FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Petrovas, C Ferrando-Martinez, S Pegu, A Boswell, K Asokan, M Ambrozak, D Kotlyar, D Gerson, M Germain, R Reyes-Teran, G del Rio, P Docobo, F Leal, M Ruiz-Mateos, E Koup, RA AF Petrovas, Constantinos Ferrando-Martinez, Sara Pegu, Amarendra Boswell, Kristin Asokan, Mangai Ambrozak, David Kotlyar, David Gerson, Michael Germain, Ronald Reyes-Teran, Gustavo del Rio, Perla Docobo, Fernando Leal, Manuel Ruiz-Mateos, Ezequiel Koup, Richard A. TI Germinal center CD8 T cells can be redirected to eliminate HIV-expressing T follicular helper cells SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Petrovas, Constantinos; Ferrando-Martinez, Sara; Pegu, Amarendra; Boswell, Kristin; Asokan, Mangai; Ambrozak, David; Kotlyar, David; Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gerson, Michael; Germain, Ronald] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Ferrando-Martinez, Sara] HGU Gregorio Maranon, Lab InmunoBiol Mol, Madrid, Spain. [Ferrando-Martinez, Sara; Leal, Manuel; Ruiz-Mateos, Ezequiel] HU Virgen Dle Rocio IBiS US, Lab Immunovirol, Seville, Spain. [Docobo, Fernando] HU Virgen Dle Rocio IBiS US, Dept Gen Surg, Seville, Spain. [Reyes-Teran, Gustavo; del Rio, Perla] Natl Inst Resp Dis, Mexico City, DF, Mexico. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA B-108 BP 47 EP 47 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800022 ER PT J AU Schlom, J AF Schlom, Jeffrey TI Therapeutic Cancer Vaccines - Fundamental Insights SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA C-101 BP 48 EP 48 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800025 ER PT J AU Berzofsky, J Terabe, M Roberson, B Wood, L AF Berzofsky, Jay Terabe, Masaki Roberson, Brenda Wood, Lauren TI Cancer vaccine strategies: translation from mice to clinical trials SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Berzofsky, Jay; Terabe, Masaki; Roberson, Brenda; Wood, Lauren] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA C-106 BP 51 EP 51 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800030 ER PT J AU Chanock, S AF Chanock, Stephen TI Towards an Understanding of the Underlying Architecture of Genetic Susceptibility to Cancer SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Chanock, Stephen] NCI, Bethesda, MD 20892 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA C-107 BP 52 EP 52 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800031 ER PT J AU Mothes, W Gorman, J Munro, J Ma, XC Kwong, P Blanchard, S AF Mothes, Walther Gorman, Jason Munro, James Ma, Xiaochu Kwong, Peter Blanchard, Scott TI Conformational dynamics of single HIV-1 Env trimers on the surface of native virions SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Mothes, Walther; Munro, James; Ma, Xiaochu] Yale Univ, Sch Med, Dept Microbial Pathogenesis, New Haven, CT 06520 USA. [Gorman, Jason; Kwong, Peter] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD USA. [Blanchard, Scott] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, Ithaca, NY 14853 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA D-103 BP 55 EP 55 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800037 ER PT J AU Kwong, P AF Kwong, Peter TI Structure, immune recognition, and conformational stabilization of the HIV-1 viral spike SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Kwong, Peter] NIH, Vaccine Res Ctr, Bethesda, MD 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA D-104 BP 56 EP 56 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800038 ER PT J AU Lusso, P Cimbro, R Gallant, T Connors, M McKee, K Mascola, J AF Lusso, Paolo Cimbro, Raffaello Gallant, Thomas Connors, Mark McKee, Krisha Mascola, John TI Tyrosine Sulfation in the Second Variable Domain (V2) of gp120 Regulates HIV-1 Sensitivity to Neutralization SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Lusso, Paolo; Cimbro, Raffaello; Gallant, Thomas; Connors, Mark] NIAID, LIR, NIH, Bethesda, MD USA. [McKee, Krisha; Mascola, John] NIAID, VRC, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 NOV PY 2014 VL 67 SU 3 MA D-106 BP 57 EP 57 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800040 ER PT J AU Roederer, M AF Roederer, Mario TI Antigenic Heterogeneity of Clonal Envelopes: A Novel Immune Evasion Mechanism SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Roederer, Mario] NIH, Vaccine Res Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA D-107 BP 57 EP 57 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800041 ER PT J AU Mascola, J AF Mascola, John TI Preventative HIV Vaccine Progress SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Mascola, John] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 4 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 NOV PY 2014 VL 67 SU 3 MA E-101 BP 59 EP 59 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800044 ER PT J AU Sui, YJ Hogg, A Wang, YC Frey, B Yu, HF Xia, Z Venzon, D McKinnon, K Smedley, J Gathuka, M Klinman, D Keele, B Langermann, S Liu, LD Franchini, G Berzofsky, J AF Sui, Yongjun Hogg, Alison Wang, Yichuan Frey, Blake Yu, Huifeng Xia, Zheng Venzon, David McKinnon, Katherine Smedley, Jeremy Gathuka, Mercy Klinman, Dennis Keele, Brandon Langermann, Sol Liu, Linda Franchini, Genoveffa Berzofsky, Jay TI Vaccine-induced myeloid cell population dampens protective immunity to SIV SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Sui, Yongjun; Hogg, Alison; Wang, Yichuan; Frey, Blake; Yu, Huifeng; Xia, Zheng; Venzon, David; McKinnon, Katherine; Smedley, Jeremy; Gathuka, Mercy; Klinman, Dennis; Keele, Brandon; Franchini, Genoveffa; Berzofsky, Jay] NIH, Bethesda, MD USA. [Langermann, Sol; Liu, Linda] Amplimmune Inc, Gaithersburg, MD 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA G-104 BP 69 EP 69 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800062 ER PT J AU Robert-Guroff, M Tuero, I Mohanram, V Vargas-Inchaustegui, D Musich, T Demberg, T LaBranche, C Montefiori, D Venzon, D Ferrari, MG Barnett, S Pal, R AF Robert-Guroff, Marjorie Tuero, Iskra Mohanram, Venkatramanan Vargas-Inchaustegui, Diego Musich, Thomas Demberg, Thorsten LaBranche, Celia Montefiori, David Venzon, David Ferrari, Maria Grazia Barnett, Susan Pal, Ranajit TI Rectal Env-specific memory B cells and plasma cells are correlated with delayed SIVmac251 acquisition following rectal challenge of vaccinated female but not male rhesus macaques SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Robert-Guroff, Marjorie; Tuero, Iskra; Mohanram, Venkatramanan; Vargas-Inchaustegui, Diego; Musich, Thomas; Demberg, Thorsten; Venzon, David] NCI, Bethesda, MD 20892 USA. [LaBranche, Celia; Montefiori, David] Duke Univ, Durham, NC 27706 USA. [Ferrari, Maria Grazia; Pal, Ranajit] Adv BioSci Labs Inc, Rockville, MD USA. RI Mohanram, Venkatramanan/I-3652-2016 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA G-106 BP 70 EP 70 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800064 ER PT J AU Felber, B Hu, XT Kulkarni, V Rosati, M Alicea, C Rolland, M Le Gall, S Sardesai, N Mothe, B Brander, C Mullins, J Pavlakis, G Valentin, A AF Felber, Barbara Hu, Xintao Kulkarni, Viraj Rosati, Margherita Alicea, Candido Rolland, Morgane Le Gall, Sylvie Sardesai, Niranjan Mothe, Beatriz Brander, Christian Mullins, James Pavlakis, George Valentin, Antonio TI Reverse vaccinology identified promising vaccine candidates focusing responses to relatively conserved regions associated with control of viremia SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Felber, Barbara; Hu, Xintao; Kulkarni, Viraj; Rosati, Margherita; Alicea, Candido; Pavlakis, George; Valentin, Antonio] NCI, Frederick, MD 21701 USA. [Rolland, Morgane; Mullins, James] Univ Washington, Seattle, WA 98195 USA. [Le Gall, Sylvie] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Sardesai, Niranjan] Inovio Pharmaceut Inc, San Diego, CA USA. [Mothe, Beatriz; Brander, Christian] Autonomous Univ Barcelona, IrsiCaixa AIDS Res Inst HIVACAT, E-08193 Barcelona, Spain. [Brander, Christian] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA G-109 BP 71 EP 71 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800067 ER PT J AU Guzzo, C Fox, J Lin, Y Volkman, B Lusso, P Miao, HY AF Guzzo, Christina Fox, Jamie Lin, Yin Volkman, Brian Lusso, Paolo Miao, Huiyi TI Inhibition of HIV-1 by the C-chemokine XCL1/Lymphotactin is dependent on high affinity binding to glycosaminoglycans (GAG) SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Guzzo, Christina; Lin, Yin; Lusso, Paolo; Miao, Huiyi] NIAID, Immunoregulat Lab, NIH, Bethesda, MD USA. [Fox, Jamie; Volkman, Brian] Med Coll Wisconsin, Dept Biochem, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA P-D4 BP 88 EP 88 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800097 ER PT J AU Liu, QB Cimbro, R Dolan, M Peterson, F Volkman, B Lusso, P AF Liu, Qingbo Cimbro, Raffaello Dolan, Michael Peterson, Francis Volkman, Brian Lusso, Paolo TI Structure-Function Relationships in the Second Variable Domain (V2) of HIV-1 gp120 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Liu, Qingbo; Dolan, Michael; Lusso, Paolo] NIAID, Bethesda, MD USA. [Cimbro, Raffaello] Johns Hopkins Sch Med, Baltimore, MD USA. [Peterson, Francis; Volkman, Brian] Med Coll Wisconsin, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA P-D6 BP 89 EP 89 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800099 ER PT J AU Townsend, K Kottilil, S AF Townsend, Kerry Kottilil, Shyam TI Rapid and Selective Increase in LDL levels in HCV genotype-1 infected patients using IFN/RBV-free regimens independent of HIV co-infection and treatment duration SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Townsend, Kerry] NIH, Bethesda, MD USA. [Kottilil, Shyam] NIAID, NIH, Baltimore, MD 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA P-D12 BP 92 EP 92 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800105 ER PT J AU Wang, YC Sui, YJ Hogg, A Steel, J Morris, J Berzofsky, J AF Wang, Yichuan Sui, Yongjun Hogg, Alison Steel, Jason Morris, John Berzofsky, Jay TI Vaginal type-II mucosa acts as an inductive site for the generation of primary CD8+T cell mucosal immune responses SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Wang, Yichuan; Sui, Yongjun; Hogg, Alison; Berzofsky, Jay] NCI, Bethesda, MD 20892 USA. [Steel, Jason] UC Coll Med, Dept Internal Med, Cincinnati, OH USA. [Morris, John] Univ Cincinnati, Cincinnati, OH 45221 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA P-D13 BP 93 EP 93 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800106 ER PT J AU Zhang, P Pancera, M Gallant, T Guzzo, C Lin, Y Kwong, P Lusso, P AF Zhang, Peng Pancera, Marie Gallant, Thomas Guzzo, Christina Lin, Yin Kwong, Peter Lusso, Paolo TI Increasing the Level of Tyrosine Sulfation Alters the Antigenic Profile of the BG505 SOSIP.664 Trimer SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Zhang, Peng] NIH, Bethesda, MD USA. [Pancera, Marie] NIAID, Vaccine Res Ctr, NIH, Baltimore, MD USA. [Gallant, Thomas; Guzzo, Christina; Lin, Yin; Lusso, Paolo] NIAID, Immunoregulat Lab, Baltimore, MD USA. [Kwong, Peter] NIAID, Vaccine Res Ctr, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA P-D14 BP 93 EP 93 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800107 ER PT J AU Billeskov, R Berzofsky, J Sui, YJ AF Billeskov, Rolf Berzofsky, Jay Sui, Yongjun TI T cell avidity can be selectively regulated by simply changing the vaccine antigen dose in a novel cationic liposomal adjuvant SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Billeskov, Rolf] NCI, CCR, NIH, Statens Serum Inst, Bethesda, MD 20892 USA. [Berzofsky, Jay; Sui, Yongjun] NCI, CCR, NIH, Bethesda, MD 20892 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA P-E1 BP 94 EP 94 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800108 ER PT J AU Valentin, A Li, JY Sardesai, N Felber, B Pavlakis, G AF Valentin, Antonio Li, Jinyao Sardesai, Niranjan Felber, Barbara Pavlakis, George TI Systemic dissemination, including mucosal sites, of cellular immunity elicited by DNA vaccines delivered by intramuscular injection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Meeting Abstract CT 16th Annual International Meeting of the Institute-of-Human-Virology (IHV) CY SEP 14-14, 2014 CL Univ Maryland Sch Med, Baltimore, MD SP Inst Human Virol HO Univ Maryland Sch Med C1 [Valentin, Antonio; Li, Jinyao; Felber, Barbara; Pavlakis, George] Natl Canc Inst Frederick, Frederick, MD USA. [Sardesai, Niranjan] Inovio Pharmaceut Inc, Plymouth Meeting, PA 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV PY 2014 VL 67 SU 3 MA P-E3 BP 95 EP 95 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CH6BF UT WOS:000354119800110 ER PT J AU Komarow, HD Arceo, S Young, M Nelson, C Metcalfe, DD AF Komarow, Hirsh D. Arceo, Sarah Young, Michael Nelson, Celeste Metcalfe, Dean D. TI Dissociation Between History and Challenge in Patients with Physical Urticaria SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Urticaria; Physical urticaria; Challenge testing; Cold; Cholinergic; Dermatographism; Delayed pressure ID CHOLINERGIC URTICARIA AB BACKGROUND: Physical urticaria is a subtype of chronic urticaria induced by a physical stimulus. OBJECTIVE: To evaluate the consistency between a history of physical urticaria and results of challenge testing. METHODS: Seventy-six subjects, ages 3 to 77 years old, were referred with the diagnosis of a physical urticaria and were evaluated by using challenge testing directed toward the presenting diagnosis, yet included other stimuli based on history. The majority of subjects were tested to 3 or more stimuli, thus 294 provocation tests were performed. Fifty-seven subjects were surveyed for the status of their physical urticaria at least 1 year after initial evaluation. RESULTS: Of the 76 subjects with a positive history of a physical urticaria, 38% (n = 29) were challenge negative to the presenting diagnosis. Eight subjects within the challenge negative group reacted positively to additional testing, thus 28% (n = 21) remained negative to all challenge testing, which allowed discontinuation of medications and avoidance behavior. A negative challenge result was less likely with subjects who presented with cold-induced urticaria (25%), delayed pressure urticaria (25%), and dermatographism (29%), yet more common with cholinergic (65%) and solar urticaria (67%). A 1-year follow-up survey of 57 subjects was consistent with initial results. Nineteen of this subgroup were rechallenged for the presenting diagnosis, and the outcome was unchanged in 17 subjects and, in 2 subjects the urticaria had resolved. CONCLUSIONS: The diagnosis by history of a physical urticaria should be verified by testing whenever possible and particularly if the condition is judged as severe and thus requires both significant life-style changes and pharmacologic intervention. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology C1 [Komarow, Hirsh D.; Arceo, Sarah; Nelson, Celeste; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Young, Michael] Leidos Biomedical Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Komarow, HD (reprint author), NIAID, NIH, LAD, Bldg 10,Room1C129A1,10 Ctr Dr, Bethesda, MD 20892 USA. EM komarowh@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Support by M. Young for this project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, 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 endorsement by the U.S. Government. NR 16 TC 3 Z9 3 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD NOV-DEC PY 2014 VL 2 IS 6 BP 786 EP + DI 10.1016/j.jaip.2014.07.008 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA CH7HW UT WOS:000354207600022 PM 25439372 ER PT J AU Williams, KW Metcalfe, DD Prussin, C Carter, MC Komarow, HD AF Williams, Kelli W. Metcalfe, Dean D. Prussin, Calman Carter, Melody C. Komarow, Hirsh D. TI Telangiectasia macularis eruptiva perstans or highly vascularized urticaria pigmentosa? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Letter ID DIAGNOSTIC-CRITERIA; MASTOCYTOSIS; CLASSIFICATION C1 [Williams, Kelli W.