry. Among these SNPs was rs242561, located within a regulatory region of the MAPT gene (encoding microtubule-associated protein Tau). It was consistently occupied by NRF2/sMAF in multiple experiments and its strong-binding allele associated with higher mRNA levels in cell lines and human brain tissue. Induction of MAPT transcription by NRF2 was confirmed using a human neuroblastoma cell line and a Nrf2-deficient mouse model. Most importantly, rs242561 displayed complete linkage disequilibrium with a highly protective allele identified in multiple GWASs of progressive supranuclear palsy, Parkinson's disease, and corticobasal degeneration. These observations suggest a potential role for NRF2/sMAF in tauopathies and a possible role for NRF2 pathway activators in disease prevention. C1 [Wang, Xuting; Campbell, Michelle R.; Wan, Ma; Crowl, Christopher L.; Chorley, Brian N.; Bell, Douglas A.] Natl Inst Environm Hlth Sci, Environm Genom Sect, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Lacher, Sarah E.; Slattery, Matthew] Univ Minnesota, Sch Med, Dept Biomed Sci, Duluth, MN 55812 USA. [Lacher, Sarah E.; Slattery, Matthew] Univ Minnesota, Ctr Dev Biol, Minneapolis, MN 55455 USA. [Cho, Hye-Youn; Kleeberger, Steven R.] Natl Inst Environm Hlth Sci, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Bond, Gareth L.] Univ Oxford, Nuffield Dept Clin Med, Ludwig Inst Canc Res, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England. [Chorley, Brian N.] US Environm Protect Agcy, Res Triangle Pk, NC 27709 USA. RP Wang, XT; Bell, DA (reprint author), Natl Inst Environm Hlth Sci, Environm Genom Sect, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM wang21@niehs.nih.gov; bell1@niehs.nih.gov OI Wang, Xuting/0000-0001-6781-8008 FU Intramural Research Program of National Institute of Environmental Health Sciences, NIH [Z01ES100475, Z01ES46008]; University of Minnesota Foundation; Ludwig Institute for Cancer Research FX This work was funded by the Intramural Research Program of National Institute of Environmental Health Sciences, NIH (projects: Z01ES100475 and Z01ES46008), the University of Minnesota Foundation (to M.S.), and the Ludwig Institute for Cancer Research (to G.L.B.). The authors would like to acknowledge Dr. Shuangshuang Dai for Linux computing support; NIEHS Epigenomics Core; NIEHS Animal Facility Core; and Dr. Jean Harry, NIEHS, for technical advice and useful comments on the manuscript. NR 53 TC 3 Z9 3 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD APR 26 PY 2016 VL 15 IS 4 BP 830 EP 842 DI 10.1016/j.celrep.2016.03.068 PG 13 WC Cell Biology SC Cell Biology GA DK2FS UT WOS:000374730600015 ER PT J AU Hong, CS Yang, CZ Zhuang, ZP AF Hong, Christopher S. Yang, Chunzhang Zhuang, Zhengping TI Application of Peptide Nucleic Acid-based Assays Toward Detection of Somatic Mosaicism SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE gene sequencing; oligonucleotide; peptide nucleic acid; polymerase chain reaction; somatic mosaicism ID CELL LUNG-CANCER; MUTATIONS; NEUROFIBROMATOSIS; DISEASE; CLAMP; GENE; PCR; DNA AB Peptide nucleic acids (PNAs) are synthetic oligonucleotides with many applications. Compared with DNA, PNAs bind their complementary DNA strand with higher specificity and strength, an attribute that can make it an effective polymerase chain reaction clamp. A growing body of work has demonstrated the utility of PNAs in detecting low levels of mutant DNA, particularly in the detection of circulating mutated tumor cells in the peripheral blood. The PNA-based assay has greater sensitivity than direct sequencing and is significantly more affordable and rapid than next-generation deep sequencing. We have previously demonstrated that PNAs can successfully detect somatic mosaicism in patients with suspected disease phenotypes. In this report, we detail our methodology behind PNA design and application. We describe our protocol for optimizing the PNA for sequencing use and for determining the sensitivity of the PNA-based assay. Lastly, we discuss the potential applications of our assay for future laboratory and clinical purposes and highlight the role of PNAs in the detection of somatic mosaicism. C1 [Hong, Christopher S.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Yang, Chunzhang] NCI, Neurooncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zhuang, ZP (reprint author), 10 Ctr Dr,Room 3D20, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) FX This study was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH). NR 31 TC 0 Z9 0 U1 5 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD APR 26 PY 2016 VL 5 AR e314 DI 10.1038/mtna.2016.22 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DK2JS UT WOS:000374741400001 PM 27115839 ER PT J AU Eddy, EM Chen, LY AF Eddy, Edward M. Chen, Liang-Yu TI Role of GDNF from peritubular myoid cells in the testis stem cell niche REPLY SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Eddy, Edward M.; Chen, Liang-Yu] NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Chen, Liang-Yu] VA San Diego Med Ctr, San Diego, CA 92161 USA. RP Eddy, EM (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 26 PY 2016 VL 113 IS 17 BP E2353 EP E2353 DI 10.1073/pnas.1603478113 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK2MK UT WOS:000374748400004 PM 27044114 ER PT J AU Sadaoka, T Depledge, DP Rajbhandari, L Venkatesan, A Breuer, J Cohen, JI AF Sadaoka, Tomohiko Depledge, Daniel P. Rajbhandari, Labchan Venkatesan, Arun Breuer, Judith Cohen, Jeffrey I. TI In vitro system using human neurons demonstrates that varicella-zoster vaccine virus is impaired for reactivation, but not latency SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE varicella-zoster virus; varicella vaccine; reactivation; latency; herpesvirus ID HERPES-ZOSTER; RNA-SEQ; MICROGLIAL PHAGOCYTOSIS; DEGENERATING AXONS; SKIN XENOGRAFTS; PARENTAL VIRUS; UNITED-STATES; LONG-TERM; CHILDREN; DNA AB Varicella-zoster virus (VZV) establishes latency in human sensory and cranial nerve ganglia during primary infection (varicella), and the virus can reactivate and cause zoster after primary infection. The mechanism of how the virus establishes and maintains latency and how it reactivates is poorly understood, largely due to the lack of robust models. We found that axonal infection of neurons derived from hESCs in a microfluidic device with cell-free parental Oka (POka) VZV resulted in latent infection with inability to detect several viral mRNAs by reverse transcriptase-quantitative PCR, no production of infectious virus, and maintenance of the viral DNA genome in endless configuration, consistent with an episome configuration. With deep sequencing, however, multiple viral mRNAs were detected. Treatment of the latently infected neurons with Ab to NGF resulted in production of infectious virus in about 25% of the latently infected cultures. Axonal infection of neurons with vaccine Oka (VOka) VZV resulted in a latent infection similar to infection with POka; however, in contrast to POka, VOka-infected neurons were markedly impaired for reactivation after treatment with Ab to NGF. In addition, viral transcription was markedly reduced in neurons latently infected with VOka compared with POka. Our in vitro system recapitulates both VZV latency and reactivation in vivo and may be used to study viral vaccines for their ability to establish latency and reactivate. C1 [Sadaoka, Tomohiko; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Depledge, Daniel P.; Breuer, Judith] UCL, MRC Ctr Med Mol Virol, Div Infect & Immun, Mortimer St, London WC1E 6BT, England. [Rajbhandari, Labchan; Venkatesan, Arun] Johns Hopkins Univ, Sch Med, Johns Hopkins Hosp, Div Neuroimmunol & Neuroinfect Dis,Dept Neurol, Baltimore, MD 21287 USA. [Sadaoka, Tomohiko] Kobe Univ, Div Clin Virol, Ctr Infect Dis, Grad Sch Med,Chuo Ku, 7-5-1 Kusunoki Cho, Kobe, Hyogo 6500017, Japan. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov OI sadaoka, tomohiko/0000-0001-7951-6904 FU intramural research program of the National Institute of Allergy and Infectious Diseases; Japan Herpesvirus Infections Forum; New Investigator Award from Medical Research Foundation [UK Medical Research Council (MRC)]; UCL/UCLH Biomedical Research Centre (BRC); Maryland Stem Cell Research Fund FX This work was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. T.S. was supported by the Japan Herpesvirus Infections Forum. D.P.D. is supported by a New Investigator Award from the Medical Research Foundation [UK Medical Research Council (MRC)]. J.B. was partially funded by the UCL/UCLH Biomedical Research Centre (BRC). A.V. received funding from the Maryland Stem Cell Research Fund. We acknowledge support from the MRC and BRC for the UCL/UCLH Pathogen Sequencing Pipeline. NR 57 TC 1 Z9 1 U1 5 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 26 PY 2016 VL 113 IS 17 BP E2403 EP E2412 DI 10.1073/pnas.1522575113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK2MK UT WOS:000374748400011 PM 27078099 ER PT J AU Jaszczur, M Bertram, JG Robinson, A van Oijen, AM Woodgate, R Cox, MM Goodman, MF AF Jaszczur, Malgorzata Bertram, Jeffrey G. Robinson, Andrew van Oijen, Antoine M. Woodgate, Roger Cox, Michael M. Goodman, Myron F. TI Mutations for Worse or Better: Low-Fidelity DNA Synthesis by SOS DNA Polymerase V Is a Tightly Regulated Double-Edged Sword SO BIOCHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; ESCHERICHIA-COLI; RECA PROTEIN; MUTAGENESIS PROTEIN; UV MUTAGENESIS; Y-FAMILY; TRANSLESION SYNTHESIS; ULTRAVIOLET-LIGHT; III HOLOENZYME; UMUD AB 1953, the year of Watson and Crick, bore witness to a less acclaimed yet highly influential discovery. Jean Weigle demonstrated that upon infection of Escherichia coli, 2 phage deactivated by UV radiation, and thus unable to form progeny, could be reactivated by irradiation of the bacterial host. Evelyn Witkin and Miroslav Radman later revealed the presence of the SOS regulon. The more than 40 regulon genes are repressed by LexA protein and induced by the coproteolytic cleavage of LexA, catalyzed by RecA protein bound to single stranded DNA, the RecA* nucleoprotein filament. Several SOS-induced proteins are engaged in repairing both cellular and extracellular damaged DNA. There's no "free lunch", however, because error-free repair is accompanied by error-prone translesion DNA synthesis (TLS), involving E. coli DNA polymerase V (UmuD'C-2) and RecA*. This review describes the biochemical mechanisms of pol V-mediated TLS. pol V is active only as a mutasomal complex, pol V Mut = UmuD'C-2-RecA-ATP. RecA* donates a single RecA subunit to pol V. We highlight three recent insights. (1) pol V Mut has an intrinsic DNA dependent ATPase activity that governs polymerase binding and dissociation from DNA. (2) Active and inactive states of pol V Mut are determined at least in part by the distinct interactions between RecA and UmuC. (3) pol V is activated by RecA*, not at a blocked replisome, but at the inner cell membrane. C1 [Jaszczur, Malgorzata; Bertram, Jeffrey G.; Goodman, Myron F.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Robinson, Andrew; van Oijen, Antoine M.] Univ Wollongong, Sch Chem, Wollongong, NSW, Australia. [Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Rockville, MD 20850 USA. [Cox, Michael M.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Goodman, Myron F.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA.; Goodman, MF (reprint author), Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. EM mgoodman@usc.edu OI Robinson, Andrew/0000-0002-3544-0976; van Oijen, Antoine/0000-0002-1794-5161 FU National Institutes of Health [ES012259, GM21422, GM32335]; Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program; Netherlands Organization for Scientific Research (NWO) [Vici 680-47-607]; European Research Council (ERC) [281098] FX This work was supported by National Institutes of Health grants to M.F.G. (ES012259 and GM21422) and M.M.C. (GM32335), funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program to R.W., and funds from The Netherlands Organization for Scientific Research (NWO; Vici 680-47-607) and the European Research Council (ERC Starting 281098) to A.M.v.O. NR 72 TC 0 Z9 0 U1 4 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 26 PY 2016 VL 55 IS 16 BP 2309 EP 2318 DI 10.1021/acs.biochem.6b00117 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK9IT UT WOS:000375244800003 PM 27043933 ER PT J AU Park, JH Sayer, JM Aniana, A Yu, XX Weber, IT Harrison, RW Louis, JM AF Park, Joon H. Sayer, Jane M. Aniana, Annie Yu, Xiaxia Weber, Irene T. Harrison, Robert W. Louis, John M. TI Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme SO BIOCHEMISTRY LA English DT Article ID VIRUS TYPE-1 PROTEASE; DRUG-RESISTANCE; NMR-SPECTROSCOPY; 20 MUTATIONS; GAG; DYNAMICS; KINETICS; MECHANISM; DARUNAVIR; MONOMER AB We have systematically validated the activity and inhibition of a HIV-1 protease (PR) variant bearing 17 mutations (PRS17), selected to represent high resistance by machine learning on genotype phenotype data. Three of five mutations in PRS17 correlating with major drug resistance, M46L, G48V, and V82S, and five of 11 natural variations differ from the mutations in two clinically derived extreme mutants, PR20 and PR22 bearing 19 and 22 mutations, respectively. PRS17, which forms a stable dimer (<10 nM), is similar to 10- and 2-fold less efficient in processing the Gag polyprotein than the wild type and PR20, respectively, but maintains the same cleavage order. Isolation of a model precursor of PRS17 flanked by the 56-amino acid transframe region (TFP-p6pol) at its N-terminus, which is impossible upon expression of an analogous PR20 precursor, allowed systematic comparison of inhibition of TFP-p6pol-PRS17 and mature PRS17. Resistance of PRS17 to eight protease inhibitors (PIs) relative to PR (K-i) increases by 1.5-5 orders of magnitude from 0.01 to 8.4 mu M. Amprenavir, darunavir, atazanavir, and lopinavir, the most effective of the eight PIs, inhibit precursor autoprocessing at the p6pol/PR site with IC50 values ranging from similar to 7.5 to 60 mu M. Thus, this process, crucial for stable dimer formation, shows inhibition similar to 200-800-fold weaker than that of the mature PRS17. TFP/p6pol cleavage, which occurs faster, is inhibited even more weakly by all PIs except darunavir (IC50 = 15 mu M); amprenavir shows a 2-fold increase in IC50 (similar to 15 mu M), and atazanavir and lopinavir show increased IC50 values of >42 and >70 mu M, respectively. C1 [Park, Joon H.; Sayer, Jane M.; Aniana, Annie; Louis, John M.] NIDDK, Chem Phys Lab, NIH, Dept Hlth & Human Serv, Bldg 2, Bethesda, MD 20892 USA. [Yu, Xiaxia; Harrison, Robert W.] Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA. [Weber, Irene T.] Georgia State Univ, Dept Biol, POB 4010, Atlanta, GA 30303 USA. RP Louis, JM (reprint author), NIDDK, LCP, NIH, Bldg 5,Room B2-29, Bethesda, MD 20892 USA. EM johnl@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Intramural AIDS-Targeted Program of the Office of the Director, NIH, National Institutes of Health [GM062920]; Georgia State University Molecular Basis of Disease Program FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), and the Intramural AIDS-Targeted Program of the Office of the Director, NIH, National Institutes of Health Grant GM062920 (I.T.W. and R.W.H.), and a fellowship from the Georgia State University Molecular Basis of Disease Program (X.Y.). NR 50 TC 2 Z9 2 U1 3 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 26 PY 2016 VL 55 IS 16 BP 2390 EP 2400 DI 10.1021/acs.biochem.6b00012 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK9IT UT WOS:000375244800010 PM 27039930 ER PT J AU Delling, FN Rong, J Larson, MG Lehman, B Fuller, D Osypiuk, E Stantchev, P Hackman, B Manning, WJ Benjamin, EJ Levine, RA Vasan, RS AF Delling, Francesca N. Rong, Jian Larson, Martin G. Lehman, Birgitta Fuller, Deborah Osypiuk, Ewa Stantchev, Plamen Hackman, Brianne Manning, Warren J. Benjamin, Emelia J. Levine, Robert A. Vasan, Ramachandran S. TI Evolution of Mitral Valve Prolapse: Insights From the Framingham Heart Study SO CIRCULATION LA English DT Article DE echocardiography; epidemiology; mitral valve ID NATURAL-HISTORY; VENA CONTRACTA; REGURGITATION; PROGRESSION; DIAGNOSIS; COMMUNITY; SEVERITY; DETERMINANTS; ASSOCIATION; PREVALENCE AB Background Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with nondiagnostic MVP morphologies (NDMs), are lacking. Methods and Results We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation jet height in 261 Framingham Offspring participants at examination 5 who had available follow-up imaging 3 to 16 years later. Study participants included MVP (n=63); NDMs, minimal systolic displacement (n=50) and the abnormal anterior coaptation phenotype (n=10, with coaptation height >40% of the annulus similar to posterior MVP); plus 138 healthy referents without MVP or NDMs. At follow-up, individuals with MVP (52% women, 5711 years) had greater increases of leaflet displacement, thickness, and jet height than referents (all P<0.05). Eleven participants with MVP (17%) had moderate or more severe mitral regurgitation (jet height 5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) participants with abnormal anterior coaptation progressed to posterior MVP; 17 (34%) subjects with minimal systolic displacement were reclassified as either posterior MVP (12) or abnormal anterior coaptation (5). In comparison with the 33 participants with minimal systolic displacement who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and mitral regurgitation jet height (all P<0.05). Conclusions NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant mitral regurgitation over a period of 3 to 16 years in one-fourth of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression. C1 [Delling, Francesca N.; Rong, Jian; Lehman, Birgitta; Osypiuk, Ewa; Stantchev, Plamen; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Framingham, MA USA. [Delling, Francesca N.; Rong, Jian; Lehman, Birgitta; Osypiuk, Ewa; Stantchev, Plamen; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Delling, Francesca N.; Fuller, Deborah; Hackman, Brianne] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc,Sch Med, Boston, MA 02215 USA. [Rong, Jian] Boston Univ, Sch Med, Dept Med, Neurol Sect, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Manning, Warren J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Radiol, Sch Med, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. RP Delling, FN (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave,E-SH-458, Boston, MA 02215 USA. EM fdelling@bidmc.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU Founders Affiliate American Heart Association Clinical Research Program; National Heart, Lung and Blood Institute Framingham Heart Study [N01-HC-25195, HHSN268201500001I, R01HL080124, RO1HL0107385, 2R01HL092577, 1R01HL128914, K23HL116652] FX This work was supported by the Founders Affiliate American Heart Association Clinical Research Program (to Dr Delling), and by the National Heart, Lung and Blood Institute Framingham Heart Study Contract No. N01-HC-25195 and HHSN268201500001I (both to Dr Vasan), and research grants R01HL080124, RO1HL0107385 (to Dr Vasan), 2R01HL092577, 1R01HL128914 (to Dr Benjamin), and K23HL116652 (to Dr Delling). NR 31 TC 2 Z9 3 U1 1 U2 2 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 APR 26 PY 2016 VL 133 IS 17 BP 1688 EP 1695 DI 10.1161/CIRCULATIONAHA.115.020621 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DK6QI UT WOS:000375049200012 PM 27006478 ER PT J AU Kaushal, M Byrnes, C Khademian, Z Duncan, N Luban, NLC Miller, JL Fasano, RM Meier, ER AF Kaushal, Megha Byrnes, Colleen Khademian, Zarir Duncan, Natalie Luban, Naomi L. C. Miller, Jeffery L. Fasano, Ross M. Meier, Emily Riehm TI Examination of Reticulocytosis among Chronically Transfused Children with Sickle Cell Anemia SO PLOS ONE LA English DT Article ID SILENT CEREBRAL INFARCTS; RED-CELL; CEREBROVASCULAR ACCIDENTS; HYDROXYUREA SWITCH; CNS INFARCTION; DISEASE; ADHESION; STROKE; BLOOD; RISK AB Sickle cell anemia (SCA) is an inherited hemolytic anemia with compensatory reticulocytosis. Recent studies have shown that increased levels of reticulocytosis during infancy are associated with increased hospitalizations for SCA sequelae as well as cerebrovascular pathologies. In this study, absolute reticulocyte counts (ARC) measured prior to transfusion were analysed among a cohort of 29 pediatric SCA patients receiving chronic transfusion therapy (CTT) for primary and secondary stroke prevention. A cross-sectional flow cytometric analysis of the reticulocyte phenotype was also performed. Mean duration of CTT was 3.1 +/- 2.6 years. Fifteen subjects with magnetic resonance angiography (MRA) - vasculopathy had significantly higher mean ARC prior to initiating CTT compared to 14 subjects without MRA-vasculopathy (427.6 +/- 109.0 K/mu l vs. 324.8 +/- 109.2 K/mu l, p<0.05). No significant differences in hemoglobin or percentage sickle hemoglobin (HbS) were noted between the two groups at baseline. Reticulocyte phenotyping further demonstrated that the percentages of circulating immature [CD36(+), CD71(+)] reticulocytes positively correlated with ARC in both groups. During the first year of CTT, neither group had significant reductions in ARC. Among this group of children with SCA, cerebrovasculopathy on MRA at initiation of CTT was associated with increased reticulocytosis, which was not reduced after 12 months of transfusions. C1 [Kaushal, Megha; Byrnes, Colleen; Miller, Jeffery L.; Meier, Emily Riehm] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Kaushal, Megha; Luban, Naomi L. C.; Fasano, Ross M.; Meier, Emily Riehm] Childrens Natl Hlth Syst, Ctr Canc & Blood Disorders, Washington, DC USA. [Khademian, Zarir] Childrens Natl Hlth Syst, Div Diagnost Imaging & Radiol, Washington, DC USA. [Kaushal, Megha; Luban, Naomi L. C.; Fasano, Ross M.; Meier, Emily Riehm] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA. [Duncan, Natalie; Meier, Emily Riehm] Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USA. [Fasano, Ross M.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Ctr Transfus & Cellular Therapies, Atlanta, GA 30322 USA. RP Meier, ER (reprint author), NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA.; Meier, ER (reprint author), Childrens Natl Hlth Syst, Ctr Canc & Blood Disorders, Washington, DC USA.; Meier, ER (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA.; Meier, ER (reprint author), Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USA. EM emeier@ihtc.org FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart Lung and Blood Institute [HL110841] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and a T32 from National Heart Lung and Blood Institute [HL110841]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 0 Z9 0 U1 1 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 APR 26 PY 2016 VL 11 IS 4 AR e0153244 DI 10.1371/journal.pone.0153244 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK5QB UT WOS:000374973600017 PM 27116614 ER PT J AU Tomasi, D Shokri-Kojori, E Volkow, ND AF Tomasi, D. Shokri-Kojori, E. Volkow, N. D. TI Temporal Changes in Local Functional Connectivity Density Reflect the Temporal Variability of the Amplitude of Low Frequency Fluctuations in Gray Matter SO PLOS ONE LA English DT Article ID GLOBAL SIGNAL REGRESSION; HUMAN CONNECTOME PROJECT; ANTI-CORRELATED NETWORKS; RESTING-STATE FMRI; ALZHEIMERS-DISEASE; HUMAN BRAIN; CORTICAL NETWORKS; DYNAMICS; SCHIZOPHRENIA; PATTERNS AB Data-driven functional connectivity density (FCD) mapping is being increasingly utilized to assess brain connectomics at rest in the healthy brain and its disruption in neuropsychiatric diseases with the underlying assumption that the spatiotemporal hub distribution is stationary. However, recent studies show that functional connectivity is highly dynamic. Here we study the temporal variability of the local FCD (lFCD) at high spatiotemporal resolution (2-mm isotropic; 0.72s) using a sliding-window approach and 'resting-state' datasets from 40 healthy subjects collected under the Human Connectome Project. Prominent functional connectivity hubs in visual and posterior parietal cortices had pronounced temporal changes in local FCD. These dynamic patterns in the strength of the lFCD hubs occurred in cortical gray matter with high sensitivity (up to 85%) and specificity (> 85%) and showed high reproducibility (up to 72%) across sessions and high test-retest reliability (ICC(3,1) > 0.5). The temporal changes in lFCD predominantly occurred in medial occipitoparietal regions and were proportional to the strength of the connectivity hubs. The temporal variability of the lFCD was associated with the amplitude of the low frequency fluctuations (ALFF). Pure randomness did not account for the probability distribution of lFCD. Shannon entropy increased in proportion to the strength of the lFCD hubs suggesting high average flow of information per unit of time in the lFCD hubs, particularly in medial occipitoparietal regions. Thus, the higher dynamic range of the lFCD hubs is consistent with their role in the complex orchestration of interacting brain networks. C1 [Tomasi, D.; Shokri-Kojori, E.; Volkow, N. D.] NIAAA, Bethesda, MD USA. [Volkow, N. D.] NIDA, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), NIAAA, Bethesda, MD USA. EM dardo.tomasi@nih.gov FU NIH [1U54MH091657]; McDonnell Center for Systems Neuroscience at Washington University; National Institutes of Alcohol Abuse and Alcoholism [Y1AA-3009] FX Data were provided by the Human Connectome Project, WU-Minn Consortium ( Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research and by the McDonnell Center for Systems Neuroscience at Washington University. This work was accomplished with support from the National Institutes of Alcohol Abuse and Alcoholism (Y1AA-3009). NR 62 TC 4 Z9 4 U1 5 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 26 PY 2016 VL 11 IS 4 AR e0154407 DI 10.1371/journal.pone.0154407 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK5QB UT WOS:000374973600065 PM 27116610 ER PT J AU Wang, YN Hu, M Liu, Q Qin, JX Dai, YX He, L Li, TM Zheng, B Zhou, F Yu, KW Fang, JY Liu, XY Otto, M Li, M AF Wang, Yanan Hu, Mo Liu, Qian Qin, Juanxiu Dai, Yingxin He, Lei Li, Tianming Zheng, Bing Zhou, Fan Yu, Kaiwen Fang, Jingyuan Liu, Xiaoyun Otto, Michael Li, Min TI Role of the ESAT-6 secretion system in virulence of the emerging community-associated Staphylococcus aureus lineage ST398 SO SCIENTIFIC REPORTS LA English DT Article ID METHICILLIN-RESISTANT; INFECTIONS; EPIDEMIOLOGY; PATHOGENESIS; PNEUMONIA; PROTEINS AB Novel Staphylococcus aureus clones continue to emerge that cause infections in otherwise healthy people. One example is the sequence type (ST) 398 lineage, which we show here is increasing in importance as a significant cause of community-associated (CA) human infections in China. We have a profound lack of understanding about what determines the considerable virulence potential of such newly emerging clones. Information about the contribution to virulence of the more recently discovered ESAT-6 secretion system (ESS) has remained particularly scarce. The Chinese ST398 isolates exhibited significantly increased expression of ESS genes as compared to predominant hospital-associated clones, which we found is likely due to increased expression of the accessory gene regulator (Agr) system and control of ESS by Agr. Importantly, deletion of essB in ST398 resulted in significantly reduced resistance to neutrophil killing and decreased virulence in murine skin and blood infection models. Our results demonstrate a key function of ESS in promoting virulence and mechanisms of resistance to innate host defense in an important emerging CA-S. aureus lineage. They suggest that ESS has a so far underestimated role in promoting aggressive virulence and epidemiological success of S. aureus. C1 [Wang, Yanan; Liu, Qian; Qin, Juanxiu; Dai, Yingxin; He, Lei; Li, Tianming; Zheng, Bing; Li, Min] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Lab Med, Shanghai 200127, Peoples R China. [Hu, Mo; Zhou, Fan; Yu, Kaiwen; Liu, Xiaoyun] Peking Univ, Coll Chem & Mol Engn, Inst Analyt Chem, Beijing 100871, Peoples R China. [Hu, Mo; Zhou, Fan; Yu, Kaiwen; Liu, Xiaoyun] Peking Univ, Coll Chem & Mol Engn, Synthet & Funct Biomol Ctr, Beijing 100871, Peoples R China. [Fang, Jingyuan] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Div Gastroenterol & Hepatol, Shanghai 200127, Peoples R China. [Fang, Jingyuan] Shanghai Inst Digest Dis, Shanghai 200127, Peoples R China. [Otto, Michael] NIAID, Bacteriol Lab, Pathogen Mol Genet Sect, NIH, Bethesda, MD 20892 USA. RP Li, M (reprint author), Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Lab Med, Shanghai 200127, Peoples R China.; Otto, M (reprint author), NIAID, Bacteriol Lab, Pathogen Mol Genet Sect, NIH, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov; ruth_limin@126.com OI Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Natural Science Foundation of China [81322025, 81421001, 81371875]; Shanghai Shuguang Talent Project [12SG03]; Shanghai Committee of Science and Technology, China [14140901000, 15411960500] FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (M.O.), the National Natural Science Foundation of China (grants 81322025, 81421001 and 81371875, M.L.), the Shanghai Shuguang Talent Project (grant 12SG03, M.L.), and the Shanghai Committee of Science and Technology, China (grants 14140901000, 15411960500, M.L.). NR 30 TC 4 Z9 5 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 26 PY 2016 VL 6 AR 25163 DI 10.1038/srep25163 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK6WK UT WOS:000375066100001 PM 27112266 ER PT J AU Gurvitz, M Burns, KM Brindis, R Broberg, CS Daniels, CJ Fuller, SMPN Honein, MA Khairy, P Kuehl, KS Landzberg, MJ Mahle, WT Mann, DL Marelli, A Newburger, JW Pearson, GD Starling, RC Tringali, GR Valente, AM Wu, JC Califf, RM AF Gurvitz, Michelle Burns, Kristin M. Brindis, Ralph Broberg, Craig S. Daniels, Curt J. Fuller, Stephanie M. P. N. Honein, Margaret A. Khairy, Paul Kuehl, Karen S. Landzberg, Michael J. Mahle, William T. Mann, Douglas L. Marelli, Ariane Newburger, Jane W. Pearson, Gail D. Starling, Randall C. Tringali, Glenn R. Valente, Anne Marie Wu, Joseph C. Califf, Robert M. TI Emerging Research Directions in Adult Congenital Heart Disease A Report From an NHLBI/ACHA Working Group SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE congenital; heart defects; outcomes; pregnancy; single ventricle; sudden cardiac death; tetralogy of Fallot ID 2009 CONSENSUS CONFERENCE; SURGICALLY REPAIRED TETRALOGY; ARTERIAL SWITCH OPERATION; AORTIC COARCTATION REPAIR; ACCESS RESEARCH TRIAL; TERM-FOLLOW-UP; FONTAN PATIENTS; GENERAL-POPULATION; GREAT-ARTERIES; UNITED-STATES AB Congenital heart disease (CHD) is the most common birth defect, affecting about 0.8% of live births. Advances in recent decades have allowed > 85% of children with CHD to survive to adulthood, creating a growing population of adults with CHD. Little information exists regarding survival, demographics, late outcomes, and comorbidities in this emerging group, and multiple barriers impede research in adult CHD. The National Heart, Lung, and Blood Institute and the Adult Congenital Heart Association convened a multidisciplinary working group to identify high-impact research questions in adult CHD. This report summarizes the meeting discussions in the broad areas of CHD-related heart failure, vascular disease, and multisystem complications. High-priority subtopics identified included heart failure in tetralogy of Fallot, mechanical circulatory support/transplantation, sudden cardiac death, vascular outcomes in coarctation of the aorta, late outcomes in single-ventricle disease, cognitive and psychiatric issues, and pregnancy. (C) 2016 by the American College of Cardiology Foundation. C1 [Gurvitz, Michelle; Landzberg, Michael J.; Valente, Anne Marie] Harvard Univ, Sch Med, Boston Adult Congenital Heart & Pulm Hypertens Pr, Boston Childrens Hosp, Boston, MA USA. [Gurvitz, Michelle; Landzberg, Michael J.; Valente, Anne Marie] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Burns, Kristin M.; Pearson, Gail D.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Brindis, Ralph] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Broberg, Craig S.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Daniels, Curt J.] Ohio State Univ, Columbus, OH 43210 USA. [Fuller, Stephanie M. P. N.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Honein, Margaret A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Khairy, Paul] Univ Montreal, Montreal, PQ, Canada. [Kuehl, Karen S.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Mahle, William T.] Emory Univ, Sch Med, Atlanta, GA USA. [Mann, Douglas L.] Washington Univ, St Louis, MO USA. [Marelli, Ariane] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Newburger, Jane W.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Starling, Randall C.] Cleveland Clin, Cleveland, OH 44106 USA. [Tringali, Glenn R.] Adult Congenital Heart Assoc, Philadelphia, PA USA. [Wu, Joseph C.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Califf, Robert M.] Duke Univ, Durham, NC USA. RP Gurvitz, M (reprint author), Boston Childrens Hosp, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA. EM Michelle.gurvitz@cardio.chboston.org FU National Heart, Lung, and Blood Institute, Bethesda, Maryland; Adult Congenital Heart Association, Philadelphia, Pennsylvania FX This research was supported by the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and the Adult Congenital Heart Association, Philadelphia, Pennsylvania. The views and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health or the Centers for Disease Control and Prevention. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Thomas Bashore, MD, served as Guest Editor for this paper. NR 66 TC 6 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 26 PY 2016 VL 67 IS 16 BP 1956 EP 1964 DI 10.1016/j.jacc.2016.01.062 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK1EG UT WOS:000374654700012 PM 27102511 ER PT J AU Barnes, TD Wozniak, DF Gutierrez, J Han, TU Drayna, D Holy, TE AF Barnes, Terra D. Wozniak, David F. Gutierrez, Joanne Han, Tae-Un Drayna, Dennis Holy, Timothy E. TI A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations SO CURRENT BIOLOGY LA English DT Article ID SPEECH; LANGUAGE; MICE; SEAGRASSES; DISORDERS; FREQUENCY; ECOSYSTEM; DEFICITS; FLUENCY AB A promising approach to understanding the mechanistic basis of speech is to study disorders that affect speech without compromising other cognitive or motor functions. Stuttering, also known as stammering, has been linked to mutations in the lysosomal enzyme-targeting pathway, but how this remarkably specific speech deficit arises from mutations in a family of general "cellular housekeeping" genes is unknown. To address this question, we asked whether a missense mutation associated with human stuttering causes vocal or other abnormalities in mice. We compared vocalizations from mice engineered to carry a mutation in the Gnptab (N-acetylglucosamine-1-phosphotransferase subunits alpha/beta) gene with wild-type littermates. We found significant differences in the vocalizations of pups with the human Gnptab stuttering mutation compared to littermate controls. Specifically, we found that mice with the mutation emitted fewer vocalizations per unit time and had longer pauses between vocalizations and that the entropy of the temporal sequence was significantly reduced. Furthermore, Gnptab missense mice were similar to wild-type mice on an extensive battery of non-vocal behaviors. We then used the same language-agnostic metrics for auditory signal analysis of human speech. We analyzed speech from people who stutter with mutations in this pathway and compared it to control speech and found abnormalities similar to those found in the mouse vocalizations. These data show that mutations in the lysosomal enzyme-targeting pathway produce highly specific effects in mouse pup vocalizations and establish the mouse as an attractive model for studying this disorder. C1 [Barnes, Terra D.; Holy, Timothy E.] Washington Univ, Sch Med St Louis, Dept Neurosci, Campus Box 8108,660 S Euclid Ave, St Louis, MO 63110 USA. [Wozniak, David F.] Washington Univ, Sch Med St Louis, Dept Psychiat, Campus Box 8134,660 S Euclid Ave, St Louis, MO 63110 USA. [Wozniak, David F.] Washington Univ, Sch Med St Louis, Taylor Family Inst Innovat Psychiat Res, Campus Box 8108,660 S Euclid Ave, St Louis, MO 63110 USA. [Gutierrez, Joanne; Han, Tae-Un; Drayna, Dennis] NIDCD, NIH, Bethesda, MD 20892 USA. RP Barnes, TD (reprint author), Washington Univ, Sch Med St Louis, Dept Neurosci, Campus Box 8108,660 S Euclid Ave, St Louis, MO 63110 USA. EM terra.barnes@gmail.com FU NIH Director's Pioneer Award [DP1 OD006437]; Intellectual and Developmental Disabilities Research Center grants [P30 HD062171, U54 HD087011]; NIDCD Intramural grant [Z1A-000046-15] FX We thank the Hollins Communication Research Institute for assistance with subject recruitment and stuttering diagnosis. We thank Peter Rietzes of StutterTalk for help with speech samples from PWS. We thank Grace Liao and Cassandra Roberts for help with vocal recordings of mice; Wayne Barnes and Thanh Loan Nguyen for their help with mouse genotyping; and Sara Conyers for her work involving the non-vocalization behavioral testing. This work was supported by the NIH Director's Pioneer Award (DP1 OD006437), Intellectual and Developmental Disabilities Research Center grants (P30 HD062171; U54 HD087011), and NIDCD Intramural grant Z1A-000046-15. NR 48 TC 3 Z9 3 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD APR 25 PY 2016 VL 26 IS 8 BP 1009 EP 1018 DI 10.1016/j.cub.2016.02.068 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DL0RG UT WOS:000375339700018 ER PT J AU Cong, XM Xu, WL Janton, S Henderson, WA Matson, A McGrath, JM Maas, K Graf, J AF Cong, Xiaomei Xu, Wanli Janton, Susan Henderson, Wendy A. Matson, Adam McGrath, Jacqueline M. Maas, Kendra Graf, Joerg TI Gut Microbiome Developmental Patterns in Early Life of Preterm Infants: Impacts of Feeding and Gender SO PLOS ONE LA English DT Article ID NEONATAL RESEARCH NETWORK; NECROTIZING ENTEROCOLITIS; INTESTINAL MICROBIOTA; MILK OLIGOSACCHARIDES; OUTCOMES; AUTOIMMUNITY; LACTATION; DIVERSITY; INFECTION; SEVERITY AB Gut microbiota plays a key role in multiple aspects of human health and disease, particularly in early life. Distortions of the gut microbiota have been found to correlate with fatal diseases in preterm infants, however, developmental patterns of gut microbiome and factors affecting the colonization progress in preterm infants remain unclear. The purpose of this prospective longitudinal study was to explore day-to-day gut microbiome patterns in preterm infants during their first 30 days of life in the neonatal intensive care unit (NICU) and investigate potential factors related to the development of the infant gut microbiome. A total of 378 stool samples were collected daily from 29 stable/healthy preterm infants. DNA extracted from stool was used to sequence the V4 region of the 16S rRNA gene region for community analysis. Operational taxonomic units (OTUs) and alpha-diversity of the community were determined using QIIME software. Proteobacteria was the most abundant phylum, accounting for 54.3% of the total reads. Result showed shift patterns of increasing Clostridium and Bacteroides, and decreasing Staphylococcus and Haemophilus over time during early life. Alpha-diversity significantly increased daily in preterm infants after birth and linear mixe-deffects models showed that postnatal days, feeding types and gender were associated with the a-diversity, p< 0.05-0.01. Male infants were found to begin with a low a-diversity, whereas females tended to have a higher diversity shortly after birth. Female infants were more likely to have higher abundance of Clostridiates, and lower abundance of Enterobacteriales than males during early life. Infants fed mother's own breastmilk (MBM) had a higher diversity of gut microbiome and significantly higher abundance in Clostridiales and Lactobacillales than infants fed non-MBM. Permanova also showed that bacterial compositions were different between males and females and between MBM and non-MBM feeding types. In conclusion, infant postnatal age, gender and feeding type significantly contribute to the dynamic development of the gut microbiome in preterm infants. C1 [Cong, Xiaomei; Xu, Wanli; McGrath, Jacqueline M.] Univ Connecticut, Sch Nursing, Storrs, CT USA. [Cong, Xiaomei; Graf, Joerg] Univ Connecticut, Inst Syst Genom, Farmington, CT USA. [Janton, Susan; Graf, Joerg] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT USA. [Henderson, Wendy A.] NINR, Digest Disorders Unit, Biobehav Branch, NIH, Bethesda, MD 20892 USA. [Matson, Adam; McGrath, Jacqueline M.] Connecticut Childrens Med Ctr, Hartford, CT USA. [Maas, Kendra] Univ Connecticut, Microbial Anal Resources & Serv, Storrs, CT USA. RP Cong, XM (reprint author), Univ Connecticut, Sch Nursing, Storrs, CT USA.; Cong, XM (reprint author), Univ Connecticut, Inst Syst Genom, Farmington, CT USA. EM xiaomei.cong@uconn.edu OI Henderson, Wendy/0000-0003-3924-7118 FU National Institute of Nursing Research of the National Institutes of Health (NIH-NINR) [K23NR014674]; Affinity Research Collaboratives award through University of Connecticut Institute for Systems Genomics FX This publication was supported by the National Institute of Nursing Research of the National Institutes of Health (NIH-NINR) under award number K23NR014674 and Affinity Research Collaboratives award through University of Connecticut Institute for Systems Genomics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 6 Z9 6 U1 8 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 25 PY 2016 VL 11 IS 4 AR e0152751 DI 10.1371/journal.pone.0152751 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK5OX UT WOS:000374970600005 PM 27111847 ER PT J AU Kilic, S Sagitova, DM Wolfish, S Bely, B Courtot, M Ciufo, S Tatusova, T O'Donovan, C Chibucos, MC Martin, MJ Erill, I AF Kilic, Sefa Sagitova, Dinara M. Wolfish, Shoshannah Bely, Benoit Courtot, Melanie Ciufo, Stacy Tatusova, Tatiana O'Donovan, Claire Chibucos, Marcus C. Martin, Maria J. Erill, Ivan TI From data repositories to submission portals: rethinking the role of domain-specific databases in CollecTF SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID SEQUENCES; ONTOLOGY; BIOLOGY; TOOLS; DNA AB Domain-specific databases are essential resources for the biomedical community, leveraging expert knowledge to curate published literature and provide access to referenced data and knowledge. The limited scope of these databases, however, poses important challenges on their infrastructure, visibility, funding and usefulness to the broader scientific community. CollecTF is a community-oriented database documenting experimentally validated transcription factor (TF)-binding sites in the Bacteria domain. In its quest to become a community resource for the annotation of transcriptional regulatory elements in bacterial genomes, CollecTF aims to move away from the conventional data-repository paradigm of domain-specific databases. Through the adoption of well-established ontologies, identifiers and collaborations, CollecTF has progressively become also a portal for the annotation and submission of information on transcriptional regulatory elements to major biological sequence resources (RefSeq, UniProtKB and the Gene Ontology Consortium). This fundamental change in database conception capitalizes on the domain-specific knowledge of contributing communities to provide high-quality annotations, while leveraging the availability of stable information hubs to promote long-term access and provide high-visibility to the data. As a submission portal, CollecTF generates TF-binding site information through direct annotation of RefSeq genome records, definition of TF-based regulatory networks in UniProtKB entries and submission of functional annotations to the Gene Ontology. As a database, CollecTF provides enhanced search and browsing, targeted data exports, binding motif analysis tools and integration with motif discovery and search platforms. This innovative approach will allow CollecTF to focus its limited resources on the generation of high-quality information and the provision of specialized access to the data. C1 [Kilic, Sefa; Sagitova, Dinara M.; Erill, Ivan] Univ Maryland Baltimore Cty, Dept Biol Sci, 1000 Hilltop Circle, Baltimore, MD 21250 USA. [Wolfish, Shoshannah; Chibucos, Marcus C.] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Bely, Benoit; Courtot, Melanie; O'Donovan, Claire; Martin, Maria J.] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. [Ciufo, Stacy; Tatusova, Tatiana] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A, Bethesda, MD 20894 USA. [Chibucos, Marcus C.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Erill, I (reprint author), Univ Maryland Baltimore Cty, Dept Biol Sci, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM erill@umbc.edu OI Courtot, Melanie/0000-0002-9551-6370; O'Donovan, Claire/0000-0001-8051-7429; Chibucos, Marcus/0000-0001-9586-0780 FU US National Science Foundation Division of Molecular and Cellular Biosciences [MCB-1158056]; US National Institutes of Health/National Human Genome Research Institute [U41HG007822, U41HG002273]; US National Science Foundation Division of Biological Infrastructure Award [DBI-1458400]; European Molecular Biology Laboratory core funds. Funding for open access charge: US National Sciences Foundation [MCB-1158056] FX This work was funded by the US National Science Foundation Division of Molecular and Cellular Biosciences award MCB-1158056 (University of Maryland Baltimore County), the US National Institutes of Health/National Human Genome Research Institute grants U41HG007822 and U41HG002273 (European Bioinformatics Institute - European Molecular Biology Laboratory), the US National Science Foundation Division of Biological Infrastructure Award DBI-1458400 (University of Maryland at Baltimore) and by the European Molecular Biology Laboratory core funds. Funding for open access charge: US National Sciences Foundation [MCB-1158056]. NR 30 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD APR 25 PY 2016 AR baw055 DI 10.1093/database/baw055 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DK1CS UT WOS:000374650700002 ER PT J AU Ghitza, UE AF Ghitza, Udi E. TI Commentary: a Gene-Based association method for mapping traits Using reference transcriptome Data SO FRONTIERS IN PSYCHIATRY LA English DT Editorial Material DE genetics; gene expression; bioinformatics; informatics; precision medicine; addiction; drug abuse; substance-use disorders ID ADDICTION; BRAIN C1 [Ghitza, Udi E.] NIDA, US Dept HHS, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. RP Ghitza, UE (reprint author), NIDA, US Dept HHS, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov NR 10 TC 0 Z9 0 U1 3 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD APR 25 PY 2016 VL 7 AR 73 DI 10.3389/fpsyt.2016.00073 PG 3 WC Psychiatry SC Psychiatry GA DK0VT UT WOS:000374631000003 PM 27199780 ER PT J AU Zhao, ZL Zhang, L Huang, CF Ma, SR Bu, LL Liu, JF Yu, GT Liu, B Gutkind, JS Kulkarni, AB Zhang, WF Sun, ZJ AF Zhao, Zhi-Li Zhang, Lu Huang, Cong-Fa Ma, Si-Rui Bu, Lin-Lin Liu, Jian-Feng Yu, Guang-Tao Liu, Bing Gutkind, J. Silvio Kulkarni, Ashok B. Zhang, Wen-Feng Sun, Zhi-Jun TI NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell SO SCIENTIFIC REPORTS LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; GAMMA-SECRETASE INHIBITOR; ADVANCED SOLID TUMORS; SIGNALING PATHWAY; GENOMIC CHARACTERIZATION; PANCREATIC-CANCER; IN-VIVO; CARCINOMA; MUTATIONS; GROWTH AB Cancer stem cells (CSCs) are considered responsible for tumor initiation and chemoresistance. This study was aimed to investigate the possibility of targeting head neck squamous cell carcinoma (HNSCC) by NOTCH1 pathway inhibition and explore the synergistic effect of combining NOTCH inhibition with conventional chemotherapy. NOTCH1/HES1 elevation was found in human HNSCC, especially in tissue post chemotherapy and lymph node metastasis, which is correlated with CSCs markers. NOTCH1 inhibitor DAPT (GSI-IX) significantly reduces CSCs population and tumor self-renewal ability in vitro and in vivo. Flow cytometry analysis showed that NOTCH1 inhibition reduces CSCs frequency either alone or in combination with chemotherapeutic agents, namely, cisplatin, docetaxel, and 5-fluorouracil. The combined strategy of NOTCH1 blockade and chemotherapy synergistically attenuated chemotherapy-enriched CSC population, promising a potential therapeutic exploitation in future clinical trial. C1 [Zhao, Zhi-Li; Zhang, Lu; Huang, Cong-Fa; Ma, Si-Rui; Bu, Lin-Lin; Liu, Jian-Feng; Yu, Guang-Tao; Sun, Zhi-Jun] Minist Educ, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan, Peoples R China. [Zhao, Zhi-Li; Zhang, Lu; Huang, Cong-Fa; Ma, Si-Rui; Bu, Lin-Lin; Liu, Jian-Feng; Yu, Guang-Tao; Sun, Zhi-Jun] Minist Educ, Key Lab Oral Biomed, Wuhan, Peoples R China. [Liu, Bing; Zhang, Wen-Feng; Sun, Zhi-Jun] Wuhan Univ, Sch & Hosp Stomatol, Dept Oral Maxillofacial Head Neck Oncol, Wuhan 430072, Peoples R China. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Kulkarni, Ashok B.; Sun, Zhi-Jun] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Sun, ZJ (reprint author), Minist Educ, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan, Peoples R China.; Sun, ZJ (reprint author), Minist Educ, Key Lab Oral Biomed, Wuhan, Peoples R China.; Sun, ZJ (reprint author), Wuhan Univ, Sch & Hosp Stomatol, Dept Oral Maxillofacial Head Neck Oncol, Wuhan 430072, Peoples R China.; Sun, ZJ (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. EM zhijundejia@163.com FU National Natural Science Foundation of China [81272963, 81472528, 81272964, 81472529, 81402241]; Division of Intramural Research, NIDCR, NIH, USA; program for new century excellent talents in university, Ministry of Education of China [NCET-13-0439] FX This work was supported by National Natural Science Foundation of China 81272963, 81472528 (Z.J.S.), 81272964, 81472529 (W.F.Z.), 81402241 (C.F.H.), and the Division of Intramural Research, NIDCR, NIH, USA (A.B.K, J.S.G.). Z.J.S. was supported by program for new century excellent talents in university (NCET-13-0439), Ministry of Education of China. NR 51 TC 6 Z9 6 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 25 PY 2016 VL 6 AR 24704 DI 10.1038/srep24704 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK0YX UT WOS:000374640100001 PM 27108536 ER PT J AU Mercredi, PY Bucca, N Loeliger, B Gaines, CR Mehta, M Bhargava, P Tedbury, PR Charlier, L Floquet, N Muriaux, D Favard, C Sanders, CR Freed, EO Marchant, J Summers, MF AF Mercredi, Peter Y. Bucca, Nadine Loeliger, Burk Gaines, Christy R. Mehta, Mansi Bhargava, Pallavi Tedbury, Philip R. Charlier, Landry Floquet, Nicolas Muriaux, Delphine Favard, Cyril Sanders, Charles R. Freed, Eric O. Marchant, Jan Summers, Michael F. TI Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1 matrix protein; PIP2; bicelles; polysomes; membrane targeting ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRION-ASSOCIATED CHOLESTEROL; COARSE-GRAINED MODEL; B METHYL-ESTER; PLASMA-MEMBRANE; LIPID RAFTS; TYPE-1 GAG; BACKBONE DYNAMICS; NMR-SPECTROSCOPY; MYRISTATE EXPOSURE AB Assembly of HIV-1 particles is initiated by the trafficking of viral Gag polyproteins from the cytoplasm to the plasma membrane, where they co-localize and bud to form immature particles. Membrane targeting is mediated by the N-terminally myristoylated matrix (MA) domain of Gag and is dependent on the plasma membrane marker phosphatidylinositol-4,5-bisphosphate [PI(4,5)P-2]. Recent studies revealed that PI(4,5)P-2 molecules containing truncated acyl chains [tr-PI(4,5)P-2] are capable of binding MA in an "extended lipid" conformation and promoting myristoyl exposure. Here we report that tr-PI(4,5)P-2 molecules also readily bind to non-membrane proteins, including HIV-1 capsid, which prompted us to re-examine MA-PI(4,5)P-2 interactions using native lipids and membrane mimetic liposomes and bicelles. Liposome binding trends observed using a recently developed NMR approach paralleled results of flotation assays, although the affinities measured under the equilibrium conditions of NMR experiments were significantly higher. Native PI(4,5)P-2 enhanced MA binding to liposomes designed to mimic non-raft-like regions of the membrane, suggesting the possibility that binding of the protein to disordered domains may precede Gag association with, or nucleation of, rafts. Studies with bicelles revealed a subset of surface and myr-associated MA residues that are sensitive to native PI(4,5)P-2, but cleft residues that interact with the 2'-acyl chains of tr-PI(4,5)P-2 molecules in aqueous solution were insensitive to native PI(4,5)P-2 in bicelles. Our findings call to question extended-lipid MA:membrane binding models, and instead support a model put forward from coarse-grained simulations indicating that binding is mediated predominantly by dynamic, electrostatic interactions between conserved basic residues of MA and multiple PI(4,5)P-2 and phosphatidylserine molecules. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Mercredi, Peter Y.; Bucca, Nadine; Loeliger, Burk; Gaines, Christy R.; Mehta, Mansi; Bhargava, Pallavi; Marchant, Jan; Summers, Michael F.] Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Tedbury, Philip R.; Freed, Eric O.] NCI, HIV Dynam & Replicat Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. [Charlier, Landry; Floquet, Nicolas] Univ Montpellier, Fac Pharm, CNRS UMR5247, Inst Biomol Max Mousseron, F-34059 Montpellier 05, France. [Muriaux, Delphine; Favard, Cyril] Univ Montpellier, CNRS, UMR 5236, Ctr Etud Agents Pathogenes & Biotechnol Sante, F-34059 Montpellier 5, France. [Sanders, Charles R.] Vanderbilt Univ, Sch Med, Struct Biol Ctr, Dept Biochem, Nashville, TN 37240 USA. [Sanders, Charles R.] Vanderbilt Univ, Sch Med, Inst Chem Biol, Nashville, TN 37240 USA. RP Marchant, J; Summers, MF (reprint author), Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Dept Chem & Biochem, Baltimore, MD 21250 USA.; Freed, EO (reprint author), NCI, HIV Dynam & Replicat Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. EM efreed@mail.nih.gov; janm@umbc.edu; summers@hhmi.umbc.edu RI Favard, Cyril/P-6392-2016; OI Favard, Cyril/0000-0002-8304-2980; Tedbury, Philip/0000-0001-8151-4967 FU NIH [AI30917, GM103297, GM106672]; NIGMS [R25-GM55036] FX Support from NIH grants AI30917 and GM103297 (to M.F.S.) and GM106672 (to C.S.) is gratefully acknowledged. P.Y.M. was supported by an NIGMS Initiative for Minority Student Development grant, R25-GM55036. NR 109 TC 8 Z9 8 U1 8 U2 20 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD APR 24 PY 2016 VL 428 IS 8 BP 1637 EP 1655 DI 10.1016/j.jmb.2016.03.005 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL0PU UT WOS:000375335800012 PM 26992353 ER PT J AU Rajpert-De Meyts, E McGlynn, KA Okamoto, K Jewett, MAS Bokemeyer, C AF Rajpert-De Meyts, Ewa McGlynn, Katherine A. Okamoto, Keisei Jewett, Michael A. S. Bokemeyer, Carsten TI Testicular germ cell tumours SO LANCET LA English DT Review ID CARCINOMA-IN-SITU; HIGH-DOSE CHEMOTHERAPY; CANCER-STUDY-GROUP; LYMPH-NODE DISSECTION; RANDOMIZED PHASE-III; SUBCENTIMETER RESIDUAL MASS; MEDICAL-RESEARCH-COUNCIL; LONG-TERM SURVIVORS; OF-THE-LITERATURE; FOLLOW-UP AB Testicular germ cell tumours are at the crossroads of developmental and neoplastic processes. Their cause has not been fully elucidated but differences in incidences suggest that a combination of genetic and environment factors are involved, with environmental factors predominating early in life. Substantial progress has been made in understanding genetic susceptibility in the past 5 years on the basis of the results of large genome-wide association studies. Testicular germ cell tumours are highly sensitive to radiotherapy and chemotherapy and hence have among the best outcomes of all tumours. Because the tumours occur mainly in young men, preservation of reproductive function, quality of life after treatment, and late effects are crucial concerns. In this Seminar, we provide an overview of advances in the understanding of the epidemiology, genetics, and biology of testicular germ cell tumours. We also summarise the consensus on how to treat testicular germ cell tumours and focus on a few controversies and improvements in the understanding of late effects of treatment and quality of life for survivors. C1 [Rajpert-De Meyts, Ewa] Rigshosp, Copenhagen Univ Hosp, Dept Growth & Reprod, DK-2100 Copenhagen, Denmark. [Rajpert-De Meyts, Ewa] Int Ctr Res & Res Training Endocrine Disrupting E, Copenhagen, Denmark. [McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Okamoto, Keisei] Shiga Univ Med Sci, Dept Urol, Shiga 5202192, Japan. [Jewett, Michael A. S.] Univ Hlth Network, Princess Margaret Canc Ctr, Dept Surg Urol, Toronto, ON, Canada. [Jewett, Michael A. S.] Univ Hlth Network, Princess Margaret Canc Ctr, Dept Surg Oncol, Toronto, ON, Canada. [Jewett, Michael A. S.] Univ Toronto, Toronto, ON, Canada. [Bokemeyer, Carsten] Univ Hosp Hamburg Eppendorf, Dept Med, Dept Oncol Haematol Bone Marrow Transplantat, Sect Pneumol, Hamburg, Germany. RP Okamoto, K (reprint author), Shiga Univ Med Sci, Dept Urol, Shiga 5202192, Japan. EM keisei@belle.shiga-med.ac.jp FU Danish Cancer Society; National Cancer Institute FX We thank Kahori Minami for assistance in the collection and collation of reference material. Our work was supported by grants from the Danish Cancer Society (to ERDM), and the National Cancer Institute's Intramural Research Program (to KAM), but the supporting institutes had no role in this Seminar. NR 157 TC 8 Z9 8 U1 2 U2 7 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 APR 23 PY 2016 VL 387 IS 10029 BP 1762 EP 1774 DI 10.1016/S0140-6736(15)00991-5 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA DJ9OD UT WOS:000374541900029 PM 26651223 ER PT J AU Urzua, U Ampuero, S Roby, KF Owens, GA Munroe, DJ AF Urzua, Ulises Ampuero, Sandra Roby, Katherine F. Owens, Garrison A. Munroe, David J. TI Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells SO BMC GENOMICS LA English DT Article DE Ovarian cancer model; Preneoplasia; Mouse ovarian surface epithelium; Transcriptome; Genome; Aneuploidy; Cytokinesis; DNA microarrays ID LONG NONCODING RNA; TUMOR-SUPPRESSOR GENES; FUNCTIONAL-CHARACTERISTICS; RACGAP1 EXPRESSION; COLORECTAL-CANCER; NUCLEAR RETENTION; INCLUSION CYSTS; MESSENGER-RNA; MURINE MODEL; RISK-FACTORS AB Background: Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE). Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE) cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model. Results: At passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p < 0.05) comprised 7 genes coding for centralspindlin, chromosome passenger and minichromosome maintenance protein complexes. The genes Ccnb1 (Cyclin B1), Birc5 (Survivin), Nusap1 and Kif23 were the most recurrent in over a dozen GO terms related to the mitotic process. On the other hand, Pten plus the large non-coding RNAs Malat1 and Neat1 were among the 80 down-regulated genes with mRNA processing, nuclear bodies, ER-stress response and tumor suppression as relevant terms. Interestingly, the earliest discrete segmental aneuploidies arose by passage 18 in chromosomes 7, 10, 11, 13, 15, 17 and 19. By passage 23, when MOSE cells express the malignant phenotype, the dysregulated gene expression repertoire expanded, DNA imbalances enlarged in size and covered additional loci. Conclusion: Prior to early aneuploidies, overexpression of genes coding for the mitotic apparatus in passage-14 pre-malignant MOSE cells indicate an increased proliferation rate suggestive of replicative stress. Concomitant down-regulation of nuclear bodies and RNA processing related genes suggests altered control of nuclear RNA maturation, features recently linked to impaired DNA damage response leading to genome instability. These results, combined with cytogenetic analysis by other authors in this model, suggest that transcriptional profile at passage 14 might induce cytokinesis failure by which tetraploid cells approach a near-tetraploid stage containing primary chromosome aberrations that initiate the tumorigenic drive. C1 [Urzua, Ulises] Univ Chile, Fac Med, Programa Biol Celular & Mol, Lab Genom Aplicada,ICBM, Santiago 1027, Chile. [Ampuero, Sandra] Univ Chile, Fac Med, Programa Virol, ICBM, Santiago 1027, Chile. [Roby, Katherine F.] Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Kansas City, KS 66103 USA. [Owens, Garrison A.; Munroe, David J.] NCI SAIC Frederick, Lab Mol Technol, Frederick, MD USA. [Munroe, David J.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. [Owens, Garrison A.] ThermoFisher Sci, Life Sci Solut Grp, 5792 Van Allen Way, Carlsbad, CA 92008 USA. RP Urzua, U (reprint author), Univ Chile, Fac Med, Programa Biol Celular & Mol, Lab Genom Aplicada,ICBM, Santiago 1027, Chile. EM uurzua@med.uchile.cl FU Fondecyt [1130292]; Ministry of Education, Chile [N01-CO-12400]; NCI-NIH, USA FX This work was funded by grant Fondecyt 1130292, Ministry of Education, Chile (UU) and contract N01-CO-12400, NCI-NIH, USA (DJM). Funding for publication was from grant Fondecyt 1130292. NR 67 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD APR 22 PY 2016 VL 17 SU 8 AR 728 DI 10.1186/s12864-016-3068-5 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EJ0UN UT WOS:000392926100004 PM 27801298 ER PT J AU Waheed, AA MacDonald, S Khan, M Mounts, M Swiderski, M Xu, Y Ye, YH Freed, EO AF Waheed, Abdul A. MacDonald, Scott Khan, Maisha Mounts, Megan Swiderski, Maya Xu, Yue Ye, Yihong Freed, Eric O. TI The Vpu-interacting Protein SGTA Regulates Expression of a Non-glycosylated Tetherin Species SO SCIENTIFIC REPORTS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RICH TETRATRICOPEPTIDE REPEAT; CYTOSOLIC QUALITY-CONTROL; TPR-CONTAINING PROTEIN; ENDOPLASMIC-RETICULUM; DOWN-REGULATION; MANNOSIDASE-I; HIV-1 VPU; FUNCTIONAL INTERACTION; MISLOCALIZED PROTEINS AB The HIV-1 accessory protein Vpu enhances virus release by counteracting the host restriction factor tetherin. To further understand the role of host cell proteins in Vpu function, we carried out yeast two-hybrid screening and identified a previously reported Vpu-interacting host factor, small glutamine-rich tetratricopeptide repeat-containing protein (SGTA). While RNAi-mediated depletion of SGTA did not significantly affect levels of tetherin or virus release efficiency, we observed that overexpression of SGTA inhibited HIV-1 release in a Vpu-and tetherin-independent manner. Overexpression of SGTA in the presence of Vpu, but not in its absence, resulted in a marked stabilization and cytosolic relocalization of a 23-kDa, non-glycosylated tetherin species. Coimmunoprecipitation studies indicated that non-glycosylated tetherin is stabilized through the formation of a ternary SGTA/Vpu/tetherin complex. This accumulation of non-glycosylated tetherin is due to inhibition of its degradation, independent of the ER-associated degradation (ERAD) pathway. Because the SGTA-stabilized tetherin species is partially localized to the cytosol, we propose that overexpression of SGTA in the presence of Vpu blocks the translocation of tetherin across the ER membrane, resulting in cytosolic accumulation of a non-glycosylated tetherin species. Although our results do not provide support for a physiological function of SGTA in HIV-1 replication, they demonstrate that SGTA overexpression regulates tetherin expression and stability, thus providing insights into the function of SGTA in ER translocation and protein degradation. C1 [Waheed, Abdul A.; MacDonald, Scott; Khan, Maisha; Mounts, Megan; Swiderski, Maya; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Xu, Yue; Ye, Yihong] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Waheed, AA (reprint author), NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM waheedab@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH; Intramural AIDS Targeted Antiviral Program FX We thank Myriad Genetics (Salt Lake City, UT) for carrying out yeast two-hybrid screening. We thank members of the Freed laboratory for helpful discussion and critical review of the manuscript. We thank K. Strebel, and P. Bieniasz for their generous gifts of plasmids. The HIV-1 Ig, anti-Vpu and anti-human tetherin antisera were obtained from the NIH AIDS Research and Reference Reagent Program. Research in the Freed laboratory is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and by the Intramural AIDS Targeted Antiviral Program. NR 64 TC 0 Z9 0 U1 2 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 APR 22 PY 2016 VL 6 AR 24934 DI 10.1038/srep24934 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK2NQ UT WOS:000374752100001 PM 27103333 ER PT J AU Tryndyak, VP Han, T Fuscoe, JC Ross, SA Beland, FA Pogribny, IP AF Tryndyak, Volodymyr P. Han, Tao Fuscoe, James C. Ross, Sharon A. Beland, Frederick A. Pogribny, Igor P. TI Status of hepatic DNA methylome predetermines and modulates the severity of non-alcoholic fatty liver injury in mice SO BMC GENOMICS LA English DT Article DE DNA methylation; Non-alcoholic fatty liver injury; Susceptibility; Mouse; Inter-strain differences ID FOLATE-DEFICIENT DIET; NAFLD PROGRESSION; WIDE ASSOCIATION; DISEASE; METHYLATION; STEATOHEPATITIS; STEATOSIS; PNPLA3; GENE; VARIANTS AB Background: Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and Western countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD; nonetheless, the effect of inter-individual differences in the normal liver epigenome with regard to the susceptibility to NAFLD has not been determined. Results: In the present study, we investigated the association between the DNA methylation status in the livers of A/J and WSB/EiJ mice and the severity of NAFLD-associated liver injury. We demonstrate that A/J and WSB/EiJ mice, which are characterized by significant differences in the severity of liver injury induced by a choline- and folate-deficient (CFD) diet exhibit substantial differences in cytosine DNA methylation in their normal livers. Furthermore, feeding A/J and WSB/EiJ mice a CFD diet for 12 weeks resulted in different trends and changes in hepatic cytosine DNA methylation. Conclusion: Our findings indicate a primary role of hepatic DNA methylation in the pathogenesis of NAFLD and suggest that individual variations in DNA methylation across the genome may be a factor determining and influencing the vulnerability to NAFLD. C1 [Tryndyak, Volodymyr P.; Beland, Frederick A.; Pogribny, Igor P.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Han, Tao; Fuscoe, James C.] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Ross, Sharon A.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Pogribny, IP (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov FU FDA-NCTR Intramural Research Program (Jefferson, AR, USA) FX This study was funded by the FDA-NCTR Intramural Research Program (Jefferson, AR, USA). NR 38 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD APR 22 PY 2016 VL 17 AR 298 DI 10.1186/s12864-016-2617-2 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DK5FO UT WOS:000374945500001 PM 27103143 ER PT J AU Hong, E Usiskin, IM Bergamaschi, C Hanlon, DJ Edelson, RL Justesen, S Pavlakis, GN Flavell, RA Fahmy, TM AF Hong, Enping Usiskin, Ilana M. Bergamaschi, Cristina Hanlon, Douglas J. Edelson, Richard L. Justesen, Sune Pavlakis, George N. Flavell, Richard A. Fahmy, Tarek M. TI Configuration-dependent Presentation of Multivalent IL-15: IL-15R alpha Enhances the Antigen-specific T Cell Response and Anti-tumor Immunity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN DENDRITIC CELLS; TUMOR-INFILTRATING LYMPHOCYTES; IN-VIVO; CROSS-PRESENTATION; ADOPTIVE IMMUNOTHERAPY; TRANS-PRESENTATION; RECEPTOR-ALPHA; BIODEGRADABLE NANOPARTICLES; SOLUBLE IL-15R-ALPHA; HUMAN INTERLEUKIN-15 AB Here we report a "configuration-dependent" mechanism of action for IL-15:IL-15R alpha (heterodimeric IL-15 or hetIL-15) where the manner by which IL-15:IL-15R alpha molecules are presented to target cells significantly affects its function as a vaccine adjuvant. Although the cellular mechanism of IL-15 trans-presentation via IL-15R alpha and its importance for IL-15 function have been described, the full effect of the IL-15:IL-15R alpha configuration on responding cells is not yet known. We found that trans-presenting IL-15:IL-15R alpha in a multivalent fashion on the surface of antigen-encapsulating nanoparticles enhanced the ability of nanoparticle-treated dendritic cells (DCs) to stimulate antigen-specific CD8(+) T cell responses. Localization of multivalent IL-15:IL-15R alpha and encapsulated antigen to the same DC led to maximal T cell responses. Strikingly, DCs incubated with IL-15:IL-15R alpha coated nanoparticles displayed higher levels of functional IL-15 on the cell surface, implicating a mechanism for nanoparticle-mediated transfer of IL-15 to the DC surface. Using artificial antigen-presenting cells to highlight the effect of IL-15 configuration on DCs, we showed that artificial antigen-presenting cells presenting IL-15:IL-15R alpha increased the sensitivity and magnitude of the T cell response, whereas IL-2 enhanced the T cell response only when delivered in a paracrine fashion. Therefore, the mode of cytokine presentation (configuration) is important for optimal immune responses. We tested the effect of configuration dependence in an aggressive model of murine melanoma and demonstrated significantly delayed tumor progression induced by IL-15:IL-15R alpha-coated nanoparticles in comparison with monovalent IL-15:IL-15R alpha. The novel mechanism of IL-15 transfer to the surface of antigen-processing DCs may explain the enhanced potency of IL-15:IL-15R alpha-coated nanoparticles for antigen delivery. C1 [Hong, Enping; Usiskin, Ilana M.; Fahmy, Tarek M.] Yale Univ, Dept Biomed Engn, 55 Prospect St, New Haven, CT 06511 USA. [Flavell, Richard A.; Fahmy, Tarek M.] Yale Univ, Sch Med, Dept Immunobiol, 55 Prospect St, New Haven, CT 06511 USA. [Hanlon, Douglas J.; Edelson, Richard L.] Yale Univ, Sch Med, Dept Dermatol, 55 Prospect St, New Haven, CT 06511 USA. [Bergamaschi, Cristina; Pavlakis, George N.] NCI, Vaccine Branch, NIH, Frederick, MD 21702 USA. [Justesen, Sune] Univ Copenhagen, Dept Sci, DK-1017 Copenhagen, Denmark. RP Fahmy, TM (reprint author), Yale Univ, Dept Biomed Engn, Dept Chem, 55 Prospect St, New Haven, CT 06511 USA.; Fahmy, TM (reprint author), Yale Univ, Dept Environm Engn, Dept Immunobiol, 55 Prospect St, New Haven, CT 06511 USA.; Fahmy, TM (reprint author), Yale Univ, Dept Obstet & Gynecol, 55 Prospect St, New Haven, CT 06511 USA. EM tarek.fahmy@yale.edu OI Flavell, Richard/0000-0003-4461-0778 NR 107 TC 1 Z9 1 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 22 PY 2016 VL 291 IS 17 BP 8931 EP 8950 DI 10.1074/jbc.M115.695304 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK3WV UT WOS:000374849000007 PM 26719339 ER PT J AU Montecinos-Franjola, F Schuck, P Sackett, DL AF Montecinos-Franjola, Felipe Schuck, Peter Sackett, Dan L. TI Tubulin Dimer Reversible Dissociation AFFINITY, KINETICS, AND DEMONSTRATION OF A STABLE MONOMER SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALPHA-BETA-TUBULIN; SEDIMENTATION-VELOCITY; PROTEIN INTERACTIONS; FLUORESCENCE ANISOTROPY; MICROTUBULE DYNAMICS; COLCHICINE BINDING; POLYMERIZATION; ASSOCIATION; SUBUNITS; COMPLEX AB Tubulins are evolutionarily conserved proteins that reversibly polymerize and direct intracellular traffic. Of the tubulin family only alpha beta-tubulin forms stable dimers. We investigated the monomer-dimer equilibrium of rat brain alpha beta-tubulin using analytical ultracentrifugation and fluorescence anisotropy, observing tubulin in virtually fully monomeric and dimeric states. Monomeric tubulin was stable for a few hours and exchanged into preformed dimers, demonstrating reversibility of dimer dissociation. Global analysis combining sedimentation velocity and fluorescence anisotropy yielded K-d = 84 (54-123) nM. Dimer dissociation kinetics were measured by analyzing the shape of the sedimentation boundary and by the relaxation of fluorescence anisotropy following rapid dilution of labeled tubulin, yielding k(off) in the range 10(-3)-10(-2) s(-1). Thus, tubulin dimers reversibly dissociate with moderately fast kinetics. Monomer-monomer association is much less sensitive than dimer-dimer association to solution changes (GTP/GDP, urea, and trimethylamine oxide). C1 [Montecinos-Franjola, Felipe; Sackett, Dan L.] Natl Inst Biomed Imaging & Bioengn NHBLI, Eunice Kennedy Shriver NICHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Schuck, Peter] Natl Inst Biomed Imaging & Bioengn NHBLI, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Montecinos-Franjola, F (reprint author), Eunice Kennedy Shriver NICHD, Program Phys Biol, NIH, Bldg 9,Rm 1E-122,9000 Rockville Pike, Bethesda, MD 20892 USA.; Sackett, DL (reprint author), Eunice Kennedy Shriver NICHD, Program Phys Biol, NIH, Bldg 9,Rm 1E-129,9000 Rockville Pike, Bethesda, MD 20892 USA. EM felipe.montecinos@nih.gov; sackettd@mail.nih.gov OI Montecinos-Franjola, Felipe/0000-0002-1823-103X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Biomedical Imaging and Bioengineering (NHBLI), National Institutes of Health, Bethesda, MD FX This work was supported by funds of the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Biomedical Imaging and Bioengineering (NHBLI), National Institutes of Health, Bethesda, MD. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 61 TC 1 Z9 1 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 22 PY 2016 VL 291 IS 17 BP 9281 EP 9294 DI 10.1074/jbc.M115.699728 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK3WV UT WOS:000374849000037 PM 26934918 ER PT J AU Sirohi, D Chen, ZG Sun, L Klose, T Pierson, TC Rossmann, MG Kuhn, RJ AF Sirohi, Devika Chen, Zhenguo Sun, Lei Klose, Thomas Pierson, Theodore C. Rossmann, Michael G. Kuhn, Richard J. TI The 3.8 angstrom resolution cryo-EM structure of Zika virus SO SCIENCE LA English DT Article ID WEST-NILE-VIRUS; DENGUE VIRUS; TRANSMISSION; MATURATION; MICRONESIA; INFECTION; COMPLEX; BRAZIL AB The recent rapid spread of Zika virus and its unexpected linkage to birth defects and an autoimmune neurological syndrome have generated worldwide concern. Zika virus is a flavivirus like the dengue, yellow fever, and West Nile viruses. We present the 3.8 angstrom resolution structure of mature Zika virus, determined by cryo-electron microscopy (cryo-EM). The structure of Zika virus is similar to other known flavivirus structures, except for the similar to 10 amino acids that surround the Asn(154) glycosylation site in each of the 180 envelope glycoproteins that make up the icosahedral shell. The carbohydrate moiety associated with this residue, which is recognizable in the cryo-EM electron density, may function as an attachment site of the virus to host cells. This region varies not only among Zika virus strains but also in other flaviviruses, which suggests that differences in this region may influence virus transmission and disease. C1 [Sirohi, Devika; Chen, Zhenguo; Sun, Lei; Klose, Thomas; Rossmann, Michael G.; Kuhn, Richard J.] Purdue Univ, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA. [Sirohi, Devika; Chen, Zhenguo; Sun, Lei; Klose, Thomas; Rossmann, Michael G.; Kuhn, Richard J.] Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA. [Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Rossmann, MG; Kuhn, RJ (reprint author), Purdue Univ, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA.; Rossmann, MG; Kuhn, RJ (reprint author), Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA. EM mr@purdue.edu; kuhnr@purdue.edu FU National Institute of Allergy and Infectious Diseases of the NIH [R01AI073755, R01AI076331]; National Institute of Allergy and Infectious Diseases FX We thank X. de Lamballerie (Emergence des Pathologies Virales, Aix-Marseille Universite, Marseille, France) and the European Virus Archive Goes Global (EVAg) for consenting to the use of the H/PF/2013 ZIKV strain for this study under a material transfer agreement with EVAg's partner, Aix-Marseille Universite, and we thank M. S. Diamond (Washington University, St. Louis, MO, USA) for sending the virus. We acknowledge E. Frye for help with sequence alignments. We also acknowledge the use of the Purdue cryo-EM facility. We are grateful to W. Jiang for his jspr program, which was used to perform the anisotropic magnification corrections, and Y. Liu for providing help in submitting the Protein Data Bank (PDB) coordinates. The work presented in this report was funded by the National Institute of Allergy and Infectious Diseases of the NIH through grants R01AI073755 and R01AI076331 to M.G.R. and R.J.K. T.C.P was supported by the intramural program of the National Institute of Allergy and Infectious Diseases. Supporting information for this research is provided in the supplementary materials. The atomic coordinates and cryo-EM density maps for the mature ZIKV are available at the PDB and Electron Microscopy Data Bank under accession codes 5IRE and EMD-8116, respectively. NR 36 TC 63 Z9 68 U1 29 U2 54 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 APR 22 PY 2016 VL 352 IS 6284 BP 467 EP 470 DI 10.1126/science.aaf5316 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ8RH UT WOS:000374479700049 PM 27033547 ER PT J AU Davey, JR Watt, KI Parker, BL Chaudhuri, R Ryall, JG Cunningham, L Qian, H Sartorelli, V Sandri, M Chamberlain, J James, DE Gregorevic, P AF Davey, Jonathan R. Watt, Kevin I. Parker, Benjamin L. Chaudhuri, Rima Ryall, James G. Cunningham, Louise Qian, Hongwei Sartorelli, Vittorio Sandri, Marco Chamberlain, Jeffrey James, David E. Gregorevic, Paul TI Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass SO JCI INSIGHT LA English DT Article ID LIGASE SPECIFICITY SUBUNIT; PROTEASOMAL DEGRADATION; CANCER CACHEXIA; ACTIVIN-A; MYOSTATIN; MICE; FOLLISTATIN; INHIBITION; SARCOPENIA; GROWTH AB The transforming growth factor-beta (TGF-beta) signaling network is a critical regulator of skeletal muscle mass and function and, thus, is an attractive therapeutic target for combating muscle disease, but the underlying mechanisms of action remain undetermined. We report that follistatin-based interventions (which modulate TGF-beta network activity) can promote muscle hypertrophy that ameliorates aging-associated muscle wasting. However, the muscles of old sarcopenic mice demonstrate reduced response to follistatin compared with healthy young-adult musculature. Quantitative proteomic and transcriptomic analyses of young-adult muscles identified a transcription/translation signature elicited by follistatin exposure, which included repression of ankyrin repeat and SOCS box protein 2 (Asb2). Increasing expression of ASB2 reduced muscle mass, thereby demonstrating that Asb2 is a TGF-beta network-responsive negative regulator of muscle mass. In contrast to young-adult muscles, sarcopenic muscles do not exhibit reduced ASB2 abundance with follistatin exposure. Moreover, preventing repression of ASB2 in young-adult muscles diminished follistatin-induced muscle hypertrophy. These findings provide insight into the program of transcription and translation events governing follistatin-mediated adaptation of skeletal muscle attributes and identify Asb2 as a regulator of muscle mass implicated in the potential mechanistic dysfunction between follistatin-mediated muscle growth in young and old muscles. C1 [Davey, Jonathan R.; Watt, Kevin I.; Cunningham, Louise; Qian, Hongwei; Gregorevic, Paul] Baker IDI Heart & Diabet Inst, POB 6492, Melbourne, Vic 3004, Australia. [Parker, Benjamin L.; Chaudhuri, Rima; James, David E.] Univ Sydney, Sch Mol Biosci, Charles Perkins Ctr, Sydney, NSW, Australia. [Ryall, James G.; Sartorelli, Vittorio] NIAMSD, NIH, Bethesda, MD 20892 USA. [Ryall, James G.; Gregorevic, Paul] Univ Melbourne, Dept Physiol, Melbourne, Vic, Australia. [Sandri, Marco] Univ Padua, Venetian Inst Mol Med, Padua, Italy. [Chamberlain, Jeffrey; Gregorevic, Paul] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [James, David E.] Univ Sydney, Sydney Med Sch, Sydney, NSW, Australia. [Gregorevic, Paul] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia. RP Gregorevic, P (reprint author), Baker IDI Heart & Diabet Inst, POB 6492, Melbourne, Vic 3004, Australia. EM Paul.Gregorevic@BakerIDI.edu.au NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD APR 21 PY 2016 VL 1 IS 5 AR e85477 DI 10.1172/jci.insight.85477 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1IV UT WOS:000387104600002 ER PT J AU Kanakry, CG Coffey, DG Towlerton, AMH Vulic, A Storer, BE Chou, J Yeung, CCS Gocke, CD Robins, HS O'Donnell, PV Luznik, L Warren, EH AF Kanakry, Christopher G. Coffey, David G. Towlerton, Andrea M. H. Vulic, Ante Storer, Barry E. Chou, Jeffrey Yeung, Cecilia C. S. Gocke, Christopher D. Robins, Harlan S. O'Donnell, Paul V. Luznik, Leo Warren, Edus H. TI Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide SO JCI INSIGHT LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; MINOR HISTOCOMPATIBILITY ANTIGENS; EPSTEIN-BARR-VIRUS; HEMATOLOGIC MALIGNANCIES; CYTOMEGALOVIRUS-SEROPOSITIVITY; PERIPHERAL-BLOOD; IMMUNE RECOVERY; SINGLE-AGENT; CHRONIC GVHD AB Posttransplantation cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD), but its immunologic impact is poorly understood. We assessed lymphocyte reconstitution via flow cytometry (n = 74) and antigen receptor sequencing (n = 35) in recipients of myeloablative, HLA-matched allogeneic BM transplantation using PTCy. Recovering T cells were primarily phenotypically effector memory with lower T cell receptor beta (TRB) repertoire diversity than input donor repertoires. Recovering B cells were predominantly naive with immunoglobulin heavy chain locus (IGH) repertoire diversity similar to donors. Numerical T cell reconstitution and TRB diversity were strongly associated with recipient cytomegalovirus seropositivity. Global similarity between input donor and recipient posttransplant repertoires was uniformly low at 1-2 months after transplant but increased over the balance of the first posttransplant year. Blood TRB repertoires at >= 3 months after transplant were often dominated by clones present in the donor blood/marrow memory CD8(+) compartment. Limited overlap was observed between the TRB repertoires of T cells infiltrating the skin or gastrointestinal tract versus the blood. Although public TRB sequences associated with herpesvirus-or alloantigen-specific CD8(+) T cells were detected in some patients, posttransplant TRB and IGH repertoires were unique to each individual. These data define the immune dynamics occurring after PTCy and establish a benchmark against which immune recovery after other transplantation approaches can be compared. C1 [Kanakry, Christopher G.; Vulic, Ante; Gocke, Christopher D.; Luznik, Leo] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Coffey, David G.; Towlerton, Andrea M. H.; Storer, Barry E.; Chou, Jeffrey; Yeung, Cecilia C. S.; O'Donnell, Paul V.; Warren, Edus H.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Coffey, David G.; Chou, Jeffrey; O'Donnell, Paul V.; Warren, Edus H.] Univ Washington, Dept Med, Seattle, WA USA. [Yeung, Cecilia C. S.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Robins, Harlan S.] FHCRC, Publ Hlth Sci Div, Seattle, WA USA. [Kanakry, Christopher G.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Warren, EH (reprint author), 1100 Fairview Ave N,D4-100, Seattle, WA 98109 USA.; Luznik, L (reprint author), 1650 Orleans St, Baltimore, MD 21287 USA. EM luznile@jhmi.edu; ehwarren@u.washington.edu NR 57 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD APR 21 PY 2016 VL 1 IS 5 AR e86252 DI 10.1172/jci.insight.86252 PG 20 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1IV UT WOS:000387104600008 ER PT J AU Her, NG Toth, JI Ma, CT Wei, Y Motamedchaboki, K Sergienko, E Petroski, MD AF Her, Nam-Gu Toth, Julia I. Ma, Chen-Ting Wei, Yang Motamedchaboki, Khatereh Sergienko, Eduard Petroski, Matthew D. TI p97 Composition Changes Causedby Allosteric Inhibition Are Suppressed by an On-Target Mechanism that Increases the Enzyme's ATPase Activity SO CELL CHEMICAL BIOLOGY LA English DT Article ID UBIQUITIN-PROTEASOME SYSTEM; AAA-ATPASE; MEMBRANE-FUSION; PROTEIN; VCP/P97; ER; CDC48/P97; DOMAIN; COMPLEX; P97/VCP AB The AAA ATPase p97/VCP regulates protein homeostasis using a diverse repertoire of cofactors to fulfill its biological functions. Here we use the allosteric p97 inhibitor NMS-873 to analyzeits effects on enzyme composition and the ability of cells to adapt to its cytotoxicity. We found that p97 inhibition changes steady state cofactor-p97 composition, leading to the enrichment of a subset of its cofactors and polyubiquitin bound to p97. We isolated cells specifically insensitive to NMS-873 and identified a new mutation (A530T) in p97. A530T is sufficient to overcome the cytotoxicity of NMS-873 and alleviates p97 composition changes caused by the molecule but not other p97 inhibitors. This mutation does not affect NMS-873 binding but increases p97 catalytic efficiency through altered ATP and ADP binding. Collectively, these findings identify cofactor-p97 interactions sensitive to p97 inhibition and reveal a new on-target mechanism to suppress the cytotoxicity of NMS-873. C1 [Her, Nam-Gu; Toth, Julia I.; Wei, Yang; Motamedchaboki, Khatereh; Petroski, Matthew D.] NCI, Tumor Initiat & Maintenance Program, Designated Canc Ctr, Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Ma, Chen-Ting; Sergienko, Eduard] NCI, Conrad Prebys Ctr Chem Genom, Designated Canc Ctr, Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA. RP Petroski, MD (reprint author), NCI, Tumor Initiat & Maintenance Program, Designated Canc Ctr, Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM petroski@sbpdiscovery.org FU National Cancer Institute of the NIH (Cancer Center Support Grant) [R01 CA180150, R21 CA182178, R01 CA185300, P30 CA030199]; American Cancer Society [RSG-11-224-01-DMC] FX We thank Brian James for STR genotyping, Tony Pinkerton for sourcing and evaluating compounds, and Dieter Wolf for helpful discussions. This work was supported in part by the National Cancer Institute of the NIH (R01 CA180150, R21 CA182178, R01 CA185300, and Cancer Center Support Grant P30 CA030199), and the American Cancer Society (RSG-11-224-01-DMC). NR 38 TC 2 Z9 2 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2451-9448 J9 CELL CHEM BIOL JI Cell Chem. Biol. PD APR 21 PY 2016 VL 23 IS 4 BP 517 EP 528 DI 10.1016/j.chembiol.2016.03.012 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DT5GA UT WOS:000381508400012 PM 27105284 ER PT J AU Kanakry, JA Hegde, AM Durand, CM Massie, AB Greer, AE Ambinder, RF Valsamakis, A AF Kanakry, Jennifer A. Hegde, Aparna M. Durand, Christine M. Massie, Allan B. Greer, Amy E. Ambinder, Richard F. Valsamakis, Alexandra TI The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases SO BLOOD LA English DT Article ID EPSTEIN-BARR-VIRUS; REAL-TIME PCR; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; POLYMERASE-CHAIN-REACTION; VIRAL LOAD; NASOPHARYNGEAL CARCINOMA; T-CELL; HODGKIN LYMPHOMA; NASAL-TYPE; B-CELLS AB Epstein-Barr virus (EBV) is a ubiquitous virus that establishes a latent infection within the host and in some cases can lead to the development of EBV-associated lymphomas, lymphoproliferative disorders, hemophagocytic lymphohistiocytosis, solid tumors, and other diseases. We studied the clinical significance of detecting EBV DNA in the plasma and peripheral blood mononuclear cells (PBMCs) of 2146 patients who had blood specimens sent to the Johns Hopkins Hospital clinical laboratory for viral quantitative real-time polymerase chain reaction assay over a 5-year period. Within this largely immunocompromised and hospitalized cohort, 535 patients (25%) had EBV detected in plasma or PBMCs. When EBV was detected in the absence of an EBV+ disease (n = 402), it was present only in PBMCs in 69% of cases. Immunocompromised patients were less likely to have EBV in plasma than in PBMCs in the absence of EBV+ disease. In patients with active, systemic EBV+ diseases (n = 105), EBV was detected in plasma in 99% of cases but detected in PBMCs in only 54%. Across a range of copy number cutoffs, EBV in plasma had higher specificity and sensitivity for EBV+ disease as compared with EBV in PBMCs. EBV copy number in plasma distinguished untreated, EBV+ lymphoma from EBV+ lymphoma in remission and EBV- lymphoma, and also distinguished untreated, EBV+ posttransplantation lymphoproliferative disorder (PTLD) from EBV+ PTLD in remission and EBV- PTLD. EBV copy number quantification is a useful diagnostic marker across the spectrum of EBV+ diseases, even among immunocompromised patients, with plasma specimens more indicative of EBV+ disease than PBMCs. C1 [Kanakry, Jennifer A.; Hegde, Aparna M.] Johns Hopkins Univ, Dept Med, Hematol, Baltimore, MD USA. [Durand, Christine M.] Johns Hopkins Univ, Dept Med, Infect Dis, Baltimore, MD USA. [Massie, Allan B.] Johns Hopkins Univ, Dept Surg, Baltimore, MD USA. [Greer, Amy E.; Valsamakis, Alexandra] Johns Hopkins Univ, Dept Pathol, Med Microbiol, Baltimore, MD USA. [Ambinder, Richard F.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Kanakry, Jennifer A.; Ambinder, Richard F.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. RP Kanakry, JA (reprint author), NIH, 10 Ctr Dr,Bldg 10-CRC,Room 4-3132, Bethesda, MD 20892 USA.; Valsamakis, A (reprint author), Johns Hopkins Univ Hosp, 600 N Wolfe St,Meyer Bldg,Room B1-193, Baltimore, MD 21287 USA. EM jennifer.kanakry@nih.gov; avalsam1@jhmi.edu FU National Institutes of Health [R21 CA188824, P30 CA006973]; Centers for AIDS Research (National Institute of Allergy and Infectious Diseases, National Institutes of Health) [P30 AI094189]; National Cancer Institute FX This study was supported by grants from the National Cancer Institute, National Institutes of Health (R21 CA188824 and P30 CA006973) (R.F.A.) and a faculty development award to J.A.K., allocated through the Centers for AIDS Research (National Institute of Allergy and Infectious Diseases, National Institutes of Health, P30 AI094189). NR 43 TC 5 Z9 5 U1 3 U2 6 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 APR 21 PY 2016 VL 127 IS 16 BP 2007 EP 2017 DI 10.1182/blood-2015-09-672030 PG 11 WC Hematology SC Hematology GA DJ8DE UT WOS:000374441900011 PM 26744460 ER PT J AU Chang, JC Miura, RM AF Chang, Joshua C. Miura, Robert M. TI Regulatory inhibition of biological tissue mineralization by calcium phosphate through post-nucleation shielding by fetuin-A SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CONTAINING CALCIPROTEIN PARTICLES; SIMULATED BODY-FLUID; POSNERS CLUSTER; CALCIFICATION INHIBITION; THEORETICAL-ANALYSIS; SERUM; PRECIPITATION; CRYSTALLIZATION; COMPLEXES; HYDROXYAPATITE AB In vertebrates, insufficient availability of calcium and inorganic phosphate ions in extracellular fluids leads to loss of bone density and neuronal hyper-excitability. To counteract this problem, calcium ions are usually present at high concentrations throughout bodily fluids-at concentrations exceeding the saturation point. This condition leads to the opposite situation where unwanted mineral sedimentation may occur. Remarkably, ectopic or out-of-place sedimentation into soft tissues is rare, in spite of the thermodynamic driving factors. This fortunate fact is due to the presence of auto-regulatory proteins that are found in abundance in bodily fluids. Yet, many important inflammatory disorders such as atherosclerosis and osteoarthritis are associated with this undesired calcification. Hence, it is important to gain an understanding of the regulatory process and the conditions under which it can go awry. In this manuscript, we extend mean-field continuum classical nucleation theory of the growth of clusters to encompass surface shielding. We use this formulation to study the regulation of sedimentation of calcium phosphate salts in biological tissues through the mechanism of post-nuclear shielding of nascent mineral particles by binding proteins. We develop a mathematical description of this phenomenon using a countable system of hyperbolic partial differential equations. A critical concentration of regulatory protein is identified as a function of the physical parameters that describe the system. Published by AIP Publishing. C1 [Chang, Joshua C.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Chang, Joshua C.] Ohio State Univ, Math Biosci Inst, Columbus, OH 43210 USA. [Miura, Robert M.] New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. RP Chang, JC (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA.; Chang, JC (reprint author), Ohio State Univ, Math Biosci Inst, Columbus, OH 43210 USA.; Miura, RM (reprint author), New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. EM joshchang@ucla.edu; miura@njit.edu FU National Science Foundation [0635561, DMS-1021818]; Army Research Office [58386MA]; NIH, Clinical Center FX The authors would like to thank Lydia L. Shook (Yale School of Medicine), Tom Chou (UCLA Mathematics and Biomathematics), Huaxiong Huang (York University Mathematics), and Jonathan J. Wylie (City University of Hong Kong Mathematics) for their comments and feedback relating to this work. This material is based upon work supported by the National Science Foundation under Agreement No. 0635561. J.C.C. also acknowledges support from the National Science Foundation through Grant No. DMS-1021818, and from the Army Research Office through Grant No. 58386MA. This research was supported in part by the Intramural Research Program of the NIH, Clinical Center. NR 46 TC 0 Z9 1 U1 0 U2 5 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD APR 21 PY 2016 VL 144 IS 15 AR 154906 DI 10.1063/1.4946002 PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DL6YM UT WOS:000375786000043 PM 27389239 ER PT J AU Duy, J Koehler, JW Honko, AN Schoepp, RJ Wauquier, N Gonzalez, JP Pitt, ML Mucker, EM Johnson, JC O'Hearn, A Bangura, J Coomber, M Minogue, TD AF Duy, Janice Koehler, Jeffrey W. Honko, Anna N. Schoepp, Randal J. Wauquier, Nadia Gonzalez, Jean-Paul Pitt, M. Louise Mucker, Eric M. Johnson, Joshua C. O'Hearn, Aileen Bangura, James Coomber, Moinya Minogue, Timothy D. TI Circulating microRNA profiles of Ebola virus infection SO SCIENTIFIC REPORTS LA English DT Article ID ZAIRE EBOLAVIRUS; SIERRA-LEONE; DISEASE; CLASSIFICATION; EXPRESSION; SUPPORT; CANCER; TIME; GLYCOPROTEIN; TRANSMISSION AB Early detection of Ebola virus (EBOV) infection is essential to halting transmission and adjudicating appropriate treatment. However, current methods rely on viral identification, and this approach can misdiagnose presymptomatic and asymptomatic individuals. In contrast, disease-driven alterations in the host transcriptome can be exploited for pathogen-specific diagnostic biomarkers. Here, we present for the first time EBOV-induced changes in circulating miRNA populations of nonhuman primates (NHPs) and humans. We retrospectively profiled longitudinally-collected plasma samples from rhesus macaques challenged via intramuscular and aerosol routes and found 36 miRNAs differentially present in both groups. Comparison of miRNA abundances to viral loads uncovered 15 highly correlated miRNAs common to EBOV-infected NHPs and humans. As proof of principle, we developed an eight-miRNA classifier that correctly categorized infection status in 64/74 (86%) human and NHP samples. The classifier identified acute infections in 27/29 (93.1%) samples and in 6/12 (50%) presymptomatic NHPs. These findings showed applicability of NHP-derived miRNAs to a human cohort, and with additional research the resulting classifiers could impact the current capability to diagnose presymptomatic and asymptomatic EBOV infections. C1 [Duy, Janice; Koehler, Jeffrey W.; Schoepp, Randal J.; O'Hearn, Aileen; Minogue, Timothy D.] US Army, Med Res Inst Infect Dis, Diagnost Syst Div, Frederick, MD USA. [Honko, Anna N.; Pitt, M. Louise; Mucker, Eric M.; Johnson, Joshua C.] US Army, Med Res Inst Infect Dis, Div Virol, Frederick, MD 21701 USA. [Wauquier, Nadia; Bangura, James; Coomber, Moinya] Metabiota, Kenema, Sierra Leone. [Gonzalez, Jean-Paul] Metabiota, Washington, DC USA. [Honko, Anna N.; Johnson, Joshua C.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. RP Minogue, TD (reprint author), US Army, Med Res Inst Infect Dis, Diagnost Syst Div, Frederick, MD USA. EM timothy.d.minogue.civ@mail.mil OI Honko, Anna/0000-0001-9165-148X; Koehler, Jeffrey/0000-0003-3225-6599 FU Defense Threat Reduction Agency award [CB3630] FX The authors would like to thank the members of the Virology Division, Pathology Division and the Center for Aerobiological Sciences at USAMRIID for study support. Specifically, we would like to thank the following for their assistance: Heather Esham, Joshua Shamblin, Ginger Donnelly, Nancy Twenhafel, Dave Dyer and Steve Orr. We would also like to thank Dr. Christopher Stefan for his assistance. Funding for this work was provided through Defense Threat Reduction Agency award #CB3630 ( awarded to Timothy D. Minogue and Jeffrey W. Koehler). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 69 TC 2 Z9 2 U1 0 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 APR 21 PY 2016 VL 6 AR 24496 DI 10.1038/srep24496 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ8SR UT WOS:000374483800001 PM 27098369 ER PT J AU Fauci, AS AF Fauci, Anthony S. TI A Dual Research Path SO CELL LA English DT Editorial Material C1 [Fauci, Anthony S.] NIAID, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD APR 21 PY 2016 VL 165 IS 3 BP 510 EP 510 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DK0XW UT WOS:000374636800003 ER PT J AU Swinstead, EE Miranda, TB Paakinaho, V Baek, S Goldstein, I Hawkins, M Karpova, TS Ball, D Mazza, D Lavis, LD Grimm, JB Morisaki, T Grontved, L Presman, DM Hager, GL AF Swinstead, Erin E. Miranda, Tina B. Paakinaho, Ville Baek, Songjoon Goldstein, Ido Hawkins, Mary Karpova, Tatiana S. Ball, David Mazza, Davide Lavis, Luke D. Grimm, Jonathan B. Morisaki, Tatsuya Grontved, Lars Presman, Diego M. Hager, Gordon L. TI Steroid Receptors Reprogram FoxA1 Occupancy through Dynamic Chromatin Transitions SO CELL LA English DT Article ID TRANSCRIPTION FACTOR; GLUCOCORTICOID-RECEPTOR; BREAST-CANCER; IN-VIVO; BINDING; ESTROGEN; REVEALS; CELLS; ACCESSIBILITY; NUCLEOSOME AB The estrogen receptor (ER), glucocorticoid receptor (GR), and forkhead box protein 1 (FoxA1) are significant factors in breast cancer progression. FoxA1 has been implicated in establishing ER-binding patterns though its unique ability to serve as a pioneer factor. However, the molecular interplay between ER, GR, and FoxA1 requires further investigation. Here we show that ER and GR both have the ability to alter the genomic distribution of the FoxA1 pioneer factor. Single-molecule tracking experiments in live cells reveal a highly dynamic interaction of FoxA1 with chromatin in vivo. Furthermore, the FoxA1 factor is not associated with detectable footprints at its binding sites throughout the genome. These findings support a model wherein interactions between transcription factors and pioneer factors are highly dynamic. Moreover, at a subset of genomic sites, the role of pioneer can be reversed, with the steroid receptors serving to enhance binding of FoxA1. C1 [Swinstead, Erin E.; Miranda, Tina B.; Paakinaho, Ville; Baek, Songjoon; Goldstein, Ido; Hawkins, Mary; Karpova, Tatiana S.; Ball, David; Morisaki, Tatsuya; Grontved, Lars; Presman, Diego M.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,41 Lib Dr, Bethesda, MD 20892 USA. [Mazza, Davide] Osped San Raffaele, Ist Sci, Ctr Imaging Sperimentale, I-20132 Milan, Italy. [Mazza, Davide] Univ Vita Salute San Raffaele, I-20132 Milan, Italy. [Lavis, Luke D.; Grimm, Jonathan B.] Howard Hughes Med Inst, Janelia Res Campus,19700 Helix Dr, Ashburn, VA 20147 USA. [Morisaki, Tatsuya] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Grontved, Lars] Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,41 Lib Dr, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov RI Mazza, Davide/R-5340-2016; OI Mazza, Davide/0000-0003-2776-4142; Lavis, Luke/0000-0002-0789-6343; Goldstein, Ido/0000-0003-0139-1499; Presman, Diego/0000-0003-4515-8058; Grontved, Lars/0000-0002-6735-8483 FU NIH, NCI, Center for Cancer Research; Howard Hughes Medical Institute; Australian Postgraduate Award; National Institute of General Medical Sciences Pharmacological Research and Training Fellowship; Sigrid Juselius Foundation; Marie Curie International Incoming Fellowship [GA: 27432]; Japan Society for the Promotion of Science; Danish Research Council; SDU2020 FX The authors thank the National Cancer Institute Advanced Technology Program Sequencing Facility for sequencing services. The research was supported, in part, by the Intramural Research Program of the NIH, NCI, Center for Cancer Research and the Howard Hughes Medical Institute. E.E.S. was supported, in part, by an Australian Postgraduate Award. T.B.M. was supported, in part, by a National Institute of General Medical Sciences Pharmacological Research and Training Fellowship. V.P. was supported, in part, by the Sigrid Juselius Foundation. D.M. was supported, in part, by a Marie Curie International Incoming Fellowship (GA: 27432). T.M. was supported, in part, by the Japan Society for the Promotion of Science. L.G. was supported by the Danish Research Council and SDU2020. The authors declare the following competing financial interests: J.B.G. and L.D.L. have filed patent applications on the Janelia Fluor dyes, such as JF549, whose value may be affected by this publication. NR 47 TC 15 Z9 15 U1 8 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD APR 21 PY 2016 VL 165 IS 3 BP 593 EP 605 DI 10.1016/j.cell.2016.02.067 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DK0XW UT WOS:000374636800018 PM 27062924 ER PT J AU Velazquez, EJ Lee, KL Jones, RH Al-Khalidi, HR Hill, JA Panza, JA Michler, RE Bonow, RO Doenst, T Petrie, MC Oh, JK She, LL Moore, VL Desvigne-Nickens, P Sopko, G Rouleau, JL AF Velazquez, Eric J. Lee, Kerry L. Jones, Robert H. Al-Khalidi, Hussein R. Hill, James A. Panza, Julio A. Michler, Robert E. Bonow, Robert O. Doenst, Torsten Petrie, Mark C. Oh, Jae K. She, Lilin Moore, Vanessa L. Desvigne-Nickens, Patrice Sopko, George Rouleau, Jean L. CA STICHES Investigators TI Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; LOW EJECTION FRACTION; FAILURE STICH TRIAL; HEART-FAILURE; RANDOMIZED-TRIAL; FOLLOW-UP; SURGICAL-TREATMENT; GRAFT-SURGERY; SURVIVAL-DATA; DISEASE AB BACKGROUND The survival benefit of a strategy of coronary-artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear. METHODS From July 2002 to May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to undergo CABG plus medical therapy (CABG group, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome was death from any cause. Major secondary outcomes included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes. The median duration of follow-up, including the current extended-follow-up study, was 9.8 years. RESULTS A primary outcome event occurred in 359 patients (58.9%) in the CABG group and in 398 patients (66.1%) in the medical-therapy group (hazard ratio with CABG vs. medical therapy, 0.84; 95% confidence interval [CI], 0.73 to 0.97; P = 0.02 by log-rank test). A total of 247 patients (40.5%) in the CABG group and 297 patients (49.3%) in the medical-therapy group died from cardiovascular causes (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P = 0.006 by log-rank test). Death from any cause or hospitalization for cardiovascular causes occurred in 467 patients (76.6%) in the CABG group and in 524 patients (87.0%) in the medical-therapy group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P<0.001 by log-rank test). CONCLUSIONS In a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone. C1 [Velazquez, Eric J.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Lee, Kerry L.; Al-Khalidi, Hussein R.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Jones, Robert H.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [She, Lilin; Moore, Vanessa L.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Hill, James A.] Univ Florida, Gainesville, FL USA. [Panza, Julio A.] Westchester Med Ctr, Valhalla, NY USA. [Panza, Julio A.] New York Med Coll, Valhalla, NY 10595 USA. [Michler, Robert E.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Cardiothorac & Vasc Surg, New York, NY USA. [Bonow, Robert O.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Doenst, Torsten] Univ Jena, Univ Hosp Jena, Dept Cardiothorac Surg, Jena, Germany. [Petrie, Mark C.] Univ Glasgow, Glasgow, Lanark, Scotland. [Petrie, Mark C.] Golden Jubilee Natl Hosp, Glasgow, Lanark, Scotland. [Oh, Jae K.] Mayo Clin, Rochester, MN USA. [Desvigne-Nickens, Patrice; Sopko, George] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Rouleau, Jean L.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. RP Velazquez, EJ (reprint author), Duke Clin Res Inst, Rm 0311 Terrace Level,2400 Pratt St, Durham, NC 27705 USA. EM eric.velazquez@duke.edu RI Nicolau, Jose/E-1487-2012 FU National Institutes of Health FX Funded by the National Institutes of Health; STICH [and STICHES] ClinicalTrials.gov number, NCT00023595. NR 28 TC 41 Z9 41 U1 12 U2 16 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 21 PY 2016 VL 374 IS 16 BP 1511 EP 1520 DI 10.1056/NEJMoa1602001 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DJ7IA UT WOS:000374383900004 PM 27040723 ER PT J AU Rohleder, F Huang, J Xue, YT Kuper, J Round, A Seidman, M Wang, WD Kisker, C AF Rohleder, Florian Huang, Jing Xue, Yutong Kuper, Jochen Round, Adam Seidman, Michael Wang, Weidong Kisker, Caroline TI FANCM interacts with PCNA to promote replication traverse of DNA interstrand crosslinks SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MAINTAIN GENOME STABILITY; ARCHAEAL HEF PROTEIN; CELL NUCLEAR ANTIGEN; ANEMIA CORE COMPLEX; HOMOLOGOUS RECOMBINATION; FLAP ENDONUCLEASE-1; PYROCOCCUS-FURIOSUS; STRUCTURAL BASIS; REPAIR NETWORK; PATHWAY AB FANCM is a highly conserved DNA remodeling enzyme that promotes the activation of the Fanconi anemia DNA repair pathway and facilitates replication traverse of DNA interstrand crosslinks. However, how FANCM interacts with the replication machinery to promote traverse remains unclear. Here, we show that FANCM and its archaeal homolog Hef from Thermoplasma acidophilum interact with proliferating cell nuclear antigen (PCNA), an essential co-factor for DNA polymerases in both replication and repair. The interaction is mediated through a conserved PIP-box; and in human FANCM, it is strongly stimulated by replication stress. A FANCM variant carrying a mutation in the PIP-box is defective in promoting replication traverse of interstrand crosslinks and is also inefficient in promoting FANCD2 monoubiquitination, a key step of the Fanconi anemia pathway. Our data reveal a conserved interaction mode between FANCM and PCNA during replication stress, and suggest that this interaction is essential for FANCM to aid replication machines to traverse DNA interstrand crosslinks prior to post-replication repair. C1 [Rohleder, Florian; Kuper, Jochen; Kisker, Caroline] Univ Wurzburg, Inst Biol Struct, Rudolf Virchow Ctr Expt Biomed, D-97080 Wurzburg, Germany. [Huang, Jing; Seidman, Michael] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Xue, Yutong; Wang, Weidong] NIA, Lab Genet, NIH, Baltimore, MD 21224 USA. [Round, Adam] European Mol Biol Lab, Grenoble Outstn, 71 Ave Martyrs, F-38042 Grenoble, France. [Round, Adam] Univ Grenoble Alpes, CNRS, EMBL, Unit Virus Host Cell Interact, 71 Ave Martyrs, F-38042 Grenoble, France. [Round, Adam] Keele Univ, Fac Nat Sci, Keele ST5 5BG, Staffs, England. RP Kisker, C (reprint author), Univ Wurzburg, Inst Biol Struct, Rudolf Virchow Ctr Expt Biomed, D-97080 Wurzburg, Germany.; Seidman, M (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA.; Wang, WD (reprint author), NIA, Lab Genet, NIH, Baltimore, MD 21224 USA. EM seidmanm@grc.nia.nih.gov; wangw@grc.nia.nih.gov; caroline.kisker@virchow.uni-wuerzburg.de FU Deutsche Forschungsgemeinschaft (DFG) [Forschungszentrum FZ-82]; Intramural Research Program of the National Institute on Aging [AG000688-07]; National Institute of Health (NIH) FX Deutsche Forschungsgemeinschaft (DFG) [Forschungszentrum FZ-82 to C.K.]; Intramural Research Program of the National Institute on Aging [AG000688-07 in part]; National Institute of Health (NIH). Funding for open access charge: Deutsche Forschungsgemeinschaft (DFG) [Forschungszentrum FZ-82 to C.K.]; Intramural Research Program of the National Institute on Aging [AG000688-07 in part]; National Institute of Health (NIH). NR 66 TC 2 Z9 2 U1 4 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 20 PY 2016 VL 44 IS 7 BP 3219 EP 3232 DI 10.1093/nar/gkw037 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL7DM UT WOS:000375800200030 PM 26825464 ER PT J AU Govindaraju, A Cortez, JD Reveal, B Christensen, SM AF Govindaraju, Aruna Cortez, Jeremy D. Reveal, Brad Christensen, Shawn M. TI Endonuclease domain of non-LTR retrotransposons: loss-of-function mutants and modeling of the R2Bm endonuclease SO NUCLEIC ACIDS RESEARCH LA English DT Article ID II RESTRICTION ENDONUCLEASES; PRIMED-REVERSE-TRANSCRIPTION; HOLLIDAY JUNCTION RESOLVASE; BOMBYX-MORI; RNA GENES; EVOLUTIONARY RELATIONSHIP; DROSOPHILA-MELANOGASTER; ECORV ENDONUCLEASE; CRYSTAL-STRUCTURE; DNA RECOGNITION AB Non-LTR retrotransposons are an important class of mobile elements that insert into host DNA by target-primed reverse transcription (TPRT). Non-LTR retrotransposons must bind to theirm RNA, recognize and cleave their target DNA, and perform TPRT at the site of DNA cleavage. As DNA binding and cleavage are such central parts of the integration reaction, a better understanding of the endonuclease encoded by non-LTR retrotransposons is needed. This paper explores the R2 endonuclease domain from Bombyx mori using in vitro studies and in silico modeling. Mutations in conserved sequences located across the putative PD-(D/E)XK endonuclease domain reduced DNA cleavage, DNA binding and TPRT. A mutation at the beginning of the first alpha-helix of the modeled endonuclease obliterated DNA cleavage and greatly reduced DNA binding. It also reduced TPRT when tested on pre-cleaved DNA substrates. The catalytic K was located to a non-canonical position within the second alpha-helix. Amutation located after the fourth beta-strand reduced DNA binding and cleavage. The motifs that showed impaired activity form an extensive basic region. The R2 biochemical and structural data are compared and contrasted with that of two other well characterized PD-(D/E) XK endonucleases, restriction endonucleases and archaeal Holliday junction resolvases. C1 [Govindaraju, Aruna; Cortez, Jeremy D.; Reveal, Brad; Christensen, Shawn M.] Univ Texas Arlington, Dept Biol, Arlington, TX 76019 USA. [Reveal, Brad] NICHD, NIH, Bethesda, MD 20814 USA. RP Christensen, SM (reprint author), Univ Texas Arlington, Dept Biol, Arlington, TX 76019 USA. EM shawnc@uta.edu FU National Science Foundation [0950983] FX National Science Foundation [0950983]. Funding for open access charge: National Science Foundation [0950983]. NR 55 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 20 PY 2016 VL 44 IS 7 BP 3276 EP 3287 DI 10.1093/nar/gkw134 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL7DM UT WOS:000375800200034 PM 26961309 ER PT J AU Tsetsarkin, KA Liu, GP Shen, K Pletnev, AG AF Tsetsarkin, Konstantin A. Liu, Guangping Shen, Kui Pletnev, Alexander G. TI Kissing-loop interaction between 5 ' and 3 ' ends of tick-borne Langat virus genome 'bridges the gap' between mosquito- and tick-borne flaviviruses in mechanisms of viral RNA cyclization: applications for virus attenuation and vaccine development SO NUCLEIC ACIDS RESEARCH LA English DT Article ID WEST-NILE-VIRUS; CENTRAL-NERVOUS-SYSTEM; YELLOW-FEVER-VIRUS; ENCEPHALITIS-VIRUS; DENGUE VIRUS; FUNCTIONAL-ANALYSIS; NONCODING REGION; NEURONAL DIFFERENTIATION; UNTRANSLATED REGION; RHESUS-MONKEYS AB Insertion of microRNA target sequences into the flavivirus genome results in selective tissue-specific attenuation and host-range restriction of live attenuated vaccine viruses. However, previous strategies for miRNA-targeting did not incorporate a mechanism to prevent target elimination under miRNA-mediated selective pressure, restricting their use in vaccine development. To overcome this limitation, we developed a new approach for miRNA-targeting of tick-borne flavivirus (Langat virus, LGTV) in the duplicated capsid gene region (DCGR). Genetic stability of viruses with DCGR was ensured by the presence of multiple cis-acting elements within the N-terminal capsid coding region, including the stem-loop structure (5' SL6) at the 3' end of the promoter. We found that the 5'SL6 functions as a structural scaffold for the conserved hexanucleotide motif at its tip and engages in a complementary interaction with the region present in the 3' NCR to enhance viral RNA replication. The resulting kissing-loop interaction, common in tick-borne flaviviruses, supports a single pair of cyclization elements (CYC) and functions as a homolog of the second pair of CYC that is present in the majority of mosquito-borne flaviviruses. Placing miRNA targets into the DCGR results in superior attenuation of LGTV in the CNS and does not interfere with development of protective immunity in immunized mice. C1 [Tsetsarkin, Konstantin A.; Liu, Guangping; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Shen, Kui] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM apletnev@niaid.nih.gov FU Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institutes of Health FX Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institutes of Health. Funding for open access charge: Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institutes of Health. NR 64 TC 1 Z9 1 U1 5 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 20 PY 2016 VL 44 IS 7 BP 3330 EP 3350 DI 10.1093/nar/gkw061 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL7DM UT WOS:000375800200038 PM 26850640 ER PT J AU Ognjenovic, J Wu, J Matthies, D Baxa, U Subramaniam, S Ling, JQ Simonovic, M AF Ognjenovic, Jana Wu, Jiang Matthies, Doreen Baxa, Ulrich Subramaniam, Sriram Ling, Jiqiang Simonovic, Miljan TI The crystal structure of human GlnRS provides basis for the development of neurological disorders SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSFER-RNA-SYNTHETASE; SPINAL-CORD INVOLVEMENT; MARIE-TOOTH-DISEASE; PONTOCEREBELLAR HYPOPLASIA; BRAIN-STEM; PERRAULT SYNDROME; HEARING-LOSS; MUTATIONS; GENE; EVOLUTION AB Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggest that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. This report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. C1 [Ognjenovic, Jana; Simonovic, Miljan] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Wu, Jiang; Ling, Jiqiang] Univ Texas Hlth Sci Ctr Houston, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. [Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram] NCI, Lab Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Simonovic, M (reprint author), Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA.; Ling, JQ (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. EM Jiqiang.ling@uth.tmc.edu; msimon5@uic.edu OI Simonovic, Miljan/0000-0002-1576-2222; Ling, Jiqiang/0000-0003-4466-8304 FU U.S. DOE [DE-AC02-06CH11357]; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor [085P1000817]; NCI [ACB-12002]; NIGMS [AGM-12006]; National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) [R01 GM115431]; startup fund from The University of Texas, Health Science Center at Houston; NIGMS; NIH FX Advanced Photon Source was supported by the U.S. DOE [DE-AC02-06CH11357]. The LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor [085P1000817]. The GM/CA@APS sector has been funded from the NCI [ACB-12002] and NIGMS [AGM-12006]. Kinetic analyses were supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) [R01 GM115431 to J.L.] and a startup fund from The University of Texas, Health Science Center at Houston [to J.L.]. The structure determination was supported by the grant from NIGMS [to M.S.]. Funding for open access charge: NIH. NR 56 TC 1 Z9 1 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 20 PY 2016 VL 44 IS 7 BP 3420 EP 3431 DI 10.1093/nar/gkw082 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL7DM UT WOS:000375800200044 PM 26869582 ER PT J AU Kim, J Sturgill, D Tran, AD Sinclair, DA Oberdoerffer, P AF Kim, Jeongkyu Sturgill, David Tran, Andy D. Sinclair, David A. Oberdoerffer, Philipp TI Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability SO NUCLEIC ACIDS RESEARCH LA English DT Article ID INFLAMMATORY CYTOKINE SECRETION; RADIATION-INDUCED APOPTOSIS; LIFE-SPAN; CELLULAR SENESCENCE; HEMATOPOIETIC STEM; INVERTED REPEATS; GENE-EXPRESSION; I-PPOI; REPAIR; CHROMATIN AB DNA double-strand breaks (DSBs) and their repair can cause extensive epigenetic changes. As a result, DSBs have been proposed to promote transcriptional and, ultimately, physiological dysfunction via both cell-intrinsic and cell-non-autonomous pathways. Studying the consequences of DSBs in higher organisms has, however, been hindered by a scarcity of tools for controlled DSB induction. Here, we describe a mouse model that allows for both tissue-specific and temporally controlled DSB formation at similar to 140 defined genomic loci. Using this model, we show that DSBs promote a DNA damage signaling-dependent decrease in gene expression in primary cells specifically at break-bearing genes, which is reversed upon DSB repair. Importantly, we demonstrate that restoration of gene expression can occur independently of cell cycle progression, underlining its relevance for normal tissue maintenance. Consistent with this, we observe no evidence for persistent transcriptional repression in response to a multi-day course of continuous DSB formation and repair in mouse lymphocytes in vivo. Together, our findings reveal an unexpected capacity of primary cells to maintain transcriptome integrity in response to DSBs, pointing to a limited role for DNA damage as a mediator of cell-autonomous epigenetic dysfunction. C1 [Kim, Jeongkyu; Sturgill, David; Tran, Andy D.; Oberdoerffer, Philipp] NCI, Lab Receptor Biol & Gene Express, 41 Lib Dr, Bethesda, MD 20892 USA. [Sinclair, David A.] Harvard Univ, Sch Med, Dept Genet, Paul F Glenn Labs Biol Mech Aging, 77 Ave Louis Pasteur, Boston, MA 02115 USA. RP Oberdoerffer, P (reprint author), NCI, Lab Receptor Biol & Gene Express, 41 Lib Dr, Bethesda, MD 20892 USA. EM Philipp.Oberdoerffer@nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); NCI; Center for Cancer Research FX Intramural Research Program of the National Institutes of Health (NIH); NCI; Center for Cancer Research. Funding for open access charge: Intramural Research Program of the National Institutes of Health (NIH); NCI; Center for Cancer Research. NR 60 TC 2 Z9 2 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 20 PY 2016 VL 44 IS 7 AR e64 DI 10.1093/nar/gkv1482 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DL7DM UT WOS:000375800200004 PM 26687720 ER PT J AU Singh, NS Rutkowska, E Plazinska, A Khadeer, M Moaddel, R Jozwiak, K Bernier, M Wainer, IW AF Singh, Nagendra S. Rutkowska, Ewelina Plazinska, Anita Khadeer, Mohammed Moaddel, Ruin Jozwiak, Krzysztof Bernier, Michel Wainer, Irving W. TI Ketamine Metabolites Enantioselectively Decrease Intracellular D-Serine Concentrations in PC-12 Cells SO PLOS ONE LA English DT Article ID MAMMALIAN TARGET; NMDA RECEPTORS; CO-AGONISTS; RACEMASE; RELEASE; NORKETAMINE; ANTAGONISTS; INHIBITION; GABAPENTIN; ACTIVATION AB D-Serine is an endogenous NMDA receptor co-agonist that activates synaptic NMDA receptors modulating neuronal networks in the cerebral cortex and plays a key role in long-term potentiation of synaptic transmission. D-serine is associated with NMDA receptor neurotoxicity and neurodegeneration and elevated D-serine concentrations have been associated with Alzheimer's and Parkinsons' diseases and amyotrophic lateral sclerosis. Previous studies have demonstrated that the ketamine metabolites (rac)-dehydronorketamine and (2S, 6S)-hydroxynorketamine decrease intracellular D-serine concentrations in a concentration dependent manner in PC-12 cells. In the current study, PC-12 cells were incubated with a series of ketamine metabolites and the IC50 values associated with attenuated intracellular D-serine concentrations were determined. The results demonstrate that structural and stereochemical features of the studied compounds contribute to the magnitude of the inhibitory effect with (2S, 6S)-hydroxynorketamine and (2R, 6R)-hydroxynorketamine displaying the most potent inhibition with IC50 values of 0.18 +/- 0.04 nM and 0.68 +/- 0.09 nM. The data was utilized to construct a preliminary 3D-QSAR/pharmacophore model for use in the design of new and more efficient modulators of D-serine. C1 [Singh, Nagendra S.; Khadeer, Mohammed; Moaddel, Ruin; Wainer, Irving W.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Rutkowska, Ewelina; Plazinska, Anita; Jozwiak, Krzysztof] Med Univ Lublin, Dept Biopharm, Lublin, Poland. [Bernier, Michel] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. EM iwwainer@gmail.com RI Singh, Nagendra/K-8966-2015; OI Plazinska, Anita/0000-0002-3698-2574 FU Intramural Research Programs of the National Institute on Aging; Foundation for Polish Science [2009 - 4/5] FX The work was funded by the Intramural Research Programs of the National Institute on Aging and by The Foundation for Polish Science (TEAM Programme 2009 - 4/5). NR 32 TC 0 Z9 0 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 20 PY 2016 VL 11 IS 4 AR e0149499 DI 10.1371/journal.pone.0149499 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ9OU UT WOS:000374543600001 PM 27096720 ER PT J AU Xu, JH Wu, XS Sheng, JS Zhang, Z Yue, HY Sun, LX Sgobio, C Lin, X Peng, SY Jin, YH Gan, L Cai, HB Wu, LG AF Xu, Jianhua Wu, Xin-Sheng Sheng, Jiansong Zhang, Zhen Yue, Hai-Yuan Sun, Lixin Sgobio, Carmelo Lin, Xian Peng, Shiyong Jin, Yinghui Gan, Lin Cai, Huaibin Wu, Ling-Gang TI alpha-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alpha-synuclein; endocytosis; nerve terminal; Parkinson's disease; transmitter; vesicle ID SYNAPTIC-VESICLE ENDOCYTOSIS; PARKINSONS-DISEASE; MEMBRANE CURVATURE; SLOW ENDOCYTOSIS; MOTOR-NEURONS; CSP-ALPHA; CALCIUM; EXPRESSION; NEURODEGENERATION; SYNAPTOBREVIN AB alpha-Synuclein (alpha-syn) missense and multiplication mutations have been suggested to cause neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies. Before causing the progressive neuronal loss, alpha-syn mutations impair exocytosis, which may contribute to eventual neurodegeneration. To understand how alpha-syn mutations impair exocytosis, we developed a mouse model that selectively expressed PD-related human alpha-syn A53T (h-alpha-syn(A53T)) mutation at the calyx of Held terminals, where release mechanisms can be dissected with a patch-clamping technique. With capacitance measurement of endocytosis, we reported that h-alpha-syn(A53T), either expressed transgenically or dialyzed in the short term in calyces, inhibited two of the most common forms of endocytosis, the slow and rapid vesicle endocytosis at mammalian central synapses. The expression of h-alpha-syn(A53T) in calyces also inhibited vesicle replenishment to the readily releasable pool. These findings may help to understand how alpha-syn mutations impair neurotransmission before neurodegeneration. C1 [Xu, Jianhua; Yue, Hai-Yuan] Med Coll Georgia, Dept Neurosci & Regenerat Med, Augusta, GA 30912 USA. [Wu, Xin-Sheng; Sheng, Jiansong; Zhang, Zhen; Peng, Shiyong; Jin, Yinghui; Wu, Ling-Gang] NINDS, NIH, Bethesda, MD 20892 USA. [Sun, Lixin; Sgobio, Carmelo; Lin, Xian; Cai, Huaibin] NIA, NIH, Bethesda, MD 20892 USA. [Gan, Lin] Univ Rochester, Sch Med & Dent, Flaum Eye Inst, Rochester, NY 14642 USA. RP Xu, JH (reprint author), Med Coll Georgia, Dept Neurosci & Regenerat Med, Augusta, GA 30912 USA.; Cai, HB (reprint author), NIA, NIH, Bethesda, MD 20892 USA. EM jxu1@gru.edu; caih@mail.nih.gov FU National Institute of Neurological Disorders; National Institute on Aging [AG-000929, AG-000928]; National Institutes of Health [1R01-NS-082759] FX This work was supported by the intramural research programs of the National Institute of Neurological Disorders and the National Institute on Aging ( Grants AG-000929 and AG-000928, to H. C.), and the extramural program of National Institutes of Health ( Grant 1R01-NS-082759). NR 44 TC 0 Z9 0 U1 1 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 20 PY 2016 VL 36 IS 16 BP 4408 EP 4414 DI 10.1523/JNEUROSCI.3627-15.2016 PG 7 WC Neurosciences SC Neurosciences & Neurology GA DK7UA UT WOS:000375130000002 PM 27098685 ER PT J AU Miller, CT Freiwald, WA Leopold, DA Mitchell, JF Silva, AC Wang, XQ AF Miller, Cory T. Freiwald, Winrich A. Leopold, David A. Mitchell, Jude F. Silva, Afonso C. Wang, Xiaoqin TI Marmosets: A Neuroscientific Model of Human Social Behavior SO NEURON LA English DT Review ID PRIMATE AUDITORY-CORTEX; VENTROLATERAL PREFRONTAL CORTEX; FACIAL EXPRESSION RECOGNITION; AUTISM SPECTRUM DISORDER; FACE-PROCESSING SYSTEM; SCENT-MARKING BEHAVIOR; CALLITHRIX-JACCHUS; COMMON MARMOSETS; RHESUS MACAQUES; MONKEY AMYGDALA AB The common marmoset (Callithrix jacchus) has garnered interest recently as a powerful model for the future of neuroscience research. Much of this excitement has centered on the species' reproductive biology and compatibility with gene editing techniques, which together have provided a path for transgenic marmosets to contribute to the study of disease as well as basic brain mechanisms. In step with technical advances is the need to establish experimental paradigms that optimally tap into the marmosets' behavioral and cognitive capacities. While conditioned task performance of a marmoset can compare unfavorably with rhesus monkey performance on conventional testing paradigms, marmosets' social behavior and cognition are more similar to that of humans. For example, marmosets are among only a handful of primates that, like humans, routinely pair bond and care cooperatively for their young. They are also notably pro-social and exhibit social cognitive abilities, such as imitation, that are rare outside of the Apes. In this Primer, we describe key facets of marmoset natural social behavior and demonstrate that emerging behavioral paradigms are well suited to isolate components of marmoset cognition that are highly relevant to humans. These approaches generally embrace natural behavior, which has been rare in conventional primate testing, and thus allow for a new consideration of neural mechanisms underlying primate social cognition and signaling. We anticipate that through parallel technical and paradigmatic advances, marmosets will become an essential model of human social behavior, including its dysfunction in neuropsychiatric disorders. C1 [Miller, Cory T.] Univ Calif San Diego, Cort Syst & Behav Lab, 9500 Gilman Dr, La Jolla, CA 92093 USA. [Freiwald, Winrich A.] Rockefeller Univ, Lab Neural Syst, 1230 York Ave, New York, NY 10065 USA. [Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. [Mitchell, Jude F.] Univ Rochester, Dept Brain & Cognit Sci, 358 Meliora Hall, Rochester, NY 14627 USA. [Silva, Afonso C.] NINDS, Sect Cerebral Microcirculat, Lab Funct & Mol Imaging, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. [Wang, Xiaoqin] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Lab Auditory Neurophysiol, 720 Rutland Ave, Baltimore, MD 21205 USA. RP Miller, CT (reprint author), Univ Calif San Diego, Cort Syst & Behav Lab, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM corymiller@ucsd.edu OI Leopold, David/0000-0002-1345-6360 FU NIH [R01 DC012087, R21 MH104756, U01 NS094330, R01 DC03180, R01 DC005808]; N.S.F. [IDBR 1254309]; Simons Collaboration on the Global Brain; New York Stem Cell Foundation; Intramural Research Program of the NIMH [ZIA MH002898, ZIA MH002838]; NSF [INSPIRE Track 2 DBI-1343174]; Intramural Research Program of the NIH, NINDS FX We thank Ed Connor, Nicho Hatsopoulos, Eric Knudsen, and Jitendra Sharma for helpful comments on previous versions of this manuscript. C.T.M. was supported by grants from the NIH (R01 DC012087 and R21 MH104756) and N.S.F. (IDBR 1254309). V.A.F. was supported by The Simons Collaboration on the Global Brain, NSF (INSPIRE Track 2 DBI-1343174), and the New York Stem Cell Foundation. D.A.L. was supported (in part) by the Intramural Research Program of the NIMH under ZIA MH002898 and ZIA MH002838. J.F.M. was supported by grants from the NIH (R21 MH104756, U01 NS094330). A.C.S. was supported by the Intramural Research Program of the NIH, NINDS. X.W. was supported by grants from the NIH (R01 DC03180 and R01 DC005808). NR 241 TC 18 Z9 18 U1 13 U2 37 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD APR 20 PY 2016 VL 90 IS 2 BP 219 EP 233 DI 10.1016/j.neuron.2016.03.018 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DJ8ZV UT WOS:000374504400006 PM 27100195 ER PT J AU De Ravin, SS Wu, XL Moir, S Anaya-O'Brien, S Kwatemaa, N Littel, P Theobald, N Choi, U Su, L Marquesen, M Hilligoss, D Lee, J Buckner, CM Zarember, KA O'Connor, G McVicar, D Kuhns, D Throm, RE Zhou, S Notarangelo, LD Hanson, IC Cowan, MJ Kang, E Hadigan, C Meagher, M Gray, JT Sorrentino, BP Malech, HL AF De Ravin, Suk See Wu, Xiaolin Moir, Susan Anaya-O'Brien, Sandra Kwatemaa, Nana Littel, Patricia Theobald, Narda Choi, Uimook Su, Ling Marquesen, Martha Hilligoss, Dianne Lee, Janet Buckner, Clarissa M. Zarember, Kol A. O'Connor, Geraldine McVicar, Daniel Kuhns, Douglas Throm, Robert E. Zhou, Sheng Notarangelo, Luigi D. Hanson, I. Celine Cowan, Mort J. Kang, Elizabeth Hadigan, Coleen Meagher, Michael Gray, John T. Sorrentino, Brian P. Malech, Harry L. TI Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; VECTOR INTEGRATION; SCID-X1; TRANSPLANTATION; DEFICIENCY; ACTIVATION; EXPRESSION; TARGETS; LISTS AB X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations in IL2RG encoding the common chain (gamma c) of several interleukin receptors. Gammaretroviral (gamma RV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector gamma c transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1. C1 [De Ravin, Suk See; Anaya-O'Brien, Sandra; Kwatemaa, Nana; Littel, Patricia; Theobald, Narda; Choi, Uimook; Marquesen, Martha; Hilligoss, Dianne; Lee, Janet; Zarember, Kol A.; Kang, Elizabeth; Malech, Harry L.] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wu, Xiaolin; Su, Ling; Kuhns, Douglas] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc Res Technol Program, Frederick, MD 21702 USA. [Moir, Susan; Buckner, Clarissa M.; Hadigan, Coleen] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [O'Connor, Geraldine; McVicar, Daniel] Natl Canc Inst Frederick, Canc & Inflammat Program, Frederick, MD 21702 USA. [Throm, Robert E.; Zhou, Sheng; Meagher, Michael; Sorrentino, Brian P.] St Jude Childrens Res Hosp, Dept Hematol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Hanson, I. Celine] Texas Childrens Hosp, Houston, TX 77030 USA. [Cowan, Mort J.] Benioff Childrens Hosp, Dept Pediat, San Francisco, CA USA. [Cowan, Mort J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gray, John T.] Audentes Therapeut, San Francisco, CA 94101 USA. RP De Ravin, SS; Malech, HL (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sderavin@niaid.nih.gov; hmalech@niaid.nih.gov FU Intramural Research Program of NIAID, NIH [Z01-A1-00644, Z01-A1-00988]; National Heart, Lung, and Blood Institute [P01HL 53749]; NIH-NIAID [U54 AI 082973]; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; ASSISI Foundation of Memphis FX This research was supported by the Intramural Research Program of NIAID, NIH (intramural project numbers Z01-A1-00644 and Z01-A1-00988), and the National Heart, Lung, and Blood Institute (grant P01HL 53749) and NIH-NIAID Grant U54 AI 082973. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E (X.W. and L.S.), and the ASSISI Foundation of Memphis. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Replication-competent viruses assay was performed by the National Gene Vector Biorepository, Indiana University. NR 32 TC 13 Z9 13 U1 10 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD APR 20 PY 2016 VL 8 IS 335 AR 335ra57 DI 10.1126/scitranslmed.aad8856 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DJ7SM UT WOS:000374412300006 PM 27099176 ER PT J AU Perovanovic, J Dell'Orso, S Gnochi, VF Jaiswal, JK Sartorelli, V Vigouroux, C Mamchaoui, K Mouly, V Bonne, G Hoffman, EP AF Perovanovic, Jelena Dell'Orso, Stefania Gnochi, Viola F. Jaiswal, Jyoti K. Sartorelli, Vittorio Vigouroux, Corinne Mamchaoui, Kamel Mouly, Vincent Bonne, Gisele Hoffman, Eric P. TI Laminopathies disrupt epigenomic developmental programs and cell fate SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NUCLEAR LAMINA INTERACTIONS; EMBRYONIC STEM-CELLS; PARTIAL LIPODYSTROPHY; ADIPOCYTE DIFFERENTIATION; MUSCULAR-DYSTROPHIES; MUSCLE REGENERATION; A/C EXPRESSION; MYOD PATHWAYS; HUMAN GENOME; MOUSE AB The nuclear envelope protein lamin A is encoded by the lamin A/C (LMNA) gene, which can contain missense mutations that cause Emery-Dreifuss muscular dystrophy (EDMD) (p.R453W). We fused mutated forms of the lamin A protein to bacterial DNA adenine methyltransferase (Dam) to define euchromatic-heterochromatin (epigenomic) transitions at the nuclear envelope during myogenesis (using DamID-seq). Lamin A missense mutations disrupted appropriate formation of lamin A-associated heterochromatin domains in an allele-specific manner-findings that were confirmed by chromatin immunoprecipitation-DNA sequencing (ChIP-seq) in murine H2K cells and DNA methylation studies in fibroblasts from muscular dystrophy patient who carried a distinct LMNA mutation (p.H222P). Observed perturbations of the epigenomic transitions included exit from pluripotency and cell cycle programs [ euchromatin (open, transcribed) to heterochromatin (closed, silent)], as well as induction of myogenic loci (heterochromatin to euchromatin). In muscle biopsies from patients with either a gain- or change-of-function LMNA gene mutation or a loss-of-function mutation in the emerin gene, both of which cause EDMD, we observed inappropriate loss of heterochromatin formation at the Sox2 pluripotency locus, which was associated with persistent mRNA expression of Sox2. Overexpression of Sox2 inhibited myogenic differentiation in human immortalized myoblasts. Our findings suggest that nuclear envelopathies are disorders of developmental epigenetic programming that result from altered formation of lamina-associated domains. C1 [Perovanovic, Jelena; Gnochi, Viola F.; Jaiswal, Jyoti K.; Hoffman, Eric P.] Childrens Natl Med Ctr, Ctr Genet Med Res, Washington, DC 20010 USA. [Perovanovic, Jelena; Jaiswal, Jyoti K.; Hoffman, Eric P.] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20010 USA. [Dell'Orso, Stefania; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Rockville, MD 20852 USA. [Vigouroux, Corinne] Hop St Antoine, AP HP, Lab Commun Biol & Genet Mol, F-75012 Paris, France. [Vigouroux, Corinne] INSERM, Ctr Rech St Antoine, UMR S938, F-75012 Paris, France. [Vigouroux, Corinne] Univ Paris 06, Sorbonne Univ, UMR S938, F-75005 Paris, France. [Vigouroux, Corinne] ICAN Inst Cardiometab & Nutr, F-75013 Paris, France. [Mamchaoui, Kamel; Mouly, Vincent; Bonne, Gisele] Univ Paris 06, Sorbonne Univ, INSERM UMRS974, Ctr Res Myol,CNRS FRE3617, F-75013 Paris, France. [Hoffman, Eric P.] SUNY Binghamton, Sch Pharm, 4400 Vestal Pkwy East, Binghamton, NY 13902 USA. RP Hoffman, EP (reprint author), Childrens Natl Med Ctr, Ctr Genet Med Res, Washington, DC 20010 USA.; Hoffman, EP (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20010 USA. EM ehoffman@binghamton.edu RI Bonne, Gisele/G-3121-2013; Jaiswal, Jyoti/M-5891-2013 OI Jaiswal, Jyoti/0000-0002-5992-5185 FU U.S. NIH [3R01 NS29525]; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; Association Francaise contre les Myopathies (A.F.M.) FX This work was supported by the U.S. NIH (grant 3R01 NS29525), the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Association Francaise contre les Myopathies (A.F.M.). NR 36 TC 1 Z9 1 U1 2 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD APR 20 PY 2016 VL 8 IS 335 AR 335ra58 DI 10.1126/scitranslmed.aad4991 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DJ7SM UT WOS:000374412300007 PM 27099177 ER PT J AU Lee, SM Backenroth, D Cheung, YKK Hershman, DL Vulih, D Anderson, B Ivy, P Minasian, L AF Lee, Shing M. Backenroth, Daniel Cheung, Ying Kuen Ken Hershman, Dawn L. Vulih, Diana Anderson, Barry Ivy, Percy Minasian, Lori TI Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MOLECULARLY TARGETED AGENTS; PHASE-I TRIAL; OF-THE-LITERATURE; PROTEASOME INHIBITOR; LIMITING TOXICITY; ADVANCED MALIGNANCIES; ANTICANCER DRUGS; ADVANCED CANCER; COMBINATION; CARBOPLATIN AB Purpose The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. Patients and Methods We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. Results A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was >50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. Conclusions When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. (C) 2016 by American Society of Clinical Oncology C1 [Lee, Shing M.; Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L.] Columbia Univ, New York, NY 10032 USA. [Vulih, Diana; Anderson, Barry] Theradex Syst, Princeton, NJ USA. [Ivy, Percy; Minasian, Lori] NCI, Bethesda, MD 20892 USA. RP Lee, SM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, 722 W 168th St,6th Fl, New York, NY 10032 USA. EM sml2114@columbia.edu FU American Cancer Society [MRSG-13-146-01-CPHPS]; National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000040] FX Supported in part by Grant No. MRSG-13-146-01-CPHPS from the American Cancer Society and by Grant No. UL1 TR000040 from the National Center for Advancing Translational Sciences, National Institutes of Health. NR 30 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 20 PY 2016 VL 34 IS 12 BP 1395 EP + DI 10.1200/JCO.2015.66.0662 PG 8 WC Oncology SC Oncology GA DJ6PJ UT WOS:000374335100020 PM 26926682 ER PT J AU Lombardi, F Herrmann, HJ Plenz, D de Arcangelis, L AF Lombardi, F. Herrmann, H. J. Plenz, D. de Arcangelis, L. TI Temporal correlations in neuronal avalanche occurrence SO SCIENTIFIC REPORTS LA English DT Article ID CORTICAL-NEURONS; SPINAL-CORD; STATISTICAL-ANALYSIS; NETWORK DEPRESSION; BRAIN ACTIVITY; VISUAL-CORTEX; IN-VITRO; TIME; DYNAMICS; VARIABILITY AB Ongoing cortical activity consists of sequences of synchronized bursts, named neuronal avalanches, whose size and duration are power law distributed. These features have been observed in a variety of systems and conditions, at all spatial scales, supporting scale invariance, universality and therefore criticality. However, the mechanisms leading to burst triggering, as well as the relationship between bursts and quiescence, are still unclear. The analysis of temporal correlations constitutes a major step towards a deeper understanding of burst dynamics. Here, we investigate the relation between avalanche sizes and quiet times, as well as between sizes of consecutive avalanches recorded in cortex slice cultures. We show that quiet times depend on the size of preceding avalanches and, at the same time, influence the size of the following one. Moreover we evidence that sizes of consecutive avalanches are correlated. In particular, we show that an avalanche tends to be larger or smaller than the following one for short or long time separation, respectively. Our analysis represents the first attempt to provide a quantitative estimate of correlations between activity and quiescence in the framework of neuronal avalanches and will help to enlighten the mechanisms underlying spontaneous activity. C1 [Lombardi, F.; Herrmann, H. J.] ETH, Inst Computat Phys Engn Mat, Zurich, Switzerland. [Herrmann, H. J.] Univ Fed Ceara, Dept Fis, BR-60451970 Fortaleza, Ceara, Brazil. [Plenz, D.] NIH, Sect Crit Brain Dynam, Bldg 10, Bethesda, MD 20892 USA. [de Arcangelis, L.] Univ Naples 2, Dept Ind & Informat Engn, INFN Gr Coll Salerno, Aversa, CE, Italy. RP Lombardi, F (reprint author), ETH, Inst Computat Phys Engn Mat, Zurich, Switzerland. EM lombardif00@gmail.com RI Universidade Federal do Ceara, Physics Department/J-4630-2016; UFC, DF/E-1564-2017 OI Universidade Federal do Ceara, Physics Department/0000-0002-9247-6780; FU SNF [205321-138074]; European Research Council (ERC) Advanced Grant [FP7-319968-FlowCCS]; Intramural Research Program of the National Institute of Mental Health FX We acknowledge financial support from the SNF project 205321-138074 and the European Research Council (ERC) Advanced Grant FP7-319968-FlowCCS. This study was supported by the Intramural Research Program of the National Institute of Mental Health. NR 57 TC 1 Z9 1 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 20 PY 2016 VL 6 AR 24690 DI 10.1038/srep24690 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7FS UT WOS:000374377900001 PM 27094323 ER PT J AU Wang, YF Liu, JY Ying, XH Lin, PC Zhou, BHP AF Wang, Yifan Liu, Jingyi Ying, Xuhua Lin, Pengnian Charles Zhou, Binhua P. TI Twist-mediated Epithelial-mesenchymal Transition Promotes Breast Tumor Cell Invasion via Inhibition of Hippo Pathway SO SCIENTIFIC REPORTS LA English DT Article ID CANCER CELLS; YAP PATHWAY; SNAIL; METASTASIS; RECEPTOR; PAR1; MIGRATION; PHOSPHORYLATION; TUMORIGENESIS; ADHESION AB Twist is a key transcription factor for Epithelial-mesenchymal transition (EMT), which is a cellular dedifferentiation program that promotes invasion and metastasis, confers tumor cells with cancer stem cell (CSC)-like characteristics, and increases therapeutic resistance. However, the mechanisms that facilitate the functions of Twist remain unclear. Here we report that Twist overexpression increased expression of PAR1, an upstream regulator of the Hippo pathway; PAR1 promotes invasion, migration, and CSC-like properties in breast cancer by activating the transcriptional co-activator TAZ. Our study indicates that Hippo pathway inhibition is required for the increased migratory and invasiveness ability of breast cancer cells in Twist-mediated EMT. C1 [Wang, Yifan; Ying, Xuhua] Zhejiang Acad Chinese Med, Canc Inst Integrat Med, Hangzhou 310007, Zhejiang, Peoples R China. [Liu, Jingyi] Chinese Acad Med Sci, State Key Lab Expt Hematol, Inst Hematol & Blood Dis Hosp, Tianjin 300020, Peoples R China. [Liu, Jingyi] Peking Union Med Coll, Tianjin 300020, Peoples R China. [Liu, Jingyi; Lin, Pengnian Charles] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Wang, Yifan; Liu, Jingyi; Zhou, Binhua P.] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA. [Wang, Yifan; Liu, Jingyi; Zhou, Binhua P.] Univ Kentucky, Coll Med, Markey Canc Ctr, Lexington, KY 40506 USA. RP Zhou, BHP (reprint author), Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA.; Zhou, BHP (reprint author), Univ Kentucky, Coll Med, Markey Canc Ctr, Lexington, KY 40506 USA. EM peter.zhou@uky.edu FU NIH [RO1s CA125454, CA188118]; DOD Breakthrough Award [BC140733P1]; Mary Kay Ash Foundation; National Natural Science Foundation of China [81402434, 81402432]; Zhejiang Provincial Natural Science Foundation of China [LQ14H280002] FX We thank Cathy Anthony for critical reading and editing of this manuscript. We also thank Dr. Kunliang Guan for providing CTGF-Luc plasmid for this study. This work was supported in part by grants from NIH (RO1s CA125454 and CA188118), DOD Breakthrough Award (BC140733P1), Mary Kay Ash Foundation (to B.P. Zhou), National Natural Science Foundation of China (No. 81402434 to Y. Wang, and No. 81402432 to J. Liu), and the Zhejiang Provincial Natural Science Foundation of China (No. LQ14H280002) (to Y. Wang). NR 29 TC 4 Z9 5 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 20 PY 2016 VL 6 AR 24606 DI 10.1038/srep24606 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7FK UT WOS:000374377100001 PM 27094683 ER PT J AU Nash, SD Katamba, A Mafigiri, DK Mbulaiteye, SM Sethi, AK AF Nash, Scott D. Katamba, Achilles Mafigiri, David Kaawa Mbulaiteye, Sam M. Sethi, Ajay K. TI Sex-related alcohol expectancies and high-risk sexual behaviour among drinking adults in Kampala, Uganda SO GLOBAL PUBLIC HEALTH LA English DT Article DE Alcohol-related expectancies; high-risk sexual behaviour; HIV; AIDS; Uganda ID TOWN SOUTH-AFRICA; CAPE-TOWN; BINGE DRINKING; HIV-INFECTION; CONDOM USE; WOMEN; CONSUMPTION; MEN; ADOLESCENTS; HIV/AIDS AB Alcohol consumption, a risk factor for HIV transmission in sub-Saharan Africa, is considered high in Uganda. A cross sectional study was conducted to determine whether sex-related expectations about the effects of alcohol explain the association between alcohol use and risky sexual behaviours in a population-based sample of adults in Kampala. Associations between alcohol use (current and higher risk drinking) and high-risk sexual behaviours (multiple regular partners and casual sex) were tested. In age-sex-adjusted models, having multiple regular partners was associated with current drinking (odds ratio [OR] = 2.76, 95% confidence intervals [CIs] = 1.15, 6.63) and higher risk drinking (OR = 3.35, 95% CI = 1.28, 8.71). Associations were similar but not statistically significant for having a causal sex partner. Sex-related alcohol outcome expectancy was associated with both alcohol use and high-risk sexual behaviour and attenuated relationships between multiple regular partners and both current drinking (OR = 1.94, 95% CI = 0.57, 6.73) and higher risk drinking (OR = 2.44, 95% CI = 0.68, 8.80). In this setting sexual behaviours related with alcohol consumption were explained, in part, by sex-related expectations about the effects of alcohol. These expectations could be an important component to target in HIV education campaigns. C1 [Nash, Scott D.] Emory Univ, Carter Ctr, Trachoma Control Program, Atlanta, GA 30322 USA. [Katamba, Achilles] Makerere Univ, Sch Med, Dept Med, Kampala, Uganda. [Mafigiri, David Kaawa] Makerere Univ, Sch Social Sci, Ctr Social Sci Res AIDS, Dept Social Work & Social Adm, Kampala, Uganda. [Mbulaiteye, Sam M.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Sethi, Ajay K.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA. RP Nash, SD (reprint author), Emory Univ, Carter Ctr, Trachoma Control Program, Atlanta, GA 30322 USA.; Sethi, AK (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA. EM scott.nash@emory.edu; aksethi@wisc.edu FU National Institutes of Alcohol Abuse and Alcoholism [AA015488] FX This study was funded by a grant from the National Institutes of Alcohol Abuse and Alcoholism [grant number AA015488]. NR 40 TC 1 Z9 1 U1 0 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1744-1692 EI 1744-1706 J9 GLOB PUBLIC HEALTH JI Glob. Public Health PD APR 20 PY 2016 VL 11 IS 4 BP 449 EP 462 DI 10.1080/17441692.2015.1068824 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG1AC UT WOS:000371796400005 PM 26315308 ER PT J AU Soliman, HH Minton, SE Han, HS Ismail-Khan, R Neuger, A Khambati, F Noyes, D Lush, R Chiappori, AA Roberts, JD Link, C Vahanian, NN Mautino, M Streicher, H Sullivan, DM Antonia, SJ AF Soliman, Hatem H. Minton, Susan E. Han, Hyo Sook Ismail-Khan, Roohi Neuger, Anthony Khambati, Fatema Noyes, David Lush, Richard Chiappori, Alberto A. Roberts, John D. Link, Charles Vahanian, Nicholas N. Mautino, Mario Streicher, Howard Sullivan, Daniel M. Antonia, Scott J. TI A Phase I study of indoximod in patients with advanced malignancies SO ONCOTARGET LA English DT Article DE indoleamine 2,3 dioxygenase; 1-methyl-D-tryptophan; indoximod; immunomodulator ID INDOLEAMINE 2,3-DIOXYGENASE IDO; T-CELL; TUMOR-SUPPRESSOR; DENDRITIC CELLS; TRYPTOPHAN; BIN1; INHIBITION; EXPRESSION; MELANOMA; CANCER AB Purpose: Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates. Experimental Design: Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age >= 18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy <= 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. Results: In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease > 6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (similar to 12 mu M at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels. Conclusions: Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease > 6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed. C1 [Soliman, Hatem H.; Minton, Susan E.; Han, Hyo Sook; Ismail-Khan, Roohi; Neuger, Anthony; Khambati, Fatema; Noyes, David; Lush, Richard; Chiappori, Alberto A.; Sullivan, Daniel M.; Antonia, Scott J.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Roberts, John D.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Link, Charles; Vahanian, Nicholas N.; Mautino, Mario] NewLink Genetics Inc, Ames, IA USA. [Streicher, Howard] NCI, Canc Therapeut Evaluat Program, Bethesda, MD 20892 USA. RP Soliman, HH (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. EM hatem.soliman@moffitt.org FU Massey Cancer Center NIH [P30-CA016059]; [HHSN261201100100C] FX The trial was supported under N01 contract HHSN261201100100C and Massey Cancer Center NIH grant P30-CA016059. NR 28 TC 5 Z9 5 U1 4 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 19 PY 2016 VL 7 IS 16 BP 22928 EP 22938 DI 10.18632/oncotarget.8216 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DO3TY UT WOS:000377705900145 PM 27008709 ER PT J AU Liang, Y Guttman, M Davenport, TM Hu, SL Lee, KK AF Liang, Yu Guttman, Miklos Davenport, Thaddeus M. Hu, Shiu-Lok Lee, Kelly K. TI Probing the Impact of Local Structural Dynamics of Conformational Epitopes on Antibody Recognition SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 ENVELOPE GLYCOPROTEIN; SMALL-ANGLE SCATTERING; HUMAN MONOCLONAL-ANTIBODIES; CD4 BINDING-SITE; NEUTRALIZING HIV-1 ANTIBODIES; EXCHANGE MASS-SPECTRA; TYPE-1 GP120; X-RAY; HYDROGEN/DEUTERIUM EXCHANGE AB Antibody antigen interactions are governed by recognition of specific residues and structural complementarity between the antigen epitope and antibody paratope. While X-ray crystallography has provided detailed insights into static conformations of antibody antigen complexes, factors such as conformational flexibility and dynamics, which are not readily apparent in the structures, can also have an impact on the binding event. Here we investigate the contribution of dynamics in the HIV-1 gp120 glycoprotein to antibody recognition of conserved conformational epitopes, including the CD4- and coreceptor-binding sites, and an inner domain site that is targeted by ADCC-active antibodies. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) was used to measure local structural dynamics across a panel of variable loop truncation mutants of HIV-1 gp120, including full-length gp120, Delta V3, Delta V1/V2, and extended core, which includes Delta V1-/V2 and V3 loop truncations. CD4-bound full-length gp120 was also examined as a reference state. HDX-MS revealed a clear trend toward an increased level of order of the conserved subunit core resulting from loop truncation. Combined with biolayer interferometry and enzyme-linked immunosorbent assay measurements of antibody antigen binding, we demonstrate that an increased level of ordering of the subunit core was associated with better recognition by an array of antibodies targeting complex conformational epitopes. These results, provide detailed insight into the influence of structural dynamics on antibody antigen interactions and suggest the importance of characterizing the structural stability of vaccine candidates to improve antibody recognition of complex epitopes. C1 [Liang, Yu; Guttman, Miklos; Davenport, Thaddeus M.; Lee, Kelly K.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. [Hu, Shiu-Lok] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. [Davenport, Thaddeus M.] NHLBI, Lab Mol & Cellular Imaging, Bethesda, MD 20814 USA. RP Lee, KK (reprint author), Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. EM kklee@uw.edu FU National Institutes of Health (NIH) [R21-AI112389, R01-GM099989]; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) Grant [OPP1033102]; Structural Molecular Biology Program, Department of Energy's Office of Biological and Environmental Research, NIH [P41-GM103393, P41-RR001209] FX The work was supported by National Institutes of Health (NIH) Grants R21-AI112389 and R01-GM099989 and by Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) Grant OPP1033102. Portions of the work were conducted at SSRL and supported by the Structural Molecular Biology Program, Department of Energy's Office of Biological and Environmental Research, NIH Grants P41-GM103393 and P41-RR001209. NR 96 TC 1 Z9 1 U1 3 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 19 PY 2016 VL 55 IS 15 BP 2197 EP 2213 DI 10.1021/acs.biochem.5b01354 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK1WX UT WOS:000374706900001 PM 27003615 ER PT J AU LaRochelle, JR Fodor, M Xu, X Durzynska, I Fan, L Status, T Chan, HM LaMarche, MJ Chopra, R Wang, P Fortin, PD Acker, MG Blacklow, SC AF LaRochelle, Jonathan R. Fodor, Michelle Xu, Xiang Durzynska, Izabela Fan, Lixin Status, Travis Chan, Ho Man LaMarche, Matthew J. Chopra, Rajiv Wang, Ping Fortin, Pascal D. Acker, Michael G. Blacklow, Stephen C. TI Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2 SO BIOCHEMISTRY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; X-RAY-SCATTERING; INSULIN-RECEPTOR SUBSTRATE-1; ACUTE MYELOID-LEUKEMIA; PTPN11 MUTATIONS; NOONAN-SYNDROME; MOUSE MODEL; SH-PTP2; DIFFERENTIATION; LEUKEMOGENESIS AB The proto-oncogene PTPN11 encodes a cytoplasmic protein tyrosine phosphatase, SHP2, which is required for normal development and sustained activation of the Ras-MAPK signaling pathway. Germline mutations in SHP2 cause developmental disorders, and somatic mutations have been identified in childhood and adult cancers and drive leukemia in mice. Despite our knowledge of the PTPN11 variations associated with pathology, the structural and functional consequences of many disease-associated mutants remain poorly understood. Here, we combine X-ray crystallography, small-angle X-ray scattering, and biochemistry to elucidate structural and mechanistic features of three cancer-associated SHP2 variants harboring single point mutations within the N-SH2:PTP interdomain autoinhibitory interface. Our findings directly compare the impact of each mutation on autoinhibition of the phosphatase and advance the development of structure-guided and mutation specific SHP2 therapies. C1 [LaRochelle, Jonathan R.; Xu, Xiang; Durzynska, Izabela; Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [LaRochelle, Jonathan R.; Xu, Xiang; Durzynska, Izabela; Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Fodor, Michelle; Status, Travis; Chopra, Rajiv] Novartis Inst Biomed Res, Ctr Prote Chem, Cambridge, MA 02139 USA. [Chan, Ho Man; Wang, Ping; Fortin, Pascal D.; Acker, Michael G.] Novartis Inst Biomed Res, Oncol, Cambridge, MA 02139 USA. [LaMarche, Matthew J.] Novartis Inst Biomed Res, Global Discovery Chem, Cambridge, MA 02139 USA. [Fan, Lixin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Bas Sci Program, Frederick, MD 21702 USA. RP Blacklow, SC (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Blacklow, SC (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM stephen_blacklow@hms.harvard.edu FU Novartis-Dana Farber Cancer Institute Drug Development Program [250 GM10718A1]; William Lawrence-Blanche Hughes Foundation; American Cancer Society [128126] FX This work was funded in part by the Novartis-Dana Farber Cancer Institute Drug Development Program, 250 GM10718A1 (X.X. and S.C.B.), and by the William Lawrence-Blanche Hughes Foundation (to S.C.B.). M.F., T.S., H.M.C., M.J.L., RC., P.W., P.D.F., and M.G.A. are employees of Novartis. J.R.L. gratefully acknowledges postdoctoral fellowship funding from the American Cancer Society (Award 128126). NR 39 TC 0 Z9 1 U1 2 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 19 PY 2016 VL 55 IS 15 BP 2269 EP 2277 DI 10.1021/acs.biochem.5b01287 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK1WX UT WOS:000374706900007 PM 27030275 ER PT J AU Platts-Mills, TF Nicholson, RJ Richmond, NL Patel, KV Simonsick, EM Domeier, RM Swor, RA Hendry, PL Peak, DA Rathlev, NK Jones, JS Lee, DC Weaver, MA Keefe, FJ McLean, SA AF Platts-Mills, Timothy F. Nicholson, Robert J. Richmond, Natalie L. Patel, Kushang V. Simonsick, Eleanor M. Domeier, Robert M. Swor, Robert A. Hendry, Phyllis L. Peak, David A. Rathlev, Niels K. Jones, Jeffrey S. Lee, David C. Weaver, Mark A. Keefe, Francis J. McLean, Samuel A. TI Restricted activity and persistent pain following motor vehicle collision among older adults: a multicenter prospective cohort study SO BMC GERIATRICS LA English DT Article DE Aged; Motor Activity; Emergency medicine; Pain; Geriatrics; Traffic accidents ID LOW-BACK-PAIN; EMERGENCY-DEPARTMENT PATIENTS; PHYSICAL-ACTIVITY SCALE; UNITED-STATES FINDINGS; 2011 NATIONAL-HEALTH; BED REST; COGNITIVE IMPAIRMENT; FUNCTIONAL DECLINE; 6-ITEM SCREENER; WHIPLASH INJURY AB Background: Restricted physical activity commonly occurs following acute musculoskeletal pain in older adults and may influence long-term outcomes. We sought to examine the relationship between restricted physical activity after motor vehicle collision (MVC) and the development of persistent pain. Methods: We examined data from a prospective study of adults >= 65 years of age presenting to the emergency department (ED) after MVC without life-threatening injuries. Restricted physical activity 6 weeks after MVC was defined in three different ways: 1) by a >= 25 point decrease in Physical Activity Scale in the Elderly (PASE) score, 2) by the answer "yes" to the question, "during the past two weeks, have you stayed in bed for at least half a day?", and 3) by the answer "yes" to the question, "during the past two weeks, have you cut down on your usual activities as compared to before the accident?" We examined relationships between each definition of restricted activity and pain severity, pain interference, and functional capacity at 6 months with adjustment for confounders. Results: Within the study sample (N = 164), adjusted average pain severity scores at 6 months did not differ between patients with and without restricted physical activity based on decreased PASE score (2.54 vs. 2.07, p = 0.32). In contrast, clinically and statistically important differences in adjusted average pain severity at 6 months were observed for patients who reported spending half a day in bed vs. those who did not (3.56 vs. 1.91, p < 0.01). In adjusted analyses, both decreased PASE score and cutting down on activity were associated with functional capacity at 6 months, but only decreased PASE score was associated with increased ADL difficulty at 6 months (0.70 vs. -0.01, p = 0.02). Conclusions: Among older adults experiencing MVC, those reporting bed rest or reduced activity 6 weeks after the collision reported higher pain and pain interference scores at 6 months. More research is needed to determine if interventions to promote activity can improve outcomes after MVC in older adults. C1 [Platts-Mills, Timothy F.; Nicholson, Robert J.; Richmond, Natalie L.] Univ N Carolina, Dept Emergency Med, 170 Manning Dr, Chapel Hill, NC USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, 1959 NE Pacific St, Seattle, WA 98195 USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Domeier, Robert M.] St Joseph Mercy Hlth Syst, Dept Emergency Med, 5301 McAuley Dr, Ypsilanti, MI USA. [Swor, Robert A.] William Beaumont Hosp, Dept Emergency Med, 3601 W 13 Mile Rd, Royal Oak, MI 48072 USA. [Hendry, Phyllis L.] Univ Florida, Coll Med Jacksonville, Dept Emergency Med, 1515 SW Archer Rd, Gainesville, FL USA. [Peak, David A.] Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St, Boston, MA 02114 USA. [Rathlev, Niels K.] Baystate Med Ctr, Dept Emergency Med, 759 Chestnut St, Springfield, MA USA. [Jones, Jeffrey S.] Spectrum Hlth, Dept Emergency Med, Butterworth Campus,100 Michigan St NE, Grand Rapids, MI 49503 USA. [Lee, David C.] N Shore Univ Hosp, Dept Emergency Med, 300 Community Dr, Manhasset, NY USA. [Weaver, Mark A.] Univ N Carolina, Dept Med, 170 Manning Dr, Chapel Hill, NC USA. [Keefe, Francis J.] Duke Univ, Dept Psychiat, 17 Chapel Dr, Durham, NC 27706 USA. [McLean, Samuel A.] Univ N Carolina, Dept Anesthesiol, 170 Manning Dr, Chapel Hill, NC USA. RP Platts-Mills, TF (reprint author), Univ N Carolina, Dept Emergency Med, 170 Manning Dr, Chapel Hill, NC USA. EM tplattsm@med.unc.edu FU National Institute on Aging [K23AG038548] FX Dr. Platts-Mills is supported by grant K23AG038548 from the National Institute on Aging. The National Institute on Aging had no role in the design of the study, the collection, analysis, and interpretation of data, or the writing of the manuscript. NR 48 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2318 J9 BMC GERIATR JI BMC Geriatr. PD APR 19 PY 2016 VL 16 AR 86 DI 10.1186/s12877-016-0260-z PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DK1KK UT WOS:000374670800003 PM 27094038 ER PT J AU Wang, HY Zhang, X Xue, L Xing, J Jouvin, MH Putney, JW Anderson, MP Trebak, M Kinet, JP AF Wang, Huiyun Zhang, Xuexin Xue, Li Xing, Juan Jouvin, Marie-Helene Putney, James W. Anderson, Matthew P. Trebak, Mohamed Kinet, Jean-Pierre TI Low-Voltage-Activated Ca(V)3.1 Calcium Channels Shape T Helper Cell Cytokine Profiles SO IMMUNITY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; COLONY-STIMULATING FACTOR; GM-CSF; LYMPHOCYTE FUNCTION; CA2+ CHANNELS; EFFECTOR FUNCTIONS; CYCLOSPORINE-A; MICE LACKING; DIFFERENTIATION; NFAT AB Activation of T cells is mediated by the engagement of T cell receptors (TCRs) followed by calcium entry via store-operated calcium channels. Here we have shown an additional route for calcium entry into T cells-through the low-voltage-activated T-type Ca(V)3.1 calcium channel. Ca(V)3.1 mediated a substantial current at resting membrane potentials, and its deficiency had no effect on TCR-initiated calcium entry. Mice deficient for Ca(V)3.1 were resistant to the induction of experimental autoimmune encephalomyelitis and had reduced productions of the granulocyte-macrophage colony-stimulating factor (GM-CSF) by central nervous system (CNS)-infiltrating T helper 1 (Th1) and Th17 cells. Ca(V)3.1 deficiency led to decreased secretion of GM-CSF from in vitro polarized Th1 and Th17 cells. Nuclear translocation of the nuclear factor of activated T cell (NFAT) was also reduced in Ca(V)3.1-deficient T cells. These data provide evidence for T-type channels in immune cells and their potential role in shaping the autoimmune response. C1 [Wang, Huiyun; Xue, Li; Jouvin, Marie-Helene; Anderson, Matthew P.; Kinet, Jean-Pierre] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Wang, Huiyun; Xue, Li; Jouvin, Marie-Helene; Anderson, Matthew P.; Kinet, Jean-Pierre] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Zhang, Xuexin; Trebak, Mohamed] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Xing, Juan; Putney, James W.] NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Anderson, Matthew P.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02115 USA. RP Kinet, JP (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA.; Kinet, JP (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM jkinet2@me.com FU NIH [5T32HL789315, HL097111, 5R01NS081916, 5R37GM53950, 1R01AI095308] FX This work was funded in part by NIH grants 5T32HL789315 to H.W., HL097111 to M.T., 5R01NS081916 to M.P.A., and 5R37GM53950 and 1R01AI095308 to J.-P.K. NR 57 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD APR 19 PY 2016 VL 44 IS 4 BP 782 EP 794 DI 10.1016/j.immuni.2016.01.015 PG 13 WC Immunology SC Immunology GA DJ8EC UT WOS:000374444300011 PM 27037192 ER PT J AU Kong, L Ju, B Chen, YJ He, LL Ren, L Liu, JD Hong, KX Su, B Wang, Z Ozorowski, G Ji, XL Hua, YZ Chen, YL Deller, MC Hao, YL Feng, Y Garces, F Wilson, R Dai, KF O'Dell, S McKee, K Mascola, JR Ward, AB Wyatt, RT Li, YX Wilson, IA Zhu, J Shao, YM AF Kong, Leopold Ju, Bin Chen, Yajing He, Linling Ren, Li Liu, Jiandong Hong, Kunxue Su, Bin Wang, Zheng Ozorowski, Gabriel Ji, Xiaolin Hua, Yuanzi Chen, Yanli Deller, Marc C. Hao, Yanling Feng, Yi Garces, Fernando Wilson, Richard Dai, Kaifan O'Dell, Sijy McKee, Krisha Mascola, John R. Ward, Andrew B. Wyatt, Richard T. Li, Yuxing Wilson, Ian A. Zhu, Jiang Shao, Yiming TI Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor SO IMMUNITY LA English DT Article ID BROADLY NEUTRALIZING ANTIBODIES; HIV-1 ENVELOPE TRIMER; HIV-1-NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; CD4-BINDING SITE; STRUCTURAL BASIS; RATIONAL DESIGN; GLYCOPROTEINS; VACCINE; IDENTIFICATION AB VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged in a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, and longitudinal antibody and virus repertoire analyses. A monoclonal antibody DRVIA7 with modest neutralizing breadth was isolated that displayed a subset of VRC01 signatures. X-ray and EM structures revealed a VRC01-like angle of approach, but less favorable interactions between the DRVIA7 light-chain CDR1 and the N terminus with N276 and V5 glycans of gp120. Although the DRVIA7 lineage was unable to acquire broad neutralization, longitudinal analysis revealed a repertoire-encoded VRC01 light-chain CDR3 signature and VRC01-like neutralizing heavy-chain precursors that rapidly matured within 2 years. Thus, light chain accommodation of the glycan shield should be taken into account in vaccine design targeting this conserved site of vulnerability. C1 [Kong, Leopold; Ozorowski, Gabriel; Hua, Yuanzi; Garces, Fernando; Ward, Andrew B.; Wilson, Ian A.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Ju, Bin; Ren, Li; Liu, Jiandong; Hong, Kunxue; Wang, Zheng; Ji, Xiaolin; Chen, Yanli; Hao, Yanling; Feng, Yi; Shao, Yiming] Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Natl Ctr AIDS STD Control & Prevent, Beijing 102206, Peoples R China. [Ju, Bin; Ren, Li; Liu, Jiandong; Hong, Kunxue; Wang, Zheng; Ji, Xiaolin; Chen, Yanli; Hao, Yanling; Feng, Yi; Shao, Yiming] Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing 102206, Peoples R China. [Kong, Leopold; Ozorowski, Gabriel; Hua, Yuanzi; Garces, Fernando; Ward, Andrew B.; Wyatt, Richard T.; Wilson, Ian A.; Zhu, Jiang] Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA. [Chen, Yajing; He, Linling; Dai, Kaifan; Wyatt, Richard T.; Zhu, Jiang] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Deller, Marc C.] Scripps Res Inst, Joint Ctr Struct Genom, La Jolla, CA 92037 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Kong, Leopold; Ozorowski, Gabriel; Hua, Yuanzi; Garces, Fernando; Wilson, Richard; Ward, Andrew B.; Wyatt, Richard T.; Wilson, Ian A.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Kong, Leopold; Ozorowski, Gabriel; Hua, Yuanzi; Garces, Fernando; Wilson, Richard; Ward, Andrew B.; Wyatt, Richard T.; Wilson, Ian A.] Scripps Res Inst, Collaborat AIDS Vaccine Discovery, La Jolla, CA 92037 USA. [Su, Bin] Jiangsu Prov Ctr Dis Control & Prevent, Nanjing 210009, Jiangsu, Peoples R China. [O'Dell, Sijy; McKee, Krisha; Mascola, John R.] NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Li, Yuxing] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Shao, Yiming] Peking Univ, Hlth Sci Ctr, Beijing 100191, Peoples R China. [Shao, Yiming] Nankai Univ, Sch Med, Tianjin 300071, Peoples R China. RP Shao, YM (reprint author), Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Natl Ctr AIDS STD Control & Prevent, Beijing 102206, Peoples R China.; Shao, YM (reprint author), Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing 102206, Peoples R China.; Zhu, J (reprint author), Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA.; Zhu, J (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.; Shao, YM (reprint author), Peking Univ, Hlth Sci Ctr, Beijing 100191, Peoples R China.; Shao, YM (reprint author), Nankai Univ, Sch Med, Tianjin 300071, Peoples R China. EM jiang@scripps.edu; yshao@bjmu.edu.cn RI Ward, Andrew/F-9203-2014 OI Ward, Andrew/0000-0001-7153-3769 FU US Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; National Major projects for Infectious Diseases Control and Prevention [2012ZX10001008]; International AIDS Vaccine Initiative Neutralizing Antibody Center; CAVD; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [UM1 AI100663]; HIV Vaccine Research and Design (HIVRAD) program [P01 AI110657]; Joint Center of Structural Genomics (JCSG) - NIH NIGMS, Protein Structure Initiative [U54 GM094586]; SKLID Development grant [2012SKLID103]; NIH NIAID [R01 AI102766, AI084817]; NIH NIAID development grant from the Center for AIDS Research at the University of California, San Diego [P30AI36214]; NIH CIPRA grant [U19AI51915]; American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research FX We are very grateful to R. Stanfield for helpful discussions; M. Elsliger for computer support; H. Tien for crystallization screening; A. Eroshkin for help with calculating N-linked glycosylation frequencies; J. Hou, P. Li, and M. Zhu for help with antibody binding assays; D. Li, H. Liang, and H. Peng for help with measuring patient CD4+ T cell counts; Q. Zhao for help with viral load assays; J. Wu and X. Ding for help with patient blood sample collection; and J. P. Verenini for manuscript formatting. X-ray data sets were collected at the Advanced Photon Source (APS) beamline 23ID-B. Use of the APS was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357. Electron microscopy data were collected at the Scripps Research Institute EM Facility. This work was supported by the National Major projects for Infectious Diseases Control and Prevention (2012ZX10001008) (Y. S.), by the International AIDS Vaccine Initiative Neutralizing Antibody Center and CAVD, by the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID UM1 AI100663) (A. B. W., I. A. W., J. Z.), by the HIV Vaccine Research and Design (HIVRAD) program (P01 AI110657) (A. B. W., I. A. W.), by the Joint Center of Structural Genomics (JCSG) funded by the NIH NIGMS, Protein Structure Initiative (U54 GM094586) (I. A. W.), by the SKLID Development grant (2012SKLID103) (Y. S.), by NIH NIAID grants R01 AI102766 (Y. L.) and AI084817 (I. A. W., A. B. W.), and by an NIH NIAID development grant from the Center for AIDS Research at the University of California, San Diego (P30AI36214) (Y. L., J. Z.). A portion of this work was supported by the NIH CIPRA grant (U19AI51915) (Y. S.) and by an American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research (L. K.). Y. S. is grateful to Dennis Burton for hosting his stay at The Scripps Research Institute to initiate this collaborative study. NR 41 TC 11 Z9 11 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD APR 19 PY 2016 VL 44 IS 4 BP 939 EP 950 DI 10.1016/j.immuni.2016.03.006 PG 12 WC Immunology SC Immunology GA DJ8EC UT WOS:000374444300023 PM 27067056 ER PT J AU Karlawish, J Kim, SYH AF Karlawish, Jason Kim, Scott Y. H. TI Acute stroke trials without informed consent: Toward an evidence-based ethical practice SO NEUROLOGY LA English DT Editorial Material ID THROMBOLYSIS; TIME AB Progress in treatment requires progress in experiment, and the treatment of acute stroke, along with many other neurologic diseases, needs more human experiments in the form of clinical trials. However, the acuity of the disease, the need for rapid intervention, and the decisional impairments in some patients present a challenge to obtaining informed consent for such trials. In addition, requiring written informed consent may select for patients who differ in clinically meaningful ways from patients who either are not able to provide it or who lack a surrogate who can do so for them. Most jurisdictions have mechanisms to allow, under certain circumstances, some types of clinical research without written informed consent. Some acute stroke trials are conducted with such waivers. C1 [Karlawish, Jason] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kim, Scott Y. H.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. RP Karlawish, J (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM jason.karlawish@uphs.upenn.edu NR 4 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD APR 19 PY 2016 VL 86 IS 16 BP 1472 EP 1473 DI 10.1212/WNL.0000000000002596 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DK4KS UT WOS:000374887700007 PM 27009260 ER PT J AU Shi, YB AF Shi, Yun-Bo TI The 2015 Ming K Jeang Award for Excellence in Cell & Bioscience SO CELL AND BIOSCIENCE LA English DT Review AB Two research groups led by Dr. Bin Gao of National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, MD, USA and Dr. Keji Zhao of National Heart, Lung, and Blood Institute, National Institutes of Health, MD, USA, respectively, won the 2015 Ming K Jeang Award for excellence in Cell & Bioscience. C1 [Shi, Yun-Bo] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD APR 19 PY 2016 VL 6 AR 27 DI 10.1186/s13578-016-0093-7 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ9UK UT WOS:000374558200001 PM 27099702 ER PT J AU Lu, SY Jang, H Zhang, J Nussinov, R AF Lu, Shaoyong Jang, Hyunbum Zhang, Jian Nussinov, Ruth TI Inhibitors of Ras-SOS Interactions SO CHEMMEDCHEM LA English DT Review DE H-Ras; KRAS; K-Ras; oncogenic mutations; peptide mimetics; protein-protein interactions ID PROTEIN-PROTEIN INTERACTIONS; GUANINE-NUCLEOTIDE EXCHANGE; SMALL-MOLECULE INHIBITORS; SMALL GTPASE K-RAS4B; CANCER-THERAPY; HYPERVARIABLE REGION; SIGNAL-TRANSDUCTION; RATIONAL DESIGN; ONCOPROTEIN-INHIBITORS; EFFECTOR INTERACTIONS AB Activating Ras mutations are found in about 30% of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still undruggable' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose pathway drug cocktails, that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal. C1 [Lu, Shaoyong; Zhang, Jian] Shanghai Jiao Tong Univ, Chinese Minist Educ, Key Lab Cell Differentiat & Apoptosis, Sch Med,Dept Pathophysiol, Shanghai 200025, Peoples R China. [Jang, Hyunbum; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Zhang, J (reprint author), Shanghai Jiao Tong Univ, Chinese Minist Educ, Key Lab Cell Differentiat & Apoptosis, Sch Med,Dept Pathophysiol, Shanghai 200025, Peoples R China.; Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD 21702 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. EM jian.zhang@sjtu.edu.cn; NussinoR@helix.nih.gov FU National Basic Research Program of China (973 Program) [2015CB910403]; National Natural Science Foundation of China [81322046, 81302698, 81473137]; Shanghai Rising-Star Program [13A1402300]; Program for New Century Excellent Talents in University [NCET-12-0355]; Shanghai Health and Family Planning Commission [20154Y0058]; Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research FX This work was supported by the National Basic Research Program of China (973 Program) (2015CB910403), the National Natural Science Foundation of China (81322046, 81302698, 81473137), the Shanghai Rising-Star Program (13A1402300) the Program for New Century Excellent Talents in University (NCET-12-0355), and the Shanghai Health and Family Planning Commission (20154Y0058). This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH), under contract HHSN261200800001E. This research was supported [ in part] by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 80 TC 6 Z9 6 U1 9 U2 17 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD APR 19 PY 2016 VL 11 IS 8 SI SI BP 814 EP 821 DI 10.1002/cmdc.201500481 PG 8 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK1SE UT WOS:000374693500008 PM 26630662 ER PT J AU Sohn, M Ivanova, P Brown, HA Toth, DJ Varnai, P Kim, YJ Balla, T AF Sohn, Mira Ivanova, Pavlina Brown, H. Alex Toth, Daniel J. Varnai, Peter Kim, Yeun Ju Balla, Tamas TI Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phosphatidylserine; phosphatidylinositol; PI 4-kinase; ER-PM junctions; lipid transfer ID PHOSPHOINOSITIDE PHOSPHATASE; TRANSFER PROTEINS; LIPID-TRANSFER; PHOSPHATIDYLSERINE; POOLS; MULTIPLE; REVEALS; CELLS; SAC1; TRAFFICKING AB Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in the PTDSS1 gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4-phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol-binding protein-related protein 8, which was recently identified as a PI4P-PS exchanger between the ER and PM, showed PI4P-dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P-dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism. C1 [Sohn, Mira; Toth, Daniel J.; Kim, Yeun Ju; Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Ivanova, Pavlina; Brown, H. Alex] Vanderbilt Univ, Dept Pharmacol & Biochem, Vanderbilt Ingram Canc Ctr, Vanderbilt Inst Chem Biol,Sch Med, Nashville, TN 37232 USA. [Varnai, Peter] Semmelweis Univ, Sch Med, Dept Physiol, H-1094 Budapest, Hungary. RP Balla, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov OI Toth, Daniel/0000-0001-6670-3348; Balla, Tamas/0000-0002-9077-3335 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health; Bixler Johnson Mayes Endowed Chair; Vanderbilt Institute of Chemical Biology; National Research, Development, and Innovation Fund [NKFI K105006] FX This work was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health. The work from the H.A.B. laboratory was supported partly by the Bixler Johnson Mayes Endowed Chair and the Vanderbilt Institute of Chemical Biology. P.V. was supported by the National Research, Development, and Innovation Fund (Grant NKFI K105006). NR 31 TC 3 Z9 3 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 19 PY 2016 VL 113 IS 16 BP 4314 EP 4319 DI 10.1073/pnas.1525719113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7LV UT WOS:000374393800038 PM 27044099 ER PT J AU Fu, Y Winter, PW Rojas, R Wang, V McAuliffe, M Patterson, GH AF Fu, Yan Winter, Peter W. Rojas, Raul Wang, Victor McAuliffe, Matthew Patterson, George H. TI Axial superresolution via multiangle TIRF microscopy with sequential imaging and photobleaching SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE total internal reflection fluorescence; axial superresolution; photobleaching ID INTERNAL-REFLECTION FLUORESCENCE; OPTICAL RECONSTRUCTION MICROSCOPY; DIFFRACTION-LIMIT; RESOLUTION; NANOSCALE; CELLS; DYNAMICS; (IM)-M-5; SAMPLES; STORM AB We report superresolution optical sectioning using a multiangle total internal reflection fluorescence (TIRF) microscope. TIRF images were constructed from several layers within a normal TIRF excitation zone by sequentially imaging and photobleaching the fluorescent molecules. The depth of the evanescent wave at different layers was altered by tuning the excitation light incident angle. The angle was tuned from the highest (the smallest TIRF depth) toward the critical angle (the largest TIRF depth) to preferentially photobleach fluorescence from the lower layers and allow straightforward observation of deeper structures withoutmasking by the brighter signals closer to the coverglass. Reconstruction of the TIRF images enabled 3D imaging of biological samples with 20-nm axial resolution. Two-color imaging of epidermal growth factor (EGF) ligand and clathrin revealed the dynamics of EGF-activated clathrin-mediated endocytosis during internalization. Furthermore, Bayesian analysis of images collected during the photobleaching step of each plane enabled lateral super-resolution (<100 nm) within each of the sections. C1 [Fu, Yan; Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, NIH, Bethesda, MD 20892 USA. [Winter, Peter W.] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. [Rojas, Raul] Natl Inst Dent & Craniofacial Res, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. [Wang, Victor; McAuliffe, Matthew] NIH, Biomed Imaging Res Serv Sect, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. RP Patterson, GH (reprint author), Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, NIH, Bethesda, MD 20892 USA. EM pattersg@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Biomedical Imaging and Bioengineering FX We thank Hari Shroff for helpful discussions and a critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, including the National Institute of Biomedical Imaging and Bioengineering. This study was performed using the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (https://hpc.nih.gov). NR 35 TC 2 Z9 2 U1 9 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 19 PY 2016 VL 113 IS 16 BP 4368 EP 4373 DI 10.1073/pnas.1516715113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7LV UT WOS:000374393800047 PM 27044072 ER PT J AU Zeitlin, L Geisbert, JB Deer, DJ Fenton, KA Bohorov, O Bohorova, N Goodman, C Kim, D Hiatt, A Pauly, MH Velasco, J Whaley, KJ Altmann, F Gruber, C Steinkellner, H Honko, AN Kuehne, AI Aman, MJ Sahandi, S Enterlein, S Zhan, XG Enria, D Geisbert, TW AF Zeitlin, Larry Geisbert, Joan B. Deer, Daniel J. Fenton, Karla A. Bohorov, Ognian Bohorova, Natasha Goodman, Charles Kim, Do Hiatt, Andrew Pauly, Michael H. Velasco, Jesus Whaley, Kevin J. Altmann, Friedrich Gruber, Clemens Steinkellner, Herta Honko, Anna N. Kuehne, Ana I. Aman, M. Javad Sahandi, Sara Enterlein, Sven Zhan, Xiaoguo Enria, Delia Geisbert, Thomas W. TI Monoclonal antibody therapy for Junin virus infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Junin; therapy; immunotherapy; hemorrhagic fever ID ARGENTINE HEMORRHAGIC-FEVER; GUINEA-PIGS; IMMUNE PLASMA; EFFICACY; DISEASE; IGG; ENCEPHALITIS; PATHOGENESIS; EXPRESSION; MODEL AB Countermeasures against potential biothreat agents remain important to US Homeland Security, and many of these pharmaceuticals could have dual use in the improvement of global public health. Junin virus, the causative agent of Argentine hemorrhagic fever (AHF), is an arenavirus identified as a category A high-priority agent. There are no Food and Drug Administration (FDA) approved drugs available for preventing or treating AHF, and the current treatment option is limited to administration of immune plasma. Whereas immune plasma demonstrates the feasibility of passive immunotherapy, it is limited in quantity, variable in quality, and poses safety risks such as transmission of transfusion-borne diseases. In an effort to develop a monoclonal antibody (mAb)-based alternative to plasma, three previously described neutralizing murine mAbs were expressed as mouse-human chimeric antibodies and evaluated in the guinea pig model of AHF. These mAbs provided 100% protection against lethal challenge when administered 2 d after infection (dpi), and one of them(J199) was capable of providing 100% protection when treatment was initiated 6 dpi and 92% protection when initiated 7 dpi. The efficacy of J199 is superior to that previously described for all other evaluated drugs, and its high potency suggests that mAbs like J199 offer an economical alternative to immune plasma and an effective dual use (bioterrorism/public health) therapeutic. C1 [Zeitlin, Larry; Bohorov, Ognian; Bohorova, Natasha; Goodman, Charles; Kim, Do; Hiatt, Andrew; Pauly, Michael H.; Velasco, Jesus; Whaley, Kevin J.] Mapp Biopharmaceut Inc, San Diego, CA 92121 USA. [Geisbert, Joan B.; Deer, Daniel J.; Fenton, Karla A.; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Geisbert, Joan B.; Deer, Daniel J.; Fenton, Karla A.; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Altmann, Friedrich; Gruber, Clemens] Univ Nat Resources & Appl Life Sci, Dept Chem, A-1190 Vienna, Austria. [Steinkellner, Herta] Univ Nat Resources & Appl Life Sci, Dept Appl Genet & Cell Biol, A-1190 Vienna, Austria. [Honko, Anna N.; Kuehne, Ana I.] US Army Med Res Inst Infect Dis, Virol Div, Frederick, MD 21702 USA. [Aman, M. Javad; Sahandi, Sara; Enterlein, Sven; Zhan, Xiaoguo] Integrated BioTherapeut Inc, Gaithersburg, MD 20878 USA. [Enria, Delia] Inst Nacl Enfermedades Virales Humanas, Buenos Aires, DF, Argentina. [Honko, Anna N.] NIAID, Integrated Res Facil, Frederick, MD 21702 USA. RP Zeitlin, L (reprint author), Mapp Biopharmaceut Inc, San Diego, CA 92121 USA.; Geisbert, TW (reprint author), Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA.; Geisbert, TW (reprint author), Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. EM larry.zeitlin@mappbio.com; twgeisbe@UTMB.EDU RI Steinkellner, Herta/N-4267-2016; OI Steinkellner, Herta/0000-0003-4823-1505; Honko, Anna/0000-0001-9165-148X FU National Institute of Allergy and Infectious Disease [AI111391] FX We thank Drs. Yuri Gleba and Victor Klimyuk (Icon Genetics) for access to the magnICON expression technology and Natalie Dobias and the Research Histopathology Core at UTMB for optimization of the immunohistochemistry protocol. This publication was made possible by National Institute of Allergy and Infectious Disease Grant AI111391. NR 33 TC 4 Z9 5 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 19 PY 2016 VL 113 IS 16 BP 4458 EP 4463 DI 10.1073/pnas.1600996113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7LV UT WOS:000374393800062 PM 27044104 ER PT J AU Chang, C Leopold, DA Scholvinck, ML Mandelkow, H Picchioni, D Liu, X Ye, FQ Turchi, JN Duyn, JH AF Chang, Catie Leopold, David A. Schoelvinck, Marieke Louise Mandelkow, Hendrik Picchioni, Dante Liu, Xiao Ye, Frank Q. Turchi, Janita N. Duyn, Jeff H. TI Tracking brain arousal fluctuations with fMRI SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE resting-state fMRI; spontaneous fluctuations; arousal; electrophysiology ID RESTING-STATE FMRI; DEFAULT MODE NETWORK; FUNCTIONAL CONNECTIVITY; ALPHA-RHYTHM; SIMULTANEOUS EEG; SLEEP; SIGNAL; WAKEFULNESS; VIGILANCE; CORTEX AB Changes in brain activity accompanying shifts in vigilance and arousal can interfere with the study of other intrinsic and task-evoked characteristics of brain function. However, the difficulty of tracking and modeling the arousal state during functional MRI (fMRI) typically precludes the assessment of arousal-dependent influences on fMRI signals. Here we combine fMRI, electrophysiology, and the monitoring of eyelid behavior to demonstrate an approach for tracking continuous variations in arousal level from fMRI data. We first characterize the spatial distribution of fMRI signal fluctuations that track a measure of behavioral arousal; taking this pattern as a template, and using the local field potential as a simultaneous and independent measure of cortical activity, we observe that the time-varying expression level of this template in fMRI data provides a close approximation of electrophysiological arousal. We discuss the potential benefit of these findings for increasing the sensitivity of fMRI as a cognitive and clinical biomarker. C1 [Chang, Catie; Mandelkow, Hendrik; Picchioni, Dante; Liu, Xiao; Duyn, Jeff H.] NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Leopold, David A.; Ye, Frank Q.] NIMH, Neurophysiol Imaging Facil, NINDS, NIH, Bethesda, MD 20892 USA. [Leopold, David A.; Ye, Frank Q.] NEI, NIH, Bethesda, MD 20892 USA. [Schoelvinck, Marieke Louise] Max Planck Gesell, Ernst Strungmann Inst Neurosci Cooperat, D-60528 Frankfurt, Germany. [Turchi, Janita N.] NIMH, Lab Neuropsychol, NIH, Bethesda, MD 20892 USA. RP Chang, C (reprint author), NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. EM catie.chang@nih.gov RI Liu, Xiao/C-5943-2016; OI Leopold, David/0000-0002-1345-6360 FU Intramural Research Programs of the National Institute of Neurological Disorders and Stroke; National Institute of Mental Health, National Institutes of Health FX We thank Brian Russ, Mikail Rubinov, Jennifer Evans, and Michael Chen for valuable discussions and David Yu and Katy Smith for assistance with experiments. This research was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health, National Institutes of Health. NR 70 TC 2 Z9 2 U1 6 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 19 PY 2016 VL 113 IS 16 BP 4518 EP 4523 DI 10.1073/pnas.1520613113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7LV UT WOS:000374393800072 PM 27051064 ER PT J AU Brauner, EV Andersen, ZJ Frederiksen, M Specht, IO Hougaard, KS Ebbehoj, N Bailey, J Giwercman, A Steenland, K Longnecker, MP Bonde, JP AF Brauner, Elvira Vaclavik Andersen, Zorana Jovanovic Frederiksen, Marie Specht, Ina Olmer Hougaard, Karin Sorig Ebbehoj, Niels Bailey, Janice Giwercman, Aleksander Steenland, Kyle Longnecker, Matthew Paul Bonde, Jens Peter TI Health Effects of PCBs in Residences and Schools (HESPERUS): PCB - health Cohort Profile SO SCIENTIFIC REPORTS LA English DT Article ID POLYCHLORINATED-BIPHENYLS PCB; NATIONAL DIABETES REGISTER; INDOOR AIR; CONTAMINATED SCHOOL; EXPOSURE; INHALATION; TEACHERS; BUILDINGS; WORKING AB Polychlorinated-biphenyls (PCBs) were introduced in the late 1920s and used until the 1970s when they were banned in most countries due to evidence of environmental build-up and possible adverse health effects. However they still persist in the environment, indoors and in humans. Indoor air in contaminated buildings may confer airborne exposure markedly above background regional PCB levels. To date, no epidemiological studies have assessed the health effects from exposure to semi-volatile PCBs in the indoor environment. Indoor air PCBs are generally less chlorinated than PCBs that are absorbed via the diet, or via past occupational exposure; therefore their health effects require separate risk assessment. Two separate cohorts of individuals who have either attended schools (n = 66,769; 26% exposed) or lived in apartment buildings (n = 37,185; 19% exposed), where indoor air PCB concentrations have been measured were created. An individual estimate of long-term airborne PCB exposure was assigned based on measurements. The cohorts will be linked to eight different national data sources on mortality, school records, residential history, socioeconomic status, and chronic disease and reproductive outcomes. The linking of indoor air exposures with health outcomes provides a dataset unprecedented worldwide. We describe a project, called HESPERUS (Health Effects of PCBs in Residences and Schools), which will be the first study of the long term health effects of the lower-chlorinated, semi-volatile PCBs in the indoor environment. C1 [Brauner, Elvira Vaclavik] Univ Copenhagen, Rigshosp Glostrup, Capital Reg Denmark, Res Ctr Prevent & Hlth,Ctr Hlth, Copenhagen, Denmark. [Brauner, Elvira Vaclavik; Specht, Ina Olmer; Ebbehoj, Niels; Bonde, Jens Peter] Univ Copenhagen, Inst Publ Hlth, Bispebjerg Frederiksberg Hosp, Dept Occupat & Environm Med, Copenhagen, Denmark. [Andersen, Zorana Jovanovic] Univ Copenhagen, Fac Hlth Sci, Ctr Epidemiol & Screening, Dept Publ Hlth, Copenhagen, Denmark. [Frederiksen, Marie] Aalborg Univ, Danish Bldg Res Inst, Dept Energy Environm & Indoor Climate, Aalborg, Denmark. [Hougaard, Karin Sorig] Natl Res Ctr Working Environm, Copenhagen, Denmark. [Bailey, Janice] Univ Laval, Dept Anim Sci, Ctr Rech Biol Reprod, Quebec City, PQ G1K 7P4, Canada. [Giwercman, Aleksander] Lund Univ, Dept Translat Med, Mol Reprod Med, S-22100 Lund, Sweden. [Steenland, Kyle] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. [Longnecker, Matthew Paul] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Brauner, EV (reprint author), Univ Copenhagen, Rigshosp Glostrup, Capital Reg Denmark, Res Ctr Prevent & Hlth,Ctr Hlth, Copenhagen, Denmark.; Brauner, EV (reprint author), Univ Copenhagen, Inst Publ Hlth, Bispebjerg Frederiksberg Hosp, Dept Occupat & Environm Med, Copenhagen, Denmark. EM elvira.vaclavik.braeuner@regionh.dk OI Hougaard, Karin/0000-0002-3386-0512; Longnecker, Matthew/0000-0001-6073-5322; Specht, Ina Olmer/0000-0002-3114-4715 FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences; National Institutes of Health applications from the Capital region of Denmark FX We thank Harald Meyer, Thomas Hougaard and Lars Gunnarsen for valuable discussions. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences and in part by a starting grant for National Institutes of Health applications from the Capital region of Denmark. NR 35 TC 1 Z9 1 U1 12 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 19 PY 2016 VL 6 AR 24571 DI 10.1038/srep24571 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7GM UT WOS:000374379900001 PM 27090775 ER PT J AU Jee, YH Lebenthal, Y Chaemsaithong, P Yan, G Peran, I Wellstein, A Romero, R Baron, J AF Jee, Youn Hee Lebenthal, Yael Chaemsaithong, Piya Yan, Gai Peran, Ivana Wellstein, Anton Romero, Roberto Baron, Jeffrey TI Midkine and Pleiotrophin Concentrations in Amniotic Fluid in Healthy and Complicated Pregnancies SO PLOS ONE LA English DT Article ID GROWTH-FACTOR PLEIOTROPHIN; ACID-RESPONSIVE GENE; ENDOGENOUS RETROVIRUS; MOUSE EMBRYOGENESIS; DIFFERENTIATION FACTOR; PRETERM DELIVERY; ADULT-RAT; EXPRESSION; MK; FETAL AB Background Midkine (MDK) and pleiotrophin (PTN) are heparin-binding growth factors that, in rodents, are highly expressed in early life and decrease to undetectable levels by adulthood. The potential roles of MDK and PTN in human growth and development are not completely elucidated. Method and Findings To delineate the role of MDK and PTN in human development, we developed high sensitivity assays to measure their concentrations in amniotic fluid (AF) at various gestational ages in both healthy and complicated pregnancies. We found that both of these growth factors could be readily measured in AF and that the concentrations were higher than most cytokines previously reported in AF. Conclusion The concentration of MDK but not that of PTN declined with gestational age. Both MDK and PTN concentrations were found to be lower in pregnancies that were complicated by chorioamnionitis at term, raising the possibility that these growth factors might be useful as markers for infection. C1 [Jee, Youn Hee; Lebenthal, Yael; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Dev, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Lebenthal, Yael] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Chaemsaithong, Piya; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res, Detroit, MI USA. [Yan, Gai; Peran, Ivana; Wellstein, Anton] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Yan, Gai; Peran, Ivana; Wellstein, Anton] Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Baron, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Dev, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM jeffrey.baron@nih.gov FU Thrasher Research Fund; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX This work was supported by a grant from the Thrasher Research Fund and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [https://www.thrasherresearch.org/default.aspx]. NR 39 TC 1 Z9 1 U1 1 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 APR 18 PY 2016 VL 11 IS 4 AR e0153325 DI 10.1371/journal.pone.0153325 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ9IK UT WOS:000374527000017 PM 27089523 ER PT J AU Rast, TJ Kullas, AL Southern, PJ Davis, DA AF Rast, Timothy J. Kullas, Amy L. Southern, Peter J. Davis, Dana A. TI Human Epithelial Cells Discriminate between Commensal and Pathogenic Interactions with Candida albicans SO PLOS ONE LA English DT Article ID TOLL-LIKE RECEPTORS; ENDOTHELIAL-CELLS; PATHWAY; INFECTIONS; ADHERENCE; PROMOTER; BINDING; GENES; SHOCK; LINE AB The commensal fungus, Candida albicans, can cause life-threatening infections in at risk individuals. C. albicans colonizes mucosal surfaces of most people, adhering to and interacting with epithelial cells. At low concentrations, C. albicans is not pathogenic nor does it cause epithelial cell damage in vitro; at high concentrations, C. albicans causes mucosal infections and kills epithelial cells in vitro. Here we show that while there are quantitative dose-dependent differences in exposed epithelial cell populations, these reflect a fundamental qualitative difference in host cell response to C. albicans. Using transcriptional profiling experiments and real time PCR, we found that wild-type C. albicans induce dose-dependent responses from a FaDu epithelial cell line. However, real time PCR and Western blot analysis using a high dose of various C. albicans strains demonstrated that these dose-dependent responses are associated with ability to promote host cell damage. Our studies support the idea that epithelial cells play a key role in the immune system by monitoring the microbial community at mucosal surfaces and initiating defensive responses when this community is dysfunctional. This places epithelial cells at a pivotal position in the interaction with C. albicans as epithelial cells themselves promote C. albicans stimulated damage. C1 [Rast, Timothy J.; Kullas, Amy L.; Southern, Peter J.; Davis, Dana A.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. [Rast, Timothy J.] Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ USA. [Kullas, Amy L.] NIH, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. RP Davis, DA (reprint author), Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. EM dadavis@umn.edu FU University of Minnesota [18805]; National Institutes of Health [1R01 AI064054-01]; Burroughs Wellcome Fund [1004419] FX Funded by University of Minnesota (http://www.research.umn.edu): #18805, National Institutes of Health (http://www.niaid.nih.gov/Pages/default.aspx): 1R01 AI064054-01, and Burroughs Wellcome Fund (http://www.bwfund.org): #1004419. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 18 PY 2016 VL 11 IS 4 AR e0153165 DI 10.1371/journal.pone.0153165 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ9IK UT WOS:000374527000011 PM 27088599 ER PT J AU Chaiworapongsa, T Romero, R Whitten, AE Korzeniewski, SJ Chaemsaithong, P Hernandez-Andrade, E Yeo, L Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Whitten, Amy E. Korzeniewski, Steven J. Chaemsaithong, Piya Hernandez-Andrade, Edgar Yeo, Lami Hassan, Sonia S. TI The use of angiogenic biomarkers in maternal blood to identify which SGA fetuses will require a preterm delivery and mothers who will develop pre-eclampsia SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Angiogenic; Anti-angiogenic factors; intrauterine growth restriction (IUGR); placental growth factor; pregnancy; soluble endoglin; sflt-1; soluble vascular endothelial growth factor receptor-1; umbilical artery Doppler; uterine artery Doppler ID FOR-GESTATIONAL-AGE; INTRAUTERINE GROWTH RESTRICTION; UTERINE ARTERY DOPPLER; FUNDAL HEIGHT-MEASUREMENT; LATE-ONSET PREECLAMPSIA; LOW-RISK POPULATION; FACTOR RECEPTOR-1 CONCENTRATION; RANDOMIZED CONTROLLED-TRIAL; TYROSINE KINASE-1 SFLT-1; NORMAL FETAL GROWTH AB Objective: To determine (1) whether maternal plasma concentrations of angiogenic and anti-angiogenic factors can predict which mothers diagnosed with suspected small for gestational age fetuses (sSGA) will develop pre-eclampsia (PE) or require an indicated early preterm delivery (34 weeks of gestation); and (2) whether risk assessment performance is improved using these proteins in addition to clinical factors and Doppler parameters.Methods: This prospective cohort study included women with singleton pregnancies diagnosed with sSGA (estimated fetal weight <10th percentile) between 24 and 34 weeks of gestation (n=314). Plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), soluble endoglin (sEng) and placental growth factor (PlGF) were determined in maternal blood obtained at the time of diagnosis. Doppler velocimetry of the umbilical (Umb) and uterine (UT) arteries was performed. The outcomes were (1) subsequent development of PE; and (2) indicated preterm delivery at 34 weeks of gestation (excluding deliveries as a result of spontaneous preterm labor, preterm pre-labor rupture of membranes or chorioamnionitis).Results: (1) The prevalence of PE and indicated preterm delivery was 9.2% (n=29/314) and 7.3% (n=23/314), respectively; (2) the area under the receiver operating characteristic curve (AUC) for the identification of patients who developed PE and/or required indicated preterm delivery was greater than 80% for the UT artery pulsatility index (PI) z-score and each biochemical marker (including their ratios) except sVEGFR-1 MoM; (3) using cutoffs at a false positive rate of 15%, women with abnormal plasma concentrations of angiogenic/anti-angiogenic factors were 7-13 times more likely to develop PE, and 12-22 times more likely to require preterm delivery than those with normal plasma MoM concentrations of these factors; (4) sEng, PlGF, PIGF/sEng and PIGF/sVEGFR-1 ratios MoM, each contributed significant information about the risk of PE beyond that provided by clinical factors and/or Doppler parameters: women who had low MoM values for these biomarkers were at 5-9 times greater risk of developing PE than women who had normal values, adjusting for clinical factors and Doppler parameters (adjusted odds ratio for PlGF: 9.1, PlGF/sEng: 5.6); (5) the concentrations of sVEGFR-1 and PlGF/sVEGFR-1 ratio MoM, each contributed significant information about the risk of indicated preterm delivery beyond that provided by clinical factors and/or Doppler parameters: women who had abnormal values were at 8-9 times greater risk for indicated preterm delivery, adjusting for clinical factors and Doppler parameters; and (6) for a two-stage risk assessment (Umb artery Doppler followed by Ut artery Doppler plus biochemical markers), among women who had normal Umb artery Doppler velocimetry (n=279), 21 (7.5%) developed PE and 11 (52%) of these women were identified by an abnormal UT artery Doppler mean PI z-score (>2SD): a combination of PlGF/sEng ratio MoM concentration and abnormal UT artery Doppler velocimetry increased the sensitivity of abnormal UT artery Doppler velocimetry to 76% (16/21) at a fixed false-positive rate of 10% (p=0.06).Conclusion: Angiogenic and anti-angiogenic factors measured in maternal blood between 24 and 34 weeks of gestation can identify the majority of mothers diagnosed with suspected SGA who subsequently developed PE or those who later required preterm delivery 34 weeks of gestation. Moreover, incorporation of these biochemical markers significantly improves risk assessment performance for these outcomes beyond that of clinical factors and uterine and umbilical artery Doppler velocimetry. C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Whitten, Amy E.; Korzeniewski, Steven J.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Chaiworapongsa, Tinnakorn; Romero, Roberto; Whitten, Amy E.; Korzeniewski, Steven J.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Whitten, Amy E.; Korzeniewski, Steven J.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI USA. RP Chaiworapongsa, T; Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM tchaiwor@med.wayne.edu; romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX The authors report no conflicts of interest. This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 203 TC 3 Z9 3 U1 2 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD APR 17 PY 2016 VL 29 IS 8 BP 1214 EP 1228 DI 10.3109/14767058.2015.1048431 PG 15 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DB7TJ UT WOS:000368718700005 PM 26303962 ER PT J AU Glas, GJ Neto, AS Horn, J Cochran, A Dixon, B Elamin, EM Faraklas, I Dissanaike, S Miller, AC Schultz, MJ AF Glas, Gerie J. Neto, Ary Serpa Horn, Janneke Cochran, Amalia Dixon, Barry Elamin, Elamin M. Faraklas, Iris Dissanaike, Sharmila Miller, Andrew C. Schultz, Marcus J. TI Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis SO ANNALS OF INTENSIVE CARE LA English DT Article DE Anticoagulants; Administration; Inhalation; Mechanical ventilation; Humans; Heparin; Intensive care ID ACUTE LUNG INJURY; RESPIRATORY-DISTRESS-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; ACTIVATED PROTEIN-C; SEVERE SEPSIS; INHALATION INJURY; ANTICOAGULANT-THERAPY; FIBRIN DEPOSITION; ANTITHROMBIN-III; N-ACETYLCYSTEINE AB Pulmonary coagulopathy is a characteristic feature of lung injury including ventilator-induced lung injury. The aim of this individual patient data meta-analysis is to assess the effects of nebulized anticoagulants on outcome of ventilated intensive care unit (ICU) patients. A systematic search of PubMed (1966-2014), Scopus, EMBASE, and Web of Science was conducted to identify relevant publications. Studies evaluating nebulization of anticoagulants in ventilated patients were screened for inclusion, and corresponding authors of included studies were contacted to provide individual patient data. The primary endpoint was the number of ventilator-free days and alive at day 28. Secondary endpoints included hospital mortality, ICU- and hospital-free days at day 28, and lung injury scores at day seven. We constructed a propensity score-matched cohort for comparisons between patients treated with nebulized anticoagulants and controls. Data from five studies (one randomized controlled trial, one open label study, and three studies using historical controls) were included in the meta-analysis, compassing 286 patients. In all studies unfractionated heparin was used as anticoagulant. The number of ventilator-free days and alive at day 28 was higher in patients treated with nebulized heparin compared to patients in the control group (14 [IQR 0-23] vs. 6 [IQR 0-22]), though the difference did not reach statistical significance (P = 0.459). The number of ICU-free days and alive at day 28 was significantly higher, and the lung injury scores at day seven were significantly lower in patients treated with nebulized heparin. In the propensity score-matched analysis, there were no differences in any of the endpoints. This individual patient data meta-analysis provides no convincing evidence for benefit of heparin nebulization in intubated and ventilated ICU patients. The small patient numbers and methodological shortcomings of included studies underline the need for high-quality well-powered randomized controlled trials. C1 [Glas, Gerie J.; Horn, Janneke; Schultz, Marcus J.] Univ Amsterdam, Acad Med Ctr, Dept Intens Care, Lab Expt Intens Care & Anesthesiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Neto, Ary Serpa] Hosp Israelita Albert Einstein, Dept Crit Care Med, Sao Paulo, Brazil. [Neto, Ary Serpa] ABC, Fac Med, Dept Crit Care Med, Santo Andre, Brazil. [Neto, Ary Serpa] ABC, Fac Med, Program Postgrad Res & Innovat, Santo Andre, Brazil. [Cochran, Amalia; Faraklas, Iris] Univ Utah, Hlth Sci Ctr, Dept Surg, Salt Lake City, UT USA. [Dixon, Barry] St Vincents Hosp, Dept Intens Care, Melbourne, Vic, Australia. [Elamin, Elamin M.] Univ S Florida, Dept Internal Med, James A Haley Vet Hosp, Div Pulm Crit Care & Sleep Med, Tampa, FL 33612 USA. [Dissanaike, Sharmila] Texas Tech Univ, Hlth Sci Ctr, Dept Surg, Lubbock, TX 79430 USA. [Miller, Andrew C.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Miller, Andrew C.] W Virginia Univ, Dept Emergency Med, Morgantown, WV 26506 USA. RP Glas, GJ (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Intens Care, Lab Expt Intens Care & Anesthesiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM g.j.glas@amc.uva.nl RI Serpa Neto, Ary/D-1927-2012; OI Serpa Neto, Ary/0000-0003-1520-9387; Miller, Andrew/0000-0001-8474-5090 FU 'de Nederlandse Brandwondenstichting' (the Dutch Burn Association, Beverwijk, the Netherlands) FX This study was funded by 'de Nederlandse Brandwondenstichting' (the Dutch Burn Association, Beverwijk, the Netherlands). NR 69 TC 0 Z9 0 U1 2 U2 51 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2110-5820 J9 ANN INTENSIVE CARE JI Ann. Intensive Care PD APR 16 PY 2016 VL 6 AR 33 DI 10.1186/s13613-016-0138-4 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA DN7ZJ UT WOS:000377298400001 PM 27083915 ER PT J AU Forlino, A Marini, JC AF Forlino, Antonella Marini, Joan C. TI Osteogenesis imperfecta SO LANCET LA English DT Review ID EHLERS-DANLOS-SYNDROME; EPITHELIUM-DERIVED FACTOR; CIS-TRANS-ISOMERASE; PROLYL 3-HYDROXYLATION COMPLEX; CARTILAGE-ASSOCIATED PROTEIN; PROCOLLAGEN C-PROTEINASE; COLLAGEN TRIPLE-HELIX; BRITTLE BONE-DISEASE; I PROCOLLAGEN; CYCLOPHILIN-B AB Osteogenesis imperfecta is a phenotypically and molecularly heterogeneous group of inherited connective tissue disorders that share similar skeletal abnormalities causing bone fragility and deformity. Previously, the disorder was thought to be an autosomal dominant bone dysplasia caused by defects in type I collagen, but in the past 10 years discoveries of novel (mainly recessive) causative genes have lent support to a predominantly collagen-related pathophysiology and have contributed to an improved understanding of normal bone development. Defects in proteins with very different functions, ranging from structural to enzymatic and from intracellular transport to chaperones, have been described in patients with osteogenesis imperfecta. Knowledge of the specific molecular basis of each form of the disorder will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches. In this Seminar, together with diagnosis, management, and treatment, we describe the defects causing osteogenesis imperfecta and their mechanism and interrelations, and classify them into five groups on the basis of the metabolic pathway compromised, specifically those related to collagen synthesis, structure, and processing; post-translational modification; folding and cross-linking; mineralisation; and osteoblast differentiation. C1 [Forlino, Antonella] Univ Pavia, Dept Mol Med, Biochem Unit, Via Palestro 3, I-27100 Pavia, Italy. [Marini, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20855 USA. RP Marini, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20855 USA. EM oidoc@helix.nih.gov FU NICHD; Fondazione Cariplo [2013-0612]; Telethon [GGP13098] FX The authors thank the members of the Marini Laboratory for critical review of the manuscript, especially Wayne A Cabral and Aileen M Barnes for feedback on figures. Figures were prepared by Jeremy Swan and Erin Fincher of The Unit on Computer Support Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). When writing this Seminar, JCM was supported by intramural funding from the NICHD and AF was supported by the Fondazione Cariplo grant n. 2013-0612 and Telethon grant n. GGP13098. The funders did not have any role in study design, the collection, analysis, and interpretation of data, the writing of the Seminar, or the decision to submit the Seminar for publication. NR 139 TC 45 Z9 45 U1 20 U2 36 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 APR 16 PY 2016 VL 387 IS 10028 BP 1657 EP 1671 DI 10.1016/S0140-6736(15)00728-X PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DJ3ZL UT WOS:000374145100033 PM 26542481 ER PT J AU Stumpo, DJ Trempus, CS Tucker, CJ Huang, WC Li, LP Kluckman, K Bortner, DM Blackshear, PJ AF Stumpo, Deborah J. Trempus, Carol S. Tucker, Charles J. Huang, Weichun Li, Leping Kluckman, Kimberly Bortner, Donna M. Blackshear, Perry J. TI Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism SO DEVELOPMENT LA English DT Article DE Deadenylation; mRNA binding proteins; mRNA decay; Placenta; Zinc finger proteins ID ZINC-FINGER PROTEINS; GROWTH-FACTOR; ENDOTHELIAL LIPASE; FACTOR-ALPHA; EXPRESSION; BINDING; GENE; DEADENYLATION; EGF; DYSREGULATION AB The ZFP36L3 protein is a rodent-specific, placenta- and yolk sacspecific member of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins. These proteins bind to AU-rich elements in target mRNAs, and promote their deadenylation and decay. We addressed the hypotheses that the absence of ZFP36L3 would result in the accumulation of target transcripts in placenta and/or yolk sac, and that some of these would be important for female reproductive physiology and overall fecundity. Mice deficient in ZFP36L3 exhibited decreased neonatal survival rates, but no apparent morphological changes in the placenta or surviving offspring. We found Zfp36l3 to be paternally imprinted, with profound parent-of-origin effects on gene expression. The protein was highly expressed in the syncytiotrophoblast cells of the labyrinth layer of the placenta, and the epithelial cells of the yolk sac. RNA-Seq of placental mRNA from Zfp36l3 knockout (KO) mice revealed many significantly upregulated transcripts, whereas there were few changes in KO yolk sacs. Many of the upregulated placental transcripts exhibited decreased decay rates in differentiated trophoblast stem cells derived from KO blastocysts. Several dozen transcripts were deemed high probability targets of ZFP36L3; these include proteins known to be involved in trophoblast and placenta physiology. Type 1 transferrin receptor mRNA was unexpectedly decreased in KO placentas, despite an increase in its stability in KO stem cells. This receptor is crucial for placental iron uptake, and its decrease was accompanied by decreased iron stores in the KO fetus, suggesting that this intrauterine deficiency might have deleterious consequences in later life. C1 [Stumpo, Deborah J.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. [Trempus, Carol S.] NIEHS, Lab Clin Res, POB 12233, Res Triangle Pk, NC 27709 USA. [Tucker, Charles J.] NIEHS, Confocal Microscopy Core, POB 12233, Res Triangle Pk, NC 27709 USA. [Huang, Weichun; Li, Leping] NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Kluckman, Kimberly; Bortner, Donna M.] TransViragen Inc, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA.; Blackshear, PJ (reprint author), Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA.; Blackshear, PJ (reprint author), Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. EM black009@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. Deposited in PMC for release after 12 months. NR 39 TC 1 Z9 1 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD APR 15 PY 2016 VL 143 IS 8 BP 1424 EP 1433 DI 10.1242/dev.130369 PG 10 WC Developmental Biology SC Developmental Biology GA DY6TN UT WOS:000385261300019 PM 26952984 ER PT J AU Maggio, R Fasciani, I Rossi, M Di Gregorio, J Pietrantoni, I Puca, V Flati, V Scarselli, M AF Maggio, Roberto Fasciani, Irene Rossi, Mario Di Gregorio, Jacopo Pietrantoni, Ilaria Puca, Valentina Flati, Vincenzo Scarselli, Marco TI Variants of G protein-coupled receptors: a reappraisal of their role in receptor regulation SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article DE dimerization; G protein-coupled receptor; internal ribosome entry site; muscarinic receptor; receptor fragment; slice variant ID MESSENGER-RNA; DOPAMINE-RECEPTORS; SPLICE VARIANT; DIMERIZATION; TRAFFICKING; MUTANT; OLIGOMERIZATION; RECONSTITUTION; PHARMACOLOGY; COEXPRESSION AB Truncated or shorter forms of G protein-coupled receptors (GPCRs), originating by alternative splicing, have been considered physiologically irrelevant for a rather long time. Nevertheless, it is now recognized that alternative splicing variants of GPCRs greatly increase the total number of receptor isoforms and can regulate receptor trafficking and signalling. Furthermore, dimerization of these truncated variants with other receptors concurs to expand receptor diversity. Highly truncated variants of GPCRs, typically, are retained in the endoplasmic reticulum (ER) and by heteromerization prevent the wild-type receptor to reach the plasma membrane, exerting a dominant-negative effect on its function. This can be responsible for some pathological conditions but in some other cases, it can offer protection from a disease because the expression of the receptor, that is necessary for binding an infectious agent, is attenuated. Here, we propose a possible new mechanism of creation of truncated GPCR variants through an internal ribosome entry site (IRES), a nucleotide sequence that allows cap independent translation of proteins by recruiting the ribosome in proximity of an internal initiation codon. We suggest that an IRES, situated in the third cytoplasmic loop, could be responsible for the translation of the last two transmembrane (TM) regions of the muscarinic M-2 receptor. IRES driven expression of this C-terminal part of the muscarinic M-2 receptor could represent a novel and additional mechanism of receptor regulation. C1 [Maggio, Roberto; Fasciani, Irene; Di Gregorio, Jacopo; Pietrantoni, Ilaria; Puca, Valentina; Flati, Vincenzo] Univ Aquila, Dept Biotechnol & Appl Clin Sci, I-67100 Laquila, Italy. [Rossi, Mario] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Scarselli, Marco] Univ Pisa, Dept Translat Res & New Technol Med & Surg, I-56126 Pisa, Italy. RP Maggio, R (reprint author), Univ Aquila, Dept Biotechnol & Appl Clin Sci, I-67100 Laquila, Italy. EM roberto.maggio@univaq.it NR 42 TC 0 Z9 0 U1 1 U2 1 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0300-5127 EI 1470-8752 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD APR 15 PY 2016 VL 44 BP 589 EP 594 DI 10.1042/BST20150239 PN 2 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO1DF UT WOS:000377518000039 PM 27068974 ER PT J AU Casado-Anguera, V Bonaventura, J Moreno, E Navarro, G Cortes, A Ferre, S Casado, V AF Casado-Anguera, Veronica Bonaventura, Jordi Moreno, Estefania Navarro, Gemma Cortes, Antoni Ferre, Sergi Casado, Vicent TI Evidence for the heterotetrameric structure of the adenosine A(2A)-dopamine D-2 receptor complex SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article DE adenosine receptors; allosteric modulation; dopamine receptors; G-protein-coupled receptor (GPCR); heteromerization; homodimerization ID PROTEIN-COUPLED RECEPTOR; TARGET RESIDENCE TIME; A(2A) RECEPTOR; DOPAMINE-D-2 RECEPTORS; FUNCTIONAL SELECTIVITY; PARKINSONS-DISEASE; L-DOPA; ALLOSTERIC MODULATION; DRUG DEVELOPMENT; HETEROMERS AB Heteromers of G-protein-coupled receptors (GPCRs) have emerged as potential novel targets for drug development. Accumulating evidence indicates that GPCRs can form homodimers and heteromers, with homodimers being the predominant species and oligomeric receptors being formed as multiples of dimers. Recently, heterotetrameric structures have been proposed for dopamine D-1 receptor (D1R)-dopamine D-3 receptor (D3R) and adenosine A(2A) receptor (A(2A)R)-dopamine D-2 receptor (D2R) heteromers. The structural model proposed for these complexes is a heteromer constituted by two receptor homodimers. The existence of GPCR homodimers and heteromers provides a structural basis for inter-protomer allosteric mechanisms that might account for a multiplicity of unique pharmacological properties. In this review, we focus on the A(2A)R-D2R heterotetramer as an example of an oligomeric structure that is key in the modulation of striatal neuronal function. We also review the interfaces involved in this and other recently reported heteromers of GPCRs. Furthermore, we discuss several published studies showing the ex vivo expression of A(2A)R-D2R heteromers. The ability of A(2A)R agonists to decrease the affinity of D2R agonists has been reported and, on the basis of this interaction, A(2A)R antagonists have been proposed as potential drugs for the treatment of Parkinson's disease. The heterotetrameric structure of the A(2A)R-D2R complex offers a novel model that can provide new clues about how to adjust the drug dosage to the expected levels of endogenous adenosine. C1 [Casado-Anguera, Veronica; Moreno, Estefania; Navarro, Gemma; Cortes, Antoni; Casado, Vicent] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain. [Casado-Anguera, Veronica; Bonaventura, Jordi; Moreno, Estefania; Navarro, Gemma; Cortes, Antoni; Ferre, Sergi; Casado, Vicent] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. [Casado-Anguera, Veronica; Moreno, Estefania; Navarro, Gemma; Cortes, Antoni; Casado, Vicent] Univ Barcelona, Inst Biomed, E-08028 Barcelona, Spain. [Bonaventura, Jordi; Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Casado-Anguera, V; Casado, V (reprint author), Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain.; Casado-Anguera, V; Casado, V (reprint author), Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain.; Casado-Anguera, V; Casado, V (reprint author), Univ Barcelona, Inst Biomed, E-08028 Barcelona, Spain. EM vcasadoanguera@gmail.com; vcasado@ub.edu RI Ferre, Sergi/K-6115-2014; OI Ferre, Sergi/0000-0002-1747-1779; Bonaventura, Jordi/0000-0002-4745-0151 FU Government of Catalonia [2014-SGR-1236]; Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas [CB06/05/0064]; Spanish Ministerio de Economia y Competitividad [SAF2014-54840-R]; National Institute on Drug Abuse FX This study was supported by the Government of Catalonia [grant number 2014-SGR-1236]; the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas [grant number CB06/05/0064]; the Spanish Ministerio de Economia y Competitividad [grant number SAF2014-54840-R]; and by intramural funds of the National Institute on Drug Abuse. NR 55 TC 3 Z9 3 U1 3 U2 6 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0300-5127 EI 1470-8752 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD APR 15 PY 2016 VL 44 BP 595 EP 600 DI 10.1042/BST20150276 PN 2 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DO1DF UT WOS:000377518000040 PM 27068975 ER PT J AU Luna, A Rajapakse, VN Sousa, FG Gao, JJ Schultz, N Varma, S Reinhold, W Sander, C Pommier, Y AF Luna, Augustin Rajapakse, Vinodh N. Sousa, Fabricio G. Gao, Jianjiong Schultz, Nikolaus Varma, Sudhir Reinhold, William Sander, Chris Pommier, Yves TI rcellminer: exploring molecular profiles and drug response of the NCI-60 cell lines in R SO BIOINFORMATICS LA English DT Article AB Purpose: The rcellminer R package provides a wide range of functionality to help R users access and explore molecular profiling and drug response data for the NCI-60. The package enables flexible programmatic access to CellMiner's unparalleled breadth of NCI-60 data, including gene and protein expression, copy number, whole exome mutations, as well as activity data for 21K compounds, with information on their structure, mechanism of action and repeat screens. Functions are available to easily visualize compound structures, activity patterns and molecular feature profiles. Additionally, embedded R Shiny applications allow interactive data exploration. C1 [Luna, Augustin; Sander, Chris] Mem Sloan Kettering Canc Ctr, Comp Biol Program, 1275 York Ave, New York, NY 10021 USA. [Rajapakse, Vinodh N.; Varma, Sudhir; Reinhold, William; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sousa, Fabricio G.] Univ Fed Mato Grosso Do Sul, Ctr Estudos Celulas Tronco Terapia Celular & Gene, Programa Posgrad Farm, BR-79070900 Campo Grande, MS, Brazil. [Gao, Jianjiong; Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10021 USA. RP Luna, A (reprint author), Mem Sloan Kettering Canc Ctr, Comp Biol Program, 1275 York Ave, New York, NY 10021 USA.; Rajapakse, VN; Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM lunaa@cbio.mskcc.org; vinodh.rajapakse@nih.gov RI Sousa, Fabricio/O-8878-2015 OI Sousa, Fabricio/0000-0003-0444-754X FU NIH, MSKCC Genome Data Analysis Center [U24 CA143840]; Ruth L. Kirschstein National Research Service Award [F32 CA192901]; Center for Cancer Research, Intramural Program of the National Cancer Institute [Z01 BC006150] FX This work was supported by the NIH grants: MSKCC Genome Data Analysis Center grant (U24 CA143840), the Ruth L. Kirschstein National Research Service Award (F32 CA192901) and by the Center for Cancer Research, Intramural Program of the National Cancer Institute (Z01 BC006150). NR 8 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD APR 15 PY 2016 VL 32 IS 8 BP 1272 EP 1274 DI 10.1093/bioinformatics/btv701 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DJ8QJ UT WOS:000374476800034 PM 26635141 ER PT J AU Machiela, MJ Lan, Q Slager, SL Vermeulen, RCH Teras, LR Camp, NJ Cerhan, JR Spinelli, JJ Wang, SS Nieters, A Vijai, J Yeager, M Wang, ZM Ghesquieres, H Mckay, J Conde, L de Bakker, PIW Cox, DG Burdett, L Monnereau, A Flowers, CR De Roos, AJ Brooks-Wilson, AR Giles, GG Melbye, M Gu, J Jackson, RD Kane, E Purdue, MP Vajdic, CM Albanes, D Kelly, RS Zucca, M Bertrand, KA Zeleniuch-Jacquotte, A Lawrence, C Hutchinson, A Zhi, DG Habermann, TM Link, BK Novak, AJ Dogan, A Asmann, YW Liebow, M Thompson, CA Ansell, SM Witzig, TE Tille, H Haioun, C Molina, TJ Hjalgrim, H Glimelius, B Adami, HO Roos, G Bracci, PM Riby, J Smith, MT Holly, EA Cozen, W Hartge, P Morton, LM Severson, RK Tinker, LF North, KE Becker, N Benavente, Y Boffetta, P Brennan, P Foretova, L Maynadie, M Staines, A Lightfoot, T Crouch, S Smith, A Roman, E Diver, WR Offit, K Zelenetz, A Klein, RJ Villano, DJ Zheng, TZ Zhang, YW Holford, TR Turner, J Southey, MC Clavel, J Virtamo, J Weinstein, S Riboli, E Vineis, P Kaaks, R Boeing, H Tjonneland, A Angelucci, E Di Lollo, S Rais, M De Vivo, I Giovannucci, E Kraft, P Huang, JY Ma, BS Ye, YQ Chiu, BCH Liang, LM Park, JH Chung, CC Weisenburger, DD Fraumeni, JF Salles, G Glenn, M Cannon-Albright, L Curtin, K Wu, XF Smedby, KE de Sanjose, S Skibola, CF Berndt, SI Birmann, BM Chanock, SJ Rothman, N AF Machiela, Mitchell J. Lan, Qing Slager, Susan L. Vermeulen, Roel C. H. Teras, Lauren R. Camp, Nicola J. Cerhan, James R. Spinelli, John J. Wang, Sophia S. Nieters, Alexandra Vijai, Joseph Yeager, Meredith Wang, Zhaoming Ghesquieres, Herve Mckay, James Conde, Lucia de Bakker, Paul I. W. Cox, David G. Burdett, Laurie Monnereau, Alain Flowers, Christopher R. De Roos, Anneclaire J. Brooks-Wilson, Angela R. Giles, Graham G. Melbye, Mads Gu, Jian Jackson, Rebecca D. Kane, Eleanor Purdue, Mark P. Vajdic, Claire M. Albanes, Demetrius Kelly, Rachel S. Zucca, Mariagrazia Bertrand, Kimberly A. Zeleniuch-Jacquotte, Anne Lawrence, Charles Hutchinson, Amy Zhi, Degui Habermann, Thomas M. Link, Brian K. Novak, Anne J. Dogan, Ahmet Asmann, Yan W. Liebow, Mark Thompson, Carrie A. Ansell, Stephen M. Witzig, Thomas E. Tilly, Herve Haioun, Corinne Molina, Thierry J. Hjalgrim, Henrik Glimelius, Bengt Adami, Hans-Olov Roos, Goran Bracci, Paige M. Riby, Jacques Smith, Martyn T. Holly, Elizabeth A. Cozen, Wendy Hartge, Patricia Morton, Lindsay M. Severson, Richard K. Tinker, Lesley F. North, Kari E. Becker, Nikolaus Benavente, Yolanda Boffetta, Paolo Brennan, Paul Foretova, Lenka Maynadie, Marc Staines, Anthony Lightfoot, Tracy Crouch, Simon Smith, Alex Roman, Eve Diver, W. Ryan Offit, Kenneth Zelenetz, Andrew Klein, Robert J. Villano, Danylo J. Zheng, Tongzhang Zhang, Yawei Holford, Theodore R. Turner, Jenny Southey, Melissa C. Clavel, Jacqueline Virtamo, Jarmo Weinstein, Stephanie Riboli, Elio Vineis, Paolo Kaaks, Rudolph Boeing, Heiner Tjonneland, Anne Angelucci, Emanuele Di Lollo, Simonetta Rais, Marco De Vivo, Immaculata Giovannucci, Edward Kraft, Peter Huang, Jinyan Ma, Baoshan Ye, Yuanqing Chiu, Brian C. H. Liang, Liming Park, Ju-Hyun Chung, Charles C. Weisenburger, Dennis D. Fraumeni, Joseph F., Jr. Salles, Gilles Glenn, Martha Cannon-Albright, Lisa Curtin, Karen Wu, Xifeng Smedby, Karin E. de Sanjose, Silvia Skibola, Christine F. Berndt, Sonja I. Birmann, Brenda M. Chanock, Stephen J. Rothman, Nathaniel TI Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; MENDELIAN RANDOMIZATION; EPIDEMIOLOGIC RESEARCH; SUSCEPTIBILITY LOCI; CANCER-RISK; HLA REGION; CLASSIFICATION; DYSFUNCTION; NEOPLASMS AB Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82, P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51, P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk. C1 [Machiela, Mitchell J.; Lan, Qing; Albanes, Demetrius; Hartge, Patricia; Morton, Lindsay M.; Weinstein, Stephanie; Chung, Charles C.; Fraumeni, Joseph F., Jr.; Berndt, Sonja I.; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Slager, Susan L.; Cerhan, James R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Habermann, Thomas M.; Novak, Anne J.; Liebow, Mark; Thompson, Carrie A.; Ansell, Stephen M.; Witzig, Thomas E.] Mayo Clin, Dept Med, Rochester, MN USA. [Asmann, Yan W.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Vermeulen, Roel C. H.] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Vermeulen, Roel C. H.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet & Epidemiol, Utrecht, Netherlands. [Teras, Lauren R.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Camp, Nicola J.] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT USA. [Spinelli, John J.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Brooks-Wilson, Angela R.] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC, Canada. [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Wang, Sophia S.] City Hope Beckman Res Inst, Div Canc Etiol, Duarte, CA USA. [Nieters, Alexandra] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Baden Wurttembe, Germany. [Vijai, Joseph; Offit, Kenneth; Zelenetz, Andrew; Villano, Danylo J.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Dogan, Ahmet] Mem Sloan Kettering Canc Ctr, Dept Lab Med, 1275 York Ave, New York, NY 10021 USA. [Dogan, Ahmet] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Yeager, Meredith; Wang, Zhaoming; Burdett, Laurie; Hutchinson, Amy] NCI, Div Canc Epidemiol & Genet, Canc Genom Res Lab, Gaithersburg, MD USA. [Ghesquieres, Herve] Ctr Leon Berard, Canc Res Ctr Lyon, Dept Hematol, F-69373 Lyon, France. [Cox, David G.] Ctr Leon Berard, Canc Res Ctr Lyon, INSERM U1052, F-69373 Lyon, France. [Ghesquieres, Herve; Salles, Gilles] CNRS, UMR5239, Lab Biol Mol Cellule, Pierre Benite, France. [Mckay, James] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Conde, Lucia; Riby, Jacques; Skibola, Christine F.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Conde, Lucia; Riby, Jacques; Skibola, Christine F.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Zhi, Degui] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Conde, Lucia; Riby, Jacques; Smith, Martyn T.; Skibola, Christine F.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Monnereau, Alain; Clavel, Jacqueline] Sorbonne Paris Cite, INSERM, Ctr Res Epidemiol & Stat, Epidemiol Childhood & Adolescent Canc Grp, Paris, France. [Monnereau, Alain; Clavel, Jacqueline] Univ Paris 05, Paris, France. [Monnereau, Alain] Inst Bergonie, Registre Hemopathies Malignes Gironde, Bordeaux, France. [Flowers, Christopher R.] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [De Roos, Anneclaire J.; Tinker, Lesley F.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Brooks-Wilson, Angela R.] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Melbye, Mads; Hjalgrim, Henrik] Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Melbye, Mads] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Gu, Jian; Ye, Yuanqing; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Kane, Eleanor; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve] Univ York, Dept Hlth Sci, York YO10 5DD, N Yorkshire, England. [Purdue, Mark P.] Ontario Hlth Study, Toronto, ON, Canada. [Vajdic, Claire M.] Univ New S Wales, Ctr Big Data Res Hlth, Sydney, NSW, Australia. [Kelly, Rachel S.; Bertrand, Kimberly A.; Adami, Hans-Olov; De Vivo, Immaculata; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kraft, Peter; Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Kelly, Rachel S.; Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Zucca, Mariagrazia] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [Rais, Marco] Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Cagliari, Italy. [Bertrand, Kimberly A.; De Vivo, Immaculata; Giovannucci, Edward; Birmann, Brenda M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA USA. [Bertrand, Kimberly A.; De Vivo, Immaculata; Giovannucci, Edward; Birmann, Brenda M.] Harvard Univ, Sch Med, Boston, MA USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Zeleniuch-Jacquotte, Anne] NYU, Langone Med Ctr, Perlmutter Canc Ctr, New York, NY USA. [Lawrence, Charles] WESTAT Corp, Rockville, MD 20850 USA. [Link, Brian K.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Tilly, Herve] Univ Rouen, Ctr Henri Becquerel, Rouen, France. [Haioun, Corinne] Henri Mondor Hosp, Lymphoid Malignancies Unit, Creteil, France. [Haioun, Corinne] Univ Paris Est, Creteil, France. [Molina, Thierry J.] Sorbonne Paris Cite, Univ Paris Descartes, AP HP, Dept Pathol,Necker Enfants Malad, Paris, France. [Glimelius, Bengt] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Roos, Goran] Umea Univ, Dept Med Biosci, Umea, Sweden. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Becker, Nikolaus; Kaaks, Rudolph] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Baden Wurttembe, Germany. [Benavente, Yolanda; de Sanjose, Silvia] Hosp Llobregat, Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Programme, Barcelona, Spain. [Benavente, Yolanda; de Sanjose, Silvia] CIBERESP, CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Klein, Robert J.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. [Foretova, Lenka] Masaryk Mem Canc Inst & MF MU, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Maynadie, Marc] Univ Burgundy, Registre Hemopathies Malignes Cote Or, EA 4184, Dijon, France. [Maynadie, Marc] Dijon Univ Hosp, Dijon, France. [Staines, Anthony] Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland. [Zheng, Tongzhang; Zhang, Yawei] Yale Univ, Dept Environm Hlth Sci, New Haven, CT USA. [Holford, Theodore R.] Yale Univ, Dept Biostat, New Haven, CT USA. [Turner, Jenny] Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW 2109, Australia. [Turner, Jenny] Douglass Hanly Moir Pathol, Dept Histopathol, Sydney, NSW, Australia. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland. [Vineis, Paolo] Human Genet Fdn, Turin, Italy. [Boeing, Heiner] German Inst Human Nutr, Dept Epidemiol, Potsdam, Germany. [Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Angelucci, Emanuele] Osped Oncol Riferimento Reg A Businco, Hematol Unit, Cagliari, Italy. [Di Lollo, Simonetta] Univ Florence, Sect Anatomopathol, Dept Surg & Translat Med, Florence, Italy. [Ma, Baoshan] Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian, Liaoning, Peoples R China. [Chiu, Brian C. H.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Park, Ju-Hyun] Dongguk Univ, Dept Stat, Seoul, South Korea. [Weisenburger, Dennis D.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Salles, Gilles] Hosp Civils Lyon, Dept Hematol, Pierre Benite, France. [Salles, Gilles] Univ Lyon 1, Dept Hematol, Pierre Benite, France. [Smedby, Karin E.] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden. RP Machiela, MJ (reprint author), 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM mitchell.machiela@nih.gov RI de Sanjose Llongueras, Silvia/H-6339-2014; Flowers, Christopher/F-1953-2010; Cox, David/A-2023-2009; Clavel, Jacqueline/Q-2750-2016; Vermeulen, Roel/F-8037-2011; Brooks-Wilson, Angela/E-9399-2012; OI Flowers, Christopher/0000-0002-9524-3990; Cox, David/0000-0002-2152-9259; Clavel, Jacqueline/0000-0002-3616-7676; Vermeulen, Roel/0000-0003-4082-8163; Brooks-Wilson, Angela/0000-0003-1009-6408; albright, lisa/0000-0003-2602-3668; Machiela, Mitchell/0000-0001-6538-9705; Giles, Graham/0000-0003-4946-9099; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Intramural Research Program of the NIH; National Cancer Institute; US Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004]; National Cancer Institute, Department of Health and Human Services [HHSN261201000006C]; American Cancer Society; Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics; National Cancer Institute Surveillance Epidemiology and End Results program; European Commission [QLK4-CT-2000-00422, FOOD-CT-2006-023103]; Spanish Ministry of Health [PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10, RTIC RD06/0020/0095]; Marato de TV3 Foundation [051210]; Agencia de Gestiod'AjutsUniversitarisi de Recerca - Generalitat de Catalunya [2014SRG756]; NIH [NO1-CO-12400]; Compagnia di San Paolo-Programma Oncologia; Federal Office for Radiation Protection [StSch4261, StSch4420]; Jose Carreras Leukemia Foundation [DJCLS-R12/23]; German Federal Ministry for Education and Research [BMBF-01-EO-1303]; Health Research Board, Ireland; Cancer Research Ireland; MH CZ - DRO (MMCI) [00209805]; RECAMO [CZ.1.05/2.1.00/03.0101]; Fondation de France; Association de Recherche Contre le Cancer; Leukemia & Lymphoma Society Career Development Award; Bernstein Family Fund for Leukemia and Lymphoma Research; National Institutes of Health [K08CA134919, CA167552, CA149445, CA098122, CA098566, K07 CA115687, CA186107, CA87969, CA49449]; National Center for Advancing Translational Science [UL1 TR000135]; NCI Specialized Programs of Research Excellence (SPORE) in Human Cancer [P50 CA97274]; Italian Association for Cancer Research (AIRC) [11855]; VicHealth and Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Geoffrey Beene Cancer Research Grant; Barbara K. Lipman Lymphoma Research Fund [74419]; Intramural Research Program of the National Cancer Institute, National Institutes of Health and Public Health Service [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105]; Australian National Health and Medical Research Council [ID990920]; Cancer Council NSW; University of Sydney Faculty of Medicine; Intramural Research Program of the National Cancer Institute; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; NCI, National Institutes of Health [CA1046282, CA154643]; California Department of Health Services [103885]; National Cancer Institute's Surveillance, Epidemiology, and End Results Program [HHSN261201000140C, HHSN261201000035C, HHSN261201000034C]; Centers for Disease Control and Prevention's National Program of Cancer Registries [1U58 DP000807-01]; Utah Population Database (UPDB); Utah Cancer Registry (UCR); Huntsman Cancer Institute (HCI); HCI Cancer Center [P30 CA42014]; NIH from the National Cancer Institute SEER Program [HHSN261201000026C]; Utah State Department of Health; University of Utah; Yorkshire Cancer Research; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; [006438]; [SP23-CT-2005-006438] FX ATBC: This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services.; CPS-II: The Cancer Prevention Study II (CPS-II) Nutrition Cohort is supported by the American Cancer Society. Genotyping for all CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The authors would also like to acknowledge the contribution to this study from central cancerregistries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and Cancer Registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program.; EPIC: Coordinated Action (contract #006438, SP23-CT-2005-006438); HuGeF (Human Genetics Foundation), Torino, Italy; Cancer Research UK.; EpiLymph: European Commission (grant references QLK4-CT-2000-00422 and FOOD-CT-2006-023103); the Spanish Ministry of Health (grant references CIBERESP, PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10 and RTIC RD06/0020/0095), the Marato de TV3 Foundation (grant reference 051210), the Agencia de Gestiod'AjutsUniversitarisi de Recerca - Generalitat de Catalunya (grant reference 2014SRG756) who had no role in the data collection, analysis or interpretation of the results; the NIH (contract NO1-CO-12400); the Compagnia di San Paolo-Programma Oncologia; the Federal Office for Radiation Protection grants StSch4261 and StSch4420, the Jose Carreras Leukemia Foundation grant DJCLS-R12/23, the German Federal Ministry for Education and Research (BMBF-01-EO-1303); the Health Research Board, Ireland and Cancer Research Ireland; Czech Republic supported by MH CZ - DRO (MMCI, 00209805) and RECAMO, CZ.1.05/2.1.00/03.0101; Fondation de France and Association de Recherche Contre le Cancer.; GEC/Mayo GWAS: National Institutes of Health (CA118444, CA148690 and CA92153). Intramural Research Program of the NIH, National Cancer Institute. Veterans Affairs Research Service. Data collection for Duke University was supported by a Leukemia & Lymphoma Society Career Development Award, the Bernstein Family Fund for Leukemia and Lymphoma Research, and the National Institutes of Health (K08CA134919), National Center for Advancing Translational Science (UL1 TR000135).; HPFS: The HPFS was supported in part by the National Institutes of Health grants CA167552, CA149445, CA098122, CA098566 and K07 CA115687 (B.M.B.). We thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions aswell as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. The authors assume full responsibility for analyses and interpretation of these data.; Iowa-Mayo SPORE: NCI Specialized Programs of Research Excellence (SPORE) in Human Cancer (P50 CA97274); National Cancer Institute (P30 CA086862 and P30 CA086862) and Henry J. Predolin Foundation.; Italian GxE: Italian Association for Cancer Research (AIRC, Investigator Grant 11855) (PC); Fondazione Banco di Sardegna 20102012, and Regione Autonoma della Sardegna (LR7 CRP-59812/2012) (MGE).; Mayo Clinic Case-Control: National Institutes of Health (R01 CA92153) and National Cancer Institute (P30 CA015083).; MCCS: The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database.; MSKCC: Geoffrey Beene Cancer Research Grant, Lymphoma Foundation (LF5541); Barbara K. Lipman Lymphoma Research Fund (74419); Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative (57470); U01 HG007033; ENCODE; U01 HG007033.; NCI-SEER: Intramural Research Program of the National Cancer Institute, National Institutes of Health and Public Health Service (N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010 and N02-PC-71105).; NHS: The NHS was supported in part by National Institutes of Health grants CA186107, CA87969, CA49449, CA149445, CA098122, CA098566 and K07 CA115687. We thank the participants and staff of the Nurses' Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. The authors assume full responsibility for analyses and interpretation of these data.; NSW: NSWwas supported by grants from the Australian National Health and Medical Research Council (ID990920), the Cancer Council NSW and the University of Sydney Faculty of Medicine.; NYU-WHS: National Cancer Institute (R01 CA098661 and P30 CA016087); National Institute of Environmental Health Sciences (ES000260).; PLCO: This research was supported by the Intramural Research Program of the National Cancer Institute and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS.; SCALE: Swedish Cancer Society (2009/659). Stockholm County Council (20110209) and the Strategic Research Program in Epidemiology at Karolinska Institute. Swedish Cancer Society grant (02 6661). National Institutes of Health (5R01 CA69669-02); Plan Denmark.; UCSF2: The UCSF studies were supported by the NCI, National Institutes of Health, CA1046282 and CA154643. The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The ideas and opinions expressed here are those of the authors, and endorsement by the State of California, the California Department of Health Services, the National Cancer Institute or the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred.; UTAH: National Institutes of Health CA134674. Partial support for data collection at the Utah site was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB is provided by the Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant P30 CA42014. The UCR is supported in part by NIH contract HHSN261201000026C from the National Cancer Institute SEER Program with additional support from the Utah State Department of Health and the University of Utah. Partial support for data collection in Sheffield, UK, was made possible by funds from Yorkshire Cancer Research. We thank the NCRI Haematooncology Clinical Studies Group, colleagues in the North Trent Cancer Network the North Trent Haemato-oncology Database.; WHI: WHI investigators are: Program Office-(National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford and Nancy Geller; Clinical Coordinating Center-(Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix and Charles Kooperberg; Investigators and Academic Centers-(Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) RobertWallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker; Women's Health Initiative Memory Study( Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C.; YALE: National Cancer Institute (CA62006) and National Cancer Institute (CA165923). NR 39 TC 5 Z9 5 U1 5 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD APR 15 PY 2016 VL 25 IS 8 BP 1663 EP 1676 DI 10.1093/hmg/ddw027 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DJ5FE UT WOS:000374231400016 PM 27008888 ER PT J AU Dorn, JF Zhang, L Phi, TT Lacroix, B Maddox, PS Liu, J Maddox, AS AF Dorn, Jonas F. Zhang, Li Phi, Tan-Trao Lacroix, Benjamin Maddox, Paul S. Liu, Jian Maddox, Amy Shaub TI A theoretical model of cytokinesis implicates feedback between membrane curvature and cytoskeletal organization in asymmetric cytokinetic furrowing SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID NONMUSCLE MYOSIN-II; CAENORHABDITIS-ELEGANS EMBRYO; CONTRACTILE RING; ACTIN-FILAMENTS; FISSION YEAST; C-ELEGANS; CELL-DIVISION; ACTOMYOSIN RING; CLEAVAGE FURROW; DIVIDING CELLS AB During cytokinesis, the cell undergoes a dramatic shape change as it divides into two daughter cells. Cell shape changes in cytokinesis are driven by a cortical ring rich in actin filaments and nonmuscle myosin II. The ring closes via actomyosin contraction coupled with actin depolymerization. Of interest, ring closure and hence the furrow ingression are nonconcentric (asymmetric) within the division plane across Metazoa. This nonconcentricity can occur and persist even without preexisting asymmetric cues, such as spindle placement or cellular adhesions. Cell-autonomous asymmetry is not explained by current models. We combined quantitative high-resolution live-cell microscopy with theoretical modeling to explore the mechanistic basis for asymmetric cytokinesis in the Caenorhabditis elegans zygote, with the goal of uncovering basic principles of ring closure. Our theoretical model suggests that feedback among membrane curvature, cytoskeletal alignment, and contractility is responsible for asymmetric cytokinetic furrowing. It also accurately predicts experimental perturbations of conserved ring proteins. The model further suggests that curvature-mediated filament alignment speeds up furrow closure while promoting energy efficiency. Collectively our work underscores the importance of membrane-cytoskeletal anchoring and suggests conserved molecular mechanisms for this activity. C1 [Dorn, Jonas F.; Zhang, Li; Phi, Tan-Trao] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3T 1J4, Canada. [Lacroix, Benjamin] Inst Jacques Monod, F-75205 Paris 13, France. [Maddox, Paul S.; Maddox, Amy Shaub] Univ N Carolina, Dept Biol, CB 3280, Chapel Hill, NC 27599 USA. [Liu, Jian] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20814 USA. [Dorn, Jonas F.] Novartis Pharma AG, CH-4056 Basel, Switzerland. RP Maddox, AS (reprint author), Univ N Carolina, Dept Biol, CB 3280, Chapel Hill, NC 27599 USA.; Liu, J (reprint author), NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20814 USA. EM jian.liu@nih.gov; asm@unc.edu FU Swiss National Science Foundation; National Institutes of Health [GM102390]; National Heart, Lung, and Blood Institute at the National Institutes of Health FX We thank Kerry Bloom, Julie Canman, and Ewa Paluch for critical reading of the manuscript. Carlos Patino Descovich and all members of the Maddox labs provided discussion and support. Jean-Claude Labbe provided feeding RNAs. James Fethiere (Institute for Research in Immunology and Cancer, Montreal, Canada) provided purified protein fragments. We acknowledge the thoughtful and constructive input from the anonymous referees. J.F.D. was supported by a post-doctoral fellowship from the Swiss National Science Foundation. This work was supported by National Institutes of Health Grant GM102390 to A.S.M. J.L. is supported by the intramural research program of the National Heart, Lung, and Blood Institute at the National Institutes of Health. NR 93 TC 0 Z9 0 U1 4 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD APR 15 PY 2016 VL 27 IS 8 BP 1286 EP 1299 DI 10.1091/mbc.E15-06-0374 PG 14 WC Cell Biology SC Cell Biology GA DL6MP UT WOS:000375753600012 PM 26912796 ER PT J AU Cekan, P Hasegawa, K Pan, Y Tubman, E Odde, D Chen, JQ Herrmann, MA Kumar, S Kalab, P AF Cekan, Pavol Hasegawa, Keisuke Pan, Yu Tubman, Emily Odde, David Chen, Jin-Qiu Herrmann, Michelle A. Kumar, Sheetal Kalab, Petr TI RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage-induced cell senescence SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID XENOPUS EGG EXTRACTS; NUCLEAR IMPORT; DRUG-RESISTANCE; CARGO TRANSPORT; CANCER; EXPORT; PROTEINS; GRADIENT; MITOSIS; PROLIFERATION AB The coordination of cell cycle progression with the repair of DNA damage supports the genomic integrity of dividing cells. The function of many factors involved in DNA damage response (DDR) and the cell cycle depends on their Ran GTPase-regulated nuclear-cytoplasmic transport (NCT). The loading of Ran with GTP, which is mediated by RCC1, the guanine nucleotide exchange factor for Ran, is critical for NCT activity. However, the role of RCC1 or Ran.GTP in promoting cell proliferation or DDR is not clear. We show that RCC1 overexpression in normal cells increased cellular Ran.GTP levels and accelerated the cell cycle and DNA damage repair. As a result, normal cells overexpressing RCC1 evaded DNA damage- induced cell cycle arrest and senescence, mimicking colorectal carcinoma cells with high endogenous RCC1 levels. The RCC1-induced inhibition of senescence required Ran and exportin 1 and involved the activation of importin beta-dependent nuclear import of 53BP1, a large NCT cargo. Our results indicate that changes in the activity of the Ran.GTP-regulated NCT modulate the rate of the cell cycle and the efficiency of DNA repair. Through the essential role of RCC1 in regulation of cellular Ran.GTP levels and NCT, RCC1 expression enables the proliferation of cells that sustain DNA damage. C1 [Cekan, Pavol; Pan, Yu; Kumar, Sheetal; Kalab, Petr] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Chen, Jin-Qiu; Herrmann, Michelle A.] NCI, Collaborat Prot Technol Resource, NIH, Bethesda, MD 20892 USA. [Hasegawa, Keisuke] Grinnell Coll, Dept Phys, Grinnell, IA 50112 USA. [Hasegawa, Keisuke; Tubman, Emily; Odde, David] Marine Biol Lab, Physiol Course, Woods Hole, MA 02543 USA. [Tubman, Emily; Odde, David] Univ Minnesota, Biomed Engn, Minneapolis, MN 55455 USA. [Kalab, Petr] Johns Hopkins Univ, Dept Chem & Biomol Engn, 3400 N Charles St, Baltimore, MD 21218 USA. RP Kalab, P (reprint author), NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA.; Kalab, P (reprint author), Johns Hopkins Univ, Dept Chem & Biomol Engn, 3400 N Charles St, Baltimore, MD 21218 USA. EM pkalab@yahoo.com OI Odde, David/0000-0001-7731-2799 FU Center for Cancer Research, NCI; National Institutes of Health [R01 GM071522] FX We thank R. Heald and K. Weis for comments and suggestions on the manuscript; P. Scaffidi, B. Vogelstein, C. Harris, and A. Schetter for cell lines, Karyopharm (Newton, MA) for the donation of KPT-330; and J. Lee and S. J. Ryu for technical assistance. Imaging was performed at the Confocal Microscopy Core Facility of the Center for Cancer Research, National Cancer Institute (NCI), in Bethesda, Maryland. P. C., K.H., Y.P., J.-Q.C., M.A.H., S. K., and P. K. were supported by the Intramural Research Program of the Center for Cancer Research, NCI. D.O. and E.T. were supported by National Institutes of Health grant R01 GM071522. NR 59 TC 0 Z9 0 U1 1 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD APR 15 PY 2016 VL 27 IS 8 BP 1346 EP 1357 DI 10.1091/mbc.E16-01-0025 PG 12 WC Cell Biology SC Cell Biology GA DL6MP UT WOS:000375753600017 PM 26864624 ER PT J AU Zerbe, CS Marciano, BE Katial, RK Santos, CB Adamo, N Hsu, AP Hanks, ME Darnell, DN Quezado, MM Frein, C Barnhart, LA Anderson, VL Uzel, G Freeman, AF Lisco, A Nath, A Major, EO Sampaio, EP Holland, SM AF Zerbe, Christa S. Marciano, Beatriz E. Katial, Rohit K. Santos, Carah B. Adamo, Nick Hsu, Amy P. Hanks, Mary E. Darnell, Dirk N. Quezado, Martha M. Frein, Cathleen Barnhart, Lisa A. Anderson, Victoria L. Uzel, Gulbu Freeman, Alexandra F. Lisco, Andrea Nath, Avindra Major, Eugene O. Sampaio, Elizabeth P. Holland, Steven M. TI Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE progressive multifocal leukoencephalopathy; PML; primary immunodeficiency; STAT1 gain of function; PID ID COMMON VARIABLE IMMUNODEFICIENCY; CHRONIC MUCOCUTANEOUS CANDIDIASIS; WISKOTT-ALDRICH SYNDROME; HYPER-IGM SYNDROME; JC-VIRUS; MULTIPLE-SCLEROSIS; PATIENT; MUTATIONS; ADULT; CHILD AB Background. Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). Methods. STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. Results. We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. Conclusions. The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system. C1 [Zerbe, Christa S.; Marciano, Beatriz E.; Adamo, Nick; Hsu, Amy P.; Hanks, Mary E.; Darnell, Dirk N.; Barnhart, Lisa A.; Anderson, Victoria L.; Uzel, Gulbu; Freeman, Alexandra F.; Lisco, Andrea; Sampaio, Elizabeth P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Katial, Rohit K.; Santos, Carah B.] Natl Jewish Hlth, Denver, CO USA. [Katial, Rohit K.; Santos, Carah B.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Quezado, Martha M.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Frein, Cathleen] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Nath, Avindra] NINDS, Translat Neurosci Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIH, Lab Clin Infect Dis, CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN261200800001E] FX This study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), and was funded in part with federal funds from the National Cancer Institute, NIH (contract number HHSN261200800001E). NR 43 TC 4 Z9 4 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2016 VL 62 IS 8 BP 986 EP 994 DI 10.1093/cid/civ1220 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DK7EU UT WOS:000375088500011 PM 26743090 ER PT J AU Calderon, MM Penzak, SR Pau, AK Kumar, P McManus, M Alfaro, RM Kovacs, JA AF Calderon, Monica M. Penzak, Scott R. Pau, Alice K. Kumar, Parag McManus, Maryellen Alfaro, Raul M. Kovacs, Joseph A. TI Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE atovaquone; efavirenz; drug interaction; Pneumocystis jiroveci pneumonia; toxoplasma encephalitis ID TOXOPLASMIC ENCEPHALITIS; PHARMACOKINETICS; LOPINAVIR/RITONAVIR; VOLUNTEERS; LAMOTRIGINE; SUSPENSION; RITONAVIR; AIDS AB Background. The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone. Methods. Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCt) and average concentration (C-avg) were calculated and compared using an unpaired t test. Results. Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUCt than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P=.01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone C-avg >15 mu g/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia. AUCt and C-avg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone C-avg >18.5 mu g/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis (TE). Conclusions. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV. C1 [Calderon, Monica M.; Penzak, Scott R.; Kumar, Parag; Alfaro, Raul M.] NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Calderon, Monica M.; McManus, Maryellen] NCI, Leidos Biomed Res Inc, Frederick, MD 21701 USA. [Pau, Alice K.] NIAID, NIH, Bethesda, MD USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Calderon, Monica M.] US FDA, Off Safety & Epidemiol, Silver Spring, MD USA. [Penzak, Scott R.] Univ North Texas Syst, Coll Pharm, Dept Pharmacotherapy, 3500 Camp Bowie Blvd,RES 411-A, Ft Worth, TX 76107 USA. RP Penzak, SR (reprint author), Univ North Texas Syst, Coll Pharm, Dept Pharmacotherapy, 3500 Camp Bowie Blvd,RES 411-A, Ft Worth, TX 76107 USA. EM scott.penzak@unthsc.edu FU Intramural NIH HHS; PHS HHS [HHSN2612008000] NR 17 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2016 VL 62 IS 8 BP 1036 EP 1042 DI 10.1093/cid/ciw028 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DK7EU UT WOS:000375088500019 PM 26797214 ER PT J AU Lovely, GA Sen, R AF Lovely, Geoffrey A. Sen, Ranjan TI Evolving adaptive immunity SO GENES & DEVELOPMENT LA English DT Editorial Material DE RAG; Transib; V(D)J recombination; evolution; transposition ID V(D)J RECOMBINATION; EVOLUTION; LOCUS; TRANSPOSITION; MECHANISM; PROTEINS; SYSTEM; RAG2 AB Generation of a diverse repertoire of antigen receptor specificities via DNA recombination underpins adaptive immunity. In this issue of Genes & Development, Carmona and colleagues (pp. 909-917) provide novel insights into the origin and function of recombination-activating gene 1 (RAG1) and RAG2, the lymphocyte-specific components of the recombinase involved in the process. C1 [Lovely, Geoffrey A.; Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Sen, R (reprint author), NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. EM senra@mail.nih.gov NR 10 TC 0 Z9 0 U1 3 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD APR 15 PY 2016 VL 30 IS 8 BP 873 EP 875 DI 10.1101/gad.281014.116 PG 3 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DK4XL UT WOS:000374923500001 PM 27083993 ER PT J AU Ghirlando, R Felsenfeld, G AF Ghirlando, Rodolfo Felsenfeld, Gary TI CTCF: making the right connections SO GENES & DEVELOPMENT LA English DT Review DE chromatin; insulators; topologically associated domains ID ENHANCER-BLOCKING ACTIVITY; INSULATOR PROTEIN CTCF; 3D GENOME ARCHITECTURE; CCCTC-BINDING FACTOR; C-MYC GENE; TRANSCRIPTIONAL INSULATION; CHROMATIN ARCHITECTURE; MEDIATED INTERACTIONS; REGULATORY LANDSCAPE; PLURIPOTENT CELLS AB The role of the zinc finger protein CTCF in organizing the genome within the nucleus is now well established. Widely separated sites on DNA, occupied by both CTCF and the cohesin complex, make physical contacts that create large loop domains. Additional contacts between loci within those domains, often also mediated by CTCF, tend to be favored over contacts between loci in different domains. A large number of studies during the past 2 years have addressed the questions: How are these loops generated? What are the effects of disrupting them? Are there rules governing large-scale genome organization? It now appears that the strongest and evolutionarily most conserved of these CTCF interactions have specific rules for the orientation of the paired CTCF sites, implying the existence of a nonequilibrium mechanism of generation. Recent experiments that invert, delete, or inactivate one of a mating CTCF pair result in major changes in patterns of organization and gene expression in the surrounding regions. What remain to be determined are the detailed molecular mechanisms for re-establishing loop domains and maintaining them after replication and mitosis. As recently published data show, some mechanisms may involve interactions with noncoding RNAs as well as protein cofactors. Many CTCF sites are also involved in other functions such as modulation of RNA splicing and specific regulation of gene expression, and the relationship between these activities and loop formation is another unanswered question that should keep investigators occupied for some time. C1 [Ghirlando, Rodolfo; Felsenfeld, Gary] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank members of our laboratory for their suggestions and encouragement. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 94 TC 11 Z9 11 U1 14 U2 29 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD APR 15 PY 2016 VL 30 IS 8 BP 881 EP 891 DI 10.1101/gad.277863.116 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DK4XL UT WOS:000374923500004 PM 27083996 ER PT J AU Jennis, M Kung, CP Basu, S Budina-Kolomets, A Leu, JIJ Khaku, S Scott, JP Cai, KQ Campbell, MR Porter, DK Wang, XT Bell, DA Li, XX Garlick, DS Liu, Q Hollstein, M George, DL Murphy, ME AF Jennis, Matthew Kung, Che-Pei Basu, Subhasree Budina-Kolomets, Anna Leu, Julia I-Ju Khaku, Sakina Scott, Jeremy P. Cai, Kathy Q. Campbell, Michelle R. Porter, Devin K. Wang, Xuting Bell, Douglas A. Li, Xiaoxian Garlick, David S. Liu, Qin Hollstein, Monica George, Donna L. Murphy, Maureen E. TI An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model SO GENES & DEVELOPMENT LA English DT Article DE p53; tumor suppression; metabolism; ferroptosis; polymorphism; Ser46 phosphorylation ID INTERACTING PROTEIN KINASE-2; NONAPOPTOTIC CELL-DEATH; DNA-DAMAGE; P53-DEPENDENT APOPTOSIS; SER46 PHOSPHORYLATION; FERROPTOSIS; MUTATIONS; MICE; SENESCENCE; RESPONSES AB A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism: Gls2 (glutaminase 2) and Sco2. We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53. C1 [Jennis, Matthew; Kung, Che-Pei; Basu, Subhasree; Budina-Kolomets, Anna; Khaku, Sakina; Scott, Jeremy P.; Liu, Qin; Murphy, Maureen E.] Wistar Inst Anat & Biol, Program Mol & Cellular Oncogenesis, 3601 Spruce St, Philadelphia, PA 19104 USA. [Jennis, Matthew] Drexel Univ, Coll Med, Program Mol & Cellular Biol & Genet, Philadelphia, PA 19102 USA. [Leu, Julia I-Ju; George, Donna L.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Cai, Kathy Q.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Campbell, Michelle R.; Porter, Devin K.; Wang, Xuting; Bell, Douglas A.] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Li, Xiaoxian] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Garlick, David S.] Wistar Inst Anat & Biol, Ctr Canc, 3601 Spruce St, Philadelphia, PA 19104 USA. [Hollstein, Monica] Univ Leeds, Leeds LS2 9JT, W Yorkshire, England. RP Murphy, ME (reprint author), Wistar Inst Anat & Biol, Program Mol & Cellular Oncogenesis, 3601 Spruce St, Philadelphia, PA 19104 USA. EM mmurphy@wistar.org OI Wang, Xuting/0000-0001-6781-8008 FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES-100475]; [R01 CA102184]; [PO1 CA114046] FX We acknowledge the Cell Culture Facility and Transgenic Facility at The Fox Chase Cancer Center as well as the members of the Microscopy Facility (Fred Keeney), the Genomics Facility (Tran Nguyen and Celia Chang), and the Laboratory Animal Facility at The Wistar Institute for assistance with these studies. Support for Core Facilities used in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute. This research was funded by R01 CA102184 (M.E.M.) and PO1 CA114046 (to D.L.G). This work was supported in part by funding from the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health Z01-ES-100475 (to D.A.B.). M.J., C.-P.K., S.B., A.B.-K., J.I.-J.L., D.A.B., Q.L., M.H., D.L.G., and M.E.M. conceived and designed the study. K.Q.C., X.L., D.S.G., and M.H. provided reagents and expertise. M.J., C.-P.K., S.B., A.B.-K., J.I.-J.L., S.K., J.P.S., M.R.C., D.K.P., X.W., D.A.B., Q.L., M.H., D.L.G., and M.E.M. acquired and analyzed the data. M.J., D.L.G., and M.E.M. drafted the manuscript, and all authors provided critical revisions. NR 41 TC 6 Z9 6 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD APR 15 PY 2016 VL 30 IS 8 BP 918 EP 930 DI 10.1101/gad.275891.115 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DK4XL UT WOS:000374923500007 PM 27034505 ER PT J AU Aerbajinai, W Liu, LH Zhu, JQ Kumkhaek, C Chin, K Rodgers, GP AF Aerbajinai, Wulin Liu, Lunhua Zhu, Jianqiong Kumkhaek, Chutima Chin, Kyung Rodgers, Griffin P. TI Glia Maturation Factor- Regulates Monocyte Migration through Modulation of 1-Integrin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE adhesion; Arp2; 3 complex; cell migration; endocytosis; integrin; ubiquitylation (ubiquitination); glia maturation factor-gamma (GMFG) ID STIMULATED GLUT4 TRANSLOCATION; CELL-MIGRATION; MEMBRANE-FUSION; FACTOR-GAMMA; NEUTROPHIL CHEMOTAXIS; LYSOSOMAL DEGRADATION; SYNIP PHOSPHORYLATION; ACTIN POLYMERIZATION; INTEGRIN TRAFFICKING; RECYCLING PATHWAYS AB Monocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle, but the complex molecular mechanisms underlying this process have not been fully elucidated. Glia maturation factor- (GMFG), a novel regulator of the Arp2/3 complex, has been shown to regulate directional migration of neutrophils and T-lymphocytes. In this study, we explored the important role of GMFG in monocyte chemotaxis, adhesion, and 1-integrin turnover. We found that knockdown of GMFG in monocytes resulted in impaired chemotactic migration toward formyl-Met-Leu-Phe (fMLP) and stromal cell-derived factor 1 (SDF-1) as well as decreased 51-integrin-mediated chemoattractant-stimulated adhesion. These GMFG knockdown impaired effects could be reversed by cotransfection of GFP-tagged full-length GMFG. GMFG knockdown cells reduced the cell surface and total protein levels of 51-integrin and increased its degradation. Importantly, we demonstrate that GMFG mediates the ubiquitination of 1-integrin through knockdown or overexpression of GMFG. Moreover, GMFG knockdown retarded the efficient recycling of 1-integrin back to the plasma membrane following normal endocytosis of 51-integrin, suggesting that the involvement of GMFG in maintaining 51-integrin stability may occur in part by preventing ubiquitin-mediated degradation and promoting 1-integrin recycling. Furthermore, we observed that GMFG interacted with syntaxin 4 (STX4) and syntaxin-binding protein 4 (STXBP4); however, only knockdown of STXBP4, but not STX4, reduced monocyte migration and decreased 1-integrin cell surface expression. Knockdown of STXBP4 also substantially inhibited 1-integrin recycling in human monocytes. These results indicate that the effects of GMFG on monocyte migration and adhesion probably occur through preventing ubiquitin-mediated proteasome degradation of 51-integrin and facilitating effective 1-integrin recycling back to the plasma membrane. C1 [Aerbajinai, Wulin; Zhu, Jianqiong; Kumkhaek, Chutima; Chin, Kyung; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. [Liu, Lunhua] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIH, Mol & Clin Hematol Branch, Bldg 10,Rm 9N-113A, Bethesda, MD 20892 USA. EM gr5n@nih.gov FU NIDDK, National Institutes of Health FX This work was supported by the Intramural Research Program of NIDDK, National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 62 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 15 PY 2016 VL 291 IS 16 BP 8549 EP 8564 DI 10.1074/jbc.M115.674200 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK2VT UT WOS:000374773200020 PM 26895964 ER PT J AU Jang, SI Ong, HL Liu, X Alevizos, I Ambudkar, IS AF Jang, Shyh-Ing Ong, Hwei Ling Liu, Xibao Alevizos, Ilias Ambudkar, Indu S. TI Up-regulation of Store-operated Ca2+ Entry and Nuclear Factor of Activated T Cells Promote the Acinar Phenotype of the Primary Human Salivary Gland Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE calcium release-activated calcium channel protein 1 (ORAI1); gene expression; NFAT transcription factor; stromal interaction molecule 1 (STIM1); water channel ID NEURAL STEM-CELLS; EPITHELIAL-CELLS; TRANSCRIPTION FACTORS; CALCIUM SIGNALS; GROWTH-FACTOR; SECRETION; NFAT; DIFFERENTIATION; EXPRESSION; CHANNELS AB The signaling pathways involved in the generation and maintenance of exocrine gland acinar cells have not yet been established. Primary human salivary gland epithelial cells, derived from salivary gland biopsies, acquired an acinar-like phenotype when the [Ca2+] in the serum-free medium (keratinocyte growth medium, KGM) was increased from 0.05 mm (KGM-L) to 1.2 mm (KGM-H). Here we examined the mechanism underlying this Ca2+-dependent generation of the acinar cell phenotype. Compared with cells in KGM-L, those in KGM-H display enhancement of Orai1, STIM1, STIM2, and nuclear factor of activated T cells 1 (NFAT1) expression together with an increase in store-operated Ca2+ entry (SOCE), SOCE-dependent nuclear translocation of pGFP-NFAT1, and NFAT-dependent but not NFB-dependent gene expression. Importantly, AQP5, an acinar-specific protein critical for function, is up-regulated in KGM-H via SOCE/NFAT-dependent gene expression. We identified critical NFAT binding motifs in the AQP5 promoter that are involved in Ca2+-dependent up-regulation of AQP5. These important findings reveal that the Ca2+-induced switch of salivary epithelial cells to an acinar-like phenotype involves remodeling of SOCE and NFAT signaling, which together control the expression of proteins critically relevant for acinar cell function. Our data provide a novel strategy for generating and maintaining acinar cells in culture. C1 [Jang, Shyh-Ing; Ong, Hwei Ling; Liu, Xibao; Alevizos, Ilias; Ambudkar, Indu S.] NIDCR, Secretory & Physiol Sect, NIH, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. [Jang, Shyh-Ing; Ong, Hwei Ling; Liu, Xibao; Alevizos, Ilias; Ambudkar, Indu S.] NIDCR, Sjogrens Syndrome & Salivary Gland Dysfunct Unit, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Alevizos, I; Ambudkar, IS (reprint author), NIDCR, Secretory & Physiol Sect, NIH, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA.; Alevizos, I; Ambudkar, IS (reprint author), NIDCR, Sjogrens Syndrome & Salivary Gland Dysfunct Unit, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM alevizosi@nidcr.nih.gov; indu.ambudkar@nih.gov NR 37 TC 3 Z9 3 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 15 PY 2016 VL 291 IS 16 BP 8709 EP 8720 DI 10.1074/jbc.M115.701607 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK2VT UT WOS:000374773200033 PM 26903518 ER PT J AU Randles, L Anchoori, RK Roden, RBS Walters, KJ AF Randles, Leah Anchoori, Ravi K. Roden, Richard B. S. Walters, Kylie J. TI The Proteasome Ubiquitin Receptor hRpn13 and Its Interacting Deubiquitinating Enzyme Uch37 Are Required for Proper Cell Cycle Progression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cancer biology; cell proliferation; proteasome; ubiquitin; ubiquitylation (ubiquitination); RA190; Uch37; cell cycle progression; hRpn13; p27Kip1 ID CDK INHIBITOR P27; 26S PROTEASOME; BORTEZOMIB RESISTANCE; REGULATORY PARTICLE; ANTICANCER THERAPY; MULTIPLE-MYELOMA; SUBUNIT; CANCER; RPN13; ACTIVATION AB Recently, we reported that bisbenzylidine piperidone RA190 adducts to Cys-88 of the proteasome ubiquitin receptor hRpn13, triggering accumulation of ubiquitinated proteins and endoplasmic reticulum stress-related apoptosis in various cancer cell lines. hRpn13 contains an N-terminal pleckstrin-like receptor for ubiquitin domain that binds ubiquitin and docks it into the proteasome as well as a C-terminal deubiquitinase adaptor (DEUBAD) domain that binds the deubiquitinating enzyme Uch37. Here we report that hRpn13 and Uch37 are required for proper cell cycle progression and that their protein knockdown leads to stalling at G(0)/G(1). Moreover, serum-starved cells display reduced hRpn13 and Uch37 protein levels with hallmarks of G(0)/G(1) stalling and recovery to their steady-state protein levels following release from nutrient deprivation. Interestingly, loss of hRpn13 correlates with a small but statistically significant reduction in Uch37 protein levels, suggesting that hRpn13 interaction may stabilize this deubiquitinating enzyme in human cells. We also find that RA190 treatment leads to a loss of S phase, suggesting a block of DNA replication, and G(2) arrest by using fluorescence-activated cell sorting. Uch37 deprivation further indicated a reduction of DNA replication and G(0)/G(1) stalling. Overall, this work implicates hRpn13 and Uch37 in cell cycle progression, providing a rationale for their function in cellular proliferation and for the apoptotic effect of the hRpn13-targeting molecule RA190. C1 [Randles, Leah; Walters, Kylie J.] NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Anchoori, Ravi K.; Roden, Richard B. S.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21231 USA. [Roden, Richard B. S.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21231 USA. [Roden, Richard B. S.] Johns Hopkins Univ, Dept Gynecol & Obstet, Baltimore, MD 21231 USA. RP Walters, KJ (reprint author), NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. EM kylie.walters@nih.gov FU NCI, National Institutes of Health Center for Cancer Research; NCI, National Institutes of Health [P50 CA098252]; Alleghany Health Network-Johns Hopkins Cancer Research Fund; PI therapeutics FX This work was supported by the Intramural Research Program of the NCI, National Institutes of Health Center for Cancer Research (to K. J. W.), NCI, National Institutes of Health Grant P50 CA098252 (to R. B. S. R.), and the Alleghany Health Network-Johns Hopkins Cancer Research Fund (to R. B. S. R.). R. K. A. and R. B. S. R. are inventors of intellectual property licensed to Pontifax/PI therapeutics and have received research funding from PI therapeutics. Under a licensing agreement between Pontifax/PI therapeutics and the Johns Hopkins University, Drs. Roden and Anchoori are entitled to a share of royalty received by the University on an invention described in this article. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 77 TC 2 Z9 2 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 15 PY 2016 VL 291 IS 16 BP 8773 EP 8783 DI 10.1074/jbc.M115.694588 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK2VT UT WOS:000374773200038 PM 26907685 ER PT J AU Pettitt, J Higgs, ES Adams, RD Jahrling, PB Hensley, LE AF Pettitt, James Higgs, Elizabeth S. Adams, Rick D. Jahrling, Peter B. Hensley, Lisa E. TI Use of Existing Diagnostic Reverse-Transcription Polymerase Chain Reaction Assays for Detection of Ebola Virus RNA in Semen SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola; PCR; semen; diagnosis ID TRANSMISSION AB Sexual transmission of Ebola virus in Liberia has now been documented and associated with new clusters in regions previously declared Ebola free. Assays that have Emergency Use Authorization (EUA) and are routinely used to detect Ebola virus RNA in whole blood and plasma specimens at the Liberian Institute for Biomedical Research were tested for their suitability in detecting the presence of Ebola virus RNA in semen. Qiagen AVL extraction protocols, as well as the Ebola Zaire Target 1 and major groove binder quantitative reverse-transcription polymerase chain reaction assays, were demonstrably suitable for this purpose and should facilitate epidemiologic investigations, including those involving long-term survivors of Ebola. C1 [Pettitt, James; Higgs, Elizabeth S.; Adams, Rick D.; Jahrling, Peter B.; Hensley, Lisa E.] NIAID, Integrated Res Facil, Div Clin Res, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. RP Jahrling, PB (reprint author), NIAID, Integrated Res Facil, Div Clin Res, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. EM jahrlingp@niaid.nih.gov FU intramural program of the Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the intramural program of the Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 7 TC 6 Z9 6 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD APR 15 PY 2016 VL 213 IS 8 BP 1237 EP 1239 DI 10.1093/infdis/jiv454 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DL0CG UT WOS:000375298700006 PM 26374912 ER PT J AU Akbar, M Essa, MM Daradkeh, G Abdelmegeed, MA Choi, Y Mahmood, L Song, BJ AF Akbar, Mohammed Essa, Musthafa Mohamed Daradkeh, Ghazi Abdelmegeed, Mohamed A. Choi, Youngshim Mahmood, Lubna Song, Byoung-Joon TI Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress SO BRAIN RESEARCH LA English DT Article DE Oxidative stress; Mitochondrial dysfunction; Neuronal cell death; Neurodegenerative diseases; Post-translational protein modifications; Antioxidants; Translational research ID TRAUMATIC BRAIN-INJURY; NITRIC-OXIDE SYNTHASE; TARGETED ANTIOXIDANT MITOQ; ACUTE LIVER-INJURY; DEPENDENT NEUROPROTECTIVE PROTEIN; AMYOTROPHIC-LATERAL-SCLEROSIS; MILD COGNITIVE IMPAIRMENT; TRANSGENIC MOUSE MODEL; AMYLOID-BETA PEPTIDE; ALZHEIMERS-DISEASE AB Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities. Published by Elsevier B.V. C1 [Akbar, Mohammed; Abdelmegeed, Mohamed A.; Choi, Youngshim; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Essa, Musthafa Mohamed; Daradkeh, Ghazi] Sultan Qaboos Univ, Coll Agr & Marine Sci, Dept Food Sci & Nutr, Muscat, Oman. [Essa, Musthafa Mohamed] Sultan Qaboos Univ, Ageing & Dementia Res Grp, Muscat, Oman. [Mahmood, Lubna] Qatar Univ, Dept Nutr Sci, Muscat, Qatar. RP Akbar, M; Song, BJ (reprint author), NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA.; Essa, MM (reprint author), Sultan Qaboos Univ, Coll Agr & Marine Sci, Dept Food Sci & Nutr, Muscat, Oman. FU National Institute on Alcohol Abuse and Alcoholism; Research Council, Oman [RC/AGR/FOOD/11/01]; Sultan Qaboos University, Oman [IG/AGR/FOOD/14/01]; KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea FX The work is supported by the Intramural Program Fund of the National Institute on Alcohol Abuse and Alcoholism. The authors (MME and GD) also highly appreciate the research supports from the Research Council, Oman (RC/AGR/FOOD/11/01 to MME) and the internal grant (IG/AGR/FOOD/14/01) from Sultan Qaboos University, Oman. Youngshim Choi is supported by the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea. NR 270 TC 6 Z9 8 U1 8 U2 28 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD APR 15 PY 2016 VL 1637 BP 34 EP 55 DI 10.1016/j.brainres.2016.02.016 PG 22 WC Neurosciences SC Neurosciences & Neurology GA DK0NY UT WOS:000374610700004 PM 26883165 ER PT J AU Liu, BJ Chen, HL Fang, F Tillander, A Wirdefeldt, K AF Liu, Bojing Chen, Honglei Fang, Fang Tillander, Annika Wirdefeldt, Karin TI Early-Life Factors and Risk of Parkinson's Disease: A Register-Based Cohort Study SO PLOS ONE LA English DT Article ID EXPOSURE; CHILDHOOD; INFLUENZA; EPIDEMIOLOGY; ASSOCIATION; INFECTIONS; SIBLINGS AB Parkinson's disease (PD) may take decades to develop and early life exposures such as infection may be important. However, few epidemiological studies have evaluated early life risk factors in relation to PD risk. We therefore examined such associations in a prospective analysis of 3 545 612 individuals born in Sweden between 1932 and 1970 without PD on January 1, 2002. Incident PD cases were identified using the Swedish Patient Register during 2002-2010. Information on sibship size, number of older and younger siblings, multiple births, parental age, birth month and season was obtained from the Swedish Multi-Generation Register. Monthly data on national burden of influenza-like illness during 1932-1970 were obtained from the Swedish Public Health Agency. Hazard ratios with 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. During the follow-up, 8779 incident PD cases were identified. As expected, older age, male sex, parental occupation as farmers, and family history of PD were associated with higher PD risk. Overall, early life factors, including flu burden in the year of birth, were not associated with PD risk, although we did find a lower PD risk among participants with older siblings than those without (HR = 0.93, 95% CI: 0.89, 0.98). Our study therefore provided little support for important etiological contributions of early life factors to the PD risk late in life. The finding of a lower PD risk among individuals with older siblings will need confirmation and further investigation. C1 [Liu, Bojing; Fang, Fang; Tillander, Annika; Wirdefeldt, Karin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Wirdefeldt, Karin] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. RP Liu, BJ (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM bojing.liu@ki.se OI Chen, Honglei/0000-0003-3446-7779 FU Swedish Research Council for Health, Working Life and Welfare [2013-1350]; KI-NIH Doctoral Partnership Program in Neuroscience; Swedish Society for Medical Research; Karolinska Institutet; NIH, the National Institute of Environmental Health Sciences [Z01-ES-101986] FX KW received funding from Swedish Research Council for Health, Working Life and Welfare (www.forte.se, 2013-1350), KI-NIH Doctoral Partnership Program in Neuroscience (www.ki.se). FF received funding from Swedish Society for Medical Research (www.ssmf.se) and Karolinska Institutet (www.ki.se). HC received funding from the intramural research program of the NIH, the National Institute of Environmental Health Sciences (www.niehs.nih.gov, Z01-ES-101986). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. NR 29 TC 1 Z9 1 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 15 PY 2016 VL 11 IS 4 AR e0152841 DI 10.1371/journal.pone.0152841 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ6AH UT WOS:000374291800010 PM 27082111 ER PT J AU Zhao, Z Zhu, XP Cui, K Mancuso, J Federley, R Fischer, K Teng, GJ Mittal, V Gao, DC Zhao, H Wong, STC AF Zhao, Zhen Zhu, Xiaoping Cui, Kemi Mancuso, James Federley, Richard Fischer, Kari Teng, Gao-jun Mittal, Vivek Gao, Dingcheng Zhao, Hong Wong, Stephen T. C. TI In Vivo Visualization and Characterization of Epithelial-Mesenchymal Transition in Breast Tumors SO CANCER RESEARCH LA English DT Article ID ALTERNATIVE SPLICING REPORTERS; CANCER METASTASIS; C-MET; PLASTICITY; GROWTH; ANGIOGENESIS; FIBROBLASTS; PROGRESSION; INHIBITION; MICROSCOPY AB The activation of the epithelial-to-mesenchymal transition (EMT) program is a critical step in cancer progression and metastasis, but visualization of this process at the single-cell level, especially in vivo, remains challenging. We established an in vivo approach to track the fate of tumor cells based on a novel EMT-driven fluorescent color switching breast cancer mouse model and intravital two-photon laser scanning microscopy. Specifically, the MMTV-PyMT, Rosa26-RFP-GFP, and Fsp1-Cre triple transgenic mouse model was used to monitor the conversion of RFP-positive epithelial cells to GFP-positive mesenchymal cells in mammary tumors under the control of the Fsp1 (ATL1) promoter, a gatekeeper of EMT initiation. RFP-positive cells were isolated from the tumors, sorted, and transplanted into mammary fat pads of SCID mice to monitor EMT during breast tumor formation. We found that the conversion from RFP-to-GFP-positive and spindle-shaped cells was a gradual process, and that GFP-positive cells preferentially localized close to blood vessels, independent of tumor size. Furthermore, cells undergoing EMT expressed high levels of the HGF receptor, c-Met, and treatment of RFP-positive cells with the c-Met inhibitor, cabozantinib, suppressed the RFP-to-GFP conversion in vitro. Moreover, administration of cabozantinib to mice with palpable RFP-positive tumors resulted in a silent EMT phenotype whereby GFP-positive cells exhibited reduced motility, leading to suppressed tumor growth. In conclusion, our imaging technique provides a novel opportunity for visualizing tumor EMT at the single-cell level and may help to reveal the intricacies underlying tumor dynamics and treatment responses. (C) 2016 AACR. C1 [Zhao, Zhen; Teng, Gao-jun; Wong, Stephen T. C.] Southeast Univ, Zhong Da Hosp, Dept Radiol, Nanjing, Jiangsu, Peoples R China. [Zhao, Zhen; Zhu, Xiaoping; Cui, Kemi; Mancuso, James; Federley, Richard; Zhao, Hong; Wong, Stephen T. C.] Weill Cornell Med, Houston Methodist Res Inst, Dept Syst Med & Bioengn, Houston, TX USA. [Fischer, Kari; Mittal, Vivek; Gao, Dingcheng] Weill Cornell Med, Dept Cell & Dev Biol, New York, NY USA. [Zhao, Hong; Wong, Stephen T. C.] Weill Cornell Med, NCI Ctr Modeling Canc Dev, Houston Methodist Res Inst, Houston, TX USA. [Wong, Stephen T. C.] Houston Methodist Hosp, Houston Methodist Canc Ctr, Houston, TX USA. RP Wong, STC (reprint author), Southeast Univ, Zhong Da Hosp, Dept Radiol, Nanjing, Jiangsu, Peoples R China.; Zhao, H; Wong, STC (reprint author), Weill Cornell Med, Houston Methodist Res Inst, Dept Syst Med & Bioengn, Houston, TX USA.; Zhao, H; Wong, STC (reprint author), Weill Cornell Med, NCI Ctr Modeling Canc Dev, Houston Methodist Res Inst, Houston, TX USA.; Wong, STC (reprint author), Houston Methodist Hosp, Houston Methodist Canc Ctr, Houston, TX USA.; Zhao, H (reprint author), Houston Methodist Res Inst, 6670 Bertner Ave, Houston, TX 77030 USA. EM hzhao@houstonmethodist.org; stwong@houstonmethodist.org FU NCI NIH HHS [U01 CA188388, U54 CA149196] NR 36 TC 7 Z9 7 U1 5 U2 16 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 APR 15 PY 2016 VL 76 IS 8 BP 2094 EP 2104 DI 10.1158/0008-5472.CAN-15-2662 PG 11 WC Oncology SC Oncology GA DJ4JH UT WOS:000374170700008 PM 26893478 ER PT J AU Cherkasova, E Scrivani, C Doh, S Weisman, Q Takahashi, Y Harashima, N Yokoyama, H Srinivasan, R Linehan, WM Lerman, MI Childs, RW AF Cherkasova, Elena Scrivani, Claire Doh, Susan Weisman, Quinn Takahashi, Yoshiyuki Harashima, Nanae Yokoyama, Hisayuki Srinivasan, Ramaprasad Linehan, W. Marston Lerman, Michael I. Childs, Richard W. TI Detection of an Immunogenic HERV-E Envelope with Selective Expression in Clear Cell Kidney Cancer SO CANCER RESEARCH LA English DT Article ID HUMAN ENDOGENOUS RETROVIRUS; BREAST-CANCER; T-LYMPHOCYTES; TRANSFORMATION; MELANOMA; SEQUENCE; ANTIGEN; TRANSCRIPTS; PROTEIN; LINES AB VHL-deficient clear cell renal cell carcinomas (ccRCC), the most common form of kidney cancer, express transcripts derived from the novel human endogenous retrovirus HERV-E (named CT-RCC HERV-E). In this study, we define a transcript encoding the entire envelope gene of HERV-E as expressed selectively in ccRCC tumors, as distinct from normal kidney tissues or other tumor types. Sequence analysis of this envelope transcript revealed long open reading frames encoding putative surface and transmembrane envelope proteins. Retroviral envelopes are known to be capable of eliciting immunity in humans. Accordingly, we found that HLA-A*0201-restricted peptides predicted to be products of the CT-RCC HERV-E envelope transcript-stimulated CD8(+) T cells, which could recognize HLA-A*0201-positive HERV-E-expressing kidney tumor cells. Overall, our results offer evidence of unique HERV-E envelope peptides presented on the surface of ccRCC cells, offering potentially useful tumor-restricted targets for T-cell-based immunotherapy of kidney cancer. (C) 2016 AACR. C1 [Cherkasova, Elena; Scrivani, Claire; Doh, Susan; Weisman, Quinn; Takahashi, Yoshiyuki; Harashima, Nanae; Yokoyama, Hisayuki; Lerman, Michael I.; Childs, Richard W.] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Srinivasan, Ramaprasad; Linehan, W. Marston] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Takahashi, Yoshiyuki] Nagoya Univ, Grad Sch Med, Dept Pediat, Nagoya, Aichi 4648601, Japan. [Harashima, Nanae] Shimane Univ, Fac Med, Dept Immunol, Matsue, Shimane, Japan. [Yokoyama, Hisayuki] Natl Hosp Org, Sendai Med Ctr, Dept Hematol, Sendai, Miyagi, Japan. [Lerman, Michael I.] Affina Biotechnol Inc, Elmsford, NY 10523 USA. RP Childs, RW (reprint author), NHLBI, NIH, 10 Ctr Dr 3E-5330, Bethesda, MD 20892 USA. EM childsr@mail.nih.gov FU NIH, National Heart, Lung, and Blood Institute, Hematology Branch FX This work was supported by the intramural research program of NIH, National Heart, Lung, and Blood Institute, Hematology Branch. NR 24 TC 1 Z9 2 U1 0 U2 2 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 APR 15 PY 2016 VL 76 IS 8 BP 2177 EP 2185 DI 10.1158/0008-5472.CAN-15-3139 PG 9 WC Oncology SC Oncology GA DJ4JH UT WOS:000374170700015 PM 26862115 ER PT J AU Farrar, JE Schuback, HL Ries, RE Wai, D Hampton, OA Trevino, LR Alonzo, TA Auvil, JMG Davidsen, TM Gesuwan, P Hermida, L Muzny, DM Dewal, N Rustagi, N Lewis, LR Gamis, AS Wheeler, DA Smith, MA Gerhard, DS Meshinchi, S AF Farrar, Jason E. Schuback, Heather L. Ries, Rhonda E. Wai, Daniel Hampton, Oliver A. Trevino, Lisa R. Alonzo, Todd A. Auvil, Jaime M. Guidry Davidsen, Tanja M. Gesuwan, Patee Hermida, Leandro Muzny, Donna M. Dewal, Ninad Rustagi, Navin Lewis, Lora R. Gamis, Alan S. Wheeler, David A. Smith, Malcolm A. Gerhard, Daniela S. Meshinchi, Soheil TI Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse SO CANCER RESEARCH LA English DT Article ID CHILDRENS-ONCOLOGY-GROUP; INTERNAL TANDEM DUPLICATION; SEQUENCING DATA; MUTANT LEVEL; FLT3; IMPACT; AML; OUTCOMES; DNMT3A; TRIAL AB The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COGTARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF > 0.4 persisted to relapse compared with 28% with VAF < 0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. (C) 2016 AACR. C1 [Farrar, Jason E.] Arkansas Childrens Hosp, Res Inst, 800 Marshall St, Little Rock, AR 72202 USA. [Farrar, Jason E.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Farrar, Jason E.; Alonzo, Todd A.; Meshinchi, Soheil] Childrens Oncol Grp, Monrovia, CA USA. [Schuback, Heather L.; Ries, Rhonda E.; Meshinchi, Soheil] Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North,D5-380, Seattle, WA 98109 USA. [Schuback, Heather L.; Ries, Rhonda E.; Meshinchi, Soheil] Univ Washington, Sch Med, Seattle, WA USA. [Wai, Daniel] Phoenix Childrens Hosp, Ron Matricaria Inst Mol Med, Tucson, AZ USA. [Wai, Daniel] Univ Arizona, Coll Med, Tucson, AZ USA. [Hampton, Oliver A.; Trevino, Lisa R.; Muzny, Donna M.; Dewal, Ninad; Rustagi, Navin; Lewis, Lora R.; Wheeler, David A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Trevino, Lisa R.] Doctors Hosp Renaissance, Edinburg, TX USA. [Alonzo, Todd A.] Univ So Calif, Los Angeles, CA USA. [Auvil, Jaime M. Guidry; Gerhard, Daniela S.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Davidsen, Tanja M.; Gesuwan, Patee; Hermida, Leandro] NCI, Ctr Bioinformat & Informat Technol, Rockville, MD USA. [Gamis, Alan S.] Childrens Mercy Hosp & Clin, Kansas City, MO USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Meshinchi, S (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North,D5-380, Seattle, WA 98109 USA. EM smeshinc@fredhutch.org FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E, R01 CA114563, U10 CA098543, U10 CA180886, U10 CA180899] NR 25 TC 8 Z9 8 U1 0 U2 2 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 APR 15 PY 2016 VL 76 IS 8 BP 2197 EP 2205 DI 10.1158/0008-5472.CAN-15-1015 PG 9 WC Oncology SC Oncology GA DJ4JH UT WOS:000374170700017 PM 26941285 ER PT J AU Travis, RC Appleby, PN Martin, RM Holly, JMP Albanes, D Black, A Bueno-de-Mesquita, HB Chan, JM Chen, C Chirlaque, MD Cook, MB Deschasaux, M Donovan, JL Ferrucci, L Galan, P Giles, GG Giovannucci, EL Gunter, MJ Habel, LA Hamdy, FC Helzlsouer, KJ Hercberg, S Hoover, RN Janssen, JAMJL Kaaks, R Kubo, T Le Marchand, L Metter, EJ Mikami, K Morris, JK Neal, DE Neuhouser, ML Ozasa, K Palli, D Platz, EA Pollak, MN Price, AJ Roobol, MJ Schaefer, C Schenk, JM Severi, G Stampfer, MJ Stattin, P Tamakoshi, A Tangen, CM Touvier, M Wald, NJ Weiss, NS Ziegler, RG Key, TJ Allen, NE AF Travis, Ruth C. Appleby, Paul N. Martin, Richard M. Holly, Jeff M. P. Albanes, Demetrius Black, Amanda Bueno-de-Mesquita, H. Bas Chan, June M. Chen, Chu Chirlaque, Maria-Dolores Cook, Michael B. Deschasaux, Melanie Donovan, Jenny L. Ferrucci, Luigi Galan, Pilar Giles, Graham G. Giovannucci, Edward L. Gunter, Marc J. Habel, Laurel A. Hamdy, Freddie C. Helzlsouer, Kathy J. Hercberg, Serge Hoover, Robert N. Janssen, Joseph A. M. J. L. Kaaks, Rudolf Kubo, Tatsuhiko Le Marchand, Loic Metter, E. Jeffrey Mikami, Kazuya Morris, Joan K. Neal, David E. Neuhouser, Marian L. Ozasa, Kotaro Palli, Domenico Platz, Elizabeth A. Pollak, Michael N. Price, Alison J. Roobol, Monique J. Schaefer, Catherine Schenk, Jeannette M. Severi, Gianluca Stampfer, Meir J. Stattin, Par Tamakoshi, Akiko Tangen, Catherine M. Touvier, Mathilde Wald, Nicholas J. Weiss, Noel S. Ziegler, Regina G. Key, Timothy J. Allen, Naomi E. CA Endogenous Hormones Nutr TI A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; FACTOR-BINDING PROTEIN-2; FACTOR (IGF)-I; SUSCEPTIBILITY LOCI; PREVENTION TRIAL; SERUM-INSULIN; FACTOR AXIS; IGFBP-3; HYPERPLASIA; DIET AB The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (P-trend all <= 0.005), and IGFBP-1 was inversely associated weakly with risk (P-trend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (P-heterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, P-heterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. (C) 2016 AACR. C1 [Travis, Ruth C.; Appleby, Paul N.; Price, Alison J.; Key, Timothy J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Martin, Richard M.; Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Martin, Richard M.] Univ Bristol, MRC, Univ Bristol Integrat Epidemiol Unit, Bristol, Avon, England. [Martin, Richard M.] Natl Inst Hlth Res Bristol, Biomed Res Unit Nutr, Bristol, Avon, England. [Holly, Jeff M. P.] Univ Bristol, Fac Med, Sch Clin Sci, Bristol, Avon, England. [Albanes, Demetrius; Black, Amanda; Cook, Michael B.; Hoover, Robert N.; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Bueno-de-Mesquita, H. Bas; Gunter, Marc J.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Chan, June M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Chan, June M.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. [Chen, Chu; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Chirlaque, Maria-Dolores] IMIB Arrixaca, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Chirlaque, Maria-Dolores] CIBER Epidemiol & Salud Publ, Madrid, Spain. [Deschasaux, Melanie; Galan, Pilar; Hercberg, Serge; Touvier, Mathilde] Univ Paris 07, Univ Paris 05, Univ Paris 13,Inserm,U1153,INRA,U1125,Cnam, Sorbonne Paris Cite,Epidemiol & Biostat Res Ctr,N, F-93017 Bobigny, France. [Ferrucci, Luigi; Metter, E. Jeffrey] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Giovannucci, Edward L.; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Med, 665 Huntington Ave, Boston, MA 02115 USA. [Habel, Laurel A.; Schaefer, Catherine] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg, Oxford, England. [Helzlsouer, Kathy J.] St Johns Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Janssen, Joseph A. M. J. L.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Kubo, Tatsuhiko] Univ Occupat & Environm Hlth, Kitakyushu, Fukuoka 807, Japan. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Metter, E. Jeffrey] Univ Tennessee, Ctr Hlth Sci, Dept Neurol, Memphis, TN 38163 USA. [Mikami, Kazuya] Kyoto Prefectural Univ Med, Kyoto, Japan. [Morris, Joan K.; Wald, Nicholas J.] Queen Mary Univ London, Wolfson Inst Prevent Med, Charterhouse Sq, London, England. [Neal, David E.] Univ Cambridge, Dept Oncol, Cambridge, England. [Ozasa, Kotaro] Radiat Effects Res Fdn, Hiroshima, Japan. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Pollak, Michael N.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Pollak, Michael N.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Roobol, Monique J.] Erasmus MC, Dept Urol, Rotterdam, Netherlands. [Schenk, Jeannette M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA. [Schenk, Jeannette M.; Weiss, Noel S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Severi, Gianluca] Human Genet Fdn, Turin, Italy. [Stampfer, Meir J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Stattin, Par] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden. [Stattin, Par] Univ Uppsala Hosp, Dept Surg Sci, Uppsala, Sweden. [Tamakoshi, Akiko] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan. [Tangen, Catherine M.] Univ Washington, Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98195 USA. [Tangen, Catherine M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Allen, Naomi E.] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England. [Allen, Naomi E.] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England. RP Travis, RC (reprint author), Univ Oxford, Roosevelt Dr, Oxford OX3 7LF, England. EM ruth.travis@ceu.ox.ac.uk RI Cook, Michael/A-5641-2009; OI Cook, Michael/0000-0002-0533-7302; Price, Alison/0000-0002-3891-3337; PALLI, Domenico/0000-0002-5558-2437; Giles, Graham/0000-0003-4946-9099; Kubo, Tatsuhiko/0000-0001-8822-9181 FU Cancer Research UK [A19169]; NCI NIH HHS [P01 CA108964, P01 CA033619, P01 CA055075, R01 CA133891, R37 CA054281, U01 CA164973, U10 CA037429, UG1 CA189974, UM1 CA182883] NR 50 TC 6 Z9 6 U1 4 U2 11 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 APR 15 PY 2016 VL 76 IS 8 BP 2288 EP 2300 DI 10.1158/0008-5472.CAN-15-1551 PG 13 WC Oncology SC Oncology GA DJ4JH UT WOS:000374170700025 PM 26921328 ER PT J AU Shafer-Weaver, KA Anderson, MJ Draper, LJ Malyguine, A Alvord, WG Greenberg, NM Hurwitz, AA AF Shafer-Weaver, Kimberly A. Anderson, Michael J. Draper, Lauren J. Malyguine, Anatoli Alvord, W. Gregory Greenberg, Norman M. Hurwitz, Arthur A. TI Immunity to Murine Prostatic Tumors: Continuous Provision of T-Cell Help Prevents CD8 T-Cell Tolerance and Activates Tumor-Infiltrating Dendritic Cells (Retraction of vol 69, pg 6256, 2009) SO CANCER RESEARCH LA English DT Correction C1 [Shafer-Weaver, Kimberly A.; Anderson, Michael J.; Draper, Lauren J.; Hurwitz, Arthur A.] SAIC Frederick Inc, Tumor Immun & Tolerance Sect, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick, MD USA. [Shafer-Weaver, Kimberly A.; Malyguine, Anatoli] SAIC Frederick Inc, Lab Cell Mediated Immun, Frederick, MD USA. [Alvord, W. Gregory] NCI, Biostat Div, Data Management Serv, Frederick, MD 21701 USA. [Greenberg, Norman M.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. RP Shafer-Weaver, KA (reprint author), SAIC Frederick Inc, Tumor Immun & Tolerance Sect, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick, MD USA.; Shafer-Weaver, KA (reprint author), SAIC Frederick Inc, Lab Cell Mediated Immun, Frederick, MD USA. NR 1 TC 0 Z9 0 U1 3 U2 3 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 APR 15 PY 2016 VL 76 IS 8 BP 2490 EP 2490 DI 10.1158/0008-5472.CAN-16-0505 PG 1 WC Oncology SC Oncology GA DJ4JH UT WOS:000374170700042 ER PT J AU Zhu, ZQ Singh, V Bronte, V Shoe, JL Feigenbaum, L Hurwitz, AA AF Zhu, Ziqiang Singh, Vinod Bronte, Vincenzo Shoe, Jennifer L. Feigenbaum, Lionel Hurwitz, Arthur A. TI High-Avidity T Cells Are Preferentially Tolerized in the Tumor Microenvironment (Retraction of vol 73, pg 595, 2013) SO CANCER RESEARCH LA English DT Correction C1 [Zhu, Ziqiang; Singh, Vinod; Hurwitz, Arthur A.] Frederick Natl Lab Canc Res, Tumor Immun & Tolerance Sect, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick, MD USA. [Bronte, Vincenzo] Univ Verona, Dept Pathol, I-37100 Verona, Italy. [Shoe, Jennifer L.; Feigenbaum, Lionel] NCI, Lab Anim Sci Program, SAIC Frederick, Frederick, MD 21701 USA. RP Zhu, ZQ (reprint author), Frederick Natl Lab Canc Res, Tumor Immun & Tolerance Sect, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick, MD USA. RI Bronte, Vincenzo/K-7902-2016 OI Bronte, Vincenzo/0000-0002-3741-5141 NR 1 TC 0 Z9 0 U1 0 U2 3 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 APR 15 PY 2016 VL 76 IS 8 BP 2491 EP 2491 DI 10.1158/0008-5472.CAN-16-0506 PG 1 WC Oncology SC Oncology GA DJ4JH UT WOS:000374170700043 ER PT J AU Thompson, KW Joshi, P Dymond, JS Gorrepati, L Smith, HE Krause, MW Eisenmann, DM AF Thompson, Kenneth W. Joshi, Pradeep Dymond, Jessica S. Gorrepati, Lakshmi Smith, Harold E. Krause, Michael W. Eisenmann, David M. TI The Paired-box protein PAX-3 regulates the choice between lateral and ventral epidermal cell fates in C-elegans SO DEVELOPMENTAL BIOLOGY LA English DT Article DE C. elegans; Fate specification; Differentiation; Gene expression; PAX; Epidermis ID HEDGEHOG-RELATED GENES; CAENORHABDITIS-ELEGANS; TRANSCRIPTION FACTOR; PRISTIONCHUS-PACIFICUS; EMBRYONIC EPIDERMIS; EXPRESSION ANALYSIS; HYPODERMAL CELLS; DIFFERENTIATION; MORPHOGENESIS; MUTATIONS AB The development of the single cell layer skin or hypodermis of Caenorhabditis elegans is an excellent model for understanding cell fate specification and differentiation. Early in C. elegans embryogenesis, six rows of hypodermal cells adopt dorsal, lateral or ventral fates that go on to display distinct behaviors during larval life. Several transcription factors are known that function in specifying these major hypodermal cell fates, but our knowledge of the specification of these cell types is sparse, particularly in the case of the ventral hypodermal cells, which become Vulval Precursor Cells and form the vulval opening in response to extracellular signals. Previously, the gene pvl-4 was identified in a screen for mutants with defects in vulval development. We found by whole genome sequencing that pvl-4 is the Paired-box gene pax-3, which encodes the sole PAX-3 transcription factor homolog in C. elegans. pax-3 mutants show embryonic and larval lethality, and body morphology abnormalities indicative of hypodermal cell defects. We report that pax-3 is expressed in ventral P cells and their descendants during embryogenesis and early larval stages, and that in pax-3 reduction-of-function animals the ventral P cells undergo a cell fate transformation and express several markers of the lateral seam cell fate. Furthermore, forced expression of pax-3 in the lateral hypodermal cells causes them to lose expression of seam cell markers. We propose that pax-3 functions in the ventral hypodermal cells to prevent these cells from adopting the lateral seam cell fate. pax-3 represents the first gene required for specification solely of the ventral hypodermal fate in C elegans providing insights into cell type diversification. (C) 2016 Elsevier Inc. All rights reserved. C1 [Thompson, Kenneth W.; Joshi, Pradeep; Dymond, Jessica S.; Gorrepati, Lakshmi; Eisenmann, David M.] Univ Maryland Baltimore Cty, Dept Biol Sci, 1000 Hilltop Circle, Baltimore, MD 21250 USA. [Smith, Harold E.; Krause, Michael W.] NIDDK, NIH, 5 Ctr Dr, Bethesda, MD 20892 USA. [Thompson, Kenneth W.] Univ Florida, Dept Med, Div Hematol & Oncol, 1600 SW Archer Rd,POB 100278, Gainesville, FL 32610 USA. [Joshi, Pradeep; Dymond, Jessica S.] Johns Hopkins Appl Phys Lab, 11100 Johns Hopkins Rd, Laurel, MD 20723 USA. [Gorrepati, Lakshmi] Carnegie Inst Sci, Dept Embryol, 3520 San Martin Dr, Baltimore, MD 21218 USA. RP Eisenmann, DM (reprint author), Univ Maryland Baltimore Cty, Dept Biol Sci, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM Kenneth.Thompson@medicine.ufl.edu; pradeep.m.joshi@lifesci.ucsb.edu; Jessica.Dymond@jhuapl.edu; gorrepati@ciwemb.edu; smithhe2@niddk.nih.gov; michaelkr@niddk.nih.gov; eisenman@umbc.edu OI Krause, Michael/0000-0001-6127-3940 FU NIH Office of Research Infrastructure Programs [P40 OD010440]; National BioResource Project of Japan; National Science Foundation (NSF) [IBN-0131485]; National Institute of Diabetes and Digestive and Kidney Diseases; University of Maryland Baltimore County FX We thank, A. Golden, I. Greenwald, I. Hamza, S. Kim, D. Miller and J. Rothman for sharing reagents and strains and we thank Wormbase for as a valuable resource of information. Some nematode and yeast strains used in this work were provided by the Caenorhabditis Genetics Center that is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440), and by the National BioResource Project of Japan. This work was supported by a National Science Foundation (NSF) grant IBN-0131485, funding from The University of Maryland Baltimore County, and the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 78 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD APR 15 PY 2016 VL 412 IS 2 BP 191 EP 207 DI 10.1016/j.ydbio.2016.03.002 PG 17 WC Developmental Biology SC Developmental Biology GA DJ4UW UT WOS:000374204600002 PM 26953187 ER PT J AU Gustin, SE Hogg, K Stringer, JM Rastetter, RH Pelosi, E Miles, DC Sinclair, AH Wilhelm, D Western, PS AF Gustin, Sonja E. Hogg, Kirsten Stringer, Jessica M. Rastetter, Raphael H. Pelosi, Emanuele Miles, Denise C. Sinclair, Andrew H. Wilhelm, Dagmar Western, Patrick S. TI WNT/beta-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary SO DEVELOPMENTAL BIOLOGY LA English DT Article DE beta-catenin; WNT4; FOXL2; Ovary; Granulosa; Follicle ID MAMMALIAN SEX DETERMINATION; TRANSCRIPTION FACTOR FOXL2; GERM-CELLS; BETA-CATENIN; MOUSE OVARY; GENE-EXPRESSION; MITOTIC ARREST; STEM-CELLS; MICE; WNT4 AB Sexual development is initiated through differentiation of testicular Sertoli cells or ovarian granulosa cells. Although these supporting cells are considered to develop from common bipotential precursors, recent evidence suggests that distinct supporting cell populations are present in the ovary, with one providing granulosa cells of the medullary follicles and the other providing granulosa cells of the cortical follicles, the latter of which support lifelong fertility. Here, we demonstrate that XX fetal gonads contain GATA4 expressing supporting cells that either enter mitotic arrest, or remain proliferative. Blocking WNT signalling reduces XX supporting cell proliferation, while stabilising beta-catenin signalling promotes proliferation, indicating that the renewal of pre-granulosa cells is dependent on WNT/beta-catenin signalling in the proliferative supporting cell population. In contrast, XX supporting cells express p27 and FOXL2 and are maintained in mitotic arrest. Although FOXL2 is required for maintaining high levels of p27 expression, it is dispensable for entry and maintenance of mitotic arrest in XX supporting cells. Combined our data suggest that both medullary and cortical precursors arise from a common GATA4 expressing cell type. In addition, this work indicates that a balance between supporting cell self-renewal and differentiation is maintained in the developing ovary by relative WNT/beta-catenin and p27/FOXL2 activities. This study provides significant new insights into the origin and formation of ovarian follicles and evidence supporting a common fetal origin of medullary and cortical granulosa cells. Crown Copyright (C) 2016 Published by Elsevier Inc. All rights reserved. C1 [Gustin, Sonja E.; Hogg, Kirsten; Stringer, Jessica M.; Miles, Denise C.; Western, Patrick S.] Monash Univ, Hudson Inst Med Res, Ctr Genet Dis, Clayton, Vic, Australia. [Gustin, Sonja E.; Hogg, Kirsten; Stringer, Jessica M.; Miles, Denise C.; Western, Patrick S.] Monash Univ, Dept Mol & Translat Sci, Clayton, Vic, Australia. [Rastetter, Raphael H.; Wilhelm, Dagmar] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic, Australia. [Pelosi, Emanuele] NIA, Genet Lab, NIH, IRP, Baltimore, MD 21224 USA. [Sinclair, Andrew H.] Univ Melbourne, Dept Paediat, Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Gustin, Sonja E.; Miles, Denise C.] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Div Mol Med, Parkville, Vic 3050, Australia. [Wilhelm, Dagmar] Univ Melbourne, Dept Anat & Neurosci, Parkville, Vic 3052, Australia. RP Western, PS (reprint author), Hudson Inst Med Res, 27-31 Wright St, Clayton, Vic 3168, Australia. EM patrick.western@hudson.org.au RI Sinclair, Andrew/A-3598-2010; Wilhelm, Dagmar/B-6915-2009; Stringer, Jessica/I-5525-2013 OI Sinclair, Andrew/0000-0003-2741-7992; Wilhelm, Dagmar/0000-0002-7757-4075; Stringer, Jessica/0000-0003-4729-3026 FU Monash University Faculty of Medicine, Nursing and Health Sciences; NHMRC [1043939, 1052195]; Victorian Government's Operational Infrastructure Support Program, an NHMRC Program; Intramural Research Program of the National Institute on Aging, NIH; ARC [FT110100327] FX This work was supported by the Monash University Faculty of Medicine, Nursing and Health Sciences and NHMRC Grant #1043939 to PW, the Victorian Government's Operational Infrastructure Support Program, an NHMRC Program grant awarded to AS and the Intramural Research Program of the National Institute on Aging, NIH. DW is supported by an ARC Future Fellowship (FT110100327). D.C.M. is supported by NHMRC Early Career Fellowship (Grant #1052195). NR 61 TC 3 Z9 3 U1 5 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD APR 15 PY 2016 VL 412 IS 2 BP 250 EP 260 DI 10.1016/j.ydbio.2016.02.024 PG 11 WC Developmental Biology SC Developmental Biology GA DJ4UW UT WOS:000374204600006 PM 26939755 ER PT J AU Watts, M Ha, J Kimchi, O Sherman, A AF Watts, Margaret Ha, Joon Kimchi, Ofer Sherman, Arthur TI Paracrine regulation of glucagon secretion: the beta/alpha/delta model SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE insulin; pancreatic alpha-cell; glucagon; islet; somatostatin; pancreatic delta-cell ID PANCREATIC ALPHA-CELLS; INSULIN-SECRETION; BETA-CELLS; SOMATOSTATIN RECEPTOR; ENDOCRINE PANCREAS; DELTA-CELLS; METABOLIC OSCILLATIONS; GLUCOSE SUPPRESSION; POTASSIUM CHANNELS; PULSATILE INSULIN AB The regulation of glucagon secretion in the pancreatic alpha-cell is not well understood. It has been proposed that glucose suppresses glucagon secretion either directly through an intrinsic mechanism within the alpha-cell or indirectly through an extrinsic mechanism. Previously, we described a mathematical model for isolated pancreatic alpha-cells and used it to investigate possible intrinsic mechanisms of regulating glucagon secretion. We demonstrated that glucose can suppress glucagon secretion through both ATP-dependent potassium channels (K-ATP) and a store-operated current (SOC). We have now developed an islet model that combines previously published mathematical models of alpha- and beta-cells with a new model of delta-cells and use it to explore the effects of insulin and somatostatin on glucagon secretion. We show that the model can reproduce experimental observations that the inhibitory effect of glucose remains even when paracrine modulators are no longer acting on the alpha-cell. We demonstrate how paracrine interactions can either synchronize alpha- nd delta-cells to produce pulsatile oscillations in glucagon and somatostatin secretion or fail to do so. The model can also account for the paradoxical observation that glucagon can be out of phase with insulin, whereas alpha-cell calcium is in phase with insulin. We conclude that both paracrine interactions and the alpha-cell's intrinsic mechanisms are needed to explain the response of glucagon secretion to glucose. C1 [Watts, Margaret; Ha, Joon; Sherman, Arthur] NIH, Lab Biol Modeling, 12A South Dr,Rm 4007, Bethesda, MD 20892 USA. [Kimchi, Ofer] Princeton Univ, Dept Phys, Princeton, NJ 08544 USA. RP Sherman, A (reprint author), NIH, Lab Biol Modeling, 12A South Dr,Rm 4007, Bethesda, MD 20892 USA. EM ArthurS@niddk.nih.gov FU Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) FX This work was supported by the Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases). NR 80 TC 0 Z9 0 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD APR 15 PY 2016 VL 310 IS 8 BP E597 EP E611 DI 10.1152/ajpendo.00415.2015 PG 15 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA DJ3IV UT WOS:000374099100002 PM 26837808 ER PT J AU Bardou, O Menou, A Francois, C Duitman, JW von der Thusen, JH Borie, R Sales, KU Mutze, K Castier, Y Sage, E Liu, LG Bugge, TH Fairlie, DP Konigshoff, M Crestani, B Borensztajn, KS AF Bardou, Olivier Menou, Awen Francois, Charlene Duitman, Jan Willem von der Thusen, Jan H. Borie, Raphael Sales, Katiuchia Uzzun Mutze, Kathrin Castier, Yves Sage, Edouard Liu, Ligong Bugge, Thomas H. Fairlie, David P. Koenigshoff, Melanie Crestani, Bruno Borensztajn, Keren S. TI Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE idiopathic pulmonary fibrosis; fibroblast; matriptase; protease-activated receptor-2; camostat mesilate ID PROTEINASE-ACTIVATED RECEPTOR-2; HEPATOCYTE GROWTH-FACTOR; PANCREATIC FIBROSIS; INHIBITOR CAMOSTAT; LUNG FIBROSIS; FACTOR XA; TGF-BETA; IN-VITRO; CELL; FIBROBLASTS AB Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies. Objectives: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. Methods: Matriptase expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptase-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate (CM), or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. Measurements and Main Results: Matriptase expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-beta. Furthermore, matriptase elicited signaling via protease-activated receptor-2 (PAR-2), and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic down-regulation, diminished lung injury, collagen production, and transforming growth factor-b expression and signaling. Conclusions: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF. C1 [Bardou, Olivier; Menou, Awen; Francois, Charlene; Crestani, Bruno; Borensztajn, Keren S.] Med Sch Xavier Bichat, Inserm UMR1152, Paris, France. [Bardou, Olivier; Menou, Awen; Francois, Charlene; Borie, Raphael; Crestani, Bruno; Borensztajn, Keren S.] Univ Paris Diderot, Sorbonne Paris Cite, Dept Hosp Univ FIRE Fibrosis Inflammat & Remodell, Paris, France. [Bardou, Olivier; Menou, Awen; Francois, Charlene; Borie, Raphael; Crestani, Bruno; Borensztajn, Keren S.] LabEx Inflamex, Paris, France. [Duitman, Jan Willem] Univ Amsterdam, Acad Med Ctr, Ctr Expt & Mol Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [von der Thusen, Jan H.] Dept Pathol, Erasmus Med Ctr, Rotterdam, Netherlands. [Borie, Raphael; Crestani, Bruno] Bichat Claude Bernard Univ Hosp, AP HP, Dept Pulmonol A, Competence Ctr Rare Lung Dis, Paris, France. [Sales, Katiuchia Uzzun; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Sales, Katiuchia Uzzun] Univ Sao Paulo Ribeirao Preto, Ribeirao Preto Sch Med, Dept Cell & Mol Biol, Sao Paulo, Brazil. [Mutze, Kathrin; Koenigshoff, Melanie] Univ Munich, Helmholtz Zentrum Munchen, Univ Hosp, Comprehens Pneumol Ctr, Munich, Germany. [Castier, Yves] Denis Diderot Univ, Bichat Claude Bernard Univ Hosp, AP HP, Dept Vasc & Thorac Surg, Paris, France. [Castier, Yves] Med Sch Paris VII, Paris, France. [Sage, Edouard] Hop Foch, Dept Thorac Surg & Lung Transplantat, Suresnes, France. [Liu, Ligong; Fairlie, David P.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia. RP Borensztajn, KS (reprint author), Univ Paris 07, INSERM UMR1152, 16 Rue Henri Huchard, F-75018 Paris, France. EM keren.borensztajn@inserm.fr RI liu, ligong/B-1690-2010; OI liu, ligong/0000-0002-2693-1896; Borie, Raphael/0000-0002-9906-0024; Fairlie, David/0000-0002-7856-8566 FU Fondation pour la Recherche Medicale [AJE201121]; Agence Nationale pour la Recherche [ANR-14-CE15-0010-01]; Dutch Lung Foundation [9.2.14.085FE]; Helmholtz Association; National Health and Medical Research Council [1047759]; Senior Principal Research Fellowship [1027369]; National Institute of Dental and Craniofacial Research Intramural Research Program FX Supported by grants from the Fondation pour la Recherche Medicale grant AJE201121 (K.S.B.) and Agence Nationale pour la Recherche ANR-14-CE15-0010-01 (O.B., A.M., and K.S.B.); Dutch Lung Foundation grant 9.2.14.085FE (J.W.D.); the Helmholtz Association (K.M. and M.K.); National Health and Medical Research Council grant 1047759 (L.L. and D.P.F.); Senior Principal Research Fellowship 1027369 (D.P.F.); and the National Institute of Dental and Craniofacial Research Intramural Research Program (T.H.B. and K.U.S.). NR 54 TC 4 Z9 4 U1 4 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD APR 15 PY 2016 VL 193 IS 8 BP 847 EP 860 DI 10.1164/rccm.201502-0299OC PG 14 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DJ3NJ UT WOS:000374112000013 PM 26599507 ER PT J AU Drilon, A Eaton, AA Schindler, K Gounder, MM Spriggs, DR Harris, P Ivy, SP Iasonos, A Lacouture, ME Hyman, DM AF Drilon, Alexander Eaton, Anne A. Schindler, Katja Gounder, Mrinal M. Spriggs, David R. Harris, Pamela Ivy, S. Percy Iasonos, Alexia Lacouture, Mario E. Hyman, David M. TI Beyond the dose-limiting toxicity period: Dermatologic adverse events of patients on phase 1 trials of the Cancer Therapeutics Evaluation Program SO CANCER LA English DT Article DE Cancer Therapeutics Evaluation Program (CTEP); dermatologic toxicity; dose-limiting toxicity (DLT) period; phase 1 trial; molecularly targeted agents ID MOLECULARLY TARGETED AGENTS; I ONCOLOGY TRIALS; THERAPIES; DESIGN; IMPACT; GRADE AB BACKGROUNDDermatologic adverse events (AEs) can be key determinants of overall drug tolerability and of the maximum tolerated and recommended phase 2 doses in phase 1 trials. The authors present the largest dedicated analysis of dermatologic AEs on phase 1 trials to date. METHODSData from a prospectively maintained database of patients with solid tumors who were enrolled onto Cancer Therapeutics Evaluation Program (CTEP)-sponsored phase 1 trials of cytotoxic or molecularly targeted agents (MTAs) from 2000 to 2010 were analyzed. Cumulative incidence, site, and type of drug-related dermatologic AEs were described and compared. The timing of worst drug-related dermatologic AEs was summarized. RESULTSIn total, 3517 patients with solid tumors and 6165 unique, drug-related dermatologic AEs were analyzed, including 1545 patients on MTA-only trials, 671 on cytotoxic-only trials, and 1392 on combination MTA and cytotoxic trials. Of 1270 patients who had drug-related dermatologic events, the timing of the worst AE was as follows: 743 (cycle 1), 303 (cycle 2), and 224 (cycle 3 or later). Although the cumulative incidence of grade 3 drug-related AEs increased to 2.4% by cycle 6, it was only 1.6% at the end of cycle 1. The cumulative incidence of drug-related AEs was highest in patients who received MTA-only therapy (P<.001) and differed by dose level (P<.001). In patients who received MTA-only therapy, drug-related AEs were most common for combination kinase inhibitor-containing therapy (P<.001). CONCLUSIONSA substantial proportion of drug-related dermatologic AEs occur after the traditional dose-limiting toxicity monitoring period of phase 1 clinical trials. Future designs should account for late toxicities. Cancer 2016;122:1228-37. (c) 2016 American Cancer Society. In 3517 patients with solid tumors who participate in Cancer Therapeutics Evaluation Program (CTEP)-sponsored phase 1 trials, a substantial proportion of drug-related dermatologic adverse events are observed after the traditional dose-limiting toxicity period. The cumulative incidence of these events is highest in patients who receive molecularly targeted agents, particularly combination kinase inhibitor-containing therapy. C1 [Drilon, Alexander; Eaton, Anne A.; Gounder, Mrinal M.; Spriggs, David R.; Iasonos, Alexia; Lacouture, Mario E.; Hyman, David M.] Mem Sloan Kettering Canc Ctr, Dept Med, 300 East 66th St BAIC 1253, New York, NY 10065 USA. [Drilon, Alexander; Gounder, Mrinal M.; Spriggs, David R.; Hyman, David M.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Schindler, Katja] Med Univ Vienna, Dept Dermatol, Vienna, Austria. [Harris, Pamela; Ivy, S. Percy] NCI, Canc Therapeut & Evaluat Program, Bethesda, MD 20892 USA. RP Drilon, A (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 300 East 66th St BAIC 1253, New York, NY 10065 USA. EM drilona@mskcc.org FU National Institutes of Health [P30 CA008748] FX This work was funded in part by the cancer center core grant P30 CA008748 from the National Institutes of Health. NR 27 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 15 PY 2016 VL 122 IS 8 BP 1228 EP 1237 DI 10.1002/cncr.29918 PG 10 WC Oncology SC Oncology GA DJ1IZ UT WOS:000373957800014 PM 26916138 ER PT J AU Jansen, LA Mahadevan, D Appelbaum, PS Klein, WMP Weinstein, ND Mori, M Daffe, R Sulmasy, DP AF Jansen, Lynn A. Mahadevan, Daruka Appelbaum, Paul S. Klein, William M. P. Weinstein, Neil D. Mori, Motomi Daffe, Racky Sulmasy, Daniel P. TI Dispositional optimism and therapeutic expectations in early-phase oncology trials SO CANCER LA English DT Article DE cancer research; dispositional optimism; informed consent; therapeutic misconception; therapeutic optimism ID CLINICAL-TRIALS; UNREALISTIC OPTIMISM; MISCONCEPTION; BENEFIT; HEALTH; CONSENT; RISKS AB BACKGROUNDPrior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early-phase oncology trials. However, optimism is not a unitary construct; it also can be defined as a general disposition, or what is called dispositional optimism. The authors assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. The authors also assessed how dispositional optimism related to unrealistic optimism. METHODSPatient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. RESULTSDispositional optimism was found to be significantly associated with higher expectations for personal therapeutic benefit (Spearman rank correlation coefficient [r], 0.333; P<.0001), but was not associated with the therapeutic misconception (Spearman r, -0.075; P = .329). Dispositional optimism was found to be weakly associated with unrealistic optimism (Spearman r, 0.215; P = .005). On multivariate analysis, both dispositional optimism (P = .02) and unrealistic optimism (P<.0001) were found to be independently associated with high expectations for personal therapeutic benefit. Unrealistic optimism (P = .0001), but not dispositional optimism, was found to be independently associated with the therapeutic misconception. CONCLUSIONSHigh expectations for therapeutic benefit among patient-subjects in early-phase oncology trials should not be assumed to result from misunderstanding of specific information regarding the trials. The data from the current study indicate that these expectations are associated with either a dispositionally positive outlook on life or biased expectations concerning specific aspects of trial participation. Not all manifestations of optimism are the same, and different types of optimism likely have different consequences for informed consent in early-phase oncology research. Cancer 2016;122:1238-46. (c) 2016 American Cancer Society. High expectations for therapeutic benefit among patient-subjects in early-phase oncology trials should not be assumed to result only from misunderstanding. Data from the current study indicate that these expectations are associated with either a dispositionally positive outlook on life or biased expectations regarding specific aspects of trial participation. C1 [Jansen, Lynn A.] Oregon Hlth & Sci Univ, Ctr Eth Hlth Care, Madeline Brill Nelson Chair Eth Educ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Mahadevan, Daruka] Univ Arizona, Ctr Canc, Med, Tucson, AZ USA. [Appelbaum, Paul S.] Columbia Univ Coll Phys & Surg, Div Law Eth & Psychiat, 630 W 168th St, New York, NY 10032 USA. [Klein, William M. P.] NCI, Behav Res Program, NIH, Bethesda, MD 20892 USA. [Weinstein, Neil D.] Rutgers State Univ, Dept Human Ecol, New Brunswick, NJ 08903 USA. [Mori, Motomi] Oregon Hlth & Sci Univ, Sch Publ Hlth & Med, Knight Canc Inst, Dept Canc Biostat, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Daffe, Racky] Oregon Hlth & Sci Univ, Knight Canc Inst, Dept Stat, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Sulmasy, Daniel P.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Sulmasy, Daniel P.] Univ Chicago, Divin Sch, Chicago, IL 60637 USA. RP Jansen, LA (reprint author), Oregon Hlth & Sci Univ, Ctr Eth Hlth Care, Madeline Brill Nelson Chair Eth Educ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM jansen@ohsu.edu FU National Institutes of Health/National Cancer [RO1CA166556]; Biostatistics Shared Resource of the Knight Cancer Institute (National Cancer Institute) [5P30CA069533-16] FX Supported by National Institutes of Health/National Cancer Institute grant RO1CA166556. Biostatistics support (Motomi Mori and Racky Daffe) was provided by the Biostatistics Shared Resource of the Knight Cancer Institute (National Cancer Institute grant 5P30CA069533-16). NR 24 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 15 PY 2016 VL 122 IS 8 BP 1238 EP 1246 DI 10.1002/cncr.29908 PG 9 WC Oncology SC Oncology GA DJ1IZ UT WOS:000373957800015 PM 26882017 ER PT J AU Land, SR Toll, BA Moinpour, CM Mitchell, SA Ostroff, JS Hatsukami, DK Duffy, SA Gritz, ER Rigotti, NA Brandon, TH Prindiville, SA Sarna, LP Schnoll, RA Herbst, RS Cinciripini, PM Leischow, SJ Dresler, CM Fiore, MC Warren, GW AF Land, Stephanie R. Toll, Benjamin A. Moinpour, Carol M. Mitchell, Sandra A. Ostroff, Jamie S. Hatsukami, Dorothy K. Duffy, Sonia A. Gritz, Ellen R. Rigotti, Nancy A. Brandon, Thomas H. Prindiville, Sheila A. Sarna, Linda P. Schnoll, Robert A. Herbst, Roy S. Cinciripini, Paul M. Leischow, Scott J. Dresler, Carolyn M. Fiore, Michael C. Warren, Graham W. TI Research Priorities, Measures, and Recommendations for Assessment of Tobacco Use in Clinical Cancer Research SO CLINICAL CANCER RESEARCH LA English DT Article ID SELF-REPORTED SMOKING; RESEARCH POLICY STATEMENT; LUNG-CANCER; AMERICAN ASSOCIATION; CESSATION SUPPORT; DIAGNOSIS; TRIALS; ONCOLOGY; OPPORTUNITIES; ACCURACY AB There is strong evidence that cigarette smoking causes adverse outcomes in people with cancer. However, more research is needed regarding those effects and the effects of alternative tobacco products and of secondhand smoke, the effects of cessation (before diagnosis, during treatment, or during survivorship), the biologic mechanisms, and optimal strategies for tobacco dependence treatment in oncology. Fundamentally, tobacco is an important source of variation in clinical treatment trials. Nevertheless, tobacco use assessment has not been uniform in clinical trials. Progress has been impeded by a lack of consensus regarding tobacco use assessment suitable for cancer patients. The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force identified priority research areas and developed recommendations for assessment items and timing of assessment in cancer research. A cognitive interview study was conducted with 30 cancer patients at the NIH Clinical Center to evaluate and improve the measurement items. The resulting Cancer Patient Tobacco Use Questionnaire (C-TUQ) includes "Core" items for minimal assessment of tobacco use at initial and follow-up time points, and an "Extension" set. Domains include the following: cigarette and other tobacco use status, intensity, and past use; use relative to cancer diagnosis and treatment; cessation approaches and history; and secondhand smoke exposure. The Task Force recommends that assessment occur at study entry and, at a minimum, at the end of protocol therapy in clinical trials. Broad adoption of the recommended measures and timing protocol, and pursuit of the recommended research priorities, will help us to achieve a clearer understanding of the significance of tobacco use and cessation for cancer patients. (C) 2016 AACR. C1 [Land, Stephanie R.; Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. [Toll, Benjamin A.; Warren, Graham W.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA. [Ostroff, Jamie S.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Hatsukami, Dorothy K.] Univ Minnesota DKH, Masonic Canc Ctr, Minneapolis, MN USA. [Duffy, Sonia A.] Ohio State Univ, Coll Nursing, Columbus, OH 43210 USA. [Duffy, Sonia A.] Ohio State Univ, HSR&D Ctr Excellence, VA Ctr Clin Management Res, Columbus, OH 43210 USA. [Gritz, Ellen R.; Cinciripini, Paul M.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. [Brandon, Thomas H.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Hlth Outcomes & Behav, Tampa, FL 33682 USA. [Prindiville, Sheila A.] NCI, Coordinating Ctr Clin Trials, Bethesda, MD 20892 USA. [Sarna, Linda P.] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. [Schnoll, Robert A.] Univ Penn, Philadelphia, PA 19104 USA. [Herbst, Roy S.] Yale Univ, Sch Med, New Haven, CT USA. [Leischow, Scott J.] Mayo Clin, Ctr Canc, Coll Med, Phoenix, AZ USA. [Fiore, Michael C.] Univ Wisconsin, Sch Med & Publ Hlth, Ctr Tobacco Res & Intervent, Madison, WI USA. [Warren, Graham W.] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Warren, Graham W.] Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA. RP Land, SR (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM landsr@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [P30 CA008748] NR 53 TC 3 Z9 3 U1 4 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 15 PY 2016 VL 22 IS 8 BP 1907 EP 1913 DI 10.1158/1078-0432.CCR-16-0104 PG 7 WC Oncology SC Oncology GA DJ3JP UT WOS:000374101400011 PM 26888828 ER PT J AU Zorn, KK Annunziata, CM AF Zorn, Kristin K. Annunziata, Christina M. TI Editorial: Inhibiting PARP as a Strategic Target in Cancer SO FRONTIERS IN ONCOLOGY LA English DT Editorial Material DE PARP inhibitors; poly(ADP-ribose) polymerase; DNA repair; PARP-1; BRCA1 protein; cancer therapy C1 [Zorn, Kristin K.] Univ Arkansas Med Sci, Dept Obstet & Gyencol, Little Rock, AR 72205 USA. [Zorn, Kristin K.] Univ Arkansas Med Sci, Div Genet, Little Rock, AR 72205 USA. [Annunziata, Christina M.] NCI, Bethesda, MD 20892 USA. RP Zorn, KK (reprint author), Univ Arkansas Med Sci, Dept Obstet & Gyencol, Little Rock, AR 72205 USA.; Zorn, KK (reprint author), Univ Arkansas Med Sci, Div Genet, Little Rock, AR 72205 USA. EM kkzorn@uams.edu RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 TC 0 Z9 0 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD APR 15 PY 2016 VL 6 AR 91 DI 10.3389/fonc.2016.00091 PG 2 WC Oncology SC Oncology GA DJ4ZL UT WOS:000374216500001 PM 27148483 ER PT J AU Du, VY Bansal, A Carlson, J Salazar-Gonzalez, JF Salazar, MG Ladell, K Gras, S Josephs, TM Heath, SL Price, DA Rossjohn, J Hunter, E Goepfert, PA AF Du, Victor Y. Bansal, Anju Carlson, Jonathan Salazar-Gonzalez, Jesus F. Salazar, Maria G. Ladell, Kristin Gras, Stephanie Josephs, Tracy M. Heath, Sonya L. Price, David A. Rossjohn, Jamie Hunter, Eric Goepfert, Paul A. TI HIV-1-Specific CD8 T Cells Exhibit Limited Cross-Reactivity during Acute Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EARLY HIV-1 INFECTION; IMMUNODEFICIENCY-VIRUS-INFECTION; CELLULAR IMMUNE-RESPONSES; LYMPHOCYTE RESPONSES; ESCAPE MUTATIONS; TYPE-1 INFECTION; POPULATION-LEVEL; SIV INFECTION; VACCINE; EPITOPES AB Prior work has demonstrated that HIV-1-specific CD8 T cells can cross-recognize variant epitopes. However, most of these studies were performed in the context of chronic infection, where the presence of viral quasispecies makes it difficult to ascertain the true nature of the original antigenic stimulus. To overcome this limitation, we evaluated the extent of CD8 T cell cross-reactivity in patients with acute HIV-1 clade B infection. In each case, we determined the transmitted founder virus sequence to identify the autologous epitopes restricted by individual HLA class I molecules. Our data show that cross-reactive CD8 T cells are infrequent during the acute phase of HIV-1 infection. Moreover, in the uncommon instances where cross-reactive responses were detected, the variant epitopes were poorly recognized in cytotoxicity assays. Molecular analysis revealed that similar antigenic structures could be cross-recognized by identical CD8 T cell clonotypes mobilized in vivo, yet even subtle differences in a single TCR-accessible peptide residue were sufficient to disrupt variant-specific reactivity. These findings demonstrate that CD8 T cells are highly specific for autologous epitopes during acute HIV-1 infection. Polyvalent vaccines may therefore be required to provide optimal immune cover against this genetically labile pathogen. C1 [Du, Victor Y.; Bansal, Anju; Salazar-Gonzalez, Jesus F.; Salazar, Maria G.; Heath, Sonya L.; Goepfert, Paul A.] Univ Alabama Birmingham, Dept Med, 908 20th St South,CCB 330, Birmingham, AL 35294 USA. [Carlson, Jonathan] Microsoft Res, Redmond, WA 98052 USA. [Ladell, Kristin; Price, David A.; Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Gras, Stephanie; Josephs, Tracy M.; Rossjohn, Jamie] Monash Univ, Biomed Discovery Inst, Infect & Immun Program, Clayton, Vic 3800, Australia. [Gras, Stephanie; Josephs, Tracy M.; Rossjohn, Jamie] Monash Univ, Biomed Discovery Inst, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Gras, Stephanie; Rossjohn, Jamie] Monash Univ, Australian Res Council, Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hunter, Eric] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30329 USA. RP Goepfert, PA (reprint author), Univ Alabama Birmingham, Dept Med, 908 20th St South,CCB 330, Birmingham, AL 35294 USA. EM paulg@uab.edu RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Salazar-Gonzalez, Jesus/0000-0003-4626-6448; Ladell, Kristin/0000-0002-9856-2938; Carlson, Jonathan/0000-0001-6618-3653; Heath , Sonya /0000-0002-3826-0954; Rossjohn, Jamie/0000-0002-2020-7522 FU National Institutes of Health; Australian Research Council; National Health and Medical Research Council of Australia; Wellcome Trust; Australia Fellowship from the National Health and Medical Research Council of Australia FX This work was supported by the National Institutes of Health, the Australian Research Council, the National Health and Medical Research Council of Australia, and the Wellcome Trust. P.A.G. is supported by a grant from the National Institutes of Health. S.G. is supported by an Australian Research Council Future Fellowship. D.A.P. is supported by a Wellcome Trust Senior Investigator Award. J.R. is supported by an Australia Fellowship from the National Health and Medical Research Council of Australia. NR 75 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2016 VL 196 IS 8 BP 3276 EP 3286 DI 10.4049/jimmunol.1502411 PG 11 WC Immunology SC Immunology GA DI8AA UT WOS:000373721900007 PM 26983786 ER PT J AU Lee-Chang, C Bodogai, M Moritoh, K Chen, X Wersto, R Sen, R Young, HA Croft, M Ferrucci, L Biragyn, A AF Lee-Chang, Catalina Bodogai, Monica Moritoh, Kanako Chen, Xin Wersto, Robert Sen, Ranjan Young, Howard A. Croft, Michael Ferrucci, Luigi Biragyn, Arya TI Aging Converts Innate B1a Cells into Potent CD8(+) T Cell Inducers SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; AGE-RELATED-CHANGES; B-CELLS; IFN-GAMMA; CLONAL EXPANSION; INTERFERON-GAMMA; DENDRITIC CELLS; 4-1BB LIGAND; B-1 CELLS; IN-VIVO AB B cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4-1BBL(+) MHC class-I-Hi CD86(Hi) B cells of unknown origin. In this article, we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. They induce expression and activation of 4-1BBL and IFN-gamma R1 on B1a cells to subsequently upregulate membrane TNF-alpha and CD86. As a result, activated B1a/4BL cells induce expression of granzyme B in CD8(+) T cells by targeting TNFR2 via membrane TNF-alpha and providing costimulation with CD86. Thus, for the first time, to our knowledge, these results indicate that aging affects the function of B1a cells. Upon aging, these cells lose their tumor-supporting activity and become inducers of potentially antitumor and autoimmune CD8(+) T cells. C1 [Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako; Biragyn, Arya] NIA, Immunoregulat Sect, Baltimore, MD 21224 USA. [Lee-Chang, Catalina] Lille Inflammat Res Int Ctr, INSERM UMR995, F-59000 Lille, France. [Lee-Chang, Catalina] Univ Lille, F-59000 Lille, France. [Chen, Xin] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Macao, Peoples R China. [Chen, Xin; Young, Howard A.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Wersto, Robert] NIA, Flow Cytometry Unit, Baltimore, MD 21244 USA. [Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Croft, Michael] La Jolla Inst Allergy & Immunol, Div Immune Regulat, La Jolla, CA 92037 USA. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Biragyn, A (reprint author), NIA, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov RI Chen, Xin/I-6601-2015; Lee-Chang, Catalina/A-5580-2015; OI Chen, Xin/0000-0002-2628-4027; Lee-Chang, Catalina/0000-0002-7675-2124; Young, Howard/0000-0002-3118-5111 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 74 TC 1 Z9 1 U1 3 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2016 VL 196 IS 8 BP 3385 EP 3397 DI 10.4049/jimmunol.1502034 PG 13 WC Immunology SC Immunology GA DI8AA UT WOS:000373721900017 PM 26983789 ER PT J AU Shive, CL Clagett, B McCausland, MR Mudd, JC Funderburg, NT Freeman, ML Younes, SA Ferrari, BM Rodriguez, B McComsey, GA Calabrese, LH Sieg, SF Lederman, MM AF Shive, Carey L. Clagett, Brian McCausland, Marie R. Mudd, Joseph C. Funderburg, Nicholas T. Freeman, Michael L. Younes, Souheil-Antoine Ferrari, Brian M. Rodriguez, Benigno McComsey, Grace A. Calabrese, Leonard H. Sieg, Scott F. Lederman, Michael M. TI Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE IL-6; senescence; immune failure; HIV; IL-1 beta; IL-7 ID T-CELL HOMEOSTASIS; ACTIVE ANTIRETROVIRAL THERAPY; GAMMA-CHAIN CYTOKINES; PROGRAMMED DEATH-1; ACTIVATION; CD4; INTERLEUKIN-7; EXPRESSION; DYSFUNCTION; RESPONSES AB Background: HIV-infected patients who fail to normalize CD4 T cells despite suppressive antiretroviral therapy have impaired immune homeostasis: diminished naive T-cell numbers, elevated T-cell turnover, senescence, and inflammation. Methods: Blood samples from immune failures (n = 60), immune successes (n = 20), and healthy controls (n = 20) were examined for plasma interleukin (IL)-7 levels, for cellular expression of the IL-7R alpha chain (CD127), for the exhaustion and senescence markers programed death 1 (PD-1) and CD57, and for the survival factor Bcl2. Because both inflammatory and homeostatic cytokines can induce T-cell cycling, we also examined the effects of these mediators on exhaustion and senescence markers. Results: Plasma levels of IL-7 were elevated and both CD4 and CD8 T-cell CD127 expression was decreased in immune failure. Plasma levels of IL-7 correlated directly with naive CD4 T-cell counts in immune success and inversely with T-cell cycling (Ki67) in healthy controls and immune success, but not in immune failure. CD4 T-cell density of PD-1 was increased and Bcl2+ CD4 T cells were decreased in immune failure but not in immune success, whereas the proportion of T cells expressing CD57 was increased in immune failure. PD-1 and CD57 were induced on CD4 but not CD8 T cells by stimulation in vitro with inflammatory IL-1 beta or homeostatic (IL-7) cytokines. Conclusions: Perturbation of the IL-7/IL-7 receptor axis, increased T-cell turnover, and increased senescence may reflect dysregulated responses to both homeostatic and inflammatory cytokines in immune failure patients. C1 [Shive, Carey L.; Clagett, Brian; McCausland, Marie R.; Freeman, Michael L.; Younes, Souheil-Antoine; Ferrari, Brian M.; Rodriguez, Benigno; Sieg, Scott F.; Lederman, Michael M.] Case Western Reserve Univ, Dept Med, Dept Med, Div Infect Dis, Cleveland, OH 44106 USA. [Mudd, Joseph C.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Funderburg, Nicholas T.] Ohio State Univ, Sch Hlth & Rehabil Sci, Columbus, OH 43210 USA. [Rodriguez, Benigno; McComsey, Grace A.; Lederman, Michael M.] Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Calabrese, Leonard H.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. RP Lederman, MM (reprint author), Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. EM lederman.michael@clevelandactu.org RI Funderburg, Nicholas/L-8022-2013 FU National Institutes of Health [AI 076174, AI 68636, AI 105937]; CWRU Center for AIDS Research [AI 36219]; Fasenmyer Foundation; National Heart, Lung, And Blood Institute of the National Institutes of Health [R00HL108743] FX This work was supported by grants from the National Institutes of Health (AI 076174, AI 68636, AI 105937) the CWRU Center for AIDS Research-(AI 36219) and the Fasenmyer Foundation. Research reported in this publication was also supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R00HL108743. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 54 TC 5 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 15 PY 2016 VL 71 IS 5 BP 483 EP 492 DI 10.1097/QAI.0000000000000913 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DG8RC UT WOS:000372350300003 PM 26627102 ER PT J AU Bunge, KE Dezzutti, CS Rohan, LC Hendrix, CW Marzinke, MA Richardson-Harman, N Moncla, BJ Devlin, B Meyn, LA Spiegel, HML Hillier, SL AF Bunge, Katherine E. Dezzutti, Charlene S. Rohan, Lisa C. Hendrix, Craig W. Marzinke, Mark A. Richardson-Harman, Nicola Moncla, Bernard J. Devlin, Brid Meyn, Leslie A. Spiegel, Hans M. L. Hillier, Sharon L. TI A Phase 1 Trial to Assess the Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics of a Novel Dapivirine Vaginal Film SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV prevention; vaginal film; microbicide; dapivirine ID HIV-NEGATIVE WOMEN; PREEXPOSURE PROPHYLAXIS; DOUBLE-BLIND; MICROBICIDE GEL; AFRICAN WOMEN; PREVENTION; INFECTION; SPERMICIDES; HEALTHY; QUANTIFICATION AB Background: Films may deliver antiretroviral drugs efficiently to mucosal tissues. In this first in-human trial of a vaginal film for delivering the nonnucleoside reverse transcriptase inhibitor dapivirine, safety, pharmacokinetics, and pharmacodynamics of film and gel formulations were compared with placebo. Methods: Sixty-one healthy HIV-negative women were randomized to daily dapivirine (0.05%) or placebo gel, or dapivirine (1.25 mg) or placebo film for seven days. The proportion of participants experiencing grade 2 and higher adverse events related to study product were compared. Plasma dapivirine concentrations were quantified. Paired cervical and vaginal tissue biopsies obtained similar to 2 hours after the last dose were measured for tissue drug concentration and exposed to HIV in an ex vivo challenge assay. Results: Two grade 2 related adverse events occurred in the placebo film group. Women randomized to gel and film products had 4 log(10) higher of dapivirine in cervical and vaginal tissues than plasma. Although gel and film users had comparable plasma dapivirine concentrations, tissue concentrations of dapivirine were 3-5 times higher in the gel users when compared with film users. HIV replication in the ex vivo challenge assay was significantly reduced in vaginal tissues from women randomized to dapivirine film or gel; furthermore, tissue drug concentrations were highly correlated with HIV protection. Women rated the film more comfortable with less leakage but found it more difficult to insert than gel. Discussion: Both film and gel delivered dapivirine at concentrations sufficient to block HIV ex vivo. This proof-of-concept study suggests film formulations for microbicides merit further investigation. C1 [Bunge, Katherine E.; Dezzutti, Charlene S.; Moncla, Bernard J.; Hillier, Sharon L.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Dezzutti, Charlene S.; Rohan, Lisa C.; Moncla, Bernard J.; Meyn, Leslie A.; Hillier, Sharon L.] Magee Womens Res Inst, Pittsburgh, PA USA. [Rohan, Lisa C.] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA. [Hendrix, Craig W.; Marzinke, Mark A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Pharmacol, Baltimore, MD 21205 USA. [Richardson-Harman, Nicola] Alpha StatConsult, Damascus, MD USA. [Devlin, Brid] Int Partnership Microbicides, Silver Spring, MD USA. [Spiegel, Hans M. L.] HJF DAIDS, Rockville, MD USA. [Spiegel, Hans M. L.] NIAID, NIH, US Dept HHS, Rockville, MD USA. RP Bunge, KE (reprint author), Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, 300 Halket Ave, Pittsburgh, PA 15213 USA. EM kbunge@mail.magee.edu RI Hendrix, Craig/G-4182-2014 OI Hendrix, Craig/0000-0002-5696-8665 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI082639, UL1 TR000005]; National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX Supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Grant AI082639 and UL1 TR000005. This project has also been funded in part with federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C. The International Partnership for Microbicides was the regulatory sponsor of the trial and donated dapivirine drug substance for the films and the dapivirine gel used in this study. The vaginal placebo gel was donated by CONRAD. NR 30 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 15 PY 2016 VL 71 IS 5 BP 498 EP 505 DI 10.1097/QAI.0000000000000897 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DG8RC UT WOS:000372350300005 PM 26565716 ER PT J AU Veronese, M Zanotti-Fregonara, P Rizzo, G Bertoldo, A Innis, RB Turkheimer, FE AF Veronese, Mattia Zanotti-Fregonara, Paolo Rizzo, Gaia Bertoldo, Alessandra Innis, Robert B. Turkheimer, Federico E. TI Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot SO NEUROIMAGE LA English DT Article DE Non-displaceable binding; PET; Lassen plot; Allen brain atlas; Pharmacological displacement; Pharmacological blockade; mRNA ID POSITRON-EMISSION-TOMOGRAPHY; KAPPA-OPIOID RECEPTOR; PEPTIDE NOP RECEPTORS; IN-VIVO; ANTAGONIST RADIOTRACER; REFERENCE REGION; QUANTIFICATION; MODEL; PHOSPHODIESTERASE-4; C-11-LY2795050 AB PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i.e. there were no significant posttranscriptional changes). This condition can be readily established a priori by assessing the correlation between PET and mRNA expression. (C) 2016 Elsevier Inc. All rights reserved. C1 [Veronese, Mattia; Turkheimer, Federico E.] Kings Coll London, Dept Neuroimaging, IoPPN, London SE5 8AF, England. [Zanotti-Fregonara, Paolo; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Zanotti-Fregonara, Paolo] Univ Bordeaux, INCIA, CNRS, UMR 5287, Bordeaux, France. [Rizzo, Gaia; Bertoldo, Alessandra] Univ Padua, Dept Informat Engn, Padua, Italy. RP Turkheimer, FE (reprint author), Kings Coll London, Ctr Neuroimaging Sci, IoPPN, P089,De Crespigny Pk,Denmark Hill, London SE5 8AF, England. EM federico.turkheimer@kcl.ac.uk RI Turkheimer, Federico/B-9485-2012; Veronese, Mattia/A-6012-2013; Rizzo, Gaia/A-8697-2013 OI Turkheimer, Federico/0000-0002-3766-3815; Veronese, Mattia/0000-0003-3562-0683; Rizzo, Gaia/0000-0001-7272-8576 FU Programme Grant "Quantitative methodologies for Positron Emission Tomography" (UK Medical Research Council) [G1100809/1]; Padova University; National Institute of Mental Health (USA) [ZIAMH002852] FX This study was supported by the Programme Grant "Quantitative methodologies for Positron Emission Tomography" (UK Medical Research Council No. G1100809/1), by the Padova University grant "Neuroimaging Genetics: Models and Methods to Integrate Brain Phenotype and Genotype" (2013), and by the Intramural Research Programme of the National Institute of Mental Health (USA) project number ZIAMH002852 under clinical trials.gov identifier NCT02230592. NR 42 TC 0 Z9 0 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD APR 15 PY 2016 VL 130 BP 1 EP 12 DI 10.1016/j.neuroimage.2016.01.058 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DH4HG UT WOS:000372745600001 PM 26850512 ER PT J AU Zhang, H Japee, S Nolan, R Chu, C Liu, N Ungerleider, LG AF Zhang, Hui Japee, Shruti Nolan, Rachel Chu, Carlton Liu, Ning Ungerleider, Leslie G. TI Face-selective regions differ in their ability to classify facial expressions SO NEUROIMAGE LA English DT Article DE Amygdala; Emotional faces; fMRI; STS; SVM ID SUPERIOR TEMPORAL SULCUS; HUMAN FUSIFORM GYRUS; HUMAN AMYGDALA; EMOTIONAL EXPRESSIONS; NEURAL RESPONSES; FMRI-ADAPTATION; FUNCTIONAL MRI; HUMAN BRAIN; IDENTITY; PERCEPTION AB Recognition of facial expressions is crucial for effective social interactions. Yet, the extent to which the various face-selective regions in the human brain classify different facial expressions remains unclear. We used functional magnetic resonance imaging (fMRI) and support vector machine pattern classification analysis to determine how well face-selective brain regions are able to decode different categories of facial expression. Subjects participated in a slow event-related fMRI experiment in which they were shown 32 face pictures, portraying four different expressions: neutral, fearful, angry, and happy and belonging to eight different identities. Our results showed that only the amygdala and the posterior superior temporal sulcus (STS) were able to accurately discriminate between these expressions, albeit in different ways: the amygdala discriminated fearful faces from non-fearful faces, whereas STS discriminated neutral from emotional (fearful, angry and happy) faces. In contrast to these findings on the classification of emotional expression, only the fusiform face area (FFA) and anterior inferior temporal cortex (aIT) could discriminate among the various facial identities. Further, the amygdala and STS were better than FFA and aIT at classifying expression, while FFA and aIT were better than the amygdala and STS at classifying identity. Taken together, our findings indicate that the decoding of facial emotion and facial identity occurs in different neural substrates: the amygdala and STS for the former and FFA and aIT for the latter. Published by Elsevier Inc. C1 [Zhang, Hui; Japee, Shruti; Nolan, Rachel; Chu, Carlton; Liu, Ning; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Zhang, H (reprint author), NIMH, Sect Neurocircuitry, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM hui.zhang@nih.gov FU Intramural Research Program of the National Institute of Mental Health [NCT01087281, 93-M-0170] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (NCT01087281; 93-M-0170). NR 71 TC 1 Z9 1 U1 11 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD APR 15 PY 2016 VL 130 BP 77 EP 90 DI 10.1016/j.neuroimage.2016.01.045 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DH4HG UT WOS:000372745600007 PM 26826513 ER PT J AU Dogo-Isonagie, C Lee, SL Lohith, K Liu, HB Mandadapu, SR Lusvarghi, S O'Connor, RD Bewley, CA AF Dogo-Isonagie, Cajetan Lee, Su-Lin Lohith, Katheryn Liu, Hongbing Mandadapu, Sivakoteswara R. Lusvarghi, Sabrina O'Connor, Robert D. Bewley, Carole A. TI Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Tyrosine sulfate; Molecular docking; HIV co-receptors; CCR5 N-terminus; Competitive inhibition ID CCR5 N-TERMINUS; ENVELOPE GLYCOPROTEIN; MEMBRANE-FUSION; CO-RECEPTORS; GP120; BINDING; CD4; DETERMINANTS; CORECEPTORS; ANTIBODIES AB In the absence of a cure or vaccine for HIV/AIDS, small molecule inhibitors remain an attractive choice for antiviral therapeutics. Recent structural and functional studies of the HIV-1 surface envelope glycoprotein gp120 have revealed sites of vulnerability that can be targeted by small molecule and peptide inhibitors, thereby inhibiting HIV-1 infection. Here we describe a series of small molecule entry inhibitors that were designed to mimic the sulfated N-terminal peptide of the HIV-1 coreceptor CCR5. From a panel of hydrazonothiazolyl pyrazolinones, we demonstrate that compounds containing naphthyl di- and trisulfonic acids inhibit HIV-1 infection in single round infectivity assays with the disulfonic acids being the most potent. Molecular docking supports the observed structure activity relationship, and SPR confirmed binding to gp120. In infectivity assays treatment with a representative naphthyl disulfonate and a disulfated CCR5 N-terminus peptide results in competitive inhibition, with combination indices >2. In total this work shows that gp120 and HIV-1 infection can be inhibited by small molecules that mimic the function of, and are competitive with the natural sulfated CCR5 N-terminus. Published by Elsevier Ltd. C1 [Dogo-Isonagie, Cajetan; Lee, Su-Lin; Lohith, Katheryn; Liu, Hongbing; Mandadapu, Sivakoteswara R.; Lusvarghi, Sabrina; O'Connor, Robert D.; Bewley, Carole A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov FU NIH Intramural Research Program (NIDDK); Intramural AIDS Targeted Antiviral Program, Office of the Director, NIH; NIH Intramural AIDS Research Fellowship FX This work was supported by the NIH Intramural Research Program (NIDDK) and the Intramural AIDS Targeted Antiviral Program, Office of the Director, NIH (C.A.B.). C.D.