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Metcalfe, Dean D.; Prussin, Calman; Carter, Melody C.; Komarow, Hirsh D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Komarow, HD (reprint author), NIAID, NIH, 10 Ctr Dr,Bldg 10,Room 1C129A1, Bethesda, MD 20892 USA. EM komarowh@mail.nih.gov FU Intramural NIH HHS [ZIA AI000249-32]; NIAID NIH HHS [ZIA AI000249-32] NR 12 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD NOV-DEC PY 2014 VL 2 IS 6 BP 813 EP 815 DI 10.1016/j.jaip.2014.07.002 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA CH7HW UT WOS:000354207600032 PM 25439382 ER PT J AU Aregawi, D Kreisl, TN Innis, E Fine, HA AF Aregawi, Dawit Kreisl, Teri N. Innis, Ellen Fine, Howard A. TI A PHASE II TRIAL OF TAMOXIFEN AND BORTEZOMIB IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Aregawi, Dawit] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Kreisl, Teri N.] Columbia Univ, Neurol Inst, New York, NY USA. [Innis, Ellen] Univ Maryland, Baltimore, MD 21201 USA. [Fine, Howard A.] NYU, Inst Canc, NYU Langone Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA AT-06 DI 10.1093/neuonc/nou237.6 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200036 ER PT J AU Garren, N Harris, S Baker, E Kreisl, T Warren, K AF Garren, Nancy Harris, Sunit Baker, Eva Kreisl, Teri Warren, Katherine TI BRAINSTEM GLIOMAS IN ADULTS: DO ADULT DIFFUSE INTRINSIC PONTINE GLIOMAS EXIST? SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Garren, Nancy; Harris, Sunit; Baker, Eva; Kreisl, Teri; Warren, Katherine] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA ED-06 DI 10.1093/neuonc/nou253.6 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200298 ER PT J AU Johnson, J Ascierto, ML Newsome, D Mittal, S Kang, L Briggs, M Tanner, K Berens, ME Marincola, FM Vande Woude, GF Xie, Q AF Johnson, Jennifer Ascierto, Maria Libera Newsome, David Mittal, Sandeep Kang, Liang Briggs, Michael Tanner, Kirk Berens, Michael E. Marincola, Francesco M. Vande Woude, George F. Xie, Qian TI GENOMIC PROFILING OF A PREDICTIVE SIGNATURE FOR MET-TARGETED THERAPY IN GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Johnson, Jennifer; Kang, Liang; Vande Woude, George F.; Xie, Qian] Van Andel Res Inst, Grand Rapids, MI USA. [Ascierto, Maria Libera; Marincola, Francesco M.] NIH, Bethesda, MD 20892 USA. [Newsome, David; Tanner, Kirk] Vertex Pharmaceut Inc, Cambridge, MA USA. [Mittal, Sandeep] Wayne State Univ, Detriot, MI USA. [Berens, Michael E.] Translat Genom Res Inst, Phoenix, AZ USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Ascierto, Maria Libera] John Hopkins Med, Baltimore, MD USA. [Briggs, Michael] Woodland Pharmaceut, Shrewsbury, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA BI-14 DI 10.1093/neuonc/nou239.14 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200104 ER PT J AU Krauze, AV Myrehaug, SD Chang, MG Holdford, DJ Smith, S Shih, J Tofilon, P Fine, H Camphausen, KA AF Krauze, Andra V. Myrehaug, Sten D. Chang, Michael G. Holdford, Diane J. Smith, Sharon Shih, Joanna Tofilon, Peter Fine, Howard Camphausen, Kevin A. TI A PHASE II STUDY OF CONCURRENT RADIATION THERAPY, TEMOZOLOMIDE AND THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID FOR PATIENTS WITH GLIOBLASTOMA MULTIFORME SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Krauze, Andra V.; Smith, Sharon; Shih, Joanna; Tofilon, Peter; Camphausen, Kevin A.] NCI, NIH, Bethesda, MD 20892 USA. [Myrehaug, Sten D.] Lakeridge Hlth DRCC, Dept Radiat Oncol, Oshawa, ON, Canada. [Chang, Michael G.; Holdford, Diane J.] Virginia Commonwealth Univ, Richmond, VA USA. [Fine, Howard] NYU, Inst Canc, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA AT-33 DI 10.1093/neuonc/nou237.33 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200063 ER PT J AU Kreisl, TN Peer, C Brown, J Figg, WD Fine, HA AF Kreisl, Teri N. Peer, Cody Brown, Jeffrey Figg, William D. Fine, Howard A. TI A PHASE I TRIAL OF AZD7451, A TROPOMYOSIN-RECEPTOR KINASE (TRK) INHIBITOR, FOR ADULTS WITH RECURRENT GLIOBLASTOMA MULTIFORME (GBM) SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Kreisl, Teri N.; Peer, Cody] NIH, Bethesda, MD 20892 USA. [Fine, Howard A.] NYU, New York, NY USA. [Brown, Jeffrey; Figg, William D.] Astra Zeneca, Boston, NY USA. [Kreisl, Teri N.] Columbia Univ, New York, NY USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA ET-30 DI 10.1093/neuonc/nou255.30 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200346 ER PT J AU Lee, MH Reilly, K AF Lee, Min-Hyung Reilly, Karlyne TI CDCA7L FUNCTIONS AS A MALE-SPECIFIC ONCOGENE IN ASTROCYTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Lee, Min-Hyung; Reilly, Karlyne] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA PM-10 DI 10.1093/neuonc/nou268.10 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200681 ER PT J AU Lobel, G Edwards, N Merrill, M AF Lobel, Graham Edwards, Nancy Merrill, Marsha TI LIPID DROPLET ACCUMULATION IN VON HIPPEL-LINDAU CNS HEMANGIOBLASTOMAS IS A MANIFESTATION OF HIF OVEREXPRESSION SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Lobel, Graham; Edwards, Nancy; Merrill, Marsha] NIH, Surg Neurol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA CB-12 DI 10.1093/neuonc/nou241.11 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200170 ER PT J AU Maachani, U Scott, T Hanson, R Zhao, SP Celiku, O Shankavaram, U Caplen, N Camphausen, K Tandle, A AF Maachani, Uday Scott, Tamalee Hanson, Ryan Zhao, Shuping Celiku, Orieta Shankavaram, Uma Caplen, Natasha Camphausen, Kevin Tandle, Anita TI TARGETING MPS1 ENHANCES RADIOSENSITIZATION OF HUMAN GLIOBLASTOMA BY MODULATING DNA REPAIR PROTEINS SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Maachani, Uday; Scott, Tamalee; Hanson, Ryan; Zhao, Shuping; Celiku, Orieta; Shankavaram, Uma; Camphausen, Kevin; Tandle, Anita] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Caplen, Natasha] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA RT-18 DI 10.1093/neuonc/nou270.15 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200757 ER PT J AU McNeill, K Iwamoto, F Kreisl, T Sul, J Shih, J Fine, H AF McNeill, Katharine Iwamoto, Fabio Kreisl, Teri Sul, Joohee Shih, Joanna Fine, Howard TI A RANDOMIZED PHASE II TRIAL OF VANDETANIB (ZD6474) IN COMBINATION WITH CARBOPLATIN VERSUS CARBOPLATIN ALONE IN ADULTS WITH RECURRENT GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [McNeill, Katharine; Fine, Howard] NYU, New York, NY USA. [Iwamoto, Fabio; Kreisl, Teri] Columbia Univ, New York, NY USA. [Sul, Joohee] NIH, Bethesda, MD 20892 USA. [Shih, Joanna] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA AT-39 DI 10.1093/neuonc/nou237.38 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200068 ER PT J AU Nesvick, C Zhang, C Montgomery, B Lee, M Yang, CZ Wang, HR Merrill, M Heiss, J Ray-Chaudhury, A Zhuang, ZP AF Nesvick, Cody Zhang, Chao Montgomery, Blake Lee, Michaela Yang, Chunzhang Wang, Herui Merrill, Marsha Heiss, John Ray-Chaudhury, Abhik Zhuang, Zhengping TI IDH1/2 MUTATIONS INFLUENCE ZEB1 EXPRESSION IN GRADES II AND III GLIOMAS SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Nesvick, Cody; Zhang, Chao; Montgomery, Blake; Lee, Michaela; Yang, Chunzhang; Wang, Herui; Merrill, Marsha; Heiss, John; Ray-Chaudhury, Abhik; Zhuang, Zhengping] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA CS-27 DI 10.1093/neuonc/nou242.27 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200237 ER PT J AU Ratner, N Keng, V Patmore, DM Kendall, JK Jousma, E Choi, K Fan, DH Schwartz, EB Fuchs, JR Zou, YS Kim, MO Dombi, E Levy, DE Cancelas, JA Stemmer-Rachamimov, A Spinner, RJ Largaespada, DA AF Ratner, Nancy Keng, Vincent Patmore, Deanna M. Kendall, Jed K. Jousma, Edwin Choi, Kwangmin Fan, Danhua Schwartz, Eric B. Fuchs, James R. Zou, Yuanshu Kim, Mi-Ok Dombi, Eva Levy, David E. Cancelas, Jose A. Stemmer-Rachamimov, Anat Spinner, Robert J. Largaespada, David A. TI EGFR-STAT3 ACTIVATES beta-CATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A ROLE IN TUMOR MAINTENANCE SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Ratner, Nancy; Patmore, Deanna M.; Kendall, Jed K.; Jousma, Edwin; Choi, Kwangmin; Kim, Mi-Ok; Cancelas, Jose A.] Cincinnati Childrens, Cincinnati, OH USA. [Keng, Vincent; Fan, Danhua; Schwartz, Eric B.; Fuchs, James R.; Zou, Yuanshu; Largaespada, David A.] Univ Minnesota, Minneapolis, MN USA. [Spinner, Robert J.] Mayo Clin, Rochester, MN USA. [Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dombi, Eva] NCI, Pediat Branch, Bethesda, MD 20892 USA. [Levy, David E.] NYU, Sch Med, New York, NY USA. RI Kim, Mi-Ok/O-9626-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA PM-18 DI 10.1093/neuonc/nou268.18 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200694 ER PT J AU Rowse, A McFarland, B Meares, G Zheng, Y Hjelmeland, A Benveniste, E AF Rowse, Amber McFarland, Braden Meares, Gordon Zheng, Ying Hjelmeland, Anita Benveniste, Etty TI PROTEIN KINASE CK2 IS IMPORTANT FOR THE FUNCTION OF GLIOBLASTOMA BRAIN TUMOR INITIATING CELLS SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Rowse, Amber; McFarland, Braden; Meares, Gordon; Hjelmeland, Anita; Benveniste, Etty] Univ Alabama Birmingham, Birmingham, AL USA. [Zheng, Ying] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA CS-30 DI 10.1093/neuonc/nou242.30 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200228 ER PT J AU Stampar, M Yadavilli, S Brown, KJ Raabe, EH Warren, KE Kambhampati, M Packer, RJ Nazarian, J AF Stampar, Mojca Yadavilli, Sridevi Brown, Kristy J. Raabe, Eric H. Warren, Kathy E. Kambhampati, Madhuri Packer, Roger J. Nazarian, Javad TI COMPARATIVE PROTEOME PROFILING OF IN VIVO AND IN VITRO MODELS OF DIPG SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Stampar, Mojca; Yadavilli, Sridevi; Brown, Kristy J.; Kambhampati, Madhuri; Packer, Roger J.; Nazarian, Javad] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Raabe, Eric H.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Warren, Kathy E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA PM-20 DI 10.1093/neuonc/nou268.20 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200689 ER PT J AU Sumita, K Davis, M Pragani, R Terakawa, J Daikoku, T Majd, N Shen, M Li, ZY Hu, X Cantley, L Boxer, M Simeonov, A Sasaki, A AF Sumita, Kazutaka Davis, Mindy Pragani, Rajan Terakawa, Jumpei Daikoku, Takiko Majd, Nazanin Shen, Min Li, Zhuyin Hu, Xin Cantley, Lewis Boxer, Matthew Simeonov, Anton Sasaki, Atsuo TI DISCOVERY OF A p53-INDEPENDENT SUPPRESSOR OF SENESCENCE OF GLIOBLASTOMA MULTIFORME SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Sumita, Kazutaka; Majd, Nazanin; Sasaki, Atsuo] Univ Cincinnati, Cincinnati, OH USA. [Terakawa, Jumpei; Daikoku, Takiko] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Davis, Mindy; Pragani, Rajan; Shen, Min; Li, Zhuyin; Hu, Xin; Boxer, Matthew; Simeonov, Anton] NIH, Chem Genom Ctr, Rockville, MD USA. [Cantley, Lewis] Weill Cornell Med Coll, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA CS-33 DI 10.1093/neuonc/nou242.33 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200231 ER PT J AU Wenger, C Miranda, PC Salvador, R Basser, PJ AF Wenger, Cornelia Miranda, Pedro Cavaleiro Salvador, Ricardo Basser, Peter J. TI INVESTIGATING THE MECHANISMS OF ACTION OF TUMOR TREATING FIELDS: A COMPUTATIONAL MODELING STUDY SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Wenger, Cornelia; Miranda, Pedro Cavaleiro; Salvador, Ricardo] Univ Lisbon, Fac Sci, Inst Biophys & Biomed Engn, P-1699 Lisbon, Portugal. [Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet STBB Eunice Kenned, Bethesda, MD USA. RI Miranda, Pedro/A-5643-2013 OI Miranda, Pedro/0000-0002-6793-8111 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA TM-16 DI 10.1093/neuonc/nou278.15 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200841 ER PT J AU Zhang, NL Lu, L Van Dyke, T AF Zhang, Nailing Lu, Lucy Van Dyke, Terry TI EXPLORATION OF BASIC AND THERAPEUTIC MECHANISMS IN NOVEL MODELS OF RTK/RAS-NETWORK-DRIVEN GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [Zhang, Nailing; Lu, Lucy; Van Dyke, Terry] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA PM-23 DI 10.1093/neuonc/nou268.23 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200692 ER PT J AU Maggio, M Snyder, PJ De Vita, F Ceda, GP Milaneschi, Y Lauretani, F Luci, M Cattabiani, C Peachey, H Valenti, G Cappola, AR Longo, DL Ferrucci, L AF Maggio, Marcello Snyder, Peter J. De Vita, Francesca Ceda, Gian Paolo Milaneschi, Yuri Lauretani, Fulvio Luci, Michele Cattabiani, Chiara Peachey, Helen Valenti, Giorgio Cappola, Anne R. Longo, Dan L. Ferrucci, Luigi TI EFFECTS OF TRANSDERMAL TESTOSTERONE TREATMENT ON INFLAMMATORY MARKERS IN ELDERLY MALES SO ENDOCRINE PRACTICE LA English DT Article ID C-REACTIVE PROTEIN; ANDROGEN DEPRIVATION THERAPY; HYPOGONADAL MEN; PROSTATE-CANCER; OLDER MEN; IMMUNOLOGICAL FEATURES; REPLACEMENT THERAPY; CYTOKINES; DISEASE; SUPPLEMENTATION AB Objective: During the male aging process, testosterone (T) levels progressively fall and inflammatory biomarkers increase. Although a relationship between these 2 phenomena has been tested in previous clinical trials, there is inconclusive evidence about the potential anti-inflammatory action of T. Methods: A total of 108 healthy males >65 years with serum T concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University and randomized to 60-cm(2) T or a placebo patch for 36 months. Ninety-six subjects completed the trial. Information and stored serum specimens from this trial were used to test the hypothesis of the inhibitory effect of T on inflammation. We evaluated 70 males (42 in the T group) who had banked specimens from multiple time points available for assays of T, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, soluble TNF-alpha receptor-1 (TNFR1), interleukin-6 (IL-6), and soluble IL-6 receptors (sIL6r and sgp130). Results: The mean age +/- SD at baseline was 71.8 +/- 4.9 years. Testosterone replacement therapy for 36 months did not induce significant decreases in inflammatory markers. A trend toward a significant increase was observed in the placebo group for TNF-alpha (P = .03) and sgp130 (P = .01). Significant differences in estimated means of TNFR1 (but not other inflammatory markers), with lower levels in the T group, were observed at the 36-month time point. In T-treated subjects we found an almost significant treatment x time interaction term TNFR1 (P = .02) independent of total body fat content as assessed by dual energy X-ray absorptiometry (DXA). No serious adverse effect was observed. Conclusions: Transdermal T treatment of older males for 36 months is not associated with significant changes in inflammatory markers. C1 [Maggio, Marcello; Ceda, Gian Paolo; Luci, Michele; Cattabiani, Chiara; Valenti, Giorgio] Univ Parma, Dept Clin & Expt Med, Sect Geriatr, I-43100 Parma, Italy. [Maggio, Marcello; De Vita, Francesca; Ceda, Gian Paolo; Lauretani, Fulvio] Univ Hosp Parma, Geriatr Rehabil Dept, Parma, Italy. [Snyder, Peter J.; Peachey, Helen; Cappola, Anne R.] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Milaneschi, Yuri] Vrije Univ Amsterdam Med Ctr, GGZ inGeest, Dept Psychiat, Amsterdam, Netherlands. [Milaneschi, Yuri; Longo, Dan L.; Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. RP Maggio, M (reprint author), Univ Parma, Dept Clin & Expt Med, Sect Geriatr, Via Gramsci 14, I-43100 Parma, Italy. EM marcellomaggio2001@yahoo.it RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU U.S. National Institute on Aging; Intramural Research Program of U.S. National Institute on Aging FX The authors have no multiplicity of interest to disclose. The Study was supported as a targeted project by the U.S. National Institute on Aging and by the Intramural Research Program of the U.S. National Institute on Aging. None of the sponsoring institutions interfered with the collection, analysis, presentation, or interpretation of the reported data. NR 34 TC 3 Z9 3 U1 0 U2 3 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD NOV PY 2014 VL 20 IS 11 BP 1170 EP 1177 DI 10.4158/EP13357.OR PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC0MN UT WOS:000350030000015 PM 25100359 ER PT J AU Elentner, A Ortner, D Sparber, F Ebner, S Del Frari, B Gonzalez, FJ Fernandez-Salguero, PM Schmuth, M Dubrac, S AF Elentner, A. Ortner, D. Sparber, F. Ebner, S. Del Frari, B. Gonzalez, F. J. Fernandez-Salguero, P. M. Schmuth, M. Dubrac, S. TI Skin response to a carcinogen involves the xenobiotic receptor pregnane X receptor SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT Inflammatory Skin Disease Summit - The Translational Revolution CY NOV 19-21, 2014 CL Austrian Acad Sci, Vienna, AUSTRIA HO Austrian Acad Sci C1 [Elentner, A.; Ortner, D.; Sparber, F.; Schmuth, M.; Dubrac, S.] Med Univ Innsbruck, Dept Dermatol & Venereol, A-6020 Innsbruck, Austria. [Ebner, S.] Med Univ Innsbruck, Dept Surg, VTT Daniel Swarovski Lab, A-6020 Innsbruck, Austria. [Del Frari, B.] Med Univ Innsbruck, Dept Plast Reconstruct & Esthet Surg, A-6020 Innsbruck, Austria. [Gonzalez, F. J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fernandez-Salguero, P. M.] Univ Extremadura, Dept Biochem Mol Biol & Genet, Fac Sci, Badajoz, Spain. RI Sparber, Florian/S-7657-2016 OI Sparber, Florian/0000-0003-4224-724X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD NOV PY 2014 VL 23 SU 2 SI SI MA P012 BP 2 EP 2 PG 1 WC Dermatology SC Dermatology GA CB9PD UT WOS:000349963100013 ER PT J AU Ochiai, S Roediger, B Shklovskaya, E de St Groth, BF Yamane, H Weninger, W Le Gros, G Ronchese, F AF Ochiai, S. Roediger, B. Shklovskaya, E. de St Groth, B. Fazekas Yamane, H. Weninger, W. Le Gros, G. Ronchese, F. TI Identification of TSLP-responsive dermal DC in murine skin hypersensitivity models SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT Inflammatory Skin Disease Summit - The Translational Revolution CY NOV 19-21, 2014 CL Austrian Acad Sci, Vienna, AUSTRIA HO Austrian Acad Sci C1 [Ochiai, S.; Le Gros, G.; Ronchese, F.] Malaghan Inst Med Res, Wellington, New Zealand. [Roediger, B.; Shklovskaya, E.; de St Groth, B. Fazekas; Weninger, W.] Centenary Inst, Sydney, NSW, Australia. [Yamane, H.