-I. acknowledges an NIH Intramural AIDS Research Fellowship. NR 34 TC 0 Z9 0 U1 7 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD APR 15 PY 2016 VL 24 IS 8 BP 1718 EP 1728 DI 10.1016/j.bmc.2016.02.044 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DH2CX UT WOS:000372592900014 PM 26968647 ER PT J AU Yin, XY Levy, D Willinger, C Adourian, A Larson, MG AF Yin, Xiaoyan Levy, Daniel Willinger, Christine Adourian, Aram Larson, Martin G. TI Multiple imputation and analysis for high-dimensional incomplete proteomics data SO STATISTICS IN MEDICINE LA English DT Article DE multiple imputation; stepwise selection; high dimension; imputation quality ID ACUTE MYOCARDIAL-INFARCTION; PROTEIN; ANGIOGENESIS; ASSOCIATION; ENDOSTATIN; DISEASE; GROWTH; MICE AB Multivariable analysis of proteomics data using standard statistical models is hindered by the presence of incomplete data. We faced this issue in a nested case-control study of 135 incident cases of myocardial infarction and 135 pair-matched controls from the Framingham Heart Study Offspring cohort. Plasma protein markers (K=861) were measured on the case-control pairs (N=135), and the majority of proteins had missing expression values for a subset of samples. In the setting of many more variables than observations (K >> N), we explored and documented the feasibility of multiple imputation approaches along with subsequent analysis of the imputed data sets. Initially, we selected proteins with complete expression data (K=261) and randomly masked some values as the basis of simulation to tune the imputation and analysis process. We randomly shuffled proteins into several bins, performed multiple imputation within each bin, and followed up with stepwise selection using conditional logistic regression within each bin. This process was repeated hundreds of times. We determined the optimal method of multiple imputation, number of proteins per bin, and number of random shuffles using several performance statistics. We then applied this method to 544 proteins with incomplete expression data (40% missing values), from which we identified a panel of seven proteins that were jointly associated with myocardial infarction. (c) 2015 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. C1 [Yin, Xiaoyan; Levy, Daniel; Willinger, Christine; Larson, Martin G.] NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. [Yin, Xiaoyan; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Levy, Daniel; Willinger, Christine] NHLBI, Div Intramural Res, Populat Sci Branch, Boston, MA USA. [Adourian, Aram] BG Med Inc, Waltham, MA USA. [Yin, Xiaoyan] Boston Univ, Dept Cardiol, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Yin, XY (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM xyin@bu.edu FU NIH [N01-HC-25195]; BG Medicine, Inc.; National Heart, Lung, and Blood Institute; Boston University FX This work is supported by NIH contract (N01-HC-25195) and Cooperative Research and Development Agreement (CRADA) between BG Medicine, Inc., the National Heart, Lung, and Blood Institute, and Boston University. NR 36 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD APR 15 PY 2016 VL 35 IS 8 BP 1315 EP 1326 DI 10.1002/sim.6800 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DF9LV UT WOS:000371683600006 PM 26565662 ER PT J AU Kunzmann, AT Coleman, HG Huang, WY Cantwell, MM Kitahara, CM Berndt, SI AF Kunzmann, Andrew T. Coleman, Helen G. Huang, Wen-Yi Cantwell, Marie M. Kitahara, Cari M. Berndt, Sonja I. TI Fruit and vegetable intakes and risk of colorectal cancer and incident and recurrent adenomas in the PLCO cancer screening trial SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE fruits; vegetables; colorectal cancer; colorectal adenoma; diet ID PROSPECTIVE COHORT; DIETARY FIBER; RECTAL-CANCER; COLON-CANCER; CONSUMPTION; HEALTH; METAANALYSIS; PREVENTION; NUTRITION; HABITS AB The roles of fruits and vegetables in colorectal cancer development are unclear. Few prospective studies have assessed the association with adenoma, a known precursor to colorectal cancer. Our aim was to evaluate the association between fruit and vegetable intake and colorectal cancer development by evaluating the risk of incident and recurrent colorectal adenoma and colorectal cancer. Study participants were identified from the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Fruit and vegetable intake was measured using a self-reported dietary questionnaire. Total fruit and vegetable intake was not associated with reduced incident or recurrent adenoma risk overall, but a protective association was observed for multiple adenomas (Odds ratio (3rd tertile) (vs.) (1st tertile)=0.61, 95% confidence interval (CI): 0.38, 1.00). Higher fruit and vegetable intakes were associated with a borderline reduced risk of colorectal cancer (Hazard ratio (HR) (3rd tertile) (vs.) (1st tertile)=0.82, 95% CI: 0.67, 1.01), which reached significance amongst individuals with high processed meat intakes (HR=0.74, 95% CI: 0.55, 0.99). Our results suggest that increased fruit and vegetable intake may protect against multiple adenoma development and may reduce the detrimental effects of high processed meat intakes on colorectal cancer risk. What's new? It's not clear how much fruits and vegetables protect against colorectal cancer, or whether they impact the growth of adenoma, a precursor to colorectal cancer. To expand on existing data, these authors conducted a prospective study, in which all participants underwent the same screening protocol, eliminating a possible source of bias. They found that eating fruits and vegetables did not reduce the overall risk of developing adenoma, but did reduce the incidence of multiple adenomas. Particularly for those who consumed high amounts of processed meat, eating more fruits and vegetables helped reduce their risk of colorectal cancer. C1 [Kunzmann, Andrew T.; Coleman, Helen G.; Cantwell, Marie M.] Queens Univ Belfast, Ctr Publ Hlth, Royal Victoria Hosp Site,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. [Huang, Wen-Yi; Kitahara, Cari M.; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kunzmann, AT (reprint author), Queens Univ Belfast, Ctr Publ Hlth, Royal Victoria Hosp Site,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland.; Kunzmann, AT (reprint author), Queens Univ Belfast, Ctr Publ Hlth, Inst Clin Sci B, Royal Victoria Hosp Site,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM A.kunzmann@qub.ac.uk RI Kitahara, Cari/R-8267-2016 FU Division of Cancer Epidemiology and Genetics (Intramural Research Program); Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services FX Grant sponsors: Division of Cancer Epidemiology and Genetics (Intramural Research Program) and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services NR 40 TC 3 Z9 3 U1 7 U2 50 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 APR 15 PY 2016 VL 138 IS 8 BP 1851 EP 1861 DI 10.1002/ijc.29922 PG 11 WC Oncology SC Oncology GA DD7CU UT WOS:000370082100006 PM 26559156 ER PT J AU Linet, MS Brown, LM Mbulaiteye, SM Check, D Ostroumova, E Landgren, A Devesa, SS AF Linet, Martha S. Brown, Linda M. Mbulaiteye, Sam M. Check, David Ostroumova, Evgenia Landgren, Annelie Devesa, Susan S. TI International long-term trends and recent patterns in the incidence of leukemias and lymphomas among children and adolescents ages 0-19 years SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE childhood; incidence; trends; Hodgkin lymphoma; lymphoid leukemia; myeloid leukemia; non-Hodgkin lymphoma ID INFORMATION-SYSTEM PROJECT; CHILDHOOD-CANCER INCIDENCE; ACUTE LYMPHOBLASTIC-LEUKEMIA; EUROPEAN CHILDREN; HODGKINS-DISEASE; UNITED-STATES; MORTALITY-RATES; TEMPORAL TRENDS; TIME TRENDS; SURVIVAL AB To enhance understanding of etiology, we examined international population-based cancer incidence data for lymphoid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma and myeloid leukemia among children aged 0-19. Based on temporal trends during 1978-2007 in 24 populations, lymphoid leukemia and myeloid leukemia incidence rates generally have not changed greatly and differences in rates for non-Hodgkin and for Hodgkin lymphoma have diminished in some regions. Lymphoid leukemia rates during 2003-2007 in 54 populations varied about 10-fold, with rates highest in US white Hispanics (50.2 per million person-years) and Ecuador (48.3) and lowest in US blacks (20.4), Tunisia (17.7) and Uganda (6.9). Non-Hodgkin lymphoma rates varied 30-fold, with very high rates in sub-Saharan Africa (146.0 in Malawi and 54.3 in Uganda) and low rates (10) in some Asian populations (China, Japan, India, the Philippines and Thailand) and U.S. Asian-Pacific Islanders, eastern and northern European populations and Puerto Rico. Hodgkin lymphoma rates varied 15-fold, with rates highest in Italy (21.3) and lowest in China (1.7) . Myeloid leukemia rates varied only about fivefold, with rates highest in the Philippines and Korea (exceeding 14.0) and lowest in Eastern Europe (5.9 in Serbia and 5.3 in the Czech Republic) and Uganda (2.7). The boy/girl average incidence rate ratios were 2.00 or lower. Age-specific patterns differed among the four hematopoietic malignancies, but were generally consistent within major categories world-wide, except for non-Hodgkin lymphoma. A systematic world-wide approach comparing postulated etiologic factors in low- versus high-risk populations may help clarify the etiology of these childhood malignancies. What's new? This first study to assess systematically long-term (1978-2007) incidence trends for childhood leukemias and lymphomas across five continents found that lymphoid and myeloid leukemia rates generally have not changed greatly, while regional differences in non-Hodgkin and Hodgkin lymphoma rates have diminished over time. During 2003-2007 age-adjusted incidence rates spanning five continents for non-Hodgkin lymphoma have varied 30-fold, Hodgkin lymphoma 15-fold, lymphoid leukemia 10-fold, and myeloid leukemia only 5-fold. C1 [Linet, Martha S.; Mbulaiteye, Sam M.; Check, David; Ostroumova, Evgenia; Landgren, Annelie; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS Room 7048, Bethesda, MD 20892 USA. [Brown, Linda M.] RTI Int, Rockville, MD USA. RP Linet, MS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS Room 7048, Bethesda, MD 20892 USA.; Linet, MS (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Room 7048, Bethesda, MD 20892 USA. EM linetm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; U.S. Public Health Service of the Department of Health and Human Services FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the U.S. Public Health Service of the Department of Health and Human Services. NR 50 TC 7 Z9 7 U1 3 U2 25 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 APR 15 PY 2016 VL 138 IS 8 BP 1862 EP 1874 DI 10.1002/ijc.29924 PG 13 WC Oncology SC Oncology GA DD7CU UT WOS:000370082100007 PM 26562742 ER PT J AU Stang, A Kowall, B Rusner, C Trabert, B Bray, F Schuz, J McGlynn, KA Kuss, O AF Stang, Andreas Kowall, Bernd Rusner, Carsten Trabert, Britton Bray, Freddie Schuez, Joachim McGlynn, Katherine A. Kuss, Oliver TI A novel method for identifying settings for well-motivated ecologic studies of cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE neoplasms; etiology; cancer registries; incidence ID AGGREGATE DATA; THYROID-CANCER; RECENT TRENDS; DISEASE RISK; MORTALITY; EPIDEMIOLOGY; PREVENTION; SURVIVAL; PATTERNS; EUROPE AB A low within-country variability and a large between-country variability in cancer incidence may indicate that ecologic factors are involved in the etiology of the disease. The aim of this study is to explore the within- and between-country variability of cancer incidence to motivate high-quality ecologic studies. We extracted age-standardized incidence rate estimates (world standard population) from 135 regions for the ten most frequent invasive cancers in Europe for non-Hispanic white populations from Cancer Incidence in Five Continents, Volume X. We fitted weighted multilevel Poisson regression models with random country effects for each cancer and sex. We estimated intraclass correlation coefficients (ICCs) and 95% confidence intervals (95% CIs). A high ICC indicates a low within- and a high between-country variability of rates. The two cancer sites with the highest ICC among men were prostate cancer (0.96, 95% CI: 0.92-0.99) and skin melanoma (0.78, 0.64-0.93). Among women, high ICCs were observed for lung cancer (0.84, 0.73-0.95) and breast cancer (0.80, 0.69-0.91). The two most prominent sex differences for ICC occurred for cancers of the head and neck (men: 0.70, 0.55-0.85, women: 0.19, 0.08-0.30) and breast cancer (men: 0.04, 0.01-0.07, women: 0.80, 0.69-0.91). ICCs were relatively low for pancreatic cancer (men: 0.23, 0.10-0.35; women: 0.13, 0.04-0.21) and leukemia (men: 0.12, 0.04-0.21; women: 0.08, 0.02-0.14). For cancers with high ICC for which systematic factors of the health care system, screening and diagnostic activities are not plausible explanations for between-country variations in incidence, cross-country sex-specific ecologic studies may be especially promising. What's new? For many cancer types, variations in incidence are larger between countries than they are within countries. Such differences suggest that population-level, or ecologic, factors significantly influence the incidence of certain malignancies. Here, incidence rate estimates for 10 invasive cancers were compared across 135 non-Hispanic white populations in countries in Europe and North America. Cancers with high intraclass correlation (ICC) values, indicating low within-country and high between-country variation, included prostate cancer and skin melanoma. Sex-specific variations in ICC were also identified. The methodology employed here could form the basis for in-depth analyses of geographical variations in cancer incidence. C1 [Stang, Andreas; Kowall, Bernd] Univ Hosp Essen, Ctr Clin Epidemiol, Inst Med Informat Biometry & Epidemiol, Hufelandstr 55, D-45147 Essen, Germany. [Stang, Andreas] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Stang, Andreas] German Consortium Translat Canc Res DKTK, Heidelberg, Germany. [Rusner, Carsten] Univ Halle Wittenberg, Fac Med, Inst Med Epidemiol Biometry & Informat, D-06108 Halle, Germany. [Trabert, Britton; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bray, Freddie] Int Agcy Res Canc, Sect Canc Surveillance, 150 Cours Albert Thomas, F-69372 Lyon, France. [Schuez, Joachim] Int Agcy Res Canc, Sect Environm & Radiat, 150 Cours Albert Thomas, F-69372 Lyon, France. [Kuss, Oliver] Univ Dusseldorf, Fac Med, Ctr Hlth & Soc, Dusseldorf, Germany. [Kuss, Oliver] Univ Dusseldorf, German Diabet Ctr, Leibniz Inst Diabet Res, Inst Epidemiol & Biometry, Dusseldorf, Germany. RP Stang, A (reprint author), Univ Hosp Essen, Ctr Clin Epidemiol, Inst Med Informat Biometry & Epidemiol, Hufelandstr 55, D-45147 Essen, Germany.; Stang, A (reprint author), Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.; Stang, A (reprint author), German Consortium Translat Canc Res DKTK, Heidelberg, Germany. EM andreas.stang@uk-halle.de RI Trabert, Britton/F-8051-2015; OI Kuss, Oliver/0000-0003-3301-5869 FU German Federal Ministry of Education and Science (BMBF) [01ER1305] FX Grant sponsor: German Federal Ministry of Education and Science (BMBF); Grant number: 01ER1305 NR 27 TC 0 Z9 0 U1 2 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD APR 15 PY 2016 VL 138 IS 8 BP 1887 EP 1893 DI 10.1002/ijc.29931 PG 7 WC Oncology SC Oncology GA DD7CU UT WOS:000370082100009 PM 26595447 ER PT J AU McCann, KL Teramoto, T Zhang, J Hall, TMT Baserga, SJ AF McCann, Kathleen L. Teramoto, Takamasa Zhang, Jun Hall, Traci M. Tanaka Baserga, Susan J. TI The molecular basis for ANE syndrome revealed by the large ribosomal subunit processome interactome SO ELIFE LA English DT Article ID PROTEIN-PROTEIN INTERACTION; RNA RECOGNITION MOTIFS; EXON JUNCTION COMPLEX; SACCHAROMYCES-CEREVISIAE; STRUCTURAL BASIS; YEAST; BIOGENESIS; EXPRESSION; COMPONENT; BINDING AB ANE syndrome is a ribosomopathy caused by a mutation in an RNA recognition motif of RBM28, a nucleolar protein conserved to yeast (Nop4). While patients with ANE syndrome have fewer mature ribosomes, it is unclear how this mutation disrupts ribosome assembly. Here we use yeast as a model system and show that the mutation confers growth and pre-rRNA processing defects. Recently, we found that Nop4 is a hub protein in the nucleolar large subunit (LSU) processome interactome. Here we demonstrate that the ANE syndrome mutation disrupts Nop4's hub function by abrogating several of Nop4's protein-protein interactions. Circular dichroism and NMR demonstrate that the ANE syndrome mutation in RRM3 of human RBM28 disrupts domain folding. We conclude that the ANE syndrome mutation generates defective protein folding which abrogates protein-protein interactions and causes faulty pre-LSU rRNA processing, thus revealing one aspect of the molecular basis of this human disease. C1 [McCann, Kathleen L.; Baserga, Susan J.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Teramoto, Takamasa; Zhang, Jun; Hall, Traci M. Tanaka] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Baserga, Susan J.] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA. [Baserga, Susan J.] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06510 USA. RP Baserga, SJ (reprint author), Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.; Hall, TMT (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.; Baserga, SJ (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA.; Baserga, SJ (reprint author), Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06510 USA. EM hall4@niehs.nih.gov; susan.baserga@yale.edu RI Zhang, Jun/R-1502-2016 OI Zhang, Jun/0000-0002-5842-7424 FU National Institute of Environmental Health Sciences [1ZIAES050165]; National Institute of General Medical Sciences [0115710]; National Institutes of Health [T32 GM 007499] FX National Institute of Environmental Health Sciences 1ZIAES050165 Takamasa Teramoto Jun Zhang Traci M Tanaka Hall; National Institute of General Medical Sciences 0115710 Kathleen L McCann Susan J Baserga; National Institutes of Health T32 GM 007499 Kathleen McCann; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 38 TC 1 Z9 1 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD APR 14 PY 2016 VL 5 AR e16381 DI 10.7554/eLife.16381 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DM3PX UT WOS:000376259600001 ER PT J AU Zhu, YZ Ma, BY Qe, RX Nussinov, R Zhang, QW AF Zhu, Yuzhen Ma, Buyong Qe, Ruxi Nussinov, Ruth Zhang, Qingwen TI Temperature-Dependent Conformational Properties of Human Neuronal Calcium Sensor-1 Protein Revealed by All-Atom Simulations SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID BURIED SALT BRIDGES; MOLECULAR-DYNAMICS; BINDING PROPERTIES; AMYLOID-BETA; WATER MODELS; C. ELEGANS; STABILITY; FREQUENIN; NETWORKS; NCS-1 AB Neuronal calcium sensor-1 (NCS-1) protein has orthologues from Saccharomyces cerevisiae to human with highly conserved amino acid sequences. NCS-1 is an important factor controlling the animal's response to temperature change. This leads us to investigate the temperature effects on the conformational dynamics of human NCS-1 at 310 and 316 K by all-atom molecular dynamics (MD) simulations and dynamic community network analysis. Four independent 500 ns MD simulations show that secondary structure content at 316 K is similar to that at 310 K, whereas the global protein structure is expanded. Loop 3 (L3) adopts an extended state occuping the hydrophobic crevice, and the number of suboptimal communication paths between residue D176 and V190 is reduced at 316 K. The dynamic community network analysis suggests that the interdomain correlation is weakened, and the intradomain coupling is strengthened at 316 K. The elevated temperature reduces the number of the salt bridges, especially in C-domain. This study suggests that the elevated temperature affects the conformational dynamics of human NCS-1 protein. Comparison of the structural dynamics of R102Q mutant and Delta 176-190 truncated NCS-1 suggests that the structural and dynamical response of NCS-1 protein to elevated temperature may be one of its intrinsic functional properties. C1 [Zhu, Yuzhen; Zhang, Qingwen] Shanghai Univ Sport, Coll Phys Educ & Training, 399 Chang Hai Rd, Shanghai 200438, Peoples R China. [Ma, Buyong; Nussinov, Ruth] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Qe, Ruxi] Fudan Univ, Dept Phys, 220 Handan Rd, Shanghai 200433, Peoples R China. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Zhang, QW (reprint author), Shanghai Univ Sport, Coll Phys Educ & Training, 399 Chang Hai Rd, Shanghai 200438, Peoples R China. EM zgw@sus.edu.cn RI Ma, Buyong/F-9491-2011; OI Ma, Buyong/0000-0002-7383-719X; Zhang, Qingwen/0000-0002-8885-1066 FU Graduate Student Education Innovation Plan of Shanghai University of Sports [yjscx2015003]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded from Graduate Student Education Innovation Plan of Shanghai University of Sports (Grant yjscx2015003). Simulations were performed at the High Performance Computing Server (PowerEdge T710) of Shanghai University of Sport. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 1 Z9 1 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD APR 14 PY 2016 VL 120 IS 14 BP 3551 EP 3559 DI 10.1021/acs.jpcb.5b12299 PG 9 WC Chemistry, Physical SC Chemistry GA DJ7ZF UT WOS:000374431000010 PM 27007011 ER PT J AU Aprelikova, O Chen, K El Touny, LH Brignatz-Guittard, C Han, J Qiu, TH Yang, HH Lee, MP Zhu, M Green, JE AF Aprelikova, Olga Chen, Kenny El Touny, Lara H. Brignatz-Guittard, Constance Han, Justin Qiu, Tinghu Yang, Howard H. Lee, Maxwell P. Zhu, Min Green, Jeffrey E. TI The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis SO CLINICAL EPIGENETICS LA English DT Article DE Mammary cancer; Myc; JMJD6; Copy number variants; Epigenetics; Tumor progression ID COMPARATIVE GENOMIC HYBRIDIZATION; HUMAN BREAST-CANCER; TRANSCRIPTIONAL PAUSE RELEASE; TAG TRANSGENIC MICE; PROTEIN 6 JMJD6; VEGF-RECEPTOR 1; GENE-EXPRESSION; ARGININE METHYLATION; INDUCED APOPTOSIS; KI-RAS AB Background: Oncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis. Secondary cooperating genetic events are generally required for oncogene-induced tumorigenesis to overcome these biologic obstacles. We employed comparative genomic hybridization for eight genetically engineered mouse models of mammary cancer to identify loci that might harbor genes that enhance oncogene-induced tumorigenesis. Results: Unlike many other mammary tumor models, the MMTV-Myc tumors displayed few copy number variants except for amplification of distal mouse chromosome 11 in 80 % of the tumors (syntenic to human 17q23-qter often amplified in human breast cancer). Analyses of candidate genes located in this region identified JMJD6 as an epigenetic regulatory gene that cooperates with Myc to enhance tumorigenesis. It suppresses Myc-induced apoptosis under varying stress conditions through inhibition of p19ARF messenger RNA (mRNA) and protein, leading to reduced levels of p53. JMJD6 binds to the p19ARF promoter and exerts its inhibitory function through demethylation of H4R3me2a. JMJD6 overexpression in MMTV-Myc cell lines increases tumor burden, induces EMT, and greatly enhances tumor metastasis. Importantly, we demonstrate that co-expression of high levels of JMJD6 and Myc is associated with poor prognosis for human ER+ breast cancer patients. Conclusions: A novel epigenetic mechanism has been identified for how JMJD6 cooperates with Myc during oncogenic transformation. Combined high expression of Myc and JMJD6 confers a more aggressive phenotype in mouse and human tumors. Given the pleiotropic pro-tumorigenic activities of JMJD6, it may be useful as a prognostic factor and a therapeutic target for Myc-driven mammary tumorigenesis. C1 [Aprelikova, Olga; Chen, Kenny; El Touny, Lara H.; Brignatz-Guittard, Constance; Han, Justin; Qiu, Tinghu; Yang, Howard H.; Lee, Maxwell P.; Zhu, Min; Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, NIH, Bldg 37,Room 4054,37 Convent Dr, Bethesda, MD 20892 USA. RP Aprelikova, O (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bldg 37,Room 4054,37 Convent Dr, Bethesda, MD 20892 USA. EM apreliko@mail.nih.gov OI Chen, Kenny/0000-0002-1939-9213 FU Intramural Research Program of the NIH; CCR; NCI FX This work was supported by the Intramural Research Program of the NIH, CCR, and NCI. We would like to thank Dr. Evan and Dr. Lazebnik for pBabe-MycER (TM) puro and hygro plasmids, Dr. Desai for pLV-JMJD6 and LacZ plasmids, Dr. Johnson for pBabe-p19ARF plasmid, Dr. Liu for depositing data into Gene Expression Omnibus, and members of Green lab for helpful discussions. We are grateful to Dr. Kent Hunter for critical reading of the manuscript. We would also like to thank the Array Core Facility of the National Cancer Institute for performing array CGH analysis. NR 69 TC 1 Z9 1 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PD APR 14 PY 2016 VL 8 AR 38 DI 10.1186/s13148-016-0205-6 PG 16 WC Oncology SC Oncology GA DK1KW UT WOS:000374672100001 PM 27081402 ER PT J AU Peng, C Yao, G Gao, BM Fan, CX Bian, C Wang, JT Cao, Y Wen, B Zhu, YB Ruan, ZQ Zhao, XF You, XX Bai, J Li, J Lin, ZL Zou, SJ Zhang, XH Qiu, Y Chen, JM Coon, SL Yang, JA Chen, JS Shi, Q AF Peng, Chao Yao, Ge Gao, Bing-Miao Fan, Chong-Xu Bian, Chao Wang, Jintu Cao, Ying Wen, Bo Zhu, Yabing Ruan, Zhiqiang Zhao, Xiaofei You, Xinxin Bai, Jie Li, Jia Lin, Zhilong Zou, Shijie Zhang, Xinhui Qiu, Ying Chen, Jieming Coon, Steven L. Yang, Jiaan Chen, Ji-Sheng Shi, Qiong TI High-throughput identification of novel conotoxins from the Chinese tubular cone snail (Conus betulinus) by multi-transcriptome sequencing SO GIGASCIENCE LA English DT Article DE Cone snail; Conopeptide; Conotoxin; Conus betulinus; Transcriptome; Venom duct; Venom bulb ID VENOM-DUCT TRANSCRIPTOME; ION-CHANNEL; RNA-SEQ; INTRASPECIFIC VARIATION; PEPTIDE THERAPEUTICS; MOLECULAR PHYLOGENY; ALPHA-CONOTOXIN; TOXIN DIVERSITY; PREY CAPTURE; CHRONIC PAIN AB Background: The venom of predatory marine cone snails mainly contains a diverse array of unique bioactive peptides commonly referred to as conopeptides or conotoxins. These peptides have proven to be valuable pharmacological probes and potential drugs because of their high specificity and affinity to important ion channels, receptors and transporters of the nervous system. Most previous studies have focused specifically on the conopeptides from piscivorous and molluscivorous cone snails, but little attention has been devoted to the dominant vermivorous species. Results: The vermivorous Chinese tubular cone snail, Conus betulinus, is the dominant Conus species inhabiting the South China Sea. The transcriptomes of venom ducts and venom bulbs from a variety of specimens of this species were sequenced using both next-generation sequencing and traditional Sanger sequencing technologies, resulting in the identification of a total of 215 distinct conopeptides. Among these, 183 were novel conopeptides, including nine new superfamilies. It appeared that most of the identified conopeptides were synthesized in the venom duct, while a handful of conopeptides were identified only in the venom bulb and at very low levels. Conclusions: We identified 215 unique putative conopeptide transcripts from the combination of five transcriptomes and one EST sequencing dataset. Variation in conopeptides from different specimens of C. betulinus was observed, which suggested the presence of intraspecific variability in toxin production at the genetic level. These novel conopeptides provide a potentially fertile resource for the development of new pharmaceuticals, and a pathway for the discovery of new conotoxins. C1 [Peng, Chao; Bian, Chao; Wang, Jintu; Wen, Bo; Zhu, Yabing; Ruan, Zhiqiang; You, Xinxin; Bai, Jie; Li, Jia; Lin, Zhilong; Zou, Shijie; Zhang, Xinhui; Qiu, Ying; Chen, Jieming; Shi, Qiong] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Yao, Ge; Fan, Chong-Xu; Cao, Ying; Chen, Ji-Sheng] Res Inst Pharmaceut Chem, Beijing 102205, Peoples R China. [Gao, Bing-Miao] Hainan Med Univ, Sch Pharmaceut Sci, Haikou 571199, Peoples R China. [Bian, Chao; Ruan, Zhiqiang; You, Xinxin; Bai, Jie; Li, Jia; Zhang, Xinhui; Qiu, Ying; Chen, Jieming; Shi, Qiong] Shenzhen Key Lab Marine Genom, Guangdong Prov Key Lab Mol Breeding Marine Econ A, State Key Lab Agr Genom, Shenzhen 518083, Peoples R China. [Zhao, Xiaofei; Yang, Jiaan] Micro Pharmatech Ltd, Wuhan 430075, Peoples R China. [Coon, Steven L.] NIH, Mol Genom Lab, Bldg 10, Bethesda, MD 20892 USA. [Shi, Qiong] BGI Zhenjiang Inst Hydrobiol, Zhenjiang 212000, Peoples R China. RP Shi, Q (reprint author), BGI Shenzhen, Shenzhen 518083, Peoples R China.; Chen, JS (reprint author), Res Inst Pharmaceut Chem, Beijing 102205, Peoples R China. EM chenjsh@cae.cn; shiqiong@genomics.cn FU China 863 Program [2014AA093501]; Shenzhen Dapeng Special Program for Industrial Development [KY20150207]; Special Project on the Integration of Industry, Education and Research of Guangdong Province [2013B090800017]; Shenzhen Scientific RD Program [CXB201108250095A]; State Key Laboratory of Agricultural Genomics [ZDSY20120618171817275]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, USA FX This work was supported by China 863 Program (No. 2014AA093501), Shenzhen Dapeng Special Program for Industrial Development (No. KY20150207), Special Project on the Integration of Industry, Education and Research of Guangdong Province (No. 2013B090800017), Shenzhen Scientific R&D Program (No. CXB201108250095A), State Key Laboratory of Agricultural Genomics (No. ZDSY20120618171817275), and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, USA. NR 85 TC 0 Z9 0 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-217X J9 GIGASCIENCE JI GigaScience PD APR 14 PY 2016 VL 5 AR 17 DI 10.1186/s13742-016-0122-9 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK0YG UT WOS:000374638000001 PM 27087938 ER PT J AU Kilicoglu, H Rosemblat, G Fiszman, M Rindflesch, TC AF Kilicoglu, Halil Rosemblat, Graciela Fiszman, Marcelo Rindflesch, Thomas C. TI Sortal anaphora resolution to enhance relation extraction from biomedical literature SO BMC BIOINFORMATICS LA English DT Article DE Natural language processing; Sortal anaphora resolution; Biomedical literature; Semantic relation extraction ID COREFERENCE RESOLUTION; DOMAIN; EVENT; CLASSIFICATION; AGREEMENT; TEXT AB Background: Entity coreference is common in biomedical literature and it can affect text understanding systems that rely on accurate identification of named entities, such as relation extraction and automatic summarization. Coreference resolution is a foundational yet challenging natural language processing task which, if performed successfully, is likely to enhance such systems significantly. In this paper, we propose a semantically oriented, rule-based method to resolve sortal anaphora, a specific type of coreference that forms the majority of coreference instances in biomedical literature. The method addresses all entity types and relies on linguistic components of SemRep, a broad-coverage biomedical relation extraction system. It has been incorporated into SemRep, extending its core semantic interpretation capability from sentence level to discourse level. Results: We evaluated our sortal anaphora resolution method in several ways. The first evaluation specifically focused on sortal anaphora relations. Our methodology achieved a F-1 score of 59.6 on the test portion of a manually annotated corpus of 320 Medline abstracts, a 4-fold improvement over the baseline method. Investigating the impact of sortal anaphora resolution on relation extraction, we found that the overall effect was positive, with 50 % of the changes involving uninformative relations being replaced by more specific and informative ones, while 35 % of the changes had no effect, and only 15 % were negative. We estimate that anaphora resolution results in changes in about 1.5 % of approximately 82 million semantic relations extracted from the entire PubMed. Conclusions: Our results demonstrate that a heavily semantic approach to sortal anaphora resolution is largely effective for biomedical literature. Our evaluation and error analysis highlight some areas for further improvements, such as coordination processing and intra-sentential antecedent selection. C1 [Kilicoglu, Halil; Rosemblat, Graciela; Fiszman, Marcelo; Rindflesch, Thomas C.] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Kilicoglu, H (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM kilicogluh@mail.nih.gov FU U.S. National Library of Medicine, National Institutes of Health FX The authors thank Dongwook Shin for his assistance with the annotation tool. This work was supported by the intramural research program at the U.S. National Library of Medicine, National Institutes of Health. NR 56 TC 1 Z9 1 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD APR 14 PY 2016 VL 17 AR 163 DI 10.1186/s12859-016-1009-6 PG 16 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DJ5WB UT WOS:000374280400001 PM 27080229 ER PT J AU Temkin, SM Minasian, L Noone, AM AF Temkin, Sarah M. Minasian, Lori Noone, Anne-Michelle TI The End of the Hysterectomy Epidemic and Endometrial Cancer Incidence: What Are the Unintended Consequences of Declining Hysterectomy Rates? SO FRONTIERS IN ONCOLOGY LA English DT Review DE hysterectomy; corpus uterus; endometrial; cancer ID UNITED-STATES; RACIAL DISPARITIES; UTERINE-CANCER; BILATERAL OOPHORECTOMY; CERVICAL-CANCER; PREVALENCE; TRENDS; WOMEN; IMPACT; CORPUS AB Population-level cancer incidence rates are one measure to estimate the cancer burden. The goal is to provide information on trends to measure progress against cancer at the population level and identify emerging patterns signifying increased risk for additional research and intervention. Endometrial cancer is the most common of the gynecologic malignancies but capturing the incidence of disease among women at risk (i.e., women with a uterus) is challenging and not routinely published. Decreasing rates of hysterectomy increase the number of women at risk for disease, which should be reflected in the denominator of the incidence rate calculation. Furthermore, hysterectomy rates vary within the United States by multiple factors including geographic location, race, and ethnicity. Changing rates of hysterectomy are important to consider when looking at endometrial cancer trends. By correcting for hysterectomy when calculating incidence rates of cancers of the uterine corpus, many of the disparities that have been assumed for this disease are diminished. C1 [Temkin, Sarah M.; Minasian, Lori] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Noone, Anne-Michelle] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Temkin, SM (reprint author), NCI, Canc Prevent Div, Bethesda, MD 20892 USA. EM sarah.temkin@nih.gov NR 50 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD APR 14 PY 2016 VL 6 AR 89 DI 10.3389/fonc.2016.00089 PG 6 WC Oncology SC Oncology GA DJ4ZG UT WOS:000374216000001 PM 27148481 ER PT J AU Zou, MF Keck, TM Kumar, V Donthamsetti, P Michino, M Burzynski, C Schweppe, C Bonifazi, A Free, RB Sibley, DR Janowsky, A Shi, L Javitch, JA Newman, AH AF Zou, Mu-Fa Keck, Thomas M. Kumar, Vivek Donthamsetti, Prashant Michino, Mayako Burzynski, Caitlin Schweppe, Catherine Bonifazi, Alessandro Free, R. Benjamin Sibley, David R. Janowsky, Aaron Shi, Lei Javitch, Jonathan A. Newman, Amy Hauck TI Novel Analogues of (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Sumanirole) Provide Clues to Dopamine D-2/D-3 Receptor Agonist Selectivity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RESTLESS LEGS SYNDROME; D3 RECEPTOR; PARKINSONS-DISEASE; D-3 RECEPTORS; FORCE-FIELD; D2 RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; MEDICINAL CHEMISTRY; ANTAGONISTS; BINDING AB Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D-2/D-3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R and D3R were higher when determined in competition with the agonist radioligand [H-3]7-hydroxy-N,N-dipropy1-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [H-3]N-methylspiperone. Although 1 was confirmed as a D2R-preferential agonist, its selectivity in binding and functional studies was lower than previously reported. All analogues were determined to be D2R/D3R agonists in both G(o)BRET and mitogenesis functional assays. Loss of efficacy was detected for the N-1-substituted analogues at D3R. In contrast, the N-5-alkyl-substituted analogues, and notably the n-butyl-arylamides (22b and 22c), all showed improved affinity at D2R over 1 with neither a loss of efficacy nor an increase in selectivity. Computational modeling provided a structural basis for the D2R selectivity of 1, illustrating how subtle differences in the highly homologous orthosteric binding site (OBS) differentially affect D2R/D3R affinity and functional efficacy. C1 [Zou, Mu-Fa; Keck, Thomas M.; Kumar, Vivek; Burzynski, Caitlin; Schweppe, Catherine; Bonifazi, Alessandro; Newman, Amy Hauck] NIDA, Med Chem Sect, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Michino, Mayako; Shi, Lei] NIDA, Computat Chem & Mol Biophys Unit, Mol Targets & Medicat Discovery Branch,Intramural, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Donthamsetti, Prashant; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. [Donthamsetti, Prashant; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10027 USA. [Donthamsetti, Prashant; Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA. [Free, R. Benjamin; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, 5625 Fishers Lane,Room 4S-04, Bethesda, MD 20892 USA. [Janowsky, Aaron] Vet Affairs Portland Hlth Care Syst, Res & Dev Serv, Portland, OR 97239 USA. [Janowsky, Aaron] Oregon Hlth & Sci Univ, Sch Med, Dept Psychiat & Behav Neurosci, Portland, OR 97239 USA. [Janowsky, Aaron] Oregon Hlth & Sci Univ, Methamphetamine Abuse Res Ctr, Portland, OR 97239 USA. [Shi, Lei] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA. [Shi, Lei] Cornell Univ, Weill Med Coll, Inst Computat Biomed, New York, NY 10065 USA. [Keck, Thomas M.] Rowan Univ, Coll Sci & Math, Dept Chem & Biochem, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. [Keck, Thomas M.] Rowan Univ, Coll Sci & Math, Dept Biomed & Translat Sci, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov RI Keck, Thomas/G-9798-2012; Kumar, Vivek/F-6183-2016 OI Keck, Thomas/0000-0003-1845-9373; FU National Institute on Drug Abuse-Intramural Research Program; National Institute of Neurological Disorders and Stroke Intramural Research Program; National Institute on Drug Abuse/Department of Veterans Affairs Interagency Agreement; Methamphetamine Abuse Research Center [P50 DA018165]; VA Merit Review and Senior Research Career Scientist Programs; [K05 DA022413]; [R01 MH054137] FX Support for this research was provided by the National Institute on Drug Abuse-Intramural Research Program (A.H.N., M.-F.Z., V.K., T.M.K., A.B., C.B., C.S., L.S., and M.M.) and National Institute of Neurological Disorders and Stroke Intramural Research Program (RB.F. and D.R.S.). Support for J.A.J. and P.D. was provided by K05 DA022413 and R01 MH054137. Support for A.J. was provided by a National Institute on Drug Abuse/Department of Veterans Affairs Interagency Agreement, by VA Merit Review and Senior Research Career Scientist Programs, and by the Methamphetamine Abuse Research Center (P50 DA018165). The authors thank Dr. Robert Luedtke for earlier in vitro binding experiments on a subset of these analogues. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 66 TC 4 Z9 4 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD APR 14 PY 2016 VL 59 IS 7 BP 2973 EP 2988 DI 10.1021/acs.jmedchem.5b01612 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DJ7ZD UT WOS:000374430800008 PM 27035329 ER PT J AU Lassalas, P Gay, B Lasfargeas, C James, MJ Tran, V Vijayendran, KG Brunden, KR Kozlowski, MC Thomas, CJ Smith, AB Huryn, DM Ballatore, C AF Lassalas, Pierrik Gay, Bryant Lasfargeas, Caroline James, Michael J. Van Tran Vijayendran, Krishna G. Brunden, Kurt R. Kozlowski, Marisa C. Thomas, Craig J. Smith, Amos B., III Huryn, Donna M. Ballatore, Carlo TI Structure Property Relationships of Carboxylic Acid Isosteres SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DRUG DESIGN; PROTEIN-BINDING; RECEPTOR ANTAGONISTS; ASYMMETRIC-SYNTHESIS; MEDICINAL CHEMISTRY; HYDROXAMIC ACIDS; TETRAZOLE; BIOISOSTERES; DERIVATIVES; INHIBITORS AB The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group. C1 [Lassalas, Pierrik; Gay, Bryant; Lasfargeas, Caroline; Van Tran; Vijayendran, Krishna G.; Kozlowski, Marisa C.; Smith, Amos B., III; Huryn, Donna M.; Ballatore, Carlo] Univ Penn, Dept Chem, Sch Arts & Sci, 231 South 34th St, Philadelphia, PA 19104 USA. [James, Michael J.; Brunden, Kurt R.; Ballatore, Carlo] Univ Penn, Ctr Neurodegenerat Dis Res, 3600 Spruce St, Philadelphia, PA 19104 USA. [Thomas, Craig J.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20850 USA. RP Huryn, DM; Ballatore, C (reprint author), Univ Penn, Dept Chem, Sch Arts & Sci, 231 South 34th St, Philadelphia, PA 19104 USA.; Ballatore, C (reprint author), Univ Penn, Ctr Neurodegenerat Dis Res, 3600 Spruce St, Philadelphia, PA 19104 USA. EM huryn@sas.upenn.edu; bcarlo@sas.upenn.edu RI Lassalas, Pierrik/A-4944-2012; OI Lassalas, Pierrik/0000-0001-9838-6973; Huryn, Donna/0000-0001-5542-4968 FU intramural program of National Center for Advancing Translational Sciences; NIH/NIA [AG044332, AG034140]; NIH/NIGMS [GM87605]; Marian S. Ware Alzheimer Program; NSF [CHE-0840438] FX Financial support for this work has been provided in part by the intramural program of the National Center for Advancing Translational Sciences (CT), the NIH/NIA (AG044332; AG034140 for PL, BG, MJ, KB, and CB), the NIH/NIGMS (GM87605 for MCK and VT), the Marian S. Ware Alzheimer Program, and the NSF (Grant CHE-0840438, X-ray facility). Finally, the authors would like to thank Mary Liang (University of Pittsburgh) for careful reading of the manuscript. NR 55 TC 6 Z9 6 U1 14 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD APR 14 PY 2016 VL 59 IS 7 BP 3183 EP 3203 DI 10.1021/acs.jmedchem.5b01963 PG 21 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DJ7ZD UT WOS:000374430800023 PM 26967507 ER PT J AU Tosh, DK Ciancetta, A Warnick, E O'Connor, R Chen, ZM Gizewski, E Crane, S Gao, ZG Auchampach, JA Salvemini, D Jacobson, KA AF Tosh, Dilip K. Ciancetta, Antonella Warnick, Eugene O'Connor, Robert Chen, Zhoumou Gizewski, Elizabeth Crane, Steven Gao, Zhan-Guo Auchampach, John A. Salvemini, Daniela Jacobson, Kenneth A. TI Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A(3) Adenosine Receptor Agonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CHRONIC NEUROPATHIC PAIN; A(2A) RECEPTOR; DRUG DESIGN; ANTAGONISTS; BINDING; HYDROAMINATION; ACTIVATION; DISCOVERY; LIGANDS; ALKYNES AB Purine (N)-methanocarba-5'-N-alkyluronamidoriboside A(3) adenosine receptor (A(3)AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A(3)AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A(3)AR K-i values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A(3)AR (MRS7220, K-i 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 mu mol/kg, po). The lack of a C6 H-bond donor while maintaining A(3)AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A(3)AR binding site. C1 [Tosh, Dilip K.; Ciancetta, Antonella; Warnick, Eugene; O'Connor, Robert; Crane, Steven; Gao, Zhan-Guo; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Lab Bioorgan Chem, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. [Chen, Zhoumou; Salvemini, Daniela] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. [Gizewski, Elizabeth; Auchampach, John A.] Med Coll Wisconsin, Dept Pharmacol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. RP Jacobson, KA (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Bioorgan Chem, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH Intramural Research Program (NIDDK) [ZIA DK031117-28]; National Cancer Institute [R01CA169519]; National Heart Lung Institute [R01HL077707, R01HL111392]; National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C] FX We thank the NIH Intramural Research Program (NIDDK, ZIA DK031117-28); National Cancer Institute (R01CA169519) and National Heart Lung Institute (R01HL077707 and R01HL111392) for support and John Lloyd and Noel Whittaker (NIDDK) for mass spectral determinations. We thank Dr. Bryan L. Roth (University of North Carolina at Chapel Hill) and National Institute of Mental Health's Psychoactive Drug Screening Program (contract no. HHSN-271-2008-00025-C) for screening data. NR 48 TC 0 Z9 0 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD APR 14 PY 2016 VL 59 IS 7 BP 3249 EP 3263 DI 10.1021/acs.jmedchem.5b01998 PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DJ7ZD UT WOS:000374430800027 PM 26890707 ER PT J AU Ranade, AR Higgins, L Markowski, TW Glaser, N Kashin, D Bai, RL Hong, KH Hamel, E Hofle, G Georg, GI AF Ranade, Adwait R. Higgins, LeeAnn Markowski, Todd W. Glaser, Nicole Kashin, Dmitry Bai, Ruoli Hong, Kwon Ho Hamel, Ernest Hoefle, Gerhard Georg, Gunda I. TI Characterizing the Epothilone Binding Site on beta-Tubulin by Photoaffinity Labeling: Identification of beta-Tubulin Peptides TARGSQQY and TSRGSQQY as Targets of an Epothilone Photoprobe for Polymerized Tubulin SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MICROTUBULE-STABILIZING AGENTS; CONFORMATION-ACTIVITY RELATIONSHIPS; POLYKETIDE NATURAL-PRODUCTS; COMMON PHARMACOPHORE; SORANGIUM-CELLULOSUM; BIOLOGICAL-ACTIVITY; CANCER-CELLS; MOUSE MODEL; SIDE-CHAIN; TAXOL AB Photoaffinity labeling with an epothilone A photoprobe led to the identification of the beta-tubulin peptides TARGSQQY and TSRGSQQY as targets of the photoprobe for polymerized tubulin. These peptides represent residues 274-281 in different beta-tubulin isotypes. Placing the carbene producing 21-diazo/triazolo moiety of the photoprobe in the vicinity of the TARGSQQY peptide in a homology model of TBB3 predicted a binding pose and conformation of the photoprobe that are very similar to the ones reported for 1) the high resolution cocrystal structure of epothilone A with an alpha,beta-tubulin complex and for 2) a saturation transfer difference NMR and transferred NOESY NMR study of dimeric and polymerized tubulin. Our findings thus provide additional support for these models as physiologically the most relevant among several modes of binding that have been proposed for epothilone A in the taxane pocket of beta-tubulin. C1 [Ranade, Adwait R.; Hong, Kwon Ho; Georg, Gunda I.] Univ Minnesota, Coll Pharm, Dept Med Chem, 717 Delaware St SE, Minneapolis, MN 55414 USA. [Ranade, Adwait R.; Hong, Kwon Ho; Georg, Gunda I.] Univ Minnesota, Coll Pharm, Inst Therapeut Discovery & Dev, 717 Delaware St SE, Minneapolis, MN 55414 USA. [Higgins, LeeAnn; Markowski, Todd W.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, 321 Church St SE, Minneapolis, MN 55455 USA. [Glaser, Nicole; Kashin, Dmitry; Hoefle, Gerhard] Helmholtz Ctr Infect Res, Dept Nat Prod Chem, Inhoffenstr 7, D-38124 Braunschweig, Germany. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. RP Georg, GI (reprint author), Univ Minnesota, Coll Pharm, Dept Med Chem, 717 Delaware St SE, Minneapolis, MN 55414 USA.; Georg, GI (reprint author), Univ Minnesota, Coll Pharm, Inst Therapeut Discovery & Dev, 717 Delaware St SE, Minneapolis, MN 55414 USA. EM georg@umn.edu FU University of Minnesota through Vince and McKnight Endowed Chairs; NSF Major Research Instrumentation Grant [9871237]; NSF [CHE-0078192]; NIH Multiuser Grant [RR15808, 2001-2002]; NSF-MRI Grant [0215759]; State of Minnesota Infrastructure Grant; University of Minnesota - College of Agriculture, Food and Environmental Sciences; College of Biological Sciences; Minnesota Graduate School; Minnesota Medical Foundation; Department of Biochemistry, Molecular Biology and Biophysics; Office of the Vice President for Health Sciences; Vice President for Research FX We greatly appreciate the financial support from the University of Minnesota through the Vince and McKnight Endowed Chairs (to G.I.G.). We thank Florenz Sasse for performing cell cytotoxicity and tubulin assembly assays. The authors recognize the Center for Mass Spectrometry and Proteomics at the University of Minnesota and various supporting agencies, including NSF Major Research Instrumentation Grant 9871237, NSF Grant CHE-0078192, NIH Multiuser Grant RR15808, 2001-2002, NSF-MRI Grant 0215759, State of Minnesota Infrastructure Grant, and University of Minnesota support from the College of Agriculture, Food and Environmental Sciences, the College of Biological Sciences, the Minnesota Graduate School, the Minnesota Medical Foundation, the Department of Biochemistry, Molecular Biology and Biophysics, the Office of the Vice President for Health Sciences, and the Vice President for Research. See http://www.cbs.umn.edu/research/resources/msp/about. We also thank the Minnesota Supercomputing Institute for their support for the computational study. NR 61 TC 2 Z9 2 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD APR 14 PY 2016 VL 59 IS 7 BP 3499 EP 3514 DI 10.1021/acs.jmedchem.6b00188 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DJ7ZD UT WOS:000374430800044 PM 26986898 ER PT J AU Castro, NP Merchant, AS Saylor, KL Anver, MR Salomon, DS Golubeva, YG AF Castro, Nadia P. Merchant, Anand S. Saylor, Karen L. Anver, Miriam R. Salomon, David S. Golubeva, Yelena G. TI Adaptation of Laser Microdissection Technique for the Study of a Spontaneous Metastatic Mammary Carcinoma Mouse Model by NanoString Technologies SO PLOS ONE LA English DT Article ID GENE-EXPRESSION ANALYSIS; MICROCAPILLARY ELECTROPHORESIS TRACES; CAPTURE MICRODISSECTION; BREAST-CANCER; RNA QUALITY; TISSUE SAMPLES; IMPACT; TARGET AB Laser capture microdissection (LCM) of tissue is an established tool in medical research for collection of distinguished cell populations under direct microscopic visualization for molecular analysis. LCM samples have been successfully analyzed in a number of genomic and proteomic downstream molecular applications. However, LCM sample collection and preparation procedure has to be adapted to each downstream analysis platform. In this present manuscript we describe in detail the adaptation of LCM methodology for the collection and preparation of fresh frozen samples for NanoString analysis based on a study of a model of mouse mammary gland carcinoma and its lung metastasis. Our adaptation of LCM sample preparation and workflow to the requirements of the NanoString platform allowed acquiring samples with high RNA quality. The NanoString analysis of such samples provided sensitive detection of genes of interest and their associated molecular pathways. NanoString is a reliable gene expression analysis platform that can be effectively coupled with LCM. C1 [Castro, Nadia P.; Saylor, Karen L.; Salomon, David S.] NCI, Tumor Growth Factor Sect, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Merchant, Anand S.] NCI, CCRIFX Bioinformat Core, Bethesda, MD 20892 USA. [Anver, Miriam R.; Golubeva, Yelena G.] Leidos Biomed Res Inc, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Castro, NP (reprint author), NCI, Tumor Growth Factor Sect, Mouse Canc Genet Program, Frederick, MD 21702 USA.; Golubeva, YG (reprint author), Leidos Biomed Res Inc, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM castron2@mail.nih.gov; yelena.golubeva@gmail.com FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 1 Z9 1 U1 1 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 APR 14 PY 2016 VL 11 IS 4 AR e0153270 DI 10.1371/journal.pone.0153270 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ3UH UT WOS:000374131700034 PM 27077656 ER PT J AU Zurawski, G Zurawski, S Flamar, AL Richert, L Wagner, R Tomaras, GD Montefiori, DC Roederer, M Ferrari, G Lacabaratz, C Bonnabau, H Klucar, P Wang, ZQ Foulds, KE Kao, SF Yates, NL LaBranche, C Jacobs, BL Kibler, K Asbach, B Kliche, A Salazar, A Reed, S Self, S Gottardo, R Galmin, L Weiss, D Cristillo, A Thiebaut, R Pantaleo, G Levy, Y AF Zurawski, Gerard Zurawski, Sandra Flamar, Anne-Laure Richert, Laura Wagner, Ralf Tomaras, Georgia D. Montefiori, David C. Roederer, Mario Ferrari, Guido Lacabaratz, Christine Bonnabau, Henri Klucar, Peter Wang, Zhiqing Foulds, Kathryn E. Kao, Shing-Fen Yates, Nicole L. LaBranche, Celia Jacobs, Bertram L. Kibler, Karen Asbach, Benedikt Kliche, Alexander Salazar, Andres Reed, Steve Self, Steve Gottardo, Raphael Galmin, Lindsey Weiss, Deborah Cristillo, Anthony Thiebaut, Rodolphe Pantaleo, Giuseppe Levy, Yves TI Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques SO PLOS ONE LA English DT Article ID T-CELL RESPONSES; NONHUMAN-PRIMATES; DENDRITIC CELLS; EFFICACY TRIAL; IMMUNOLOGICAL CHARACTERIZATION; LANGERHANS CELLS; VACCINIA VIRUS; ANTIBODIES; PROTEIN; ANTIGENS AB Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4(+) and CD8(+) Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4(+) T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1. C1 [Zurawski, Gerard; Zurawski, Sandra; Flamar, Anne-Laure; Lacabaratz, Christine; Klucar, Peter; Wang, Zhiqing; Levy, Yves] Univ Paris Est, Vaccine Res Inst, Fac Med, INSERM,U955, Creteil, France. [Zurawski, Gerard; Zurawski, Sandra; Flamar, Anne-Laure; Lacabaratz, Christine; Klucar, Peter; Wang, Zhiqing; Levy, Yves] Grp Henri Mondor Albert Chenevier, AP HP, Serv Immunol Clin, INRIA SISTM, Creteil, France. [Zurawski, Gerard; Zurawski, Sandra; Flamar, Anne-Laure; Klucar, Peter; Wang, Zhiqing] Baylor Inst Immunol Res, Dallas, TX USA. [Zurawski, Gerard; Zurawski, Sandra; Flamar, Anne-Laure; Klucar, Peter; Wang, Zhiqing] INSERM, U955, Dallas, TX USA. [Richert, Laura; Bonnabau, Henri; Thiebaut, Rodolphe] Univ Bordeaux Segalen, INSERM, U897, INRIA SISTM, Bordeaux, France. [Wagner, Ralf; Asbach, Benedikt; Kliche, Alexander] Univ Regensburg, Inst Med Microbiol & Hyg, Mol Microbiol & Gene Therapy Unit, D-93053 Regensburg, Germany. [Tomaras, Georgia D.; Montefiori, David C.; Ferrari, Guido; Yates, Nicole L.; LaBranche, Celia] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Tomaras, Georgia D.; Montefiori, David C.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Roederer, Mario; Foulds, Kathryn E.; Kao, Shing-Fen] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Jacobs, Bertram L.; Kibler, Karen] Arizona State Univ, Sch Life Sci, Ctr Infect Dis & Vaccinol, Tempe, AZ USA. [Self, Steve; Gottardo, Raphael] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Self, Steve; Gottardo, Raphael] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Salazar, Andres] Oncovir, Washington, DC USA. [Reed, Steve] Infect Dis Res Inst, Seattle, WA USA. [Galmin, Lindsey; Weiss, Deborah; Cristillo, Anthony] Adv BioSci Labs Inc, Rockville, MD USA. [Pantaleo, Giuseppe] CHU Vaudois, CH-101 Lausanne, Switzerland. RP Zurawski, G (reprint author), Univ Paris Est, Vaccine Res Inst, Fac Med, INSERM,U955, Creteil, France.; Zurawski, G (reprint author), Grp Henri Mondor Albert Chenevier, AP HP, Serv Immunol Clin, INRIA SISTM, Creteil, France.; Zurawski, G (reprint author), Baylor Inst Immunol Res, Dallas, TX USA. EM gerardz@baylorhealth.edu RI Tomaras, Georgia/J-5041-2016; Pantaleo, Giuseppe/K-6163-2016; OI Zurawski, Gerard/0000-0002-0168-3523 FU Vaccine Research Institute HIV vaccine program (ANRS/INSERM); Vaccine Research Institute HIV vaccine program (Investissements d'Avenir program) [ANR-10-LABX-77]; Poxvirus T-cell Vaccine Consortium - Bill & Melinda Gates Foundation [OPP38599]; Vaccine Immune Monitoring Centers - Bill & Melinda Gates Foundation [OPP1032325, OPP1032144]; Vaccine Immunology Statistical Center - Bill & Melinda Gates Foundation [OPP1032317] FX The study was funded within the Vaccine Research Institute HIV vaccine program (ANRS/INSERM and was supported by the Investissements d'Avenir program managed by the ANR under reference ANR-10-LABX-77). Support from the Poxvirus T-cell Vaccine Consortium funded by the Bill & Melinda Gates Foundation (OPP38599) for the development of NYVAC-KC vector. Support for the ICS and antibody immune monitoring assays was provided by the Vaccine Immune Monitoring Centers (OPP1032325 & OPP1032144), and support for the statistical analysis from the Vaccine Immunology Statistical Center (OPP1032317), all part of the Collaboration for AIDS Vaccine Discovery (CAVD) funded by the Bill & Melinda Gates Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The study was funded within the Vaccine Research Institute HIV vaccine program (ANRS/INSERM and was supported by the Investissements d'Avenir program managed by the ANR under reference ANR-10-LABX-77). Support from the Poxvirus T-cell Vaccine Consortium funded by the Bill & Melinda Gates Foundation (OPP38599) for the development of NYVAC-KC vector. Support for the ICS and antibody immune monitoring assays was provided by the Vaccine Immune Monitoring Centers (OPP1032325 & OPP1032144), and support for the statistical analysis from the Vaccine Immunology Statistical Center (OPP1032317), all part of the Collaboration for AIDS Vaccine Discovery (CAVD) funded by the Bill & Melinda Gates Foundation. Alicia Sato (Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center) and Jason Skinner (BIIR) are thanked for valuable edits. Matthew Baker (Antitope, Ltd) provided humanization of the alpha LOX-1 15C4 mAb. Lauren Hudacik (ABL), Cecile Peltekian (INSERM U955) and Song Ding (EuroVacc Foundation) are thanked for excellent project coordination. NR 43 TC 1 Z9 1 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 14 PY 2016 VL 11 IS 4 AR e0153484 DI 10.1371/journal.pone.0153484 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ3UH UT WOS:000374131700063 PM 27077384 ER PT J AU Kaur, A Webster, MR Marchbank, K Behera, R Ndoye, A Kugel, CH Dang, VM Appleton, J O'Connell, MP Cheng, P Valiga, AA Morissette, R McDonnell, NB Ferrucci, L Kossenkov, AV Meeth, K Tang, HY Yin, XF Wood, WH Lehrmann, E Becker, KG Flaherty, KT Frederick, DT Wargo, JA Cooper, ZA Tetzlaff, MT Hudgens, C Aird, KM Zhang, RG Xu, XW Liu, Q Bartlett, E Karakousis, G Eroglu, Z Lo, RS Chan, M Menzies, AM Long, GV Johnson, DB Sosman, J Schilling, B Schadendorf, D Speicher, DW Bosenberg, M Ribas, A Weeraratna, AT AF Kaur, Amanpreet Webster, Marie R. Marchbank, Katie Behera, Reeti Ndoye, Abibatou Kugel, Curtis H., III Dang, Vanessa M. Appleton, Jessica O'Connell, Michael P. Cheng, Phil Valiga, Alexander A. Morissette, Rachel McDonnell, Nazli B. Ferrucci, Luigi Kossenkov, Andrew V. Meeth, Katrina Tang, Hsin-Yao Yin, Xiangfan Wood, William H., III Lehrmann, Elin Becker, Kevin G. Flaherty, Keith T. Frederick, Dennie T. Wargo, Jennifer A. Cooper, Zachary A. Tetzlaff, Michael T. Hudgens, Courtney Aird, Katherine M. Zhang, Rugang Xu, Xiaowei Liu, Qin Bartlett, Edmund Karakousis, Giorgos Eroglu, Zeynep Lo, Roger S. Chan, Matthew Menzies, Alexander M. Long, Georgina V. Johnson, Douglas B. Sosman, Jeffrey Schilling, Bastian Schadendorf, Dirk Speicher, David W. Bosenberg, Marcus Ribas, Antoni Weeraratna, Ashani T. TI sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance SO NATURE LA English DT Article ID BETA-CATENIN; OXIDATIVE STRESS; CELLS; TUMOR; GROWTH; PROGRESSION; PHENOTYPE; CANCER; MITF AB Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression(1-4), we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in beta-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly. C1 [Kaur, Amanpreet; Webster, Marie R.; Marchbank, Katie; Behera, Reeti; Ndoye, Abibatou; Kugel, Curtis H., III; Dang, Vanessa M.; Appleton, Jessica; O'Connell, Michael P.; Valiga, Alexander A.; Kossenkov, Andrew V.; Tang, Hsin-Yao; Yin, Xiangfan; Aird, Katherine M.; Zhang, Rugang; Liu, Qin; Speicher, David W.; Weeraratna, Ashani T.] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. [Kaur, Amanpreet] Univ Sci, Philadelphia, PA 19104 USA. [Cheng, Phil] Univ Zurich, Dept Dermatol, CH-8006 Zurich, Switzerland. [Morissette, Rachel; McDonnell, Nazli B.; Ferrucci, Luigi; Wood, William H., III; Lehrmann, Elin; Becker, Kevin G.] NIA, NIH, Baltimore, MD 21224 USA. [Meeth, Katrina; Bosenberg, Marcus] Yale Univ, Dept Dermatol & Pathol, New Haven, CT 06511 USA. [Flaherty, Keith T.; Frederick, Dennie T.] Massachusetts Gen Hosp, Ctr Canc, Dev Therapeut, Boston, MA 02114 USA. [Wargo, Jennifer A.; Cooper, Zachary A.; Tetzlaff, Michael T.; Hudgens, Courtney] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Xu, Xiaowei; Bartlett, Edmund; Karakousis, Giorgos] Univ Penn, Dept Surg, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Xu, Xiaowei; Bartlett, Edmund; Karakousis, Giorgos] Univ Penn, Dept Pathol, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Eroglu, Zeynep] City Hope Med Ctr, Dept Med Oncol, Duarte, CA 91010 USA. [Lo, Roger S.; Ribas, Antoni] Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Chan, Matthew] Westmead Hosp, Crown Princess Mary Canc Ctr, Westmead, NSW 2145, Australia. [Menzies, Alexander M.; Long, Georgina V.] Melanoma Inst Australia, Sydney, NSW 2000, Australia. [Menzies, Alexander M.; Long, Georgina V.] Univ Sydney, Sydney, NSW 2000, Australia. [Johnson, Douglas B.; Sosman, Jeffrey] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. [Schilling, Bastian; Schadendorf, Dirk] Univ Duesburg Essen, Dept Dermatol, Univ Hosp, West German Canc Ctr, Essen, Germany. [Schilling, Bastian; Schadendorf, Dirk] German Canc Consortium DKTK, D-45127 Heidelberg, Germany. RP Weeraratna, AT (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM aweeraratna@wistar.org OI Bartlett, Edmund/0000-0002-0923-153X; Cooper, Zachary/0000-0003-1059-0940 FU National Institute on Aging, Baltimore, Maryland; Harry J. Lloyd Foundation; ACS-IRG; Melanoma Research Foundation; Cancer Center Support Grant [P30 CA010815]; [P01 CA 114046-06]; [T32 CA 9171-36]; [RO1 CA174746-01] FX We thank D. Altieri, R. Marais, Z. Ronai, M. McMahon, and B. Vogelstein for comments on the manuscript. We thank R. Somasundaram for advice on immune analyses, M. Herlyn for the WM cell lines, and G. Bollag for PLX4720. We also thank R. Delgiacco, D. Gourevitch, F. Keeney, and D. Schultz. We thank A. Dias-Wanigasekera, E. Gaddy, and M. Ha for technical assistance, and R. Locke for editing the manuscript. This work was supported in part by funds from the Intramural Program of the National Institute on Aging, Baltimore, Maryland (N.M., K.G.B., R. M., W.H.W., L.F.), The Harry J. Lloyd Foundation (K.M., A.T.W.), P01 CA 114046-06 (A.T.W., Q.L.), T32 CA 9171-36 (M.R.W., C.H.K.), an ACS-IRG award (A.T.W.), the Melanoma Research Foundation (A.T.W.), and RO1 CA174746-01 (A.T.W., A.K.). Core facilities at the Wistar are supported by Cancer Center Support Grant P30 CA010815. NR 29 TC 20 Z9 20 U1 9 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD APR 14 PY 2016 VL 532 IS 7598 BP 250 EP + DI 10.1038/nature17392 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ7TJ UT WOS:000374415100043 PM 27042933 ER PT J AU Zou, M Baitei, EY Al-Rijjal, RA Parhar, RS Al-Mohanna, FA Kimura, S Pritchard, C Binessa, HA Alzahrani, AS Al-Khalaf, HH Hawwari, A Akhtar, M Assiri, AM Meyer, BF Shi, Y AF Zou, M. Baitei, E. Y. Al-Rijjal, R. A. Parhar, R. S. Al-Mohanna, F. A. Kimura, S. Pritchard, C. Binessa, H. A. Alzahrani, A. S. Al-Khalaf, H. H. Hawwari, A. Akhtar, M. Assiri, A. M. Meyer, B. F. Shi, Y. TI TSH overcomes Braf(V600E)-induced senescence to promote tumor progression via downregulation of p53 expression in papillary thyroid cancer SO ONCOGENE LA English DT Article ID ONCOGENE-INDUCED SENESCENCE; SERUM TSH; TRANSGENIC MICE; BRAF MUTATIONS; MOUSE MODEL; IN-VIVO; CARCINOMA; PTEN; CELLS; RAS AB The BRAF(V600E) mutation is found in approximately 40% of papillary thyroid cancers (PTC). Mice with thyroid-specific expression of BRAF(V600E) (TPO-BRAF(V600E)) develop PTC rapidly with high levels of serum thyroid-stimulating hormone (TSH). It is unclear to what extent the elevated TSH contributes to tumor progression. To investigate the progression of BRAF(V600E)-induced PTC (BVE-PTC) under normal TSH, we transplanted BVE-PTC tumors subcutaneously into nude and TPO-Braf(WT) mice. Regression of the transplanted tumors was observed in both nude and TPO-Braf(WT) mice. They were surrounded by heavy lymphocyte infiltration and oncogene-induced senescence (OIS) was demonstrated by strong beta-gal staining and absence of Ki-67 expression. In contrast, BVE-PTC transplants continued to grow when transplanted into TPO-BRAF(V600E) mice. The expression of Trp53 was increased in tumor transplants undergoing OIS. Trp53 inactivation reversed OIS and enabled tumor transplants to grow in nude mice with characteristic cell morphology of anaplastic thyroid cancer (ATC). PTC-to-ATC transformation was also observed in primary BVE-PTC tumors. ATC cells derived from Trp53 knockout tumors had increased PI3K/AKT signaling and became resistant to BRAF(V600E) inhibitor PLX4720, which could be overcome by combined treatment of PI3K inhibitor LY294002 and PLX4720. In conclusion, BVE-PTC progression could be contained via p53-dependent OIS and TSH is a major disruptor of this balance. Simultaneous targeting of both MAPK and PI3K/AKT pathways offer a better therapeutic outcome against ATC. The current study reinforces the importance of rigorous control of serum TSH in PTC patients. C1 [Zou, M.; Baitei, E. Y.; Al-Rijjal, R. A.; Binessa, H. A.; Hawwari, A.; Meyer, B. F.; Shi, Y.] King Faisal Specialist Hosp & Res Ctr, Dept Genet, MBC 3,Takhassusi St,POB 3354, Riyadh 11211, Saudi Arabia. [Parhar, R. S.; Al-Mohanna, F. A.] King Faisal Specialist Hosp & Res Ctr, Dept Cell Biol, Riyadh 11211, Saudi Arabia. [Kimura, S.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Pritchard, C.] Univ Leicester, Dept Biochem, Lancaster Rd, Leicester LE1 7RH, Leics, England. [Alzahrani, A. S.] King Faisal Specialist Hosp & Res Ctr, Dept Med, POB 3354, Riyadh 11211, Saudi Arabia. [Al-Khalaf, H. H.] King Faisal Specialist Hosp & Res Ctr, Dept Mol Oncol, Riyadh 11211, Saudi Arabia. [Akhtar, M.] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, POB 3354, Riyadh 11211, Saudi Arabia. [Assiri, A. M.] King Faisal Specialist Hosp & Res Ctr, Dept Comparat Med, Riyadh 11211, Saudi Arabia. RP Shi, Y (reprint author), King Faisal Specialist Hosp & Res Ctr, Dept Genet, MBC 3,Takhassusi St,POB 3354, Riyadh 11211, Saudi Arabia. EM yufei@kfshrc.edu.sa FU KACST [11-BIO1434-20] FX We would like to thank Mr Wilfredo Antiquera for excellent technical support. This study is supported by KACST grant 11-BIO1434-20. NR 59 TC 0 Z9 0 U1 8 U2 17 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 APR 14 PY 2016 VL 35 IS 15 BP 1909 EP 1918 DI 10.1038/onc.2015.253 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DJ2CC UT WOS:000374010300004 PM 26477313 ER PT J AU Du Toit, G Sayre, PH Roberts, G Sever, ML Lawson, K Bahnson, HT Brough, HA Santos, AF Harris, KM Radulovic, S Basting, M Turcanu, V Plaut, M Lack, G AF Du Toit, George Sayre, Peter H. Roberts, Graham Sever, Michelle L. Lawson, Kaitie Bahnson, Henry T. Brough, Helen A. Santos, Alexandra F. Harris, Kristina M. Radulovic, Suzana Basting, Monica Turcanu, Victor Plaut, Marshall Lack, Gideon CA Immune Tolerance Network LEAP-On TI Effect of Avoidance on Peanut Allergy after Early Peanut Consumption SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TERM CLINICAL-EFFICACY; FOOD ALLERGY; ORAL IMMUNOTHERAPY; ANAPHYLAXIS; EPIDEMIOLOGY; MANAGEMENT; CHILDREN; INFANTS; PROTEIN; EUROPE AB BACKGROUND In a randomized trial, the early introduction of peanuts in infants at high risk for allergy was shown to prevent peanut allergy. In this follow-up study, we investigated whether the rate of peanut allergy remained low after 12 months of peanut avoidance among participants who had consumed peanuts during the primary trial (peanut-consumption group), as compared with those who had avoided peanuts (peanut-avoidance group). METHODS At the end of the primary trial, we instructed all the participants to avoid peanuts for 12 months. The primary outcome was the percentage of participants with peanut allergy at the end of the 12-month period, when the participants were 72 months of age. RESULTS We enrolled 556 of 628 eligible participants (88.5%) from the primary trial; 550 participants (98.9%) had complete primary-outcome data. The rate of adherence to avoidance in the follow-up study was high (90.4% in the peanut-avoidance group and 69.3% in the peanut-consumption group). Peanut allergy at 72 months was significantly more prevalent among participants in the peanut-avoidance group than among those in the peanut-consumption group (18.6% [52 of 280 participants] vs. 4.8% [13 of 270], P< 0.001). Three new cases of allergy developed in each group, but after 12 months of avoidance there was no significant increase in the prevalence of allergy among participants in the consumption group (3.6% [10 of 274 participants] at 60 months and 4.8% [13 of 270] at 72 months, P = 0.25). Fewer participants in the peanut-consumption group than in the peanut-avoidance group had high levels of Ara h2 (a component of peanut protein)-specific IgE and peanut-specific IgE; in addition, participants in the peanut-consumption group continued to have a higher level of peanut-specific IgG4 and a higher peanut-specific IgG4: IgE ratio. CONCLUSIONS Among children at high risk for allergy in whom peanuts had been introduced in the first year of life and continued until 5 years of age, a 12-month period of peanut avoidance was not associated with an increase in the prevalence of peanut allergy. Longer-term effects are not known. C1 [Du Toit, George; Brough, Helen A.; Santos, Alexandra F.; Radulovic, Suzana; Basting, Monica; Turcanu, Victor; Lack, Gideon] Kings Coll London, Div Asthma Allergy & Lung Biol, Dept Pediat Allergy, London, England. [Du Toit, George; Brough, Helen A.; Santos, Alexandra F.; Radulovic, Suzana; Basting, Monica; Turcanu, Victor; Lack, Gideon] Guys & St Thomas NHS Fdn Trust, London, England. [Roberts, Graham] Univ Southampton, Southampton, Hants, England. [Roberts, Graham] Natl Inst Hlth Res Resp, Biomed Res Unit, Southampton, Hants, England. [Roberts, Graham] David Hide Ctr, Newport, Isle Of Wight, England. [Sayre, Peter H.] Univ Calif San Francisco, Dept Med, Div Hematol & Oncol, San Francisco, CA 94143 USA. [Sever, Michelle L.; Lawson, Kaitie; Bahnson, Henry T.] Rho Fed Syst Div, Chapel Hill, NC USA. [Harris, Kristina M.] Immune Tolerance Network, Bethesda, MD USA. [Plaut, Marshall] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Lack, G (reprint author), Guys & St Thomas NHS Fdn Trust, Childrens Allergy Unit, 2nd Fl,South Wing,Westminster Bridge Rd, London SE1 7EH, England. EM gideon.lack@kcl.ac.uk FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [NO1-AI-15416, UM1AI109565, HHSN272200800029C, UM2AI117870]; Food Allergy Research and Education; Medical Research Council; Asthma U.K. Centre; U.K. Department of Health through a National Institute for Health Research comprehensive Biomedical Research Centre; King's College London; King's College Hospital NHS Foundation Trust; National Peanut Board, Atlanta; U.K. Food Standards Agency FX Supported by grants (NO1-AI-15416, UM1AI109565, HHSN272200800029C, and UM2AI117870) from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and by Food Allergy Research and Education, the Medical Research Council and Asthma U.K. Centre, and the U.K. Department of Health through a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's and St. Thomas' NHS Foundation Trust, in partnership with King's College London and King's College Hospital NHS Foundation Trust. The clinical trials unit was supported by the National Peanut Board, Atlanta. The U.K. Food Standards Agency provided additional support for the costs of phlebotomy. NR 16 TC 48 Z9 48 U1 10 U2 17 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 14 PY 2016 VL 374 IS 15 BP 1435 EP 1443 DI 10.1056/NEJMoa1514209 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DJ3TD UT WOS:000374128400007 PM 26942922 ER PT J AU Berthon, A Drelon, C Val, P AF Berthon, Annabel Drelon, Coralie Val, Pierre TI Pregnancy, Primary Aldosteronism, and Somatic CTNNB1 Mutations SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ADENOMA C1 [Berthon, Annabel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Drelon, Coralie; Val, Pierre] Ctr Natl Rech Sci, UMR 6293, Clermont Ferrand, France. RP Val, P (reprint author), Ctr Natl Rech Sci, UMR 6293, Clermont Ferrand, France. EM pierre.val@univ-bpclermont.fr NR 4 TC 1 Z9 1 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 APR 14 PY 2016 VL 374 IS 15 BP 1493 EP 1494 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DJ3TD UT WOS:000374128400023 PM 27074082 ER PT J AU Ribas, V Drew, BG Zhou, ZQ Phun, J Kalajian, NY Soleymani, T Daraei, P Widjaja, K Wanagat, J Vallim, TQD Fluitt, AH Bensinger, S Le, T Radu, C Whitelegge, JP Beaven, SW Tontonoz, P Lusis, AJ Parks, BW Vergnes, L Reue, K Singh, H Bopassa, JC Toro, L Stefani, E Watt, MJ Schenk, S Akerstrom, T Kelly, M Pedersen, BK Hewitt, SC Korach, KS Hevener, AL AF Ribas, Vicent Drew, Brian G. Zhou, Zhenqi Phun, Jennifer Kalajian, Nareg Y. Soleymani, Teo Daraei, Pedram Widjaja, Kevin Wanagat, Jonathan Vallim, Thomas Q. de Aguiar Fluitt, Amy H. Bensinger, Steven Thuc Le Radu, Caius Whitelegge, Julian P. Beaven, Simon W. Tontonoz, Peter Lusis, Aldons J. Parks, Brian W. Vergnes, Laurent Reue, Karen Singh, Harpreet Bopassa, Jean C. Toro, Ligia Stefani, Enrico Watt, Matthew J. Schenk, Simon Akerstrom, Thorbjorn Kelly, Meghan Pedersen, Bente K. Hewitt, Sylvia C. Korach, Kenneth S. Hevener, Andrea L. TI Skeletal muscle action of estrogen receptor a is critical for the maintenance of mitochondrial function and metabolic homeostasis in females SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PERMEABILITY TRANSITION PORE; INDUCED INSULIN-RESISTANCE; SYNDROME CRITICAL REGION; FISSION PROTEIN DRP1; ER-ALPHA; AUTOPHAGOSOMAL DEGRADATION; MONITORING AUTOPHAGY; OXIDATIVE-METABOLISM; INHIBITS CALCINEURIN; ADIPOSE-TISSUE AB Impaired estrogen receptor a (ERa) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERa expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERa knockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A-regulator of calcineurin 1-calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERa deficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERa in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women. C1 [Ribas, Vicent; Drew, Brian G.; Zhou, Zhenqi; Phun, Jennifer; Kalajian, Nareg Y.; Soleymani, Teo; Daraei, Pedram; Widjaja, Kevin; Fluitt, Amy H.; Hevener, Andrea L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA. [Wanagat, Jonathan] Univ Calif Los Angeles, David Geffen Sch Med, Div Geriatr, Los Angeles, CA 90095 USA. [Vallim, Thomas Q. de Aguiar; Lusis, Aldons J.] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, Los Angeles, CA 90095 USA. [Fluitt, Amy H.; Bensinger, Steven; Thuc Le; Radu, Caius] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Thuc Le; Radu, Caius] Univ Calif Los Angeles, David Geffen Sch Med, Ahmanson Translat Imaging Div, Los Angeles, CA 90095 USA. [Whitelegge, Julian P.] Univ Calif Los Angeles, David Geffen Sch Med, Pasarow Mass Spectrometry Lab, Los Angeles, CA 90095 USA. [Whitelegge, Julian P.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Neuropsychiat Inst, Los Angeles, CA 90095 USA. [Beaven, Simon W.; Tontonoz, Peter] Univ Calif Los Angeles, David Geffen Sch Med, Howard Hughes Med Inst, Los Angeles, CA 90095 USA. [Beaven, Simon W.; Tontonoz, Peter] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Lusis, Aldons J.; Parks, Brian W.; Vergnes, Laurent; Reue, Karen] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Singh, Harpreet; Bopassa, Jean C.; Toro, Ligia; Stefani, Enrico] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Los Angeles, CA 90095 USA. [Watt, Matthew J.] Monash Univ, Dept Physiol, Clayton, Vic 3800, Australia. [Schenk, Simon] Univ Calif San Diego, Dept Orthopaed Surg, La Jolla, CA 92093 USA. [Akerstrom, Thorbjorn; Kelly, Meghan; Pedersen, Bente K.] Univ Copenhagen, Rigshosp, Ctr Inflammat & Metab, DK-2200 Copenhagen, Denmark. [Akerstrom, Thorbjorn; Kelly, Meghan; Pedersen, Bente K.] Univ Copenhagen, Rigshosp, Ctr Phys Act Res, DK-2200 Copenhagen, Denmark. [Hewitt, Sylvia C.; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Hevener, Andrea L.] UCLA Iris Cantor Womens Hlth Res Ctr, Los Angeles, CA 90095 USA. [Kelly, Meghan] Univ Rochester, Sch Med & Dent, Dept Orthopaed & Rehabil, Rochester, NY 14642 USA. RP Hevener, AL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA.; Hevener, AL (reprint author), UCLA Iris Cantor Womens Hlth Res Ctr, Los Angeles, CA 90095 USA. EM ahevener@mednet.ucla.edu RI Watt, Matthew/B-2089-2014; OI Korach, Kenneth/0000-0002-7765-418X; Pedersen, Bente Klarlund/0000-0001-6508-6288; Singh, Harpreet/0000-0002-6135-1897 FU NIH [DK060484, DK073227, HL28481, HL30568, DK063491]; Nuclear Receptor Signaling Atlas (NURSA) Data Source Project [DK097748]; UCLA Department of Medicine; UCLA Iris Cantor Women's Health Center-UCLA Clinical and Translational Science Institute [UL1TR000124]; Spanish Ministry of Health; Australian National Health and Medical Research Council; UCLA Jonsson Comprehensive Cancer Center; Danish National Research Foundation [DNRF55]; NIH R00 [HL123021]; NIH National Center for Research Resources [S10RR026744] FX These studies were supported in part by research grants from the NIH [DK060484, DK073227, and Nuclear Receptor Signaling Atlas (NURSA) Data Source Project grant DK097748], UCLA Department of Medicine, and UCLA Iris Cantor Women's Health Center-UCLA Clinical and Translational Science Institute (UL1TR000124) to A.L.H. and Z.Z. V.R. was supported by the Spanish Ministry of Health, and B.G.D. was supported by the Australian National Health and Medical Research Council and the UCLA Jonsson Comprehensive Cancer Center. During the study period, the Centre of Inflammation and Metabolism was supported by a grant from the Danish National Research Foundation (DNRF55) to B.K.P. A.J.L. is supported by NIH (grants HL28481 and HL30568), and B.W.P. is supported by NIH R00 grant HL123021. The Centre for Physical Activity Research is supported by a grant from TrygFonden. A.J.L. is supported by NIH grants HL28481 and HL30568, and L.V. and K.R. are supported in part by NIH grant HL28481. The Seahorse XF24 instrument was acquired by a shared instrument grant from the NIH National Center for Research Resources (S10RR026744). P.T. is an investigator of the Howard Hughes Medical Institute and is supported by NIH (DK063491). NR 86 TC 6 Z9 6 U1 2 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD APR 13 PY 2016 VL 8 IS 334 AR 334ra54 DI 10.1126/scitranslmed.aad3815 PG 21 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DJ5IW UT WOS:000374241500006 PM 27075628 ER PT J AU Brazhnik, E McCoy, AJ Novikov, N Hatch, CE Walters, JR AF Brazhnik, Elena McCoy, Alex J. Novikov, Nikolay Hatch, Christina E. Walters, Judith R. TI Ventral Medial Thalamic Nucleus Promotes Synchronization of Increased High Beta Oscillatory Activity in the Basal Ganglia-Thalamocortical Network of the Hemiparkinsonian Rat SO JOURNAL OF NEUROSCIENCE LA English DT Article DE basal ganglia; beta oscillations; motor cortex; Parkinson's disease; substantia nigra; ventral medial thalamus ID EXTERNAL GLOBUS-PALLIDUS; LONG-TERM DEPRESSION; SUBTHALAMIC NUCLEUS; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; PATHOLOGICAL SYNCHRONIZATION; VENTROMEDIAL NUCLEUS; EFFERENT CONNECTIONS; NEURONAL DISCHARGE; MOVEMENT-DISORDERS AB Loss of dopamine is associated with increased synchronization and oscillatory activity in the subthalamic nucleus and basal ganglia (BG) output nuclei in both Parkinson's disease (PD) patients and animal models of PD. We have previously observed substantial increases in spectral power in the 25-40 Hz range in LFPs recorded in the substantia nigra pars reticulata (SNpr) and motor cortex (MCx) in the hemiparkinsonian rat during treadmill walking. The current study explores the hypothesis that SNpr output entrains activity in the ventral medial thalamus (VM) in this frequency range after loss of dopamine, which in turn contributes to entrainment of the MCx and BG. Electrode bundles were implanted in MCx, SNpr, and VM of rats with unilateral dopamine cell lesions. Spiking and LFP activity were recorded during epochs of rest and walking on a circular treadmill. After dopamine cell lesion, 30 - 36 Hz LFP activity in the VM became more robust during treadmill walking and more coherent with LFP activity in the same range in MCx and SNpr. Infusion of the GABAA antagonist picrotoxin into the VM reduced both high beta power in MCx and SNpr and coherence between MCx and SNpr while temporarily restoring walking ability. Infusion of the GABAA agonist muscimol into the VM also reduced MCx-SNpr coherence and beta power but failed to improve walking. These results support the view that synchronized neuronal activity in the VM contributes to the emergence of high beta oscillations throughout the BG-thalamocortical network in the behaving parkinsonian rat. C1 [Brazhnik, Elena; McCoy, Alex J.; Novikov, Nikolay; Hatch, Christina E.; Walters, Judith R.] NINDS, Neurophysiol Pharmacol Sect, NIH, 35 Convent Dr,Bldg 35 Room 1C905, Bethesda, MD 20892 USA. RP Walters, JR (reprint author), NINDS, Neurophysiol Pharmacol Sect, NIH, 35 Convent Dr,Bldg 35 Room 1C905, Bethesda, MD 20892 USA. EM waltersj@ninds.nih.gov FU Intramural Research Program of the National Institutes of Health-National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health-National Institute of Neurological Disorders and Stroke. We thank Newlin Morgan, Tom Talbot, and Daryl Brandy in the National Institute of Mental Health Section on Instrumentation for design and fabrication of the rotary treadmill. NR 62 TC 1 Z9 1 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 13 PY 2016 VL 36 IS 15 BP 4196 EP 4208 DI 10.1523/JNEUROSCI.3582-15.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DK7TX UT WOS:000375129700007 PM 27076419 ER PT J AU Johnson, SP Ramasawmy, R Campbell-Washburn, AE Wells, JA Robson, M Rajkumar, V Lythgoe, MF Pedley, RB Walker-Samuel, S AF Johnson, S. Peter Ramasawmy, Rajiv Campbell-Washburn, Adrienne E. Wells, Jack A. Robson, Mathew Rajkumar, Vineeth Lythgoe, Mark F. Pedley, R. Barbara Walker-Samuel, Simon TI Acute changes in liver tumour perfusion measured non-invasively with arterial spin labelling SO BRITISH JOURNAL OF CANCER LA English DT Article DE perfusion; MRI; liver; cancer; metastasis; vascular disrupting agents ID VASCULAR-DISRUPTING AGENT; COMBRETASTATIN A-4; SOLID TUMORS; MRI MEASUREMENTS; NUDE-MICE; OXI4503; CANCER; COMBINATION; XENOGRAFTS; ANTIBODY AB Background: Non-invasive measures of tumour vascular perfusion are desirable, in order to assess response to vascular targeting (or modifying) therapies. In this study, hepatic arterial spin labelling (ASL) magnetic resonance imaging (MRI) was investigated to measure acute changes in perfusion of colorectal cancer in the liver, in response to vascular disruption therapy with OXi4503. Methods: SW1222 and LS174T tumours were established in the liver of MF1 nu/nu mice via intrasplenic injection. Perfusion and R-2* MRI measurements were acquired with an Agilent 9.4T horizontal bore scanner, before and at 90 min after 40 mg kg(-1) OXi4503. Results: A significant decrease in SW1222 tumour perfusion was observed (similar to 43 +/- 33%, P<0.005). LS174T tumours had a significantly lower baseline level of perfusion. Intrinsic susceptibility MRI showed a significant increase in R-2* in LS174T tumours (28 +/- 25%, P<0.05). An association was found between the change in tumour perfusion and the proximity to large vessels, with pre-treatment blood flow predictive of subsequent response. Histological evaluation confirmed the onset of necrosis and evidence of heterogeneous response between tumour deposits. Conclusions: Hepatic ASL-MRI can detect acute response to targeted tumour vascular disruption entirely non-invasively. Hepatic ASL of liver tumours has potential for use in a clinical setting. C1 [Johnson, S. Peter; Ramasawmy, Rajiv; Robson, Mathew; Rajkumar, Vineeth; Pedley, R. Barbara] UCL, Inst Canc, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England. [Johnson, S. Peter; Ramasawmy, Rajiv; Campbell-Washburn, Adrienne E.; Wells, Jack A.; Lythgoe, Mark F.; Walker-Samuel, Simon] UCL, Ctr Adv Biomed Imaging, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England. [Campbell-Washburn, Adrienne E.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Johnson, SP (reprint author), UCL, Inst Canc, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England.; Johnson, SP (reprint author), UCL, Ctr Adv Biomed Imaging, Paul OGorman Bldg,72 Huntley St, London WC1E 6DD, England. EM peter.johnson@cancer.ucl.ac.uk OI Wells, Jack/0000-0002-4171-3539 FU MRC [MRC 1028351, MR/J013110/1]; Medical Research Funding DPFS grant [MRC G100149]; National Centre for the Replacement, Reduction and Refinement of Animal in Research [NC3Rs]; UK Regenerative Medicine Platform Safety Hub [MRC: MR/K026739/1]; Wellcome Trust [WT100247MA]; Medical Research Council [42450] FX We would like to thank OXiGENE (CA, USA) for kindly supplying the vascular disrupting agent OXi4503. This work was carried out as part of King's College London and UCL Comprehensive Cancer Imaging Centre, Cancer Research UK & Engineering and Physical Sciences Research Council, in association with the Medical Research Council (MRC), Department of Health and British Heart Foundation (England) (C1519/A10331, C1519/A16463). RR receives funding from the MRC (MRC 1028351). RBP receives funding from Medical Research Funding DPFS grant (MRC G100149). MFL receives funding from MRC (MR/J013110/1); the National Centre for the Replacement, Reduction and Refinement of Animal in Research (NC3Rs); UK Regenerative Medicine Platform Safety Hub (MRC: MR/K026739/1). SW-S and SPJ receive funding from the Wellcome Trust (WT100247MA). JW receives funding from the Medical Research Council (Grant code: 42450). NR 35 TC 0 Z9 0 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD APR 13 PY 2016 VL 114 IS 8 BP 897 EP 904 DI 10.1038/bjc.2016.51 PG 8 WC Oncology SC Oncology GA DJ3TJ UT WOS:000374129200007 PM 27031853 ER PT J AU Shchekotikhin, AE Dezhenkova, LG Tsvetkov, VB Luzikov, YN Volodina, YL Tatarskiy, VV Kalinina, AA Treshalin, MI Treshalina, HM Romanenko, VI Kaluzhny, DN Kubbutat, M Schols, D Pommier, Y Shtil, AA Preobrazhenskaya, MN AF Shchekotikhin, Andrey E. Dezhenkova, Lyubov G. Tsvetkov, Vladimir B. Luzikov, Yuri N. Volodina, Yulia L. Tatarskiy, Victor V., Jr. Kalinina, Anastasia A. Treshalin, Michael I. Treshalina, Helen M. Romanenko, Vladimir I. Kaluzhny, Dmitry N. Kubbutat, Michael Schols, Dominique Pommier, Yves Shtil, Alexander A. Preobrazhenskaya, Maria N. TI Discovery of antitumor anthra[2,3-b]furan-3-carboxamides: Optimization of synthesis and evaluation of antitumor properties SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Anthra[2,3-b]furan-3-carboxamides; DNA ligands; Topoisomerase inhibitors; Protein kinase inhibitors; Cytotoxicity; Circumvention of multidrug resistance; Antitumor activity ID TOPOISOMERASE-I INHIBITORS; PROTEIN-KINASE CK2; CYTOTOXIC PROPERTIES; CANCER CELLS; DNA; DOXORUBICIN; COMPLEXES; ANTHRACYCLINES; IDENTIFICATION; INDUCTION AB Anthraquinones and their analogues, in particular heteroarene-fused anthracendiones, are prospective scaffolds for new compounds with improved antitumor characteristics. We herein report the use of a 'scaffold hopping' approach for the replacement of the core structure in the previously discovered hit compound naphtho[2,3-f]indole-5,10-dione 2 with an alternative anthra[2,3-b]furan-5,10-dione scaffold. Among 13 newly synthesized derivatives the majority of 4,11-dihydroxy-2-methyl-5,10-dioxoanthra[2,3-b] furan-3-carboxamides demonstrated a high antiproliferative potency against a panel of wild type and drug resistant tumor cell lines, a property superior over the reference drug doxorubicin or lead naphtho[2,3-f] indole-5,10-dione 2. At low micromolar concentrations the selected derivative of (R)-3-aminopyrrolidine 3c and its stereoisomer (S)-3-aminopyrrolidine 3d caused an apoptotic cell death preceded by an arrest in the G2/M phase. Studies of intracellular targets showed that 3c and 3d formed stable intercalative complexes with the duplex DNA as determined by spectral analysis and molecular docking. Both 3c and 3d attenuated topoisomerase 1 and 2 mediated unwinding of the supercoiled DNA via a mechanism different from conventional DNA-enzyme tertiary complex formation. Furthermore, 3d decreased the activity of selected human protein kinases in vitro, indicating multiple targeting by the new chemotype. Finally, 3d demonstrated an antitumor activity in a model of murine intraperitoneally transplanted P388 leukemia, achieving the increase of animal life span up to 262% at tolerable doses. Altogether, the 'scaffold hopping' demonstrated its productivity for obtaining new perspective antitumor drug candidates. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Shchekotikhin, Andrey E.; Dezhenkova, Lyubov G.; Luzikov, Yuri N.; Treshalin, Michael I.; Shtil, Alexander A.; Preobrazhenskaya, Maria N.] Gause Inst New Antibiot, 11 B Pirogovskaya St, Moscow 119021, Russia. [Shchekotikhin, Andrey E.] Mendeleyev Univ Chem Technol, 9 Miusskaya Sq, Moscow 125190, Russia. [Tsvetkov, Vladimir B.] Russian Acad Sci, Topchiev Inst Petrochem Synth, 29 Leninsky Ave, Moscow 119991, Russia. [Tsvetkov, Vladimir B.] Inst Phys Chem Med, 1A M Pirogovskaya St, Moscow 119435, Russia. [Volodina, Yulia L.; Tatarskiy, Victor V., Jr.; Kalinina, Anastasia A.; Treshalina, Helen M.; Romanenko, Vladimir I.; Shtil, Alexander A.] Minist Hlth Russian Federat, NN Blokhin Canc Res Ctr, Fed State Budgetary Sci Inst, 24 Kashirskoye Shosse, Moscow 115478, Russia. [Kaluzhny, Dmitry N.] Russian Acad Sci, Engelhardt Inst Mol Biol, 32 Vavilov St, Moscow 119991, Russia. [Kubbutat, Michael] ProQinase GmbH, Breisacher Str 117, D-79106 Freiburg, Germany. [Schols, Dominique] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Leuven, Belgium. [Pommier, Yves] NCI, Dev Therapeut Branch, NIH, 37 Convent Dr,37-5068, Bethesda, MD 20892 USA. RP Shchekotikhin, AE (reprint author), Gause Inst New Antibiot, 11 B Pirogovskaya St, Moscow 119021, Russia. EM shchekotikhin@mail.ru RI Tsvetkov, Vladimir/L-9399-2013; Kaluzhny, Dmitry/G-7256-2014 FU Ministry of Industry and Trade of the Russian Federation [12411.1008799.13.007] FX This study was supported by the Ministry of Industry and Trade of the Russian Federation (state contract 12411.1008799.13.007). NR 47 TC 4 Z9 4 U1 3 U2 19 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD APR 13 PY 2016 VL 112 BP 114 EP 129 DI 10.1016/j.ejmech.2016.01.050 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DH1PU UT WOS:000372558200012 PM 26890118 ER PT J AU Cai, XY Hu, YY Tang, H Hu, H Pang, LJ Xing, JY Liu, ZY Luo, YH Jiang, B Liu, T Gorospe, M Chen, C Wang, WG AF Cai, Xiaoyu Hu, Yuanyuan Tang, Hao Hu, Han Pang, Lijun Xing, Junyue Liu, Zhenyun Luo, Yuhong Jiang, Bin Liu, Te Gorospe, Myriam Chen, Chuan Wang, Wengong TI RNA methyltransferase NSUN2 promotes stress-induced HUVEC senescence SO ONCOTARGET LA English DT Article DE NSUN2; SHC mRNA methylation; translational regulation; HUVEC; premature senescence; Gerotarget ID DELAYS REPLICATIVE SENESCENCE; 16S RIBOSOMAL-RNA; OXIDATIVE STRESS; ESCHERICHIA-COLI; SIGNALING PATHWAY; LONGEVITY GENE; MESSENGER-RNA; LIFE-SPAN; P66SHC; P66(SHC) AB The tRNA methyltransferase NSUN2 delays replicative senescence by regulating the translation of CDK1 and CDKN1B mRNAs. However, whether NSUN2 influences premature cellular senescence remains untested. Here we show that NSUN2 methylates SHC mRNA in vitro and in cells, thereby enhancing the translation of the three SHC proteins, p66SHC, p52SHC, and p46SHC. Our results further show that the elevation of SHC expression by NSUN2-mediated mRNA methylation increased the levels of ROS, activated p38MAPK, thereby accelerating oxidative stress- and high-glucose-induced senescence of human vascular endothelial cells (HUVEC). Our findings highlight the critical impact of NSUN2-mediated mRNA methylation in promoting premature senescence. C1 [Cai, Xiaoyu; Hu, Yuanyuan; Hu, Han; Pang, Lijun; Xing, Junyue; Liu, Zhenyun; Jiang, Bin; Wang, Wengong] Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100871, Peoples R China. [Tang, Hao; Luo, Yuhong] Peking Univ, Hlth Sci Ctr, Dept Physiol & Pathophysiol, Beijing 100871, Peoples R China. [Gorospe, Myriam] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Liu, Te; Chen, Chuan] Shanghai Geriatr Inst Chinese Med, Shanghai, Peoples R China. RP Wang, WG (reprint author), Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100871, Peoples R China.; Chen, C (reprint author), Shanghai Geriatr Inst Chinese Med, Shanghai, Peoples R China. EM ch9453@126.com; wwg@bjmu.edu.cn FU National Science Foundation of China [81373706, 81230008, 81420108016, 91339114]; (111 project) from the Ministry of Education of People's Republic of China [B07001]; NIA-IRP, NIH FX This work was supported by Grants 81373706, 81230008, 81420108016, and 91339114 from the National Science Foundation of China; Grant B07001 (111 project) from the Ministry of Education of People's Republic of China. M.G. was supported by the NIA-IRP, NIH. NR 33 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 19099 EP 19110 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000003 PM 26992231 ER PT J AU Thanos, PK Hamilton, J O'Rourke, JR Napoli, A Febo, M Volkow, ND Blum, K Gold, M AF Thanos, Panayotis K. Hamilton, John O'Rourke, Joseph R. Napoli, Anthony Febo, Marcelo Volkow, Nora D. Blum, Kenneth Gold, Mark TI Dopamine D-2 gene expression interacts with environmental enrichment to impact lifespan and behavior SO ONCOTARGET LA English DT Article DE aging; D-2; environmental enrichment; exercise; cognition; Gerotarget ID REWARD DEFICIENCY SYNDROME; PREFRONTAL CORTEX; D2 RECEPTORS; BRAIN DOPAMINE; LOCOMOTOR-ACTIVITY; PARKINSONS-DISEASE; NUCLEUS-ACCUMBENS; WORKING-MEMORY; MICE; RAT AB Aging produces cellular, molecular, and behavioral changes affecting many areas of the brain. The dopamine (DA) system is known to be vulnerable to the effects of aging, which regulate behavioral functions such as locomotor activity, body weight, and reward and cognition. In particular, age-related DA D-2 receptor (D2R) changes have been of particular interest given its relationship with addiction and other rewarding behavioral properties. Male and female wild-type (Drd(2) +/+), heterozygous (Drd(2) +/-) and knockout (Drd(2) -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D-2 gene. Drd(2) +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd(2) +/+ and Drd(2) +/- EE mice lived 22% and 21% longer than Drd(2) -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity. C1 [Thanos, Panayotis K.; Hamilton, John; O'Rourke, Joseph R.] Univ Buffalo, Res Inst Addict, Behav Neuropharmacol & Neuroimaging Lab Addict, Buffalo, NY USA. [Napoli, Anthony] Suffolk Community Coll, Dept Psychol, Riverhead, NY USA. [Febo, Marcelo; Blum, Kenneth; Gold, Mark] Univ Florida, Dept Psychiat, Gainesville, FL 32611 USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Thanos, PK (reprint author), Univ Buffalo, Res Inst Addict, Behav Neuropharmacol & Neuroimaging Lab Addict, Buffalo, NY USA. EM pthanos@ria.buffalo.edu RI Febo, Marcelo/G-5718-2011 FU Research Foundation of NY [RIAQ094]; NIH [AA 11034] FX This work was supported by the Research Foundation of NY (RIAQ094) and NIH (AA 11034). NR 87 TC 0 Z9 0 U1 4 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 19111 EP 19123 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000004 PM 26992232 ER PT J AU Romashkan, SV Das, SK Villareal, DT Ravussin, E Redman, LM Rochon, J Bhapkar, M Kraus, WE AF Romashkan, Sergei V. Das, Sai Krupa Villareal, Dennis T. Ravussin, Eric Redman, Leanne M. Rochon, James Bhapkar, Manjushri Kraus, William E. CA CALERIE Study Grp TI Safety of two-year caloric restriction in non-obese healthy individuals SO ONCOTARGET LA English DT Article DE calorie restriction; safety; humans; dietary energy restriction; Gerotarget ID BONE-MINERAL DENSITY; WEIGHT-LOSS; COMPREHENSIVE ASSESSMENT; POSTMENOPAUSAL WOMEN; REDUCING INTAKE; CALERIE; SPAN; INTERVENTION; DESIGN; ENERGY AB Background: The extent to which sustained caloric restriction (CR) in healthy non-obese adults is safe has not been previously investigated. Objective: Assess the safety and tolerability of sustained two-year CR intervention in healthy, non-obese adults. Design: A multi-center, randomized controlled trial. Participants were randomized using a 2: 1 allocation in favor of 25% CR vs. Ad-Libitum intake (AL). Adverse and serious adverse events (AE, SAE), safety laboratory tests, and other safety parameters were closely monitored. Results: Three participants were withdrawn from the CR intervention because of the safety concerns. No deaths and one SAE was reported by participants in the CR group. Although the difference in AE between AL and CR groups was not significant, within the CR group, the incidence of nervous system (p = 0.02), musculoskeletal (p = 0.02) and reproductive system (p = 0.002) disorders was significantly higher in the normal-weight than in the overweight participants. At months 12 and 24, bone mineral densities at the lumbar spine, total hip, and femoral neck of participants in the CR group were significantly lower than in those in the AL group. Conclusions: Two-years of CR at levels achieved in CALERIE was safe and well tolerated. Close monitoring for excessive bone loss and anemia is important. C1 [Romashkan, Sergei V.] NIA, Bethesda, MD 20892 USA. [Das, Sai Krupa] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr, Boston, MA 02111 USA. [Villareal, Dennis T.] Washington Univ, Sch Med, St Louis, MO USA. [Villareal, Dennis T.] Baylor Coll Med, Houston, TX 77030 USA. [Villareal, Dennis T.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Ravussin, Eric; Redman, Leanne M.] Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Rochon, James] Rho Fed Syst, Chapel Hill, NC USA. [Rochon, James; Bhapkar, Manjushri; Kraus, William E.] Duke Clin Res Inst, Durham, NC USA. [Rochon, James; Bhapkar, Manjushri; Kraus, William E.] Duke Univ, Sch Med, Durham, NC USA. RP Das, SK (reprint author), Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr, Boston, MA 02111 USA. EM sai.das@tufts.edu FU National Institute on Aging (NIA); National Institute of Diabetes and Kidney Diseases, National Institute of Health [U01AG022132, U01AG020478, U01AG020487, U01AG020480] FX This study was supported by the National Institute on Aging (NIA) and National Institute of Diabetes and Kidney Diseases, National Institute of Health (U01AG022132, U01AG020478, U01AG020487 and U01AG020480) NR 17 TC 0 Z9 0 U1 4 U2 8 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 19124 EP 19133 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000005 PM 26992237 ER PT J AU Menard, C Rezende, FA Miloudi, K Wilson, A Tetreault, N Hardy, P SanGiovanni, JP De Guire, V Sapieha, P AF Menard, Catherine Rezende, Flavio A. Miloudi, Khalil Wilson, Ariel Tetreault, Nicolas Hardy, Pierre SanGiovanni, John Paul De Guire, Vincent Sapieha, Przemyslaw TI MicroRNA signatures in vitreous humour and plasma of patients with exudative AMD SO ONCOTARGET LA English DT Article DE age-related macular degeneration; AMD; microRNAs; miRNA; biomarkers; Gerotarget ID MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; MESSENGER-RNAS; CELLS; DISEASES; BIOMARKERS; RAPAMYCIN; INTERLEUKIN-1-BETA; PROLIFERATION; ANGIOGENESIS AB Age-related macular degeneration (AMD) is a leading cause of blindness worldwide affecting individuals over the age of 50. The neovascular form (NV AMD) is characterized by choroidal neovascularization (CNV) and responsible for the majority of central vision impairment. Using non-biased microRNA arrays and individual TaqMan qPCRs, we profiled miRNAs in the vitreous humour and plasma of patients with NV AMD. We identified a disease-associated increase in miR-146a and a decrease in miR-106b and miR-152 in the vitreous humour which was reproducible in plasma. Moreover, miR-146a/miR-106b ratios discriminated patients with NV AMD with an area under the Receiver Operating Characteristic curve (ROC AUC) of 0,977 in vitreous humour and 0,915 in plasma suggesting potential for a blood-based diagnostic. Furthermore, using the AMD Gene Consortium (AGC) we mapped a NV AMD-associated SNP (rs1063320) in a binding site for miR-152-3p in the HLA-G gene. The relationship between our detected miRNAs and NV AMD related genes was also investigated using gene sets derived from the Ingenuity Pathway Analysis (IPA). To our knowledge, our study is the first to correlate vitreal and plasma miRNA signatures with NV AMD, highlighting potential future worth as biomarkers and providing insight on NV AMD pathogenesis. C1 [Menard, Catherine; Tetreault, Nicolas; Sapieha, Przemyslaw] Univ Montreal, Dept Biochem, Hop Maison Neuve Rosemont, Res Ctr, Montreal, PQ H3C 3J7, Canada. [Rezende, Flavio A.; Sapieha, Przemyslaw] Univ Montreal, Hop Maison Neuve Rosemont, Res Ctr, Dept Ophthalmol, Montreal, PQ, Canada. [Wilson, Ariel] Ecole Polytech, Dept Engn Phys, Laser Proc & Plasmon Lab, Montreal, PQ H3C 3A7, Canada. [Miloudi, Khalil; Sapieha, Przemyslaw] McGill Univ, Dept Neurosci, Montreal, PQ, Canada. [Hardy, Pierre] Univ Montreal, Dept Pediat, Montreal, PQ H3C 3J7, Canada. [Hardy, Pierre] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada. [SanGiovanni, John Paul] NIAAA, Lab Membrane Biochem & Biophys, Nutr Neurosci Sect, NIH, Bethesda, MD USA. [De Guire, Vincent] Hop Maison Neuve Rosemont, Dept Clin Biochem, Quebec City, PQ, Canada. RP Sapieha, P (reprint author), Univ Montreal, Dept Biochem, Hop Maison Neuve Rosemont, Res Ctr, Montreal, PQ H3C 3J7, Canada.; Sapieha, P (reprint author), Univ Montreal, Hop Maison Neuve Rosemont, Res Ctr, Dept Ophthalmol, Montreal, PQ, Canada.; Sapieha, P (reprint author), McGill Univ, Dept Neurosci, Montreal, PQ, Canada.; De Guire, V (reprint author), Hop Maison Neuve Rosemont, Dept Clin Biochem, Quebec City, PQ, Canada. EM vdeguire.hmr@ssss.gouv.qc.ca; mike.sapieha@umontreal.ca FU Foundation Fighting Blindness Canada; Canadian Institutes of Health Research [221478]; Natural Sciences and Engineering Research Council of Canada [418637]; Fondation HMR; Reseau en Recherche en Sante de la Vision du Quebec; Fond en Recherche en Opthalmologie de l'UdeM FX PS holds a Canada Research Chair in Retinal Cell Biology and The Alcon Research Institute Young Investigator Award. This work was supported by operating grants to PS from the Foundation Fighting Blindness Canada and the Canadian Institutes of Health Research (221478) and Natural Sciences and Engineering Research Council of Canada (418637). Additional support was obtained from the Fondation HMR, Reseau en Recherche en Sante de la Vision du Quebec and the Fond en Recherche en Opthalmologie de l'UdeM. NR 53 TC 3 Z9 3 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 APR 12 PY 2016 VL 7 IS 15 BP 19171 EP 19184 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000008 PM 27015561 ER PT J AU Liu, F Zhang, SM Zhao, Z Mao, XR Huang, JL Wu, ZX Zheng, L Wang, Q AF Liu, Fei Zhang, Shimeng Zhao, Zhen Mao, Xinru Huang, Jinlan Wu, Zixian Zheng, Lei Wang, Qian TI MicroRNA-27b up-regulated by human papillomavirus 16 E7 promotes proliferation and suppresses apoptosis by targeting polo-like kinase2 in cervical cancer SO ONCOTARGET LA English DT Article DE microRNA-27b; HPV16 E7; cervical cancer; polo-like kinase2; DGCR8 ID TUMOR-SUPPRESSOR; CELL-GROWTH; EXPRESSION; LINES AB The infection with high-risk human papillomavirus is linked to cervical cancer, nevertheless, the role of miRNAs regulated by HPV oncogenes in cancer progression remain largely unknown. Here, we knocked down endogenous E6/E7 in HPV16-positive CaSki cell lines, screened differences in miRNA expression profile with control using miRNA array. 38 miRNAs were down-regulated and 6 miRNAs were up-regulated in the E6/E7 silenced CaSki cells (> 2-fold changes with P < 0.05). The levels of miR-27b, miR-20a, miR-24, miR-93, and miR-106b were verified by qPCR in E6/E7 silenced CaSki and SiHa cells. MiR-27b, up-regulated by E7, promoted CaSki and SiHa cell proliferation and invasion, inhibit paclitaxel-induced apoptosis. Dual-luciferase experiment confirmed miR-27b down-regulated its target gene PLK2 through the "seed regions". The tumor suppressor PLK2 inhibited SiHa cell proliferation, reduced cell viability, and promoted paclitaxel/cisplatin -induced apoptosis. Furthermore, DGCR8 was found to mediate the up-regulation of miR-27b by HPV16 E7. Our study demonstrated that HPV16 E7 could increase DGCR8 to promote the generation of miR-27b, which accelerated cell proliferation and inhibited paclitaxel-induced cell apoptosis through down-regulating PLK2. These findings provide an insight into the interaction network of viral oncogene, miR-27b and PLK2, and support the potential strategies using antisense nucleic acid of miR-27b for therapy of cervical cancer in the future. C1 [Liu, Fei; Zhang, Shimeng; Mao, Xinru; Huang, Jinlan; Wu, Zixian; Zheng, Lei; Wang, Qian] Southern Med Univ, Nanfang Hosp, Dept Lab Med, Guangzhou 510515, Guangdong, Peoples R China. [Liu, Fei] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Dept Clin Lab, Guangzhou 510623, Guangdong, Peoples R China. [Zhang, Shimeng] Shenzhen Shekou Peoples Hosp, Cent Lab, Shenzhen 518000, Peoples R China. [Zhao, Zhen] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Zheng, L; Wang, Q (reprint author), Southern Med Univ, Nanfang Hosp, Dept Lab Med, Guangzhou 510515, Guangdong, Peoples R China. EM nfyyzhenglei@smu.edu.cn; wangqian@smu.edu.cn FU National Natural Science Foundation of China [81371901]; Specialized Research Fund for the Doctoral Program of Higher Education of China [20134433110010]; Intramural Research Programs of the Clinical Center of the National Institutes of Health; CPOCT grant American Association of Clinical Chemistry (A new electrochemical biosensor for circulating microRNA); Science and Technology Innovation Cultivation Project of Guangdong Undergraduate Students [pdjh2015b0116]; National Undergraduate Training Programs for Innovation and Entrepreneurship [201512121031] FX We thank Professor Chunlin Chen (Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University) to provide cervical cancer tissue samples. This research was supported by the National Natural Science Foundation of China (NO. 81371901), Specialized Research Fund for the Doctoral Program of Higher Education of China (NO.20134433110010), Intramural Research Programs of the Clinical Center of the National Institutes of Health (ZZ) and CPOCT grant American Association of Clinical Chemistry (A new electrochemical biosensor for circulating microRNA). Science and Technology Innovation Cultivation Project of Guangdong Undergraduate Students (pdjh2015b0116), National Undergraduate Training Programs for Innovation and Entrepreneurship (201512121031). NR 40 TC 5 Z9 6 U1 2 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 19666 EP 19679 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000045 PM 26910911 ER PT J AU Zhu, Z Pang, BX Iglesias-Bartolome, R Wu, XS Hu, L Zhang, CM Wang, JS Gutkind, JS Wang, SL AF Zhu, Zhao Pang, Baoxing Iglesias-Bartolome, Ramiro Wu, Xiaoshan Hu, Lei Zhang, Chunmei Wang, Jinsong Gutkind, J. Silvio Wang, Songlin TI Prevention of irradiation-induced salivary hypofunction by rapamycin in swine parotid glands SO ONCOTARGET LA English DT Article DE radiotherapy; salivary hypofunction; miniature pig; rapamycin; mTOR ID HUMAN AQUAPORIN-1 CDNA; MINIATURE PIG; SUBMANDIBULAR-GLAND; CLINICAL-ONCOLOGY; INDUCED MUCOSITIS; AMERICAN-SOCIETY; NECK IRRADIATION; FLUID SECRETION; CANCER-PATIENTS; MOUSE MODEL AB Radiotherapy is commonly used in patients with oral cavity and pharyngeal cancers, usually resulting in irreversible salivary hypofunction. Currently management of radiation damage to salivary glands still remains a great challenge. Recent studies show that activation of mammalian target of rapamycin (mTOR) occurs in salivary gland lesions, making it possible to apply mTOR inhibitor for treatment. Our results indicate inhibition of mTOR by rapamycin significantly alleviated irradiation-induced salivary hypofunction by restoring 46% salivary flow rate and protecting histological structures in swine. Furthermore, rapamycin protected human submandibular gland cell line (HSG) from irradiation-induced cell depletion and loss of cell proliferation capacity. These findings lay the foundation for a new clinical application of rapamycin to prevent irradiation-induced salivary hypofunction. C1 [Zhu, Zhao; Pang, Baoxing; Wu, Xiaoshan; Hu, Lei; Zhang, Chunmei; Wang, Jinsong; Wang, Songlin] Capital Med Univ, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Mol Lab Gene Therapy & Tooth Regenerat, Sch Stomatol, Beijing 100050, Peoples R China. [Iglesias-Bartolome, Ramiro] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20852 USA. [Gutkind, J. Silvio] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Gutkind, J. Silvio] Moores Canc Ctr, La Jolla, CA 92093 USA. RP Wang, SL (reprint author), Capital Med Univ, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Mol Lab Gene Therapy & Tooth Regenerat, Sch Stomatol, Beijing 100050, Peoples R China.; Gutkind, JS (reprint author), Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.; Gutkind, JS (reprint author), Moores Canc Ctr, La Jolla, CA 92093 USA. EM sgutkind@ucsd.edu; slwang@ccmu.edu.cn FU Beijing Municipality Government grants (Beijing Scholar Program) [PXM2014_014226_000180, PXM2014_014226_000048, PXM2014_014226_000013, PXM2014_014226_000053, Z121100005212004, PXM2013_014226_000021, PXM2013_014226_07_000080, TJSHG201310025005]; National Basic Research Program of China [2010CB944801] FX This work was supported by a grant from the Beijing Municipality Government grants (Beijing Scholar Program-PXM2014_014226_000180, PXM2014_014226_000048, PXM2014_014226_000013, PXM2014_014226_000053, Z121100005212004, PXM2013_014226_000021, PXM2013_014226_07_000080, and TJSHG201310025005 to S.W.), the National Basic Research Program of China (2010CB944801 to S.W.) NR 51 TC 0 Z9 0 U1 2 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 20271 EP 20281 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000089 PM 26958808 ER PT J AU Guo, ZJ Yang, L Qian, F Wang, YX Yu, X Ji, CD Cui, W Xiang, DF Zhang, X Zhang, P Wang, JM Cui, YH Bian, XW AF Guo, Zheng-Jun Yang, Lang Qian, Feng Wang, Yan-Xia Yu, Xi Ji, Cheng-Dong Cui, Wei Xiang, Dong-Fang Zhang, Xia Zhang, Peng Wang, Ji Ming Cui, You-Hong Bian, Xiu-Wu TI Transcription factor RUNX2 up-regulates chemokine receptor CXCR4 to promote invasive and metastatic potentials of human gastric cancer SO ONCOTARGET LA English DT Article DE RUNX2; gastric cancer; invasion; metastasis; CXCR4 ID STEM-CELLS; OSTEOBLAST DIFFERENTIATION; EXPRESSION; FAMILY; GENE; IDENTIFICATION; TRAFFICKING; ASSOCIATION; SUPPRESSOR; CARCINOMA AB Runt-related transcription factor 2 (RUNX2) is a regulator of embryogenesis and development, but has also been implicated in the progression of certain human cancer. This study aimed to elucidate the role of RUNX2 in the invasive and metastatic potentials of human gastric cancer (GC) and the underlying mechanisms. We found that the levels of RUNX2 expression in gastric cancer tissues were correlated with the differentiation degrees, invasion depth and lymph node metastasis. COX regression analysis indicated that RUNX2 was an independent prognostic indicator for GC patients. RUNX2 significantly increased the migration and invasion ability of GC cells in vitro and enhanced the invasion and metastatic potential of GC cells in an orthotopic GC model of nude mice. Mechanistically, RUNX2 directly bound to the promoter region of the gene coding for the chemokine receptor CXCR4 to enhance its transcription. CXCR4 knockdown or treatment with AMD3100, a CXCR4 inhibitor, attenuated RUNX2-promoted invasion and metastasis. These results demonstrate that RUNX2 promotes the invasion and metastasis of human GC by transcriptionally up-regulating the chemokine receptor CXCR4. Therefore, the RUNX2-CXCR4 axis is a potential therapeutic target for GC. C1 [Guo, Zheng-Jun; Yang, Lang; Wang, Yan-Xia; Yu, Xi; Ji, Cheng-Dong; Cui, Wei; Xiang, Dong-Fang; Zhang, Xia; Zhang, Peng; Cui, You-Hong; Bian, Xiu-Wu] Third Mil Med Univ, Inst Pathol, Minist Educ China, Chongqing, Peoples R China. [Guo, Zheng-Jun; Yang, Lang; Wang, Yan-Xia; Yu, Xi; Ji, Cheng-Dong; Cui, Wei; Xiang, Dong-Fang; Zhang, Xia; Zhang, Peng; Cui, You-Hong; Bian, Xiu-Wu] Third Mil Med Univ, Southwest Canc Ctr, Minist Educ China, Chongqing, Peoples R China. [Guo, Zheng-Jun; Yang, Lang; Wang, Yan-Xia; Yu, Xi; Ji, Cheng-Dong; Cui, Wei; Xiang, Dong-Fang; Zhang, Xia; Zhang, Peng; Cui, You-Hong; Bian, Xiu-Wu] Third Mil Med Univ, Key Lab Tumor Immunopathol, Minist Educ China, Chongqing, Peoples R China. [Qian, Feng] Third Mil Med Univ, Southwest Hosp, Dept Gen Surg, Chongqing, Peoples R China. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Bian, Xiu-Wu] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, Guangzhou 510275, Guangdong, Peoples R China. RP Cui, YH; Bian, XW (reprint author), Third Mil Med Univ, Inst Pathol, Minist Educ China, Chongqing, Peoples R China.; Cui, YH; Bian, XW (reprint author), Third Mil Med Univ, Southwest Canc Ctr, Minist Educ China, Chongqing, Peoples R China.; Cui, YH; Bian, XW (reprint author), Third Mil Med Univ, Key Lab Tumor Immunopathol, Minist Educ China, Chongqing, Peoples R China.; Bian, XW (reprint author), Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, Guangzhou 510275, Guangdong, Peoples R China. EM cuiyouhongx@yahoo.com; bianxiuwu@263.net RI Bian, Xiu-wu/D-4736-2017; Zhang, Xia/B-8152-2008 OI Bian, Xiu-wu/0000-0003-4383-0197; Zhang, Xia/0000-0002-9040-1486 FU National Natural Science Foundation of China (NSFC) [81230062, 81071771, 81372555]; Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NCI, NIH FX This work was supported by grants from the National Natural Science Foundation of China (NSFC Nos. 81230062, 81071771 and 81372555). JMW has been funded in part with Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Contract No. HHSN261200800001E as well as supported in part by the Intramural Research Program of the NCI, NIH. NR 50 TC 2 Z9 3 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 12 PY 2016 VL 7 IS 15 BP 20999 EP 21012 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL7ES UT WOS:000375804000143 PM 27007162 ER PT J AU Cheung, KH Keerthikumar, S Roncaglia, P Subramanian, SL Roth, ME Samuel, M Anand, S Gangoda, L Gould, S Alexander, R Galas, D Gerstein, MB Hill, AF Kitchen, RR Lotvall, J Patel, T Procaccini, DC Quesenberry, P Rozowsky, J Raffai, RL Shypitsyna, A Su, AI Thery, C Vickers, K Wauben, MHM Mathivanan, S Milosavljevic, A Laurent, LC AF Cheung, Kei-Hoi Keerthikumar, Shivakumar Roncaglia, Paola Subramanian, Sai Lakshmi Roth, Matthew E. Samuel, Monisha Anand, Sushma Gangoda, Lahiru Gould, Stephen Alexander, Roger Galas, David Gerstein, Mark B. Hill, Andrew F. Kitchen, Robert R. Lotvall, Jan Patel, Tushar Procaccini, Dena C. Quesenberry, Peter Rozowsky, Joel Raffai, Robert L. Shypitsyna, Aleksandra Su, Andrew I. Thery, Clotilde Vickers, Kasey Wauben, Marca H. M. Mathivanan, Suresh Milosavljevic, Aleksandar Laurent, Louise C. TI Extending gene ontology in the context of extracellular RNA and vesicle communication SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Ontology; Extracellular RNA; Extracellular vesicle; Metadata; Faceted search; Atlas ID VIRUS-LIKE PARTICLES; HUMAN PLASMA; MEDIATED TRANSFER; MICRORNAS; PROTEINS; EXOSOMES; CANCER; CELLS; TOOL; IDENTIFICATION AB Background: To address the lack of standard terminology to describe extracellular RNA (exRNA) data/metadata, we have launched an inter-community effort to extend the Gene Ontology (GO) with subcellular structure concepts relevant to the exRNA domain. By extending GO in this manner, the exRNA data/metadata will be more easily annotated and queried because it will be based on a shared set of terms and relationships relevant to extracellular research. Methods: By following a consensus-building process, we have worked with several academic societies/consortia, including ERCC, ISEV, and ASEMV, to identify and approve a set of exRNA and extracellular vesicle-related terms and relationships that have been incorporated into GO. In addition, we have initiated an ongoing process of extractions of gene product annotations associated with these terms from Vesiclepedia and ExoCarta, conversion of the extracted annotations to Gene Association File (GAF) format for batch submission to GO, and curation of the submitted annotations by the GO Consortium. As a use case, we have incorporated some of the GO terms into annotations of samples from the exRNA Atlas and implemented a faceted search interface based on such annotations. Results: We have added 7 new terms and modified 9 existing terms (along with their synonyms and relationships) to GO. Additionally, 18,695 unique coding gene products (mRNAs and proteins) and 963 unique non-coding gene products (ncRNAs) which are associated with the terms: "extracellular vesicle", "extracellular exosome", "apoptotic body", and "microvesicle" were extracted from ExoCarta and Vesiclepedia. These annotations are currently being processed for submission to GO. Conclusions: As an inter-community effort, we have made a substantial update to GO in the exRNA context. We have also demonstrated the utility of some of the new GO terms for sample annotation and metadata search. C1 [Cheung, Kei-Hoi] Yale Univ, Sch Med, Dept Emergency Med, Yale Ctr Med Informat, New Haven, CT USA. [Cheung, Kei-Hoi] VA Connecticut Healthcare Syst, West Haven, CT USA. [Keerthikumar, Shivakumar; Samuel, Monisha; Anand, Sushma; Gangoda, Lahiru; Hill, Andrew F.; Mathivanan, Suresh] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem & Genet, Melbourne, Vic 3086, Australia. [Roncaglia, Paola; Shypitsyna, Aleksandra] European Mol Biol Lab, European Bioinformat Inst EMBL EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. [Subramanian, Sai Lakshmi; Roth, Matthew E.; Milosavljevic, Aleksandar] Baylor Coll Med, Dept Mol & Human Genet, Bioinformat Res Lab, Houston, TX 77030 USA. [Gould, Stephen] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Alexander, Roger; Galas, David] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Gerstein, Mark B.; Kitchen, Robert R.; Rozowsky, Joel] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA. [Gerstein, Mark B.] Yale Univ, Dept Comp Sci, POB 2158, New Haven, CT 06520 USA. [Gerstein, Mark B.; Rozowsky, Joel] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT USA. [Lotvall, Jan] Univ Gothenburg, Gothenburg, Sweden. [Patel, Tushar] Mayo Clin Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Procaccini, Dena C.] NIDA, Div Neurosci & Behav, Rockville, MD USA. [Quesenberry, Peter] Univ Med Comprehens Canc Ctr, Providence, RI USA. [Raffai, Robert L.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Raffai, Robert L.] VA Med Ctr, San Francisco, CA USA. [Su, Andrew I.] Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Thery, Clotilde] PSL Res Univ, Inst Curie, INSERM, U932, Paris, France. [Vickers, Kasey] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Wauben, Marca H. M.] Univ Utrecht, Dept Biochem & Cell Biol, Utrecht, Netherlands. [Laurent, Louise C.] Univ Calif San Diego, Dept Reprod Med, La Jolla, CA 92093 USA. RP Cheung, KH (reprint author), Yale Univ, Sch Med, Dept Emergency Med, Yale Ctr Med Informat, New Haven, CT USA.; Laurent, LC (reprint author), Univ Calif San Diego, Dept Reprod Med, La Jolla, CA 92093 USA. EM kei.cheung@yale.edu; llaurent@ucsd.edu RI Mathivanan, Suresh/D-2045-2009; KEERTHIKUMAR, SHIVAKUMAR/B-4673-2011; thery, clotilde/F-6373-2013; OI Mathivanan, Suresh/0000-0002-7290-5795; KEERTHIKUMAR, SHIVAKUMAR/0000-0001-9865-9767; thery, clotilde/0000-0001-8294-6884; Roncaglia, Paola/0000-0002-2825-0621; Rozowsky, Joel/0000-0002-3565-0762 FU NIH Common Fund, through the Office of Strategic Coordination; NIH Common Fund, through the Office of the NIH Director [U54DA036134, UH2TR000906, U01HL126494, UH3TR000884, U19CA179512]; Gene Ontology Consortium (P41 grant from the National Human Genome Research Institute (NHGRI)) [5U41HG002273-14]; European Molecular Biology Laboratory (EMBL) FX This work was supported in part by the NIH Common Fund, through the Office of Strategic Coordination and the Office of the NIH Director (AM: U54DA036134, LCL: UH2TR000906 and U01HL126494, TP: UH3TR000884, and RR: U19CA179512). Paola Roncaglia and Aleksandra Shypitsyna are funded by the Gene Ontology Consortium (P41 grant from the National Human Genome Research Institute (NHGRI), grant 5U41HG002273-14). Aleksandra Shypitsyna is also funded from the European Molecular Biology Laboratory (EMBL). We would like to give special thanks to Dena C. Procaccini for coordinating meetings and conference calls facilitating discussion and collaboration as part of the manuscript writing. We would like to thank Tony Sawford (Protein Function Development team, EMBL-EBI) for running the set of ExoCarta and Vesiclepedia annotations through the validation pipeline for inclusion in the GOA database. We would also like to thank Xandra O. Breakefield for her insights and comments. Finally we would like to acknowledge the community support offered by the following Consortiums: Extracellular RNA Communication (ERC) Consortium, Gene Ontology Consortium (GOC), and International Society for Extracellular Vesicles (ISEV), and American Society for Exosomes and Microvesicles (ASEMV). NR 50 TC 3 Z9 3 U1 10 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD APR 12 PY 2016 VL 7 AR UNSP 19 DI 10.1186/s13326-016-0061-5 PG 9 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DK4ZD UT WOS:000374928000002 PM 27076901 ER PT J AU Ramsden, CE Zamora, D Majchrzak-Hong, S Faurot, KR Broste, SK Frantz, RP Davis, JM Ringel, A Suchindran, CM Hibbeln, JR AF Ramsden, Christopher E. Zamora, Daisy Majchrzak-Hong, Sharon Faurot, Keturah R. Broste, Steven K. Frantz, Robert P. Davis, John M. Ringel, Amit Suchindran, Chirayath M. Hibbeln, Joseph R. TI Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73) SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID LINOLEIC-ACID METABOLITES; ESTROGEN REPLACEMENT THERAPY; SERUM CHOLESTEROL RESPONSE; LOW-DENSITY LIPOPROTEINS; FATTY LIVER-DISEASE; CLINICAL-TRIAL DATA; SECONDARY PREVENTION; METAANALYSIS; LIPIDS; RISK AB OBJECTIVE To examine the traditional diet-heart hypothesis through recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE) and to put findings in the context of existing diet-heart randomized controlled trials through a systematic review and meta-analysis. DESIGN The MCE (1968-73) is a double blind randomized controlled trial designed to test whether replacement of saturated fat with vegetable oil rich in linoleic acid reduces coronary heart disease and death by lowering serum cholesterol. Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators. Further, a systematic review and meta-analyses of randomized controlled trials that lowered serum cholesterol by providing vegetable oil rich in linoleic acid in place of saturated fat without confounding by concomitant interventions was conducted. SETTING One nursing home and six state mental hospitals in Minnesota, United States. PARTICIPANTS Unpublished documents with completed analyses for the randomized cohort of 9423 women and men aged 20-97; longitudinal data on serum cholesterol for the 2355 participants exposed to the study diets for a year or more; 149 completed autopsy files. INTERVENTIONS Serum cholesterol lowering diet that replaced saturated fat with linoleic acid (from corn oil and corn oil polyunsaturated margarine). Control diet was high in saturated fat from animal fats, common margarines, and shortenings. MAIN OUTCOME MEASURES Death from all causes; association between changes in serum cholesterol and death; and coronary atherosclerosis and myocardial infarcts detected at autopsy. RESULTS The intervention group had significant reduction in serum cholesterol compared with controls (mean change from baseline -13.8% v -1.0%; P<0.001). Kaplan Meier graphs showed no mortality benefit for the intervention group in the full randomized cohort or for any prespecified subgroup. There was a 22% higher risk of death for each 30 mg/dL (0.78 mmol/L) reduction in serum cholesterol in covariate adjusted Cox regression models (hazard ratio 1.22, 95% confidence interval 1.14 to 1.32; P<0.001). There was no evidence of benefit in the intervention group for coronary atherosclerosis or myocardial infarcts. Systematic review identified five randomized controlled trials for inclusion (n= 10 808). In meta-analyses, these cholesterol lowering interventions showed no evidence of benefit on mortality from coronary heart disease (1.13, 0.83 to 1.54) or all cause mortality (1.07, 0.90 to 1.27). CONCLUSIONS Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes. Findings from the Minnesota Coronary Experiment add to growing evidence that incomplete publication has contributed to overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid. C1 [Ramsden, Christopher E.; Majchrzak-Hong, Sharon; Ringel, Amit; Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Ramsden, Christopher E.; Faurot, Keturah R.] Univ N Carolina, Dept Phys Med & Rehabil, Program Integrat Med, Chapel Hill, NC USA. [Zamora, Daisy; Davis, John M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Broste, Steven K.] Medtronic, Minneapolis, MN USA. [Frantz, Robert P.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Davis, John M.] Univ Illinois, Inst Psychiat, Chicago, IL USA. [Suchindran, Chirayath M.] UNC Gillings Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC USA. RP Ramsden, CE (reprint author), NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA.; Ramsden, CE (reprint author), Univ N Carolina, Dept Phys Med & Rehabil, Program Integrat Med, Chapel Hill, NC USA. EM Chris.Ramsden@nih.gov FU US Public Health Service; National Heart Institute through R01 mechanism [HE09686]; intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; University of North Carolina Program on Integrative Medicine (National Institutes of Health) [T-32 AT003378] FX The MCE was funded by the US Public Health Service and the National Heart Institute through the R01 mechanism (grant HE09686). The intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, and the University of North Carolina Program on Integrative Medicine (National Institutes of Health grant T-32 AT003378) supported data recovery and evaluation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the US Public Health Service. NR 78 TC 3 Z9 4 U1 5 U2 15 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD APR 12 PY 2016 VL 353 AR i1246 DI 10.1136/bmj.i1246 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA DJ7ER UT WOS:000374375200001 PM 27071971 ER PT J AU Fu, G Ding, Y Seal, A Chen, B Sun, YZ Bolton, E AF Fu, Gang Ding, Ying Seal, Abhik Chen, Bin Sun, Yizhou Bolton, Evan TI Predicting drug target interactions using meta-path-based semantic network analysis SO BMC BIOINFORMATICS LA English DT Article DE Semantic network analysis; Link prediction; Meta-path topological feature; Machine learning; Random forest ID SYSTEMS CHEMICAL BIOLOGY; DISCOVERY; PUBCHEM; DATABASES; FRAMEWORK; SUBSTANCE; COMPOUND AB Background: In the context of drug discovery, drug target interactions (DTIs) can be predicted based on observed topological features of a semantic network across the chemical and biological space. In a semantic network, the types of the nodes and links are different. In order to take into account the heterogeneity of the semantic network, meta-path-based topological patterns were investigated for link prediction. Results: Supervised machine learning models were constructed based on meta-path topological features of an enriched semantic network, which was derived from Chem2Bio2RDF, and was expanded by adding compound and protein similarity neighboring links obtained from the PubChem databases. The additional semantic links significantly improved the predictive performance of the supervised learning models. The binary classification model built upon the enriched feature space using the Random Forest algorithm significantly outperformed an existing semantic link prediction algorithm, Semantic Link Association Prediction (SLAP), to predict unknown links between compounds and protein targets in an evolving network. In addition to link prediction, Random Forest also has an intrinsic feature ranking algorithm, which can be used to select the important topological features that contribute to link prediction. Conclusions: The proposed framework has been demonstrated as a powerful alternative to SLAP in order to predict DTIs using the semantic network that integrates chemical, pharmacological, genomic, biological, functional, and biomedical information into a unified framework. It offers the flexibility to enrich the feature space by using different normalization processes on the topological features, and it can perform model construction and feature selection at the same time. C1 [Fu, Gang; Bolton, Evan] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD USA. [Ding, Ying; Seal, Abhik] Indiana Univ, Sch Informat & Comp, 107 S Indiana Ave, Bloomington, IN USA. [Ding, Ying] Wuhan Univ, Sch Informat Management, Wuhan 430072, Hubei, Peoples R China. [Chen, Bin] Stanford Univ, Dept Med, 450 Serra Mall, Stanford, CA 94305 USA. [Sun, Yizhou] Northeastern Univ, Coll Comp & Informat Sci, 360 Huntington Ave, Boston, MA 02115 USA. RP Fu, G (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD USA. EM gang.fu@nih.gov FU Intramural Research Program of the National Library of Medicine, NIH FX This research was supported [in part] by the Intramural Research Program of the National Library of Medicine, NIH. Many thanks to the PubChem team, who provided database API functions to retrieve data from Compound and BioAssay databases. Many thanks to Ming Hao in the discussion about R packages and calculations. Many thanks to Jeremy Yang in the discussion and help to maintain Chem2Bio2RDF web server. NR 31 TC 2 Z9 2 U1 14 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD APR 12 PY 2016 VL 17 AR 160 DI 10.1186/s12859-016-1005-x PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DJ5VX UT WOS:000374280000001 PM 27071755 ER PT J AU Lee, P Bova, R Schofield, L Bryant, W Dieckmann, W Slattery, A Govendir, MA Emmett, L Greenfield, JR AF Lee, Paul Bova, Ron Schofield, Lynne Bryant, Wendy Dieckmann, William Slattery, Anthony Govendir, Matt A. Emmett, Louise Greenfield, Jerry R. TI Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans SO CELL METABOLISM LA English DT Article ID BETA-ADRENERGIC STIMULATION; ADULT HUMANS; MESSENGER-RNA; COLD-EXPOSURE; ADIPOCYTES; INSULIN; FAT; METABOLISM; ACTIVATION; HEAT AB High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined. In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erb alpha biorhythms. Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes. C1 [Lee, Paul; Schofield, Lynne; Govendir, Matt A.; Greenfield, Jerry R.] Garvan Inst Med Res, Diabet & Metab Div, Sydney, NSW 2010, Australia. [Lee, Paul; Schofield, Lynne; Greenfield, Jerry R.] St Vincents Hosp, Dept Endocrinol, Sydney, NSW 2010, Australia. [Bova, Ron] St Vincents Hosp, Dept Surg, Sydney, NSW 2010, Australia. [Slattery, Anthony; Emmett, Louise] St Vincents Hosp, Dept PET & Nucl Med, Sydney, NSW 2010, Australia. [Bryant, Wendy; Greenfield, Jerry R.] St Vincents Hosp, Ctr Diabet, Sydney, NSW 2010, Australia. [Dieckmann, William] NIH, Dept Positron Emiss Tomog, Bldg 10, Bethesda, MD 20892 USA. [Lee, Paul; Greenfield, Jerry R.] Univ New S Wales, Fac Med, Sydney, NSW 2052, Australia. RP Lee, P (reprint author), Garvan Inst Med Res, Diabet & Metab Div, Sydney, NSW 2010, Australia.; Lee, P (reprint author), St Vincents Hosp, Dept Endocrinol, Sydney, NSW 2010, Australia.; Lee, P (reprint author), Univ New S Wales, Fac Med, Sydney, NSW 2052, Australia. EM p.lee@garvan.org.au FU Australian National Health Medical Research Council (NHMRC) [APP1035997]; NHMRC, Australia [APP1088123]; Diabetes Australia Research Trust (DART) Grant; Royal Australasian College of Physicians (RACP) Foundations Establishment Fellowship; Ramaciotti Establishment Fellowship FX P.L. was supported by an Australian National Health Medical Research Council (NHMRC) Early Career Fellowship (APP1035997). This study was supported by Project Grant (APP1088123) NHMRC, Australia, Diabetes Australia Research Trust (DART) Grant, the Royal Australasian College of Physicians (RACP) Foundations Establishment Fellowship and Ramaciotti Establishment Fellowship. The authors thank Professor Don Chisholm for helpful discussions and Ms. Samarina Musaad from LabTests New Zealand for provision of glycated haemoglobin data. NR 24 TC 9 Z9 12 U1 5 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD APR 12 PY 2016 VL 23 IS 4 BP 602 EP 609 DI 10.1016/j.cmet.2016.02.007 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DJ3RL UT WOS:000374123200009 PM 26972823 ER PT J AU Xu, BB Luo, ZP Gao, WX Wilson, AJ He, C Chen, X Yuan, GL Dai, HL Rao, Y Willets, K Dauter, Z Ren, SQ AF Xu, Beibei Luo, Zhipu Gao, Wenxiu Wilson, Andrew J. He, Chao Chen, Xing Yuan, Guoliang Dai, Hai-Lung Rao, Yi Willets, Katherine Dauter, Zbigniew Ren, Shenqiang TI Solution-Processed Molecular Opto-Ferroic Crystals SO CHEMISTRY OF MATERIALS LA English DT Article ID ORGANIC SEMICONDUCTING MATERIALS; CHARGE-TRANSFER INTERFACES; FIELD-EFFECT TRANSISTORS; TRANSFER COMPLEXES; MOTT INSULATOR; TRANSFER SALT; C-60; MULTIFERROICS; MAGNETISM; FERROELECTRICITY AB Supramolecular assembly utilizing noncovalent interaction to construct ordered molecular charge-transfer solids has led to significant advancement and breakthrough in energy-efficient molecular electronics, memories and solar cells. However, to exploit the coupling across these different energy regimes, the method that is capable of manipulating charge-spinlattice interactions is indispensable. Here, by rational chemical design of the supramolecular assembled charge-transfer networks, opto-ferroic properties can be coupled, in which a collective electron transfer and ordering strongly influence the dipole and spin orders, as well as their coupling. The supramolecular charge-transfer crystal presented here opens up a new route for the development of multifunctional organics that can lead to significant advancement in molecular ferronics. C1 [Xu, Beibei; Ren, Shenqiang] Temple Univ, Dept Mech Engn, Philadelphia, PA 19122 USA. [Xu, Beibei; Ren, Shenqiang] Temple Univ, Temple Mat Inst, Philadelphia, PA 19122 USA. [Luo, Zhipu; Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, NCI, 9700 S Cass Ave, Argonne, IL 60439 USA. [Gao, Wenxiu; Yuan, Guoliang] Nanjing Univ Sci & Technol, Sch Mat Sci & Engn, Nanjing 210094, Jiangsu, Peoples R China. [Wilson, Andrew J.; He, Chao; Dai, Hai-Lung; Rao, Yi; Willets, Katherine] Temple Univ, Dept Chem, Philadelphia, PA 19122 USA. [He, Chao] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China. [He, Chao] Univ Sci & Technol China, Dept Chem Phys, Hefei 230026, Anhui, Peoples R China. [Chen, Xing] Argonne Natl Lab, Div Energy Syst, Argonne, IL 60439 USA. RP Ren, SQ (reprint author), Temple Univ, Dept Mech Engn, Philadelphia, PA 19122 USA.; Ren, SQ (reprint author), Temple Univ, Temple Mat Inst, Philadelphia, PA 19122 USA. EM shenqiang.ren@temple.edu OI Wilson, Andrew/0000-0003-3427-810X FU Army Research Office - Young Investigator Program [W911NF-15-1-0610]; U.S. Department of Energy-Basic Energy Sciences [DE-SC0014902]; Department of Energy (DOE), Office of Science, Basic Energy Science (BES) [DE-SC0010307]; Energy Frontier Research Center at Temple University - U.S. Department of Energy, Office of Science, Basic Energy Sciences [DE-SC0012575]; Targeted Research Grant from Temple University Office of the Vice Provost for Research; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX Work at Temple University (S.R) was supported by the Army Research Office - Young Investigator Program (W911NF-15-1-0610, material design/self-assembly of carbon photovoltaics), U.S. Department of Energy-Basic Energy Sciences Award No. DE-SC0014902 (organic synthesis and physical property measurement). Work at Temple University (A.W. and K.W.) was supported by the Department of Energy (DOE), Office of Science, Basic Energy Science (BES) under Award #DE-SC0010307. Y.R and H.L.D acknowledge the seed funding from an Energy Frontier Research Center at Temple University funded by the U.S. Department of Energy, Office of Science, Basic Energy Sciences under Award # DE-SC0012575, a Targeted Research Grant from the Temple University Office of the Vice Provost for Research. Diffraction data were collected at the SER-CAT beamline 22BM at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. The authors thank Temple Materials Institute and Prof. X. Xi for the AFM measurements. The authors also thank X. Chen at University of Maryland for the dielectric measurements. NR 49 TC 3 Z9 3 U1 7 U2 28 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0897-4756 EI 1520-5002 J9 CHEM MATER JI Chem. Mat. PD APR 12 PY 2016 VL 28 IS 7 BP 2441 EP 2448 DI 10.1021/acs.chemmater.6b00836 PG 8 WC Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA DJ4RS UT WOS:000374196000060 ER PT J AU Sansone, VA Burge, J McDermott, MP Smith, PC Herr, B Tawil, R Pandya, S Kissel, J Ciafaloni, E Shieh, P Ralph, JW Amato, A Cannon, SC Trivedi, J Barohn, R Crum, B Mitsumoto, H Pestronk, A Meola, G Conwit, R Hanna, MG Griggs, RC AF Sansone, Valeria A. Burge, James McDermott, Michael P. Smith, Patty C. Herr, Barbara Tawil, Rabi Pandya, Shree Kissel, John Ciafaloni, Emma Shieh, Perry Ralph, Jeffrey W. Amato, Antony Cannon, Steve C. Trivedi, Jaya Barohn, Richard Crum, Brian Mitsumoto, Hiroshi Pestronk, Alan Meola, Giovanni Conwit, Robin Hanna, Michael G. Griggs, Robert C. CA Muscle Study Grp TI Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis SO NEUROLOGY LA English DT Article ID SKELETAL-MUSCLE CHANNELOPATHIES; SODIUM-CHANNEL MUTATIONS; HEALTH SURVEY SF-36; ACETAZOLAMIDE TREATMENT; GENE-MUTATIONS; WEAKNESS; INACTIVATION; PHENOTYPE; DYSTROPHY; DIAGNOSIS AB Objective:To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis.Methods:Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase.Results:The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form-36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined).Conclusions:DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis.Classification of evidence:These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP. C1 [Sansone, Valeria A.] Univ Milan, NEMO Clin Ctr, I-20122 Milan, Italy. [Meola, Giovanni] Univ Milan, IRCCS Policlin San Donato, I-20122 Milan, Italy. [Burge, James; Hanna, Michael G.] UCL Inst Neurol, Ctr Neuromuscular Dis, MRC, Queen Sq, London, England. [McDermott, Michael P.; Smith, Patty C.; Herr, Barbara; Tawil, Rabi; Pandya, Shree; Ciafaloni, Emma; Griggs, Robert C.] Univ Rochester, Rochester, NY 14627 USA. [Kissel, John] Ohio State Univ, Columbus, OH 43210 USA. [Shieh, Perry] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Ralph, Jeffrey W.] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Amato, Antony] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Cannon, Steve C.; Trivedi, Jaya] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Barohn, Richard] Univ Kansas, Med Ctr, Lawrence, KS 66045 USA. [Crum, Brian] Mayo Clin, Rochester, MN USA. [Mitsumoto, Hiroshi] Columbia Univ, New York, NY USA. [Pestronk, Alan] Washington Univ, St Louis, MO USA. [Conwit, Robin] NINDS, Off Clin Res, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Sansone, VA (reprint author), Univ Milan, NEMO Clin Ctr, I-20122 Milan, Italy. EM valeria.sansone@unimi.it OI meola, giovanni/0000-0001-6396-717X FU NIH National Institute of Neurological Disorders and Stroke [R01 NS045686]; Muscular Dystrophy Association [93615]; NIH NCATS [UL1 TR000042, UL1 TR000040, UL1TR001070, UL1TR000001, UL1TR000124, UL1 TR000004, UL1 TR001105, UL1 TR000135]; NIH NCRR; NCATS [UL1 RR024160, UL1 RR024131]; NIH NCRR [C06 RR20092, M01-02635, 1 UL1 RR025758]; NIH NINDS [U10NS077384, R37-AR42703, RO1-AR063182]; MRC Centre Grant; UCL Biomedical Research Centre Grant; NINDS; MDA FX This study was supported by NIH National Institute of Neurological Disorders and Stroke award R01 NS045686 (Robert C. Griggs, principal investigator); the Muscular Dystrophy Association award 93615; NIH NCATS awards UL1 TR000042, UL1 TR000040, UL1TR001070, UL1TR000001, UL1TR000124, UL1 TR000004, UL1 TR001105, UL1 TR000135, and NIH NCRR; NCATS awards UL1 RR024160 and UL1 RR024131; NIH NCRR awards C06 RR20092, M01-02635, and 1 UL1 RR025758; NIH NINDS awards U10NS077384, R37-AR42703, and RO1-AR063182 (S. Cannon, principal investigator); and MRC Centre Grant and UCL Biomedical Research Centre Grant (M. Hanna, principal investigator, Institute of Neurology, Queen Square, London). NINDS and MDA funding was provided for participant travel support. NR 36 TC 5 Z9 5 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD APR 12 PY 2016 VL 86 IS 15 BP 1408 EP 1416 DI 10.1212/WNL.0000000000002416 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DI9LW UT WOS:000373825300001 PM 26865514 ER PT J AU Richter, B Sliter, DA Herhaus, L Stolz, A Wang, CX Beli, P Zaffagnini, G Wild, P Martens, S Wagner, SA Youle, RJ Dikic, I AF Richter, Benjamin Sliter, Danielle A. Herhaus, Lina Stolz, Alexandra Wang, Chunxin Beli, Petra Zaffagnini, Gabriele Wild, Philipp Martens, Sascha Wagner, Sebastian A. Youle, Richard J. Dikic, Ivan TI Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mitophagy; TBK1; OPTN; ubiquitin; phosphorylation ID AMYOTROPHIC-LATERAL-SCLEROSIS; PARKIN-MEDIATED MITOPHAGY; PINK1-DEPENDENT PHOSPHORYLATION; ACTIVATE PARKIN; KINASE 1; UBIQUITIN; OPTINEURIN; PINK1; MUTATIONS; DEGENERATION AB Selective autophagy of damaged mitochondria requires autophagy receptors optineurin (OPTN), NDP52 (CALCOCO2), TAX1BP1, and p62 (SQSTM1) linking ubiquitinated cargo to autophagic membranes. By using quantitative proteomics, we show that Tank-binding kinase 1 (TBK1) phosphorylates all four receptors on several autophagy-relevant sites, including the ubiquitin-and LC3-binding domains of OPTN and p62/SQSTM1 as well as the SKICH domains of NDP52 and TAX1BP1. Constitutive interaction of TBK1 with OPTN and the ability of OPTN to bind to ubiquitin chains are essential for TBK1 recruitment and kinase activation on mitochondria. TBK1 in turn phosphorylates OPTN's UBAN domain at S473, thereby expanding the binding capacity of OPTN to diverse Ub chains. In combination with phosphorylation of S177 and S513, this posttranslational modification promotes recruitment and retention of OPTN/TBK1 on ubiquitinated, damaged mitochondria. Moreover, phosphorylation of OPTN on S473 enables binding to pS65 Ub chains and is also implicated in PINK1-driven and Parkin-independent mitophagy. Thus, TBK1-mediated phosphorylation of autophagy receptors creates a signal amplification loop operating in selective autophagy of damaged mitochondria. C1 [Richter, Benjamin; Herhaus, Lina; Stolz, Alexandra; Wild, Philipp; Dikic, Ivan] Goethe Univ Frankfurt, Sch Med, Inst Biochem 2, D-60590 Frankfurt, Germany. [Sliter, Danielle A.; Wang, Chunxin; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Beli, Petra] Inst Mol Biol, D-55128 Mainz, Germany. [Zaffagnini, Gabriele; Martens, Sascha] Univ Vienna, Max F Perutz Labs, Vienna Bioctr, A-1030 Vienna, Austria. [Wagner, Sebastian A.] Goethe Univ Frankfurt, Dept Med, Hematol Oncol, D-60590 Frankfurt, Germany. [Dikic, Ivan] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, D-60438 Frankfurt, Germany. [Dikic, Ivan] Univ Split, Sch Med, Inst Immunol, Split 21000, Croatia. [Wild, Philipp] ETH, Inst Biochem, CH-8093 Zurich, Switzerland. RP Dikic, I (reprint author), Goethe Univ Frankfurt, Sch Med, Inst Biochem 2, D-60590 Frankfurt, Germany.; Dikic, I (reprint author), Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, D-60438 Frankfurt, Germany.; Dikic, I (reprint author), Univ Split, Sch Med, Inst Immunol, Split 21000, Croatia. EM ivan.dikic@biochem2.de RI Dikic, Ivan/O-4650-2015; OI Dikic, Ivan/0000-0001-8156-9511; Beli, Petra/0000-0001-9507-9820; Martens, Sascha/0000-0003-3786-8199 FU Deutsche Forschungsgemeinschaft [DI 931/3-1]; Cluster of Excellence "Macromolecular Complexes" of the Goethe University Frankfurt [EXC115]; LOEWE Grant Ub-Net; LOEWE Centrum for Gene and Cell Therapy Frankfurt; NIH-NINDS intramural program; European Molecular Biology Organization (EMBO) long-term postdoctoral fellowship FX We thank Simin Rahighi and Masato Akutsu for helpful discussions; Evgenij Fiskin for the generation of HA-Parkin cells; Wade J. Harper and Alban Ordureau for purified pS65 Ub chains; Patricia Boya for mitophagy assays in mouse embryonic fibroblasts (MEFs); Giulio Superti-Furga for complementary DNA constructs; Jochen H. Weishaupt and Stephen Taylor for cells; and Dragan Maric and the National Institute of Neurological Disorders and Stroke (NINDS) Flow Cytometry Core for FACS. This work was supported by Deutsche Forschungsgemeinschaft Grant DI 931/3-1 (to I.D.); the Cluster of Excellence "Macromolecular Complexes" of the Goethe University Frankfurt (EXC115; to I.D.); LOEWE Grant Ub-Net (to I.D.) and LOEWE Centrum for Gene and Cell Therapy Frankfurt (I.D. and B.R.); the NIH-NINDS intramural program (R.J.Y., D.A.S., and C.W.); and an European Molecular Biology Organization (EMBO) long-term postdoctoral fellowship (to L.H.). NR 43 TC 28 Z9 28 U1 10 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 12 PY 2016 VL 113 IS 15 BP 4039 EP 4044 DI 10.1073/pnas.1523926113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI8PG UT WOS:000373762400047 PM 27035970 ER PT J AU Hall, AB Papathanos, PA Sharma, A Cheng, CD Akbari, OS Assour, L Bergman, NH Cagnetti, A Crisanti, A Dottorini, T Fiorentini, E Galizi, R Hnath, J Jiang, XF Koren, S Nolan, T Radune, D Sharakhova, MV Steele, A Timoshevskiy, VA Windbichler, N Zhang, SM Hahn, MW Phillippy, AM Emrich, SJ Sharakhov, IV Tu, ZJ Besansky, NJ AF Hall, Andrew Brantley Papathanos, Philippos-Aris Sharma, Atashi Cheng, Changde Akbari, Omar S. Assour, Lauren Bergman, Nicholas H. Cagnetti, Alessia Crisanti, Andrea Dottorini, Tania Fiorentini, Elisa Galizi, Roberto Hnath, Jonathan Jiang, Xiaofang Koren, Sergey Nolan, Tony Radune, Diane Sharakhova, Maria V. Steele, Aaron Timoshevskiy, Vladimir A. Windbichler, Nikolai Zhang, Simo Hahn, Matthew W. Phillippy, Adam M. Emrich, Scott J. Sharakhov, Igor V. Tu, Zhijian Jake Besansky, Nora J. TI Radical remodeling of the Y chromosome in a recent radiation of malaria mosquitoes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Anopheles gambiae; PacBio; RNA-Seq; tandem repetitive DNA; Y-chromosome ID ANOPHELES-GAMBIAE COMPLEX; DROSOPHILA-MELANOGASTER; SATELLITE DNA; SEX-CHROMOSOMES; EVOLUTION; GENE; SEQUENCES; GENOME; HETEROCHROMATIN; STEPHENSI AB Y chromosomes control essential male functions in many species, including sex determination and fertility. However, because of obstacles posed by repeat-rich heterochromatin, knowledge of Y chromosome sequences is limited to a handful of model organisms, constraining our understanding of Y biology across the tree of life. Here, we leverage long single-molecule sequencing to determine the content and structure of the nonrecombining Y chromosome of the primary African malaria mosquito, Anopheles gambiae. We find that the An. gambiae Y consists almost entirely of a few massively amplified, tandemly arrayed repeats, some of which can recombine with similar repeats on the X chromosome. Sex-specific genome resequencing in a recent species radiation, the An. gambiae complex, revealed rapid sequence turnover within An. gambiae and among species. Exploiting 52 sex-specific An. gambiae RNA-Seq datasets representing all developmental stages, we identified a small repertoire of Y-linked genes that lack X gametologs and are not Y-linked in any other species except An. gambiae, with the notable exception of YG2, a candidate male-determining gene. YG2 is the only gene conserved and exclusive to the Y in all species examined, yet sequence similarity to YG2 is not detectable in the genome of a more distant mosquito relative, suggesting rapid evolution of Y chromosome genes in this highly dynamic genus of malaria vectors. The extensive characterization of the An. gambiae Y provides a long-awaited foundation for studying male mosquito biology, and will inform novel mosquito control strategies based on the manipulation of Y chromosomes. C1 [Hall, Andrew Brantley; Jiang, Xiaofang; Sharakhov, Igor V.; Tu, Zhijian Jake] Virginia Polytech Inst & State Univ, Interdisciplinary PhD Program Genet Bioinformat &, Blacksburg, VA 24061 USA. [Papathanos, Philippos-Aris; Cagnetti, Alessia; Crisanti, Andrea] Univ Perugia, Dept Expt Med, Sect Genom & Genet, I-06132 Perugia, Italy. [Papathanos, Philippos-Aris; Crisanti, Andrea; Dottorini, Tania; Fiorentini, Elisa; Galizi, Roberto; Windbichler, Nikolai] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London SW7 2AZ, England. [Sharma, Atashi; Sharakhova, Maria V.; Timoshevskiy, Vladimir A.; Sharakhov, Igor V.] Virginia Polytech Inst & State Univ, Dept Entomol, Blacksburg, VA 24061 USA. [Cheng, Changde; Emrich, Scott J.; Besansky, Nora J.] Univ Notre Dame, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Besansky, Nora J.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Akbari, Omar S.] Univ Calif Riverside, Inst Integrat Genome Biol, Riverside Ctr Dis Vector Res, Dept Entomol, Riverside, CA 92521 USA. [Assour, Lauren; Steele, Aaron; Emrich, Scott J.] Univ Notre Dame, Dept Comp Sci & Engn, Notre Dame, IN 46556 USA. [Bergman, Nicholas H.; Hnath, Jonathan; Radune, Diane] Natl Biodefense Anal & Countermeasures Ctr, Frederick, MD 21702 USA. [Koren, Sergey; Phillippy, Adam M.] NHGRI, Genome Informat Sect, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Sharakhova, Maria V.; Sharakhov, Igor V.] Tomsk State Univ, Lab Evolutionary Cytogenet, Tomsk 634050, Russia. [Zhang, Simo; Hahn, Matthew W.] Indiana Univ, Sch Informat & Comp, Bloomington, IN 47405 USA. [Hahn, Matthew W.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Tu, Zhijian Jake] Virginia Polytech Inst & State Univ, Dept Biochem, Blacksburg, VA 24061 USA. [Cheng, Changde] Univ Texas Austin, Dept Integrat Biol, Austin, TX 78712 USA. RP Sharakhov, IV; Tu, ZJ (reprint author), Virginia Polytech Inst & State Univ, Interdisciplinary PhD Program Genet Bioinformat &, Blacksburg, VA 24061 USA.; Sharakhov, IV (reprint author), Virginia Polytech Inst & State Univ, Dept Entomol, Blacksburg, VA 24061 USA.; Besansky, NJ (reprint author), Univ Notre Dame, Eck Inst Global Hlth, Notre Dame, IN 46556 USA.; Besansky, NJ (reprint author), Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA.; Sharakhov, IV (reprint author), Tomsk State Univ, Lab Evolutionary Cytogenet, Tomsk 634050, Russia.; Tu, ZJ (reprint author), Virginia Polytech Inst & State Univ, Dept Biochem, Blacksburg, VA 24061 USA. EM igor@vt.edu; jaketu@vt.edu; nbesansk@nd.edu FU Eck Institute for Global Health, University of Notre Dame; European Community [228421]; National Institutes of Health [R01AI076584, R21AI112734, R21AI101459, R21AI094289, R21AI099528, R21AI105575, HHSN272200900039C]; Foundation of the National Institutes of Health through the VCTR program of the Grand Challenges in Global Health Initiative; European Commission; Regione Umbria Grant I-MOVE; Rita-Levi Montalcini Career Development Award; Marie Curie Intra-European Fellowship for Career Development [PIEFGA-273268]; European Research Council [335724]; National Science Foundation [DGE-1519168]; Department of Education Graduate Assistance in Areas of National Need Fellowship; Fralin Life Science Institute of Virginia Tech; National Human Genome Research Institute, National Institutes of Health; Department of Homeland Security (DHS) Science and Technology Directorate [HSHQDC-07-C-00020] FX We thank F. Catteruccia and S. N. Mitchell for sharing unpublished data; J. Pease for assistance with simulations; M. Kern, M. Menichelli, M. K. Lawniczak, I. Antoshechkin, T. Persampieri, R. Carballar, and R. D'Amato for technical assistance and discussion; and two anonymous reviewers for helpful suggestions. Genomic sequencing was funded in part by a grant from the Eck Institute for Global Health, University of Notre Dame. RNA-Seq was funded in part from a European Community Seventh Framework Programme (FP7/2007-2013) under Grant 228421 (INFRAVEC). Individual laboratories were funded as follows: National Institutes of Health Grants R01AI076584 (to N.J.B. and M.W.H.), R21AI112734 (to N.J.B. and S.J.E.), R21AI101459 (to N.J.B.), R21AI094289 and R21AI099528 (to I.V.S.), R21AI105575 (to Z.J.T.), and HHSN272200900039C (to S.J.E.); the Foundation of the National Institutes of Health through the VCTR program of the Grand Challenges in Global Health Initiative (to N.J.B., A. Crisanti, P.-A.P., and T. N.); European Commission and Regione Umbria Grant I-MOVE (to R.G., E.F., and P.-A.P.); Rita-Levi Montalcini Career Development Award (to P.-A.P.); Marie Curie Intra-European Fellowship for Career Development PIEFGA-273268 (to T.D.); European Research Council Grant 335724 (to N.W.); National Science Foundation Graduate Research Fellowship Grant DGE-1519168 (to A.B.H.); Department of Education Graduate Assistance in Areas of National Need Fellowship (to A. Steele); and Fralin Life Science Institute of Virginia Tech (to I.V.S. and Z.J.T.). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (to S. K. and A.M.P.). The contributions of N.H.B., J.H., and D.R. were funded under Agreement HSHQDC-07-C-00020 awarded by the Department of Homeland Security (DHS) Science and Technology Directorate for the management and operation of the National Biodefense Analysis and Countermeasures Center (NBACC), a Federally Funded Research and Development Center. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the US Department of Homeland Security. In no event shall the DHS, NBACC, or Battelle National Biodefense Institute (BNBI) have any responsibility or liability for any use, misuse, inability to use, or reliance upon the information contained herein. The Department of Homeland Security does not endorse any products or commercial services mentioned in this publication. NR 74 TC 7 Z9 7 U1 15 U2 23 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 12 PY 2016 VL 113 IS 15 BP E2114 EP E2123 DI 10.1073/pnas.1525164113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI8PG UT WOS:000373762400006 PM 27035980 ER PT J AU Tincati, C Douek, DC Marchetti, G AF Tincati, Camilla Douek, Daniel C. Marchetti, Giulia TI Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection SO AIDS RESEARCH AND THERAPY LA English DT Review DE Microbial translocation; Gastrointestinal barrier; Mucosal immunity; Microbiota ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; TRYPTOPHAN CATABOLISM; SYSTEMIC INFLAMMATION; EPITHELIAL BARRIER; PREDICT MORTALITY; VIRAL REPLICATION; TYPE-1 INFECTION; PLASMA-LEVELS AB Over the past 10 years, extensive work has been carried out in the field of microbial translocation in HIV infection, ranging from studies on its clinical significance to investigations on its pathogenic features. In the present work, we review the most recent findings on this phenomenon, focusing on the predictive role of microbial translocation in HIV-related morbidity and mortality, the mechanisms by which it arises and potential therapeutic approaches. From a clinical perspective, current work has shown that markers of microbial translocation may be useful in predicting clinical events in untreated HIV infection, while conflicting data exist on their role in cART-experienced subjects, possibly due to the inclusion of extremely varied patient populations in cohort studies. Results from studies addressing the pathogenesis of microbial translocation have improved our knowledge of the damage of the gastrointestinal epithelial barrier occurring in HIV infection. However, the extent to which mucosal impairment translates directly to increased gastrointestinal permeability remains an open issue. In this respect, novel work has established a role for IL-17 and IL-22-secreting T cell populations in limiting microbial translocation and systemic T-cell activation/inflammation, thus representing a possible target of immune-therapeutic interventions shown to be promising in the animal model. Further, recent reports have not only confirmed the presence of a dysbiotic intestinal community in the course of HIV infection but have also shown that it may be linked to mucosal damage, microbial translocation and peripheral immune activation. Importantly, technical advances have also shed light on the metabolic activity of gut microbes, highlighting the need for novel therapeutic approaches to correct the function, as well as the composition, of the gastrointestinal microbiota. C1 [Tincati, Camilla; Marchetti, Giulia] Univ Milan, San Paolo Hosp, Dept Hlth Sci, Clin Infect Dis, Via Rudini 8, I-20142 Milan, Italy. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Marchetti, G (reprint author), Univ Milan, San Paolo Hosp, Dept Hlth Sci, Clin Infect Dis, Via Rudini 8, I-20142 Milan, Italy. EM giulia.marchetti@unimi.it FU Italian Ministry of Health (Regione Lombardia, "Giovani Ricercatori") [GR-2009-1592029] FX GM received a grant from the Italian Ministry of Health (Regione Lombardia, "Giovani Ricercatori" #GR-2009-1592029). NR 76 TC 6 Z9 6 U1 10 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PD APR 11 PY 2016 VL 13 AR 19 DI 10.1186/s12981-016-0103-1 PG 11 WC Infectious Diseases SC Infectious Diseases GA DK3KR UT WOS:000374816000001 PM 27906073 ER PT J AU Gerlits, O Wymore, T Das, A Shen, CH Parks, JM Smith, JC Weiss, KL Keen, DA Blakeley, MP Louis, JM Langan, P Weber, IT Kovalevsky, A AF Gerlits, Oksana Wymore, Troy Das, Amit Shen, Chen-Hsiang Parks, Jerry M. Smith, Jeremy C. Weiss, Kevin L. Keen, David A. Blakeley, Matthew P. Louis, John M. Langan, Paul Weber, Irene T. Kovalevsky, Andrey TI Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE aspartic protease; enzymes; neutron crystallography; proton transfer; QM; MM modeling ID X-RAY CRYSTALLOGRAPHY; BARRIER HYDROGEN-BOND; PROTON-TRANSFER; HIV-1 PROTEASE; FLUORESCENT PROTEIN; ATOMIC-RESOLUTION; CRYSTAL-STRUCTURES; BINDING-SITES; INHIBITOR; MECHANISM AB Neutron crystallography was used to directly locate two protons before and after a pH-induced two-proton transfer between catalytic aspartic acid residues and the hydroxy group of the bound clinical drug darunavir, located in the catalytic site of enzyme HIV-1 protease. The two-proton transfer is triggered by electrostatic effects arising from protonation state changes of surface residues far from the active site. The mechanism and pH effect are supported by quantum mechanics/molecular mechanics (QM/MM) calculations. The low-pH proton configuration in the catalytic site is deemed critical for the catalytic action of this enzyme and may apply more generally to other aspartic proteases. Neutrons therefore represent a superb probe to obtain structural details for proton transfer reactions in biological systems at a truly atomic level. C1 [Gerlits, Oksana; Weiss, Kevin L.; Langan, Paul; Kovalevsky, Andrey] Oak Ridge Natl Lab, Biol & Soft Matter Div, Oak Ridge, TN 37831 USA. [Wymore, Troy; Parks, Jerry M.; Smith, Jeremy C.] Oak Ridge Natl Lab, UT ORNL Ctr Mol Biophys, Biosci Div, Oak Ridge, TN 37831 USA. [Das, Amit] BARC Trombay, Div Solid State Phys, Mumbai 400085, Maharashtra, India. [Shen, Chen-Hsiang; Weber, Irene T.] Georgia State Univ, Dept Chem, Atlanta, GA 30302 USA. [Shen, Chen-Hsiang; Weber, Irene T.] Georgia State Univ, Dept Biol, POB 4010, Atlanta, GA 30302 USA. [Keen, David A.] Rutherford Appleton Lab, ISIS Facil, Didcot OX11 0QX, Oxon, England. [Blakeley, Matthew P.] Inst Laue Langevin, Large Scale Structures Grp, 71 Ave Martyrs CS 20156, F-38042 Grenoble 9, France. [Louis, John M.] NIDDK, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Kovalevsky, A (reprint author), Oak Ridge Natl Lab, Biol & Soft Matter Div, Oak Ridge, TN 37831 USA. EM kovalevskyay@ornl.gov RI Weiss, Kevin/I-4669-2013; Blakeley, Matthew/G-7984-2015; Langan, Paul/N-5237-2015; OI Weiss, Kevin/0000-0002-6486-8007; Blakeley, Matthew/0000-0002-6412-4358; Langan, Paul/0000-0002-0247-3122; Kovalevsky, Andrey/0000-0003-4459-9142 FU DOE Office of Biological and Environmental Research (BER); DOE Office of Basic Energy Sciences (BES); CSMB; NIH [R01GM02920] FX We thank the Center for Structural Molecular Biology (CSMB) at BES Scientific User Facilities Division, supported by the DOE Office of Biological and Environmental Research (BER), for facility use. O. G., P. L., and A. K. were partly supported by the DOE Office of Basic Energy Sciences (BES). K. L. W. was partly supported by CSMB. I. T. W. was partly supported by an NIH grant R01GM02920. The authors thank Institut Laue Langevin (beamline LADI-III) and Oak Ridge National Laboratory (IMAGINE beamline) for neutron beam time. NR 41 TC 5 Z9 5 U1 10 U2 32 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD APR 11 PY 2016 VL 55 IS 16 BP 4924 EP 4927 DI 10.1002/anie.201509989 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DJ8XB UT WOS:000374496100007 PM 26958828 ER PT J AU Zhang, T Ye, YH AF Zhang, Ting Ye, Yihong TI Doa1 is a MAD adaptor for Cdc48 SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material ID UBIQUITIN-BINDING DOMAIN; PROTEIN-DEGRADATION; QUALITY-CONTROL; AAA-ATPASE; P97; PROTEASOME; COFACTORS; INTERACTS; MEDIATE; SYSTEM C1 [Zhang, Ting; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov NR 20 TC 0 Z9 0 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD APR 11 PY 2016 VL 213 IS 1 BP 7 EP 9 DI 10.1083/jcb.201603078 PG 3 WC Cell Biology SC Cell Biology GA DJ4WL UT WOS:000374208700004 PM 27044894 ER PT J AU Yang, YB Kelly, P Shaffer, AL Schmitz, R Yoo, HM Liu, XY Huang, DW Webster, D Young, RM Nakagawa, M Ceribelli, M Wright, GW Yang, YD Zhao, H Yu, X Xu, WH Chan, WC Jaffe, ES Gascoyne, RD Campo, E Rosenwald, A Ott, G Delabie, J Rimsza, L Staudt, LM AF Yang, Yibin Kelly, Priscilla Shaffer, Arthur L. Schmitz, Roland Yoo, Hee Min Liu, Xinyue Huang, Da Wei Webster, Daniel Young, Ryan M. Nakagawa, Masao Ceribelli, Michele Wright, George W. Yang, Yandan Zhao, Hong Yu, Xin Xu, Weihong Chan, Wing C. Jaffe, Elaine S. Gascoyne, Randy D. Campo, Elias Rosenwald, Andreas Ott, German Delabie, Jan Rimsza, Lisa Staudt, Louis M. TI Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma SO CANCER CELL LA English DT Article ID NF-KAPPA-B; CHAIN ASSEMBLY COMPLEX; ALPHA-DEPENDENT APOPTOSIS; SIGNALING COMPLEX; ANTAGONISTS INDUCE; SOMATIC MUTATIONS; MULTIPLE-MYELOMA; CARD11 MUTATIONS; CODING GENOME; IKK COMPLEX AB Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate I kappa B kinase (IKK) and the classical NF-kappa B pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-kappa B activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetics target cIAP1/2 for destruction, and consequently suppress NF-kB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL. C1 [Kelly, Priscilla; Shaffer, Arthur L.; Schmitz, Roland; Yoo, Hee Min; Liu, Xinyue; Huang, Da Wei; Webster, Daniel; Young, Ryan M.; Nakagawa, Masao; Ceribelli, Michele; Yang, Yandan; Zhao, Hong; Yu, Xin; Xu, Weihong; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 4N115, Bethesda, MD 20892 USA. [Wright, George W.] NCI, Biometr Res Branch, Div Canc Diag & Treatment, NIH, 9000 Rockville Pike,Bldg 10,Room 4N115, Bethesda, MD 20892 USA. [Chan, Wing C.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Jaffe, Elaine S.] NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Campo, Elias] Univ Barcelona, Hosp Clin, E-08036 Barcelona, Spain. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dr Margarete Fischer Bosch Inst Clin Pharmacol, Dept Clin Pathol, D-70376 Stuttgart, Germany. [Delabie, Jan] Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2C4, Canada. [Rimsza, Lisa] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 4N115, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov RI Campo, elias/O-7192-2016 OI Campo, elias/0000-0001-9850-9793 FU Lymphoma/Leukemia Molecular Profiling Project (LLMPP); Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe) FX The authors thank the patients for their participation. We wish to thank Kathleen Meyer for her assistance with GEO submissions, and the members of the Coriell Genotyping and Microarray Center for their assistance with Affymetrix SNP6.0 array. This study was conducted under the auspices of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. R.S. was supported by the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe). D.W. is the Philip O'Bryan Montgomery, Jr., MD, Fellow of the Damon Runyon Cancer Research Foundation (DRG-2208-14). NR 72 TC 13 Z9 13 U1 5 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD APR 11 PY 2016 VL 29 IS 4 BP 494 EP 507 DI 10.1016/j.ccell.2016.03.006 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DI9WY UT WOS:000373854600013 PM 27070702 ER PT J AU Ricketts, CJ Crooks, DR Sourbier, C Schmidt, LS Srinivasan, R Linehan, WM AF Ricketts, Christopher J. Crooks, Daniel R. Sourbier, Carole Schmidt, Laura S. Srinivasan, Ramaprasad Linehan, W. Marston TI SnapShot: Renal Cell Carcinoma SO CANCER CELL LA English DT Editorial Material ID CANCER; MUTATIONS; GERMLINE; FUMARATE C1 [Ricketts, Christopher J.; Crooks, Daniel R.; Sourbier, Carole; Schmidt, Laura S.; Srinivasan, Ramaprasad; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ricketts, CJ (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 1 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD APR 11 PY 2016 VL 29 IS 4 BP 610 EP + DI 10.1016/j.ccell.2016.03.021 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DI9WY UT WOS:000373854600024 PM 27070709 ER PT J AU Zimmer, ER Torrez, VR Kalinine, E Augustin, MC Zenki, KC Almeida, RF Hansel, G Muller, AP Souza, DO Machado-Vieira, R Portela, LV AF Zimmer, Eduardo R. Torrez, Vitor R. Kalinine, Eduardo Augustin, Marina C. Zenki, Kamila C. Almeida, Roberto F. Hansel, Gisele Muller, Alexandre P. Souza, Diogo O. Machado-Vieira, Rodrigo Portela, Luis V. TI Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype (vol 9, 219, 2015) SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Correction DE anxiety; astrocytes; behavior; glutamate; memantine C1 [Zimmer, Eduardo R.; Torrez, Vitor R.; Kalinine, Eduardo; Augustin, Marina C.; Zenki, Kamila C.; Almeida, Roberto F.; Hansel, Gisele; Muller, Alexandre P.; Souza, Diogo O.; Portela, Luis V.] Univ Fed Rio Grande do Sul, Dept Biochem, Porto Alegre, RS, Brazil. [Kalinine, Eduardo] Univ Fed Sergipe, Dept Physiol, Sao Cristovao, Brazil. [Muller, Alexandre P.] Univ Extremo Sul Catarinense, Lab Exercise Biochem & Physiol, Criciuma, Brazil. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, Lab Neurosci, LIM 27, Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. RP Portela, LV (reprint author), Univ Fed Rio Grande do Sul, Dept Biochem, Porto Alegre, RS, Brazil. EM roskaportela@gmail.com RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Zimmer, Eduardo/I-2932-2015 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Zimmer, Eduardo/0000-0002-5349-0053 NR 1 TC 0 Z9 0 U1 1 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD APR 11 PY 2016 VL 10 AR 93 DI 10.3389/fncel.2016.00093 PG 2 WC Neurosciences SC Neurosciences & Neurology GA DI8IU UT WOS:000373745500001 PM 27147966 ER PT J AU Naydenov, NG Feygin, A Wang, DD Kuemmerle, JF Harris, G Conti, MA Adelstein, RS Ivanov, AI AF Naydenov, Nayden G. Feygin, Alex Wang, Dongdong Kuemmerle, John F. Harris, Gianni Conti, Mary Anne Adelstein, Robert S. Ivanov, Andrei I. TI Nonmuscle Myosin IIA Regulates Intestinal Epithelial Barrier in vivo and Plays a Protective Role During Experimental Colitis SO SCIENTIFIC REPORTS LA English DT Article ID APICAL JUNCTIONAL COMPLEX; INFLAMMATORY-BOWEL-DISEASE; TIGHT JUNCTION; LIGHT-CHAIN; CELL-ADHESION; PERMEABILITY; ACTIVATION; EXPRESSION; MEMBRANE; PROTEIN AB The actin cytoskeleton is a critical regulator of intestinal mucosal barrier permeability, and the integrity of epithelial adherens junctions (AJ) and tight junctions (TJ). Non muscle myosin II (NM II) is a key cytoskeletal motor that controls actin filament architecture and dynamics. While NM II has been implicated in the regulation of epithelial junctions in vitro, little is known about its roles in the intestinal mucosa in vivo. In this study, we generated a mouse model with an intestinal epithelial-specific knockout of NM IIA heavy chain (NM IIA cKO) and examined the structure and function of normal gut barrier, and the development of experimental colitis in these animals. Unchallenged NM IIA cKO mice showed increased intestinal permeability and altered expression/localization of several AJ/TJ proteins. They did not develop spontaneous colitis, but demonstrated signs of a low-scale mucosal inflammation manifested by prolapses, lymphoid aggregates, increased cytokine expression, and neutrophil infiltration in the gut. NM IIA cKO animals were characterized by a more severe disruption of the gut barrier and exaggerated mucosal injury during experimentally-induced colitis. Our study provides the first evidence that NM IIA plays important roles in establishing normal intestinal barrier, and protection from mucosal inflammation in vivo. C1 [Naydenov, Nayden G.; Feygin, Alex; Wang, Dongdong; Ivanov, Andrei I.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Kuemmerle, John F.] Virginia Commonwealth Univ, Dept Internal Med, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Harris, Gianni] Univ Rochester, Sch Med, Dept Med, Rochester, NY USA. [Conti, Mary Anne; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Ivanov, Andrei I.] Virginia Commonwealth Univ, VCU Massey Canc Ctr, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Ivanov, Andrei I.] Virginia Inst Mol Med, Richmond, VA 23298 USA. RP Ivanov, AI (reprint author), Virginia Commonwealth Univ, Dept Human & Mol Genet, Med Coll Virginia Campus, Richmond, VA 23298 USA.; Ivanov, AI (reprint author), Virginia Commonwealth Univ, VCU Massey Canc Ctr, Med Coll Virginia Campus, Richmond, VA 23298 USA.; Ivanov, AI (reprint author), Virginia Inst Mol Med, Richmond, VA 23298 USA. EM Andrei.Ivanov@vcuhealth.org OI Adelstein, Robert/0000-0002-8683-2144 FU VCU Massey Cancer Center; NIH-NCI [P30CA016059]; NIH-NINDS Center [5P30NS047463]; National Institute of Health [RO1 DK083968, R01 DK084953]; Crohn's and Colitis Foundation of America [254881] FX Services in support of this study were provided by the VCU Massey Cancer Center, supported in part with funding from NIH-NCI core grant P30CA016059. Microscopy was performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, supported, in part, with funding from the NIH-NINDS Center core grant 5P30NS047463. This work was supported by National Institute of Health grants RO1 DK083968, R01 DK084953 to A.I.I. and by the Crohn's and Colitis Foundation of America research fellowship award 254881 to N.G.N. NR 53 TC 6 Z9 6 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 11 PY 2016 VL 6 AR 24161 DI 10.1038/srep24161 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI8PP UT WOS:000373763400001 PM 27063635 ER PT J AU Wang, CS Wee, Y Yang, CH Melvin, JE Baker, OJ AF Wang, Ching-Shuen Wee, Yinshen Yang, Chieh-Hsiang Melvin, James E. Baker, Olga J. TI ALX/FPR2 Modulates Anti-Inflammatory Responses in Mouse Submandibular Gland SO SCIENTIFIC REPORTS LA English DT Article ID RESOLVING LIPID MEDIATORS; SALIVARY-GLAND; ACUTE-INFLAMMATION; SJOGRENS-SYNDROME; MICROGLIAL ACTIVATION; ACINAR-CELLS; HOST-DEFENSE; RECEPTOR; RESOLUTION; EXPRESSION AB Activation of the G-protein coupled formyl peptide receptor 2 (ALX/FPR2) by the lipid mediators lipoxin A(4) and resolvin D1 (RvD1) promotes resolution of inflammation. Our previous in vitro studies indicate that RvD1 activation of ALX/FPR2 resolves cytokine-mediated inflammatory responses in mammalian cells. However, the impact of ALX/FPR2 activation on salivary gland function in vivo is unknown. The objective of this study was to determine whether submandibular glands (SMG) from ALX/FPR2(-/-) mice display enhanced inflammatory responses to lipopolysaccharides (LPS) stimulation. For these studies, C57BL/6 and ALX/FPR2(-/-) mice at age 8-12-week-old were treated with LPS by i.p for 24 h. Salivary gland structure and function were analyzed by histopathological assessment, saliva flow rate, quantitative PCR, Western blot analyses and immunofluorescence. Our results showed the following events in the ALX/FPR2(-/-) mice treated with LPS: a) upregulated inflammatory cytokines and decreased M3R (Muscarinic Acetylcholine receptor M3) and AQP5 (Aquaporin 5) protein expression, b) decreased saliva secretion, c) increased apoptosis, d) alteration of tight junction and neuronal damage. Overall, our data suggest that the loss of ALX/FPR2 results in unresolved acute inflammation and SMG dysfunction (xerostomia) in response to LPS that is similar to human salivary gland dysfunction induced by bacterial infection. C1 [Wang, Ching-Shuen; Baker, Olga J.] Univ Utah, Sch Dent, Salt Lake City, UT 84108 USA. [Wee, Yinshen] Univ Utah, Sch Med, Dept Pathol, Div Microbiol & Immunol, Salt Lake City, UT 84102 USA. [Yang, Chieh-Hsiang] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. [Melvin, James E.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Baker, OJ (reprint author), Univ Utah, Sch Dent, Salt Lake City, UT 84108 USA. EM olga.baker@hsc.utah.edu FU National Institutes of Health-National Institute of Dental and Craniofacial Research Grants [R01DE022971, R01DE021697, R01DE021697S1, R01DE021697S2]; Intramural Research Program of the NIH, NIDCR FX We thank Dr. Mauro Perretti (William Harvey Research Institute, Barts and The London School of Medicine, United Kingdom) for sharing ALX/FPR2-/- mice for our study. This study is supported by the National Institutes of Health-National Institute of Dental and Craniofacial Research Grants R01DE022971, R01DE021697, R01DE021697S1 and R01DE021697S2 (to OB) and in part by the Intramural Research Program of the NIH, NIDCR (to JEM). NR 60 TC 2 Z9 2 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 11 PY 2016 VL 6 AR 24244 DI 10.1038/srep24244 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI8QG UT WOS:000373765300001 PM 27064029 ER PT J AU Doyle, AD Yamada, KM AF Doyle, Andrew D. Yamada, Kenneth M. TI Mechanosensing via cell-matrix adhesions in 3D microenvironments SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE Adhesion; Mechanotransduction; Collagen; 3D migration; Contractility; Dynamics ID 3-DIMENSIONAL COLLAGEN MATRICES; FOCAL ADHESIONS; EXTRACELLULAR-MATRIX; MYOSIN-IIA; MIGRATION; INTEGRIN; DYNAMICS; VINCULIN; FORCE; FIBROBLASTS AB The extracellular matrix (ECM) microenvironment plays a central role in cell migration by providing physiochemical information that influences overall cell behavior. Much of this external information is accessed by direct interaction of the cell with ECM ligands and structures via integrin-based adhesions that are hypothesized to act as mechanosensors for testing the surrounding microenvironment. Our current understanding of these mechanical complexes is derived primarily from studies of cellular adhesions formed on two-dimensional (2D) substrates in vitro. Yet the rules of cell/ECM engagement and mechanosensing in three-dimensional (3D) microenvironments are invariably more complex under both in vitro and in vivo conditions. Here we review the current understanding of how cellular mechanosensing occurs through adhesion complexes within 3D microenvironments and discuss how these mechanisms can vary and differ from interactions on 2D substrates. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Doyle, Andrew D.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Doyle, AD; Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. EM adoyle@mail.nih.gov; kyamada@dir.nidcr.nih.gov FU NIDCR Division of Intramural Research [ZIA DE000524, ZIA DE000718] FX We would like to thank Brian DuChez, Will Daley, Josh Collins, and Dan Sykora for critical reading of this review. This work was supported by the NIDCR Division of Intramural Research (ZIA DE000524 and ZIA DE000718). NR 80 TC 7 Z9 7 U1 15 U2 29 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD APR 10 PY 2016 VL 343 IS 1 SI SI BP 60 EP 66 DI 10.1016/j.yexcr.2015.10.033 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL2WF UT WOS:000375495200010 PM 26524505 ER PT J AU Li, L Chen, JG Chen, X Tang, J Guo, H Wang, XF Qian, J Luo, GJ He, FP Lu, XM Ding, YB Yang, YC Huang, WT Hou, GJ Lin, XM Ouyang, Q Li, HY Wang, RY Jiang, F Pu, R Lu, JH Jin, M Tan, YX Gonzalez, FJ Cao, GW Wu, MC Wen, H Wu, TC Jin, L Chen, L Wang, HY AF Li, Liang Chen, Jianguo Chen, Xin Tang, Jing Guo, Huan Wang, Xiaofeng Qian, Ji Luo, Guijuan He, Fangping Lu, Xiaomei Ding, Yibo Yang, Yingchen Huang, Wentao Hou, Guojun Lin, Ximeng Ouyang, Qin Li, Hengyu Wang, Ruoyu Jiang, Feng Pu, Rui Lu, Jianhua Jin, Mudan Tan, Yexiong Gonzalez, Frank J. Cao, Guangwen Wu, Mengchao Wen, Hao Wu, Tangchun Jin, Li Chen, Lei Wang, Hongyang TI Serum miRNAs as predictive and preventive biomarker for pre-clinical hepatocellular carcinoma SO CANCER LETTERS LA English DT Article DE Hepatocellular carcinoma; Circulating miRNAs; Biomarker; Prediction; Prevention ID ALPHA-FETOPROTEIN; CHRONIC HEPATITIS; CANCER; MICRORNAS; MANAGEMENT; DIAGNOSIS; DESIGN AB The extremely poor prognosis of patients with symptomatic hepatocellular carcinoma (HCC) diagnosed clinically at advanced stages suggests an urgent need for biomarkers that can be used for prospective surveillance and pre-clinical screening for early presence of pre-malignant lesions and tumors. In a retrospective longitudinal phase 3 biomarker study in seven medical centers of China, time-series and 6 months interval-serum samples were collected from chronic hepatitis B virus infected (CHB) patient cohorts at the pre-malignant or pre-clinical stages (average 6 months prior to clinical diagnosis) and CHB patients that did not develop cancer, and circulating miRNAs measured. A set of serum miRNAs including miR-193a-3p, miR-369-5p, miR-672, miR-429 and let-7i* were identified in pre-clinical HCC patients and have the potential to screen for CHB patients at high risk to develop HCC 6-12 months after miRNAs measurement. These circulating miRNAs combined with the conventional screening tools using alpha-fetoprotein and ultrasound, may have great promise for the prediction and prevention of HCC in high-risk populations. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Li, Liang; Chen, Xin; Tang, Jing; Luo, Guijuan; Yang, Yingchen; Huang, Wentao; Hou, Guojun; Lin, Ximeng; Ouyang, Qin; Li, Hengyu; Jin, Mudan; Tan, Yexiong; Chen, Lei; Wang, Hongyang] Second Mil Med Univ, Eastern Hepatobiliary Surg Inst, Int Cooperat Lab Signal Transduct, Shanghai 200438, Peoples R China. [Li, Liang; Chen, Xin; Tang, Jing; Luo, Guijuan; Tan, Yexiong; Chen, Lei; Wang, Hongyang] Natl Ctr Liver Canc, Shanghai, Peoples R China. [Chen, Jianguo; Lu, Jianhua] Qidong Liver Canc Inst, Qidong 226200, Jiangsu, Peoples R China. [Chen, Jianguo; Lu, Jianhua] Nantong Univ, Liver Canc Inst, Qidong 226200, Jiangsu, Peoples R China. [Guo, Huan; Wu, Tangchun] Huazhong Univ Sci & Technol, Sch Publ Hlth, Tongji Med Coll, MOE Key Lab Environm & Hlth, 13 Hangkong Rd, Wuhan 430030, Peoples R China. [Wang, Xiaofeng; Qian, Ji; Jin, Li] Fudan Univ, TaiZhou Inst Hlth Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Wang, Xiaofeng; Qian, Ji; Jin, Li] Fudan Univ, TaiZhou Inst Hlth Sci, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Wang, Xiaofeng; Qian, Ji; Jin, Li] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, Shanghai 200433, Peoples R China. [He, Fangping; Lu, Xiaomei; Wen, Hao] Xinjiang Med Univ, Affiliated Hosp 1, State Key Lab Breeding Base Xinjiang Major Dis Re, Xinjiang 830054, Peoples R China. [Ding, Yibo; Pu, Rui; Cao, Guangwen] Second Mil Med Univ, Dept Epidemiol, Shanghai 200433, Peoples R China. [Wang, Ruoyu; Wu, Mengchao] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Shanghai 200438, Peoples R China. [Jiang, Feng] Canc Hosp Jiangsu Prov, Jiangsu Key Lab Mol & Translat Canc Res, Nanjing, Jiangsu, Peoples R China. [Gonzalez, Frank J.; Chen, Lei] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Hongyang] Shanghai Jiao Tong Univ, RenJi Hosp, Inst Canc, Natl Lab Oncogenes & Related Genes, Shanghai 200441, Peoples R China. RP Chen, L; Wang, HY (reprint author), Second Mil Med Univ, Eastern Hepatobiliary Surg Inst, Int Cooperat Lab Signal Transduct, Shanghai 200438, Peoples R China.; Chen, L; Wang, HY (reprint author), Natl Ctr Liver Canc, Shanghai, Peoples R China.; Chen, L (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Wang, HY (reprint author), Shanghai Jiao Tong Univ, RenJi Hosp, Inst Canc, Natl Lab Oncogenes & Related Genes, Shanghai 200441, Peoples R China. EM Chenlei@smmu.edu.cn; hywangk@vip.sina.com RI Jin, Li/C-1468-2009 OI Jin, Li/0000-0002-4546-2415 FU State Key Project for Liver Cancer [2012ZX10002-009]; National Research Program of China [2012CB316503, 2012AA02A201]; National Natural Science Foundation of China [81221061, 81422032, 81272212, 81300306, 81372674]; Natural Science Foundation of Shanghai [134119a3700, 20154Y0054] FX We gratefully acknowledge the support from the State Key Project for Liver Cancer (2012ZX10002-009), the National Research Program of China (2012CB316503, 2012AA02A201), National Natural Science Foundation of China (81221061, 81422032, 81272212, 81300306 and 81372674) and Natural Science Foundation of Shanghai (134119a3700, 20154Y0054). NR 22 TC 2 Z9 3 U1 6 U2 22 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD APR 10 PY 2016 VL 373 IS 2 BP 234 EP 240 DI 10.1016/j.canlet.2016.01.028 PG 7 WC Oncology SC Oncology GA DG1OR UT WOS:000371837900011 PM 26850373 ER PT J AU Jacobs, M Benovoy, M Chang, LC Arai, AE Hsu, LY AF Jacobs, Matthew Benovoy, Mitchel Chang, Lin-Ching Arai, Andrew E. Hsu, Li-Yueh TI Evaluation of an automated method for arterial input function detection for first-pass myocardial perfusion cardiovascular magnetic resonance SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Cardiovascular magnetic resonance; Myocardial perfusion imaging; Arterial input function ID CONTRAST-ENHANCED MRI; QUANTITATIVE CORONARY-ANGIOGRAPHY; POSITRON-EMISSION-TOMOGRAPHY; BLOOD-FLOW; QUANTIFICATION; VALIDATION; DISEASE; ACCURACY; IMAGES; CMR AB Background: Quantitative assessment of myocardial blood flow (MBF) with first-pass perfusion cardiovascular magnetic resonance (CMR) requires a measurement of the arterial input function (AIF). This study presents an automated method to improve the objectivity and reduce processing time for measuring the AIF from first-pass perfusion CMR images. This automated method is used to compare the impact of different AIF measurements on MBF quantification. Methods: Gadolinium-enhanced perfusion CMR was performed on a 1.5 T scanner using a saturation recovery dual-sequence technique. Rest and stress perfusion series from 270 clinical studies were analyzed. Automated image processing steps included motion correction, intensity correction, detection of the left ventricle (LV), independent component analysis, and LV pixel thresholding to calculate the AIF signal. The results were compared with manual reference measurements using several quality metrics based on the contrast enhancement and timing characteristics of the AIF. The median and 95 % confidence interval (CI) of the median were reported. Finally, MBF was calculated and compared in a subset of 21 clinical studies using the automated and manual AIF measurements. Results: Two clinical studies were excluded from the comparison due to a congenital heart defect present in one and a contrast administration issue in the other. The proposed method successfully processed 99.63 % of the remaining image series. Manual and automatic AIF time-signal intensity curves were strongly correlated with median correlation coefficient of 0.999 (95 % CI [0.999, 0.999]). The automated method effectively selected bright LV pixels, excluded papillary muscles, and required less processing time than the manual approach. There was no significant difference in MBF estimates between manually and automatically measured AIFs (p = NS). However, different sizes of regions of interest selection in the LV cavity could change the AIF measurement and affect MBF calculation (p = NS to p = 0.03). Conclusion: The proposed automatic method produced AIFs similar to the reference manual method but required less processing time and was more objective. The automated algorithm may improve AIF measurement from the first-pass perfusion CMR images and make quantitative myocardial perfusion analysis more robust and readily available. C1 [Jacobs, Matthew; Benovoy, Mitchel; Arai, Andrew E.; Hsu, Li-Yueh] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Jacobs, Matthew; Chang, Lin-Ching] Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. [Benovoy, Mitchel] Ecole Polytech, Dept Biomed Engn, Montreal, PQ H3C 3A7, Canada. RP Hsu, LY (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lyhsu@mail.nih.gov FU National Heart, Lung and Blood Institute [ZIA HL006137-05] FX This project was funded and supported by the intramural research program of the National Heart, Lung and Blood Institute (ZIA HL006137-05). NR 33 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD APR 8 PY 2016 VL 18 AR 17 DI 10.1186/s12968-016-0239-0 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DK4CP UT WOS:000374864800001 PM 27055445 ER PT J AU Wang, J Zhao, SD Shugart, YY Zhou, ZH Jin, CH Yuan, JM Wang, GQ Wang, D Cheng, ZH Zhang, FQ AF Wang, Jun Zhao, Shuidi Shugart, Yin Yao Zhou, Zhenhe Jin, Chunhui Yuan, Jianmin Wang, Guoqiang Wang, Dong Cheng, Zaohuo Zhang, Fuquan TI No association between ZNF804A rs1344706 and schizophrenia in a case-control study of Han Chinese SO NEUROSCIENCE LETTERS LA English DT Article DE Schizophrenia; Zinc finger protein 804A; rs1344706; Han Chinese ID BIPOLAR DISORDER; GENE; POLYMORPHISM; VARIANTS; SUSCEPTIBILITY; POPULATION; PSYCHOSIS; PROTEIN; RISK AB Previous studies indicated that the single nucleotide polymorphism (SNP) rs1344706 within the gene ZNF804A was a promising risk variant for schizophrenia in European populations. However, existing results are inconsistent in Han Chinese. Hoping to validate the association of rs1344706 with schizophrenia susceptibility in Han Chinese, we conducted a case-control study in 1284 cases and 990 healthy controls from Jiangsu Province, China. We did not detect any significant between-group difference (all P > 0.05) in either allele or genotype frequency under any genetic model between cases and controls. Stratified analysis by sex also failed to find any significant association. Our results did not support the association of rs1344706 with schizophrenia in Han Chinese, and further association studies with large samples from other ethnic backgrounds and focus on more SNPs of ZNF804A are warranted. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Wang, Jun; Zhou, Zhenhe; Jin, Chunhui; Yuan, Jianmin; Wang, Guoqiang; Wang, Dong; Cheng, Zaohuo; Zhang, Fuquan] Nanjing Med Univ, Wuxi Mental Hlth Ctr, Wuxi 214151, Jiangsu, Peoples R China. [Zhao, Shuidi] Nanjing Med Univ, Affiliated Hosp 2, Nanjing 210011, Jiangsu, Peoples R China. [Shugart, Yin Yao] NIMH, Unit Stat Genom, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Cheng, ZH; Zhang, FQ (reprint author), Nanjing Med Univ, Wuxi Mental Hlth Ctr, Wuxi 214151, Jiangsu, Peoples R China. EM chengzaohuo@126.com; zhangfq@njmu.edu.cn FU National Natural Science Foundation of China [81471364]; Joint project of Management Center of Wuxi Hospital [YGZXL1307] FX We thank all participants in the study. This work was supported by the National Natural Science Foundation of China (Grant number: 81471364), and the Joint project of Management Center of Wuxi Hospital (Grant number: YGZXL1307). NR 33 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD APR 8 PY 2016 VL 618 BP 14 EP 18 DI 10.1016/j.neulet.2016.02.048 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DK0NS UT WOS:000374610100003 PM 26934312 ER PT J AU Hu, JX Stern, M Gimenez, LE Wanka, L Zhu, L Rossi, M Meister, J Inoue, A Beck-Sickinger, AG Gurevich, VV Wess, J AF Hu, Jianxin Stern, Matthew Gimenez, Luis E. Wanka, Lizzy Zhu, Lu Rossi, Mario Meister, Jaroslawna Inoue, Asuka Beck-Sickinger, Annette G. Gurevich, Vsevolod V. Wess, Juergen TI A G Protein-biased Designer G Protein-coupled Receptor Useful for Studying the Physiological Relevance of G(q/11)-dependent Signaling Pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE 7-helix receptor; arrestin; cell signaling; G protein; G protein-coupled receptor (GPCR); DREADD; biased signaling ID IN-VIVO; FUNCTIONAL SELECTIVITY; NONVISUAL ARRESTINS; LIPID-METABOLISM; STRUCTURAL BASIS; INSULIN-RELEASE; ACTIVATION; DESENSITIZATION; RESIDUES; AGONISM AB Designer receptors exclusively activated by a designer drug (DREADDs) are clozapine-N-oxide-sensitive designer G protein-coupled receptors (GPCRs) that have emerged as powerful novel chemogenetic tools to study the physiological relevance of GPCR signaling pathways in specific cell types or tissues. Like endogenous GPCRs, clozapine-N-oxide-activated DREADDs do not only activate heterotrimeric G proteins but can also trigger -arrestin-dependent (G protein-independent) signaling. To dissect the relative physiological relevance of G protein-mediated versus -arrestin-mediated signaling in different cell types or physiological processes, the availability of G protein- and -arrestin-biased DREADDs would be highly desirable. In this study, we report the development of a mutationally modified version of a non-biased DREADD derived from the M-3 muscarinic receptor that can activate G(q/11) with high efficacy but lacks the ability to interact with -arrestins. We also demonstrate that this novel DREADD is active in vivo and that cell type-selective expression of this new designer receptor can provide novel insights into the physiological roles of G protein (G(q/11))-dependent versus -arrestin-dependent signaling in hepatocytes. Thus, this novel G(q/11)-biased DREADD represents a powerful new tool to study the physiological relevance of G(q/11)-dependent signaling in distinct tissues and cell types, in the absence of -arrestin-mediated cellular effects. Such studies should guide the development of novel classes of functionally biased ligands that show high efficacy in various pathophysiological conditions but display a reduced incidence of side effects. C1 [Hu, Jianxin; Stern, Matthew; Zhu, Lu; Rossi, Mario; Meister, Jaroslawna; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. [Gimenez, Luis E.; Gurevich, Vsevolod V.] Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA. [Wanka, Lizzy; Beck-Sickinger, Annette G.] Univ Leipzig, Inst Biochem, D-04103 Leipzig, Germany. [Inoue, Asuka] Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi 9808578, Japan. [Inoue, Asuka] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol PRESTO, Kawaguchi, Saitama 3320012, Japan. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Gurevich, Vsevolod/A-3236-2008 OI Gurevich, Vsevolod/0000-0002-3950-5351 FU National Institutes of Health Intramural Research Program; NIDDK; United States Department of Health and Human Services; Deutsche Forschungsgemeinschaft [DCRC1052-A3]; National Institutes of Health [GM077561, GM109955]; PRESTO, Japan Science and Technology Agency FX This work was supported by the National Institutes of Health Intramural Research Program, NIDDK, United States Department of Health and Human Services (to J. H., M. S., L. Z., M. R., J. M., and J. W.), Deutsche Forschungsgemeinschaft Grant DCRC1052-A3 (to L. W.), National Institutes of Health RO1 Grants GM077561 and GM109955 (to V. V. G.), and PRESTO, Japan Science and Technology Agency (to A. I.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 50 TC 1 Z9 1 U1 2 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 8 PY 2016 VL 291 IS 15 BP 7809 EP 7820 DI 10.1074/jbc.M115.702282 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ2SZ UT WOS:000374056700005 PM 26851281 ER PT J AU Fan, MH Zhu, Q Li, HH Ra, HJ Majumdar, S Gulick, DL Jerome, JA Madsen, DH Christofidou-Solomidou, M Speicher, DW Bachovchin, WW Feghali-Bostwick, C Pure, E AF Fan, Ming-Hui Zhu, Qiang Li, Hui-Hua Ra, Hyun-Jeong Majumdar, Sonali Gulick, Dexter L. Jerome, Jacob A. Madsen, Daniel H. Christofidou-Solomidou, Melpo Speicher, David W. Bachovchin, William W. Feghali-Bostwick, Carol Pure, Ellen TI Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE collagen; extracellular matrix; fibroblast; pulmonary fibrosis; serine protease; gelatinase; interstitial lung disease ID IDIOPATHIC PULMONARY-FIBROSIS; SERINE-PROTEASE; EXTRACELLULAR-MATRIX; STROMAL FIBROBLASTS; PROTEOLYTIC ACTIVATION; PROCOLLAGEN PRODUCTION; REMODELING INTERFACE; NEUTROPHIL ELASTASE; TISSUE INHIBITORS; TUMOR-GROWTH AB Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent with in vitro studies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung. C1 [Fan, Ming-Hui; Li, Hui-Hua; Gulick, Dexter L.; Jerome, Jacob A.] Univ Pittsburgh, Dept Med, Pulm Allergy & Crit Care Div, 930 Scaife Hall, Pittsburgh, PA 15213 USA. [Zhu, Qiang] Univ N Carolina, Mol & Cellular Pathol Grad Program, Chapel Hill, NC 27599 USA. [Ra, Hyun-Jeong; Christofidou-Solomidou, Melpo] Univ Penn, Dept Hematol & Oncol, Philadelphia, PA 19104 USA. [Pure, Ellen] Univ Penn, Dept Biomed Sci, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. [Pure, Ellen] Univ Penn, Dept Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. [Majumdar, Sonali; Speicher, David W.] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. [Madsen, Daniel H.] NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, Ctr Canc Immune Therapy,NIH, Bethesda, MD 20892 USA. [Bachovchin, William W.] Tufts Univ, Sackler Sch Biomed Grad Sci, Boston, MA 02111 USA. [Feghali-Bostwick, Carol] Med Univ S Carolina, Div Rheumatol & Immunol, Dept Med, Charleston, SC 29425 USA. RP Fan, MH (reprint author), Univ Pittsburgh, Dept Med, Pulm Allergy & Crit Care Div, 930 Scaife Hall, Pittsburgh, PA 15213 USA. EM fanm@upmc.edu OI Madsen, Daniel Hargboel/0000-0002-3183-6201 FU National Institutes of Health [R01 CA141144, R01 CA133470, K08HL102266, P30AR05891, K24 AR060297, R01 CA131582]; Dalsemer Research Award from the American Lung Association [DA167003]; Intramural Research Program of the National Institutes of Health from NIDCR; NCI [P30 CA010815] FX This work was supported by National Institutes of Health Grants R01 CA141144 (to E. P.), R01 CA133470 (to M. C. S.), K08HL102266 (to M. H. F.), P30AR05891 (to PI Mark Gladwin; funding provided to M. H. F.), and K24 AR060297 (to C. F. B.), Dalsemer Research Award DA167003 (M. H. F.) from the American Lung Association, and in part by the Intramural Research Program of the National Institutes of Health from NIDCR (to D. H. M.), National Institutes of Health Grant R01 CA131582 (to D. W. S.), and Core Grant P30 CA010815 from NCI (to The Wistar Institute). M. C. S. has patents PCT/US14/41636 and PCT/US15/22501 pending and has a founder's equity position in LignaMed, LLC, but these have no connection to the data reported in this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 75 TC 2 Z9 2 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 8 PY 2016 VL 291 IS 15 BP 8070 EP 8089 DI 10.1074/jbc.M115.701433 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ2SZ UT WOS:000374056700026 PM 26663085 ER PT J AU Varmus, H AF Varmus, Harold TI The transformation of oncology SO SCIENCE LA English DT Editorial Material C1 [Varmus, Harold] Weill Cornell Med, Meyer Canc Ctr, New York, NY USA. [Varmus, Harold] US Natl Canc Inst, Rockville, MD 20850 USA. RP Varmus, H (reprint author), Weill Cornell Med, Meyer Canc Ctr, New York, NY USA.; Varmus, H (reprint author), US Natl Canc Inst, Rockville, MD 20850 USA. EM varmus@med.cornell.edu NR 0 TC 0 Z9 0 U1 20 U2 20 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 APR 8 PY 2016 VL 352 IS 6282 BP 123 EP 123 DI 10.1126/science.aaf7301 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI7LM UT WOS:000373681600001 PM 27124426 ER PT J AU Churchman, ML Evans, K Richmond, J Robbins, A Jones, L Shapiro, IM Pachter, JA Weaver, DT Houghton, PJ Smith, MA Lock, RB Mullighan, CG AF Churchman, Michelle L. Evans, Kathryn Richmond, Jennifer Robbins, Alissa Jones, Luke Shapiro, Irina M. Pachter, Jonathan A. Weaver, David T. Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. Mullighan, Charles G. TI Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL SO JCI INSIGHT LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; FOCAL ADHESION KINASE; GENETIC ALTERATIONS; MOUSE MODEL; BCR-ABL; IKAROS; IMATINIB; CELLS; HAPLOINSUFFICIENCY; PHOSPHORYLATION AB BCR-ABL1(+) B progenitor acute lymphoblastic leukemia (Ph+ B-ALL) is an aggressive disease that frequently responds poorly to currently available therapies. Alterations in IKZF1, which encodes the lymphoid transcription factor Ikaros, are present in over 80% of Ph+ ALL and are associated with a stem cell-like phenotype, aberrant adhesion molecule expression and signaling, leukemic cell adhesion to the bone marrow stem cell niche, and poor outcome. Here, we show that FAK1 is upregulated in Ph+ B-ALL with further overexpression in IKZF1-altered cells and that the FAK inhibitor VS-4718 potently inhibits aberrant FAK signaling and leukemic cell adhesion, potentiating responsiveness to tyrosine kinase inhibitors, inducing cure in vivo. Thus, targeting FAK with VS-4718 is an attractive approach to overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, particularly in abrogating the adhesive phenotype induced by Ikaros alterations, and warrants evaluation in clinical trials for Ph+ B-ALL, regardless of IKZF1 status. C1 [Churchman, Michelle L.; Mullighan, Charles G.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Evans, Kathryn; Richmond, Jennifer; Robbins, Alissa; Jones, Luke; Lock, Richard B.] Univ New South Wales, Lowy Canc Res Ctr, Childrens Canc Inst, Sydney, NSW, Australia. [Shapiro, Irina M.; Pachter, Jonathan A.; Weaver, David T.] Verastem Inc, Needham, MA USA. [Houghton, Peter J.] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Mullighan, CG (reprint author), St Jude Childrens Res Hosp, Pathol, 262 Danny Thomas Pl,Mail Stop 342, Memphis, TN 38105 USA. EM charles.mullighan@stjude.org RI Lock, Richard/G-4253-2013 NR 38 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD APR 7 PY 2016 VL 1 IS 4 AR e86082 DI 10.1172/jci.insight.86082 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1IU UT WOS:000387104400005 ER PT J AU Kozlenkov, A Wang, MH Roussos, P Rudchenko, S Barbu, M Bibikova, M Klotzle, B Dwork, AJ Zhang, B Hurd, YL Koonin, EV Wegner, M Dracheva, S AF Kozlenkov, Alexey Wang, Minghui Roussos, Panos Rudchenko, Sergei Barbu, Mihaela Bibikova, Marina Klotzle, Brandy Dwork, Andrew J. Zhang, Bin Hurd, Yasmin L. Koonin, Eugene V. Wegner, Michael Dracheva, Stella TI Substantial DNA methylation differences between two major neuronal subtypes in human brain SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EMBRYONIC STEM-CELLS; HUMAN HOUSEKEEPING GENES; RETT-SYNDROME; GABAERGIC INTERNEURONS; EPIGENETIC MEMORY; PREFRONTAL CORTEX; SITE RESOLUTION; MECP2 BINDS; RNA-SEQ; SCHIZOPHRENIA AB The brain is built from a large number of cell types which have been historically classified using location, morphology and molecular markers. Recent research suggests an important role of epigenetics in shaping and maintaining cell identity in the brain. To elucidate the role of DNA methylation in neuronal differentiation, we developed a new protocol for separation of nuclei from the two major populations of human prefrontal cortex neurons-GABAergic interneurons and glutamatergic (GLU) projection neurons. Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG). A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons. Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype-specific gene expression compared to CpG methylation. Regions that are differentially methylated in GABA and GLU neurons were significantly enriched for schizophrenia risk loci. Collectively, our findings suggest that functional differences between neuronal subtypes are linked to their epigenetic specification. C1 [Kozlenkov, Alexey; Roussos, Panos; Dracheva, Stella] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Kozlenkov, Alexey; Roussos, Panos; Hurd, Yasmin L.; Dracheva, Stella] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Kozlenkov, Alexey; Roussos, Panos; Hurd, Yasmin L.; Dracheva, Stella] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Wang, Minghui; Roussos, Panos; Zhang, Bin] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Rudchenko, Sergei; Barbu, Mihaela] Hosp Special Surg, New York, NY 10021 USA. [Bibikova, Marina; Klotzle, Brandy] Illumina Inc, San Diego, CA 92122 USA. [Dwork, Andrew J.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Wegner, Michael] Univ Erlangen Nurnberg, Emil Fischer Zentrum, Inst Biochem, D-91054 Erlangen, Germany. RP Dracheva, S (reprint author), James J Peters VA Med Ctr, Bronx, NY 10468 USA.; Dracheva, S (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA.; Dracheva, S (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. EM Stella.Dracheva@mssm.edu RI Roussos, Panos/J-7090-2013 OI Roussos, Panos/0000-0002-4640-6239 FU National Institute of Mental Health [R21MH103877]; U.S. Department of Veterans Affairs [BX001829]; U.S. Department of Health and Human Services; National Institute of Health FX National Institute of Mental Health [R21MH103877 that is a part of the PsychENCODE consortium to S.D.]; U.S. Department of Veterans Affairs [Merit Review Award BX001829 to S.D.]; Intramural funds of the U.S. Department of Health and Human Services to National Library of Medicine (to E.V.K.). Funding for open access charge: National Institute of Health. NR 96 TC 7 Z9 7 U1 5 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 7 PY 2016 VL 44 IS 6 BP 2593 EP 2612 DI 10.1093/nar/gkv1304 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ9YW UT WOS:000374570500020 PM 26612861 ER PT J AU Dahmane, N Gadelle, D Delmas, S Criscuolo, A Eberhard, S Desnoues, N Collin, S Zhang, HL Pommier, Y Forterre, P Sezonov, G AF Dahmane, Narimane Gadelle, Daniele Delmas, Stephane Criscuolo, Alexis Eberhard, Stephan Desnoues, Nicole Collin, Sylvie Zhang, Hongliang Pommier, Yves Forterre, Patrick Sezonov, Guennadi TI toplb, a phylogenetic hallmark gene of Thaumarchaeota encodes a functional eukaryote- like topoisomerase IB SO NUCLEIC ACIDS RESEARCH LA English DT Article ID AMMONIA-OXIDIZING ARCHAEON; DNA TOPOISOMERASE; NITROSOSPHAERA-VIENNENSIS; CLEAVAGE COMPLEXES; VACCINIA VIRUS; CAMPTOTHECIN; MECHANISM; SEQUENCE; ORIGIN; INHIBITORS AB Type IB DNA topoisomerases can eliminate torsional stresses produced during replication and transcription. These enzymes are found in all eukaryotes and a short version is present in some bacteria and viruses. Among prokaryotes, the long eukaryotic version is only observed in archaea of the phylum Thaumarchaeota. However, the activities and the roles of these topoisomerases have remained an open question. Here, we demonstrate that all available thaumarchaeal genomes contain a topoisomerase IB gene that defines a monophyletic group closely related to the eukaryotic enzymes. We show that the topIB gene is expressed in the model thaumarchaeon Nitrososphaera viennensis and we purified the recombinant enzyme from the uncultivated thaumarchaeon Candidatus Caldiarchaeum subterraneum. This enzyme is active in vitro at high temperature, making it the first thermophilic topoisomerase IB characterized so far. We have compared this archaeal type IB enzyme to its human mitochondrial and nuclear counterparts. The archaeal enzyme relaxes both negatively and positively supercoiled DNA like the eukaryotic enzymes. However, its pattern of DNA cleavage specificity is different and it is resistant to camptothecins (CPTs) and non-CPT Top1 inhibitors, LMP744 and lamellarin D. This newly described thermostable topoisomerases IB should be a promising new model for evolutionary, mechanistic and structural studies. C1 [Dahmane, Narimane; Delmas, Stephane; Eberhard, Stephan; Collin, Sylvie; Sezonov, Guennadi] Univ Paris 06, Unite Evolut Paris Seine UMR 7138, Sorbonne Univ, IBPS,CNRS, F-75005 Paris, France. [Gadelle, Daniele; Forterre, Patrick] Univ Paris Saclay, Univ Paris 11, CNRS, I2BC,CEA, F-91198 Gif Sur Yvette, France. [Criscuolo, Alexis] USR 3756 IP CNRS, Inst Pasteur, Hub Bioinformat & Biostat C3BI, 25-28 Rue Docteur Roux, F-75724 Paris 15, France. [Desnoues, Nicole; Forterre, Patrick] Inst Pasteur, Unit Biol Mol Gene Chez Extremophiles, Dept Microbiol, 25-28 Rue Docteur Roux, F-75724 Paris 15, France. [Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Sezonov, G (reprint author), Univ Paris 06, Unite Evolut Paris Seine UMR 7138, Sorbonne Univ, IBPS,CNRS, F-75005 Paris, France.; Forterre, P (reprint author), Univ Paris Saclay, Univ Paris 11, CNRS, I2BC,CEA, F-91198 Gif Sur Yvette, France.; Forterre, P (reprint author), Inst Pasteur, Unit Biol Mol Gene Chez Extremophiles, Dept Microbiol, 25-28 Rue Docteur Roux, F-75724 Paris 15, France.; Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov; forterre@pasteur.fr; guennadi.sezonov@courriel.upmc.fr FU LabeX 'Initiative d'Excellence' program [ANR-11-LABX-0011-01]; NCI Intramural Program, Center for Cancer Research [BC-006161]; Institut Pasteur FX LabeX 'Initiative d'Excellence' program [Grant 'DYNAMO,' ANR-11-LABX-0011-01]; NCI Intramural Program, Center for Cancer Research [BC-006161]. Funding for open access charge: Institut Pasteur. NR 59 TC 0 Z9 0 U1 3 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 7 PY 2016 VL 44 IS 6 BP 2795 EP 2805 DI 10.1093/nar/gkw097 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ9YW UT WOS:000374570500033 PM 26908651 ER PT J AU Kuschal, C Botta, E Orioli, D Digiovanna, JJ Seneca, S Keymolen, K Tamura, D Heller, E Khan, SG Caligiuri, G Lanzafame, M Nardo, T Ricotti, R Peverali, FA Stephens, R Zhao, YM Lehmann, AR Baranello, L Levens, D Kraemer, KH Stefanini, M AF Kuschal, Christiane Botta, Elena Orioli, Donata Digiovanna, John J. Seneca, Sara Keymolen, Kathelijn Tamura, Deborah Heller, Elizabeth Khan, Sikandar G. Caligiuri, Giuseppina Lanzafame, Manuela Nardo, Tiziana Ricotti, Roberta Peverali, Fiorenzo A. Stephens, Robert Zhao, Yongmei Lehmann, Alan R. Baranello, Laura Levens, David Kraemer, Kenneth H. Stefanini, Miria TI GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RNA-POLYMERASE-II; GENOTYPE-PHENOTYPE RELATIONSHIPS; C7ORF11 TTDN1 GENE; XERODERMA-PIGMENTOSUM; BASAL TRANSCRIPTION; XPD MUTATIONS; EXCISION-REPAIR; BETA-SUBUNIT; DISORDER TRICHOTHIODYSTROPHY; COCKAYNE-SYNDROME AB The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.A1a150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIE beta). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIE alpha and TFIIE beta) as well as decreased phosphorylation of TFIIE alpha in cells from both children. Interestingly, decreased phosphorylation of TFIIE alpha was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP. C1 [Kuschal, Christiane; Digiovanna, John J.; Tamura, Deborah; Heller, Elizabeth; Khan, Sikandar G.; Kraemer, Kenneth H.] NCI, Dermatol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Botta, Elena; Orioli, Donata; Caligiuri, Giuseppina; Lanzafame, Manuela; Nardo, Tiziana; Ricotti, Roberta; Peverali, Fiorenzo A.; Stefanini, Miria] CNR, Ist Genet Mol, Via Abbiategrasso 207, I-27100 Pavia, Italy. [Seneca, Sara; Keymolen, Kathelijn] Vrije Univ Brussel, UZ Brussel, Res Grp Reprod & Genet, Ctr Med Genet, Laarbeeklaan 101, B-1090 Brussels, Belgium. [Stephens, Robert] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Cancer Res Technol Program, Frederick, MD 21702 USA. [Stephens, Robert; Zhao, Yongmei] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. [Lehmann, Alan R.] Univ Sussex, Sch Life Sci, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England. [Baranello, Laura; Levens, David] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kuschal, Christiane] Natl Univ Singapore, Canc Sci Inst, 14 Med Dr, Singapore 117599, Singapore. RP Kraemer, KH (reprint author), NCI, Dermatol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.; Stefanini, M (reprint author), CNR, Ist Genet Mol, Via Abbiategrasso 207, I-27100 Pavia, Italy. EM kraemerk@nih.gov; stefanini@igm.cnr.it OI Kuschal, Christiane/0000-0001-6113-3585; BOTTA, ELENA/0000-0003-2060-0110 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Associazione Italiana per la Ricerca sul Cancro Grant [IG 13537, IG 17710]; Telethon Grant [GEP13022] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (C.K., K.H.K., J.J.D., S.G.K., D.T., D.L., L.B., R.S.), the Associazione Italiana per la Ricerca sul Cancro Grant IG 13537 (M.S.), and IG 17710 (D.O.) and Telethon Grant GEP13022 (E.B.). We thank Dr. Wei Yang (NIDDK, NIH) for the schematic image of TFIIE mutations, Russell Bandle (NCI) for helpful suggestions in the procedure of nuclear protein isolation, and Heather Fawcett (Sussex University) for technical assistance. We would also like to thank the Genomics Laboratory and CCR Sequencing Facility at Frederick National Laboratory for Cancer Research including Dan Soppett and Kristen Pike for DNA target preparation, Bao Tran for performing the sequencing, Ming Yi for help perfecting the GATK workflow, and Shashi Ratanayke and Keyur Talsania for assistance running the analysis. NR 62 TC 0 Z9 0 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD APR 7 PY 2016 VL 98 IS 4 BP 627 EP 642 DI 10.1016/j.ajhg.2016.02.008 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA DJ4UO UT WOS:000374203800003 PM 26996949 ER PT J AU Chen, H Wang, CL Conomos, MP Stilp, AM Li, ZL Sofer, T Szpiro, AA Chen, W Brehm, JM Celedon, JC Redline, S Papanicolaou, GJ Thornton, TA Laurie, CC Rice, K Lin, XH AF Chen, Han Wang, Chaolong Conomos, Matthew P. Stilp, Adrienne M. Li, Zilin Sofer, Tamar Szpiro, Adam A. Chen, Wei Brehm, John M. Celedon, Juan C. Redline, Susan Papanicolaou, George J. Thornton, Timothy A. Laurie, Cathy C. Rice, Kenneth Lin, Xihong TI Control for Population Structure and Relatedness for Binary Traits in Genetic Association Studies via Logistic Mixed Models SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; STRATIFICATION; POWER; LOCI; LATINOS; SUSCEPTIBILITY; REGRESSION; DISEASE; TESTS AB Linear mixed models (LMMs) are widely used in genome-wide association studies (GWASs) to account for population structure and relatedness, for both continuous and binary traits. Motivated by the failure of LMMs to control type I errors in a GWAS of asthma, a binary trait, we show that LMMs are generally inappropriate for analyzing binary traits when population stratification leads to violation of the LMM's constant-residual variance assumption. To overcome this problem, we develop a computationally efficient logistic mixed model approach for genome-wide analysis of binary traits, the generalized linear mixed model association test (GMMAT). This approach fits a logistic mixed model once per GWAS and performs score tests under the null hypothesis of no association between a binary trait and individual genetic variants. We show in simulation studies and real data analysis that GMMAT effectively controls for population structure and relatedness when analyzing binary traits in a wide variety of study designs. C1 [Chen, Han; Wang, Chaolong; Li, Zilin; Lin, Xihong] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Wang, Chaolong] Genome Inst Singapore, Computat & Syst Biol, Singapore 138672, Singapore. [Conomos, Matthew P.; Stilp, Adrienne M.; Sofer, Tamar; Szpiro, Adam A.; Thornton, Timothy A.; Laurie, Cathy C.; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Li, Zilin] Tsinghua Univ, Dept Math, Beijing 100084, Peoples R China. [Chen, Wei; Brehm, John M.; Celedon, Juan C.] Univ Pittsburgh, UPMC, Childrens Hosp Pittsburgh, Div Pediat Pulm Med Allergy & Immunol, Pittsburgh, PA 15224 USA. [Redline, Susan] Brigham & Womens Hosp, Dept Med & Neurol, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. [Papanicolaou, George J.] NHLBI, Prevent & Populat Sci Program, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lin, XH (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM xlin@hsph.harvard.edu OI Chen, Han/0000-0002-9510-4923; Sofer, Tamar/0000-0001-8520-8860 FU China Scholarship Council; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [N01-HC65235]; Northwestern University [N01-HC65236]; San Diego State University [N01-HC65237]; NHLBI: National Institute on Minority Health and Health Disparities; National Institute on Deafness and Other Communication Disorders; National Institute of Dental and Craniofacial Research (NIDCR); National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; NIH Office of Dietary Supplements; NIDCR [HHSN268201300005C AM03, MOD03]; NHLBI [HSN26220/20054C]; National Center for Advancing Translational Science Clinical Translational Science Institute [UL1TR000124]; NIDDK Diabetes Research Center [DK063491]; [P01 CA134294]; [R35 CA197449]; [R01 HL113338]; [K99 HL130593]; [R37 CA076404] FX This work was supported by grants P01 CA134294, R35 CA197449, and R01 HL113338 (to H.C., Z.L., and X.L.), K99 HL130593 (to H.C.), and R37 CA076404 (to C.W., Z.L., and X.L.). Z.L. was also supported in part by a scholarship from the China Scholarship Council. We thank the participants and staff of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) for their contributions to this study. The baseline examination of HCHS/SOL was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following institutes, centers, and offices contributed to the first phase of HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, and NIH Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Genotyping efforts were supported by NHLBI (HSN26220/20054C), National Center for Advancing Translational Science Clinical Translational Science Institute (UL1TR000124), and NIDDK Diabetes Research Center (DK063491). This manuscript has been reviewed by the HCHS/SOL Publications Committee for scientific content and consistency of data interpretation with previous HCHS/SOL publications. NR 38 TC 7 Z9 7 U1 4 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD APR 7 PY 2016 VL 98 IS 4 BP 653 EP 666 DI 10.1016/j.ajhg.2016.02.012 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DJ4UO UT WOS:000374203800005 PM 27018471 ER PT J AU Joubert, BR Felix, JF Yousefi, P Bakulski, KM Just, AC Breton, C Reese, SE Markunas, CA Richmond, RC Xu, CJ Kupers, LK Oh, SS Hoyo, C Gruzieva, O Soderhal, C Salas, LA Baiz, N Zhang, HM Lepeule, J Ruiz, C Ligthart, S Wang, TY Taylor, JA Duijts, L Sharp, GC Jankipersadsing, SA Nilsen, RM Vaez, A Fallin, MD Hu, DL Litonjua, AA Fuemmeler, BF Huen, K Kere, J Kull, I Munthe-Kaas, MC Gehring, U Bustamante, M Saurel-Coubizolles, MJ Quraishi, BM Ren, J Tost, J Gonzalez, JR Peters, MJ Haberg, SE Xu, ZL van Meurs, JB Gaunt, TR Kerkhof, M Corpeleijn, E Feinberg, AP Eng, C Baccarelli, AA Neelon, SEB Bradman, A Merid, SK Bergstrom, A Herceg, Z Hernandez-Vargas, H Brunekreef, B Pinart, M Heude, B Ewart, S Yao, J Lemonnier, N Franco, OH Wu, MC Hofman, A McArdle, W Van der Vlies, P Falahi, F Gillman, MW Barcellos, LF Kumar, A Wickman, M Guerra, S Charles, MA Holloway, J Auffray, C Tiemeier, HW Smith, GD Postma, D Hivert, MF Eskenazi, B Vrijheid, M Arshad, H Anto, JM Dehghan, A Karmaus, W Annesi-Maesano, I Sunyer, J Ghantous, A Pershagen, G Hollands, N Murphy, SK DeMeo, DL Burchard, EG Ladd-Acosta, C Snieder, H Nystad, W Koppelman, GH Relton, CL Jaddoe, VWV Wilcox, A Melen, E London, SJ AF Joubert, Bonnie R. Felix, Janine F. Yousefi, Paul Bakulski, Kelly M. Just, Allan C. Breton, Carrie Reese, Sarah E. Markunas, Christina A. Richmond, Rebecca C. Xu, Cheng-Jian Kupers, Leanne K. Oh, Sam S. Hoyo, Cathrine Gruzieva, Olena Soderhal, Cilla Salas, Lucas A. Baiz, Nour Zhang, Hongmei Lepeule, Johanna Ruiz, Carlos Ligthart, Symen Wang, Tianyuan Taylor, Jack A. Duijts, Liesbeth Sharp, Gemma C. Jankipersadsing, Soesma A. Nilsen, Roy M. Vaez, Ahmad Fallin, M. Daniele Hu, Donglei Litonjua, Augusto A. Fuemmeler, Bernard F. Huen, Karen Kere, Juha Kull, Inger Munthe-Kaas, Monica Cheng Gehring, Ulrike Bustamante, Mariona Saurel-Coubizolles, Marie Jose Quraishi, Bilal M. Ren, Jie Tost, Jorg Gonzalez, Juan R. Peters, Marjolein J. Haberg, Siri E. Xu, Zongli van Meurs, Joyce B. Gaunt, Tom R. Kerkhof, Marjan Corpeleijn, Eva Feinberg, Andrew P. Eng, Celeste Baccarelli, Andrea A. Neelon, Sara E. Benjamin Bradman, Asa Merid, Simon Kebede Bergstrom, Anna Herceg, Zdenko Hernandez-Vargas, Hector Brunekreef, Bert Pinart, Mariona Heude, Barbara Ewart, Susan Yao, Jin Lemonnier, Nathanael Franco, Oscar H. Wu, Michael C. Hofman, Albert McArdle, Wendy Van der Vlies, Pieter Falahi, Fahimeh Gillman, Matthew W. Barcellos, Lisa F. Kumar, Ashish Wickman, Magnus Guerra, Stefano Charles, Marie-Aline Holloway, John Auffray, Charles Tiemeier, Henning W. Smith, George Davey Postma, Dirkje Hivert, Marie-France Eskenazi, Brenda Vrijheid, Martine Arshad, Hasan Anto, Josep M. Dehghan, Abbas Karmaus, Wilfried Annesi-Maesano, Isabella Sunyer, Jordi Ghantous, Akram Pershagen, Goran Hollands, Nina Murphy, Susan K. DeMeo, Dawn L. Burchard, Esteban G. Ladd-Acosta, Christine Snieder, Harold Nystad, Wenche Koppelman, Gerard H. Relton, Caroline L. Jaddoe, Vincent W. V. Wilcox, Allen Melen, Erik London, Stephanie J. TI DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HYDROCARBON RECEPTOR REPRESSOR; AUTISM SPECTRUM DISORDERS; LYMPH-NODE METASTASIS; LUNG-FUNCTION DECLINE; CIGARETTE-SMOKING; NEUROPILIN-2 EXPRESSION; BREAST-CANCER; IN-UTERO; POSTSYNAPTIC DENSITY; PRENATAL EXPOSURE AB Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 x 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure. C1 [Joubert, Bonnie R.; Reese, Sarah E.; Markunas, Christina A.; Wang, Tianyuan; Taylor, Jack A.; Xu, Zongli] NIEHS, NIH, US Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Felix, Janine F.; Ligthart, Symen; Duijts, Liesbeth; Franco, Oscar H.; Dehghan, Abbas] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Felix, Janine F.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Pediat, NL-3000 CA Rotterdam, Netherlands. [Felix, Janine F.; Duijts, Liesbeth; Tiemeier, Henning W.] Univ Med Ctr Rotterdam, Erasmus MC, Generat Study Grp R, NL-3000 CA Rotterdam, Netherlands. [Yousefi, Paul; Huen, Karen; Bradman, Asa; Barcellos, Lisa F.; Eskenazi, Brenda] Univ Calif Berkeley, Sch Publ Hlth, CERCH, Berkeley, CA 94720 USA. [Bakulski, Kelly M.; Fallin, M. Daniele; Neelon, Sara E. Benjamin] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Just, Allan C.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Breton, Carrie; Ren, Jie; Yao, Jin] Univ So Calif, Los Angeles, CA 90032 USA. [Markunas, Christina A.] Duke Univ, Med Ctr, Duke Mol Physiol Inst, Durham, NC 27710 USA. [Richmond, Rebecca C.; Sharp, Gemma C.; Gaunt, Tom R.; Smith, George Davey; Relton, Caroline L.] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Xu, Cheng-Jian; Jankipersadsing, Soesma A.; Van der Vlies, Pieter] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Xu, Cheng-Jian; Jankipersadsing, Soesma A.; Postma, Dirkje] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, NL-9700 RB Groningen, Netherlands. [Xu, Cheng-Jian; Kerkhof, Marjan; Postma, Dirkje; Koppelman, Gerard H.] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst Groningen, NL-9700 RB Groningen, Netherlands. [Kupers, Leanne K.; Vaez, Ahmad; Corpeleijn, Eva; Falahi, Fahimeh; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Oh, Sam S.; Hu, Donglei; Eng, Celeste; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Hoyo, Cathrine] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Hoyo, Cathrine] N Carolina State Univ, Ctr Human Hlth & Environm, Raleigh, NC 27695 USA. [Gruzieva, Olena; Kull, Inger; Merid, Simon Kebede; Bergstrom, Anna; Kumar, Ashish; Wickman, Magnus; Pershagen, Goran; Melen, Erik] Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden. [Soderhal, Cilla; Kere, Juha] Karolinska Inst, Dept Biosci & Nutr, S-14183 Stockholm, Sweden. [Salas, Lucas A.; Ruiz, Carlos; Bustamante, Mariona; Gonzalez, Juan R.; Pinart, Mariona; Guerra, Stefano; Vrijheid, Martine; Anto, Josep M.; Sunyer, Jordi] Ctr Res Environm Epidemiol CREAL, Barcelona 08003, Spain. [Salas, Lucas A.; Ruiz, Carlos; Bustamante, Mariona; Gonzalez, Juan R.; Pinart, Mariona; Vrijheid, Martine; Anto, Josep M.; Sunyer, Jordi] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08003, Spain. [Salas, Lucas A.; Ruiz, Carlos; Bustamante, Mariona; Gonzalez, Juan R.; Pinart, Mariona; Vrijheid, Martine; Anto, Josep M.; Sunyer, Jordi] UPF, Barcelona 08003, Spain. [Baiz, Nour; Annesi-Maesano, Isabella] Univ Paris 06, Sorbonne Univ,St Antoine Med Sch, INSERM,Epidemiol Allerg & Resp Dis Dept EPAR, Pierre Louis Inst Epidemiol & Publ Hlth IPLESP UM, F-75012 Paris, France. [Zhang, Hongmei; Quraishi, Bilal M.; Karmaus, Wilfried] Univ Memphis, Sch Publ Hlth, Div Epidemiol Biostat & Environm Hlth, Memphis, TN 38152 USA. [Lepeule, Johanna] Univ Grenoble, Ctr Hosp, Univ Grenoble Alpes,Team Environm Epidemiol Appl, Inst Natl Sante & Rech Med,Inst Albert Bonniot, F-38000 Grenoble, France. [Duijts, Liesbeth] Univ Med Ctr Rotterdam, Erasmus MC, Div Neonatol, Dept Pediat, NL-3000 CA Rotterdam, Netherlands. [Duijts, Liesbeth] Univ Med Ctr Rotterdam, Erasmus MC, Dept Pediat, Div Resp Med, NL-3000 CA Rotterdam, Netherlands. [Nilsen, Roy M.] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5018 Bergen, Norway. [Vaez, Ahmad] Isfahan Univ Med Sci, Sch Med, Esfahan 8174673461, Iran. [Litonjua, Augusto A.; DeMeo, Dawn L.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Fuemmeler, Bernard F.] Duke Univ, Sch Med, Dept Community & Family Med, Durham, NC 27710 USA. [Munthe-Kaas, Monica Cheng] Oslo Univ Hosp, Dept Pediat, N-424 Oslo, Norway. [Gehring, Ulrike; Brunekreef, Bert] Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands. [Bustamante, Mariona] Ctr Genom Regulat CRG, Barcelona 08003, Spain. [Saurel-Coubizolles, Marie Jose] INSERM, Epidemiol Res Unit Perinatal Hlth & Womens & Chil, F-75654 Paris, France. [Tost, Jorg] CEA, Inst Genom, Ctr Natl Genotypage, Lab Epigenet & Environm, F-91000 Evry, France. [Peters, Marjolein J.; van Meurs, Joyce B.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Haberg, Siri E.; Nystad, Wenche] Norwegian Inst Publ Hlth, Div Mental & Phys Hlth, N-0403 Oslo, Norway. [Feinberg, Andrew P.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Baccarelli, Andrea A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Herceg, Zdenko; Hernandez-Vargas, Hector; Ghantous, Akram] IARC, Epigenet Grp, F-69008 Lyon, France. [Brunekreef, Bert] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3508 TD Utrecht, Netherlands. [Pinart, Mariona; Anto, Josep M.; Sunyer, Jordi] Hosp Mar Med Res Inst IMIM, Barcelona 08003, Spain. [Heude, Barbara; Charles, Marie-Aline] Univ Paris 05, INSERM, UMR 1153,Ctr Rech Epidemiol & Stat Sorbonne Paris, Early Origin Childs Hlth & Dev ORCHAD Team, F-94807 Villejuif, France. [Ewart, Susan] Michigan State Univ, Dept Large Anim Clin Sci, E Lansing, MI 48824 USA. [Lemonnier, Nathanael; Auffray, Charles] Univ Lyon 1, Ctr Natl Rech Sci, Ecole Normale Super, European Inst Syst Biol & Med, F-69007 Lyon, France. [Wu, Michael C.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Hofman, Albert] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [McArdle, Wendy] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England. [Gillman, Matthew W.; Hivert, Marie-France] Harvard Univ, Sch Med, Dept Populat Med, Obes Prevent Program, Boston, MA 02215 USA. [Gillman, Matthew W.; Hivert, Marie-France] Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA. [Kumar, Ashish] Swiss Trop & Publ Hlth Inst, Unit Chron Dis Epidemiol, Dept Publ Hlth Epidemiol, CH-4051 Basel, Switzerland. [Kumar, Ashish] Univ Basel, CH-4001 Basel, Switzerland. [Wickman, Magnus; Melen, Erik] Stockholm Cty Council, Sachs Childrens Hosp, S-17177 Stockholm, Sweden. [Wickman, Magnus; Melen, Erik] Stockholm Cty Council, Ctr Occupat & Environm Med, S-17177 Stockholm, Sweden. [Holloway, John; Arshad, Hasan] Univ Southampton, Fac Med Clin & Expt Sci, Southampton SO16 6YD, Hants, England. [Holloway, John] Univ Southampton, Fac Med Human Dev & Hlth, Southampton SO16 6YD, Hants, England. [Murphy, Susan K.] Duke Univ, Sch Med, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Murphy, Susan K.] Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA. [Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Koppelman, Gerard H.] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergol, Beatrix Childrens Hosp, NL-9700 RB Groningen, Netherlands. RP London, SJ (reprint author), NIEHS, NIH, US Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM london2@niehs.nih.gov RI Pinart, Mariona/L-1931-2015; Anto, J/H-2676-2014; Annesi-Maesano, Isabella/D-9173-2016; Holloway, John/B-5424-2009; LEPEULE, Johanna/K-1085-2016; Gaunt, Tom/O-3918-2014; Heude, Barbara/G-3095-2016; Kere, Juha/A-9179-2008; Sunyer, J/G-6909-2014; Davey Smith, George/A-7407-2013; GHANTOUS, Akram/C-1689-2017; Vrijheid, M/H-2702-2014 OI Just, Allan/0000-0003-4312-5957; Dehghan, Abbas/0000-0001-6403-016X; London, Stephanie/0000-0003-4911-5290; Wu, Michael C./0000-0002-3357-6570; Ruiz Arenas, Carlos/0000-0002-6014-3498; Kumar, Ashish/0000-0002-7075-5930; Sharp, Gemma/0000-0003-2906-4035; Gruzieva, Olena/0000-0003-4147-5654; xu, zongli/0000-0002-9034-8902; BAIZ, Nour/0000-0001-6165-3935; Wilcox, Allen/0000-0002-3376-1311; taylor, jack/0000-0001-5303-6398; Salas, Lucas A/0000-0002-2279-4097; Kull, Inger/0000-0001-6096-3771; Pinart, Mariona/0000-0002-8223-1325; Anto, J/0000-0002-4736-8529; Holloway, John/0000-0001-9998-0464; Gaunt, Tom/0000-0003-0924-3247; Heude, Barbara/0000-0002-1565-1629; Kere, Juha/0000-0003-1974-0271; Sunyer, J/0000-0002-2602-4110; Davey Smith, George/0000-0002-1407-8314; GHANTOUS, Akram/0000-0002-2582-6402; Vrijheid, M/0000-0002-7090-1758 FU Medical Research Council [MC_PC_15018, MC_UU_12013/1, MC_UU_12013/2, MC_UU_12013/8]; NIDDK NIH HHS [R01 DK085173]; NIEHS NIH HHS [P30 ES007048, R01 ES016772, R21 ES014947]; Wellcome Trust [102215] NR 92 TC 41 Z9 41 U1 8 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD APR 7 PY 2016 VL 98 IS 4 BP 680 EP 696 DI 10.1016/j.ajhg.2016.02.019 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA DJ4UO UT WOS:000374203800007 PM 27040690 ER PT J AU Qin, HD Liao, XY Chen, YB Huang, SY Xue, WQ Li, FF Ge, XS Liu, DQ Cai, QY Long, JR Li, XZ Hu, YZ Zhang, SD Zhang, LJ Lehrman, B Scott, AF Lin, DX Zeng, YX Shugart, YY Jia, WH AF Qin, Hai-De Liao, Xiao-Yu Chen, Yuan-Bin Huang, Shao-Yi Xue, Wen-Qiong Li, Fang-Fang Ge, Xiao-Song Liu, De-Qing Cai, Qiuyin Long, Jirong Li, Xi-Zhao Hu, Ye-Zhu Zhang, Shao-Dan Zhang, Lan-Jun Lehrman, Benjamin Scott, Alan F. Lin, Dongxin Zeng, Yi-Xin Shugart, Yin Yao Jia, Wei-Hua TI Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HUMAN HEPATOCELLULAR-CARCINOMA; COPY-NUMBER ALTERATION; WIDE ASSOCIATION; CANCER-CELLS; FUNCTIONAL ANNOTATION; SUSCEPTIBILITY LOCI; TUMOR PROGRESSION; MICRORNA TARGETS; SEQUENCING DATA; KITENIN AB The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets. C1 [Qin, Hai-De; Liao, Xiao-Yu; Chen, Yuan-Bin; Huang, Shao-Yi; Xue, Wen-Qiong; Li, Fang-Fang; Ge, Xiao-Song; Liu, De-Qing; Li, Xi-Zhao; Hu, Ye-Zhu; Zhang, Shao-Dan; Zhang, Lan-Jun; Zeng, Yi-Xin; Jia, Wei-Hua] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. [Qin, Hai-De; Lehrman, Benjamin; Shugart, Yin Yao] NIMH, Unit Stat Genom, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Ge, Xiao-Song] Jiangnan Univ, Affiliated Hosp, Wuxi 214062, Peoples R China. [Cai, Qiuyin; Long, Jirong] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Ingram Canc Ctr, Nashville, TN 37240 USA. [Cai, Qiuyin; Long, Jirong] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37240 USA. [Scott, Alan F.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. [Lin, Dongxin] Chinese Acad Med Sci, State Key Lab Mol Oncol, Beijing 100021, Peoples R China. [Lin, Dongxin] Peking Union Med Coll, Beijing 100021, Peoples R China. RP Jia, WH (reprint author), Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China.; Shugart, YY (reprint author), NIMH, Unit Stat Genom, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. EM kay1yao@mail.nih.gov; jiawh@sysucc.org.cn FU National Science Fund for Distinguished Young Scholars of China [81325018]; Key Project for International Cooperation and Exchange of the National Natural Science Foundation of China [81220108022]; National Basic Research Program of China (973 program) [2011CB504303]; Intramural Research Program, National Institute of Mental Health (NIMH), NIH (IRP-NIMH-NIH) [MH002930-05] FX We'd like to thank Profs. Xiao-ou Shu and Wei Zheng of the Vanderbilt-Ingram Cancer Center for their kind advice in the course of sample preparation, exon capture, and deep sequencing. We thank Prof. Song Gao for his kind help in protein structure prediction. We also thank Bank of Tumor Resources, Cancer Center Sun Yat-sen University for providing the ESCC samples in this study. This work was supported by the grants from the National Science Fund for Distinguished Young Scholars of China (grant no. 81325018), the Key Project for International Cooperation and Exchange of the National Natural Science Foundation of China (grant no. 81220108022), the National Basic Research Program of China (973 program no. 2011CB504303). The authors gratefully acknowledge the support of the Intramural Research Program, National Institute of Mental Health (NIMH), NIH (IRP-NIMH-NIH, grant no. MH002930-05). The views expressed in this presentation do not necessarily represent the views of the the NIMH, the NIH, the US Department of Health and Human Services, or the United States Government. NR 59 TC 4 Z9 6 U1 4 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD APR 7 PY 2016 VL 98 IS 4 BP 709 EP 727 DI 10.1016/j.ajhg.2016.02.021 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA DJ4UO UT WOS:000374203800009 PM 27058444 ER PT J AU Leslie, EJ Liu, H Carlson, JC Shaffer, JR Feingold, E Wehby, G Laurie, CA Jain, D Laurie, CC Doheny, KF McHenry, T Resick, J Sanchez, C Jacobs, J Emanuele, B Vieira, AR Neiswanger, K Standley, J Czeize, AE Deleyiannis, F Christensen, K Munger, RG Lie, RT Wilcox, A Romitti, PA Field, LL Padilla, CD Cutiongco-de la Paz, EMC Lidral, AC Valencia-Ramirez, LC Lopez-Palacio, AM Valencia, DR Arcos-Burgos, M Castilla, EE Mereb, JC Poletta, FA Orioli, IM Carvalho, FM Hecht, JT Blanton, SH Buxo, CJ Butali, A Mossey, PA Adeyemo, WL James, O Braimah, RO Aregbesola, BS Eshete, MA Deribew, M Koruyucu, M Seymen, F Ma, L de Salamanca, JE Weinberg, SM Moreno, L Cornell, RA Murray, JC Marazita, ML AF Leslie, Elizabeth J. Liu, Huan Carlson, Jenna C. Shaffer, John R. Feingold, Eleanor Wehby, George Laurie, Cecelia A. Jain, Deepti Laurie, Cathy C. Doheny, Kimberly F. McHenry, Toby Resick, Judith Sanchez, Carla Jacobs, Jennifer Emanuele, Beth Vieira, Alexandre R. Neiswanger, Katherine Standley, Jennifer Czeize, Andrew E. Deleyiannis, Frederic Christensen, Kaare Munger, Ronald G. Lie, Rolv T. Wilcox, Allen Romitti, Paul A. Field, L. Leigh Padilla, Carmencita D. Cutiongco-de la Paz, Eva Maria C. Lidral, Andrew C. Valencia-Ramirez, Luz Consuelo Lopez-Palacio, Ana Maria Valencia, Dora Rivera Arcos-Burgos, Mauricio Castilla, Eduardo E. Mereb, Juan C. Poletta, Fernando A. Orioli, Ieda M. Carvalho, Flavia M. Hecht, Jacqueline T. Blanton, Susan H. Buxo, Carmen J. Butali, Azeez Mossey, Peter A. Adeyemo, Wasiu L. James, Olutayo Braimah, Ramat O. Aregbesola, Babatunde S. Eshete, Mekonen A. Deribew, Milliard Koruyucu, Mine Seymen, Figen Ma, Lian de Salamanca, Javier Enriquez Weinberg, Seth M. Moreno, Lina Cornell, Robert A. Murray, Jeffrey C. Marazita, Mary L. TI A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CAUSE VAN; LIP; RISK; LINKAGE; LOCI; MUTATIONS; DEFECTS; COHORT; GENES; WOUDE AB Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 x 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis. C1 [Leslie, Elizabeth J.; Carlson, Jenna C.; Shaffer, John R.; Feingold, Eleanor; McHenry, Toby; Resick, Judith; Sanchez, Carla; Jacobs, Jennifer; Emanuele, Beth; Vieira, Alexandre R.; Neiswanger, Katherine; Weinberg, Seth M.; Marazita, Mary L.] Univ Pittsburgh, Ctr Craniofacial & Dent Genet, Dept Oral Biol, Sch Dent Med, Pittsburgh, PA 15219 USA. [Liu, Huan; Cornell, Robert A.] Univ Iowa, Dept Anat & Cell Biol, Iowa City, IA 52242 USA. [Liu, Huan] Wuhan Univ, State Key Lab Breeding Base Basic Sci Stomatol Hu, Sch & Hosp Stomatol, Wuhan 430079, Peoples R China. [Liu, Huan] Wuhan Univ, Key Lab Oral Biomed, Minist Educ, Sch & Hosp Stomatol, Wuhan 430079, Peoples R China. [Carlson, Jenna C.; Feingold, Eleanor] Univ Pittsburgh, Depat Biostat, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Shaffer, John R.; Feingold, Eleanor; Vieira, Alexandre R.; Marazita, Mary L.] Univ Pittsburgh, Dept Human Genet, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Wehby, George] Univ Iowa, Dept Hlth Management & Policy, Coll Publ Hlth, Iowa City, IA 52246 USA. [Laurie, Cecelia A.; Jain, Deepti; Laurie, Cathy C.] Univ Washington, Dept Biostat, Genet Coordinating Ctr, Seattle, WA 98195 USA. [Doheny, Kimberly F.] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD 21224 USA. [Standley, Jennifer; Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Czeize, Andrew E.] Fdn Community Control Hereditary Dis, H-1051 Budapest, Hungary. [Deleyiannis, Frederic] Univ Colorado, Sch Med, Dept Surg Plast & Reconstruct Surg, Denver, CO 80045 USA. [Christensen, Kaare] Univ Southern Denmark, Dept Epidemiol, Inst Publ Hlth, DK-5230 Odense, Denmark. [Munger, Ronald G.] Utah State Univ, Dept Nutr Dietet & Food Sci, Logan, UT 84322 USA. [Lie, Rolv T.] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5020 Bergen, Norway. [Wilcox, Allen] NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Romitti, Paul A.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA 52246 USA. [Field, L. Leigh] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. [Padilla, Carmencita D.; Cutiongco-de la Paz, Eva Maria C.] Univ Philippines Manila, Inst Human Genet, Natl Inst Hlth, Manila 1000, Philippines. [Cutiongco-de la Paz, Eva Maria C.] Univ Philippines Manila, Dept Pediat, Coll Med, Manila 1000, Philippines. [Cutiongco-de la Paz, Eva Maria C.] Univ Philippines, Philippine Genome Ctr, Manila 1101, Philippines. [Lidral, Andrew C.; Moreno, Lina] Univ Iowa, Dept Orthodont, Coll Dent, Iowa City, IA 52242 USA. [Valencia-Ramirez, Luz Consuelo] Fdn Unica Noel, Medellin 050012, Colombia. [Lopez-Palacio, Ana Maria] Univ Antioquia, Dept Basic Integrated Studies, Coll Dent, Medellin 050001, Colombia. [Valencia, Dora Rivera] Univ Antioquia, Populat Genet & Mutacarcinogenesis Grp, Medellin 050001, Colombia. [Arcos-Burgos, Mauricio] Australian Natl Univ, Genom & Predict Med, Genome Biol Dept, John Curtin Sch Med Res,ANU Coll Med Biol & Envir, Canberra, ACT 0200, Australia. [Castilla, Eduardo E.; Poletta, Fernando A.; Carvalho, Flavia M.] CEMIC Ctr Med Educ & Clin Res, RA-1431 Buenos Aires, DF, Argentina. [Castilla, Eduardo E.; Poletta, Fernando A.; Carvalho, Flavia M.] Fiocruz MS, Lab Congenital Malformat Epidemiol, Inst Oswaldo Cruz, BR-21040360 Rio De Janeiro, Brazil. [Castilla, Eduardo E.; Poletta, Fernando A.; Orioli, Ieda M.] INAGEMP Natl Inst Populat Med Genet, ECLAMC Latin Amer Collaborat Study Congenital Mal, BR-21941617 Rio De Janeiro, Brazil. [Mereb, Juan C.] Hosp Area, ECLAMC Latin Amer Collaborat Study Congenital Mal, RA-8430 El Bolson, Argentina. [Orioli, Ieda M.] Univ Fed Rio de Janeiro, Dept Genet, Inst Biol, BR-21941617 Rio De Janeiro, Brazil. [Hecht, Jacqueline T.] Univ Texas Houston, Hlth Sci Ctr, Dept Pediat, Houston, TX 77030 USA. [Blanton, Susan H.] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Hussman Inst Human Gen,Mailman Sch Med, Miami, FL 33124 USA. [Buxo, Carmen J.] Univ Puerto Rico, Sch Dent Med, San Juan, PR 00936 USA. [Butali, Azeez] Univ Iowa, Dept Oral Pathol Radiol & Med, Dows Inst Dent Res, Coll Dent, Iowa City, IA 52242 USA. [Mossey, Peter A.] Univ Dundee, Dept Orthodont, Dundee DD1 4HN, Scotland. [Adeyemo, Wasiu L.; James, Olutayo] Univ Lagos, Dept Oral & Maxillofacial Surg, Coll Med, PMB 12003, Lagos, Nigeria. [Braimah, Ramat O.; Aregbesola, Babatunde S.] Obafemi Awolowo Univ Ile Ife, Dept Oral & Maxillofacial Surg, PMB 13, Ife, Nigeria. [Eshete, Mekonen A.; Deribew, Milliard] Univ Addis Ababa, Dept Surg, Sch Med, POB 26493, Addis Ababa, Ethiopia. [Koruyucu, Mine; Seymen, Figen] Istanbul Univ, Dept Pedodont, TR-34116 Istanbul, Turkey. [Ma, Lian] Peking Univ, Sch Stomatol, Beijing 100081, Peoples R China. [de Salamanca, Javier Enriquez] Univ Nino Jesus, Hosp Infantil, Unidad Cirugia Plast, Madrid 28009, Spain. [Marazita, Mary L.] Univ Pittsburgh, Sch Med, Clin & Translat Sci, Pittsburgh, PA 15213 USA. RP Marazita, ML (reprint author), Univ Pittsburgh, Ctr Craniofacial & Dent Genet, Dept Oral Biol, Sch Dent Med, Pittsburgh, PA 15219 USA.; Marazita, ML (reprint author), Univ Pittsburgh, Dept Human Genet, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA.; Marazita, ML (reprint author), Univ Pittsburgh, Sch Med, Clin & Translat Sci, Pittsburgh, PA 15213 USA. EM marazita@pitt.edu RI Christensen, Kaare/C-2360-2009; OI Christensen, Kaare/0000-0002-5429-5292; Wilcox, Allen/0000-0002-3376-1311 FU NIH [X01-HG007845, R01-DE016148, HHSN268201200008I, R01-DE020895, U01-DE018993] FX We dedicate this paper to the memory of our colleagues Dr. Andrew Czeizel and Dr. Juan C. Mereb; they will be missed. Many thanks to the participating families who made the studies summarized here possible and who provided on-going inspiration to the investigators. The tireless effort by the dedicated field staff and collaborators was similarly essential to the success of this study. This work was supported by grants from the NIH including X01-HG007845 and R01-DE016148 (to M.L.M.), and genotyping and data cleaning were provided via an NIH contract to the Johns Hopkins Center for Inherited Disease Research (HHSN268201200008I). The replication studies were funded by NIH grants R01-DE020895 (to G.L.W.) and U01-DE018993 to Dr. Tern Beaty at Johns Hopkins University School of Public Health. See the Supplemental Acknowledgments for additional grant support and full acknowledgments. NR 49 TC 6 Z9 6 U1 3 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD APR 7 PY 2016 VL 98 IS 4 BP 744 EP 754 DI 10.1016/j.ajhg.2016.02.014 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DJ4UO UT WOS:000374203800012 PM 27018472 ER PT J AU Baranello, L Wojtowicz, D Cui, KR Devaiah, BN Chung, HJ Chan-Salis, KY Guha, R Wilson, K Zhang, XH Zhang, HL Piotrowski, J Thomas, CJ Singer, DS Pugh, BF Pommier, Y Przytycka, TM Kouzine, F Lewis, BA Zhao, KJ Levens, D AF Baranello, Laura Wojtowicz, Damian Cui, Kairong Devaiah, Ballachanda N. Chung, Hye-Jung Chan-Salis, Ka Yim Guha, Rajarshi Wilson, Kelli Zhang, Xiaohu Zhang, Hongliang Piotrowski, Jason Thomas, Craig J. Singer, Dinah S. Pugh, B. Franklin Pommier, Yves Przytycka, Teresa M. Kouzine, Fedor Lewis, Brian A. Zhao, Keji Levens, David TI RNA Polymerase II Regulates Topoisomerase 1 Activity to Favor Efficient Transcription SO CELL LA English DT Article ID BROMODOMAIN PROTEIN BRD4; CARBOXY-TERMINAL DOMAIN; P-TEFB; IN-VIVO; DEPENDENT TRANSCRIPTION; SELECTIVE-INHIBITION; CLEAVAGE COMPLEXES; PAUSE RELEASE; GENOME-WIDE; CTD CODE AB We report a mechanism through which the transcription machinery directly controls topoisomerase 1 (TOP1) activity to adjust DNA topology throughout the transcription cycle. By comparing TOP1 occupancy using chromatin immunoprecipitation sequencing (ChIP-seq) versus TOP1 activity using topoisomerase 1 sequencing (TOP1-seq), a method reported here to map catalytically engaged TOP1, TOP1 bound at promoters was discovered to become fully active only after pause-release. This transition coupled the phosphorylation of the carboxyl-terminal-domain (CTD) of RNA polymerase II (RNAPII) with stimulation of TOP1 above its basal rate, enhancing its processivity. TOP1 stimulation is strongly dependent on the kinase activity of BRD4, a protein that phosphorylates Ser2-CTD and regulates RNAPII pause-release. Thus the coordinated action of BRD4 and TOP1 overcame the torsional stress opposing transcription as RNAPII commenced elongation but preserved negative supercoiling that assists promotermelting at start sites. This nexus between transcription and DNA topology promises to elicit new strategies to intercept pathological gene expression. C1 [Baranello, Laura; Chung, Hye-Jung; Kouzine, Fedor; Levens, David] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wojtowicz, Damian; Przytycka, Teresa M.] NCBI, Computat Biol Branch, NIH, Bethesda, MD 20892 USA. [Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Devaiah, Ballachanda N.; Singer, Dinah S.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Chan-Salis, Ka Yim; Pugh, B. Franklin] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Guha, Rajarshi; Wilson, Kelli; Zhang, Xiaohu; Thomas, Craig J.] NCATS, Div Preclin Innovat, NIH, Rockville, MD 20850 USA. [Zhang, Hongliang; Pommier, Yves] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Piotrowski, Jason; Lewis, Brian A.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Levens, D (reprint author), NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA.; Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov; levens@helix.nih.gov FU Intramural Research Program of the US NIH; Center for Cancer Research of the National Cancer Institute; National Heart, Lung and Blood Institute; National Library of Medicine FX Our research is supported by the Intramural Research Program of the US NIH, Center for Cancer Research of the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Library of Medicine. The ChIP-seq and RNA-seq libraries were sequenced by the NHLBI DNA Sequencing and Genomics Core Facility. NR 74 TC 12 Z9 12 U1 10 U2 29 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD APR 7 PY 2016 VL 165 IS 2 BP 357 EP 371 DI 10.1016/j.cell.2016.02.036 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DJ3RJ UT WOS:000374123000014 PM 27058666 ER PT J AU Bonsignori, M Zhou, TQ Sheng, ZZ Chen, L Gao, F Joyce, MG Ozorowski, G Chuang, GY Schramm, CA Wiehe, K Alam, SM Bradley, T Gladden, MA Hwang, KK Iyengar, S Kumar, A Lu, XZ Luo, K Mangiapani, MC Parks, RJ Song, HS Acharya, P Bailer, RT Cao, A Druz, A Georgiev, IS Kwon, YD Louder, MK Zhang, BS Zheng, AQ Hill, BJ Kong, R Soto, C Mullikin, JC Douek, DC Montefiori, DC Moody, MA Shaw, GM Hahn, BH Kelsoe, G Hraber, PT Korber, BT Boyd, SD Fire, AZ Kepler, TB Shapiro, L Ward, AB Mascola, JR Liao, HX Kwong, PD Haynes, BF AF Bonsignori, Mattia Zhou, Tongqing Sheng, Zizhang Chen, Lei Gao, Feng Joyce, M. Gordon Ozorowski, Gabriel Chuang, Gwo-Yu Schramm, Chaim A. Wiehe, Kevin Alam, S. Munir Bradley, Todd Gladden, Morgan A. Hwang, Kwan-Ki Iyengar, Sheelah Kumar, Amit Lu, Xiaozhi Luo, Kan Mangiapani, Michael C. Parks, Robert J. Song, Hongshuo Acharya, Priyamvada Bailer, Robert T. Cao, Allen Druz, Aliaksandr Georgiev, Ivelin S. Kwon, Young D. Louder, Mark K. Zhang, Baoshan Zheng, Anqi Hill, Brenna J. Kong, Rui Soto, Cinque Mullikin, James C. Douek, Daniel C. Montefiori, David C. Moody, Michael A. Shaw, George M. Hahn, Beatrice H. Kelsoe, Garnett Hraber, Peter T. Korber, Bette T. Boyd, Scott D. Fire, Andrew Z. Kepler, Thomas B. Shapiro, Lawrence Ward, Andrew B. Mascola, John R. Liao, Hua-Xin Kwong, Peter D. Haynes, Barton F. CA NISC Comparative Sequencing Progra TI Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody SO CELL LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; B-CELL RECEPTORS; VACCINE DEVELOPMENT; IMMUNOGEN DESIGN; FOUNDER VIRUS; AUTOREACTIVITY; INFECTION; INDUCTION; MEMBRANE; BINDING AB Antibodies with ontogenies from V(H)1-2 or V(H)1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a V(H)1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the V(H)1-46 gene, which closely resembled V(H)1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages. C1 [Bonsignori, Mattia; Gao, Feng; Wiehe, Kevin; Alam, S. Munir; Bradley, Todd; Gladden, Morgan A.; Hwang, Kwan-Ki; Iyengar, Sheelah; Kumar, Amit; Lu, Xiaozhi; Luo, Kan; Mangiapani, Michael C.; Parks, Robert J.; Song, Hongshuo; Montefiori, David C.; Moody, Michael A.; Kelsoe, Garnett; Liao, Hua-Xin; Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Bonsignori, Mattia; Gao, Feng; Wiehe, Kevin; Alam, S. Munir; Liao, Hua-Xin; Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. [Zhou, Tongqing; Chen, Lei; Joyce, M. Gordon; Chuang, Gwo-Yu; Acharya, Priyamvada; Bailer, Robert T.; Cao, Allen; Druz, Aliaksandr; Georgiev, Ivelin S.; Kwon, Young D.; Louder, Mark K.; Zhang, Baoshan; Zheng, Anqi; Hill, Brenna J.; Kong, Rui; Soto, Cinque; Douek, Daniel C.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Sheng, Zizhang; Schramm, Chaim A.; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Sheng, Zizhang; Schramm, Chaim A.; Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA. [Ozorowski, Gabriel; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Ozorowski, Gabriel; Ward, Andrew B.] Scripps Res Inst, CAVD, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Ozorowski, Gabriel; Ward, Andrew B.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Dept Elect Engn & Comp Sci, Nashville, TN 37232 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN 37232 USA. [Mullikin, James C.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Montefiori, David C.] Duke Univ, Sch Med, Dept Surg, Durham, NC 27710 USA. [Montefiori, David C.; Moody, Michael A.] Duke Univ, Sch Med, Dept Pediat, Durham, NC 27710 USA. [Montefiori, David C.; Moody, Michael A.; Kelsoe, Garnett; Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Durham, NC 27710 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Hraber, Peter T.; Korber, Bette T.] Los Alamos Natl Lab, POB 1663, Los Alamos, NM 87544 USA. [Boyd, Scott D.; Fire, Andrew Z.] Stanford Sch Med, Dept Pathol, Palo Alto, CA 94305 USA. [Kepler, Thomas B.] Boston Univ, Dept Microbiol, Boston, MA 02118 USA. [Kepler, Thomas B.] Boston Univ, Dept Math & Stat, Boston, MA 02118 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Duke Global Hlth Inst, Durham, NC 27710 USA. RP Haynes, BF (reprint author), Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA.; Haynes, BF (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA.; Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA.; Haynes, BF (reprint author), Duke Univ, Sch Med, Dept Immunol, Durham, NC 27710 USA.; Haynes, BF (reprint author), Duke Univ, Sch Med, Duke Global Hlth Inst, Durham, NC 27710 USA. EM pdkwong@nih.gov; barton.haynes@duke.edu RI Ward, Andrew/F-9203-2014; Zhou, Tongqing/A-6880-2010; Kwon, Young Do/A-6957-2010; OI Ward, Andrew/0000-0001-7153-3769; Zhou, Tongqing/0000-0002-3935-4637; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU Division of AIDS, NIAID, NIH Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery [UM1 AI100645]; Scripps CHAVI-ID [UM1 AI100663]; International AIDS Vaccine Initiative; Bill and Melinda Gates Foundation; Intramural Research Program of the Vaccine Research Center, NIAID, NIH; NIH [P01-AI104722]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX The authors thank K. Lloyd, A. Eaton, T. Von Holle, T. Gurley, L. Armand, D. Kozink, A. Cooper, F. Perrin, J. Pritchett, A. Foulger, G. Hernandez, S. Arora, R. Kauffman, A. Trama of the Duke Human Vaccine Institute, J. Whitesides, D. Marshall and the DHVI Flow Cytometry Core for technical assistance, and K. Soderberg for project coordination; members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript; J. Baalwa, D. Ellenberger, K. Hong, J. Kim, F. McCutchan, L. Morris, J. Overbaugh, E. Sanders-Buell, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson, and L. Zhang for contributing HIV-1 Envelope plasmids. The authors also thank Gift Kamanga, Michael S. Cohen, and the CHAVI clinical team for clinical trial participant recruitment and sample provision. Supported by a grant from the Division of AIDS, NIAID, NIH Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery UM1 AI100645 (Duke CHAVI-ID), the Scripps CHAVI-ID (UM1 AI100663), the International AIDS Vaccine Initiative, and the Bill and Melinda Gates Foundation (CAVD) to A.B.W. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH, and by NIH grant P01-AI104722. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science (contract W-31-109-Eng-38). M.B., P.T.H., B.T.K., H.-X.L. and B.F.H. have filed patent applications directed to antibodies and use of various envelopes as immunogens. None of the authors declared conflicts of interest. NR 44 TC 35 Z9 35 U1 4 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD APR 7 PY 2016 VL 165 IS 2 BP 449 EP 463 DI 10.1016/j.cell.2016.02.022 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DJ3RJ UT WOS:000374123000022 PM 26949186 ER PT J AU Goncalves, BP Prevots, DR Kabyemela, E Fried, M Duffy, PE AF Goncalves, Bronner P. Prevots, D. Rebecca Kabyemela, Edward Fried, Michal Duffy, Patrick E. TI Preparing for future efficacy trials of severe malaria vaccines SO VACCINE LA English DT Article DE Severe malaria; Vaccine; Clinical trial; Immunity; Sample size ID PLASMODIUM-FALCIPARUM MALARIA; TRANSMISSION; CHILDREN; AFRICA; MORBIDITY AB Severe malaria is a major cause of mortality in children, but comprises only a small proportion of Plasmodium falciparum infections in naturally exposed populations. The evaluation of vaccines that prevent severe falciparum disease will require clinical trials whose primary efficacy endpoint will be severe malaria risk during follow-up. Here, we show that such trials are feasible with fewer than 1000 participants in areas with intense malaria transmission during the age interval when severe malaria incidence peaks. Published by Elsevier Ltd. C1 [Goncalves, Bronner P.; Fried, Michal; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Goncalves, Bronner P.; Prevots, D. Rebecca] NIAID, Lab Clin Infect Dis, Epidemiol Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kabyemela, Edward; Fried, Michal; Duffy, Patrick E.] Ctr Infect Dis Res, MOMS Project, Seattle, WA USA. [Kabyemela, Edward; Fried, Michal; Duffy, Patrick E.] Muheza Designated Dist Hosp, Muheza, Tanzania. RP Duffy, PE (reprint author), NIAID, NIH, Lab Malaria Immunol & Vaccinol, Twinbrook 1,Rm 1111,5640 Fishers Ln, Rockville, MD 20852 USA. EM Patrick.duffy@mail.nih.gov FU National Institute of Allergy and Infectious Diseases, NIH [R01AI52059]; Bill & Melinda Gates Foundation [29202]; Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative [1364]; US National Institutes of Health Fogarty International Center (FIC) [D43 TW005509] FX This work was supported by the Division of Intramural Research (DIR) and the extramural program [grant R01AI52059] of the National Institute of Allergy and Infectious Diseases, NIH; the Bill & Melinda Gates Foundation [grant 29202]; the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative [grant 1364]; the US National Institutes of Health Fogarty International Center (FIC) [grant D43 TW005509]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD APR 7 PY 2016 VL 34 IS 16 BP 1865 EP 1867 DI 10.1016/j.vaccine.2016.02.053 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DJ4SO UT WOS:000374198500002 PM 26923455 ER PT J AU Kumar, S Rajagopalan, S Sarkar, P Dorward, DW Peterson, ME Liao, HS Guillermier, C Steinhauser, ML Vogel, SS Long, EO AF Kumar, Santosh Rajagopalan, Sumati Sarkar, Pabak Dorward, David W. Peterson, Mary E. Liao, Hsien-Shun Guillermier, Christelle Steinhauser, Matthew L. Vogel, Steven S. Long, Eric O. TI Zinc-Induced Polymerization of Killer-Cell Ig-like Receptor into Filaments Promotes Its Inhibitory Function at Cytotoxic Immunological Synapses SO MOLECULAR CELL LA English DT Article ID NK CELLS; SELF-ASSOCIATION; ACTIVATION; INNATE; PROTEIN; RECRUITMENT; MECHANISM; PARADIGM; IMMUNITY; DISEASE AB The inhibitory function of killer cell immunoglobulin-like receptors (KIR) that bind HLA-C and block activation of human natural killer (NK) cells is dependent on zinc. We report that zinc induced the assembly of soluble KIR into filamentous polymers, as detected by electron microscopy, which depolymerized after zinc chelation. Similar KIR filaments were isolated from lysates of cells treated with zinc, and membrane protrusions enriched in zinc were detected on whole cells by scanning electron microscopy and imaging mass spectrometry. Two independent mutations in the extracellular domain of KIR, away from the HLA-C binding site, impaired zinc-driven polymerization and inhibitory function. KIR filaments formed spontaneously, without the addition of zinc, at functional inhibitory immunological synapses of NK cells with HLA-C+ cells. Adding to the recent paradigm of signal transduction through higher order molecular assemblies, zinc-induced polymerization of inhibitory KIR represents an unusual mode of signaling by a receptor at the cell surface. C1 [Kumar, Santosh; Rajagopalan, Sumati; Peterson, Mary E.; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Sarkar, Pabak; Vogel, Steven S.] NIAAA, Lab Mol Physiol, NIH, Rockville, MD 20852 USA. [Dorward, David W.] NIAID, Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Liao, Hsien-Shun] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Guillermier, Christelle; Steinhauser, Matthew L.] Brigham & Womens Hosp, Ctr NanoImaging, Cambridge, MA 02138 USA. [Guillermier, Christelle; Steinhauser, Matthew L.] Brigham & Womens Hosp, Div Genet, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Guillermier, Christelle; Steinhauser, Matthew L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Liao, Hsien-Shun] Natl Taiwan Univ, Dept Mech Engn, Taipei 10617, Taiwan. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM elong@nih.gov FU National Institute of Allergy and Infectious Diseases; National Institute on Alcohol Abuse and Alcoholism; National Institute of Biomedical Imaging and Bioengineering; NIH [K08DK090147, RO3DK106477] FX We thank David Narum and Karine Reiter for assistance with circular dichroism and Shailesh Kumar for amyloid fibrils of Ure-2. HLA-C*0401 tetramer was made at the NIH Tetramer Core Facility. This work was supported by the Intramural Research Programs at the National Institute of Allergy and Infectious Diseases (to E.O.L.), National Institute on Alcohol Abuse and Alcoholism (to S.S.V.), and National Institute of Biomedical Imaging and Bioengineering (to H.-S.L.), NIH, and by NIH grants K08DK090147 and RO3DK106477 (to M.L.S.). NR 43 TC 0 Z9 0 U1 3 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD APR 7 PY 2016 VL 62 IS 1 BP 21 EP 33 DI 10.1016/j.molcel.2016.03.009 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DJ3QB UT WOS:000374119600005 PM 27058785 ER PT J AU Roma, EH Macedo, JP Goes, GR Goncalves, JL de Castro, W Cisalpino, D Vieira, LQ AF Roma, Eric Henrique Macedo, Juan Pereira Goes, Grazielle Ribeiro Goncalves, Juliana Lauar de Castro, Waldione Cisalpino, Daniel Vieira, Leda Quercia TI Impact of reactive oxygen species (ROS) on the control of parasite loads and inflammation in Leishmania amazonensis infection SO PARASITES & VECTORS LA English DT Article DE Leishmania amazonensis; ROS; NOX2; Neutrophils; Inflammation ID CHRONIC GRANULOMATOUS-DISEASE; PHAGOCYTE NADPH OXIDASE; MURINE CUTANEOUS LEISHMANIASIS; DEPENDENT KILLING MECHANISM; NECROSIS-FACTOR-ALPHA; CD4(+) T-CELLS; NITRIC-OXIDE; IN-VIVO; NEUTROPHIL APOPTOSIS; INTERFERON-GAMMA AB Background: Reactive oxygen species (ROS) protect the host against a large number of pathogenic microorganisms. ROS have different effects on parasites of the genus Leishmania: some parasites are susceptible to their action, while others seem to be resistant. The role of ROS in L. amazonensis infection in vivo has not been addressed to date. Methods: In this study, C57BL/6 wild-type mice (WT) and mice genetically deficient in ROS production by phagocytes (gp91(phox-/-)) were infected with metacyclic promastigotes of L. amazonensis to address the effect of ROS in parasite control. Inflammatory cytokines, parasite loads and myeloperoxidase (MPO) activity were evaluated. In parallel, in vitro infection of peritoneal macrophages was assessed to determine parasite killing, cytokine, NO and ROS production. Results: In vitro results show induction of ROS production by infected peritoneal macrophages, but no effect in parasite killing. Also, ROS do not seem to be important to parasite killing in vivo, but they control lesion sizes at early stages of infection. IFN-gamma, TNF-alpha and IL-10 production did not differ among mouse strains. Myeloperoxidase assay showed augmented neutrophils influx 6 h and 72 h post-infection in gp91(phox-/-) mice, indicating a larger inflammatory response in gp91(phox-/-) even at early time points. At later time points, neutrophil numbers in lesions correlated with lesion size: larger lesions in gp91(phox-/-) at earlier times of infection corresponded to larger neutrophil infiltrates, while larger lesions in WT mice at the later points of infection also displayed larger numbers of neutrophils. Conclusion: ROS do not seem to be important in L. amazonensis killing, but they regulate the inflammatory response probably by controlling neutrophils numbers in lesions. C1 [Roma, Eric Henrique; Macedo, Juan Pereira; Goes, Grazielle Ribeiro; Goncalves, Juliana Lauar; de Castro, Waldione; Vieira, Leda Quercia] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil. [Cisalpino, Daniel] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Microbiol, Belo Horizonte, MG, Brazil. [Roma, Eric Henrique; Goncalves, Juliana Lauar] Fiocruz MS, Inst Nacl Infectol, BR-21045900 Rio De Janeiro, RJ, Brazil. [de Castro, Waldione] NIAID, Lab Malaria & Vector Res, Vector Mol Biol Sect, NIH, Rockville, MD USA. RP Vieira, LQ (reprint author), Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil. EM lqvieira@icb.ufmg.br RI Macedo, Juan/B-4151-2017; OI Macedo, Juan/0000-0001-5759-1196; Roma, Eric /0000-0001-5265-5277 FU Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [CDS-RED-00013-14, APQ-02308-13, APQ-01419-14] FX EHR, GRG, JLG, DC and LQV are CNPq fellows. JPM was a CAPES fellow. This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG, CDS-RED-00013-14, APQ-02308-13 and APQ-01419-14). The authors are members of the INCT de Processos Redox em Biomedicina-Redoxoma (FAPESP/CNPq/CAPES, proc 573530/2008-4). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 2 Z9 2 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD APR 7 PY 2016 VL 9 AR 193 DI 10.1186/s13071-016-1472-y PG 13 WC Parasitology SC Parasitology GA DJ3WB UT WOS:000374136300001 PM 27056545 ER PT J AU Kobayashi, W Takaku, M Machida, S Tachiwana, H Maehara, K Ohkawa, Y Kurumizaka, H AF Kobayashi, Wataru Takaku, Motoki Machida, Shinichi Tachiwana, Hiroaki Maehara, Kazumitsu Ohkawa, Yasuyuki Kurumizaka, Hitoshi TI Chromatin architecture may dictate the target site for DMC1, but not for RAD51, during homologous pairing SO SCIENTIFIC REPORTS LA English DT Article ID DOUBLE-STRAND BREAK; MEIOTIC RECOMBINATION INITIATION; SYNAPTONEMAL COMPLEX-FORMATION; ESCHERICHIA-COLI RECA; SACCHAROMYCES-CEREVISIAE; CHROMOSOME SYNAPSIS; YEAST MEIOSIS; PHD FINGER; HOT-SPOT; DNA AB In eukaryotes, genomic DNA is compacted as chromatin, in which histones and DNA form the nucleosome as the basic unit. DMC1 and RAD51 are essential eukaryotic recombinases that mediate homologous chromosome pairing during homologous recombination. However, the means by which these two recombinases distinctly function in chromatin have remained elusive. Here we found that, in chromatin, the human DMC1-single-stranded DNA complex bypasses binding to the nucleosome, and preferentially promotes homologous pairing at the nucleosome-depleted regions. Consistently, DMC1 forms ternary complex recombination intermediates with the nucleosome-free DNA or the nucleosome-depleted DNA region. Surprisingly, removal of the histone tails improperly enhances the nucleosome binding by DMC1. In contrast, RAD51 does not specifically target the nucleosome-depleted region in chromatin. These are the first demonstrations that the chromatin architecture specifies the sites to promote the homologous recombination reaction by DMC1, but not by RAD51. C1 [Kobayashi, Wataru; Takaku, Motoki; Machida, Shinichi; Tachiwana, Hiroaki; Kurumizaka, Hitoshi] Waseda Univ, Grad Sch Adv Sci & Engn, Struct Biol Lab, Shinjuku Ku, 2-2 Wakamatsu Cho, Tokyo 1628480, Japan. [Maehara, Kazumitsu; Ohkawa, Yasuyuki] Kyushu Univ, Med Inst Bioregulat, Div Transcript, Fukuoka 8128582, Japan. [Kurumizaka, Hitoshi] Waseda Univ, Inst Med Oriented Struct Biol, Shinjuku Ku, 2-2 Wakamatsu Cho, Tokyo 1628480, Japan. [Takaku, Motoki] NIEHS, Epigenet & Stem Cell Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RP Kurumizaka, H (reprint author), Waseda Univ, Grad Sch Adv Sci & Engn, Struct Biol Lab, Shinjuku Ku, 2-2 Wakamatsu Cho, Tokyo 1628480, Japan.; Kurumizaka, H (reprint author), Waseda Univ, Inst Med Oriented Struct Biol, Shinjuku Ku, 2-2 Wakamatsu Cho, Tokyo 1628480, Japan. EM kurumizaka@waseda.jp RI Ohkawa, Yasuyuki/C-4087-2016 OI Ohkawa, Yasuyuki/0000-0001-6440-9954 FU MEXT KAKENHI [25116002, 25131706]; JSPS KAKENHI [25250023, 26890023]; Platform for Drug Discovery, Informatics, and Structural Life Science from MEXT, Japan; Waseda Research Institute for Science and Engineering; Waseda University; Japan Society for the Promotion of Science for Young Scientists FX We thank Dr. Craig L. Peterson for providing the plasmid DNA containing the tandem 5S DNA arrays. We also thank Mr. A. Esaki (Waseda University) for his contribution in the initial stage of this project. This work was supported in part by MEXT KAKENHI Grant Numbers 25116002 [to H.K.] and 25131706 [to Y.O.], JSPS KAKENHI Grant Numbers 25250023 [to H.K.] and 26890023 [to S.M.], and the Platform for Drug Discovery, Informatics, and Structural Life Science from MEXT, Japan [to H.K.]. H.K. was also supported by the Waseda Research Institute for Science and Engineering and Waseda University. W.K. was supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists. NR 62 TC 0 Z9 0 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 7 PY 2016 VL 6 AR 24228 DI 10.1038/srep24228 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI5ZZ UT WOS:000373580300001 PM 27052786 ER PT J AU Collins, PY Saxena, S AF Collins, Pamela Y. Saxena, Shekhar TI Action on mental health needs global cooperation SO NATURE LA English DT Editorial Material ID DISORDERS; COUNTRIES C1 [Collins, Pamela Y.] US Natl Inst Mental Hlth, Off Res Dispar & Global Mental Hlth, Bethesda, MD USA. [Saxena, Shekhar] WHO, Dept Mental Hlth & Subst Abuse, CH-1211 Geneva, Switzerland. RP Collins, PY (reprint author), US Natl Inst Mental Hlth, Off Res Dispar & Global Mental Hlth, Bethesda, MD USA.; Saxena, S (reprint author), WHO, Dept Mental Hlth & Subst Abuse, CH-1211 Geneva, Switzerland. EM pamela.collins@nih.gov; saxenas@who.int FU World Health Organization [001] NR 7 TC 7 Z9 7 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD APR 7 PY 2016 VL 532 IS 7597 BP 25 EP 27 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI5RE UT WOS:000373555500013 PM 27078549 ER PT J AU Gyamfi-Bannerman, C Thom, EA Blackwell, SC Tita, ATN Reddy, UM Saade, GR Rouse, DJ McKenna, DS Clark, EAS Thorp, JM Chien, EK Peaceman, AM Gibbs, RS Swamy, GK Norton, ME Casey, BM Caritis, SN Tolosa, JE Sorokin, Y VanDorsten, JP Jain, L AF Gyamfi-Bannerman, C. Thom, E. A. Blackwell, S. C. Tita, A. T. N. Reddy, U. M. Saade, G. R. Rouse, D. J. McKenna, D. S. Clark, E. A. S. Thorp, J. M., Jr. Chien, E. K. Peaceman, A. M. Gibbs, R. S. Swamy, G. K. Norton, M. E. Casey, B. M. Caritis, S. N. Tolosa, J. E. Sorokin, Y. VanDorsten, J. P. Jain, L. CA NICHD Maternal-Fetal Med Units Net TI Antenatal Betamethasone for Women at Risk for Late Preterm Delivery SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FETAL LUNG MATURATION; RESPIRATORY-DISTRESS; INFANTS; CORTICOSTEROIDS; TRIAL; BIRTH; TERM; MORBIDITY; OUTCOMES AB BACKGROUND Infants who are born at 34 to 36 weeks of gestation (late preterm) are at greater risk for adverse respiratory and other outcomes than those born at 37 weeks of gestation or later. It is not known whether betamethasone administered to women at risk for late preterm delivery decreases the risks of neonatal morbidities. METHODS We conducted a multicenter, randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days). The participants were assigned to receive two injections of betamethasone or matching placebo 24 hours apart. The primary outcome was a neonatal composite of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery. RESULTS The primary outcome occurred in 165 of 1427 infants (11.6%) in the betamethasone group and 202 of 1400 (14.4%) in the placebo group (relative risk in the betamethasone group, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P = 0.02). Severe respiratory complications, transient tachypnea of the newborn, surfactant use, and bronchopulmonary dysplasia also occurred significantly less frequently in the betamethasone group. There were no significant between-group differences in the incidence of chorioamnionitis or neonatal sepsis. Neonatal hypoglycemia was more common in the betamethasone group than in the placebo group (24.0% vs. 15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001). CONCLUSIONS Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications.(Funded by the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01222247.) C1 [Gyamfi-Bannerman, C.] Columbia Univ, 622 W 168th St,PH-16, New York, NY 10032 USA. [Thom, E. A.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Blackwell, S. C.] 3niv Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. [Saade, G. R.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Casey, B. M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Tita, A. T. N.] Univ Alabama Birmingham, Birmingham, AL USA. [Reddy, U. M.] Kennedy Shriver Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. [Rouse, D. J.] Brown Univ, Providence, RI 02912 USA. [McKenna, D. S.] Ohio State Univ, Columbus, OH 43210 USA. [Chien, E. K.] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Clark, E. A. S.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Thorp, J. M., Jr.] Univ N Carolina, Chapel Hill, NC USA. [Swamy, G. K.] Duke Univ, Durham, NC USA. [Peaceman, A. M.] Northwestern Univ, Chicago, IL USA. [Gibbs, R. S.] Univ Colorado, Sch Med, Anschutz Med Campus, Aurora, CO USA. [Norton, M. E.] Stanford Univ, Stanford, CA 94305 USA. [Caritis, S. N.] Univ Pittsburgh, Pittsburgh, PA USA. [Tolosa, J. E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Sorokin, Y.] Wayne State Univ, Detroit, MI USA. [VanDorsten, J. P.] Med Univ S Carolina, Charleston, SC USA. [Jain, L.] Emory Univ, Atlanta, GA 30322 USA. RP Gyamfi-Bannerman, C (reprint author), Columbia Univ, Med Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, 622 W 168th St,PH-16, New York, NY 10032 USA. EM cg2231@cumc.columbia.edu FU NHLBI [HL098554, HL098354]; NICHD [HD21410, HD27915, HD27917, HD27869, HD34116, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, HD68268, HD68258, HD68282, HD36801]; National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000040] FX Supported by grants (HL098554 and HL098354) from the NHLBI, by grants (HD21410, HD27915, HD27917, HD27869, HD34116, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, HD68268, HD68258, HD68282, and HD36801) from the NICHD, and by a grant (UL1 TR000040) from the National Center for Advancing Translational Sciences, National Institutes of Health. NR 20 TC 28 Z9 28 U1 5 U2 12 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 7 PY 2016 VL 374 IS 14 BP 1311 EP 1320 DI 10.1056/NEJMoa1516783 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DI3UW UT WOS:000373425000005 PM 26842679 ER PT J AU Kernan, WN Viscoli, CM Furie, KL Young, LH Inzucchi, SE Gorman, M Guarino, PD Lovejoy, AM Peduzzi, PN Conwit, R Brass, LM Schwartz, GG Adams, HP Berger, L Carolei, A Clark, W Coull, B Ford, GA Kleindorfer, D O'Leary, JR Parsons, MW Ringleb, P Sen, S Spence, JD Tanne, D Wang, D Winder, TR AF Kernan, W. N. Viscoli, C. M. Furie, K. L. Young, L. H. Inzucchi, S. E. Gorman, M. Guarino, P. D. Lovejoy, A. M. Peduzzi, P. N. Conwit, R. Brass, L. M. Schwartz, G. G. Adams, H. P., Jr. Berger, L. Carolei, A. Clark, W. Coull, B. Ford, G. A. Kleindorfer, D. O'Leary, J. R. Parsons, M. W. Ringleb, P. Sen, S. Spence, J. D. Tanne, D. Wang, D. Winder, T. R. CA IRIS Trial Investigators TI Pioglitazone after Ischemic Stroke or Transient Ischemic Attack SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR RISK-FACTORS; IMPAIRED GLUCOSE-TOLERANCE; HEALTH-CARE PROFESSIONALS; INSULIN-RESISTANCE; NONDIABETIC PATIENTS; BLADDER-CANCER; MACROVASCULAR EVENTS; SECONDARY PREVENTION; DIABETIC-PATIENTS AB BACKGROUND Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. METHODS In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. RESULTS By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P = 0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P = 0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P = 0.003). CONCLUSIONS In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.) C1 [Kernan, W. N.; Viscoli, C. M.; Young, L. H.; Inzucchi, S. E.; Lovejoy, A. M.; Brass, L. M.; O'Leary, J. R.] Yale Univ, Sch Med, New Haven, CT USA. [Guarino, P. D.; Peduzzi, P. N.; O'Leary, J. R.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Guarino, P. D.; Peduzzi, P. N.] Connecticut HealthCare Syst, Cooperat Studies Program Coordinating Ctr, VA, West Haven, CT USA. [Furie, K. L.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Gorman, M.] Vermont Coll Med, Burlington, VT USA. [Conwit, R.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Schwartz, G. G.] VA Med Ctr, Denver, CO USA. [Schwartz, G. G.] Univ Colorado, Sch Med, Denver, CO USA. [Adams, H. P., Jr.] Univ Iowa, Iowa City, IA USA. [Berger, L.] Hop Charles LeMoyne, Greenfield Pk, IN USA. [Spence, J. D.] Univ Western Ontario, London, ON N6A 3K7, Canada. [Winder, T. R.] Ctr Neurol Res, Lethbridge, AB, Canada. [Carolei, A.] Univ Aquila, I-67100 Laquila, Italy. [Clark, W.] Oregon Hlth & Sci Univ, Portland, OR USA. [Coull, B.] Univ Arizona, Tucson, AZ USA. [Ford, G. A.] Univ Oxford, Oxford OX1 2JD, Oxon, England. [Ford, G. A.] Oxford Univ Hosp NHS Fdn Trust, Oxford, Oxon, England. [Kleindorfer, D.] Univ Cincinnati, Cincinnati, OH USA. [Parsons, M. W.] Univ Newcastle, John Hunter Hosp, New Lambton Hts, NSW, Australia. [Ringleb, P.] Heidelberg Univ, Heidelberg, Germany. [Sen, S.] Univ S Carolina, Sch Med, Columbia, SC 29208 USA. [Tanne, D.] Tel Aviv Univ, Sheba Med Ctr, IL-69978 Tel Aviv, Israel. [Wang, D.] Univ Illinois, Coll Med, OSF St Francis Med Ctr, Illinois Neurol Inst, Peoria, IL 61656 USA. [Wang, D.] Univ Illinois, Coll Med, Dept Neurol, Peoria, IL 61656 USA. RP Kernan, WN (reprint author), 2 Church St S,Suite 515, New Haven, CT 06519 USA. EM walter.kernan@yale.edu RI Spence, J. David/K-6396-2013; OI Strain, William/0000-0002-6826-418X; Spence, J. David/0000-0001-7478-1098; Groschel, Klaus/0000-0002-0244-6116 FU National Institute of Neurological Disorders and Stroke [U01NS044876]; Merck; Mifcor; Janssen; Sanofi; Poxel; Boehringer Ingelheim; Eli Lilly; AstraZeneca; Novo Nordisk; Intarcia; Lexicon; Abbott; Millennium; Cerenis; Roche; Resverlogix; Medicines Company; Lundbeck; Cerevast; Pfizer; Athersys; Daiichi Sankyo; Covidien; Bayer; Bristol-Myers Squibb FX Supported by a grant (U01NS044876) from the National Institute of Neurological Disorders and Stroke. Pioglitazone and placebo were provided by Takeda Pharmaceuticals International.; Dr. Young reports receiving grant support through his institution from Merck and Mifcor; Dr. Inzucchi, receiving fees for serving on advisory boards from Merck, Janssen, Sanofi, Poxel, Boehringer Ingelheim, Eli Lilly, and AstraZeneca, fees for serving on a data monitoring committee from Novo Nordisk and Intarcia, and fees for serving on a steering committee from Lexicon, serving as an expert witness on behalf of Takeda in a patent litigation deposition, and participating in projects for which funding for continuing medical education has been provided to Yale University by Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbott, Merck, and Sanofi; Dr. Peduzzi, receiving consulting fees from Millennium; Dr. Schwartz, receiving grant support from Cerenis, Roche, Resverlogix, Sanofi, and the Medicines Company; Dr. Ford, receiving fees for serving on a trial steering committee from Lundbeck, fees for serving on a data safety monitoring board from Cerevast, fees for serving on advisory boards from Pfizer, Athersys, and Daiichi Sankyo, consulting fees from Pfizer, and lecture fees and travel support from AstraZeneca and Boehringer Ingelheim; Dr. Ringleb, receiving fees for serving on advisory boards from Boehringer Ingelheim, Covidien, Bayer, and Daiichi Sankyo and lecture fees and travel support from Boehringer Ingelheim, Bayer, and Daiichi Sankyo; Dr. Spence, receiving consulting and lecture fees from Bayer and Bristol-Myers Squibb, serving as an officer of and having an equity interest in Vascularis, and performing contract research for Bayer, Bristol-Myers Squibb, Pfizer, Acasti Pharma, POM Wonderful, CVRx, AGA Medical, and W.L. Gore. No other potential conflict of interest relevant to this article was reported. NR 52 TC 74 Z9 74 U1 13 U2 27 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 7 PY 2016 VL 374 IS 14 BP 1321 EP 1331 DI 10.1056/NEJMoa1506930 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DI3UW UT WOS:000373425000006 PM 26886418 ER PT J AU Li, J Malley, JD Andrew, AS Karagas, MR Moore, JH AF Li, Jing Malley, James D. Andrew, Angeline S. Karagas, Margaret R. Moore, Jason H. TI Detecting gene-gene interactions using a permutation-based random forest method SO BIODATA MINING LA English DT Article DE Random forest; GWAS; Machine learning; Scale invariant ID MULTIFACTOR DIMENSIONALITY REDUCTION; GENOME-WIDE ASSOCIATION; EPISTATIC MODELS; COMPLEX TRAITS; LUNG-CANCER; DISEASE; RISK; POLYMORPHISMS; NETWORKS; STRICT AB Background: Identifying gene-gene interactions is essential to understand disease susceptibility and to detect genetic architectures underlying complex diseases. Here, we aimed at developing a permutation-based methodology relying on a machine learning method, random forest (RF), to detect gene-gene interactions. Our approach called permuted random forest (pRF) which identified the top interacting single nucleotide polymorphism (SNP) pairs by estimating how much the power of a random forest classification model is influenced by removing pairwise interactions. Results: We systematically tested our approach on a simulation study with datasets possessing various genetic constraints including heritability, number of SNPs, sample size, etc. Our methodology showed high success rates for detecting the interaction SNP pair. We also applied our approach to two bladder cancer datasets, which showed consistent results with well-studied methodologies, such as multifactor dimensionality reduction (MDR) and statistical epistasis network (SEN). Furthermore, we built permuted random forest networks (PRFN), in which we used nodes to represent SNPs and edges to indicate interactions. Conclusions: We successfully developed a scale-invariant methodology to detect pure gene-gene interactions based on permutation strategies and the machine learning method random forest. This methodology showed great potential to be used for detecting gene-gene interactions to study underlying genetic architectures in a scale-free way, which could be benefit to uncover the complex disease mechanisms. C1 [Li, Jing] Dartmouth Coll, Geisel Sch Med, Dept Genet, Hanover, NH 03755 USA. [Malley, James D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Andrew, Angeline S.; Karagas, Margaret R.] Dartmouth Coll, Geisel Sch Med, Dept Epidemiol, Hanover, NH 03755 USA. [Moore, Jason H.] Univ Penn, Inst Biomed Informat, Philadelphia, PA 19104 USA. [Moore, Jason H.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Moore, JH (reprint author), Univ Penn, Inst Biomed Informat, Philadelphia, PA 19104 USA.; Moore, JH (reprint author), Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. EM jhmoore@upenn.edu FU National Institutes of Health (NIH) [LM009012, LM010098, LM011360, EY022300, GM103506, GM103534, CA057494, P42ES0073737] FX This work was supported by the National Institutes of Health (NIH) R01 grants LM009012, LM010098, LM011360, EY022300, GM103506, GM103534, CA057494 and P42ES0073737. NR 40 TC 5 Z9 5 U1 6 U2 24 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-0381 J9 BIODATA MIN JI BioData Min. PD APR 6 PY 2016 VL 9 AR 14 DI 10.1186/s13040-016-0093-5 PG 17 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DI7FC UT WOS:000373663700001 PM 27053949 ER PT J AU Myles, IA Reckhow, JD Williams, KW Sastalla, I Frank, KM Datta, SK AF Myles, Ian A. Reckhow, Jensen D. Williams, Kelli W. Sastalla, Inka Frank, Karen M. Datta, Sandip K. TI A method for culturing Gram-negative skin microbiota SO BMC MICROBIOLOGY LA English DT Article DE Bacteriology; Skin; Microbiome; Culture techniques ID DESORPTION IONIZATION-TIME; FLIGHT MASS-SPECTROMETRY; IDENTIFICATION; MEDIA AB Background: Commensal Gram-negative (CGN) microbiota have been identified on human skin by DNA sequencing; however, methods to reliably culture viable Gram-negative skin organisms have not been previously described. Results: Through the use of selective antibiotics and minimal media we developed methods to culture CGN from skin swabs. We identified several previously uncharacterized CGN at the species level by optimizing growth conditions and limiting the inhibitory effects of nutrient shock, temperature, and bacterial competition, factors that may have previously limited CGN isolation from skin cultures. Conclusions: Our protocol will permit future functional studies on the influences of CGN on skin homeostasis and disease. C1 [Myles, Ian A.; Reckhow, Jensen D.; Williams, Kelli W.; Sastalla, Inka; Datta, Sandip K.] NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Frank, Karen M.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Myles, IA (reprint author), NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mylesi@niaid.nih.gov OI Datta, Sandip/0000-0003-0243-7815 FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Disease FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Allergy and Infectious Disease. NR 16 TC 1 Z9 1 U1 6 U2 10 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 APR 6 PY 2016 VL 16 AR 60 DI 10.1186/s12866-016-0684-9 PG 6 WC Microbiology SC Microbiology GA DI6CD UT WOS:000373585900001 PM 27052736 ER PT J AU Rhee, C Kadri, SS Danner, RL Suffredini, AF Massaro, AF Kitch, BT Lee, G Klompas, M AF Rhee, Chanu Kadri, Sameer S. Danner, Robert L. Suffredini, Anthony F. Massaro, Anthony F. Kitch, Barrett T. Lee, Grace Klompas, Michael TI Diagnosing sepsis is subjective and highly variable: a survey of intensivists using case vignettes SO CRITICAL CARE LA English DT Article ID SEPTIC SHOCK; INTERNATIONAL GUIDELINES; CLINICAL-DATA; DEFINITIONS; MANAGEMENT; CAMPAIGN; EPIDEMIOLOGY; DYSFUNCTION; CLAIMS; CARE AB Background: Sepsis is the focus of national quality improvement programs and a recent public reporting measure from the Centers for Medicare and Medicaid Services. However, diagnosing sepsis requires interpreting nonspecific signs and can therefore be subjective. We sought to quantify interobserver variability in diagnosing sepsis. Methods: We distributed five case vignettes of patients with suspected or confirmed infection and organ dysfunction to a sample of practicing intensivists. Respondents classified cases as systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, or none of the above. Interobserver variability was calculated using Fleiss' kappa for the five-level classification, and for answers dichotomized as severe sepsis/septic shock versus not-severe sepsis/septic shock and any sepsis category (sepsis, severe sepsis, or septic shock) versus not-sepsis. Results: Ninety-four physicians completed the survey. Most respondents (88 %) identified as critical care specialists; other specialties included pulmonology (39 %), anesthesia (19 %), surgery (9 %), and emergency medicine (9 %). Respondents had been in practice for a median of 8 years, and 90 % practiced at academic hospitals. Almost all respondents (83 %) felt strongly or somewhat confident in their ability to apply the traditional consensus sepsis definitions. However, overall interrater agreement in sepsis diagnoses was poor (Fleiss' kappa 0.29). When responses were dichotomized into severe sepsis/septic shock versus not-severe sepsis/septic shock or any sepsis category versus not-sepsis, agreement was still poor (Fleiss' kappa 0.23 and 0.18, respectively). Seventeen percent of respondents classified one of the five cases as severe sepsis/septic shock, 27.7 % rated two cases, 33.0 % respondents rated three cases, 19.2 % rated four cases, and 3.2 % rated all five cases as severe sepsis/septic shock. Among respondents who felt strongly confident in their ability to use sepsis definitions (n = 45), agreement was no better (Fleiss' kappa 0.28 for the five-category classification, and Fleiss' kappa 0.21 for the dichotomized severe sepsis/septic shock classification). Cases were felt to be extremely or very realistic in 74 % of responses; only 3 % were deemed unrealistic. Conclusions: Diagnosing sepsis is extremely subjective and variable. Objective criteria and standardized methodology are needed to enhance consistency and comparability in sepsis research, surveillance, benchmarking, and reporting. C1 [Rhee, Chanu; Lee, Grace; Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA USA. [Rhee, Chanu; Lee, Grace; Klompas, Michael] Harvard Pilgrim Hlth Care Inst, 401 Pk Dr,Suite 401, Boston, MA USA. [Rhee, Chanu; Massaro, Anthony F.; Klompas, Michael] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Kadri, Sameer S.; Danner, Robert L.; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Kitch, Barrett T.] North Shore Med Ctr, Dept Med, Salem, MA USA. RP Rhee, C (reprint author), Harvard Univ, Sch Med, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA USA.; Rhee, C (reprint author), Harvard Pilgrim Hlth Care Inst, 401 Pk Dr,Suite 401, Boston, MA USA.; Rhee, C (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM crhee1@partners.org FU Department of Population Medicine, Harvard Medical School; Harvard Pilgrim Health Care Institute; National Institutes of Health [T32 AI007061] FX We thank the leadership of the U.S. Critical Illness and Injury Trials Group, particularly Dr. Charles Cairns, for help in disseminating the survey to the group. Gift cards for survey respondents were funded by the Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute. CR received support from the National Institutes of Health (grant T32 AI007061). NR 24 TC 5 Z9 5 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1466-609X EI 1364-8535 J9 CRIT CARE JI Crit. Care PD APR 6 PY 2016 VL 20 AR 89 DI 10.1186/s13054-016-1266-9 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA DI7HO UT WOS:000373670400001 PM 27048508 ER PT J AU Rossi, PJ Gunduz, A Judy, J Wilson, L Machado, A Giordano, JJ Elias, WJ Rossi, MA Butson, CL Fox, MD McIntyre, CC Pouratian, N Swann, NC de Hemptinne, C Gross, RE Chizeck, HJ Tagliati, M Lozano, AM Goodman, W Langevin, JP Alterman, RL Akbar, U Gerhardt, GA Grill, WM Hallett, M Herrington, T Herron, J van Horne, C Kopell, BH Lang, AE Lungu, C Martinez-Ramirez, D Mogilner, AY Molina, R Opri, E Otto, KJ Oweiss, KG Pathak, Y Shukla, A Shute, J Sheth, SA Shih, LC Steinke, GK Troster, AI Vanegas, N Zaghloul, KA Cendejas-Zaragoza, L Verhagen, L Foote, KD Okun, MS AF Rossi, P. Justin Gunduz, Aysegul Judy, Jack Wilson, Linda Machado, Andre Giordano, James J. Elias, W. Jeff Rossi, Marvin A. Butson, Christopher L. Fox, Michael D. McIntyre, Cameron C. Pouratian, Nader Swann, Nicole C. de Hemptinne, Coralie Gross, Robert E. Chizeck, Howard J. Tagliati, Michele Lozano, Andres M. Goodman, Wayne Langevin, Jean-Philippe Alterman, Ron L. Akbar, Umer Gerhardt, Greg A. Grill, Warren M. Hallett, Mark Herrington, Todd Herron, Jeffrey van Horne, Craig Kopell, Brian H. Lang, Anthony E. Lungu, Codrin Martinez-Ramirez, Daniel Mogilner, Alon Y. Molina, Rene Opri, Enrico Otto, Kevin J. Oweiss, Karim G. Pathak, Yagna Shukla, Aparna Shute, Jonathan Sheth, Sameer A. Shih, Ludy C. Steinke, G. Karl Troester, Alexander I. Vanegas, Nora Zaghloul, Kareem A. Cendejas-Zaragoza, Leopoldo Verhagen, Leonard Foote, Kelly D. Okun, Michael S. TI Proceedings of the Third Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies SO FRONTIERS IN NEUROSCIENCE LA English DT Review DE deep brain stimulation; local field potentials; neuromodulation; closed-loop; electrodes ID POSTTRAUMATIC-STRESS-DISORDER; FOCUSED ULTRASOUND THALAMOTOMY; PARKINSONS-DISEASE; ESSENTIAL TREMOR; SUBTHALAMIC NUCLEUS; TOURETTE SYNDROME; MOVEMENT-DISORDERS; LATERAL HABENULA; GLOBUS-PALLIDUS; DEPRESSION AB The proceedings of the 3rd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, imaging, and computational work on DBS for the treatment of neurological and neuropsychiatric disease. Significant innovations of the past year are emphasized. The Think Tank's contributors represent a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers, and members of industry. Presentations and discussions covered a broad range of topics, including policy and advocacy considerations for the future of DBS, connectomic approaches to DBS targeting, developments in electrophysiology and related strides toward responsive DBS systems, and recent developments in sensor and device technologies. C1 [Rossi, P. Justin; Gunduz, Aysegul; Judy, Jack; Martinez-Ramirez, Daniel; Molina, Rene; Opri, Enrico; Otto, Kevin J.; Oweiss, Karim G.; Shukla, Aparna; Shute, Jonathan; Foote, Kelly D.; Okun, Michael S.] Univ Florida, Dept Neurosci, Ctr Movement Disorders & Neurorestorat, Gainesville, FL 32610 USA. [Wilson, Linda] Int Technol Roadmap Semicond, Washington, DC USA. [Machado, Andre] Cleveland Clin, Neurol Inst, Cleveland, OH 44106 USA. [Giordano, James J.] Georgetown Univ, Med Ctr, Dept Neurol, Neuroeth Studies Program, Washington, DC 20007 USA. [Elias, W. Jeff] Univ Virginia, Hlth Sci Ctr, Dept Neurosurg, Neurol Surg & Neurol,Stereotact & Funct Neurosurg, Charlottesville, VA 22908 USA. [Rossi, Marvin A.; Cendejas-Zaragoza, Leopoldo; Verhagen, Leonard] Rush Univ, Med Ctr, Dept Neurol, Chicago, IL 60612 USA. [Butson, Christopher L.] Univ Utah, Sci Comp & Imaging Inst, Salt Lake City, UT USA. [Fox, Michael D.; Alterman, Ron L.; Shih, Ludy C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [McIntyre, Cameron C.] Case Western Reserve Univ, Dept Biomed Engn, Sch Med, Cleveland, OH 44106 USA. [Pouratian, Nader] Univ Calif Los Angeles, Dept Neurosurg, Los Angeles, CA USA. [Swann, Nicole C.; de Hemptinne, Coralie] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gross, Robert E.] Emory Univ, Emory Clin, Atlanta, GA 30322 USA. [Chizeck, Howard J.; Herron, Jeffrey] Univ Washington, Dept Elect Engn, Seattle, WA 98195 USA. [Tagliati, Michele] Cedars Sinai Med Ctr, Dept Neurol, Movement Disorders Program, Los Angeles, CA 90048 USA. [Lozano, Andres M.; Lang, Anthony E.] Univ Toronto, Dept Neurosurg, Toronto, ON, Canada. [Goodman, Wayne; Kopell, Brian H.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Langevin, Jean-Philippe] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. [Akbar, Umer] Brown Univ, Dept Neurol, Alpert Med Sch, Providence, RI 02912 USA. [Gerhardt, Greg A.; van Horne, Craig] Univ Kentucky, Med Ctr, Lexington, KY USA. [Grill, Warren M.] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. [Hallett, Mark; Lungu, Codrin; Zaghloul, Kareem A.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Herrington, Todd] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Mogilner, Alon Y.] NYU, Dept Neurosurg, Ctr Neuromodulat, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. [Pathak, Yagna; Sheth, Sameer A.; Vanegas, Nora] Columbia Univ, Med Ctr, Neurol Inst, New York, NY USA. [Steinke, G. Karl] Boston Sci Neuromodulat, Valencia, CA USA. [Troester, Alexander I.] Barrow Neurol Inst, Dept Clin Neuropsychol, Phoenix, AZ 85013 USA. RP Rossi, PJ (reprint author), Univ Florida, Dept Neurosci, Ctr Movement Disorders & Neurorestorat, Gainesville, FL 32610 USA. EM pjrossi@ufl.edu RI Martinez-Ramirez, Daniel/H-2546-2016; Gunduz, Aysegul/Q-2336-2016; OI Martinez-Ramirez, Daniel/0000-0001-8003-0610; Mogilner, Alon/0000-0003-1493-0463 FU NICHD NIH HHS [T32 HD043730]; NINDS NIH HHS [R01 NS040894, R37 NS040894] NR 103 TC 2 Z9 2 U1 13 U2 30 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD APR 6 PY 2016 VL 10 AR 119 DI 10.3389/fnins.2016.00119 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DI4GU UT WOS:000373459200001 PM 27092042 ER PT J AU Quaia, C Optican, LM Cumming, BG AF Quaia, Christian Optican, Lance M. Cumming, Bruce G. TI A Motion-from-Form Mechanism Contributes to Extracting Pattern Motion from Plaids SO JOURNAL OF NEUROSCIENCE LA English DT Article DE flicker; motion; MT; unikinetic ID VISUAL AREA MT; OCULAR-FOLLOWING RESPONSES; TRACKING EYE-MOVEMENTS; SPATIOTEMPORAL ENERGY MODELS; PERCEIVED DIRECTION; 2-DIMENSIONAL PATTERNS; FREQUENCY SELECTIVITY; TEMPORAL DYNAMICS; SPATIAL-FREQUENCY; BINOCULAR-RIVALRY AB Since the discovery of neurons selective for pattern motion direction in primate middle temporal area MT (Albright, 1984; Movshon et al., 1985), the neural computation of this signal has been the subject of intense study. The bulk of this work has explored responses to plaids obtained by summing two drifting sinusoidal gratings. Unfortunately, with these stimuli, many different mechanisms are similarly effective at extracting pattern motion. We devised a new set of stimuli, obtained by summing two random line stimuli with different orientations. This allowed several novel manipulations, including generating plaids that do not contain rigid 2D motion. Importantly, these stimuli do not engage most of the previously proposed mechanisms. We then recorded the ocular following responses that such stimuli induce in human subjects. We found that pattern motion is computed even with stimuli that do not cohere perceptually, including those without rigid motion, and even when the two gratings are presented separately to the two eyes. Moderate temporal and/or spatial separation of the gratings impairs the computation. We show that, of the models proposed so far, only those based on the intersection-of-constraints rule, embedding a motion-from-form mechanism (in which orientation signals are used in the computation of motion direction signals), can account for our results. At least for the eye movements reported here, a motion-from-form mechanism is thus involved in one of the most basic functions of the visual motion system: extracting motion direction from complex scenes. C1 [Quaia, Christian; Optican, Lance M.; Cumming, Bruce G.] NEI, Sensorimotor Res Lab, NIH, Dept Hlth & Human Serv, 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA. RP Quaia, C (reprint author), NEI, Sensorimotor Res Lab, NIH, Dept Hlth & Human Serv, 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA. EM quaiac@nei.nih.gov FU Intramural Research Program of the National Eye Institute/National Institutes of Health/Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Eye Institute/National Institutes of Health/Department of Health and Human Services. We thank Boris Sheliga for assistance in running the experiments and two anonymous reviewers for their thoughtful and constructive comments. We thank J. Anthony Movshon and Pascal Wallisch for helpful discussions. NR 82 TC 2 Z9 2 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 6 PY 2016 VL 36 IS 14 BP 3903 EP 3918 DI 10.1523/JNEUROSCI.3398-15.2016 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DI4GC UT WOS:000373457400003 PM 27053199 ER PT J AU Jocham, G Brodersen, KH Constantinescu, AO Kahn, MC Ianni, AM Walton, ME Rushworth, MFS Behrens, TEJ AF Jocham, Gerhard Brodersen, Kay H. Constantinescu, Alexandra O. Kahn, Martin C. Ianni, Angela M. Walton, Mark E. Rushworth, Matthew F. S. Behrens, Timothy E. J. TI Reward-Guided Learning with and without Causal Attribution SO NEURON LA English DT Article ID ORBITOFRONTAL CORTEX; PREFRONTAL CORTEX; DECISION-MAKING; FRONTAL-CORTEX; BRAIN IMAGES; CHOICES; REINFORCEMENT; LESIONS; AMYGDALA; NEURONS AB When an organism receives a reward, it is crucial to know which of many candidate actions caused this reward. However, recent work suggests that learning is possible even when this most fundamental assumption is not met. We used novel reward-guided learning paradigms in two fMRI studies to show that humans deploy separable learning mechanisms that operate in parallel. While behavior was dominated by precise contingent learning, it also revealed hallmarks of noncontingent learning strategies. These learning mechanisms were separable behaviorally and neurally. Lateral orbitofrontal cortex supported contingent learning and reflected contingencies between outcomes and their causal choices. Amygdala responses around reward times related to statistical patterns of learning. Time-based heuristic mechanisms were related to activity in sensorimotor corticostriatal circuitry. Our data point to the existence of several learning mechanisms in the human brain, of which only one relies on applying known rules about the causal structure of the task. C1 [Jocham, Gerhard; Brodersen, Kay H.; Constantinescu, Alexandra O.; Kahn, Martin C.; Ianni, Angela M.; Behrens, Timothy E. J.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford Ctr Funct MRI Brain, Oxford OX3 9DU, England. [Jocham, Gerhard] Otto Von Guericke Univ, Ctr Behav Brain Sci, Univ Pl 2, D-39106 Magdeburg, Germany. [Jocham, Gerhard] Otto Von Guericke Univ, Fac Econ & Management, Univ Pl 2, D-39106 Magdeburg, Germany. [Ianni, Angela M.] NIMH, Sect Integrat Neuroimaging, Clin & Translat Neurosci Branch, NIH,Intramural Res Program,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Brodersen, Kay H.; Walton, Mark E.; Rushworth, Matthew F. S.] Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. [Behrens, Timothy E. J.] UCL, Wellcome Trust Ctr Neuroimaging, 12 Queen Sq, London WC1N 3BG, England. RP Jocham, G (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford Ctr Funct MRI Brain, Oxford OX3 9DU, England.; Jocham, G (reprint author), Otto Von Guericke Univ, Ctr Behav Brain Sci, Univ Pl 2, D-39106 Magdeburg, Germany.; Jocham, G (reprint author), Otto Von Guericke Univ, Fac Econ & Management, Univ Pl 2, D-39106 Magdeburg, Germany.; Brodersen, KH (reprint author), Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. EM jocham@ovgu.de; khbrodersen@gmail.com FU Federal State of Saxony Anhalt; Center for Behavioral Brain Sciences; Wellcome Trust [099715/Z/12/Z, WT088312AIA, WT104765MA, WT090051MA]; James S. McDonnel Foundation award [JSMF220020372] FX This work was supported by a grant from the Federal State of Saxony Anhalt to G.J., project: Center for Behavioral Brain Sciences; a Wellcome Trust 4-year PhD studentship (099715/Z/12/Z) to A.O.C. and a Wellcome Trust Research Career Development Fellowship (WT088312AIA); a Wellcome Trust Senior Research Fellowship (WT104765MA) and a James S. McDonnel Foundation award (JSMF220020372) to T.E.J.B.; and a Wellcome Trust Research Career Development Fellowship (WT090051MA) to M.E.W. NR 44 TC 4 Z9 4 U1 8 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD APR 6 PY 2016 VL 90 IS 1 BP 177 EP 190 DI 10.1016/j.neuron.2016.02.018 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DI5UK UT WOS:000373565800018 PM 26971947 ER PT J AU Jain, S Park, G Sproule, TJ Christianson, GJ Leeth, CM Wang, HS Roopenian, DC Morse, HC AF Jain, Shweta Park, Giljun Sproule, Thomas J. Christianson, Gregory J. Leeth, Caroline M. Wang, Hongsheng Roopenian, Derry C. Morse, Herbert C., III TI Interleukin 6 Accelerates Mortality by Promoting the Progression of the Systemic Lupus Erythematosus-Like Disease of BXSB. Yaa Mice SO PLOS ONE LA English DT Article ID CD4(+) T-CELLS; TOLL-LIKE RECEPTORS; ACTIVATE B-CELLS; MURINE LUPUS; ANTI-DNA; IN-VIVO; IL-6; TLR7; DIFFERENTIATION; EXPRESSION AB IL6 is a multifunctional cytokine that drives terminal B cell differentiation and secretion of immunoglobulins. IL6 also cooperates with IL21 to promote differentiation of CD4(+) T follicular helper cells (TFH). Elevated serum levels of IL6 correlate with disease flares in patients with systemic lupus erythematosus (SLE). We previously reported that IL21 produced by T-FH plays a critical role in the development of the SLE-like disease of BXSB. Yaa mice. To examine the possible contributions of IL6 to disease, we compared disease parameters in IL6-deficient and IL6-competent BXSB. Yaa mice. We report that survival of IL6-deficient BXSB. Yaa mice was significantly prolonged in association with significant reductions in a variety of autoimmune manifestations. Moreover, B cells stimulated by co-engagement of TLR7 and B cell receptor (BCR) produced high levels of IL6 that was further augmented by stimulation with Type I interferon (IFN1). Importantly, the frequencies of T-FH and serum levels of IL21 were significantly reduced in IL6-deficient mice. These findings suggest that high-level production of IL6 by B cells induced by integrated signaling from the IFN1 receptor, TLR7 and BCR promotes the differentiation of IL21-secreting T-FH in a signaling sequence that drives the lethal autoimmune disease of BXSB. Yaa mice. C1 [Jain, Shweta; Wang, Hongsheng; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD USA. [Park, Giljun; Sproule, Thomas J.; Christianson, Gregory J.; Roopenian, Derry C.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. [Park, Giljun] Univ Helsinki, Cent Hosp, Ctr Canc, Hematol Res Unit,Biomedicum Helsinki 1, Helsinki, Finland. [Leeth, Caroline M.] Virginia Tech, Coll Agr & Life Sci, Dept Anim & Poultry Sci, Blacksburg, VA USA. RP Morse, HC (reprint author), NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD USA.; Roopenian, DC (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM dcr@jax.org; hmorse@niaid.nih.gov FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (NIAID); Alliance for Lupus Research FX This work was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (NIAID), and by the Alliance for Lupus Research. NR 60 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 6 PY 2016 VL 11 IS 4 AR e0153059 DI 10.1371/journal.pone.0153059 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI6IX UT WOS:000373603500090 PM 27050763 ER PT J AU Oga, EA Schumaker, LM Alabi, BS Obaseki, D Umana, A Bassey, IA Ebughe, G Oluwole, O Akeredolu, T Adebamowo, SN Dakum, P Cullen, K Adebamowo, CA AF Oga, Emmanuel A. Schumaker, Lisa M. Alabi, Biodun Sulyman Obaseki, Darlington Umana, Aniefon Bassey, Ima-Abasi Ebughe, Godwin Oluwole, Olabode Akeredolu, Teniola Adebamowo, Sally N. Dakum, Patrick Cullen, Kevin Adebamowo, Clement A. TI Paucity of HPV-Related Head and Neck Cancers (HNC) in Nigeria SO PLOS ONE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS INFECTION; UNITED-STATES; ALCOHOL-DRINKING; INCIDENCE TRENDS; TOBACCO SMOKING; ORAL SEX; PREVALENCE; RISK; ADOLESCENTS AB Introduction The burden of HPV-related Head and Neck Cancers (HNC) has been rising in the U.S. and other developed countries but this trend has not been reported in Africa. Objective of study was to evaluate the prevalence of HPV infection in HNC cancer cases seen between 1990 and 2011 at the tertiary health care institutions in Nigeria. Methods We retrieved 149 head and neck cancer formalin fixed, paraffin embedded tumor specimens diagnosed between 1990 and 2011 from four teaching hospitals in Nigeria. One hundred and twenty-three blocks (83%) contained appropriate HNC for analysis while DNA extraction was successful in 60% (90/149). PCR amplification was successful in 33% (49/149) and Linear Array genotyping for HPV was successful in 11% (17/149) of these cases. These were in tumors from the larynx (6), cervical lymph nodes (3), nasal cavity (2), parotid (1), palate (1), maxillary sinus (1) and mandible (1). Two cases were non-specific and none were from the oropharynx. Histologically, 41% (7/17) of the successfully genotyped blocks were squamous cell carcinomas (larynx 6, maxillary sinus 1). Results and Conclusion We were unable to detect HPV in any of the HNC samples in our study. Our result may suggest that there is a low prevalence of HPV-related HNC among the adult population in Nigeria. Our results provide a benchmark to compare future incidence of HPV-related HNC in this community in future. We had significant analytical challenges from possible poor tissue processing and urge that future studies should prospectively collect samples and ensure high quality sample processing. C1 [Oga, Emmanuel A.; Adebamowo, Clement A.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Oga, Emmanuel A.; Akeredolu, Teniola; Adebamowo, Sally N.; Dakum, Patrick; Adebamowo, Clement A.] Inst Human Virol Nigeria, Off Res Training & Strateg Informat, Abuja, Fct, Nigeria. [Schumaker, Lisa M.; Cullen, Kevin; Adebamowo, Clement A.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Alabi, Biodun Sulyman] Univ Ilorin Teaching Hosp, Dept Ear Nose & Throat Head & Neck Surg, Ilorin, Kwara State, Nigeria. [Obaseki, Darlington] Univ Benin Teaching Hosp, Benin, Edo State, Nigeria. [Umana, Aniefon; Bassey, Ima-Abasi; Ebughe, Godwin] Univ Calabar Teaching Hosp, Calabar, Cross River Sta, Nigeria. [Oluwole, Olabode] Univ Abuja Teaching Hosp, Abuja, Fct, Nigeria. [Adebamowo, Sally N.; Adebamowo, Clement A.] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Adebamowo, Sally N.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Oga, EA (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA.; Oga, EA (reprint author), Inst Human Virol Nigeria, Off Res Training & Strateg Informat, Abuja, Fct, Nigeria. EM eoga@umaryland.edu OI Adebamowo, Sally/0000-0003-4713-2433; Oga, Emmanuel/0000-0002-0744-5681 FU NCI/NIH [D43CA153792-01] FX The project described was supported by Grant Number D43CA153792-01 (PI - Adebamowo) from the NCI/NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 54 TC 2 Z9 2 U1 1 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 APR 6 PY 2016 VL 11 IS 4 AR e0152828 DI 10.1371/journal.pone.0152828 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI6IX UT WOS:000373603500057 PM 27050815 ER PT J AU Bentolila, LA Prakash, R Mihic-Probst, D Wadehra, M Kleinman, HK Carmichael, TS Peault, B Barnhill, RL Lugassy, C AF Bentolila, Laurent A. Prakash, Roshini Mihic-Probst, Daniela Wadehra, Madhuri Kleinman, Hynda K. Carmichael, Thomas S. Peault, Bruno Barnhill, Raymond L. Lugassy, Claire TI Imaging of Angiotropism/Vascular Co-Option in a Murine Model of Brain Melanoma: Implications for Melanoma Progression along Extravascular Pathways SO SCIENTIFIC REPORTS LA English DT Article ID MIGRATORY METASTASIS; MALIGNANT-MELANOMA; CELL INVASION; CANCER-CELLS; STEM-CELLS; TUMORS; ANGIOGENESIS; PLASTICITY; GROWTH; MICROENVIRONMENT AB Angiotropism/pericytic mimicry and vascular co-option involve tumor cell interactions with the abluminal vascular surface. These two phenomena may be closely related. However, investigations of the two processes have developed in an independent fashion and different explanations offered as to their biological nature. Angiotropism describes the propensity of tumor cells to spread distantly via continuous migration along abluminal vascular surfaces, or extravascular migratory metastasis (EVMM). Vascular co-option has been proposed as an alternative mechanism by which tumors cells may gain access to a blood supply. We have used a murine brain melanoma model to analyze the interactions of GFP human melanoma cells injected into the mouse brain with red fluorescent lectin-labeled microvascular channels. Results have shown a striking spread of melanoma cells along preexisting microvascular channels and features of both vascular co-option and angiotropism/pericytic mimicry. This study has also documented the perivascular expression of Serpin B2 by angiotropic melanoma cells in the murine brain and in human melanoma brain metastases. Our findings suggest that vascular cooption and angiotropism/pericytic mimicry are closely related if not identical processes. Further studies are needed in order to establish whether EVMM is an alternative form of cancer metastasis in addition to intravascular cancer dissemination. C1 [Bentolila, Laurent A.] California NanoSyst Inst, Los Angeles, CA 90095 USA. [Bentolila, Laurent A.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Prakash, Roshini; Carmichael, Thomas S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Mihic-Probst, Daniela] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland. [Wadehra, Madhuri] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Wadehra, Madhuri] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Kleinman, Hynda K.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Peault, Bruno] Univ Calif Los Angeles, David Geffen Sch Med, Orthoped Hosp, Res Ctr, Los Angeles, CA 90095 USA. [Peault, Bruno] Univ Calif Los Angeles, David Geffen Sch Med, Broad Stem Cell Ctr, Los Angeles, CA 90095 USA. [Peault, Bruno] Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh, Midlothian, Scotland. [Peault, Bruno] Univ Edinburgh, BHF Ctr Cardiovasc Sci, Queens Med Res Inst, Edinburgh, Midlothian, Scotland. [Barnhill, Raymond L.] Inst Curie, Dept Pathol, Paris, France. [Barnhill, Raymond L.] Univ Paris 05, Paris, France. [Lugassy, Claire] Inst Curie, Dept Translat Res, Paris, France. RP Barnhill, RL (reprint author), Inst Curie, Dept Pathol, Paris, France.; Barnhill, RL (reprint author), Univ Paris 05, Paris, France. EM raymond.barnhill@gmail.com FU NIH/National Center for Advancing Translational Science UCLA CTSI Grant [UL1TR000124] FX Confocal imaging was performed at the California NanoSystems Institute (CNSI) Advanced Light Microscopy/Spectroscopy Shared Resource Facility at UCLA with support from a NIH/National Center for Advancing Translational Science UCLA CTSI Grant (UL1TR000124). The authors also thanks Olivier Brun from Leica Microsystems for providing access to the SP8 X microscope used in Figure 3 and Supplementary Movie S1. NR 46 TC 3 Z9 3 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 6 PY 2016 VL 6 AR 23834 DI 10.1038/srep23834 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI3WJ UT WOS:000373430500001 PM 27048955 ER PT J AU Habes, M Janowitz, D Erus, G Toledo, JB Resnick, SM Doshi, J Van der Auwera, S Wittfeld, K Hegenscheid, K Hosten, N Biffar, R Homuth, G Volzke, H Grabe, HJ Hoffmann, W Davatzikos, C AF Habes, M. Janowitz, D. Erus, G. Toledo, J. B. Resnick, S. M. Doshi, J. Van der Auwera, S. Wittfeld, K. Hegenscheid, K. Hosten, N. Biffar, R. Homuth, G. Volzke, H. Grabe, H. J. Hoffmann, W. Davatzikos, C. TI Advanced brain aging: relationship with epidemiologic and genetic risk factors, and overlap with Alzheimer disease atrophy patterns SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID MIDLIFE BLOOD-PRESSURE; GRAY-MATTER VOLUME; COGNITIVE DECLINE; SPATIAL-PATTERNS; OLDER-ADULTS; SEGMENTATION; DEMENTIA; MRI; CLASSIFICATION; METAANALYSIS AB We systematically compared structural imaging patterns of advanced brain aging (ABA) in the general-population, herein defined as significant deviation from typical BA to those found in Alzheimer disease (AD). The hypothesis that ABA would show different patterns of structural change compared with those found in AD was tested via advanced pattern analysis methods. In particular, magnetic resonance images of 2705 participants from the Study of Health in Pomerania (aged 20-90 years) were analyzed using an index that captures aging atrophy patterns (Spatial Pattern of Atrophy for Recognition of BA (SPARE-BA)), and an index previously shown to capture atrophy patterns found in clinical AD (Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease (SPARE-AD)). We studied the association between these indices and risk factors, including an AD polygenic risk score. Finally, we compared the ABA-associated atrophy with typical AD-like patterns. We observed that SPARE-BA had significant association with: smoking (P < 0.05), anti-hypertensive (P < 0.05), anti-diabetic drug use (men P < 0.05, women P = 0.06) and waist circumference for the male cohort (P < 0.05), after adjusting for age. Subjects with ABA had spatially extensive gray matter loss in the frontal, parietal and temporal lobes (false-discovery-rate-corrected q < 0.001). ABA patterns of atrophy were partially overlapping with, but notably deviating from those typically found in AD. Subjects with ABA had higher SPARE-AD values; largely due to the partial spatial overlap of associated patterns in temporal regions. The AD polygenic risk score was significantly associated with SPARE-AD but not with SPARE-BA. Our findings suggest that ABA is likely characterized by pathophysiologic mechanisms that are distinct from, or only partially overlapping with those of AD. C1 [Habes, M.; Volzke, H.; Hoffmann, W.] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Habes, M.; Erus, G.; Doshi, J.; Davatzikos, C.] Univ Penn, Dept Radiol, Ctr Biomed Image Comp & Analyt, 3700 Hamilton Walk, Philadelphia, PA 19104 USA. [Habes, M.; Janowitz, D.; Van der Auwera, S.; Grabe, H. J.] Ernst Moritz Arndt Univ Greifswald, Dept Psychiat, Greifswald, Germany. [Toledo, J. B.] Univ Penn, Dept Pathol & Lab Med, Inst Aging, Ctr Neurodegenerat Dis Res, Philadelphia, PA USA. [Resnick, S. M.] NIA, Lab Behav Neurosci, Biomed Res Ctr, Baltimore, MD 21224 USA. [Wittfeld, K.; Grabe, H. J.; Hoffmann, W.] German Ctr Neurodegenerat Dis DZNE, Greifswald, Germany. [Hegenscheid, K.; Hosten, N.] Ernst Moritz Arndt Univ Greifswald, Dept Radiol, Greifswald, Germany. [Biffar, R.] Ernst Moritz Arndt Univ Greifswald, Dept Dent, Greifswald, Germany. [Homuth, G.] Ernst Moritz Arndt Univ Greifswald, Inst Genet & Funct Genom, Greifswald, Germany. RP Habes, M (reprint author), Univ Penn, Dept Radiol, Ctr Biomed Image Comp & Analyt, 3700 Hamilton Walk, Philadelphia, PA 19104 USA. EM habesm@uphs.upenn.edu RI Habes, Mohamad/M-2865-2016; OI Habes, Mohamad/0000-0001-9447-5805; Janowitz, Deborah/0000-0003-4324-9298; Toledo, Jon/0000-0003-4366-9268 FU Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; NIH [R01-AG014971]; 'Alfried Krupp von Bohlen und Halbach' foundation FX SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data in SHIP and MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. Genome-wide genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (grant no. 03ZIK012). This work has been supported in part by NIH (grant no. R01-AG014971). MH was supported by 'Alfried Krupp von Bohlen und Halbach' foundation. NR 55 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD APR 5 PY 2016 VL 6 AR e775 DI 10.1038/tp.2016.39 PG 8 WC Psychiatry SC Psychiatry GA DN8BJ UT WOS:000377303600005 PM 27045845 ER PT J AU Galiatsatos, P Win, T Monti, J Johnston, P Herzog, W Trost, J Hwang, CW Wang, NY Silber, H AF Galiatsatos, Panagis Win, Theingi Monti, Jennifer Johnston, Peter Herzog, William Trost, Jeffrey Hwang, Chao-Wei Wang, Nae-Yuh Silber, Harry TI A NONINVASIVE HAND-HELD DEVICE IDENTIFIES ELEVATED LEFT VENTRICULAR FILLING PRESSURE USING FINGER PHOTOPLETHYSMOGRAPHY DURING THE VALSALVA MANEUVER SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 65th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY APR 02-04, 2016 CL Chicago, IL SP Amer Coll Cardiol C1 Johns Hopkins Med, Baltimore, MD USA. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 5 PY 2016 VL 67 IS 13 SU S MA 1171-070 BP 1427 EP 1427 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK8PH UT WOS:000375188702273 ER PT J AU Mehta, NN Kabbany, MT Ahlman, M Rodante, J Lerman, J Aberra, T Silverman, J Aridi, T Dahiya, A Bluemke, D Playford, M Joshi, A AF Mehta, Nehal N. Kabbany, Mohammad Tarek Ahlman, Mark Rodante, Justin Lerman, Joseph Aberra, Tsion Silverman, Joanna Aridi, Tarek Dahiya, Asha Bluemke, David Playford, Martin Joshi, Aditya TI DETERMINANTS OF VASCULAR INFLAMMATION BY 18-FLUORODEOXYGLUCOSE PET/MRI: FINDINGS FROM THE PSORIASIS, ATHEROSCLEROSIS AND CARDIOMETABOLIC DISEASE INITIATIVE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 65th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY APR 02-04, 2016 CL Chicago, IL SP Amer Coll Cardiol C1 [Mehta, Nehal N.; Kabbany, Mohammad Tarek; Ahlman, Mark; Rodante, Justin; Lerman, Joseph; Aberra, Tsion; Silverman, Joanna; Aridi, Tarek; Dahiya, Asha; Bluemke, David; Playford, Martin; Joshi, Aditya] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 5 PY 2016 VL 67 IS 13 SU S MA 1182-223 BP 1692 EP 1692 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK8PH UT WOS:000375188702538 ER PT J AU Joshi, AA Kabbany, MT Ahlman, M Lerman, J Aberra, T Natarajan, B Salahuddin, T Rodante, J Playford, M Chen, M Bluemke, D Mehta, N AF Joshi, Aditya A. Kabbany, Mohammad Tarek Ahlman, Mark Lerman, Joseph Aberra, Tsion Natarajan, Balaji Salahuddin, Taufiq Rodante, Justin Playford, Martin Chen, Marcus Bluemke, David Mehta, Nehal TI AORTIC VASCULAR INFLAMMATION BY 18-FDG PET/MRI IS RELATED TO CORONARY PLAQUE BURDEN BY QUANTITATIVE CORONARY CT ANGIOGRAPHY IN PSORIASIS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 65th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY APR 02-04, 2016 CL Chicago, IL SP Amer Coll Cardiol C1 [Joshi, Aditya A.; Kabbany, Mohammad Tarek; Ahlman, Mark; Lerman, Joseph; Aberra, Tsion; Natarajan, Balaji; Salahuddin, Taufiq; Rodante, Justin; Playford, Martin; Chen, Marcus; Bluemke, David; Mehta, Nehal] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 5 PY 2016 VL 67 IS 13 SU S MA 1230-237 BP 1754 EP 1754 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK8PH UT WOS:000375188702600 ER PT J AU Vargas, JD Manichaikul, A Liu, CY Rich, S Post, W Judge, D Bluemke, D AF Vargas, Jose D. Manichaikul, Ani Liu, Chia-Ying Rich, Stephen Post, Wendy Judge, Daniel Bluemke, David TI COMMON GENETIC VARIANTS AND LEFT VENTRICULAR STRUCTURE IN THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 65th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY APR 02-04, 2016 CL Chicago, IL SP Amer Coll Cardiol C1 [Vargas, Jose D.; Manichaikul, Ani; Liu, Chia-Ying; Rich, Stephen; Post, Wendy; Judge, Daniel; Bluemke, David] NIH, Bldg 10, Bethesda, MD 20892 USA. OI Manichaikul, Ani/0000-0002-5998-795X NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 5 PY 2016 VL 67 IS 13 SU S MA 1263-261 BP 1835 EP 1835 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK8PH UT WOS:000375188702681 ER PT J AU Mehta, NN Natarajan, B Playford, M Lerman, J Kabbany, MT Aberra, T Ng, Q Teague, H Rodante, J Joshi, A AF Mehta, Nehal N. Natarajan, Balaji Playford, Martin Lerman, Joseph Kabbany, Mohammad Tarek Aberra, Tsion Qimin Ng Teague, Heather Rodante, Justin Joshi, Aditya TI SMALL DENSE LOW-DENSITY LIPOPROTEIN (LDL) PARTICLE NUMBER PREDICTS VASCULAR INFLAMMATION INDEPENDENT OF TRADITIONAL LIPID CARDIOVASCULAR RISK FACTORS IN PSORIASIS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 65th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY APR 02-04, 2016 CL Chicago, IL SP Amer Coll Cardiol C1 [Mehta, Nehal N.; Natarajan, Balaji; Playford, Martin; Lerman, Joseph; Kabbany, Mohammad Tarek; Aberra, Tsion; Qimin Ng; Teague, Heather; Rodante, Justin; Joshi, Aditya] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 5 PY 2016 VL 67 IS 13 SU S MA 1156-376 BP 1916 EP 1916 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK8PH UT WOS:000375188702762 ER PT J AU Lerman, J Joshi, A Rodante, J Aberra, T Kabbany, MT Salahuddin, T Ng, Q Silverman, J Chen, M Bluemke, D Playford, M Mehta, N AF Lerman, Joseph Joshi, Aditya Rodante, Justin Aberra, Tsion Kabbany, Mohammad Tarek Salahuddin, Taufiq Qimin Ng Silverman, Joanna Chen, Marcus Bluemke, David Playford, Martin Mehta, Nehal TI IMPROVEMENT IN PSORIASIS SKIN DISEASE SEVERITY IS ASSOCIATED WITH REDUCTION OF CORONARY PLAQUE BURDEN SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 65th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY APR 02-04, 2016 CL Chicago, IL SP Amer Coll Cardiol C1 [Lerman, Joseph; Joshi, Aditya; Rodante, Justin; Aberra, Tsion; Kabbany, Mohammad Tarek; Salahuddin, Taufiq; Qimin Ng; Silverman, Joanna; Chen, Marcus; Bluemke, David; Playford, Martin; Mehta, Nehal] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 5 PY 2016 VL 67 IS 13 SU S MA 1156-378 BP 1918 EP 1918 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK8PH UT WOS:000375188702764 ER PT J AU Albaeni, A Beydoun, MA Eid, S Beydoun, HA Chandra-Strobos, N AF Albaeni, Aiham Beydoun, May A. Eid, Shaker Beydoun, Hind A. Chandra-Strobos, Nisha TI RACE AND OUTCOMES FOLLOWING OUT OF HOSPITAL CARDIAC ARREST: THE CHANGING PLAYING FIELD 2002 TO 2012 SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 65th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY APR 02-04, 2016 CL Chicago, IL SP Amer Coll Cardiol C1 Johns Hopkins Univ, Baltimore, MD USA. NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 5 PY 2016 VL 67 IS 13 SU S MA 1271-388 BP 2030 EP 2030 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK8PH UT WOS:000375188702876 ER PT J AU Mehta, FF Son, J Hewitt, SC Jang, EJ Lydon, JP Korach, KS Chung, SH AF Mehta, Fabiola F. Son, Jieun Hewitt, Sylvia C. Jang, Eunjung Lydon, John P. Korach, Kenneth S. Chung, Sang-Hyuk TI Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus SO ONCOTARGET LA English DT Article DE progesterone receptor; estrogen receptor alpha; epithelium; female reproductive tract; mouse model; Pathology Section ID FEMALE REPRODUCTIVE-TRACT; PARACRINE REGULATION; MAMMARY-GLAND; BREAST-CANCER; ESTROUS-CYCLE; ER-ALPHA; IN-VIVO; GENE; BINDING; MICE AB While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P-4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P-4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor alpha (ER alpha) in the female reproductive tracts. Using knock-in mouse models expressing ERa mutants, we determined that the DNA-binding domain (DBD) and AF2 domain of ERa were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERa AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERa DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERa. Epithelial ERa was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus. C1 [Mehta, Fabiola F.; Son, Jieun; Jang, Eunjung; Chung, Sang-Hyuk] Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA. [Hewitt, Sylvia C.; Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Lydon, John P.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Chung, SH (reprint author), Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA. EM schung@uh.edu OI Korach, Kenneth/0000-0002-7765-418X FU Cancer Prevention and Research Institute of Texas [RP120617]; NIH [R01 CA188646, R01 HD042311]; Division of Intramural Research of the NIH, National Institute of Environmental Health Sciences Project [1ZIAES070065] FX The work was supported by the Cancer Prevention and Research Institute of Texas grant RP120617 (S.-H.C) and NIH grants R01 CA188646 (S.-H.C.) and R01 HD042311 (J.P.L.) and by the Division of Intramural Research of the NIH, National Institute of Environmental Health Sciences Project 1ZIAES070065 (S.C.H. and K.S.K.). NR 39 TC 1 Z9 1 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 5 PY 2016 VL 7 IS 14 BP 17455 EP 17467 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5TE UT WOS:000375699000016 PM 27007157 ER PT J AU Symonds, JM Ohm, AM Tan, AC Reyland, ME AF Symonds, Jennifer M. Ohm, Angela M. Tan, Aik-Choon Reyland, Mary E. TI PKC delta regulates integrin alpha(V)beta(3) expression and transformed growth of K-ras dependent lung cancer cells SO ONCOTARGET LA English DT Article DE PKC delta; lung cancer; integrins; KRAS; anchorage independent growth ID KINASE-C-DELTA; ANOIKIS RESISTANCE; NADPH OXIDASE; CYCLE ARREST; IN-VIVO; ALPHA; ACTIVATION; SURVIVAL; PHOSPHORYLATION; INVASIVENESS AB We have previously shown that Protein Kinase C delta (PKC delta) functions as a tumor promoter in non-small cell lung cancer (NSCLC), specifically in the context of K-ras addiction. Here we define a novel PKC delta -> integrin alpha(V)beta(3) -> Extracellular signal-Regulated Kinase (ERK) pathway that regulates the transformed growth of K-ras dependent NSCLC cells. To explore how PKC delta regulates tumorigenesis, we performed mRNA expression analysis in four KRAS mutant NSCLC cell lines that stably express scrambled shRNA or a PKC delta targeted shRNA. Analysis of PKC delta-dependent mRNA expression identified 3183 regulated genes, 210 of which were specifically regulated in K-ras dependent cells. Genes that regulate extracellular matrix and focal adhesion pathways were most highly represented in this later group. In particular, expression of the integrin pair, alpha(V)beta(3), was specifically reduced in K-ras dependent cells with depletion of PKC delta, and correlated with reduced ERK activation and reduced transformed growth as assayed by clonogenic survival. Re-expression of PKC delta restored ITGAV and ITGB3 mRNA expression, ERK activation and transformed growth, and this could be blocked by pretreatment with a alpha(V)beta(3) function-blocking antibody, demonstrating a requirement for integrin alpha(V)beta(3) downstream of PKC delta. Similarly, expression of integrin alpha(V) restored ERK activation and transformed growth in PKC delta depleted cells, and this could also be inhibited by pretreatment with PD98059. Our studies demonstrate an essential role for alpha(V)beta(3) and ERK signaling downstream of PKC delta in regulating the survival of K-ras dependent NSCLC cells, and identify PKC delta as a novel therapeutic target for the subset of NSCLC patients with K-ras dependent tumors. C1 [Symonds, Jennifer M.] Grad Sch, Program Canc Biol, Aurora, CO USA. [Ohm, Angela M.; Reyland, Mary E.] Sch Dent Med, Dept Craniofacial Biol, Aurora, CO USA. [Tan, Aik-Choon] Univ Colorado Anschutz Med Campus, Sch Med, Dept Med Oncol, Aurora, CO USA. [Symonds, Jennifer M.] NIDCR, Matrix & Morphogenesis Sect, NIH, Bethesda, MD USA. RP Reyland, ME (reprint author), Sch Dent Med, Dept Craniofacial Biol, Aurora, CO USA. EM Mary.Reyland@ucdenver.edu FU United Against Lung Cancer research award; NIH Lung SPORE grant [P50 CA58187, R01DE015648] FX This work was supported by a United Against Lung Cancer research award, a pilot grant from NIH Lung SPORE grant P50 CA58187, and R01DE015648 to MER. NR 51 TC 2 Z9 2 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 5 PY 2016 VL 7 IS 14 BP 17905 EP 17919 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5TE UT WOS:000375699000050 PM 26918447 ER PT J AU De Luca, P Dalton, GN Scalise, GD Moiola, CP Porretti, J Massillo, C Kordon, E Gardner, K Zalazar, F Flumian, C Todaro, L Vazquez, ES Meiss, R De Siervi, A AF De Luca, Paola Dalton, Guillermo N. Scalise, Georgina D. Moiola, Cristian P. Porretti, Juliana Massillo, Cintia Kordon, Edith Gardner, Kevin Zalazar, Florencia Flumian, Carolina Todaro, Laura Vazquez, Elba S. Meiss, Roberto De Siervi, Adriana TI CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs SO ONCOTARGET LA English DT Article DE CtBP1; metabolic syndrome; high fat diet; breast cancer; miRNAs ID MAMMARY-GLAND DEVELOPMENT; CANCER RISK; HIGH-FAT; PROSTATE-CANCER; PROGRESSION; PREVENTION; CELLS; TUMORIGENESIS; APOPTOSIS; EXPOSURE AB Metabolic syndrome (MeS) has been identified as a risk factor for breast cancer. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. High fat diet (HFD) increases intracellular NADH. We investigated the effect of CtBP1 hyperactivation by HFD intake on mouse breast carcinogenesis. We generated a MeS-like disease in female mice by chronically feeding animals with HFD. MeS increased postnatal mammary gland development and generated prominent duct patterns with markedly increased CtBP1 and Cyclin D1 expression. CtBP1 induced breast cancer cells proliferation. Serum from animals with MeS enriched the stem-like/progenitor cell population from breast cancer cells. CtBP1 increased breast tumor growth in MeS mice modulating multiple genes and miRNA expression implicated in cell proliferation, progenitor cells phenotype, epithelial to mesenchymal transition, mammary development and cell communication in the xenografts. These results define a novel function for CtBP1 in breast carcinogenesis. C1 [De Luca, Paola; Dalton, Guillermo N.; Scalise, Georgina D.; Moiola, Cristian P.; Porretti, Juliana; Massillo, Cintia; Zalazar, Florencia; De Siervi, Adriana] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt IBYME, Lab Oncol Mol & Nuevos Blancos Terapeut, RA-1033 Buenos Aires, DF, Argentina. [Kordon, Edith] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol Biol Mol & Celular, Buenos Aires, DF, Argentina. [Kordon, Edith] Consejo Nacl Invest Cient & Tecn, Inst Fisiol Biol Mol & Neurociencias IFIBYNE, RA-1033 Buenos Aires, DF, Argentina. [Gardner, Kevin] NCI, NIH, Bethesda, MD 20892 USA. [Flumian, Carolina; Todaro, Laura] Univ Buenos Aires, Inst Oncol AH Roffo, Area Invest, Buenos Aires, DF, Argentina. [Vazquez, Elba S.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Biol, Lab Inflamac & Canc,IQUIBICEN,CONICET, Buenos Aires, DF, Argentina. [Meiss, Roberto] Acad Nacl Med Buenos Aires, Inst Estudios Oncol, Dept Patol, Buenos Aires, DF, Argentina. RP De Siervi, A (reprint author), Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt IBYME, Lab Oncol Mol & Nuevos Blancos Terapeut, RA-1033 Buenos Aires, DF, Argentina. EM adrianadesiervi@gmail.com FU Argentinean Agency of Science and Technology (ANPCyT) [PICT 2014-324, PICT 2013-2151, PICT 2012-00374]; Fundacion Williams (Argentina); Fundacion Rene Baron (Argentina) FX This research was supported by the Argentinean Agency of Science and Technology (ANPCyT PICT 2014-324; ANPCyT PICT 2013-2151; ANPCyT PICT 2012-00374). We thank the Fundacion Williams (Argentina) and Fundacion Rene Baron (Argentina) for their support. Part of the figures in this work was completed for the undergraduate thesis of G.N. Dalton. NR 43 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD APR 5 PY 2016 VL 7 IS 14 BP 18798 EP 18811 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5TE UT WOS:000375699000121 PM 26933806 ER PT J AU Yuan, L Zhi, W Liu, YS Smiley, E Gallagher, D Chen, X Dietrich, AM Zhang, HS AF Yuan, Li Zhi, Wei Liu, Yangsheng Smiley, Elizabeth Gallagher, Daniel Chen, Xi Dietrich, Andrea M. Zhang, Husen TI Degradation of cis- and trans-(4-methylcyclohexyl) methanol in activated sludge SO JOURNAL OF HAZARDOUS MATERIALS LA English DT Article DE West Virginia Chemical Spill; Crude (4-methylcyclohexyl)methanol; Activated sludge; Biodegradation kinetics; Transformation products ID WATER TREATMENT PLANTS; VOLATILE FATTY-ACIDS; FLOW CONSTRUCTED WETLAND; VIRGINIA CHEMICAL SPILL; WEST-VIRGINIA; WASTE-WATER; COMMUNITY COMPOSITION; NITRATE REDUCTION; FUNCTIONAL GENES; NITROGEN REMOVAL AB Crude (4-methylcyclohexyl)methanol (MCHM) caused extensive contamination of drinking water, wastewater, and the environment during the 2014 West Virginia Chemical Spill. However, information related to the environmental degradation of cis- and trans-4-MCHM, the main components of the crude 4-MCHM mixture, remains largely unknown. This study is among the first to investigate the degradation kinetics and transformation of 4-MCHM isomers in activated sludge. The 4-MCHM loss was mainly due to biodegradation to form carbon dioxide (CO2), plus acetic, propionic, isobutyric, and isovaleric acids with little contribution from adsorption. The biodegradation of 4-MCHM isomers followed the first-order kinetic model with half-lives higher than 0.50 days. Nitrate augmented the degradation of 4-MCHM isomers, while glucose and acetate decreased their degradation. One 4-MCHM-degrading bacterium isolated from activated sludge was identified as Acinetobacter bouvetii strain EU40 based on 16S rRNA gene sequences. This study will enhance the prediction of the environmental fate of 4-MCHM in water treatment systems. (C) 2015 Elsevier B.V. All rights reserved. C1 [Yuan, Li; Zhi, Wei; Smiley, Elizabeth; Gallagher, Daniel; Dietrich, Andrea M.; Zhang, Husen] Virginia Polytech Inst & State Univ, Dept Civil & Environm Engn, Blacksburg, VA 24061 USA. [Yuan, Li; Liu, Yangsheng] Peking Univ, Coll Environm Sci & Engn, Beijing 100871, Peoples R China. [Chen, Xi] Columbia Univ, Dept Earth & Environm Engn, New York, NY 10027 USA. RP Zhang, HS (reprint author), NCI, Bldg 37,Room 4137,37 Convent Dr, Bethesda, MD 20892 USA. EM husen@vt.edu RI Chen, Xi/B-1539-2008 OI Chen, Xi/0000-0002-2428-180X FU Virginia Tech College of Engineering; China Scholarship Council (CSC); National Natural Science Foundation of China [11172231, 11372241]; AFOSR [FA9550-12-1-0159]; ARPA-E [DE-AR0000396]; National Science Foundation, CBET [1424234] FX This work was supported by Dr. Zhang's startup funds provided by Virginia Tech College of Engineering. Li Yuan acknowledges support from the China Scholarship Council (CSC) visiting scholarship. The work of Xi Chen was supported by National Natural Science Foundation of China (11172231 and 11372241), AFOSR (FA9550-12-1-0159), and ARPA-E (DE-AR0000396). The research was performed in conjunction with National Science Foundation, CBET Award # 1424234 in which the headspace and GC-MS methods for 4-MCHM were developed. NR 55 TC 1 Z9 1 U1 5 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3894 EI 1873-3336 J9 J HAZARD MATER JI J. Hazard. Mater. PD APR 5 PY 2016 VL 306 BP 247 EP 256 DI 10.1016/j.jhazmat.2015.12.016 PG 10 WC Engineering, Environmental; Engineering, Civil; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA DK3FV UT WOS:000374803400027 PM 26745518 ER PT J AU Jensen, CD Corley, DA Quinn, VP Doubeni, CA Zauber, AG Lee, JK Zhao, WK Marks, AR Schottinger, JE Ghai, NR Lee, AT Contreras, R Klabunde, CN Quesenberry, CP Levin, TR Mysliwiec, PA AF Jensen, Christopher D. Corley, Douglas A. Quinn, Virginia P. Doubeni, Chyke A. Zauber, Ann G. Lee, Jeffrey K. Zhao, Wei K. Marks, Amy R. Schottinger, Joanne E. Ghai, Nirupa R. Lee, Alexander T. Contreras, Richard Klabunde, Carrie N. Quesenberry, Charles P. Levin, Theodore R. Mysliwiec, Pauline A. TI Fecal Immunochemical Test Program Performance Over 4 Rounds of Annual Screening A Retrospective Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID OCCULT-BLOOD-TEST; COLORECTAL-CANCER MORTALITY; RANDOMIZED-CLINICAL-TRIAL; COLLEGE-OF-RADIOLOGY; SERVICES TASK-FORCE; AMERICAN-COLLEGE; ADENOMATOUS POLYPS; QUALITY INDICATORS; JOINT GUIDELINE; COLONOSCOPY AB Background: The fecal immunochemical test (FIT) is a common method for colorectal cancer (CRC) screening, yet its acceptability and performance over several rounds of annual testing are largely unknown. Objective: To assess FIT performance characteristics over 4 rounds of annual screening. Design: Retrospective cohort study. Setting: Kaiser Permanente Northern and Southern California. Patients: 323 349 health plan members aged 50 to 70 years on their FIT mailing date in 2007 or 2008 who completed the first round of FIT and were followed for up to 4 screening rounds. Measurements: Screening participation, FIT positivity (>= 20 mu g of hemoglobin/g), positive predictive values for adenoma and CRC, and FIT sensitivity for detecting CRC obtained from Kaiser Permanente electronic databases and cancer registries. Results: Of the patients invited for screening, 48.2% participated in round 1. Of those who remained eligible, 75.3% to 86.1% participated in subsequent rounds. Median follow-up was 4.0 years, and 32% of round 1 participants crossed over to endoscopy over 4 screening rounds-7.0% due to a positive FIT result. The FIT positivity rate (5.0%) and positive predictive values (adenoma, 51.5%; CRC, 3.4%) were highest in round 1. Overall, programmatic FIT screening detected 80.4% of patients with CRC diagnosed within 1 year of testing, including 84.5% in round 1 and 73.4% to 78.0% in subsequent rounds. Limitation: Screening detection, rather than long-term cancer prevention, was evaluated. Conclusion: Annual FIT screening was associated with high sensitivity for CRC, with high adherence to annual follow-up screening among initial participants. The findings indicate that annual programmatic FIT screening is feasible and effective for population-level CRC screening. C1 Kaiser Permanente No Calif, Oakland, CA USA. [Quinn, Virginia P.; Ghai, Nirupa R.; Contreras, Richard] Kaiser Permanente So Calif, Dept Res & Evaluat, 100 South Los Robles,2nd Floor, Pasadena, CA 91101 USA. [Doubeni, Chyke A.] Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, 3400 Spruce St,Gate 2, Philadelphia, PA 19104 USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, 485 Lexington Ave,2063A, New York, NY 10017 USA. [Lee, Jeffrey K.] Univ Calif San Francisco, Div Gastroenterol, 1701 Divisadero St,Suite 120, San Francisco, CA 94115 USA. [Klabunde, Carrie N.] NIH, Off Dis Prevent, 6100 Execut Blvd,Suite 2B03, Rockville, MD 20852 USA. [Schottinger, Joanne E.] Kaiser Permanente So Calif, Permanente Med Grp, 393 East Walnut St, Pasadena, CA 91188 USA. [Lee, Alexander T.] Kaiser Permanente So Calif, Permanente Med Grp, Woodland Hills Med Ctr, 5601 De Soto Ave, Woodland Hills, CA 91365 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, 1425 South Main St, Walnut Creek, CA 94596 USA. [Mysliwiec, Pauline A.] Permanente Med Grp Inc, 975 Sereno Dr, Vallejo, CA 94589 USA. RP Corley, DA (reprint author), Kaiser Permanente, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM douglas.corley@kp.org FU National Institutes of Health FX National Institutes of Health. NR 33 TC 20 Z9 20 U1 1 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD APR 5 PY 2016 VL 164 IS 7 BP 456 EP + DI 10.7326/M15-0983 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DI6QP UT WOS:000373625300007 PM 26811150 ER PT J AU Taichman, DB Backus, J Baethge, C Bauchner, H de Leeuw, PW Drazen, JM Fletcher, J Frizelle, FA Groves, T Haileamlak, A James, A Laine, C Peiperl, L Pinborg, A Sahni, P AF Taichman, Darren B. Backus, Joyce Baethge, Christopher Bauchner, Howard de Leeuw, Peter W. Drazen, Jeffrey M. Fletcher, John Frizelle, Frank A. Groves, Trish Haileamlak, Abraham James, Astrid Laine, Christine Peiperl, Larry Pinborg, Anja Sahni, Peush TI Sharing Clinical Trial Data: A Proposal From the International Committee of Medical Journal Editors SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Taichman, Darren B.] ICMJE, Bethesda, MD USA. [Backus, Joyce] Natl Lib Med, Lib Operat, Bethesda, MD 20894 USA. [Sahni, Peush] World Assoc Med Editors, New York, NY USA. RP Taichman, DB (reprint author), Amer Coll Physicians, 190 N Independence Mall West, Philadelphia, PA 19106 USA. EM dtaichman@acponline.org OI Groves, Trish/0000-0001-7915-6419 NR 1 TC 13 Z9 13 U1 2 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD APR 5 PY 2016 VL 164 IS 7 BP 505 EP 506 DI 10.7326/M15-2928 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DI6QP UT WOS:000373625300015 PM 26792258 ER PT J AU Liang, M Raley, C Zheng, X Kutty, G Gogineni, E Sherman, BT Sun, Q Chen, XF Skelly, T Jones, K Stephens, R Zhou, B Lau, W Johnson, C Imamichi, T Jiang, MK Dewar, R Lempicki, RA Tran, B Kovacs, JA Huang, DW AF Liang, Ma Raley, Castle Zheng, Xin Kutty, Geetha Gogineni, Emile Sherman, Brad T. Sun, Qiang Chen, Xiongfong Skelly, Thomas Jones, Kristine Stephens, Robert Zhou, Bin Lau, William Johnson, Calvin Imamichi, Tomozumi Jiang, Minkang Dewar, Robin Lempicki, Richard A. Tran, Bao Kovacs, Joseph A. Huang, Da Wei TI Distinguishing highly similar gene isoforms with a clustering-based bioinformatics analysis of PacBio single-molecule long reads SO BIODATA MINING LA English DT Article DE PacBio; Bioinformatics analysis; Gene isoforms; Repetitive sequences; Major surface glycoprotein; Pneumocystis; NGS; Uclust ID SURFACE GLYCOPROTEIN GENES; PNEUMOCYSTIS-CARINII; HUMAN TRANSCRIPTOME; ANTIGENIC VARIATION; GENOME; COMPLEXITY; CHALLENGES; PATHOGENS; SEQUENCE; TIME AB Background: Gene isoforms are commonly found in both prokaryotes and eukaryotes. Since each isoform may perform a specific function in response to changing environmental conditions, studying the dynamics of gene isoforms is important in understanding biological processes and disease conditions. However, genome-wide identification of gene isoforms is technically challenging due to the high degree of sequence identity among isoforms. Traditional targeted sequencing approach, involving Sanger sequencing of plasmid-cloned PCR products, has low throughput and is very tedious and time-consuming. Next-generation sequencing technologies such as Illumina and 454 achieve high throughput but their short read lengths are a critical barrier to accurate assembly of highly similar gene isoforms, and may result in ambiguities and false joining during sequence assembly. More recently, the third generation sequencer represented by the PacBio platform offers sufficient throughput and long reads covering the full length of typical genes, thus providing a potential to reliably profile gene isoforms. However, the PacBio long reads are error-prone and cannot be effectively analyzed by traditional assembly programs. Results: We present a clustering-based analysis pipeline integrated with PacBio sequencing data for profiling highly similar gene isoforms. This approach was first evaluated in comparison to de novo assembly of 454 reads using a benchmark admixture containing 10 known, cloned msg genes encoding the major surface glycoprotein of Pneumocystis jirovecii. All 10 msg isoforms were successfully reconstructed with the expected length (similar to 1.5 kb) and correct sequence by the new approach, while 454 reads could not be correctly assembled using various assembly programs. When using an additional benchmark admixture containing 22 known P. jirovecii msg isoforms, this approach accurately reconstructed all but 4 these isoforms in their full-length (similar to 3 kb); these 4 isoforms were present in low concentrations in the admixture. Finally, when applied to the original clinical sample from which the 22 known msg isoforms were cloned, this approach successfully identified not only all known isoforms accurately (similar to 3 kb each) but also 48 novel isoforms. Conclusions: PacBio sequencing integrated with the clustering-based analysis pipeline achieves high-throughput and high-resolution discrimination of highly similar sequences, and can serve as a new approach for genome-wide characterization of gene isoforms and other highly repetitive sequences. C1 [Liang, Ma; Kutty, Geetha; Gogineni, Emile; Kovacs, Joseph A.] Ctr Clin, Crit Care Med Dept, Frederick, MD USA. [Raley, Castle; Zheng, Xin; Sherman, Brad T.; Sun, Qiang; Chen, Xiongfong; Skelly, Thomas; Jones, Kristine; Stephens, Robert; Imamichi, Tomozumi; Jiang, Minkang; Dewar, Robin; Lempicki, Richard A.; Tran, Bao; Huang, Da Wei] NIH, Leidos BioMed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Zhou, Bin; Lau, William; Johnson, Calvin] NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Huang, Da Wei] NCI, NIH, Bethesda, MD 20892 USA. RP Huang, DW (reprint author), NIH, Leidos BioMed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. EM huangdawei@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH Clinical Center; National Institute of Allergy and Infectious Disease FX We thank Biswajit Das, Dun Liang, Jun Yang, Xiaoli Jiao, Xiaojun Hu and Ju Qiu for technical support and discussions throughout the course of this research. This work was supported by the National Cancer Institute, National Institutes of Health (Contract HHSN261200800001E); the Intramural Research Program of the NIH Clinical Center; and the National Institute of Allergy and Infectious Disease. The contents do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 35 TC 1 Z9 1 U1 4 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-0381 J9 BIODATA MIN JI BioData Min. PD APR 5 PY 2016 VL 9 AR 13 DI 10.1186/s13040-016-0090-8 PG 13 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DI7FB UT WOS:000373663600001 PM 27051465 ER PT J AU Ordonez-Mena, JM Schottker, B Mons, U Jenab, M Freisling, H Bueno-De-Mesquita, B O'Doherty, MG Scott, A Kee, F Stricker, BH Hofman, A de Keyser, CE Ruiter, R Soderberg, S Jousilahti, P Kuulasmaa, K Freedman, ND Wilsgaard, T de Groot, LCPGM Kampman, E Hakansson, N Orsini, N Wolk, A Nilsson, LM Tjonneland, A Pajak, A Malyutina, S Kubinova, R Tamosiunas, A Bobak, M Katsoulis, M Orfanos, P Boffetta, P Trichopoulou, A Brenner, H AF Ordonez-Mena, Jose Manuel Schoettker, Ben Mons, Ute Jenab, Mazda Freisling, Heinz Bueno-de-Mesquita, Bas O'Doherty, Mark G. Scott, Angela Kee, Frank Stricker, Bruno H. Hofman, Albert de Keyser, Catherine E. Ruiter, Rikje Soderberg, Stefan Jousilahti, Pekka Kuulasmaa, Kari Freedman, Neal D. Wilsgaard, Tom de Groot, Lisette C. P. G. M. Kampman, Ellen Hakansson, Niclas Orsini, Nicola Wolk, Alicja Nilsson, Lena Maria Tjonneland, Anne Pajak, Andrzej Malyutina, Sofia Kubinova, Ruzena Tamosiunas, Abdonas Bobak, Martin Katsoulis, Michail Orfanos, Philippos Boffetta, Paolo Trichopoulou, Antonia Brenner, Hermann CA Consortium Hlth & Ageing Network C TI Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium SO BMC MEDICINE LA English DT Article DE Smoking; Cancer; Incidence; Mortality; Cohort; Meta-analysis ID CIGARETTE-SMOKING; BREAST-CANCER; LUNG-CANCER; PROSTATE-CANCER; EPIDEMIOLOGIC EVIDENCE; MEDITERRANEAN DIET; COLORECTAL-CANCER; PANCREATIC-CANCER; QUITTING SMOKING; SMOKERS AB Background: Smoking is the most important individual risk factor for many cancer sites but its association with breast and prostate cancer is not entirely clear. Rate advancement periods (RAPs) may enhance communication of smoking related risk to the general population. Thus, we estimated RAPs for the association of smoking exposure (smoking status, time since smoking cessation, smoking intensity, and duration) with total and site-specific (lung, breast, colorectal, prostate, gastric, head and neck, and pancreatic) cancer incidence and mortality. Methods: This is a meta-analysis of 19 population-based prospective cohort studies with individual participant data for 897,021 European and American adults. For each cohort we calculated hazard ratios (HRs) for the association of smoking exposure with cancer outcomes using Cox regression adjusted for a common set of the most important potential confounding variables. RAPs (in years) were calculated as the ratio of the logarithms of the HRs for a given smoking exposure variable and age. Meta-analyses were employed to summarize cohort-specific HRs and RAPs. Results: Overall, 140,205 subjects had a first incident cancer, and 53,164 died from cancer, during an average follow-up of 12 years. Current smoking advanced the overall risk of developing and dying from cancer by eight and ten years, respectively, compared with never smokers. The greatest advancements in cancer risk and mortality were seen for lung cancer and the least for breast cancer. Smoking cessation was statistically significantly associated with delays in the risk of cancer development and mortality compared with continued smoking. Conclusions: This investigation shows that smoking, even among older adults, considerably advances, and cessation delays, the risk of developing and dying from cancer. These findings may be helpful in more effectively communicating the harmful effects of smoking and the beneficial effect of smoking cessation. C1 [Ordonez-Mena, Jose Manuel; Schoettker, Ben; Brenner, Hermann] Heidelberg Univ, Network Aging Res, Heidelberg, Germany. [Ordonez-Mena, Jose Manuel; Schoettker, Ben; Mons, Ute; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. [Jenab, Mazda; Freisling, Heinz] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Bueno-de-Mesquita, Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Chron Dis, Bilthoven, Netherlands. [Bueno-de-Mesquita, Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, Bas] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Div Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, Bas] Univ Malaya, Dept Social Prevent Med, Fac Med, Kuala Lumpur, Malaysia. [O'Doherty, Mark G.; Scott, Angela; Kee, Frank] Queens Univ Belfast, UKCRC Ctr Excellence Publ Hlth, Belfast, Antrim, North Ireland. [Stricker, Bruno H.; Hofman, Albert; de Keyser, Catherine E.; Ruiter, Rikje] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Soderberg, Stefan] Umea Univ, Dept Publ Hlth & Clin Med, Cardiol & Heart Ctr, Umea, Sweden. [Jousilahti, Pekka; Kuulasmaa, Kari] Natl Inst Hlth & Welf THL, Helsinki, Finland. [Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Wilsgaard, Tom] UiT Arctic Univ Norway, Dept Community Med, Tromso, Norway. [de Groot, Lisette C. P. G. M.; Kampman, Ellen] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Hakansson, Niclas; Orsini, Nicola; Wolk, Alicja] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Nilsson, Lena Maria] Umea Univ, Dept Publ Hlth & Clin Med, Nutr Res, Arctic Res Ctr, Umea, Sweden. [Nilsson, Lena Maria] Umea Univ, Arcum, Arctic Res Ctr, Umea, Sweden. [Tjonneland, Anne] Danish Canc Soc, Res Ctr, Diet Genes & Environm, Copenhagen, Denmark. [Pajak, Andrzej] Jagiellonian Univ, Coll Med, Fac Hlth Sci, Krakow, Poland. [Malyutina, Sofia] Inst Internal & Prevent Med, Novosibirsk, Russia. [Kubinova, Ruzena] Natl Inst Publ Hlth, Prague, Czech Republic. [Tamosiunas, Abdonas] Lithuanian Univ Hlth Sci, Inst Cardiol, Kaunas, Lithuania. [Bobak, Martin] UCL, Dept Epidemiol & Publ Hlth, London, England. [Katsoulis, Michail; Boffetta, Paolo; Trichopoulou, Antonia] Hellen Hlth Fdn, Athens, Greece. [Orfanos, Philippos; Trichopoulou, Antonia] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. RP Brenner, H (reprint author), Heidelberg Univ, Network Aging Res, Heidelberg, Germany.; Brenner, H (reprint author), German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Neuenheimer Feld 581, D-69120 Heidelberg, Germany.; Brenner, H (reprint author), German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany.; Brenner, H (reprint author), German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. EM h.brenner@dkfz.de RI Brenner, Hermann/B-4627-2017; OI Brenner, Hermann/0000-0002-6129-1572; Kuulasmaa, Kari/0000-0003-2165-1411; Ordonez-Mena, Jose Manuel/0000-0002-8965-104X; Kontto, Jukka/0000-0003-3899-9852 FU FP7 framework program of DG-RESEARCH the European Commission [242244]; Swedish Research Council; Swedish Cancer Foundation; Baden-Wurttemberg state Ministry of Science, Research and Arts (Stuttgart, Germany); Federal Ministry of Education and Research (Berlin, Germany); Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany); Hellenic Health Foundation; European Commission (DG SANCO); Dutch Ministry of Public Health, Welfare and Sports (VWS); National Institute for Public Health and the Environment (RIVM); Netherlands Cancer Registry (NKR); Netherlands Organizaton for Health Research and Development (ZONMW); World Cancer Research Fund (WCRF); Statistics Netherlands; Health Research Fund (FIS) of the Spanish Ministry of Health RTICC 'Red Tematica de Investigacion Cooperativa en Cancer [Rd06/0070/0091, Rd12/0036/0018]; Regional Governments of Andalucia, Asturias, Basque Country, Murcia [6236]; Navarra, Institute de Salud Carlos III, Redes de Investigacion Cooperativa [RD06/0020]; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane; Danish Cancer Society; Welcome Trust [064947, 081081]; US National Institute on Ageing [R01 AG23522]; Mac Arthur Foundation; Institut National de la Sante et de la Recherche Medicale (INSERM), Merck; Sharp & Dohme-Chibret Laboratory; Department of Health and Social Services; Personal Safety for Northern Ireland; European Union [HEALTH-F4-2007-201413, 278913]; Intramural Program of the National Cancer Institute; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Ministry of 'Education Culture, and Science; Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; EU; Norwegian Research Council; Vasterbotten county Council; Swedish Council for Working Life and Social Research FX This work was supported by the FP7 framework program of DG-RESEARCH the European Commission (Grant no. 242244). The CHANCES project (www.chancesfp7.eu) is coordinated by the Hellenic Health Foundation, Greece. The Cohort of Swedish Men (CORM) and the Swedish Mammography Cohort (SMC) were supported by research grants from the Swedish Research Council and the Swedish Cancer Foundation. The ESTHER study was funded by the Baden-Wurttemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), and the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany). The EPIC Greece study was funded by the Hellenic Health Foundation. The EPIC Netherlands study was funded by European Commission (DG SANCO), Dutch Ministry of Public Health, Welfare and Sports (VWS), The National Institute for Public Health and the Environment (RIVM), the Netherlands Cancer Registry (NKR), the Netherlands Organizaton for Health Research and Development (ZONMW), the World Cancer Research Fund (WCRF) and Statistics Netherlands. The EPIC Spain study was supported by Health Research Fund (FIS) of the Spanish Ministry of Health RTICC 'Red Tematica de Investigacion Cooperativa en Cancer (Grant numbers: Rd06/0070/0091 and Rd12/0036/0018), Regional Governments of Andalucia, Asturias, Basque Country, Murcia (project 6236) and Navarra, Institute de Salud Carlos III, Redes de Investigacion Cooperativa (RD06/0020). The EPIC Sweden study was funded by the Swedish Cancer Society, the Swedish Scientific Council and the Regional Government of Skane. The EPIC Denmark study was funded by the Danish Cancer Society. The HAPIEE study was funded by the Welcome Trust (064947 and 081081), the US National Institute on Ageing (R01 AG23522), and a grant from Mac Arthur Foundation. MORGAM PRIME was supported by grants from the Institut National de la Sante et de la Recherche Medicale (INSERM), Merck, Sharp & Dohme-Chibret Laboratory and the Department of Health and Social Services and Personal Safety for Northern Ireland. In addition to the FP7 ftmding for CHANCES, the MORGAM project received funding from the European Union FP7 projects ENGAGE (HEALTH-F4-2007-201413) and BiomarCaRE (278913). This supported central coordination, workshops and part of the activities of the MORGAM Data Center at THL in Helsinki, Finland. MORGAM Participating Centers are funded by regional and national governments, research councils, charities, and other local Socities. The National Institutes of Health (NIH)-AARP cohort was funded by the Intramural Program of the National Cancer Institute. The Rotterdam Study (RS) is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of 'Education Culture, and Science; the Ministry of Health, Welfare, and Sports; the European Commission; and the Municipality of Rotterdam. The SENECA study was funded as a Concerted Action within the EURONUT programme of the EU. The TROMSO Study was funded by the Norwegian Research Council and peformed by the University of Tromso in cooperation the National Health Screening Service. The Vasterbotten Intervention Program (VIP) was supported by grants from the Vasterbotten county Council, the Swedish Council for Working Life and Social Research, and the Swedish Research Council.; The study's funders had no influence on the design of the study, analysis and interpretation of the data, writing, review, approval or submission of the manuscript. NR 42 TC 1 Z9 1 U1 4 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD APR 5 PY 2016 VL 14 AR 62 DI 10.1186/s12916-016-0607-5 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DI3YY UT WOS:000373438100001 PM 27044418 ER PT J AU Pasquali, SK Jacobs, JP Farber, GK Bertoch, D Blume, ED Burns, KM Campbell, R Chang, AC Chung, WK Riehle-Colarusso, T Curtis, LH Forrest, CB Gaynor, WJ Gaies, MG Go, AS Henchey, P Martin, GR Pearson, G Pemberton, VL Schwartz, SM Vincent, R Kaltman, JR AF Pasquali, Sara K. Jacobs, Jeffrey P. Farber, Gregory K. Bertoch, David Blume, Elizabeth D. Burns, Kristin M. Campbell, Robert Chang, Anthony C. Chung, Wendy K. Riehle-Colarusso, Tiffany Curtis, Lesley H. Forrest, Christopher B. Gaynor, William J. Gaies, Michael G. Go, Alan S. Henchey, Paul Martin, Gerard R. Pearson, Gail Pemberton, Victoria L. Schwartz, Steven M. Vincent, Robert Kaltman, Jonathan R. TI Report of the National Heart, Lung, and Blood Institute Working Group An Integrated Network for Congenital Heart Disease Research SO CIRCULATION LA English DT Article DE database [publication type]; heart diseases; outcome assessment; health care ID LEARNING HEALTH SYSTEM; PEDIATRIC CARDIAC-DISEASE; CLINICAL REGISTRY DATA; INDIRECT IDENTIFIERS; ADMINISTRATIVE DATA; SURGERY; LINKING; OUTCOMES; QUALITY; CARE AB The National Heart, Lung, and Blood Institute convened a working group in January 2015 to explore issues related to an integrated data network for congenital heart disease research. The overall goal was to develop a common vision for how the rapidly increasing volumes of data captured across numerous sources can be managed, integrated, and analyzed to improve care and outcomes. This report summarizes the current landscape of congenital heart disease data, data integration methodologies used across other fields, key considerations for data integration models in congenital heart disease, and the short- and long-term vision and recommendations made by the working group. C1 [Pasquali, Sara K.; Gaies, Michael G.] Univ Michigan, CS Mott Childrens Hosp, Dept Pediat & Communicable Dis, Ann Arbor, MI 48105 USA. [Jacobs, Jeffrey P.] Johns Hopkins All Childrens Heart Inst, Dept Surg, St Petersburg, FL USA. [Farber, Gregory K.] NIMH, NIH, Bethesda, MD 20892 USA. [Bertoch, David] Childrens Hosp Assoc, Overland Pk, KS USA. [Blume, Elizabeth D.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Burns, Kristin M.; Pearson, Gail; Pemberton, Victoria L.; Kaltman, Jonathan R.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Campbell, Robert; Vincent, Robert] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Chang, Anthony C.] Childrens Hosp Orange Cty, Dept Pediat, Orange, CA 92668 USA. [Chung, Wendy K.] Columbia Univ, Dept Pediat & Med, New York, NY USA. [Riehle-Colarusso, Tiffany] Ctr Dis Control & Prevent, Div Birth Defects & Dev Disabil, Atlanta, GA USA. [Curtis, Lesley H.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Forrest, Christopher B.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA USA. [Gaynor, William J.] Childrens Hosp Philadelphia, Dept Surg, Philadelphia, PA USA. [Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Henchey, Paul] ArborMetrix Inc, Ann Arbor, MI USA. [Martin, Gerard R.] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Pediat, Washington, DC USA. [Schwartz, Steven M.] Hosp Sick Children, Dept Crit Care Med, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Schwartz, Steven M.] Hosp Sick Children, Dept Paediat, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Schwartz, Steven M.] Univ Toronto, Sch Med, Toronto, ON M5S 1A1, Canada. RP Pasquali, SK (reprint author), Univ Michigan, CS Mott Childrens Hosp, 1540 E Hosp Dr, Ann Arbor, MI 48105 USA. EM pasquali@med.umich.edu FU NHLBI FX This working group was funded by the NHLBI. The views and conclusions expressed in this report are those of the authors and do not necessarily represent the official position of the NHLBI, the National Institutes of Health, or the Centers for Disease Control and Prevention. NR 40 TC 6 Z9 6 U1 0 U2 5 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 APR 5 PY 2016 VL 133 IS 14 BP 1410 EP 1418 DI 10.1161/CIRCULATIONAHA.115.019506 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DI1ZE UT WOS:000373294700009 PM 27045129 ER PT J AU Drummond, RA Lionakis, MS AF Drummond, Rebecca A. Lionakis, Michail S. TI Mechanistic Insights into the Role of C-Type Lectin Receptor/CARD9 Signaling in Human Antifungal Immunity SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Review DE CARD9; lectins; fungi; Candida; neutrophils; innate immunity ID PATTERN-RECOGNITION RECEPTOR; CANDIDA-ALBICANS INFECTIONS; INHERITED CARD9 DEFICIENCY; HOST-DEFENSE; FUNGAL-INFECTION; COMBINED IMMUNODEFICIENCY; INNATE IMMUNITY; CELL-DIFFERENTIATION; DEEP DERMATOPHYTOSIS; INDUCED ACTIVATION AB Human CARD9 deficiency is an autosomal recessive primary immunodeficiency disorder caused by biallelic mutations in the gene CARD9, which encodes a signaling protein that is found downstream of many C-type lectin receptors (CLRs). CLRs encompass a large family of innate recognition receptors, expressed predominantly by myeloid and epithelial cells, which bind fungal carbohydrates and initiate antifungal immune responses. Accordingly, human CARD9 deficiency is associated with the spontaneous development of persistent and severe fungal infections that primarily localize to the skin and subcutaneous tissue, mucosal surfaces and/or central nervous system (CNS). In the last 3 years, more than 15 missense and nonsense CARD9 mutations have been reported which associate with the development of a wide spectrum of fungal infections caused by a variety of fungal organisms. The mechanisms by which CARD9 provides organ-specific protection against these fungal infections are now emerging. In this review, we summarize recent immunological and clinical advances that have provided significant mechanistic insights into the pathogenesis of human CARD9 deficiency. We also discuss how genetic mutations in CARD9-coupled receptors (Dectin-1, Dectin-2) and CARD9-binding partners (MALT1, BCL10) affect human antifungal immunity relative to CARD9 deficiency, and we highlight major understudied research questions which merit future investigation. C1 [Drummond, Rebecca A.; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lionakism@mail.nih.gov OI Drummond, Rebecca/0000-0001-5424-7074 FU Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases) FX This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases). NR 67 TC 3 Z9 3 U1 3 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD APR 5 PY 2016 VL 6 AR 39 DI 10.3389/fcimb.2016.00039 PG 11 WC Immunology; Microbiology SC Immunology; Microbiology GA DI3WI UT WOS:000373430400001 PM 27092298 ER PT J AU Thurm, A Tierney, E Farmer, C Albert, P Joseph, L Swedo, S Bianconi, S Bukelis, I Wheeler, C Sarphare, G Lanham, D Wassif, CA Porter, FD AF Thurm, Audrey Tierney, Elaine Farmer, Cristan Albert, Phebe Joseph, Lisa Swedo, Susan Bianconi, Simona Bukelis, Irena Wheeler, Courtney Sarphare, Geeta Lanham, Diane Wassif, Christopher A. Porter, Forbes D. TI Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update SO JOURNAL OF NEURODEVELOPMENTAL DISORDERS LA English DT Article DE Smith-Lemli-Opitz; Autism; Developmental delay; Sterols ID AUTISM SPECTRUM DISORDERS; DIAGNOSTIC OBSERVATION SCHEDULE; CHOLESTEROL-SYNTHESIS; GENETIC SYNDROMES; REDUCTASE GENE; FRAGILE-X; PHENOTYPE; CHILDREN; PREVALENCE; MUTATIONS AB Background: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive inborn error of cholesterol metabolism syndrome with neurocognitive manifestations. SLOS is the result of mutations in the gene encoding the 7-dehydrocholesterol reductase, which results in the elevation of the cholesterol precursor 7-dehydrocholesterol (7-DHC). Previous reports indicate that intellectual disability, behavioral disturbances, and autism symptoms are frequently part of the SLOS behavioral phenotype. In the current study, we characterize the developmental history and current behavior of 33 individuals with SLOS aged 4 to 23 years and report on biomarkers 7-DHC and 8-DHC in relation to cognition and behavior. Methods: This was an observational case series, wherein participants with SLOS underwent extensive behavioral evaluation of cognitive function, adaptive function, autism symptoms, and problem behaviors, in addition to parent report of developmental milestones. Serum and CSF were contemporaneously obtained from the majority of participants. Results: Developmental milestones such as walking, talking, and toileting were uniformly delayed. Overall levels of cognitive and adaptive functioning were low; no participant received adaptive behavior scores in the average range, and the mean level of cognitive functioning in the full sample was in the moderate range of impairment. Aggressive behavior was present in nearly half of participants. Although the majority of participants had elevated scores on the gold standard autism diagnostic instruments, only about half of participants received a clinical diagnosis of autism spectrum disorder. Finally, while CSF cholesterol was not found to correlate with cognitive or adaptive functioning, both serum and CSF 7-DHC and 8-DHC (and their ratios with cholesterol) were moderately and negatively correlated with functioning in this group. Conclusions: A history of developmental delay, followed by intellectual disability, is common in individuals with SLOS. Although autism spectrum disorder appears to be a frequent diagnosis in this population, it is apparent that the low level of functioning observed in SLOS may artificially inflate scores on standard autism assessments. Our findings further support that cholesterol precursors 7-DHC and 8-DHC are important biomarkers of the level of functioning in SLOS, especially regarding cognitive abilities, and thus may be to explore as mediators within the context of treatment trials. C1 [Thurm, Audrey; Farmer, Cristan; Albert, Phebe; Joseph, Lisa; Swedo, Susan] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Tierney, Elaine; Bukelis, Irena; Wheeler, Courtney; Sarphare, Geeta; Lanham, Diane] Kennedy Krieger Inst, 716 N Broadway, Baltimore, MD 21205 USA. [Bianconi, Simona; Wassif, Christopher A.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, Bethesda, MD 20892 USA. [Tierney, Elaine] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Tierney, E (reprint author), Kennedy Krieger Inst, 716 N Broadway, Baltimore, MD 21205 USA.; Tierney, E (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM tierney@kennedykrieger.org FU Intramural Research Program of the National Institute of Mental Health of the National Institutes of Health [ZIA MH002914]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Autism Speaks; Johns Hopkins Institute for Clinical and Translational Research (ICTR); National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) [UL1 TR 001079]; NIH Roadmap for Medical Research FX This work was supported by the Intramural Research Program (ZIA MH002914) of the National Institute of Mental Health of the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Autism Speaks, and by the Johns Hopkins Institute for Clinical and Translational Research (ICTR) which is funded in part by Grant Number UL1 TR 001079 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors, and the views expressed in this paper do not necessarily represent the views of the NIMH, NICHD, NIH, HHS, Johns Hopkins ICTR, NCATS, or the US Government. We give thanks to the individuals who have SLOS and their family members who participated in the clinical studies from which this data is derived. NR 39 TC 2 Z9 2 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1866-1947 EI 1866-1955 J9 J NEURODEV DISORD JI J. Neurodev. Disord. PD APR 5 PY 2016 VL 8 AR 12 DI 10.1186/s11689-016-9145-x PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI3VR UT WOS:000373427900001 PM 27053961 ER PT J AU Falcone, EL Abusleme, L Swamydas, M Lionakis, MS Ding, L Hsu, AP Zelazny, AM Moutsopoulos, NM Kuhns, DB Deming, C Quinones, M Segre, JA Bryant, CE Holland, SM AF Falcone, E. Liana Abusleme, Loreto Swamydas, Muthulekha Lionakis, Michail S. Ding, Li Hsu, Amy P. Zelazny, Adrian M. Moutsopoulos, Niki M. Kuhns, Douglas B. Deming, Clay Quinones, Mariam Segre, Julia A. Bryant, Clare E. Holland, Steven M. TI Colitis susceptibility in p47(phox-/-) mice is mediated by the microbiome SO MICROBIOME LA English DT Article DE Chronic granulomatous disease; NADPH; Reactive oxygen species; p47(phox); Microbiome; Inflammatory bowel disease; Colitis; Dextran sodium sulfate ID CHRONIC GRANULOMATOUS-DISEASE; OXIDASE COMPLEX; NADPH OXIDASE; CELLS; DIFFERENTIATION; IDENTIFICATION; SURVIVAL; BACTERIA; MUCOSA; MUCIN AB Background: Chronic granulomatous disease (CGD) is caused by defects in nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) complex subunits (gp91(phox) (a.k.a. Nox2), p47(phox), p67(phox), p22(phox), p40(phox)) leading to reduced phagocyte-derived reactive oxygen species production. Almost half of patients with CGD develop inflammatory bowel disease, and the involvement of the intestinal microbiome in relation to this predisposing immunodeficiency has not been explored. Results: Although CGD mice do not spontaneously develop colitis, we demonstrate that p47(phox-/-) mice have increased susceptibility to dextran sodium sulfate colitis in association with a distinct colonic transcript and microbiome signature. Neither restoring NOX2 reactive oxygen species production nor normalizing the microbiome using cohoused adult p47(phox-/-) with B6Tac (wild type) mice reversed this phenotype. However, breeding p47(phox+/-) mice and standardizing the microflora between littermate p47(phox-/-) and B6Tac mice from birth significantly reduced dextran sodium sulfate colitis susceptibility in p47(phox-/-) mice. We found similarly decreased colitis susceptibility in littermate p47(phox-/-) and B6Tac mice treated with Citrobacter rodentium. Conclusions: Our findings suggest that the microbiome signature established at birth may play a bigger role than phagocyte-derived reactive oxygen species in mediating colitis susceptibility in CGD mice. These data further support bacteria-related disease in CGD colitis. C1 [Falcone, E. Liana; Ding, Li; Hsu, Amy P.; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Abusleme, Loreto; Moutsopoulos, Niki M.] Natl Inst Dent & Craniofacial Res, Oral Immun & Inflammat Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Swamydas, Muthulekha; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] Leidos Biomed Res Inc, Neutrophil Monitoring Lab, Appl Dev Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA. [Deming, Clay; Segre, Julia A.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Quinones, Mariam] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bryant, Clare E.] Univ Cambridge, Dept Vet Med, Madingley Rd, Cambridge, England. RP Falcone, EL (reprint author), NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM emilia.falcone@nih.gov OI Falcone, Emilia/0000-0002-5486-1549 FU Division of Intramural Research, the NIAID, NIH; National Cancer Institute, NIH [HHSN261200800001E] FX This project was supported by the Division of Intramural Research, the NIAID, NIH, and in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. NR 29 TC 2 Z9 2 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD APR 5 PY 2016 VL 4 AR 13 DI 10.1186/s40168-016-0159-0 PG 16 WC Microbiology SC Microbiology GA DI7IN UT WOS:000373673000001 PM 27044504 ER PT J AU Bane, CE Ivanov, I Matafonov, A Boyd, KL Cheng, QF Sherwood, ER Tucker, EI Smiley, ST McCarty, OJT Gruber, A Gailani, D AF Bane, Charles E., Jr. Ivanov, Ivan Matafonov, Anton Boyd, Kelli L. Cheng, Qiufang Sherwood, Edward R. Tucker, Erik I. Smiley, Stephen T. McCarty, Owen J. T. Gruber, Andras Gailani, David TI Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice SO PLOS ONE LA English DT Article ID MOLECULAR-WEIGHT KININOGEN; COAGULATION-FACTOR-XI; FORMATION IN-VIVO; CECAL LIGATION; BLOOD-COAGULATION; HAGEMAN-FACTOR; HUMAN-PLASMA; ANTITHROMBOTIC THERAPY; MYOCARDIAL-INFARCTION; LIGHT-CHAIN AB Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-alpha and IL-10 and delayed IL-1 beta and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI(-/-)mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI(-/-)animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other. C1 [Bane, Charles E., Jr.; Ivanov, Ivan; Matafonov, Anton; Boyd, Kelli L.; Cheng, Qiufang; Gailani, David] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Matafonov, Anton] Tomsk Polytech Univ, Dept Bioengn & Organ Chem, Tomsk, Russia. [Sherwood, Edward R.] Vanderbilt Univ, Dept Anesthesiol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Tucker, Erik I.; Gruber, Andras] Aronora Inc, Portland, OR USA. [Smiley, Stephen T.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [McCarty, Owen J. T.; Gruber, Andras] Oregon Hlth & Sci Univ, Dept Biomed Engn, Portland, OR 97201 USA. RP Gailani, D (reprint author), Vanderbilt Univ, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA. EM dave.gailani@vanderbilt.edu FU National Institutes of Health [HL81326, HL58837, GM116184] FX The authors wish to acknowledge the support of National Institutes of Health grants HL81326 and HL58837 (DG) and GM116184 (OJM). DG is a consultant, and receives consultant's fees from several pharmaceutical companies. These fees were not used to support the work described in this manuscript. EIT and AG are employees of the company Aronora. Aronora provided support in the form of salaries for these individuals, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 74 TC 3 Z9 3 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 APR 5 PY 2016 VL 11 IS 4 AR e0152968 DI 10.1371/journal.pone.0152968 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI6HK UT WOS:000373599600053 PM 27046148 ER PT J AU Buck, CB AF Buck, Christopher B. TI Exposing the Molecular Machinery of BK Polyomavirus SO STRUCTURE LA English DT Editorial Material AB BK polyomavirus (BKV) is an opportunistic pathogen that poses a serious threat to organ transplant recipients. In this issue of Structure, Hurdiss and colleagues' (Hurdiss et al., 2016) beautiful new high-resolution cryo-EM reconstruction of BKV provides a structural roadmap for the ongoing development of therapeutic antibodies and vaccines targeting this potentially deadly virus. The study also serves as a platform for exploring the basic biology of virion assembly and infectious entry. C1 [Buck, Christopher B.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Buck, CB (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM buckc@mail.nih.gov NR 7 TC 0 Z9 0 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD APR 5 PY 2016 VL 24 IS 4 BP 495 EP 495 DI 10.1016/j.str.2016.03.011 PG 1 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DI5VN UT WOS:000373568700001 PM 27050683 ER PT J AU Adams, PD Aertgeerts, K Bauer, C Bell, JA Berman, HM Bhat, TN Blaney, JM Bolton, E Bricogne, G Brown, D Burley, SK Case, DA Clark, KL Darden, T Emsley, P Feher, VA Feng, ZK Groom, CR Harris, SF Hendle, J Holder, T Joachimiak, A Kleywegt, GJ Krojer, T Marcotrigiano, J Mark, AE Markley, JL Miller, M Minor, W Montelione, GT Murshudov, G Nakagawa, A Nakamura, H Nicholls, A Nicklaus, M Nolte, RT Padyana, AK Peishoff, CE Pieniazek, S Read, RJ Shao, CH Sheriff, S Smart, O Soisson, S Spurlino, J Stouch, T Svobodova, R Tempel, W Terwilliger, TC Tronrud, D Velankar, S Ward, SC Warren, GL Westbrook, JD Williams, P Yang, HW Young, J AF Adams, Paul D. Aertgeerts, Kathleen Bauer, Cary Bell, Jeffrey A. Berman, Helen M. Bhat, Talapady N. Blaney, Jeff M. Bolton, Evan Bricogne, Gerard Brown, David Burley, Stephen K. Case, David A. Clark, Kirk L. Darden, Tom Emsley, Paul Feher, Victoria A. Feng, Zukang Groom, Colin R. Harris, Seth F. Hendle, Jorg Holder, Thomas Joachimiak, Andrzej Kleywegt, Gerard J. Krojer, Tobias Marcotrigiano, Joseph Mark, Alan E. Markley, John L. Miller, Matthew Minor, Wladek Montelione, Gaetano T. Murshudov, Garib Nakagawa, Atsushi Nakamura, Haruki Nicholls, Anthony Nicklaus, Marc Nolte, Robert T. Padyana, Anil K. Peishoff, Catherine E. Pieniazek, Susan Read, Randy J. Shao, Chenghua Sheriff, Steven Smart, Oliver Soisson, Stephen Spurlino, John Stouch, Terry Svobodova, Radka Tempel, Wolfram Terwilliger, Thomas C. Tronrud, Dale Velankar, Sameer Ward, Suzanna C. Warren, Gregory L. Westbrook, John D. Williams, Pamela Yang, Huanwang Young, Jasmine TI Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop SO STRUCTURE LA English DT Article ID PROTEIN DATA-BANK; CAMBRIDGE STRUCTURAL DATABASE; ELECTRON-DENSITY; TASK-FORCE; INFORMATION; MACROMOLECULES; GENERATION; MOLECULES; TOOLS; PDB AB Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank (PDB) archive, similar to 75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery and design, and the goodness-of-fit of ligand models to electron-density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide PDB/Cambridge Crystallographic Data Center/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30-31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the PDB? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated. C1 [Adams, Paul D.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging Div, Berkeley, CA 94720 USA. [Aertgeerts, Kathleen] LLC, DART NeuroSci, San Diego, CA 92131 USA. [Bauer, Cary] Bruker AXS Inc, Madison, WI 53711 USA. [Bell, Jeffrey A.; Holder, Thomas] Schrodinger Inc, New York, NY 10036 USA. [Berman, Helen M.; Burley, Stephen K.; Feng, Zukang; Shao, Chenghua; Westbrook, John D.; Yang, Huanwang; Young, Jasmine] State Univ New Jersey, Ctr Integrat Prote Res, Res Collaboratory Struct Bioinformat Prot D, Piscataway, NJ 08854 USA. [Berman, Helen M.; Burley, Stephen K.; Feng, Zukang; Marcotrigiano, Joseph; Westbrook, John D.; Yang, Huanwang; Young, Jasmine] State Univ New Jersey, Dept Chem & Chem Biol Rutgers, Piscataway, NJ 08854 USA. [Bhat, Talapady N.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Blaney, Jeff M.; Harris, Seth F.] South San Francisco, Genentech Inc, San Francisco, CA 94080 USA. [Bolton, Evan] US Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Bricogne, Gerard] Global Phasing Ltd, Cambridge CB3 0AX, England. [Brown, David] Charles River Ltd, Struct Biol & Biophys, Cambridge CB10 1XL, England. [Burley, Stephen K.] Univ Calif San Diego, San Diego Supercomputer Ctr, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Clark, Kirk L.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. [Darden, Tom] OpenEye Sci, Cambridge, MA 02142 USA. [Emsley, Paul; Nicholls, Anthony; Warren, Gregory L.] MRC Lab Mol Biol, Cambridge CB2 0QH, England. [Feher, Victoria A.; Murshudov, Garib] Univ Calif San Diego, Dept Chem & Biochem, Drug Design Data Resource, La Jolla, CA 92093 USA. [Groom, Colin R.] Cambridge Crystallog Data Ctr, Cambridge CB2 1EZ, England. [Hendle, Jorg; Ward, Suzanna C.] Lilly Biotechnol Ctr, Structural Biol, San Diego, CA 92121 USA. [Joachimiak, Andrzej] Argonne Natl Lab, Biosci, Structural Biol Ctr, Argonne, IL 60439 USA. [Kleywegt, Gerard J.] European Bioinformat Inst, European Mol Biol Lab, Protein Data Bank Europe, Cambridge CB10 1SD, England. [Krojer, Tobias; Velankar, Sameer] Univ Oxford, Structural Genom Consortium, Oxford OX3 7DQ, England. [Marcotrigiano, Joseph; Montelione, Gaetano T.; Smart, Oliver] State Univ New Jersey, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Mark, Alan E.; Miller, Matthew] Univ Queensland, Sch Chem & Mol Biosci, St Lucia, Qld 4072, Australia. [Markley, John L.] Univ Wisconsin, Dept Biochem, BioMagResBank, Madison, WI 53706 USA. [Minor, Wladek] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. [Montelione, Gaetano T.] State Univ New Jersey, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Nakagawa, Atsushi; Nakamura, Haruki] Osaka Univ, Inst Prot Res, Protein Data Bank Japan, Osaka 5650871, Japan. [Nicklaus, Marc] Natl Inst Hlth, Natl Canc Inst, Ctr Canc Res, Computer Aided Drug Design Grp, Frederick, MD 21702 USA. [Nolte, Robert T.; Peishoff, Catherine E.] Collegeville, GlaxoSmithKline, Collegeville, PA 19426 USA. [Padyana, Anil K.] Agios Pharmaceut Inc, Cambridge, MA 02139 USA. [Pieniazek, Susan] Bristol Myers Squibb Res & Dev, Pennington, NJ 08534 USA. [Read, Randy J.] Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 0XY, England. [Soisson, Stephen] Bristol Myers Squibb Res & Dev, Princeton, NJ 08543 USA. [Soisson, Stephen] Merck Res Labs, West Point, PA 19486 USA. [Spurlino, John] Janssen Pharmaceut Inc, Spring House, PA 19002 USA. [Stouch, Terry] Sci Solut LLC, West Windsor, NJ 08550 USA. [Svobodova, Radka] Masaryk Univ, Natl Ctr Biomol Res, CEITEC Cent European Inst Technol, Brno 62500, Czech Republic. [Tempel, Wolfram] Univ Toronto, Structural Genom Consortium, Toronto, ON M5G IL7, Canada. [Terwilliger, Thomas C.] Alamos Natl Lab, Biosci Div, Los Alamos, NM 87545 USA. [Tronrud, Dale] Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USA. [Williams, Pamela] Atex Pharmaceut, Cambridge CB4 0QA, England. RP Burley, SK (reprint author), State Univ New Jersey, Ctr Integrat Prote Res, Res Collaboratory Struct Bioinformat Prot D, Piscataway, NJ 08854 USA.; Burley, SK (reprint author), State Univ New Jersey, Dept Chem & Chem Biol Rutgers, Piscataway, NJ 08854 USA.; Burley, SK (reprint author), Univ Calif San Diego, San Diego Supercomputer Ctr, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA.; Feher, VA (reprint author), Univ Calif San Diego, Dept Chem & Biochem, Drug Design Data Resource, La Jolla, CA 92093 USA.; Groom, CR (reprint author), Cambridge Crystallog Data Ctr, Cambridge CB2 1EZ, England. EM stephen.burley@rcsb.org; vfeher@ucsd.edu; groom@ccdc.cam.ac.uk RI Svobodova Varekova, Radka/E-2867-2012; Terwilliger, Thomas/K-4109-2012; Marcotrigiano, Joseph /K-6697-2016; Read, Randy/L-1418-2013; Mark, Alan/A-8799-2011; OI Minor, Wladek/0000-0001-7075-7090; Terwilliger, Thomas/0000-0001-6384-0320; Marcotrigiano, Joseph /0000-0003-0346-3353; Read, Randy/0000-0001-8273-0047; Mark, Alan/0000-0001-5880-4798; Smart, Oliver/0000-0002-9669-1998; Kleywegt, Gerard J./0000-0002-4670-0331; Velankar, Sameer/0000-0002-8439-5964; Nicklaus, Marc/0000-0002-4775-7030 FU National Science Foundation [DBI 1338415]; Wellcome Trust [104948]; JST-NBDC; National Institute of General Medical Sciences [GM109046, GM111528] FX The workshop was supported by funding to RCSB PDB by the National Science Foundation (DBI 1338415); PDBe by the Wellcome Trust (104948); PDBj by JST-NBDC; BMRB by the National Institute of General Medical Sciences (GM109046); D3R by the National Institute of General Medical Sciences (GM111528); registration fees from industrial participants; and a tax-deductible donation to the wwPDB Foundation by the Bristol-Myers Squibb Foundation. NR 38 TC 11 Z9 11 U1 7 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD APR 5 PY 2016 VL 24 IS 4 BP 502 EP 508 DI 10.1016/j.str.2016.02.017 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DI5VN UT WOS:000373568700005 PM 27050687 ER PT J AU Fang, ZY Li, H Chen, G Yang, JJ AF Fang, Zhiyong Li, Han Chen, Gang Yang, JiongJiong TI Unconscious Processing of Negative Animals and Objects: Role of the Amygdala Revealed by fMRI SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE category; amygdala; awareness; emotion; context ID SOCIAL COGNITION; CORTICAL RESPONSES; FEAR-RELEVANT; STIMULI; PERCEPTION; AWARENESS; EMOTION; PATHWAYS; BRAIN; CONSCIOUSNESS AB Previous studies have shown that emotional stimuli can be processed through the amygdala without conscious awareness. The amygdala is also involved in processing animate and social information. However, it is unclear whether different categories of pictures (e.g., animals, objects) elicit different activity in the amygdale and other regions without conscious awareness. The objective of this study was to explore whether the factors of category, emotion and picture context modulate brain activation for unconscious processing. Pictures denoting different nonhuman animals and objects in negative and neutral emotional valences were presented using a sandwich-masking paradigm. Half of them were presented with human-related information in the contexts, and half were not. Our results showed significant interaction among category, emotion and context in the amygdala and subcortical regions. Specifically, negative animals elicited stronger activation in these regions than negative objects, especially with human contexts. In addition, there were different correlation patterns between the amygdala and cortical regions according to whether they included human context. There were limited activations in cortical category-related networks. These results suggest that the amygdala and subcortical regions dominantly process negative animals, and contextual information modulates their activities, making threatening stimuli that are most relevant to human survival preferentially processed without conscious awareness. C1 [Fang, Zhiyong; Li, Han; Yang, JiongJiong] Peking Univ, Dept Psychol, Beijing 100871, Peoples R China. [Fang, Zhiyong; Li, Han; Yang, JiongJiong] Peking Univ, Beijing Lab Behav & Mental Hlth, Beijing 100871, Peoples R China. [Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Yang, JJ (reprint author), Peking Univ, Dept Psychol, Beijing 100871, Peoples R China.; Yang, JJ (reprint author), Peking Univ, Beijing Lab Behav & Mental Hlth, Beijing 100871, Peoples R China. EM yangjj@pku.edu.cn FU Global Research Initiative Program, National Institutes of Health (NIH), USA [R01TW007897]; National Science Foundation of China [31571114] FX This research was supported by grants from the Global Research Initiative Program, National Institutes of Health (NIH), USA (R01TW007897, JY), and the National Science Foundation of China (31571114, JY). NR 62 TC 1 Z9 1 U1 5 U2 14 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD APR 5 PY 2016 VL 10 AR 146 DI 10.3389/fnhum.2016.00146 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DI2PJ UT WOS:000373338500001 PM 27092067 ER PT J AU King, WC Chen, JY Belle, SH Courcoulas, AP Dakin, GF Elder, KA Flum, DR Hinojosa, MW Mitchell, JE Pories, WJ Wolfe, BM Yanovski, SZ AF King, Wendy C. Chen, Jia-Yuh Belle, Steven H. Courcoulas, Anita P. Dakin, Gregory F. Elder, Katherine A. Flum, David R. Hinojosa, Marcelo W. Mitchell, James E. Pories, Walter J. Wolfe, Bruce M. Yanovski, Susan Z. TI Change in Pain and Physical Function Following Bariatric Surgery for Severe Obesity SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-LIFE; OSTEOARTHRITIS INDEX WOMAC; WESTERN-ONTARIO-UNIVERSITY; GASTRIC BYPASS-SURGERY; LONGITUDINAL ASSESSMENT; MUSCULOSKELETAL PAIN; OLDER-ADULTS; WEIGHT-LOSS; LONG-TERM; KNEE OSTEOARTHRITIS AB IMPORTANCE The variability and durability of improvements in pain and physical function following Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB) are not well described. OBJECTIVES To report changes in pain and physical function in the first 3 years following bariatric surgery, and to identify factors associated with improvement. DESIGN, SETTING, AND PARTICIPANTS The Longitudinal Assessment of Bariatric Surgery-2 is an observational cohort study at 10 US hospitals. Adults with severe obesity undergoing bariatric surgery were recruited between February 2005 and February 2009. Research assessments were conducted prior to surgery and annually thereafter. Three-year follow-up through October 2012 is reported. EXPOSURES Bariatric surgery as clinical care. MAIN OUTCOMES AND MEASURES Primary outcomes were clinically meaningful presurgery to postsurgery improvements in pain and function using scores from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (ie, improvement of >= 5 points on the norm-based score [range, 0-100]) and 400-meter walk time (ie, improvement of >= 24 seconds) using established thresholds. The secondary outcome was clinically meaningful improvement using the Western Ontario McMaster Osteoarthritis Index (ie, improvement of >= 9.7 pain points and >= 9.3 function points on the transformed score [range, 0-100]). RESULTS Of 2458 participants, 2221 completed baseline and follow-up assessments (1743 [78.5%] were women; median age was 47 years; median body mass index [BMI] was 45.9; 70.4% underwent RYGB; 25.0% underwent LAGB). At year 1, clinically meaningful improvements were shown in 57.6%(95% CI, 55.3%-59.9%) of participants for bodily pain, 76.5%(95% CI, 74.6%-78.5%) for physical function, and 59.5%(95% CI, 56.4%-62.7%) for walk time. Additionally, among participants with severe knee or disability (633), or hip pain or disability (500) at baseline, approximately three-fourths experienced joint-specific improvements in knee pain (77.1%[95% CI, 73.5%-80.7%]) and in hip function (79.2%[95% CI, 75.3%-83.1%]). Between year 1 and year 3, rates of improvement significantly decreased to 48.6%(95% CI, 46.0%-51.1%) for bodily pain and to 70.2%(95% CI, 67.8%-72.5%) for physical function, but improvement rates for walk time, knee and hip pain, and knee and hip function did not (P for all >=.05). Younger age, male sex, higher income, lower BMI, and fewer depressive symptoms presurgery; no diabetes and no venous edema with ulcerations postsurgery (either no history or remission); and presurgery-to-postsurgery reductions in weight and depressive symptoms were associated with presurgery-to-postsurgery improvements in multiple outcomes at years 1, 2, and 3. CONCLUSIONS AND RELEVANCE Among a cohort of participants with severe obesity undergoing bariatric surgery, a large percentage experienced improvement, compared with baseline, in pain, physical function, and walk time over 3 years, but the percentage with improvement in pain and physical function decreased between year 1 and year 3. C1 [King, Wendy C.; Chen, Jia-Yuh; Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Courcoulas, Anita P.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15261 USA. [Dakin, Gregory F.] Weill Cornell Med Ctr, New York, NY USA. [Elder, Katherine A.; Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Elder, Katherine A.] Univ Pacific, Forest Grove, OR USA. [Flum, David R.; Hinojosa, Marcelo W.] Univ Washington, Seattle, WA 98195 USA. [Mitchell, James E.] Neuropsychiat Res Inst, Fargo, ND USA. [Pories, Walter J.] E Carolina Univ, Brody Sch Med, Greenville, NC USA. [Yanovski, Susan Z.] NIDDK, Bethesda, MD 20892 USA. RP King, WC (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Room 105,130 DeSoto St, Pittsburgh, PA 15261 USA. EM kingw@edc.pitt.edu OI King, Wendy/0000-0002-0740-0029 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Columbia University Medical Center [U01-DK66667]; Cornell University Medical Center CTRC [UL1-RR024996]; University of Washington [U01-DK66568]; CTRC [M01RR-00037, UL1-RR024153]; Neuropsychiatric Research Institute [U01-DK66471]; East Carolina University [U01-DK66526]; University of Pittsburgh Medical Center [U01-DK66585]; Oregon Health & Science University [U01-DK66555]; [U01 DK066557] FX LABS-2 was a cooperative agreement funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Grant numbers: Data Coordinating Center-U01 DK066557; Columbia University Medical Center-U01-DK66667 (in collaboration with Cornell University Medical Center CTRC, grant UL1-RR024996); University of Washington-U01-DK66568 (in collaboration with CTRC, grant M01RR-00037); Neuropsychiatric Research Institute-U01-DK66471; East Carolina University-U01-DK66526; University of Pittsburgh Medical Center-U01-DK66585 (in collaboration with CTRC, grant UL1-RR024153); Oregon Health & Science University-U01-DK66555. NR 40 TC 9 Z9 9 U1 5 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD APR 5 PY 2016 VL 315 IS 13 BP 1362 EP 1371 DI 10.1001/jama.2016.3010 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EP UT WOS:000373381500020 PM 27046364 ER PT J AU Leary, PJ Tedford, RJ Bluemke, DA Bristow, MR Heckbert, SR Kawut, SM Krieger, EV Lima, JA Masri, CS Ralph, DD Shea, S Weiss, NS Kronmal, RA AF Leary, Peter J. Tedford, Ryan J. Bluemke, David A. Bristow, Michael R. Heckbert, Susan R. Kawut, Steven M. Krieger, Eric V. Lima, Joao A. Masri, Carolina S. Ralph, David D. Shea, Steven Weiss, Noel S. Kronmal, Richard A. TI Histamine H-2 Receptor Antagonists, Left Ventricular Morphology, and Heart Failure Risk The MESA Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiac magnetic resonance imaging; heart failure; prevention ID PRESERVED EJECTION FRACTION; ATHEROSCLEROSIS RISK; COMMUNITIES; MEDIATION; FIBROSIS; GEOMETRY; RABBITS; MASS AB BACKGROUND Myocardial H-2 receptor activation may promote cardiac fibrosis and apoptosis in pre-clinical models and histamine H-2 receptor antagonist (H2RA) use may improve symptoms in participants with heart failure (HF); however, relationships between H2RA use, incident HF, and longitudinal change in left ventricular (LV) morphology are not known. OBJECTIVES This study sought to determine whether H2RA use is associated with incident HF and change in LV morphology over time. METHODS We included 6,378 men and women from MESA (Multi-Ethnic Study of Atherosclerosis), a multicenter prospective observational cohort of participants without cardiovascular disease at baseline. Cox proportional hazards were used to estimate the association between H2RA use and incident HF in adjusted models. In participants with cardiac magnetic resonance imaging, associations between H2RA use, baseline LV morphology (n = 4,691), and longitudinal change in the LV (n = 2,806) were estimated using linear regression. RESULTS H2RAs were used by 313 participants but not by the other 6,065 individuals. During a median follow-up of 11.2 years, 236 participants developed HF. In adjusted models, baseline H2RA use relative to nonuse was associated with 62% lower risk for incident HF (p = 0.02). H2RA use was associated with preserved stroke volume, LV end-diastolic volume, and mass/volume ratio as measured by cardiac magnetic resonance imaging over approximately 10 years (all p < 0.05). There were no associations between H2RA use and LV mass or ejection fraction. CONCLUSIONS H2RA use was associated with reduced risk for incident HF. Left heart morphology over time suggests less age-related change in H2RA users. These associations suggest histamine signaling may be important in the pathogenesis of HF. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487) (C) 2016 by the American College of Cardiology Foundation. C1 [Leary, Peter J.; Krieger, Eric V.; Masri, Carolina S.; Ralph, David D.] Univ Washington, Dept Med, Seattle, WA USA. [Tedford, Ryan J.; Lima, Joao A.] Johns Hopkins Univ Hosp, Dept Med, Baltimore, MD 21287 USA. [Bluemke, David A.] NIH, Ctr Clin, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Bristow, Michael R.] Univ Colorado, Dept Med, Aurora, CO USA. [Heckbert, Susan R.; Weiss, Noel S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kawut, Steven M.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Dept Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lima, Joao A.] Johns Hopkins Univ Hosp, Dept Radiol, Baltimore, MD 21287 USA. [Shea, Steven] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Dept Epidemiol, New York, NY USA. [Kronmal, Richard A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Leary, PJ (reprint author), Univ Washington, Med Ctr, Div Pulm & Crit Care, BB-1361,Campus Box 356522,1959 NE Pacific St, Seattle, WA 98195 USA. EM learyp@uw.edu OI Leary, Peter/0000-0001-5716-248X FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NCRR [UL1-TR-000040, UL1-TR-001079]; National Center For Advancing Translational Sciences of the National Institutes of Health [KL2TR000421] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR. This publication was supported by the National Center For Advancing Translational Sciences of the National Institutes of Health under Award KL2TR000421. MESA investigators reviewed the manuscript for scientific content and consistency of data interpretation with previous MESA publications. Significant comments were incorporated before submission for publication. A full list of participating MESA investigators and institutions can be found at https://www.mesa-nhlbi.org/aboutMESAPersonnel.aspx. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 23 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 5 PY 2016 VL 67 IS 13 BP 1544 EP 1552 DI 10.1016/j.jacc.2016.01.045 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DH6ID UT WOS:000372893300008 PM 27150686 ER PT J AU Introne, WJ Westbroek, W Cullinane, AR Groden, CA Bhambhani, V Golas, GA Baker, EH Lehky, TJ Snow, J Ziegler, SG Adams, DR Dorward, HM Hess, RA Huizing, M Gahl, WA Toro, C AF Introne, Wendy J. Westbroek, Wendy Cullinane, Andrew R. Groden, Catherine A. Bhambhani, Vikas Golas, Gretchen A. Baker, Eva H. Lehky, Tanya J. Snow, Joseph Ziegler, Shira G. Adams, David R. Dorward, Heidi M. Hess, Richard A. Huizing, Marjan Gahl, William A. Toro, Camilo TI Neurologic involvement in patients with atypical Chediak-Higashi disease SO NEUROLOGY LA English DT Article ID PARKINSONIAN-SYNDROME; CLINICAL PHENOTYPE; LYST; IDENTIFICATION; LYSOSOMES; MUTATIONS; GENOTYPE; DOMAIN; CELLS; BEIGE AB Objective:To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study.Methods:Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation.Results:In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism.Conclusions:Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders. C1 [Introne, Wendy J.; Groden, Catherine A.; Bhambhani, Vikas; Golas, Gretchen A.; Gahl, William A.; Toro, Camilo] NIH, Off Clin Director, Bldg 10, Bethesda, MD 20892 USA. [Westbroek, Wendy; Cullinane, Andrew R.; Ziegler, Shira G.; Adams, David R.; Dorward, Heidi M.; Hess, Richard A.; Gahl, William A.] NIH, Human Biochem Genet Sect, Med Genet Branch, Bldg 10, Bethesda, MD 20892 USA. [Baker, Eva H.] NIH, Natl Human Genome Res Inst, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lehky, Tanya J.] NIH, Electromyog Sect, Off Clin Director, Natl Inst Neurol Disorders & Stroke, Bldg 10, Bethesda, MD 20892 USA. [Snow, Joseph] NIH, Off Clin Director, Natl Inst Mental Hlth, Bldg 10, Bethesda, MD 20892 USA. [Bhambhani, Vikas] Childrens Hosp & Clin Minnesota, Metab & Clin Geneticist, Dept Med Genet, Minneapolis, MN USA. RP Introne, WJ (reprint author), NIH, Off Clin Director, Bldg 10, Bethesda, MD 20892 USA. EM wintrone@mail.nih.gov FU Intramural Research Programs of the National Human Genome Research Institute; National Institute of Neurological Disorders and Stroke; Hatfield Clinical Center, NIH, Bethesda, MD FX Supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Neurological Disorders and Stroke, and the Hatfield Clinical Center, NIH, Bethesda, MD. NR 32 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD APR 5 PY 2016 VL 86 IS 14 BP 1320 EP 1328 DI 10.1212/WNL.0000000000002551 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DI1YE UT WOS:000373292100009 PM 26944273 ER PT J AU Little, MP Wakeford, R Bouville, A Simon, SL AF Little, Mark P. Wakeford, Richard Bouville, Andre Simon, Steven L. TI Measurement of Fukushima-related radioactive contamination in aquatic species SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID RADIONUCLIDES; JAPAN C1 [Little, Mark P.; Bouville, Andre; Simon, Steven L.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20892 USA. [Wakeford, Richard] Univ Manchester, Inst Populat Hlth, Ctr Occupat & Environm Hlth, Manchester M13 9PL, Lancs, England. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20892 USA. EM mark.little@nih.gov OI Wakeford, Richard/0000-0002-2934-0987 NR 15 TC 0 Z9 0 U1 5 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 5 PY 2016 VL 113 IS 14 BP 3720 EP 3721 DI 10.1073/pnas.1602648113 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI2UI UT WOS:000373354000030 PM 27035996 ER PT J AU Zhu, JJ Kwan, KM Mackem, S AF Zhu, Jianjian Kwan, Kin Ming Mackem, Susan TI Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE notochord; Brachyury; cell fate; EMT ID MESENCHYMAL-LIKE PHENOTYPE; VERTEBRATE DEVELOPMENT; CRE RECOMBINASE; GENE-FUNCTION; MOUSE; MICE; CHORDOMA; IDENTIFICATION; DUPLICATION; EXPRESSION AB The transcription factor Brachyury (T) gene is expressed throughout primary mesoderm (primitive streak and notochord) during early embryonic development and has been strongly implicated in the genesis of chordoma, a sarcoma of notochord cell origin. Additionally, T expression has been found in and proposed to play a role in promoting epithelial-mesenchymal transition (EMT) in various other types of human tumors. However, the role of T in normal mammalian notochord development and function is still not well-understood. We have generated an inducible knockdown model to efficiently and selectively deplete T from notochord in mouse embryos. In combination with genetic lineage tracing, we show that T function is essential for maintaining notochord cell fate and function. Progenitors adopt predominantly a neural fate in the absence of T, consistent with an origin from a common chordoneural progenitor. However, T function is dispensable for progenitor cell survival, proliferation, and EMT, which has implications for the therapeutic targeting of T in chordoma and other cancers. C1 [Zhu, Jianjian; Mackem, Susan] NCI, CDBL, CCR, Frederick, MD 21702 USA. [Kwan, Kin Ming] Chinese Univ Hong Kong, Sch Life Sci, Hong Kong, Hong Kong, Peoples R China. RP Mackem, S (reprint author), NCI, CDBL, CCR, Frederick, MD 21702 USA. EM mackems@mail.nih.gov FU intramural program of the CCR, NCI FX We thank CDBL members for discussions and comments on the manuscript; Richard Behringer for providing the T-KO mice; Hiroshi Sasaki and the Riken CDB Animal Resources and Genetic Engineering for Foxa2CreER knock-in mice; Brian Harfe, Bernhard Herrmann, Andrew McMahon, and Mark Udey for probes and antibody; and Lionel Feigenbaum for generating transgenic mice. This research was supported by the intramural program of the CCR, NCI. NR 40 TC 0 Z9 0 U1 3 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 5 PY 2016 VL 113 IS 14 BP 3820 EP 3825 DI 10.1073/pnas.1601252113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI2UI UT WOS:000373354000047 PM 27006501 ER PT J AU Ray, P De, S Mitra, A Bezstarosti, K Demmers, JAA Pfeifer, K Kassis, JA AF Ray, Payal De, Sandip Mitra, Apratim Bezstarosti, Karel Demmers, Jeroen A. A. Pfeifer, Karl Kassis, Judith A. TI Combgap contributes to recruitment of Polycomb group proteins in Drosophila SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Polycomb; PREs; gene expression; Combgap; PcG recruitment ID RESPONSE ELEMENTS; HOMEOTIC GENE; DNA-BINDING; TRANSCRIPTIONAL REGULATION; CUBITUS-INTERRUPTUS; BITHORAX COMPLEX; MELANOGASTER; CHROMATIN; REPRESSION; PREDICTION AB Polycomb group (PcG) proteins are responsible for maintaining the silenced transcriptional state of many developmentally regulated genes. PcG proteins are organized into multiprotein complexes that are recruited to DNA via cis-acting elements known as "Polycomb response elements" (PREs). In Drosophila, PREs consist of binding sites for many different DNA-binding proteins, some known and others unknown. Identification of these DNA-binding proteins is crucial to understanding the mechanism of PcG recruitment to PREs. We report here the identification of Combgap (Cg), a sequence-specific DNA-binding protein that is involved in recruitment of PcG proteins. Cg can bind directly to PREs via GTGT motifs and colocalizes with the PcG proteins Pleiohomeotic (Pho) and Polyhomeotic (Ph) at the majority of PREs in the genome. In addition, Cg colocalizes with Ph at a number of targets independent of Pho. Loss of Cg leads to decreased recruitment of Ph at only a subset of sites; some of these sites are binding sites for other Polycomb repressive complex 1 (PRC1) components, others are not. Our data suggest that Cg can recruit Ph in the absence of PRC1 and illustrate the diversity and redundancy of PcG protein recruitment mechanisms. C1 [Ray, Payal; De, Sandip; Mitra, Apratim; Pfeifer, Karl; Kassis, Judith A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Bezstarosti, Karel; Demmers, Jeroen A. A.] Erasmus Univ, Med Ctr, Prote Ctr, NL-3015 GE Rotterdam, Netherlands. [Bezstarosti, Karel; Demmers, Jeroen A. A.] Erasmus Univ, Med Ctr, Dept Cell Biol, NL-3015 GE Rotterdam, Netherlands. RP Kassis, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM jkassis@mail.nih.gov OI Kassis, Judith/0000-0001-9268-3213; Pfeifer, Karl/0000-0002-0254-682X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Netherlands Proteomics Centre FX We thank Gerard Campbell (University of Pittsburgh) for cgA22/CyO flies; William Brook (University of Calgary) for the anti-Cg antibody; Jim Kennison, Hyuck Joon Kang, and Mitzi I. Kuroda for helpful discussions during the project; Victoria Blake for staining the discs in Fig. S8B; Lesley Brown, Elissa Lei, Yuzhong Cheng, and Victoria Blake for comments on this manuscript; and the Bloomington Stock Center for fly stocks. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and the Netherlands Proteomics Centre. NR 49 TC 4 Z9 4 U1 4 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 5 PY 2016 VL 113 IS 14 BP 3826 EP 3831 DI 10.1073/pnas.1520926113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI2UI UT WOS:000373354000048 PM 27001825 ER PT J AU Hodson, DJ Shaffer, AL Xiao, WM Wright, GW Schmitz, R Phelan, JD Yang, YD Webster, DE Rui, LX Kohlhammer, H Nakagawa, M Waldmann, TA Staudt, LM AF Hodson, Daniel J. Shaffer, Arthur L. Xiao, Wenming Wright, George W. Schmitz, Roland Phelan, James D. Yang, Yandan Webster, Daniel E. Rui, Lixin Kohlhammer, Holger Nakagawa, Masao Waldmann, Thomas A. Staudt, Louis M. TI Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer biology; lymphoma; germinal center ID BINDING TRANSCRIPTION FACTORS; OCTAMER DNA MOTIF; OCA-B; COACTIVATOR OBF-1; UP-REGULATION; IN-VIVO; LYMPHOMA; IMMUNOGLOBULIN; ACTIVATION; EXPRESSION AB The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3. Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface, we reveal a requirement for this protein-protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell-restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity. C1 [Hodson, Daniel J.; Shaffer, Arthur L.; Xiao, Wenming; Wright, George W.; Schmitz, Roland; Phelan, James D.; Yang, Yandan; Webster, Daniel E.; Rui, Lixin; Kohlhammer, Holger; Nakagawa, Masao; Waldmann, Thomas A.; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Hodson, Daniel J.] Univ Cambridge, Dept Haematol, Cambridge CB2 0AH, England. [Xiao, Wenming] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Kay Kendall Leukaemia Fund Intermediate Fellowship from the United Kingdom FX We thank the EUCOMM Consortium for the Pou2f2 ES cells. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. D.J.H. was supported by a Kay Kendall Leukaemia Fund Intermediate Fellowship from the United Kingdom. The views presented in this article do not necessarily reflect current or future opinion or policy of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as endorsement. NR 50 TC 0 Z9 1 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 5 PY 2016 VL 113 IS 14 BP E2039 EP E2046 DI 10.1073/pnas.1600557113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI2UI UT WOS:000373354000014 PM 26993806 ER PT J AU Huber, BR Meabon, JS Hoffer, ZS Zhang, J Hoekstra, JG Pagulayan, KF McMillan, PJ Mayer, CL Banks, WA Kraemer, BC Raskind, MA McGavern, DB Peskind, ER Cook, DG AF Huber, B. R. Meabon, J. S. Hoffer, Z. S. Zhang, J. Hoekstra, J. G. Pagulayan, K. F. McMillan, P. J. Mayer, C. L. Banks, W. A. Kraemer, B. C. Raskind, M. A. McGavern, D. B. Peskind, E. R. Cook, D. G. TI BLAST EXPOSURE CAUSES DYNAMIC MICROGLIAL/MACROPHAGE RESPONSES AND MICRODOMAINS OF BRAIN MICROVESSEL DYSFUNCTION SO NEUROSCIENCE LA English DT Article DE blood-brain barrier; two-photon microscopy; neuropathology; microglia; macrophages ID CHRONIC TRAUMATIC ENCEPHALOPATHY; IN-VIVO; MICROGLIAL ACTIVATION; WHITE-MATTER; MOUSE MODEL; INJURY; BLOOD; BARRIER; CORTEX; IMPACT AB Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. Microglial/macrophage activation was specifically associated with these restricted microdomains, as evidenced by rapid microglial process retraction, increased ameboid morphology, and escape of blood-borne Q-dot tracers that were internalized in microglial/macrophage cell bodies and phagosome-like compartments. Microdomains of cortical vascular disruption and microglial/macrophage activation were also associated with aberrant tight junction morphology that was more prominent after repetitive (3 x) blast exposure. Repetitive, but not single, BOPs also caused TNF alpha elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuro-inflammatory responses. Published by Elsevier Ltd. on behalf of IBRO. C1 [Huber, B. R.] Boston Univ, VA Jamaica Plain, Dept Neurol, Sch Med, Jamaica Plain, MA USA. [Meabon, J. S.; Pagulayan, K. F.; McMillan, P. J.; Mayer, C. L.; Raskind, M. A.; Peskind, E. R.] VA Puget Sound Healthcare Syst, Northwest Network Mental Illness Res Educ & Clin, Seattle, WA USA. [Meabon, J. S.; Pagulayan, K. F.; McMillan, P. J.; Mayer, C. L.; Raskind, M. A.; Peskind, E. R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA. [Hoffer, Z. S.] US Army, Madigan Army Med Ctr, Joint Base Lewis Mcchord, WA USA. [Zhang, J.; Hoekstra, J. G.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98108 USA. [Banks, W. A.; Kraemer, B. C.; Cook, D. G.] Vet Affairs Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Banks, W. A.; Kraemer, B. C.; Cook, D. G.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98108 USA. [McGavern, D. B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Cook, D. G.] Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98108 USA. RP Cook, DG (reprint author), Univ Washington, VA Puget Sound Hlth Care Syst, Dept Med, 1660 South Columbian Way, Seattle, WA 98108 USA. EM dgcook@u.washington.edu OI Hoekstra, Jake/0000-0001-6597-5878 FU Department of Veterans Affairs Office of Research and Development Medical Research Service; VA Rehabilitation Research and Development Service; University of Washington Royalty Research Fund [R01AG046619]; Northwest Network Mental Illness Research, Education and Clinical Center; Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs; NIH [T32 AG000258]; VA CSR&D Career Development Award [IK2 CX00516] FX This work was supported by the Department of Veterans Affairs Office of Research and Development Medical Research Service (D.G.C., B.C.K.), VA Rehabilitation Research and Development Service (E.R.P.), University of Washington Royalty Research Fund (D.G.C.); R01AG046619 (W.A.B.); Northwest Network Mental Illness Research, Education and Clinical Center (E.R.P., B.R.H., J.S.M., K.F.P., P.J.M., C.L.M.), Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs (B.R.H.); NIH T32 AG000258 (J.S.M.), VA CSR&D Career Development Award Program #IK2 CX00516 (K.F.P.). We thank Dr. Gerard Schellenberg (Univ. Pennsylvania) for providing Tau knock-out samples. NR 41 TC 2 Z9 2 U1 2 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD APR 5 PY 2016 VL 319 BP 206 EP 220 DI 10.1016/j.neuroscience.2016.01.022 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DD9RD UT WOS:000370262400019 PM 26777891 ER PT J AU Althoff, KN Rebeiro, PF Hanna, DB Padgett, D Horberg, MA Grinsztejn, B Abraham, AG Hogg, R Gill, MJ Wolff, MJ Mayor, A Rachlis, A Williams, C Sterling, TR Kitahata, MM Buchacz, K Thorne, JE Cesar, C Cordero, FM Rourke, SB Sierra-Madero, J Pape, JW Cahn, P McGowan, C AF Althoff, Keri N. Rebeiro, Peter F. Hanna, David B. Padgett, Denis Horberg, Michael A. Grinsztejn, Beatriz Abraham, Alison G. Hogg, Robert Gill, M. John Wolff, Marcelo J. Mayor, Angel Rachlis, Anita Williams, Carolyn Sterling, Timothy R. Kitahata, Mari M. Buchacz, Kate Thorne, Jennifer E. Cesar, Carina Cordero, Fernando M. Rourke, Sean B. Sierra-Madero, Juan Pape, Jean W. Cahn, Pedro McGowan, Catherine CA na-Accord Caribbean Cent South Amer Network TI A picture is worth a thousand words: maps of HIV indicators to inform research, programs, and policy from NA-ACCORD and CCASAnet clinical cohorts SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article DE Map; HIV indicators; CD4 T-lymphocyte count; retention in care; antiretroviral therapy; HIV RNA suppression; North America; Central America; South America; implementation science ID ANTIRETROVIRAL THERAPY; INFECTION; CARE; PREVENTION; STATES AB Introduction: Maps are powerful tools for visualization of differences in health indicators by geographical region, but multicountry maps of HIV indicators do not exist, perhaps due to lack of consistent data across countries. Our objective was to create maps of four HIV indicators in North, Central, and South American countries. Methods: Using data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and the Caribbean, Central, and South America network for HIV epidemiology (CCASAnet), we mapped median CD4 at presentation for HIV clinical care, proportion retained in HIV primary care, proportion prescribed antiretroviral therapy (ART), and the proportion with suppressed plasma HIV viral load (VL) from 2010 to 2012 for North, Central, and South America. The 15 Canadian and US clinical cohorts and 7 clinical cohorts in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru represented approximately 2 similar to 7% of persons known to be living with HIV in these countries. Results: Study populations were selected for each indicator: median CD4 at presentation for care was estimated among 14,811 adults; retention was estimated among 87,979 adults; ART use was estimated among 84,757 adults; and suppressed VL was estimated among 51,118 adults. Only three US states and the District of Columbia had a median CD4 at presentation similar to 350 cells/mm(3). Haiti, Mexico, and several states had >85% retention in care; lower (50 74%) retention in care was observed in the US West, South, and Mid-Atlantic, and in Argentina, Brazil, and Peru. ART use was highest (90%) in Mexico. The percentages of patients with suppressed VL in the US South and Northeast were lower than in most of Central and South America. Conclusions: These maps provide visualization of gaps in the quality of HIV care and allow for comparison between and within countries as well as monitoring policy and programme goals within geographical boundaries. C1 [Althoff, Keri N.; Abraham, Alison G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Rebeiro, Peter F.; Sterling, Timothy R.; McGowan, Catherine] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Hanna, David B.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Padgett, Denis] Inst Hondureno Seguridad Social, Infect Dis Serv, Dept Internal Med, Tegucigalpa, Honduras. [Horberg, Michael A.] Kaiser Permanente Mid Atlantic States, Mid Atlantic Permanente Res Inst, Rockville, MD USA. [Grinsztejn, Beatriz] Fiocruz MS, Evandro Chagas Natl Inst Infect Dis, BR-21045900 Rio De Janeiro, Brazil. [Hogg, Robert] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Gill, M. John] Univ Calgary, Dept Med, Calgary, AB, Canada. [Wolff, Marcelo J.] Univ Chile, Fac Med, Dept Med, Santiago 7, Chile. [Wolff, Marcelo J.] Fdn Arriaran, Santiago, Chile. [Mayor, Angel] Univ Cent Caribe, Dept Internal Med, Bayamon, PR USA. [Rachlis, Anita; Thorne, Jennifer E.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Med, Toronto, ON, Canada. [Williams, Carolyn] NIAID, Epidemiol, Basic Sci Program, Div Aids, Rockville, MD USA. [Kitahata, Mari M.] Univ Washington, Dept Med, Seattle, WA USA. [Buchacz, Kate] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Cesar, Carina; Cahn, Pedro] Fdn Huesped, Invest Clin, Buenos Aires, DF, Argentina. [Cordero, Fernando M.] Univ Peruana Cayetano Heredia, Inst Medicina Trop Alexander von Humboldt, HIV Res Grp, Lima, Peru. [Rourke, Sean B.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Sierra-Madero, Juan] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Infectol, Mexico City, DF, Mexico. [Pape, Jean W.] Grp Haitien Etud Sarcome Kaposi & Infect Opportun, Port Au Prince, Haiti. [Pape, Jean W.] Weill Cornell Med Coll, Dept Med, New York, NY USA. RP Althoff, KN (reprint author), 615 N Wolfe St,Rm E7142, Baltimore, MD 21201 USA. EM kalthoff@jhu.edu OI Mayor, Angel M./0000-0002-7705-837X; Rebeiro, Peter/0000-0003-1951-9104; Hogg, Robert/0000-0003-3463-5488; Justice, Amy/0000-0003-0139-5502 FU National Institutes of Health, USA [P30-AI094189, P30-AI27757, P30-AI27767, P30-AI036219, P30-AI50410, P30-AI54999, P30-MH62246, R01-AA16893, R01-CA165937, R01-DA04334, R01-DA11602, R01-DA12568, R24-AI067039, R56-AI102622, Z01-CP010214, Z01-CP010176]; Center's for Disease Control and Prevention, USA [CDC200-2006-18797]; Agency for Healthcare Research and Quality, USA [90047713]; Health Resources and Services Administration, USA [90051652]; Canadian Institutes of Health Research, Canada [TGF-96118, HCP-97105, CBR-86906, CBR-94036]; Canadian Institutes of Health Research (CIHR) New Investigator award; Ontario Ministry of Health and Long Term Care; Government of Alberta, Canada; Intramural Research Program of the National Cancer Institute; National Institutes of Health; [U01-AI69434]; [U01-DA036935]; [U01-HD32632]; [U10-EY08052]; [U10-EY08057]; [U10-EY08067]; [U24-AA020794]; [U54-MD007587]; [UL1-RR024131]; [UL1-TR000083]; [F31-DA037788]; [F31-DA030254]; [G12-MD007583]; [K01-AI071754]; [K01-AI093197]; [K23-EY013707]; [K24-DA00432]; [K24-AI065298]; [KL2-TR000421]; [MO1-RR-00052]; [N02-CP55504]; [P30-AI027763]; [U01-AI069918]; [U01-AA013566]; [U01-AA020790]; [U01-AI31834]; [U01-AI34989]; [U01-AI34993]; [U01-AI34994]; [U01-AI35004]; [U01-AI35039]; [U01-AI35040]; [U01-AI35041]; [U01-AI35042]; [UM1-AI35043]; [U01-AI37613]; [U01-AI37984]; [U01AI38855]; [U01-AI38858]; [U01-AI42590]; [U01-AI68634]; [U01-AI68636]; [U01-AI69432] FX The NA-ACCORD and collaborating cohorts were supported by grants U01-AI069918, U01-AA013566, U01-AA020790, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, UM1-AI35043, U01-AI37613, U01-AI37984, U01AI38855, U01-AI38858, U01-AI42590, U01-AI68634, U01-AI68636, U01-AI69432, U01-AI69434, U01-DA036935, U01-HD32632, U10-EY08052, U10-EY08057, U10-EY08067, U24-AA020794, U54-MD007587, UL1-RR024131, UL1-TR000083, F31-DA037788, F31-DA030254, G12-MD007583, K01-AI071754, K01-AI093197, K23-EY013707, K24-DA00432, K24-AI065298, KL2-TR000421, MO1-RR-00052, N02-CP55504, P30-AI027763, P30-AI094189, P30-AI27757, P30-AI27767, P30-AI036219, P30-AI50410, P30-AI54999, P30-MH62246, R01-AA16893, R01-CA165937, R01-DA04334, R01-DA11602, R01-DA12568, R24-AI067039, R56-AI102622, Z01-CP010214, and Z01-CP010176 from the National Institutes of Health, USA; contract CDC200-2006-18797 from the Center's for Disease Control and Prevention, USA; contract 90047713 from the Agency for Healthcare Research and Quality, USA; contract 90051652 from the Health Resources and Services Administration, USA; grants TGF-96118, HCP-97105, CBR-86906, CBR-94036 from the Canadian Institutes of Health Research, Canada; Canadian Institutes of Health Research (CIHR) New Investigator award (A. Burchell); Ontario Ministry of Health and Long Term Care; and the Government of Alberta, Canada. Additional support was provided by the Intramural Research Program of the National Cancer Institute, and National Institutes of Health. NR 24 TC 1 Z9 1 U1 0 U2 1 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD APR 4 PY 2016 VL 19 AR 20707 DI 10.7448/IAS.19.1.20707 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DM2JY UT WOS:000376174100001 PM 27049052 ER PT J AU Herz, DM Zavala, BA Bogacz, R Brown, P AF Herz, Damian M. Zavala, Baltazar A. Bogacz, Rafal Brown, Peter TI Neural Correlates of Decision Thresholds in the Human Subthalamic Nucleus SO CURRENT BIOLOGY LA English DT Article ID DEEP BRAIN-STIMULATION; BASAL GANGLIA; FRONTAL-CORTEX; MODEL; CONFLICT AB If humans are faced with difficult choices when making decisions, the ability to slow down responses becomes critical in order to avoid suboptimal choices. Current models of decision making assume that the subthalamic nucleus (STN) mediates this function by elevating decision thresholds, thereby requiring more evidence to be accumulated before responding [1-9]. However, direct electrophysiological evidence for the exact role of STN during adjustment of decision thresholds is lacking. Here, we show that trial-by-trial variations in STN low-frequency oscillatory activity predict adjustments of decision thresholds before subjects make a response. The relationship between STN activity and decision thresholds critically depends on the subjects' level of cautiousness. While increased oscillatory activity of the STN predicts elevated decision thresholds during high levels of cautiousness, it predicts decreased decision thresholds during low levels of cautiousness. This context-dependent relationship may be mediated by increased influence of the medial prefrontal cortex (mPFC)-STN pathway on decision thresholds during high cautiousness. Subjects who exhibit a stronger increase in phase alignment of low-frequency oscillatory activity in mPFC and STN before making a response have higher decision thresholds and commit fewer erroneous responses. Together, our results demonstrate that STN low-frequency oscillatory activity and corresponding mPFC-STN coupling are involved in determining how much evidence subjects accumulate before making a decision. This finding might explain why deep-brain stimulation of the STN can impair subjects' ability to slow down responses and can induce impulsive suboptimal decisions. C1 [Herz, Damian M.; Bogacz, Rafal; Brown, Peter] Univ Oxford, MRC, Brain Network Dynam Unit, Mansfield Rd, Oxford OX1 3TH, England. [Herz, Damian M.; Zavala, Baltazar A.; Bogacz, Rafal; Brown, Peter] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Level 6,West Wing, Oxford OX3 9DU, England. [Zavala, Baltazar A.] NIH, Surg Neurol Branch, 10 Ctr Dr,3D 20, Bethesda, MD 20814 USA. RP Brown, P (reprint author), Univ Oxford, MRC, Brain Network Dynam Unit, Mansfield Rd, Oxford OX1 3TH, England.; Brown, P (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Level 6,West Wing, Oxford OX3 9DU, England. EM peter.brown@ndcn.ox.ac.uk RI Brown, Peter/J-4307-2016 OI Brown, Peter/0000-0002-5201-3044 FU Medical Research Council [MC_UU_12024/1]; European Union [655605] FX We would like to thank H. Tan, S. Little, K. Ashkan, M. Hariz, T. Foltynie, L. Zrinzo, and K. Zaghloul for their contributions to acquisition and analysis of the primary data and the patients for volunteering to take part in the study. All patients provided written informed consent to participate, in accordance with the Declaration of Helsinki, and the study was approved by the local ethics committee. This project has received funding from the Medical Research Council (award MC_UU_12024/1) and the European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement 655605. Original behavioral and electrophysiological data are available on request. NR 18 TC 7 Z9 7 U1 5 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD APR 4 PY 2016 VL 26 IS 7 BP 916 EP 920 DI 10.1016/j.cub.2016.01.051 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DI1RP UT WOS:000373273600026 PM 26996501 ER PT J AU Storz, G AF Storz, Gisela TI New perspectives: Insights into oxidative stress from bacterial studies SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE OxyR; OxyS; MntS ID OXYR TRANSCRIPTION FACTOR; ESCHERICHIA-COLI; SALMONELLA-TYPHIMURIUM; HYDROGEN-PEROXIDE; STRUCTURAL BASIS; ACTIVATION; REGULATOR; ENZYMES; PROTEIN; DAMAGE AB Studies of the response to hydrogen peroxide as well as the characterization of small, noncoding RNAs and small proteins of less than 50 amino acids in Escherichia coli have given new perspectives on redox sensing, the nature of regulators and gene organization that are relevant to all organisms. Published by Elsevier Inc. C1 [Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM storzg@mail.nih.gov FU Intramural Research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [ZIA HD001608, ZIA HD008855] FX I am thankful for the many interesting and stimulating colleagues such as Helmut Sies with whom I have had the great pleasure of interacting over the years. Work carried out in my laboratory was supported by the Intramural Research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIA HD001608 and ZIA HD008855). NR 26 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD APR 2 PY 2016 VL 595 SI SI BP 25 EP 27 DI 10.1016/j.abb.2015.11.022 PG 3 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DK1WF UT WOS:000374705000007 PM 27095210 ER PT J AU Eicher, JD Wakabayashi, Y Vitseva, O Esa, N Yang, YQ Zhu, J Freedman, JE McManus, DD Johnson, AD AF Eicher, John D. Wakabayashi, Yoshiyuki Vitseva, Olga Esa, Nada Yang, Yanqin Zhu, Jun Freedman, Jane E. McManus, David D. Johnson, Andrew D. TI Characterization of the platelet transcriptome by RNA sequencing in patients with acute myocardial infarction SO PLATELETS LA English DT Article DE RNA-seq; myocardial infarction; platelet aggregation; Gene expression ID GROWTH IN-VITRO; MESSENGER-RNA; ALPHA-GRANULES; PDGF-C; ACTIVATION; EXPRESSION; REACTIVITY; COLLAGEN; PROTEIN; VIVO AB Transcripts in platelets are largely produced in precursor megakaryocytes but remain physiologically active as platelets translate RNAs and regulate protein/RNA levels. Recent studies using transcriptome sequencing (RNA-seq) characterized the platelet transcriptome in limited number of non-diseased individuals. Here, we expand upon these RNA-seq studies by completing RNA-seq in platelets from 32 patients with acute myocardial infarction (MI). Our goals were to characterize the platelet transcriptome using a population of patients with acute MI and relate gene expression to platelet aggregation measures and ST-segment elevation MI (STEMI) (n = 16) vs. non-STEMI (NSTEMI) (n = 16) subtypes. Similar to other studies, we detected 9565 expressed transcripts, including several known platelet-enriched markers (e.g. PPBP, OST4). Our RNA-seq data strongly correlated with independently ascertained platelet expression data and showed enrichment for platelet-related pathways (e.g. wound response, hemostasis, and platelet activation), as well as actin-related and post-transcriptional processes. Several transcripts displayed suggestively higher (FBXL4, ECHDC3, KCNE1, TAOK2, AURKB, ERG, and FKBP5) and lower (MIAT, PVRL3, and PZP) expression in STEMI platelets compared to NSTEMI. We also identified transcripts correlated with platelet aggregation to TRAP (ATP6V1G2, SLC2A3), collagen (CEACAM1, ITGA2), and ADP (PDGFB, PDGFC, ST3GAL6). Our study adds to current platelet gene expression resources by providing transcriptome-wide analyses in platelets isolated from patients with acute MI. In concert with prior studies, we identify various genes for further study in regards to platelet function and acute MI. Future platelet RNA-seq studies examining more diverse sets of healthy and diseased samples will add to our understanding of platelet thrombotic and non-thrombotic functions. C1 [Eicher, John D.; Johnson, Andrew D.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Div Intramural Res, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA. [Wakabayashi, Yoshiyuki; Yang, Yanqin; Zhu, Jun] NHLBI, Div Intramural Res, DNA Sequencing & Genom Core Lab, Bldg 10, Bethesda, MD 20892 USA. [Vitseva, Olga] Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA USA. [Esa, Nada; Freedman, Jane E.; McManus, David D.] Univ Massachusetts, Mem Heart & Vasc Ctr, Worcester, MA 01605 USA. RP Johnson, AD (reprint author), NHLBI, Populat Sci Branch, Framingham Heart Study, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU University of Massachusetts Medical School [KL2RR031981]; National Heart, Lung and Blood Institute (NHLBI) [1U01HL105268-01, RFA-HL-12-008] FX The authors report no declarations of interest. Participant ascertainment and data collection were supported by University of Massachusetts Medical School (KL2RR031981) and the National Heart, Lung and Blood Institute (NHLBI) (1U01HL105268-01, RFA-HL-12-008). Platelet function and RNA sequencing studies and analysis were supported via the NHLBI intramural research program. NR 59 TC 7 Z9 7 U1 4 U2 11 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0953-7104 EI 1369-1635 J9 PLATELETS JI Platelets PD APR 2 PY 2016 VL 27 IS 3 BP 230 EP 239 DI 10.3109/09537104.2015.1083543 PG 10 WC Cell Biology; Hematology SC Cell Biology; Hematology GA DI9VB UT WOS:000373849700007 PM 26367242 ER PT J AU Danis, M Wilson, Y White, A AF Danis, Marion Wilson, Yolonda White, Amina TI Bioethicists Can and Should Contribute to Addressing Racism SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE inequity; racism; racial violence; health disparities; bioethics; discrimination ID HEALTH; DISCRIMINATION; RESILIENCE; FRAMEWORK; DECISION; STRESS; FAMILY; BIAS; RACE AB The problems of racism and racially motivated violence in predominantly African American communities in the United States are complex, multifactorial, and historically rooted. While these problems are also deeply morally troubling, bioethicists have not contributed substantially to addressing them. Concern for justice has been one of the core commitments of bioethics. For this and other reasons, bioethicists should contribute to addressing these problems. We consider how bioethicists can offer meaningful contributions to the public discourse, research, teaching, training, policy development, and academic scholarship in response to the alarming and persistent patterns of racism and implicit biases associated with it. To make any useful contribution, bioethicists will require preparation and should expect to play a significant role through collaborative action with others. C1 [Danis, Marion; White, Amina] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Wilson, Yolonda] Howard Univ, Washington, DC USA. RP Danis, M (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,RM,1C118, Bethesda, MD 20892 USA. EM mdanis@nih.gov FU National Institutes of Health (NIH), Department of Bioethics in the Clinical Center of the National Institutes of Health FX The work was supported by the intramural program of the National Institutes of Health (NIH), particularly the Department of Bioethics in the Clinical Center of the National Institutes of Health. NR 50 TC 13 Z9 13 U1 1 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD APR 2 PY 2016 VL 16 IS 4 BP 3 EP 12 DI 10.1080/15265161.2016.1145283 PG 10 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DG5CE UT WOS:000372089500002 PM 26982911 ER PT J AU Chen, SC AF Chen, Stephanie C. TI Fair Participant Selection: A Negative Obligation Not to Exclude SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID CLINICAL-TRIALS C1 [Chen, Stephanie C.] NIH, Bethesda, MD USA. RP Chen, SC (reprint author), Natl Inst Hlth Bioeth, Dept Bioeth, 10 Ctr Dr,Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM stephanie.chen2@nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD APR 2 PY 2016 VL 16 IS 4 BP 71 EP 72 DI 10.1080/15265161.2016.1145297 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DG5CE UT WOS:000372089500026 PM 26982935 ER PT J AU Taveira-Dasilva, AM Moss, J AF Taveira-Dasilva, Angelo M. Moss, Joel TI Epidemiology, pathogenesis and diagnosis of lymphangioleiomyomatosis SO EXPERT OPINION ON ORPHAN DRUGS LA English DT Review DE Lymphangioleiomyomatosis; Tuberous sclerosis complex (TSC); TSC 1 and TSC2 mutations; mTOR ID TUBEROUS SCLEROSIS COMPLEX; GROWTH FACTOR-D; PULMONARY-FUNCTION TESTS; AIR-FLOW OBSTRUCTION; SERUM VEGF-D; MATRIX METALLOPROTEINASES; TISSUE INHIBITORS; DIURNAL-VARIATION; LUNG-DISEASES; GENE-PRODUCTS AB Introduction. Lymphangioleiomyomatosis (LAM) is a disease of women characterized by cystic lung destruction, lymphatic involvement, and renal angiomyolipomas. Areas covered. LAM is caused by proliferation of abnormal smooth muscle-like LAM cells containing mutations and perhaps epigenetic modifications of the TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins controlling the mechanistic target of rapamycin (mTOR) signaling pathway. LAM occurs sporadically or in association with tuberous sclerosis complex. LAM may present with dyspnea, recurrent pneumothorax or chylothorax. Pulmonary function tests show reduced flow rates and lung diffusion capacity. Exercise testing may reveal hypoxemia and ventilatory limitation. The severity and progression of disease may be assessed by computer tomography, and pulmonary function and exercise testing. mTOR inhibitors, (e.g., sirolimus) are effective in stabilizing lung function, and reducing the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas. Expert opinion. Different clinical phenotypes including variable rates of disease progression and variable responses to therapy are seen in LAM patients. No one test is available that predicts the course of disease at the time of diagnosis. Further research regarding the molecular biology of LAM clinical phenotypes is warranted. Recent advances in the characterization of the pathogenesis of LAM are leading to the development of new therapies. C1 [Taveira-Dasilva, Angelo M.; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Taveira-Dasilva, AM (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM dasilvaa@nhlbi.nih.gov FU Intermural Research Program, National Heart Lung and Blood Institute of the NIH [95-H0186] FX This paper has been supported by the Intermural Research Program, National Heart Lung and Blood Institute of the NIH, grant number 95-H0186. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. NR 98 TC 0 Z9 0 U1 2 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 2167-8707 J9 EXPERT OPIN ORPHAN D JI Exp. Opin. Orphan Drugs PD APR 2 PY 2016 VL 4 IS 4 BP 369 EP 378 DI 10.1517/21678707.2016.1148597 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG8ND UT WOS:000372340000001 PM 27833825 ER PT J AU Whitehead, SS AF Whitehead, Stephen S. TI Development of TV003/TV005, a single dose, highly immunogenic live attenuated dengue vaccine; what makes this vaccine different from the Sanofi-Pasteur CYD (TM) vaccine? SO EXPERT REVIEW OF VACCINES LA English DT Review DE vaccine infectivity; vaccine attenuation strategies; vaccine immunogenicity; vaccine efficacy; Dengue; live attenuated dengue vaccine ID FLAVIVIRUS-NAIVE ADULTS; HEMORRHAGIC-FEVER; VIRUS TYPE-4; TETRAVALENT; HEALTHY; INFECTIONS; RESPONSES; TRIAL; SAFE; ENHANCEMENT AB Dengue is caused by four serotype-distinct dengue viruses (DENVs), and developing a multivalent vaccine against dengue has not been straightforward since partial immunity to DENV may predispose to more severe disease upon subsequent DENV infection. The vaccine that is furthest along in development is CYD (TM), a live attenuated tetravalent vaccine (LATV) produced by Sanofi Pasteur. Although the multi-dose vaccine demonstrated protection against severe dengue, its overall efficacy was limited by DENV serotype, serostatus at vaccination, region and age. The National Institute of Allergy and Infectious Diseases has developed the LATV dengue vaccines TV003/TV005. A single dose of either TV003 or TV005 induced seroconversion to four DENV serotypes in 74-92% (TV003) and 90% (TV005) of flavivirus seronegative adults and elicited near-sterilizing immunity to a second dose of vaccine administered 6-12 months later. The important differences in the structure, infectivity and immune responses to TV003/TV005 are compared with CYD (TM). C1 [Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Whitehead, SS (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM swhitehead@niaid.nih.gov FU NIH FX The NIAID research described in this review was supported by the Intramural Research Program of the NIH. SS Whitehead is a co-inventor of intellectual property owned by the US Department of Health and Human Services relating to TV005 and other formulations of the NIAID tetravalent dengue vaccine. The Laboratory of Infectious Diseases at NIAID has entered into a collaborative research agreement with Merck for co-development of the TV005 vaccine. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 27 TC 6 Z9 6 U1 3 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD APR 2 PY 2016 VL 15 IS 4 SI SI BP 509 EP 517 DI 10.1586/14760584.2016.1115727 PG 9 WC Immunology SC Immunology GA DG6CP UT WOS:000372170100002 PM 27822982 ER PT J AU Hodes, RJ Buckholtz, N AF Hodes, Richard J. Buckholtz, Neil TI Accelerating Medicines Partnership: Alzheimer's Disease (AMP-AD) Knowledge Portal Aids Alzheimer's Drug Discovery through Open Data Sharing SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Editorial Material ID LOCI C1 [Hodes, Richard J.; Buckholtz, Neil] NIA, NIH, Bethesda, MD 20892 USA. RP Buckholtz, N (reprint author), NIA, NIH, Bethesda, MD 20892 USA. EM nbucky11@gmail.com NR 17 TC 4 Z9 4 U1 1 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1472-8222 EI 1744-7631 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD APR 2 PY 2016 VL 20 IS 4 BP 389 EP 391 DI 10.1517/14728222.2016.1135132 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DE6HQ UT WOS:000370735000001 PM 26853544 ER PT J AU Lee, JS Romero, R Han, YM Kim, HC Kim, CJ Hong, JS Huh, D AF Lee, Ji Soo Romero, Roberto Han, Yu Mi Kim, Hee Chan Kim, Chong Jai Hong, Joon-Seok Huh, Dongeun TI Placenta-on-a-chip: a novel platform to study the biology of the human placenta SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Glucose transfer; microfluidics; organ-on-a-chip; placenta in vitro model; placental barrier ID INTRAUTERINE GROWTH RESTRICTION; GESTATIONAL DIABETES-MELLITUS; COTYLEDON PERFUSION MODEL; AMINO ISOBUTYRIC ACID; IN-VITRO SIMULATION; LOW-PROTEIN DIET; EX-VIVO; FETAL-GROWTH; LISTERIA-MONOCYTOGENES; TRYPANOSOMA-CRUZI AB Objective: Studying the biology of the human placenta represents a major experimental challenge. Although conventional cell culture techniques have been used to study different types of placenta-derived cells, current in vitro models have limitations in recapitulating organ-specific structure and key physiological functions of the placenta. Here we demonstrate that it is possible to leverage microfluidic and microfabrication technologies to develop a microengineered biomimetic model that replicates the architecture and function of the placenta.Materials and methods: A Placenta-on-a-Chip microdevice was created by using a set of soft elastomer-based microfabrication techniques known as soft lithography. This microsystem consisted of two polydimethylsiloxane (PDMS) microfluidic channels separated by a thin extracellular matrix (ECM) membrane. To reproduce the placental barrier in this model, human trophoblasts (JEG-3) and human umbilical vein endothelial cells (HUVECs) were seeded onto the opposite sides of the ECM membrane and cultured under dynamic flow conditions to form confluent epithelial and endothelial layers in close apposition. We tested the physiological function of the microengineered placental barrier by measuring glucose transport across the trophoblast-endothelial interface over time. The permeability of the barrier study was analyzed and compared to that obtained from acellular devices and additional control groups that contained epithelial or endothelial layers alone.Results: Our microfluidic cell culture system provided a tightly controlled fluidic environment conducive to the proliferation and maintenance of JEG-3 trophoblasts and HUVECs on the ECM scaffold. Prolonged culture in this model produced confluent cellular monolayers on the intervening membrane that together formed the placental barrier. This in vivo-like microarchitecture was also critical for creating a physiologically relevant effective barrier to glucose transport. Quantitative investigation of barrier function was conducted by calculating permeability coefficients and metabolic rates in varying conditions of barrier structure. The rates of glucose transport and metabolism were consistent with previously reported in vivo observations.Conclusion: The Placenta-on-a-Chip microdevice described herein provides new opportunities to simulate and analyze critical physiological responses of the placental barrier. This system may be used to address the major limitations of existing placenta model systems and serve to enable research platforms for reproductive biology and medicine. C1 [Lee, Ji Soo] Seoul Natl Univ, Grad Sch, Interdisciplinary Program Bioengn, Seoul, South Korea. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI USA. [Han, Yu Mi; Hong, Joon-Seok] Seoul Natl Univ, Bundang Hosp, Dept Obstet & Gynecol, 82 Gumi Ro 173 Beon Gil, Songnam 463707, Gyeonggi Do, South Korea. [Kim, Hee Chan] Seoul Natl Univ, Med Res Ctr, Inst Med & Biol Engn, Seoul, South Korea. [Kim, Hee Chan] Seoul Natl Univ, Coll Med, Dept Biomed Engn, Seoul, South Korea. [Kim, Hee Chan] Seoul Natl Univ Hosp, Dept Biomed Engn, Seoul 110744, South Korea. [Kim, Chong Jai] Univ Ulsan, Coll Med, Dept Pathol, Asan Med Ctr, Seoul, South Korea. [Huh, Dongeun] Univ Penn, Dept Bioengn, 240 Skirkanich Hall,210 S 33rd St, Philadelphia, PA 19104 USA. RP Hong, JS (reprint author), Seoul Natl Univ, Bundang Hosp, Dept Obstet & Gynecol, 82 Gumi Ro 173 Beon Gil, Songnam 463707, Gyeonggi Do, South Korea.; Huh, D (reprint author), Univ Penn, Dept Bioengn, 240 Skirkanich Hall,210 S 33rd St, Philadelphia, PA 19104 USA.; Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD NIH DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov; hjsobgy@gmail.com; huhd@seas.upenn.edu FU Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/DHHS; Federal funds from NICHD, NIH [HSN275201300006C]; Seoul National University Bundang Hospital Research Fund [03-2013-001]; National Research Foundation of Korea [2012M3A7B4035286, 2013R1A2A2A04013379]; National Medical Center and Asan Medical Center in Seoul, Republic of Korea; NIH Director's New innovator Award [1DP2HL127720-01]; Perinatology Research Branch FX The authors report no conflicts of interest. This work was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/DHHS; and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C, and by the Seoul National University Bundang Hospital Research Fund (Grant No. 03-2013-001) and the National Research Foundation of Korea (2012M3A7B4035286 and 2013R1A2A2A04013379). We also acknowledge support from the National Medical Center and Asan Medical Center in Seoul, Republic of Korea. D. H. is a recipient of the NIH Director's New innovator Award (1DP2HL127720-01). NR 100 TC 11 Z9 11 U1 27 U2 103 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD APR 2 PY 2016 VL 29 IS 7 BP 1046 EP 1054 DI 10.3109/14767058.2015.1038518 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DB7QL UT WOS:000368710600005 PM 26075842 ER PT J AU Mhatre, SS Nagrani, RT Budukh, A Chiplunkar, S Badwe, R Patil, P Laversanne, M Rajaraman, P Bray, F Dikshit, R AF Mhatre, S. S. Nagrani, R. T. Budukh, A. Chiplunkar, S. Badwe, R. Patil, P. Laversanne, M. Rajaraman, P. Bray, F. Dikshit, R. TI Place of birth and risk of gallbladder cancer in India SO INDIAN JOURNAL OF CANCER LA English DT Article DE Birth region; gallbladder cancer; population-based cancer registries AB CONTEXT: Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear. AIMS: To evaluate the role of place of birth, length of residence, and effect of migration from high-to low-risk region on GBC development. SETTINGS AND DESIGN: Population-based cancer registries (PBCRs); case-control study. SUBJECTS AND METHODS: Data of PBCRs were used to demonstrate geographical variation in GBC incidence rates. A case-control study data examined the role of birth place, residence length, and effect of migration in etiology of GBC. STATISTICAL ANALYSIS: Rate ratios for different PBCRs were estimated using Chennai Cancer Registry as the reference population. Odds ratios (ORs) for developing GBC in a high-risk region compared to a low-risk region and associated 95% confidence interval (CI) were estimated through unconditional logistic regression models using case-control study. RESULTS: GBC shows marked variation in incidence with risk highest in Northeast regions and lowest in South India. OR of 4.82 (95% CI: 3.87-5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region after adjusting for confounders. A dose-response relationship with increased risk with increased length of residence in a high-risk region was observed (OR lifetime 5.58 [95% CI: 4.42-7.05]; P-trend <= 0.001). The risk persisted even if study participant migrated from high-to low-risk region (OR = 1.36; 95% CI: 1.02-1.82). CONCLUSIONS: The present study signifies the importance of place of birth, length of stay, and effect of migration from high-to low-risk region in the development of GBC. The data indicate role of environmental and genetic factors in etiology of disease. C1 [Mhatre, S. S.; Nagrani, R. T.; Budukh, A.; Dikshit, R.] Tata Mem Hosp, Ctr Canc Epidemiol, Mumbai, Maharashtra, India. [Badwe, R.] Tata Mem Hosp, Dept Surg Oncol, Mumbai, Maharashtra, India. [Patil, P.] Tata Mem Hosp, Dept Digest Dis & Clin Nutr, Mumbai, Maharashtra, India. [Chiplunkar, S.] Tata Mem Hosp, Adv Ctr Treatment Res & Educ Canc, Chiplunkar Lab, Navi Mumbai, Maharashtra, India. [Laversanne, M.] Int Agcy Res Canc, Sect Canc Surveillance, Lyon, France. [Rajaraman, P.] NCI, Ctr Global Hlth, NIH, DHSS, Bethesda, MD 20892 USA. RP Dikshit, R (reprint author), Tata Mem Hosp, Ctr Canc Epidemiol, Mumbai, Maharashtra, India. EM dixr24@hotmail.com OI nagrani, rajini/0000-0002-1708-2319 NR 8 TC 0 Z9 0 U1 0 U2 0 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0019-509X EI 1998-4774 J9 INDIAN J CANCER JI Indian J. Cancer PD APR-JUN PY 2016 VL 53 IS 2 BP 304 EP 308 DI 10.4103/0019-509X.197723 PG 5 WC Oncology SC Oncology GA EJ0XG UT WOS:000392933700025 PM 28071634 ER PT J AU Chaudhary, DV Patel, DP Shah, PA Shah, JV Sanyal, M Shrivastav, PS AF Chaudhary, Darshan V. Patel, Daxesh P. Shah, Priyanka A. Shah, Jaivik V. Sanyal, Mallika Shrivastav, Pranav S. TI Determination of lercanidipine in human plasma by an improved UPLC-MS/MS method for a bioequivalence study SO JOURNAL OF PHARMACEUTICAL ANALYSIS LA English DT Article AB An improved and reliable ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for the determination of lercanidipine in human plasma. Plasma samples with lercanidipine-d3 as an internal standard (IS) were prepared by solid phase extraction on Phenomenex Strata-X cartridges using 100 mu L of human plasma. Chromatographic analysis was performed on UPLC BEH C-18 (50 mm x 2.1 mm, 1.7 mu m) column under isocratic conditions. Linear calibration curves were obtained over a wide dynamic concentration range of 0.010-20.0 ng/mL. Matrix effect was assessed by post-column infusion, post-extraction spiking and standard-line slope methods. The mean extraction recovery was > 94% for the analyte and IS. Inter-batch and intra-batch precision (% CV) across five quality controls was <5.8%. Bioequivalence study was performed with 36 healthy subjects after oral administration of 10 mg of lercanidipine and the assay reproducibility was evaluated by reanalysis of 133 incurred samples. (C) 2015 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. C1 [Chaudhary, Darshan V.; Shah, Priyanka A.; Shah, Jaivik V.; Shrivastav, Pranav S.] Gujarat Univ, Sch Sci, Dept Chem, Ahmadabad 380009, Gujarat, India. [Patel, Daxesh P.] NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. [Sanyal, Mallika] St Xaviers Coll, Dept Chem, Ahmadabad 380009, Gujarat, India. RP Shrivastav, PS (reprint author), Gujarat Univ, Sch Sci, Dept Chem, Ahmadabad 380009, Gujarat, India. EM pranav_shrivastav@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2095-1779 EI 2214-0883 J9 J PHARM ANA JI J. Pharm. Anal. PD APR PY 2016 VL 6 IS 2 BP 87 EP 94 DI 10.1016/j.jpha.2015.09.001 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DJ1TQ UT WOS:000373987600003 ER PT J AU Collins, H Calvo, S Greenberg, K Neall, LF Morrison, S AF Collins, Heather Calvo, Sherri Greenberg, Kathleen Neall, Lisa Forman Morrison, Stephanie TI Information Needs in the Precision Medicine Era: How Genetics Home Reference Can Help SO INTERACTIVE JOURNAL OF MEDICAL RESEARCH LA English DT Article DE individualized medicine; patient education as topic; databases; genetic; health resources ID GENOMIC MEDICINE; HEALTH; KNOWLEDGE AB Precision medicine focuses on understanding individual variability in disease prevention, care, and treatment. The Precision Medicine Initiative, launched by President Obama in early 2015, aims to bring this approach to all areas of health care. However, few consumer-friendly resources exist for the public to learn about precision medicine and the conditions that could be affected by this approach to care. Genetics Home Reference, a website from the US National Library of Medicine, seeks to support precision medicine education by providing the public with summaries of genetic conditions and their associated genes, as well as information about issues related to precision medicine such as disease risk and pharmacogenomics. With the advance of precision medicine, consumer-focused resources like Genetics Home Reference can be foundational in providing context for public understanding of the increasing amount of data that will become available. C1 [Collins, Heather; Greenberg, Kathleen] ICF Int, 9300 Lee Highway, Fairfax, VA 22031 USA. [Calvo, Sherri; Morrison, Stephanie] NIH, US Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Neall, Lisa Forman] Med Sci Comp LLC, Rockville, MD USA. RP Collins, H (reprint author), ICF Int, 9300 Lee Highway, Fairfax, VA 22031 USA. EM Heather.Collins@icfi.com NR 25 TC 0 Z9 0 U1 3 U2 3 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1929-073X J9 INTERACT J MED RES JI Interact. J. Med. Res. PD APR-JUN PY 2016 VL 5 IS 2 BP 94 EP 99 AR e13 DI 10.2196/ijmr.5199 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ED1PO UT WOS:000388617600010 PM 27122232 ER PT J AU Kozinetz, CA Royse, K Graham, SC Yu, XY Moye, J Selwyn, BJ Forman, MR Caviness, C AF Kozinetz, Claudia A. Royse, Kathryn Graham, Sarah C. Yu, Xiaoying Moye, Jack Selwyn, Beatrice J. Forman, Michele R. Caviness, Chantal TI Consenting postpartum women for use of routinely collected biospecimens and/or future biospecimen collection SO JOURNAL OF COMMUNITY GENETICS LA English DT Article DE Residual; Biospecimen; Postpartum; Consent ID INFORMED-CONSENT; OPT-IN; SPECIMENS; ATTITUDES; BIOBANKS AB The National Children's Study (NCS) Harris County, Texas Study Center participated in the NCS Provider Based Sampling (PBS) substudy of the NCS Vanguard Phase pilot. As part of the hospital-based birth cohort component of the PBS substudy, we conducted a secondary data analysis to evaluate the proportion of postpartum women who consented to future biospecimen collection alone and to both future collection and use of residual birth biospecimens. In phase 1, 32 postpartum women at one hospital were asked to consent only to maternal future biospecimen collection. In phase 2, 40 other postpartum women from the same hospital were asked for an additional consent to use residual clinical biospecimens from the birth event that otherwise would be discarded, including cord blood and maternal blood and urine. Among 103 eligible women, a total of 72 participated. They were 28.3 +/- 5.9 years old on average; 58 % were Hispanic; 63 % consented in English, and 37 % in Spanish; 39 % had some college education; 42 % were married; 60 % had an annual family income <$ 30,000; and 51 % were employed. In phase 1, 59 % consented to future biospecimen collection, and in phase 2, 95 % consented to both future collection and use of at least one residual birth biospecimen, with a difference between phases of 36 % [95 % CI 17-54 %]. Demographic characteristics did not differ among those who did and did not consent. Postpartum women were significantly more likely to grant consent for use of future and residual hospital-obtained biospecimens than future biospecimen collection alone. C1 [Kozinetz, Claudia A.] East Tennessee State Univ, Coll Publ Hlth, Dept Biostat & Epidemiol, Box 70259, Johnson City, TN 37614 USA. [Royse, Kathryn; Yu, Xiaoying] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Graham, Sarah C.; Caviness, Chantal] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Moye, Jack] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. [Selwyn, Beatrice J.] Univ Texas Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Forman, Michele R.] Univ Texas Austin, Sch Human Ecol, Dept Nutr Sci, Austin, TX 78712 USA. RP Kozinetz, CA (reprint author), East Tennessee State Univ, Coll Publ Hlth, Dept Biostat & Epidemiol, Box 70259, Johnson City, TN 37614 USA. EM kozinetz@etsu.edu OI Kozinetz, Claudia/0000-0002-3535-0698 FU NICHD NIH HHS [HHSN275200800020C] NR 16 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1868-310X EI 1868-6001 J9 J COMMUN GENET JI J. Commun. Genet. PD APR PY 2016 VL 7 IS 2 BP 153 EP 158 DI 10.1007/s12687-016-0261-9 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EA6ZR UT WOS:000386778300006 PM 26869364 ER PT J AU Fox, CS Hwang, SJ Nieto, K Valentino, M Mutalik, K Massaro, JM Benjamin, EJ Murabito, JM AF Fox, Caroline S. Hwang, Shih-Jen Nieto, Kenneth Valentino, Maureen Mutalik, Karen Massaro, Joseph M. Benjamin, Emelia J. Murabito, Joanne M. TI Digital Connectedness in the Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cardiovascular risk; eHealth; epidemiology; mHealth; smartphones; technology ID MOBILE HEALTH; EPIDEMIOLOGY; COMMUNITY AB Background-New avenues of data collection such as eHealth and mobile technology have the potential to revolutionize the way large populations can be assessed and managed outside of standard research and clinical settings. Methods and Results-A digital connectedness survey was administered within the Framingham Heart Study from 2014 to 2015. The exposure was usage of the Internet, email, cell phones, and smartphones in relation to demographic and cardiovascular disease risk factors; all results were adjusted for age and sex. Among 8096 living study participants, 6503 (80.3%) completed the digital survey. Among survey responders, 5678 (87.4%) reported regular Internet use. Participants reporting regular Internet use were younger (aged 59.1 versus 76.5 years, P<0.0001), were more likely to be employed (70.3% versus 23.7%, P=0.002), and had more favorable cardiovascular disease risk factors than those who did not use the Internet (all P <= 0.05). Overall, 5946 (92.1%) responders reported using cell phones. Among cell phone users, 3907 (67.8%) had smartphones. Smartphone users were younger (aged 55.4 versus 68.5 years, P<0.0001), more likely to be employed (81.1% versus 43.9%, P<0.0001) and to have a college education, and less likely to have hypertension (27.9% versus 55.7%, P=0.0002) than those who did not use smartphones. Conclusions-Digital connectedness varies substantially by age; connected persons tend to be younger and better educated and to have more favorable cardiovascular disease risk factor profiles. Less than two-thirds of study participants who completed the survey had a smartphone. The generalizability of studies focused on digitally connected persons may have limitations. C1 [Fox, Caroline S.; Hwang, Shih-Jen] NHLBI, Ctr Populat Studies, NIH, Framingham, MA USA. [Fox, Caroline S.] Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol Hypertens & Metab, Boston, MA USA. [Nieto, Kenneth; Valentino, Maureen; Mutalik, Karen; Benjamin, Emelia J.; Murabito, Joanne M.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Dept Med, Sect Cardiol & Prevent Med, Sch Med, Boston, MA 02215 USA. [Murabito, Joanne M.] Boston Univ, Dept Med, Gen Internal Med Sect, Sch Med, Boston, MA 02215 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU [N01-HC-25195]; [HHSN268201500001I]; [2R01HL092577]; [1R01HL128914]; [1P50HL120163] FX The National Heart, Lung, and Blood Institute's Framingham Heart Study is supported by contract N01-HC-25195 and HHSN268201500001I; 2R01HL092577; 1R01HL128914; 1P50HL120163. NR 17 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD APR PY 2016 VL 5 IS 4 AR e003193 DI 10.1161/JAHA.116.003193 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ1PI UT WOS:000385609900027 PM 27076568 ER PT J AU Morid, MA Fiszman, M Raja, K Jonnalagadda, SR Del Fiol, G AF Morid, Mohammad Amin Fiszman, Marcelo Raja, Kalpana Jonnalagadda, Siddhartha R. Del Fiol, Guilherme TI Classification of clinically useful sentences in clinical evidence resources SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Text summarization; Clinical decision support; Natural language processing; Machine learning ID BAYESIAN CLASSIFIERS; DENSITY-ESTIMATION; DECISION-SUPPORT; QUESTIONS; KNOWLEDGE; TEXT; CARE; UPTODATE; SYSTEMS; DOMAIN AB Most patient care questions raised by clinicians can be answered by online clinical knowledge resources. However, important barriers still challenge the use of these resources at the point of care. Objective: To design and assess a method for extracting clinically useful sentences from synthesized online clinical resources that represent the most clinically useful information for directly answering clinicians' information needs. Materials and methods: We developed a Kernel-based Bayesian Network classification model based on different domain-specific feature types extracted from sentences in a gold standard composed of 18 UpToDate documents. These features included UMLS concepts and their semantic groups, semantic predications extracted by SemRep, patient population identified by a pattern-based natural language processing (NLP) algorithm, and cue words extracted by a feature selection technique. Algorithm performance was measured in terms of precision, recall, and F-measure. Results: The feature-rich approach yielded an F-measure of 74% versus 37% for a feature co-occurrence method (p < 0.001). Excluding predication, population, semantic concept or text-based features reduced the F-measure to 62%, 66%, 58% and 69% respectively (p < 0.01). The classifier applied to Medline sentences reached an F-measure of 73%, which is equivalent to the performance of the classifier on UpToDate sentences (p = 0.62). Conclusions: The feature-rich approach significantly outperformed general baseline methods. This approach significantly outperformed classifiers based on a single type of feature. Different types of semantic features provided a unique contribution to overall classification performance. The classifier's model and features used for UpToDate generalized well to Medline abstracts. (C) 2016 Elsevier Inc. All rights reserved. C1 [Morid, Mohammad Amin] Univ Utah, Dept Operat & Informat Syst, David Eccles Sch Business, Salt Lake City, UT USA. [Fiszman, Marcelo] Natl Lib Med, Lister Hill Ctr, Bethesda, MD USA. [Raja, Kalpana; Jonnalagadda, Siddhartha R.] Northwestern Univ, Feinberg Sch Med, Div Hlth & Biomed Informat, Dept Prevent Med, Chicago, IL 60611 USA. [Del Fiol, Guilherme] Univ Utah, Dept Biomed Informat, 421 Wakara Way, Salt Lake City, UT 84108 USA. RP Del Fiol, G (reprint author), Univ Utah, Dept Biomed Informat, 421 Wakara Way, Salt Lake City, UT 84108 USA. EM guilherme.delfiol@utah.edu OI Morid, Mohammad/0000-0002-8818-6545; Del Fiol, Guilherme/0000-0001-9954-6799 FU National Library of Medicine [1R01LM011416-01, 4R00LM011389-02] FX This project was supported by Grants 1R01LM011416-01 and 4R00LM011389-02 from the National Library of Medicine. NR 53 TC 2 Z9 2 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD APR PY 2016 VL 60 BP 14 EP 22 DI 10.1016/j.jbi.2016.01.003 PG 9 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA DX9HL UT WOS:000384704100002 PM 26774763 ER PT J AU Workman, TE Fiszman, M Cairelli, MJ Nahl, D Rindflesch, TC AF Workman, T. Elizabeth Fiszman, Marcelo Cairelli, Michael J. Nahl, Diane Rindflesch, Thomas C. TI Spark, an application based on Serendipitous Knowledge Discovery SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Knowledge discovery; Information-seeking behavior; Application development ID INFORMATION-RETRIEVAL; BIOMEDICAL TEXT; FRAMEWORK; SEARCH AB Findings from information-seeking behavior research can inform application development. In this report we provide a system description of Spark, an application based on findings from Serendipitous Knowledge Discovery studies and data structures known as semantic predications. Background information and the previously published IF-SKD model (outlining Serendipitous Knowledge Discovery in online environments) illustrate the potential use of information-seeking behavior in application design. A detailed overview of the Spark system illustrates how methodologies in design and retrieval functionality enable production of semantic predication graphs tailored to evoke Serendipitous Knowledge Discovery in users. (C) 2016 Published by Elsevier Inc. C1 [Workman, T. Elizabeth; Fiszman, Marcelo; Cairelli, Michael J.; Rindflesch, Thomas C.] NIH, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bldg 10, Bethesda, MD 20892 USA. [Nahl, Diane] Univ Hawaii, Lib & Informat Sci Program, Dept Informat & Comp Sci, Honolulu, HI 96822 USA. RP Workman, TE (reprint author), NIH, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bldg 10, Bethesda, MD 20892 USA. EM workmante@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine; National Library of Medicine FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. This research was supported in part by an appointment of the first author to the Lister Hill Center Fellows Program sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education. NR 50 TC 0 Z9 0 U1 5 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD APR PY 2016 VL 60 BP 23 EP 37 DI 10.1016/j.jbi.2015.12.014 PG 15 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA DX9HL UT WOS:000384704100003 PM 26732995 ER PT J AU Hume, S Aerts, J Sarnikar, S Huser, V AF Hume, Sam Aerts, Jozef Sarnikar, Surendra Huser, Vojtech TI Current applications and future directions for the CDISC Operational Data Model standard: A methodological review SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Review DE ODM; Define-XML; CDISC; Interoperability; Clinical trial; EHR ID DATA INTERCHANGE STANDARDS; CLINICAL-RESEARCH; SEMANTIC INTEROPERABILITY; METADATA REGISTRIES; SINGLE-SOURCE; HEALTH-CARE; ODM; TRIAL; ARCHETYPES; EXCHANGE AB Introduction: In order to further advance research and development on the Clinical Data Interchange Standards Consortium (CDISC) Operational Data Model (ODM) standard, the existing research must be well understood. This paper presents a methodological review of the ODM literature. Specifically, it develops a classification schema to categorize the ODM literature according to how the standard has been applied within the clinical research data lifecycle. This paper suggests areas for future research and development that address ODM's limitations and capitalize on its strengths to support new trends in clinical research informatics. Methods: A systematic scan of the following databases was performed: (1) ABI/Inform, (2) ACM Digital, (3) AIS eLibrary, (4) Europe Central PubMed, (5) Google Scholar, (5) IEEE Xplore, (7) PubMed, and (8) ScienceDirect. A Web of Science citation analysis was also performed. The search term used on all databases was "CDISC ODM." The two primary inclusion criteria were: (1) the research must examine the use of ODM as an information system solution component, or (2) the research must critically evaluate ODM against a stated solution usage scenario. Out of 2686 articles identified, 266 were included in a title level review, resulting in 183 articles. An abstract review followed, resulting in 121 remaining articles; and after a full text scan 69 articles met the inclusion criteria. Results: As the demand for interoperability has increased, ODM has shown remarkable flexibility and has been extended to cover a broad range of data and metadata requirements that reach well beyond ODM's original use cases. This flexibility has yielded research literature that covers a diverse array of topic areas. A classification schema reflecting the use of ODM within the clinical research data lifecycle was created to provide a categorized and consolidated view of the ODM literature. The elements of the framework include: (1) EDC (Electronic Data Capture) and EHR (Electronic Health Record) infrastructure; (2) planning; (3) data collection; (4) data tabulations and analysis; and (5) study archival. The analysis reviews the strengths and limitations of ODM as a solution component within each section of the classification schema. This paper also identifies opportunities for future ODM research and development, including improved mechanisms for semantic alignment with external terminologies, better representation of the CDISC standards used end-to-end across the clinical research data lifecycle, improved support for real-time data exchange, the use of EHRs for research, and the inclusion of a complete study design. Conclusions: ODM is being used in ways not originally anticipated, and covers a diverse array of use cases across the clinical research data lifecycle. ODM has been used as much as a study metadata standard as it has for data exchange. A significant portion of the literature addresses integrating EHR and clinical research data. The simplicity and readability of ODM has likely contributed to its success and broad implementation as a data and metadata standard. Keeping the core ODM model focused on the most fundamental use cases, while using extensions to handle edge cases, has kept the standard easy for developers to learn and use. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hume, Sam; Sarnikar, Surendra] Dakota State Univ, Coll Business & Informat Syst, 820 N Washington Ave, Madison, SD 57042 USA. [Aerts, Jozef] FH Joanneum Univ Appl Sci, Eggenberger Allee 11, A-8020 Graz, Austria. [Huser, Vojtech] NIH, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike,Bld 38a,Rm 9N919, Bethesda, MD 20894 USA. RP Hume, S (reprint author), Dakota State Univ, Coll Business & Informat Syst, 820 N Washington Ave, Madison, SD 57042 USA. EM swhume@gmail.com; jozef.aerts@fh-joanneum.at; surendra.sarnikar@dsu.edu; vojtech.huser@nih.gov OI Hume, Sam/0000-0002-6045-7251 FU Intramural Research Program of the National Institutes of Health (NIH)/National Library of Medicine (NLM)/Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported in part (VH) by the Intramural Research Program of the National Institutes of Health (NIH)/National Library of Medicine (NLM)/Lister Hill National Center for Biomedical Communications (LHNCBC). We wish to thank Wayne Kubick, Rebecca Kush, and Landen Bain of CDISC, and Sally Cassells of Next Step Clinical Systems for their insightful comments on a draft version of this work. Sam Hume and Sally Cassells co-lead the CDISC XML Technologies Team. NR 101 TC 0 Z9 0 U1 2 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD APR PY 2016 VL 60 BP 352 EP 362 DI 10.1016/j.jbi.2016.02.016 PG 11 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA DX9HL UT WOS:000384704100036 PM 26944737 ER PT J AU Squiers, L Brown, D Parvanta, S Dolina, S Kelly, B Dever, J Southwell, BG Sanders, A Augustson, E AF Squiers, Linda Brown, Derick Parvanta, Sarah Dolina, Suzanne Kelly, Bridget Dever, Jill Southwell, Brian G. Sanders, Amy Augustson, Erik TI The SmokefreeTXT (SFTXT) Study: Web and Mobile Data Collection to Evaluate Smoking Cessation for Young Adults SO JMIR RESEARCH PROTOCOLS LA English DT Article DE tobacco use cessation; text messaging; clinical trial; survey methods; cell phones; telemedicine ID RANDOMIZED-TRIAL; PROGRAM AB Background: Text messaging (short message service, SMS) has been shown to be effective in delivering interventions for various diseases and health conditions, including smoking cessation. While there are many published studies regarding smoking cessation text messaging interventions, most do not provide details about the study's operational methods. As a result, there is a gap in our understanding of how best to design studies of smoking cessation text messaging programs. Objective: The purpose of this paper is to detail the operational methods used to conduct a randomized trial comparing three different versions of the National Cancer Institute's SmokefreeText (SFTXT) program, designed for smokers 18 to 29 years of age. We detail our methods for recruiting participants from the Internet, reducing fraud, conducting online data collection, and retaining panel study participants. Methods: Participants were recruited through website advertisements and market research online panels. Screening questions established eligibility for the study (eg, 18 to 29 years of age, current smoker). Antifraud measures screened out participants who could not meet the study requirements. After completing a baseline survey, participants were randomized to one of three study arms, which varied by type and timing of text message delivery. The study offered US $20 gift cards as incentives to complete each of four follow-up surveys. Automated email reminders were sent at designated intervals to increase response rates. Researchers also provided telephone reminders to those who had not completed the survey after multiple email reminders. We calculated participation rates across study arms and compared the final sample characteristics to the Current Population Survey to examine generalizability. Results: Recruitment methods drove 153,936 unique visitors to the SFTXT Study landing page and 27,360 began the screener. Based on the screening questions, 15,462 out of 27,360 responders (56.51%) were eligible to participate. Of the 15,462 who were eligible, 9486 passed the antifraud measures that were implemented; however, 3882 failed to verify their email addresses or cell phone numbers, leaving 5604 who were invited to complete the baseline survey. Of the 5604 who were invited, 4432 completed the baseline survey, but only 4027 were retained for analysis because 405 did not receive the intervention. Conclusions: Although antifraud measures helped to catch participants who failed study requirements and could have biased the data collected, it is possible that the email and cell phone verification check excluded some potentially eligible participants from the study. Future research should explore ways to implement verification methods without risking the loss of so many potential participants. C1 [Squiers, Linda] RTI Int, Ctr Commun Sci, 6110 Execut Blvd,Suite 902, Rockville, MD 20852 USA. [Brown, Derick; Parvanta, Sarah; Dolina, Suzanne; Southwell, Brian G.] RTI Int, Res Triangle Pk, NC USA. [Kelly, Bridget; Dever, Jill] RTI Int, Washington, DC USA. [Sanders, Amy] ICF Int, Rockville, MD USA. [Augustson, Erik] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Squiers, L (reprint author), RTI Int, Ctr Commun Sci, 6110 Execut Blvd,Suite 902, Rockville, MD 20852 USA. EM lsquiers@rti.org RI Emchi, Karma/Q-1952-2016 NR 10 TC 0 Z9 0 U1 0 U2 0 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1929-0748 J9 JMIR RES PROTOC JI JMIR RES. Protoc. PD APR-JUN PY 2016 VL 5 IS 2 AR e134 DI 10.2196/resprot.5653 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DT1AH UT WOS:000381213600056 PM 27349898 ER PT J AU Li, M Kandror, O Akopian, T Dharkar, P Wlodawer, A Maurizi, MR Goldberg, AL AF Li, Mi Kandror, Olga Akopian, Tatos Dharkar, Poorva Wlodawer, Alexander Maurizi, Michael R. Goldberg, Alfred L. TI Structure and Functional Properties of the Active Form of the Proteolytic Complex, ClpP1P2, from Mycobacterium tuberculosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ATP-DEPENDENT PROTEASE; COLI CLPAP PROTEASE; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; AXIAL CHANNEL; TRANSLOCATION; DEGRADATION; MECHANISM; PEPTIDE; BINDING AB The ClpP protease complex and its regulatory ATPases, ClpC1 and ClpX, in Mycobacterium tuberculosis (Mtb) are essential and, therefore, promising drug targets. The Mtb ClpP protease consists of two heptameric rings, one composed of ClpP1 and the other of ClpP2 subunits. Formation of the enzymatically active ClpP1P2 complex requires binding of N-blocked dipeptide activators. We have found a new potent activator, benzoyl-leucine-leucine (Bz-LL), that binds with higher affinity and promotes 3-4-fold higher peptidase activity than previous activators. Bz-LL-activated ClpP1P2 specifically stimulates the ATPase activity of Mtb ClpC1 and ClpX. The ClpC1P1P2 and ClpXP1P2 complexes exhibit 2-3-fold enhanced ATPase activity, peptide cleavage, and ATP-dependent protein degradation. The crystal structure of ClpP1P2 with bound Bz-LL was determined at a resolution of 3.07 angstrom and with benzyloxycarbonyl-Leu-Leu (Z-LL) bound at 2.9 angstrom. Bz-LL was present in all 14 active sites, whereas Z-LL density was not resolved. Surprisingly, Bz-LL adopts opposite orientations in ClpP1 and ClpP2. In ClpP1, Bz-LL binds with the C-terminal leucine side chain in the S1 pocket. One C-terminal oxygen is close to the catalytic serine, whereas the other contacts backbone amides in the oxyanion hole. In ClpP2, Bz-LL binds with the benzoyl group in the S1 pocket, and the peptide hydrogen bonded between parallel beta-strands. The ClpP2 axial loops are extended, forming an open axial channel as has been observed with bound ADEP antibiotics. Thus occupancy of the active sites of ClpP allosterically alters sites on the surfaces thereby affecting the association of ClpP1 and ClpP2 rings, interactions with regulatory ATPases, and entry of protein substrates. C1 [Li, Mi; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. [Li, Mi] Frederick Natl Lab, Leidos Biomed Res, Basic Res Program, Frederick, MD 21702 USA. [Kandror, Olga; Akopian, Tatos; Goldberg, Alfred L.] Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA. [Dharkar, Poorva; Maurizi, Michael R.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Goldberg, AL (reprint author), Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA.; Maurizi, MR (reprint author), NCI, Bldg 37,Rm 2128,37 Convent Dr, Bethesda, MD 20892 USA. EM mmaurizi@helix.nih.gov; Alfred_Goldberg@hms.harvard.edu FU United States Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX Diffraction data were collected on the SER-CAT 22ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract W-31-109-Eng-38. NR 56 TC 3 Z9 3 U1 4 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 1 PY 2016 VL 291 IS 14 BP 7465 EP 7476 DI 10.1074/jbc.M115.700344 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW2BJ UT WOS:000383447600022 PM 26858247 ER PT J AU Chen, PW Jian, XY Heissler, SM Le, K Luo, RH Jenkins, LM Nagy, A Moss, J Sellers, JR Randazzo, PA AF Chen, Pei-Wen Jian, Xiaoying Heissler, Sarah M. Le, Kang Luo, Ruibai Jenkins, Lisa M. Nagy, Attila Moss, Joel Sellers, James R. Randazzo, Paul A. TI The Arf GTPase-activating Protein, ASAP1, Binds Nonmuscle Myosin 2A to Control Remodeling of the Actomyosin Network SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CIRCULAR DORSAL RUFFLES; ACTIN CYTOSKELETON; CELL-MIGRATION; ANIONIC PHOSPHOLIPIDS; FOCAL ADHESIONS; PHOSPHORYLATION; DOMAIN; ASSOCIATION; EXPRESSION; PODOSOMES AB ASAP1 regulates F-actin-based structures and functions, including focal adhesions (FAs) and circular dorsal ruffles (CDRs), cell spreading and migration. ASAP1 function requires its N-terminal BAR domain. We discovered that nonmuscle myosin 2A (NM2A) directly bound the BAR-PH tandem of ASAP1 in vitro. ASAP1 and NM2A co-immunoprecipitated and colocalized in cells. Knockdown of ASAP1 reduced colocalization of NM2A and F-actin in cells. Knockdown of ASAP1 or NM2A recapitulated each other's effects on FAs, cell migration, cell spreading, and CDRs. The NM2A-interacting BAR domain contributed to ASAP1 control of cell spreading and CDRs. Exogenous expression of NM2A rescued the effect of ASAP1 knockdown on CDRs but ASAP1 did not rescue NM2A knockdown defect in CDRs. Our results support the hypothesis that ASAP1 is a positive regulator of NM2A. Given other binding partners of ASAP1, ASAP1 may directly link signaling and the mechanical machinery of cell migration. C1 [Chen, Pei-Wen; Jian, Xiaoying; Luo, Ruibai; Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Jenkins, Lisa M.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. [Heissler, Sarah M.; Nagy, Attila; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Le, Kang; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Chen, Pei-Wen] Grinnell Coll, Dept Biol, Grinnell, IA 50112 USA. RP Randazzo, PA (reprint author), NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov FU NCI, National Institutes of Health [BC 007365]; NHLBI, National Institutes of Health FX This work was supported by the intramural program of the NCI, National Institutes of Health (to P. W. C., X. J., R. L., and P. R., Project BC 007365) and NHLBI, National Institutes of Health (to K. L., J. M., A. N., S. H., and J. S.). The authors declare that they have no conflicts of interest with the contents of this article. NR 32 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 1 PY 2016 VL 291 IS 14 BP 7517 EP 7526 DI 10.1074/jbc.M115.701292 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW2BJ UT WOS:000383447600026 PM 26893376 ER PT J AU Yingling, LR Brooks, AT Wallen, GR Peters-Lawrence, M McClurkin, M Cooper-McCann, R Wiley, KL Mitchell, V Saygbe, JN Johnson, TD Curry, KE Johnson, AA Graham, AP Graham, LA Powell-Wiley, TM AF Yingling, Leah R. Brooks, Alyssa T. Wallen, Gwenyth R. Peters-Lawrence, Marlene McClurkin, Michael Cooper-McCann, Rebecca Wiley, Kenneth L., Jr. Mitchell, Valerie Saygbe, Johnetta N. Johnson, Twanda D. Curry, Kendrick E. Johnson, Allan A. Graham, Avis P. Graham, Lennox A. Powell-Wiley, Tiffany M. TI Community Engagement to Optimize the Use of Web-Based and Wearable Technology in a Cardiovascular Health and Needs Assessment Study: A Mixed Methods Approach SO JMIR MHEALTH AND UHEALTH LA English DT Article DE mHealth; physical activity; community-based participatory research; obesity; African Americans; activity monitoring; qualitative research; focus groups; community ID WEIGHT-LOSS INTERVENTION; AMERICAN-HEART-ASSOCIATION; PHYSICAL-ACTIVITY; PARTICIPATORY RESEARCH; PUBLIC-HEALTH; INTERNET; TRACKING; OBESITY; ADULTS; ENVIRONMENT AB Background: Resource-limited communities in Washington, D. C. have high rates of obesity-related cardiovascular disease in addition to inadequate physical activity ( PA) facilities and limited Internet access. Engaging community members in the design and implementation of studies to address these health disparities is essential to the success of community-based PA interventions. Objective: The objective of the study was to use qualitative and quantitative methods to evaluate the feasibility and acceptability of PA-monitoring wristbands and Web-based technology by predominantly African American, church-based populations in resource-limited Washington, D. C. neighborhoods. Methods: To address cardiovascular health in at-risk populations in Washington, D. C., we joined community leaders to establish a community advisory board, the D. C. Cardiovascular Health and Obesity Collaborative ( D. C. CHOC). As their first initiative, the Washington, D. C. Cardiovascular Health and Needs Assessment intends to evaluate cardiovascular health, social determinants of health, and PA-monitoring technologies. At the recommendation of D. C. CHOC members, we conducted a focus group and piloted the proposed PA-monitoring system with community members representing churches that would be targeted by the Cardiovascular Health and Needs Assessment. Participants ( n= 8) agreed to wear a PA-monitoring wristband for two weeks and to log cardiovascular health factors on a secure Internet account. Wristbands collected accelerometer-based data that participants uploaded to a wireless hub at their church. Participants agreed to return after two weeks to participate in a moderated focus group to share experiences using this technology. Feasibility was measured by Internet account usage, wristband utilization, and objective PA data. Acceptability was evaluated through thematic analysis of verbatim focus group transcripts. Results: Study participants ( 5 males, 3 females) were African American and age 28-70 years. Participant wristbands recorded data on 10.1+/-1.6 days. Two participants logged cardiovascular health factors on the website. Focus group transcripts revealed that participants felt positively about incorporating the device into their church-based populations, given improvements were made to device training, hub accessibility, and device feedback. Conclusions: PA-monitoring wristbands for objectively measuring PA appear to be a feasible and acceptable technology in Washington, D. C., resource-limited communities. User preferences include immediate device feedback, hands-on device training, explicit instructions, improved central hub accessibility, and designation of a church member as a trained point-of-contact. When implementing technology-based interventions in resource-limited communities, engaging the targeted community may aid in early identification of issues, suggestions, and preferences. C1 [Yingling, Leah R.; McClurkin, Michael; Mitchell, Valerie; Saygbe, Johnetta N.; Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,5-3330 10 Ctr Dr, Bethesda, MD 20892 USA. [Brooks, Alyssa T.; Wallen, Gwenyth R.; Cooper-McCann, Rebecca; Johnson, Twanda D.] NIH, Clin Ctr, Bethesda, MD USA. [Peters-Lawrence, Marlene] NHLBI, Off Clin Director, Div Intramural Res, NIH, Bethesda, MD USA. [Wiley, Kenneth L., Jr.] NHGRI, Div Genom Med, NIH, Bethesda, MD USA. [Curry, Kendrick E.] Penn Ave Baptist Church, Washington, DC USA. [Johnson, Allan A.; Graham, Avis P.; Graham, Lennox A.] Howard Univ, Coll Nursing & Allied Hlth Sci, Washington, DC USA. RP Powell-Wiley, TM (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,5-3330 10 Ctr Dr, Bethesda, MD 20892 USA. EM tiffany.powell@nih.gov OI Yingling, Leah/0000-0002-7851-690X FU NHGRI NIH HHS [HHSN268201400023C] NR 47 TC 1 Z9 1 U1 10 U2 10 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 2291-5222 J9 JMIR MHEALTH UHEALTH JI JMIR mHealth uHealth PD APR-JUN PY 2016 VL 4 IS 2 BP 38 EP 55 AR e38 DI 10.2196/mhealth.4489 PG 18 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DT0OH UT WOS:000381182400004 PM 27113680 ER PT J AU Taber, JM Klein, WMP Ferrer, RA Augustson, E Patrick, H AF Taber, Jennifer M. Klein, William M. P. Ferrer, Rebecca A. Augustson, Erik Patrick, Heather TI A Pilot Test of Self-Affirmations to Promote Smoking Cessation in a National Smoking Cessation Text Messaging Program SO JMIR MHEALTH AND UHEALTH LA English DT Article DE self-affirmation; smoking cessation; mHealth; text messaging; theoretical study; self concept; motivation ID SOCIAL-PSYCHOLOGICAL INTERVENTION; HEALTH-RISK INFORMATION; ACHIEVEMENT GAP; BEHAVIOR-CHANGE; METAANALYSIS; SMOKERS; DEFENSIVENESS; TRIAL AB Background: Although effective smoking cessation treatments, including mHealth interventions, have been empirically validated and are widely available, smoking relapse is likely. Self-affirmation, a process through which individuals focus on their strengths and behaviors, has been shown to reduce negative effects of self-threats and to promote engagement in healthier behavior. Objective: To assess the feasibility of incorporating self-affirmations into an existing text messaging-based smoking cessation program ( Smokefree TXT) and to determine whether self-affirmation led to greater engagement and higher cessation rates than the standard intervention. Methods: Data were collected from smokers ( n= 1261) who subscribed to a free smoking cessation program and met eligibility criteria. The intervention lasted 42 days. The original design was a 2 ( Baseline affirmation: 5-item questionnaire present vs absent) x 2 ( Integrated affirmation: texts present vs absent) factorial design. Only 17 eligible users completed all baseline affirmation questions and these conditions did not influence any outcomes, so we collapsed across baseline affirmation conditions in analysis. In the integrated affirmation conditions, affirmations replaced approximately 20% of texts delivering motivational content. Results: In all, 687 users remained enrolled throughout the 42-day intervention and 81 reported smoking status at day 42. Among initiators ( n= 1261), self-affirmation did not significantly improve ( 1) intervention completion, ( 2) days enrolled, ( 3) 1-week smoking status, or ( 4) 6-week smoking status ( all Ps>.10); and among the 687 completers, there were no significant effects of affirmation on cessation ( Ps>.25). However, among the 81 responders, those who received affirmations were more likely to report cessation at 6 weeks ( 97.5%; 39 of 40) than those not given affirmations ( 78.1%; 32 of 41;.2( 1)= 7.08, P=. 008). Conclusion: This proof-of-concept study provides preliminary evidence that self-affirmation can be integrated into existing text-based cessation programs, as the affirmations did not lead to any adverse effects ( ie, less engagement or lower rates of cessation). Among those who reported smoking status at the end of the intervention period ( 6.4% of eligible respondents), affirmations facilitated cessation. This study provides a "proof-of-concept" that brief, low-touch interventions may be integrated into a text messaging program with potential benefits, minimal disruption to the program or users, and little cost. Many questions remain regarding how self-affirmation and similar approaches can promote engagement in population interventions. C1 [Taber, Jennifer M.; Klein, William M. P.; Augustson, Erik] NCI, Behav Res Program, NIH, Rockville, MD USA. [Ferrer, Rebecca A.] NCI, Basic Biobehav & Psychol Sci Branch, Behav Res Program, NIH, Rockville, MD USA. [Patrick, Heather] Envolve PeopleCare, Appl Behav Change Sci, Bethesda, MD USA. RP Taber, JM (reprint author), Kent State Univ, Dept Psychol Sci, 309 Kent Hall Annex, Kent, OH 44242 USA. EM jtaber1@kent.edu NR 18 TC 0 Z9 0 U1 3 U2 3 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 2291-5222 J9 JMIR MHEALTH UHEALTH JI JMIR mHealth uHealth PD APR-JUN PY 2016 VL 4 IS 2 BP 373 EP 378 AR e71 DI 10.2196/mhealth.5635 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DT0OH UT WOS:000381182400029 PM 27278108 ER PT J AU Wheelock, KM Sinha, M Knowler, WC Nelson, RG Fufaa, GD Hanson, RL AF Wheelock, Kevin M. Sinha, Madhumita Knowler, William C. Nelson, Robert G. Fufaa, Gudeta D. Hanson, Robert L. TI Metabolic Risk Factors and Type 2 Diabetes Incidence in American Indian Children SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BODY-MASS INDEX; PIMA-INDIANS; INSULIN-RESISTANCE; CARDIOVASCULAR RISK; MELLITUS; OBESITY; CHILDHOOD; ADOLESCENTS; PREVALENCE; PREDICTORS AB Context: Data are lacking on how metabolic risk factors during childhood affect the long-term risk of type 2 diabetes. Objectives: Assess four metabolic risk factors as predictors of type 2 diabetes and determine whether the risk differs between younger and older children. Design: In a prospective cohort study conducted between 1965 and 2007, participants were followed for development of diabetes. Baseline measurements included body mass index (BMI), blood pressure, serum cholesterol, and 2-hour plasma glucose after an oral glucose tolerance test. Additional analyses divided subjects into two groups according to baseline age, 5-11 and 12-19 years. Setting: Gila River Indian Community in Arizona. Participants: A total of 5532 nondiabetic Pima Indian children 5-19 years old. Results: A total of 1281 children developed diabetes (median follow-up, 12.4 years). Diabetes incidence was higher in overweight children (BMI >= 85th percentile) than in nonoverweight children. Nonoverweight children had the lowest risk of diabetes (20-year cumulative incidence, 9.5%), whereas overweight children with impaired glucose tolerance (2-hour glucose >= 140 mg/dL) had the highest (79.0%). The relative risk for children with metabolic abnormalities compared with their healthy counterparts was higher in younger children than in older children early in follow-up. BMI and 2-hour glucose were related to incident diabetes in multivariable models (predicted 15-year cumulative incidence for the highest vs lowest quartile was 3.9 and 1.8 times as high for BMI and 2-hour glucose, respectively; P < .001), whereas blood pressure and cholesterol were not. Conclusions: BMI and impaired glucose tolerance in children are strong predictors of type 2 diabetes. Other components of the "metabolic syndrome" are not. C1 [Wheelock, Kevin M.; Sinha, Madhumita; Knowler, William C.; Nelson, Robert G.; Fufaa, Gudeta D.; Hanson, Robert L.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85014 USA. RP Sinha, M (reprint author), NIDDK, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM madhumita.Sinha@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Part of this work was presented at the American Diabetes Association 75th Scientific Sessions, June 5-9, 2015, Boston, MA. NR 34 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2016 VL 101 IS 4 BP 1437 EP 1444 DI 10.1210/jc.2015-4309 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YP UT WOS:000381931400016 PM 26913636 ER PT J AU Aroda, VR Edelstein, SL Goldberg, RB Knowler, WC Marcovina, SM Orchard, TJ Bray, GA Schade, DS Temprosa, MG White, NH Crandall, JP AF Aroda, Vanita R. Edelstein, Sharon L. Goldberg, Ronald B. Knowler, William C. Marcovina, Santica M. Orchard, Trevor J. Bray, George A. Schade, David S. Temprosa, Marinella G. White, Neil H. Crandall, Jill P. CA Diabet Prevention Program Res Grp TI Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; PLACEBO-CONTROLLED TRIAL; THERAPY; HOMOCYSTEINE; ASSOCIATION; NEUROPATHY; ABSORPTION; BIGUANIDES; DIAGNOSIS; COBALAMIN AB Context: Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use. Objective: To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). Design: Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years. Setting: Twenty-seven study centers in the United States. Patients: DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and over-weight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively. Interventions: Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS). Main Outcome Measures: B12 deficiency, anemia, and peripheral neuropathy. Results: Low B12 (<= 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs5.4%; P = .12). Combined low and borderline-low B12(<= 298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06-1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels. Conclusions: Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered. C1 [Aroda, Vanita R.] MedStar Hlth Res Inst, Hyattsville, MD 20782 USA. [Edelstein, Sharon L.; Temprosa, Marinella G.] George Washington Univ, Rockville, MD 20852 USA. [Goldberg, Ronald B.] Univ Miami, Miami, FL 33146 USA. [Knowler, William C.] NIDDK, Phoenix, AZ 85014 USA. [Marcovina, Santica M.] Univ Washington, Seattle, WA 98185 USA. [Orchard, Trevor J.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Bray, George A.] Pennington Biomed Res Inst, Baton Rouge, LA 70808 USA. [Schade, David S.] Univ New Mexico, Albuquerque, NM 87131 USA. [White, Neil H.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Crandall, Jill P.] Albert Einstein Coll Med, Bronx, NY 10461 USA. RP Crandall, JP (reprint author), George Washington Univ, Diabet Prevent Program Coordinating Ctr, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Intramural Research Program; Indian Health Service; National Institute of Child Health and Human Development; National Institute on Aging; Office of Research on Women's Health; National Center for Minority Health and Human Disease; Centers for Disease Control and Prevention; American Diabetes Association; Bristol-Myers Squibb; Parke-Davis; National Eye Institute; National Heart, Lung, and Blood Institute FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health is the primary funding agency for this study.; During the DPP and DPPOS, the NIDDK provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study, and the collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart, Lung, and Blood Institute, the Office of Research on Women's Health, the National Center for Minority Health and Human Disease, the Centers for Disease Control and Prevention, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP, Lipha (Merck-Sante) provided medication, and LifeScan Inc donated materials during the DPP and DPPOS. The opinions expressed are those of the investigators and do not necessarily reflect the views of the funding agencies. A complete list of centers, investigators, and staff can be found in the Supplemental Data. NR 40 TC 8 Z9 8 U1 9 U2 10 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2016 VL 101 IS 4 BP 1754 EP 1761 DI 10.1210/jc.2015-3754 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YP UT WOS:000381931400050 PM 26900641 ER PT J AU Yin, XY Subramanian, S Willinger, CM Chen, G Juhasz, P Courchesne, P Chen, BH Li, XH Hwang, SJ Fox, CS O'Donnell, CJ Muntendam, P Fuster, V Bobeldijk-Pastorova, I Sookoian, SC Pirola, CJ Gordon, N Adourian, A Larson, MG Levy, D AF Yin, Xiaoyan Subramanian, Subha Willinger, Christine M. Chen, George Juhasz, Peter Courchesne, Paul Chen, Brian H. Li, Xiaohang Hwang, Shih-Jen Fox, Caroline S. O'Donnell, Christopher J. Muntendam, Pieter Fuster, Valentin Bobeldijk-Pastorova, Ivana Sookoian, Silvia C. Pirola, Carlos J. Gordon, Neal Adourian, Aram Larson, Martin G. Levy, Daniel TI Metabolite Signatures of Metabolic Risk Factors and their Longitudinal Changes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORONARY-HEART-DISEASE; LYSOPHOSPHATIDIC ACID; CARDIOVASCULAR-DISEASE; ALANINE AMINOTRANSFERASE; INSULIN-RESISTANCE; LACTATE LEVELS; PLANT STEROLS; STUDY DESIGN; AMINO-ACID; AUTOTAXIN AB Context: Metabolic dysregulation underlies key metabolic risk factors-obesity, dyslipidemia, and dysglycemia. Objective: To uncover mechanistic links between metabolomic dysregulation and metabolic risk by testing metabolite associations with risk factors cross-sectionally and with risk factor changes over time. Design: Cross-sectional-discovery samples (n = 650; age, 36-69 years) from the Framingham Heart Study (FHS) and replication samples (n = 670; age, 61-76 years) from the BioImage Study, both following a factorial design sampled from high vs low strata of body mass index, lipids, and glucose. Longitudinal-FHS participants (n = 554) with 5-7 years of follow-up for risk factor changes. Setting: Observational studies. Participants: Cross-sectional samples with or without obesity, dysglycemia, and dyslipidemia, excluding prevalent cardiovascular disease and diabetes or dyslipidemia treatment. Age-and sex-matched by group. Interventions: None. Main Outcome Measure(s): Gas chromatography-mass spectrometry detected 119 plasma metabolites. Cross-sectional associations with obesity, dyslipidemia, and dysglycemia were tested in discovery, with external replication of 37 metabolites. Single-and multi-metabolite markers were tested for association with longitudinal changes in risk factors. Results: Cross-sectional metabolite associations were identified with obesity (n = 26), dyslipidemia (n = 21), and dysglycemia (n = 11) in discovery. Glutamic acid, lactic acid, and sitosterol associated with all three risk factors in meta-analysis (P < 4.5 x 10(-4)). Metabolites associated with longitudinal risk factor changes were enriched for bioactive lipids. Multi-metabolite panels explained 2.5-15.3% of longitudinal changes in metabolic traits. Conclusions: Cross-sectional results implicated dysregulated glutamate cycling and amino acid metabolism in metabolic risk. Certain bioactive lipids were associated with risk factors cross-sectionally and over time, suggesting their upstream role in risk factor progression. Functional studies are needed to validate findings and facilitate translation into treatments or preventive measures. C1 [Yin, Xiaoyan; Subramanian, Subha; Willinger, Christine M.; Chen, George; Courchesne, Paul; Chen, Brian H.; Hwang, Shih-Jen; Fox, Caroline S.; O'Donnell, Christopher J.; Larson, Martin G.; Levy, Daniel] Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Yin, Xiaoyan; Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02118 USA. [Yin, Xiaoyan; Larson, Martin G.] Sch Publ Hlth, Boston, MA 02118 USA. [Subramanian, Subha; Willinger, Christine M.; Chen, George; Chen, Brian H.; Hwang, Shih-Jen; Fox, Caroline S.; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Juhasz, Peter; Li, Xiaohang; Muntendam, Pieter; Gordon, Neal; Adourian, Aram] BG Med Inc, 610 Lincoln St, Waltham, MA 02451 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA 02115 USA. [O'Donnell, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Fuster, Valentin] Mt Sinai Sch Med, New York, NY 10029 USA. [Fuster, Valentin] Ctr Nacl Invest Cardiovasc, Madrid 28029, Spain. [Bobeldijk-Pastorova, Ivana] TNO Triskel BV Inc, NL-3704 HE Zeist, Netherlands. [Sookoian, Silvia C.; Pirola, Carlos J.] Univ Buenos Aires, Inst Med Res A Lanari IDIM, Natl Sci & Tech Res Council, C11428, Buenos Aires, DF, Argentina. [Levy, Daniel] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Larson, MG; Levy, D (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA.; Adourian, A (reprint author), BG Med Inc, 610 Lincoln St, Waltham, MA 02451 USA. EM aadourian@bg-medicine.com; mlarson@bu.edu; levyd@nih.gov RI Fuster, Valentin/H-4319-2015 OI Fuster, Valentin/0000-0002-9043-9986 FU National Institutes of Health [N01-HC-25195]; Division of Intramural Research of the National Heart, Lung, and Blood Institute FX The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195; this research was also supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute. This study was made possible by a cooperative research and development agreement between BG Medicine, Inc, Boston University, and the National Heart, Lung, and Blood Institute. NR 65 TC 0 Z9 0 U1 1 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2016 VL 101 IS 4 BP 1779 EP 1789 DI 10.1210/jc.2015-2555 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YP UT WOS:000381931400053 PM 26908103 ER PT J AU Kassai, A Muniyappa, R Levenson, AE Walter, MF Abel, BS Ring, M Taylor, SI Biddinger, SB Skarulis, MC Gorden, P Brown, RJ AF Kassai, Andrea Muniyappa, Ranganath Levenson, Amy E. Walter, Mary F. Abel, Brent S. Ring, Michael Taylor, Simeon I. Biddinger, Sudha B. Skarulis, Monica C. Gorden, Phillip Brown, Rebecca J. TI Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID C-III; NONFASTING TRIGLYCERIDES; LIPOPROTEIN METABOLISM; APOC-III; A-I; RISK; RECEPTOR; INSULIN; LIPASE; MEN AB Context: Apolipoprotein CIII (apoCIII), an inhibitor of lipoprotein lipase, plays an important role in triglyceride metabolism. However, the role of apoCIII in hypertriglyceridemia in lipodystrophy and the effects of leptin replacement on apoCIII levels are unknown. Objective: The objective of the study was to test the hypotheses that apoCIII is elevated in hypertriglyceridemic patients with lipodystrophy and that leptin replacement in these patients lowers circulating apoCIII. Design, Setting, Study Participants, Intervention, and Outcome Measures: Using a post hoc crosssectional case-control design, we compared serum apoCIII levels from patients with lipodystrophy not associated with HIV (n = 60) and age-, gender-, race-, and ethnicity-matched controls (n = 54) participating in ongoing studies at the National Institutes of Health. In a prospective, open-label, ongoing study, we studied the effects of 6-12 months of leptin replacement on apoCIII in lipodystrophy patients as an exploratory outcome. Results: ApoCIII was higher in lipodystrophy patients (geometric mean [25th and 75th percentiles]) (23.9 mg/dL [14.6, 40.3]) compared with controls (14.9 mg/dL [12.3, 17.7]) (P < .0001). ApoCIII and triglyceride levels were positively correlated in patients with lipodystrophy (R = 0.72, P < .0001) and healthy controls (R = 0.6, P < .0001). Leptin replacement (6-12 mo) did not significantly alter apoCIII (before leptin: 23.4 mg/dL [14.5, 40.1]; after leptin: 21.4 mg/dL [16.7, 28.3]; P = .34). Conclusions: Leptin replacement in lipodystrophy did not alter serum apoCIII levels. Elevated apoCIII may play a role in the hypertriglyceridemia of lipodystrophy independent of leptin deficiency and replacement. C1 [Kassai, Andrea; Muniyappa, Ranganath; Abel, Brent S.; Ring, Michael; Skarulis, Monica C.; Gorden, Phillip; Brown, Rebecca J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Walter, Mary F.] NIDDK, Clin Core Lab, NIH, Bethesda, MD 20892 USA. [Levenson, Amy E.; Biddinger, Sudha B.] Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Taylor, Simeon I.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. RP Brown, RJ (reprint author), NIDDK, NIH, Bldg 10-CRC,Room 6-5942,10 Ctr Dr, Bethesda, MD 20892 USA. EM brownrebecca@niddk.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; Inter-Institute Endocrinology Fellowship Program at the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, and by the Inter-Institute Endocrinology Fellowship Program at the National Institute of Diabetes and Digestive and Kidney Diseases. NR 31 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2016 VL 101 IS 4 BP 1790 EP 1797 DI 10.1210/jc.2015-3891 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YP UT WOS:000381931400054 PM 26900642 ER PT J AU Larsen, BA Wassel, CL Kritchevsky, SB Strotmeyer, ES Criqui, MH Kanaya, AM Fried, LF Schwartz, AV Harris, TB Ix, JH AF Larsen, Britta A. Wassel, Christina L. Kritchevsky, Stephen B. Strotmeyer, Elsa S. Criqui, Michael H. Kanaya, Alka M. Fried, Linda F. Schwartz, Ann V. Harris, Tamara B. Ix, Joachim H. CA Hlth ABC Study TI Association of Muscle Mass, Area, and Strength With Incident Diabetes in Older Adults: The Health ABC Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SKELETAL-MUSCLE; INSULIN SENSITIVITY; GLUCOSE-TOLERANCE; BODY-COMPOSITION; ADIPOSE-TISSUE; WOMEN; RESISTANCE; MORTALITY; MEN; OVERWEIGHT AB Context: Skeletal muscle plays a key role in glucose regulation, yet the association between muscle quantity or quality and the risk of developing type 2 diabetes has not been explored. Objective: The objective of the study was to assess the association between muscle quantity and strength and incident diabetes and to explore whether this association differs by body mass index (BMI) category. Design and Setting: Participants were 2166 older adults in the Health, Aging, and Body Composition Study who were free of diabetes at baseline (1997-1998). Computed tomography and dual-energy x-ray absorptiometry were used to measure abdominal and thigh muscle area and total body lean mass, respectively. Strength was quantified by grip and knee extensions. Main Outcome Measure: Incident diabetes, defined as fasting glucose of 126 mg/dL or greater, a physician's diagnosis, and/or the use of hypoglycemic medication were measured. Results: After a median 11.3 years of follow-up, there were 265 incident diabetes cases (12.2%). In fully adjusted models, no association was found between muscle or strength measures and incident diabetes (for all, P > .05). For women, there was a significant interaction with BMI category for both abdominal and thigh muscle, such that greater muscle predicted lower risk of incident diabetes for normal-weight women(hazard ratio 0.37 [0.17-0.83] and 0.58 [0.27-1.27] per SD, respectively) and a greater risk for overweight and obese women(hazard ratio 1.23 [0.98-1.54] and 1.28 [1.00-1.64], respectively). No significant interactions by BMI category existed for strength measures or any measures for men (for all, P > .05). Conclusions: Greater muscle area is associated with a lower risk of incident diabetes for older normal-weight women but not for men or overweight women. C1 [Larsen, Britta A.; Criqui, Michael H.; Ix, Joachim H.] Univ Calif San Diego, Dept Family Med & Publ Hlth, 9500 Gilman Dr, San Diego, CA 92093 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, San Diego, CA 92093 USA. [Wassel, Christina L.] Univ Vermont, Coll Med, Dept Pathol & Lab Med, Burlington, VT 05446 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Winston Salem, NC 27157 USA. [Kritchevsky, Stephen B.] Sch Med, Winston Salem, NC 27157 USA. [Strotmeyer, Elsa S.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15219 USA. [Schwartz, Ann V.] Univ Calif San Francisco, Div Gen Internal Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Fried, Linda F.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15261 USA. [Fried, Linda F.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. RP Larsen, BA (reprint author), Univ Calif San Diego, Dept Family Med & Publ Hlth, 9500 Gilman Dr, San Diego, CA 92093 USA. EM blarsen@ucsd.edu FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research Grant [R01-NR012459]; Intramural Research Program of the National Institute on Aging; Career Development Grant from National Institute of Diabetes and Digestive and Kidney Diseases [K01 DK101650]; Established Investigator Award from American Heart Association [14EIA18560026] FX This work was supported Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 from the National Institute on Aging, National Institute on Aging Grant R01-AG028050 and National Institute of Nursing Research Grant R01-NR012459. This research was also supported in part by the Intramural Research Program of the National Institute on Aging. B.L. was supported by Career Development Grant K01 DK101650 from the National Institute of Diabetes and Digestive and Kidney Diseases. J.I. was supported by an Established Investigator Award from the American Heart Association (14EIA18560026). NR 26 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2016 VL 101 IS 4 BP 1847 EP 1855 DI 10.1210/jc.2015-3643 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YP UT WOS:000381931400060 PM 26930180 ER PT J AU Wang, XY Jung, M Mossavar-Rahmani, Y Sotres-Alvarez, D Giacinto, RAE Pirzada, A Reina, SA Casagrande, SS Wang, T Aviles-Santa, ML Kaplan, RC Qi, QB AF Wang, Xueyin Jung, Molly Mossavar-Rahmani, Yasmin Sotres-Alvarez, Daniela Giacinto, Rebeca A. Espinoza Pirzada, Amber Reina, Samantha A. Casagrande, Sarah S. Wang, Tao Aviles-Santa, M. Larissa Kaplan, Robert C. Qi, Qibin TI Macronutrient Intake, Diagnosis Status, and Glycemic Control Among US Hispanics/Latinos With Diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NUTRITION EXAMINATION SURVEY; MONOUNSATURATED FATTY-ACIDS; ETHNIC-DIFFERENCES; LATINO POPULATION; NATIONAL-HEALTH; ENERGY-INTAKE; WEIGHT-LOSS; ADULTS; DIET; THERAPY AB Context: Diet modification is a mainstay of diabetes management. US Hispanics/Latinos are disproportionately affected by diabetes, but few studies have examined dietary intake among US Hispanics/Latinos with diabetes, and little is known regarding the influence of diabetes awareness on dietary intake. Objective: We evaluated macronutrient intake and its associations with diabetes awareness and glycemic control among US Hispanics/Latinos with diabetes. Participants: This analysis included 3310 diabetic adults aged 18-74 years from the Hispanic Community Health Study/Study of Latinos (2008-2011). Main Outcome Measures: Diabetes was defined as diagnosed (based on medical history or antihyperglycemic medication use) or undiagnosed diabetes (based on fasting glucose >= 126 mg/dL, glycated hemoglobin [ HbA1c] >= 6.5%, or 2 h glucose >= 200 mg/dL in the absence of a physician diagnosis). Dietary intake was assessed using two 24-hour recalls. Results: Among Hispanic/Latino adults with diabetes, 21.2%, 55.7%, and 71.2% met the American Diabetes Association recommendations for fiber (>= 14 g per 1000 kcal), saturated fat (< 10% of total energy), and cholesterol intake (< 300 mg), respectively. Compared with those with undiagnosed diabetes, people with diagnosed diabetes consumed less carbohydrate (50.3 vs 52.4% of total energy; P = .017), total sugar (19.1 vs 21.5% of total energy; P = .002), added sugar (9.8 vs 12.1% of total energy; P < .001), and more total fat (30.7 vs 29.3% of total energy; P = .048) and monounsaturated fat (11.5 vs 10.7% of total energy; P = .021). Association between diabetes awareness and low total and added sugar intake was observed in individuals of Mexican and Puerto Rican background but not in other groups (P for interaction < .05). Among people with diagnosed diabetes, those with HbA1c of 7% or greater consumed more total fat, saturated fat, and cholesterol than those with HbA1c less than 7% (all P < .05). Conclusions: Among US Hispanics/Latinos with diabetes, fiber intake is low, and diabetes awareness is associated with reduced carbohydrate and sugar intake and increased monounsaturated fat intake. Sugar intake may require special attention in certain Hispanic/Latino background groups. C1 [Wang, Xueyin; Jung, Molly; Mossavar-Rahmani, Yasmin; Wang, Tao; Kaplan, Robert C.; Qi, Qibin] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Wang, Xueyin] Peking Univ, Hlth Sci Ctr, Sch Publ Hlth, Dept Epidemiol & Biostat, Beijing 100191, Peoples R China. [Sotres-Alvarez, Daniela] Univ N Carolina, Collaborat Studies Coordinating Ctr, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Giacinto, Rebeca A. Espinoza] San Diego State Univ, San Diego, CA 92182 USA. [Pirzada, Amber] Univ Illinois, Inst Minor Hlth Res, Chicago, IL 60637 USA. [Reina, Samantha A.] Univ Miami, Dept Psychol, Miami, FL 33136 USA. [Casagrande, Sarah S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Aviles-Santa, M. Larissa] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20824 USA. RP Qi, QB (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM qibin.qi@einstein.yu.edu RI DeMarcus, Forrest/O-9190-2016; Sotres-Alvarez, Daniela/O-9085-2016 OI Sotres-Alvarez, Daniela/0000-0002-3226-6140 FU National Heart, Lung, and Blood Institute [N01-HC65233]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [N01-HC65235]; Northwestern University [N01-HC65236]; San Diego State University [N01-HC65237]; China Scholarship Council FX This work was supported by contracts from the National Heart, Lung, and Blood Institute to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following institutes/centers/offices contributed to the Hispanic Community Health Study/Study of Latinos through a transfer of funds to the National Heart, Lung, and Blood Institute: National Center on Minority Health and Health Disparities, the National Institute of Deadness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. X.W. was supported by the China Scholarship Council. NR 32 TC 1 Z9 1 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2016 VL 101 IS 4 BP 1856 EP 1864 DI 10.1210/jc.2015-3237 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YP UT WOS:000381931400061 PM 26950682 ER PT J AU Dias, JP Melvin, D Shardell, M Ferrucci, L Chia, CW Gharib, M Egan, JM Basaria, S AF Dias, Jenny Pena Melvin, Denise Shardell, Michelle Ferrucci, Luigi Chia, Chee W. Gharib, Mohsen Egan, Josephine M. Basaria, Shehzad TI Effects of Transdermal Testosterone Gel or an Aromatase Inhibitor on Prostate Volume in Older Men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ESTROGEN-RECEPTOR-BETA; MIDDLE-AGED MEN; HYPOGONADAL MEN; REPLACEMENT THERAPY; ANDROGEN RECEPTOR; CONTROLLED-TRIAL; DOG PROSTATE; ELDERLY-MEN; HYPERPLASIA; CANCER AB Context: T replacement is being increasingly offered to older men with age-related low T; hence, monitoring prostate health is important during T therapy. Data suggest that estrogens have an independent effect on the prostate and some effects of T on the prostate might be mediated via its aromatization to estradiol. Although some studies have assessed the effects of T replacement on prostate volume, the differential effects of T and estradiol have not been delineated. Objective: The objective of the study was to investigate the relative effects of T and estradiol on prostate volume in older men with low T. Participants: Thirty-one men, 65 years old or older with total T less than 350 ng/dL (measured by mass spectrometry) participated in the study. Intervention: The intervention included randomization to 5 g transdermal T gel (TT), 1 mg oral aromatase inhibitor (AI), or placebo daily for 12 months. Main Outcome Measures: The primary outcome was prostate volume measured by transrectal ultrasound at baseline and 12 months. Secondary outcomes included prostate-specific antigen levels and lower urinary tract symptoms score. Results: Serum T levels increased in both intervention groups; estradiol levels increased in the TT group, whereas it decreased in the AI group. At 12 months, prostate volume significantly increased (4.5 +/- 1.76 cc, P < .05) only in the TT group. Increase in prostate-specific antigen levels were seen in both intervention groups at 6 months (P < .01 and P < .001). The lower urinary tract symptoms score increased only in the TT group (P < .05). Conclusion: The tropic effects of T on the prostate are mediated via its aromatization to estradiol. Administration of AI for 12 months to older men was not detrimental to the prostate. C1 [Dias, Jenny Pena; Melvin, Denise; Egan, Josephine M.] Medstar Harbor Hosp, Lab Clin Invest, Baltimore, MD 21225 USA. [Shardell, Michelle; Ferrucci, Luigi; Chia, Chee W.] Medstar Harbor Hosp, Translat Gerontol Branch, Baltimore, MD 21225 USA. [Gharib, Mohsen] Medstar Harbor Hosp, NIA, Baltimore, MD 21225 USA. [Gharib, Mohsen] Medstar Harbor Hosp, Imaging Sect, Baltimore, MD 21225 USA. [Basaria, Shehzad] Harvard Med Sch, Sect Mens Hlth Aging & Metab, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Basaria, S (reprint author), Harvard Med Sch, Sect Mens Hlth Aging & Metab, Brigham & Womens Hosp, Boston, MA 02115 USA. EM sbasaria@partners.org FU Intramural Research Program of National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 48 TC 0 Z9 0 U1 3 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2016 VL 101 IS 4 BP 1865 EP 1871 DI 10.1210/jc.2016-1111 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YP UT WOS:000381931400062 PM 26950683 ER PT J AU Baron, KB Choi, AD Chen, MY AF Baron, Kaitlin B. Choi, Andrew D. Chen, Marcus Y. TI Low Radiation Dose Calcium Scoring: Evidence and Techniques SO CURRENT CARDIOVASCULAR IMAGING REPORTS LA English DT Article DE Coronary artery calcium (CAC) scoring; Low dose radiation; Iterative Reconstruction; Rescan variability; Coronary artery disease; Computed tomography (CT); Atherosclerotic cardiovascular disease (ASCVD) ID CORONARY-ARTERY CALCIUM; STATISTICAL ITERATIVE RECONSTRUCTION; FILTERED BACK-PROJECTION; COMPUTED-TOMOGRAPHY; IMAGE-RECONSTRUCTION; AMERICAN-COLLEGE; CT; IMPACT; QUANTIFICATION; REDUCTION AB Coronary computed tomography (CT) allows for the acquisition of thin slices of the heart and coronary arteries, which can be used to detect and quantify coronary artery calcium (CAC), a marker of atherosclerotic cardiovascular disease. Despite the proven clinical value in cardiac risk prognostication, there remain concerns regarding radiation exposure from CAC CT scans. There have been several recent technical advancements that allow for significant radiation dose reduction in CAC scoring. This paper reviews the clinical utility and recent literature in low radiation dose CAC scoring. C1 [Baron, Kaitlin B.; Choi, Andrew D.] George Washington Univ, Div Cardiol, Sch Med, Washington, DC USA. [Choi, Andrew D.; Chen, Marcus Y.] NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH, 10 Ctr Dr,Bldg 10,B1D416, Bethesda, MD 20891 USA. RP Chen, MY (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH, 10 Ctr Dr,Bldg 10,B1D416, Bethesda, MD 20891 USA. EM Marcus.Chen@nih.gov NR 41 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1941-9066 EI 1941-9074 J9 CURR CARDIOVASC IMAG JI CURR. CARDIOVASC. IMAGING REP. PD APR PY 2016 VL 9 IS 4 AR UNSP 12 DI 10.1007/s12410-016-9373-1 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DU5KD UT WOS:000382249700001 ER PT J AU Han, JF An, SJ Su, WM Chen, ZH Su, J Yan, HH Guo, WB Chen, SL Huang, Y Xie, Z Lan, Q Rothman, N Wu, YL Yang, JJ AF Han, Jie-Fei An, She-Juan Su, Wen-Mei Chen, Zhi-Hong Su, Jian Yan, Hong-hong Guo, Wei-Bang Chen, Shi-Liang Huang, Ying Xie, Zhi Lan, Qing Rothman, Nathaniel Wu, Yi-Long Yang, Jin-Ji TI Polymorphism of rs9387478 correlates with overall survival in female nonsmoking patients with lung cancer SO INTERNATIONAL JOURNAL OF BIOLOGICAL MARKERS LA English DT Article DE EGFR mutation; Lung cancer; Overall survival; Polymorphism ID GENOME-WIDE ASSOCIATION; NEVER SMOKERS; ROS1 REARRANGEMENT; RISK; ADENOCARCINOMA; SUSCEPTIBILITY; EXPRESSION; PROLIFERATION; CHEMOTHERAPY; POPULATION AB Background: Our previous study identified rs9387478 as a new susceptibility locus associated with lung cancer in never-smoking women in Asia; however, the clinical and prognostic significance of this finding is not known. Methods: We analyzed the relationship between the rs9387478 single nucleotide polymorphism and i) clinical parameters and ii) overall survival time in 505 female nonsmoking lung cancer patients, using the chi-square test and Kaplan-Meier analysis with the log-rank test, respectively. We further established the epidermal growth factor receptor (EGFR) mutation status and assessed its association with rs9387478 genotypes as well as the efficacy of EGFR tyrosine kinase inhibitors. Results: The frequency of the AA genotype was significantly higher in the EGFR-mutation-negative group than in the EGFR-mutation-positive group (32% vs. 16%, chi(2) = 13.025, p = 0.011). Patients with the CC genotype had a better overall survival time than patients with the AA/AC genotype (median survival time: 54.2 vs. 32.9 months,chi(2) = 4.593, p = 0.032). The distribution of rs9387478 genotypes differed according to the clinical disease stage. Conclusions: This study indicates that the rs9387478 genotype was associated with overall survival in nonsmoking female patients with lung cancer, although it was not significant after adjusting for multiple testing. The identification of the location of the rs9387478 single nucleotide polymorphism in the genomic interval containing the DCBLD1 and ROS1 genes, together with the finding that the rs9387478 polymorphism correlates with EGFR mutation status, may have important implications for therapeutic approaches targeting EGFR or ROS1 in patients with lung cancer. C1 [Han, Jie-Fei] Southern Med Univ, Guangzhou, Guangdong, Peoples R China. [Han, Jie-Fei; An, She-Juan; Su, Wen-Mei; Chen, Zhi-Hong; Su, Jian; Yan, Hong-hong; Guo, Wei-Bang; Chen, Shi-Liang; Huang, Ying; Xie, Zhi; Wu, Yi-Long; Yang, Jin-Ji] Guangdong Gen Hosp, Guangdong Lung Canc Inst, 106 Zhongshan 2 Rd, Guangzhou 510080, Guangdong, Peoples R China. [Han, Jie-Fei; An, She-Juan; Su, Wen-Mei; Chen, Zhi-Hong; Su, Jian; Yan, Hong-hong; Guo, Wei-Bang; Chen, Shi-Liang; Huang, Ying; Xie, Zhi; Wu, Yi-Long; Yang, Jin-Ji] Guangdong Acad Med Sci, Guangdong Key Lab Lung Canc Translat Med, Guangzhou, Guangdong, Peoples R China. [Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Yang, JJ (reprint author), Guangdong Gen Hosp, Guangdong Lung Canc Inst, 106 Zhongshan 2 Rd, Guangzhou 510080, Guangdong, Peoples R China.; Yang, JJ (reprint author), Guangdong Acad Med Sci, Guangdong Key Lab Lung Canc Translat Med, Guangzhou, Guangdong, Peoples R China. EM yangjinji2003@163.com FU National Natural Science Foundation of China [81101549, 30772531, 81272618]; Nonprofit Research and Special Projects of National Health and Family Planning Committee of China [201402031] FX This work was supported by the National Natural Science Foundation of China (Nos. 81101549, 30772531 and 81272618) and Nonprofit Research and Special Projects of National Health and Family Planning Committee of China (No. 201402031). NR 35 TC 0 Z9 0 U1 1 U2 1 PU WICHTIG PUBLISHING PI MILAN PA 72/74 VIA FRIULI, 20135 MILAN, ITALY SN 0393-6155 EI 1724-6008 J9 INT J BIOL MARKER JI Int. J. Biol. Markers PD APR-JUN PY 2016 VL 31 IS 2 BP E144 EP E152 DI 10.5301/jbm.5000180 PG 9 WC Biotechnology & Applied Microbiology; Oncology SC Biotechnology & Applied Microbiology; Oncology GA DS7KT UT WOS:000380963100006 PM 26689248 ER PT J AU Nair, RP Zheng, CY Sunavala-Dossabhoy, G AF Nair, Renjith Parameswaran Zheng, Changyu Sunavala-Dossabhoy, Gulshan TI Retroductal Submandibular Gland Instillation and Localized Fractionated Irradiation in a Rat Model of Salivary Hypofunction SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 110; Human Gene Therapy; Volume 24; salivary gland; cannulation; collimation; fractions; ionizing radiation; rat; animal model; salivary hypofunction ID RADIATION-INDUCED XEROSTOMIA; GENE THERAPEUTICS; PROTECTION; DELIVERY; DAMAGE; CDNA AB Normal tissues that lie within the portals of radiation are inadvertently damaged. Salivary glands are often injured during head and neck radiotherapy. Irreparable cell damage results in a chronic loss of salivary function that impairs basic oral activities, and increases the risk of oral infections and dental caries. Salivary hypofunction and its complications gravely impact a patient's comfort. Current symptomatic management of the condition is ineffective, and newer therapies to assuage the condition are needed. Salivary glands are exocrine glands, which expel their secretions into the mouth via excretory ducts. Cannulation of these ducts provides direct access to the glands. Retroductal delivery of a contrast agent to major salivary glands is a routine out-patient procedure for diagnostic imaging. Using a similar procedure, localized treatment of the glands is feasible. However, performing this technique in preclinical studies with small animals poses unique challenges. In this study we describe the technique of retroductal administration in rat submandibular glands, a procedure that was refined in Dr. Bruce Baum's laboratory (NIH)(1), and lay out a procedure for local gland irradiation. C1 [Nair, Renjith Parameswaran; Sunavala-Dossabhoy, Gulshan] Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Baton Rouge, LA 70803 USA. [Zheng, Changyu] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, DHHS, Bethesda, MD USA. RP Sunavala-Dossabhoy, G (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Baton Rouge, LA 70803 USA. EM GSunav@lsuhsc.edu FU American Cancer Society [116945-RSG-09-038-01-CCE]; National Institute of Health [R21CA173162]; Feist-Weiller Cancer Center FX We thank Dr. John Chang (Radiation Oncology, LSU Health Science Center) for assistance with radiation dose measurements. The study was supported by the American Cancer Society (Grant number: 116945-RSG-09-038-01-CCE), National Institute of Health (Grant number: R21CA173162) and the Feist-Weiller Cancer Center. NR 21 TC 0 Z9 0 U1 1 U2 1 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD APR PY 2016 IS 110 AR e53785 DI 10.3791/53785 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9ZX UT WOS:000380256000040 ER PT J AU Blackley, DJ Wiley, MR Ladner, JT Fallah, M Lo, T Gilbert, ML Gregory, C D'ambrozio, J Coulter, S Mate, S Balogun, Z Kugelman, J Nwachukwu, W Prieto, K Yeiah, A Amegashie, F Kearney, B Wisniewski, M Saindon, J Schroth, G Fakoli, L Diclaro, JW Kuhn, JH Hensley, LE Jahrling, PB Stroher, U Nichol, ST Massaquoi, M Kateh, F Clement, P Gasasira, A Bolay, F Monroe, SS Rambaut, A Sanchez-Lockhart, M Laney, AS Nyenswah, T Christie, A Palacios, G AF Blackley, David J. Wiley, Michael R. Ladner, Jason T. Fallah, Mosoka Lo, Terrence Gilbert, Merle L. Gregory, Christopher D'ambrozio, Jonathan Coulter, Stewart Mate, Suzanne Balogun, Zephaniah Kugelman, Jeffrey Nwachukwu, William Prieto, Karla Yeiah, Adolphus Amegashie, Fred Kearney, Brian Wisniewski, Meagan Saindon, John Schroth, Gary Fakoli, Lawrence Diclaro, Joseph W., II Kuhn, Jens H. Hensley, Lisa E. Jahrling, Peter B. Stroher, Ute Nichol, Stuart T. Massaquoi, Moses Kateh, Francis Clement, Peter Gasasira, Alex Bolay, Fatorma Monroe, Stephan S. Rambaut, Andrew Sanchez-Lockhart, Mariano Laney, A. Scott Nyenswah, Tolbert Christie, Athalia Palacios, Gustavo TI Reduced evolutionary rate in reemerged Ebola virus transmission chains SO SCIENCE ADVANCES LA English DT Article ID LIBERIA; SURVEILLANCE; OUTBREAK; SPREAD AB On 29 June 2015, Liberia's respite from Ebola virus disease (EVD) was interrupted for the second time by a renewed outbreak ("flare-up") of seven confirmed cases. We demonstrate that, similar to the March 2015 flare-up associated with sexual transmission, this new flare-up was a reemergence of a Liberian transmission chain originating from a persistently infected source rather than a reintroduction from a reservoir or a neighboring country with active transmission. Although distinct, Ebola virus (EBOV) genomes from both flare-ups exhibit significantly low genetic divergence, indicating a reduced rate of EBOV evolution during persistent infection. Using this rate of change as a signature, we identified two additional EVD clusters that possibly arose from persistently infected sources. These findings highlight the risk of EVD flare-ups even after an outbreak is declared over. C1 [Blackley, David J.; Lo, Terrence; Gregory, Christopher; Coulter, Stewart; Balogun, Zephaniah; Nwachukwu, William; Saindon, John; Stroher, Ute; Monroe, Stephan S.; Laney, A. Scott; Christie, Athalia] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. [Wiley, Michael R.; Ladner, Jason T.; Gilbert, Merle L.; D'ambrozio, Jonathan; Mate, Suzanne; Kugelman, Jeffrey; Prieto, Karla; Kearney, Brian; Wisniewski, Meagan; Sanchez-Lockhart, Mariano; Palacios, Gustavo] US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Fallah, Mosoka; Yeiah, Adolphus; Amegashie, Fred; Massaquoi, Moses; Kateh, Francis; Nyenswah, Tolbert] Minist Hlth, Monrovia, Liberia. [Schroth, Gary] Illumina Inc, San Diego, CA 92122 USA. [Fakoli, Lawrence; Bolay, Fatorma] Liberian Inst Biomed Res, Charlesville, Liberia. [Diclaro, Joseph W., II] US Navy, Naval Med Res Unit 3, Cairo, Egypt. [Kuhn, Jens H.; Hensley, Lisa E.; Jahrling, Peter B.; Nichol, Stuart T.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Clement, Peter; Gasasira, Alex] WHO, CH-1211 Geneva 27, Switzerland. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3FL, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Rambaut, Andrew] Univ Edinburgh, Ctr Immunol Infect & Evolut, Edinburgh EH9 3FL, Midlothian, Scotland. RP Christie, A (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30329 USA.; Palacios, G (reprint author), US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA.; Nyenswah, T (reprint author), Minist Hlth, Monrovia, Liberia. EM tgnyenswah74@yahoo.com; akc9@cdc.gov; gustavo.f.palacios.ctr@mail.mil RI Palacios, Gustavo/I-7773-2015 OI Palacios, Gustavo/0000-0001-5062-1938 FU NIAID NIH HHS [HHSN272200700016I]; PHS HHS [HHSN272200700016I] NR 25 TC 7 Z9 7 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 2375-2548 J9 SCI ADV JI Sci. Adv. PD APR PY 2016 VL 2 IS 4 AR e1600378 DI 10.1126/sciadv.1600378 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR7IB UT WOS:000380072100053 PM 27386513 ER PT J AU Shah, NG Seam, N Woods, CJ Fessler, HE Goyal, M McAreavey, D Lee, BW AF Shah, Nirav G. Seam, Nitin Woods, Christian J. Fessler, Henry E. Goyal, Munish McAreavey, Dorothea Lee, Burton W. CA DC Baltimore Critical Care Educati TI A Longitudinal Regional Educational Model for Pulmonary and Critical Care Fellows Emphasizing Small Group- and Simulation-based Learning SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article AB Recent trends have necessitated a renewed focus on how we deliver formal didactic and simulation experiences to pulmonary and critical care medicine (PCCM) fellows. To address the changing demands of training PCCM fellows, as well as the variability in the clinical training, fund of knowledge, and procedural competence of incoming fellows, we designed a PCCM curriculum that is delivered regionally in the Baltimore/Washington, DC area in the summer and winter. The educational curriculum began in 2008 as a collaboration between the Critical Care Medicine Department at the National Institutes of Health and the Pulmonary and Critical Care Section of the Department of Medicine at MedStar Washington Hospital Center and now includes 13 individual training programs in PCCM, critical care medicine, and pulmonary diseases in Baltimore and Washington, DC. Informal and formal feedback from the fellows who participated led to substantial changes to the course curriculum, allowing for continuous improvement. The educational consortium has helped build a local community of educators to share ideas, support each other's career development, and collaborate on other endeavors. In this article, we describe how we developed and deliver this curriculum and report on lessons learned. C1 [Shah, Nirav G.] Univ Maryland, Sch Med, Div Pulm & Crit Care, Baltimore, MD USA. [Seam, Nitin; McAreavey, Dorothea; Lee, Burton W.] NIH, Dept Crit Care Med, Bethesda, MD USA. [Woods, Christian J.; Goyal, Munish; Lee, Burton W.] MedStar Washington Hosp Ctr, Div Pulm Crit Care & Resp Serv, Washington, DC USA. [Goyal, Munish] MedStar Washington Hosp Ctr, Dept Emergency Med, Washington, DC USA. [Fessler, Henry E.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care, Baltimore, MD USA. [Lee, Burton W.] AIC Kijabe Hosp, Dept Med, Kijabe, Kenya. RP Shah, NG (reprint author), Univ Maryland, Med Ctr, 110 S Paca St,2nd Floor,Room 2-N-144, Baltimore, MD 21201 USA. EM nshah1@medicine.umaryland.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 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD APR PY 2016 VL 13 IS 4 BP 469 EP 474 DI 10.1513/AnnalsATS.201601-027AR PG 6 WC Respiratory System SC Respiratory System GA DR6BT UT WOS:000379986900007 PM 26845063 ER PT J AU Duncan, GA Lockett, A Villegas, LR Almodovar, S Gomez, JL Flores, SC Wilkes, DS Tigno, XT AF Duncan, Gregg A. Lockett, Angelia Villegas, Leah R. Almodovar, Sharilyn Gomez, Jose L. Flores, Sonia C. Wilkes, David S. Tigno, Xenia T. TI National Heart, Lung, and Blood Institute Workshop Summary: Enhancing Opportunities for Training and Retention of a Diverse Biomedical Workforce SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article AB Rationale: Committed to its mission of conducting and supporting research that addresses the health needs of all sectors of the nation's population, the Division of Lung Diseases, National Heart, Lung, and Blood Institute of the National Institutes of Health (NHLBI/NIH) seeks to identify issues that impact the training and retention of underrepresented individuals in the biomedical research workforce. Objectives: Early-stage investigators who received grant support through the NIH Research Supplements to Promote Diversity in Health Related Research Program were invited to a workshop held in Bethesda, Maryland in June, 2015, in order to (1) assess the effectiveness of the current NHLBI diversity program, (2) improve its strategies towards achieving its goal, and (3) provide guidance to assist the transition of diversity supplement recipients to independent NIH grant support. Methods: Workshop participants participated in five independent focus groups to discuss specific topics affecting underrepresented individuals in the biomedical sciences: (1) Socioeconomic barriers to success for diverse research scientists; (2) role of the academic research community in promoting diversity; (3) life beyond a research project grant: non-primary investigator career paths in research; (4) facilitating career development of diverse independent research scientists through NHLBI diversity programs; and (5) effectiveness of current NHLBI programs for promoting diversity of the biomedical workforce. Measurements and Main Results: Several key issues experienced by young, underrepresented biomedical scientists were identified, and solutions were proposed to improve on training and career development for diverse students, from the high school to postdoctoral trainee level, and address limitations of currently available diversity programs. Although some of the challenges mentioned, such as cost of living, limited parental leave, and insecure extramural funding, are also likely faced by nonminority scientists, these issues are magnified among diversity scientists and are complicated by unique circumstances in this group, such as limited exposure to science at a young age, absence of role models and mentors from underrepresented backgrounds, and social norms that relegate their career endeavors, particularly among women, to being subordinate to their expected cultural role. Conclusions: The factors influencing the participation of underrepresented minorities in the biomedical workforce are complex and span several continuous or overlapping stages in the professional development of scientists from these groups. Therefore, amultipronged approach is needed to enable the professional development and retention of underrepresented minorities in biomedical research. This approach should address both individual and social factors and should involve funding agencies, academic institutions, mentoring teams, professional societies, and peer collaboration. Implementation of some of the recommendations, such as access to child care, institutional support and health benefits for trainees, teaching and entrepreneurial opportunities, grant-writing webinars, and pre-NIH career development (Pre-K) pilot programs would not only benefit biomedical scientists from underrepresented groups but also improve the situation of nondiverse junior scientists. However, other issues, such as opportunities for early exposure to science of disadvantaged/minority groups, and identifying mentors/life coaches/peer mentors who come from similar cultural backgrounds and vantage points, are unique to this group. C1 [Duncan, Gregg A.] Johns Hopkins Univ, Sch Med, Ctr Nanomed, Baltimore, MD USA. [Lockett, Angelia] Indiana Univ Sch Med, Dept Physiol, Indianapolis, IN USA. [Wilkes, David S.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN USA. [Wilkes, David S.] Indiana Univ Sch Med, Dept Microbiol, Indianapolis, IN USA. [Wilkes, David S.] Indiana Univ Sch Med, Dept Immunol, Indianapolis, IN USA. [Villegas, Leah R.] Univ Colorado Anschutz Med Campus, Dept Pediat & Cardiovasc Pulm Res, Aurora, CO USA. [Almodovar, Sharilyn; Flores, Sonia C.] Univ Colorado Anschutz Med Campus, Div Pulm Sci & Crit Care Med, Aurora, CO USA. [Gomez, Jose L.] Yale Univ, Sch Med, Dept Pulm Crit Care & Sleep Med, New Haven, CT USA. [Tigno, Xenia T.] NHLBI, Div Lung Dis, NIH, Bethesda, MD USA. RP Wilkes, DS (reprint author), Univ Virginia, Sch Med, POB 800793, Charlottesville, VA 22908 USA. EM dsw4n@hscmail.mcc.virginia.edu NR 0 TC 0 Z9 0 U1 2 U2 4 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 APR PY 2016 VL 13 IS 4 BP 562 EP 567 DI 10.1513/AnnalsATS.201509-624OT PG 6 WC Respiratory System SC Respiratory System GA DR6BT UT WOS:000379986900020 PM 27058184 ER PT J AU Nikitskaya, EA Grive, JC Maryukhnich, EV Lebedeva, AM Ivanova, OI Savvinova, PP Shpektor, AV Margolis, LB Vasilieva, EY AF Nikitskaya, E. A. Grive, J. -C. Maryukhnich, E. V. Lebedeva, A. M. Ivanova, O. I. Savvinova, P. P. Shpektor, A. V. Margolis, L. B. Vasilieva, E. Yu. TI Cytomegalovirus in Plasma of Acute Coronary Syndrome Patients SO ACTA NATURAE LA English DT Article DE coronary artery disease; acute coronary syndrome; human herpes viruses; cytomegalovirus; polymerase chain reaction ID HERPES-SIMPLEX-VIRUS; MYOCARDIAL-INFARCTION; CHLAMYDIA-PNEUMONIAE; ESC GUIDELINES; ATHEROSCLEROSIS; INFECTION; RISK; DISEASE; ANGIOGRAPHY; MECHANISMS AB The relationship between acute coronary syndrome (ACS) and local and systemic inflammation, including accumulation of macrophages in atherosclerotic plaques and upregulation of blood cytokines (e.g., C-reactive protein (CRP)), has been known for more than 100 years. The atherosclerosis-associated inflammatory response has been traditionally considered as an immune system reaction to low-density lipoproteins. At the same time, some data have indicated a potential involvement of cytomegalovirus (CMV) in the activation and progression of atherosclerosis-associated inflammation, leading to ACS. However, these data have been tangential and mainly concerned the relationship between a coronary artery disease (CAD) prognosis and the anti-CMV antibody titer. We assumed that ACS might be associated with CMV reactivation and virus release into the bloodstream. The study's aim was to test this assumption through a comparison of the plasma CMV DNA level in patients with various CAD forms and in healthy subjects. To our knowledge, no similar research has been undertaken yet. A total of 150 subjects (97 CAD patients and 53 healthy subjects) were examined. Real-time polymerase chain reaction (RT-PCR) was used to determine the number of plasma CMV DNA copies. We demonstrated that the number of plasma CMV genome copies in ACS patients was significantly higher than that in healthy subjects (p = 0.01). The CMV genome copy number was correlated with the plasma CRP level (p = 0.002). These findings indicate a potential relationship between CMV activation and atherosclerosis exacerbation that, in turn, leads to the development of unstable angina and acute myocardial infarction. Monitoring of the CMV plasma level in CAD patients may be helpful in the development of new therapeutic approaches to coronary atherosclerosis treatment. C1 [Nikitskaya, E. A.; Maryukhnich, E. V.; Lebedeva, A. M.; Ivanova, O. I.; Savvinova, P. P.; Shpektor, A. V.; Vasilieva, E. Yu.] Evdokimov Moscow State Univ Med & Dent, Dept Cardiol, Lab Afherothrombosis, Delegatskaya Str 20-1, Moscow 127473, Russia. [Grive, J. -C.; Margolis, L. B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Intercellular Interact, NIH, Bethesda, MD USA. [Grive, J. -C.] Sidra Med & Res Ctr, POB 26999, Doha, Qatar. RP Vasilieva, EY (reprint author), Evdokimov Moscow State Univ Med & Dent, Dept Cardiol, Lab Afherothrombosis, Delegatskaya Str 20-1, Moscow 127473, Russia. EM vasilievahelena@gmail.com RI Ivanova, Oxana/L-8578-2016 OI Ivanova, Oxana/0000-0002-8477-9706 FU Ministry of Education and Science of the Russian Federation [14.V25.31.0016] FX This work was supported by a grant of the Ministry of Education and Science of the Russian Federation (o. 14.V25.31.0016). NR 44 TC 1 Z9 1 U1 0 U2 0 PU RUSSIAN FEDERATION AGENCY SCIENCE & INNOVATION PI MOSCOW PA NAUCHNY PARK MGU, VLAD 1, STROENIYE 75G, LENINSKIYE GORY, MOSCOW, 119991, RUSSIA SN 2075-8251 J9 ACTA NATURAE JI Acta Naturae PD APR-JUN PY 2016 VL 8 IS 2 BP 102 EP 107 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DR0WV UT WOS:000379628500012 PM 27437144 ER PT J AU Jonsdottir, G Lund, SH Bjorkholm, M Turesson, I Wahlin, A Mailankody, S Blimark, C Hultcrantz, M Porwit, A Landgren, O Kristinsson, SY AF Jonsdottir, Gudbjorg Lund, Sigrun H. Bjorkholm, Magnus Turesson, Ingemar Wahlin, Anders Mailankody, Sham Blimark, Cecilie Hultcrantz, Malin Porwit, Anna Landgren, Ola Kristinsson, Sigurdur Y. TI Survival in multiple myeloma patients who develop second malignancies: a population-based cohort study SO HAEMATOLOGICA LA English DT Letter DE multiple myeloma; second malignancy; survival; population-based ID LEUKEMIA; THERAPY C1 [Jonsdottir, Gudbjorg; Lund, Sigrun H.; Kristinsson, Sigurdur Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Bjorkholm, Magnus; Hultcrantz, Malin; Kristinsson, Sigurdur Y.] Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden. [Bjorkholm, Magnus; Hultcrantz, Malin; Kristinsson, Sigurdur Y.] Karolinska Inst, Stockholm, Sweden. [Turesson, Ingemar] Skane Univ Hosp, Dept Hematol & Coagulat Disorders, Malmo, Sweden. [Wahlin, Anders] Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden. [Mailankody, Sham] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Blimark, Cecilie] Sahlgrens Univ Hosp, Dept Med, Sect Hematol & Coagulat, Gothenburg, Sweden. [Porwit, Anna] Univ Hlth Network, Dept Lab Med & Pathobiol, Toronto Gen Hosp, Toronto, ON, Canada. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. RP Kristinsson, SY (reprint author), Univ Iceland, Fac Med, Reykjavik, Iceland.; Kristinsson, SY (reprint author), Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden.; Kristinsson, SY (reprint author), Karolinska Inst, Stockholm, Sweden. EM sigurdur.Kristinsson@ki.se RI Lund, Sigrun Helga/K-9144-2015 OI Lund, Sigrun Helga/0000-0002-3806-2296 NR 15 TC 3 Z9 3 U1 1 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD APR PY 2016 VL 101 IS 4 DI 10.3324/haematol.2015.134049 PG 4 WC Hematology SC Hematology GA DQ7NA UT WOS:000379393100007 PM 26681760 ER PT J AU Kepple, AL Lee, EE Haq, N Rubinow, DR Schmidt, PJ AF Kepple, Alyson L. Lee, Ellen E. Haq, Nazli Rubinow, David R. Schmidt, Peter J. TI History of Postpartum Depression in a Clinic-Based Sample of Women With Premenstrual Dysphoric Disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID MOOD DISORDERS; RISK-FACTORS; PERIMENOPAUSAL DEPRESSION; ANXIETY DISORDERS; GONADAL-STEROIDS; SYMPTOMS; PREVALENCE; VULNERABILITY; COMMUNITY; ILLNESS AB Objective: Overlapping comorbidities between premenstrual dysphoric disorder (PMDD) and postpartum depression (PPD) suggest that these disorders represent a continuum of vulnerability with shared pathophysiology. We report the past histories of PPD (and other Axis I psychiatric illnesses) in a clinic-based sample of women meeting criteria for PMDD. Methods: 215 women, ages 19 to 51 years, who attended the National Institute of Mental Health Mood Disorders Clinic between 1988 and 2013 seeking treatment for PMDD and in whom we confirmed the diagnosis of PMDD (DSM-IV), were identified. All were administered the Structured Clinical Interview for DSM-III-R or -IV. The frequency of PPD (major or minor) was established in the subgroup of women (n = 137) who had delivered at least 1 child. Results: Ninety-three women (43.3%) had a past history of a mood disorder (ie, either major [n = 67; 31.2%] or minor [n = 10; 4.7%] depression or PPD [n = 16; 7.4%; 11.7% of parous women]). Nine of the 16 women with PMDD and a past PPD had either a past major depressive episode (MDE) or subsyndromal anxiety disorder. Thirty-three women (15.3%) had a past history of an Axis I anxiety disorder. A total of 40 women (18.6%) met criteria for past alcohol or drug abuse, 3 (1.4%) met criteria for bulimia nervosa, and 2 (0.9%) met criteria for anorexia nervosa. Conclusions: Our data demonstrate that PMDD and PPD do not frequently co-occur. These data do not suggest that PMDD and PPD share similar pathophysiology beyond being ovarian-steroid-triggered mood disorders. The high comorbidity of past MDE could contribute to the increased risk both for future MDE and for PPD in some women with PMDD. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Kepple, Alyson L.] Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15260 USA. [Lee, Ellen E.] Univ Maryland, Dept Psychiat, Baltimore, MD 21201 USA. [Haq, Nazli; Schmidt, Peter J.] NIMH, Behav Endocrinol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. [Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Schmidt, PJ (reprint author), NIMH, Behav Endocrinol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM PeterSchmidt@mail.NIH.gov FU National Institute of Mental Health (NIMH) [81-M-0126, MH002865] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH; NIMH protocol 81-M-0126; project MH002865). NR 49 TC 0 Z9 0 U1 9 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD APR PY 2016 VL 77 IS 4 BP E415 EP E420 DI 10.4088/JCP.15m09779 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ5LU UT WOS:000379247700002 PM 27035701 ER PT J AU Solomon, SS Mehta, SH McFall, AM Srikrishnan, AK Saravanan, S Laeyendecker, O Balakrishnan, P Celentano, DD Solomon, S Lucas, GM AF Solomon, Sunil Suhas Mehta, Shruti H. McFall, Allison M. Srikrishnan, Aylur K. Saravanan, Shanmugam Laeyendecker, Oliver Balakrishnan, Pachamuthu Celentano, David D. Solomon, Suniti Lucas, Gregory M. TI Community viral load, antiretroviral therapy coverage, and HIV incidence in India: a cross-sectional, comparative study SO LANCET HIV LA English DT Article ID HIDDEN POPULATIONS; PREVENTION; RNA; SURVEILLANCE; INFECTION AB Background HIV incidence is the best measure of treatment-programme effectiveness, but its measurement is difficult and expensive. The concept of community viral load as a modifiable driver of new HIV infections has attracted substantial attention. We set out to compare several measures of community viral load and antiretroviral therapy (ART) coverage as correlates of HIV incidence in high-risk populations. Methods We analysed data from a sample of people who inject drugs and men who have sex with men, who were participants of the baseline assessment of a cluster-randomised trial in progress across 22 cities in India (ClinicalTrials.gov number NCT01686750). We recruited the study population by use of respondent-driven sampling and did the baseline assessment at 27 community-based sites (12 for men who have sex with men and 15 for people who inject drugs). We estimated HIV incidence with a multiassay algorithm and calculated five community-based measures of HIV control: mean log 10 HIV RNA in participants with HIV in a community either engaged in care (in-care viral load), aware of their status but not necessarily in care (aware viral load), or all HIV-positive individuals whether they were aware, in care, or not (population viral load); participants with HIV in a community with HIV RNA more than 150 copies per mL (prevalence of viraemia); and the proportion of participants with HIV who self-reported ART use in the previous 30 days (population ART coverage). All participants were tested for HIV, with additional testing in HIV-positive individuals. We assessed correlations between the measures and HIV incidence with Spearman correlation coefficients and linear regression analysis. Findings Between Oct 1, 2012, and Dec 19, 2013, we recruited 26 503 participants, 12 022 men who have sex with men and 14 481 people who inject drugs. Median incidence of HIV was 0.87% (IQR 0.40-1.17) in men who have sex with men and 1.43% (0.60-4.00) in people who inject drugs. Prevalence of viraemia was more strongly correlated with HIV incidence (correlation 0.81, 95% CI 0.62-0.91; p<0.0001) than all other measures, although correlation was signifi cant with aware viral load (0.59, 0.27-0.79; p=0.001), population viral load (0.51, 0.16-0.74; p=0.007), and population ART coverage (-0.54,-0.76 to -0.20; p=0.004). In-care viral load was not correlated with HIV incidence (0.29, -0.10 to 0.60; p=0.14). With regression analysis, we estimated that to reduce HIV incidence by 1 percentage point in a community, prevalence of viraemia would need to be reduced by 4.34%, and ART use in HIV-positive individuals would need to increase by 19.5%. Interpretati on Prevalence of viraemia had the strongest correlation with HIV incidence in this sample and might be a useful measure of the effectiveness of a treatment programme. C1 [Solomon, Sunil Suhas; Laeyendecker, Oliver; Lucas, Gregory M.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Solomon, Sunil Suhas; Mehta, Shruti H.; McFall, Allison M.; Celentano, David D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Srikrishnan, Aylur K.; Saravanan, Shanmugam; Balakrishnan, Pachamuthu; Solomon, Suniti] YR Gaitonde Ctr AIDS Res & Educ, Madras, Tamil Nadu, India. [Laeyendecker, Oliver] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Solomon, SS (reprint author), Johns Hopkins Sch Med, Baltimore, MD 21287 USA. EM sss@jhmi.edu FU US National Institutes of Health; Elton John AIDS Foundation FX US National Institutes of Health, Elton John AIDS Foundation. NR 30 TC 3 Z9 3 U1 2 U2 3 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD APR PY 2016 VL 3 IS 4 BP E183 EP E190 DI 10.1016/S2352-3018(16)00019-9 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DQ1GQ UT WOS:000378949900011 PM 27036994 ER PT J AU Gill, CM Torriani, M Murphy, R Harris, TB Miller, KK Klibanski, A Bredella, MA AF Gill, Corey M. Torriani, Martin Murphy, Rachel Harris, Tamara B. Miller, Karen K. Klibanski, Anne Bredella, Miriam A. TI Fat Attenuation at CT in Anorexia Nervosa SO RADIOLOGY LA English DT Article ID SUBCUTANEOUS ADIPOSE-TISSUE; COMPUTED-TOMOGRAPHY; PREMENOPAUSAL WOMEN; ABDOMINAL FAT; CANCER CACHEXIA; FEMALE-PATIENTS; WEIGHT-LOSS; RISK-FACTOR; BODY-FAT; OBESITY AB Purpose: To investigate the composition, cross-sectional area (CSA), and hormonal correlates of different fat depots in women with anorexia nervosa (AN) and control subjects with normal weights to find out whether patients with AN have lower fat CSA but higher attenuation than did control subjects and whether these changes may be mediated by gonadal steroids, cortisol, and thyroid hormones. Materials and Methods: This study was institutional review board approved and HIPAA compliant. Written informed consent was obtained. Forty premenopausal women with AN and 40 normal-weight women of comparable age (mean age 6 standard deviation, 26 years 6 5) were studied. All individuals underwent computed tomography of the abdomen and thigh with a calibration phantom. Abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), thigh SAT, and thigh intermuscular adipose tissue CSA and attenuation were quantified. Serum estradiol, thyroid hormones, and urinary free cortisol levels were assessed. Variables were compared by using analysis of variance. Associations were examined by using linear regression analysis. Results: Women with AN had higher fat attenuation than did control subjects (-100.1 to -46.7 HU vs -117.6 to -61.8 HU, P < .0001), despite lower fat CSA (2.0-62.8 cm(2) vs 5.5-185.9 cm(2), P < .0001). VAT attenuation but not CSA was inversely associated with lowest prior lifetime body mass index in AN (r = -0.71, P = .006). Serum estradiol levels were inversely associated with fat attenuation (r = -0.34 to -0.61, P = .03 to <.0001) and were positively associated with fat CSA of all compartments (r = 0.42-0.64, P = .007 to <.0001). Thyroxine levels and urinary free cortisol levels were positively associated with thigh SAT attenuation (r = 0.64 [P = .006] and r = 0.68 [P = .0004], respectively) and were inversely associated with abdominal SAT and VAT CSA (r = 20.44 to 20.58, P = .04 to .02). Conclusion: Women with AN have differences in fat composition, with higher fat attenuation than that of control subjects, as well as low fat mass. VAT attenuation but not CSA is inversely associated with lowest prior lifetime body mass index, suggesting that fat attenuation may serve as a biomarker of prior and current disease status in AN. (C) RSNA, 2015 C1 [Gill, Corey M.; Torriani, Martin; Bredella, Miriam A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Miller, Karen K.; Klibanski, Anne] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroendocrine Unit, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. [Murphy, Rachel; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Bredella, MA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. EM mbredella@mgh.harvard.edu FU National Institutes of Health [R01 MH083657, R01 DK052625, R03 DK59297, M01 RR01066, UL1 RR025758, T32 DK 007028, K23 RR-23090] FX This research was supported by the National Institutes of Health (grants R01 MH083657, R01 DK052625, R03 DK59297, M01 RR01066, UL1 RR025758, T32 DK 007028, and K23 RR-23090). NR 27 TC 0 Z9 0 U1 3 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2016 VL 279 IS 1 BP 151 EP 157 DI 10.1148/radiol.2015151104 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP7WK UT WOS:000378709700014 PM 26509295 ER PT J AU Pourmorteza, A Symons, R Sandfort, V Mallek, M Fuld, MK Henderson, G Jones, EC Malayeri, AA Folio, LR Bluemke, DA AF Pourmorteza, Amir Symons, Rolf Sandfort, Veit Mallek, Marissa Fuld, Matthew K. Henderson, Gregory Jones, Elizabeth C. Malayeri, Ashkan A. Folio, Les R. Bluemke, David A. TI Abdominal Imaging with Contrast-enhanced Photon-counting CT: First Human Experience SO RADIOLOGY LA English DT Article ID DUAL-ENERGY CT; DOSE REDUCTION AB Purpose: To evaluate the performance of a prototype photon-counting detector (PCD) computed tomography (CT) system for abdominal CT in humans and to compare the results with a conventional energy-integrating detector (EID). Materials and Methods: The study was HIPAA-compliant and institutional review board-approved with informed consent. Fifteen asymptomatic volunteers (seven men; mean age, 58.2 years +/- 9.8 [standard deviation]) were prospectively enrolled between September 2 and November 13, 2015. Radiation dose-matched delayed contrast agent-enhanced spiral and axial abdominal EID and PCD scans were acquired. Spiral images were scored for image quality (Wilcoxon signed-rank test) in five regions of interest by three radiologists blinded to the detector system, and the axial scans were used to assess Hounsfield unit accuracy in seven regions of interest (paired t test). Intraclass correlation coefficient (ICC) was used to assess reproducibility. PCD images were also used to calculate iodine concentration maps. Spatial resolution, noise-power spectrum, and Hounsfield unit accuracy of the systems were estimated by using a CT phantom. Results: In both systems, scores were similar for image quality (median score, 4; P = .19), noise (median score, 3; P = .30), and artifact (median score, 1; P = .17), with good interrater agreement (image quality, noise, and artifact ICC: 0.84, 0.88, and 0.74, respectively). Hounsfield unit values, spatial resolution, and noise-power spectrum were also similar with the exception of mean Hounsfield unit value in the spinal canal, which was lower in the PCD than the EID images because of beam hardening (20 HU vs 36.5 HU; P < .001). Contrast-to-noise ratio of enhanced kidney tissue was improved with PCD iodine mapping compared with EID (5.2 +/- 1.3 vs 4.0 +/- 1.3; P < .001). Conclusion: The performance of PCD showed no statistically significant difference compared with EID when the abdomen was evaluated in a conventional scan mode. PCD provides spectral information, which may be used for material decomposition. (C) RSNA, 2016 C1 [Pourmorteza, Amir; Symons, Rolf; Sandfort, Veit; Mallek, Marissa; Henderson, Gregory; Jones, Elizabeth C.; Malayeri, Ashkan A.; Folio, Les R.; Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. [Fuld, Matthew K.] Siemens Med Solut, Malvern, PA USA. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM david.bluemke@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [ZIACL090019, ZIAEB000072] FX R.S. supported by National Institutes of Health Intramural research program http://dx.doi.org/ (ZIACL090019; ZIAEB000072). NR 13 TC 5 Z9 5 U1 3 U2 5 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2016 VL 279 IS 1 BP 239 EP 245 DI 10.1148/radiol.2016152601 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP7WK UT WOS:000378709700023 PM 26840654 ER PT J AU Rodriguez, EK Munasinghe, J AF Rodriguez, Edward K. Munasinghe, Jeeva TI A Chick Embryo in-Vitro Model of Knee SO ARCHIVES OF BONE AND JOINT SURGERY-ABJS LA English DT Article DE chick embryo; chick embryo culture; Glycosaminoglycan; in-vitro loaded limb culture; joint morphogenesis; paralyzed chick embryo ID SKELETAL DEVELOPMENT; JOINT DEVELOPMENT; MOVEMENT; MORPHOGENESIS; PARALYSIS; CARTILAGE; SYSTEM; HIP AB Background: In this feasibility study, a mechanically loaded in-vitro tissue culture model of joint morphogenesis using the isolated lower extremity of the 8 day old chick embryo was developed to assess the effects of mechanical loading on joint morphogenesis. Methods: The developed in-vitro system allows controlled flexion and extension of the chick embryonic knee with a range of motion of 20 degrees from a resting position of 90-100 degrees of flexion. Joint morphogenesis at 2, 3, 4 and 7 days of culture was assessed by histology and micro MRI in 4 specimen types: undisturbed in-ovo control embryos, in-ovo paralyzed embryos, in-vitro unloaded limb cultures, and in-vitro loaded limb cultures. Relative glycosaminoglycan (GAG) concentration across the joint was assessed with an MRI technique referred to as dGEMRIC (delayed gadolinium enhanced MRI of cartilage) where T1 is proportional to glycosaminoglycan concentration. Results: Average T1 over the entire tissue image for the normal control (IC) knee was 480 msec; for the 4 day loaded specimen average T1 was 354 msec; and for the 7 day loaded specimens T1 was 393 msec. The 4 day unloaded specimen had an average T1 of 279 msec while the 7 day unloaded specimen had an average T1 of 224 msec. The higher T1 values in loaded than unloaded specimens suggest that more glycosaminoglycan is produced in the loaded culture than in the unloaded preparation. Conclusion: Isolated limb tissue cultures under flexion-extension load can be viable and exhibit more progression of joint differentiation and glycosaminoglycan production than similarly cultured but unloaded specimens. However, when compared with controls consisting of intact undisturbed embryos in-ovo, the isolated loaded limbs in culture do not demonstrate equivalent amounts of absolute growth or joint differentiation. C1 [Rodriguez, Edward K.; Munasinghe, Jeeva] Beth Israel Deaconess Med Ctr, Dept Orthoped Surg, Boston, MA 02215 USA. [Rodriguez, Edward K.] Harvard Univ, Sch Med, Orthoped Trauma Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Munasinghe, Jeeva] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Rodriguez, EK (reprint author), Harvard Univ, Sch Med, Orthoped Trauma Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. EM Ekrodrig@bidmc.harvard.edu NR 21 TC 1 Z9 1 U1 3 U2 3 PU MASHHAD UNIV MED SCIENCES PI MASHHAD PA VICE-CHANCELLOR FOR RES CTR OFF IJBMS, DANESHGAH ST, PO BOX 9138813944 - 445, MASHHAD, 00000, IRAN SN 2345-4644 EI 2345-461X J9 ARCH BONE JT SURG-AB JI Arch. Bone Jt. Surg.-ABJS PD APR PY 2016 VL 4 IS 2 BP 109 EP 115 PG 7 WC Orthopedics SC Orthopedics GA DP7NG UT WOS:000378685500004 PM 27200386 ER PT J AU Barmpari, ME Savvidis, C Dede, AD Markogiannakis, H Dikoglou, C Xekouki, P Stratakis, CA Andreas, M Malaktari-Skarantavou, S AF Barmpari, Maria E. Savvidis, Christos Dede, Anastasia D. Markogiannakis, Haridimos Dikoglou, Christina Xekouki, Paraskevi Stratakis, Constantine A. Andreas, Manouras Malaktari-Skarantavou, Sofia TI Adrenal malignant melanoma masquerading as a pheochromocytoma in a patient with a history of a multifocal papillary and medullary thyroid carcinoma SO HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM LA English DT Article DE Adrenal melanoma; Dopamine; Metastasis; Pheochromocytoma; Primary ID FOLLOW-UP; INCIDENTALOMAS; SCINTIGRAPHY; METASTASES; MANAGEMENT; SURVIVAL; GLANDS; TUMORS; CT AB OBJECTIVE: Adrenal masses usually represent benign and nonfunctional adrenal adenomas; however, primary or metastatic malignancy should also be considered. Discovery of an adrenal mass needs further evaluation in order to exclude malignancy and hormonal secretion. We present a rare case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. CASE REPORT: A 61-year-old male farmer was referred for evaluation of a mass in the right supraclavicular region and a left adrenal lesion. The patient had a history of a multifocal papillary and medullary thyroid carcinoma. Laboratory tests revealed increased 24hour urinary dopamine and also increased serum calcitonin and neuron specific enolase. A pathology report of the resected right supraclavicular mass and left adrenal showed a malignant melanoma. CONCLUSION: This is a case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. Although this case is very rare and there are rigid diagnostic criteria for the diagnosis of primary adrenal melanoma, it underlines the fact that the differential diagnosis of a dopamine secreting adrenal mass should include primary or metastatic malignant melanoma in order to determine the best diagnostic approach for the patient and select the most appropriate surgical management. C1 [Barmpari, Maria E.; Savvidis, Christos; Dede, Anastasia D.; Malaktari-Skarantavou, Sofia] Hippokrateion Hosp, Dept Endocrinol & Metab, Athens, Greece. [Markogiannakis, Haridimos; Andreas, Manouras] Univ Athens, Dept Endocrine Surg, Dept Propaedeut Surg 1, Hippokrat Hosp,Athens Med Sch, GR-10679 Athens, Greece. [Dikoglou, Christina] Hippokrateion Hosp, Dept Pathol, Athens, Greece. [Xekouki, Paraskevi; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, NIH, Bethesda, MD USA. RP Barmpari, ME (reprint author), 114 Vas Sofias Av, Athens 11527, Greece. EM barbari_maria@yahoo.com NR 35 TC 0 Z9 0 U1 0 U2 0 PU HELLENIC ENDOCRINE SOC PI ATHENS PA 14 ALEXANDRAS AVE, ATHENS, 106 82, GREECE SN 1109-3099 J9 HORM-INT J ENDOCRINO JI Horm.-Int. J. Endocrinol. Metab. PD APR-JUN PY 2016 VL 15 IS 2 BP 283 EP 290 DI 10.14310/horm.2002.1653 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9RG UT WOS:000378833900014 PM 27376430 ER PT J AU Muthumani, K Falzarano, D Reuschel, EL Kraynyak, K Ugen, K Kim, P Maslow, J Kim, JJ Sardesai, NY Kobinger, G Feldmann, H Weiner, D AF Muthumani, K. Falzarano, D. Reuschel, E. L. Kraynyak, K. Ugen, K. Kim, P. Maslow, J. Kim, J. J. Sardesai, N. Y. Kobinger, G. Feldmann, H. Weiner, D. TI A synthetic consensus anti-Spike protein DNA vaccine induces protective immunity against Middle East Respiratory Syndrome Coronavirus in non-human primates SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Muthumani, K.; Reuschel, E. L.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Falzarano, D.] Univ Saskatchewan, Saskatoon, SK, Canada. [Kraynyak, K.; Kim, J. J.; Sardesai, N. Y.] Inovio Pharmaceut Inc, Plymouth Meeting, PA USA. [Ugen, K.] Univ S Florida, Morsani Coll Med, Tampa, FL USA. [Kim, P.; Maslow, J.] GeneOne Life Sci, Seoul, South Korea. [Kobinger, G.] Natl Microbiol Lab, Special Pathogens, Winnipeg, MB, Canada. [Feldmann, H.] NIAID, NIH, Hamilton, MT USA. [Weiner, D.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD APR PY 2016 VL 45 SU 1 MA 14.009 BP 23 EP 23 DI 10.1016/j.ijid.2016.02.083 PG 1 WC Infectious Diseases SC Infectious Diseases GA DK4GZ UT WOS:000374876700043 ER PT J AU Singh, N Kumar, R Nylen, S Sacks, D Sundar, S AF Singh, N. Kumar, R. Nylen, S. Sacks, D. Sundar, S. TI The effect of TNF-alpha neutralization on parasite load and cytokine production in human visceral leishmaniasis SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Singh, N.] Banaras Hindu Univ, Inst Med Sci, Varanasi 221005, Uttar Pradesh, India. [Kumar, R.] Netaji Subhas Inst Technol, New Delhi, India. [Nylen, S.] Karolinska Inst, Stockholm, Sweden. [Sacks, D.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sundar, S.] BHU, Inst Med Sci, Varanasi, Uttar Pradesh, India. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD APR PY 2016 VL 45 SU 1 MA 35.010 BP 62 EP 62 DI 10.1016/j.ijid.2016.02.180 PG 1 WC Infectious Diseases SC Infectious Diseases GA DK4GZ UT WOS:000374876700126 ER PT J AU Kharod, G Haberling, D Person, M Folkema, A Galloway, R Elrod, M Perniciaro, J Nicholson, W Patel, N Bwogi, J Bukenya, H Drakeley, C Mbulaiteye, S Blaney, D Shadomy, S AF Kharod, G. Haberling, D. Person, M. Folkema, A. Galloway, R. Elrod, M. Perniciaro, J. Nicholson, W. Patel, N. Bwogi, J. Bukenya, H. Drakeley, C. Mbulaiteye, S. Blaney, D. Shadomy, S. TI Uganda National Acute Febrile Illness Agent Detection Serosurvey 2004-2005 SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Kharod, G.; Haberling, D.; Person, M.; Galloway, R.; Elrod, M.; Perniciaro, J.; Nicholson, W.; Patel, N.; Blaney, D.; Shadomy, S.] CDC, Atlanta, GA 30333 USA. [Folkema, A.] CDC, Reg Waterloo Publ Hlth, Waterloo, ON, Canada. [Bwogi, J.; Bukenya, H.] UVRI, Entebbe, Uganda. [Drakeley, C.] Univ London London Sch Hyg & Trop Med, Keppel St, London WC1E 7HT, England. [Mbulaiteye, S.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD APR PY 2016 VL 45 SU 1 MA 41.234 BP 180 EP 180 DI 10.1016/j.ijid.2016.02.422 PG 1 WC Infectious Diseases SC Infectious Diseases GA DK4GZ UT WOS:000374876700366 ER PT J AU Singh, N Kumar, R Chauhan, SB Nylen, S Sacks, D Engwerda, C Sundar, S AF Singh, N. Kumar, R. Chauhan, S. B. Nylen, S. Sacks, D. Engwerda, C. Sundar, S. TI Investigating changes in monocyte phenotypes and functions in active visceral leishmaniasis patients SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Singh, N.; Chauhan, S. B.; Sundar, S.] BHU, Inst Med Sci, Varanasi, Uttar Pradesh, India. [Kumar, R.] Netaji Subhas Inst Technol, New Delhi, India. [Nylen, S.] Karolinska Inst, Stockholm, Sweden. [Sacks, D.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Engwerda, C.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD APR PY 2016 VL 45 SU 1 MA 43.076 BP 380 EP 381 DI 10.1016/j.ijid.2016.02.815 PG 2 WC Infectious Diseases SC Infectious Diseases GA DK4GZ UT WOS:000374876700759 ER PT J AU Virk-Baker, MK Parascandola, M AF Virk-Baker, Mandeep K. Parascandola, Mark TI Dietary adequacy in tobacco-user and non-user households in Bangladesh SO LANCET GLOBAL HEALTH LA English DT Meeting Abstract C1 [Virk-Baker, Mandeep K.] NCI, Hlth Behav Res Branch, NIH, 9609 Med Ctr Dr 3E632, Rockville, MD 20892 USA. [Parascandola, Mark] NCI, Tobacco Control Res Branch, Behav Res Program, NIH, 9609 Med Ctr Dr 3E632, Rockville, MD 20892 USA. EM mandeep.virk-baker@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD APR PY 2016 VL 4 SU 1 BP 8 EP 8 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP8DM UT WOS:000378728100008 ER PT J AU Coleman, CN Formenti, SC Chao, N Grover, S Rodin, D Petereit, DG Vikram, B Pistenmaa, DA Mohiuddin, M Williams, TR Wendling, N Roth, L Gospodarowicz, M Jaffray, D AF Coleman, C. Norman Formenti, Silvia C. Chao, Nelson Grover, Surbhi Rodin, Danielle Petereit, Daniel G. Vikram, Bhadrasain Pistenmaa, David A. Mohiuddin, Majid Williams, Tim R. Wendling, Nina Roth, Lawrence Gospodarowicz, Mary Jaffray, D. TI Establishing global health cancer care partnerships across common ground: bridging nuclear security, equitable access, education, outreach, and mentorship SO LANCET GLOBAL HEALTH LA English DT Meeting Abstract C1 [Coleman, C. Norman; Pistenmaa, David A.; Wendling, Nina] Int Canc Expert Corps, 70 East 96th St,Suite 11A, New York, NY 10128 USA. [Formenti, Silvia C.] Cornell Univ, Sch Med, New York, NY 10021 USA. [Chao, Nelson] Duke Canc Inst, Durham, NC USA. [Grover, Surbhi] Univ Penn, Philadelphia, PA 19104 USA. [Rodin, Danielle; Gospodarowicz, Mary; Jaffray, D.] Univ Toronto, Toronto, ON, Canada. [Petereit, Daniel G.] Amer Indian Walking Forward Program, Rapid City, SD USA. [Vikram, Bhadrasain] NCI, Bethesda, MD 20892 USA. [Mohiuddin, Majid] Radiat Oncol Consultants Ltd, Chicago, IL USA. [Williams, Tim R.] Boca Raton Reg Hosp, Lynn Canc Inst, Boca Raton, FL USA. [Gospodarowicz, Mary; Jaffray, D.] Union Int Canc Control, Task Force Radiat Canc Control, Geneva, Switzerland. EM norm.coleman@iceccancer.org NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD APR PY 2016 VL 4 SU 1 BP 14 EP 14 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP8DM UT WOS:000378728100014 ER PT J AU Siddharthan, T Nassali, F Kalyesubula, R Coca, S Rastegar, A Rabin, T Knauf, F AF Siddharthan, Trishul Nassali, Faith Kalyesubula, Robert Coca, Steve Rastegar, Asghar Rabin, Tracy Knauf, Felix TI An educational booklet for patient-centred health education about a non-communicable disease in low-income and middle-income countries SO LANCET GLOBAL HEALTH LA English DT Meeting Abstract C1 [Siddharthan, Trishul] Johns Hopkins Univ, Baltimore, MD USA. [Siddharthan, Trishul] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Nassali, Faith] Mulago Hosp, Kampala, Uganda. [Kalyesubula, Robert] Makerere Univ, Kampala, Uganda. [Coca, Steve] Ichan Sch Med Mt Sinai, New York, NY USA. [Rastegar, Asghar; Rabin, Tracy] Yale Univ, New Haven, CT 06520 USA. [Knauf, Felix] Univ Erlangen Nurnberg, D-91054 Erlangen, Germany. EM tsiddha1@jhmi.edu NR 0 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD APR PY 2016 VL 4 SU 1 BP 25 EP 25 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP8DM UT WOS:000378728100025 ER PT J AU Elumogo, CO Kochenderfer, JN Civelek, AC Bluemke, DA AF Elumogo, Comfort O. Kochenderfer, James N. Civelek, A. Cahid Bluemke, David A. TI Pigmented villonodular synovitis mimics metastases on fluorine 18 fluorodeoxyglucose position emission tomography-computed tomography SO QUANTITATIVE IMAGING IN MEDICINE AND SURGERY LA English DT Article DE Pigmented villonodular synovitis (PVNS); position emission tomography-computed tomography (PET-CT); surveillance imaging ID LYMPHOMA; PET; CT AB Pigmented villonodular synovitis (PVNS) is a benign joint disease best characterized on magnetic resonance imaging (MRI). The role of fluorine 18 fluorodeoxyglucose (F-18-FDG) position emission tomography-computed tomography (PET-CT) in the diagnosis or characterization remains unclear. PVNS displays as a focal FDG avid lesion, which can masquerade as a metastatic lesion, on PET-CET. We present a case of PVNS found on surveillance imaging of a lymphoma patient. C1 [Elumogo, Comfort O.; Civelek, A. Cahid; Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm 1C355, Bethesda, MD 20892 USA. [Kochenderfer, James N.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Bluemke, David/0000-0002-8323-8086 NR 11 TC 1 Z9 1 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-4292 EI 2223-4306 J9 QUANT IMAGING MED SU JI Quant. Imaging Med. Surg. PD APR PY 2016 VL 6 IS 2 BP 218 EP 223 DI 10.21037/qims.2016.01.04 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP6XT UT WOS:000378643800015 PM 27190776 ER PT J AU Marks, AB Smith, OK Aladjem, MI AF Marks, Anna B. Smith, Owen K. Aladjem, Mirit I. TI Replication origins: determinants or consequences of nuclear organization? SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID TOPOLOGICALLY ASSOCIATING DOMAINS; PROTEIN PHOSPHATASE 1; G-QUADRUPLEX MOTIFS; DNA-REPLICATION; S-PHASE; MAMMALIAN-CELLS; HUMAN GENOME; C-MYC; CHROMATIN-STRUCTURE; TRANSCRIPTIONAL CONTROL AB Chromosome replication, gene expression and chromatin assembly all occur on the same template, necessitating a tight spatial and temporal coordination to maintain genomic stability. The distribution of replication initiation events is responsive to local and global changes in chromatin structure and is affected by transcriptional activity. Concomitantly, replication origin sequences, which determine the locations of replication initiation events, can affect chromatin structure and modulate transcriptional efficiency. The flexibility observed in the replication initiation landscape might help achieve complete and accurate genome duplication while coordinating the DNA replication program with transcription and other nuclear processes in a cell-type specific manner. This review discusses the relationships among replication origin distribution, local and global chromatin structures and concomitant nuclear metabolic processes. C1 [Marks, Anna B.; Smith, Owen K.; Aladjem, Mirit I.] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Aladjem, MI (reprint author), NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov FU intramural program of the CCR, National Cancer Institute, National Institutes of Health FX We thank Drs. Haiqing Fu and Christophe Redon for critical reading of the review. We thank many colleagues at the NCI Developmental Therapeutics Branch for helpful comments and apologize to our colleagues whose primary work could not be cited due to lack of space. This work was funded by the intramural program of the CCR, National Cancer Institute, National Institutes of Health. NR 91 TC 6 Z9 6 U1 3 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X EI 1879-0380 J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD APR PY 2016 VL 37 BP 67 EP 75 DI 10.1016/j.gde.2015.11.008 PG 9 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA DO8WX UT WOS:000378067300010 PM 26845042 ER PT J AU Nix, AT Huber, JT Shapiro, RM Pfeifle, A AF Nix, A. Tyler Huber, Jeffrey T. Shapiro, Robert M., II Pfeifle, Andrea TI Examining care navigation: librarian participation in a team-based approach? SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article DE Patient Navigation; Librarians; Cooperative Behavior; Delivery of Health Care ID PATIENT NAVIGATION; HEALTH; INFORMATION; BARRIERS; WORKERS; BREAST; MODEL AB Objective: This study investigated responsibilities, skill sets, degrees, and certifications required of health care navigators in order to identify areas of potential overlap with health sciences librarianship. Method: The authors conducted a content analysis of health care navigator position announcements and developed and assigned forty-eight category terms to represent the sample's responsibilities and skill sets. Results: Coordination of patient care and a bachelor's degree were the most common responsibility and degree requirements, respectively. Results also suggest that managing and providing health information resources is an area of overlap between health care navigators and health sciences librarians, and that librarians are well suited to serve on navigation teams. Conclusion: Such overlap may provide an avenue for collaboration between navigators and health sciences librarians. C1 [Nix, A. Tyler; Huber, Jeffrey T.] Univ Kentucky, Sch Informat Sci, 320 Little Lib Bldg, Lexington, KY 40506 USA. [Shapiro, Robert M., II] Univ Kentucky, Med Ctr Lib, 298 William R Willard Med Educ Bldg, Lexington, KY 40506 USA. [Pfeifle, Andrea] Univ Kentucky, Ctr Interprofess Healthcare Educ Res & Practice, 292 Biopharmaceut Bldg, Lexington, KY 40506 USA. [Pfeifle, Andrea] Univ Kentucky, Family & Community Med, 292 Biopharmaceut Bldg, Lexington, KY 40506 USA. [Nix, A. Tyler] Natl Lib Med, BG 38 RM 2N109,8600 Rockville Pike, Bethesda, MD 20894 USA. [Pfeifle, Andrea] Indiana Univ, Ctr Interprofess Hlth Educ & Practice, 591A Gatch Hall, Indianapolis, IN 46202 USA. [Pfeifle, Andrea] Indiana Univ, Family Med, 591A Gatch Hall, Indianapolis, IN 46202 USA. RP Nix, AT (reprint author), Univ Kentucky, Sch Informat Sci, 320 Little Lib Bldg, Lexington, KY 40506 USA. EM tyler.nix@uky.edu; jeffrey.huber@uky.edu; shapiro.rm@uky.edu; andrea.pfeifle@uky.edu OI Nix, Tyler/0000-0002-0503-386X NR 25 TC 0 Z9 0 U1 2 U2 4 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD APR PY 2016 VL 104 IS 2 BP 131 EP 137 DI 10.3163/1536-5050.104.2.007 PG 7 WC Information Science & Library Science SC Information Science & Library Science GA DP1OW UT WOS:000378260300009 PM 27076800 ER PT J AU Wesolowski, A Mensah, K Brook, CE Andrianjafimasy, M Winter, A Buckee, CO Razafindratsimandresy, R Tatem, AJ Heraud, JM Metcalf, CJE AF Wesolowski, Amy Mensah, Keitly Brook, Cara E. Andrianjafimasy, Miora Winter, Amy Buckee, Caroline O. Razafindratsimandresy, Richter Tatem, Andrew J. Heraud, Jean-Michel Metcalf, C. Jessica E. TI Introduction of rubella-containing-vaccine to Madagascar: implications for roll-out and local elimination SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE rubella; vaccination; Madagascar; congenital rubella syndrome; evaluation of vaccination programmes; Africa ID CHILDHOOD INFECTIONS; DEVELOPING-COUNTRIES; ADDIS-ABABA; MEASLES; DYNAMICS; EPIDEMIOLOGY; SEASONALITY; SEROEPIDEMIOLOGY; POPULATION; CHALLENGES AB Few countries in Africa currently include rubella-containing vaccination (RCV) in their immunization schedule. The Global Alliance for Vaccines Initiative (GAVI) recently opened a funding window that has motivated more widespread roll-out of RCV. As countries plan RCV introductions, an understanding of the existing burden, spatial patterns of vaccine coverage, and the impact of patterns of local extinction and reintroduction for rubella will be critical to developing effective programmes. As one of the first countries proposing RCV introduction in part with GAVI funding, Madagascar provides a powerful and timely case study. We analyse serological data from measles surveillance systems to characterize the epidemiology of rubella in Madagascar. Combining these results with data on measles vaccination delivery, we develop an age-structured model to simulate rubella vaccination scenarios and evaluate the dynamics of rubella and the burden of congenital rubella syndrome (CRS) across Madagascar. We additionally evaluate the drivers of spatial heterogeneity in age of infection to identify focal locations where vaccine surveillance should be strengthened and where challenges to successful vaccination introduction are expected. Our analyses indicate that characteristics of rubella in Madagascar are in line with global observations, with an average age of infection near 7 years, and an impact of frequent local extinction with reintroductions causing localized epidemics. Modelling results indicate that introduction of RCV into the routine programme alone may initially decrease rubella incidence but then result in cumulative increases in the burden of CRS in some regions (and transient increases in this burden in many regions). Deployment of RCV with regular supplementary campaigns will mitigate these outcomes. Results suggest that introduction of RCV offers a potential for elimination of rubella in Madagascar, but also emphasize both that targeted vaccination is likely to be a lynchpin of this success, and the public health vigilance that this introduction will require. C1 [Wesolowski, Amy; Buckee, Caroline O.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wesolowski, Amy; Buckee, Caroline O.] Harvard TH Chan Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA USA. [Mensah, Keitly; Andrianjafimasy, Miora; Razafindratsimandresy, Richter; Heraud, Jean-Michel] Inst Pasteur Madagascar, Virol Unit, Antananarivo, Madagascar. [Mensah, Keitly; Andrianjafimasy, Miora; Razafindratsimandresy, Richter; Heraud, Jean-Michel] Inst Pasteur Madagascar, Measles & Rubella WHO Natl Reference Lab, Antananarivo, Madagascar. [Brook, Cara E.; Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Winter, Amy; Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, Stockholm, Sweden. [Metcalf, C. Jessica E.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Metcalf, C. Jessica E.] Princeton Univ, Woodrow Wilson Sch, Off Populat Res, Princeton, NJ 08544 USA. RP Metcalf, CJE (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA.; Metcalf, CJE (reprint author), Princeton Univ, Woodrow Wilson Sch, Off Populat Res, Princeton, NJ 08544 USA. EM cmetcalf@princeton.edu FU James S. McDonnell Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [P2CHD047879]; Wellcome Trust [106866/Z/15/Z]; Princeton's Center for Health and Wellbeing; Bill and Melinda Gates Foundation; Science and Technology Directorate; Department of Homeland Security [HSHQDC-12-C-00058]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Models of Infectious Disease Agent Study program [1U54GM088558]; NIH/NIAID [U19AI089674]; Bill & Melinda Gates Foundation [OPP1106427, 1032350] FX This work supported by the James S. McDonnell Foundation (A. Wesolowski), the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, grant no. P2CHD047879 (A. Winter), a Wellcome Trust Sustaining Health grant, no. 106866/Z/15/Z (A. Wesolowski, C.O.B., C.J.E. M. and A.J.T.), a grant from Princeton's Center for Health and Wellbeing (C.J.E. M.), the Bill and Melinda Gates Foundation, the Science and Technology Directorate (C.J.E. M. and B.T.G.), Department of Homeland Security contract HSHQDC-12-C-00058 (C.J.E. M.), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health (C.J.E. M., A.J.T. and B.T.G.), the Models of Infectious Disease Agent Study program (cooperative agreement 1U54GM088558; C.O.B., A. Wesolowski). A.J.T. is supported by funding from NIH/NIAID (U19AI089674), the Bill & Melinda Gates Foundation (OPP1106427, 1032350). NR 43 TC 0 Z9 0 U1 3 U2 3 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD APR 1 PY 2016 VL 13 IS 117 AR 20151101 DI 10.1098/rsif.2015.1101 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP2IM UT WOS:000378311800007 ER PT J AU Bourhy, H Nakoune, E Hall, M Nouvellet, P Lepelletier, A Talbi, C Watier, L Holmes, EC Cauchemez, S Lemey, P Donnelly, CA Rambaut, A AF Bourhy, Herve Nakoune, Emmanuel Hall, Matthew Nouvellet, Pierre Lepelletier, Anthony Talbi, Chiraz Watier, Laurence Holmes, Edward C. Cauchemez, Simon Lemey, Philippe Donnelly, Christl A. Rambaut, Andrew TI Revealing the Micro-scale Signature of Endemic Zoonotic Disease Transmission in an African Urban Setting SO PLOS PATHOGENS LA English DT Article ID DOG RABIES VIRUS; METAPOPULATION DYNAMICS; IDENTIFYING RESERVOIRS; PHYLOGENETIC ANALYSIS; REPRODUCTION NUMBERS; POPULATION-DYNAMICS; INFECTIOUS-DISEASES; CANINE RABIES; ELIMINATION; EPIDEMIC AB The development of novel approaches that combine epidemiological and genomic data provides new opportunities to reveal the spatiotemporal dynamics of infectious diseases and determine the processes responsible for their spread and maintenance. Taking advantage of detailed epidemiological time series and viral sequence data from more than 20 years reported by the National Reference Centre for Rabies of Bangui, the capital city of Central African Republic, we used a combination of mathematical modeling and phylogenetic analysis to determine the spatiotemporal dynamics of rabies in domestic dogs as well as the frequency of extinction and introduction events in an African city. We show that although dog rabies virus (RABV) appears to be endemic in Bangui, its epidemiology is in fact shaped by the regular extinction of local chains of transmission coupled with the introduction of new lineages, generating successive waves of spread. Notably, the effective reproduction number during each wave was rarely above the critical value of 1, such that rabies is not self-sustaining in Bangui. In turn, this suggests that rabies at local geographic scales is driven by human-mediated dispersal of RABV among sparsely connected peri-urban and rural areas as opposed to dispersion in a relatively large homogenous urban dog population. This combined epidemiological and genomic approach enables development of a comprehensive framework for understanding disease persistence and informing control measures, indicating that control measures are probably best targeted towards areas neighbouring the city that appear as the source of frequent incursions seeding outbreaks in Bangui. C1 [Bourhy, Herve; Lepelletier, Anthony; Talbi, Chiraz] WHO Collaborating Ctr Reference & Res Rabies, Unit Lyssavirus Dynam & Host Adaptat, Inst Pasteur, Paris, France. [Nakoune, Emmanuel] Inst Pasteur, Bangui, Cent Afr Republ. [Hall, Matthew; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh, Midlothian, Scotland. [Hall, Matthew; Nouvellet, Pierre; Cauchemez, Simon; Donnelly, Christl A.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London, England. [Nouvellet, Pierre; Cauchemez, Simon; Donnelly, Christl A.] Univ London Imperial Coll Sci Technol & Med, Med Res Council, Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, London, England. [Watier, Laurence] INSERM, UMR 1181, Paris, France. [Watier, Laurence] Inst Pasteur, B2PHI, Paris, France. [Watier, Laurence] Univ Versailles St Quentin, Fac Med Paris Ile France Ouest, Versailles, France. [Holmes, Edward C.] Sch Life & Environm Sci, Charles Perkins Ctr, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW, Australia. [Holmes, Edward C.] Sydney Med Sch, Sydney, NSW, Australia. [Cauchemez, Simon] Inst Pasteur, Math Modelling Infect Dis Unit, Paris, France. [Lemey, Philippe] Katholieke Univ Leuven, Rega Inst, Leuven, Belgium. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Bourhy, H (reprint author), WHO Collaborating Ctr Reference & Res Rabies, Unit Lyssavirus Dynam & Host Adaptat, Inst Pasteur, Paris, France. EM hbourhy@pasteur.fr RI Watier, Laurence/K-8213-2013; OI Watier, Laurence/0000-0002-4057-1102; Holmes, Edward/0000-0001-9596-3552 FU European Union Seventh Framework Programme PREDEMICS [278433]; NHMRC Australia Fellowship FX This work was supported by European Union Seventh Framework Programme PREDEMICS (grant number 278433). ECH is supported by an NHMRC Australia Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 2 Z9 2 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2016 VL 12 IS 4 AR e1005525 DI 10.1371/journal.ppat.1005525 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CZ UT WOS:000378156900021 PM 27058957 ER PT J AU Buck, CB Van Doorslaer, K Peretti, A Geoghegan, EM Tisza, MJ An, P Katz, JP Pipas, JM McBride, AA Camus, AC McDermott, AJ Dill, JA Delwart, E Ng, TFF Farkas, K Austin, C Kraberger, S Davison, W Pastrana, DV Varsani, A AF Buck, Christopher B. Van Doorslaer, Koenraad Peretti, Alberto Geoghegan, Eileen M. Tisza, Michael J. An, Ping Katz, Joshua P. Pipas, James M. McBride, Alison A. Camus, Alvin C. McDermott, Alexa J. Dill, Jennifer A. Delwart, Eric Ng, Terry F. F. Farkas, Kata Austin, Charlotte Kraberger, Simona Davison, William Pastrana, Diana V. Varsani, Arvind TI The Ancient Evolutionary History of Polyomaviruses SO PLOS PATHOGENS LA English DT Article ID MERKEL CELL POLYOMAVIRUS; GOOSE HEMORRHAGIC POLYOMAVIRUS; MULTIPLE SEQUENCE ALIGNMENT; LARGE T-ANTIGEN; AVIAN POLYOMAVIRUS; MOLECULAR PHYLOGENY; PYGOSCELIS-ADELIAE; DIVERGENCE TIMES; MIDDLE T; VIRUS AB Polyomaviruses are a family of DNA tumor viruses that are known to infect mammals and birds. To investigate the deeper evolutionary history of the family, we used a combination of viral metagenomics, bioinformatics, and structural modeling approaches to identify and characterize polyomavirus sequences associated with fish and arthropods. Analyses drawing upon the divergent new sequences indicate that polyomaviruses have been gradually co-evolving with their animal hosts for at least half a billion years. Phylogenetic analyses of individual polyomavirus genes suggest that some modern polyomavirus species arose after ancient recombination events involving distantly related polyomavirus lineages. The improved evolutionary model provides a useful platform for developing a more accurate taxonomic classification system for the viral family Polyomaviridae. C1 [Buck, Christopher B.; Peretti, Alberto; Geoghegan, Eileen M.; Tisza, Michael J.; Pastrana, Diana V.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Van Doorslaer, Koenraad; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [An, Ping; Katz, Joshua P.; Pipas, James M.] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Camus, Alvin C.; Dill, Jennifer A.] Univ Georgia, Dept Pathol, Athens, GA 30602 USA. [McDermott, Alexa J.] Georgia Aquarium Inc, Dept Anim Hlth, Atlanta, GA USA. [Delwart, Eric; Ng, Terry F. F.] Blood Syst Res Inst, San Francisco, CA USA. [Delwart, Eric; Ng, Terry F. F.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Farkas, Kata; Austin, Charlotte; Kraberger, Simona; Davison, William; Varsani, Arvind] Univ Canterbury, Sch Biol Sci, Christchurch 1, New Zealand. [Varsani, Arvind] Univ Cape Town, Dept Clin Lab Sci, Struct Biol Res Unit, ZA-7925 Cape Town, South Africa. [Varsani, Arvind] Univ Florida, Dept Plant Pathol, Gainesville, FL 32611 USA. [Varsani, Arvind] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Ng, Terry F. F.] Ctr Dis Control, DVD, NCIRD, Atlanta, GA 30333 USA. RP Buck, CB (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM buckc@mail.nih.gov OI Van Doorslaer, Koenraad/0000-0002-2985-0733; Ng, Terry Fei Fan/0000-0002-4815-8697; McBride, Alison/0000-0001-5607-5157 FU National Institutes of Health; National Cancer Institute Center for Cancer Research; National Institute of Allergy and Infectious Disease; Antarctica New Zealand [K057]; National Institute of Allergy and Infectious Diseases [AI109339]; Italian Foundation for Cancer Research (FIRC) FX This work was funded in part by the National Institutes of Health Intramural Research Program, with support from the National Cancer Institute Center for Cancer Research. AAM and KVD were funded by the Intramural Research Program of the National Institute of Allergy and Infectious Disease. Trematomus pennellii were collected in the Antarctic under the 2011/08R animal ethics permit and the field work was supported by a grant (K057) awarded to WD from Antarctica New Zealand. The Trematomus pennelli molecular work was supported by personal funds of AV. The structural analyses for the large T antigens by PA, JPK and JMP were supported by an R21 grant AI109339 awarded to JMP by National Institute of Allergy and Infectious Diseases. AP is supported by a grant from the Italian Foundation for Cancer Research (FIRC). Aside from the contribution of personal funds by AV, other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 103 TC 6 Z9 6 U1 3 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2016 VL 12 IS 4 AR e1005574 DI 10.1371/journal.ppat.1005574 PG 26 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CZ UT WOS:000378156900052 PM 27093155 ER PT J AU Carroll, JA Striebel, JF Rangel, A Woods, T Phillips, K Peterson, KE Race, B Chesebro, B AF Carroll, James A. Striebel, James F. Rangel, Alejandra Woods, Tyson Phillips, Katie Peterson, Karin E. Race, Brent Chesebro, Bruce TI Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains SO PLOS PATHOGENS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; SCRAPIE-INFECTED MICE; INDUCED NEUROLOGICAL DISEASE; MURINE RETROVIRUS; DNA MICROARRAY; MOUSE SCRAPIE; AGENT-STRAIN; PROTEIN; PATHOGENESIS; BRAIN AB Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice. C1 [Carroll, James A.; Striebel, James F.; Rangel, Alejandra; Woods, Tyson; Phillips, Katie; Peterson, Karin E.; Race, Brent; Chesebro, Bruce] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Rangel, Alejandra] Univ Western Sydney, Pharmacol, Campbelltown, NSW, Australia. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM bchesebro@nih.gov FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX This work was supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 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 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2016 VL 12 IS 4 AR e1005551 DI 10.1371/journal.ppat.1005551 PG 26 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CZ UT WOS:000378156900035 PM 27046083 ER PT J AU Mason, RD Welles, HC Adams, C Chakrabarti, BK Gorman, J Zhou, TQ Nguyen, R O'Dell, S Lusvarghi, S Bewley, CA Li, H Shaw, GM Sheng, ZZ Shapiro, L Wyatt, R Kwong, PD Mascola, JR Roederer, M AF Mason, Rosemarie D. Welles, Hugh C. Adams, Cameron Chakrabarti, Bimal K. Gorman, Jason Zhou, Tongqing Nguyen, Richard O'Dell, Sijy Lusvarghi, Sabrina Bewley, Carole A. Li, Hui Shaw, George M. Sheng, Zizhang Shapiro, Lawrence Wyatt, Richard Kwong, Peter D. Mascola, John R. Roederer, Mario TI Targeted Isolation of Antibodies Directed against Major Sites of SIV Env Vulnerability SO PLOS PATHOGENS LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; BROADLY NEUTRALIZING ANTIBODIES; RHESUS MONOCLONAL-ANTIBODIES; POTENT HIV-1 NEUTRALIZATION; ENVELOPE GLYCOPROTEINS; CYANOVIRIN-N; SHIV CHALLENGE; NONNEUTRALIZING ANTIBODIES; MOLECULAR CHARACTERIZATION; CONFORMATIONAL-CHANGES AB The simian immunodeficiency virus (SIV) challenge model of lentiviral infection is often used as a model to human immunodeficiency virus type 1 (HIV-1) for studying vaccine mediated and immune correlates of protection. However, knowledge of the structure of the SIV envelope (Env) glycoprotein is limited, as is knowledge of binding specificity, function and potential efficacy of SIV antibody responses. In this study we describe the use of a competitive probe binding sort strategy as well as scaffolded probes for targeted isolation of SIV Env-specific monoclonal antibodies (mAbs). We isolated nearly 70 SIV-specific mAbs directed against major sites of SIV Env vulnerability analogous to broadly neutralizing antibody (bnAb) targets of HIV-1, namely, the CD4 binding site (CD4bs), CD4-induced (CD4i)-site, peptide epitopes in variable loops 1, 2 and 3 (V1, V2, V3) and potentially glycan targets of SIV Env. The range of SIV mAbs isolated includes those exhibiting varying degrees of neutralization breadth and potency as well as others that demonstrated binding but not neutralization. Several SIV mAbs displayed broad and potent neutralization of a diverse panel of 20 SIV viral isolates with some also neutralizing HIV-2(7312A). This extensive panel of SIV mAbs will facilitate more effective use of the SIV non-human primate (NHP) model for understanding the variables in development of a HIV vaccine or immunotherapy. C1 [Mason, Rosemarie D.; Welles, Hugh C.; Adams, Cameron; Gorman, Jason; Zhou, Tongqing; Nguyen, Richard; O'Dell, Sijy; Kwong, Peter D.; Mascola, John R.; Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chakrabarti, Bimal K.] Translat Hlth Sci & Technol Inst, IAVI, HIV Vaccine Design Program, Pali, Haryana, India. [Lusvarghi, Sabrina; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Li, Hui; Shaw, George M.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Li, Hui; Shaw, George M.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sheng, Zizhang; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. [Sheng, Zizhang; Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY USA. [Wyatt, Richard] Scripps Res Inst, Dept Immunol & Microbial Sci, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. RP Mason, RD; Roederer, M (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rosemarie.mason@nih.gov; marior@mail.nih.gov RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Vaccine Research Center, NIAID, NIH; NIDDK, NIH; National Institutes of Health (NIH) [P01 AI088564] FX This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH and the Intramural Research Program of NIDDK, NIH. HL and GMS were supported in part by a grant from the National Institutes of Health (NIH P01 AI088564). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 112 TC 4 Z9 4 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2016 VL 12 IS 4 AR e1005537 DI 10.1371/journal.ppat.1005537 PG 33 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CZ UT WOS:000378156900027 PM 27064278 ER PT J AU Utay, NS Roque, A Timmer, JK Morcock, DR DeLeage, C Somasunderam, A Weintrob, AC Agan, BK Estes, JD Crum-Cianflone, NF Douek, DC AF Utay, Netanya S. Roque, Annelys Timmer, J. Katherina Morcock, David R. DeLeage, Claire Somasunderam, Anoma Weintrob, Amy C. Agan, Brian K. Estes, Jacob D. Crum-Cianflone, Nancy F. Douek, Daniel C. TI MRSA Infections in HIV-Infected People Are Associated with Decreased MRSA-Specific Th1 Immunity SO PLOS PATHOGENS LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; HERPES-SIMPLEX-VIRUS; HYPER-IGE SYNDROME; GAMMA-INTERFERON; T-CELLS; ANTIRETROVIRAL THERAPY; IFN-GAMMA; DEFICIENCY; INTERLEUKIN-2; ZOSTER AB People with HIV infection are at increased risk for community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft tissue infections (SSTIs). Lower CD4 T-cell counts, higher peak HIV RNA levels and epidemiological factors may be associated with increased risk but no specific immune defect has been identified. We aimed to determine the immunologic perturbations that predispose HIV-infected people to MRSA SSTIs. Participants with or without HIV infection and with MRSA SSTI, MRSA colonization or negative for MRSA were enrolled. Peripheral blood and skin biopsies from study participants were collected. Flow cytometry, flow cytometry with microscopy, multiplex assays of cell culture supernatants and immunohistochemistry were used to evaluate the nature of the immune defect predisposing HIV-infected people to MRSA infections. We found deficient MRSA-specific IFN gamma(+) CD4 T-cell responses in HIV-infected people with MRSA SSTIs compared to MRSA-colonized participants and HIV-uninfected participants with MRSA SSTIs. These IFN gamma(+) CD4 T cells were less polyfunctional in HIV-infected participants with SSTIs compared to those without SSTIs. However, IFN gamma responses to cytomegalovirus and Mycobacterium avium antigens and MRSA-specific IL-17 responses by CD4 T cells were intact. Upon stimulation with MRSA, peripheral blood mononuclear cells from HIV-infected participants produced less IL-12 and IL-15, key drivers of IFN gamma production. There were no defects in CD8 T-cell responses, monocyte responses, opsonization, or phagocytosis of Staphylococcus aureus. Accumulation of CD3 T cells, CD4 T cells, IL-17(+) cells, myeloperoxidase(+) neutrophils and macrophage/myeloid cells to the skin lesions were similar between HIV-infected and HIV-uninfected participants based on immunohistochemistry. Together, these results indicate that MRSA-specific IFN gamma(+) CD4 T-cell responses are essential for the control of initial and recurrent MRSA infections in HIV-infected people. C1 [Utay, Netanya S.; Somasunderam, Anoma] Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, Galveston, TX 77555 USA. [Roque, Annelys; Timmer, J. Katherina; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Morcock, David R.; DeLeage, Claire; Estes, Jacob D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Weintrob, Amy C.; Agan, Brian K.; Crum-Cianflone, Nancy F.] Uniformed Serv Univ Hlth Sci, IDCRP, Dept Prevent Med & Biostat, Bethesda, MD 20814 USA. [Weintrob, Amy C.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Agan, Brian K.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Crum-Cianflone, Nancy F.] Naval Med Ctr San Diego, Infect Dis Clin, San Diego, CA USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov OI Agan, Brian/0000-0002-5114-1669 FU Infectious Disease Clinical Research Program, a Department of Defense [IDCRP-023]; National Institute of Allergy and Infectious Diseases/National Institutes of Health [Y1-AI-5072]; National Cancer Institute/National Institutes of Health [HHSN261200800001E] FX Support for this work (IDCRP-023) was provided by Infectious Disease Clinical Research Program, a Department of Defense program executed through Uniformed Services University of the Health Sciences and in part by National Institute of Allergy and Infectious Diseases/National Institutes of Health, under Inter-Agency Agreement Y1-AI-5072, and National Cancer Institute/National Institutes of Health, under Contract No. HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 0 Z9 0 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2016 VL 12 IS 4 AR e1005580 DI 10.1371/journal.ppat.1005580 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CZ UT WOS:000378156900056 PM 27093273 ER PT J AU Faulkner, LM Kisser, J Waldstein, SR Sutin, AR Evans, MK Zonderman, AB AF Faulkner, Lauren M. Kisser, Jason Waldstein, Shari R. Sutin, Angelina R. Evans, Michele K. Zonderman, Alan B. TI EFFECTS OF EMOTIONAL SUPPORT ON COGNITIVE PERFORMANCE MAY BE MODERATED BY PERSONALITY FACTORS SO PSYCHOSOMATIC MEDICINE LA English DT Meeting Abstract CT 74th Annual Meeting of the American-Psychosomatic-Society CY MAR 09-12, 2015 CL Denver, CO SP Amer Psychosomat Soc C1 [Faulkner, Lauren M.; Kisser, Jason; Waldstein, Shari R.] Univ Maryland Baltimore Cty, Psychol, Baltimore, MD 21228 USA. [Sutin, Angelina R.] Florida State Univ, Behav Sci & Social Med, Tallahassee, FL 32306 USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, NIH, Baltimore, MD 21224 USA. [Zonderman, Alan B.] NIA, Behav Epidemiol Sect, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2016 VL 78 IS 3 MA 1475 BP A121 EP A121 PG 1 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DJ1FX UT WOS:000373949800393 ER PT J AU Leibel, DK Waldstein, SR Evans, MK Zonderman, AB AF Leibel, Daniel K. Waldstein, Shari R. Evans, Michele K. Zonderman, Alan B. TI INTERACTIVE RELATIONS OF AGE, SEX, RACE, AND POVERTY STATUS TO PHYSICAL FUNCTIONING IN AN URBAN-DWELLING SAMPLE OF ADULTS SO PSYCHOSOMATIC MEDICINE LA English DT Meeting Abstract CT 74th Annual Meeting of the American-Psychosomatic-Society CY MAR 09-12, 2015 CL Denver, CO SP Amer Psychosomat Soc C1 [Leibel, Daniel K.; Waldstein, Shari R.] Univ Maryland, Psychol, Baltimore, MD 21201 USA. [Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2016 VL 78 IS 3 MA 1264 BP A136 EP A136 PG 1 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DJ1FX UT WOS:000373949800440 ER PT J AU Loucks, EB Gilman, SE Britton, WB Gutman, R Eaton, CB Buka, SL AF Loucks, Eric B. Gilman, Stephen E. Britton, Willoughby B. Gutman, Roee Eaton, Charles B. Buka, Stephen L. TI ASSOCIATIONS OF MINDFULNESS WITH GLUCOSE REGULATION AND DIABETES: NEW ENGLAND FAMILY STUDY SO PSYCHOSOMATIC MEDICINE LA English DT Meeting Abstract CT 74th Annual Meeting of the American-Psychosomatic-Society CY MAR 09-12, 2015 CL Denver, CO SP Amer Psychosomat Soc C1 [Loucks, Eric B.; Buka, Stephen L.] Brown Univ, Sch Publ Hlth, Epidemiol, Providence, RI 02912 USA. [Gilman, Stephen E.] NICHHD, Hlth Behav Branch, Washington, DC USA. [Britton, Willoughby B.] Brown Univ, Psychiat, Providence, RI 02912 USA. [Gutman, Roee] Brown Univ, Sch Publ Hlth, Biostat, Providence, RI 02912 USA. [Eaton, Charles B.] Brown Univ, Family Med, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 9 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2016 VL 78 IS 3 MA 1258 BP A76 EP A76 PG 1 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DJ1FX UT WOS:000373949800235 ER PT J AU Lovallo, WR Enoch, MA Acheson, A Cohoon, AJ Sorocco, KH Vincent, AS Goldman, D AF Lovallo, William R. Enoch, Mary-Anne Acheson, Ashley Cohoon, Andrew J. Sorocco, Kristen H. Vincent, Andrea S. Goldman, David TI EARLY-LIFE ADVERSITY INTERACTS WITH FKBP5 GENOTYPES: GENE-BY-ENVIRONMENT INTERACTION IN THE OKLAHOMA FAMILY HEALTH PATTERNS PROJECT SO PSYCHOSOMATIC MEDICINE LA English DT Meeting Abstract CT 74th Annual Meeting of the American-Psychosomatic-Society CY MAR 09-12, 2015 CL Denver, CO SP Amer Psychosomat Soc C1 [Lovallo, William R.] VA Med Ctr, Psychiat & Behav Sci, Oklahoma City, OK USA. [Lovallo, William R.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Enoch, Mary-Anne; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [Acheson, Ashley] Univ Texas Hlth Sci Ctr San Antonio, Psychiat, San Antonio, TX 78229 USA. [Cohoon, Andrew J.] Univ Oklahoma, Hlth Sci Ctr, Psychiat & Behav Sci, Oklahoma City, OK USA. [Sorocco, Kristen H.] Univ Oklahoma, Hlth Sci Ctr, Donald W Reynolds Dept Geriatr Med, Oklahoma City, OK USA. [Vincent, Andrea S.] Univ Oklahoma, Cognit Sci Res Ctr, Norman, OK 73019 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Department of Veterans Affairs; NIH, NIAAA [AA12207] FX Supported by the Department of Veterans Affairs and NIH, NIAAA AA12207 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2016 VL 78 IS 3 MA 1166 BP A30 EP A30 PG 1 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DJ1FX UT WOS:000373949800095 ER PT J AU Taylor, AD Agurs-Collins, T Persoskie, A Perna, F AF Taylor, Antione D. Agurs-Collins, Tanya Persoskie, Alexander Perna, Frank TI BMI AS A MEDIATOR IN THE RELATION OF DISCRIMINATION AND INFLAMMATION SO PSYCHOSOMATIC MEDICINE LA English DT Meeting Abstract CT 74th Annual Meeting of the American-Psychosomatic-Society CY MAR 09-12, 2015 CL Denver, CO SP Amer Psychosomat Soc C1 [Taylor, Antione D.] Univ Maryland Baltimore Cty, Psychol, Baltimore, MD 21228 USA. [Agurs-Collins, Tanya; Perna, Frank] NCI, Behav Res Program, Rockville, MD USA. [Persoskie, Alexander] US FDA, Populat Hlth Sci Ctr Tobacco Prod, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2016 VL 78 IS 3 MA 1125 BP A88 EP A88 PG 1 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DJ1FX UT WOS:000373949800278 ER PT J AU Xiao, Q Signorello, LB Brinton, LA Cohen, SS Blot, WJ Matthews, CE AF Xiao, Qian Signorello, Lisa B. Brinton, Louise A. Cohen, Sarah S. Blot, William J. Matthews, Charles E. TI Sleep duration and breast cancer risk among black and white women SO SLEEP MEDICINE LA English DT Article DE Sleep; Breast cancer; Black women; Hormone receptor-positive breast cancer; Hormone receptor-negative breast cancer ID URINARY MELATONIN LEVELS; CHINESE WOMEN; COHORT; SINGAPORE; NURSES; HEALTH; US AB Background: Sleep has been suggested to influence breast cancer risk; however, the evidence is mixed. Black women have a higher prevalence of both short (<6 h) and long (>= 9 h) sleep duration and are more likely to develop more aggressive, hormone receptor-negative breast cancer. No study has examined the relationship between sleep and breast cancer in blacks. We focused on race-specific associations among the blacks. Methods: In the Southern Community Cohort Study (SCCS), a prospective study of which two-thirds of the population were black, we prospectively investigated self-reported sleep duration in relation to overall breast cancer risk by estrogen (ER) and progesterone receptor (PR) status in all women and in black women alone. Results: Sleep duration was not associated with risk of total or hormone receptor-positive breast cancer. However, we found an inverse relationship between sleep duration and risk of ER- and PR-breast cancer among all women and in black women alone. Compared to the reference group (8 h), black women who reported shorter sleep duration had an increased risk of ER-PR-breast cancer (odds ratios; ORs (95% confidence intervals; CIs): 2.13 (1.15, 3.93), 1.66 (0.92, 3.02), and 2.22 (1.19, 4.12) for <6, 6, and 7 h, respectively, (p for trend, 0.04). Conclusions: Short sleep duration may be a risk factor for hormone receptor-negative breast cancer among black women. Published by Elsevier B.V. C1 [Xiao, Qian; Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Signorello, Lisa B.] NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Cohen, Sarah S.; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Blot, William J.] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Xiao, Q (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM qian.xiao@nih.gov FU Intramural Research Program of National Institutes of Health; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 25 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD APR PY 2016 VL 20 BP 25 EP 29 DI 10.1016/j.sleep.2015.11.010 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA DO8RO UT WOS:000378051400005 PM 27318222 ER PT J AU Sharov, A Maran, T Tonnessen, M AF Sharov, Alexei Maran, Timo Tonnessen, Morten TI Comprehending the Semiosis of Evolution SO BIOSEMIOTICS LA English DT Editorial Material C1 [Sharov, Alexei] NIA, Lab Genet & Genom, Baltimore, MD 21224 USA. [Maran, Timo] Univ Tartu, Dept Semiot, Ulikooli 18, EE-50090 Tartu, Estonia. [Tonnessen, Morten] Univ Stavanger, Dept Social Studies, Stavanger, Norway. [Tonnessen, Morten] Univ Stavanger, Dept Hlth Studies, Stavanger, Norway. RP Sharov, A (reprint author), NIA, Lab Genet & Genom, Baltimore, MD 21224 USA. EM sharoval@mail.nih.gov FU National Institute on Aging (NIA/NIH) FX The contribution of A. S. was supported entirely by the Intramural Research Program of the National Institute on Aging (NIA/NIH). NR 12 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1875-1342 EI 1875-1350 J9 BIOSEMIOTICS-NETH JI Biosemiotics PD APR PY 2016 VL 9 IS 1 BP 1 EP 6 DI 10.1007/s12304-016-9262-7 PG 6 WC Humanities, Multidisciplinary; History & Philosophy Of Science SC Arts & Humanities - Other Topics; History & Philosophy of Science GA DO5FD UT WOS:000377808100001 PM 27547273 ER PT J AU Sharov, AA AF Sharov, Alexei A. TI Evolution of Natural Agents: Preservation, Advance, and Emergence of Functional Information SO BIOSEMIOTICS LA English DT Article DE Extended evolutionary synthesis; Epigenetic inheritance; Inclusive heritability; Selective reproduction; Plasticity; Levels of semiosis ID BIOLOGY; ORIGIN; BIOSEMIOTICS; FEATHERS; LIFE AB Biological evolution is often viewed narrowly as a change of morphology or allele frequency in a sequence of generations. Here I pursue an alternative informational concept of evolution, as preservation, advance, and emergence of functional information in natural agents. Functional information is a network of signs (e.g., memory, transient messengers, and external signs) that are used by agents to preserve and regulate their functions. Functional information is preserved in evolution via complex interplay of copying and construction processes: the digital components are copied, whereas interpreting subagents together with scaffolds, tools, and resources, are constructed. Some of these processes are simple and invariant, whereas others are complex and contextual. Advance of functional information includes improvement and modification of already existing functions. Although the genome information may change passively and randomly, the interpretation is active and guided by the logic of agent behavior and embryonic development. Emergence of new functions is based on the reinterpretation of already existing information, when old tools, resources, and control algorithms are adopted for novel functions. Evolution of functional information progressed from protosemiosis, where signs correspond directly to actions, to eusemiosis, where agents associate signs with objects. Language is the most advanced form of eusemiosis, where the knowledge of objects and models is communicated between agents. C1 [Sharov, Alexei A.] NIA, Lab Genet & Gen, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Sharov, AA (reprint author), NIA, Lab Genet & Gen, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sharoval@grc.nia.nih.gov FU National Institute on Aging (NIA/NIH) [ZIA AG000656-13] FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging (NIA/NIH), project ZIA AG000656-13. The content of the paper is not endorsed or suggested by the funding organization. NR 63 TC 1 Z9 1 U1 4 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1875-1342 EI 1875-1350 J9 BIOSEMIOTICS-NETH JI Biosemiotics PD APR PY 2016 VL 9 IS 1 BP 103 EP 120 DI 10.1007/s12304-015-9250-3 PG 18 WC Humanities, Multidisciplinary; History & Philosophy Of Science SC Arts & Humanities - Other Topics; History & Philosophy of Science GA DO5FD UT WOS:000377808100008 PM 27525048 ER PT J AU Taichman, CDB Backus, J Baethge, C Bauchner, H de Leeuwe, PW Drazen, JM Fletcher, J Frizelle, FA Groves, T Haileamlak, A James, A Laine, C Peiperl, L Pinborg, A Sahni, CP Wu, S AF Taichman, C. Darren B. Backus, Joyce Baethge, Christopher Bauchner, Howard de Leeuwe, Peter W. Drazen, Jeffrey M. Fletcher, John Frizelle, Frank A. Groves, Trish Haileamlak, Abraham James, Astrid Laine, Christine Peiperl, Larry Pinborg, Anja Sahni, C. Peush Wu, Sinan TI Sharing Clinical Trial Data - A Proposal from the International Committee of Medical Journal Editors SO CORSALUD LA Spanish DT Editorial Material DE Clinical trial; Research data; Medical journal; Editors C1 [Taichman, C. Darren B.] ICMJE, Philadelphia, PA USA. [Backus, Joyce] Natl Lib Med, Lib Operat, Bethesda, MD 20894 USA. RP Taichman, CDB (reprint author), Amer Coll Physicians, Int Comm Med Journal Editors, 190 N Independence Mall West, Philadelphia, PA 19106 USA. EM dtaichman@acponline.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU CARDIOCENTRO ERNESTO CHE GUEVARA PI VILLA CLARA PA CALLE CUBA 610, E-BARCELONA & CAPITAN VELAZCO, SANTA CLARA, VILLA CLARA, CP 50200, CUBA SN 2078-7170 J9 CORSALUD JI CorSalud PD APR-JUN PY 2016 VL 8 IS 2 BP 88 EP 91 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO7ZY UT WOS:000378003000001 ER PT J AU Daly, AF Yuan, B Fina, F Caberg, JH Trivellin, G Rostomyan, L de Herder, WW Naves, LA Metzger, D Cuny, T Rabl, W Shah, N Jaffrain-Rea, ML Zatelli, MC Faucz, FR Castermans, E Nanni-Metellus, I Lodish, M Muhammad, A Palmeira, L Potorac, I Mantovani, G Neggers, SJ Klein, M Barlier, A Liu, PF Ouafik, L Bours, V Lupski, JR Stratakis, CA Beckers, A AF Daly, Adrian F. Yuan, Bo Fina, Frederic Caberg, Jean-Hubert Trivellin, Giampaolo Rostomyan, Liliya de Herder, Wouter W. Naves, Luciana A. Metzger, Daniel Cuny, Thomas Rabl, Wolfgang Shah, Nalini Jaffrain-Rea, Marie-Lise Zatelli, Maria Chiara Faucz, Fabio R. Castermans, Emilie Nanni-Metellus, Isabelle Lodish, Maya Muhammad, Ammar Palmeira, Leonor Potorac, Iulia Mantovani, Giovanna Neggers, Sebastian J. Klein, Marc Barlier, Anne Liu, Pengfei Ouafik, L'Houcine Bours, Vincent Lupski, James R. Stratakis, Constantine A. Beckers, Albert TI Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects SO ENDOCRINE-RELATED CANCER LA English DT Article DE X-LAG syndrome; mosaicism; gigantism; pituitary; molecular genetics ID MCCUNE-ALBRIGHT-SYNDROME; DE-LANGE-SYNDROME; GENOMIC DISORDERS; COPY-NUMBER; TRANSMISSION GENETICS; ACTIVATING MUTATION; PITUITARY-ADENOMAS; GERMLINE MUTATION; RECURRENCE RISK; ARRAY CGH AB Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (n = 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2 ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes. C1 [Daly, Adrian F.; Rostomyan, Liliya; Palmeira, Leonor; Potorac, Iulia; Beckers, Albert] Univ Liege, Ctr Hosp Univ Liege, Dept Endocrinol, Liege, Belgium. [Yuan, Bo; Liu, Pengfei; Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Fina, Frederic; Nanni-Metellus, Isabelle] Hop Nord Marseille, AP HM, Serv Transfert Oncol Biol, Marseille, France. [Fina, Frederic; Ouafik, L'Houcine] Lab Biol Med, Marseille, France. [Fina, Frederic; Ouafik, L'Houcine] Aix Marseille Univ, INSERM, CRO2 UMR S 911, Marseille, France. [Caberg, Jean-Hubert; Castermans, Emilie; Potorac, Iulia; Bours, Vincent] Univ Liege, Ctr Hosp Univ Liege, Dept Human Genet, Liege, Belgium. [Trivellin, Giampaolo; Faucz, Fabio R.; Lodish, Maya; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. [de Herder, Wouter W.; Muhammad, Ammar; Neggers, Sebastian J.] Erasmus Univ, Med Ctr Rotterdam, Dept Med, Sect Endocrinol, Rotterdam, Netherlands. [de Herder, Wouter W.; Muhammad, Ammar; Neggers, Sebastian J.] Pituitary Ctr Rotterdam, Rotterdam, Netherlands. [Naves, Luciana A.] Univ Brasilia, Dept Endocrinol, Brasilia, DF, Brazil. [Metzger, Daniel] BC Childrens Hosp, Endocrinol & Diabet Unit, Vancouver, BC, Canada. [Cuny, Thomas; Klein, Marc] Univ Hosp, Dept Endocrinol, Nancy, France. [Rabl, Wolfgang] Tech Univ Munich, Kinderklin, D-80290 Munich, Germany. [Shah, Nalini] King Edward Mem Hosp, Dept Endocrinol, Bombay, Maharashtra, India. [Jaffrain-Rea, Marie-Lise] Univ LAquila, Dept Biotechnol & Appl Clin Sci, LAquila & Neuromed Inst, IRCCS, Pozzilli, Italy. [Zatelli, Maria Chiara] Univ Ferrara, Dept Med Sci, Sect Endocrinol, I-44100 Ferrara, Italy. [Mantovani, Giovanna] Univ Milan, Fdn IRCCS Ca Granda Osped Maggiore Policlin, Endocrinol & Diabetol Unit, Dept Clin Sci & Community Hlth, Milan, Italy. [Barlier, Anne] Aix Marseille Univ, Hop Concept, APHM, Lab Mol Biol, Marseilles, France. [Barlier, Anne] CRNS, CRN2M UMR 7286, Marseille, France. [Lupski, James R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Lupski, James R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Lupski, James R.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP Beckers, A (reprint author), Univ Liege, Ctr Hosp Univ Liege, Dept Endocrinol, Liege, Belgium. EM albert.beckers@chu.ulg.ac.be RI Trivellin, Giampaolo/J-6583-2016; Daly, Adrian /E-2178-2011; Jaffrain-Rea, Marie-Lise/D-1129-2009; OI Trivellin, Giampaolo/0000-0003-2384-4153; Daly, Adrian /0000-0001-6130-2975; Jaffrain-Rea, Marie-Lise/0000-0002-5916-8997; Cuny, Thomas/0000-0003-2944-5997 FU Fonds D'Investissement de Recherche Scientifique, CHU de Liege, Belgium; US National Human Genome Research Institute/National Heart Lung and Blood Institute [U54HG006542]; National Institute of Neurological Disorders and Stroke [RO1 NS058529] FX The work was supported in part by Fonds D'Investissement de Recherche Scientifique, CHU de Liege, Belgium, and by the US National Human Genome Research Institute/National Heart Lung and Blood Institute grant no. U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and the National Institute of Neurological Disorders and Stroke grant RO1 NS058529. NR 49 TC 14 Z9 14 U1 3 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD APR PY 2016 VL 23 IS 4 BP 221 EP 233 DI 10.1530/ERC-16-0082 PG 13 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DO3OU UT WOS:000377691700005 PM 26935837 ER PT J AU Kaewkhaw, R Swaroop, M Homma, K Nakamura, J Brooks, M Kaya, KD Chaitankar, V Michael, S Tawa, G Zou, JZ Rao, M Zheng, W Cogliati, T Swaroop, A AF Kaewkhaw, Rossukon Swaroop, Manju Homma, Kohei Nakamura, Jutaro Brooks, Matthew Kaya, Koray Dogan Chaitankar, Vijender Michael, Sam Tawa, Gregory Zou, Jizhong Rao, Mahendra Zheng, Wei Cogliati, Tiziana Swaroop, Anand TI Treatment Paradigms for Retinal and Macular Diseases Using 3-D Retina Cultures Derived From Human Reporter Pluripotent Stem Cell Lines SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE human retina development; disease modeling; photoreceptor; high throughput screening; chemical screens; drug discovery; transcriptome; next generation sequencing; three-dimensional organoid culture; fluorescent reporter ID HUMAN IPS CELLS; GENE-THERAPY; PHOTORECEPTOR PRECURSORS; NEURAL RETINA; REGENERATIVE MEDICINE; FATE DETERMINATION; VERTEBRATE RETINA; HUMAN ESCS; DEGENERATION; EXPRESSION AB We discuss the use of pluripotent stem cell lines carrying fluorescent reporters driven by retinal promoters to derive three-dimensional (3-D) retina in culture and how this system can be exploited for elucidating human retinal biology, creating disease models in a dish, and designing targeted drug screens for retinal and macular degeneration. Furthermore, we realize that stem cell investigations are labor-intensive and require extensive resources. To expedite scientific discovery by sharing of resources and to avoid duplication of efforts, we propose the formation of a Retinal Stem Cell Consortium. In the field of vision, such collaborative approaches have been enormously successful in elucidating genetic susceptibility associated with age-related macular degeneration. C1 [Kaewkhaw, Rossukon; Homma, Kohei; Nakamura, Jutaro; Brooks, Matthew; Kaya, Koray Dogan; Chaitankar, Vijender; Cogliati, Tiziana; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Kaewkhaw, Rossukon] Mahidol Univ, Ramathibodi Hosp, Fac Med, Res Ctr, Bangkok 10400, Thailand. [Swaroop, Manju; Michael, Sam; Tawa, Gregory; Zheng, Wei] NIH, Natl Therapeut Rare & Neglected Dis, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Zou, Jizhong] NHLBI, iPSC Core, Ctr Mol Med, Bldg 10, Bethesda, MD 20892 USA. [Rao, Mahendra] New York Stem Cell Fdn, Res Inst, New York, NY USA. [Homma, Kohei] Nippon Med Sch, Dept Physiol, 1-1-5 Sendagi, Tokyo 113, Japan. [Nakamura, Jutaro] Yokohama City Univ, Dept Ophthalmol, Sch Med, Yokohama, Kanagawa 232, Japan. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov RI Zheng, Wei/J-8889-2014; OI Zheng, Wei/0000-0003-1034-0757; Swaroop, Anand/0000-0002-1975-1141 FU Intramural Research Program of the National Eye Institute, National Institutes of Health [ZO1 EY000450, EY000474]; Japan Society for the Promotion of Science (JSPS); JSPS Postdoctoral Fellowships for Research Abroad (Kaitoku-NIH) FX Supported by Intramural Research Program (ZO1 EY000450 and EY000474) of the National Eye Institute, National Institutes of Health. KH and JN were supported by grant-in-aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS) and JSPS Postdoctoral Fellowships for Research Abroad (Kaitoku-NIH). NR 68 TC 0 Z9 0 U1 1 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2016 VL 57 IS 5 SI SI DI 10.1167/iovs.15-17639 PG 11 WC Ophthalmology SC Ophthalmology GA DO8NC UT WOS:000378039300011 ER PT J AU Silson, EH Groen, IIA Kravitz, DJ Baker, CI AF Silson, Edward H. Groen, Iris I. A. Kravitz, Dwight J. Baker, Chris I. TI Evaluating the correspondence between face-, scene-, and object-selectivity and retinotopic organization within lateral occipitotemporal cortex SO JOURNAL OF VISION LA English DT Article DE retinotopy; category-selectivity; population receptive fields ID HUMAN VISUAL-CORTEX; OCCIPITAL CORTEX; FIELD MAPS; EXTRASTRIATE CORTEX; AREA; REPRESENTATIONS; PERCEPTION; BODY; RECOGNITION; ORIENTATION AB The organization of human lateral occipitotemporal cortex (lOTC) has been characterized largely according to two distinct principles: retinotopy and category-selectivity. Whereas category-selective regions were originally thought to exist beyond retinotopic maps, recent evidence highlights overlap. Here, we combined detailed mapping of retinotopy, using population receptive fields (pRF), and category-selectivity to examine and contrast the retinotopic profiles of scene-(occipital place area, OPA), face- (occipital face area, OFA) and object- (lateral occipital cortex, LO) selective regions of lOTC. We observe striking differences in the relationship each region has to underlying retinotopy. Whereas OPA overlapped multiple retinotopic maps (including V3A, V3B, LO1, and LO2), and LO overlapped two maps (LO1 and LO2), OFA overlapped almost none. There appears no simple consistent relationship between category-selectivity and retinotopic maps, meaning category-selective regions are not constrained spatially to retinotopic map borders consistently. The multiple maps that overlap OPA suggests it is likely not appropriate to conceptualize it as a single scene-selective region, whereas the inconsistency in any systematic map overlapping OFA suggests it may constitute a more uniform area. Beyond their relationship to retinotopy, all three regions evidenced strongly retinotopic voxels, with pRFs exhibiting a significant bias towards the contralateral lower visual field, despite differences in pRF size, contributing to an emerging literature suggesting this bias is present across much of lOTC. Taken together, these results suggest that whereas category-selective regions are not constrained to consistently contain ordered retinotopic maps, they nonetheless likely inherit retinotopic characteristics of the maps from which they draw information. C1 [Silson, Edward H.; Groen, Iris I. A.; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Kravitz, Dwight J.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. RP Silson, EH (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM ed.silson@nih.gov RI Groen, Iris/A-1462-2017 OI Groen, Iris/0000-0002-5536-6128 FU Intramural Research Program of the National Institute of Mental Health [MH002909-08] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (MH002909-08). NR 49 TC 1 Z9 1 U1 9 U2 10 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 1534-7362 J9 J VISION JI J. Vision PD APR PY 2016 VL 16 IS 6 AR 14 DI 10.1167/16.6.14 PG 21 WC Ophthalmology SC Ophthalmology GA DO7BX UT WOS:000377938300014 PM 27105060 ER PT J AU Ladner, JT Kuhn, JH Palacios, G AF Ladner, J. T. Kuhn, J. H. Palacios, G. TI Standard finishing categories for high-throughput sequencing of viral genomes SO REVUE SCIENTIFIQUE ET TECHNIQUE-OFFICE INTERNATIONAL DES EPIZOOTIES LA English DT Article DE Data curation; Genome assembly; High-throughput sequencing; Medical countermeasure development; Molecular epidemiology; Population genomics; Virus ID EBOLA-VIRUS; DIVERSITY; EVOLUTION; DISCOVERY; VARIANTS; SURVEILLANCE; CORONAVIRUS; POPULATION; EMERGENCE; EPIDEMIC AB Viral genome sequencing has become the cornerstone of almost all aspects of virology. In particular, high-throughput, next-generation viral genome sequencing has become an integral part of molecular epidemiological investigations into outbreaks of viral disease, such as the recent outbreaks of Middle Eastern respiratory syndrome, Ebola virus disease and Zika virus infection. Multiple institutes have acquired the expertise and necessary infrastructure to perform such investigations, as evidenced by the accumulation of thousands of novel viral sequences over progressively shorter time periods. The authors recently proposed a nomenclature comprised of five high-throughput sequencing standard categories to describe the quality of determined viral genome sequences. These five categories (standard draft, high quality, coding complete, complete and finished) cover all levels of viral genome finishing and can be applied to sequences determined by any technology platform or assembly technique. C1 [Ladner, J. T.; Palacios, G.] US Army, Med Res Inst Infect Dis, Ctr Genome Sci, Frederick, MD 21702 USA. [Kuhn, J. H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. RP Palacios, G (reprint author), US Army, Med Res Inst Infect Dis, Ctr Genome Sci, Frederick, MD 21702 USA. EM gustavo.f.palacios.ctr@mail.mil RI Palacios, Gustavo/I-7773-2015 OI Palacios, Gustavo/0000-0001-5062-1938 FU Defense Threat Reduction Agency [1881290]; Battelle Memorial Institute's prime contract; US National Institute of Allergy and Infectious Diseases [HHSN272200700016I] FX This work was partly funded by Defense Threat Reduction Agency Project No. 1881290 and by Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases under Contract No. HHSN272200700016I. A subcontractor who performed this work is JHK, an employee of Tunnell Government Services. The authors thank Laura Bollinger for editing this manuscript. NR 42 TC 1 Z9 1 U1 42 U2 46 PU OFFICE INT EPIZOOTIES PI PARIS PA 12 RUE DE PRONY, 75017 PARIS, FRANCE SN 0253-1933 J9 REV SCI TECH OIE JI Rev. Sci. Tech. Off. Int. Epizoot. PD APR PY 2016 VL 35 IS 1 BP 43 EP 52 DI 10.20506/rst.35.1.2416 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA DO8EA UT WOS:000378014200004 PM 27217167 ER PT J AU Hall, MD Woolhouse, MEJ Rambaut, A AF Hall, M. D. Woolhouse, M. E. J. Rambaut, A. TI Using genomics data to reconstruct transmission trees during disease outbreaks SO REVUE SCIENTIFIQUE ET TECHNIQUE-OFFICE INTERNATIONAL DES EPIZOOTIES LA English DT Article DE Molecular epidemiology; Phylodynamics; Phylogenetics; Sequence analysis; Transmission trees ID MITOCHONDRIAL-DNA; VIRUS; DISTANCES AB Genetic sequence data from pathogens present a novel means to investigate the spread of infectious disease between infected hosts or infected premises, complementing traditional contact-tracing approaches, and much recent work has gone into developing methods for this purpose. The objective is to recover the epidemic transmission tree, which identifies who infected whom. This paper reviews the various approaches that have been taken. The first step is to define a measure of difference between sequences, which must be done while taking into account such factors as recombination and convergent evolution. Three broad categories of method exist, of increasing complexity: those that assume no within host genetic diversity or mutation, those that assume no within-host diversity but allow mutation, and those that allow both. Until recently, the assumption was usually made that every host in the epidemic could be identified, but this is now being relaxed, and some methods are intended for sparsely sampled data, concentrating on the identification of pairs of sequences that are likely to be the result of direct transmission rather than inferring the complete transmission tree. Many of the procedures described here are available to researchers as free software. C1 [Hall, M. D.; Woolhouse, M. E. J.; Rambaut, A.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Hall, M. D.; Woolhouse, M. E. J.; Rambaut, A.] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. [Hall, M. D.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London SW7 2AZ, England. [Rambaut, A.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Hall, MD (reprint author), Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland.; Hall, MD (reprint author), Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland.; Hall, MD (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London SW7 2AZ, England. EM matthew.hall@imperial.ac.uk FU Scottish Government; European Research Council (ERC) under the European Community [278433-PREDEMICS]; ERC [260864]; European Union [643476] FX MDH was supported by a PhD studentship from the Scottish Government-funded EPIC program. AR has received funding from the European Research Council (ERC) under the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement No. 278433-PREDEMICS and ERC Grant Agreement No. 260864. MEJW acknowledges support from a European Union Horizon 2020 grant (COMPARE, #643476). NR 28 TC 0 Z9 0 U1 7 U2 7 PU OFFICE INT EPIZOOTIES PI PARIS PA 12 RUE DE PRONY, 75017 PARIS, FRANCE SN 0253-1933 J9 REV SCI TECH OIE JI Rev. Sci. Tech. Off. Int. Epizoot. PD APR PY 2016 VL 35 IS 1 BP 287 EP 296 DI 10.20506/rst.35.1.2433 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA DO8EA UT WOS:000378014200021 PM 27217184 ER PT J AU McClelland, KS Bowles, J AF McClelland, Kathryn S. Bowles, Josephine TI Culturing murine embryonic organs: Pros, cons, tips and tricks SO DIFFERENTIATION LA English DT Article DE Organ culture; Ex vivo; Filter culture; Agar block culture; Hanging drop; Culture conditions ID GERM-CELL FATE; XY GONAD; MOUSE; MICE; PANCREAS; MORPHOGENESIS; MIGRATION; MEIOSIS; SYSTEM; KIDNEY AB There are three established techniques described for ex vivo culture of the early embryonic organs: filter culture, agar block culture and hanging drop culture. Each of these protocols has advantages and disadvantages; here we assess the merits of each approach. Agar block culture has a long history and has been well described. This method results in good embryonic organ morphology. Filter culture has been used to culture a number of different embryonic organs and there are a variety of filter choices available. The key disadvantage of agar-block and filter based culture is that the large amount of media required can make the approach expensive, especially if biologicals such as growth factors are necessary; in addition, using these methods it can be difficult to track particular samples. Hanging drop culture is most commonly used to enable the aggregation of embryonic stem cells into embryoid bodies but it has also been employed for ex vivo organ culture. This method requires only 40 mu L of media per drop and isolates every organ to a trackable unit. We describe each of these methods and the use of different medias and provide the user with a matrix to help determine the optimal culture method for their needs. Glass based culture methods required for live imaging are not discussed here. Crown Copyright (C) 2016 Published by Elsevier B.V. on behalf of International Society of Differentiation All rights reserved. C1 [McClelland, Kathryn S.; Bowles, Josephine] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [McClelland, Kathryn S.] NIEHS, Dev Reprod Biol Grp, Reprod Dev Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RP Bowles, J (reprint author), Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. EM j.bowles@imb.uq.edu.au RI Bowles, Josephine/B-6583-2013; OI Bowles, Josephine/0000-0003-2867-7438; McClelland, Kathryn S/0000-0003-2845-5448 FU Australian Research Council (ARC) [DP140104059]; National Health and Medical Research Council of Australia (NHMRC) [APP1074258] FX We thank Peter Koopman for supervising the work that refined these protocols. We thank Alex Combes, Lee Niswander and Lori Sussel for helpful discussions and sharing personal and lab culture experience. We thank Humphrey Yao for helpful comments on this manuscript and Barbara Nicol for her assistance. This work was supported by research Grants from the Australian Research Council (grant number DP140104059) (ARC) and National Health and Medical Research Council of Australia (grant number APP1074258) (NHMRC). Confocal microscopy was performed at the Australian Cancer Research Foundation Dynamic Imaging Centre for Cancer Biology. NR 30 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 EI 1432-0436 J9 DIFFERENTIATION JI Differentiation PD APR-JUN PY 2016 VL 91 IS 4-5 BP 50 EP 56 DI 10.1016/j.diff.2016.01.008 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DO2OQ UT WOS:000377619800008 PM 26988290 ER PT J AU McClelland, KS Ng, ET Bowles, J AF McClelland, Kathryn S. Ee Ting Ng Bowles, Josephine TI Agarose/gelatin immobilisation of tissues or embryo segments for orientated paraffin embedding and sectioning SO DIFFERENTIATION LA English DT Review DE Embedding; Sectioning; Orientated sample; Agarose; Immobilisation AB The technique described in this protocol allows the user to position small tissues in the optimal orientation for paraffin embedding and sectioning by first immobilising the tissue in an agarose/gelatin cube. This method is an adaptation of methods used for early embryos and can be used for any small tissues or embryo segments. Processing of larger tissue sections using molds to create agarose/gelatin blocks has been described previously; this detailed protocol provides a method for dealing with much smaller tissues or embryos (<= 5 mm). The tissue is briefly fixed then an agarose/gelatin drop is created to surround the tissue. The tissue can be orientated as per the user's preference in the drop before it sets as is carved into a cube with a domed top. The cube is then dehydrated and goes through the embedding and sectioning process. The domed cube is easy to orientate when embedding the tissue in a wax block giving the user assured orientation of the small tissue for sectioning. Additionally, the agarose/gelatin cube is easy to see in the unmolded wax once embedded, making the region of interest easy to identify. Crown Copyright (C) 2016 Published by Elsevier B.V. on behalf of International Society of Differentiation All rights reserved. C1 [McClelland, Kathryn S.; Ee Ting Ng; Bowles, Josephine] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [McClelland, Kathryn S.] Natl Inst Environm Hlth Sci, Reprod Dev Biol Lab, Dev Reprod Biol Grp, Res Triangle Pk, NC USA. RP Bowles, J (reprint author), Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. EM j.bowles@imb.uq.edu.au RI Bowles, Josephine/B-6583-2013; OI Bowles, Josephine/0000-0003-2867-7438; McClelland, Kathryn S/0000-0003-2845-5448 FU Australian Research Council (ARC); National Health and Medical Research Council of Australia (NHMRC) FX We thank Terje Svingen and Peter Koopman for supervising the work that refined this protocol. We thank Ivy Chiang for helpful discussions. This work was supported by research grants from the Australian Research Council (ARC) and the National Health and Medical Research Council of Australia (NHMRC). Confocal microscopy was performed at the Australian Cancer Research Foundation Dynamic Imaging Centre for Cancer Biology. NR 5 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 EI 1432-0436 J9 DIFFERENTIATION JI Differentiation PD APR-JUN PY 2016 VL 91 IS 4-5 BP 68 EP 71 DI 10.1016/j.diff.2015.12.001 PG 4 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DO2OQ UT WOS:000377619800010 PM 26742717 ER PT J AU Tanigawa, S Perantoni, AO AF Tanigawa, Shunsuke Perantoni, Alan O. TI Modeling renal progenitors - defining the niche SO DIFFERENTIATION LA English DT Review ID EMBRYONIC STEM-CELLS; METANEPHRIC MESENCHYME; KIDNEY DEVELOPMENT; SELF-RENEWAL; URETERAL BUD; NEPHRON PROGENITORS; MAMMALIAN KIDNEY; MOUSE KIDNEY; EPITHELIAL TRANSFORMATION; INTERMEDIATE MESODERM AB Significant recent advances in methodologies for the differentiation of pluripotent stem cells to renal progenitors as well as the definition of niche conditions for sustaining those progenitors have dramatically enhanced our understanding of their biology and developmental programing, prerequisites for establishing viable approaches to renal regeneration. In this article, we review the evolution of culture techniques and models for the study of metanephric development, describe the signaling mechanisms likely to be driving progenitor self-renewal, and discuss current efforts to generate de novo functional tissues, providing in depth protocols and niche conditions for the stabilization of the nephronic Six2+ progenitor. Published by Elsevier B.V. on behalf of International Society of Differentiation C1 [Tanigawa, Shunsuke] Kumamoto Univ, Inst Mol Embryol & Genet, Dept Kidney Dev, 2-2-1 Honjo, Kumamoto 8600811, Japan. [Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Perantoni, AO (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM perantoa@mail.nih.gov FU Japanese Society for the Promotion of Science; grant KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [KAKENHI 26860640]; Intramural Research Program of the NIH, NCI, CCR FX This work was supported by a fellowship from the Japanese Society for the Promotion of Science (to S.T.), grant KAKENHI 26860640 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to S.T.), and the Intramural Research Program of the NIH, NCI, CCR. NR 57 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 EI 1432-0436 J9 DIFFERENTIATION JI Differentiation PD APR-JUN PY 2016 VL 91 IS 4-5 BP 152 EP 158 DI 10.1016/j.diff.2016.01.007 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DO2OQ UT WOS:000377619800019 PM 26856661 ER PT J AU Campbell, LA Ritchie, C Heathward, E Harvey, BK AF Campbell, L. A. Ritchie, C. Heathward, E. Harvey, B. K. TI USING CRISPR/CAS9 TO CREATE HIV-NANOLUC CHME-5, A NOVEL MICROGLIA CELL LINE. SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 [Campbell, L. A.; Ritchie, C.; Heathward, E.; Harvey, B. K.] NIDA, Optogenet & Transgen Technol Core, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD APR PY 2016 VL 11 SU 1 BP S8 EP S8 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DO1UY UT WOS:000377566000016 ER PT J AU Harry, GJ AF Harry, G. J. TI NEUROINFLAMMATION: DISSECTING MICROGLIA PHENOTYPES AND CONTRIBUTIONS TO INJURY AND REPAIR SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 [Harry, G. J.] NIEHS, Neurotoxicol Grp, Natl Toxicol Program Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD APR PY 2016 VL 11 SU 1 BP S53 EP S53 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DO1UY UT WOS:000377566000136 ER PT J AU Mocchetti, I Tessarollo, L Bachis, A AF Mocchetti, Italo Tessarollo, L. Bachis, A. TI PROBDNF, P75NTR AND HIV-MEDIATED NEUROTOXICITY SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 [Mocchetti, Italo; Bachis, A.] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. [Tessarollo, L.] NCI, MCGP, Ft Detrick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD APR PY 2016 VL 11 SU 1 BP S54 EP S54 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DO1UY UT WOS:000377566000138 ER PT J AU Rom, S Zuluaga-Ramirez, V Reichenbach, NL Dykstra, H Gajghate, S Pacher, P Persidsky, Y AF Rom, S. Zuluaga-Ramirez, V Reichenbach, N. L. Dykstra, H. Gajghate, S. Pacher, P. Persidsky, Y. TI EFFECTS ON INTEGRINS/CYTOSKELETON BY PARP INHIBITION IN LEUKOCYTES DIMINISH INFLAMMATION AND PROTECTS THE BLOOD BRAIN BARRIER. SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 [Rom, S.; Zuluaga-Ramirez, V; Reichenbach, N. L.; Dykstra, H.; Gajghate, S.; Persidsky, Y.] Temple Univ, Lewis Katz Sch Med, Dept Pathol, Philadelphia, PA 19140 USA. [Pacher, P.] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD APR PY 2016 VL 11 SU 1 BP S42 EP S42 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DO1UY UT WOS:000377566000107 ER PT J AU Goldstein, DS Sims-O'Neil, C AF Goldstein, David S. Sims-O'Neil, Cathy TI Systemic hemodynamics during orthostasis in multiple system atrophy SO PARKINSONISM & RELATED DISORDERS LA English DT Letter DE Multiple system atrophy; Total peripheral resistance; Stroke volume; Orthostatic hypotension; Autonomic failure C1 [Goldstein, David S.; Sims-O'Neil, Cathy] NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, NIH, 9000 Rockville Pike,10-5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov OI Goldstein, David/0000-0002-5709-9940 FU Intramural NIH HHS [ZIA NS003034-10, ZIA NS003033-10, Z01 NS003033-01]; PHS HHS [1ZIANS003034] NR 3 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD APR PY 2016 VL 25 BP 106 EP 107 DI 10.1016/j.parkreldis.2016.02.009 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DK0QD UT WOS:000374616400019 PM 26920338 ER PT J AU Sun, R Urban, JF Notari, L Vanuytsel, T Madden, KB Bohl, JA Ramalingam, TR Wynn, TA Zhao, AP Shea-Donohue, T AF Sun, Rex Urban, Joseph F., Jr. Notari, Luigi Vanuytsel, Tim Madden, Kathleen B. Bohl, Jennifer A. Ramalingam, Thirumalai R. Wynn, Thomas A. Zhao, Aiping Shea-Donohue, Terez TI Interleukin-13 Receptor alpha 1-Dependent Responses in the Intestine Are Critical to Parasite Clearance SO INFECTION AND IMMUNITY LA English DT Article ID ALTERNATIVELY ACTIVATED MACROPHAGES; EPITHELIAL-CELL FUNCTION; NIPPOSTRONGYLUS-BRASILIENSIS INFECTION; HELIGMOSOMOIDES-POLYGYRUS; PROTECTIVE IMMUNITY; NEMATODE INFECTIONS; ENTERIC NEMATODES; TH2 CYTOKINE; MURINE GUT; T-CELLS AB Nematode infection upregulates interleukin-4 (IL-4) and IL-13 and induces STAT6-dependent changes in gut function that promote worm clearance. IL-4 and IL-13 activate the type 2 IL-4 receptor (IL-4R), which contains the IL-13R alpha 1 and IL-4R alpha chains. We used mice deficient in IL-13R alpha 1 (IL-13R alpha 1(-/-)) to examine the contribution of IL-13 acting at the type 2 IL-4R to immune and functional responses to primary (Hb1) and secondary (Hb2) infections with the gastrointestinal nematode parasite Heligmosomoides bakeri. There were differences between strains in the IL-4 and IL-13 expression responses to Hb1 but not Hb2 infection. Following Hb2 infection, deficient mice had impaired worm expulsion and higher worm fecundity despite normal production of Th2-derived cytokines. The upregulation of IL-25 and IL-13R alpha 2 in Hb1- and Hb2-infected wild-type (WT) mice was absent in IL-13R alpha 1(-/-) mice. Goblet cell numbers and resistin-like molecule beta (RELM-beta) expression were attenuated significantly in IL-13R alpha 1(-/-) mice following Hb2 infections. IL-13R alpha 1 contributes to the development of alternatively activated macrophages, but the type 1 IL-4R is also important. Hb1 infection had no effects on smooth muscle function or epithelial permeability in either strain, while the enhanced mucosal permeability and changes in smooth muscle function and morphology observed in response to Hb2 infection in WT mice were absent in IL-13R alpha 1(-/-) mice. Notably, the contribution of claudin-2, which has been linked to IL-13, does not mediate the increased mucosal permeability following Hb2 infection. These results show that activation of IL-13R alpha 1 is critical for key aspects of the immune and functional responses to Hb2 infection that facilitate expulsion. C1 [Sun, Rex; Notari, Luigi; Bohl, Jennifer A.; Zhao, Aiping; Shea-Donohue, Terez] Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Sun, Rex; Notari, Luigi; Bohl, Jennifer A.; Zhao, Aiping; Shea-Donohue, Terez] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Vanuytsel, Tim] Univ Leuven, Translat Res Ctr Gastrointestinal Disorders TARGI, Leuven, Belgium. [Madden, Kathleen B.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. [Ramalingam, Thirumalai R.; Wynn, Thomas A.] NIAID, Div Parasitol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Urban, Joseph F., Jr.] ARS, USDA, Beltsville Human Nutr Res Ctr, Diet Genom & Immunol Lab, Beltsville, MD USA. RP Shea-Donohue, T (reprint author), Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA.; Shea-Donohue, T (reprint author), Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. EM tdonohue@mbrc.umaryland.edu FU NIH [R01-AI/DK49316, R01-DK083418]; USDA [1235-51000-055] FX NIH provided funding to Terez Shea-Donohue under grant number R01-AI/DK49316. NIH provided funding to Aiping Zhao under grant number R01-DK083418. USDA provided funding to Joseph F. Urban under grant number CRIS project #1235-51000-055. NR 41 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2016 VL 84 IS 4 BP 1032 EP 1044 DI 10.1128/IAI.00990-15 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JV UT WOS:000377103600015 PM 26810038 ER PT J AU De Pascalis, R Mittereder, L Kennett, NJ Elkins, KL AF De Pascalis, Roberto Mittereder, Lara Kennett, Nikki J. Elkins, Karen L. TI Activities of Murine Peripheral Blood Lymphocytes Provide Immune Correlates That Predict Francisella tularensis Vaccine Efficacy SO INFECTION AND IMMUNITY LA English DT Article ID T-CELL RESPONSES; MYCOBACTERIAL GROWTH; PROTECTIVE IMMUNITY; LVS INFECTION; B-CELLS; STRAIN; TULAREMIA; TUBERCULOSIS; ANTIBODIES; SUBPOPULATIONS AB We previously identified potential correlates of vaccine-induced protection against Francisella tularensis using murine splenocytes and further demonstrated that the relative levels of gene expression varied significantly between tissues. In contrast to splenocytes, peripheral blood leukocytes (PBLs) represent a means to bridge vaccine efficacy in animal models to that in humans. Here we take advantage of this easily accessible source of immune cells to investigate cell-mediated immune responses against tularemia, whose sporadic incidence makes clinical trials of vaccines difficult. Using PBLs from mice vaccinated with F. tularensis Live Vaccine Strain (LVS) and related attenuated strains, we combined the control of in vitro Francisella replication within macrophages with gene expression analyses. The in vitro functions of PBLs, particularly the control of intramacrophage LVS replication, reflected the hierarchy of in vivo protection conferred by LVS-derived vaccines. Moreover, several genes previously identified by the evaluation of splenocytes were also found to be differentially expressed in immune PBLs. In addition, more extensive screening identified additional potential correlates of protection. Finally, expression of selected genes in mouse PBLs obtained shortly after vaccination, without ex vivo restimulation, was different among vaccine groups, suggesting a potential tool to monitor efficacious vaccine-induced immune responses against F. tularensis. Our studies demonstrate that murine PBLs can be used productively to identify potential correlates of protection against F. tularensis and to expand and refine a comprehensive set of protective correlates. C1 [De Pascalis, Roberto; Mittereder, Lara; Kennett, Nikki J.; Elkins, Karen L.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Mittereder, Lara] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP De Pascalis, R (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM roberto.depascalis@fda.hhs.gov NR 38 TC 2 Z9 2 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2016 VL 84 IS 4 BP 1054 EP 1061 DI 10.1128/IAI.01348-15 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JV UT WOS:000377103600017 PM 26810039 ER PT J AU Roffe, E Marino, APMP Weaver, J Wan, WZ de Araujo, FF Hoffman, V Santiago, HC Murphy, PM AF Roffe, Ester Marino, Ana Paula M. P. Weaver, Joseph Wan, Wuzhou de Araujo, Fernanda F. Hoffman, Victoria Santiago, Helton C. Murphy, Philip M. TI Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice SO INFECTION AND IMMUNITY LA English DT Article ID CHRONIC CHAGAS-DISEASE; CD8(+) T-CELLS; POLYARTERITIS-NODOSA; AMERICAN TRYPANOSOMIASIS; PARASITE PERSISTENCE; SKELETAL-MUSCLE; MYOCARDITIS; INFECTION; INVOLVEMENT; NOMENCLATURE AB Infectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80(+) macrophages, and T. cruzi tetramer-specific CD8(+) T lymphocytes capable of producing gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus, T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses. C1 [Roffe, Ester; Marino, Ana Paula M. P.; Weaver, Joseph; Wan, Wuzhou; Murphy, Philip M.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [de Araujo, Fernanda F.] US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Lab Emerging Pathogens, Silver Spring, MD USA. [Hoffman, Victoria] NIH, Div Vet Resources, Off Res Serv, Off Director, Bethesda, MD USA. [Santiago, Helton C.] NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Roffe, Ester] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, Lab Imunol Celular & Mol, Belo Horizonte, MG, Brazil. [Marino, Ana Paula M. P.] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, Lab Imunopatol, Belo Horizonte, MG, Brazil. [de Araujo, Fernanda F.] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, Lab Biomarcadores Diagnost & Monitoracao, Belo Horizonte, MG, Brazil. [Santiago, Helton C.] Univ Fed Minas Gerais, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil. RP Murphy, PM (reprint author), NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmm@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 40 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2016 VL 84 IS 4 BP 1123 EP 1136 DI 10.1128/IAI.01497-15 PG 14 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JV UT WOS:000377103600024 PM 26857570 ER PT J AU Binkley, N Dawson-Hughes, B Durazo-Arvizu, R Thamm, M Merkel, J Sempos, C AF Binkley, N. Dawson-Hughes, B. Durazo-Arvizu, R. Thamm, M. Merkel, J. Sempos, C. TI VITAMIN D MEASUREMENT STANDARDIZATION: THE WAY OUT OF THE CHAOS SO OSTEOPOROSIS INTERNATIONAL LA English DT Meeting Abstract CT WCO-IOF-ESCEO World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases CY APR 14-17, 2016 CL Malaga, SPAIN SP WCO, IOF, ESCEO C1 [Binkley, N.] Univ Wisconsin, Osteoporosis Clin Res Program, Madison, WI 53706 USA. [Binkley, N.] Univ Wisconsin, Inst Aging, Madison, WI 53706 USA. [Dawson-Hughes, B.] Tufts Univ, USDA Nutr Res Ctr, Boston, MA 02111 USA. [Durazo-Arvizu, R.] Loyola Univ Chicago, Stritch Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL USA. [Thamm, M.] Robert Koch Inst, Berlin, Germany. [Merkel, J.; Sempos, C.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD APR PY 2016 VL 27 SU 1 MA OC18 BP S49 EP S49 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM6NH UT WOS:000376469100029 ER PT J AU Schaap, LA Simonsick, EM Newman, AB Schwartz, AV Caserotti, P Kritchevsky, SB Goodpaster, BH Harris, TB Visser, M AF Schaap, L. A. Simonsick, E. M. Newman, A. B. Schwartz, A. V. Caserotti, P. Kritchevsky, S. B. Goodpaster, B. H. Harris, T. B. Visser, M. TI SARCOPENIA DEFINITION PARAMETERS AND INCIDENT DISABILITY SO OSTEOPOROSIS INTERNATIONAL LA English DT Meeting Abstract CT WCO-IOF-ESCEO World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases CY APR 14-17, 2016 CL Malaga, SPAIN SP WCO, IOF, ESCEO C1 [Schaap, L. A.; Visser, M.] Vrije Univ Amsterdam, Fac Earth & Life Sci, Dept Hlth Sci, Amsterdam, Netherlands. [Simonsick, E. M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Newman, A. B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Schwartz, A. V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Caserotti, P.] Univ Southern Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Kritchevsky, S. B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Goodpaster, B. H.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD APR PY 2016 VL 27 SU 1 MA OC25 BP S53 EP S53 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM6NH UT WOS:000376469100036 ER PT J AU Scott, JR Courter, JD Saldana, SN Widemann, BC Fisher, M Weiss, B Perentesis, J Vinks, AA AF Scott, Jeffrey R. Courter, Joshua D. Saldana, Shannon N. Widemann, Brigitte C. Fisher, Michael Weiss, Brian Perentesis, John Vinks, Alexander A. CA Neurofibromatosis Clinical Trials TI Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1 (vol 35, pg 332, 2013) SO THERAPEUTIC DRUG MONITORING LA English DT Correction C1 [Scott, Jeffrey R.; Courter, Joshua D.; Saldana, Shannon N.] Cincinnati Childrens Hosp Med Ctr, Div Pharma, Cincinnati, OH 45229 USA. [Saldana, Shannon N.; Vinks, Alexander A.] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, 3333 Burnet Ave,MLC 6018, Cincinnati, OH 45229 USA. [Saldana, Shannon N.; Weiss, Brian; Perentesis, John; Vinks, Alexander A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45221 USA. [Weiss, Brian; Perentesis, John] Cincinnati Childrens Hosp Med Ctr, Div Oncol, Canc & Blood Dis Inst, Cincinnati, OH 45229 USA. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Fisher, Michael] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Scott, Jeffrey R.] St Jude Childrens Res Hosp, Dept Pharm, Memphis, TN 38105 USA. RP Vinks, AA (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, 3333 Burnet Ave,MLC 6018, Cincinnati, OH 45229 USA. EM Sander.vinks@cchmc.org NR 1 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0163-4356 EI 1536-3694 J9 THER DRUG MONIT JI Ther. Drug Monit. PD APR PY 2016 VL 38 IS 2 BP 284 EP 284 PG 1 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA DN3BT UT WOS:000376938000014 ER PT J AU Lockhart, SR Fothergill, AW Iqbal, N Bolden, CB Grossman, NT Garvey, EP Brand, SR Hoekstra, WJ Schotzinger, RJ Ottinger, E Patterson, TF Wiederhold, NP AF Lockhart, Shawn R. Fothergill, Annette W. Iqbal, Naureen Bolden, Carol B. Grossman, Nina T. Garvey, Edward P. Brand, Stephen R. Hoekstra, William J. Schotzinger, Robert J. Ottinger, Elizabeth Patterson, Thomas F. Wiederhold, Nathan P. TI The Investigational Fungal Cyp51 Inhibitor VT-1129 Demonstrates Potent In Vitro Activity against Cryptococcus neoformans and Cryptococcus gattii SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ANTIFUNGAL SUSCEPTIBILITIES AB The in vitro activities of the novel fungal Cyp51 inhibitor VT-1129 were evaluated against a large panel of Cryptococcus neoformans and Cryptococcus gattii isolates. VT-1129 demonstrated potent activities against both Cryptococcus species as demonstrated by low MIC50 and MIC90 values. For C. gattii, the in vitro potency was maintained against all genotypes. In addition, significantly lower geometric mean MICs were observed for VT-1129 than for fluconazole against C. neoformans, including isolates with reduced fluconazole susceptibility. C1 [Lockhart, Shawn R.; Iqbal, Naureen; Bolden, Carol B.; Grossman, Nina T.] Ctr Dis Control & Prevent, Mycot Dis Branch, Atlanta, GA USA. [Fothergill, Annette W.; Patterson, Thomas F.; Wiederhold, Nathan P.] Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX USA. [Garvey, Edward P.; Brand, Stephen R.; Hoekstra, William J.; Schotzinger, Robert J.] Viamet Pharmaceut Inc, Durham, NC USA. [Ottinger, Elizabeth] NIH, Therapeut Rare & Neglected Dis Bethesda, Bldg 10, Bethesda, MD 20892 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Wiederhold, NP (reprint author), Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX USA. EM wiederholdn@uthscsa.edu FU National Institutes of Health National Institute of Allergy and Infectious Diseases [N01-AI-25475]; National Institutes of Health, National Center for Advancing Translational Sciences, Therapeutics for Rare and Neglected Diseases (TRND) Program; Viamet Pharmaceuticals, Inc. FX This project was funded by the National Institutes of Health National Institute of Allergy and Infectious Diseases under contract no. N01-AI-25475 (Thomas F. Patterson), the National Institutes of Health, National Center for Advancing Translational Sciences, Therapeutics for Rare and Neglected Diseases (TRND) Program (Shawn R. Lockhart), and Viamet Pharmaceuticals, Inc. (Nathan P. Wiederhold). VT-1129 powder was provided by Viamet Pharmaceuticals, Inc. NR 18 TC 2 Z9 2 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD APR PY 2016 VL 60 IS 4 BP 2528 EP 2531 DI 10.1128/AAC.02770-15 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6XL UT WOS:000376496100072 PM 26787697 ER PT J AU Tadesse, DA Singh, A Zhao, SH Bartholomew, M Womack, N Ayers, S Fields, PI McDermott, PF AF Tadesse, Daniel A. Singh, Aparna Zhao, Shaohua Bartholomew, Mary Womack, Niketta Ayers, Sherry Fields, Patricia I. McDermott, Patrick F. TI Antimicrobial Resistance in Salmonella in the United States from 1948 to 1995 SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ESCHERICHIA-COLI; DRUG-RESISTANCE; FOOD ANIMALS; INFECTIONS; TYPHIMURIUM; STRAINS; HUMANS; EMERGENCE; INCREASE AB We conducted a retrospective study of 2,149 clinical Salmonella strains to help document the historical emergence of antimicrobial resistance. There were significant increases in resistance to older drugs, including ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline, which were most common in Salmonella enterica serotype Typhimurium. An increase in multidrug resistance was observed for each decade since the 1950s. These data help show how Salmonella evolved over the past 6 decades, after the introduction of new antimicrobial agents. C1 [Tadesse, Daniel A.; Zhao, Shaohua; Womack, Niketta; Ayers, Sherry; McDermott, Patrick F.] US FDA, Ctr Vet Med, US Dept Hlth & Human Serv, Laurel, MD USA. [Singh, Aparna] NIH, US Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. [Bartholomew, Mary] US FDA, Ctr Vet Med, US Dept Hlth & Human Serv, Rockville, MD 20857 USA. [Fields, Patricia I.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, US Dept Hlth & Human Serv, Atlanta, GA USA. RP McDermott, PF (reprint author), Ctr Dis Control & Prevent, Ctr Surveillance Epidemiol & Lab Serv, US Dept Hlth & Human Serv, Atlanta, GA USA. EM patrick.mcdermott@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research [223-02-7010] FX The study isolates were collected by American Type Culture Collection (ATCC) through a contract agreement with the U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research (contract 223-02-7010). NR 28 TC 1 Z9 1 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD APR PY 2016 VL 60 IS 4 BP 2567 EP 2571 DI 10.1128/AAC.02536-15 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6XL UT WOS:000376496100082 PM 26856840 ER PT J AU Espinoza, JA Bizama, C Garcia, P Ferreccio, C Javle, M Miguel, JF Koshiol, J Roa, JC AF Espinoza, Jaime A. Bizama, Carolina Garcia, Patricia Ferreccio, Catterina Javle, Milind Miguel, Juan F. Koshiol, Jill Roa, Juan C. TI The inflammatory inception of gallbladder cancer SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Gallbladder cancer; Gallstones; Chronic inflammation; Metaplasia; Salmonella Typhi; TP53 ID PRIMARY SCLEROSING CHOLANGITIS; BILIARY-TRACT CANCERS; CHOLESTEROL GALLSTONE FORMATION; LIVER X RECEPTORS; PANCREATICOBILIARY MALJUNCTION; INTESTINAL METAPLASIA; PRENEOPLASTIC LESIONS; GENE POLYMORPHISMS; SALMONELLA-TYPHI; BILE-DUCT AB Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasiadysplasia-carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti-inflammatory drugs in high-risk populations may be warranted. (C) 2016 Published by Elsevier B.V. C1 [Espinoza, Jaime A.] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, SciLifeLab, SE-17176 Stockholm, Sweden. [Bizama, Carolina; Garcia, Patricia; Roa, Juan C.] Pontificia Univ Catolica Chile, Sch Med, UC Ctr Invest Oncol CITO, Dept Pathol,Adv Ctr Chron Dis ACCDiS, Santiago 8330024, Chile. [Ferreccio, Catterina] Pontificia Univ Catolica Chile, Sch Med, Adv Ctr Chron Dis ACCDiS, Dept Publ Hlth, Santiago 8330024, Chile. [Javle, Milind] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Miguel, Juan F.] Pontificia Univ Catolica Chile, Sch Med, Dept Gastroenterol, Santiago 8330024, Chile. [Koshiol, Jill] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20850 USA. RP Roa, JC (reprint author), Pontificia Univ Catolica Chile, Marcoleta 377,7th Floor, Santiago, Chile. EM jcroa@med.puc.cl OI Espinoza, Jaime/0000-0002-0731-2715 FU FONDECYT Fondo Nacional de Investigation y Tecnologia [JAE-3140308, CA-3140426, PG-11130515, JFM-1130303, JCR-1130204]; FONDAP Fondo de Financiamiento de Centros de Investigation en Areas Prioritarias ACCDiS [JCR-15130011]; Intramural Research Program of the National Institutes of Health and National Cancer Institute, Division of Cancer Epidemiology and Genetics (DCEG) FX This review was supported by FONDECYT Fondo Nacional de Investigation y Tecnologia (JAE-3140308, CA-3140426, PG-11130515, JFM-1130303, and JCR-1130204), FONDAP Fondo de Financiamiento de Centros de Investigation en Areas Prioritarias ACCDiS (JCR-15130011), and general funds from the Intramural Research Program of the National Institutes of Health and National Cancer Institute, Division of Cancer Epidemiology and Genetics (DCEG). We thank Maria Jose Apud for her expert work in figure design. NR 152 TC 2 Z9 2 U1 5 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X EI 0006-3002 J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD APR PY 2016 VL 1865 IS 2 BP 245 EP 254 DI 10.1016/j.bbcan.2016.03.004 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA DM7NB UT WOS:000376546200016 PM 26980625 ER PT J AU Cumming, BG Nienborg, H AF Cumming, Bruce G. Nienborg, Hendrikje TI Feedforward and feedback sources of choice probability in neural population responses SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID DECISION-RELATED ACTIVITY; PRIMARY VISUAL-CORTEX; SENSORY NEURONS; AREA MT; CORTICAL AREA; INTERNEURONAL CORRELATIONS; DISPARITY DISCRIMINATION; CORRELATED VARIABILITY; BEHAVIORAL PERFORMANCE; BAYESIAN-INFERENCE AB How the processing of signals carried by sensory neurons supports perceptual decisions is a long-standing question in neuroscience. The ability to record neuronal activity in awake animals while they perform psychophysical tasks near threshold has been a key advance in studying these questions. Trial-to-trial correlations between the activity of sensory neurons and the decisions reported by animals ('hoice probabilities'), even when measured across repeated presentations of an identical stimulus provide insights into this problem. But understanding the sources of such co-variability between sensory neurons and behavior has proven more difficult than it initially appeared. Below, we discuss our current understanding of what gives rise to these correlations. C1 [Cumming, Bruce G.] NEI, NIH, Bethesda, MD 20892 USA. [Nienborg, Hendrikje] Univ Tubingen, Werner Reichardt Ctr Integrat Neurosci, D-72076 Tubingen, Germany. RP Cumming, BG (reprint author), NEI, NIH, Bethesda, MD 20892 USA.; Nienborg, H (reprint author), Univ Tubingen, Werner Reichardt Ctr Integrat Neurosci, D-72076 Tubingen, Germany. EM bgc@lsr.nei.nih.gov; hendrikje.nienborg@cin.uni-tuebingen.de FU National Institutes of Health-National Eye Institute; European Research Council (NEUROOPTOGEN) FX This work was supported by the Intramural Research Program of the National Institutes of Health-National Eye Institute and a Starting Independent Researcher grant to H.N. from the European Research Council (project acronym: NEUROOPTOGEN). NR 70 TC 3 Z9 3 U1 2 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 EI 1873-6882 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD APR PY 2016 VL 37 BP 126 EP 132 DI 10.1016/j.conb.2016.01.009 PG 7 WC Neurosciences SC Neurosciences & Neurology GA DM7NC UT WOS:000376546300019 PM 26922005 ER PT J AU Leoncini, E Edefonti, V Hashibe, M Parpinel, M Cadoni, G Ferraroni, M Serraino, D Matsuo, K Olshan, AF Zevallos, JP Winn, DM Moysich, K Zhang, ZF Morgenstern, H Levi, F Kelsey, K McClean, M Bosetti, C Schantz, S Yu, GP Boffetta, P Lee, YCA Chuang, SC Decarli, A La Vecchia, C Boccia, S AF Leoncini, Emanuele Edefonti, Valeria Hashibe, Mia Parpinel, Maria Cadoni, Gabriella Ferraroni, Monica Serraino, Diego Matsuo, Keitaro Olshan, Andrew F. Zevallos, Jose P. Winn, Deborah M. Moysich, Kirsten Zhang, Zuo-Feng Morgenstern, Hal Levi, Fabio Kelsey, Karl McClean, Michael Bosetti, Cristina Schantz, Stimson Yu, Guo-Pei Boffetta, Paolo Lee, Yuan-Chin Amy Chuang, Shu-Chun Decarli, Adriano La Vecchia, Carlo Boccia, Stefania TI Carotenoid intake and head and neck cancer: a pooled analysis in the International Head and Neck Cancer Epidemiology Consortium SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Carotenoids; Head and neck cancer; Nutrients; Diet ID UPPER AERODIGESTIVE TRACT; PHARYNGEAL CANCER; BETA-CAROTENE; LARYNGEAL-CANCER; PROSPECTIVE COHORT; LUNG-CANCER; ORAL-CANCER; VITAMIN-A; RISK; DIET AB Food and nutrition play an important role in head and neck cancer (HNC) etiology; however, the role of carotenoids remains largely undefined. We explored the relation of HNC risk with the intake of carotenoids within the International Head and Neck Cancer Epidemiology Consortium. We pooled individual-level data from 10 case-control studies conducted in Europe, North America, and Japan. The analysis included 18,207 subjects (4414 with oral and pharyngeal cancer, 1545 with laryngeal cancer, and 12,248 controls), categorized by quintiles of carotenoid intake from natural sources. Comparing the highest with the lowest quintile, the risk reduction associated with total carotenoid intake was 39 % (95 % CI 29-47 %) for oral/pharyngeal cancer and 39 % (95 % CI 24-50 %) for laryngeal cancer. Intakes of beta-carotene equivalents, beta-cryptoxanthin, lycopene, and lutein plus zeaxanthin were associated with at least 18 % reduction in the rate of oral and pharyngeal cancer (95 % CI 6-29 %) and 17 % reduction in the rate of laryngeal cancer (95 % CI 0-32 %). The overall protective effect of carotenoids on HNC was stronger for subjects reporting greater alcohol consumption (p < 0.05). The odds ratio for the combined effect of low carotenoid intake and high alcohol or tobacco consumption versus high carotenoid intake and low alcohol or tobacco consumption ranged from 7 (95 % CI 5-9) to 33 (95 % CI 23-49). A diet rich in carotenoids may protect against HNC. Persons with both low carotenoid intake and high tobacco or alcohol are at substantially higher risk of HNC. C1 [Leoncini, Emanuele; Boccia, Stefania] Univ Cattolica Sacro Cuore, Inst Publ Hlth, Sect Hyg, Largo F Vito 1, I-00168 Rome, Italy. [Edefonti, Valeria; Ferraroni, Monica; Decarli, Adriano; La Vecchia, Carlo] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Hashibe, Mia; Lee, Yuan-Chin Amy] Univ Utah, Sch Med, Dept Family & Prevent Med, Huntsman Canc Inst,Div Publ Hlth, Salt Lake City, UT 84112 USA. [Parpinel, Maria] Univ Udine, Inst Hyg & Epidemiol, Dept Med & Biol Sci, I-33100 Udine, Italy. [Cadoni, Gabriella] Univ Cattolica Sacro Cuore, Inst Otorhinolaryngol, Rome, Italy. [Serraino, Diego] Aviano Canc Ctr, I-33081 Aviano, Italy. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Kyushu, Japan. [Olshan, Andrew F.; Zevallos, Jose P.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Winn, Deborah M.] NCI, Bethesda, MD 20892 USA. [Moysich, Kirsten] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Levi, Fabio] Univ Lausanne, CHU Vaudois, IUMSP, Lausanne, Switzerland. [Kelsey, Karl] Brown Univ, Providence, RI 02912 USA. [McClean, Michael] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Bosetti, Cristina] IRCCS Ist Ric Farmacol Mario Negri, Dept Epidemiol, Milan, Italy. [Schantz, Stimson] New York Eye & Ear Infirm, New York, NY 10003 USA. [Yu, Guo-Pei] Peking Univ, Med Informat Ctr, Beijing 100871, Peoples R China. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Chuang, Shu-Chun] Natl Hlth Res Inst, Inst Populat Hlth Sci, Zhunan, Taiwan. RP Boccia, S (reprint author), Univ Cattolica Sacro Cuore, Inst Publ Hlth, Sect Hyg, Largo F Vito 1, I-00168 Rome, Italy. EM sboccia@rm.unicatt.it RI Parpinel, Maria/B-1605-2012; Decarli, Adriano/C-3129-2017; Ferraroni, Monica/D-6548-2017; , emanuele/A-5466-2010 OI Matsuo, Keitaro/0000-0003-1761-6314; Serraino, Diego/0000-0003-0565-8920; Parpinel, Maria/0000-0003-1309-4467; Decarli, Adriano/0000-0003-1451-8292; Ferraroni, Monica/0000-0002-4542-4996; La Vecchia, Carlo/0000-0003-1441-897X; EDEFONTI, VALERIA CARLA/0000-0002-1995-1477; , emanuele/0000-0002-7669-8535 FU NIH (NCI) [R03CA113157]; NIH (NIDCR) [R03DE016611]; Italian Foundation for Research on Cancer (Italian Ministry of Health, General Directorate of European and International Relations); Italian Ministry of Education [PRIN 2009 X8YCBN]; Italian Association for Research on Cancer (AIRC); Italian League Against Cancer; Italian Ministry of Research; Swiss League against Cancer; Swiss Research against Cancer/Oncosuisse [KFS-700, OCS-1633]; National Institutes of Health (NIH) US [R01CA078609, R01CA100679, R01CA061188]; National Institute of Health (NIH) US [P50CA090388, R01DA011386, R03CA077954, T32CA009142, U01CA096134, R21ES011667]; Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; National Institute of Environmental Health Sciences [P30ES010126]; NCI, NIH, United States; Ministry of Education, Science, Sports, Culture and Technology of Japan [17015052]; Ministry of Health, Labor and Welfare of Japan [H20-002]; Fondazione Veronesi; Italian Association for Research on Cancer (AIRC) [10491 - 2010/2013]; NIH [R01CA051845] FX The authors would like to thank all of the participants who took part in this research for providing us very insightful and constructive comments, which helped improve this manuscript. The INHANCE core data pooling was supported by NIH Grants (NCI R03CA113157 and NIDCR R03DE016611). The individual studies were supported by the following grants: Milan study (2006-2009): Italian Foundation for Research on Cancer (Italian Ministry of Health, General Directorate of European and International Relations) and Italian Ministry of Education (PRIN 2009 X8YCBN). Italy Multicenter study: Italian Association for Research on Cancer (AIRC), Italian League Against Cancer and Italian Ministry of Research. Swiss study: Swiss League against Cancer and the Swiss Research against Cancer/Oncosuisse (KFS-700, OCS-1633). Boston study: National Institutes of Health (NIH) US (R01CA078609, R01CA100679). Los Angeles study: National Institute of Health (NIH) US (P50CA090388, R01DA011386, R03CA077954, T32CA009142, U01CA096134, R21ES011667) and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center. MSKCC study: NIH (R01CA051845). North Carolina (1994-1997): National Institutes of Health (NIH) US (R01CA061188), and in part by a Grant from the National Institute of Environmental Health Sciences (P30ES010126). US Multicenter study: The Intramural Program of the NCI, NIH, United States. Japan (2001-2005): Scientific Research Grant from the Ministry of Education, Science, Sports, Culture and Technology of Japan (17015052) and Grant for the Third-Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan (H20-002). The work of EL was supported by Fondazione Veronesi and Italian Association for Research on Cancer (AIRC, Grant No. 10491 - 2010/2013). NR 61 TC 0 Z9 0 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 EI 1573-7284 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD APR PY 2016 VL 31 IS 4 BP 369 EP 383 DI 10.1007/s10654-015-0036-3 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DM9HC UT WOS:000376675000004 PM 25930054 ER PT J AU Striegel, DA Wojtowicz, D Przytycka, TM Periwal, V AF Striegel, D. A. Wojtowicz, D. Przytycka, T. M. Periwal, V. TI Correlated rigid modes in protein families SO PHYSICAL BIOLOGY LA English DT Article DE protein families; normal modes; pattern recognition ID ALLOSTERIC TRANSITIONS; BIOLOGICAL NANOMACHINES; SEQUENCE VARIATIONS; EMPIRICAL BAYES; DYNAMICS; PATHWAYS; RESIDUES; ROBUST; CONFORMATIONS; COMMUNICATION AB A great deal of evolutionarily conserved information is contained in genomes and proteins. Enormous effort has been put into understanding protein structure and developing computational tools for protein folding, and many sophisticated approaches take structure and sequence homology into account. Several groups have applied statistical physics approaches to extracting information about proteins from sequences alone. Here, we develop a new method for sequence analysis based on first principles, in information theory, in statistical physics and in Bayesian analysis. We provide a complete derivation of our approach and we apply it to a variety of systems, to demonstrate its utility and its limitations. We show in some examples that phylogenetic alignments of amino-acid sequences of families of proteins imply the existence of a small number of modes that appear to be associated with correlated global variation. These modes are uncovered efficiently in our approach by computing a non-perturbative effective potential directly from the alignment. We show that this effective potential approaches a limiting form inversely with the logarithm of the number of sequences. Mapping symbol entropy flows along modes to underlying physical structures shows that these modes arise due to correlated compensatory adjustments. In the protein examples, these occur around functional binding pockets. C1 [Striegel, D. A.; Periwal, V.] NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. [Wojtowicz, D.; Przytycka, T. M.] NCBI, Computat Biol Branch, NLM, NIH, Bethesda, MD 20892 USA. RP Periwal, V (reprint author), NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov FU National Institutes of Health, NCBI; National Institutes of Health, NIDDK FX This work was supported by the Intramural Research Program of the National Institutes of Health, NIDDK and NCBI. We are grateful to C Chow and A Sherman for helpful discussions. NR 48 TC 0 Z9 0 U1 3 U2 7 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 EI 1478-3975 J9 PHYS BIOL JI Phys. Biol. PD APR PY 2016 VL 13 IS 2 AR 025003 DI 10.1088/1478-3975/13/2/025003 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DM5UJ UT WOS:000376415400003 PM 27063781 ER PT J AU Striegel, DA Hara, M Periwal, V AF Striegel, Deborah A. Hara, Manami Periwal, Vipul TI Adaptation of pancreatic islet cyto-architecture during development SO PHYSICAL BIOLOGY LA English DT Article DE pancreatic islets; beta cells; cyto-architecture ID INSULIN-SECRETION; BETA-CELLS; LANGERHANS; CONTACT; MICROANATOMY; MODULATION; APOPTOSIS; RELEASE; ALPHA AB Plasma glucose in mammals is regulated by hormones secreted by the islets of Langerhans embedded in the exocrine pancreas. Islets consist of endocrine cells, primarily alpha, beta, and delta cells, which secrete glucagon, insulin, and somatostatin, respectively. beta cells form irregular locally connected clusters within islets that act in concert to secrete insulin upon glucose stimulation. Varying demands and available nutrients during development produce changes in the local connectivity of beta cells in an islet. We showed in earlier work that graph theory provides a framework for the quantification of the seemingly stochastic cyto-architecture of beta cells in an islet. To quantify the dynamics of endocrine connectivity during development requires a framework for characterizing changes in the probability distribution on the space of possible graphs, essentially a Fokker-Planck formalism on graphs. With large-scale imaging data for hundreds of thousands of islets containing millions of cells from human specimens, we show that this dynamics can be determined quantitatively. Requiring that rearrangement and cell addition processes match the observed dynamic developmental changes in quantitative topological graph characteristics strongly constrained possible processes. Our results suggest that there is a transient shift in preferred connectivity for beta cells between 1-35 weeks and 12-24 months. C1 [Striegel, Deborah A.; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Hara, Manami] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. RP Periwal, V (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NIDDK FX This research was supported by the Intramural Research Program of the National Institutes of Health, NIDDK. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://hpc.nih.gov). NR 36 TC 0 Z9 0 U1 4 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 EI 1478-3975 J9 PHYS BIOL JI Phys. Biol. PD APR PY 2016 VL 13 IS 2 AR 025004 DI 10.1088/1478-3975/13/2/025004 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DM5UJ UT WOS:000376415400004 PM 27063927 ER PT J AU Dao, P Wojtowicz, D Nelson, S Levens, D Przytycka, TM AF Dao, Phuong Wojtowicz, Damian Nelson, Steevenson Levens, David Przytycka, Teresa M. TI Ups and Downs of Poised RNA Polymerase II in B-Cells SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID EMBRYONIC STEM-CELLS; HYBRID G-QUADRUPLEX; C-MYC; POL-II; DROSOPHILA-MELANOGASTER; TRANSCRIPTION INITIATION; GENE-TRANSCRIPTION; PREPARES GENES; HUMAN GENOME; PROMOTERS AB Recent genome-wide analyses have uncovered a high accumulation of RNA polymerase II (Pol II) at the 50 end of genes. This elevated Pol II presence at promoters, referred to here as Poll II poising, is mainly (but not exclusively) attributed to temporal pausing of transcription during early elongation which, in turn, has been proposed to be a regulatory step for processes that need to be activated "on demand". Yet, the full genome-wide regulatory role of Pol II poising is yet to be delineated. To elucidate the role of Pol II poising in B cell activation, we compared Pol II profiles in resting and activated B cells. We found that while Pol II poised genes generally overlap functionally among different B cell states and correspond to the functional groups previously identified for other cell types, non-poised genes are B cell state specific. Focusing on the changes in transcription activity upon B cell activation, we found that the majority of such changes were from poised to non-poised state. The genes showing this type of transition were functionally enriched in translation, RNA processing and mRNA metabolic process. Interestingly, we also observed a transition from non-poised to poised state. Within this set of genes we identified several Immediate Early Genes (IEG), which were highly expressed in resting B cell and shifted from non-poised to poised state after B cell activation. Thus Pol II poising does not only mark genes for rapid expression in the future, but it is also associated with genes that are silenced after a burst of their expression. Finally, we performed comparative analysis of the presence of G4 motifs in the context of poised versus non-poised but active genes. Interestingly we observed a differential enrichment of these motifs upstream versus downstream of TSS depending on poising status. The enrichment of G4 sequence motifs upstream of TSS of non-poised active genes suggests a potential role of quadruplexes in expression regulation. C1 [Dao, Phuong; Wojtowicz, Damian; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Nelson, Steevenson] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Levens, David] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Przytycka, TM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM przytyck@ncbi.nlm.nih.gov FU National Library of Medicine, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NAIMS); National Cancer Institute (Center for Cancer Research) of the National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Library of Medicine, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NAIMS), and the National Cancer Institute (Center for Cancer Research) of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2016 VL 12 IS 4 AR e1004821 DI 10.1371/journal.pcbi.1004821 PG 19 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DM8BA UT WOS:000376584400057 PM 27078128 ER PT J AU Maximova, T Moffatt, R Ma, BY Nussinov, R Shehu, A AF Maximova, Tatiana Moffatt, Ryan Ma, Buyong Nussinov, Ruth Shehu, Amarda TI Principles and Overview of Sampling Methods for Modeling Macromolecular Structure and Dynamics SO PLOS COMPUTATIONAL BIOLOGY LA English DT Review ID PROTEIN-STRUCTURE PREDICTION; INTRINSICALLY DISORDERED PROTEINS; FREE-ENERGY LANDSCAPES; AMINO-ACID-SEQUENCE; NMR CHEMICAL-SHIFTS; MARKOV STATE MODELS; ACCELERATED MOLECULAR-DYNAMICS; RESIDUAL DIPOLAR COUPLINGS; LENNARD-JONES CLUSTERS; SIDE-CHAIN PREDICTION AB Investigation of macromolecular structure and dynamics is fundamental to understanding how macromolecules carry out their functions in the cell. Significant advances have been made toward this end in silico, with a growing number of computational methods proposed yearly to study and simulate various aspects of macromolecular structure and dynamics. This review aims to provide an overview of recent advances, focusing primarily on methods proposed for exploring the structure space of macromolecules in isolation and in assemblies for the purpose of characterizing equilibrium structure and dynamics. In addition to surveying recent applications that showcase current capabilities of computational methods, this review highlights state-of-the-art algorithmic techniques proposed to overcome challenges posed in silico by the disparate spatial and time scales accessed by dynamic macromolecules. This review is not meant to be exhaustive, as such an endeavor is impossible, but rather aims to balance breadth and depth of strategies for modeling macromolecular structure and dynamics for a broad audience of novices and experts. C1 [Maximova, Tatiana; Moffatt, Ryan; Shehu, Amarda] George Mason Univ, Dept Comp Sci, Fairfax, VA 22030 USA. [Ma, Buyong; Nussinov, Ruth] Leidos Biomed Res Inc, Basic Sci Program, Canc & Inflammat Program, NCI, Frederick, MD USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. [Shehu, Amarda] George Mason Univ, Dept Bioengn, Fairfax, VA 22030 USA. [Shehu, Amarda] George Mason Univ, Sch Syst Biol, Manassas, VA USA. RP Shehu, A (reprint author), George Mason Univ, Dept Comp Sci, Fairfax, VA 22030 USA.; Nussinov, R (reprint author), Leidos Biomed Res Inc, Basic Sci Program, Canc & Inflammat Program, NCI, Frederick, MD USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel.; Shehu, A (reprint author), George Mason Univ, Dept Bioengn, Fairfax, VA 22030 USA.; Shehu, A (reprint author), George Mason Univ, Sch Syst Biol, Manassas, VA USA. EM nussinor@helix.nih.gov; amarda@gmu.edu RI Ma, Buyong/F-9491-2011; OI Ma, Buyong/0000-0002-7383-719X; Shehu, Amarda/0000-0001-5230-4610; Maximova, Tatiana/0000-0002-5605-0678 FU National Science Foundation [1421001, 1440581, 1144106]; Thomas F. and Kate Miller Jeffress Memorial Trust Award; NCI, NIH [HHSN261200800001E]; NIH, NCI, Center for Cancer Research FX Funding for this work is provided in part by the National Science Foundation (Grant No. 1421001, Grant No. 1440581, and CAREER Award No. 1144106 to AS) and the Thomas F. and Kate Miller Jeffress Memorial Trust Award. This work has also been funded in whole or in part with Federal funds from the NCI, NIH, under contract number HHSN261200800001E to BM and RN. This study was supported (in part) by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 675 TC 10 Z9 10 U1 22 U2 45 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2016 VL 12 IS 4 AR e1004619 DI 10.1371/journal.pcbi.1004619 PG 70 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DM8BA UT WOS:000376584400042 PM 27124275 ER PT J AU Ruktanonchai, NW DeLeenheer, P Tatem, AJ Alegana, VA Caughlin, TT Erbach-Schoenberg, EZ Lourenco, C Ruktanonchai, CW Smith, DL AF Ruktanonchai, Nick W. DeLeenheer, Patrick Tatem, Andrew J. Alegana, Victor A. Caughlin, T. Trevor Erbach-Schoenberg, Elisabeth Zu Lourenco, Christopher Ruktanonchai, Corrine W. Smith, David L. TI Identifying Malaria Transmission Foci for Elimination Using Human Mobility Data SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PLASMODIUM-FALCIPARUM TRANSMISSION; ANOPHELES MOSQUITOS; HUMAN MOVEMENT; INFECTION; DYNAMICS; STRATEGIES; DISEASES; AFRICA; AREAS; SINKS AB Humans move frequently and tend to carry parasites among areas with endemic malaria and into areas where local transmission is unsustainable. Human-mediated parasite mobility can thus sustain parasite populations in areas where they would otherwise be absent. Data describing human mobility and malaria epidemiology can help classify landscapes into parasite demographic sources and sinks, ecological concepts that have parallels in malaria control discussions of transmission foci. By linking transmission to parasite flow, it is possible to stratify landscapes for malaria control and elimination, as sources are disproportionately important to the regional persistence of malaria parasites. Here, we identify putative malaria sources and sinks for pre-elimination Namibia using malaria parasite rate (PR) maps and call data records from mobile phones, using a steady-state analysis of a malaria transmission model to infer where infections most likely occurred. We also examined how the landscape of transmission and burden changed from the pre-elimination setting by comparing the location and extent of predicted pre-elimination transmission foci with modeled incidence for 2009. This comparison suggests that while transmission was spatially focal pre-elimination, the spatial distribution of cases changed as burden declined. The changing spatial distribution of burden could be due to importation, with cases focused around importation hotspots, or due to heterogeneous application of elimination effort. While this framework is an important step towards understanding progressive changes in malaria distribution and the role of subnational transmission dynamics in a policy-relevant way, future work should account for international parasite movement, utilize real time surveillance data, and relax the steady state assumption required by the presented model. C1 [Ruktanonchai, Nick W.; Tatem, Andrew J.; Alegana, Victor A.; Erbach-Schoenberg, Elisabeth Zu; Lourenco, Christopher; Ruktanonchai, Corrine W.] Univ Southampton, WorldPop Project Geog & Environm, Southampton, Hants, England. [Ruktanonchai, Nick W.; Tatem, Andrew J.; Alegana, Victor A.; Erbach-Schoenberg, Elisabeth Zu; Lourenco, Christopher; Ruktanonchai, Corrine W.] Flowminder Fdn, Stockholm, Sweden. [DeLeenheer, Patrick] Oregon State Univ, Dept Math, Corvallis, OR 97331 USA. [Caughlin, T. Trevor] Sch Forest Resources & Conservat, Gainesville, FL USA. [Lourenco, Christopher] Clinton Hlth Access Initiat, Boston, MA USA. [Smith, David L.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Smith, David L.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Smith, David L.] Sanaria Inst Global Hlth & Trop Med, Rockville, MD USA. [Smith, David L.] Univ Oxford, Dept Zool, Spatial Epidemiol & Evolut Grp, S Parks Rd, Oxford, England. RP Ruktanonchai, NW (reprint author), Univ Southampton, WorldPop Project Geog & Environm, Southampton, Hants, England.; Ruktanonchai, NW (reprint author), Flowminder Fdn, Stockholm, Sweden. EM nrukt00@gmail.com OI Alegana, Victor/0000-0001-5177-9227 FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674]; Bill and Melinda Gates Foundation [OPP1106427, 1032350]; Wellcome Trust Sustaining Health Grant [106866/Z/15/Z]; National Science Foundation in the Quantitative Spatial Ecology, Evolution and Environment Program at the University of Florida [0801544]; Economic and Social Research Council's Doctoral Training Center at the University of Southampton; National Science Foundation Division of Mathematical Sciences [NSF-DMS-1411853] FX AJT & DLS acknowledge funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and are also supported by grants from NIH/NIAID (U19AI089674) and the Bill and Melinda Gates Foundation (OPP1106427 and #1032350). AJT also acknowledges funding support from the Wellcome Trust Sustaining Health Grant (106866/Z/15/Z). NWR acknowledges funding support from the National Science Foundation under Grant No. 0801544 in the Quantitative Spatial Ecology, Evolution and Environment Program at the University of Florida. CWR acknowledges funding from the Economic and Social Research Council's Doctoral Training Center at the University of Southampton. PD acknowledges funding support in part from the National Science Foundation Division of Mathematical Sciences (NSF-DMS-1411853). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 7 Z9 8 U1 4 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2016 VL 12 IS 4 AR e1004846 DI 10.1371/journal.pcbi.1004846 PG 19 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DM8BA UT WOS:000376584400029 PM 27043913 ER PT J AU Chodick, G Sigurdson, AJ Kleinerman, RA Sklar, CA Leisenring, W Mertens, AC Stovall, M Smith, SA Weathers, RE Veiga, LHS Robison, LL Inskip, PD AF Chodick, Gabriel Sigurdson, Alice J. Kleinerman, Ruth A. Sklar, Charles A. Leisenring, Wendy Mertens, Ann C. Stovall, Marilyn Smith, Susan A. Weathers, Rita E. Veiga, Lene H. S. Robison, Leslie L. Inskip, Peter D. TI The Risk of Cataract among Survivors of Childhood and Adolescent Cancer: A Report from the Childhood Cancer Survivor Study SO RADIATION RESEARCH LA English DT Article ID BONE-MARROW-TRANSPLANTATION; IONIZING-RADIATION; OCULAR COMPLICATIONS; UNITED-STATES; SURGERY; IRRADIATION; EXPOSURE; COHORT AB With therapeutic successes and improved survival after a cancer diagnosis in childhood, increasing numbers of cancer survivors are at risk of subsequent treatment-related morbidities, including cataracts. While it is well known that the lens of the eye is one of the most radiosensitive tissues in the human body, the risks associated with radiation doses less than 2 Gy are less understood, as are the long-and short-term cataract risks from exposure to ionizing radiation at a young age. In this study, we followed 13,902 five-year survivors of childhood cancer in the Childhood Cancer Survivor Study cohort an average of 21.4 years from the date of first cancer diagnosis. For patients receiving radiotherapy, lens dose (mean: 2.2 Gy; range: 0-66 Gy) was estimated based on radiotherapy records. We used unconditional multivariable logistic regression models to evaluate prevalence of self-reported cataract in relationship to cumulative radiation dose both at five years after the initial cancer diagnosis and at the end of follow-up. We modeled the radiation effect in terms of the excess odds ratio (EOR) per Gy. We also analyzed cataract incidence starting from five years after initial cancer diagnosis to the end of follow-up using Cox regression. A total of 483 (3.5%) cataract cases were identified, including 200 (1.4%) diagnosed during the first five years of follow-up. In a multivariable logistic regression model, cataract prevalence at the end of follow-up was positively associated with lens dose in a manner consistent with a linear dose-response relationship (EOR per Gy = 0.92; 95% CI: 0.65-1.20). The odds ratio for doses between 0.5 and 1.5 Gy was elevated significantly relative to doses,0.5 Gy (OR = 2.2; 95% CI: 1.3-3.7). The results from this study indicate a strong association between ocular exposure to ionizing radiation and long-term risk of pre-senile cataract. The risk of cataract increased with increasing exposure, beginning at lens doses as low as 0.5 Gy. Our findings are in agreement with a growing body of evidence of an elevated risk for lens opacities in populations exposed to doses of ionizing radiation below the previously suggested threshold level of 2 Gy. (C) 2016 by Radiation Research Society C1 [Chodick, Gabriel; Sigurdson, Alice J.; Kleinerman, Ruth A.; Inskip, Peter D.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Chodick, Gabriel] Tel Aviv Univ, Fac Med, IL-69978 Tel Aviv, Israel. [Sklar, Charles A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA. [Leisenring, Wendy] Fred Hutchinson Canc Res Ctr, Share Clin Res Div, 1124 Columbia St, Seattle, WA 98104 USA. [Mertens, Ann C.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stovall, Marilyn; Smith, Susan A.; Weathers, Rita E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Veiga, Lene H. S.] Brazilian Nucl Energy Commiss, Inst Radiat Protect & Dosimetry, Rio De Janeiro, Brazil. [Robison, Leslie L.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Chodick, G (reprint author), Maccabi Healthcare Serv, Maccabitech, Hamered St 27, IL-6812509 Tel Aviv, Israel. EM hodik_g@mac.org.il FU Intramural Research Program of the National Cancer Institute (NCI) Division of Cancer Epidemiology and Genetics (Bethesda, MD); Maccabi Institute for Health Services Research (Tel Aviv, Israel); National Cancer Institute [U24 CA55727]; American Lebanese Syrian Associated Charities FX This project would not have been possible without the generous participation of the survivors who have contributed to the Childhood Cancer Survivor Study (CCSS), as well as the efforts of the CCSS data abstractors and survey interviewers. We thank the investigators of the institutions that participated in the CCSS. This study was supported, in part, by the Intramural Research Program of the National Cancer Institute (NCI) Division of Cancer Epidemiology and Genetics (Bethesda, MD) and the Maccabi Institute for Health Services Research (Tel Aviv, Israel). The Childhood Cancer Survivor Study is supported by the National Cancer Institute [grant no. U24 CA55727 (GT Armstrong, Principal Investigator)] and funding from the American Lebanese Syrian Associated Charities. NR 41 TC 0 Z9 0 U1 0 U2 2 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD APR PY 2016 VL 185 IS 4 BP 366 EP 374 DI 10.1667/RR14276.1 PG 9 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA DN0KG UT WOS:000376752200004 PM 27023263 ER PT J AU Gadina, M AF Gadina, Massimo TI APPLIED CYTOKINE SIGNALING: FROM JAK INHIBITORS TO SUPER-ENHANCERS SO RHEUMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the British-Society-for-Rheumatology, British-Health-Professionals-in-Rheumatology and the British-Society-for-Paediatric-and-Adolescent-Rheumatology (Rheumatology) CY APR 26-28, 2016 CL Glasgow, SCOTLAND SP British Soc Rheumatol, British Hlth Profess Rheumatol, British Soc Paediat & Adolescent Rheumatol C1 [Gadina, Massimo] NIAMSD, Translat Immunol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD APR PY 2016 VL 55 SU 1 MA I50 BP 11 EP 11 PG 1 WC Rheumatology SC Rheumatology GA DM9AO UT WOS:000376656000041 ER PT J AU Reynolds, JA Smith, CK Sergeant, JC Rosenberg, AZ Rice, GI Briggs, T Bruce, IN Kaplan, MJ AF Reynolds, John A. Smith, Carolyne K. Sergeant, Jamie C. Rosenberg, Avi Z. Rice, Gillian I. Briggs, Tracy Bruce, Ian N. Kaplan, Mariana J. TI VITAMIN D DEFICIENCY PROMOTES VASCULAR DAMAGE AND DISEASE ACTIVITY IN A MURINE MODEL OF SYSTEMIC LUPUS ERYTHEMATOSUS SO RHEUMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the British-Society-for-Rheumatology, British-Health-Professionals-in-Rheumatology and the British-Society-for-Paediatric-and-Adolescent-Rheumatology (Rheumatology) CY APR 26-28, 2016 CL Glasgow, SCOTLAND SP British Soc Rheumatol, British Hlth Profess Rheumatol, British Soc Paediat & Adolescent Rheumatol C1 [Reynolds, John A.; Sergeant, Jamie C.; Briggs, Tracy; Bruce, Ian N.] Cent Manchester Univ Hosp NHS Fdn Trust, NIHR Manchester Musculoskeletal Biomed Res Unit, Manchester, Lancs, England. [Reynolds, John A.; Smith, Carolyne K.; Kaplan, Mariana J.] NIAMSD, System Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Sergeant, Jamie C.] Univ Manchester, Ctr Musculoskeletal Res, Arthrit Res UK Ctr Epidemiol, Manchester, Lancs, England. [Rosenberg, Avi Z.] Childrens Natl Med Ctr, Pathol, Washington, DC 20010 USA. [Rosenberg, Avi Z.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Rice, Gillian I.] Univ Manchester, Genom Med, Inst Human Dev, Manchester, Lancs, England. [Briggs, Tracy] Manchester Acad Hlth Sci Ctr, Cent Manchester Univ Hosp NHS Fdn Trust, Genet Med, Manchester, Lancs, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD APR PY 2016 VL 55 SU 1 MA 269 BP 170 EP 170 PG 1 WC Rheumatology SC Rheumatology GA DM9AO UT WOS:000376656000433 ER PT J AU Hajishengallis, G Moutsopoulos, NM Hajishengallis, E Chavakis, T AF Hajishengallis, George Moutsopoulos, Niki M. Hajishengallis, Evlambia Chavakis, Triantafyllos TI Immune and regulatory functions of neutrophils in inflammatory bone loss SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Neutrophils; Inflammation; Bone loss; Periodontitis; Leukocyte-adhesion deficiency; Del-1 ID LEUKOCYTE ADHESION DEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; GINGIVAL CREVICULAR FLUID; LONG PENTRAXIN PTX3; PAPILLON-LEFEVRE-SYNDROME; DEVELOPMENTAL ENDOTHELIAL LOCUS-1; COLONY-STIMULATING FACTOR; GENOME-WIDE ASSOCIATION; CHRONIC PERIODONTITIS; PORPHYROMONAS-GINGIVALIS AB Although historically viewed as merely anti-microbial effectors in acute infection or injury, neutrophils are now appreciated to be functionally versatile with critical roles also in chronic inflammation. Periodontitis, a chronic inflammatory disease that destroys the tooth-supporting gums and bone, is particularly affected by alterations in neutrophil numbers or function, as revealed by observations in monogenic disorders and relevant mouse models. Besides being a significant debilitating disease and health burden in its own right, periodontitis is thus an attractive model to dissect uncharted neutrophil-associated (patho)physiological pathways. Here, we summarize recent evidence that neutrophils can contribute to inflammatory bone loss not only through the typical bystander injury dogma but intriguingly also through their absence from the affected tissue, where they normally perform important immunomodulatory functions. Moreover, we discuss recent advances in the interactions of neutrophils with the vascular endothelium and - upon extravasation - with bacteria, and how the dysregulation of these interactions leads to inflammatory tissue damage. Overall, neutrophils have both protective and destructive roles in periodontitis, as they are involved in both the maintenance of periodontal tissue homeostasis and the induction of inflammatory bone loss. This highlights the importance of developing approaches that promote or sustain a fine balance between homeostatic immunity and inflammatory pathology. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Hajishengallis, George] Univ Penn, Dept Microbiol, Penn Dent Med, Philadelphia, PA 19104 USA. [Moutsopoulos, Niki M.] Natl Inst Dent & Craniofacial Res, Oral Immun & Inflammat Unit, NIH, Bethesda, MD 20892 USA. [Hajishengallis, Evlambia] Univ Penn, Penn Dent Med, Dept Prevent & Restorat Sci, Div Pediat Dent, Philadelphia, PA 19104 USA. [Chavakis, Triantafyllos] Tech Univ Dresden, Fac Med, Dept Clin Pathobiochem, D-01062 Dresden, Germany. [Chavakis, Triantafyllos] Inst Clin Chem & Lab Med, Dresden, Germany. RP Hajishengallis, G (reprint author), Univ Penn, Penn Dent Med, 240 South 40th St, Philadelphia, PA 19104 USA. EM geoh@upenn.edu FU Intramural Research Program of the NIH, NIDCR; European Community [602699]; Else-Kroner-Fresenius-Stiftung [2014_A137]; U.S. Public Health Service [AI068730, DE015254, DE017138, DE021685, DE024716] FX The authors are supported by the following sources: The Intramural Research Program of the NIH, NIDCR (N.M.M.); the European Community's Seventh Framework Programme under grant agreement n602699 (DIREKT) and the Else-Kroner-Fresenius-Stiftung (2014_A137) (TC); and by U.S. Public Health Service grants AI068730 (E.H. and G.H.) and DE015254, DE017138, DE021685, and DE024716 (GH). We thank Debbie Maizels (Zoobotanica Scientific Illustration) for drawing Fig. 2 and Toshiharu Abe for help with the drawing of Fig. 3. NR 212 TC 8 Z9 8 U1 4 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD APR PY 2016 VL 28 IS 2 BP 146 EP 158 DI 10.1016/j.smim.2016.02.002 PG 13 WC Immunology SC Immunology GA DM6OO UT WOS:000376472500008 PM 26936034 ER PT J AU Vagida, MS Arakelyan, A Lebedeva, AM Grivel, JC Shpektor, AV Vasilieva, EY Margolis, LB AF Vagida, M. S. Arakelyan, A. Lebedeva, A. M. Grivel, J. -Ch. Shpektor, A. V. Vasilieva, E. Yu. Margolis, L. B. TI Analysis of extracellular vesicles using magnetic nanoparticles in blood of patients with acute coronary syndrome SO BIOCHEMISTRY-MOSCOW LA English DT Article DE extracellular vesicles; platelets; acute coronary syndrome; flow cytometry ID ELEVATION MYOCARDIAL-INFARCTION; PLATELET-DERIVED MICROPARTICLES; PATHOLOGICAL CONDITIONS; STABLE ANGINA; EXOSOMES; ATHEROTHROMBOSIS; PATHOPHYSIOLOGY; ACTIVATION; DISEASE; CELLS AB Extracellular vesicles (EVs) are released from various cell types and play an important role in intercellular interactions. In our study, we investigated abundance of individual EVs in patients with acute forms of ischemic heart disease. Previously, we developed an approach for individual analysis of EVs conjugated with magnetic nanoparticles (MNPs), which was applied in the current study for analyzing phenotypic composition of EVs (by staining for markers CD31, CD41a, and CD63). EVs were isolated using fluorescently labeled MNPs containing anti-CD31, CD41a, or CD63 antibodies and analyzed by combining fluorescently labeled anti-CD41a and CD63, CD31 and CD63, or CD41a and CD31 antibodies, respectively. EVs were analyzed in 30 individuals: 17 healthy volunteers and 13 patients with acute coronary syndrome (ACS). Six and seven ACS patients were with acute myocardial infarction and unstable angina, respectively. It was found that patients with ACS and healthy volunteers contained a dominant subset of EVs expressing surface CD41a antigen, suggesting that they originated from platelets. In addition, the total number of EVs isolated using either of the surface markers examined in our study was higher in patients with ACS compared to healthy volunteers. The subgroup of patients with acute myocardial infarction was found to contain significantly higher number of blood EVs compared to the control group. Moreover, increased number of EVs in patients with ACS is mainly due to the increased number of EVs in the subset of EVs bearing CD41a. By analyzing individual EVs, we found that plasma of patients with ACS, particularly upon developing of myocardial infarction, contained dominant platelet-derived EVs fraction, which may reflect activation of platelets in such patients. C1 [Vagida, M. S.; Lebedeva, A. M.; Shpektor, A. V.; Vasilieva, E. Yu.] Moscow State Univ Med & Dent, Lab Atherothrombosis, Moscow 109240, Russia. [Arakelyan, A.; Grivel, J. -Ch.; Margolis, L. B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Intercellular Interact, NIH, Bethesda, MD 20892 USA. RP Lebedeva, AM (reprint author), Moscow State Univ Med & Dent, Lab Atherothrombosis, Moscow 109240, Russia. EM asya.lebedev@mail.ru FU Government of the Russian Federation [14.B25.31.0016] FX This study was financially supported by the Government of the Russian Federation (project No. 14.B25.31.0016). NR 44 TC 0 Z9 0 U1 2 U2 2 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0006-2979 EI 0320-9725 J9 BIOCHEMISTRY-MOSCOW+ JI Biochem.-Moscow PD APR PY 2016 VL 81 IS 4 BP 382 EP 391 DI 10.1134/S0006297916040088 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DM4FQ UT WOS:000376302400008 PM 27293095 ER PT J AU Jaiswal, M Fufaa, GD Martin, CL Pop-Busui, R Nelson, RG Feldman, EL AF Jaiswal, Mamta Fufaa, Gudeta D. Martin, Catherine L. Pop-Busui, Rodica Nelson, Robert G. Feldman, Eva L. TI Burden of Diabetic Peripheral Neuropathy in Pima Indians With Type 2 Diabetes SO DIABETES CARE LA English DT Letter ID RISK-FACTORS; COMPLICATIONS C1 [Jaiswal, Mamta; Feldman, Eva L.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Fufaa, Gudeta D.; Nelson, Robert G.] NIDDK, Phoenix, AZ USA. [Martin, Catherine L.; Pop-Busui, Rodica] Univ Michigan, Dept Endocrinol, Ann Arbor, MI 48109 USA. RP Feldman, EL (reprint author), Univ Michigan, Dept Neurol, Ann Arbor, MI USA. EM efeldman@umich.edu FU NIDDK NIH HHS [P30 DK020572] NR 5 TC 1 Z9 1 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD APR PY 2016 VL 39 IS 4 BP E63 EP E64 DI 10.2337/dc16-0082 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DM3IP UT WOS:000376240400006 PM 26908916 ER PT J AU Dohan, D Garrett, SB Rendle, KA Halley, M Abramson, C AF Dohan, Daniel Garrett, Sarah B. Rendle, Katharine A. Halley, Meghan Abramson, Corey TI The Importance Of Integrating Narrative Into Health Care Decision Making SO HEALTH AFFAIRS LA English DT Article ID MANAGEMENT RESEARCH; QUALITATIVE METHODS; SERVICES AB When making health care decisions, patients and consumers use data but also gather stories from family and friends. When advising patients, clinicians consult the medical evidence but also use professional judgment. These stories and judgments, as well as other forms of narrative, shape decision making but remain poorly understood. Furthermore, qualitative research methods to examine narrative are rarely included in health science research. We illustrate how narratives shape decision making and explain why it is difficult but necessary to integrate qualitative research on narrative into the health sciences. We draw on social-scientific insights on rigorous qualitative research and our ongoing studies of decision making by patients with cancer, and we describe new tools and approaches that link qualitative research findings with the predominantly quantitative health science scholarship. Finally, we highlight the benefits of more fully integrating qualitative research and narrative analysis into the medical evidence base and into evidence-based medical practice. C1 [Dohan, Daniel; Garrett, Sarah B.] Univ Calif San Francisco, Philip R Lee Inst Hlth Policy Studies, San Francisco, CA 94143 USA. [Dohan, Daniel] Univ Calif San Francisco, Dept Anthropol Hist & Social Med, San Francisco, CA 94143 USA. [Rendle, Katharine A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Halley, Meghan] Palo Alto Med Fdn, Res Inst, Palo Alto, CA USA. [Abramson, Corey] Univ Arizona, Sch Sociol, Tucson, AZ USA. RP Dohan, D (reprint author), Univ Calif San Francisco, Philip R Lee Inst Hlth Policy Studies, San Francisco, CA 94143 USA. EM daniel.dohan@ucsf.edu FU Patient-Centered Outcomes Research Institute (PCORI) [ME-1409-22996]; National Cancer Institute (NCI) [NIH R01 CA152195]; Richard and Susan Levy Fund FX All authors were supported by the Patient-Centered Outcomes Research Institute (PCORI; Grant No. ME-1409-22996; principal investigator: Daniel Dohan). Additionally, Dohan, Sarah Garrett, and Corey Abramson received support from the National Cancer Institute (NCI; Grant No. NIH R01 CA152195; principal investigator: Dohan); and Meghan Halley received support from the Richard and Susan Levy Fund. The authors thank Stuart Henderson, Dominick Frosch, Suepattra May, and anonymous reviewers for their helpful feedback. The authors are also deeply grateful to those who participated in our studies of decision making and the experiences of patients with cancer, on which the insights presented in this article are based. The statements presented in this publication are solely the responsibility of the authors and do not necessarily represent the views of the National Institutes of Health or of PCORI, its Board of Governors, or its Methodology Committee. NR 23 TC 1 Z9 1 U1 5 U2 6 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD APR PY 2016 VL 35 IS 4 BP 720 EP 725 DI 10.1377/hlthaff.2015.1373 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DK2SG UT WOS:000374764100023 PM 27044974 ER PT J AU Brenner, TA Rice, TA Anderson, ED Percopo, CM Rosenberg, HF AF Brenner, Todd A. Rice, Tyler A. Anderson, Erik D. Percopo, Caroline M. Rosenberg, Helene F. TI Immortalized MH-S cells lack defining features of primary alveolar macrophages and do not support mouse pneumovirus replication SO IMMUNOLOGY LETTERS LA English DT Article DE Macrophage; Inflammation; Siglec F; Pneumovirus; Pattern recognition receptor; Granulocyte-macrophage colony stimulating factor ID RESPIRATORY VIRUS-INFECTION; SIGLEC-F; PNEUMONIA VIRUS; GM-CSF; LEGIONELLA-PNEUMOPHILA; FLOW-CYTOMETRY; IN-VITRO; MURINE; LINE; EOSINOPHILS AB The SV-40-transformed MH-S cell line maintains some, but not all, features of primary alveolar macrophages (AMs) from BALB/c mice. We show here that MH-S cells produce inflammatory cytokines IL-6 and CXCL10 in response to challenge with Gram-positive Lactobacillus reuteri, and to TLR2 and NOD2 ligands Pam3CSK4 and MDP, respectively. In contrast, although wild-type AMs are infected in vivo by pneumonia virus of mice (PVM), no virus replication was detected in MH-S cells. Interestingly, the surface immunophenotype of MH-S cells (CD11c(+)Siglec F-) differs from that of wild-type AMs (CD11c(+) Siglec F+) and is similar to that of immature AMs isolated from granulocyte macrophage-colony stimulating factor (GM-CSF) gene-deleted mice; AMs from GM-CSF-/- mice also support PVM replication. However, MH-S cells do not express the GM-CSF receptor alpha chain (CD116) and do not respond to GM-CSF. Due to these unusual features, MH-S cells should be used with caution as experimental models of AMs. Published by Elsevier B.V. on behalf of European Federation of Immunological Societies. C1 [Brenner, Todd A.; Rice, Tyler A.; Anderson, Erik D.; Percopo, Caroline M.; Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, NIH, Bethesda, MD 20892 USA. [Rice, Tyler A.] Yale Univ, Grad Dept Immunobiol, New Haven, CT USA. RP Rosenberg, HF (reprint author), NIAID, IIS, LAD, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU NIAID Division of Intramural Research [AI000943] FX The authors wish to thank Dr. Kimberly D. Dyer (IIS/LAD/NIAID) for her advice on flow cytometry and use of the recombinant rK2-PVM virus. We also thank Dr. Glenn Dranoff (Harvard University) for permission to use, and Dr. Karen Elkins (FDA) and Dr. June Kwon-Chung (NIAID) for assistance in obtaining the GM-CSF-/- gene-deleted mouse strain. We also thank Dr. Rakesh Kumar, University of New South Wales, Sydney, Australia, for sharing his experiences with the MH-S cell line. This work was performed with support from the NIAID Division of Intramural Research (AI000943 to HFR). NR 52 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 EI 1879-0542 J9 IMMUNOL LETT JI Immunol. Lett. PD APR PY 2016 VL 172 BP 106 EP 112 DI 10.1016/j.imlet.2016.02.012 PG 7 WC Immunology SC Immunology GA DM3AB UT WOS:000376218100013 PM 26916143 ER PT J AU Chen, P Urzua, CA Knickelbein, JE Kim, JS Li, ZY Hannes, S Kuo, D Chaigne-Delalande, B Armbrust, K Tucker, W Liu, B Agron, E Sen, HN Nussenblatt, RB AF Chen, Ping Urzua, Cristhian A. Knickelbein, Jared E. Kim, Jane S. Li, Zhiyu Hannes, Susan Kuo, David Chaigne-Delalande, Benjamin Armbrust, Karen Tucker, William Liu, Baoying Agron, Elvira Sen, H. Nida Nussenblatt, Robert B. TI Elevated CD1c(+) Myeloid Dendritic Cell Proportions Associate With Clinical Activity and Predict Disease Reactivation in Noninfectious Uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE CD1c(+) myeloid dendritic cells; noninfectious uveitis; clinical activity; disease reactivation ID RECURRENCE RATE; TH17 CELLS; GLUCOCORTICOIDS; EXPRESS; MDC1 AB PURPOSE. To test the association between elevated proportions of CD1c(+) myeloid dendritic cells (mDCs) and disease activation/reactivation in noninfectious uveitis. METHODS. Noninfectious uveitis patients (n = 89) and healthy controls (n = 111) were recruited. The proportion of CD1c(+) mDCs in the total dendritic cell (DC) population of peripheral blood was measured by flow cytometry (CD1c(+) mDCs gated on Lineage 1(+)HLADR(+) DCs). Disease activity was assessed per Standardization of Uveitis Nomenclature criteria. Uveitis reactivation was ascribed to clinically quiescent patients who developed reactivation of intraocular inflammation within 6 months. RESULTS. The proportions of CD1c(+) mDCs were increased in noninfectious uveitis patients, especially in active disease, compared to healthy controls. This CD1c(+) mDC elevation was not associated with underlying systemic diseases, anatomic locations of uveitis, medications, or demographic factors. Longitudinal data showed that the dynamics of CD1c(+) mDC levels were correlated with disease activity. The average proportion of CD1c(+) mDCs in active uveitis patients was 60% so we set this as the cutoff between high and low CD1c(+) mDC levels. Although 74% of quiescent patients had low proportions of CD1c(+) mDCs, 26% still had high proportions. Quiescent patients with high CD1c(+) mDC proportions showed increased risk of disease reactivation, compared to quiescent patients with low CD1c(+) mDC proportions. CONCLUSIONS. Increased proportions of CD1c(+) mDCs were associated with clinical activity, and quiescent patients with elevated CD1c(+) mDCs were more likely to undergo reactivation. This suggests that CD1c(+) mDC proportion may be a potential biomarker for assessing clinical activation and reactivation in noninfectious uveitis. C1 [Chen, Ping; Urzua, Cristhian A.; Knickelbein, Jared E.; Kim, Jane S.; Li, Zhiyu; Hannes, Susan; Kuo, David; Chaigne-Delalande, Benjamin; Armbrust, Karen; Tucker, William; Liu, Baoying; Sen, H. Nida; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Urzua, Cristhian A.] Univ Chile, Dept Ophthalmol, Santiago, Chile. [Kim, Jane S.; Kuo, David] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Agron, Elvira] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM nussenblattr@nei.nih.gov OI Armbrust, Karen/0000-0001-9381-4756 FU National Institutes of Health (NIH)/National Eye Institute (NEI); NIH Medical Research Scholars Program; Pan-American Ophthalmological Foundation/Retina Research Foundation; CONICYT FX Supported by the Intramural Research Program of the National Institutes of Health (NIH)/National Eye Institute (NEI). JSK and DK were supported by the NIH Medical Research Scholars Program. CAU was supported by the Pan-American Ophthalmological Foundation/Retina Research Foundation (Guillingham fellowship) and the CONICYT (Becas Chile Program). The authors alone are responsible for the content and writing of the paper. NR 19 TC 1 Z9 1 U1 1 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2016 VL 57 IS 4 BP 1765 EP 1772 DI 10.1167/iovs.15-18357 PG 8 WC Ophthalmology SC Ophthalmology GA DL8XY UT WOS:000375926700033 PM 27070110 ER PT J AU Ko, F Boland, MV Gupta, P Gadkaree, SK Vitale, S Guallar, E Zhao, D Friedman, DS AF Ko, Fang Boland, Michael V. Gupta, Priya Gadkaree, Shekhar K. Vitale, Susan Guallar, Eliseo Zhao, Di Friedman, David S. TI Diabetes, Triglyceride Levels, and Other Risk Factors for Glaucoma in the National Health and Nutrition Examination Survey 2005-2008 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE glaucoma; glaucoma risk factors; NHANES ID OPEN-ANGLE GLAUCOMA; NORMAL-TENSION GLAUCOMA; INTRAOCULAR-PRESSURE; CIGARETTE-SMOKING; BLOOD-PRESSURE; METAANALYSIS; EYE; ASSOCIATION; POPULATION; ONSET AB PURPOSE. To determine risk factors for glaucoma in a population-based study in the United States. METHODS. Participants age 40 and older from the National Health and Nutrition Examination Survey underwent questionnaires, physical examination, laboratory tests, and vision tests including fundus imaging. Glaucoma was determined based on expert grading of fundus photographs. Regression modeling of glaucoma risk factors was performed. RESULTS. Participants with glaucoma (172) were older (mean age 68.1 [95% confidence interval (CI) 65.6-70.7] vs. 56.4 years [95% CI 55.6-57.2, P < 0.001]), likely to have less than high school education (25.1% vs. 18.1%, P = 0.05), to have diabetes (23.1% vs. 10.8%, P < 0.001), to have central obesity (72.5% vs. 60.7%, P = 0.01), to have systolic hypertension (30.3% vs. 20.1%, P = 0.01), to have diastolic hypotension (30.3% vs. 13.9%, P < 0.001), and to be nonsmokers (91.0% vs. 79.3%, P = 0.002). Sex, poverty, access to health care, fasting glucose, insulin dependence, body mass index, cholesterol levels, diastolic hypertension, systolic hypotension, obstructive sleep apnea, and marijuana were not associated with glaucoma. Multivariable modeling showed associations between glaucoma and older age (odds ratio [OR] 1.09 per year, 95% CI 1.04-1.14), black race (OR 4.40, 95% CI 1.71-11.30), and poverty (OR 3.39, 95% CI 1.73-6.66). Diabetes was no longer associated with glaucoma after adjustment for triglyceride levels. Sex, education, insurance status, body mass index, blood pressure, obstructive sleep apnea, and smoking were not associated with glaucoma. CONCLUSIONS. People who are older, of black race, and with lower income levels have a higher prevalence of glaucoma. A novel association between diabetes, triglyceride levels, and glaucoma is also identified. C1 [Ko, Fang] Moorfields Eye Hosp, Glaucoma, London, England. [Boland, Michael V.; Friedman, David S.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Glaucoma Ctr Excellence, Baltimore, MD 21205 USA. [Gupta, Priya] Surrey Eye Care Ctr, Surrey, BC, Canada. [Gadkaree, Shekhar K.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Guallar, Eliseo; Zhao, Di] Johns Hopkins Univ, Sch Med, Welch Ctr Epidemiol, Baltimore, MD USA. [Guallar, Eliseo; Zhao, Di; Friedman, David S.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21205 USA. RP Friedman, DS (reprint author), Johns Hopkins Univ, 600 N Wolfe St,Wilmer 120, Baltimore, MD 21287 USA. EM david.friedman@jhu.edu FU National Institutes of Health [EY01766]; Research to Prevent Blindness FX Research at the Wilmer Eye Institute is supported by National Institutes of Health Grant EY01766 and by a grant from Research to Prevent Blindness. The funding agencies had no role in the design or conduct of this research. NR 30 TC 2 Z9 2 U1 1 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2016 VL 57 IS 4 BP 2152 EP 2157 DI 10.1167/iovs.15-18373 PG 6 WC Ophthalmology SC Ophthalmology GA DL8XY UT WOS:000375926700068 PM 27111561 ER PT J AU Chomistek, AK Shiroma, EJ Lee, IM AF Chomistek, Andrea K. Shiroma, Eric J. Lee, I-Min TI The Relationship Between Time of Day of Physical Activity and Obesity in Older Women SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE exercise; accelerometry; overweight; epidemiology ID PREVENTION; PATTERNS; BEHAVIOR AB Background: Physical activity is important for maintaining healthy weight. The time of day when exercise is performed a highly discretionary aspect of behavior may impact weight control, but evidence is limited. Thus, we examined the association between the timing of physical activity and obesity risk in women. Methods: A cross-sectional analysis was conducted among 7157 Women's Health Study participants who participated in an ancillary study begun in 2011 that is measuring physical activity using accelerometers. The exposure was percentage of total accelerometer counts accumulated before 12:00 noon and the outcome was obesity. Results: Mean (+/- SD) BMI among participants was 26.1 (+/- 4.9) kg/m(2) and 1322 women were obese. The mean activity counts per day was 203,870 (95,811) of which a mean 47.1% (+/- 11.5%) were recorded in the morning. In multivariable-adjusted models, women who recorded < 39% (lowest quartile) of accelerometer counts before 12:00 noon had a 26% higher odds of being obese, compared with those recording >= 54% (highest quartile) of counts before noon (P-trend = 0.02). Conclusions: These study findings-that women who are less active during morning hours may be at higher risk of obesity-if confirmed can provide a novel strategy to help combat the important health problem of obesity. C1 [Chomistek, Andrea K.] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA. [Shiroma, Eric J.] NIA, NIH, Bethesda, MD 20892 USA. [Lee, I-Min] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Lee, I-Min] Harvard Univ, Sch Med, Boston, MA USA. RP Chomistek, AK (reprint author), Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA. EM achomist@indiana.edu RI Chomistek, Andrea/A-2104-2017 OI Chomistek, Andrea/0000-0002-8764-1446 FU National Institutes of Health [CA154647, CA047988, HL043851, HL080467, HL099355] FX We are grateful to the staff of the Women's Health Study (Brigham and Women's Hospital), particularly Ara Sarkissian, MM, Bonnie Church, BA, Colby Smith, BS, and Jane Jones, MEd as well as Dr. Patty Freedson, PhD. This research was supported by research grants CA154647, CA047988, HL043851, HL080467, and HL099355 from the National Institutes of Health. NR 14 TC 1 Z9 1 U1 0 U2 1 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 EI 1543-5474 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD APR PY 2016 VL 13 IS 4 BP 416 EP 418 DI 10.1123/jpah.2015-0152 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DM3BG UT WOS:000376221200009 PM 26445277 ER PT J AU Baba, M Toyama, H Sun, L Takubo, K Suh, HC Hasumi, H Nakamura-Ishizu, A Hasumi, Y Klarmann, KD Nakagata, N Schmidt, LS Linehan, WM Suda, T Keller, JR AF Baba, Masaya Toyama, Hirofumi Sun, Lei Takubo, Keiyo Suh, Hyung-Chan Hasumi, Hisashi Nakamura-Ishizu, Ayako Hasumi, Yukiko Klarmann, Kimberly D. Nakagata, Naomi Schmidt, Laura S. Linehan, W. Marston Suda, Toshio Keller, Jonathan R. TI Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure SO STEM CELLS LA English DT Article DE Hematopoiesis; Stem cells; Bone marrow failure; Folliculin ID BIRT-HOGG-DUBE; TUMOR-SUPPRESSOR FUNCTION; SIGNALING PATHWAYS; POLYCYSTIC KIDNEYS; MTOR ACTIVATION; CRITICAL ROLES; PROTEIN; PTEN; FLCN; TRANSCRIPTION AB Folliculin (FLCN) is an autosomal dominant tumor suppressor gene that modulates diverse signaling pathways required for growth, proliferation, metabolism, survival, motility, and adhesion. FLCN is an essential protein required for murine embryonic development, embryonic stem cell (ESC) commitment, and Drosophila germline stem cell maintenance, suggesting that Flcn may be required for adult stem cell homeostasis. Conditional inactivation of Flcn in adult hematopoietic stem/progenitor cells (HSPCs) drives hematopoietic stem cells (HSC) into proliferative exhaustion resulting in the rapid depletion of HSPC, loss of all hematopoietic cell lineages, acute bone marrow (BM) failure, and mortality after 40 days. HSC that lack Flcn fail to reconstitute the hematopoietic compartment in recipient mice, demonstrating a cell-autonomous requirement for Flcn in HSC maintenance. BM cells showed increased phosphorylation of Akt and mTorc1, and extramedullary hematopoiesis was significantly reduced by treating mice with rapamycin in vivo, suggesting that the mTorc1 pathway was activated by loss of Flcn expression in hematopoietic cells in vivo. Tfe3 was activated and preferentially localized to the nucleus of Flcn knockout (KO) HSPCs. Tfe3 overexpression in HSPCs impaired long-term hematopoietic reconstitution in vivo, recapitulating the Flcn KO phenotype, and supporting the notion that abnormal activation of Tfe3 contributes to the Flcn KO phenotype. Flcn KO mice develop an acute histiocytic hyperplasia in multiple organs, suggesting a novel function for Flcn in macrophage development. Thus, Flcn is intrinsically required to maintain adult HSC quiescence and homeostasis, and Flcn loss leads to BM failure and mortality in mice. Stem Cells2016;34:1068-1082 C1 [Baba, Masaya; Hasumi, Hisashi; Hasumi, Yukiko; Schmidt, Laura S.