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD NOV PY 2014 VL 23 SU 2 SI SI MA P009 BP 2 EP 2 PG 1 WC Dermatology SC Dermatology GA CB9PD UT WOS:000349963100010 ER PT J AU Homer, J Wile, K Yarnoff, B Trogdon, JG Hirsch, G Cooper, L Soler, R Orenstein, D AF Homer, Jack Wile, Kristina Yarnoff, Benjamin Trogdon, Justin G. Hirsch, Gary Cooper, Lawton Soler, Robin Orenstein, Diane TI Using Simulation to Compare Established and Emerging Interventions to Reduce Cardiovascular Disease Risk in the United States SO PREVENTING CHRONIC DISEASE LA English DT Article ID DYNAMICS; PREVENTION AB Introduction Computer simulation offers the ability to compare diverse interventions for reducing cardiovascular disease risks in a controlled and systematic way that cannot be done in the real world. Methods We used the Prevention Impacts Simulation Model (PRISM) to analyze the effect of 50 intervention levers, grouped into 6 (2 x 3) clusters on the basis of whether they were established or emerging and whether they acted in the policy domains of care (clinical, mental health, and behavioral services), air (smoking, secondhand smoke, and air pollution), or lifestyle (nutrition and physical activity). Uncertainty ranges were established through probabilistic sensitivity analysis. Results Results indicate that by 2040, all 6 intervention clusters combined could result in cumulative reductions of 49% to 54% in the cardiovascular risk-related death rate and of 13% to 21% in risk factor-attributable costs. A majority of the death reduction would come from Established interventions, but Emerging interventions would also contribute strongly. A slim majority of the cost reduction would come from Emerging interventions. Conclusion PRISM allows public health officials to examine the potential influence of different types of interventions - both established and emerging - for reducing cardiovascular risks. Our modeling suggests that established interventions could still contribute much to reducing deaths and costs, especially through greater use of well-known approaches to preventive and acute clinical care, whereas emerging interventions have the potential to contribute significantly, especially through certain types of preventive care and improved nutrition. C1 [Homer, Jack] Homer Consulting, Barrytown, NY USA. [Wile, Kristina] Sustainabil Inst, Charleston, SC USA. [Trogdon, Justin G.] Univ N Carolina, Chapel Hill, NC USA. [Hirsch, Gary] Creator Learning Environm, Wayland, MA USA. [Cooper, Lawton] NIH, Bethesda, MD 20892 USA. [Soler, Robin; Orenstein, Diane] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Yarnoff, B (reprint author), RTI Int, 3040 Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. EM byarnoff@rti.org FU Centers for Disease Control and Prevention [200-2008-27958]; National Heart, Lung, and Blood Institute FX This research was supported by contract no. 200-2008-27958 Task Order 12 from the Centers for Disease Control and Prevention and National Heart, Lung, and Blood Institute. NR 16 TC 5 Z9 5 U1 0 U2 4 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD NOV PY 2014 VL 11 AR E195 DI 10.5888/pcd11.140130 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CB8BB UT WOS:000349852100002 PM 25376017 ER PT J AU Wallace, BD Williams, RS AF Wallace, Bret D. Williams, R. Scott TI Ribonucleotide triggered DNA damage and RNA-DNA damage responses SO RNA BIOLOGY LA English DT Editorial Material DE Aprataxin; Aptx; RNase H2; Tyrosyl-DNA phosphodiesterase 2 (Tdp2); Topoisomerase 1 (Top1); Top1cc; Topoisomerase 2 (Top2); Top2cc; Flap Endonuclease 1 (FEN-1); DNA ligase; 2-3-cyclic PO4; Ribonucleotide Excision Repair (RER); abortive ligation; DNA adenylation; DNA damage; RNA-DNA damage; Genome Stability; DNA repair; Ataxia Oculomotor Apraxia; AOA1; Acardi-Goutieres syndrome ID MAINTAIN GENOME INTEGRITY; TOPOISOMERASE-II; NEURODEGENERATIVE DISEASE; PHOSPHODIESTERASE 2; CRYSTAL-STRUCTURES; 2'-HYDROXYL GROUP; MISMATCH REPAIR; H2; APRATAXIN; TDP2 AB Research indicates that the transient contamination of DNA with ribonucleotides exceeds all other known types of DNA damage combined. The consequences of ribose incorporation into DNA, and the identity of protein factors operating in this RNA-DNA realm to protect genomic integrity from RNA-triggered events are emerging. Left unrepaired, the presence of ribonucleotides in genomic DNA impacts cellular proliferation and is associated with chromosome instability, gross chromosomal rearrangements, mutagenesis, and production of previously unrecognized forms of ribonucleotide-triggered DNA damage. Here, we highlight recent findings on the nature and structure of DNA damage arising from ribonucleotides in DNA, and the identification of cellular factors acting in an RNA-DNA damage response (RDDR) to counter RNA-triggered DNA damage. C1 [Wallace, Bret D.; Williams, R. Scott] NIEHS, Genome Integr & Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Williams, RS (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM williamsrs@niehs.nih.gov RI Williams, Robert/A-6059-2015 FU Intramural NIH HHS [ZIA ES102765-05]; NIEHS NIH HHS [1Z01ES102765] NR 57 TC 6 Z9 6 U1 1 U2 10 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD NOV PY 2014 VL 11 IS 11 BP 1340 EP 1346 DI 10.4161/15476286.2014.992283 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CC0KJ UT WOS:000350024000004 PM 25692233 ER PT J AU Coyne, GO Gulley, JL AF Coyne, Geraldine O'Sullivan Gulley, James L. TI Adding fuel to the fire: Immunogenic intensification SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Review DE activated T cell; cancer; checkpoint inhibitor; immunogenic intensification; PD-L1; vaccine; APC; antigen-presenting cells; TAP; transporter of antigen processing; CARs; chimeric antigen receptors; HER2; epidermal growth factor receptor 2; MHC I; major histocompatibility class I molecules; mCRPC; metastatic castration-resistant prostate cancer; mAB; monoclonal antibodies; MDSCs; myeloid-derived suppressor cells; PD-1; programmed death-1; PD-L1; programmed death-ligand-1; TAA; tumor-associated antigen; TILs; tumor infiltrating lymphocytes; Tregs; regulatory T cells ID RESISTANT PROSTATE-CANCER; DOSE-ESCALATION TRIAL; MHC CLASS-I; T-LYMPHOCYTES; TUMOR-ANTIGENS; ADVANCED MELANOMA; PLUS IPILIMUMAB; CELL-DEATH; IMMUNOTHERAPY; SURVIVAL AB The durable long term clinical benefits seen for certain patients treated with immunotherapy agents has suggested there is significant therapeutic potential to be derived from these agents, as shown by the increasing prominence of this treatment strategy in upcoming clinical trials. There has been a renewed interest and focus on the drivers of tumoral antigen recognition, and the pathways by which various cells of the immune system can stimulate, propagate and execute an effective anti-tumor response. Various challenges lie ahead in the further development of these treatments, including induction of an endogenous anti-tumor response, tumor microenvironment modulation, and T-cell response amplification. Novel treatment combinations may prove of significant added benefit by immunogenic intensification. C1 [Coyne, Geraldine O'Sullivan; Gulley, James L.] NCI, Genitourinary Malignancies Branch, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Genitourinary Malignancies Branch, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016; OI Gulley, James/0000-0002-6569-2912; O'Sullivan Coyne, Geraldine/0000-0002-2918-6326 NR 49 TC 0 Z9 0 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD NOV PY 2014 VL 10 IS 11 BP 3306 EP 3312 DI 10.4161/21645515.2014.973318 PG 7 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA CB1CN UT WOS:000349364300032 ER PT J AU Melzer, D Joehanes, R Pilling, L Levy, D Munson, P Ferrucci, L AF Melzer, D. Joehanes, R. Pilling, L. Levy, D. Munson, P. Ferrucci, L. TI INFLAMMATION IN AGING: RESULTS FROM TRANSCRIPTOME-WIDE ANALYSIS IN TWO HUMAN COHORTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Melzer, D.; Pilling, L.] Univ Exeter, Exeter, Devon, England. [Joehanes, R.; Levy, D.; Munson, P.] NHLBI, Framingham, MA USA. [Joehanes, R.; Levy, D.; Munson, P.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Ferrucci, L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Joehanes, R.; Munson, P.] Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 32 EP 32 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337500163 ER PT J AU Peters, MJ Joehanes, R Pilling, L Murabito, JM Levy, D Ferrucci, L Johnson, AD AF Peters, M. J. Joehanes, R. Pilling, L. Murabito, J. M. Levy, D. Ferrucci, L. Johnson, A. D. TI AGE AND BLOOD GENE EXPRESSION STUDIES IN similar to 20,000 HUMANS REVEAL NEW AGING GENES SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Joehanes, R.; Levy, D.; Johnson, A. D.] NHLBI, Bethesda, MD 20892 USA. [Peters, M. J.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Murabito, J. M.] Boston Univ, Gen Internal Med Sect, Boston, MA 02215 USA. [Joehanes, R.; Murabito, J. M.; Levy, D.; Johnson, A. D.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Pilling, L.] Univ Exeter, Sch Med, Exeter, Devon, England. [Ferrucci, L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RI Johnson, Andrew/G-6520-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 32 EP 32 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337500162 ER PT J AU Chen, BH Horvath, S Murabito, JM Kiel, DP Lunetta, K Levy, D AF Chen, B. H. Horvath, S. Murabito, J. M. Kiel, D. P. Lunetta, K. Levy, D. TI DNA METHYLATION AGE PREDICTS ALL-CAUSE MORTALITY IN THE FRAMINGHAM HEART STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Chen, B. H.; Levy, D.] NHLBI, Framingham, MA USA. [Chen, B. H.; Murabito, J. M.; Kiel, D. P.; Lunetta, K.; Levy, D.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Horvath, S.] Univ Calif Los Angeles, Los Angeles, CA USA. [Lunetta, K.] Boston Univ, Boston, MA 02215 USA. [Murabito, J. M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kiel, D. P.] Hebrew SeniorLife, Boston, MA USA. [Kiel, D. P.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 33 EP 33 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337500164 ER PT J AU Sutphin, GL Bean, S Peters, MJ van Meurs, J Murabito, JM Johnson, AD Korstanje, R AF Sutphin, G. L. Bean, S. Peters, M. J. van Meurs, J. Murabito, J. M. Johnson, A. D. Korstanje, R. TI A MULTI-ORGANISM APPROACH TO IDENTIFY NOVEL AGING FACTORS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Sutphin, G. L.; Bean, S.; Korstanje, R.] Jackson Lab, Bar Harbor, ME 04609 USA. [Peters, M. J.; van Meurs, J.] Erasmus Univ, Med Ctr, Rotterdam Study, Rotterdam, Netherlands. [Murabito, J. M.; Johnson, A. D.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Murabito, J. M.] Boston Univ, Boston, MA 02215 USA. [Johnson, A. D.] NHLBI, NIH, Bethesda, MD 20892 USA. RI Johnson, Andrew/G-6520-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 33 EP 33 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337500165 ER PT J AU Kitner-Triolo, M An, Y O'Brien, RJ Resnick, S AF Kitner-Triolo, M. An, Y. O'Brien, R. J. Resnick, S. TI CLINICAL DEMENTIA RATING SCALE PREDICTION OF DEMENTIA DIAGNOSIS: SUBJECT VERSUS INFORMANT REPORTS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Kitner-Triolo, M.; An, Y.; O'Brien, R. J.; Resnick, S.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 40 EP 40 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337500201 ER PT J AU Mortenson, W Demers, L Fuhrer, M Jutai, J Lenker, J DeRuyter, F AF Mortenson, W. Demers, L. Fuhrer, M. Jutai, J. Lenker, J. DeRuyter, F. TI DEVELOPMENT AND PRELIMINARY EVALUATION OF THE CAREGIVER ASSISTIVE TECHNOLOGY OUTCOME MEASURE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Mortenson, W.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Demers, L.] Univ Montreal, Montreal, PQ, Canada. [Fuhrer, M.] NIH, Bethesda, MD 20892 USA. [Jutai, J.] Univ Ottawa, Ottawa, ON, Canada. [Lenker, J.] SUNY Buffalo, Buffalo, NY 14260 USA. [DeRuyter, F.] Duke Univ, Charlotte, NC USA. RI Mortenson, William/L-7441-2013 OI Mortenson, William/0000-0002-0183-6163 NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 69 EP 70 PG 2 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501049 ER PT J AU Tian, Q Resnick, S Studenski, S AF Tian, Q. Resnick, S. Studenski, S. TI BRAIN VOLUME AND CARDIORESPIRATORY FITNESS ACROSS 40 YEARS IN THE BALTIMORE LONGITUDINAL STUDY OF AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Tian, Q.; Resnick, S.; Studenski, S.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 90 EP 90 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501133 ER PT J AU Deshpande, N Ferrucci, L AF Deshpande, N. Ferrucci, L. TI 3-YEAR INCIDENCE OF FEAR OF FALLING IN OLDER PERSONS WITH NO HISTORY OF A FALL SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Deshpande, N.] Queens Univ, Kingston, ON, Canada. [Ferrucci, L.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 109 EP 110 PG 2 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501221 ER PT J AU Strotmeyer, ES Boudreau, RM Cauley, JA Caserotti, P Vinik, AI Kritchevsky, SB Harris, TB Newman, AB AF Strotmeyer, E. S. Boudreau, R. M. Cauley, J. A. Caserotti, P. Vinik, A. I. Kritchevsky, S. B. Harris, T. B. Newman, A. B. TI WORSE SENSORIMOTOR NERVE FUNCTION IS ASSOCIATED WITH HIGHER TOTAL MORTALITY RISK SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Strotmeyer, E. S.; Boudreau, R. M.; Cauley, J. A.; Newman, A. B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Caserotti, P.] Univ Southern Denmark, Odense, Denmark. [Vinik, A. I.] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Kritchevsky, S. B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Harris, T. B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 117 EP 117 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501256 ER PT J AU Lange-Maia, B Newman, AB Caserotti, P Glynn, NW Harris, T Kritchevsky, SB Simonsick, EM Strotmeyer, ES AF Lange-Maia, B. Newman, A. B. Caserotti, P. Glynn, N. W. Harris, T. Kritchevsky, S. B. Simonsick, E. M. Strotmeyer, E. S. TI SENSORIMOTOR PERIPHERAL NERVE FUNCTIONING AND THE LONGITUDINAL RELATIONSHIP WITH ENDURANCE WALKING IN THE HEALTH, AGING AND BODY COMPOSITION STUDY SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Lange-Maia, B.; Newman, A. B.; Glynn, N. W.; Strotmeyer, E. S.] Univ Pittsburgh, Pittsburgh, PA USA. [Caserotti, P.] Univ Southern Denmark, Odense, Denmark. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Kritchevsky, S. B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Simonsick, E. M.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 118 EP 118 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501258 ER PT J AU Ferrucci, L AF Ferrucci, L. TI LESSONS FROM THE BALTIMORE LONGITUDINAL STUDY OF AGING SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Ferrucci, L.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 131 EP 131 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501325 ER PT J AU Harrris, TB AF Harrris, T. B. TI MUSCLE, FAT, AND BONE IN HEALTH ABC: A MOLECULAR EPIDEMIOLOGY TRIANGLE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Harrris, T. B.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 131 EP 131 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501326 ER PT J AU Stenholm, S Koster, A Valkeinen, H Patel, K Bandinelli, S Guralnik, J Ferrucci, L AF Stenholm, S. Koster, A. Valkeinen, H. Patel, K. Bandinelli, S. Guralnik, J. Ferrucci, L. TI LIFE-LONG PHYSICAL INACTIVITY AND MOBILITY LOSS IN OLD AGE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Stenholm, S.] Univ Turku, Turku, Finland. [Stenholm, S.; Valkeinen, H.] Natl Inst Hlth & Welf, Turku, Finland. [Koster, A.] Maastricht Univ, NL-6200 MD Maastricht, Netherlands. [Patel, K.] Univ Washington, Seattle, WA 98195 USA. [Bandinelli, S.] Azienda Sanitaria Firenze, Florence, Italy. [Guralnik, J.] Univ Maryland, Baltimore, MD 21201 USA. [Ferrucci, L.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 150 EP 151 PG 2 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501424 ER PT J AU van der Berg, J Bosma, H Caserotti, P Eiriksdottir, G Brychta, RJ Stehouwer, C Harrris, TB Koster, A AF van der Berg, J. Bosma, H. Caserotti, P. Eiriksdottir, G. Brychta, R. J. Stehouwer, C. Harrris, T. B. Koster, A. TI MOVEMENT DURING SEDENTARY TIME IS ASSOCIATED WITH METABOLIC OUTCOMES SO GERONTOLOGIST LA English DT Meeting Abstract C1 [van der Berg, J.; Bosma, H.; Koster, A.] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, NL-6200 MD Maastricht, Netherlands. [Caserotti, P.] Univ Southern Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Eiriksdottir, G.] Iceland Heart Assoc, Kopavogur, Iceland. [Brychta, R. J.] NIDDK, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. [Stehouwer, C.] Maastricht Univ, Med Ctr, Dept Internal Med, Cardiovasc Res Inst Maastricht CARIM, NL-6200 MD Maastricht, Netherlands. [Harrris, T. B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. RI Bosma, Hans/A-6184-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 151 EP 151 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501425 ER PT J AU Westbrook, R Langdon, JM Roy, CN De Cabo, R Walston, JD AF Westbrook, R. Langdon, J. M. Roy, C. N. De Cabo, R. Walston, J. D. TI THE METABOLIC CHARACTERIZATION OF THE INTERLEUKIN-10(TM1CGN) MOUSE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Westbrook, R.; Langdon, J. M.; Roy, C. N.; Walston, J. D.] Johns Hopkins Univ, Baltimore, MD USA. [De Cabo, R.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 159 EP 159 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501470 ER PT J AU Cogger, V Mohamad, M Wu, L De Cabo, R Le Couteur, DG AF Cogger, V. Mohamad, M. Wu, L. De Cabo, R. Le Couteur, D. G. TI DEFENESTRATION OF THE LIVER SINUSOIDAL ENDOTHELIAL CELL IMPAIRS INSULIN AND GLUCOSE UPTAKE SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Cogger, V.; Mohamad, M.; Le Couteur, D. G.] Ctr Educ & Res Ageing, Concord, NSW, Australia. [Cogger, V.; Le Couteur, D. G.] Charles Perkins Ctr, Sydney, NSW, Australia. [Cogger, V.; Mohamad, M.; Le Couteur, D. G.] ANZAC Res Inst, Sydney, NSW, Australia. [Mohamad, M.] Univ Teknol MARA, Fac Pharm, Shah Alam, Selangor, Malaysia. [Wu, L.] Univ New S Wales, Fac Med, Sydney, NSW, Australia. [De Cabo, R.] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 164 EP 164 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501490 ER PT J AU Arnardottir, N Koster, A Sigurdsson, S Launer, LJ Gudnason, V Harris, T Chen, KY Sveinsson, T AF Arnardottir, N. Koster, A. Sigurdsson, S. Launer, L. J. Gudnason, V. Harris, T. Chen, K. Y. Sveinsson, T. TI ASSOCIATION OF BRAIN ANATOMY WITH PHYSICAL ACTIVITY AND SEDENTARY BEHAVIOR IN OLDER ICELANDERS SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Arnardottir, N.; Sveinsson, T.] Univ Iceland, Res Ctr Movement Sci, Reykjavik, Iceland. [Arnardottir, N.; Sigurdsson, S.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Koster, A.] Maastricht Univ, Dept Social Med, Sch Publ Hlth & Primary Care, NL-6200 MD Maastricht, Netherlands. [Chen, K. Y.] NIDDKD, Metab Res Core, Bethesda, MD USA. [Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Launer, L. J.; Harris, T.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RI Gudnason, Vilmundur/K-6885-2015; Sveinsson, Thorarinn/F-7554-2010 OI Gudnason, Vilmundur/0000-0001-5696-0084; Sveinsson, Thorarinn/0000-0001-8989-5514 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2014 VL 54 SU 2 BP 166 EP 166 PG 1 WC Gerontology SC Geriatrics & Gerontology GA AW5TU UT WOS:000346337501498 ER PT J AU Kota, KP Soloveva, V Wanner, LM Gomba, G Kiris, E Panchal, RG Kane, CD Bavari, S AF Kota, Krishna P. Soloveva, Veronica Wanner, Laura M. Gomba, Glenn Kiris, Erkan Panchal, Rekha G. Kane, Christopher D. Bavari, Sina TI A High Content Imaging Assay for Identification of Botulinum Neurotoxin Inhibitors SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Neuroscience; Issue 93; neuroscience; neurobiology; Botulinum neurotoxin; Clostridium botulinum; high content imaging system; neurotoxicity ID SEROTYPE AB Synaptosomal-associated protein-25 (SNAP-25) is a component of the soluble NSF attachment protein receptor (SNARE) complex that is essential for synaptic neurotransmitter release. Botulinum neurotoxin serotype A (BoNT/A) is a zinc metalloprotease that blocks exocytosis of neurotransmitter by cleaving the SNAP-25 component of the SNARE complex. Currently there are no licensed medicines to treat BoNT/A poisoning after internalization of the toxin by motor neurons. The development of effective therapeutic measures to counter BoNT/A intoxication has been limited, due in part to the lack of robust high-throughput assays for screening small molecule libraries. Here we describe a high content imaging (HCI) assay with utility for identification of BoNT/A inhibitors. Initial optimization efforts focused on improving the reproducibility of inter-plate results across multiple, independent experiments. Automation of immunostaining, image acquisition, and image analysis were found to increase assay consistency and minimize variability while enabling the multiparameter evaluation of experimental compounds in a murine motor neuron system. C1 [Kota, Krishna P.] Perkin Elmer Inc, Waltham, MA 02451 USA. [Soloveva, Veronica; Kane, Christopher D.] Henry M Jackson Fdn, Bethesda, MD USA. [Wanner, Laura M.; Kiris, Erkan] Geneva Fdn, Tacoma, WA USA. [Gomba, Glenn] ORISE, Oak Ridge, TN USA. [Kiris, Erkan] Frederick Natl Lab Canc Res, Frederick, MD USA. [Kota, Krishna P.; Soloveva, Veronica; Wanner, Laura M.; Gomba, Glenn; Kiris, Erkan; Panchal, Rekha G.; Kane, Christopher D.; Bavari, Sina] US Army Med Res Inst Infect Dis, Div Mol & Translat Sci, Frederick, MD USA. [Soloveva, Veronica; Kane, Christopher D.] USAMRMC, TATRC, DoD Biotechnol High Performance Comp Software App, Frederick, MD USA. RP Kota, KP (reprint author), Perkin Elmer Inc, Waltham, MA 02451 USA. EM krishna.p.kota.ctr@mail.mil FU Joint Science and Technology Office - Chemical Biological Defense (JSTO-CBD) Defense Threat Reduction Agency (DTRA) [CB3675]; National Institutes of Health [1 R21 AI101387-01, 5 U01AI082051-05] FX Funding was provided by the Joint Science and Technology Office - Chemical Biological Defense (JSTO-CBD) Defense Threat Reduction Agency (DTRA) under sponsor project number CCAR# CB3675 and National Institutes of Health (1 R21 AI101387-01 and 5 U01AI082051-05). NR 14 TC 2 Z9 2 U1 1 U2 3 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 NOV PY 2014 IS 93 AR e51915 DI 10.3791/51915 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0JH UT WOS:000349311400022 PM 25489815 ER PT J AU Kim, HY AF Kim, Hee-Yong TI Neuroprotection by Docosahexaenoic Acid in Brain Injury SO MILITARY MEDICINE LA English DT Article ID N-3 FATTY-ACIDS; TRAUMATIC AXONAL INJURY; ALZHEIMERS-DISEASE; PEROXISOMAL DISORDERS; HIPPOCAMPAL-NEURONS; CEREBRAL-ISCHEMIA; LEARNING-ABILITY; OXIDATIVE STRESS; LIPID MEDIATORS; RAT HIPPOCAMPUS AB Docosahexaenoic acid (DHA, 22:6 n-3) is an omega-3 polyunsaturated fatty acid highly enriched in the brain and is recognized as an essential nutrient for proper development of brain function. Common brain injuries often cause lifelong neurological and cognitive impairments, especially in learning and memory. Optimizing the nutritional DHA status in neural tissues may allow significantly improved resilience for the central nervous system to injury and optimized recovery. This article discusses neuroprotective effects of DHA, which are potentially important for improving injury outcome, thus reducing the risk of lifelong neurological impairment associated with brain injury. C1 NIAAA, Lab Mol Signaling, DICBR, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Lab Mol Signaling, DICBR, NIH, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health FX The author thanks Dr. Arthur Spector and Ms. Lori Flax Levin for editorial assistance. This work was supported by the Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health. NR 73 TC 2 Z9 2 U1 4 U2 8 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2014 VL 179 IS 11 SU S BP 106 EP 111 DI 10.7205/MILMED-D-14-00162 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA CA7LS UT WOS:000349099400008 PM 25373093 ER PT J AU Hibbeln, JR Gow, RV AF Hibbeln, Joseph R. Gow, Rachel V. TI The Potential for Military Diets to Reduce Depression, Suicide, and Impulsive Aggression: A Review of Current Evidence for Omega-3 and Omega-6 Fatty Acids SO MILITARY MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; YOUNG-ADULT PRISONERS; MAJOR DEPRESSION; FISH CONSUMPTION; DOUBLE-BLIND; SEAFOOD CONSUMPTION; MENTAL-HEALTH; MEDITERRANEAN DIET; DOCOSAHEXAENOIC ACID AB The current burden of psychological distress and illness poses as a significant barrier to optimal force efficacy. Here we assess nutrients in military diets, specifically highly unsaturated essential fatty acids, in the reduction of risk or treatment of psychiatric distress. Moderate to strong evidence from several meta-analyses of prospective cohort trials indicate that Mediterranean diet patterns reduce risk of clinical depressions. Specific nutrients and foods of biological interest in relation to mental health outcomes are then discussed and evaluated. Moderate evidence indicates that when fish consumption decreases and simultaneously omega-6 increases, the risk of clinical depressive symptoms are elevated. One meta-analysis examining tissue compositions provides moderate to strong evidence that higher levels of omega-3 highly unsaturated fatty acids (HUFAs) (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) are associated with decreased risk of clinical depressions. Other meta-analytic reviews of randomized placebo-controlled trials provide moderate to strong evidence of significantly improving clinically depressive symptoms when the formulation given was >50% in eicosapentaenoic acid. Finally, a meta-analysis of omega-3 HUFAs provides modest evidence of clinical efficacy for attention-deficit hyperactivity disorder. This article recommends that a rebalancing of the essential fatty acid composition of U. S. military diets, achieve tissue compositions of HUFAs consistent with traditional Mediterranean diets, may help reduce military psychiatric distress and simultaneously increase force efficacy substantially. C1 [Hibbeln, Joseph R.; Gow, Rachel V.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Hibbeln, JR (reprint author), NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Lane,Room 3N-07,MSC 9410, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism FX Support was provided by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism. NR 103 TC 7 Z9 7 U1 8 U2 25 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2014 VL 179 IS 11 SU S BP 117 EP 128 DI 10.7205/MILMED-D-14-00153 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA CA7LS UT WOS:000349099400010 PM 25373095 ER PT J AU Hamazaki, T Colleran, H Hamazaki, K Matsuoka, Y Itomura, M Hibbeln, J AF Hamazaki, Tomohito Colleran, Heather Hamazaki, Kei Matsuoka, Yutaka Itomura, Miho Hibbeln, Joseph TI The Safety of Fish Oils for Those Whose Risk of Injury is High SO MILITARY MEDICINE LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; COD-LIVER OIL; PLATELET-AGGREGATION; HEMORRHAGIC STROKE; DIALYSIS PATIENTS; BLOOD-PRESSURE; BLEEDING-TIME; DOUBLE-BLIND; HEMOSTASIS; LIPIDS AB A diet rich in omega-3 polyunsaturated fatty acids (PUFAs) may decrease risk of cardiovascular disease by improving the blood lipid profile. The purpose of this review was to (1) determine if fish oil (omega-3) consumption increased the risk of hemorrhaging after a military injury and (2) whether an improvement in the omega-3 PUFA profile had an impact on survivability from military wounds. The authors found no evidence to contradict the existing U.S. Food and Drug Administration safety ruling that 3 g of omega-3 PUFA per day is generally regarded as safe. However, there is insufficient data with regard to the safety of consuming more than 3 g of omega-3 PUFA per day. More research is needed to safely recommend use of higher doses omega-3 PUFA. C1 [Hamazaki, Tomohito] Toyama Jonan Onsen Daini Hosp, Toyama 9398271, Japan. [Colleran, Heather] Elon Univ, Elon, NC USA. [Colleran, Heather] High Point Univ, High Point, NC USA. [Hamazaki, Kei] Toyama Univ, Sch Med, Dept Publ Hlth, Toyama 9300194, Japan. [Matsuoka, Yutaka] Natl Ctr Neurol & Psychiat, Dept Clin Epidemiol, Translat Med Ctr, Kodaira, Tokyo 1878551, Japan. [Itomura, Miho] Toyama Univ, Sect Clin Applicat, Dept Clin Sci, Inst Nat Med, Toyama 9300194, Japan. [Hibbeln, Joseph] NIAAA, NIH, Bethesda, MD 20892 USA. RP Hamazaki, T (reprint author), Toyama Jonan Onsen Daini Hosp, Taromaru Nishimachi, Toyama 9398271, Japan. FU Polyene Project Corp; Open Research Center (Kinjogakuin University) FX This work was partly supported by Polyene Project Corp and Open Research Center (Kinjogakuin University). NR 30 TC 2 Z9 2 U1 0 U2 2 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2014 VL 179 IS 11 SU S BP 134 EP 137 DI 10.7205/MILMED-D-14-00157 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CA7LS UT WOS:000349099400012 PM 25373097 ER PT J AU Marriott, BP Yu, K Majchrzak-Hong, S Johnson, J Hibbeln, JR AF Marriott, Bernadette P. Yu, Karina Majchrzak-Hong, Sharon Johnson, Jeremiah Hibbeln, Joseph R. TI Understanding Diet and Modeling Changes in the Omega-3 and Omega-6 Fatty Acid Composition of US Garrison Foods for Active Duty Personnel SO MILITARY MEDICINE LA English DT Article ID OMEGA-3-FATTY-ACID STATUS; PLASMA; POPULATION; SUICIDE AB Research indicates that dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are important in reducing the risk of mental illness. We used the DoD Survey of Health Related Behaviors among Active Duty Military Personnel (HRBS) to assess current military dietary patterns and meal locations. We used the Lands Equation to model PUFAs in a sample Garrison diet and the nutritional impact of substitution of foods higher in omega-3 PUFAs and lower in omega-6 PUFAs on tissue composition. The military diet was very poor quality compared to 2010 Healthy People Guidelines. A representative Garrison diet does not meet our estimated healthy n-3 HUFA intake at 3.5 g/d, corresponding with a tissue composition of 60% n-3 in HUFA (i.e., 40% n-6 in HUFA). Substitution of n-3 rich eggs, poultry, pork and other food commodities, combined with use on low linoleic acid oils, may contribute significantly to attaining healthier n-6/n-3 proportions in the tissue. C1 [Marriott, Bernadette P.] Samueli Inst, Alexandria, VA 22314 USA. [Yu, Karina; Majchrzak-Hong, Sharon; Johnson, Jeremiah; Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, LMBB,NIH, Bethesda, MD 20892 USA. RP Marriott, BP (reprint author), Med Univ S Carolina, 114 Doughty St,STB 629A, Charleston, SC 29425 USA. RI Majchrzak, Sharon/F-1830-2013 OI Majchrzak, Sharon/0000-0001-8934-7294 FU National Institute on Alcohol Abuse and Alcoholism FX The authors gratefully acknowledge the assistance of Viviane Enslein and Samantha Wise for their work in formatting and editing various versions of this article. The Intramural program of the National Institute on Alcohol Abuse and Alcoholism provided support for this work. NR 20 TC 1 Z9 1 U1 1 U2 5 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2014 VL 179 IS 11 SU S BP 168 EP 175 DI 10.7205/MILMED-D-14-00199 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CA7LS UT WOS:000349099400017 PM 25373102 ER PT J AU Salas, LA Villanueva, CM Tajuddin, SM Amaral, AFS Fernandez, AF Moore, LE Carrato, A Tardon, A Serra, C Garcia-Closas, R Basagana, X Rothman, N Silverman, DT Cantor, KP Kogevinas, M Real, FX Fraga, MF Malats, N AF Salas, Lucas A. Villanueva, Cristina M. Tajuddin, Salman M. Amaral, Andre F. S. Fernandez, Agustin F. Moore, Lee E. Carrato, Alfredo Tardon, Adonina Serra, Consol Garcia-Closas, Reina Basagana, Xavier Rothman, Nathaniel Silverman, Debra T. Cantor, Kenneth P. Kogevinas, Manolis Real, Francisco X. Fraga, Mario F. Malats, Nuria TI LINE-1 methylation in granulocyte DNA and trihalomethane exposure is associated with bladder cancer risk SO EPIGENETICS LA English DT Article DE DNA methylation; epigenetic repression; long interspersed nucleotide elements; LINE-1; trihalomethanes; urinary bladder cancer; DBP; Disinfection by-products; LINE-1; Long Interspersed Element 1; OR; Odds ratio; SBC; EPICURO; Spanish Bladder Cancer; EPICURO Study; THM; Trihalomethanes; UBC; Urothelial bladder cancer; y; years; %5mC; Percentage of 5-methylcytosine; 95%; CI; 95%; confidence intervals ID BY-PRODUCT BROMODICHLOROMETHANE; DRINKING-WATER; LEUKOCYTE DNA; BLOOD-CELLS; HYPOMETHYLATION; INDUCTION; MOUSE; LIVER; GENE; RETROTRANSPOSONS AB DNA methylation changes contribute to bladder carcinogenesis. Trihalomethanes (THM), a class of disinfection by-products, are associated with increased urothelial bladder cancer (UBC) risk. THM exposure in animal models produces DNA hypomethylation. We evaluated the relationship of LINE-1 5-methylcytosine levels (LINE-1%5mC) as outcome of long-term THM exposure among controls and as an effect modifier in the association between THM exposure and UBC risk. We used a case-control study of UBC conducted in Spain. We obtained personal lifetime residential THM levels and measured LINE-1%5mC by pyrosequencing in granulocyte DNA from blood samples in 548 incident cases and 559 hospital controls. Two LINE-1%5mC clusters (above and below 64%) were identified through unsupervised hierarchical cluster analysis. The association between THM levels and LINE-1%5mC was evaluated with regression analyses and logistic regression was used to estimate odds ratios (OR) adjusting for covariables. LINE-1%5mC change between percentiles 75(th) and 25(th) of THM levels was 1.8% (95% confidence interval (CI): 0.1, 3.4%) among controls. THM levels above vs. below the median (26g/L) were associated with increased UBC risk, OR = 1.86 (95% CI: 1.25, 2.75), overall and among subjects with low levels of LINE-1%5mC (n = 975), OR = 2.14 (95% CI: 1.39, 3.30), but not associated with UBC risk among subjects' high levels of LINE-1%5mC (n = 162), interaction P = 0.03. Results suggest a positive association between LINE-1%5mC and THM levels among controls, and LINE-1%5mC status may modify the association between UBC risk and THM exposure. Because reverse causation and chance cannot be ruled out, confirmation studies are warranted. C1 [Salas, Lucas A.; Villanueva, Cristina M.; Basagana, Xavier; Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Salas, Lucas A.; Villanueva, Cristina M.; Basagana, Xavier; Kogevinas, Manolis; Real, Francisco X.] UPF, Barcelona, Spain. [Salas, Lucas A.; Villanueva, Cristina M.; Tardon, Adonina; Basagana, Xavier; Kogevinas, Manolis] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Villanueva, Cristina M.; Kogevinas, Manolis] IMIM Hosp del Mar Med Res Inst, Barcelona, Spain. [Tajuddin, Salman M.; Amaral, Andre F. S.; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Fernandez, Agustin F.; Fraga, Mario F.] Univ Oviedo, Canc Epigenet Lab, Inst Univ Oncol Principado Asturias IUOPA HUCA, Oviedo, Spain. [Moore, Lee E.; Rothman, Nathaniel; Silverman, Debra T.; Cantor, Kenneth P.] NCI, Bethesda, MD 20892 USA. [Carrato, Alfredo] Univ Hosp Elche, Elche, Spain. [Carrato, Alfredo] Hosp Ramon & Cajal, E-28034 Madrid, Spain. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Serra, Consol] UPF, Ctr Res Occupat Hlth, Madrid, Spain. [Serra, Consol] Consorci Hosp Parc Tauli, Sabadell, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, San Cristobal la Laguna, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Real, Francisco X.] Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain. RP Malats, N (reprint author), Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. EM cvillanueva@creal.cat; nmalats@cnio.es RI Benavides, Fernando/A-5137-2008; Malats, Nuria/H-7041-2015; Kogevinas, Manolis/C-3918-2017; Amaral, Andre/A-7662-2008; Villanueva, Cristina/N-1942-2014; Real Arribas, Francisco/H-5275-2015; Fernandez, Agustin/N-7302-2014; Basagana, Xavier/C-3901-2017 OI Tajuddin, Salman M./0000-0002-7919-8528; Salas, Lucas A/0000-0002-2279-4097; Benavides, Fernando/0000-0003-0747-2660; Malats, Nuria/0000-0003-2538-3784; Amaral, Andre/0000-0002-0369-9449; Villanueva, Cristina/0000-0002-0783-1259; Real Arribas, Francisco/0000-0001-9501-498X; Fernandez, Agustin/0000-0002-3792-4085; Basagana, Xavier/0000-0002-8457-1489 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [NCI NO2-CP-11015]; Spanish Health Ministry (Fondo de Investigaciones Sanitarias-FIS, Instituto de Salud Carlos III, Spain) [00/0745, ISIII-GO3/174, PI080533, PI051436, PI061614, PI09-02102, PI11/00226]; European Union [BMH4-98-3243]; Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0050-RTICC]; Fundacion Cientifica de la AECC; Fundacio Marato TV3; Association for International Cancer Research (AICR) [09-0780]; Colciencias PhD Scholarship, Colombia [529/2011]; Instituto de Salud Carlos III FEDER [PI11/00226]; [USA-NIH-RO1-CA089715] FX This study was partially supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Contract NCI NO2-CP-11015); the Spanish Health Ministry (Fondo de Investigaciones Sanitarias-FIS, Instituto de Salud Carlos III, Spain 00/0745, ISIII-GO3/174, PI080533, PI051436, PI061614, PI09-02102, and PI11/00226) and the European Union (BMH4-98-3243); Red Tematica de Investigacion Cooperativa en Cancer- RD12/0036/0050-RTICC; USA-NIH-RO1-CA089715; a postdoctoral fellowship awarded to AFSA from the Fundacion Cientifica de la AECC; Fundacio Marato TV3. The work was partially supported by the Association for International Cancer Research (AICR, #09-0780, including a PhD scholarship awarded to S.M.T.). The current analyses were supported by a Colciencias PhD Scholarship, Colombia (Grant: 529/2011 to L. A.S.). This work was also supported by grants from the Instituto de Salud Carlos III FEDER, (PI11/00226). NR 45 TC 8 Z9 8 U1 1 U2 8 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD NOV PY 2014 VL 9 IS 11 BP 1532 EP 1539 DI 10.4161/15592294.2014.983377 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AZ8CI UT WOS:000348442000011 PM 25482586 ER PT J AU Srinivasan, R Su, D Stamatakis, L Siddiqui, MM Singer, E Shuch, B Nix, J Friend, J Hawks, G Shih, J Choyke, R Linehan, WM AF Srinivasan, R. Su, D. Stamatakis, L. Siddiqui, M. M. Singer, E. Shuch, B. Nix, J. Friend, J. Hawks, G. Shih, J. Choyke, R. Linehan, W. M. TI Mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Srinivasan, R.; Su, D.; Stamatakis, L.; Siddiqui, M. M.; Singer, E.; Shuch, B.; Nix, J.; Friend, J.; Hawks, G.; Shih, J.; Choyke, R.; Linehan, W. M.] NCI, Urol Oncol Branch, 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 5 BP 8 EP 8 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700006 ER PT J AU Figg, W Sissung, TM Peer, CJ Schrump, D AF Figg, W. Sissung, T. M. Peer, C. J. Schrump, D. TI Pharmacogenomics of mithramycin in thoracic malignancies SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Figg, W.; Sissung, T. M.; Peer, C. J.] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Schrump, D.] NCI, Thorac Oncol Sect, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 21 BP 13 EP 13 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700022 ER PT J AU Evans, D Delosh, R Laudeman, J Ogle, C Reinhart, R Selby, M Silvers, T Monks, A Polley, E Kaur, G Morris, J Teicher, BA AF Evans, D. Delosh, R. Laudeman, J. Ogle, C. Reinhart, R. Selby, M. Silvers, T. Monks, A. Polley, E. Kaur, G. Morris, J. Teicher, B. A. TI A comprehensive in vitro screen to identify therapeutic candidates for inclusion with etoposide/platin combinations to improve treatment of SCLC SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Evans, D.; Delosh, R.; Laudeman, J.; Ogle, C.; Reinhart, R.; Selby, M.; Silvers, T.; Monks, A.] MPB DCTD, Frederick Natl Lab Canc Res, Frederick, MD USA. [Polley, E.; Kaur, G.; Morris, J.; Teicher, B. A.] NCI, DCTD, Rockville, MD 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 78 BP 30 EP 30 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700079 ER PT J AU Bando, H Lih, J Polley, EC Holbeck, SL Das, B Sims, D Doi, T Ohtsu, A Williams, M Takebe, N AF Bando, H. Lih, J. Polley, E. C. Holbeck, S. L. Das, B. Sims, D. Doi, T. Ohtsu, A. Williams, M. Takebe, N. TI PIK3CA mutation-targeting compounds analyses using NCI60 cell line panel SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Bando, H.; Takebe, N.] NCI, NIH, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD USA. [Lih, J.; Das, B.; Sims, D.; Williams, M.] NCI, NIH, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Polley, E. C.] NCI, NIH, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD USA. [Holbeck, S. L.] NCI, NIH, Dev Therapeut Program, Div Canc Treatment & Diag, Rockville, MD USA. [Doi, T.; Ohtsu, A.] Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, Kashiwa, Chiba, Japan. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 101 BP 36 EP 37 PG 2 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700102 ER PT J AU Holbeck, S Collins, JM Doroshow, JD AF Holbeck, S. Collins, J. M. Doroshow, J. D. TI Combination screening of investigational oncology agents SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Holbeck, S.] NCI, Rockville, MD USA. [Collins, J. M.] NCI, DCTD, Rockville, MD USA. [Doroshow, J. D.] NCI, DCTD, 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 99 BP 36 EP 36 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700100 ER PT J AU Hose, CD Zhao, Y Polley, EC Fang, J Fer, ND Rapisarda, A Teicher, BA Simon, RM Doroshow, JD Monks, A AF Hose, C. D. Zhao, Y. Polley, E. C. Fang, J. Fer, N. D. Rapisarda, A. Teicher, B. A. Simon, R. M. Doroshow, J. D. Monks, A. TI Antagonistic interaction between gemcitabine and erlotinib is influenced by EGR1 (early growth response 1) transcription factor expression SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Hose, C. D.; Fer, N. D.; Rapisarda, A.; Monks, A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Zhao, Y.; Polley, E. C.; Fang, J.; Teicher, B. A.; Simon, R. M.; Doroshow, J. D.] NCI, DCTD, Frederick, MD 21701 USA. 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 171 BP 57 EP 57 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700172 ER PT J AU Dunn, B Steele, VE Fagerstrom, RM Topp, CF Ransohoff, D Cunningham, C Lubet, R Ford, LG Kramer, BS AF Dunn, B. Steele, V. E. Fagerstrom, R. M. Topp, C. F. Ransohoff, D. Cunningham, C. Lubet, R. Ford, L. G. Kramer, B. S. TI Estimating predictive values of short-term morphologic assays of cancer chemoprevention for efficacy in animal tumor assays SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Dunn, B.; Steele, V. E.; Fagerstrom, R. M.] NCI, NIH, Canc Prevent Div, Bethesda, MD 20892 USA. [Topp, C. F.] CCS Associates, Preclin Res & Dev Resources, Mclean, VA USA. [Ransohoff, D.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Cunningham, C.] Informat Management Serv Inc, Rockville, MD USA. [Lubet, R.; Ford, L. G.; Kramer, B. S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 222 BP 75 EP 75 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700223 ER PT J AU Shoemaker, RH Dunn, BK Suen, C Lubet, RA Boring, DL Klein, BD Miller, MS Steele, VE AF Shoemaker, R. H. Dunn, B. K. Suen, C. Lubet, R. A. Boring, D. L. Klein, B. D. Miller, M. S. Steele, V. E. TI Molecular targets of interest to the NCI PREVENT cancer preclinical drug development program SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Shoemaker, R. H.; Dunn, B. K.; Suen, C.; Lubet, R. A.; Boring, D. L.; Klein, B. D.; Miller, M. S.; Steele, V. E.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 225 BP 76 EP 76 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700226 ER PT J AU Steele, VE Grubbs, C Rao, CV Lubet, RA AF Steele, V. E. Grubbs, C. Rao, C. V. Lubet, R. A. TI Efficacy of cancer preventing drugs administered by intermittent dosing regimens SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Steele, V. E.; Lubet, R. A.] NCI, NIH, Canc Prevent Div, Bethesda, MD 20892 USA. [Grubbs, C.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Rao, C. V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, Oklahoma City, OK 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 226 BP 76 EP 76 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700227 ER PT J AU Yang, SX Nguyen, D Rubinstein, L Kummar, S Tomaszewski, JE Doroshow, JH AF Yang, S. X. Nguyen, D. Rubinstein, L. Kummar, S. Tomaszewski, J. E. Doroshow, J. H. TI DNA methyltransferase 1 expression in human solid tumors and lymphomas by immunohistochemistry SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Yang, S. X.; Nguyen, D.; Rubinstein, L.; Kummar, S.; Tomaszewski, J. E.; Doroshow, J. H.] NCI, NIH, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 229 BP 77 EP 77 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700230 ER PT J AU Lih, C Sims, DJ Harrington, RD Polley, EC Zhao, Y Simon, RM Mehaffey, MG Forbes, TD Walsh, WD Datta, V Conley, BA Chen, AP Kummar, S Doroshow, JH Williams, PM AF Lih, C. Sims, D. J. Harrington, R. D. Polley, E. C. Zhao, Y. Simon, R. M. Mehaffey, M. G. Forbes, T. D. Walsh, W. D. Datta, V. Conley, B. A. Chen, A. P. Kummar, S. Doroshow, J. H. Williams, P. M. TI Analytical validation and application of the MPACT assay, a next generation sequencing based targeted mutation detection assay for treatment selection SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Lih, C.; Sims, D. J.; Harrington, R. D.; Mehaffey, M. G.; Forbes, T. D.; Walsh, W. D.; Datta, V.; Williams, P. M.] Leidos Biomed Inc, Frederick Natl Lab Canc Res, Mol Characterizat Lab, Baltimore, MD USA. [Polley, E. C.; Zhao, Y.; Simon, R. M.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Conley, B. A.] NCI, Canc Diag Program, Bethesda, MD 20892 USA. [Chen, A. P.; Kummar, S.; Doroshow, J. H.] NCI, Div Canc Treatment & Diag, 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 233 BP 78 EP 78 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700234 ER PT J AU Williams, M Sims, D Lih, J Datta, A Hamilton, S Iafrate, AJ Sklar, J Sadis, S Takabe, N Tricoli, J Doroshow, J Conley, B AF Williams, M. Sims, D. Lih, J. Datta, A. Hamilton, S. Iafrate, A. J. Sklar, J. Sadis, S. Takabe, N. Tricoli, J. Doroshow, J. Conley, B. TI Development of a targeted NGS assay system for patient enrollment to the NCI-MATCH study SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Williams, M.; Sims, D.; Lih, J.; Datta, A.] NCI, Mol Charterizat & Clin Assay Dev Lab, Frederick, MD 21701 USA. [Hamilton, S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Iafrate, A. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sklar, J.] Yale Univ, Med Ctr, New Haven, CT USA. [Sadis, S.] Life Technol, Compendia, Foster City, CA USA. [Takabe, N.] NCI, CTEP, Bethesda, MD 20892 USA. [Tricoli, J.; Conley, B.] NCI, CDP, Shady Grove, MD USA. [Doroshow, J.] NCI, DCTD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 232 BP 78 EP 78 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700233 ER PT J AU Josse, R Martin, SE Guha, R Ormanoglu, P Pfister, T Morris, J Doroshow, J Pommier, Y AF Josse, R. Martin, S. E. Guha, R. Ormanoglu, P. Pfister, T. Morris, J. Doroshow, J. Pommier, Y. TI Use of ATR inhibitor in combination with topoisomerase I inhibitor kills cancer cells by disabling DNA replication initiation and fork elongation SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Josse, R.; Pommier, Y.] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Martin, S. E.; Guha, R.; Ormanoglu, P.] NCATS, Div Preclin Innovat, Rockville, MD USA. [Pfister, T.] Leidos Biomed Res Inc, Lab Human Toxicol & Pharmacol, Frederick, MD USA. [Morris, J.; Doroshow, J.] DTP DCTD, Drug Synth & Chem Branch, Bethesda, MD 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 248 BP 83 EP 83 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700249 ER PT J AU Pommier, Y Bilke, SW Sousa, F Yamade, M Murai, J Rajapakse, V Helman, L Meltzer, P AF Pommier, Y. Bilke, S. W. Sousa, F. Yamade, M. Murai, J. Rajapakse, V. Helman, L. Meltzer, P. TI The DNA damage response gene Schlafen 11 (SLFN11) is a transcriptional target of ETS transcription factors in Ewing's sarcoma and other cancers SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Pommier, Y.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Bilke, S. W.; Meltzer, P.] NCI, Genet Branch, Bethesda, MD 20892 USA. [Sousa, F.; Yamade, M.; Murai, J.; Rajapakse, V.] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Helman, L.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 252 BP 84 EP 84 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700253 ER PT J AU Wishka, DG Kumar, V Teicher, B Kaur, G Fang, B Risbood, P Hollingshead, M Zais, J Morris, J AF Wishka, D. G. Kumar, V. Teicher, B. Kaur, G. Fang, B. Risbood, P. Hollingshead, M. Zais, J. Morris, J. TI The NCI-60 as an effective tool for scaffold hopping: A phenotypic systems-based approach to the design of novel chemotherapeutics SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Wishka, D. G.] NCI, Drug Synth & Chem Branch, Frederick, MD 21701 USA. [Kumar, V.] Leidos Biomed Res, Drug Synth & Chem Branch, Frederick, MD USA. [Teicher, B.] NCI, Mol Pharmacol Branch, Rockville, MD USA. [Kaur, G.] NCI, Mol Pharmacol Branch, Frederick, MD 21701 USA. [Fang, B.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Risbood, P.; Morris, J.] NCI, Drug Synth & Chem Branch, Rockville, MD USA. [Hollingshead, M.; Zais, J.] NCI, Biol Testing Branch, Frederick, MD 21701 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 269 BP 89 EP 90 PG 2 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700270 ER PT J AU Gameiro, S Ardiani, A Kwilas, AR Donahue, RN Hodge, JW AF Gameiro, S. Ardiani, A. Kwilas, A. R. Donahue, R. N. Hodge, J. W. TI Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Gameiro, S.; Ardiani, A.; Kwilas, A. R.; Donahue, R. N.; Hodge, J. W.] NCI, CCRILTIB, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 308 BP 101 EP 101 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700309 ER PT J AU Wan, X Yeung, C Heske, C Mendoza, A Himan, LJ AF Wan, X. Yeung, C. Heske, C. Mendoza, A. HIman, L. J. TI IGF-1R inhibition induced activation of Yes/SFK acts as a by-pass resistance pathway in rhabdomyosarcoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Wan, X.; Yeung, C.; Heske, C.; Mendoza, A.; HIman, L. J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 311 BP 101 EP 101 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700312 ER PT J AU Thomas, A Chen, Y Steinberg, S Luo, J Giaccone, G Pastan, I Miettinen, M Hassan, R AF Thomas, A. Chen, Y. Steinberg, S. Luo, J. Giaccone, G. Pastan, I. Miettinen, M. Hassan, R. TI The prognostic role of mesothelin expression and its association with KRAS mutation in advanced lung adenocarcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Thomas, A.] NCI, Bethesda, MD 20892 USA. [Chen, Y.; Hassan, R.] NCI, Thorac & GI Oncol Branch, Bethesda, MD 20892 USA. [Steinberg, S.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Luo, J.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Giaccone, G.] Georgetown Univ, Washington, DC USA. [Pastan, I.] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Miettinen, M.] NCI, Pathol Lab, 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 312 BP 102 EP 102 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700313 ER PT J AU Kim, M Min, DJ Wright, G Annunziata, C AF Kim, M. Min, D. J. Wright, G. Annunziata, C. TI Cytosolic p21 is a pharmacodynamic marker of CHEK1 and IKK epsilon inhibition in ovarian cancer cells SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Kim, M.; Min, D. J.; Wright, G.; Annunziata, C.] NCI, CCR, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 363 BP 117 EP 117 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700364 ER PT J AU Bekdash, A Liu, SH Leppla, SH Frankel, AE Abi-Habib, R AF Bekdash, A. Liu, S. H. Leppla, S. H. Frankel, A. E. Abi-Habib, R. TI Sensitivity of acute myeloid leukemia cells to a urokinase-activated anthrax lethal toxin (PrAgU2/lf) is dependent on uPAR expression and phospho-MEK1/2 levels SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Bekdash, A.; Abi-Habib, R.] Lebanese Amer Univ, Dept Nat Sci, Beirut, Lebanon. [Liu, S. H.; Leppla, S. H.] NIAID, NIH, Bethesda, MD 20892 USA. [Frankel, A. E.] UT Southwestern Med Ctr, Simmons Comprehens Canc Ctr, Dallas, TX USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 394 BP 126 EP 126 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700395 ER PT J AU Houghton, P Lock, R Carol, H Gorlick, R Kolb, A Maris, J Keir, S Wu, J Kang, M Reynolds, P Kurmasheva, R Smith, M AF Houghton, P. Lock, R. Carol, H. Gorlick, R. Kolb, A. Maris, J. Keir, S. Wu, J. Kang, M. Reynolds, P. Kurmasheva, R. Smith, M. TI The Pediatric Preclinical Testing Program (PPTP): Analysis of the first 10 years in vivo testing SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Houghton, P.; Kurmasheva, R.] Nationwide Childrens Hosp, Ctr Childhood Canc, Columbus, OH USA. [Lock, R.; Carol, H.] Childrens Canc Inst, Leukemia Biol Program, Randwick, NSW, Australia. [Gorlick, R.] Montefiore Med Ctr, Dept Pediat, Bronx, NY 10467 USA. [Kolb, A.] Alfred I DuPont Hosp Children, Dept Oncol, Wilmington, NC USA. [Maris, J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Keir, S.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27706 USA. [Wu, J.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kang, M.; Reynolds, P.] Texas Tech Univ, Hlth Sci Ctr, Ctr Canc, Lubbock, TX 79430 USA. [Smith, M.] NCI, Canc Therapy Evaluat Program, 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 412 BP 131 EP 132 PG 2 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700413 ER PT J AU Smith, M Kang, M Reynolds, P Lock, R Carol, H Gorlick, R Kolb, A Maris, J Keir, S Wu, J Kurmasheva, R Houghton, P AF Smith, M. Kang, M. Reynolds, P. Lock, R. Carol, H. Gorlick, R. Kolb, A. Maris, J. Keir, S. Wu, J. Kurmasheva, R. Houghton, P. TI Pediatric Preclinical Testing Program (PPTP) Evaluation of the p53-MDM2 Antagonist MK-8242 SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Smith, M.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Kang, M.; Reynolds, P.] Texas Tech Univ, Hlth Sci Ctr, Ctr Canc, Lubbock, TX 79430 USA. [Lock, R.; Carol, H.] Childrens Canc Inst Australia, Leukemia Biol Program, Randwick, NSW, Australia. [Gorlick, R.] Montefiore Med Ctr, Dept Pediat, Bronx, NY 10467 USA. [Kolb, A.] Alfred I DuPont Hosp Children, Dept Oncol, Wilmington, NC USA. [Maris, J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Keir, S.