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Baba, Masaya; Suda, Toshio] Kumamoto Univ, IRCMS, Kumamoto, Japan. [Toyama, Hirofumi; Takubo, Keiyo; Nakamura-Ishizu, Ayako; Suda, Toshio] Keio Univ, Sch Med, Dept Cell Differentiat, Sakaguchi Lab Dev Biol,Shinjuku Ku, 35 Shinano Machi, Tokyo, Japan. [Sun, Lei; Suh, Hyung-Chan; Klarmann, Kimberly D.; Keller, Jonathan R.] Mouse Canc Genet Program, Frederick, MD USA. [Sun, Lei; Suh, Hyung-Chan; Klarmann, Kimberly D.; Schmidt, Laura S.; Keller, Jonathan R.] Leidos Biomed Res Inc, Basic Sci Program, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD USA. [Takubo, Keiyo] Natl Ctr Global Hlth & Med, Dept Stem Cell Biol, Res Inst, Tokyo, Japan. [Nakagata, Naomi] Kumamoto Univ, Div Reprod Engn, CARD, Kumamoto, Japan. [Nakamura-Ishizu, Ayako; Suda, Toshio] Natl Univ Singapore, CSI, Singapore 117548, Singapore. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Suda, T (reprint author), Kumamoto Univ, IRCMS, Kumamoto, Japan.; Keller, JR (reprint author), Leidos Biomed Res Inc, Basic Sci Program, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD USA. EM linehanm@mail.nih.gov; sudato@z3.keio.jp; kellerjo@mail.nih.gov FU National Institutes of Health (NIH), National Cancer Institute (NCI); Center for Cancer Research; Keio University; BioLegend/Tomy Digital Biology Research Grant Program; JSPS KAKENHI; JSPS KAKENHI [15H04975, 15K14370]; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E] FX We wish to thank Steven Stull, Terri Stull, and Louise Cromwell for excellent animal technical support. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), and Center for Cancer Research, and by Keio University Grant-in-Aid for Encouragement of Young Medical Scientists, by BioLegend/Tomy Digital Biology Research Grant Program 2013 (Latter Term). T.S. and M.B. were supported in part by a JSPS KAKENHI Grant-in-Aid for Scientific Research (S). M.B. was supported by JSPS KAKENHI, Grant-in-Aid for Scientific Research (B), Grant Number 15H04975; and Grant-in-Aid for Challenging Exploratory Research, Grant Number 15K14370. This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, NIH, under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsements by the US Government. NCI-Frederick is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the "Guide for Care and Use of Laboratory Animals" (National Research Council; 1996; National Academy Press; Washington DC). NR 43 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD APR PY 2016 VL 34 IS 4 BP 1068 EP 1082 DI 10.1002/stem.2293 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DK1TR UT WOS:000374697700022 PM 27095138 ER PT J AU Agbor-Enoh, S Tunc, I Doveikis, J Khush, K De Vlaminck, I Davis, A Wang, X Solomon, MA Zhu, J Valantine, HA AF Agbor-Enoh, S. Tunc, I. Doveikis, J. Khush, K. De Vlaminck, I. Davis, A. Wang, X. Solomon, M. A. Zhu, J. Valantine, H. A. TI Reproducibility of Genomic Data Using Standards-Cell Free DNA to Monitor Rejection after Heart Transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT) CY APR 27-30, 2016 CL Washington, DC SP Int Soc Heart & Lung Transplantat C1 [Agbor-Enoh, S.; Tunc, I.; Doveikis, J.; Davis, A.; Wang, X.; Solomon, M. A.; Zhu, J.; Valantine, H. A.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Khush, K.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [De Vlaminck, I.] Cornell Univ, Ithaca, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2016 VL 35 IS 4 SU S MA 421 BP S161 EP S161 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA DK2AX UT WOS:000374718100418 ER PT J AU Agbor-Enoh, S Fideli, U Doveikis, J Zhu, J Tunc, I Shah, P Russell, S Feller, E Shah, K Rodrigo, M Shah, P Pham, S Iacono, A Nathan, S Orens, J Valantine, H AF Agbor-Enoh, S. Fideli, U. Doveikis, J. Zhu, J. Tunc, I. Shah, P. Russell, S. Feller, E. Shah, K. Rodrigo, M. Shah, P. Pham, S. Iacono, A. Nathan, S. Orens, J. Valantine, H. CA N GRAfT Investigators TI Genomic Research Alliance for Transplantation (GRAfT): A Model for Long Term Transplant Studies in Thoracic Organ Transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT) CY APR 27-30, 2016 CL Washington, DC SP Int Soc Heart & Lung Transplantat C1 [Agbor-Enoh, S.; Fideli, U.; Doveikis, J.; Zhu, J.; Tunc, I.; Valantine, H.; N GRAfT Investigators] NIH, Bldg 10, Bethesda, MD 20892 USA. [Shah, P.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Russell, S.] Johns Hopkins Univ Hosp, Cardiol, Baltimore, MD 21287 USA. [Feller, E.] Univ Maryland, Med Ctr, Cadiol, Baltimore, MD 21201 USA. [Shah, K.] Virginia Commonwealth Univ, Cardiol, Richmond, VA USA. [Rodrigo, M.] Medstar Washington Hosp Ctr, Cardiol, Washington, DC USA. [Shah, P.] INOVA Fairfax Hosp, Cardiol, Fairfax, VA USA. [Pham, S.] Univ Maryland, Med Ctr, Cadiothorac Surg, Baltimore, MD 21201 USA. [Iacono, A.] Univ Maryland, Med Ctr, Pulm & Crit Care Med, Baltimore, MD 21201 USA. [Nathan, S.] INOVA Fairfax Hosp, Pulm & Crit Care Med, Fairfax, VA USA. [Orens, J.] Johns Hopkins Univ Hosp, Pulm & Crit Care Med, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2016 VL 35 IS 4 SU S MA 422 BP S161 EP S161 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA DK2AX UT WOS:000374718100419 ER PT J AU Zhao, XZ Smith, SJ Maskell, DP Metifiot, M Pye, VE Fesen, K Marchand, C Pommier, Y Cherepanov, P Hughes, SH Burke, TR AF Zhao, Xue Zhi Smith, Steven J. Maskell, Daniel P. Metifiot, Mathieu Pye, Valerie E. Fesen, Katherine Marchand, Christophe Pommier, Yves Cherepanov, Peter Hughes, Stephen H. Burke, Terrence R., Jr. TI HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases SO ACS CHEMICAL BIOLOGY LA English DT Article ID CROSS-RESISTANCE; RALTEGRAVIR; DOLUTEGRAVIR; ELVITEGRAVIR; DERIVATIVES; MECHANISMS; MUTATIONS; EVOLUTION; INFECTION; FREQUENCY AB HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3'-processing and the bound host DNA prior to strand transfer. Using this concept of "bi-substrate mimicry," we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs. C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Chem Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Smith, Steven J.] NCI, HIV Dynam & Replicat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Metifiot, Mathieu; Fesen, Katherine; Marchand, Christophe; Pommier, Yves; Hughes, Stephen H.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Metifiot, Mathieu; Fesen, Katherine; Marchand, Christophe; Pommier, Yves; Hughes, Stephen H.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Maskell, Daniel P.; Pye, Valerie E.; Cherepanov, Peter] Francis Crick Inst, Clare Hall Labs, Blanche Lane, S Mimms EN6 3LD, Herts, England. [Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, St Marys Campus,Norfolk Pl, London W2 1PG, England. RP Burke, TR (reprint author), NCI, Chem Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM burkete@helix.nih.gov RI Cherepanov, Peter/F-6859-2010; OI Cherepanov, Peter/0000-0002-0634-538X; Pye, Valerie E/0000-0001-9616-2992 FU NIH Intramural Program, Center for Cancer Research, National Cancer Institute [ZIA BC 007363, Z01 BC 007333]; NIH Intramural AIDS Targeted Antiviral Program (IATAP) FX We thank the staff of the Diamond Light Source beamline I04 for assistance with X-ray data collection. Our studies are supported by the NIH Intramural Program, Center for Cancer Research (ZIA BC 007363, Z01 BC 007333), National Cancer Institute and by grants from the NIH Intramural AIDS Targeted Antiviral Program (IATAP). NR 43 TC 4 Z9 4 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD APR PY 2016 VL 11 IS 4 BP 1074 EP 1081 DI 10.1021/acschembio.5b00948 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ8BL UT WOS:000374437000028 PM 26808478 ER PT J AU Dankwa-Mullan, I Perez-Stable, EJ AF Dankwa-Mullan, Irene Perez-Stable, Eliseo J. TI Addressing Health Disparities Is a Place-Based Issue SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Dankwa-Mullan, Irene] Natl Inst Minor Hlth & Hlth Dispar, Div Sci Programs, NIH, Bethesda, MD USA. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. RP Perez-Stable, EJ (reprint author), 6707 Democracy Blvd,Suite 800, Bethesda, MD 20892 USA. EM eliseo.perez-stable@nih.gov NR 9 TC 2 Z9 2 U1 0 U2 4 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD APR PY 2016 VL 106 IS 4 BP 637 EP 639 DI 10.2105/AJPH.2016.303077 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DL8SY UT WOS:000375913000024 PM 26959267 ER PT J AU Jones, CM Lurie, PG Compton, WM AF Jones, Christopher M. Lurie, Peter G. Compton, Wilson M. TI Increase in Naloxone Prescriptions Dispensed in US Retail Pharmacies Since 2013 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article AB Distribution of naloxone, traditionally through community-based naloxone programs, is a component of a comprehensive strategy to address the epidemic of prescription opioid and heroin overdose deaths in the United States. Recently, there has been increased focus on naloxone prescription in the outpatient setting, particularly through retail pharmacies, yet data on this practice are sparse. We found an 1170% increase in naloxone dispensing from US retail pharmacies between the fourth quarter of 2013 and the second quarter of 2015. These findings suggest that prescribing naloxone in the outpatient setting complements traditional community-based naloxone programs. C1 [Jones, Christopher M.] US Dept Hlth & Human Serv, Off Assistant Secretary Planning & Evaluat, Div Sci Policy, 200 Independence Ave SW, Washington, DC 20201 USA. [Lurie, Peter G.] US FDA, Off Publ Hlth Strategy & Anal, Silver Spring, MD USA. [Compton, Wilson M.] NIDA, NIH, Rockville, MD USA. RP Jones, CM (reprint author), US Dept Hlth & Human Serv, Off Assistant Secretary Planning & Evaluat, Div Sci Policy, 200 Independence Ave SW, Washington, DC 20201 USA. EM christopher.m.jones@fda.hhs.gov NR 8 TC 5 Z9 5 U1 1 U2 3 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD APR PY 2016 VL 106 IS 4 BP 689 EP 690 DI 10.2105/AJPH.2016.303062 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DL8SY UT WOS:000375913000036 PM 26890174 ER PT J AU Kuijpers, E Bekker, C Fransman, W Brouwer, D Tromp, P Vlaanderen, J Godderis, L Hoet, P Lan, Q Silverman, D Vermeulen, R Pronk, A AF Kuijpers, Eelco Bekker, Cindy Fransman, Wouter Brouwer, Derk Tromp, Peter Vlaanderen, Jelle Godderis, Lode Hoet, Peter Lan, Qing Silverman, Debra Vermeulen, Roel Pronk, Anjoeka TI Occupational Exposure to Multi-Walled Carbon Nanotubes During Commercial Production Synthesis and Handling SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE Commercial production; multi-walled carbon nanotubes; occupational exposure ID ASSESSMENT TECHNIQUE NEAT; INHALATION EXPOSURE; NANO-OBJECTS; NANOMATERIALS; PARTICLES; RELEASE; IDENTIFICATION; COMPOSITES; SCENARIOS; FIBERS AB The world-wide production of carbon nanotubes (CNTs) has increased substantially in the last decade, leading to occupational exposures. There is a paucity of exposure data of workers involved in the commercial production of CNTs. The goals of this study were to assess personal exposure to multi-walled carbon nanotubes (MWCNTs) during the synthesis and handling of MWCNTs in a commercial production facility and to link these exposure levels to specific activities. Personal full-shift filter-based samples were collected, during commercial production and handling of MWCNTs, R&D activities, and office work. The concentrations of MWCNT were evaluated on the basis of EC concentrations. Associations were studied between observed MWCNT exposure levels and location and activities. SEM analyses showed MWCNTs, present as agglomerates ranging between 200nm and 100 A mu m. Exposure levels of MWCNTs observed in the production area during the full scale synthesis of MWCNTs (N = 23) were comparable to levels observed during further handling of MWCNTs (N = 19): (GM (95% lower confidence limit-95% upper confidence limit)) 41 mu g m(-3) (20-88) versus 43 mu g m(-3) (22-86), respectively. In the R&D area (N = 11) and the office (N = 5), exposure levels of MWCNTs were significantly (P < 0.05) lower: 5 mu g m(-3) (2-11) and 7 mu g m(-3) (2-28), respectively. Bagging, maintenance of the reactor, and powder conditioning were associated with higher exposure levels in the production area, whereas increased exposure levels in the R&D area were related to handling of MWCNTs powder. C1 [Kuijpers, Eelco; Bekker, Cindy; Fransman, Wouter; Brouwer, Derk; Tromp, Peter; Pronk, Anjoeka] TNO, POB 360, Zeist, Netherlands. [Bekker, Cindy; Vlaanderen, Jelle; Vermeulen, Roel] IRAS, Inst Risk Assessment Sci Mol Epidemiol & Risk Ass, Yalelaan 1, NL-3584 CL Utrecht, Netherlands. [Godderis, Lode; Hoet, Peter] Katholieke Univ Leuven, Ctr Environm & Hlth, Kapucijnenvoer 35-5, B-3000 Louvain, Belgium. [Godderis, Lode] IDEWE, External Serv Prevent & Protect Work, Interleuvenlaan 58, B-3001 Heverlee, Belgium. [Lan, Qing; Silverman, Debra] Natl Canc Inst, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Executive Blvd, Bethesda, MD USA. RP Kuijpers, E (reprint author), TNO, POB 360, Zeist, Netherlands. EM eelco.kuijpers@tno.nl RI Vermeulen, Roel/F-8037-2011; Hoet, Peter/H-9987-2013 OI Vermeulen, Roel/0000-0003-4082-8163; Hoet, Peter/0000-0002-0292-6603 FU NanoNextNL; micro and nanotechnology consortium of the Government of the Netherlands; 130 partners FX The research was partly funded by NanoNextNL, a micro and nanotechnology consortium of the Government of the Netherlands and 130 partners. The paper was reviewed by the funder and studied company prior to submission. We thank Roel Engel, Ruud Boessen and the supportive studied company for their contributions. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. NR 42 TC 2 Z9 2 U1 3 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 EI 1475-3162 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD APR PY 2016 VL 60 IS 3 BP 305 EP 317 DI 10.1093/annhyg/mev082 PG 13 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA DJ5FY UT WOS:000374233400005 PM 26613611 ER PT J AU Xu, L Verdoodt, F Wentzensen, N Bergeron, C Arbyn, M AF Xu, Lan Verdoodt, Freija Wentzensen, Nicolas Bergeron, Christine Arbyn, Marc TI Triage of ASC-H: A meta-analysis of the accuracy of high-risk HPV testing and other markers to detect cervical precancer SO CANCER CYTOPATHOLOGY LA English DT Article DE atypical squamous cells; cannot exclude high-grade squamous intraepithelial lesion (ASC-H); cervical cancer; cervical intraepithelial neoplasia; diagnostic test accuracy; human papillomavirus (HPV); meta-analysis; triage ID ATYPICAL SQUAMOUS-CELLS; PATHOLOGY SCREENING GUIDELINES; HUMAN-PAPILLOMAVIRUS GENOTYPES; GRADE INTRAEPITHELIAL LESION; AMERICAN-CANCER-SOCIETY; HYBRID-CAPTURE-II; FOLLOW-UP; 5-YEAR RISKS; UNDETERMINED SIGNIFICANCE; DIAGNOSTIC PERFORMANCE AB BACKGROUNDWomen with a cytological diagnosis of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) are usually immediately referred for colposcopy. However, triage may reduce the burden of the diagnostic workup and prevent overtreatment. METHODSA meta-analysis was conducted to assess the accuracy of high-risk human papillomavirus (hrHPV) testing and testing for other molecular markers for the detection of grade 2 cervical intraepithelial neoplasia or worse (CIN2+) or grade 3 cervical intraepithelial neoplasia or worse (CIN3+) in women with ASC-H. An additional question that was assessed was whether triage would be useful in light of the relatively high pretriage probability of underlying precancer. RESULTSThe pooled absolute sensitivity and specificity of the Hybrid Capture 2 (HC2) assay for CIN2+(derived from 19 studies) were 93% (95% confidence interval [CI], 89%-95%) and 45% (95% CI, 41%-50%), respectively. p16(INK4a) staining (only 3 studies) had similar sensitivity (93%; 95% CI, 75%-100%) but superior specificity (specificity ratio, 1.69) to HC2 for CIN2+. Testing for paired box 1 gene methylation (only 1 study) showed a superior specificity of 95% (specificity ratio, 2.08). The average pretest risk was 34% for CIN2+and 20% for CIN3+. A negative HC2 result decreased this to 8% and 5%, respectively, whereas a positive result upgraded the risk to 47% and 28%, respectively. CONCLUSIONSBecause of the high probability of precancer with a diagnosis of ASC-H, the utility of triage is limited. The usual recommendation for referring women with ASC-H for colposcopy is not altered by a positive triage test, whatever test is used. A negative hrHPV DNA or p16(INK4a) test may allow repeat testing, but this recommendation will depend on local decision thresholds for referral. Cancer Cytopathol 2016;124:261-72. (c) 2015 American Cancer Society. Because of the high probability of precancer in patients with a diagnosis of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H), the utility of triage is limited. The usual recommendation of referring women with ASC-H to colposcopy is not altered by a positive triage test, whatever test is used. A negative high-risk human papillomavirus DNA or p16(INK4a) test may allow repeat testing, but this recommendation will depend on local decision thresholds for referral. C1 [Xu, Lan; Verdoodt, Freija; Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, Belgian Canc Ctr, Juliette Wytsmanstr 14, B-1050 Brussels, Belgium. [Verdoodt, Freija] Danish Canc Soc, Res Ctr, Unit Virus Lifestyle & Genes, Copenhagen, Denmark. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Bergeron, Christine] Lab Cerba, Cergy Pontoise, France. RP Arbyn, M (reprint author), Sci Inst Publ Hlth, Canc Epidemiol Unit, Belgian Canc Ctr, Juliette Wytsmanstr 14, B-1050 Brussels, Belgium. EM marc.arbyn@wiv-isp.be FU Directorate-General for Research of the European Commission through the comparing health services interventions for the prevention of HPV-related cancer (COHEAHR) network [603019]; German Guideline Program in Oncology (German Cancer Aid project) [110163]; Joint Action on Comprehensive Cancer Control; European Union FX Marc Arbyn, Lan Xu, and Freija Verdoodt were supported by the Seventh Framework Program of the Directorate-General for Research of the European Commission through the comparing health services interventions for the prevention of HPV-related cancer (COHEAHR) network (grant 603019). Other funding was received from the German Guideline Program in Oncology (German Cancer Aid project 110163). Marc Arbyn's work was supported by the Joint Action on Comprehensive Cancer Control, which has received funding from the European Union within the framework of the Health Programme (2008-2013). NR 60 TC 5 Z9 5 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD APR PY 2016 VL 124 IS 4 BP 261 EP 272 DI 10.1002/cncy.21661 PG 12 WC Oncology; Pathology SC Oncology; Pathology GA DJ6QQ UT WOS:000374338400007 PM 26618614 ER PT J AU Davis, FM Goulding, EH D'Agostin, DM Janardhan, KS Cummings, CA Bird, GS Eddy, EM Putney, JW AF Davis, Felicity M. Goulding, Eugenia H. D'Agostin, Diane M. Janardhan, Kyathanahalli S. Cummings, Connie A. Bird, Gary S. Eddy, Edward M. Putney, James W. TI Male infertility in mice lacking the store-operated Ca2+ channel Orai1 SO CELL CALCIUM LA English DT Article DE Ca2+; Orai1; Store-operated calcium entry (SOCE); Reproduction; Fertility; Spermatogenesis ID CALCIUM-CHANNELS; MALE-FERTILITY; EGG ACTIVATION; ION CHANNELS; HUMAN SPERM; CELLS; ENTRY; STIM1; GENE; PROGESTERONE AB Store-operated calcium entry (SOCE) is an important Ca2+ influx pathway in somatic cells. In addition to maintaining endoplasmic reticulum (ER) Ca2+ stores, Ca2+ entry through store-operated channels regulates essential signaling pathways in numerous cell types. Patients with mutations in the store-operated channel subunit ORAI1 exhibit defects in store-operated Ca2+ influx, along with severe immunodeficiency, congenital myopathy and ectodermal dysplasia. However, little is known about the functional role of ORAI1 in germ cells and reproductive function in mice, or in men, since men with loss-of-function or null mutations in ORAI1 rarely survive to reproductive age. In this study, we investigated the role of ORAI1 in male reproductive function. We reveal that Orai1(-/-) male mice are sterile and have severe defects in spermatogenesis, with prominent deficiencies in mid- to late-stage elongating spermatid development. These studies establish an essential in vivo role for store-operated ORAI1 channels in male reproductive function and identify these channels as potential non-steroidal regulators of male fertility. Published by Elsevier Ltd. C1 [Davis, Felicity M.; D'Agostin, Diane M.; Bird, Gary S.; Putney, James W.] NIEHS, Signal Transduct Lab, NIH, Res Triangle Pk, NC 27709 USA. [Goulding, Eugenia H.; Eddy, Edward M.] NIEHS, Reprod & Dev Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Janardhan, Kyathanahalli S.] Integrated Lab Syst Inc, Res Triangle Pk, NC 27709 USA. [Cummings, Connie A.] UltraPath Imaging, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Signal Transduct Lab, NIH, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov RI Davis, Felicity/P-1387-2016 OI Davis, Felicity/0000-0001-9112-118X FU National Institutes of Health, National Institute of Environmental Health Sciences FX We thank John Brodie, Agnes Janoshazi, Page Myers, Pamela Ovwigho, Deloris Sutton and Victor Sutton for technical assistance. We thank Pathology Support Group, Cellular and Molecular Pathology Branch for their help with histology. Orair1+/- (Cracm1+/-) mice were provided by Dr. Jean-Pierre Kinet (Harvard Medical School). We thank Dr. Carl Bortner, in the NIEHS Flow Cytometry Center for his help in sorting and characterizing testicular cell populations. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 35 TC 0 Z9 0 U1 4 U2 5 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 EI 1532-1991 J9 CELL CALCIUM JI Cell Calcium PD APR PY 2016 VL 59 IS 4 BP 189 EP 197 DI 10.1016/j.ceca.2016.02.007 PG 9 WC Cell Biology SC Cell Biology GA DL7GZ UT WOS:000375810300006 PM 26969191 ER PT J AU Michaud, CR Qin, J Elkins, WR Gozalo, AS AF Michaud, Carmen R. Qin, Jing Elkins, William R. Gozalo, Alfonso S. TI Comparison of 3 Topical Treatments against Ulcerative Dermatitis in Mice with a C57BL/6 Background SO COMPARATIVE MEDICINE LA English DT Article ID VITAMIN-E; HYPOCHLORITE; ASSOCIATION; VASCULITIS; INFECTION AB Ulcerative dermatitis (UD) is a common condition in C57BL/6 mice and strains with this background. The etiology of UD is unclear but appears to have a genetic component associated with the C57BL/6 strain and has been reported as secondary to a variety of conditions. Treatment is unrewarding, resulting in euthanasia in many cases. In the present study we compared 3 topical treatments against spontaneous UD in mice with a C57BL/6 background. In total, 301 mice of both sexes were included in this study, and the tested treatments comprised bacitracin-neomycin sulfate-polymixin B sulfate ointment twice daily, 10% povidone-iodine ointment plus 1% silver sulfadiazine cream once daily, and 0.005% sodium hypochlorite once daily. Lesion healing was defined as complete skin reepithelialization with or without hair regrowth. Sex, age, lesion location, and type and length of treatment were analyzed by using univariate and multivariate logistic regression. Of the 79 mice treated with triple-antibiotic ointment, 27 (34%) healed, compared with 43 of the 125 (34%) treated with povidone-iodine and sulfadiazine and 69 of the 97 (71%) treated with hypochlorite. Lesion size and treatment with 0.005% sodium hypochlorite were the only significant predictors of healing; all other variables were not statistically significant in multivariate analysis. We conclude that 0.005% sodium hypochlorite is an effective topical treatment alternative for UD in C57BL/6 mice and strains on this background, and a favorable prognosis depends on the early identification and treatment of those lesions. C1 [Michaud, Carmen R.; Elkins, William R.; Gozalo, Alfonso S.] NIAID, Comparat Med Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Gozalo, AS (reprint author), NIAID, Comparat Med Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gozaloa@niaid.nih.gov FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases, Comparative Medicine Branch FX This study was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases, Comparative Medicine Branch. We are very grateful to the investigators and technical staff who made it possible for us to conduct this study. NR 33 TC 1 Z9 1 U1 3 U2 4 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD APR PY 2016 VL 66 IS 2 BP 100 EP 104 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA DL0VN UT WOS:000375350800003 PM 27053563 ER PT J AU Updegrove, TB Zhang, AX Storz, G AF Updegrove, Taylor B. Zhang, Aixia Storz, Gisela TI Hfq: the flexible RNA matchmaker SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID ESCHERICHIA-COLI HFQ; SM-LIKE PROTEIN; MESSENGER-RNA; SOLUBLE-RNAS; BINDING PROPERTIES; RECOGNITION; CHAPERONE; COMPLEX; RPOS; TRANSLATION AB The RNA chaperone protein Hfq is critical to the function of small, base pairing RNAs in many bacteria. In the past few years, structures and modeling of wild type Hfq and assays of various mutants have documented that the homohexameric Hfq ring can contact RNA at four sites (proximal face, distal face, rim and C-terminal tail) and that different RNAs bind to these sites in various configurations. These studies together with novel in vitro and in vivo experimental approaches are beginning to give mechanistic insights into how Hfq acts to promote small RNA-mRNA pairing and indicate that flexibility is integral to the Hfq role in RNA matchmaking. C1 [Updegrove, Taylor B.; Zhang, Aixia; Storz, Gisela] NICHD, Div Mol & Cellular Biol, NIH, 18 Lib Dr MSC 5430, Bethesda, MD 20892 USA. RP Storz, G (reprint author), NICHD, Div Mol & Cellular Biol, NIH, 18 Lib Dr MSC 5430, Bethesda, MD 20892 USA. EM storzg@mail.nih.gov OI Updegrove, Taylor/0000-0002-9763-3618 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [ZIA HD001608] FX We thank S Gottesman and S Woodson and members of their groups for comments. Work in the Storz laboratory is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Project ZIA HD001608). NR 45 TC 10 Z9 10 U1 11 U2 22 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD APR PY 2016 VL 30 BP 133 EP 138 DI 10.1016/j.mib.2016.02.003 PG 6 WC Microbiology SC Microbiology GA DK2AI UT WOS:000374716600018 PM 26907610 ER PT J AU Roederer, M AF Roederer, Mario TI Distributions of Autofluorescence After Compensation: Be Panglossian, Fret Not SO CYTOMETRY PART A LA English DT Article DE instrumentation; controls; data analysis AB In this technical note, I describe an in silico model of multiparameter fluorescence measurements that takes into account intrinsic cellular autofluorescence and stained dye fluorescence distributions, fluorescence spectrum spillovers, and photon counting statistics. Using this model, it is easy to manipulate spectral variables as well as error terms to understand the impact of each on the distributions of estimated cell-associated dyes (e.g., conjugated monoclonal antibodies in immunophenotyping). An application of this model was to understand the genesis of unusual autofluorescence distributions that occasionally happen in multi-color immunophenotyping. These unusual distributions show striking correlated patterns (diagonals) for graphs of certain pairs of parameters. Here I show that these arise from combinations of spillover-spreading from unviewed parameters. While disconcerting to researchers taught to look for diagonals in distributions as heralding improper compensation, these distributions are in fact appropriate. In general, one can ignore the characteristics of cell distributions within the same limits as background (e.g., as proscribed by a fluorescence-minus-one, or FMO, control), as there is essentially no information content in that region. Published 2016 International Society for Advancement of Cytometry. C1 [Roederer, Mario] NIAID, Flow Cytometry Core, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. EM Roederer@nih.gov FU Intramural Research Program of the Vaccine Research Center, NIAID, NIH FX Grant sponsor: Intramural Research Program of the Vaccine Research Center, NIAID, NIH. NR 5 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD APR PY 2016 VL 89A IS 4 BP 398 EP 402 DI 10.1002/cyto.a.22820 PG 5 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DK2FQ UT WOS:000374730400010 PM 26859757 ER PT J AU Darr, RW Lenzner, S Eggermann, T Darr, WH AF Daerr, Roland Wolfgang Lenzner, Steffen Eggermann, Thomas Daerr, Wolfgang Hermann TI Xanthinuria Type 1 in a Patient with Joint Pains SO DEUTSCHE MEDIZINISCHE WOCHENSCHRIFT LA German DT Article ID ACUTE-RENAL-FAILURE; INBORN-ERRORS; HEREDITARY XANTHINURIA; CLASSICAL XANTHINURIA; HYPOURICEMIA; MUTATIONS; EXERCISE; DEFICIENCY; METABOLISM; GENE C1 [Daerr, Roland Wolfgang] NICHD, Innere Med Diabetol & Endokrinol, Zeit Stipendiat Deutsch Forschungsgemeinsch, NIH,Bereich Neuroendokrinol, Bethesda, MD USA. [Lenzner, Steffen] Inst Med Diagnost GmbH, Abteilungsleiter Teilbereich Mol Genet, Ingelheim, Germany. [Eggermann, Thomas] Inst Humangenet RWTH, Aachen, Germany. [Daerr, Wolfgang Hermann] Vivantes Klinikum Friedrichshain, Klin Innere Med Nephrol, Berlin, Germany. [Daerr, Wolfgang Hermann] Klinikum Dobeln, Dobeln, Germany. RP Darr, RW (reprint author), NICHD, Innere Med Diabetol & Endokrinol, Zeit Stipendiat Deutsch Forschungsgemeinsch, NIH,Bereich Neuroendokrinol, Bethesda, MD USA.; Lenzner, S (reprint author), Inst Med Diagnost GmbH, Abteilungsleiter Teilbereich Mol Genet, Ingelheim, Germany.; Eggermann, T (reprint author), Inst Humangenet RWTH, Aachen, Germany.; Darr, WH (reprint author), Vivantes Klinikum Friedrichshain, Klin Innere Med Nephrol, Berlin, Germany.; Darr, WH (reprint author), Klinikum Dobeln, Dobeln, Germany. EM roland_daerr@web.de; steffen.lenzner@bioscientia.de; teggermann@ukaachen.de; wolfgang-daerr@t-online.de NR 35 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0012-0472 EI 1439-4413 J9 DEUT MED WOCHENSCHR JI Dtsch. Med. Wochenschr. PD APR PY 2016 VL 141 IS 8 BP 571 EP + DI 10.1055/s-0041-106053 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DJ8XC UT WOS:000374496200022 PM 27078247 ER PT J AU Levenson, AE Haas, ME Miao, J Brown, RJ de Ferranti, SD Muniyappa, R Biddinger, SB AF Levenson, Amy E. Haas, Mary E. Miao, Ji Brown, Rebecca J. de Ferranti, Sarah D. Muniyappa, Ranganath Biddinger, Sudha B. TI Effect of Leptin Replacement on PCSK9 in ob/ob Mice and Female Lipodystrophic Patients SO ENDOCRINOLOGY LA English DT Article ID DENSITY-LIPOPROTEIN RECEPTOR; LONG-TERM EFFICACY; LDL CHOLESTEROL; PLASMA PCSK9; GENERALIZED LIPODYSTROPHY; INSULIN-RESISTANCE; OBESE MICE; PROTEIN; HYPERCHOLESTEROLEMIA; METABOLISM AB Leptin treatment has beneficial effects on plasma lipids in patients with lipodystrophy, but the underlying mechanism is unknown. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases low-density lipoprotein (LDL) clearance, promotes hypercholesterolemia, and has recently emerged as a novel therapeutic target. To determine the effect of leptin on PCSK9, we treated male and female ob/ob mice with leptin for 4 days via sc osmotic pumps (similar to 24 mu g/d). Leptin reduced body weight and food intake in all mice, but the effects of leptin on plasma PCSK9 and lipids differed markedly between the sexes. In male mice, leptin suppressed PCSK9 but had no effect on plasma triglycerides or cholesterol. In female mice, leptin suppressed plasma triglycerides and cholesterol but had no effect on plasma PCSK9. In parallel, we treated female lipodystrophic patients (8 females, ages 5-23 y) with sc metreleptin injections (similar to 4.4 mg/d) for 4-6 months. In this case, leptin reduced plasma PCSK9 by 26% (298 +/- 109 vs 221 +/- 102 ng/mL; n = 8; P = .008), and the change in PCSK9 was correlated with a decrease in LDL cholesterol (r(2) = 0.564, P = .03). In summary, in leptin-deficient ob/ob mice, the effects of leptin on PCSK9 and plasma lipids appeared to be independent of one another and strongly modified by sex. On the other hand, in lipodystrophic females, leptin treatment reduced plasma PCSK9 in parallel with LDL cholesterol. C1 [Levenson, Amy E.; Haas, Mary E.; Miao, Ji; Biddinger, Sudha B.] Harvard Univ, Sch Med, Div Endocrinol, Boston Childrens Hosp, Boston, MA 02115 USA. [Brown, Rebecca J.; Muniyappa, Ranganath] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [de Ferranti, Sarah D.] Harvard Univ, Sch Med, Dept Cardiol, Boston Childrens Hosp, Boston, MA 02115 USA. RP Biddinger, SB (reprint author), Boston Childrens Hosp, CLSB 16027,300 Longwood Ave, Boston, MA 02115 USA. EM sudha.biddinger@childrens.harvard.edu OI Haas, Mary Elizabeth/0000-0002-2816-9268 FU National Institutes of Health [R01HL109650-05, 5K12DK094721-05, K99DK100539-02]; Department of Defense through the National Defense Science and Engineering Graduate Fellowship Program; Farb Family Fund; Kostin Family Innovation Fund; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by National Institutes of Health Grants R01HL109650-05 (to S.B.B.), 5K12DK094721-05 (to A.E.L.), and K99DK100539-02 to (J.M.); M.E.H. was supported by the Department of Defense through the National Defense Science and Engineering Graduate Fellowship Program; S.D.d.F. was supported by the Farb Family Fund and by the Kostin Family Innovation Fund. Human studies were funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 52 TC 0 Z9 0 U1 2 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2016 VL 157 IS 4 BP 1421 EP 1429 DI 10.1210/en.2015-1624 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK0CK UT WOS:000374579800013 PM 26824363 ER PT J AU Zemkova, H Tomic, M Kucka, M Aguilera, G Stojilkovic, SS AF Zemkova, Hana Tomic, Melanija Kucka, Marek Aguilera, Greti Stojilkovic, Stanko S. TI Spontaneous and CRH-Induced Excitability and Calcium Signaling in Mice Corticotrophs Involves Sodium, Calcium, and Cation-Conducting Channels SO ENDOCRINOLOGY LA English DT Article ID HYPOPHYSEAL PORTAL BLOOD; ANTERIOR-PITUITARY-CELLS; SECRETING ADENOMA CELLS; PROTEIN-KINASE-A; K+ BK CHANNELS; ARGININE-VASOPRESSIN; RAT CORTICOTROPES; CA2+ ENTRY; ELECTRICAL-ACTIVITY; ARACHIDONIC-ACID AB Transgenic mice expressing the tdimer2(12) form of Discosoma red fluorescent protein under control of the proopiomelanocortin gene's regulatory elements are a useful model for studying corticotrophs. Using these mice, we studied the ion channels and mechanisms controlling corticotroph excitability. Corticotrophs were either quiescent or electrically active, with a 22-mV difference in the resting membrane potential (RMP) between the 2 groups. In quiescent cells, CRH depolarized the membrane, leading to initial single spiking and sustained bursting; in active cells, CRH further facilitated or inhibited electrical activity and calcium spiking, depending on the initial activity pattern and CRH concentration. The stimulatory but not inhibitory action of CRH on electrical activity was mimicked by cAMP independently of the presence or absence of arachidonic acid. Removal of bath sodium silenced spiking and hyperpolarized the majority of cells; in contrast, the removal of bath calcium did not affect RMP but reduced CRH-induced depolarization, which abolished bursting electrical activity and decreased the spiking frequency but not the amplitude of single spikes. Corticotrophs with inhibited voltage-gated sodium channels fired calcium-dependent action potentials, whereas cells with inhibited L-type calcium channels fired sodium-dependent spikes; blockade of both channels abolished spiking without affecting the RMP. These results indicate that the background voltage-insensitive sodium conductance influences RMP, the CRH-depolarization current is driven by a cationic conductance, and the interplay between voltage-gated sodium and calcium channels plays a critical role in determining the status and pattern of electrical activity and calcium signaling. C1 [Zemkova, Hana] Acad Sci Czech Republic, Inst Physiol, Dept Cellular & Mol Neuroendocrinol, Videnska 1083, CR-14220 Prague 4, Czech Republic. [Zemkova, Hana; Tomic, Melanija; Kucka, Marek; Stojilkovic, Stanko S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Signaling, NIH, Bethesda, MD 20892 USA. [Aguilera, Greti] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrine Physiol, NIH, Bethesda, MD 20892 USA. RP Zemkova, H (reprint author), Acad Sci Czech Republic, Inst Physiol, Videnska 1083, CR-14220 Prague 4, Czech Republic. EM zemkova@biomed.cas.cz RI Zemkova, Hana/C-1844-2012 FU Grant Agency of the Czech Republic [P304/12/G069]; Ministry of Education, Youth and Sports of CR within National Sustainability Program II (Project BIOCEV-FAR) [LQ1604]; project "BIOCEV" [CZ.1.05/1.1.00/02.0109]; Intramural Research Program of the National Institute of Child Health and Human Development, National Institute of Health FX This work was supported by the Grant Agency of the Czech Republic P304/12/G069, the Ministry of Education, Youth and Sports of CR within the LQ1604 National Sustainability Program II (Project BIOCEV-FAR) and by the project "BIOCEV" (CZ.1.05/1.1.00/02.0109) (to H.Z.), and by a grant from the Intramural Research Program of the National Institute of Child Health and Human Development, National Institute of Health (M.T., M.K., G.A., and S.S.S.). NR 46 TC 1 Z9 1 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2016 VL 157 IS 4 BP 1576 EP 1589 DI 10.1210/en.2015-1899 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DK0CK UT WOS:000374579800026 PM 26901094 ER PT J AU Charmoy, M Hurrell, BP Romano, A Lee, SH Ribeiro-Gomes, F Riteau, N Mayer-Barber, K Tacchini-Cottier, F Sacks, DL AF Charmoy, Melanie Hurrell, Benjamin P. Romano, Audrey Lee, Sang Hun Ribeiro-Gomes, Flavia Riteau, Nicolas Mayer-Barber, Katrin Tacchini-Cottier, Fabienne Sacks, David L. TI The Nlrp3 inflammasome, IL-1 beta, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE IL-1 beta; Leishmaniasis; Nlrp3 inflammasome; Neutrophils; Skin ID CUTANEOUS LEISHMANIASIS; IMMUNE-RESPONSE; NATURAL MODEL; CXCR2 LIGAND; KC/GRO-ALPHA; INFECTION; DEFICIENT; CELLS; RESISTANCE; APOPTOSIS AB Infection of C57BL/6 mice with most Leishmania major strains results in a healing lesion and clearance of parasites from the skin. Infection of C57BL/6 mice with the L. major Seidman strain (LmSd), isolated from a patient with chronic lesions, despite eliciting a strong Th1 response, results in a nonhealing lesion, poor parasite clearance, and complete destruction of the ear dermis. We show here that in comparison to a healing strain, LmSd elicited early upregulation of IL-1 beta mRNA and IL-1 beta-producing dermal cells and prominent neutrophil recruitment to the infected skin. Mice deficient in Nlrp3, apoptosis-associated speck-like protein containing a caspase recruitment domain, or caspase-1/11, or lacking IL-1 beta or IL-1 receptor signaling, developed healing lesions and cleared LmSd from the infection site. Mice resistant to LmSd had a stronger antigen-specific Th1 response. The possibility that IL-1 beta might act through neutrophil recruitment to locally suppress immunity was supported by the healing observed in neutropenic Genista mice. Secretion of mature IL-1 beta by LmSd-infected macrophages in vitro was dependent on activation of the Nlrp3 inflammasome and caspase-1. These data reveal that Nlrp3 inflammasome-dependent IL-1 beta, associated with localized neutrophil recruitment, plays a crucial role in the development of a nonhealing form of cutaneous leishmaniasis in conventionally resistant mice. C1 [Charmoy, Melanie; Romano, Audrey; Lee, Sang Hun; Ribeiro-Gomes, Flavia; Riteau, Nicolas; Mayer-Barber, Katrin; Sacks, David L.] NIAID, Parasit Dis Lab, NIH, Bldg 4,Rm B1-12,Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. [Hurrell, Benjamin P.; Tacchini-Cottier, Fabienne] Univ Lausanne, Dept Biochem, WHO Immunol Res & Training Ctr, Lausanne, Switzerland. RP Sacks, DL (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Rm B1-12,Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. EM dsacks@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Swiss National Foundation [310030.146187/1] FX We thank Kim Beacht for assistance with the animal infection studies, and Dragana Jankovic for helpful discussions and provision of the IL-27Ra-/- mice, and Marie and Bernard Malissen for the Genista mice. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part by the Swiss National Foundation, grant 310030.146187/1 to F.T.C. NR 41 TC 6 Z9 6 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD APR PY 2016 VL 46 IS 4 BP 897 EP 911 DI 10.1002/eji.201546015 PG 15 WC Immunology SC Immunology GA DJ9SH UT WOS:000374552700012 PM 26689285 ER PT J AU Cabrera, SM Wang, XJ Chen, YG Jia, S Kaldunski, ML Greenbaum, CJ Mandrup-Poulsen, T Hessner, MJ AF Cabrera, Susanne M. Wang, Xujing Chen, Yi-Guang Jia, Shuang Kaldunski, Mary L. Greenbaum, Carla J. Mandrup-Poulsen, Thomas Hessner, Martin J. CA Type 1 Diabet TrialNet Canakinumab AIDA Study Grp TI Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Anakinra; Canakinumab; Interleukin-1; Transcriptional signatures; Type 1 diabetes ID RAT PANCREATIC-ISLETS; MELLITUS; SERUM; EXPRESSION; MOUSE; BIOINFORMATICS; IDENTIFICATION; BIOSYNTHESIS; LANGERHANS; IL-1-ALPHA AB It was hypothesized that IL-1 antagonism would preserve beta-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured by stimulated C-peptide response. Additional measures are needed to define immune state changes associated with therapeutic responses. Here, we studied these trial participants with plasma-induced transcriptional analysis. In blinded analyses, 70.2% of AIDA and 68.9% of TN-14 participants were correctly called to their treatment arm. While the transcriptional signatures from the two trials were distinct, both therapies achieved varying immunomodulation consistent with IL-1 inhibition. On average, IL-1 antagonism resulted in modest normalization relative to healthy controls. At endpoint, signatures were quantified using a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1 alpha and IL-1 beta additively contribute to the T1D inflammatory state. Finally, analyses of baseline signatures were indicative of later therapeutic response. Despite the absence of clinical efficacy by IL-1 antagonist therapy, transcriptional analysis detected immunomodulation and may yield new insight when applied to other clinical trials. C1 [Cabrera, Susanne M.; Chen, Yi-Guang; Jia, Shuang; Kaldunski, Mary L.; Hessner, Martin J.] Childrens Hosp Wisconsin, Max McGee Natl Res Ctr Juvenile Diabet, Childrens Res Inst, Milwaukee, WI 53201 USA. [Cabrera, Susanne M.; Chen, Yi-Guang; Jia, Shuang; Kaldunski, Mary L.; Hessner, Martin J.; Type 1 Diabet TrialNet Canakinumab; AIDA Study Grp] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Wang, Xujing] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Greenbaum, Carla J.] Benaroya Res Inst, Diabet Res Program, Seattle, WA USA. [Mandrup-Poulsen, Thomas] Univ Copenhagen, Dept Biomed Sci, Fac Hlth & Med Sci, Copenhagen, Denmark. [Mandrup-Poulsen, Thomas] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. RP Hessner, MJ (reprint author), Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. EM mhessner@mcw.edu OI Castano, Luis/0000-0003-0437-9401 FU Juvenile Diabetes Research Foundation [1-2008-1026, 5-2012-220, 17-2012-621, 2-SRA-2015-109-Q-R]; American Diabetes Association [7-12-BS-075]; National Institutes of Health [R01AI078713, DP3DK098161, R01DK080100]; National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000055]; Children's Hospital of Wisconsin Foundation; National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, U01 DK085509, HHSN267200800019C]; National Center for Research Resources, through Clinical Translational Science Awards [UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986]; General Clinical Research Center Award [M01 RR00400]; JDRF; American Diabetes Association; Type 1 Diabetes TrialNet Study Group FX This ancillary study was supported by The Juvenile Diabetes Research Foundation International (grants 1-2008-1026, 5-2012-220, 17-2012-621, 2-SRA-2015-109-Q-R to M.J.H.); American Diabetes Association (grant 7-12-BS-075 to M.J.H.); National Institutes of Health (grants R01AI078713 to M.J.H., DP3DK098161 to M.J.H./C.J.G., R01DK080100 to X.W., and the National Center for Advancing Translational Sciences, National Institutes of Health grant 8UL1TR000055); and The Children's Hospital of Wisconsin Foundation.; The canakinumab trial was sponsored by the Type 1 Diabetes TrialNet Study Group. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through the cooperative agreements U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, U01 DK085509, and contract HHSN267200800019C; the National Center for Research Resources, through Clinical Translational Science Awards UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, and General Clinical Research Center Award M01 RR00400; the JDRF; and the American Diabetes Association. Novartis (Basel, Switzerland) provided canakinumab (Ilaris), input regarding dosage, and other suggestions but had no direct involvement with study design, conduct, or management; data collection, analysis or interpretation; or manuscript preparation. Roche Diagnostics provided blood glucose monitoring meters and strips to research participants in the canakinumab trial. NR 38 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD APR PY 2016 VL 46 IS 4 BP 1030 EP 1046 DI 10.1002/eji.201546005 PG 17 WC Immunology SC Immunology GA DJ9SH UT WOS:000374552700025 PM 26692253 ER PT J AU Fansiri, T Pongsiri, A Klungthong, C Ponlawat, A Thaisomboonsuk, B Jarman, RG Scott, TW Lambrechts, L AF Fansiri, Thanyalak Pongsiri, Arissara Klungthong, Chonticha Ponlawat, Alongkot Thaisomboonsuk, Butsaya Jarman, Richard G. Scott, Thomas W. Lambrechts, Louis TI No evidence for local adaptation of dengue viruses to mosquito vector populations in Thailand SO EVOLUTIONARY APPLICATIONS LA English DT Article DE Aedes aegypti; dengue virus; genotype x genotype interactions; local adaptation; population structure ID AEDES-AEGYPTI POPULATIONS; KAMPHAENG-PHET; ORAL-SUSCEPTIBILITY; GLOBAL DISTRIBUTION; CLADE REPLACEMENT; GENETIC-STRUCTURE; TRANSMISSION; INFECTION; STRAINS; MEXICO AB Despite their epidemiological importance, the evolutionary forces that shape the spatial structure of dengue virus genetic diversity are not fully understood. Fine-scale genetic structure of mosquito vector populations and evidence for genotype x genotype interactions between dengue viruses and their mosquito vectors are consistent with the hypothesis that the geographical distribution of dengue virus genetic diversity may reflect viral adaptation to local mosquito populations. To test this hypothesis, we measured vector competence in all sympatric and allopatric combinations of 14 low-passage dengue virus isolates and two wild-type populations of Aedes aegypti mosquitoes sampled in Bangkok and Kamphaeng Phet, two sites located about 300km apart in Thailand. Despite significant genotype x genotype interactions, we found no evidence for superior vector competence in sympatric versus allopatric vector-virus combinations. Viral phylogenetic analysis revealed no geographical clustering of the 14 isolates, suggesting that high levels of viral migration (gene flow) in Thailand may counteract spatially heterogeneous natural selection. We conclude that it is unlikely that vector-mediated selection is a major driver of dengue virus adaptive evolution at the regional scale that we examined. Dengue virus local adaptation to mosquito vector populations could happen, however, in places or times that we did not test, or at a different geographical scale. C1 [Fansiri, Thanyalak; Pongsiri, Arissara; Ponlawat, Alongkot] Armed Forces Res Inst Med Sci, Dept Entomol, Bangkok 10400, Thailand. [Klungthong, Chonticha; Thaisomboonsuk, Butsaya; Jarman, Richard G.] Armed Forces Res Inst Med Sci, Dept Virol, Bangkok 10400, Thailand. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Lambrechts, Louis] Inst Pasteur, Dept Genomes & Genet, Insect Virus Interact Grp, 28 Rue Docteur Roux, F-75724 Paris 15, France. [Lambrechts, Louis] Ctr Natl Rech Sci, Unite Rech Associee, Paris, France. [Jarman, Richard G.] Walter Reed Army Inst Res, Viral Dis Branch, Silver Spring, MD USA. RP Lambrechts, L (reprint author), Inst Pasteur, Dept Genomes & Genet, Insect Virus Interact Grp, 28 Rue Docteur Roux, F-75724 Paris 15, France. EM louis.lambrechts@pasteur.fr RI Lambrechts, Louis/A-2057-2010 OI Lambrechts, Louis/0000-0001-5958-2138 FU United States National Institutes of Health [R01-GM083224]; United States Military Infectious Diseases Research Program; French Agence Nationale de la Recherche [ANR-09-RPDOC-007-01]; French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases [ANR-10-LABX-62-IBEID]; City of Paris Emergence(s) program in Biomedical Research; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, United States National Institutes of Health; United States National Institutes of Health and Human Services [P01-AI098670] FX We acknowledge the invaluable contributions of the clinical, laboratory, and entomological personnel of AFRIMS and Kamphaeng Phet AFRIMS Virology Research Unit (KAVRU). We are grateful to Robert Gibbons, Stefan Fernandez, Timothy Endy, Anthony Schuster, and three anonymous reviewers for their insights. The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the official views of the United States Army, Royal Thai Army, or the United States Department of Defense. This study was primarily supported by grant R01-GM083224 from the United States National Institutes of Health and by the United States Military Infectious Diseases Research Program. L.L. received funding from the French Agence Nationale de la Recherche (grant ANR-09-RPDOC-007-01), the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (grant ANR-10-LABX-62-IBEID), and the City of Paris Emergence(s) program in Biomedical Research. T.W.S. received support from the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and Fogarty International Center, United States National Institutes of Health. L.L. and T.W.S. received support from the United States National Institutes of Health and Human Services (grant P01-AI098670). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-4571 J9 EVOL APPL JI Evol. Appl. PD APR PY 2016 VL 9 IS 4 BP 608 EP 618 DI 10.1111/eva.12360 PG 11 WC Evolutionary Biology SC Evolutionary Biology GA DJ9SM UT WOS:000374553200007 PM 27099625 ER PT J AU Thorgeirsson, SS AF Thorgeirsson, Snorri S. TI Stemness and Reprogramming in Liver Cancer SO HEPATOLOGY LA English DT Editorial Material ID BILIARY ORIGIN; CELL ORIGIN; HEPATOCYTES C1 [Thorgeirsson, Snorri S.] NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NIH, Human Carcinogenesis Lab, Ctr Canc Res, 37 Convent Dr,MSC 4262,Bldg 37,Room 4128B, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov NR 20 TC 0 Z9 0 U1 4 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2016 VL 63 IS 4 BP 1068 EP 1070 DI 10.1002/hep.28362 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK2HW UT WOS:000374736300001 PM 26600290 ER PT J AU Unalp-Arida, A Ruhl, CE AF Unalp-Arida, Aynur Ruhl, Constance E. TI Noninvasive Fatty Liver Markers Predict Liver Disease Mortality in the US Population SO HEPATOLOGY LA English DT Article ID SERUM ALANINE AMINOTRANSFERASE; NUTRITION EXAMINATION SURVEY; UNITED-STATES POPULATION; SUPERFAMILY MEMBER 2; 3RD NATIONAL-HEALTH; CARDIOVASCULAR-DISEASE; NONALCOHOLIC STEATOHEPATITIS; CONFERS SUSCEPTIBILITY; CAFFEINE CONSUMPTION; HEPATIC STEATOSIS AB Nonalcoholic fatty liver disease (NAFLD) contributes to premature death along with obesity, diabetes, and cardiovascular disease (CVD). We examined whether hepatic steatosis (HS) on ultrasound and liver enzyme activities were associated with increased liver disease mortality in the U.S. National Health and Nutrition Examination Survey (NHANES), 1988-1994, with up to 23 years of linked-mortality data. Survey-linked National Death Index records were analyzed among 14,527 adult participants who were negative for viral hepatitis B and C and iron overload. HS on ultrasound was categorized as normal, mild, moderate, or severe. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) elevation was defined as the highest sex-specific decile. Cumulative mortality was 36.2% from all causes, including 16.3% from CVD, 10.8% from cancer, 5.4% from diabetes, and 1.1% from liver disease. Severe HS was associated with increased liver disease mortality in both age-adjusted (hazard ratio [HR]: 3.92; 95% confidence interval [CI]: 1.49-10.27; P for trend: 0.011) and multivariate-adjusted analyses (HR, 2.68; 95% CI: 1.02-7.03; P for trend: 0.072). HS was not independently associated with mortality from all causes, CVD, cancer, or diabetes. Higher liver disease mortality was found with elevated ALT (HR, 4.08; 95% CI: 1.99-8.33), AST (HR, 4.33; 95% CI: 2.18-8.59), and GGT (HR, 7.91; 95% CI: 3.06-20.46). GGT elevation was associated with increased overall mortality (HR, 1.45; 95% CI: 1.21-1.74). Liver enzymes were otherwise unrelated to overall or cause-specific mortality. Conclusions: In the U. S. population, severe hepatic steatosis on ultrasound and liver enzyme elevation were associated with increased liver disease mortality, but were not independently associated with mortality from all causes (except for GGT), CVD, cancer, or diabetes. C1 [Unalp-Arida, Aynur] NIDDK, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Ruhl, Constance E.] Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM cruhl@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases [HHSN276201200161U] FX The work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN276201200161U). NR 47 TC 2 Z9 2 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2016 VL 63 IS 4 BP 1170 EP 1183 DI 10.1002/hep.28390 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DK2HW UT WOS:000374736300015 PM 26663021 ER PT J AU Chrysostomou, PP Lodish, MB Turkbey, EB Papadakis, GZ Stratakis, CA AF Chrysostomou, P. P. Lodish, M. B. Turkbey, E. B. Papadakis, G. Z. Stratakis, C. A. TI Use of 3-Dimensional Volumetric Modeling of Adrenal Gland Size in Patients with Primary Pigmented Nodular Adrenocortical Disease SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE PPNAD; 3D imaging; CT; adrenals; cushing's syndrome ID CUSHINGS-SYNDROME; COMPUTED-TOMOGRAPHY; PRKAR1A GENE; DIAGNOSIS; TUMORS; DEXAMETHASONE; HYPERPLASIAS; MUTATIONS; COMPLEX AB Primary pigmented nodular adrenocortical disease (PPNAD) is a rare type of bilateral adrenal hyperplasia leading to hypercortisolemia. Adrenal nodularity is often appreciable with computed tomography (CT); however, accurate radiologic characterization of adrenal size in PPNAD has not been studied well. We used 3-dimensional (3D) volumetric analysis to characterize and compare adrenal size in PPNAD patients, with and without Cushing's syndrome (CS). Patients diagnosed with PPNAD and their family members with known mutations in PRKAR1A were screened. CT scans were used to create 3D models of each adrenal. Criteria for biochemical diagnosis of CS included loss of diurnal variation and/or elevated midnight cortisol levels, and paradoxical increase in urinary free cortisol and/or urinary 17-hydroxysteroids after dexamethasone administration. Forty-five patients with PPNAD (24 females, 27.8 +/- 17.6 years) and 8 controls (19 +/- 3 years) were evaluated. 3D volumetric modeling of adrenal glands was performed in all. Thirty-eight patients out of 45 (84.4%) had CS. Their mean adrenal volume was 8.1 cc +/- 4.1, 7.2 cc +/- 4.5 (p=0.643) for non-CS, and 8.0cc +/- 1.6 for controls. Mean values were corrected for body surface area; 4.7cc/kg/m(2)+/- 2.2 for CS, and 3.9cc/kg/m(2)+/- 1.3 for non-CS (p=0.189). Adrenal volume and midnight cortisol in both groups was positively correlated, r=0.35, p=0.03. We conclude that adrenal volume measured by 3D CT in patients with PPNAD and CS was similar to those without CS, confirming empirical CT imaging-based observations. However, the association between adrenal volume and midnight cortisol levels may be used as a marker of who among patients with PPNAD may develop CS, something that routine CT cannot do. C1 [Chrysostomou, P. P.; Lodish, M. B.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. [Turkbey, E. B.] NIH, Ctr Clin, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Turkbey, E. B.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Papadakis, G. Z.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NIH, Div Intramural Res, 31 Ctr Dr Bldg 31 Room 2A46 MSC 2425, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU NICHO, NIH FX This work was supported by the Intramural Research Program, NICHO, NIH. NR 17 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD APR PY 2016 VL 48 IS 4 BP 242 EP 246 DI 10.1055/s-0042-103686 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DJ5JF UT WOS:000374242700005 PM 27065461 ER PT J AU Osinga, TE Xekouki, P Nambuba, J Faucz, FR Sierra, MD Links, TP Kema, IP Adams, K Stratakis, CA van der Horst-Schrivers, ANA Pacak, K AF Osinga, T. E. Xekouki, P. Nambuba, J. Faucz, F. R. Sierra, M. de la Luz Links, T. P. Kema, I. P. Adams, K. Stratakis, C. A. van der Horst-Schrivers, A. N. A. Pacak, K. TI SDH Subunit Mutation Status in Saliva: Genetic Testing in Patients with Pheochromocytoma SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE SDHx mutations; pheochromocytoma; paraganglioma; DNA; saliva ID PARAGANGLIOMA AB Germline mutations occur in up to 30-40% of pheochromocytoma/paraganglioma, with mutations in the succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD) being the most common. Blood samples are favored for obtaining high quality DNA, however, leukocytes can also be obtained by collecting saliva. The aim of this study was to determine whether SDHB and SDHD gene mutations in patients with pheochromocytoma/paraganglioma could be determined using a salivary sample. Paired blood and salivary samples were collected from 30 patients: 9 SDHB mutation positive, 13 with a SDHD mutation, and 8 without any SDHx mutations. The Oragene DISCOVER kit was used to collect and extract DNA from saliva. Blood DNA was extracted from EDTA blood samples. The DNA purification and concentration were measured by spectrophotometry. The 8 exons of SDHB and the 4 exons of SDHD were amplified and sequenced by PCR-based bidirectional Sanger sequencing. Total DNA yields from blood DNA were similar to those obtained from saliva DNA [mean (+/- SD) saliva vs. blood DNA concentration 514.6 (+/- 580.8)ng/mu l vs. 360.9 (+/- 262.7)ng/mu l; p=0.2)]. The purity of the saliva DNA samples was lower than that of blood [mean OD260/OD280 ratio 1.78 (+/- 0.13) vs. 1.87 (+/- 0.04); p=0.001, respectively], indicating more protein contamination in the saliva-extracted DNA. This study shows that salivary DNA collected from patients with pheochromocytoma/paraganglioma is a good alternative for extraction of genomic DNA for its high DNA concentration and acceptable purity and can be used as an alternative to blood derived DNA in screening for SDHB and SDHD mutations. C1 [Osinga, T. E.; Nambuba, J.; Adams, K.; Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Osinga, T. E.; Links, T. P.; van der Horst-Schrivers, A. N. A.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol & Metab Dis, Groningen, Netherlands. [Xekouki, P.; Faucz, F. R.; Sierra, M. de la Luz; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. [Kema, I. P.] Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, Groningen, Netherlands. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Med, NIH, Bldg 10,CRC,Room 1E-3140 10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NR 9 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD APR PY 2016 VL 48 IS 4 BP 247 EP 250 DI 10.1055/s-0035-1569265 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DJ5JF UT WOS:000374242700006 PM 26916530 ER PT J AU Vinnakota, KC Cha, CY Rorsman, P Balaban, RS La Gerche, A Wade-Martins, R Beard, DA Jeneson, JAL AF Vinnakota, Kalyan C. Cha, Chae Y. Rorsman, Patrik Balaban, Robert S. La Gerche, Andre Wade-Martins, Richard Beard, Daniel A. Jeneson, Jeroen A. L. TI Improving the physiological realism of experimental models SO INTERFACE FOCUS LA English DT Review DE physiology; experimental models; human ID PANCREATIC BETA-CELLS; RAT-HEART MITOCHONDRIA; WORKING RABBIT HEART; PLURIPOTENT STEM-CELLS; OXIDATIVE-PHOSPHORYLATION; SKELETAL-MUSCLE; PARKINSONS-DISEASE; INSULIN-SECRETION; CALCIUM UNIPORTER; MYOCARDIAL OXYGENATION AB The Virtual Physiological Human (VPH) project aims to develop integrative, explanatory and predictive computational models (C-Models) as numerical investigational tools to study disease, identify and design effective therapies and provide an in silico platform for drug screening. Ultimately, these models rely on the analysis and integration of experimental data. As such, the success of VPH depends on the availability of physiologically realistic experimental models (E-Models) of human organ function that can be parametrized to test the numerical models. Here, the current state of suitable E-models, ranging from in vitro non-human cell organelles to in vivo human organ systems, is discussed. Specifically, challenges and recent progress in improving the physiological realism of E-models that may benefit the VPH project are highlighted and discussed using examples from the field of research on cardiovascular disease, musculoskeletal disorders, diabetes and Parkinson's disease. C1 [Vinnakota, Kalyan C.; Beard, Daniel A.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Cha, Chae Y.; Rorsman, Patrik] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Oxford OX3 7LJ, England. [Balaban, Robert S.] NHLBI, Lab Cardiac Energet, Bldg 10, Bethesda, MD 20892 USA. [La Gerche, Andre] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Wade-Martins, Richard] Univ Oxford, Oxford Parkinsons Dis Ctr, Oxford, England. [Wade-Martins, Richard] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Jeneson, Jeroen A. L.] Univ Groningen, Univ Med Ctr Groningen, Div Neurosci, Neuroimaging Ctr, NL-9713 AV Groningen, Netherlands. [Jeneson, Jeroen A. L.] Univ Amsterdam, Acad Med Ctr Amsterdam, Dept Radiol, Amsterdam, Netherlands. RP Jeneson, JAL (reprint author), Univ Groningen, Univ Med Ctr Groningen, Div Neurosci, Neuroimaging Ctr, NL-9713 AV Groningen, Netherlands. EM j.a.l.jeneson@umcg.nl OI Vinnakota, Kalyan/0000-0003-2185-2213 FU NIH [HL072011, GM094503]; Wellcome Trust FX This work was supported in part by NIH grants HL072011 (JALJ and DAB) and GM094503 (DAB) and by a Wellcome Trust senior investigator award (PR). NR 112 TC 1 Z9 1 U1 1 U2 4 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 2042-8898 EI 2042-8901 J9 INTERFACE FOCUS JI Interface Focus PD APR PY 2016 VL 6 IS 2 AR 20150076 DI 10.1098/rsfs.2015.0076 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DL1RY UT WOS:000375410900002 PM 27051507 ER PT J AU Agbor-Enoh, S Doveikis, J Zhu, J Tunc, I Wang, X Jackson, A Solomon, M Valentine, H AF Agbor-Enoh, S. Doveikis, J. Zhu, J. Tunc, I. Wang, X. Jackson, A. Solomon, M. Valentine, H. TI Urine Cell-Free Donor-Derived DNA (ucfdDNA) after Heart Transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT) CY APR 27-30, 2016 CL Washington, DC SP Int Soc Heart & Lung Transplantat C1 [Agbor-Enoh, S.; Doveikis, J.; Zhu, J.; Tunc, I.; Wang, X.; Solomon, M.; Valentine, H.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Jackson, A.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2016 VL 35 IS 4 SU S MA 20 BP S16 EP S16 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA DK2AX UT WOS:000374718100021 ER PT J AU Chan, JL Singh, AK Thomas, ML Ayares, DL Horvath, KA Mohiuddin, MM AF Chan, J. L. Singh, A. K. Thomas, M. L. Ayares, D. L. Horvath, K. A. Mohiuddin, M. M. TI Multi-Transgenic Expression for Improved Xenograft Survival in Pig-to-Baboon Heart Xenotransplantation Model SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT) CY APR 27-30, 2016 CL Washington, DC SP Int Soc Heart & Lung Transplantat C1 [Chan, J. L.; Singh, A. K.; Horvath, K. A.; Mohiuddin, M. M.] NHLBI, Cardiothorac Surg Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. [Thomas, M. L.] NIH, Div Vet Resources, Off Res Serv, Bldg 10, Bethesda, MD 20892 USA. [Ayares, D. L.] Revivicor Inc, Blacksburg, VA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2016 VL 35 IS 4 SU S MA 104 BP S47 EP S48 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA DK2AX UT WOS:000374718100105 ER PT J AU Danziger-Isakov, L Buller, R Williams, N Mason, S Fenchel, M Astor, T Conrad, C Faro, A Goldfarb, S Hayes, D Melicoff-Portillo, E Schecter, M Visner, G Ikle, D Storch, G Sweet, S AF Danziger-Isakov, L. Buller, R. Williams, N. Mason, S. Fenchel, M. Astor, T. Conrad, C. Faro, A. Goldfarb, S. Hayes, D. Melicoff-Portillo, E. Schecter, M. Visner, G. Ikle, D. Storch, G. Sweet, S. TI Respiratory Viral Infections Are Common in the First Year After Pediatric Lung Transplantation: A Multi-Center Prospective Study SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT) CY APR 27-30, 2016 CL Washington, DC SP Int Soc Heart & Lung Transplantat C1 [Danziger-Isakov, L.; Fenchel, M.; Schecter, M.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Buller, R.; Mason, S.; Faro, A.; Storch, G.; Sweet, S.] Washington Univ, St Louis, MO USA. [Williams, N.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Astor, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Conrad, C.] Lucille Packard Childrens Hosp, Palo Alto, CA USA. [Goldfarb, S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Hayes, D.] Nationwide Childrens Hosp, Columbus, OH USA. [Melicoff-Portillo, E.] Texas Childrens Hosp, Houston, TX 77030 USA. [Visner, G.] Boston Childrens Hosp, Boston, MA USA. [Ikle, D.] Rho Inc, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2016 VL 35 IS 4 SU S MA 71 BP S35 EP S35 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA DK2AX UT WOS:000374718100072 ER PT J AU Evans, CF Sanchez, PG Kon, ZN Wang, X Valantine, H Agbor-Enoh, S Iacono, AT Griffith, BP Pham, SM AF Evans, C. F. Sanchez, P. G. Kon, Z. N. Wang, X. Valantine, H. Agbor-Enoh, S. Iacono, A. T. Griffith, B. P. Pham, S. M. TI The Association between Donor-Recipient Race Matching and Survival Following Lung Transplantation Differs Based on Recipient Race SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT) CY APR 27-30, 2016 CL Washington, DC SP Int Soc Heart & Lung Transplantat C1 [Evans, C. F.; Sanchez, P. G.; Kon, Z. N.; Wang, X.; Griffith, B. P.; Pham, S. M.] Univ Maryland, Sch Med, Surg, Baltimore, MD 21201 USA. [Valantine, H.; Agbor-Enoh, S.] NHLBI, Genom Res Alliance Organ Transplantat, Baltimore, MD USA. [Iacono, A. T.] R Adams Cowley Shock Trauma Ctr, Pulm & Transplant Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2016 VL 35 IS 4 SU S MA 1036 BP S371 EP S371 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA DK2AX UT WOS:000374718101386 ER PT J AU Parrish, A Fenchel, M Storch, G Bulle, R Mason, S Mason, S Williams, N Ikle, D Sweet, S Danziger-Isakov, L AF Parrish, A. Fenchel, M. Storch, G. Bulle, R. Mason, S. Mason, S. Williams, N. Ikle, D. Sweet, S. Danziger-Isakov, L. TI Evaluation of Epstein-Barr Viral Loads as a Predictor of Development of Post-Transplant Lymphoproliferative Disorder SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT) CY APR 27-30, 2016 CL Washington, DC SP Int Soc Heart & Lung Transplantat C1 [Parrish, A.; Fenchel, M.; Danziger-Isakov, L.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Storch, G.; Bulle, R.; Mason, S.; Mason, S.; Sweet, S.] Washington Univ, St Louis, MO USA. [Williams, N.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Ikle, D.] Rho Inc, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2016 VL 35 IS 4 SU S MA 969 BP S349 EP S349 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA DK2AX UT WOS:000374718101324 ER PT J AU Siddiqui, AH Weir, NA WoldeHanna, ML Mazer, AJ Biancotto, A Cai, R Grariingen, G Harper, B Sun, J Nathan, SD Danner, RL Solomon, MA Elinoff, JM AF Siddiqui, A. H. Weir, N. A. WoldeHanna, M. Lemma Mazer, A. J. Biancotto, A. Cai, R. Grariingen, G. Harper, B. Sun, J. Nathan, S. D. Danner, R. L. Solomon, M. A. Elinoff, J. M. TI Serum Cytokine Profiling in Pulmonary Arterial Hypertension SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT) CY APR 27-30, 2016 CL Washington, DC SP Int Soc Heart & Lung Transplantat C1 [Siddiqui, A. H.; Mazer, A. J.; Cai, R.; Grariingen, G.; Harper, B.; Sun, J.; Danner, R. L.; Elinoff, J. M.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Weir, N. A.; WoldeHanna, M. Lemma; Nathan, S. D.] Inova Fainfax Hosp, Inova Adv Lung Dis & Transplant Program, Falls Church, VA USA. [Biancotto, A.] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bldg 10, Bethesda, MD 20892 USA. [Solomon, M. A.] NHLBI, Dept Crit Care Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Solomon, M. A.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2016 VL 35 IS 4 SU S MA 1003 BP S360 EP S360 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA DK2AX UT WOS:000374718101354 ER PT J AU Bowsher, K Civillico, EF Coburn, J Collinger, J Contreras-Vidal, JL Denison, T Donoghue, J French, J Getzoff, N Hochberg, LR Hoffmann, M Judy, J Kleitman, N Knaack, G Krauthamer, V Ludwig, K Moynahan, M Pancrazio, JJ Peckham, PH Pena, C Pinto, V Ryan, T Saha, D Scharen, H Shermer, S Skodacek, K Takmakov, P Tyler, D Vasudevan, S Wachrathit, K Weber, D Welle, CG Ye, M AF Bowsher, K. Civillico, E. F. Coburn, J. Collinger, J. Contreras-Vidal, J. L. Denison, T. Donoghue, J. French, J. Getzoff, N. Hochberg, L. R. Hoffmann, M. Judy, J. Kleitman, N. Knaack, G. Krauthamer, V. Ludwig, K. Moynahan, M. Pancrazio, J. J. Peckham, P. H. Pena, C. Pinto, V. Ryan, T. Saha, D. Scharen, H. Shermer, S. Skodacek, K. Takmakov, P. Tyler, D. Vasudevan, S. Wachrathit, K. Weber, D. Welle, C. G. Ye, M. TI Brain-computer interface devices for patients with paralysis and amputation: a meeting report SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE brain-computer interface; neuroprosthetic; regulation; translation; medical device ID PRIORITIES AB Objective. The Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) believes it is important to help stakeholders (e.g., manufacturers, health-care professionals, patients, patient advocates, academia, and other government agencies) navigate the regulatory landscape for medical devices. For innovative devices involving brain-computer interfaces, this is particularly important. Approach. Towards this goal, on 21 November, 2014, CDRH held an open public workshop on its White Oak, MD campus with the aim of fostering an open discussion on the scientific and clinical considerations associated with the development of brain-computer interface (BCI) devices, defined for the purposes of this workshop as neuroprostheses that interface with the central or peripheral nervous system to restore lost motor or sensory capabilities. Main results. This paper summarizes the presentations and discussions from that workshop. Significance. CDRH plans to use this information to develop regulatory considerations that will promote innovation while maintaining appropriate patient protections. FDA plans to build on advances in regulatory science and input provided in this workshop to develop guidance that provides recommendations for premarket submissions for BCI devices. These proceedings will be a resource for the BCI community during the development of medical devices for consumers. C1 [Bowsher, K.; Getzoff, N.; Hoffmann, M.; Pena, C.; Pinto, V.; Saha, D.; Scharen, H.; Shermer, S.; Skodacek, K.; Wachrathit, K.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. [Civillico, E. F.; Coburn, J.; Knaack, G.; Krauthamer, V.; Takmakov, P.; Vasudevan, S.; Welle, C. G.; Ye, M.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. [Collinger, J.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Contreras-Vidal, J. L.] Univ Houston, Elect & Comp Engn, Houston, TX USA. [Denison, T.] Medtronic Inc, Minneapolis, MN USA. [Donoghue, J.; Hochberg, L. R.] Brown Univ, Brown Inst Brain Sci, Sch Engn, Providence, RI 02912 USA. [French, J.] Neurotech Network, Tampa, FL 33623 USA. [Hochberg, L. R.] Ctr Neurorestorat & Neurotechnol, Rehabil R&D Serv, Dept Vet Affairs Med Ctr, Providence, RI USA. [Hochberg, L. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Judy, J.] Univ Florida, Coll Engn, Nanosci Inst Med & Engn Technol, Gainesville, FL 32611 USA. [Kleitman, N.] Craig H Neilsen Fdn, Encino, CA USA. [Ludwig, K.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ludwig, K.] Mayo Clin, Dept Neurol Surg, Rochester, MN USA. [Moynahan, M.] Case Western Reserve Univ, Inst Funct Restorat, Cleveland, OH 44106 USA. [Pancrazio, J. J.] Univ Texas Dallas, Bioengn, Dallas, TX 75230 USA. [Peckham, P. H.; Tyler, D.] Case Western Reserve Univ, Sch Engn, Cleveland, OH 44106 USA. [Ryan, T.] Adv Arm Dynam, Redono Beach, CA 90277 USA. [Weber, D.] Def Adv Res Projects Agcy, Biol Technol Off, Arlington, VA USA. RP Bowsher, K (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. RI Tyler, Dustin/C-7995-2015; OI Tyler, Dustin/0000-0002-2298-8510; Welle, Cristin/0000-0001-8735-0983; Pancrazio, Joseph/0000-0001-8276-3690; Takmakov, Pavel/0000-0001-6591-0257 NR 21 TC 3 Z9 3 U1 4 U2 7 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD APR PY 2016 VL 13 IS 2 AR 023001 DI 10.1088/1741-2560/13/2/023001 PG 13 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA DL5NM UT WOS:000375683800004 PM 26924826 ER PT J AU Harris, LN Ismaila, N McShane, LM Hayes, DF AF Harris, Lyndsay N. Ismaila, Nofisat McShane, Lisa M. Hayes, Daniel F. TI Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Summary SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. [Harris, Lyndsay N.] Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. NCI, Bethesda, MD 20892 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Harris, LN (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD APR PY 2016 VL 12 IS 4 BP 384 EP + DI 10.1200/JOP.2016.010868 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DJ6LW UT WOS:000374325700026 PM 26957642 ER PT J AU Roth, ME O'Mara, AM Seibel, NL Dickens, DS Langevin, AM Pollock, BH Freyer, DR AF Roth, Michael E. O'Mara, Ann M. Seibel, Nita L. Dickens, David S. Langevin, Anne-Marie Pollock, Brad H. Freyer, David R. TI Low Enrollment of Adolescents and Young Adults Onto Cancer Trials: Insights From the Community Clinical Oncology Program SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID OLDER ADOLESCENTS; PARTICIPATION; INSTITUTE; CARE; CHALLENGES; DIAGNOSIS; SURVIVAL AB Purpose Stagnant outcomes for adolescents and young adults (AYAs; 15 to 39 years old) with cancer are partly attributed to poor enrollment onto clinical trials. The National Cancer Institute (NCI) Community Clinical Oncology Program (CCOP) was developed to improve clinical trial participation in the community setting, where AYAs are most often treated. Further, many CCOP sites had pediatric and medical oncologists with collaborative potential for AYA recruitment and care. For these reasons, we hypothesized that CCOP sites enrolled proportionately more AYAs than non-CCOP sites onto Children's Oncology Group (COG) trials. Methods For the 10-year period 2004 through 2013, the NCI Division of Cancer Prevention database was queried to evaluate enrollments into relevant COG studies. The proportional enrollment of AYAs at CCOP and non-CCOP sites was compared and the change in AYA enrollment patterns assessed. All sites were COG member institutions. Results Although CCOP sites enrolled a higher proportion of patients in cancer control studies than non-CCOP sites (3.5% v 1.8%; P < .001), they enrolled a lower proportion of AYAs (24.1% v 28.2%, respectively; P < .001). Proportional AYA enrollment at CCOP sites decreased during the intervals 2004 through 2008 and 2009 through 2013 (26.7% v 21.7%; P < .001). Conclusion Despite oncology practice settings that might be expected to achieve otherwise, CCOP sites did not enroll a larger proportion of AYAs in clinical trials than traditional COG institutions. Our findings suggest that the CCOP (now the NCI Community Oncology Research Program) can be leveraged for developing targeted interventions for overcoming AYA enrollment barriers. C1 Albert Einstein Coll Med, Bronx, NY 10467 USA. NCI, Bethesda, MD 20892 USA. Helen DeVos Childrens Hosp Spectrum Hlth, Grand Rapids, MI USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Univ Calif Davis, Davis, CA 95616 USA. Univ So Calif, Los Angeles, CA USA. RP Freyer, DR (reprint author), Childrens Hosp Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM DFreyer@CHLA.usc.edu OI Dickens, David/0000-0001-8821-6022 FU NCI NIH HHS [K12 CA-132783-04, K12 CA132783, U10 CA098543, U10-CA98543] NR 35 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD APR PY 2016 VL 12 IS 4 BP E388 EP E395 DI 10.1200/JOP.2015.009084 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DJ6LW UT WOS:000374325700005 PM 27026648 ER PT J AU Neely, AL Thumbigere-Math, V Somerman, MJ Foster, BL AF Neely, Anthony L. Thumbigere-Math, Vivek Somerman, Martha J. Foster, Brian L. TI A Familial Pattern of Multiple Idiopathic Cervical Root Resorption With a 30-Year Follow-Up SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Dental cementum; root resorption; tooth; tooth loss; tooth; resorption; x-ray microtomography ID TEETH; CLASSIFICATION; MANAGEMENT; DIAGNOSIS; ETIOLOGY AB Background: Multiple idiopathic cervical root resorption (MICRR) is a rare entity distinct from pathologic root resorption that occurs as a result of several local and systemic factors. Methods: This report describes a familial pattern of MICRR, including a recently identified case and a 30-year follow-up on previously described cases. Results: The previously reported father (aged 95 years) and son (aged 64 years), and the recently affected daughter (aged 61 years) recounted non-contributory medical history. The resorptive lesions were asymptomatic, unassociated with any predisposing factors, and first identified during the fourth to sixth decades of life. All tooth types were affected, with posterior teeth being affected earlier and with greater frequency; however, distal root surfaces were never affected. The resorptive lesions were progressive in nature, with additional teeth becoming involved as the condition was followed over time. In many instances, surrounding alveolar bone extended into the existing resorptive defects, but without clinical evidence of ankylosis. Gingival tissues, periodontal probing, and tooth mobility were within normal limits. Microcomputed tomography of extracted teeth demonstrated that the lesions were more extensive than clinically evident and rarely invaded the pulp chamber. Histologically, many resorptive lesions were noted along the cementum surface, with evidence of isolated cemental repair. Management of MICRR focused on restoring damaged root surfaces and extracting teeth with extensive root resorption. Conclusions: MICRR is a challenging entity with unknown etiology and a lack of well-established preventive and management strategies. The familial pattern noted in this report necessitates future studies to investigate the role of genetic components in MICRR development. C1 [Neely, Anthony L.] Univ Detroit Mercy, Sch Dent, Dept Periodontol & Dent Hyg, Detroit, MI 48208 USA. [Thumbigere-Math, Vivek; Somerman, Martha J.; Foster, Brian L.] NIAMSD, Lab Oral & Connect Tissue Biol, NIH, Bethesda, MD 20892 USA. [Foster, Brian L.] Ohio State Univ, Coll Dent, Biosci Div, Columbus, OH 43210 USA. RP Neely, AL (reprint author), Univ Detroit Mercy, Sch Dent, Periodontol & Dent Hyg, 2700 Martin Luther King Jr Blvd, Detroit, MI 48208 USA. EM neelya@udmercy.edu FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland FX This work was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland (MJS). The authors thank Dr. Robert Nyberg and Dr. Jeffery R. Thomas, New Bern, North Carolina, for providing clinical photos and radiographs related to case 3. ALN and VT-M contributed equally to this study. The authors report no conflicts of interest related to this study. NR 43 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD APR PY 2016 VL 87 IS 4 BP 426 EP 433 DI 10.1902/jop.2015.150536 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DL7TK UT WOS:000375842800013 PM 26561999 ER PT J AU Richardson, A Fischer, KE Speakman, JR de Cabo, R Mitchell, SJ Peterson, CA Rabinovitch, P Chiao, YA Taffet, G Miller, RA Renteria, RC Bower, J Ingram, DK Ladiges, WC Ikeno, Y Sierra, F Austad, SN AF Richardson, Arlan Fischer, Kathleen E. Speakman, John R. de Cabo, Rafael Mitchell, Sarah J. Peterson, Charlotte A. Rabinovitch, Peter Chiao, Ying A. Taffet, George Miller, Richard A. Renteria, Rene C. Bower, James Ingram, Donald K. Ladiges, Warren C. Ikeno, Yuji Sierra, Felipe Austad, Steven N. TI Measures of Healthspan as Indices of Aging in Mice-A Recommendation SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Healthspan; Lifespan; Physiological function; Age ID CALORIC RESTRICTION; FRAILTY INDEX; C57BL/6 MICE; LIFE-SPAN; RAPAMYCIN AB Over the past decade, a large number of discoveries have shown that interventions (genetic, pharmacological, and nutritional) increase the lifespan of invertebrates and laboratory rodents. Therefore, the possibility of developing antiaging interventions for humans has gone from a dream to a reality. However, it has also become apparent that we need more information than just lifespan to evaluate the translational potential of any proposed antiaging intervention to humans. Information is needed on how an intervention alters the "healthspan" of an animal, that is, how the physiological functions that change with age are altered. In this report, we describe the utility and the limitations of assays in mice currently available for measuring a wide range of physiological functions that potentially impact quality of life. We encourage investigators and reviewers alike to expect at minimum an overall assessment of health in several domains across several ages before an intervention is labeled as "increasing healthspan." In addition, it is important that investigators indicate any tests in which the treated group did worse or did not differ statistically from controls because overall health is a complex phenotype, and no intervention discovered to date improves every aspect of health. Finally, we strongly recommend that functional measurements be performed in both males and females so that sex differences in the rate of functional decline in different domains are taken into consideration. C1 [Richardson, Arlan] Univ Oklahoma, Dept Geriatr Med, Hlth Sci Ctr, Norman, OK 73019 USA. [Richardson, Arlan] Univ Alabama Birmingham, Oklahoma City VA Med Ctr, Birmingham, AL 35487 USA. [Fischer, Kathleen E.; Austad, Steven N.] Univ Alabama Birmingham, Dept Biol, Birmingham, AL 35487 USA. [Speakman, John R.] Univ Aberdeen, Aberdeen AB9 1FX, Scotland. [Speakman, John R.] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Mol Dev Biol, Beijing, Peoples R China. [de Cabo, Rafael; Mitchell, Sarah J.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Peterson, Charlotte A.] Univ Kentucky, Coll Hlth Sci, Lexington, KY 40506 USA. [Rabinovitch, Peter; Chiao, Ying A.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Taffet, George] Baylor Coll Med, Sect Cardiovasc Res, Dept Med, Houston, TX 77030 USA. [Miller, Richard A.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Miller, Richard A.] Univ Michigan, Geriatr Ctr, Ann Arbor, MI 48109 USA. [Renteria, Rene C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Renteria, Rene C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Hlth Restorat, San Antonio, TX 78229 USA. [Renteria, Rene C.] Univ Texas Hlth Sci Ctr San Antonio, Care Syst Management, San Antonio, TX 78229 USA. [Renteria, Rene C.] Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA. [Bower, James] Univ Calif Santa Cruz, Dept Comp Sci, Santa Cruz, CA 95064 USA. [Ingram, Donald K.] Louisiana State Univ, Nutr Neurosci & Aging Lab, Pennington Biomed Res Ctr, Baton Rouge, LA 70803 USA. [Ladiges, Warren C.] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. [Ikeno, Yuji] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Richardson, Arlan; Sierra, Felipe] NIA, Biol Aging Program, Bethesda, MD 20892 USA. RP Richardson, A (reprint author), Univ Oklahoma, Dept Geriatr Med, 975 NE 10th Street SLY BRC 1303, Oklahoma City, OK 73104 USA. EM arlan-richardson@ouhsc.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIA NIH HHS [P30 AG013319, P30 AG024824, R01 AG019899, R24 AG047115, T32 AG000057, U01 AG022303, U01 AG022307] NR 20 TC 11 Z9 11 U1 4 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2016 VL 71 IS 4 BP 427 EP 430 DI 10.1093/gerona/glv080 PG 4 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DJ4ZA UT WOS:000374215400002 PM 26297941 ER PT J AU Stenholm, S Koster, A Valkeinen, H Patel, KV Bandinelli, S Guralnik, JM Ferrucci, L AF Stenholm, Sari Koster, Annemarie Valkeinen, Heli Patel, Kushang V. Bandinelli, Stefania Guralnik, Jack M. Ferrucci, Luigi TI Association of Physical Activity History With Physical Function and Mortality in Old Age SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Physical activity; Physical performance; Disability; Mortality ID LOWER-EXTREMITY FUNCTION; SUBSEQUENT DISABILITY; PERFORMANCE BATTERY; MOBILITY LIMITATION; HEALTH; ADULTS; ADIPOSITY; INCHIANTI; VALIDITY; COHORT AB We examined whether physical activity in early adulthood, late midlife, and old age as well as cumulative physical activity history are associated with changes in physical functioning and mortality in old age. Data are from participants aged 65 years or older enrolled in the InCHIANTI study who were followed up from 1998-2000 to 2007-2008 (n = 1,149). At baseline, participants recalled their physical activity levels at ages 20-40, 40-60, and in the previous year, and they were categorized as physically inactive, moderately active, and physically active. Physical performance was assessed with the Short Physical Performance Battery and self-reported mobility disability was evaluated at the 3-, 6- and 9-year follow-up. Mortality follow-up was assessed until the end of 2010. Physical inactivity at baseline was associated with greater decline in Short Physical Performance Battery score (mean 9-year change: -2.72, 95% CI: -3.08, -2.35 vs -0.98, 95% -1.57, -0.39) and greater rate of incident mobility disability (hazard ratio 4.66, 95% CI 1.14-19.07) and mortality (hazard ratio 2.18, 95% CI 1.01-4.70) compared to physically active participants at baseline. Being physically active throughout adulthood was associated with smaller decline in physical performance as well as with lower risk of incident mobility disability and premature death compared with those who had been less active during their adult life. Higher cumulative physical activity over the life course was associated with less decline in physical performance and reduced rate of incident mobility disability and mortality in older ages. C1 [Stenholm, Sari] Univ Turku, Dept Publ Hlth, Lemminkaisenkatu 1, FI-20014 Turun, Finland. [Stenholm, Sari] Univ Tampere, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Stenholm, Sari; Valkeinen, Heli] Natl Inst Hlth & Welf THL, Ageing Disabil & Functioning Unit, Helsinki, Finland. [Koster, Annemarie] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, NL-6200 MD Maastricht, Netherlands. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Florence, Italy. [Guralnik, Jack M.] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Stenholm, S (reprint author), Univ Turku, Dept Publ Hlth, Lemminkaisenkatu 1, FI-20014 Turun, Finland. EM sari.stenholm@utu.fi RI Koster, Annemarie/E-7438-2010 FU Academy of Finland [264944, 286294]; Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, 1 Z01 AG001050-01] FX This work was supported by grant from the Academy of Finland (264944 and 286294) and in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" by the Italian Ministry of Health (ICS110.1/RF97.71) and in part by the U.S. National Institute on Aging (263 MD 9164, 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging (N.1-AG-1-1, N.1-AG-1-2111); the InCHIANTI Follow-up 2 study (2004-2006) was financed by the U.S. National Institute on Aging (N01-AG-5-0002) and the InCHIANTI Follow-up 3 study (2007-2008) was financed by the U.S. National Institute on Aging (1 Z01 AG001050-01). NR 31 TC 4 Z9 4 U1 3 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2016 VL 71 IS 4 BP 496 EP 501 DI 10.1093/gerona/glv111 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DJ4ZA UT WOS:000374215400011 PM 26290538 ER PT J AU Chang, M Snaedal, J Einarsson, B Bjornsson, S Saczynski, JS Aspelund, T Garcia, M Gudnason, V Harris, TB Launer, LJ Jonsson, PV AF Chang, Milan Snaedal, Jon Einarsson, Bjorn Bjornsson, Sigurbjorn Saczynski, Jane S. Aspelund, Thor Garcia, Melissa Gudnason, Vilmundur Harris, Tamara B. Launer, Lenore J. Jonsson, Palmi V. TI The Association Between Midlife Physical Activity and Depressive Symptoms in Late Life: Age Gene/Environment Susceptibility-Reykjavik Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Mid-life physical activity; Aging; Depressive symptomatology; Cognitive function ID OLDER-ADULTS; GERIATRIC DEPRESSION; ALZHEIMER-DISEASE; CONTROLLED-TRIAL; ELDERLY-MEN; EXERCISE; RISK; VALIDATION; EFFICACY; PEOPLE AB Background. There is little evidence on the long-term association between physical activity (PA) and depressive symptoms in old age. We examined the association of midlife PA and depressive symptoms in late life. Methods. A large community-based population residing in Reykjavik, Iceland, participated in a longitudinal study with an average of 25 years of follow up. Midlife PA was categorized as active and inactive groups (n = 4,140, Active = 1,292, Inactive = 2,848, mean age 52 +/- 7 years). The main outcome had six or higher depressive symptoms assessed by the 15-item Geriatric Depression scale. Participants who had a history of depression (n = 226), and were diagnosed with dementia (n = 393), and had incomplete cognitive data (n = 595) and incomplete analytical data (n = 422) were excluded. Level of weekly PA was ascertained by a questionnaire at midlife. Depressive symptoms were assessed on average 25 (+/-4) years later. Results. After controlling for demographic and health-related risk factors, those who were active at midlife were less likely to have high level of depressive symptomatology (6 or higher Geriatric Depression scale scores, odds ratio = 0.58, 95% confidence interval: 0.41-0.83, p <.005) compared with those who were inactive in midlife. After full adjustment of three domains of late-life cognitive function the results remained significant (odds ratio = 0.61, 95% confidence interval: 0.43-0.86, p =.005). Conclusion. Our study shows that midlife PA is associated with lower depressive symptoms 25 years later. Participating in regular PA in midlife may improve mental health in late life. C1 [Chang, Milan; Snaedal, Jon; Einarsson, Bjorn; Bjornsson, Sigurbjorn; Jonsson, Palmi V.] Natl Univ Hosp Iceland, Iceland Gerongol Res Ctr, IS-101 Reykjavik, Iceland. [Chang, Milan] Reykjavik Univ, Sch Sci & Engn, Dept Sport Sci, Reykjavik, Iceland. [Snaedal, Jon; Gudnason, Vilmundur; Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA USA. [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Worcester, MA USA. [Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor] Univ Iceland, Fac Sci, Reykjavik, Iceland. [Garcia, Melissa; Harris, Tamara B.; Launer, Lenore J.] Natl Inst Aging, Lab Epidemiol & Populat Sci, Bethesda, MD USA. RP Chang, M (reprint author), Natl Univ Hosp Iceland, Iceland Gerongol Res Ctr Landakot, IS-101 Reykjavik, Iceland. EM changmilan@gmail.com FU National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program; Icelandic Heart Association; Landspitali University Hospital; Icelandic Parliament FX This study was funded by the National Institutes of Health (contract N01-AG-12100), the National Institute on Aging Intramural Research Program, the Icelandic Heart Association, Landspitali University Hospital, and the Icelandic Parliament. NR 38 TC 2 Z9 2 U1 4 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2016 VL 71 IS 4 BP 502 EP 507 DI 10.1093/gerona/glv196 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DJ4ZA UT WOS:000374215400012 PM 26525090 ER PT J AU McMahon, FJ AF McMahon, Francis J. TI Genetic association studies in psychiatry: time for pay-off SO LANCET PSYCHIATRY LA English DT Editorial Material ID SCHIZOPHRENIA; MUTATIONS; PROJECT C1 [McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP McMahon, FJ (reprint author), NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov OI McMahon, Francis/0000-0002-9469-305X FU National Institute of Mental Health FX I declare no competing interests. This work was supported by the Intramural Research Program of the National Institute of Mental Health. This work was written as part of my official duties as a Government employee. The views expressed in this article do not necessarily represent the views of the National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, or the US Government. NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD APR PY 2016 VL 3 IS 4 BP 309 EP 310 DI 10.1016/S2215-0366(16)00016-X PG 3 WC Psychiatry SC Psychiatry GA DJ5NE UT WOS:000374254600004 PM 26915513 ER PT J AU Noyce, AJ Nalls, MA AF Noyce, Alastair J. Nalls, Mike A. TI Mendelian Randomization the Key to Understanding Aspects of Parkinson's Disease Causation? SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; Mendelian randomization; observational study; causation ID GLUCOCEREBROSIDASE MUTATIONS; SEQUENCE VARIANTS; RISK-FACTORS; METAANALYSIS; ASSOCIATION; INSTRUMENTS AB Parkinson's disease has multiple determinants and is associated with a wide range of exposures that appear to modify risk in traditional observational studies, including numerous lifestyle and environmental factors. Across other fields of medicine, Mendelian randomization has emerged as a powerful method to examine whether associations between exposures and disease outcomes are causal. Here we discuss the concept of Mendelian randomization, its potential relevance to Parkinson's disease, and suggest avenues through which the method could be employed to further understanding of the causal basis of Parkinson's disease. (c) 2015 International Parkinson and Movement Disorder Society C1 [Noyce, Alastair J.] UCL Inst Neurol, Reta Lila Weston Inst Neurol Studies, London WC1N 1PJ, England. [Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Noyce, AJ (reprint author), UCL Inst Neurol, Reta Lila Weston Inst, 1 Wakefield St, London WC1N 1PJ, England. EM a.noyce@ucl.ac.uk FU Parkinson's UK [F-1201] NR 32 TC 2 Z9 2 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD APR PY 2016 VL 31 IS 4 BP 478 EP 483 DI 10.1002/mds.26492 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DJ9PV UT WOS:000374546300005 PM 26695521 ER PT J AU Comella, CL Perlmutter, JS Jinnah, HA Waliczek, TA Rosen, AR Galpern, WR Adler, CA Barbano, RL Factor, SA Goetz, CG Jankovic, J Reich, SG Rodriguez, RL Severt, WL Zurowski, M Fox, SH Stebbins, GT AF Comella, Cynthia L. Perlmutter, Joel S. Jinnah, Hyder A. Waliczek, Tracy A. Rosen, Ami R. Galpern, Wendy R. Adler, Charles A. Barbano, Richard L. Factor, Stewart A. Goetz, Christopher G. Jankovic, Joseph Reich, Stephen G. Rodriguez, Ramon L. Severt, William L. Zurowski, Mateusz Fox, Susan H. Stebbins, Glenn T. TI Clinimetric testing of the comprehensive cervical dystonia rating scale SO MOVEMENT DISORDERS LA English DT Article DE cervical dystonia; focal dystonia; rating scale; Toronto Western Spasmodic Torticollis Rating Scale; Cervical Dystonia Impact Profile-58 ID QUALITY-OF-LIFE; BECK DEPRESSION INVENTORY; BOTULINUM TOXIN TREATMENT; IMPACT PROFILE CDIP-58; SPASMODIC TORTICOLLIS; OUTCOME ASSESSMENT; HOSPITAL ANXIETY; HEALTH; DETERMINANTS; VALIDATION AB IntroductionThe aim of this study was to test the clinimetric properties of the Comprehensive Cervical Dystonia Rating Scale. This is a modular scale with modifications of the Toronto Western Spasmodic Torticollis Rating Scale (composed of three subscales assessing motor severity, disability, and pain) now referred to as the revised Toronto Western Spasmodic Torticollis Scale-2; a newly developed psychiatric screening instrument; and the Cervical Dystonia Impact Profile-58 as a quality of life measure. MethodsTen dystonia experts rated subjects with cervical dystonia using the comprehensive scale. Clinimetric techniques assessed each module of the scale for reliability, item correlation, and factor structure. ResultsThere were 208 cervical dystonia patients (73% women; age, 5910 years; duration, 15 +/- 12 years). Internal consistency of the motor severity subscale was acceptable (Cronbach's alpha=0.57). Item to total correlations showed that elimination of items with low correlations (<0.20) increased alpha to 0.71. Internal consistency estimates for the subscales for disability and pain were 0.88 and 0.95, respectively. The psychiatric screening scale had a Cronbach's alpha of 0.84 and satisfactory item to total correlations. When the subscales of the Toronto Western Spasmodic Torticollis Scale-2 were combined with the psychiatric screening scale, Cronbach's alpha was 0.88, and construct validity assessment demonstrated four rational factors: motor; disability; pain; and psychiatric disorders. The Cervical Dystonia Impact Profile-58 had an alpha of 0.98 and its construction was validated through a confirmatory factor analysis. ConclusionsThe modules of the Comprehensive Cervical Dystonia Rating Scale are internally consistent with a logical factor structure. (c) 2016 International Parkinson and Movement Disorder Society C1 [Comella, Cynthia L.; Waliczek, Tracy A.; Goetz, Christopher G.; Stebbins, Glenn T.] Rush Univ, Med Ctr, 1725 West Harrison St,Suite 755, Chicago, IL 60612 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, St Louis, MO USA. [Jinnah, Hyder A.; Rosen, Ami R.; Factor, Stewart A.] Emory Univ, Atlanta, GA 30322 USA. [Galpern, Wendy R.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Adler, Charles A.] Mayo Clin, Scottsdale, AZ USA. [Barbano, Richard L.] Univ Rochester, Rochester, NY USA. [Jankovic, Joseph] Baylor Coll Med, Houston, TX 77030 USA. [Reich, Stephen G.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Rodriguez, Ramon L.] Univ Florida, Movement Disorders Ctr, Gainesville, FL USA. [Severt, William L.] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Zurowski, Mateusz; Fox, Susan H.] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. RP Comella, CL (reprint author), Rush Univ, Med Ctr, 1725 West Harrison St,Suite 755, Chicago, IL 60612 USA. EM ccomella@rush.edu RI zurowski, mateusz/D-1536-2010 OI zurowski, mateusz/0000-0002-6407-4629 FU NCATS NIH HHS [U54 TR001456]; NINDS NIH HHS [NS 065701, U54 NS065701, R01 NS074343] NR 42 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD APR PY 2016 VL 31 IS 4 BP 563 EP 569 DI 10.1002/mds.26534 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DJ9PV UT WOS:000374546300021 PM 26971359 ER PT J AU Kleinstreuer, NC Sullivan, K Allen, D Edwards, S Mendrick, DL Embry, M Matheson, J Rowlands, JC Munn, S Maull, E Casey, W AF Kleinstreuer, Nicole C. Sullivan, Kristie Allen, David Edwards, Stephen Mendrick, Donna L. Embry, Michelle Matheson, Joanna Rowlands, J. Craig Munn, Sharon Maull, Elizabeth Casey, Warren TI Adverse outcome pathways: From research to regulation scientific workshop report SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE AOP; Workshop; Toxicology; Pathway; Regulatory; Quantitative; Application; Acceptance; Criteria; Computational ID DILUTION MASS-SPECTROMETRY; EARLY FISH DEVELOPMENT; THYROPEROXIDASE INHIBITION; CONCEPTUAL-FRAMEWORK; VASCULAR DEVELOPMENT; TESTING STRATEGY; DECISION-MAKING; IPCS FRAMEWORK; MODE; CONFIDENCE AB An adverse outcome pathway (AOP) helps to organize existing knowledge on chemical mode of action, starting with a molecular initiating event such as receptor binding, continuing through key events, and ending with an adverse outcome such as reproductive impairment. AOPs can help identify knowledge gaps where more research is needed to understand the underlying mechanisms, aid in chemical hazard characterization, and guide the development of new testing approaches that use fewer or no animals. A September 2014 workshop in Bethesda, Maryland considered how the AOP concept could improve regulatory assessments of chemical toxicity. Scientists from 21 countries, representing industry, academia, regulatory agencies, and special interest groups, attended the workshop, titled Adverse Outcome Pathways: From Research to Regulation. Workshop plenary presentations were followed by breakout sessions that considered regulatory acceptance of AOPs and AOP-based tools, criteria for building confidence in an AOP for regulatory use, and requirements to build quantitative AOPs and AOP networks. Discussions during the closing session emphasized a need to increase transparent and inclusive collaboration, especially with disciplines outside of toxicology. Additionally, to increase impact, working groups should be established to systematically prioritize and develop AOPs. Multiple collaborative projects and follow-up activities resulted from the workshop. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kleinstreuer, Nicole C.; Maull, Elizabeth; Casey, Warren] NIEHS, Natl Toxicol Program, Interagency Ctr Evaluat Alternat Toxicol Methods, POB 12233, Res Triangle Pk, NC 27709 USA. [Sullivan, Kristie] Phys Comm Responsible Med, Washington, DC USA. [Allen, David] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Edwards, Stephen] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Mendrick, Donna L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Embry, Michelle] ILSI Hlth & Environm Sci Inst, Washington, DC USA. [Matheson, Joanna] US Consumer Prod Safety Commiss, Rockville, MD USA. [Rowlands, J. Craig] Dow Chem Co USA, Midland, MI 48674 USA. [Munn, Sharon] Commiss European Communities, Joint Res Ctr, I-21020 Ispra, Italy. RP Kleinstreuer, NC (reprint author), POB 13501, Res Triangle Pk, NC 27709 USA. EM Nicole.kleinstreuer@nih.gov OI Kleinstreuer, Nicole/0000-0002-7914-3682 FU federal funds from the NIEHS, NIH [HHSN273201400003C, HHSN273201500010C]; NICEATM FX The authors would like to thank all of the workshop presenters and breakout group moderators, Hristo Aladjov for assisting in creation of Fig. 3, George Daston for his contributions to the workshop steering committee discussions, Catherine Sprankle for editorial comments, NICEATM staff Michael Paris, Steven Morefield, Neepa Choksi, and Catherine Sprankle for assistance with organizing and running the workshop, and PCRM staff Arya Birdie and Mallory Huff for their assistance with organizing the workshop. Nicole Kleinstreuer and David Allen were supported by federal funds from the NIEHS, NIH under Contract Numbers HHSN273201400003C and HHSN273201500010C to Integrated Laboratory Systems, Inc., in support of NICEATM. The views represented in this paper are those of the authors solely, and do not represent the official policy of the U.S. EPA, FDA, NIH, or any other federal government organization. NR 45 TC 6 Z9 6 U1 8 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD APR PY 2016 VL 76 BP 39 EP 50 DI 10.1016/j.yrtph.2016.01.007 PG 12 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DL3DK UT WOS:000375514200005 PM 26774756 ER PT J AU Reider, EE Sims, BE AF Reider, Eve E. Sims, Belinda E. TI Family-Based Preventive Interventions: Can the Onset of Suicidal Ideation and Behavior Be Prevented? SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article AB Suicide is the second leading cause of death for youth aged 10-24. Research informed prevention efforts have the opportunity to decrease risk for suicidal ideation and behavior before it is manifested. Indeed, there is a small body of research findings demonstrating both proximal and distal effects of preventive interventions delivered in childhood and adolescence on suicidal ideation and/or behavior. These efforts build off of other secondary analyses of prevention research that has demonstrated benefits for multiple types of youth outcomes. This supplement provides proof of concept that family-based preventive interventions aimed at reducing a number of risk factors for suicide (e.g., substance use, externalizing, and internalizing behavior) can prevent suicidal ideation and behaviors. C1 [Reider, Eve E.] NCCIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. [Sims, Belinda E.] NIDA, Bethesda, MD USA. RP Reider, EE (reprint author), NCCIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM ereider@mail.nih.gov FU Intramural NIH HHS [Z99 AT999999] NR 15 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0363-0234 EI 1943-278X J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD APR PY 2016 VL 46 SU 1 BP S3 EP S7 DI 10.1111/sltb.12252 PG 5 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DK1UL UT WOS:000374699900001 PM 27094108 ER PT J AU Szabo, ST Harry, GJ Hayden, KM Szabo, DT Birnbaum, L AF Szabo, Steven T. Harry, G. Jean Hayden, Kathleen M. Szabo, David T. Birnbaum, Linda TI Comparison of Metal Levels between Postmortem Brain and Ventricular Fluid in Alzheimer's Disease and Nondemented Elderly Controls SO TOXICOLOGICAL SCIENCES LA English DT Article DE heavy metals; brain; cerebral spinal fluid; amyloid beta; neurodegenerative disease ID CEREBROSPINAL-FLUID; AMYLOID-BETA; NEURODEGENERATIVE DISORDERS; OXIDATIVE STRESS; IRON LEVELS; COPPER; ZINC; ALUMINUM; PLASMA; HIPPOCAMPUS AB An essential metal hypothesis for neurodegenerative disease suggests an alteration in metal homeostasis contributing to the onset and progression of disease. Similar associations have been proposed for nonessential metals. To examine the relationship between metal levels in brain tissue and ventricular fluid (VF), postmortem samples of frontal cortex (FC) and VF from Alzheimer's disease (AD) cases and nondemented elderly subjects were analyzed for arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), tin (Sn), vanadium (V), and zinc (Zn) using inductively coupled plasma sector field mass spectrometry. All metals, with exception of equivalent Pb levels, were lower in the VF, compared to FC. Within-subject comparisons demonstrated that VF levels were not representative of levels within brain tissue. The essential metals Cu, Fe, and Zn were found highest in both compartments. Cd, Hg, and V levels in the VF were below the limit of quantification. In AD cases, FC levels of Fe were higher and As and Cd were lower than levels in controls, while levels of As in the VF were higher. Parameter estimates for FC metal levels indicated an association of Braak stage and higher Fe levels and an association of Braak stage and lower As, Mn, and Zn levels. The data showed no evidence of an accumulation of nonessential metals within the AD brain and, with the exception of As, showed no significant shift in the ratio of FC to VF levels to indicate differential clearance. C1 [Szabo, Steven T.] Vet Adm Med Ctr, Mental Hlth Serv Line, Durham, NC 27705 USA. [Szabo, Steven T.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27705 USA. [Harry, G. Jean] NIEHS, Neurotoxicol Grp, Natl Toxicol Program Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Hayden, Kathleen M.] Duke Univ, Med Ctr, Joseph & Kathleen ADRC, Dept Psychiat & Behav Sci, Durham, NC 27705 USA. [Szabo, David T.] RAI Serv Co, Winston Salem, NC 27102 USA. [Birnbaum, Linda] NCI, NIH, Res Triangle Pk, NC 27709 USA. [Hayden, Kathleen M.] Wake Forest Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC 27157 USA. RP Szabo, ST (reprint author), Vet Adm Med Ctr, Mental Hlth Serv Line, Durham, NC 27705 USA.; Szabo, ST (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27705 USA. EM steven.szabo@duke.edu FU NTP [HHSN27320100003C]; Division of Intramural Research and Division National Toxicology Program, National Institute of Environmental Health Sciences [1Z01ES101623, ES021164]; National Cancer Institute [ZIA BC 011476]; Joseph and Kathleen Bryan Alzheimer's Disease Research Center [NIA P30AG028377] FX NTP contract HHSN27320100003C to Research Triangle Institute; the Division of Intramural Research and Division National Toxicology Program, National Institute of Environmental Health Sciences, no. 1Z01ES101623, ES021164; the National Cancer Institute no. ZIA BC 011476; the Joseph and Kathleen Bryan Alzheimer's Disease Research Center grant NIA P30AG028377. NR 60 TC 1 Z9 1 U1 13 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2016 VL 150 IS 2 BP 292 EP 300 DI 10.1093/toxsci/kfv325 PG 9 WC Toxicology SC Toxicology GA DJ5ET UT WOS:000374230300005 PM 26721301 ER PT J AU Su, TP Su, TC Nakamura, Y Tsai, SY AF Su, Tsung-Ping Su, Tzu-Chieh Nakamura, Yoki Tsai, Shang-Yi TI The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; ENDOPLASMIC-RETICULUM MEMBRANE; GUINEA-PIG BRAIN; MOUSE MODEL; MECHANICAL ALLODYNIA; OPIOID ANALGESIA; NEUROPATHIC PAIN; NMDA RECEPTOR; ALZHEIMERS-DISEASE; P38 MAPK AB The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein that resides specifically in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), an interface between ER and mitochondria. In addition to being able to translocate to the plasma membrane (PM) to interact with ion channels and other receptors, Sig-1R also occurs at the nuclear envelope, where it recruits chromatin-remodeling factors to affect the transcription of genes. Sig-1Rs have also been reported to interact with other membranous or soluble proteins at other loci, including the cytosol, and to be involved in several central nervous system (CNS) diseases. Here, we propose that Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in living systems. C1 [Su, Tsung-Ping; Su, Tzu-Chieh; Nakamura, Yoki; Tsai, Shang-Yi] NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Sect, Integrat Neurosci Res Branch, Intramural Res Program,NIH,US Dept HHS, Baltimore, MD 21224 USA. EM TSU@intra.nida.nih.gov RI Nakamura, Yoki/P-7785-2016 OI Nakamura, Yoki/0000-0001-9226-676X FU National Institute on Drug Abuse; Dragon Gate Program of the Ministry of Science and Technology of Taiwan (MOST) [105-2911-1-038 -503]; Japanese Society for Promotion of Sciences FX This work is supported by the Intramural Research Program of the National Institute on Drug Abuse. T-C.S. is supported, in part, by the Dragon Gate Program of the Ministry of Science and Technology of Taiwan (MOST #105-2911-1-038 -503). Y. N. is supported in part by the Japanese Society for Promotion of Sciences. NR 140 TC 7 Z9 7 U1 8 U2 13 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD APR PY 2016 VL 37 IS 4 BP 262 EP 278 DI 10.1016/j.tips.2016.01.003 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK1XK UT WOS:000374708300006 PM 26869505 ER PT J AU Bilgel, M An, Y Zhou, Y Wong, DF Prince, JL Ferrucci, L Resnick, SM AF Bilgel, Murat An, Yang Zhou, Yun Wong, Dean F. Prince, Jerry L. Ferrucci, Luigi Resnick, Susan M. TI Individual estimates of age at detectable amyloid onset for risk factor assessment SO ALZHEIMERS & DEMENTIA LA English DT Article DE APOE; Pittsburgh compound B; PET; Amyloid imaging; Age at onset ID APOLIPOPROTEIN-E EPSILON-4; NORMAL OLDER-ADULTS; ALZHEIMER-DISEASE; APOE GENOTYPE; A-BETA; LIFE-SPAN; BRAIN; DEPOSITION; ASSOCIATION; BIOMARKERS AB Introduction: Individualized estimates of age at detectable amyloid-beta (A beta) accumulation, distinct from amyloid positivity, allow for analysis of onset age of A beta accumulation as an outcome measure to understand risk factors. Methods: Using longitudinal Pittsburgh compound B (PiB) positron emission tomography data from Baltimore Longitudinal Study of Aging, we estimated the age at which each PiB+ individual began accumulating A beta. We used survival analysis methods to quantify risk of accumulating A beta and differences in onset age of A beta accumulation in relation to APOE epsilon 4 status and sex among 36 APOE epsilon 4 carriers and 83 noncarriers. Results: Age at onset of A beta accumulation for the APOE epsilon 4- and epsilon 4+ groups was 73.1 and 60.7, respectively. APOE epsilon 4 positivity conferred a threefold risk of accumulating A beta after adjusting for sex and education. Discussion: Estimation of onset age of amyloid accumulation may help gauge treatment efficacy in interventions to delay symptom onset in Alzheimer's disease. Published by Elsevier Inc. on behalf of the Alzheimer's Association. C1 [Bilgel, Murat; An, Yang; Resnick, Susan M.] NIA, Lab Behav Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Bilgel, Murat; Prince, Jerry L.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Zhou, Yun; Wong, Dean F.; Prince, Jerry L.] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21205 USA. [Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Bilgel, M (reprint author), NIA, Lab Behav Neurosci, Intramural Res Program, Baltimore, MD 21224 USA.; Bilgel, M (reprint author), Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. EM murat.bilgel@nih.gov OI Bilgel, Murat/0000-0001-5042-7422 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The authors are grateful to the BLSA participants and staff for their dedication to these studies and the staff of the Johns Hopkins PET facility for their assistance. The authors thank Brieana Viscomi and Wendy Elkins for assistance with coordination and data collection for the PET studies. NR 43 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD APR PY 2016 VL 12 IS 4 BP 373 EP 379 DI 10.1016/j.jalz.2015.08.166 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DK7YC UT WOS:000375142000001 PM 26588863 ER PT J AU Mwachiro, MM Burgert, SL Lando, J Chepkwony, R Bett, C Bosire, C Abnet, CC Githanga, J Waweru, W Giffen, CA Murphy, G White, RE Topazian, MD Dawsey, SM AF Mwachiro, Michael M. Burgert, Stephen L. Lando, Justus Chepkwony, Robert Bett, Collins Bosire, Claire Abnet, Christian C. Githanga, Jessie Waweru, Wairimu Giffen, Carol A. Murphy, Gwen White, Russell E. Topazian, Mark D. Dawsey, Sanford M. TI Esophageal Squamous Dysplasia is Common in Asymptomatic Kenyans: A Prospective, Community-Based, Cross-Sectional Study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID HIGH-RISK AREA; CELL CARCINOMA; FOLLOW-UP; PRECANCEROUS LESIONS; CYTOLOGIC DETECTION; CANCER STATISTICS; CHINA; LINXIAN; POPULATION; IRAN AB OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is endemic in east Africa and is a leading cause of cancer death among Kenyans. The asymptomatic precursor lesion of ESCC is esophageal squamous dysplasia (ESD). We aimed to determine the prevalence of ESD in asymptomatic adult residents of southwestern Kenya. METHODS: In this prospective, community-based, cross-sectional study, 305 asymptomatic adult residents completed questionnaires and underwent video endoscopy with Lugol's iodine chromoendoscopy and mucosal biopsy for detection of ESD. RESULTS: Study procedures were well tolerated, and there were no adverse events. The overall prevalence of ESD was 14.4% (95% confidence interval (CI): 10-19%), including 11.5% with low-grade dysplasia and 2.9% with high-grade dysplasia. The prevalence of ESD was >20% among men aged >50 years and women aged >60 years. Residence location was significantly associated with ESD (Zone A adjusted odds ratio (OR) 2.37, 95% CI: 1.06-5.30 and Zone B adjusted OR 2.72, 95% CI: 1.12-6.57, compared with Zone C). Iodine chromoendoscopy with biopsy of unstained lesions was more sensitive than white-light endoscopy or random mucosal biopsy for detection of ESD and had 67% sensitivity and 70% specificity. CONCLUSIONS: ESD is common among asymptomatic residents of southwestern Kenya and is especially prevalent in persons aged >50 years and those living in particular local regions. Lugol's iodine chromoendoscopy is necessary for detection of most ESD but has only moderate sensitivity and specificity in this setting. Screening for ESD is warranted in this high-risk population, and endoscopic screening of Kenyans is feasible, safe, and acceptable, but more accurate and less invasive screening tests are needed. C1 [Mwachiro, Michael M.; Burgert, Stephen L.; Lando, Justus; Chepkwony, Robert; Bett, Collins; White, Russell E.] Tenwek Hosp, POB 39, Bomet 20400, Kenya. [Bosire, Claire; Abnet, Christian C.; Murphy, Gwen; Dawsey, Sanford M.] NCI, Bethesda, MD 20892 USA. [Githanga, Jessie; Waweru, Wairimu] Univ Nairobi, Dept Pathol, Nairobi, Kenya. [Giffen, Carol A.] Informat Management Serv Inc, Calverton, MD USA. [Topazian, Mark D.] Mayo Clin, Rochester, MN USA. RP Mwachiro, MM (reprint author), Tenwek Hosp, POB 39, Bomet 20400, Kenya. EM deche2002@yahoo.com RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; Mwachiro, Michael/0000-0002-3779-5324 FU BIG CAT (Beginning Investigator Grant for Catalytic Research) grant from the African Organization for Research and Training in Cancer (AORTIC); US National Cancer Institute (NCI) FX This work was supported by BIG CAT (Beginning Investigator Grant for Catalytic Research) grant from the African Organization for Research and Training in Cancer (AORTIC) and the US National Cancer Institute (NCI). NR 24 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 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD APR PY 2016 VL 111 IS 4 BP 500 EP 507 DI 10.1038/ajg.2016.26 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DL2DE UT WOS:000375442300016 PM 26902228 ER PT J AU Insel, TR AF Insel, Thomas R. TI RAISE-ing Our Expectations for First-Episode Psychosis SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID TRIAL C1 [Insel, Thomas R.] NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, Bethesda, MD 20892 USA. EM insel@mail.nih.gov NR 4 TC 0 Z9 0 U1 3 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2016 VL 173 IS 4 BP 311 EP 312 DI 10.1176/appi.ajp.2015.15091204 PG 2 WC Psychiatry SC Psychiatry GA DK9ZH UT WOS:000375290400001 PM 26481175 ER PT J AU Kane, JM Robinson, DG Schooler, NR Mueser, KT Penn, DL Rosenheck, RA Addington, J Brunette, MF Correll, CU Estroff, SE Marcy, P Robinson, J Meyer-Kalos, PS Gottlieb, JD Glynn, SM Lynde, DW Pipes, R Kurian, BT Miller, AL Azrin, ST Goldstein, AB Severe, JB Lin, HQ Sint, KJ John, M Heinssen, RK AF Kane, John M. Robinson, Delbert G. Schooler, Nina R. Mueser, Kim T. Penn, David L. Rosenheck, Robert A. Addington, Jean Brunette, Mary F. Correll, Christoph U. Estroff, Sue E. Marcy, Patricia Robinson, James Meyer-Kalos, Piper S. Gottlieb, Jennifer D. Glynn, Shirley M. Lynde, David W. Pipes, Ronny Kurian, Benji T. Miller, Alexander L. Azrin, Susan T. Goldstein, Amy B. Severe, Joanne B. Lin, Haiqun Sint, Kyaw J. John, Majnu Heinssen, Robert K. TI Comprehensive Versus Usual Community Care for First-Episode Psychosis: 2-Year Outcomes From the NIMH RAISE Early Treatment Program SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; NEGATIVE SYNDROME SCALE; 5-YEAR FOLLOW-UP; EARLY INTERVENTION; UNITED-STATES; UNTREATED PSYCHOSIS; STANDARD TREATMENT; COST-EFFECTIVENESS; MULTICENTER TRIAL; SPECIALIZED CARE AB Objective: The primary aim of this study was to compare the impact of NAVIGATE, a comprehensive, multidisciplinary, team-based treatment approach for first-episode psychosis designed for implementation in the U.S. health care system, with community care on quality of life. Method: Thirty-four clinics in 21 states were randomly assigned to NAVIGATE or community care. Diagnosis, duration of untreated psychosis, and clinical outcomes were assessed via live, two-way video by remote, centralized raters masked to study design and treatment. Participants (mean age, 23) with schizophrenia and related disorders and <= 6 months of antipsychotic treatment (N=404) were enrolled and followed for >= 2 years. The primary outcome was the total score of the Heinrichs-Carpenter Quality of Life Scale, a measure that includes sense of purpose, motivation, emotional and social interactions, role functioning, and engagement in regular activities. Results: The 223 recipients of NAVIGATE remained in treatment longer, experienced greater improvement in quality of life and psychopathology, and experienced greater involvement in work and school compared with 181 participants in community care. The median duration of untreated psychosis was 74 weeks. NAVIGATE participants with duration of untreated psychosis of,74 weeks had greater improvement in quality of life and psychopathology compared with those with longer duration of untreated psychosis and those in community care. Rates of hospitalization were relatively low compared with other first-episode psychosis clinical trials and did not differ between groups. Conclusions: Comprehensive care for first-episode psychosis can be implemented in U.S. community clinics and improves functional and clinical outcomes. Effects are more pronounced for those with shorter duration of untreated psychosis. C1 [Kane, John M.] North Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USA. Hofstra North Shore Long Isl Jewish Sch Med, Dept Psychiat, Hempstead, NY USA. Hofstra North Shore Long Isl Jewish Sch Med, Dept Mol Med, Hempstead, NY USA. Hofstra Univ, Dept Math, Hempstead, NY 11550 USA. Feinstein Inst Med Res, Manhasset, NY USA. Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. Suny Downstate Med Ctr, Dept Psychiat, Brooklyn, NY 11203 USA. Boston Univ, Ctr Psychiat Rehabil, Dept Occupat Therapy, Boston, MA 02215 USA. Boston Univ, Ctr Psychiat Rehabil, Dept Psychiat, Boston, MA 02215 USA. Boston Univ, Ctr Psychiat Rehabil, Dept Psychol, Boston, MA 02215 USA. Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. Univ N Carolina, Dept Social Med, Chapel Hill, NC USA. Australian Catholic Univ, Sch Psychol, Melbourne, Vic, Australia. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Yale Univ, Sch Publ Hlth, New Haven, CT USA. Univ Calgary, Hotchkiss Brain Inst, Dept Psychiat, Calgary, AB, Canada. Dartmouth Coll, Geisel Sch Med, 1 Med Ctr Dr, Lebanon, NH 03756 USA. Bur Behav Hlth, New Hampshire Dept Hlth & Human Serv, Concord, NH USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. Univ Minnesota, Sch Social Work, Minnesota Ctr Chem & Mental Hlth, St Paul, MN 55108 USA. Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. NIMH, Div Serv & Intervent Res, Rockville, MD 20857 USA. RP Kane, JM (reprint author), North Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USA. EM psychiatry@nshs.edu FU American Recovery and Reinvestment Act and from NIMH [HHSN271200900019C]; NIMH Advanced Centers for Intervention and/or Services Research award [P30MH090590]; Bristol-Myers Squibb; Janssen; Otsuka; Genentech; Neurocrine; Alkermes; Johnson and Johnson; Novo Nordisk; Takeda; Evotec; Forest; Naurex; Pfizer; Rexahn; Targacept FX This work has been funded in whole or in part with funds from the American Recovery and Reinvestment Act and from NIMH under contract HHSN271200900019C. Additional support for these analyses was provided by an NIMH Advanced Centers for Intervention and/or Services Research award (P30MH090590) to Dr. Kane.; Dr. Kane has been a consultant for Alkermes, Amgen, Bristol-Myers Squibb, Eli Lilly, EnVivo Pharmaceuticals (Forum), Forest, Genentech, H. Lundbeck, Intra-Cellular Therapies, Janssen Pharmaceutica, Johnson and Johnson, Merck, Novartis, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, and Teva; he has received honoraria for lectures from Bristol-Myers Squibb, Genentech, Janssen, Lundbeck, and Otsuka; and he is a shareholder in MedAvante and in Vanguard Research Group. Dr. Robinson has been a consultant to Asubio, Otsuka, and Shire; and he has received grants from Bristol-Myers Squibb, Janssen, and Otsuka. Dr. Schooler has served on advisory boards or as a consultant for Abbott, Alkermes, Amgen, Eli Lilly, Forum(formerly EnVivo), Janssen Psychiatry, Roche, and Sunovion; she has received grant or research support from Genentech, Neurocrine, and Otsuka; and she has served on a data monitoring board for Shire and on the faculty of the Lundbeck International Neuroscience Foundation. Dr. Brunette has received grant support from Alkermes. Dr. Correll has been a consultant or adviser to or has received honoraria from AbbVie, Actavis, Actelion, Alexza, Alkermes, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen, Johnson and Johnson, Lundbeck, MedAvante, Medscape, Merck, Otsuka, Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, Takeda, Teva, and Vanda; and he has received grant support from Bristol-Myers Squibb, Janssen, Johnson and Johnson, Novo Nordisk, Otsuka, and Takeda. Ms. Marcy is a shareholder in Pfizer. Mr. Robinson has received grant support from Otsuka and is a shareholder in Pfizer. Dr. Kurian has received grant support from Evotec, Forest, Johnson and Johnson, Naurex, Pfizer, Rexahn, and Targacept. Dr. Miller has received payments for serving on a data monitoring committee for a study sponsored by Otsuka. The authors and their associates provide training and consultation about implementing NAVIGATE treatment that can include compensation. These activities started only after data collection for the article was completed. At the time of publication, Dr. Meyer-Kalos, Dr. Glynn, and Dr. Robinson had received compensation for these activities. The other authors report no financial relationships with commercial interests. NR 38 TC 27 Z9 28 U1 11 U2 15 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2016 VL 173 IS 4 BP 362 EP 372 DI 10.1176/appi.ajp.2015.15050632 PG 11 WC Psychiatry SC Psychiatry GA DK9ZH UT WOS:000375290400011 PM 26481174 ER PT J AU Sheng, Y Filichia, E Shick, E Preston, KL Phillips, KA Cooperman, L Lin, ZC Tesar, P Hoffer, BJ Luo, Y AF Sheng, Yang Filichia, Emily Shick, Elizabeth Preston, Kenzie L. Phillips, Karran A. Cooperman, Leslie Lin, Zhicheng Tesar, Paul Hoffer, Barry J. Luo, Yu TI Lower Dopamine D-2 Receptor Expression Levels in Human Dopaminergic Neurons Derived From Opioid-Dependent iPSCs SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Letter C1 [Sheng, Yang] Case Western Reserve Univ, Sch Med, Dept Neurol Surg, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Genome Sci, Cleveland, OH 44106 USA. NIDA, Intramural Res Program, Clin Trials Treatment Branch, Baltimore, MD USA. NIDA, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD USA. NIDA, Cellular Neurobiol Branch, Baltimore, MD USA. Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA USA. RP Sheng, Y (reprint author), Case Western Reserve Univ, Sch Med, Dept Neurol Surg, Cleveland, OH 44106 USA. FU Intramural NIH HHS; NIDA NIH HHS [R21DA032962, R21 DA032962, R01 DA021409, DA021409] NR 6 TC 1 Z9 1 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2016 VL 173 IS 4 BP 429 EP 431 DI 10.1176/appi.ajp.2015.15121545 PG 3 WC Psychiatry SC Psychiatry GA DK9ZH UT WOS:000375290400018 PM 27035534 ER PT J AU Ziegler, TR May, AK Hebbar, G Easley, KA Griffith, DP Dave, N Collier, BR Cotsonis, GA Hao, L Leong, T Manatunga, AK Rosenberg, ES Jones, DP Martin, GS Jensen, GL Sax, HC Kudsk, KA Galloway, JR Blumberg, HM Evans, ME Wischmeyer, PE AF Ziegler, Thomas R. May, Addison K. Hebbar, Gautam Easley, Kirk A. Griffith, Daniel P. Dave, Nisha Collier, Bryan R. Cotsonis, George A. Hao, Li Leong, Traci Manatunga, Amita K. Rosenberg, Eli S. Jones, Dean P. Martin, Gregory S. Jensen, Gordon L. Sax, Harry C. Kudsk, Kenneth A. Galloway, John R. Blumberg, Henry M. Evans, Mary E. Wischmeyer, Paul E. TI Efficacy and Safety of Glutamine-supplemented Parenteral Nutrition in Surgical ICU Patients: An American Multicenter Randomized Controlled Trial SO ANNALS OF SURGERY LA English DT Article DE critical care; critical illness; glutamine; hospital-acquired infection; nutrition support; parenteral nutrition ID CRITICALLY-ILL PATIENTS; INTENSIVE-CARE-UNIT; MAJOR ABDOMINAL-SURGERY; ACUTE LUNG INJURY; DOUBLE-BLIND; CRITICAL ILLNESS; MECHANICAL VENTILATION; NITROGEN-BALANCE; CLINICAL-TRIAL; ORGAN FAILURE AB Objective:To determine whether glutamine (GLN)-supplemented parenteral nutrition (PN) improves clinical outcomes in surgical intensive care unit (SICU) patients.Summary Background Data:GLN requirements may increase with critical illness. GLN-supplemented PN may improve clinical outcomes in SICU patients.Methods:A parallel-group, multicenter, double-blind, randomized, controlled clinical trial in 150 adults after gastrointestinal, vascular, or cardiac surgery requiring PN and SICU care. Patients were without significant renal or hepatic failure or shock at entry. All received isonitrogenous, isocaloric PN [1.5g/kg/d amino acids (AAs) and energy at 1.3x estimated basal energy expenditure]. Controls (n=75) received standard GLN-free PN (STD-PN); the GLN group (n=75) received PN containing alanyl-GLN dipeptide (0.5g/kg/d), proportionally replacing AA in PN (GLN-PN). Enteral nutrition (EN) was advanced and PN weaned as indicated. Hospital mortality and infections were primary endpoints.Results:Baseline characteristics, days on study PN and daily macronutrient intakes via PN and EN, were similar between groups. There were 11 hospital deaths (14.7%) in the GLN-PN group and 13 deaths in the STD-PN group (17.3%; difference, -2.6%; 95% confidence interval, -14.6% to 9.3%; P=0.66). The 6-month cumulative mortality was 31.4% in the GLN-PN group and 29.7% in the STD-PN group (P=0.88). Incident bloodstream infection rate was 9.6 and 8.4 per 1000 hospital days in the GLN-PN and STD-PN groups, respectively (P=0.73). Other clinical outcomes and adverse events were similar.Conclusions:PN supplemented with GLN dipeptide was safe, but did not alter clinical outcomes among SICU patients. C1 [Ziegler, Thomas R.; Hebbar, Gautam; Hao, Li] Emory Univ, Sch Med, Dept Med, Div Endocrinol Metab & Lipids, Atlanta, GA USA. [Ziegler, Thomas R.; Jones, Dean P.; Galloway, John R.] Emory Univ, Sch Med, Ctr Clin & Mol Nutr, Atlanta, GA USA. [Ziegler, Thomas R.; Hebbar, Gautam; Griffith, Daniel P.; Dave, Nisha; Galloway, John R.] Emory Univ Hosp, Nutr & Metab Support Serv, Suite GG-23,1364 Clifton Rd, Atlanta, GA 30322 USA. [May, Addison K.; Collier, Bryan R.] Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN USA. [Easley, Kirk A.; Cotsonis, George A.; Leong, Traci; Manatunga, Amita K.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Collier, Bryan R.] Virginia Tech, Inst Caril Sch Med, Dept Surg, Roanoke, VA USA. [Rosenberg, Eli S.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Martin, Gregory S.] Emory Univ, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Atlanta, GA USA. [Jensen, Gordon L.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Sax, Harry C.] Miriam Hosp, Dept Surg, Providence, RI 02906 USA. [Sax, Harry C.] Cedars Sinai Med Ctr, Dept Surg, Los Angeles, CA 90048 USA. [Kudsk, Kenneth A.] Univ Wisconsin, Sch Med, Dept Surg, Madison, WI USA. [Kudsk, Kenneth A.] Univ Wisconsin, Sch Publ Hlth, Madison, WI USA. [Galloway, John R.] Emory Univ, Sch Med, Dept Surg, Atlanta, GA 30322 USA. [Blumberg, Henry M.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. [Blumberg, Henry M.] Emory Univ, Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Atlanta, GA 30322 USA. [Evans, Mary E.] NIDDK, NIH, Bethesda, MD 20892 USA. [Wischmeyer, Paul E.] Univ Colorado, Sch Med, Dept Anesthesiol, Aurora, CO USA. RP Ziegler, TR (reprint author), Emory Univ Hosp, Atlanta Clin & Translat Sci Inst, Suite GG-23,1364 Clifton Rd, Atlanta, GA 30322 USA. EM tzieg01@emory.edu RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU National Institutes of Health [U01 DK069322, K24 DK096574, UL1 TR000454, K23 RR018379, R01 GM078312]; Fresenius Kabi FX This work was supported, in part, by National Institutes of Health grants U01 DK069322 and K24 DK096574 (T.R.Z.), UL1 TR000454 (Atlanta Clinical and Translational Science Institute), K23 RR018379 and R01 GM078312 (P.E.W.) and an investigator-initiated grant from Fresenius Kabi (T.R.Z.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 7 Z9 8 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD APR PY 2016 VL 263 IS 4 BP 646 EP 655 DI 10.1097/SLA.0000000000001487 PG 10 WC Surgery SC Surgery GA DK2YZ UT WOS:000374782700014 PM 26501700 ER PT J AU Illei, PB Alewine, C Zahurak, M Cowan, ML Montgomery, E Hassan, R Xiang, LM Pastan, I Kelly, RJ AF Illei, Peter B. Alewine, Christine Zahurak, Marianna Cowan, Morgan L. Montgomery, Elizabeth Hassan, Raffit Xiang, Laiman Pastan, Ira Kelly, Ronan J. TI Mesothelin Expression in Advanced Gastroesophageal Cancer Represents a Novel Target for Immunotherapy SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY LA English DT Article DE carcinoma; expression; gastric; gastroesophageal; immunotherapy mesothelin; target ID GASTRIC-CANCER; JUNCTION ADENOCARCINOMA; ANTITUMOR-ACTIVITY; SERUM MESOTHELIN; IMMUNOTOXIN SS1P; OVARIAN CANCERS; BREAST-CANCER; COMBINATION; VALIDATION; CISPLATIN AB The identification of new therapeutic targets is of profound importance if we are to improve outcomes in gastroesophageal cancer. This study assessed the rate of mesothelin expression in tumors of western patients with upper gastrointestinal tract carcinomas. In addition, the AGS gastric cancer cell line was tested for sensitivity to SS1(dsFv)PE38, a mesothelin-targeting immunotoxin. Previously constructed tissue microarrays containing samples from 127 patients with gastroesophageal adenocarcinomas were examined by immunohistochemistry (IHC) for mesothelin expression. Labeling for HER2-neu, E-cadherin, and c-met were also assessed. Tumors were considered positive for mesothelin if at least moderate cytoplasmic/membranous or luminal staining was present in minimum 10% of the neoplastic cells. The AGS gastric cancer cell line was assessed for surface mesothelin expression by flow cytometry and the viability of cells treated with SS1P was measured. Gastroesophageal cancers were mesothelin positive in 64 of 127 tumors [50.4%; 95% confidence interval (CI), 41.4%-59.4%], whereas only 9 carcinomas (7.1%; 95% CI, 3.3%-13.0%) were HER2-neu IHC 3+ positive and 8 (6.6%; 95% CI, 2.9%-12.5%) were c-met positive. Mesothelin expression increased from stage I to stage IV tumors (37.5% to 56.3%, respectively, P=0.10). The AGS gastric cancer cell line was sensitive to the immunotoxin with an EC50 value in the low picomolar range (0.4 ng/mL). A gastric cancer cell line derived from a western patient was exquisitely sensitive to the mesothelin-targeted immunotoxin SS1P. Clinical trials involving novel mesothelin targeted immunotherapeutics in gastroesophageal cancer are currently in development. C1 [Illei, Peter B.; Cowan, Morgan L.; Montgomery, Elizabeth] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Kelly, Ronan J.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, 406 N Broadway, Baltimore, MD 21287 USA. [Alewine, Christine; Zahurak, Marianna; Hassan, Raffit; Xiang, Laiman; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kelly, RJ (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, 406 N Broadway, Baltimore, MD 21287 USA. EM rkelly25@jhmi.edu FU Sidney Kimmel Comprehensive Cancer Center Core Grant [P30 CA006973]; Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research FX Supported in part by the Sidney Kimmel Comprehensive Cancer Center Core Grant P30 CA006973 and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 30 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 1541-2016 EI 1533-4058 J9 APPL IMMUNOHISTO M M JI Appl. Immunohistochem. PD APR PY 2016 VL 24 IS 4 BP 246 EP 252 DI 10.1097/PAI.0000000000000292 PG 7 WC Anatomy & Morphology; Medical Laboratory Technology; Pathology SC Anatomy & Morphology; Medical Laboratory Technology; Pathology GA DK6MH UT WOS:000375037700005 PM 26894650 ER PT J AU Katz, JL Hong, WC Hiranita, T Su, TP AF Katz, Jonathan L. Hong, Weimin C. Hiranita, Takato Su, Tsung-Ping TI A role for sigma receptors in stimulant self-administration and addiction SO BEHAVIOURAL PHARMACOLOGY LA English DT Review DE chaperone protein; cocaine; drug abuse; methamphetamine; reinforcing effects; self-administration; sigma receptors ID CONDITIONED PLACE PREFERENCE; LIPID RAFT RECONSTITUTION; UNFOLDED PROTEIN RESPONSE; DOPAMINE TRANSPORTER; ENDOPLASMIC-RETICULUM; PC12 CELLS; UPTAKE INHIBITORS; COCAINE BINDING; LIGAND; BRAIN AB Sigma-1 receptors (sigma 1Rs) are structurally unique intracellular proteins that function as chaperones. sigma 1Rs translocate from the mitochondria-associated membrane to other subcellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to sigma Rs can induce or block the actions of sigma Rs. Studies indicate that stimulant self-administration induces the reinforcing effects of sigma R agonists, because of dopamine transporter actions. Once established, the reinforcing effects of sigma R agonists are independent of dopaminergic mechanisms traditionally thought to be critical to the reinforcing effects of stimulants. Self-administered doses of sigma R agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for the reinforcing effects of abused drugs. However, self-administration of sigma R agonists is blocked by sigma R antagonists. Several effects of stimulants have been blocked by sigma R antagonists, including the reinforcing effects, assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by sigma R antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess the reinforcing effects. When sigma R antagonists are administered in combination with dopamine uptake inhibitors, an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in sigma R activity and the changes induced potentially create redundant and, once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and sigma R proteins produces a selective antagonism of stimulant self-administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Katz, Jonathan L.; Hong, Weimin C.; Hiranita, Takato] NIDA, Psychobiol, Dept Hlth & Human Serv, Baltimore, MD USA. [Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Intramural Res Program, Dept Hlth & Human Serv,NIH, Baltimore, MD USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 FU National Institute on Drug Abuse Intramural Research Program; NIDA IRP; Japan Society for the Promotion of Science FX The authors thank Gianluigi Tanda, Paul L. Soto, Christopher R. McCurdy, and Theresa Kopajtic for their many contributions to the experiments, conceptual approaches, and all-around collegiality. The staff of the Medicinal Chemistry Section of the NIDA Intramural Research Program kindly synthesized some of the compounds used in the studies described. Funding for the experiments originating in our laboratories was provided by the National Institute on Drug Abuse Intramural Research Program. Takato Hiranita was supported in part by the NIDA IRP and by a fellowship from the Japan Society for the Promotion of Science. Subjects used in the studies published from the NIDA Intramural Research Program were maintained in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care, and those experiments were conducted in accordance with the guidelines of the institute's Animal Care and Use Committee. NR 98 TC 2 Z9 3 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8810 EI 1473-5849 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD APR PY 2016 VL 27 IS 2-3 SI SI BP 100 EP 115 DI 10.1097/FBP.0000000000000209 PG 16 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA DK4MQ UT WOS:000374892900003 PM 26650253 ER PT J AU Radke, AK Zlebnik, NE Holtz, NA Carroll, ME AF Radke, Anna K. Zlebnik, Natalie E. Holtz, Nathan A. Carroll, Marilyn E. TI Cocaine-induced reward enhancement measured with intracranial self-stimulation in rats bred for low versus high saccharin intake SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE cocaine; intracranial self-stimulation; motivation; rat; selective breeding; sweet preference ID BRAIN; WITHDRAWAL; THRESHOLDS; TASTE; ESCALATION; PREFERENCE; NICOTINE; SUCROSE; FACILITATION; CONSUMPTION AB Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug-abuse vulnerability, with HiS rats being more likely to consume sweets and cocaine than LoS rats. Still, the nature of these differences is poorly understood. This study examined whether the motivational consequences of cocaine exposure are differentially expressed in HiS and LoS rats by measuring intracranial self-stimulation (ICSS) thresholds following acute injections of cocaine (10mg/kg). Reductions in ICSS thresholds following cocaine injection were greater in HiS rats than in LoS rats, suggesting that the reward-enhancing effects of cocaine are greater in the drug-vulnerable HiS than LoS rats. Higher cocaine-induced reward, indicated by lower ICSS thresholds, may explain the higher rates of drug consumption in sweet-preferring animal models, providing a clue to the etiology of cocaine addiction in vulnerable populations. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Radke, Anna K.; Zlebnik, Natalie E.; Holtz, Nathan A.; Carroll, Marilyn E.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. RP Radke, AK (reprint author), NIAAA, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM anna.radke@nih.gov FU NIH [R01 DA003240-28] FX The authors thank Dr Andrew Harris for advice on intracranial self-stimulation and Seth Johnson for superb technical assistance. This research was supported by NIH grant R01 DA003240-28 (M.E.C.). NR 37 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8810 EI 1473-5849 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD APR PY 2016 VL 27 IS 2-3 SI SI BP 133 EP 136 DI 10.1097/FBP.0000000000000182 PG 4 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA DK4MQ UT WOS:000374892900005 PM 26292189 ER PT J AU Karev, GP Kareva, I AF Karev, G. P. Kareva, I. TI Mathematical Modeling of Extinction of Inhomogeneous Populations SO BULLETIN OF MATHEMATICAL BIOLOGY LA English DT Article DE Extinction of heterogeneous populations; Principle of minimal information gain; Population extinction; Non-homogeneous models; Frequency-dependent models; Minimum information loss; Internal time; Time perception ID TIME PERCEPTION; INFORMATION; DYNAMICS; DEATH AB Mathematical models of population extinction have a variety of applications in such areas as ecology, paleontology and conservation biology. Here we propose and investigate two types of sub-exponential models of population extinction. Unlike the more traditional exponential models, the life duration of sub-exponential models is finite. In the first model, the population is assumed to be composed of clones that are independent from each other. In the second model, we assume that the size of the population as a whole decreases according to the sub-exponential equation. We then investigate the "unobserved heterogeneity," i.e., the underlying inhomogeneous population model, and calculate the distribution of frequencies of clones for both models. We show that the dynamics of frequencies in the first model is governed by the principle of minimum of Tsallis information loss. In the second model, the notion of "internal population time" is proposed; with respect to the internal time, the dynamics of frequencies is governed by the principle of minimum of Shannon information loss. The results of this analysis show that the principle of minimum of information loss is the underlying law for the evolution of a broad class of models of population extinction. Finally, we propose a possible application of this modeling framework to mechanisms underlying time perception. C1 [Karev, G. P.] NIH, Natl Ctr Biotechnol Informat, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20892 USA. [Kareva, I.] Floating Hosp Children, Tufts Med Ctr, Boston, MA 02111 USA. [Kareva, I.] Arizona State Univ, Simon A Levin Math Computat & Modeling Sci Ctr, Engn Ctr A, Tempe, AZ 85287 USA. RP Karev, GP (reprint author), NIH, Natl Ctr Biotechnol Informat, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20892 USA. EM karev@ncbi.nlm.nih.gov; ikareva@asu.edu FU Intramural Research Program of the NCBI, NIH FX This research was partially supported by the Intramural Research Program of the NCBI, NIH. The authors would also like to thank the anonymous reviewers, whose comments and suggestions contributed to significant improvement of the manuscript. NR 32 TC 1 Z9 1 U1 3 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0092-8240 EI 1522-9602 J9 B MATH BIOL JI Bull. Math. Biol. PD APR PY 2016 VL 78 IS 4 BP 834 EP 858 DI 10.1007/s11538-016-0166-0 PG 25 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA DL1UX UT WOS:000375419200009 PM 27090117 ER PT J AU Zdanov, S Mandapathil, M Abu Eid, R Adamson-Fadeyi, S Wilson, W Qian, JH Carnie, A Tarasova, N Mkrtichyan, M Berzofsky, JA Whiteside, TL Khleif, SN AF Zdanov, Stephanie Mandapathil, Magis Abu Eid, Rasha Adamson-Fadeyi, Saudat Wilson, Willie Qian, Jiahua Carnie, Andrea Tarasova, Nadya Mkrtichyan, Mikayel Berzofsky, Jay A. Whiteside, Theresa L. Khleif, Samir N. TI Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID K-RAS; SIGNALING PATHWAYS; TUMOR MICROENVIRONMENT; KINASE INHIBITORS; EPITHELIAL-CELLS; TGF-BETA; C-JUN; MELANOMA; CANCER; ACTIVATION AB Constitutive activation of the KRAS oncogene in human malignancies is associated with aggressive tumor growth and poor prognosis. Similar to other oncogenes, KRAS acts in a cell-intrinsic manner to affect tumor growth or survival. However, we describe here a different, cell-extrinsic mechanism through which mutant KRAS contributes to tumor development. Tumor cells carrying mutated KRAS induced highly suppressive T cells, and silencing KRAS reversed this effect. Overexpression of the mutant KRAS(G12V) gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-beta 1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway. Finally, we report that inhibition of KRAS reduces the infiltration of Tregs in KRAS-driven lung tumorigenesis even before tumor formation. This cell-extrinsic mechanism allows tumor cells harboring a mutant KRAS oncogene to escape immune recognition. Thus, an oncogene can promote tumor progression independent of its transforming activity by increasing the number and function of Tregs. This has a significant clinical potential, in which targeting KRAS and its downstream signaling pathways could be used as powerful immune modulators in cancer immunotherapy. (C) 2016 AACR. C1 [Zdanov, Stephanie; Abu Eid, Rasha; Adamson-Fadeyi, Saudat; Qian, Jiahua; Carnie, Andrea; Mkrtichyan, Mikayel; Khleif, Samir N.] NCI, Canc Vaccine Sect, Vaccine Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mandapathil, Magis; Whiteside, Theresa L.] Univ Pittsburgh, Dept Pathol, IMPCL, Inst Canc, Pittsburgh, PA USA. [Abu Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N.] Augusta Univ, Georgia Regents Univ, Georgia Canc Ctr, 1120 15th St,CN-2101A, Augusta, GA 30912 USA. [Wilson, Willie] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Tarasova, Nadya] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD USA. [Berzofsky, Jay A.] NIH, Mol Immunogenet & Vac Res Sect, Vaccine Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Adamson-Fadeyi, Saudat] Meharry Med Coll, Dept Canc Biol, Nashville, TN 37208 USA. [Mandapathil, Magis] Univ Marburg, Dept Otorhinolaryngol, Marburg, Germany. [Qian, Jiahua] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Mkrtichyan, Mikayel] FivePrime Therapeut, San Francisco, CA USA. RP Khleif, SN (reprint author), Augusta Univ, Georgia Regents Univ, Georgia Canc Ctr, 1120 15th St,CN-2101A, Augusta, GA 30912 USA. EM SKHLEIF@gru.edu FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (S.N. Khleif). NR 50 TC 1 Z9 1 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD APR PY 2016 VL 4 IS 4 BP 354 EP 365 DI 10.1158/2326-6066.CIR-15-0241 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA DL1RP UT WOS:000375410000010 PM 26880715 ER PT J AU Contijoch, F Rogers, K Rears, H Shahid, M Kellman, P Gorman, J Gorman, RC Yushkevich, P Zado, ES Supple, GE Marchlinski, FE Witschey, WRT Han, Y AF Contijoch, Francisco Rogers, Kelly Rears, Hannah Shahid, Mohammed Kellman, Peter Gorman, Joseph, III Gorman, Robert C. Yushkevich, Paul Zado, Erica S. Supple, Gregory E. Marchlinski, Francis E. Witschey, Walter R. T. Han, Yuchi TI Quantification of Left Ventricular Function With Premature Ventricular Complexes Reveals Variable Hemodynamics SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE cardiac arrhythmias; echocardiography; magnetic resonance imaging; stroke volume; ventricular premature complexes ID CONTRACTION-INDUCED CARDIOMYOPATHY; ATRIAL-FIBRILLATION; QRS DETECTION; ANIMAL-MODEL; MRI; RECONSTRUCTION; ECTOPY; INTERVAL AB Background Premature ventricular complexes (PVCs) are prevalent in the general population and are sometimes associated with reduced ventricular function. Current echocardiographic and cardiovascular magnetic resonance imaging techniques do not adequately address the effect of PVCs on left ventricular function. Methods and Results Fifteen subjects with a history of frequent PVCs undergoing cardiovascular magnetic resonance imaging had real-time slice volume quantification performed using a 2-dimensional (2D) real-time cardiovascular magnetic resonance imaging technique. Synchronization of 2D real-time imaging with patient ECG allowed for different beats to be categorized by the loading beat RR duration and beat RR duration. For each beat type, global volumes were quantified via summation over all slices covering the entire ventricle. Different patterns of ectopy, including isolated PVCs, bigeminy, trigeminy, and interpolated PVCs, were observed. Global functional measurement of the different beat types based on timing demonstrated differences in preload, stroke volume, and ejection fraction. An average of hemodynamic function was quantified for each subject depending on the frequency of each observed beat type. Conclusions Application of real-time cardiovascular magnetic resonance imaging in patients with PVCs revealed differential contribution of PVCs to hemodynamics. C1 [Contijoch, Francisco] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Rogers, Kelly; Zado, Erica S.; Supple, Gregory E.; Marchlinski, Francis E.; Han, Yuchi] Univ Penn, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. [Rears, Hannah; Shahid, Mohammed; Yushkevich, Paul; Witschey, Walter R. T.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Gorman, Joseph, III; Gorman, Robert C.] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Han, Y (reprint author), Hosp Univ Penn, Div Cardiovasc, Room 9022,East Gates 3400 Spruce St, Philadelphia, PA 19104 USA. EM yuchi.han@uphs.upenn.edu FU National Institutes of Health [F31-HL120580, R00-HL108157, R01-EB014346, R01-HL103723, R01-HL63954, T32-HL007954, T32-EB009384]; Cardiovascular Medical Research and Education Fund (Philadelphia, PA) FX This study was supported by grants from National Institutes of Health (F31-HL120580, R00-HL108157, R01-EB014346, R01-HL103723, R01-HL63954, T32-HL007954, and T32-EB009384) and Cardiovascular Medical Research and Education Fund (Philadelphia, PA). NR 31 TC 1 Z9 1 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3149 EI 1941-3084 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD APR PY 2016 VL 9 IS 4 AR e003520 DI 10.1161/CIRCEP.115.003520 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK3DK UT WOS:000374796100005 PM 27009416 ER PT J AU Pashakhanloo, F Herzka, DA Ashikaga, H Mori, S Gai, N Bluemke, DA Trayanova, NA McVeigh, ER AF Pashakhanloo, Farhad Herzka, Daniel A. Ashikaga, Hiroshi Mori, Susumu Gai, Neville Bluemke, David A. Trayanova, Natalia A. McVeigh, Elliot R. TI Myofiber Architecture of the Human Atria as Revealed by Submillimeter Diffusion Tensor Imaging SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE arrhythmias; cardiac; atrial function; atrial myoarchitecture; fiber orientation; heart atria; diffusion tensor imaging; diffusion magnetic resonance imaging ID CANINE PULMONARY VEINS; STRUCTURAL COMPLEXITIES; RADIOFREQUENCY ABLATION; HISTOLOGICAL VALIDATION; ELECTRICAL ACTIVATION; FIBER-ORIENTATION; SPIN ECHOES; HUMAN HEART; FIBRILLATION; CONDUCTION AB Background Accurate knowledge of the human atrial fibrous structure is paramount in understanding the mechanisms of atrial electric function in health and disease. Thus far, such knowledge has been acquired from destructive sectioning, and there is a paucity of data about atrial fiber architecture variability in the human population. Methods and Results In this study, we have developed a customized 3-dimensional diffusion tensor magnetic resonance imaging sequence on a clinical scanner that makes it possible to image an entire intact human heart specimen ex vivo at submillimeter resolution. The data from 8 human atrial specimens obtained with this technique present complete maps of the fibrous organization of the human atria. The findings demonstrate that the main features of atrial anatomy are mostly preserved across subjects although the exact location and orientation of atrial bundles vary. Using the full tractography data, we were able to cluster, visualize, and characterize the distinct major bundles in the human atria. Furthermore, quantitative characterization of the fiber angles across the atrial wall revealed that the transmural fiber angle distribution is heterogeneous throughout different regions of the atria. Conclusions The application of submillimeter diffusion tensor magnetic resonance imaging provides an unprecedented level of information on both human atrial structure, as well as its intersubject variability. The high resolution and fidelity of this data could enhance our understanding of structural contributions to atrial rhythm and pump disorders and lead to improvements in their targeted treatment. C1 [Pashakhanloo, Farhad; Herzka, Daniel A.; Trayanova, Natalia A.; McVeigh, Elliot R.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Ashikaga, Hiroshi] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Mori, Susumu; McVeigh, Elliot R.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Gai, Neville; Bluemke, David A.] NIH, Ctr Clin, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [McVeigh, Elliot R.] Univ Calif San Diego, Dept Bioengn, 9500 Gilman Dr MC0412, La Jolla, CA 92093 USA. [McVeigh, Elliot R.] Univ Calif San Diego, Dept Med, 9500 Gilman Dr MC0412, La Jolla, CA 92093 USA. [McVeigh, Elliot R.] Univ Calif San Diego, Dept Radiol, 9500 Gilman Dr MC0412, La Jolla, CA 92093 USA. RP McVeigh, ER (reprint author), Univ Calif San Diego, Dept Bioengn, 9500 Gilman Dr MC0412, La Jolla, CA 92093 USA.; McVeigh, ER (reprint author), Univ Calif San Diego, Dept Med, 9500 Gilman Dr MC0412, La Jolla, CA 92093 USA.; McVeigh, ER (reprint author), Univ Calif San Diego, Dept Radiol, 9500 Gilman Dr MC0412, La Jolla, CA 92093 USA. EM emcveigh@ucsd.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health (NIH) [DP1HL123271]; NIH FX This study was supported by the National Institutes of Health (NIH) Director's Pioneer Award to N.A. Trayanova (DP1HL123271) and the NIH intramural research program. NR 49 TC 3 Z9 3 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3149 EI 1941-3084 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD APR PY 2016 VL 9 IS 4 AR e004133 DI 10.1161/CIRCEP.116.004133 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK3DK UT WOS:000374796100019 PM 27071829 ER PT J AU Rogers, T Mahapatra, S Kim, S Eckhaus, MA Schenke, WH Mazal, JR Campbell-Washburn, A Sonmez, M Faranesh, AZ Ratnayaka, K Lederman, RJ AF Rogers, Toby Mahapatra, Srijoy Kim, Steven Eckhaus, Michael A. Schenke, William H. Mazal, Jonathan R. Campbell-Washburn, Adrienne Sonmez, Merdim Faranesh, Anthony Z. Ratnayaka, Kanishka Lederman, Robert J. TI Transcatheter Myocardial Needle Chemoablation During Real-Time Magnetic Resonance Imaging: A New Approach to Ablation Therapy for Rhythm Disorders SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE cardiac electrophysiology; catheter ablation; electrophysiology; magnetic resonance imaging; magnetic resonance imaging; interventional; tachycardia; ventricular ID HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY; VENTRICULAR-TACHYCARDIA ABLATION; CATHETER ABLATION; ATRIAL-FIBRILLATION; CHEMICAL ABLATION; SCAR FORMATION; ETHANOL; ENHANCEMENT; ARRHYTHMIA; FEASIBILITY AB Background Radiofrequency ablation for ventricular arrhythmias is limited by inability to visualize tissue destruction, by reversible conduction block resulting from edema surrounding lesions, and by insufficient lesion depth. We hypothesized that transcatheter needle injection of caustic agents doped with gadolinium contrast under real-time magnetic resonance imaging (MRI) could achieve deep, targeted, and irreversible myocardial ablation, which would be immediately visible. Methods and Results Under real-time MRI guidance, ethanol or acetic acid was injected into the myocardium of 8 swine using MRI-conspicuous needle catheters. Chemoablation lesions had identical geometry by in vivo and ex vivo MRI and histopathology, both immediately and after 12 (7-17) days. Ethanol caused stellate lesions with patchy areas of normal myocardium, whereas acetic acid caused homogeneous circumscribed lesions of irreversible necrosis. Ischemic cardiomyopathy was created in 10 additional swine by subselective transcoronary ethanol administration into noncontiguous territories. After 12 (8-15) days, real-time MRI-guided chemoablationwith 2 to 5 injections to create a linear lesionsuccessfully eliminated the isthmus and local abnormal voltage activities. Conclusions Real-time MRI-guided chemoablation with acetic acid enabled the intended arrhythmic substrate, whether deep or superficial, to be visualized immediately and ablated irreversibly. In an animal model of ischemic cardiomyopathy, obliteration of a conductive isthmus both anatomically and functionally and abolition of local abnormal voltage activities in areas of heterogeneous scar were feasible. This represents the first report of MRI-guided myocardial chemoablation, an approach that could improve the efficacy of arrhythmic substrate ablation in the thick ventricular myocardium. C1 [Rogers, Toby; Schenke, William H.; Mazal, Jonathan R.; Campbell-Washburn, Adrienne; Sonmez, Merdim; Faranesh, Anthony Z.; Ratnayaka, Kanishka; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Eckhaus, Michael A.] NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. [Mahapatra, Srijoy] St Jude Med, Global Med Affairs, St Paul, MN USA. [Kim, Steven] St Jude Med, Therapy Dev, St Paul, MN USA. [Ratnayaka, Kanishka] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. RP Lederman, RJ (reprint author), NHLBI, NIH, Bldg 10,Room 2c713, Bethesda, MD 20892 USA. EM lederman@nih.gov OI Rogers, Toby/0000-0002-6043-3137 FU National Heart, Lung, and Blood Institute, National Institutes of Health [Z01-HL005062] FX This work was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health (Z01-HL005062). NR 32 TC 0 Z9 0 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3149 EI 1941-3084 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD APR PY 2016 VL 9 IS 4 AR e003926 DI 10.1161/CIRCEP.115.003926 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK3DK UT WOS:000374796100013 PM 27053637 ER PT J AU Fleg, JL AF Fleg, Jerome L. TI Healthy Lifestyle and Risk of Heart Failure: An Ounce of Prevention Well Worth the Effort SO CIRCULATION-HEART FAILURE LA English DT Editorial Material DE Editorials; cardiovascular disease; heart failure; lifestyle; prevention; risk factors ID CARDIOVASCULAR-DISEASE PREVENTION; WOMEN; DIET; REDUCTION; STROKE; ADULTS; MEN C1 [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8154, Bethesda, MD 20892 USA. RP Fleg, JL (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8154, Bethesda, MD 20892 USA. EM flegj@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 16 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD APR PY 2016 VL 9 IS 4 AR e003155 DI 10.1161/CIRCHEARTFAILURE.116.003155 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DK3DJ UT WOS:000374796000015 PM 27072862 ER PT J AU Hsu, DC Sereti, I AF Hsu, Denise C. Sereti, Irini TI Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection SO DRUGS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; T-CELL-ACTIVATION; C-REACTIVE PROTEIN; PLACEBO-CONTROLLED TRIAL; CORONARY-HEART-DISEASE; INDIVIDUAL PARTICIPANT METAANALYSIS; SUSTAINED VIROLOGICAL RESPONSE; TISSUE FACTOR EXPRESSION; HEPATITIS-C AB In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available. C1 [Hsu, Denise C.; Sereti, Irini] NIAID, NIH, Bg 10 Rm 11B07 10 Ctr Dr, Bethesda, MD 20814 USA. RP Sereti, I (reprint author), NIAID, NIH, Bg 10 Rm 11B07 10 Ctr Dr, Bethesda, MD 20814 USA. EM isereti@niaid.nih.gov FU intramural research program of NIAID/NIH FX The work of the authors was supported by the intramural research program of NIAID/NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 241 TC 1 Z9 1 U1 0 U2 0 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0012-6667 EI 1179-1950 J9 DRUGS JI Drugs PD APR PY 2016 VL 76 IS 5 BP 533 EP 549 DI 10.1007/s40265-016-0546-7 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DK6RH UT WOS:000375052300002 PM 26915027 ER PT J AU Ibrahim, M Thearle, MS Krakoff, J Gluck, ME AF Ibrahim, Mostafa Thearle, Marie S. Krakoff, Jonathan Gluck, Marci E. TI Perceived stress and anhedonia predict short-and long-term weight change, respectively, in healthy adults SO EATING BEHAVIORS LA English DT Article DE Depression; Mood; Emotional eating; Longitudinal; Weight gain ID EATING BEHAVIOR; DIETARY RESTRAINT; PHYSICAL-ACTIVITY; FOOD-INTAKE; OBESITY; DEPRESSION; DISINHIBITION; OVERWEIGHT; APPETITE; DISEASE AB Objective: Perceived stress; emotional eating; anhedonia; depression and dietary restraint, hunger, and disinhibition have been studied as risk factors for obesity. However, the majority of studies have been cross-sectional and the directionality of these relationships remains unclear. In this longitudinal study, we assess their impact on future weight change. Methods: Psychological predictors of weight change in short- (6 month) and long-term (>1 year) periods were studied in 65 lean and obese individuals in two cohorts. Subjects participated in studies of food intake and metabolism that did not include any type of medication or weight loss interventions. They completed psychological questionnaires at baseline and weight change was monitored at follow-up visits. Results: At six months, perceived stress predicted weight gain (r(2) = 0.23, P = 0.02). There was a significant interaction (r(2) = .38, P = 0.009) between perceived stress and positive emotional eating, such that higher scores in both predicted greater weight gain, while those with low stress but high emotional eating scores lost weight. For long-term, higher anhedonia scores predicted weight gain (r(2) = 0.24, P = 0.04). Depression moderated these effects such that higher scores in both predicted weight gain but higher depression and lower anhedonia scores predicted weight loss. Conclusion: There are different behavioral determinants for short-and long-term weight change. Targeting perceived stress may help with short-term weight loss while depression and anhedonia may be better targets for long-term weight regulation. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ibrahim, Mostafa; Thearle, Marie S.; Krakoff, Jonathan; Gluck, Marci E.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Ibrahim, M (reprint author), 4212 N 16th St, Phoenix, AZ 85016 USA. EM mostafa928@gmail.com FU NIH/NIDDK FX MI and MST collected and analyzed data. All authors had equal involvement in writing the manuscript and reviewing submitted version. This research was supported by the Intramural Research Program of the NIH/NIDDK (Clinical trial IDs are NCT00523627, NCT00342732). NR 48 TC 0 Z9 0 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD APR PY 2016 VL 21 BP 214 EP 219 DI 10.1016/j.eatbeh.2016.03.009 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DK7XQ UT WOS:000375140600037 PM 27002703 ER PT J AU Semba, RD Shardell, M Ashour, FAS Moaddel, R Trehan, I Maleta, KM Ordiz, MI Kraemer, K Khadeer, MA Ferrucci, L Manary, MJ AF Semba, Richard D. Shardell, Michelle Ashour, Fayrouz A. Sakr Moaddel, Ruin Trehan, Indi Maleta, Kenneth M. Ordiz, M. Isabel Kraemer, Klaus Khadeer, Mohammed A. Ferrucci, Luigi Manary, Mark J. TI Child Stunting is Associated with Low Circulating Essential Amino Acids SO EBIOMEDICINE LA English DT Article DE Amino acids; Children; Glycerophospholipids; Malnutrition; Sphingolipids; Stunting ID RANDOMIZED CONTROLLED-TRIAL; CHOLINE KINASE BETA; GROWTH; HEALTH; NUTRIENT; PHOSPHATIDYLCHOLINE; SUPPLEMENTATION; METABOLISM; MECHANISMS; NUTRITION AB Background: Stunting affects about one-quarter of children under five worldwide. The pathogenesis of stunting is poorly understood. Nutritional interventions have had only modest effects in reducing stunting. We hypothesized that insufficiency in essential amino acids may be limiting the linear growth of children. Methods: We used a targeted metabolomics approach to measure serum amino acids, glycerophospholipids, sphingolipids, and other metabolites using liquid chromatography-tandem mass spectrometry in 313 children, aged 12-59 months, from rural Malawi. Children underwent anthropometry. Findings: Sixty-two percent of the children were stunted. Children with stunting had lower serum concentrations of all nine essential amino acids (tryptophan, isoleucine, leucine, valine, methionine, threonine, histidine, phenylalanine, lysine) compared with nonstunted children (p < 0.01). In addition, stunted children had significantly lower serum concentrations of conditionally essential amino acids (arginine, glycine, glutamine), non-essential amino acids (asparagine, glutamate, serine), and six different sphingolipids compared with nonstunted children. Stunting was also associated with alterations in serum glycerophospholipid concentrations. Interpretation: Our findings support the idea that children with a high risk of stunting may not be receiving an adequate dietary intake of essential amino acids and choline, an essential nutrient for the synthesis of sphingolipids and glycerophospholipids. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Shardell, Michelle; Moaddel, Ruin; Khadeer, Mohammed A.; Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. [Ashour, Fayrouz A. Sakr] Univ Maryland, Coll Agr & Nat Resources, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Trehan, Indi; Ordiz, M. Isabel; Manary, Mark J.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Trehan, Indi; Maleta, Kenneth M.; Manary, Mark J.] Univ Malawi, Coll Med, Sch Publ Hlth & Family Med, Blantyre, Malawi. [Kraemer, Klaus] Sight & Life, Basel, Switzerland. [Kraemer, Klaus] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. RP Semba, RD (reprint author), Smith Bldg M015,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu OI Maleta, Ken/0000-0002-2536-3938 FU NEI NIH HHS [R01 EY024596]; NIA NIH HHS [R01 AG027012] NR 38 TC 13 Z9 13 U1 4 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD APR PY 2016 VL 6 BP 246 EP 252 DI 10.1016/j.ebiom.2016.02.030 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DK7BS UT WOS:000375080400038 PM 27211567 ER PT J AU Buhnerkempe, MG Webb, CT Merton, AA Buhnerkempe, JE Givens, GH Miller, RS Hoeting, JA AF Buhnerkempe, Michael G. Webb, Colleen T. Merton, Andrew A. Buhnerkempe, John E. Givens, Geof H. Miller, Ryan S. Hoeting, Jennifer A. TI Identification of migratory bird flyways in North America using community detection on biological networks SO ECOLOGICAL APPLICATIONS LA English DT Article DE Anas acuta; Anas carolinensis; Anas platyrhnchos; Branta canadensis; community detection; consolidation factor; flyways; migration; network; waterfowl ID ADAPTIVE MANAGEMENT; WATERFOWL HARVESTS; HUMAN INFECTION; INFLUENZA; ORIGIN; VIRUS; UNCERTAINTY; MOVEMENTS; HABITAT; PRAIRIE AB Migratory behavior of waterfowl populations in North America has traditionally been broadly characterized by four north-south flyways, and these flyways have been central to the management of waterfowl populations for more than 80 yr. However, previous flyway characterizations are not easily updated with current bird movement data and fail to provide assessments of the importance of specific geographical regions to the identification of flyways. Here, we developed a network model of migratory movement for four waterfowl species, Mallard (Anas platyrhnchos), Northern Pintail (A. acuta), American Green-winged Teal (A. carolinensis), and Canada Goose (Branta canadensis), in North America, using bird band and recovery data. We then identified migratory flyways using a community detection algorithm and characterized the importance of smaller geographic regions in identifying flyways using a novel metric, the consolidation factor. We identified four main flyways for Mallards, Northern Pintails, and American Green-winged Teal, with the flyway identification in Canada Geese exhibiting higher complexity. For Mallards, flyways were relatively consistent through time. However, consolidation factors revealed that for Mallards and Green-winged Teal, the presumptive Mississippi flyway was potentially a zone of high mixing between other flyways. Our results demonstrate that the network approach provides a robust method for flyway identification that is widely applicable given the relatively minimal data requirements and is easily updated with future movement data to reflect changes in flyway definitions and management goals. C1 [Buhnerkempe, Michael G.; Merton, Andrew A.; Givens, Geof H.; Hoeting, Jennifer A.] Colorado State Univ, Dept Stat, Ft Collins, CO 80523 USA. [Buhnerkempe, Michael G.; Webb, Colleen T.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Buhnerkempe, Michael G.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Buhnerkempe, Michael G.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Buhnerkempe, John E.] Illinois Dept Nat Resources, Div Wildlife Resources, Springfield, IL 62702 USA. [Miller, Ryan S.] USDA, Anim & Plant Hlth Inspect Serv, Ctr Epidemiol, Ft Collins, CO 80521 USA. [Miller, Ryan S.] USDA, Anim & Plant Hlth Inspect Serv, Ctr Anim Hlth, Ft Collins, CO 80521 USA. [Givens, Geof H.] Givens Stat Solut LLC, Ft Collins, CO 80526 USA. RP Buhnerkempe, MG (reprint author), Colorado State Univ, Dept Stat, Ft Collins, CO 80523 USA.; Buhnerkempe, MG (reprint author), Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA.; Buhnerkempe, MG (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA.; Buhnerkempe, MG (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM michael.buhnerkempe@gmail.com OI Miller, Ryan/0000-0003-3892-0251 FU Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; USDA [07-7100-0228-CA9, 09-7100-0305-CA, 11-9208-0269-CA, 09-9208-0235-CA] FX M. G. Buhnerkempe and C. T. Webb acknowledge funding from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. Funding for this work was also provided by USDA Cooperative Agreements 07-7100-0228-CA9, 09-7100-0305-CA, 11-9208-0269-CA and 09-9208-0235-CA. We would like to thank Shweta Bansal, Dan Grear, and Clint Leach for useful discussions on conceptual and methodological issues related to network analyses. NR 42 TC 2 Z9 2 U1 10 U2 25 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-0761 EI 1939-5582 J9 ECOL APPL JI Ecol. Appl. PD APR PY 2016 VL 26 IS 3 BP 740 EP 751 DI 10.1890/15-0934 PG 12 WC Ecology; Environmental Sciences SC Environmental Sciences & Ecology GA DK3TO UT WOS:000374840500008 PM 27411247 ER PT J AU Weidemann, E Andersson, PL Bidleman, T Boman, C Carlin, DJ Collina, E Cormier, SA Gouveia-Figueira, SC Gullett, BK Johansson, C Lucas, D Lundin, L Lundstedt, S Marklund, S Nording, ML Ortuno, N Sallam, AA Schmidt, FM Jansson, S AF Weidemann, Eva Andersson, Patrik L. Bidleman, Terry Boman, Christoffer Carlin, Danielle J. Collina, Elena Cormier, Stephania A. Gouveia-Figueira, Sandra C. Gullett, Brian K. Johansson, Christer Lucas, Donald Lundin, Lisa Lundstedt, Staffan Marklund, Stellan Nording, Malin L. Ortuno, Nuria Sallam, Asmaa A. Schmidt, Florian M. Jansson, Stina TI 14th congress of combustion by-products and their health effects-origin, fate, and health effects of combustion-related air pollutants in the coming era of bio-based energy sources SO ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH LA English DT Article DE Products of incomplete combustion; Human health; Soot; Particles; Polychlorinated dibenzo-p-dioxins; Polychlorinated dibenzofurans; Congress paper ID MASS-SPECTROMETRY; VIRUS-INFECTION; FLUE-GAS; WASTE; PYROLYSIS; DECOMPOSITION; EMISSION; LIGNINS; DIOXINS; CARBON AB The 14th International Congress on Combustion By-Products and Their Health Effects was held in UmeAyen, Sweden from June 14th to 17th, 2015. The Congress, mainly sponsored by the National Institute of Environmental Health Sciences Superfund Research Program and the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, focused on the "Origin, fate and health effects of combustion-related air pollutants in the coming era of bio-based energy sources". The international delegates included academic and government researchers, engineers, scientists, policymakers and representatives of industrial partners. The Congress provided a unique forum for the discussion of scientific advances in this research area since it addressed in combination the health-related issues and the environmental implications of combustion by-products. The scientific outcomes of the Congress included the consensus opinions that: (a) there is a correlation between human exposure to particulate matter and increased cardiac and respiratory morbidity and mortality; (b) because currently available data does not support the assessment of differences in health outcomes between biomass smoke and other particulates in outdoor air, the potential human health and environmental impacts of emerging air-pollution sources must be addressed. Assessment will require the development of new approaches to characterize combustion emissions through advanced sampling and analytical methods. The Congress also concluded the need for better and more sustainable e-waste management and improved policies, usage and disposal methods for materials containing flame retardants. C1 [Weidemann, Eva; Andersson, Patrik L.; Bidleman, Terry; Gouveia-Figueira, Sandra C.; Lundin, Lisa; Lundstedt, Staffan; Nording, Malin L.; Jansson, Stina] Umea Univ, Dept Chem, Umea, Sweden. [Boman, Christoffer; Schmidt, Florian M.] Umea Univ, Dept Appl Phys & Elect, Thermochem Energy Convers Lab, Umea, Sweden. [Carlin, Danielle J.] NIEHS, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Collina, Elena] Univ Milano Bicocca, Dept Earth & Environm Sci, Milan, Italy. [Cormier, Stephania A.; Sallam, Asmaa A.