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27706 USA. [Wu, J.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, R.; Houghton, P.] Nationwide Childrens Hosp, Ctr Childhood Canc, Columbus, OH USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 410 BP 131 EP 131 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700411 ER PT J AU Hose, C Fer, ND Burkett, M Connelly, J Harris, E Lih, J Williams, M Evans, D Silvers, T Monks, A Parchment, R Teicher, BA Doroshow, JH Rapisarda, A AF Hose, C. Fer, N. D. Burkett, M. Connelly, J. Harris, E. Lih, J. Williams, M. Evans, D. Silvers, T. Monks, A. Parchment, R. Teicher, B. A. Doroshow, J. H. Rapisarda, A. TI Precise gene editing of mutant NRAS using CRISPR to determine sensitivity to trametinib SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Hose, C.; Fer, N. D.; Burkett, M.; Connelly, J.; Harris, E.; Evans, D.; Silvers, T.; Monks, A.; Rapisarda, A.] Leidos Biomed Res Inc DTP MPB, Frederick Natl Lab Canc Res, Frederick, MD USA. [Lih, J.; Williams, M.] Leidos Biomed Res Inc DCTD CDP, Frederick Natl Lab Canc Res, Frederick, MD USA. [Parchment, R.] Leidos Biomed Res Inc DCTD LSS, Frederick Natl Lab Canc Res, Frederick, MD USA. [Teicher, B. A.] NCI, DCTD DTP MPB, Rockville, MD USA. [Doroshow, J. H.] NCI, DCTD, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 450 BP 147 EP 148 PG 2 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700451 ER PT J AU Chiu, JW Hotte, SJ Kollmannsberger, CK Renout, DJ Cescon, DW Hedley, D Chow, S Moscow, J Perry, M Diaz-Padilla, I Tan, D Hirte, H McWhirter, E Chen, H Siu, LL Bedard, PL AF Chiu, J. W. Hotte, S. J. Kollmannsberger, C. K. Renout, D. J. Cescon, D. W. Hedley, D. Chow, S. Moscow, J. Perry, M. Diaz-Padilla, I. Tan, D. Hirte, H. McWhirter, E. Chen, H. Siu, L. L. Bedard, P. L. TI A phase Ib trial of AMG386 and temsirolimus in patients with advanced sold tumors (PJC-008/NCI#9041) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Chiu, J. W.; Cescon, D. W.; Hedley, D.; Chow, S.; Perry, M.; Diaz-Padilla, I.; Tan, D.; Siu, L. L.; Bedard, P. L.] Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada. [Hotte, S. J.; Hirte, H.; McWhirter, E.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Hotte, S. J.; Hirte, H.; McWhirter, E.] Escarpment Canc Res Inst, Hamilton, ON, Canada. [Kollmannsberger, C. K.; Renout, D. J.] BC Canc Agcy, Vancouver, BC, Canada. [Moscow, J.; Chen, H.] NCI, Canc Therapy Evaluat Program, 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 508 BP 165 EP 166 PG 2 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700509 ER PT J AU Cecchi, F Liao, WL Thyparambil, S Bengali, K Uzzell, J Darflar, M Krizman, D Burrows, J Hembrough, T Veenstra, T Bottaro, DP Karrison, T Henderson, L Xu, P Rambo, B Xiao, SY Zhao, L Hart, J Catenacci, D AF Cecchi, F. Liao, W. L. Thyparambil, S. Bengali, K. Uzzell, J. Darflar, M. Krizman, D. Burrows, J. Hembrough, T. Veenstra, T. Bottaro, D. P. Karrison, T. Henderson, L. Xu, P. Rambo, B. Xiao, S. Y. Zhao, L. Hart, J. Catenacci, D. TI Absolute quantitation of MET using mass spectrometry for clinical application: assay precision, stability, and correlation with MET gene amplification in FFPE tumor tissue SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Cecchi, F.; Liao, W. L.; Thyparambil, S.; Bengali, K.; Uzzell, J.; Darflar, M.; Krizman, D.; Burrows, J.; Hembrough, T.; Veenstra, T.] OncoPlex Diagnost, Rockville, MD USA. [Bottaro, D. P.] NCI, UOB, Bethesda, MD 20892 USA. [Karrison, T.] Univ Chicago Med, Dept Hlth Studies, Chicago, IL USA. [Henderson, L.; Xu, P.; Rambo, B.; Catenacci, D.] Univ Chicago Med, Dept Med, Chicago, IL USA. [Xiao, S. Y.; Zhao, L.; Hart, J.] Univ Chicago Med, Dept Pathol, Chicago, IL 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 537 BP 175 EP 175 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700538 ER PT J AU Chomej, K Lindberg, ML Zong, D Juntti, T Kanter, L Stenke, L Lewensohn, R Viktorsson, K Haag, P AF Chomej, K. Lindberg, M. Lagergren Zong, D. Juntti, T. Kanter, L. Stenke, L. Lewensohn, R. Viktorsson, K. Haag, P. TI Modulation of chromatin-related processes in DNA damage response as a potential strategy to treat acute myeloid leukemia SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 18-21, 2014 CL European Org Res & Treatment Canc, Barcelona, SPAIN SP Natl Canc Inst, Amer Assoc Canc Res HO European Org Res & Treatment Canc C1 [Chomej, K.; Lindberg, M. Lagergren; Juntti, T.; Kanter, L.; Stenke, L.; Lewensohn, R.; Viktorsson, K.; Haag, P.] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Zong, D.] NCI, NIH, Lab Genome Integr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2014 VL 50 SU 6 MA 570 BP 184 EP 184 PG 1 WC Oncology SC Oncology GA AY7RC UT WOS:000347755700571 ER PT J AU Panackal, AA Parisini, E Proschan, M AF Panackal, Anil A. Parisini, Emilio Proschan, Michael TI Salvage combination antifungal therapy for acute invasive aspergillosis may improve outcomes: a systematic review and meta-analysis SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Review DE Invasive aspergillosis; Combination antifungal therapy; Outcomes; Salvage therapy ID LIPOSOMAL AMPHOTERICIN-B; SURVEILLANCE NETWORK TRANSNET; ORGAN TRANSPLANT RECIPIENTS; MYCOSES STUDY-GROUP; FUNGAL-INFECTIONS; PULMONARY ASPERGILLOSIS; EUROPEAN-ORGANIZATION; CLINICAL-TRIALS; SOLID-ORGAN; HEMATOLOGIC MALIGNANCIES AB Objective: A meta-analysis was performed to compare mold-active triazoles or lipid amphotericin B plus an echinocandin to non-echinocandin monotherapy for acute invasive aspergillosis (IA). Methods: We searched PubMed, EMBASE, and other databases through May 2013 unrestricted by language. We included observational and experimental studies wherein patients with proven or probable IA by EORTC/MSG criteria underwent our comparative intervention. PRISMA and MOOSE guidelines were followed and quality was assessed using the Jadad and Newcastle-Ottawa criteria. Meta-regression with fixed and random effects and sensitivity analyses were performed. The primary study outcome measure was 12-week overall mortality. The secondary outcome assessed was complete and partial response. Results: Only observational studies of primary 12-week survival showed heterogeneity (I-2 = 48.96%, p = 0.05). For salvage IA therapy, fixed effects models demonstrated improved 12-week survival (Peto odds ratio (OR) 1.80, 95% confidence interval (CI) 1.08-3.01) and success (Peto OR 2.17, 95% CI 1.21-3.91) of combination therapy. Significance remained after applying random effects as a sensitivity analysis (12-week survival: Peto OR 1.90, 95% CI 1.04-3.46, and unchanged value for success). Restriction to high quality studies and including echinocandins as the comparator for refractory IA revealed an adjusted OR of 1.72 (95% CI 0.96-3.09; p = 0.07) for global success, while the survival endpoint remained unaltered. Conclusions: Combination antifungals for IA demonstrate improved outcomes over monotherapy in the salvage setting. Clinicians should consider this approach in certain situations. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. C1 [Panackal, Anil A.] NIAID, Lab Clin Infect Dis, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Panackal, Anil A.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Med, Div Infect Dis, Bethesda, MD 20814 USA. [Parisini, Emilio] Politecn Milan, Ist Italiano Tecnol, Ctr Nano Sci & Technol, I-20133 Milan, Italy. [Proschan, Michael] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Panackal, AA (reprint author), NIAID, Lab Clin Infect Dis, NIH, Clin Res Ctr, Bldg 10,Room 11N222,10 Ctr Dr,MSC 1888, Bethesda, MD 20892 USA. EM anil.panackal@nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) FX We thank the NIH Library, Dr Jin Qiu, and Dr Guowu Hu for their efforts in providing us translations of non-English articles in order to be as inclusive as possible in this analysis. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH). NR 57 TC 6 Z9 7 U1 0 U2 3 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 NOV PY 2014 VL 28 BP 80 EP 94 DI 10.1016/j.ijid.2014.07.007 PG 15 WC Infectious Diseases SC Infectious Diseases GA AZ1UN UT WOS:000348023300015 PM 25240416 ER PT J AU Yang, JC Sherry, RM AF Yang, James C. Sherry, Richard M. TI MSLT-I-response of clinical trial investigators Reply SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Letter ID RANDOMIZED-TRIAL; NODE BIOPSY; MELANOMA; DISSECTION; IMMEDIATE C1 [Yang, James C.; Sherry, Richard M.] NCI, Ctr Canc Res, Surg Branch, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Ctr Canc Res, Surg Branch, 9000 Rockville Pk, Bethesda, MD 20892 USA. EM jamesyang@mail.nih.gov NR 8 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 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD NOV PY 2014 VL 11 IS 11 DI 10.1038/nrclinonc.2014.65-c2 PG 1 WC Oncology SC Oncology GA AS7IC UT WOS:000344429100013 ER PT J AU Monteiro, JP Cruz, MLS Mussi-Pinhata, MM Salomao, RG Jordao, A Hance, LF Read, JS Pilotto, JHD Cohen, RA Stoszek, SK Siberry, GK AF Monteiro, Jacqueline Pontes Santos Cruz, Maria Leticia Mussi-Pinhata, Marisa Marcia Salomao, Roberta Garcia Jordao Junior, Alceu Hance, Laura Freimanis Read, Jennifer Suzanne da Silva Pilotto, Jose Henrique Cohen, Rachel Ann Stoszek, Sonia Karolina Siberry, George Kelly TI Vitamin A, vitamin E, iron and zinc status in a cohort of HIV-infected mothers and their uninfected infants SO REVISTA DA SOCIEDADE BRASILEIRA DE MEDICINA TROPICAL LA English DT Article DE Micronutrients; HIV infection; Pregnancy; Infant; Nutrition; Cohort ID BETA-CAROTENE; PREGNANT-WOMEN; DEVELOPING-COUNTRIES; OXIDATIVE STRESS; SERUM-LEVELS; SUPPLEMENTATION; CHILDREN; ANEMIA; MICRONUTRIENTS; MORBIDITY AB Introduction: We hypothesized that nutritional deficiency would be common in a cohort of postpartum, human immunodeficiency virus (HIV)-infected women and their infants. Methods: Weight and height, as well as blood concentrations of retinol, alpha-tocopherol, ferritin, hemoglobin, and zinc, were measured in mothers after delivery and in their infants at birth and at 6-12 weeks and six months of age. Retinol and alpha-tocopherol levels were quantified by high performance liquid chromatography, and zinc levels were measured by atomic absorption spectrophotometry. The maternal body mass index during pregnancy was adjusted for gestational age (adjBMI). Results: Among the 97 women 19.6% were underweight. Laboratory abnormalities were most frequently observed for the hemoglobin (46.4%), zinc (41.1%), retinol (12.5%) and ferritin (6.5%) levels. Five percent of the women had mean corpuscular hemoglobin concentrations < 31g/dL. The most common deficiency in the infants was alpha-tocopherol (81%) at birth; however, only 18.5% of infants had deficient levels at six months of age. Large percentages of infants had zinc (36.8%) and retinol (29.5%) deficiencies at birth; however, these percentages decreased to 17.5% and 18.5%, respectively, by six months of age. No associations between infant micronutrient deficiencies and either the maternal adjBMI category or maternal micronutrient deficiencies were found. Conclusions: Micronutrient deficiencies were common in HIV-infected women and their infants. Micronutrient deficiencies were less prevalent in the infants at six months of age. Neither underweight women nor their infants at birth were at increased risk for micronutrient deficiencies. C1 [Monteiro, Jacqueline Pontes; Mussi-Pinhata, Marisa Marcia; Salomao, Roberta Garcia] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Puericultura & Pediatria, Ribeirao Preto, SP, Brazil. [Santos Cruz, Maria Leticia] Hosp Fed Servidores Estado, Dept Doencas Infecciosas, Rio De Janeiro, RJ, Brazil. [Jordao Junior, Alceu] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Clin Med, Sao Paulo, Brazil. [Hance, Laura Freimanis; Cohen, Rachel Ann; Stoszek, Sonia Karolina] Westat Corp, Rockville, MD USA. [Read, Jennifer Suzanne; Siberry, George Kelly] NICHHD, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. [Read, Jennifer Suzanne] George Washington Univ, Sch Med, Dept Pediat, Div Infect Dis, Washington, DE USA. [da Silva Pilotto, Jose Henrique] Hosp Geral Nova Iguacu, Dept Doencas Infecciosas, Nova Iguacu, RJ, Brazil. [da Silva Pilotto, Jose Henrique] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Lab AIDS & Imunol Mol, Rio De Janeiro, RJ, Brazil. RP Monteiro, JP (reprint author), Univ Sao Paulo, Dept Puericultura Pediatria FMRP, Av Bandeirantes 3900,Campus USP, BR-14049900 Ribeirao Preto, SP, Brazil. EM jacque@fmrp.usp.br RI Monteiro, Jacqueline/F-6987-2012 FU National Institute of Child Health and Human Development (NICHD) [N01-HD-3-3345, HHSN267200800001C, N01-HD-8-0001] FX National Institute of Child Health and Human Development (NICHD) for financial support (Contract # N01-HD-3-3345, 2002-2007, and Contract # HHSN267200800001C, Control # N01-HD-8-0001, 2007-2012). NR 49 TC 0 Z9 0 U1 0 U2 6 PU SOC BRASILEIRA MEDICINA TROPICAL PI BRASILIA PA UNIV BRASILIA, NUCLEO MEDICINA TROPICAL E NUTRICAO, CAIXA POSTAL 4356, BRASILIA, DF 70919-970, BRAZIL SN 0037-8682 J9 REV SOC BRAS MED TRO JI Rev. Soc. Bras. Med. Trop. PD NOV-DEC PY 2014 VL 47 IS 6 BP 692 EP 700 DI 10.1590/0037-8682-0226-2014 PG 9 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA AZ4PE UT WOS:000348204000004 PM 25626647 ER PT J AU Bektas, A Zhang, YQ Lehmann, E Wood, WH Becker, KG Madara, K Ferrucci, L Sen, RJ AF Bektas, Arsun Zhang, Yongqing Lehmann, Elin Wood, William H., III Becker, Kevin G. Madara, Karen Ferrucci, Luigi Sen, Ranjan TI Age-associated changes in basal NF-kappa B function in human CD4(+) T lymphocytes via dysregulation of PI3 kinase SO AGING-US LA English DT Article DE CD4+T cells; NF-kappa B; PI3K; human aging; gene expression ID LIFE-SPAN; CAENORHABDITIS-ELEGANS; HUMAN IMMUNOSENESCENCE; CELLULAR SENESCENCE; SIGNALING PATHWAYS; GENE-EXPRESSION; TRANSCRIPTION; CELLS; MICE; ACTIVATION AB Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dys-regulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation gene expression mediated by the transcription factor NF-kappa B is higher in purified and rested human CD4(+) T lymphocytes from older compared to younger individuals. This increase of NF-kappa B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-kappa B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dys-regulated basal NF-kappa B activity may contribute to the mild pro-inflammatory state of aging. C1 [Bektas, Arsun; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Zhang, Yongqing; Lehmann, Elin; Wood, William H., III; Becker, Kevin G.] NIA, Genet Lab, Baltimore, MD 21224 USA. [Madara, Karen] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Sen, RJ (reprint author), NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. EM ferruccilu@mail.nih.gov; senra@mail.nih.gov FU Intramural Research Program of the National Institute on Aging (Baltimore, MD) FX We thank Drs. Nan-Ping Weng and Jyoti Sen for discussions throughout this work. This research was supported entirely by the Intramural Research Program of the National Institute on Aging (Baltimore, MD). NR 49 TC 10 Z9 10 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD NOV PY 2014 VL 6 IS 11 BP 957 EP 974 PG 18 WC Cell Biology SC Cell Biology GA AZ2HO UT WOS:000348055200005 PM 25553802 ER PT J AU Winstanley, A Sperotto, RG Putnick, DL Cherian, S Bornstein, MH Gattis, M AF Winstanley, A. Sperotto, R. G. Putnick, D. L. Cherian, S. Bornstein, M. H. Gattis, M. TI Consistency of maternal cognitions and principles across the first five months following preterm and term deliveries SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article DE Parenting; Prematurity; Principles; Cognitions; Caregiving; Infancy ID BORN EXTREMELY PRETERM; BIRTH-WEIGHT INFANTS; KANGAROO MOTHER CARE; PARENTING COGNITIONS; GESTATIONAL-AGE; ACCULTURATING CULTURES; CHILD OUTCOMES; COMPLEXITY; INTERVENTION; BEHAVIORS AB The aims of this study were to examine and compare the development of parenting cognitions and principles in mothers following preterm and term deliveries. Parenting cognitions about child development, including thinking that is restricted to single causes and single outcomes (categorical thinking) and thinking that takes into account multiple perspectives (perspectivist thinking), have been shown to relate to child outcomes. Parenting principles about using routines (structure) or infant cues (attunement) to guide daily caregiving have been shown to relate to caregiving practices. We investigated the continuity and stability of parenting cognitions and principles in the days following birth to 5 months postpartum for mothers of infants born term and preterm. All parenting cognitions were stable across time. Categorical thinking increased at a group level across time in mothers of preterm, but not term, infants. Perspectivist thinking increased at a group level for first-time mothers (regardless of birth status) and tended to be lower in mothers of preterm infants. Structure at birth did not predict later structure (and so was unstable) in mothers of preterm, but not term, infants and neither group changed in mean level across time. Attunement was consistent across time in both groups of mothers. These results indicate that prematurity has multiple, diverse effects on parenting beliefs, which may in turn influence maternal behavior and child outcomes. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). C1 [Winstanley, A.] Univ Cambridge, Dept Psychol, Cambridge, England. [Winstanley, A.; Sperotto, R. G.; Gattis, M.] Cardiff Univ, Sch Psychol, Cardiff CF10 3AT, S Glam, Wales. [Putnick, D. L.; Bornstein, M. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Cherian, S.] Univ Wales Hosp, Dept Child Hlth, Cardiff CF4 4XW, S Glam, Wales. RP Winstanley, A (reprint author), Cardiff Univ, Sch Psychol, Pk Pl, Cardiff CF10 3AT, S Glam, Wales. EM avw30@cam.ac.uk; gattism@cardiff.ac.uk RI Winstanley, Alice/B-5243-2015; Gattis, Merideth/A-1785-2010; OI Winstanley, Alice/0000-0002-7515-2485; Gattis, Merideth/0000-0002-8665-7577; Putnick, Diane/0000-0002-6323-749X FU Wellcome Trust [084911/Z/08/Z] NR 55 TC 1 Z9 1 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 EI 1879-0453 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD NOV PY 2014 VL 37 IS 4 BP 760 EP 771 DI 10.1016/j.infbeh.2014.09.005 PG 12 WC Psychology, Developmental SC Psychology GA AZ1RZ UT WOS:000348016800031 PM 25459794 ER PT J AU Kerridge, BT Castor, D Tran, P Barnhart, M Pickering, R AF Kerridge, Bradley T. Castor, Delivette Tran, Phu Barnhart, Matthew Pickering, Roger TI Association between intoxication at last sexual intercourse and unprotected sex among men and women in Uganda SO JOURNAL OF INFECTION IN DEVELOPING COUNTRIES LA English DT Article DE Intoxication; alcohol; unprotected sex; Africa; HIV; gender differences ID SUB-SAHARAN AFRICA; ALCOHOL-USE; SOUTH-AFRICA; CONDOM USE; RISK-FACTORS; HIV; HIV/AIDS; INTERVENTIONS; INDIVIDUALS; PREVENTION AB Introduction: This study examined the association between intoxication at last sexual intercourse and unprotected sex using data derived from a nationally representative survey conducted in Uganda in 2011. Methodology: Multivariable logistic regression analyses were used to examine the intoxication-unprotected sex association separately among men and women, adjusted for sociodemographic and behavioral covariates that were also examined as moderators of the association. Results: Among men, intoxication at last sexual intercourse was almost entirely attributed to their own drinking, while women most frequently reported intoxication among their partners only. Among women, there was a significant association between their partner's intoxication and unprotected sex (adjusted odds ratio (AOR) = 1.36; 95% confidence interval (CI) = 1.07-1.73. Intoxication was associated with unprotected sex among unmarried men (AOR = 2.09; 95%; CI = 1.45-2.84), an association not observed among married men. Conclusions: The results suggest that the alcohol-unprotected sex link should be incorporated within Ugandan National HIV Prevention Strategy. These interventions should be designed to target unmarried men. Programs that combine alcohol reduction and address structural factors that constrain women's ability to negotiate condom use are also needed. C1 [Kerridge, Bradley T.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Castor, Delivette; Barnhart, Matthew] US Agcy Int Dev, Bur Global Hlth, Off HIV AIDS, Washington, DC 20523 USA. [Tran, Phu] St Georges Univ, SGU Caribbean Med Sch, True Blue, Grenada. [Pickering, Roger] NIAAA, Lab Epidemiol & Biometry, Intramural Div Clin & Biol Res, NIH, Rockville, MD 20852 USA. RP Kerridge, BT (reprint author), Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. EM bradleykerridge@gmail.com OI Kerridge, Bradley/0000-0003-0459-9439 FU USAID Global Health Fellows II Program [OAA-A-11-00025]; National Institute on Drug Abuse, National Institutes of Health [5F32DA0364431]; NIAAA, National Institutes of Health FX The authors would like to give special thanks to Billy Pick and Noah Bartlett at the United States Agency for International Development (USAID) for their insights and support in conceptualizing this manuscript. This research was supported through the USAID Global Health Fellows II Program (OAA-A-11-00025), and also by the National Institute on Drug Abuse, National Institutes of Health (5F32DA0364431: Dr. Kerridge). Support also gratefully acknowledged from the Intramural Program, NIAAA, National Institutes of Health (Mr. Pickering). NR 33 TC 1 Z9 1 U1 1 U2 2 PU J INFECTION DEVELOPING COUNTRIES PI TRAMANIGLIO PA JIDC CENT OFF PORTO CONTE RICERCHE RES CTR, S P 55, PORTO CONTE CAPO CACCIA KM 8.400 LOC, TRAMANIGLIO, 07041, ITALY SN 1972-2680 J9 J INFECT DEV COUNTR JI J. Infect. Dev. Ctries. PD NOV PY 2014 VL 8 IS 11 BP 1461 EP 1469 DI 10.3855/jidc.4832 PG 9 WC Infectious Diseases SC Infectious Diseases GA AY5OF UT WOS:000347621000013 PM 25390059 ER PT J AU Dai, CL Yao, XL Vaisman, B Brenner, T Meyer, KS Gao, MX Keeran, KJ Nugent, GZ Qu, X Yu, ZX Dagur, PK Mccoy, JP Remaley, AT Levine, SJ AF Dai, Cuilian Yao, Xianglan Vaisman, Boris Brenner, Todd Meyer, Katharine S. Gao, Meixia Keeran, Karen J. Nugent, Gayle Z. Qu, Xuan Yu, Zu-Xi Dagur, Pradeep K. Mccoy, J. Philip Remaley, Alan T. Levine, Stewart J. TI ATP-Binding Cassette Transporter 1 Attenuates Ovalbumin-Induced Neutrophilic Airway Inflammation SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE vascular endothelial cells; airway inflammation; ovalbumin; neutrophil; ATP-binding cassette transporter 1 ID CHOLESTEROL EFFLUX; ASTHMA PHENOTYPES; GENE-EXPRESSION; IL-8 RECEPTOR; MACROPHAGES; ABCA1; MICE; CELLS; HDL; IDENTIFICATION AB Apolipoprotein A-I (apoA-I) is an important component of high-density lipoprotein particles that mediates reverse cholesterol transport out of cells by interacting with the ATP-binding cassette transporter 1 (ABCA1). apoA-I has also been shown to attenuate neutrophilic airway inflammation in experimental ovalbumin (OVA)-induced asthma by reducing the expression of granulocyte colony-stimulating factor (G-CSF). Here, we hypothesized that overexpression of the ABCA1 transporter might similarly attenuate OVA-induced neutrophilic airway inflammation. Tie2-human ABCA1 (hABCA1) mice expressing human ABCA1 under the control of the Tie2 promoter, which is primarily expressed by vascular endothelial cells, but can also be expressed by macrophages, received daily intranasal OVA challenges, 5 d/wk for 5 weeks. OVA-challenged Tie2-hABCA1 mice had significant reductions in total bronchoalveolar lavage fluid (BALF) cells that reflected a decrease in neutrophils, as well as reductions in peribronchial inflammation, OVA-specific IgE levels, and airway epithelial thickness. The reduced airway neutrophilia in OVA-challenged Tie2-hABCA1 mice was associated with significant decreases in G-CSF protein levels in pulmonary vascular endothelial cells, alveolar macrophages, and BALF. Intranasal administration of recombinant murine G-CSF to OVA-challenged Tie2-hABCA1 mice for 5 days increased BALF neutrophils to a level comparable to that of OVA-challenged wildtype mice. We conclude that ABCA1 suppresses OVA-induced airway neutrophilia by reducing G-CSF production by vascular endothelial cells and alveolar macrophages. These findings suggest that ABCA1 expressed by vascular endothelial cells and alveolar macrophages may play important roles in attenuating the severity of neutrophilic airway inflammation in asthma. C1 [Dai, Cuilian; Yao, Xianglan; Vaisman, Boris; Brenner, Todd; Meyer, Katharine S.; Gao, Meixia; Remaley, Alan T.; Levine, Stewart J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Keeran, Karen J.; Nugent, Gayle Z.] NHLBI, Anim Surg & Resources Core Facil, NIH, Bethesda, MD 20892 USA. [Qu, Xuan; Yu, Zu-Xi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. [Dagur, Pradeep K.; Mccoy, J. Philip] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov OI Brenner, Todd/0000-0003-0541-2234 FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 48 TC 6 Z9 6 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD NOV PY 2014 VL 51 IS 5 BP 626 EP 636 DI 10.1165/rcmb.2013-0264OC PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA AY2KP UT WOS:000347419400004 PM 24813055 ER PT J AU Veldman, MP Maffiuletti, NA Hallett, M Zijdewind, I Hortobagyi, T AF Veldman, M. P. Maffiuletti, N. A. Hallett, M. Zijdewind, I. Hortobagyi, T. TI Direct and crossed effects of somatosensory stimulation on neuronal excitability and motor performance in humans SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Afferent stimulation; Motor cortex; Primary sensorimotor cortex; Motor practice; Cross-education ID PAIRED-ASSOCIATIVE STIMULATION; MEDIAN NERVE-STIMULATION; INDUCED MOVEMENT THERAPY; FUNCTIONAL ELECTRICAL-STIMULATION; RANDOMIZED CONTROLLED-TRIAL; POSTERIOR CORPUS-CALLOSUM; HUMAN SENSORIMOTOR CORTEX; COMMON PERONEAL NERVE; CEREBRAL-BLOOD-FLOW; CORTICAL EXCITABILITY AB This analytic review reports how prolonged periods of somatosensory electric stimulation (SES) with repetitive transcutaneous nerve stimulation can have 'direct' and 'crossed' effects on brain activation, corticospinal excitability, and motor performance. A review of 26 studies involving 315 healthy and 78 stroke and dystonia patients showed that the direct effects of SES increased corticospinal excitability up to 40% (effect size: 0.2 to 6.1) and motor performance up to 14% (effect size: 0.3 to 3.1) but these two features did not correlate. SES did not affect measures of intracortical excitability. Most likely, a long-term potentiation-like mechanism in the excitatory glutamatergic connections between the primary sensory and motor cortices mediates the direct effects of SES on corticospinal excitability and motor performance. We propose two models for the untested hypothesis that adding SES to unilateral motor practice could magnify the magnitude of inter-limb transfer. If tenable, the hypothesis would expand the evolving repertoire of sensory augmentation of cross-education using mirrors and add SES as an alternative to conventional rehabilitation strategies such as constraint-induced movement therapy. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Veldman, M. P.; Hortobagyi, T.] Univ Groningen, Univ Med Ctr Groningen, Ctr Human Movement Sci, Groningen, Netherlands. [Maffiuletti, N. A.] Schulthess Clin, Neuromuscular Res Lab, Zurich, Switzerland. [Hallett, M.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Zijdewind, I.] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, Groningen, Netherlands. [Hortobagyi, T.] Northumbria Univ, Fac Hlth & Life Sci, Newcastle Upon Tyne NE1 8ST, Tyne & Wear, England. RP Hortobagyi, T (reprint author), Univ Med Ctr Groningen, Ctr Human Movement Sci, A Deusinglaan 1, NL-9700 AD Groningen, Netherlands. EM t.hortobagyi@umcg.nl RI Zijdewind, inge/A-7506-2008 OI Zijdewind, inge/0000-0003-2146-1212 FU University Medical Center Groningen, The University of Groningen, The Netherlands FX We thank Drs. Paul De Vita, Jonathan Farthing, Glyn Howatson for their insightful comments. Funded in part by start-up funds from the University Medical Center Groningen, The University of Groningen, The Netherlands. NR 193 TC 12 Z9 13 U1 4 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD NOV PY 2014 VL 47 BP 22 EP 35 DI 10.1016/j.neubiorev.2014.07.013 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AY3QY UT WOS:000347498900003 PM 25064816 ER PT J AU Michelis, KC Boehm, M Kovacic, JC AF Michelis, Katherine C. Boehm, Manfred Kovacic, Jason C. TI New vessel formation in the context of cardiomyocyte regeneration - the role and importance of an adequate perfusing vasculature SO STEM CELL RESEARCH LA English DT Review ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; LEFT-VENTRICULAR FUNCTION; IMPROVES CARDIAC-FUNCTION; MARROW MONONUCLEAR-CELLS; MESENCHYMAL STEM-CELLS; CHRONIC HIBERNATING MYOCARDIUM; ENDOTHELIAL PROGENITOR CELLS; RANDOMIZED CLINICAL-TRIALS; COLONY-STIMULATING FACTOR AB The history of revascularization for cardiac ischemia dates back to the early 1960's when the first coronary artery bypass graft procedures were performed in humans. With this 50 year history of providing a new vasculature to ischemic and hibernating myocardium, a profound depth of experience has been amassed in clinical cardiovascular medicine as to what does, and does not work in the context of cardiac revascularization, alleviating ischemia and adequacy of myocardial perfusion. These issues are of central relevance to contemporary cell-based cardiac regenerative approaches. While the cardiovascular cell therapy field is surging forward on many exciting fronts, several well accepted clinical axioms related to the cardiac arterial supply appear to be almost overlooked by some of our current basic conceptual and experimental cell therapy paradigms. We present here information drawn from five decades of the clinical revascularization experience, review relevant new data on vascular formation via cell therapy, and put forward the case that for optimal cell-based cardiac regeneration due attention must be paid to providing an adequate vascular supply. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Michelis, Katherine C.; Kovacic, Jason C.] Icahn Sch Med Mt Sinai, Zena & Michael Wiener Cardiovasc Inst, New York, NY 10029 USA. [Boehm, Manfred] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Kovacic, JC (reprint author), Mt Sinai Hosp, One Gustave L Levy Pl,Box 1030, New York, NY 10029 USA. EM jason.kovacic@mountsinai.org FU National Institutes of Health (NIH) [T32HL007824]; NIH [K08HL111330]; Leducq Foundation (Transatlantic Network of Excellence Award); AstraZeneca FX Katherine Michelis is supported by National Institutes of Health (NIH) grant T32HL007824. Jason Kovacic acknowledges research support from the NIH (K08HL111330), The Leducq Foundation (Transatlantic Network of Excellence Award) and AstraZeneca. Fig. 2 was created using Servier medical art. NR 122 TC 7 Z9 7 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD NOV PY 2014 VL 13 IS 3 BP 666 EP 682 DI 10.1016/j.scr.2014.04.009 PN B PG 17 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AY7HQ UT WOS:000347732100013 PM 24841067 ER PT J AU Shore, MF AF Shore, Milton F. TI MARKING TIME IN THE LAND OF PLENTY: Reflections on Mental Health in the United States SO AMERICAN JOURNAL OF ORTHOPSYCHIATRY LA English DT Article C1 NIMH, Mental Hlth Study Ctr, Adelphi, MD 20852 USA. RP Shore, MF (reprint author), NIMH, Mental Hlth Study Ctr, Adelphi, MD 20852 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0002-9432 EI 1939-0025 J9 AM J ORTHOPSYCHIAT JI Am. J. Orthopsychiatr. PD NOV PY 2014 VL 84 IS 6 BP 611 EP 618 DI 10.1037/h0100165 PG 8 WC Psychiatry; Social Work SC Psychiatry; Social Work GA AX4TM UT WOS:000346924100003 PM 25545428 ER PT J AU Shore, MF Massimo, JL AF Shore, Milton F. Massimo, Joseph L. TI FIFTEEN YEARS AFTER TREATMENT: A Follow-Up Study of Comprehensive Vocationally-Oriented Psychotherapy SO AMERICAN JOURNAL OF ORTHOPSYCHIATRY LA English DT Article ID ADOLESCENT DELINQUENT BOYS AB The fourth follow-up study of adolescent delinquent boys treated in a community-based program that combined job placement, remedial education, and psychotherapy indicates that the better overall adjustment of the treated group, compared to untreated controls, is maintained well into adulthood. It reaffirms the importance of developing sound, innovative means of reaching adolescents in crisis, and suggests the value of a fullscale replication of the original program. C1 [Shore, Milton F.] NIMH, Mental Hlth Study Ctr, Bethesda, MD 20892 USA. [Massimo, Joseph L.] Newton Publ Sch, Newton, MA USA. RP Shore, MF (reprint author), NIMH, Mental Hlth Study Ctr, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0002-9432 EI 1939-0025 J9 AM J ORTHOPSYCHIAT JI Am. J. Orthopsychiatr. PD NOV PY 2014 VL 84 IS 6 BP 619 EP 623 DI 10.1037/h0100166 PG 5 WC Psychiatry; Social Work SC Psychiatry; Social Work GA AX4TM UT WOS:000346924100004 PM 25545429 ER PT J AU Choi, K Forster, JL AF Choi, Kelvin Forster, Jean L. TI Frequency and Characteristics Associated With Exposure to Tobacco Direct Mail Marketing and Its Prospective Effect on Smoking Behaviors Among Young Adults From the US Midwest SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PERCEPTIONS; CESSATION AB Objectives. We examined the exposure to tobacco direct mail marketing and its effect on subsequent smoking behaviors in a US Midwest regional cohort of young adults. Methods. Data were collected from 2622 young adults (mean age = 24 years) in 2010 to 2011 (baseline) and 2011 to 2012 (follow-up). We collected information on demographics, tobacco use, and exposure to tobacco direct mail materials in the previous 6 months at baseline. Smoking behaviors were reassessed at follow-up. We investigated the characteristics associated with receiving these materials at baseline, and the associations between receiving cigarette coupons in the mail at baseline and smoking behaviors at follow-up. Results. Thirteen percent of participants reported receiving tobacco direct mail materials in the previous 6 months. Receipt of these materials was associated with age, education, and tobacco use (P <. 05). Among those who received these materials, 77% and 56% reported receiving coupons for cigarettes and other tobacco products, respectively. Among baseline nonsmokers and ex-smokers, receiving coupons was associated with becoming current smokers at follow-up (P < .05). Among baseline current smokers, receiving coupons was associated with lower likelihood of smoking cessation at follow-up (P <. 05). Conclusions. Tobacco direct mail marketing promoted and sustained smoking behaviors among US Midwest young adults. Regulating this marketing strategy might reduce the prevalence of smoking in this population. C1 [Choi, Kelvin] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, Bethesda, MD 20892 USA. [Forster, Jean L.