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. [Cormier, Stephania A.; Sallam, Asmaa A.] Le Bonheur Childrens Hosp, Childrens Fdn Res Inst, Memphis, TN USA. [Gullett, Brian K.] US EPA, Off Res & Dev, Natl Risk Management Res Lab, Res Triangle Pk, NC 27711 USA. [Johansson, Christer] Stockholm Univ, Dept Environm Sci & Analyt Chem, S-10691 Stockholm, Sweden. [Johansson, Christer] Environm & Hlth Adm, Stockholm, Sweden. [Lucas, Donald] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [Marklund, Stellan] Umea Univ, Bio4Energy, Umea, Sweden. [Ortuno, Nuria] Univ Alicante, Dept Chem Engn, E-03080 Alicante, Spain. RP Weidemann, E (reprint author), Umea Univ, Dept Chem, Umea, Sweden. EM eva.weidemann@umu.se RI Ortuno Garcia, Nuria/E-7127-2017; OI Ortuno Garcia, Nuria/0000-0003-0442-4890; Nording, Malin/0000-0002-1732-8147; Weidemann, Eva/0000-0001-5415-9330 FU National Institutes of Environmental Health Sciences; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning-Formas [219-2014-291] FX The 14th Combustion By-Products and Their Health Effects Congress was supported by funds from National Institutes of Environmental Health Sciences to SC, and the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning-Formas (219-2014-291) to SJ, CB, MLN, LL, and EW. NR 23 TC 0 Z9 0 U1 9 U2 19 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0944-1344 EI 1614-7499 J9 ENVIRON SCI POLLUT R JI Environ. Sci. Pollut. Res. PD APR PY 2016 VL 23 IS 8 BP 8141 EP 8159 DI 10.1007/s11356-016-6308-y PG 19 WC Environmental Sciences SC Environmental Sciences & Ecology GA DK5XN UT WOS:000374994600105 PM 26906006 ER PT J AU Ferrington, DA Kapphahn, RJ Leary, MM Atilano, SR Terluk, MR Karunadharma, P Chen, GKJ Ratnapriya, R Swaroop, A Montezuma, SR Kenney, MC AF Ferrington, Deborah A. Kapphahn, Rebecca J. Leary, Michaela M. Atilano, Shari R. Terluk, Marcia R. Karunadharma, Pabalu Chen, George Kuei-Jie Ratnapriya, Rinki Swaroop, Anand Montezuma, Sandra R. Kenney, M. Cristina TI Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE Age-related macular degeneration; Complement factor H; Eyebank tissue; Mitochondria; mtDNA; Haplogroups; Inflammation ID COMPLEMENT FACTOR-H; MITOCHONDRIAL-DNA HAPLOGROUPS; PIGMENT EPITHELIAL-CELLS; DISEASE-ASSOCIATED FORM; C-REACTIVE PROTEIN; PROGRESSIVE STAGES; OXIDATIVE STRESS; BRUCHS MEMBRANE; ACTIVATION; BINDING AB Age-related macular degeneration (AMD) is a major cause of blindness among the elderly in the developed world. Genetic analysis of AMD has identified 34 high-risk loci associated with AMD. The genes at these high risk loci belong to diverse biological pathways, suggesting different mechanisms leading to AMD pathogenesis. Thus, therapies targeting a single pathway for all AMD patients will likely not be universally effective. Recent evidence suggests defects in mitochondria (mt) of the retinal pigment epithelium (RPE) may constitute a key pathogenic event in some AMD patients. The purpose of this study is to determine if individuals with a specific genetic background have a greater propensity for mtDNA damage. We used human eyebank tissues from 76 donors with AMD and 42 age-matched controls to determine the extent of mtDNA damage in the RPE that was harvested from the macula using a long extension polymerase chain reaction assay. Genotype analyses were performed for ten common AMD-associated nuclear risk alleles (ARMS2, TNFRSF10A, CFH, C2, C3, APOE, CETP, LIPC, VEGF and COL10A1) and mtDNA haplogroups. Sufficient samples were available for genotype association with mtDNA damage for TNFRSF10A, CFH, CETP, VEGFA, and COL10A1. Our results show that AMD donors carrying the high risk allele for CFH (C) had significantly more mtDNA damage compared with donors having the wild-type genetic profile. The data from an additional 39 donors (12 controls and 27 AMD) genotyped for CFH alleles further supported these findings. Taken together, these studies provide the rationale for a more personalized approach for treating AMD by uncovering a significant correlation between the CFH high risk allele and accelerated mtDNA damage. Patients harboring this genetic risk factor may benefit from therapies that stabilize and protect the mt in the RPE. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ferrington, Deborah A.; Kapphahn, Rebecca J.; Leary, Michaela M.; Terluk, Marcia R.; Karunadharma, Pabalu; Montezuma, Sandra R.] Univ Minnesota, Dept Ophthalmol & Visual Neurosci, Minneapolis, MN 55455 USA. [Atilano, Shari R.; Chen, George Kuei-Jie; Kenney, M. Cristina] Univ Calif Irvine, Gavin Herbert Eye Inst, Irvine, CA 92697 USA. [Ratnapriya, Rinki; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. RP Ferrington, DA (reprint author), 380 Lions Res Bldg,2001 6th St SE, Minneapolis, MN 55455 USA. EM ferri013@umn.edu OI Swaroop, Anand/0000-0002-1975-1141 FU Elaine and Robert Larson Endowed Vision Research Chair; Beckman Initiative for Macular Research [1004, 1303]; Foundation Fighting Blindness [TA-NMT-0613-0620-UMN]; National Institutes of Health [T32-AG29796]; Discovery Eye Foundation; Polly and Michael Smith Foundation; National Eye Institute Intramural Research Program; Research to Prevent Blindness FX This work was supported by the Elaine and Robert Larson Endowed Vision Research Chair (to DAF); Beckman Initiative for Macular Research (#1004, #1303 to DAF); Foundation Fighting Blindness (TA-NMT-0613-0620-UMN to DAF); An Anonymous Donor for Macular Degeneration Research and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Neurosciences; National Institutes of Health (T32-AG29796 to MRT); Discovery Eye Foundation (to MCK); Polly and Michael Smith Foundation (to MCK) and the National Eye Institute Intramural Research Program (to AS). NR 47 TC 2 Z9 2 U1 1 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD APR PY 2016 VL 145 BP 269 EP 277 DI 10.1016/j.exer.2016.01.018 PG 9 WC Ophthalmology SC Ophthalmology GA DL1DL UT WOS:000375372300030 PM 26854823 ER PT J AU Boyle, EB Viet, SM Wright, DJ Merrill, LS Alwis, KU Blount, BC Mortensen, ME Moye, J Dellarco, M AF Boyle, Elizabeth Barksdale Viet, Susan M. Wright, David J. Merrill, Lori S. Alwis, K. Udeni Blount, Benjamin C. Mortensen, Mary E. Moye, John, Jr. Dellarco, Michael TI Assessment of Exposure to VOCs among Pregnant Women in the National Children's Study SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE birth cohort study; pregnant women; tobacco; volatile organic compounds; urinary metabolites; National Children's Study ID VOLATILE ORGANIC-COMPOUNDS; TANDEM MASS-SPECTROMETRY; URINARY METABOLITES; SERUM COTININE; NONSMOKERS; BENZENE; SMOKERS; DISTRIBUTIONS; DETERMINANTS; BIOMARKERS AB Epidemiologic studies can measure exposure to volatile organic compounds (VOCs) using environmental samples, biomarkers, questionnaires, or observations. These different exposure assessment approaches each have advantages and disadvantages; thus, evaluating relationships is an important consideration. In the National Children's Vanguard Study from 2009 to 2010, participants completed questionnaires and data collectors observed VOC exposure sources and collected urine samples from 488 third trimester pregnant women at in-person study visits. From urine, we simultaneously quantified 28 VOC metabolites of exposure to acrolein, acrylamide, acrylonitrile, benzene, 1-bromopropane, 1,3-butadiene, carbon disulfide, crotonaldehyde, cyanide, N,N-dimethylformamide, ethylbenzene, ethylene oxide, propylene oxide, styrene, tetrachloroethylene, toluene, trichloroethylene, vinyl chloride, and xylene exposures using ultra high performance liquid chromatography coupled with an electrospray ionization tandem mass spectrometry (UPLC-ESI/MSMS) method. Urinary thiocyanate was measured using an ion chromatography coupled with an electrospray ionization tandem mass spectrometry method (IC-ESI/MSMS). We modeled the relationship between urinary VOC metabolite concentrations and sources of VOC exposure. Sources of exposure were assessed by participant report via questionnaire (use of air fresheners, aerosols, paint or varnish, organic solvents, and passive/active smoking) and by observations by a trained data collector (presence of scented products in homes). We found several significant (p < 0.01) relationships between the urinary metabolites of VOCs and sources of VOC exposure. Smoking was positively associated with metabolites of the tobacco constituents acrolein, acrylamide, acrylonitrile, 1,3-butadiene, crotonaldehyde, cyanide, ethylene oxide, N,N-dimethylformamide, propylene oxide, styrene, and xylene. Study location was negatively associated with the toluene metabolite N-acetyl-S-(benzyl)-L-cysteine (BMA), and paint use was positively associated with the xylene metabolites 2-methylhippuric acid (2MHA) and 3-Methylhippuric acid & 4-methylhippuric acid (3MHA + 4MHA). A near-significant (p = 0.06) relationship was observed between acrylamide metabolites and observation of incense. C1 [Boyle, Elizabeth Barksdale; Viet, Susan M.; Wright, David J.; Merrill, Lori S.] Westat Corp, Hlth Studies, 1600 Res Blvd, Rockville, MD 20850 USA. [Alwis, K. Udeni; Blount, Benjamin C.] Ctr Dis Control & Prevent, Div Sci Lab, Tobacco & Volatiles Branch, Atlanta, GA 30341 USA. [Mortensen, Mary E.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Atlanta, GA 30341 USA. [Moye, John, Jr.; Dellarco, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Boyle, EB (reprint author), Westat Corp, Hlth Studies, 1600 Res Blvd, Rockville, MD 20850 USA. EM eboyle@nas.edu; SusanViet@westat.com; DavidWright@Westat.com; LoriMerrill@westat.com; eoe3@cdc.gov; bkb3@cdc.gov; zeo4@cdc.gov; moyej@exchange.nih.go; dellarcom@mail.nih.gov OI Boyle, Elizabeth/0000-0002-9412-7998 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Office of the Director of the National Institutes of Health; NICHD [HHSN275201200120U/GS-234-8144H] FX This manuscript, a "primary NCS publication", was developed by a writing team assembled by the NCS Publications Committee for the purpose of sharing centrally collected NCS data. The analysis was conducted as part of the National Children's Study, supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and funded, through its appropriation, by the Office of the Director of the National Institutes of Health. Supported in part by NICHD Contract No. HHSN275201200120U/GS-234-8144H. The authors thank the participants of the National Children's Study and the study investigators and study center staff. NR 42 TC 1 Z9 1 U1 4 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD APR PY 2016 VL 13 IS 4 AR 376 DI 10.3390/ijerph13040376 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DK9DR UT WOS:000375231300024 PM 27043585 ER PT J AU Gorai, AK Tchounwou, PB Tuluri, F AF Gorai, Amit Kr. Tchounwou, Paul B. Tuluri, Francis TI Association between Ambient Air Pollution and Asthma Prevalence in Different Population Groups Residing in Eastern Texas, USA SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE air pollution; asthma; age; gender; race; Texas; USA ID EMERGENCY-DEPARTMENT VISITS; LONG-TERM EXPOSURE; GEOGRAPHIC INFORMATION-SYSTEMS; TIME-SERIES ANALYSIS; NEW-YORK-CITY; DAILY MORTALITY; PARTICULATE MATTER; HOSPITAL ADMISSIONS; CARDIOVASCULAR MORTALITY; SPATIAL-ANALYSIS AB Air pollution has been an on-going research focus due to its detrimental impact on human health. However, its specific effects on asthma prevalence in different age groups, genders and races are not well understood. Thus, the present study was designed to examine the association between selected air pollutants and asthma prevalence in different population groups during 2010 in the eastern part of Texas, USA. The pollutants considered were particulate matter (PM2.5 with an aerodynamic diameter less than 2.5 micrometers) and surface ozone. The population groups were categorized based on age, gender, and race. County-wise asthma hospital discharge data for different age, gender, and racial groups were obtained from Texas Asthma Control Program, Office of Surveillance, Evaluation and Research, Texas Department of State Health Services. The annual means of the air pollutants were obtained from the United States Environmental Protection Agency (U.S. EPA)'s air quality system data mart program. Pearson correlation analyzes were conducted to examine the relationship between the annual mean concentrations of pollutants and asthma discharge rates (ADR) for different age groups, genders, and races. The results reveal that there is no significant association or relationship between ADR and exposure of air pollutants (PM2.5, and O-3). The study results showed a positive correlation between PM2.5 and ADR and a negative correlation between ADR and ozone in most of the cases. These correlations were not statistically significant, and can be better explained by considering the local weather conditions. The research findings facilitate identification of hotspots for controlling the most affected populations from further environmental exposure to air pollution, and for preventing or reducing the health impacts. C1 [Gorai, Amit Kr.] Natl Inst Technol, Dept Min Engn, Rourkela 769008, Odisha, India. [Tchounwou, Paul B.] Jackson State Univ, Coll Sci Engn & Technol, NIMHD RCMI Ctr Environm Hlth, NIH, Jackson, MS 39217 USA. [Tuluri, Francis] Jackson State Univ, Dept Ind Syst & Technol, Jackson, MS 39217 USA. RP Gorai, AK (reprint author), Natl Inst Technol, Dept Min Engn, Rourkela 769008, Odisha, India.; Tchounwou, PB (reprint author), Jackson State Univ, Coll Sci Engn & Technol, NIMHD RCMI Ctr Environm Hlth, NIH, Jackson, MS 39217 USA. EM amit_gorai@yahoo.co.uk; paul.b.tchounwou@jsums.edu; francis.tuluri@jsums.edu FU Department of Science and Technology, New Delhi [SR/FTP/17/2012]; National Institutes of Health (NIMHD-RCMI) [G12MD007581] FX Authors are thankful to U.S. EPA for providing the air pollution data available on the website for public use, and to Texas Department of State Health Services for providing the quarterly county wise asthma data. The supports from the Department of Science and Technology, New Delhi Grant No. SR/FTP/17/2012 and National Institutes of Health (NIMHD-RCMI Grant No. G12MD007581) are also acknowledged. NR 88 TC 0 Z9 0 U1 7 U2 17 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD APR PY 2016 VL 13 IS 4 AR 378 DI 10.3390/ijerph13040378 PG 17 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DK9DR UT WOS:000375231300026 PM 27043587 ER PT J AU Patlolla, AK Randolph, J Kumari, SA Tchounwou, PB AF Patlolla, Anita K. Randolph, Jonathan Kumari, S. Anitha Tchounwou, Paul B. TI Toxicity Evaluation of Graphene Oxide in Kidneys of Sprague-Dawley Rats SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE graphene oxide; serum creatine; blood urea nitrogen; catalase; glutathione peroxidase; superoxide dismutase; lipid hydroperoxide; Sprague-Dawley rats ID OXIDATIVE STRESS; CARBON NANOTUBES; MICE; EFFICIENCY; BACTERIA; DELIVERY AB Recently, graphene and graphene-related materials have attracted a great deal of attention due their unique physical, chemical, and biocompatibility properties and to their applications in biotechnology and medicine. However, the reports on the potential toxicity of graphene oxide (GO) in biological systems are very few. The present study investigated the response of kidneys in male Sprague-Dawley rats following exposure to 0, 10, 20 and 40 mg/Kg GO for five days. The results showed that administration of GOs significantly increased the activities of superoxide dismutase, catalase and glutathione peroxidase in a dose-dependent manner in the kidneys compared with control group. Serum creatinine and blood urea nitrogen levels were also significantly increased in rats intoxicated with GO compared with the control group. There was a significant elevation in the levels of hydrogen peroxide and lipid hydro peroxide in GOs-treated rats compared to control animals. Histopathological evaluation showed significant morphological alterations of kidneys in GO-treated rats compared to controls. Taken together, the results of this study demonstrate that GO is nephrotoxic and its toxicity may be mediated through oxidative stress. In the present work, however, we only provided preliminary information on toxicity of GO in rats; further experimental verification and mechanistic elucidation are required before GO widely used for biomedical applications. C1 [Patlolla, Anita K.; Tchounwou, Paul B.] Jackson State Univ, Coll Sci Engn & Technol, Ctr Environm Hlth, NIH, Jackson, MS 39217 USA. [Patlolla, Anita K.; Tchounwou, Paul B.] Jackson State Univ, Dept Biol, Jackson, MS 39217 USA. [Randolph, Jonathan] Jackson State Univ, CESTEME Program Teacher, Jackson Publ Sch, Jackson, MS 39217 USA. [Kumari, S. Anitha] Osmania Univ, Coll Women, Hyderabad 500001, Andhra Pradesh, India. RP Patlolla, AK (reprint author), Jackson State Univ, Coll Sci Engn & Technol, Ctr Environm Hlth, NIH, Jackson, MS 39217 USA.; Patlolla, AK (reprint author), Jackson State Univ, Dept Biol, Jackson, MS 39217 USA. EM anita.k.patlolla@jsums.edu; mustang4762@gmail.com; anitha_shinde2001@yahoo.com; paul.b.tchounwou@jsums.edu FU U.S. Department of Defense [W911NF-11-1-0123]; National Institutes of Health [G12MD007581] FX This research was made possible by CESTEME (Grant # W911NF-11-1-0123) funded by the U.S. Department of Defense and by RCMI (Grant # G12MD007581) funded by the National Institutes of Health. NR 30 TC 3 Z9 3 U1 0 U2 4 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD APR PY 2016 VL 13 IS 4 AR 380 DI 10.3390/ijerph13040380 PG 15 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DK9DR UT WOS:000375231300028 PM 27043588 ER PT J AU Adams, JW Watts, DH Phelps, BR AF Adams, Joella W. Watts, D. Heather Phelps, B. Ryan TI A systematic review of the effect of HIV infection and antiretroviral therapy on the risk of pre-eclampsia SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Review DE Antiretroviral therapy; HIV/AIDS; HIV in women; Pre-eclampsia ID PREGNANT-WOMEN; ECLAMPSIA; HIV/AIDS; OUTCOMES AB Background: The associations between HIV infection, antiretroviral therapy (ART), and pre-eclampsia are unclear. Objectives: To summarize research and clarify the implications of HIV and ART on pre-eclampsia risk. Search strategy: MedLine, PubMed, Web of Science, and the Cochrane Library were searched for studies published between 2003 and July 2014, using relevant keywords. Selection criteria: Full-text review was dependent on the inclusion of pre-eclampsia as an outcome and original data. Data collection and analysis: Data for population, confounders, limitations, and measures of association were qualitatively assessed. Main results: Among 550 records identified, 70 were screened, and 13 were included. Five of the nine studies comparing pre-eclampsia risk between women with and without HIV infection found no significant difference; only one found that women living with HIV were more likely to experience pre-eclampsia. Two studies found that women living with HIV who were receiving ART at conception were more likely to experience pre-eclampsia than were those not receiving ART at conception. Two studies reported that pre-eclampsia rates did not differ by ART regimen. Conclusions: There is insufficient evidence to conclude that women living with HIV and receiving ART have a higher risk of pre-eclampsia than do women without HIV infection; further research is needed to assess the association between ART and pre-eclampsia. (C) 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Adams, Joella W.; Phelps, B. Ryan] US Agcy Int Dev, Washington, DC 20523 USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. RP Adams, JW (reprint author), Bur Global Hlth, Global Hlth Fellows Program 2, USAID Off HIV AIDS, 2100 Crystal Dr,9040A, Arlington, VA 22202 USA. EM joella_adams@brown.edu OI Adams, Joella/0000-0002-7703-5944 NR 24 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD APR PY 2016 VL 133 IS 1 BP 17 EP 21 DI 10.1016/j.ijgo.2015.08.007 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DJ7CT UT WOS:000374370200004 PM 26797203 ER PT J AU Ayres-de-Campos, D Spong, CY Chandraharan, E AF Ayres-de-Campos, Diogo Spong, Catherine Y. Chandraharan, Edwin CA FIGO Intrapartum Fetal Monitoring TI FIGO consensus guidelines on intrapartum fetal monitoring: Cardiotocography (vol 131, pg 13, 2015) SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Correction C1 [Ayres-de-Campos, Diogo] Univ Porto, S Joao Hosp, Inst Biomed Engn, Sch Med, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Chandraharan, Edwin] St Georges Univ Hosp NHS Fdn Trust, London, England. RP Ayres-de-Campos, D (reprint author), Univ Porto, S Joao Hosp, Inst Biomed Engn, Sch Med, Rua Campo Alegre 823, P-4100 Oporto, Portugal. NR 1 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD APR PY 2016 VL 133 IS 1 BP 130 EP 130 DI 10.1016/j.ijgo.2016.02.005 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DJ7CT UT WOS:000374370200031 ER PT J AU Inamura, K Song, MY Jung, S Nishihara, R Yamauchi, M Lochhead, P Qian, ZR Kim, SA Mima, K Sukawa, Y Masuda, A Imamura, Y Zhang, XH Pollak, MN Mantzoros, CS Harris, CC Giovannucci, E Fuchs, CS Cho, E Chan, AT Wu, KN Ogino, S AF Inamura, Kentaro Song, Mingyang Jung, Seungyoun Nishihara, Reiko Yamauchi, Mai Lochhead, Paul Qian, Zhi Rong Kim, Sun A. Mima, Kosuke Sukawa, Yasutaka Masuda, Atsuhiro Imamura, Yu Zhang, Xuehong Pollak, Michael N. Mantzoros, Christos S. Harris, Curtis C. Giovannucci, Edward Fuchs, Charles S. Cho, Eunyoung Chan, Andrew T. Wu, Kana Ogino, Shuji TI Prediagnosis Plasma Adiponectin in Relation to Colorectal Cancer Risk According to KRAS Mutation Status SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; LIFE-STYLE FACTORS; KI-RAS MUTATIONS; PIK3CA MUTATION; WEIGHT ADIPONECTIN; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; PROGNOSTIC ROLE; ASSOCIATIONS; PREVENTION AB Background: Low levels of adiponectin (ADIPOQ; HGNC ID; HGNC: 13633), an adipokine, are associated with obesity, adiposity, excess energy balance, and increased risk of colorectal neoplasia. Given the reported association of increased body mass index (BMI) and low-level physical activity with KRAS-mutated colorectal tumor, we hypothesized that low-level plasma adiponectin might be associated with increased risk of KRAS-mutant colorectal carcinoma but not with risk of KRAS wild-type carcinoma. Methods: We conducted molecular pathological epidemiology research using a nested case-control study design (307 incident rectal and colon cancer case patients and 593 matched control individuals) within prospective cohort studies, the Nurses' Health Study (152 case patients and 297 control individuals, with blood collection in 1989-1990) and the Health Professionals Follow-up Study (155 case patients and 296 control individuals, with blood collection in 1993-1995). Multivariable conditional logistic regression models and two-sided likelihood ratio tests were used to assess etiologic heterogeneity of the associations. Results: The association of low-level plasma adiponectin with colorectal cancer risk statistically significantly differed by KRAS mutation status (P-heterogeneity = .004). Low levels of plasma adiponectin were associated with KRAS-mutant colorectal cancer (for the lowest vs highest tertile: multivariable odds ratio [OR] = 2.83, 95% confidence interval [CI] = 1.50 to 5.34, P-trend = .002) but not with KRAS wild-type cancer (for the lowest vs highest tertile: multivariable OR = 0.83, 95% CI = 0.49 to 1.43, P-trend = .48). In secondary analyses, the association between plasma adiponectin and colorectal cancer did not appreciably differ by BRAF or PIK3CA oncogene mutation status. Conclusions: Low-level plasma adiponectin is associated with KRAS-mutant colorectal cancer risk but not with KRAS wildtype cancer risk. C1 [Inamura, Kentaro; Nishihara, Reiko; Yamauchi, Mai; Lochhead, Paul; Qian, Zhi Rong; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Imamura, Yu; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Inamura, Kentaro; Nishihara, Reiko; Yamauchi, Mai; Lochhead, Paul; Qian, Zhi Rong; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Imamura, Yu; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Inamura, Kentaro; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Inamura, Kentaro] Japanese Fdn Canc Res, Inst Canc, Div Pathol, Tokyo 170, Japan. [Song, Mingyang; Nishihara, Reiko; Giovannucci, Edward; Wu, Kana] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, 655 Huntington Ave,Bldg 2,Room 302, Boston, MA 02115 USA. [Song, Mingyang; Giovannucci, Edward; Ogino, Shuji] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Nishihara, Reiko] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Jung, Seungyoun; Zhang, Xuehong; Giovannucci, Edward; Fuchs, Charles S.; Cho, Eunyoung; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Lochhead, Paul; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Pollak, Michael N.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Endocrinol Sect, Boston VA Healthcare Syst, Boston, MA USA. [Cho, Eunyoung] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI USA. RP Wu, KN (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, 655 Huntington Ave,Bldg 2,Room 302, Boston, MA 02115 USA.; Ogino, S (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM kana.wu@channing.harvard.edu; shuji_ogino@dfci.harvard.edu FU National Institutes of Health (NIH) [P01 CA87969, P01 CA55075, UM1 CA167552, UM1 CA186107, P50 CA127003, R01 CA136950, R01 CA137178, K24 DK098311, R01 CA151993, R35 CA197735, K07 CA190673]; Paula and Russell Agrusa Fund for Colorectal Cancer Research; Friends of the Dana-Farber Cancer Institute; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Japan Society for the Promotion of Science; Takashi Tsuruo Memorial Fund; Harvard University Frank Knox Memorial Fellowship; Asan Medical Center; Uehara Memorial Foundation FX This work was supported by National Institutes of Health (NIH) grants (P01 CA87969 to SEH; P01 CA55075 to WCW; UM1 CA167552 to WCW; UM1 CA186107 to MJS; P50 CA127003 to CSF; R01 CA136950 to EC; R01 CA137178 and K24 DK098311 to ATC; R01 CA151993 and R35 CA197735 to SO; and K07 CA190673 to RN) and by grants from the Paula and Russell Agrusa Fund for Colorectal Cancer Research (to CSF), the Friends of the Dana-Farber Cancer Institute (to SO), and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. KI was supported by a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad and by Takashi Tsuruo Memorial Fund. MS is a trainee of the Harvard Transdisciplinary Research Center on Energetics and Cancer (TREC). PL is a Scottish Government Clinical Academic Fellow and was supported by a Harvard University Frank Knox Memorial Fellowship. SAK was supported by an early exchange postdoctoral fellowship grant from Asan Medical Center. KM is supported by a fellowship grant from the Uehara Memorial Foundation. ATC is a Damon Runyon Clinical Investigator. NR 63 TC 1 Z9 1 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD APR PY 2016 VL 108 IS 4 AR djv363 DI 10.1093/jnci/djv363 PG 10 WC Oncology SC Oncology GA DK6RR UT WOS:000375053400025 ER PT J AU Land, SR Walcott, FL Liu, Q Wickerham, DL Costantino, JP Ganz, PA AF Land, Stephanie R. Walcott, Farzana L. Liu, Qing Wickerham, D. Lawrence Costantino, Joseph P. Ganz, Patricia A. TI Symptoms and QOL as Predictors of Chemoprevention Adherence in NRG Oncology/NSABP Trial P-1 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SURGICAL ADJUVANT BREAST; CANCER PREVENTION TRIAL; BOWEL PROJECT P-1; QUALITY-OF-LIFE; CIGARETTE-SMOKING; ENDOCRINE THERAPY; PHYSICAL-ACTIVITY; TAMOXIFEN USE; US WOMEN; RISK AB Background: Tamoxifen provides a 50% reduction in the incidence of breast cancer (BC) among high-risk women, yet many do not adhere to the five-year course of therapy. Using the prospective double-blind National Surgical Adjuvant Breast and Bowel Project P-1 study, we evaluated whether participant-reported outcomes were associated with drug adherence and whether baseline behavioral risk factors modified those associations. Methods: P-1 participants were randomly assigned to placebo vs tamoxifen (20 mg/day). Mixed effects logistic regression was used to evaluate whether baseline or three-month SF-36 quality of life (QOL) mental and physical component summaries (MCS, PCS), and participant-reported symptoms (gynecologic, vasomotor, sexual, and other) predicted 12-month drug adherence (76-100% of assigned medication). The evaluation accounted for age, treatment, estimated breast cancer risk, education, baseline smoking, alcohol consumption, and obesity. All statistical tests were two-sided. Results: Participants enrolled at least three years before trial unblinding and without medically indicated discontinuation before 12 months were eligible for the present analyses (n = 10 576). At 12 months, 84.3% were adherent. Statistically significant predictors of adherence were: three-month MCS (odds ratio [OR] = 1.15 per 10 points, 95% confidence interval [CI] = 1.06 to 1.25); three-month gynecologic symptoms among moderate alcohol drinkers (OR = .79, 95% CI = 0.72 to 0.88); baseline vasomotor symptoms among participants assigned tamoxifen (OR = .88, 95% CI = 0.80 to 0.97); and three-month sexual symptoms among younger participants (OR = .89 at age 41 years, 95% CI = 0.80 to 0.99). The strongest association was with three-month other symptoms (OR = .77, 95% CI = 0.63 to 0.93). PCS was not associated with adherence. Symptom and QOL associations were not modified by smoking or obesity. Conclusions: Promoting QOL and managing symptoms early in therapy may be important strategies to improve adherence. C1 [Land, Stephanie R.; Wickerham, D. Lawrence; Ganz, Patricia A.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Land, Stephanie R.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Walcott, Farzana L.] NCI, Canc Prevent Div, Rockville, MD USA. [Liu, Qing; Costantino, Joseph P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Wickerham, D. Lawrence] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Dept Hlth Serv, Los Angeles, CA 90024 USA. RP Land, SR (reprint author), 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM stephanie.land@nih.gov FU Public Health Service from the National Cancer Institute, Department of Health and Human Services [U10-CA-37377, U10-CA-69974, U10-CA-180868, U10-CA-180822, UG1-CA-189867, R03CA134199-02] FX This work was supported by: Public Health Service Grants U10-CA-37377 (SRL, DLW, JPC, PAG) and U10-CA-69974 (SRL, DLW, JPC, PAG); U10-CA-180868 and U10-CA-180822 (NRG Oncology); UG1-CA-189867 (NCORP); R03CA134199-02 (SRL, PAG) from the National Cancer Institute, Department of Health and Human Services, and Zeneca Pharmaceuticals (which supplied tamoxifen/placebo). NR 33 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD APR PY 2016 VL 108 IS 4 AR djv365 DI 10.1093/jnci/djv365 PG 6 WC Oncology SC Oncology GA DK6RR UT WOS:000375053400027 ER PT J AU Resnik, DB AF Resnik, David B. TI Scientific Realism and the Patent System SO JOURNAL FOR GENERAL PHILOSOPHY OF SCIENCE LA English DT Article DE Patents; Inventions; Realism; Anti-realism; Nature; Causation ID ANTICOMMONS AB The patent system appears to make three ontological assumptions often associated with scientific realism: there is a natural world that is independent of human knowledge and technology; invented products can be unobservable things; and invented products have causal powers. Although a straightforward reading of patent laws implies these ontological commitments, it is not at all clear that what the patent system has to say about the world has any bearing on issues of scientific realism. While realists might embrace the patent system's apparent ontology as providing additional support for their view, anti-realists could propose an alternative interpretation of patent law that does not involve realist ontological commitments. Thus, questions about the patent system's ontology depend on whether one takes patent laws at face value or defends an interpretation of patent law motivated by philosophical theory. Philosophers of science should pay attention to the practice of patenting, even if they ultimately reject the patent system's apparent ontology and offer an alternative interpretation. C1 [Resnik, David B.] NIEHS, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 31 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-4560 EI 1572-8587 J9 J GEN PHILOS SCI JI J. Gen. Philos. Sci. PD APR PY 2016 VL 47 IS 1 BP 69 EP 77 DI 10.1007/s10838-016-9326-z PG 9 WC History & Philosophy Of Science SC History & Philosophy of Science GA DK3TA UT WOS:000374839100005 ER PT J AU Takeda, T Wang, YL Bryant, SH AF Takeda, Takako Wang, Yanli Bryant, Stephen H. TI Structural insights of a PI3K/mTOR dual inhibitor with the morpholino-triazine scaffold SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE PI3K; mTOR; Pharmacophore; 3D-QSAR; Docking; PKI-587 ID HUMAN HEAD; IN-VIVO; PKI-587; PI3K; IDENTIFICATION; LESSONS; MODELS; TARGET AB Stimulation of the PI3K/Akt/mTOR pathway, which controls cell proliferation and growth, is often observed in cancer cell. Inhibiting both PI3K and mTOR in this pathway can switch off Akt activation and hence, plays a powerful role for modulating this pathway. PKI-587, a drug containing the structure of morpholino-triazines, shows a dual and nano-molar inhibition activity and is currently in clinical trial. To provide an insight into the mechanism of this dual inhibition, pharmacophore and QSAR models were developed in this work using compounds based on the morpholino-triazines scaffold, followed by a docking study. Pharmacophore model suggested the mechanism of the inhibition of PI3K alpha and mTOR by the compounds were mostly the same, which was supported by the docking study showing similar docking modes. The analysis also suggested the importance of the flat plane shape of the ligands, the space surrounding the ligands in the binding pocket, and the slight difference in the shape of the binding sites between PI3K alpha and mTOR. C1 [Takeda, Takako; Wang, Yanli; Bryant, Stephen H.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH) National Library of Medicine (NLM); NIGMS [P41-GM103311] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) National Library of Medicine (NLM). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). The authors acknowledge Dr. Ming Hao for useful comments on the manuscript. We thank Douglas Joubert, NIH Library Writing Center, for manuscript editing assistance. Figures 2 and 3 were drawn with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311) [26]. NR 22 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD APR PY 2016 VL 30 IS 4 BP 323 EP 330 DI 10.1007/s10822-016-9905-4 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA DJ7SY UT WOS:000374413900005 PM 26956874 ER PT J AU Yuan, WP Cheng, SM Fu, WT Zhao, M Li, XB Cai, YP Dong, JY Huang, KX Gustafson, KR Yan, PC AF Yuan, Weiping Cheng, Shimiao Fu, Weitao Zhao, Min Li, Xiubao Cai, Yuepiao Dong, Jianyong Huang, Kexin Gustafson, Kirk R. Yan, Pengcheng TI Structurally Diverse Metabolites from the Soft Coral Sinularia verruca Collected in the South China Sea SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID NATURAL-PRODUCTS; LOBOPHYTUM SP; CEMBRANOIDS; CAPILLOSA; CYCLOPENTENONE; DERIVATIVES; FLEXIBILIS; HIV-1 AB Nineteen metabolites with diverse structures, including the rare pyrroloindoline alkaloid verrupyrroloindoline (1), the unprecedented highly fused benzosesquiterpenoid verrubenzospirolactone (2), the new asteriscane-type sesquiterpenoid 10-deoxocapillosanane D (3), and the two new cyclopentenone derivatives (4S*,5S*)-4-hydroxy-5-(hydroxymethyl)-2,3-dimethyl-4-pentylcydopent-2-en-1-one (4) and (S)-4-hydroxy-5-methylene-2,3dimethyl-4-pentylcydopent-2-en-1-one (5), were isolated from a South China Sea collection of the soft coral Sinularia verruca. Eleven previously described marine metabolites (7-15, 18, and 19) were also obtained as well as three new EtOH-adduct artifacts (6, 16, and 17). The structures of the new compounds were elucidated by extensive spectroscopic analysis and by comparison with previously reported data. Compounds 4, 5, and 16 showed protection against the cytopathic effects of HIV-1 infection with EC50 values of 5.8-34 mu M, and 4, 6, and 16 exhibited inhibition against LPS-induced NO production with IC50 values of 24-28 mu M. C1 [Yuan, Weiping; Fu, Weitao; Zhao, Min; Cai, Yuepiao; Dong, Jianyong; Huang, Kexin; Yan, Pengcheng] Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Zhejiang, Peoples R China. [Cheng, Shimiao] Wenzhou Med Univ, Affiliated Hosp 5, Lishui 323000, Zhejiang, Peoples R China. [Li, Xiubao] Chinese Acad Sci, South China Sea Inst Oceanol, Key Lab Marine Bioresources Sustainable Utilizat, Guangzhou 510301, Guangdong, Peoples R China. [Gustafson, Kirk R.; Yan, Pengcheng] NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. RP Yan, PC (reprint author), Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Zhejiang, Peoples R China.; Gustafson, KR; Yan, PC (reprint author), NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. EM gustafki@mail.nih.gov; yanpc@wzmc.edu.cn FU NSFC [21202123]; ZJNSF [LQ12B02002]; CSC [201408330121]; Wenzhou Medical University [QTJ10018]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from NSFC (No. 21202123), ZJNSF (No. LQ12B02002), CSC (No. 201408330121), and Start-Up Funding from Wenzhou Medical University (No. QTJ10018). This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 24 TC 0 Z9 0 U1 2 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD APR PY 2016 VL 79 IS 4 BP 1124 EP 1131 DI 10.1021/acs.jnatprod.6b00031 PG 8 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA DK4UM UT WOS:000374915800056 PM 27010413 ER PT J AU Choi, Y Abdelmegeed, MA Akbar, M Song, BJ AF Choi, Youngshim Abdelmegeed, Mohamed A. Akbar, Mohammed Song, Byoung-Joon TI Dietary walnut reduces hepatic triglyceride content in high-fat-fed mice via modulation of hepatic fatty acid metabolism and adipose tissue inflammation SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Walnut; High-fat diet; Liver; Steatosis; Triglyceride; Adipose tissue; Inflammation ID NECROSIS-FACTOR-ALPHA; INSULIN-RESISTANCE; LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; MACROPHAGE INFILTRATION; ADIPOCYTE DEATH; GENE-EXPRESSION; INDUCED OBESITY; DEFICIENT MICE; STEATOSIS AB In this study, we evaluated the protective effects of dietary walnuts on high-fat diet (HFD)-induced fatty liver and studied the underlying mechanisms. Male C57BL/6J mice were fed either a regular rodent chow or HFD (45% energy-derived) with or without walnuts (21.5% energy-derived) for 20 weeks. Walnut supplementation did not change HFD-induced increase in body weight or visceral fat mass. However, dietary walnuts significantly decreased the amounts of hepatic triglyceride (TG) observed in HFD-fed mice. The addition of walnuts significantly altered the levels of proteins, involved in the hepatic lipid homeostasis, including AMP-activated protein kinase, fatty acid synthase and peroxisome proliferator-activated receptor-a. Since adipocyte inflammation and apoptosis are reportedly important in regulating hepatic fat accumulation, we also evaluated the protective effects of walnuts on adipose tissue injury. Real-time polymerase chain reaction results revealed that adipose tissues isolated from mice fed the HFD + walnut diets showed significantly decreased levels of macrophage infiltration with suppressed expression of proinflammatory genes compared to those significantly elevated in mice fed HFD alone. These improvements also coincided with reduction of HFD-induced apoptosis of adipocytes by dietary walnuts. However, the supplemented walnuts did not significantly alter HFD-induced peripheral glucose intolerance or insulin resistance despite a trend of improvement. Collectively, these results demonstrate that the protective effects of walnuts against HFD-induced hepatic TG accumulation in mice are mediated, at least partially, by modulating the key proteins in hepatic lipid homeostasis and suppression of the genes related to adipose tissue inflammation and macrophage infiltration as well as prevention of adipocyte apoptosis. Published by Elsevier Inc. C1 [Choi, Youngshim; Abdelmegeed, Mohamed A.; Akbar, Mohammed; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bj.song@nih.gov FU National Institute on Alcohol Abuse and Alcoholism; KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea FX This research was supported by the Intramural Program of National Institute on Alcohol Abuse and Alcoholism. This work was also supported by a grant to Youngshim Choi from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea. The authors are thankful to Dr. Klaus Gawrisch for supporting this study. NR 64 TC 2 Z9 2 U1 2 U2 5 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 APR PY 2016 VL 30 BP 116 EP 125 DI 10.1016/j.jnutbio.2015.12.005 PG 10 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA DJ6TY UT WOS:000374347300013 PM 27012628 ER PT J AU Ortiz, MV Meier, ER Hsieh, MM AF Ortiz, Michael V. Meier, Emily R. Hsieh, Matthew M. TI Identification and Clinical Characterization of Children With Benign Ethnic Neutropenia SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE neutropenia; benign ethnic neutropenia; pediatric hematology; oncology ID YEMENITE-JEWS; BONE-MARROW AB Benign ethnic neutropenia (BEN) is an asymptomatic condition reported in adults of African and Middle Eastern descent. The clinical description in children is currently lacking. In our urban outpatient pediatric hematology clinic, the median neutrophil count of children with BEN was lower than previous reports in adults at 893x10(6) cells/L, but increased with older age. There was an equal male to female ratio and 24% of our BEN children reported ethnicities other than African or Middle Eastern. Children with BEN had a clinical course comparable with other healthy children including otherwise normal blood counts, except for mild anemia. C1 [Ortiz, Michael V.; Meier, Emily R.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Meier, Emily R.] George Washington Sch Med & Hlth Sci, Dept Pediat, Washington, DC USA. [Ortiz, Michael V.] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave,POB 139, New York, NY 10065 USA. [Ortiz, Michael V.] Weill Cornell Med Ctr, New York Presbyterian, Div Pediat Hematol & Oncol, New York, NY USA. [Meier, Emily R.] Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USA. [Hsieh, Matthew M.] NIDDK, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Hsieh, Matthew M.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Ortiz, Michael V.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Ortiz, Michael V.] Weill Cornell Med Ctr, New York Presbyterian, New York, NY USA. [Meier, Emily R.] Indiana Hemophilia & Thrombosis Ctr Inc, 8326 Naab Rd, Indianapolis, IN 46260 USA. RP Ortiz, MV (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave,POB 139, New York, NY 10065 USA.; Ortiz, MV (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA.; Ortiz, MV (reprint author), Weill Cornell Med Ctr, New York Presbyterian, New York, NY USA. EM ortizm2@mskcc.org FU Intramural NIH HHS [Z99 HL999999] NR 14 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 1077-4114 EI 1536-3678 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD APR PY 2016 VL 38 IS 3 BP E140 EP E143 DI 10.1097/MPH.0000000000000528 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DK2XO UT WOS:000374777900012 PM 26925714 ER PT J AU Dhavle, AA Ward-Charlerie, S Rupp, MT Kilbourne, J Amin, VP Ruiz, J AF Dhavle, Ajit A. Ward-Charlerie, Stacy Rupp, Michael T. Kilbourne, John Amin, Vishal P. Ruiz, Joshua TI Evaluating the implementation of RxNorm in ambulatory electronic prescriptions SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE RxNorm; E-Prescribing; electronic prescriptions; NDC; quality ID CONTROLLED MEDICAL VOCABULARIES; CONSEQUENCES; DESIDERATA; PHARMACIES AB Methods We analyzed a random sample of 49 997 e-prescriptions that were received by 7391 locations of a national retail pharmacy chain during a single day in April 2014. The e-prescriptions in the sample were generated by 37 801 ambulatory care prescribers using 519 different e-prescribing software applications. Results We found that 97.9% of e-prescriptions in the study sample could be accurately represented by an RxNorm identifier. However, RxNorm identifiers were actually used as drug identifiers in only 16 433 (33.0%) e-prescriptions. Another 431 (2.5%) e-prescriptions that used RxNorm identifiers had a discrepancy in the corresponding Drug Database Code qualifier field or did not have a qualifier (Term Type) at all. In 10 e-prescriptions (0.06%), the free-text drug description and the RxNorm concept unique identifier pointed to completely different drug concepts, and in 7 e-prescriptions (0.04%), the NDC and RxNorm drug identifiers pointed to completely different drug concepts. Discussion The National Library of Medicine continues to enhance the RxNorm terminology and expand its scope. This study illustrates the need for technology vendors to improve their implementation of RxNorm; doing so will accelerate the adoption of RxNorm as the preferred alternative to using the NDC terminology in e-prescribing. C1 [Dhavle, Ajit A.; Ward-Charlerie, Stacy; Ruiz, Joshua] Surescripts LLC, Clin Qual, Arlington, VA 22202 USA. [Rupp, Michael T.] Midwestern Univ, Pharm Adm, Glendale, AZ USA. [Kilbourne, John] Natl Lib Med, Med Subject Headings MeSH, Bethesda, MD USA. [Amin, Vishal P.] CVS Hlth Patient Safety & Qual Assurance, Woonsocket, RI USA. RP Dhavle, AA (reprint author), Surescripts LLC, 2800 Crystal Dr, Arlington, VA 22202 USA. EM ajit.dhavle@surescripts.com NR 26 TC 0 Z9 0 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD APR PY 2016 VL 23 IS E1 BP E99 EP E107 DI 10.1093/jamia/ocv131 PG 9 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DL0AD UT WOS:000375292600014 PM 26510879 ER PT J AU Laverdure, S Polakowski, N Hoang, K Lemasson, I AF Laverdure, Sylvain Polakowski, Nicholas Hoang, Kimson Lemasson, Isabelle TI Permissive Sense and Antisense Transcription from the 5 ' and 3 ' Long Terminal Repeats of Human T-Cell Leukemia Virus Type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ZIPPER FACTOR HBZ; NF-KAPPA-B; BZIP FACTOR; VIRAL TRANSCRIPTION; CPG METHYLATION; TAX PROTEIN; IN-VITRO; HTLV-1; GENE AB Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus, and, as such, its genome becomes chromosomally integrated following infection. The resulting provirus contains identical 5' and 3' peripheral long terminal repeats (LTRs) containing bidirectional promoters. Antisense transcription from the 3' LTR regulates expression of a single gene, hbz, while sense transcription from the 5' LTR controls expression of all other viral genes, including tax. Both the HBZ and Tax proteins are implicated in the development of adult T-cell leukemia (ATL), a T-cell malignancy caused by HTLV-1 infection. However, these proteins appear to harbor opposing molecular functions, indicating that they may act independently and at different time points prior to leukemogenesis. Here, we used bidirectional reporter constructs to test whether transcriptional interference serves as a mechanism that inhibits simultaneous expression of Tax and HBZ. We found that sense transcription did not interfere with antisense transcription from the 3' LTR and vice versa, even with strong transcription emanating from the opposing direction. Therefore, bidirectional transcription across the provirus might not restrict hbz or tax expression. Single-cell analyses revealed that antisense transcription predominates in the absence of Tax, which transactivates viral sense transcription. Interestingly, a population of Tax-expressing cells exhibited antisense but not activated sense transcription. Consistent with the ability of Tax to induce cell cycle arrest, this population was arrested in G(0)/G(1) phase. These results imply that cell cycle arrest inhibits Tax-mediated activation of sense transcription without affecting antisense transcription, which may be important for long-term viral latency. C1 [Laverdure, Sylvain; Polakowski, Nicholas; Hoang, Kimson; Lemasson, Isabelle] E Carolina Univ, Brody Sch Med, Dept Microbiol & Immunol, Greenville, NC USA. [Laverdure, Sylvain] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Laverdure, S; Lemasson, I (reprint author), E Carolina Univ, Brody Sch Med, Dept Microbiol & Immunol, Greenville, NC USA. EM sylvain.laverdure@nih.gov; lemassoni@ecu.edu FU HHS \ NIH \ National Cancer Institute (NCI) [CA128800] FX HHS vertical bar NIH vertical bar National Cancer Institute (NCI) provided funding to Isabelle Lemasson under grant number CA128800. NR 50 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD APR PY 2016 VL 90 IS 7 BP 3600 EP 3610 DI 10.1128/JVI.02634-15 PG 11 WC Virology SC Virology GA DK7QQ UT WOS:000375121200027 PM 26792732 ER PT J AU Eller, MA Goonetilleke, N Tassaneetrithep, B Eller, LA Costanzo, MC Johnson, S Betts, MR Krebs, SJ Slike, BM Nitayaphan, S Rono, K Tovanabutra, S Maganga, L Kibuuka, H Jagodzinski, L Peel, S Rolland, M Marovich, MA Kim, JH Michael, NL Robb, ML Streeck, H AF Eller, Michael A. Goonetilleke, Nilu Tassaneetrithep, Boonrat Eller, Leigh Anne Costanzo, Margaret C. Johnson, Susan Betts, Michael R. Krebs, Shelly J. Slike, Bonnie M. Nitayaphan, Sorachai Rono, Kathleen Tovanabutra, Sodsai Maganga, Lucas Kibuuka, Hannah Jagodzinski, Linda Peel, Sheila Rolland, Morgane Marovich, Mary A. Kim, Jerome H. Michael, Nelson L. Robb, Merlin L. Streeck, Hendrik TI Expansion of Inefficient HIV-Specific CD8 T Cells during Acute Infection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC VIRAL-INFECTION; ANTIRETROVIRAL THERAPY; TYPE-1 INFECTION; DISEASE PROGRESSION; CD27 EXPRESSION; SIV INFECTION; HEPATITIS-B; RESPONSES; VIREMIA AB Attrition within the CD4(+) T cell compartment, high viremia, and a cytokine storm characterize the early days after HIV infection. When the first emerging HIV-specific CD8(+) T cell responses gain control over viral replication it is incomplete, and clearance of HIV infection is not achieved even in the rare cases of individuals who spontaneously control viral replication to nearly immeasurably low levels. Thus, despite their partial ability to control viremia, HIV-specific CD8(+) T cell responses are insufficient to clear HIV infection. Studying individuals in the first few days of acute HIV infection, we detected the emergence of a unique population of CD38(+) CD27- CD8(+) T cells characterized by the low expression of the CD8 receptor (CD8(dim)). Interestingly, while high frequencies of HIV-specific CD8(+) T cell responses occur within the CD38(+) CD27(-) CD8(dim) T cell population, the minority populations of CD8(bright) T cells are significantly more effective in inhibiting HIV replication. Furthermore, the frequency of CD8(dim) T cells directly correlates with viral load and clinical predictors of more rapid disease progression. We found that a canonical burst of proliferative cytokines coincides with the emergence of CD8(dim) T cells, and the size of this population inversely correlates with the acute loss of CD4(+) T cells. These data indicate, for the first time, that early CD4(+) T cell loss coincides with the expansion of a functionally impaired HIV-specific CD8(dim) T cell population less efficient in controlling HIV viremia. IMPORTANCE A distinct population of activated CD8(+) T cells appears during acute HIV infection with diminished capacity to inhibit HIV replication and is predictive of viral set point, offering the first immunologic evidence of CD8(+) T cell dysfunction during acute infection. C1 [Eller, Michael A.; Eller, Leigh Anne; Costanzo, Margaret C.; Johnson, Susan; Krebs, Shelly J.; Slike, Bonnie M.; Tovanabutra, Sodsai; Jagodzinski, Linda; Peel, Sheila; Rolland, Morgane; Marovich, Mary A.; Kim, Jerome H.; Michael, Nelson L.; Robb, Merlin L.; Streeck, Hendrik] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Eller, Michael A.; Eller, Leigh Anne; Costanzo, Margaret C.; Johnson, Susan; Krebs, Shelly J.; Slike, Bonnie M.; Tovanabutra, Sodsai; Rolland, Morgane; Robb, Merlin L.; Streeck, Hendrik] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Goonetilleke, Nilu] Univ N Carolina, Dept Immunol & Microbiol, Chapel Hill, NC USA. [Tassaneetrithep, Boonrat] Mahidol Univ, Siriraj Hosp, Fac Med, Off Res & Dev, Bangkok 10700, Thailand. [Betts, Michael R.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Nitayaphan, Sorachai] USAMC AFRIMS, Dept Retrovirol, Bangkok, Thailand. [Rono, Kathleen] Walter Reed Project Kenya, Kericho, Kenya. [Maganga, Lucas] Walter Reed Program Tanzania, Mbeya, Tanzania. [Kibuuka, Hannah] Makerere Univ, Walter Reed Project, Kampala, Uganda. [Streeck, Hendrik] Univ Duisburg Essen, Univ Hosp Essen, Inst HIV Res, Essen, Germany. [Kim, Jerome H.] Int Vaccine Inst, Seoul, South Korea. [Marovich, Mary A.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Streeck, H (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA.; Streeck, H (reprint author), Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA.; Streeck, H (reprint author), Univ Duisburg Essen, Univ Hosp Essen, Inst HIV Res, Essen, Germany. EM Hendrik.streeck@uk-essen.de FU Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-11-2-0174]; U.S. Department of Defense (DoD) [W81XWH-11-2-0174] FX This work was supported by a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DoD). NR 38 TC 3 Z9 3 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD APR PY 2016 VL 90 IS 8 BP 4005 EP 4016 DI 10.1128/JVI.02785-15 PG 12 WC Virology SC Virology GA DK7RQ UT WOS:000375123800019 PM 26842474 ER PT J AU Asbach, B Kliche, A Kostler, J Perdiguero, B Esteban, M Jacobs, BL Montefiori, DC LaBranche, CC Yates, NL Tomaras, GD Ferrari, G Foulds, KE Roederer, M Landucci, G Forthal, DN Seaman, MS Hawkins, N Self, SG Sato, A Gottardo, R Phogat, S Tartaglia, J Barnett, SW Burke, B Cristillo, AD Weiss, DE Francis, J Galmin, L Ding, S Heeney, JL Pantaleo, G Wagner, R AF Asbach, Benedikt Kliche, Alexander Koestler, Josef Perdiguero, Beatriz Esteban, Mariano Jacobs, Bertram L. Montefiori, David C. LaBranche, Celia C. Yates, Nicole L. Tomaras, Georgia D. Ferrari, Guido Foulds, Kathryn E. Roederer, Mario Landucci, Gary Forthal, Donald N. Seaman, Michael S. Hawkins, Natalie Self, Steven G. Sato, Alicia Gottardo, Raphael Phogat, Sanjay Tartaglia, James Barnett, Susan W. Burke, Brian Cristillo, Anthony D. Weiss, Deborah E. Francis, Jesse Galmin, Lindsey Ding, Song Heeney, Jonathan L. Pantaleo, Giuseppe Wagner, Ralf TI Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL RESPONSES; RECOMBINANT ADENOVIRAL VECTORS; PHASE-I TRIAL; CLADE-C; NEUTRALIZING ANTIBODIES; EFFICACY TRIAL; NYVAC-C; PROTECTIVE EFFICACY; NONHUMAN-PRIMATES; IMMUNE-RESPONSES AB In a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the pox-viral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C+ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8(+) and CD4(+) T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings. IMPORTANCE Within the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols. C1 [Asbach, Benedikt; Kliche, Alexander; Wagner, Ralf] Univ Regensburg, Inst Med Microbiol & Hyg, D-93053 Regensburg, Germany. [Koestler, Josef] Univ Regensburg, Inst Clin Microbiol & Hyg, D-93053 Regensburg, Germany. [Perdiguero, Beatriz; Esteban, Mariano] CSIC, Dept Mol & Cellular Biol, Ctr Nacl Biotecnol, Madrid, Spain. [Jacobs, Bertram L.] Arizona State Univ, Biodesign Inst, Tempe, AZ USA. [Montefiori, David C.; LaBranche, Celia C.; Yates, Nicole L.; Tomaras, Georgia D.; Ferrari, Guido] Duke Univ, Med Ctr, Durham, NC USA. [Foulds, Kathryn E.; Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Landucci, Gary; Forthal, Donald N.] Univ Calif Irvine, Sch Med, Dept Med, Div Infect Dis, Irvine, CA 92717 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Hawkins, Natalie; Self, Steven G.; Sato, Alicia; Gottardo, Raphael] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, 1124 Columbia St, Seattle, WA 98104 USA. [Phogat, Sanjay; Tartaglia, James] Sanofi Pasteur, Swiftwater, PA USA. [Barnett, Susan W.; Burke, Brian] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [Cristillo, Anthony D.; Weiss, Deborah E.; Francis, Jesse; Galmin, Lindsey] Adv BioSci Labs Inc, Rockville, MD USA. [Ding, Song] EuroVacc Fdn, Lausanne, Switzerland. [Heeney, Jonathan L.] Univ Cambridge, Dept Vet Med, Lab Viral Zoonot, Cambridge, England. [Pantaleo, Giuseppe] Univ Lausanne, CHU Vaudois, Dept Med, Div Immunol & Allergy, Lausanne, Switzerland. [Weiss, Deborah E.] Bioqual Inc, Rockville, MD USA. RP Wagner, R (reprint author), Univ Regensburg, Inst Med Microbiol & Hyg, D-93053 Regensburg, Germany. EM ralf.wagner@klinik.uni-regensburg.de RI Tomaras, Georgia/J-5041-2016; Pantaleo, Giuseppe/K-6163-2016 FU Bill & Melinda Gates Foundation Poxvirus T-Cell Vaccine Discovery Consortium (PTVDC) [38599]; Vaccine Immune Monitoring Centers [OPP1032144, OPP1032325]; Vaccine Immunology Statistical Center as part of the Collaboration for AIDS Vaccine Discovery (CAVD) [OPP1032317]; Bill & Melinda Gates Foundation; DAIDS [HHSN266200500007C]; NIAID; NIH FX This investigation was funded by the Bill & Melinda Gates Foundation Poxvirus T-Cell Vaccine Discovery Consortium (PTVDC) (grant 38599). The Vaccine Immune Monitoring Centers (grants OPP1032144 and OPP1032325) and the Vaccine Immunology Statistical Center (grant OPP1032317), as part of the Collaboration for AIDS Vaccine Discovery (CAVD), were funded by the Bill & Melinda Gates Foundation. Novartis Vaccines received support for this work under contract number HHSN266200500007C from DAIDS, NIAID, NIH. NR 70 TC 1 Z9 1 U1 3 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD APR PY 2016 VL 90 IS 8 BP 4133 EP 4149 DI 10.1128/JVI.03135-15 PG 17 WC Virology SC Virology GA DK7RQ UT WOS:000375123800030 PM 26865719 ER PT J AU Bamunusinghe, D Naghashfar, Z Buckler-White, A Plishka, R Baliji, S Liu, QP Kassner, J Oler, AJ Hartley, J Kozak, CA AF Bamunusinghe, Devinka Naghashfar, Zohreh Buckler-White, Alicia Plishka, Ronald Baliji, Surendranath Liu, Qingping Kassner, Joshua Oler, Andrew J. Hartley, Janet Kozak, Christine A. TI Sequence Diversity, Intersubgroup Relationships, and Origins of the Mouse Leukemia Gammaretroviruses of Laboratory and Wild Mice SO JOURNAL OF VIROLOGY LA English DT Article ID FOCUS-FORMING VIRUSES; MUS MUSCULUS CASTANEUS; CELL-SURFACE RECEPTOR; PROLINE-RICH REGION; HOST-RANGE; XENOTROPIC GAMMARETROVIRUSES; NUCLEOTIDE-SEQUENCE; RETROVIRUS XMRV; ECOTROPIC VIRUS; MURINE RETROVIRUSES AB Mouse leukemia viruses (MLVs) are found in the common inbred strains of laboratory mice and in the house mouse subspecies of Mus musculus. Receptor usage and envelope (env) sequence variation define three MLV host range subgroups in laboratory mice: ecotropic, polytropic, and xenotropic MLVs (E-, P-, and X-MLVs, respectively). These exogenous MLVs derive from endogenous retroviruses (ERVs) that were acquired by the wild mouse progenitors of laboratory mice about 1 million years ago. We analyzed the genomes of seven MLVs isolated from Eurasian and American wild mice and three previously sequenced MLVs to describe their relationships and identify their possible ERV progenitors. The phylogenetic tree based on the receptor-determining regions of env produced expected host range clusters, but these clusters are not maintained in trees generated from other virus regions. Colinear alignments of the viral genomes identified segmental homologies to ERVs of different host range subgroups. Six MLVs show close relationships to a small xenotropic ERV subgroup largely confined to the inbred mouse Y chromosome. env variations define three E-MLV subtypes, one of which carries duplications of various sizes, sequences, and locations in the proline-rich region of env. Outside the env region, all E-MLVs are related to different nonecotropic MLVs. These results document the diversity in gammaretroviruses isolated from globally distributed Mus subspecies, provide insight into their origins and relationships, and indicate that recombination has had an important role in the evolution of these mutagenic and pathogenic agents. IMPORTANCE Laboratory mice carry mouse leukemia viruses (MLVs) of three host range groups which were acquired from their wild mouse progenitors. We sequenced the complete genomes of seven infectious MLVs isolated from geographically separated Eurasian and American wild mice and compared them with endogenous germ line retroviruses (ERVs) acquired early in house mouse evolution. We did this because the laboratory mouse viruses derive directly from specific ERVs or arise by recombination between different ERVs. The six distinctively different wild mouse viruses appear to be recombinants, often involving different host range subgroups, and most are related to a distinctive, largely Y-chromosome-linked MLV ERV subtype. MLVs with ecotropic host ranges show the greatest variability with extensive inter-and intrasubtype envelope differences and with homologies to other host range subgroups outside the envelope. The sequence diversity among these wild mouse isolates helps define their relationships and origins and emphasizes the importance of recombination in their evolution. C1 [Bamunusinghe, Devinka; Buckler-White, Alicia; Plishka, Ronald; Baliji, Surendranath; Liu, Qingping; Kassner, Joshua; Kozak, Christine A.] NIAID, Mol Microbiol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Naghashfar, Zohreh; Hartley, Janet] NIAID, Immunogenet Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Oler, Andrew J.] NIAID, Bioinformat & Computat Biosci Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Baliji, Surendranath] Bayer CropSci, Nunhems USA, Acampo, CA USA. RP Kozak, CA (reprint author), NIAID, Mol Microbiol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov FU HHS\ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI000300-34] FX HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Devinka Bamunusinghe, Alicia Buckler-White, Ronald Plishka, Surendranath Baliji, Qingping Liu, Joshua Kassner, and Christine Kozak under grant number AI000300-34. NR 83 TC 1 Z9 1 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD APR PY 2016 VL 90 IS 8 BP 4186 EP 4198 DI 10.1128/JVI.03186-15 PG 13 WC Virology SC Virology GA DK7RQ UT WOS:000375123800034 PM 26865715 ER PT J AU Alfano, N Kolokotronis, SO Tsangaras, K Roca, AL Xu, WQ Eiden, MV Greenwood, AD AF Alfano, Niccolo Kolokotronis, Sergios-Orestis Tsangaras, Kyriakos Roca, Alfred L. Xu, Wenqin Eiden, Maribeth V. Greenwood, Alex D. TI Episodic Diversifying Selection Shaped the Genomes of Gibbon Ape Leukemia Virus and Related Gammaretroviruses (vol 90, pg 1757, 2016) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Alfano, Niccolo; Tsangaras, Kyriakos; Greenwood, Alex D.] Leibniz Inst Zoo & Wildlife Res, Berlin, Germany. [Kolokotronis, Sergios-Orestis] Fordham Univ, Dept Biol Sci, Bronx, NY 10458 USA. [Kolokotronis, Sergios-Orestis] Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA. [Kolokotronis, Sergios-Orestis] Amer Museum Nat Hist, Div Invertebrate Zool, New York, NY 10024 USA. [Roca, Alfred L.] Univ Illinois, Dept Anim Sci, Urbana, IL USA. [Xu, Wenqin; Eiden, Maribeth V.] NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. [Greenwood, Alex D.] Free Univ Berlin, Dept Vet Med, Berlin, Germany. RP Alfano, N (reprint author), Leibniz Inst Zoo & Wildlife Res, Berlin, Germany. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD APR PY 2016 VL 90 IS 8 BP 4254 EP 4254 DI 10.1128/JVI.00210-16 PG 1 WC Virology SC Virology GA DK7RQ UT WOS:000375123800040 PM 27022099 ER PT J AU Ryu, S Atzmon, G Barzilai, N Raghavachari, N Suh, Y AF Ryu, Seungjin Atzmon, Gil Barzilai, Nir Raghavachari, Nalini Suh, Yousin TI Genetic landscape of APOE in human longevity revealed by high-throughput sequencing SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE APOE; Centenarian; Genetic variant; Longevity; Pooled target capture sequencing ID GENOME-WIDE ASSOCIATION; EXCEPTIONAL LONGEVITY; GENOTYPE; SURVIVAL AB Apolipoprotein E (APOE) gene has been the most replicated longevity-associated gene in humans. Two common APOE alleles are either significantly depleted (epsilon 4 allele) or enriched (epsilon 2 allele) in long-lived individuals as compared to controls. We performed high-throughput sequencing analysis of exons and 2 kb proximal promoter of APOE in 450 centenarians and 500 controls of Ashkenazi Jewish decent. We found two common regulatory variants, rs405509 (p = 0.006) and rs769449 (p = 0.036), that were significantly depleted in centenarians. Genotyping analysis of rs7412 and rs429358 showed significant enrichment of epsilon 2 allele (p = 0.003) and epsilon 2/epsilon 3 genotype (p = 0.005), and significant depletion of epsilon 3/epsilon 4 genotype (p = 0.005) in centenarians. Our findings support the hypothesis that variants in both coding and regulatory regions of APOE may contribute to longevity in humans. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Ryu, Seungjin; Atzmon, Gil; Barzilai, Nir; Suh, Yousin] Albert Einstein Coll Med, Dept Genet, 1301 Morris Pk Ave, Bronx, NY 10461 USA. [Atzmon, Gil; Barzilai, Nir; Suh, Yousin] Albert Einstein Coll Med, Dept Med, 1301 Morris Pk Ave, Bronx, NY 10461 USA. [Raghavachari, Nalini] NIA, Div Geriatr & Clin Gerontol, Bethesda, MD 20892 USA. [Suh, Yousin] Albert Einstein Coll Med, Dept Ophthalmol & Visual Sci, Bronx, NY 10461 USA. RP Suh, Y (reprint author), Albert Einstein Coll Med, Dept Genet, 1301 Morris Pk Ave, Bronx, NY 10461 USA.; Suh, Y (reprint author), Albert Einstein Coll Med, Dept Med, 1301 Morris Pk Ave, Bronx, NY 10461 USA. EM yousin.suh@einstein.yu.edu FU NIH [AG024391, AG027734, AG17242]; Paul F. Glenn Center for the Biology of Human Aging; Glenn/AFAR Scholarships FX We would like to thank Archana Tare for critical reading of the manuscript. This work was funded by NIH grants AG024391, AG027734, and AG17242 (Y. S.) and a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y. S.). S. R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. NR 15 TC 3 Z9 3 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD APR PY 2016 VL 155 BP 7 EP 9 DI 10.1016/j.mad.2016.02.010 PG 3 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DJ7WE UT WOS:000374423100002 PM 26930295 ER PT J AU Koch, IJ Clark, MM Thompson, MJ Deere-Machemer, KA Wang, J Duarte, L Gnanadesikan, GE McCoy, EL Rubbi, L Stahler, DR Pellegrini, M Ostrander, EA Wayne, RK Sinsheimer, JS Vonholdt, BM AF Koch, Ilana Janowitz Clark, Michelle M. Thompson, Michael J. Deere-Machemer, Kerry A. Wang, Jun Duarte, Lionel Gnanadesikan, Gitanjali E. McCoy, Eskender L. Rubbi, Liudmilla Stahler, Daniel R. Pellegrini, Matteo Ostrander, Elaine A. Wayne, Robert K. Sinsheimer, Janet S. Vonholdt, Bridgett M. TI The concerted impact of domestication and transposon insertions on methylation patterns between dogs and grey wolves SO MOLECULAR ECOLOGY LA English DT Article DE canid; domestication; genome regulation; methylation ID EPIGENOME-WIDE ASSOCIATION; DNA METHYLATION; GENE-EXPRESSION; ANIMAL DOMESTICATION; EPIGENETIC VARIATION; PERIPHERAL-BLOOD; TRANSGENERATIONAL INHERITANCE; ARABIDOPSIS-THALIANA; PHENOTYPIC VARIATION; LIFE-HISTORY AB The process of domestication can exert intense trait-targeted selection on genes and regulatory regions. Specifically, rapid shifts in the structure and sequence of genomic regulatory elements could provide an explanation for the extensive, and sometimes extreme, variation in phenotypic traits observed in domesticated species. Here, we explored methylation differences from >24 000 cytosines distributed across the genomes of the domesticated dog (Canis familiaris) and the grey wolf (Canis lupus). PCA and model-based cluster analyses identified two primary groups, domestic vs. wild canids. A scan for significantly differentially methylated sites (DMSs) revealed species-specific patterns at 68 sites after correcting for cell heterogeneity, with weak yet significant hypermethylation typical of purebred dogs when compared to wolves (59% and 58%, P < 0.05, respectively). Additionally, methylation patterns at eight genes significantly deviated from neutrality, with similar trends of hypermethylation in purebred dogs. The majority (>66%) of differentially methylated regions contained or were associated with repetitive elements, indicative of a genotype-mediated trend. However, DMSs were also often linked to functionally relevant genes (e.g. neurotransmitters). Finally, we utilized known genealogical relationships among Yellowstone wolves to survey transmission stability of methylation marks, from which we found a substantial fraction that demonstrated high heritability (both H-2 and h(2) > 0.99). These analyses provide a unique epigenetic insight into the molecular consequences of recent selection and radiation of our most ancient domesticated companion, the dog. These findings suggest selection has acted on methylation patterns, providing a new genomic perspective on phenotypic diversification in domesticated species. C1 [Koch, Ilana Janowitz; Deere-Machemer, Kerry A.; Gnanadesikan, Gitanjali E.; Vonholdt, Bridgett M.] Princeton Univ, Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Clark, Michelle M.; Duarte, Lionel; Sinsheimer, Janet S.] Univ Calif Los Angeles, Dept Biostat, UCLA Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. [Thompson, Michael J.; Rubbi, Liudmilla; Pellegrini, Matteo] Univ Calif Los Angeles, Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Wang, Jun] Wayne State Univ, Dept Biol Sci, Detroit, MI 48085 USA. [McCoy, Eskender L.] Yale Univ, Sch Management, New Haven, CT 06511 USA. [Stahler, Daniel R.] Natl Pk Serv, Yellowstone Ctr Resources, Yellowstone Natl Pk, WY 82190 USA. [Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Wayne, Robert K.] Univ Calif Los Angeles, Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Sinsheimer, Janet S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet & Biomath, Los Angeles, CA 90095 USA. RP Vonholdt, BM (reprint author), Princeton Univ, Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM vonHoldt@princeton.edu RI Gnanadesikan, Gitanjali/I-3571-2016; OI Gnanadesikan, Gitanjali/0000-0002-1485-5574; Ostrander, Elaine/0000-0001-6075-9738 FU National Science Foundation [DEB-0613730, DEB-1245373, DMS-1264153]; Yellowstone National Park; Intramural Program of the National Human Genome Research Institute; AKC OAK (CHF) [1822]; NIH [T32 HG002536, GM053275] FX The authors would like to thank the purebred dog owners for providing blood samples, and Brian Peckinpaugh for providing Boz samples. In addition, we would like to thank Jennifer Listgarten for providing support for the program FaST-LMM-EWASher. We would also like to thank the Princeton University Computational Science & Engineering Support (CSES) group for providing computational assistance for multiple components of our work. This study was supported in part by the National Science Foundation grants DEB-0613730 and DEB-1245373, Yellowstone National Park, and many donors through the Yellowstone Park Foundation. This work was also partially funded through the Intramural Program of the National Human Genome Research Institute and the following additional grants: AKC OAK (CHF #1822), NIH T32 HG002536, National Science Foundation DMS-1264153, and NIH GM053275. NR 148 TC 2 Z9 2 U1 22 U2 52 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1083 EI 1365-294X J9 MOL ECOL JI Mol. Ecol. PD APR PY 2016 VL 25 IS 8 BP 1838 EP 1855 DI 10.1111/mec.13480 PG 18 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA DK2WY UT WOS:000374776300016 ER PT J AU Day, T AF Day, Troy TI Interpreting phenotypic antibiotic tolerance and persister cells as evolution via epigenetic inheritance SO MOLECULAR ECOLOGY LA English DT Article DE antibiotic resistance; dormancy; drug resistance; infectious disease; nongenetic; transgenerational inheritance ID ESCHERICHIA-COLI; NONGENETIC INHERITANCE; BACTERIAL PERSISTENCE; DRUG-RESISTANCE; FLUCTUATING ENVIRONMENTS; CHANGING ENVIRONMENTS; MULTIDRUG TOLERANCE; MECHANISMS; HETEROGENEITY; FREQUENCY AB Epigenetic inheritance is the transmission of nongenetic material such as gene expression levels, RNA and other biomolecules from parents to offspring. There is a growing realization that such forms of inheritance can play an important role in evolution. Bacteria represent a prime example of epigenetic inheritance because a large array of cellular components is transmitted to offspring, in addition to genetic material. Interestingly, there is an extensive and growing empirical literature showing that many bacteria can form 'persister' cells that are phenotypically resistant or tolerant to antibiotics, but most of these results are not interpreted within the context of epigenetic inheritance. Instead, persister cells are usually viewed as a genetically encoded bet-hedging strategy that has evolved in response to a fluctuating environment. Here I show, using a relatively simple model, that many of these empirical findings can be more simply understood as arising from a combination of epigenetic inheritance and cellular noise. I therefore suggest that phenotypic drug tolerance in bacteria might represent one of the best-studied examples of evolution under epigenetic inheritance. C1 [Day, Troy] Queens Univ, Dept Math & Stat, Jeffery Hall, Kingston, ON K7L 3N6, Canada. [Day, Troy] Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. [Day, Troy] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Day, T (reprint author), Queens Univ, Dept Math & Stat, Jeffery Hall, Kingston, ON K7L 3N6, Canada.; Day, T (reprint author), Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada.; Day, T (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM tday@mast.queensu.ca FU Research and Policy in Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate; Department of Homeland Security; Fogarty International Center; National Institutes of Health; Natural Sciences and Engineering Research Council of Canada FX I thank the Research and Policy in Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, the Department of Homeland Security, the Fogarty International Center, the National Institutes of Health, and the Natural Sciences and Engineering Research Council of Canada for support. NR 71 TC 2 Z9 2 U1 7 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1083 EI 1365-294X J9 MOL ECOL JI Mol. Ecol. PD APR PY 2016 VL 25 IS 8 BP 1869 EP 1882 DI 10.1111/mec.13603 PG 14 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA DK2WY UT WOS:000374776300018 PM 26946044 ER PT J AU Cho, N Moon, EH Kim, HW Hong, J Beutler, JA Sung, SH AF Cho, Namki Moon, Eun Hye Kim, Hyun Woo Hong, Jaewoo Beutler, John A. Sung, Sang Hyun TI Inhibition of Nitric Oxide Production in BV2 Microglial Cells by Triterpenes from Tetrapanax papyriferus SO MOLECULES LA English DT Article DE Tetrapanax papyriferus; triterpenes; BV2 microglial cells; NO; COX-2 ID LEAVES; FLOWERS; FRUIT AB It is well known that activated microglia produce nitric oxide (NO), which has an important role in the pathophysiology of several neurodegenerative diseases such as Alzheimer's disease. In the course of searching for novel therapeutic agents from medicinal plants against neuroinflammatory diseases, the methanolic extract of Tetrapanax papyriferus was found to have significant NO inhibitory activity in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. Nine oleanane-type triterpenes, including two new compounds, epipapyriogenin C-3-O-beta-D-glucopyranoside (6) and 11-O-butylpapyrioside LIIc (9), were isolated from the leaves and stems of Tetrapanax papyriferus. The structures of these compounds were elucidated with 1D- and 2D-NMR and MS data. Among these Delta(11,13) oleanane-type triterpenes, compound 3 showed significant NO inhibitory activity in BV-2 cells, reducing the LPS-induced expression of COX-2 and pro-inflammatory cytokines such as TNF-alpha and IL-6. Compounds 7 and 9 also showed NO inhibitory activities among the Delta(12) oleanane-type triterpene saponins. These results show that oleanane-type triterpenes isolated from T. papyriferus could be a potential natural resource of NO inhibitors used in the treatment of neurodegenerative disorders. C1 [Cho, Namki; Moon, Eun Hye; Kim, Hyun Woo; Sung, Sang Hyun] Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea. [Cho, Namki; Moon, Eun Hye; Kim, Hyun Woo; Sung, Sang Hyun] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. [Cho, Namki; Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Hong, Jaewoo] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Sung, SH (reprint author), Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea.; Sung, SH (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. EM cnamki@naver.com; arsinoe@snu.ac.kr; kimkami2@snu.ac.kr; jaewoo.hong@nih.gov; beutlerj@mail.nih.gov; shsung@snu.ac.kr FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [NRF-2013R1A2A2A01016296]; KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea; Intramural program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A2A2A01016296). Additionally, this work was supported by a grant from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea and supported in part by the Intramural program of the NIH, National Cancer Institute, Center for Cancer Research. NR 17 TC 0 Z9 0 U1 3 U2 4 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD APR PY 2016 VL 21 IS 4 AR 459 DI 10.3390/molecules21040459 PG 9 WC Chemistry, Organic SC Chemistry GA DK8CO UT WOS:000375155000072 PM 27070561 ER PT J AU Couch, FJ Kuchenbaecker, KB Michailidou, K Mendoza-Fandino, GA Nord, S Lilyquist, J Olswold, C Hallberg, E Agata, S Ahsan, H Aittomaki, K Ambrosone, C Andrulis, IL Anton-Culver, H Arndt, V Arun, BK Arver, B Barile, M Barkardottir, RB Barrowdale, D Beckmann, L Beckmann, MW Benitez, J Blank, SV Blomqvist, C Bogdanova, NV Bojesen, SE Bolla, MK Bonanni, B Brauch, H Brenner, H Burwinkel, B Buys, SS Caldes, T Caligo, MA Canzian, F Carpenter, J Chang-Claude, J Chanock, SJ Chung, WK Claes, KBM Cox, A Cross, SS Cunningham, JM Czene, K Daly, MB Damiola, F Darabi, H de la Hoya, M Devilee, P Diez, O Ding, YC Dolcetti, R Domchek, SM Dorfling, CM dos-Santos-Silva, I Dumont, M Dunning, AM Eccles, DM Ehrencrona, H Ekici, AB Eliassen, H Ellis, S Fasching, PA Figueroa, J Flesch-Janys, D Forsti, A Fostira, F Foulkes, WD Friebel, T Friedman, E Frost, D Gabrielson, M Gammon, MD Ganz, PA Gapstur, SM Garber, J Gaudet, MM Gayther, SA Gerdes, AM Ghoussaini, M Giles, GG Glendon, G Godwin, AK Goldberg, MS Goldgar, DE Gonzalez-Neira, A Greene, MH Gronwald, J Guenel, P Gunter, M Haeberle, L Haiman, CA Hamann, U Hansen, TVO Hart, S Healey, S Heikkinen, T Henderson, BE Herzog, J Hogervorst, FBL Hollestelle, A Hooning, MJ Hoover, RN Hopper, JL Humphreys, K Hunter, DJ Huzarski, T Imyanitov, EN Isaacs, C Jakubowska, A James, P Janavicius, R Jensen, UB John, EM Jones, M Kabisch, M Kar, S Karlan, BY Khan, S Khaw, KT Kibriya, MG Knight, JA Ko, YD Konstantopoulou, I Kosma, VM Kristensen, V Kwong, A Laitman, Y Lambrechts, D Lazaro, C Lee, E Le Marchand, L Lester, J Lindblom, A Lindor, N Lindstrom, S Liu, J Long, J Lubinski, J Mai, PL Makalic, E Malone, KE Mannermaa, A Manoukian, S Margolin, S Marme, F Martens, JWM McGuffog, L Meindl, A Miller, A Milne, RL Miron, P Montagna, M Mazoyer, S Mulligan, AM Muranen, TA Nathanson, KL Neuhausen, SL Nevanlinna, H Nordestgaard, BG Nussbaum, RL Offit, K Olah, E Olopade, OI Olson, JE Osorio, A Park, SK Peeters, PH Peissel, B Peterlongo, P Peto, J Phelan, CM Pilarski, R Poppe, B Pylkas, K Radice, P Rahman, N Rantala, J Rappaport, C Rennert, G Richardson, A Robson, M Romieu, I Rudolph, A Rutgers, EJ Sanchez, MJ Santella, RM Sawyer, EJ Schmidt, DF Schmidt, MK Schmutzler, RK Schumacher, F Scott, R Senter, L Sharma, P Simard, J Singer, CF Sinilnikova, OM Soucy, P Southey, M Steinemann, D Stenmark-Askmalm, M Stoppa-Lyonnet, D Swerdlow, A Szabo, CI Tamimi, R Tapper, W Teixeira, MR Teo, SH Terry, MB Thomassen, M Thompson, D Tihomirova, L Toland, AE Tollenaar, RAEM Tomlinson, I Truong, T Tsimiklis, H Teule, A Tumino, R Tung, N Turnbull, C Ursin, G van Deurzen, CHM van Rensburg, EJ Varon-Mateeva, R Wang, ZM Wang-Gohrke, S Weiderpass, E Weitzel, JN Whittemore, A Wildiers, H Winqvist, R Yang, XHR Yannoukakos, D Yao, S Zamora, MP Zheng, W Hall, P Kraft, P Vachon, C Slager, S Chenevix-Trench, G Pharoah, PDP Monteiro, AAN Garcia-Closas, M Easton, DF Antoniou, AC AF Couch, Fergus J. Kuchenbaecker, Karoline B. Michailidou, Kyriaki Mendoza-Fandino, Gustavo A. Nord, Silje Lilyquist, Janna Olswold, Curtis Hallberg, Emily Agata, Simona Ahsan, Habibul Aittomaeki, Kristiina Ambrosone, Christine Andrulis, Irene L. Anton-Culver, Hoda Arndt, Volker Arun, Banu K. Arver, Brita Barile, Monica Barkardottir, Rosa B. Barrowdale, Daniel Beckmann, Lars Beckmann, Matthias W. Benitez, Javier Blank, Stephanie V. Blomqvist, Carl Bogdanova, Natalia V. Bojesen, Stig E. Bolla, Manjeet K. Bonanni, Bernardo Brauch, Hiltrud Brenner, Hermann Burwinkel, Barbara Buys, Saundra S. Caldes, Trinidad Caligo, Maria A. Canzian, Federico Carpenter, Jane Chang-Claude, Jenny Chanock, Stephen J. Chung, Wendy K. Claes, Kathleen B. M. Cox, Angela Cross, Simon S. Cunningham, Julie M. Czene, Kamila Daly, Mary B. Damiola, Francesca Darabi, Hatef de la Hoya, Miguel Devilee, Peter Diez, Orland Ding, Yuan C. Dolcetti, Riccardo Domchek, Susan M. Dorfling, Cecilia M. dos-Santos-Silva, Isabel Dumont, Martine Dunning, Alison M. Eccles, Diana M. Ehrencrona, Hans Ekici, Arif B. Eliassen, Heather Ellis, Steve Fasching, Peter A. Figueroa, Jonine Flesch-Janys, Dieter Foersti, Asta Fostira, Florentia Foulkes, William D. Friebel, Tara Friedman, Eitan Frost, Debra Gabrielson, Marike Gammon, Marilie D. Ganz, Patricia A. Gapstur, Susan M. Garber, Judy Gaudet, Mia M. Gayther, Simon A. Gerdes, Anne-Marie Ghoussaini, Maya Giles, Graham G. Glendon, Gord Godwin, Andrew K. Goldberg, Mark S. Goldgar, David E. Gonzalez-Neira, Anna Greene, Mark H. Gronwald, Jacek Guenel, Pascal Gunter, Marc Haeberle, Lothar Haiman, Christopher A. Hamann, Ute Hansen, Thomas V. O. Hart, Steven Healey, Sue Heikkinen, Tuomas Henderson, Brian E. Herzog, Josef Hogervorst, Frans B. L. Hollestelle, Antoinette Hooning, Maartje J. Hoover, Robert N. Hopper, John L. Humphreys, Keith Hunter, David J. Huzarski, Tomasz Imyanitov, Evgeny N. Isaacs, Claudine Jakubowska, Anna James, Paul Janavicius, Ramunas Jensen, Uffe Birk John, Esther M. Jones, Michael Kabisch, Maria Kar, Siddhartha Karlan, Beth Y. Khan, Sofia Khaw, Kay-Tee Kibriya, Muhammad G. Knight, Julia A. Ko, Yon-Dschun Konstantopoulou, Irene Kosma, Veli-Matti Kristensen, Vessela Kwong, Ava Laitman, Yael Lambrechts, Diether Lazaro, Conxi Lee, Eunjung Le Marchand, Loic Lester, Jenny Lindblom, Annika Lindor, Noralane Lindstrom, Sara Liu, Jianjun Long, Jirong Lubinski, Jan Mai, Phuong L. Makalic, Enes Malone, Kathleen E. Mannermaa, Arto Manoukian, Siranoush Margolin, Sara Marme, Frederik Martens, John W. M. McGuffog, Lesley Meindl, Alfons Miller, Austin Milne, Roger L. Miron, Penelope Montagna, Marco Mazoyer, Sylvie Mulligan, Anna M. Muranen, Taru A. Nathanson, Katherine L. Neuhausen, Susan L. Nevanlinna, Heli Nordestgaard, Borge G. Nussbaum, Robert L. Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I. Olson, Janet E. Osorio, Ana Park, Sue K. Peeters, Petra H. Peissel, Bernard Peterlongo, Paolo Peto, Julian Phelan, Catherine M. Pilarski, Robert Poppe, Bruce Pylkaes, Katri Radice, Paolo Rahman, Nazneen Rantala, Johanna Rappaport, Christine Rennert, Gad Richardson, Andrea Robson, Mark Romieu, Isabelle Rudolph, Anja Rutgers, Emiel J. Sanchez, Maria-Jose Santella, Regina M. Sawyer, Elinor J. Schmidt, Daniel F. Schmidt, Marjanka K. Schmutzler, Rita K. Schumacher, Fredrick Scott, Rodney Senter, Leigha Sharma, Priyanka Simard, Jacques Singer, Christian F. Sinilnikova, Olga M. Soucy, Penny Southey, Melissa Steinemann, Doris Stenmark-Askmalm, Marie Stoppa-Lyonnet, Dominique Swerdlow, Anthony Szabo, Csilla I. Tamimi, Rulla Tapper, William Teixeira, Manuel R. Teo, Soo-Hwang Terry, Mary B. Thomassen, Mads Thompson, Deborah Tihomirova, Laima Toland, Amanda E. Tollenaar, Robert A. E. M. Tomlinson, Ian Truong, Therese Tsimiklis, Helen Teule, Alex Tumino, Rosario Tung, Nadine Turnbull, Clare Ursin, Giski van Deurzen, Carolien H. M. van Rensburg, Elizabeth J. Varon-Mateeva, Raymonda Wang, Zhaoming Wang-Gohrke, Shan Weiderpass, Elisabete Weitzel, Jeffrey N. Whittemore, Alice Wildiers, Hans Winqvist, Robert Yang, Xiaohong R. Yannoukakos, Drakoulis Yao, Song Zamora, M. Pilar Zheng, Wei Hall, Per Kraft, Peter Vachon, Celine Slager, Susan Chenevix-Trench, Georgia Pharoah, Paul D. P. Monteiro, Alvaro A. N. Garcia-Closas, Montserrat Easton, Douglas F. Antoniou, Antonis C. TI Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; BRCA2 MUTATION CARRIERS; PANCREATIC-CANCER; COMMON VARIANTS; CONFER SUSCEPTIBILITY; GENE-EXPRESSION; TELOMERE LENGTH; RISK; METAANALYSIS; IDENTIFY AB Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. C1 [Couch, Fergus J.; Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Couch, Fergus J.; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Hart, Steven; Olson, Janet E.; Vachon, Celine; Slager, Susan] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Barrowdale, Daniel; Bolla, Manjeet K.; Ellis, Steve; Frost, Debra; McGuffog, Lesley; Thompson, Deborah; Easton, Douglas F.; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Mendoza-Fandino, Gustavo A.; Phelan, Catherine M.; Monteiro, Alvaro A. N.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA. [Nord, Silje; Kristensen, Vessela] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. [Agata, Simona; Montagna, Marco] IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy. [Ahsan, Habibul; Kibriya, Muhammad G.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA. [Aittomaeki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland. [Ambrosone, Christine] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA. [Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Arver, Brita; Margolin, Sara] Karolinska Univ Hosp, Dept Oncol, SE-17176 Stockholm, Sweden. [Barile, Monica; Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy. [Barkardottir, Rosa B.] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland. [Barkardottir, Rosa B.] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland. [Beckmann, Lars] Inst Qual & Efficiency Hlth Care IQWiG, D-50670 Cologne, Germany. [Beckmann, Matthias W.; Fasching, Peter A.; Haeberle, Lothar] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany. [Benitez, Javier; Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain. [Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Genotyping Unit CeGen, Madrid 28029, Spain. [Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid 28029, Spain. [Blank, Stephanie V.] NYU, Sch Med, NYU Womens Canc Program, New York, NY 10016 USA. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, FI-00029 Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, D-72074 Tubingen, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany. [Burwinkel, Barbara; Heikkinen, Tuomas; Marme, Frederik; Muranen, Taru A.] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany. [Buys, Saundra S.] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Caldes, Trinidad; de la Hoya, Miguel] IdISSC, Hosp Clin San Carlos, Mol Oncol Lab, Madrid 28040, Spain. 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[Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2HQ, S Yorkshire, England. [Czene, Kamila; Darabi, Hatef; Gabrielson, Marike; Humphreys, Keith; Weiderpass, Elisabete; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Daly, Mary B.] Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA. [Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.] Univ Lyon, CNRS, UMR5286, Ctr Rech Cancerol Lyon,INSERM,U1052, F-69373 Lyon, France. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZC Leiden, Netherlands. [Diez, Orland] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona 08035, Spain. [Diez, Orland] Univ Autonoma Barcelona, Barcelona 08035, Spain. [Ding, Yuan C.; Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Dolcetti, Riccardo] CRO Aviano Natl Canc Inst, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Dorfling, Cecilia M.; van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, ZA-0007 Pretoria, South Africa. [dos-Santos-Silva, Isabel; Peto, Julian] Univ London London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, Keppel St, London WC1E 7HT, England. [Dumont, Martine] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ G1V 4G2, Canada. [Dumont, Martine] Univ Laval, Quebec City, PQ G1V 4G2, Canada. [Dunning, Alison M.; Ghoussaini, Maya; Kar, Siddhartha; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Eccles, Diana M.; Tapper, William] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England. [Ehrencrona, Hans] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden. [Ehrencrona, Hans] Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden. [Ekici, Arif B.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany. [Ekici, Arif B.] Comprehens Canc Ctr EMN, D-91054 Erlangen, Germany. [Eliassen, Heather; Tamimi, Rulla] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Eliassen, Heather; Tamimi, Rulla] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Eliassen, Heather; Lindstrom, Sara; Tamimi, Rulla; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, D-20246 Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany. [Foersti, Asta] German Canc Res Ctr, Div Mol Genet Epidemiol, D-69120 Heidelberg, Germany. [Foersti, Asta] Lund Univ, Ctr Primary Hlth Care Res, SE-22100 Malmo, Sweden. [Fostira, Florentia; Konstantopoulou, Irene; Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece. [Foulkes, William D.] McGill Univ, Program Canc Genet, Montreal, PQ H3A 0G4, Canada. [Friebel, Tara] Univ Philadelphia, Philadelphia, PA 19104 USA. [Friedman, Eitan; Laitman, Yael] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Ganz, Patricia A.] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, Los Angeles, CA 90095 USA. [Gapstur, Susan M.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. 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[Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zamora, M. Pilar] Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia. [Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. RP Couch, FJ (reprint author), Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA.; Couch, FJ (reprint author), Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. EM couch.fergus@mayo.edu RI Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Osorio, Ana/I-4324-2014; Weiderpass, Elisabete/M-4029-2016; Teo, Soo-hwang/H-2353-2014; Knight, Julia/A-6843-2012; Zheng, Wei/O-3351-2013; Nord, Silje/R-5212-2016; Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; montagna, marco/E-2225-2012 OI Ehrencrona, Hans/0000-0002-5589-3622; Khan, Sofia/0000-0003-4185-8882; Muranen, Taru/0000-0002-5895-1808; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166; Giles, Graham/0000-0003-4946-9099; Dolcetti, Riccardo/0000-0003-1625-9853; Osorio, Ana/0000-0001-8124-3984; Weiderpass, Elisabete/0000-0003-2237-0128; Zheng, Wei/0000-0003-1226-070X; Nord, Silje/0000-0002-3271-5356; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; montagna, marco/0000-0002-4929-2150 FU European Community Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A10710, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C12292/A11174]; National Institutes of Health [CA116201, CA128978, CA176785, CA192393]; National Institutes of Health, Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; National Institutes of Health, GAME-ON initiative; Canadian Institutes of Health Research (CIHR); Breast Cancer Res. Foundation; Ovarian Cancer Research Fund; Department of Defence [W81XWH-10-1-0341]; Florida Breast Cancer Foundation FX B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1. NR 48 TC 4 Z9 4 U1 12 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2016 VL 7 AR 11375 DI 10.1038/ncomms11375 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK4NF UT WOS:000374894400001 PM 27117709 ER PT J AU Freedman, JE Gerstein, M Mick, E Rozowsky, J Levy, D Kitchen, R Das, S Shah, R Danielson, K Beaulieu, L Navarro, FCP Wang, YY Galeev, TR Holman, A Kwong, RY Murthy, V Tanriverdi, SE Koupenova-Zamor, M Mikhalev, E Tanriverdi, K AF Freedman, Jane E. Gerstein, Mark Mick, Eric Rozowsky, Joel Levy, Daniel Kitchen, Robert Das, Saumya Shah, Ravi Danielson, Kirsty Beaulieu, Lea Navarro, Fabio C. P. Wang, Yaoyu Galeev, Timur R. Holman, Alex Kwong, Raymond Y. Murthy, Venkatesh Tanriverdi, Selim E. Koupenova-Zamor, Milka Mikhalev, Ekaterina Tanriverdi, Kahraman TI Diverse human extracellular RNAs are widely detected in human plasma SO NATURE COMMUNICATIONS LA English DT Article ID SEQUENCING EXPERIMENTS; CIRCULATING MICRORNAS; SMALL NUCLEOLAR; C-ELEGANS; EXPRESSION; BIOMARKERS; PLATELET; DATABASE; BLOOD; TRANSCRIPTOME AB There is growing appreciation for the importance of non-protein-coding genes in development and disease. Although much is known about microRNAs, limitations in bioinformatic analyses of RNA sequencing have precluded broad assessment of other forms of small-RNAs in humans. By analysing sequencing data from plasma-derived RNA from 40 individuals, here we identified over a thousand human extracellular RNAs including microRNAs, piwi-interacting RNA (piRNA), and small nucleolar RNAs. Using a targeted quantitative PCR with reverse transcription approach in an additional 2,763 individuals, we characterized almost 500 of the most abundant extracellular transcripts including microRNAs, piRNAs and small nucleolar RNAs. The presence in plasma of many non-microRNA small-RNAs was confirmed in an independent cohort. We present comprehensive data to demonstrate the broad and consistent detection of diverse classes of circulating non-cellular small-RNAs from a large population. C1 [Freedman, Jane E.; Beaulieu, Lea; Tanriverdi, Selim E.; Koupenova-Zamor, Milka; Mikhalev, Ekaterina; Tanriverdi, Kahraman] Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA 01605 USA. [Gerstein, Mark; Rozowsky, Joel; Kitchen, Robert; Navarro, Fabio C. P.; Galeev, Timur R.] Yale Univ, Sch Med, Computat Biol & Bioinformat Program, 333 Cedar St, New Haven, CT 06520 USA. [Mick, Eric] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA 01605 USA. [Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20824 USA. [Das, Saumya; Shah, Ravi; Danielson, Kirsty] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [Wang, Yaoyu; Holman, Alex] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02215 USA. [Kwong, Raymond Y.] Brigham & Womens Hosp, Dept Med, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. [Murthy, Venkatesh] Univ Michigan, Ann Arbor, MI 48409 USA. RP Freedman, JE (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA 01605 USA. EM jane.freedman@umassmed.edu OI Navarro, Fabio/0000-0002-5640-9070; Murthy, Venkatesh/0000-0002-7901-1321; Rozowsky, Joel/0000-0002-3565-0762 FU NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director [N01-HC 25195, P01-HL085381, UH2TR000921, U01HL126495, UH2TR000901] FX This work was supported by N01-HC 25195, P01-HL085381 (to J.E.F.); UH2TR000921, U01HL126495 (to J.E.F.); and UH2TR000901 (to S.D.), that are supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. We thank Lillian Kuo, Danilo Tagle and Pothur Srinivas of the NIH Common Fund for their assistance and guidance. NR 48 TC 13 Z9 13 U1 4 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2016 VL 7 AR 11106 DI 10.1038/ncomms11106 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK4MK UT WOS:000374892300001 PM 27112789 ER PT J AU Jiang, X Hu, C Arnovitz, S Bugno, J Yu, M Zuo, ZX Chen, P Huang, H Ulrich, B Gurbuxani, S Weng, HY Strong, J Wang, YG Li, YY Salat, J Li, SL Elkahloun, AG Yang, Y Neilly, MB Larson, RA Le Beau, MM Herold, T Bohlander, SK Liu, PP Zhang, JW Li, ZJ He, C Jin, J Hong, S Chen, JJ AF Jiang, Xi Hu, Chao Arnovitz, Stephen Bugno, Jason Yu, Miao Zuo, Zhixiang Chen, Ping Huang, Hao Ulrich, Bryan Gurbuxani, Sandeep Weng, Hengyou Strong, Jennifer Wang, Yungui Li, Yuanyuan Salat, Justin Li, Shenglai Elkahloun, Abdel G. Yang, Yang Neilly, Mary Beth Larson, Richard A. Le Beau, Michelle M. Herold, Tobias Bohlander, Stefan K. Liu, Paul P. Zhang, Jiwang Li, Zejuan He, Chuan Jin, Jie Hong, Seungpyo Chen, Jianjun TI miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia SO NATURE COMMUNICATIONS LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; CELL SELF-RENEWAL; STEM-CELLS; MYELODYSPLASTIC SYNDROMES; TUMOR-SUPPRESSOR; DELETED REGION; TRANSFORMATION; MLL; TARGETS; TET2 AB MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy. C1 [Jiang, Xi; Hu, Chao; Zuo, Zhixiang; Weng, Hengyou; Strong, Jennifer; Wang, Yungui; Chen, Jianjun] Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45219 USA. [Jiang, Xi; Hu, Chao; Arnovitz, Stephen; Zuo, Zhixiang; Chen, Ping; Huang, Hao; Ulrich, Bryan; Weng, Hengyou; Wang, Yungui; Li, Yuanyuan; Salat, Justin; Li, Shenglai; Neilly, Mary Beth; Larson, Richard A.; Le Beau, Michelle M.; Li, Zejuan; Chen, Jianjun] Univ Chicago, Hematol Oncol Sect, Dept Med, Chicago, IL 60637 USA. [Hu, Chao; Wang, Yungui; Jin, Jie] Zhejiang Univ, Dept Hematol, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China. [Bugno, Jason; Yang, Yang; Hong, Seungpyo] Univ Illinois, Coll Pharm, Dept Biopharmaceut Sci, Chicago, IL 60612 USA. [Yu, Miao; He, Chuan] Univ Chicago, Dept Chem, 5735 S Ellis Ave, Chicago, IL 60637 USA. [Yu, Miao; He, Chuan] Univ Chicago, Howard Hughes Med Inst, Inst Biophys Dynam, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Zuo, Zhixiang] Sun Yat Sen Univ, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. [Gurbuxani, Sandeep] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Elkahloun, Abdel G.; Liu, Paul P.] NHGRI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Herold, Tobias] Univ Munich, Univ Hosp Grosshadern, Dept Internal Med 3, D-81377 Munich, Germany. [Bohlander, Stefan K.] Univ Auckland, Dept Mol Med & Pathol, Auckland 1142, New Zealand. [Zhang, Jiwang] Loyola Univ, Med Ctr, Inst Oncol, Cardinal Bernardin Canc Ctr, 2160 S 1st Ave, Maywood, IL 60153 USA. [Li, Zejuan] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Hong, Seungpyo] Yonsei Univ, Integrated Sci & Engn Div, Underwood Int Coll, Inchon 406840, South Korea. RP Chen, JJ (reprint author), Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45219 USA.; Chen, JJ (reprint author), Univ Chicago, Hematol Oncol Sect, Dept Med, Chicago, IL 60637 USA. EM chen3jj@ucmail.uc.edu RI Zuo, Zhixiang/M-4441-2016; OI Zuo, Zhixiang/0000-0002-2492-2689; Herold, Tobias/0000-0002-9615-9432; Larson, Richard/0000-0001-9168-3203 FU Leukemia & Lymphoma Society (LLS) Translational Research Grant; National Institutes of Health (NIH) R01 Grant [CA178454, CA182528, CA127277]; American Cancer Society (ACS) Research Scholar grant; University of Chicago Committee on Cancer Biology (CCB) Fellowship Program; LLS Special Fellowship; Gabrielle's Angel Foundation for Cancer Research; Intramural Research Program of National Human Genome Research Institute, NIH FX Special thanks to the late Dr Janet Rowley for her long-term support. We also thank Drs Pier P. Pandolfi, Sheena Josselyn, Dong-Er Zhang, Scott Armstrong, Michael Cleary, James Mulloy, Robert Slany, Lin He and Michael Thirman for providing mouse models, retroviral constructs or cell lines, and the German AMLCG study group for AML microarray data. This work was supported by Leukemia & Lymphoma Society (LLS) Translational Research Grant (J.C.), the National Institutes of Health (NIH) R01 Grants CA178454, CA182528 and CA127277 (J.C.), American Cancer Society (ACS) Research Scholar grant (J.C.), The University of Chicago Committee on Cancer Biology (CCB) Fellowship Program (X.J.), LLS Special Fellowship (Z.L.), Gabrielle's Angel Foundation for Cancer Research (J.C., Z.L., X.J. and H.H.) and Intramural Research Program of National Human Genome Research Institute, NIH (A.G.E. and P.P.L.). C.H. is an investigator of the Howard Hughes Medical Institute. NR 70 TC 12 Z9 12 U1 6 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2016 VL 7 AR 11452 DI 10.1038/ncomms11452 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK4NU UT WOS:000374896000001 PM 27116251 ER PT J AU Leusink, M Maitland-van der Zee, AH Ding, B Drenos, F van Iperen, EPA Warren, HR Caulfield, MJ Cupples, LA Cushman, M Hingorani, AD Hoogeveen, RC Hovingh, GK Kumari, M Lange, LA Munroe, PB Nyberg, F Schreiner, PJ Sivapalaratnam, S de Bakker, PIW de Boer, A Keating, BJ Asselbergs, FW Onland-Moret, NC AF Leusink, Maarten Maitland-van der Zee, Anke H. Ding, Bo Drenos, Fotios van Iperen, Erik P. A. Warren, Helen R. Caulfield, Mark J. Cupples, L. Adrienne Cushman, Mary Hingorani, Aroon D. Hoogeveen, Ron C. Hovingh, G. Kees Kumari, Meena Lange, Leslie A. Munroe, Patricia B. Nyberg, Fredrik Schreiner, Pamela J. Sivapalaratnam, Suthesh de Bakker, Paul I. W. de Boer, Anthonius Keating, Brendan J. Asselbergs, Folkert W. Onland-Moret, N. Charlotte TI A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering SO PHARMACOGENOMICS LA English DT Article DE pharmacogenetics cholesterol; risk score; statin therapy ID GENOME-WIDE ASSOCIATION; CENTRIC METAANALYSIS; RANDOMIZED-TRIALS; LDL CHOLESTEROL; THERAPY; LOCI; REDUCTION; VARIANTS; DISEASE; ROSUVASTATIN AB Aim: To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome. Patients & methods: In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 x 10(-4) (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG2, LPA and APOE. Results: No new SNPs were found associated with statin response. The GRS was associated with reduced statin response: 0.0394 mmol/l per allele (95% CI: 0.0171-0.0617, p = 5.37 x 10(-4)). Conclusion: The GRS was associated with statin response, but the small effect size (similar to 2% of the average low-density lipoprotein cholesterol reduction) limits applicability. C1 [Leusink, Maarten; de Bakker, Paul I. W.; Onland-Moret, N. Charlotte] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Leusink, Maarten; Maitland-van der Zee, Anke H.; de Boer, Anthonius] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Fac Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands. [Ding, Bo; Nyberg, Fredrik] AstraZeneca R&D Gothenburg, Global Med Affairs, Med Evidence & Observat Res Ctr, Molndal, Sweden. [Drenos, Fotios] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Drenos, Fotios] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol, Avon, England. [van Iperen, Erik P. A.; Asselbergs, Folkert W.] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. [van Iperen, Erik P. A.] Acad Med Ctr Amsterdam, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands. [Warren, Helen R.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol, London, England. [Warren, Helen R.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Hingorani, Aroon D.] UCL, Dept Epidemiol & Publ Hlth, UCL Inst Epidemiol & Hlth Care, London, England. [Hoogeveen, Ron C.] Baylor Coll Med, Dept Med, Div Atherosclerosis & Vasc Med, Houston, TX 77030 USA. [Hovingh, G. Kees; Sivapalaratnam, Suthesh] Acad Med Ctr Amsterdam, Dept Vasc Med, Amsterdam, Netherlands. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Sch Med Chapel Hill, Chapel Hill, NC USA. [Nyberg, Fredrik] Univ Gothenburg, Dept Publ Hlth & Community Med, Sahlgrenska Acad, Occupat & Environm Med,Inst Med, Gothenburg, Sweden. [Schreiner, Pamela J.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Keating, Brendan J.] Hosp Univ Penn, Dept Surg, Div Transplantat, 3400 Spruce St, Philadelphia, PA 19104 USA. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands. [Asselbergs, Folkert W.] UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England. RP Onland-Moret, NC (reprint author), Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. EM N.C.Onland@umcutrecht.nl RI Onland-Moret, N. Charlotte/G-9185-2011; OI Kumari, Meena/0000-0001-9716-1035 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HH-SN268201100006C, HHSN268201100007C, HHSN26820-1100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH [HHSN268200625226C, N01-HC-25195, R01-HL-092577, R01-HL-076784, R01-AG-028321]; National Institutes of Health [UL1RR025005]; Pfizer, NY, USA; Leo Laboratories, Copenhagen, Denmark; National Heart, Lung and Blood Institute; NHLBI [HHSN268200960009C]; NIH Intramural Research Program; AstraZeneca; University of Washington [N01-HC-95159]; University of California, Los Angeles [N01-HC-95160]; Columbia University [N01-HC-95161]; Johns Hopkins University [N01-HC-95162, N01-HC-95168]; University of Minnesota [N01-HC-95163]; Northwestern University [N01-HC-95164]; Wake Forest University [N01-HC-95165]; University of Vermont [N01-HC-95166]; New England Medical Center [N01-HC-95167]; Harbor-UCLA Research and Education Institute [N01-HC-95169]; Cedars-Sinai Medical Center [R01-HL-071205]; University of Virginia; Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute [HL36310]; US, NIH: National Institute on Aging [AG13196]; US, NIH [HS06516]; John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health; Netherlands Organisation for Health Research and Development (ZonMw grant) [90700342]; Utrecht University ('Epidemiology - Program'); NIH Roadmap for Medical Research; Agency for Health Care Policy Research FX This work was supported by: ARIC: The Athero-sclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HH-SN268201100006C, HHSN268201100007C, HHSN26820-1100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research; ASCOT: This work was supported by Pfizer, NY, USA, for the ASCOT study and the collection of the ASCOT DNA repository; by Servier Research Group, Paris, France; and by Leo Laboratories, Copenhagen, Denmark. We thank all ASCOT trial participants, physicians, nurses and practices in the participating countries for their important contribution to the study. We thank the Centre National de Genotypage for genotyping. This work forms part of the research themes contributing to the translational research portfolio for the NIHR Barts Cardiovascular Biomedical Research Unit (Warren, Munroe and Caulfield); CARe: wishes to acknowledge the support of the National Heart, Lung and Blood Institute and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research (NHLBI contract number HHSN268200960009C); FHS: The Framingham Heart Study research included in this study is funded by NIH grant/contract N01-HC-25195, R01-HL-092577, R01-HL-076784, R01-AG-028321, and by the NIH Intramural Research Program; JUPITER: The Jupiter study and genotyping of the study participants was funded by AstraZeneca; MESA: MESA was supported by the following: University of Washington (N01-HC-95159), University of California, Los Angeles (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205) and University of Virginia. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org; WHII: We thank all participating women and men in the Whitehall II Study, as well as all Whitehall II research scientists, study and data managers and clinical and administrative staff who make the study possible. The Whitehall II study has been supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (HL36310), US, NIH: National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. AD Hingorani holds a British Heart Foundation Senior Research - Fellowship.; A clinical fellowship from The Netherlands Organisation for Health Research and Development (ZonMw grant 90700342 to FW Asselbergs); Utrecht University ('Epidemiology - Program' to M Leusink). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 29 TC 1 Z9 1 U1 1 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD APR PY 2016 VL 17 IS 6 BP 583 EP 591 DI 10.2217/pgs.16.8 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK8AG UT WOS:000375148200007 PM 27045730 ER PT J AU Bonfrate, A Farah, J De Marzi, L Delacroix, S Herault, J Sayah, R Lee, C Bolch, WE Clairand, I AF Bonfrate, A. Farah, J. De Marzi, L. Delacroix, S. Herault, J. Sayah, R. Lee, C. Bolch, W. E. Clairand, I. TI Influence of beam incidence and irradiation parameters on stray neutron doses to healthy organs of pediatric patients treated for an intracranial tumor with passive scattering proton therapy SO PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS LA English DT Article DE Proton therapy; Stray neutron doses; Intracranial treatments; Beam incidence ID ACCELERATOR-DRIVEN SYSTEMS; MONTE-CARLO; 2ND CANCER; EQUIVALENT; RADIATION; PHANTOMS; RISK; RADIOTHERAPY; EXPOSURES; DOSIMETRY AB Purpose: In scattering proton therapy, the beam incidence, i.e. the patient's orientation with respect to the beam axis, can significantly influence stray neutron doses although it is almost not documented in the literature. Methods: MCNPX calculations were carried out to estimate stray neutron doses to 25 healthy organs of a 10-year-old female phantom treated for an intracranial tumor. Two beam incidences were considered in this article, namely a superior (SUP) field and a right lateral (RLAT) field. For both fields, a parametric study was performed varying proton beam energy, modulation width, collimator aperture and thickness, compensator thickness and air gap size. Results: Using a standard beam line configuration for a craniopharyngioma treatment, neutron absorbed doses per therapeutic dose of 63 mu Gy Gy(-1) and 149 mu Gy Gy(-1) were found at the heart for the SUP and the RLAT fields, respectively. This dose discrepancy was explained by the different patient's orientations leading to changes in the distance between organs and the final collimator where external neutrons are mainly produced. Moreover, investigations on neutron spectral fluence at the heart showed that the number of neutrons was 2.5 times higher for the RLAT field compared against the SUP field. Finally, the influence of some irradiation parameters on neutron doses was found to be different according to the beam incidence. Conclusion: Beam incidence was thus found to induce large variations in stray neutron doses, proving that this parameter could be optimized to enhance the radiation protection of the patient. (C) 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved. C1 [Bonfrate, A.; Farah, J.; Sayah, R.; Clairand, I.] IRSN Inst Radioprotect & Surete Nucl, Serv Dosimetrie Externe, BP17, F-92262 Fontenay Aux Roses, France. [De Marzi, L.; Delacroix, S.] Inst Curie, Ctr Protontherapie Orsay CPO, Campus Univ Batiment 101, F-91898 Orsay, France. [Herault, J.] Ctr Antoine Lacassagne CAL Cyclotron Biomed, 227 Ave Lanterne, F-06200 Nice, France. [Lee, C.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Bolch, W. E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. RP Bonfrate, A; Farah, J (reprint author), IRSN Inst Radioprotect & Surete Nucl, Serv Dosimetrie Externe, BP17, F-92262 Fontenay Aux Roses, France. EM anthony.bonfrate@irsn.fr; jad.farah@irsn.fr NR 38 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1120-1797 EI 1724-191X J9 PHYS MEDICA JI Phys. Medica PD APR PY 2016 VL 32 IS 4 BP 590 EP 599 DI 10.1016/j.ejmp.2016.03.009 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DK7SK UT WOS:000375125800008 PM 27050170 ER PT J AU Bai, L Yang, HH Hu, Y Shukla, A Ha, NH Doran, A Faraji, F Goldberger, N Lee, MP Keane, T Hunter, KW AF Bai, Ling Yang, Howard H. Hu, Ying Shukla, Anjali Ngoc-Han Ha Doran, Anthony Faraji, Farhoud Goldberger, Natalie Lee, Maxwell P. Keane, Thomas Hunter, Kent W. TI An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes SO PLOS GENETICS LA English DT Article ID MAMMARY-TUMORS; PROGRESSION; EXPRESSION; METFORMIN; PROGNOSIS; IDENTIFICATION; ARCHITECTURE; SIGNATURE; MODIFIERS; SURVIVAL AB Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. C1 [Bai, Ling; Yang, Howard H.; Shukla, Anjali; Ngoc-Han Ha; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P.; Hunter, Kent W.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Hu, Ying] NCI, Ctr Bioinformat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Doran, Anthony; Keane, Thomas] Welcome Trust Sanger Ctr, Computat Genom Program, Cambridge, England. RP Hunter, KW (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov OI Doran, Anthony/0000-0003-3061-4102; Faraji, Farhoud/0000-0001-5078-813X FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 2 Z9 2 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD APR PY 2016 VL 12 IS 4 AR e1005989 DI 10.1371/journal.pgen.1005989 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA DK9DW UT WOS:000375231900035 PM 27074153 ER PT J AU Santiago, PB Assumpcao, TCF de Araujo, CN Bastos, IMD Neves, D da Silva, IG Charneau, S Queiroz, RML Raiol, T Oliveira, JVD de Sousa, MV Calvo, E Ribeiro, JMC Santana, JM AF Santiago, Paula Beatriz Assumpcao, Teresa C. F. de Araujo, Carla Nunes Dourado Bastos, Izabela Marques Neves, David da Silva, Ionizete Garcia Charneau, Sebastien Queiroz, Rayner Myr L. Raiol, Taina de Araujo Oliveira, Joao Victor de Sousa, Marcelo Valle Calvo, Eric Ribeiro, Jose M. C. Santana, Jaime M. TI A Deep Insight into the Sialome of Rhodnius neglectus, a Vector of Chagas Disease SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID SNAKE-VENOM METALLOPROTEINASE; PHEROMONE-BINDING-PROTEIN; BLOOD-FEEDING ARTHROPODS; KAZAL-TYPE INHIBITOR; TICK IXODES-RICINUS; PLATELET-AGGREGATION; THROMBIN INHIBITOR; TRIATOMA-INFESTANS; SERINE-PROTEASE; SALIVARY-GLANDS AB Background Triatomines are hematophagous insects that act as vectors of Chagas disease. Rhodnius neglectus is one of these kissing bugs found, contributing to the transmission of this American trypanosomiasis. The saliva of hematophagous arthropods contains bioactive molecules responsible for counteracting host haemostatic, inflammatory, and immune responses. Methods/Principal Findings Next generation sequencing and mass spectrometry-based protein identification were performed to investigate the content of triatomine R. neglectus saliva. We deposited 4,230 coding DNA sequences (CDS) in GenBank. A set of 636 CDS of proteins of putative secretory nature was extracted from the assembled reads, 73 of them confirmed by proteomic analysis. The sialome of R. neglectus was characterized and serine protease transcripts detected. The presence of ubiquitous protein families was revealed, including lipocalins, serine protease inhibitors, and antigen-5. Metalloproteases, disintegrins, and odorant binding protein families were less abundant. Conclusions/Significance The data presented improve our understanding of hematophagous arthropod sialomes, and aid in understanding hematophagy and the complex interplay among vectors and their vertebrate hosts. C1 [Santiago, Paula Beatriz; Assumpcao, Teresa C. F.; de Araujo, Carla Nunes; Dourado Bastos, Izabela Marques; Neves, David; Charneau, Sebastien; Queiroz, Rayner Myr L.; Raiol, Taina; de Sousa, Marcelo Valle; Santana, Jaime M.] Univ Brasilia, Dept Cell Biol, Brasilia, DF, Brazil. [Assumpcao, Teresa C. F.; Calvo, Eric; Ribeiro, Jose M. C.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, Rockville, MD USA. [de Araujo, Carla Nunes] Univ Brasilia, Ceilandia Fac, Brasilia, DF, Brazil. [da Silva, Ionizete Garcia] Univ Goias, Dept Parasitol, Jatai, Brazil. [Raiol, Taina] Inst Leonidas & Maria Deane Fiocruz Amazonia, Manaus, Amazonas, Brazil. [de Araujo Oliveira, Joao Victor] Univ Brasilia, Dept Comp Sci, Brasilia, DF, Brazil. RP Santana, JM (reprint author), Univ Brasilia, Dept Cell Biol, Brasilia, DF, Brazil. EM jsantana@unb.br OI Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Brazilian National Council for Scientific and Technological Development (CNPq) [476252/2012-1]; PROAP from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); CT-Infra from the Financiadora de Estudos e Projetos (Finep); Fundacao de Apoio a Pesquisa do Distrito Federal (FAPDF) [Pronex 476252/2012-5]; National Institute of Allergy and Infectious Diseases (NIAID); [Z01 AI000810-18] FX This work was supported by grants 476252/2012-1 (http://www.cnpq.br) from the Brazilian National Council for Scientific and Technological Development (CNPq), PROAP-2013 (http://www.capes.gov.br) from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), CT-Infra 2011 (http://www.finep.gov.br) from the Financiadora de Estudos e Projetos (Finep), and Pronex 476252/2012-5 (http://www.fap.df.gov.br) from the Fundacao de Apoio a Pesquisa do Distrito Federal (FAPDF) to JMS; and Z01 AI000810-18 (http://www.niaid.nih.gov/Pages/default.aspx) to Vector-Borne Diseases: Biology of Vector Host Relationship, from the National Institute of Allergy and Infectious Diseases (NIAID) to JMCR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 107 TC 2 Z9 2 U1 4 U2 7 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 APR PY 2016 VL 10 IS 4 AR e0004581 DI 10.1371/journal.pntd.0004581 PG 25 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DL1FC UT WOS:000375376700028 PM 27129103 ER PT J AU Schioler, KL Alifrangis, M Kitron, U Konradsen, F AF Schioler, Karin L. Alifrangis, Michael Kitron, Uriel Konradsen, Flemming TI Insecticidal Paints: A Realistic Approach to Vector Control? SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID DELTAMETHRIN; POPULATIONS; MORTALITY; NETS C1 [Schioler, Karin L.; Konradsen, Flemming] Univ Copenhagen, Dept Publ Hlth, Global Hlth Sect, Copenhagen, Denmark. [Alifrangis, Michael] Univ Copenhagen, Dept Immunol & Microbiol, Ctr Med Parasitol, Copenhagen, Denmark. [Alifrangis, Michael] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen, Denmark. [Kitron, Uriel] Emory Univ, Dept Environm Sci, Atlanta, GA 30322 USA. [Kitron, Uriel] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Schioler, KL (reprint author), Univ Copenhagen, Dept Publ Hlth, Global Hlth Sect, Copenhagen, Denmark. EM ksch@sund.ku.dk NR 14 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2016 VL 10 IS 4 AR e0004518 DI 10.1371/journal.pntd.0004518 PG 5 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DL1FC UT WOS:000375376700013 PM 27101473 ER PT J AU Treangen, TJ Schoeler, G Phillippy, AM Bergman, NH Turell, MJ AF Treangen, Todd J. Schoeler, George Phillippy, Adam M. Bergman, Nicholas H. Turell, Michael J. TI Identification and Genomic Analysis of a Novel Group C Orthobunyavirus Isolated from a Mosquito Captured near Iquitos, Peru SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID AEDES-ALBOPICTUS; DIPTERA-CULICIDAE; UNITED-STATES; SINGLE-CELL; VIRUS; SEQUENCES; ALIGNMENT; VALLEY; BUNYAVIRUSES; TRANSMISSION AB Group C orthobunyaviruses are single-stranded RNA viruses found in both South and North America. Until very recently, and despite their status as important vector-borne human pathogens, no Group C whole genome sequences containing all three segments were available in public databases. Here we report a Group C orthobunyavirus, named El Huayo virus, isolated from a pool of Culex portesi mosquitoes captured near Iquitos, Peru. Although initial metagenomic analysis yielded only a handful of reads belonging to the genus Orthobunyavirus, single contig assemblies were generated for L, M, and S segments totaling over 200,000 reads (similar to 0.5% of sample). Given the moderately high viremia in hamsters (>10(7) plaque-forming units/ml) and the propensity for Cx. portesi to feed on rodents, it is possible that El Huayo virus is maintained in nature in a Culex portesi/rodent cycle. El Huayo virus was found to be most similar to Peruvian Caraparu virus isolates and constitutes a novel sub-clade within Group C. C1 [Treangen, Todd J.; Phillippy, Adam M.; Bergman, Nicholas H.] Natl Biodef Anal & Countermeasures Ctr, Frederick, MD USA. [Schoeler, George] US Naval Med Res Unit 6, Dept Entomol, Callao, Peru. [Turell, Michael J.] US Army, Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD 21702 USA. [Schoeler, George] Bur Med & Surg, Falls Church, VA USA. [Phillippy, Adam M.] NHGRI, Genome Informat Sect, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. RP Treangen, TJ (reprint author), Natl Biodef Anal & Countermeasures Ctr, Frederick, MD USA. EM treangent@nbacc.net FU Department of Homeland Security (DHS) Science and Technology Directorate (ST) [HSHQDC-07-C-00020]; Federally Funded Research and Development Center FX This work was funded under Agreement No. HSHQDC-07-C-00020 awarded by the Department of Homeland Security (DHS) Science and Technology Directorate (S&T) for the management and operation of the National Biodefense Analysis and Countermeasures Center (NBACC), a Federally Funded Research and Development Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2016 VL 10 IS 4 AR e0004440 DI 10.1371/journal.pntd.0004440 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DL1FC UT WOS:000375376700007 PM 27074162 ER PT J AU Herman, SEM Wiestner, A AF Herman, Sarah E. M. Wiestner, Adrian TI Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade SO SEMINARS IN ONCOLOGY LA English DT Review DE Chronic lymphocytic leukemia; Co-culture systems; Mouse models ID B-CELL RECEPTOR; TYROSINE KINASE INHIBITOR; NURSE-LIKE CELLS; MARROW STROMAL CELLS; BONE-MARROW; TUMOR PROLIFERATION; IN-VITRO; HEMATOLOGICAL MALIGNANCIES; TARGETED THERAPIES; TRANSGENIC MOUSE AB In the last decade our understanding of chronic lymphocytic leukemia (CLL) biology and pathogenesis has increased substantially. These insights have led to the development of several new agents with novel mechanisms of action prompting a change in therapeutic approaches from chemotherapy-based treatments to targeted therapies. Multiple preclinical models for drug development in CLL are available; however, with the advent of these targeted agents, it is becoming clear that not all models and surrogate readouts of efficacy are appropriate for all drugs. In this review we discuss in vitro and in vivo preclinical models, with a particular focus on the benefits and possible pitfalls of different model systems in the evaluation of novel therapeutics for the treatment of CLL. Published by Elsevier Inc. C1 [Herman, Sarah E. M.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5256,10 Ctr Dr, Bethesda, MD 20892 USA. RP Herman, SEM (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5256,10 Ctr Dr, Bethesda, MD 20892 USA. EM hermanse@mail.nih.gov FU Intramural NIH HHS [Z01 HL002346-04, Z99 HL999999] NR 98 TC 2 Z9 2 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD APR PY 2016 VL 43 IS 2 BP 222 EP 232 DI 10.1053/j.seminoncol.2016.02.007 PG 11 WC Oncology SC Oncology GA DK8IP UT WOS:000375170700005 PM 27040700 ER PT J AU Fourie, NH Brown, JL Jolly, CJ Phillips-Conroy, JE Rogers, J Bernstein, RM AF Fourie, Nicolaas H. Brown, Janine L. Jolly, Clifford J. Phillips-Conroy, Jane E. Rogers, Jeffrey Bernstein, Robin M. TI Sources of variation in hair cortisol in wild and captive non-human primates SO ZOOLOGY LA English DT Article DE Cortisol; Hair cortisol analysis; Stress; Primates; Chronic stress ID CHIMPANZEES PAN-TROGLODYTES; ARCHAEOLOGICAL HAIR; SALIVARY CORTISOL; ANABOLIC-STEROIDS; BODY REGION; STRESS; BABOONS; AGE; CORTICOSTEROIDS; POPULATIONS AB Hair cortisol analysis is a potentially powerful tool for evaluating adrenal function and chronic stress. However, the technique has only recently been applied widely to studies of wildlife, including primates, and there are numerous practical and technical factors that should be considered to ensure good quality data and the validity of results and conclusions. Here we report on various intrinsic and extrinsic sources of variation in hair cortisol measurements in wild and captive primates. Hair samples from both wild and captive primates revealed that age and sex can affect hair cortisol concentrations; these effects need to be controlled for when making comparisons between individual animals or populations. Hair growth rates also showed considerable inter-specific variation among a number of primate species. We describe technical limitations of hair analyses and variation in cortisol concentrations as a function of asynchronous hair growth, anatomical site of collection, and the amount and numbers of hair/s used for cortisol extraction. We discuss these sources of variation and their implications for proper study design and interpretation of results. Published by Elsevier GmbH. C1 [Fourie, Nicolaas H.; Bernstein, Robin M.] George Washington Univ, Ctr Adv Study Hominid Paleobiol, Dept Anthropol, 2110 G St NW, Washington, DC 20052 USA. [Brown, Janine L.] Smithsonian Conservat Biol Inst, Ctr Species Survival, Front Royal, VA 22630 USA. [Jolly, Clifford J.] NYU, Dept Anthropol, Rufus D Smith Hall,25 Waverly Pl, New York, NY 10003 USA. [Phillips-Conroy, Jane E.] Washington Univ, Sch Med, Dept Anat & Neurobiol, 660 South Euclid Ave, St Louis, MO 63110 USA. [Phillips-Conroy, Jane E.] Washington Univ, Dept Anthropol, McMillan Hall,Room 112,One Brookings Dr, St Louis, MO 63130 USA. [Rogers, Jeffrey] Baylor Coll Med, Human Genome Sequencing Ctr, 1 Baylor Plaza, Houston, TX 77030 USA. [Rogers, Jeffrey] Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza, Houston, TX 77030 USA. [Bernstein, Robin M.] Univ Colorado, Dept Anthropol, 1350 Pleasant St, Boulder, CO 80309 USA. RP Fourie, NH (reprint author), NIH, Biobehav Branch, Div Intramural Res, Bethesda, MD 20892 USA. EM fourienh@mail.nih.gov OI Fourie, Nicolaas/0000-0002-5167-8570 FU San Diego Zoo; Center for the Advanced Study of Hominid Paleobiology at the George Washington University; Lewis Cotlow Grant FX We would like to thank Jean-Yves Robert and Dr. Benoit Quintard from the Museum de Besancon for arranging for the collection of Papio papio samples. We would like to thank Dr. Antoinette Kotze, Dr. Adrian Tordif and Mark Howitt from the National Zoological Gardens in South Africa for providing wild Papio ursinus samples from their collections and projects, and the Tanzanian National Parks Authority (TANAPA) for providing permission to conduct research in Mikumi National Park. We would like to thank the San Diego Zoo for its support in this research. We would also like to thank Dr. Rui Diogo for allowing the collection of hair samples in the course of his research. We would also like to thank Sarah Putman from the Smithsonian's Conservation Research Center for her support and advice. We would like to thank Michael Holland for his assistance in the laboratory. The research was supported with funds provided by the Center for the Advanced Study of Hominid Paleobiology at the George Washington University and through a Lewis Cotlow Grant. The opinions expressed herein and the interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official recommendation, interpretation, or policy of the National Institutes of Health or the United States Government. The research presented in this paper was conducted as part of Dr. Fourie's doctoral research at the George Washington University before joining the NINR. NR 57 TC 0 Z9 0 U1 10 U2 12 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0944-2006 J9 ZOOLOGY JI Zoology PD APR PY 2016 VL 119 IS 2 BP 119 EP 125 DI 10.1016/j.zool.2016.01.001 PG 7 WC Zoology SC Zoology GA DJ7AQ UT WOS:000374364700005 PM 26884274 ER PT J AU Hall, MD Simeonov, A Davis, MI AF Hall, Matthew D. Simeonov, Anton Davis, Mindy I. TI Avoiding Fluorescence Assay InterferenceThe Case for Diaphorase SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID SMALL-MOLECULE INHIBITORS; CHEMICAL LIBRARIES; RHODAMINE DIMERS; POTENT; DISCOVERY; IDH1 AB Fluorescence is utilized as the output for a range of assay formats used in high-throughput screening (HTS). Interference with these assays from the compounds in libraries utilized in HTS is a well-recognized phenomenon, particularly for assays relying on UV excitation such as for direct detection of the oxidoreductase cofactors NADH or NADPH. In this study, we discuss these interference challenges and highlight the specific case of the diaphorase/resazurin system that can be coupled to enzymes utilizing NADH or NADPH. We review the utilization of this assay system in the literature and argue that the diaphorase/resazurin system is underutilized in assay development. It is the authors' hope that this Perspective and the accompanying Technical Brief in this issue will stimulate interest in a robust and sensitive coupling system to avoid assay fluorescence interference. C1 [Hall, Matthew D.; Simeonov, Anton; Davis, Mindy I.] NIH, NCATS Chem Genom Ctr, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. RP Davis, MI (reprint author), NIH, NCATS Chem Genom Ctr, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM davismi2@mail.nih.gov FU NCATS Intramural Research Program of the National Institutes of Health FX The authors thank Kyle Brimacombe for designing Figure 2. This work was supported by the NCATS Intramural Research Program of the National Institutes of Health. The content of this publication does not necessarily reflect the views of policies of 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 31 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X EI 1557-8127 J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD APR PY 2016 VL 14 IS 3 SI SI BP 175 EP 179 DI 10.1089/adt.2016.707 PG 5 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA DK0ZM UT WOS:000374641700004 PM 27078679 ER PT J AU Davis, MI Shen, M Simeonov, A Hall, MD AF Davis, Mindy I. Shen, Min Simeonov, Anton Hall, Matthew D. TI Diaphorase Coupling Protocols for Red-Shifting Dehydrogenase Assays SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID CHEMICAL LIBRARIES; IDH1 AB Dehydrogenases are an important target for the development of cancer therapeutics. Dehydrogenases either produce or consume NAD(P)H, which is fluorescent but at a wavelength where many compounds found in chemical libraries are also fluorescent. By coupling dehydrogenases to diaphorase, which utilizes NAD(P)H to produce the fluorescent molecule resorufin from resazurin, the assay can be red-shifted into a spectral region that reduces interference from compound libraries. Dehydrogenases that produce NAD(P)H, such as isocitrate dehydrogenase 1 (IDH1), can be read in kinetic mode. Dehydrogenases that consume NAD(P)H, such as mutant IDH1 R132H, can be read in endpoint mode. Here, we report protocols for robust and miniaturized 1,536-well assays for WT IDH1 and IDH1 R132H coupled to diaphorase, and the counterassays used to further detect compound interference with the coupling reagents. This coupling technique is applicable to dehydrogenases that either produce or consume NAD(P)H, and the examples provided here can act as guidelines for the development of high-throughput screens against this enzyme class. C1 [Davis, Mindy I.; Shen, Min; Simeonov, Anton; Hall, Matthew D.] NIH, NCATS Chem Genom Ctr, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. RP Hall, MD (reprint author), NIH, NCATS Chem Genom Ctr, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM hallma@mail.nih.gov FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health FX This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. The content of this publication does not necessarily reflect the views of policies of 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 16 TC 2 Z9 2 U1 2 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X EI 1557-8127 J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD APR PY 2016 VL 14 IS 3 SI SI BP 207 EP 212 DI 10.1089/adt.2016.706 PG 6 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA DK0ZM UT WOS:000374641700007 PM 27078681 ER PT J AU Kim, C Lee, H Kang, H Shin, JJ Tak, H Kim, W Gorospe, M Lee, EK AF Kim, Chongtae Lee, Heejin Kang, Hoin Shin, Jung Jae Tak, Hyosun Kim, Wook Gorospe, Myriam Lee, Eun Kyung TI RNA-binding protein HuD reduces triglyceride production in pancreatic beta cells by enhancing the expression of insulin-induced gene 1 SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE RNA-binding protein; HuD; Triglyceride; INSIG1; SREBP1c ID STEROL REGULATORY ELEMENT; FATTY-ACIDS; PROTEASOMAL DEGRADATION; CHOLESTEROL HOMEOSTASIS; NEURITE OUTGROWTH; MESSENGER-RNAS; PC12 CELLS; SREBP-1C; INSIG-1; PATHWAY AB Although triglyceride (TG) accumulation in the pancreas leads to beta-cell dysfunction and raises the chance to develop metabolic disorders such as type 2 diabetes (T2DM), the molecular mechanisms whereby intracellular TG levels are regulated in pancreatic beta cells have not been fully elucidated. Here, we present evidence that the RNA-binding protein HuD regulates TG production in pancreatic beta cells. Mouse insulinoma beta TC6 cells stably expressing a small hairpin RNA targeting HuD (shHuD) (beta TC6-shHuD) contained higher TG levels compared to control cells. Moreover, downregulation of HuD resulted in a decrease in insulin-induced gene 1 (INSIG1) levels but not in the levels of sterol regulatory element-binding protein 1 (SREBP1c), a key transcription factor for lipid production. We identified Insig1 mRNA as a direct target of HuD by using ribonucleoprotein immunoprecipitation (RIP) and biotin pulldown analyses. By associating with the 3'-untranslated region (3'UTR) of Insig1 mRNA, HuD promoted INSIG1 translation; accordingly, HuD downregulation reduced while ectopic HuD expression increased INSIG1 levels. We further observed that HuD downregulation facilitated the nuclear localization of SREBP1c, thereby increasing the transcriptional activity of SREBP1c and the expression of target genes involved in lipogenesis; likewise, we observed lower INSIG1 levels in the pancreatic islets of HuD-null mice. Taken together, our results indicate that HuD functions as a novel repressor of lipid synthesis in pancreatic beta cells. (C) 2016 Elsevier B.V. All rights reserved. C1 [Kim, Chongtae; Lee, Heejin; Kang, Hoin; Tak, Hyosun; Lee, Eun Kyung] Catholic Univ Korea, Coll Med, Dept Biochem, 222 Banpodaero, Seoul 137701, South Korea. [Shin, Jung Jae; Kim, Wook] Ajou Univ, Dept Mol Sci & Technol, Suwon 443749, South Korea. [Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Lee, Eun Kyung] Catholic Univ Korea, Coll Med, Inst Aging & Metab Dis, Seoul 137701, South Korea. RP Lee, EK (reprint author), Catholic Univ Korea, Coll Med, Dept Biochem, 222 Banpodaero, Seoul 137701, South Korea. EM leeek@catholic.ac.kr OI Lee, Eun Kyung/0000-0003-4207-2080 FU National Research Foundation of Korea (NRF) - Korea government [2014R1A2A1A11053431, 2012R1A5A2047939, 2012M3A9D1054517, 2009-0093826]; NIA-IRP, NIH FX We appreciate Jun Gi Rho for the technical assistance. We also thank Professors Wado Akamatsu and Hideyuki Okano for providing pancreases of HuD null mice. This work is supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (2014R1A2A1A11053431, 2012R1A5A2047939 and 2012M3A9D1054517 for EKL and 2009-0093826 for WK). MG is supported by the NIA-IRP, NIH. NR 62 TC 3 Z9 3 U1 3 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD APR PY 2016 VL 1859 IS 4 BP 675 EP 685 DI 10.1016/j.bbagrm.2016.02.017 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DJ7CW UT WOS:000374370500013 PM 26945853 ER PT J AU Greenlee, H Molmenti, CLS Falci, L Ulmer, R Deming-Halverson, S DeRoo, LA Sandler, DP AF Greenlee, Heather Molmenti, Christine L. Sardo Falci, Laura Ulmer, Ross Deming-Halverson, Sandra DeRoo, Lisa A. Sandler, Dale P. TI High use of complementary and alternative medicine among a large cohort of women with a family history of breast cancer: the Sister Study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Complementary and alternative medicine; Breast cancer; Breast cancer risk; Gail model ID LIFE-STYLE BEHAVIORS; NATIONAL-SURVEY; OVARIAN-CANCER; HIGH-RISK; WHITE; INFORMATION; CHOICES; CAM AB Use of complementary and alternative medicine (CAM) is high among U.S. women, yet information is limited on use among women at increased breast cancer risk. We analyzed CAM use among women with a family history of breast cancer. CAM use was analyzed among women enrolled 2003-2009 in the Sister Study cohort. Eligible women were aged 35-74, U.S. or Puerto Rican residents, no personal history of breast cancer, and had a parts per thousand yen1 sister with breast cancer. Baseline data on CAM use in the past year were available for 49,734 women. Logistic regression models examined the association between CAM use and Gail Model breast cancer risk score. Results were compared to female participants in the 2007 National Health Interview Survey (n = 7965). Among Sister Study participants, there was high use of vitamin/mineral supplements (79 %), mind-body practices (41 %), manipulative/body-based practices (32 %), and botanicals (23 %). Overall use was higher than the U.S. female population. No association was observed between familial breast cancer risk and CAM use. Black women were more likely to use spirituality/meditation-based CAM modalities, while non-Hispanic white and Asian women were high users of dietary supplements. In a cohort of women with increased breast cancer risk due to family history, CAM use is higher than women in the general U.S. population and is associated with race/ethnicity. Use was not associated with breast cancer risk. Given the high prevalence of CAM use among women at risk for breast caner, research on the effectiveness of CAM use for disease prevention is needed. C1 [Greenlee, Heather; Molmenti, Christine L. Sardo; Falci, Laura] Columbia Univ, Mailman Sch Publ Hlth, 722 W 168th St, New York, NY 10032 USA. [Greenlee, Heather; Molmenti, Christine L. Sardo] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Ulmer, Ross] WESTAT Corp, Durham, NC USA. [Deming-Halverson, Sandra] Social & Sci Syst Inc, Durham, NC USA. [Deming-Halverson, Sandra] Vanderbilt Univ, Sch Med, Div Epidemiol, Nashville, TN 37212 USA. [DeRoo, Lisa A.; Sandler, Dale P.] Natl Inst Environm Hlth Sci, Res Triangle Pk, Durham, NC USA. [DeRoo, Lisa A.] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. RP Greenlee, H (reprint author), Columbia Univ, Mailman Sch Publ Hlth, 722 W 168th St, New York, NY 10032 USA.; Greenlee, H (reprint author), Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY USA. EM hg2120@columbia.edu OI Sandler, Dale/0000-0002-6776-0018 FU National Cancer Institute at the National Institutes of Health [K23CA141052, T32CA009529-25]; Intramural Research Program of the NIH, National Institute of Environmental Health Science [Z1A ES044005] FX Funding was provided by the National Cancer Institute at the National Institutes of Health (Grants K23CA141052 to H.G. and T32CA009529-25 to C.S.M.) and the Intramural Research Program of the NIH, National Institute of Environmental Health Science (Z1A ES044005). NR 32 TC 0 Z9 0 U1 8 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD APR PY 2016 VL 156 IS 3 BP 527 EP 538 DI 10.1007/s10549-016-3740-0 PG 12 WC Oncology SC Oncology GA DK1IU UT WOS:000374666500014 PM 27017506 ER PT J AU Yang, SX Polley, E Lipkowitz, S AF Yang, Sherry X. Polley, Eric Lipkowitz, Stanley TI New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer SO CANCER TREATMENT REVIEWS LA English DT Review DE Breast cancer; Chemotherapy; HER2; Paclitaxel; pAKT; PIK3CA mutations ID FACTOR RECEPTOR 2; DOXORUBICIN PLUS CYCLOPHOSPHAMIDE; PATHOLOGICAL COMPLETE RESPONSE; PIK3CA MUTATIONS; ESTROGEN-RECEPTOR; ADJUVANT CHEMOTHERAPY; PTEN LOSS; PHOSPHORYLATED AKT; PHASE-III; TRASTUZUMAB RESISTANCE AB PI3K/AKT signaling pathway plays an important role in tumorigenesis and regulates critical cellular functions including survival, proliferation and metabolism. PIK3CA mutations and AKT activation by phosphorylation (pAKT) are often detected in many cancers and especially at high frequencies in breast cancer. Mounting data suggest that PIK3CA mutations or pAKT are mostly associated with better or insignificant outcomes in estrogen receptor-positive (ER+) early stage breast cancer and tend to be with worse prognosis in ER disease. pAKT expression has been identified to predict paclitaxel chemotherapy benefit in node-positive breast cancer. Preclinical and neoadjuvant trial data suggest that PIK3CA alterations confer resistance to HER2-targeted therapy and are associated with lower pathological complete response (pCR) rate in HER2-positive breast cancer. However, recent results from randomized clinical trials of adjuvant and metastatic settings show that patients with mutant and wildtype PIK3CA tumors derived similar benefit from anti-HER2 therapy. This article, with our new insights, aims to decipher the mixed data and discusses the influence of the potential confounding factors in the assessments. We also share our views for validation of PI3K/AKT alterations in relation to clinical outcome in the context of specific breast cancer subtypes and treatment modalities towards further advance of the precision medicine for breast cancer treatment. Published by Elsevier Ltd. C1 [Yang, Sherry X.] NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Polley, Eric] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Lipkowitz, Stanley] NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Polley, Eric] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. RP Yang, SX (reprint author), Bldg 37-Rm 1048,37 Convent Dr, Bethesda, MD 20892 USA. EM Sherry.Yang@nih.gov FU Division of Cancer Treatment and Diagnosis; Center for Cancer Research of the National cancer Institute, National Institutes of Health, USA FX Supported in part by the Division of Cancer Treatment and Diagnosis and the Center for Cancer Research of the National cancer Institute, National Institutes of Health, USA. NR 104 TC 18 Z9 19 U1 4 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0305-7372 EI 1532-1967 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD APR PY 2016 VL 45 BP 87 EP 96 DI 10.1016/j.ctrv.2016.03.004 PG 10 WC Oncology SC Oncology GA DK0OG UT WOS:000374611500011 PM 26995633 ER PT J AU White, AJ Bradshaw, PT Herring, AH Teitelbaum, SL Beyea, J Stellman, SD Steck, SE Mordukhovich, I Eng, SM Engel, LS Conway, K Hatch, M Neugut, AI Santella, RM Gammon, MD AF White, Alexandra J. Bradshaw, Patrick T. Herring, Amy H. Teitelbaum, Susan L. Beyea, Jan Stellman, Steven D. Steck, Susan E. Mordukhovich, Irina Eng, Sybil M. Engel, Lawrence S. Conway, Kathleen Hatch, Maureen Neugut, Alfred I. Santella, Regina M. Gammon, Marilie D. TI Exposure to multiple sources of polycyclic aromatic hydrocarbons and breast cancer incidence SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Breast cancer; Polycyclic aromatic hydrocarbons; Smoking; Environmental tobacco smoke; Grilled meat; Indoor air; Outdoor air ID INDOOR AIR-POLLUTION; DIOXIN EXPOSURE; TOBACCO-SMOKE; MISSING-DATA; RED MEAT; RISK; ASSOCIATION; PROJECT; COHORT; WOMEN AB Background: Despite studies having consistently linked exposure to single-source polycyclic aromatic hydrocarbons (PAHs) to breast cancer, it is unclear whether single sources or specific groups of PAH sources should be targeted for breast cancer risk reduction. Objectives: This study considers the impact on breast cancer incidence from multiple PAH exposure sources in a single model, which better reflects exposure to these complex mixtures. Methods: In a population-based case-control study conducted on Long Island, New York (N =1508 breast cancer cases/1556 controls), a Bayesian hierarchical regression approach was used to estimate adjusted posterior means and credible intervals (CrI) for the adjusted odds ratios (ORs) for PAH exposure sources, considered singly and as groups: active smoking; residential environmental tobacco smoke (ETS); indoor and outdoor air pollution; and grilled/smoked meat intake. Results: Most women were exposed to PAHs from multiple sources, and the most commonincluded active/passive smoking and grilled/smoked food intake. In multiple-PAH source models, breast cancer incidence was associated with residential ETS from a spouse (OR =1.20, 95%CrI = 1.03,1.40) and synthetic firelog burning (OR = 1.29, 95%CrI = 1.06, 1.57); these estimates are similar, but slightly attenuated, to those from single-source models. Additionally when we considered PAH exposure groups, the most pronounced significant associations included total indoor sources (active smoking, ETS from spouse, grilled/smoked meat intake, stove/fireplace use, OR = 1.45, 95%CrI = 1.02, 2.04). Conclusions: Groups of PAH sources, particularly indoor sources, were associated with a 30-50% increase in breast cancer incidence. PAH exposure is ubiquitous and a potentially modifiable breast cancer risk factor. (C) 2016 Elsevier Ltd. All rights reserved. C1 [White, Alexandra J.; Mordukhovich, Irina; Engel, Lawrence S.; Conway, Kathleen; Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, CB 7435,McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. [Bradshaw, Patrick T.] Univ N Carolina, Dept Nutr, CB 7435,McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. [Herring, Amy H.] Univ N Carolina, Dept Biostat, CB 7435,McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. [Teitelbaum, Susan L.] Ichan Sch Med Mt Sinai, Dept Prevent Med, New York, NY USA. [Beyea, Jan] Consulting Publ Interest CIPI, Lambertville, NJ USA. [Stellman, Steven D.; Eng, Sybil M.; Neugut, Alfred I.] Columbia Univ, Dept Epidemiol, New York, NY 10027 USA. [Neugut, Alfred I.] Columbia Univ, Dept Med, New York, NY 10027 USA. [Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10027 USA. [Steck, Susan E.] Univ S Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Hatch, Maureen] NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP White, AJ (reprint author), Univ N Carolina, Dept Epidemiol, CB 7435,McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. EM whitea@unc.edu OI Beyea, Jan/0000-0002-0547-880X; Engel, Lawrence/0000-0001-9268-4830 FU National Institute of Health [CA/ES66572, ES07018, ES10126, ES019459, CA094061, CA57726] FX Supported in part by National Institute of Health grants: CA/ES66572, ES07018, ES10126, ES019459, CA094061 and CA57726. NR 62 TC 7 Z9 7 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD APR-MAY PY 2016 VL 89-90 BP 185 EP 192 DI 10.1016/j.envint.2016.02.009 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA DK0LI UT WOS:000374603900021 PM 26878284 ER PT J AU Christiansen, K Dillingham, CM Wright, NF Saunders, RC Vann, SD Aggleton, JP AF Christiansen, Kat Dillingham, Christopher M. Wright, Nicholas F. Saunders, Richard C. Vann, Seralynne D. Aggleton, John P. TI Complementary subicular pathways to the anterior thalamic nuclei and mammillary bodies in the rat and macaque monkey brain SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE anatomy; fornix; hippocampus; memory; subiculum ID MAMILLARY-BODY LESIONS; HIPPOCAMPAL-FORMATION; ENTORHINAL CORTEX; RHESUS-MONKEY; HORSERADISH-PEROXIDASE; TEMPORAL-LOBE; LAMINAR ORGANIZATION; MACACA-FASCICULARIS; CEREBRAL-CORTEX; TOPOGRAPHIC ORGANIZATION AB The origins of the hippocampal (subicular) projections to the anterior thalamic nuclei and mammillary bodies were compared in rats and macaque monkeys using retrograde tracers. These projections form core components of the Papez circuit, which is vital for normal memory. The study revealed a complex pattern of subicular efferents, consistent with the presence of different, parallel information streams, whose segregation appears more marked in the rat brain. In both species, the cells projecting to the mammillary bodies and anterior thalamic nuclei showed laminar separation but also differed along other hippocampal axes. In the rat, these diencephalic inputs showed complementary topographies in the proximal-distal (columnar) plane, consistent with differential involvement in object-based (proximal subiculum) and context-based (distal subiculum) information. The medial mammillary inputs, which arose along the anterior-posterior extent of the rat subiculum, favoured the central subiculum (septal hippocampus) and the more proximal subiculum (temporal hippocampus). In contrast, anterior thalamic inputs were largely confined to the dorsal (i.e. septal and intermediate) subiculum, where projections to the anteromedial nucleus favoured the proximal subiculum while those to the anteroventral nucleus predominantly arose in the distal subiculum. In the macaque, the corresponding diencephalic inputs were again distinguished by anterior-posterior topographies, as subicular inputs to the medial mammillary bodies predominantly arose from the posterior hippocampus while subicular inputs to the anteromedial thalamic nucleus predominantly arose from the anterior hippocampus. Unlike the rat, there was no clear evidence of proximal-distal separation as all of these medial diencephalic projections preferentially arose from the more distal subiculum. C1 [Christiansen, Kat; Dillingham, Christopher M.; Wright, Nicholas F.; Vann, Seralynne D.; Aggleton, John P.] Cardiff Univ, Sch Psychol, Tower Bldg 70,Pk Pl, Cardiff CF10 3AT, S Glam, Wales. [Saunders, Richard C.] NIMH, Neuropsychol Lab, Bldg 9, Bethesda, MD 20892 USA. RP Aggleton, JP (reprint author), Cardiff Univ, Sch Psychol, Tower Bldg 70,Pk Pl, Cardiff CF10 3AT, S Glam, Wales. EM aggleton@cf.ac.uk OI Aggleton, John/0000-0002-5573-1308 FU Wellcome Trust [WT103722/Z/14/Z, WT090954AIA] FX This work was supported by the Wellcome Trust (grant numbers WT103722/Z/14/Z and WT090954AIA). NR 136 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2016 VL 43 IS 8 BP 1044 EP 1061 DI 10.1111/ejn.13208 PG 18 WC Neurosciences SC Neurosciences & Neurology GA DK1BA UT WOS:000374645700006 PM 26855336 ER PT J AU Panyakaew, P Cho, HJ Srivanitchapoom, P Popa, T Wu, TX Hallett, M AF Panyakaew, Pattamon Cho, Hyun Joo Srivanitchapoom, Prachaya Popa, Traian Wu, Tianxia Hallett, Mark TI Cerebellar brain inhibition in the target and surround muscles during voluntary tonic activation SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE cerebellar brain inhibition (CBI); cerebellum; surround muscles; TMS; tonic activation ID TRANSCRANIAL MAGNETIC STIMULATION; FOCAL HAND DYSTONIA; HUMAN MOTOR SYSTEM; BASAL GANGLIA; CORTEX; MOVEMENT; HUMANS; ROLES AB Motor surround inhibition is the neural mechanism that selectively favours the contraction of target muscles and inhibits nearby muscles to prevent unwanted movements. This inhibition was previously reported at the onset of a movement, but not during a tonic contraction. Cerebellar brain inhibition (CBI) is reduced in active muscles during tonic activation; however, it has not been studied in the surround muscles. CBI was evaluated in the first dorsal interosseus (FDI) muscle as the target muscle, and the abductor digiti minimi, flexor carpi radialis and extensor carpi radialis muscles as surround muscles, during rest and tonic activation of the FDI muscle in 21 subjects. Cerebellar stimulation was performed under magnetic resonance imaging-guided neuronavigation targeting lobule VIII of the cerebellar hemisphere. Stimulus intensities for cerebellar stimulation were based on the resting motor cortex threshold (RMT) and adjusted for the depth difference between the cerebellar and motor cortices. We used 90-120% of the adjusted RMT as the conditioning stimulus intensity during rest. The intensity that generated the best CBI at rest in the FDI muscle was selected for use during tonic activation. During selective tonic activation of the FDI muscle, CBI was significantly reduced only for the FDI muscle, and not for the surround muscles. Unconditioned motor evoked potential sizes were increased in all muscles during FDI muscle tonic activation as compared with rest, despite background electromyography activity increasing only for the FDI muscle. Our study suggests that the cerebellum may play an important role in selective tonic finger movement by reducing its inhibition in the motor cortex only for the relevant agonist muscle. C1 [Panyakaew, Pattamon; Cho, Hyun Joo; Srivanitchapoom, Prachaya; Popa, Traian; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Panyakaew, Pattamon] Chulalongkorn Univ, Fac Med, Dept Med, Chulalongkorn Ctr Excellence Parkinson Dis & Rela, Bangkok, Thailand. [Panyakaew, Pattamon] King Chulalongkorn Mem Hosp, Thai Red Cross Soc, Bangkok, Thailand. [Srivanitchapoom, Prachaya] Mahidol Univ, Siriraj Hosp, Fac Med, Div Neurol,Dept Med, Bangkok 10700, Thailand. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), 10 Ctr Dr MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Popa, Traian/B-7691-2016 OI Popa, Traian/0000-0003-1160-4830 FU NINDS, NIH Intramural Program FX This research was supported by the NINDS, NIH Intramural Program. NR 32 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2016 VL 43 IS 8 BP 1075 EP 1081 DI 10.1111/ejn.13211 PG 7 WC Neurosciences SC Neurosciences & Neurology GA DK1BA UT WOS:000374645700008 PM 26900871 ER PT J AU Chen, YW Sagar, V Len, HS Peterson, K Fan, JG Mishra, S McMurtry, J Wilmarth, PA David, LL Wistow, G AF Chen, Yingwei Sagar, Vatsala Len, Hoay-Shuen Peterson, Katherine Fan, Jianguo Mishra, Sanghamitra McMurtry, John Wilmarth, Phillip A. David, Larry L. Wistow, Graeme TI gamma-Crystallins of the chicken lens: remnants of an ancient vertebrate gene family in birds SO FEBS JOURNAL LA English DT Article DE crystallin; evolution; eye; promoter; protein folding; proteomics ID SEQUENCE TAG ANALYSIS; S-CRYSTALLIN; EYE LENS; NEIBANK PROJECT; SEARCH TOOL; EXPRESSION; PROTEIN; EVOLUTION; RECRUITMENT; ENZYME AB gamma-Crystallins, abundant proteins of vertebrate lenses, were thought to be absent from birds. However, bird genomes contain well-conserved genes for S- and N-crystallins. Although expressed sequence tag analysis of chicken eye found no transcripts for these genes, RT-PCR detected spliced transcripts for both genes in chicken lens, with lower levels in cornea and retina/retinal pigment epithelium. The level of mRNA for S in chicken lens was relatively very low even though the chicken crygs gene promoter had lens-preferred activity similar to that of mouse. Chicken S was detected by a peptide antibody in lens, but not in other ocular tissues. Low levels of S and N proteins were detected in chicken lens by shotgun mass spectroscopy. Water-soluble and water-insoluble lens fractions were analyzed and 1934 proteins (< 1% false discovery rate) were detected, increasing the known chicken lens proteome 30-fold. Although chicken S is well conserved in protein sequence, it has one notable difference in leucine 16, replacing a surface glutamine conserved in other -crystallins, possibly affecting solubility. However, L16 and engineered Q16 versions were both highly soluble and had indistinguishable circular dichroism, tryptophan fluorescence and heat stability (melting temperature T-m similar to 65 degrees C) profiles. L16 has been present in birds for over 100 million years and may have been adopted for a specific protein interaction in the bird lens. However, evolution has clearly reduced or eliminated expression of ancestral -crystallins in bird lenses. The conservation of genes for S- and N-crystallins suggests they may have been preserved for reasons unrelated to the bulk properties of the lens. C1 [Chen, Yingwei; Sagar, Vatsala; Len, Hoay-Shuen; Peterson, Katherine; Fan, Jianguo; Mishra, Sanghamitra; Wistow, Graeme] NEI, Sect Mol Struct & Funct Genom, NIH, Bg 6,Rm 106, Bethesda, MD 20892 USA. [McMurtry, John] ARS, USDA, Southern Plains Area, East Coll Stn, Dallas, TX USA. [Wilmarth, Phillip A.; David, Larry L.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Sch Med, Portland, OR 97201 USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct Genom, NIH, Bg 6,Rm 106, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov FU NEI Intramural Program; NIH [EY010572, EY007755] FX This work was performed with the support of the NEI Intramural Program and NIH grants EY010572 and EY007755. Some experiments were performed at the NHLBI Biophysics Core. NR 58 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD APR PY 2016 VL 283 IS 8 BP 1516 EP 1530 DI 10.1111/febs.13689 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK1NV UT WOS:000374680500012 PM 26913478 ER PT J AU Barker, DJ Root, DH Zhang, SL Morales, M AF Barker, David J. Root, David H. Zhang, Shiliang Morales, Marisela TI Multiplexed neurochemical signaling by neurons of the ventral tegmental area SO JOURNAL OF CHEMICAL NEUROANATOMY LA English DT Review DE Reward; Addiction; Depression; Aversion; Co-transmission; Dopamine; Glutamate; GABA ID VESICULAR GLUTAMATE TRANSPORTER; MIDBRAIN DOPAMINE NEURONS; MEDIOLATERAL FUNCTIONAL DICHOTOMY; NUCLEUS-ACCUMBENS DOPAMINE; SUBSTANTIA-NIGRA COMPACTA; GABA-CONTAINING NEURONS; PHASIC FIRING PATTERNS; LATERAL HABENULA; GABAERGIC PHENOTYPE; AVERSIVE STIMULI AB The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in 'multiplexed' neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression. Published by Elsevier B.V. C1 [Barker, David J.; Root, David H.; Zhang, Shiliang; Morales, Marisela] NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, 251 Bayview Blvd Suite 200, Baltimore, MD 21224 USA. RP Morales, M (reprint author), NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, 251 Bayview Blvd Suite 200, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov OI Root, David/0000-0002-1927-2175 FU Intramural Research Program of the National Institute on Drug Abuse, US National Institutes of Health (IRP/NIDA/NIH) FX The Intramural Research Program of the National Institute on Drug Abuse, US National Institutes of Health (IRP/NIDA/NIH) supported this work. NR 170 TC 5 Z9 5 U1 5 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0891-0618 EI 1873-6300 J9 J CHEM NEUROANAT JI J. Chem. Neuroanat. PD APR PY 2016 VL 73 SI SI BP 33 EP 42 DI 10.1016/j.jchemneu.2015.12.016 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DK0ST UT WOS:000374623200005 PM 26763116 ER PT J AU Piccart-Gebhart, M Holmes, E Baselga, J de Azambuja, E Dueck, AC Viale, G Zujewski, JA Goldhirsch, A Armour, A Pritchard, KI McCullough, AE Dolci, S McFadden, E Holmes, AP Liu, TH Eidtmann, H Dinh, P Di Cosimo, S Harbeck, N Tjulandin, S Im, YH Huang, CS Dieras, V Hillman, DW Wolff, AC Jackisch, C Lang, I Untch, M Smith, I Boyle, F Xu, BH Gomez, H Suter, T Gelber, RD Perez, EA AF Piccart-Gebhart, Martine Holmes, Eileen Baselga, Jose de Azambuja, Evandro Dueck, Amylou C. Viale, Giuseppe Zujewski, Jo Anne Goldhirsch, Aron Armour, Alison Pritchard, Kathleen I. McCullough, Ann E. Dolci, Stella McFadden, Eleanor Holmes, Andrew P. Liu Tonghua Eidtmann, Holger Phuong Dinh Di Cosimo, Serena Harbeck, Nadia Tjulandin, Sergei Im, Young-Hyuck Huang, Chiun-Sheng Dieras, Veronique Hillman, David W. Wolff, Antonio C. Jackisch, Christian Lang, Istvan Untch, Michael Smith, Ian Boyle, Frances Xu, Binghe Gomez, Henry Suter, Thomas Gelber, Richard D. Perez, Edith A. TI Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID OPEN-LABEL; PLUS CAPECITABINE; CHEMOTHERAPY; THERAPY; SURVIVAL; EFFICACY; SAFETY; COMBINATION; INHIBITOR; DOCETAXEL AB Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T. L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P <= .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T. L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care. C1 [de Azambuja, Evandro] Inst Jules Bordet, Blvd Waterloo 121, B-1000 Brussels, Belgium. [Piccart-Gebhart, Martine] Univ Libre Bruxelles, Brussels, Belgium. [Holmes, Eileen; McFadden, Eleanor; Holmes, Andrew P.] Frontier Sci Scotland, Kincraig, Kingussie, Scotland. [Baselga, Jose] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [de Azambuja, Evandro; Dolci, Stella] Breast European Adjuvant Study Team, Brussels, Belgium. [Dueck, Amylou C.; McCullough, Ann E.] Mayo Clin, Scottsdale, AZ USA. [Viale, Giuseppe] Univ Milan, Milan, Italy. [Viale, Giuseppe; Goldhirsch, Aron] Ist Europeo Oncol, Milan, Italy. [Zujewski, Jo Anne] NCI, Bethesda, MD 20892 USA. [Goldhirsch, Aron] Osped Reg Lugano, Viganello Lugano, Switzerland. [Armour, Alison] GlaxoSmithKline, Collegeville, PA USA. [Pritchard, Kathleen I.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Pritchard, Kathleen I.] Univ Toronto, Toronto, ON, Canada. [Liu Tonghua] Beijing Union Med Coll Hosp, Beijing, Peoples R China. [Liu Tonghua; Xu, Binghe] China Acad Chinese Med Sci, Beijing, Peoples R China. [Eidtmann, Holger] Univ Hosp Kiel, Kiel, Germany. [Phuong Dinh] Breast Int Grp, Brussels, Belgium. [Di Cosimo, Serena] Ist Nazl Tumori, Via Venezian 1, I-20133 Milan, Italy. [Di Cosimo, Serena] SOLTI Breast Canc Res Grp, Barcelona, Spain. [Harbeck, Nadia] Frauenklin Univ Munchen, Munich, Germany. [Tjulandin, Sergei] RAMS, Blokhin Russian Canc Res Ctr, Moscow, Russia. [Im, Young-Hyuck] Korean Canc Study Grp, Seoul, South Korea. [Im, Young-Hyuck] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Huang, Chiun-Sheng] Natl Taiwan Univ Hosp, Taipei, Taiwan. [Dieras, Veronique] Inst Curie, Paris, France. [Hillman, David W.] Mayo Clin, Rochester, MN USA. [Wolff, Antonio C.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Jackisch, Christian] Klinikum Offenbach, Offenbach, Germany. [Lang, Istvan] Natl Inst Oncol, Budapest, Hungary. [Untch, Michael] Helios Klinikum Berlin Buch, Berlin, Germany. [Smith, Ian] Royal Marsden Hosp NHS Trust Surrey, Sutton, Surrey, England. [Boyle, Frances] Univ Sydney, Mater Hosp, Patricia Ritchie Ctr Canc Care & Res, Sydney, NSW, Australia. [Gomez, Henry] Inst Nacl Enfermedades Neoplas, Lima, Peru. [Suter, Thomas] Univ Hosp Bern, CH-3010 Bern, Switzerland. [Gelber, Richard D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. RP Piccart-Gebhart, M (reprint author), Inst Jules Bordet, Blvd Waterloo 121, B-1000 Brussels, Belgium. EM martine.piccart@bordet.be RI Serena, Di Cosimo/E-9418-2017 OI Serena, Di Cosimo/0000-0002-4666-8052 FU GlaxoSmithKline; National Cancer Institute of the National Institutes of Health [U10CA180821, U10CA180882, CA025224] FX Supported by GlaxoSmithKline and the National Cancer Institute of the National Institutes of Health under Grant No. U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology and CA025224 to the legacy North Central Cancer Treatment Group. NR 33 TC 29 Z9 29 U1 0 U2 10 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 APR 1 PY 2016 VL 34 IS 10 BP 1034 EP + DI 10.1200/JCO.2015.62.1797 PG 25 WC Oncology SC Oncology GA DJ6PA UT WOS:000374334200008 PM 26598744 ER PT J AU Brudno, JN Somerville, RPT Shi, V Rose, JJ Halverson, DC Fowler, DH Gea-Banacloche, JC Pavletic, SZ Hickstein, DD Lu, TYL Feldman, SA Iwamoto, AT Kurlander, R Maric, I Goy, A Hansen, BG Wilder, JS Blacklock-Schuver, B Hakim, FT Rosenberg, SA Gress, RE Kochenderfer, JN AF Brudno, Jennifer N. Somerville, Robert P. T. Shi, Victoria Rose, Jeremy J. Halverson, David C. Fowler, Daniel H. Gea-Banacloche, Juan C. Pavletic, Steven Z. Hickstein, Dennis D. Lu, Tangying L. Feldman, Steven A. Iwamoto, Alexander T. Kurlander, Roger Maric, Irina Goy, Andre Hansen, Brenna G. Wilder, Jennifer S. Blacklock-Schuver, Bazetta Hakim, Frances T. Rosenberg, Steven A. Gress, Ronald E. Kochenderfer, James N. TI Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LEUKEMIA; LYMPHOMA; LYMPHOCYTES; DIAGNOSIS; RELAPSE; CANCER; CD19; MANAGEMENT; RESPONSES; CRITERIA AB Purpose Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues. Methods We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient's alloHSCT donor. Results Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease-negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels. Conclusion Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT. C1 [Brudno, Jennifer N.; Somerville, Robert P. T.; Shi, Victoria; Rose, Jeremy J.; Halverson, David C.; Fowler, Daniel H.; Gea-Banacloche, Juan C.; Pavletic, Steven Z.; Hickstein, Dennis D.; Lu, Tangying L.; Feldman, Steven A.; Iwamoto, Alexander T.; Hansen, Brenna G.; Blacklock-Schuver, Bazetta; Hakim, Frances T.; Rosenberg, Steven A.; Gress, Ronald E.; Kochenderfer, James N.] NCI, Bethesda, MD 20892 USA. [Kurlander, Roger; Maric, Irina] NIH, Bldg 10, Bethesda, MD 20892 USA. [Wilder, Jennifer S.] Frederick Natl Lab Canc Res, Frederick, MD USA. [Goy, Andre] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. RP Kochenderfer, JN (reprint author), NCI, NIH, Bldg 10,Room 3-3330, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov FU Center for Cancer Research, National Cancer Institute; National Cancer Institute [HHSN261200800001E] FX Supported by intramural funding of the Center for Cancer Research, National Cancer Institute. This project has been funded in part with federal funds from the National Cancer Institute, under contract HHSN261200800001E. NR 42 TC 43 Z9 46 U1 6 U2 14 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 APR 1 PY 2016 VL 34 IS 10 BP 1112 EP + DI 10.1200/JCO.2015.64.5929 PG 12 WC Oncology SC Oncology GA DJ6PA UT WOS:000374334200018 PM 26811520 ER PT J AU Harris, LN Ismaila, N McShane, LM Andre, F Collyar, DE Gonzalez-Angulo, AM Hammond, EH Kuderer, NM Liu, MC Mennel, RG Van Poznak, C Bast, RC Hayes, DF AF Harris, Lyndsay N. Ismaila, Nofisat McShane, Lisa M. Andre, Fabrice Collyar, Deborah E. Gonzalez-Angulo, Ana M. Hammond, Elizabeth H. Kuderer, Nicole M. Liu, Minetta C. Mennel, Robert G. Van Poznak, Catherine Bast, Robert C. Hayes, Daniel F. TI Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LATE-DISTANT RECURRENCE; 70-GENE PROGNOSIS-SIGNATURE; TOPOISOMERASE-II-ALPHA; TUMOR-INFILTRATING LYMPHOCYTES; ESTROGEN-RECEPTOR; RANDOMIZED-TRIALS; PREDICTIVE-VALUE; PAM50 RISK; POSTMENOPAUSAL WOMEN; ENDOCRINE THERAPY AB Purpose To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. Methods A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert panel members used informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 50 relevant studies. One randomized clinical trial and 18 prospective-retrospective studies were found to have evaluated the clinical utility, as defined by the guideline, of specific biomarkers for guiding decisions on the need for adjuvant systemic therapy. No studies that met guideline criteria for clinical utility were found to guide choice of specific treatments or regimens. Recommendations In addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer. No biomarker except for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was found to guide choices of specific treatment regimens. Treatment decisions should also consider disease stage, comorbidities, and patient preferences. C1 [Harris, Lyndsay N.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Ismaila, Nofisat] Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. [McShane, Lisa M.] NCI, Bethesda, MD 20892 USA. [Andre, Fabrice] Inst Gustave Roussy, Paris, France. [Collyar, Deborah E.] Patient Advocates Res, Mitrowski, CA USA. [Hammond, Elizabeth H.] Univ Utah, Salt Lake City, UT USA. [Hammond, Elizabeth H.] Intermt Hlth Care, Salt Lake City, UT USA. [Gonzalez-Angulo, Ana M.; Bast, Robert C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Mennel, Robert G.] Baylor Univ, Med Ctr, Dallas, TX USA. [Mennel, Robert G.] Texas Oncol PA, Dallas, TX USA. [Kuderer, Nicole M.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Liu, Minetta C.] Mayo Clin, Coll Med, Rochester, MN USA. [Van Poznak, Catherine; Hayes, Daniel F.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Harris, LN (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org RI Bast, Robert/E-6585-2011 OI Bast, Robert/0000-0003-4621-8462 FU NCI NIH HHS [P50 CA058223] NR 83 TC 49 Z9 50 U1 11 U2 17 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 APR 1 PY 2016 VL 34 IS 10 BP 1134 EP + DI 10.1200/JCO.2015.65.2289 PG 19 WC Oncology SC Oncology GA DJ6PA UT WOS:000374334200021 PM 26858339 ER PT J AU Qiang, GF Kong, HW Fang, DF McCann, M Yang, XY Du, GH Bluher, M Zhu, JF Liew, CW AF Qiang, Guifen Kong, Hyerim Whang Fang, Difeng McCann, Maximilian Yang, Xiuying Du, Guanhua Bluher, Matthias Zhu, Jinfang Liew, Chong Wee TI The obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation SO NATURE COMMUNICATIONS LA English DT Article ID ADIPOSE-TISSUE; INSULIN-RESISTANCE; ADIPOCYTE DIFFERENTIATION; WAIST CIRCUMFERENCE; MOUSE MODEL; BODY-FAT; EXPRESSION; DEPOTS; GATA; THERMOGENESIS AB The intimate link between location of fat accumulation and metabolic disease risk and depot-specific differences is well established, but how these differences between depots are regulated at the molecular level remains largely unclear. Here we show that TRIP-Br2 mediates endoplasmic reticulum (ER) stress-induced inflammatory responses in visceral fat. Using in vitro, ex vivo and in vivo approaches, we demonstrate that obesity-induced circulating factors upregulate TRIP-Br2 specifically in visceral fat via the ER stress pathway. We find that ablation of TRIP-Br2 ameliorates both chemical and physiological ER stress-induced inflammatory and acute phase response in adipocytes, leading to lower circulating levels of inflammatory cytokines. Using promoter assays, as well as molecular and pharmacological experiments, we show that the transcription factor GATA3 is responsible for the ER stress-induced TRIP-Br2 expression in visceral fat. Taken together, our study identifies molecular regulators of inflammatory response in visceral fat that-given that these pathways are conserved in humans-might serve as potential therapeutic targets in obesity. C1 [Qiang, Guifen; Kong, Hyerim Whang; McCann, Maximilian; Liew, Chong Wee] Univ Illinois, Dept Physiol & Biophys, Coll Med, 835 S Wolcott Ave,M-C901,MSB E-202, Chicago, IL 60612 USA. [Fang, Difeng; Zhu, Jinfang] NIAID, Immunol Lab, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Yang, Xiuying; Du, Guanhua] Chinese Acad Med Sci, State Key Lab Bioact Subst & Funct Nat Med, Inst Mat Med, Beijing 100050, Peoples R China. [Yang, Xiuying; Du, Guanhua] Peking Union Med Coll, Beijing 100050, Peoples R China. [Bluher, Matthias] Univ Leipzig, Dept Med, Liebigstr 18, D-04103 Leipzig, Germany. RP Liew, CW (reprint author), Univ Illinois, Dept Physiol & Biophys, Coll Med, 835 S Wolcott Ave,M-C901,MSB E-202, Chicago, IL 60612 USA. EM cwliew@uic.edu RI Zhu, Jinfang/B-7574-2012; OI 杨, 秀颖/0000-0001-8500-3128 FU Research Open Access Publishing (ROAAP) Fund of the University of Illinois at Chicago; Novo Nordisk Great Lakes Science Forum Award; RayBiotech Innovative Research Grant Award; Center for Society for Clinical and Translational Research Early Career Development Award; UIC Startup fund; Deutsche Forschungsgemeinschaft [SFB 1052]; intramural research program of NIAID, NIH; [K99 DK090210]; [R00 DK090210] FX We thank J.L Kirkland MD PhD and Martin Wabitsch MD PhD for providing human preadipocyte and SBGS cell lines. This publication is partly supported by the Research Open Access Publishing (ROAAP) Fund of the University of Illinois at Chicago. This work was supported by K99 DK090210, R00 DK090210, Novo Nordisk Great Lakes Science Forum Award, RayBiotech Innovative Research Grant Award, Center for Society for Clinical and Translational Research Early Career Development Award and UIC Startup fund (C.W.L.). The human studies were supported by a grant of the Deutsche Forschungsgemeinschaft, Obesity Mechanisms (SFB 1052, B01 to M.B.). D. Fang and J. Zhu are supported by the intramural research program of NIAID, NIH. NR 43 TC 3 Z9 3 U1 4 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2016 VL 7 AR 11378 DI 10.1038/ncomms11378 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DK1PB UT WOS:000374684000001 PM 27109496 ER PT J AU Ewers, EC Pratt, WD Twenhafel, NA Shamblin, J Donnelly, G Esham, H Wlazlowski, C Johnson, JC Botto, M Hensley, LE Goff, AJ AF Ewers, Evan C. Pratt, William D. Twenhafel, Nancy A. Shamblin, Joshua Donnelly, Ginger Esham, Heather Wlazlowski, Carly Johnson, Joshua C. Botto, Miriam Hensley, Lisa E. Goff, Arthur J. TI Natural History of Aerosol Exposure with Marburg Virus in Rhesus Macaques SO VIRUSES-BASEL LA English DT Article DE filovirus; nonhuman primate; Marburg virus; aerosol; telemetry; animal model ID EBOLA HEMORRHAGIC-FEVER; CYNOMOLGUS MACAQUES; INFECTED PATIENTS; ANGOLA INFECTION; ZAIRE-EBOLAVIRUS; DISEASE; PATHOGENESIS; APOPTOSIS; COAGULATION; RESPONSES AB Marburg virus causes severe and often lethal viral disease in humans, and there are currently no Food and Drug Administration (FDA) approved medical countermeasures. The sporadic occurrence of Marburg outbreaks does not allow for evaluation of countermeasures in humans, so therapeutic and vaccine candidates can only be approved through the FDA animal rule-a mechanism requiring well-characterized animal models in which efficacy would be evaluated. Here, we describe a natural history study where rhesus macaques were surgically implanted with telemetry devices and central venous catheters prior to aerosol exposure with Marburg-Angola virus, enabling continuous physiologic monitoring and blood sampling without anesthesia. After a three to four day incubation period, all animals developed fever, viremia, and lymphopenia before developing tachycardia, tachypnea, elevated liver enzymes, decreased liver function, azotemia, elevated D-dimer levels and elevated pro-inflammatory cytokines suggesting a systemic inflammatory response with organ failure. The final, terminal period began with the onset of sustained hypotension, dehydration progressed with signs of major organ hypoperfusion (hyperlactatemia, acute kidney injury, hypothermia), and ended with euthanasia or death. The most significant pathologic findings were marked infection of the respiratory lymphoid tissue with destruction of the tracheobronchial and mediastinal lymph nodes, and severe diffuse infection in the liver, and splenitis. C1 [Ewers, Evan C.; Twenhafel, Nancy A.; Goff, Arthur J.] Tripler Army Med Ctr, Dept Med, Honolulu, HI 96859 USA. [Pratt, William D.; Twenhafel, Nancy A.; Shamblin, Joshua; Donnelly, Ginger; Esham, Heather; Wlazlowski, Carly; Botto, Miriam; Goff, Arthur J.] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Johnson, Joshua C.; Hensley, Lisa E.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. RP Pratt, WD (reprint author), US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. EM evan.c.ewers.mil@mail.mil; william.d.pratt4.ctr@mail.mil; nancy.a.twenhafel.mil@mail.mil; joshua.d.shamblin1.civ@mail.mil; ginger.c.donnelly.ctr@mail.mil; heather.l.esham.civ@mail.mil; carly.b.wlazlowski.ctr@mail.mil; joshua.johnson@nih.gov; miriam.a.botto.civ@mail.mil; lisa.hensley@nih.gov; arthur.j.goff.civ@mail.mil OI Johnson, Joshua/0000-0002-5677-3841; Ewers, Evan/0000-0002-1384-9973 FU Defense Threat Reduction Agency FX Financial contributions for this work were provided by the Defense Threat Reduction Agency. The authors acknowledge the contributions of Shannan Hall-Ursone for implant and catheter surgery of the animals, and David O'Brien and Wendy Giles for technical expertise with these studies. NR 40 TC 0 Z9 0 U1 2 U2 3 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD APR PY 2016 VL 8 IS 4 AR 87 DI 10.3390/v8040087 PG 16 WC Virology SC Virology GA DK8DQ UT WOS:000375157800001 PM 27043611 ER PT J AU Carter, CA Rajan, A Keen, C Szabo, E Khozin, S Thomas, A Brzezniak, C Guha, U Doyle, LA Steinberg, SM Xi, L Raffeld, M Tomita, Y Lee, MJ Lee, S Trepel, JB Reckamp, KL Koehler, S Gitlitz, B Salgia, R Gandara, D Vokes, E Giaccone, G AF Carter, C. A. Rajan, A. Keen, C. Szabo, E. Khozin, S. Thomas, A. Brzezniak, C. Guha, U. Doyle, L. A. Steinberg, S. M. Xi, L. Raffeld, M. Tomita, Y. Lee, M. J. Lee, S. Trepel, J. B. Reckamp, K. L. Koehler, S. Gitlitz, B. Salgia, R. Gandara, D. Vokes, E. Giaccone, G. TI Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer SO ANNALS OF ONCOLOGY LA English DT Article DE nonsmall-cell lung cancer; MEK; EGFR; KRAS; selumetinib; erlotinib ID MEK INHIBITION; AZD6244 ARRY-142886; OPEN-LABEL; PHASE-II; IN-VITRO; MUTATIONS; THERAPY; RESISTANCE; TUMORS; TRIAL AB This study failed to show improvement of combination therapy using an epidermal growth factor receptor tyrosine kinase inhibitor combined with an MEK inhibitor over single-agent therapy in KRAS wild-type and mutant patients. Toxicity was significantly increased when the two drugs are combined.KRAS mutations in NSCLC are associated with a lack of response to epidermal growth factor receptor inhibitors. Selumetinib (AZD6244; ARRY-142886) is an oral selective MEK kinase inhibitor of the Ras/Raf/MEK/ERK pathway. Advanced nonsmall-cell lung cancer (NSCLC) patients failing one to two prior regimens underwent KRAS profiling. KRAS wild-type patients were randomized to erlotinib (150 mg daily) or a combination of selumetinib (150 mg daily) with erlotinib (100 mg daily). KRAS mutant patients were randomized to selumetinib (75 mg b.i.d.) or the combination. The primary end points were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Biomarker studies of ERK phosphorylation and immune subsets were carried out. From March 2010 to May 2013, 89 patients were screened; 41 KRAS mutant and 38 KRAS wild-type patients were enrolled. Median PFS in the KRAS wild-type arm was 2.4 months [95% confidence interval (CI) 1.3-3.7] for erlotinib alone and 2.1 months (95% CI 1.8-5.1) for the combination. The ORR in the KRAS mutant group was 0% (95% CI 0.0% to 33.6%) for selumetinib alone and 10% (95% CI 2.1% to 26.3%) for the combination. Combination therapy resulted in increased toxicities, requiring dose reductions (56%) and discontinuation (8%). Programmed cell death-1 expression on regulatory T cells (Tregs), Tim-3 on CD8+ T cells and Th17 levels were associated with PFS and overall survival in patients receiving selumetinib. This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies. C1 [Carter, C. A.; Brzezniak, C.] Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Bethesda, MD USA. [Rajan, A.; Keen, C.; Khozin, S.; Thomas, A.; Guha, U.; Tomita, Y.; Lee, M. J.; Lee, S.; Trepel, J. B.; Giaccone, G.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Szabo, E.] NCI, Lung & Upper Aerodigest Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Doyle, L. A.] NIH, Canc Therapy Evaluat Program, Bldg 10, Bethesda, MD 20892 USA. [Steinberg, S. M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Xi, L.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Reckamp, K. L.; Koehler, S.] City Hope Comprehens Canc Ctr, Dept Hematol & Med Oncol, Duarte, CA USA. [Gitlitz, B.] Univ So Calif, Dept Internal Med, Los Angeles, CA USA. [Salgia, R.; Vokes, E.] Univ Chicago, Radiat & Cellular Oncol, Med & Biol Sci, Chicago, IL 60637 USA. [Gandara, D.] Univ Calif Davis, Div Hematol & Oncol, Ctr Canc, Sacramento, CA 95817 USA. [Giaccone, G.] Georgetown Univ, Lombardi Comprehens Canc Ctr, 3970 Reservoir Rd, Washington, DC 20007 USA. RP Giaccone, G (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, 3970 Reservoir Rd, Washington, DC 20007 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Reckamp, Karen/0000-0002-9213-0325 FU National Cancer Institute, National Institutes of Health; CTEP grant system: NO1 contract system [NCT: 01229150 CTEP: 8444] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health. NCT: 01229150 CTEP: 8444, supported by the CTEP grant system: NO1 contract system. NR 30 TC 9 Z9 9 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2016 VL 27 IS 4 BP 693 EP 699 DI 10.1093/annonc/mdw008 PG 7 WC Oncology SC Oncology GA DJ5HO UT WOS:000374237700020 PM 26802155 ER EF