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Choi, K (reprint author), Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kelvin.choi@nih.gov RI Choi, Kelvin/H-1544-2015 FU National Cancer Institute [R01 CA86191]; Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health FX The study was funded by the National Cancer Institute (grant R01 CA86191; Principal Investigator: J. L. F.). K. Choi was supported by the Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health. The data for the analysis were collected when K. Choi was at the University of Minnesota. NR 13 TC 3 Z9 3 U1 0 U2 2 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 NOV PY 2014 VL 104 IS 11 BP 2179 EP 2183 DI 10.2105/AJPH.2014.302123 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AX8UR UT WOS:000347184400055 PM 25211739 ER PT J AU Shapiro, AJ Davis, SD Ferkol, T Dell, SD Rosenfeld, M Olivier, KN Sagel, SD Milla, C Zariwala, MA Wolf, W Carson, JL Hazucha, MJ Burns, K Robinson, B Knowles, MR Leigh, MW AF Shapiro, Adam J. Davis, Stephanie D. Ferkol, Thomas Dell, Sharon D. Rosenfeld, Margaret Olivier, Kenneth N. Sagel, Scott D. Milla, Carlos Zariwala, Maimoona A. Wolf, Whitney Carson, Johnny L. Hazucha, Milan J. Burns, Kimberlie Robinson, Blair Knowles, Michael R. Leigh, Margaret W. CA Genetic Disorders Mucociliary Clea TI Laterality Defects Other Than Situs Inversus Totalis in Primary Ciliary Dyskinesia Insights Into Situs Ambiguus and Heterotaxy SO CHEST LA English DT Article ID CONGENITAL HEART-DISEASE; NITRIC-OXIDE; ZIC3 MUTATIONS; NASAL; PREVALENCE; CHILDREN; SPECTRUM AB BACKGROUND: Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied. METHODS: In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD. RESULTS: Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P<.001; year-round nasal congestion, P <.015; neonatal respiratory distress, P <.009; digital clubbing, P <.021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P<.001). CONCLUSIONS: At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects. C1 [Shapiro, Adam J.] McGill Univ, Montreal Childrens Hosp, Dept Pediat, Montreal, PQ H3H 1P3, Canada. [Davis, Stephanie D.] Indiana Univ, Riley Hosp Children, Dept Pediat, Indianapolis, IN 46204 USA. [Ferkol, Thomas] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Dell, Sharon D.] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Dell, Sharon D.] Univ Toronto, Toronto, ON, Canada. [Rosenfeld, Margaret] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA. [Rosenfeld, Margaret] Univ Washington, Seattle, WA 98195 USA. [Olivier, Kenneth N.] NIAID, Bethesda, MD 20892 USA. [Sagel, Scott D.] Childrens Hosp Colorado, Dept Pediat, Aurora, CO USA. [Sagel, Scott D.] Univ Colorado, Sch Med, Aurora, CO USA. [Milla, Carlos] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA. [Zariwala, Maimoona A.] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Wolf, Whitney; Hazucha, Milan J.; Burns, Kimberlie; Knowles, Michael R.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Carson, Johnny L.; Robinson, Blair; Leigh, Margaret W.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC USA. RP Shapiro, AJ (reprint author), McGill Univ, Montreal Childrens Hosp, Dept Pediat, 2300 Tupper,D-380, Montreal, PQ H3H 1P3, Canada. EM adam.shapiro@muhc.mcgill.ca FU National Institutes of Health (NIH), Office of Rare Diseases Research, National Heart, Lung, and Blood Institute (NHLBI) [5US54HL096458-06]; NIH, NHLBI [5R01HL071798]; NIH, National Center for Advancing Translational Science (NCATS) [UL1TR000083]; NIH/NCATS [UL1TR000423]; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases; NIH/NCATS Colorado Clinical and Translational Sciences Institute [UL1TR000154]; Genetic Disorders of Mucociliary Clearance Consortium [U54HL096458]; NIH Rare Diseases Clinical Research Network supported through collaboration between the NIH Office of Rare Diseases Research at the NCATS; National Heart, Lung, and Blood Institute FX Funding for this research was provided to Drs Shapiro, Davis, Ferkol, Dell, Rosenfeld, Olivier, Sagel, Milla, Zariwala, Carson, Hazucha, Knowles, and Leigh and Mss Wolf and Burns by National Institutes of Health (NIH), Office of Rare Diseases Research, National Heart, Lung, and Blood Institute (NHLBI) [Grant 5US54HL096458-06] and to Drs Zariwala and Knowles by NIH, NHLBI [Grant 5R01HL071798] and NIH, National Center for Advancing Translational Science (NCATS) [Grant UL1TR000083]. Funding for Dr Rosenfeld was provided by NIH/NCATS [Grant UL1TR000423]. Funding for Dr Olivier was provided by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. Funding for Dr Sagel was by NIH/NCATS Colorado Clinical and Translational Sciences Institute [Grant UL1TR000154]. The Genetic Disorders of Mucociliary Clearance Consortium [U54HL096458] is a part of the NIH Rare Diseases Clinical Research Network supported through collaboration between the NIH Office of Rare Diseases Research at the NCATS and the National Heart, Lung, and Blood Institute. NR 35 TC 28 Z9 28 U1 0 U2 12 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD NOV PY 2014 VL 146 IS 5 BP 1176 EP 1186 DI 10.1378/chest.13-1704 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AX9HZ UT WOS:000347215500034 PM 24577564 ER PT J AU Mishra, PJ AF Mishra, Prasun J. TI Non-coding RNAs as clinical biomarkers for cancer diagnosis and prognosis SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Editorial Material DE biomarker; circulating microRNAs; diagnostics; miRNA; miRNA polymorphisms; microvesicles or exosomes; pharmacogenomics; precision medicine; prognosis; variants ID PERSONALIZED MEDICINE; MICRORNA SIGNATURES; SITE POLYMORPHISM; OVARIAN-CANCER; COLON-CANCER; RESISTANCE; MIR-215; CELLS AB Developing more precise diagnostics approaches to predict cancer progression and prognosis is the key to precision medicine. Overwhelming evidence now suggests that small non-coding RNAs such as miRNAs can be useful tools as biomarkers for molecular diagnostics. miRNAs can serve as biomarkers in a variety of diseases, such as neurological disorders, cardiovascular disease, Type II diabetes, cancer and so on. miRNAs can not only be utilized for monitoring treatment but also for patient stratification and hence are promising predictive biomarkers in cancer progression and prognosis, as well as in predicting drug response. This article focuses on some of the recent findings in the field of miRNA biomarkers and discusses its implications for cancer diagnostics and precision medicine. C1 NCI, US Dept Hlth & Human Serv, NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Mishra, PJ (reprint author), NCI, US Dept Hlth & Human Serv, NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM mishrapj@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 25 TC 10 Z9 10 U1 1 U2 8 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD NOV PY 2014 VL 14 IS 8 BP 917 EP 919 DI 10.1586/14737159.2014.971761 PG 3 WC Pathology SC Pathology GA AX4KB UT WOS:000346900500001 PM 25327490 ER PT J AU Jelovsek, JE Chen, Z Markland, AD Brubaker, L Dyer, KY Meikle, S Rahn, DD Siddiqui, NY Tuteja, A Barber, MD AF Jelovsek, John Eric Chen, Zhen Markland, Alayne D. Brubaker, Linda Dyer, Keisha Y. Meikle, Susie Rahn, David D. Siddiqui, Nazeema Y. Tuteja, Ashok Barber, Matthew D. TI Minimum Important Differences for Scales Assessing Symptom Severity and Quality of Life in Patients With Fecal Incontinence SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE fecal incontinence; health-related quality of life; minimum important difference; questionnaire; responsiveness; patient-reported outcomes ID MINIMALLY IMPORTANT DIFFERENCES; PELVIC FLOOR DISORDERS; IMPACT QUESTIONNAIRE; DISTRESS INVENTORY; REPORTED OUTCOMES; WOMEN; RESPONSIVENESS; RELIABILITY; INSTRUMENT; INDEX AB Objectives: The objective of this study was to estimate the minimum important difference (MID) for the Fecal Incontinence Severity Index (FIST), the Colorectal-Anal Distress Inventory (CRADI) scale of the Pelvic Floor Distress Inventory, the Colorectal-Anal Impact Questionnaire (CRAIQ) scale of the Pelvic Floor Impact Questionnaire, and the Modified Manchester Health Questionnaire (MMHQ). Methods: We calculated the M1Ds using anchor-based and distribution-based approaches from a multicenter prospective cohort study investigating adaptive behaviors among women receiving nonsurgical and surgical management for fecal incontinence (Fl). Patient responses were primarily anchored using a Global Impression of Change scale. The MID was defined as the difference in mean change from baseline between those who indicated they were "a little better" and those who reported "no change" on the Global Impression of Change scale 3 months after treatment. The effect size and SE of measurement were the distribution methods used. Results: The mean changes (SD) in FISI, CRADI, CRAIQ, and MMTIQ scores from baseline to 3 months after treatment were -8.8 (12.0), -52.7 (70.0),- 60.6 (90.0), and -12.6 (19.2), respectively. The anchor-based MID estimates suggested by an improvement from no change to a little better were -3.6, -11.4 and -4.7, -18.1 and -8.0, and -3.2 for the FISI, CRADI (long and short version), CRAIQ (long and short version), and MMHQ, respectively. These data were supported by 2 distributionbased estimates. Conclusions: The MID values for the FISI are -4, CRADI (full version, -11; short version, -5), CRAIQ (full version, -18; short version, -8), and MMHQ 3-. Statistically significant improvements that meet these thresholds are likely to be clinically important. C1 [Jelovsek, John Eric; Barber, Matthew D.] Cleveland Clin, Cleveland, OH 44195 USA. [Chen, Zhen] Univ Michigan, Ann Arbor, MI 48109 USA. [Markland, Alayne D.] Dept Vet Affairs, Birmingham, AL USA. [Markland, Alayne D.] Univ Alabama Birmingham, Birmingham, AL USA. [Brubaker, Linda] Loyola Univ, Chicago, IL 60611 USA. [Dyer, Keisha Y.] Univ Calif San Diego, San Diego, CA 92103 USA. [Meikle, Susie] Eunice Kennedy Shriver Natl Inst Hlth, Bethesda, MD USA. [Rahn, David D.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Siddiqui, Nazeema Y.] Duke Univ, Durham, NC USA. [Tuteja, Ashok] Dept Vet Affairs, Salt Lake City, UT USA. [Tuteja, Ashok] Univ Utah, Salt Lake City, UT USA. RP Jelovsek, JE (reprint author), Cleveland Clin, 9500 Euclid Ave,Desk A81, Cleveland, OH 44195 USA. EM jelovsj@ccf.org OI Markland, Alayne/0000-0002-6567-6744 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH Office of Research on Women's Health [U01 HD41249, U10 HD41250, U10 HD41261, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215, U10 HD54241] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the NIH Office of Research on Women's Health (U01 HD41249, U10 HD41250, U10 HD41261, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215, and U10 HD54241). Dr Tuteja (Consultant: Salix Pharmaceuticals, Guidepoint and GIG Consultancy; Forest Ironwood, Proctor & Gamble Pharmaceuticals) and Dr. Siddiqui (Grants: Medtronic, Astellas). NR 22 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2151-8378 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD NOV-DEC PY 2014 VL 20 IS 6 BP 342 EP 348 DI 10.1097/SPV.0000000000000078 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AX7TQ UT WOS:000347118000014 PM 25185630 ER PT J AU Barta, SK Xue, XN Wang, D Lee, JY Kaplan, LD Ribera, JM Oriol, A Spina, M Tirelli, U Boue, F Wilson, WH Wyen, C Dunleavy, K Noy, A Sparano, JA AF Barta, Stefan K. Xue, Xiaonan Wang, Dan Lee, Jeannette Y. Kaplan, Lawrence D. Ribera, Josep-Maria Oriol, Albert Spina, Michele Tirelli, Umberto Boue, Francois Wilson, Wyndham H. Wyen, Christoph Dunleavy, Kieron Noy, Ariela Sparano, Joseph A. TI A new prognostic score for AIDS-related lymphomas in the rituximab-era SO HAEMATOLOGICA LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; NON-HODGKIN-LYMPHOMA; VIRUS-INFECTION STATUS; LARGE-CELL LYMPHOMA; BURKITTS-LYMPHOMA; INTENSIVE CHEMOTHERAPY; SURVIVAL; LEUKEMIA; PETHEMA-LAL3/97; CONSORTIUM AB While the International Prognostic Index is commonly used to predict outcomes in immunocompetent patients with aggressive B-cell non-Hodgkin lymphomas, HIV-infection is an important competing risk for death in patients with AIDS-related lymphomas. We investigated whether a newly created prognostic score (AIDS-related lymphoma International Prognostic Index) could better assess risk of death in patients with AIDS-related lymphomas. We randomly divided a dataset of 487 patients newly diagnosed with AIDS-related lymphomas and treated with rituximab-containing chemoimmunotherapy into a training (n=244) and validation (n=243) set. We examined the association of HIV-related and other known risk factors with overall survival in both sets independently. We defined a new score (AIDS-related lymphoma International Prognostic Index) by assigning weights to each significant predictor [age-adjusted International Prognostic Index, extranodal sites, HIV-score (composed of CD4 count, viral load, and prior history of AIDS)] with three risk categories similar to the age-adjusted International Prognostic Index (low, intermediate and high risk). We compared the prognostic value for overall survival between AIDS-related lymphoma International Prognostic Index and age-adjusted International Prognostic Index in the validation set and found that the AIDS-related lymphoma International Prognostic Index performed significantly better in predicting risk of death than the age-adjusted International Prognostic Index (P=0.004) and better discriminated risk of death between each risk category (P=0.015 vs. P=0.13). Twenty-eight percent of patients were defined as low risk by the ARL-IPI and had an estimated 5-year overall survival (OS) of 78% (52% intermediate risk, 5-year OS 60%; 20% high risk, 5-year OS 50%). C1 [Barta, Stefan K.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Xue, Xiaonan; Wang, Dan; Sparano, Joseph A.] Albert Einstein Canc Ctr, Bronx, NY USA. [Lee, Jeannette Y.] Univ Arkansas, Little Rock, AR 72204 USA. [Kaplan, Lawrence D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ribera, Josep-Maria; Oriol, Albert] ICO Hosp Germans Trias I Pujol, Jose Carreras Res Inst, Badalona, Spain. [Ribera, Josep-Maria; Oriol, Albert] PETHEMA Grp, Badalona, Spain. [Spina, Michele; Tirelli, Umberto] Natl Canc Inst, Aviano, Italy. [Boue, Francois] Hop Antoine Beclere, Clamart, France. [Wilson, Wyndham H.; Dunleavy, Kieron] NCI, Bethesda, MD 20892 USA. [Wyen, Christoph] Univ Hosp Cologne, Cologne, Germany. [Noy, Ariela] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Noy, Ariela] Weill Cornell Med Coll, New York, NY USA. RP Barta, SK (reprint author), Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. EM Stefan.Barta@fccc.ed OI Noy, Ariela/0000-0002-3001-4898 FU AIDS Malignancy Consortium (AMC) [UO1CA121947]; Paul Calabresi Career Development Award for Clinical Oncology [K12CA132783-03]; ASCO Cancer Foundation Young Investigator Award; RTICC [RD12/0036/0029]; Instituto de Salud Carlos III, Spain; CTSA Grants from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1 RR025750, KL2 RR025749, TL1 RR025748]; NIH roadmap for Medical Research FX The authors would like to thank the AIDS Malignancy Consortium (AMC; grant UO1CA121947), the Paul Calabresi Career Development Award for Clinical Oncology (K12CA132783-03 Grant), The ASCO Cancer Foundation 2010 Young Investigator Award, grant RD12/0036/0029 from RTICC, Instituto de Salud Carlos III, Spain, and by the CTSA Grants UL1 RR025750 and KL2 RR025749 and TL1 RR025748 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research, for their support. NR 29 TC 4 Z9 4 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD NOV PY 2014 VL 99 IS 11 BP 1731 EP 1737 DI 10.3324/haematol.2014.111112 PG 7 WC Hematology SC Hematology GA AX6EO UT WOS:000347016300014 PM 25150257 ER PT J AU Dominical, VM Samsel, L Nichols, JS Costa, FF McCoy, JP Conran, N Kato, GJ AF Dominical, Venina M. Samsel, Leigh Nichols, James S. Costa, Fernando F. McCoy, J. Phillip Conran, Nicola Kato, Gregory J. TI Prominent role of platelets in the formation of circulating neutrophil-red cell heterocellular aggregates in sickle cell anemia SO HAEMATOLOGICA LA English DT Letter DE sickle cell anemia; platelets; circulating neutrophil-red cell heterocellular aggregates ID ADHERENT LEUKOCYTES; ADHESION; DISEASE; VASOOCCLUSION; ERYTHROCYTES; ACTIVATION; INJURY; FLOW C1 [Dominical, Venina M.; Costa, Fernando F.; Conran, Nicola] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, INCT Sangue, Campinas, SP, Brazil. [Samsel, Leigh; McCoy, J. Phillip] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Nichols, James S.; Kato, Gregory J.] NHLBI, Hematol Branch, Sickle Cell Vasc Dis Sect, NIH, Bethesda, MD 20892 USA. RP Conran, N (reprint author), Univ Estadual Campinas, Hematol & Hemotherapy Ctr, INCT Sangue, Campinas, SP, Brazil. EM conran@unicamp.br RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS; NHLBI NIH HHS [ZIA HL006013, 1 ZIA HL006013-03] NR 15 TC 2 Z9 2 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD NOV PY 2014 VL 99 IS 11 AR e214 DI 10.3324/haematol.2014.108555 PG 4 WC Hematology SC Hematology GA AX6EO UT WOS:000347016300019 PM 25420284 ER PT J AU Hejtmancik, JF AF Hejtmancik, J. Fielding TI Hexokinase 1 and Retinitis Pigmentosa: Insights Into the Retina and the Molecule SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Editorial Material C1 NEI, Ophthalm Mol Genet Sect, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Hejtmancik, JF (reprint author), NEI, Ophthalm Mol Genet Sect, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD NOV PY 2014 VL 55 IS 11 BP 7165 EP 7165 DI 10.1167/iovs.14-15621 PG 1 WC Ophthalmology SC Ophthalmology GA AX9IR UT WOS:000347217300017 PM 25381353 ER PT J AU Qi, L Pujanauski, LM Davis, AS Schwartzman, LM Chertow, DS Baxter, D Scherler, K Hartshorn, KL Slemons, RD Walters, KA Kash, JC Taubenberger, JK AF Qi, Li Pujanauski, Lindsey M. Davis, A. Sally Schwartzman, Louis M. Chertow, Daniel S. Baxter, David Scherler, Kelsey Hartshorn, Kevan L. Slemons, Richard D. Walters, Kathie-Anne Kash, John C. Taubenberger, Jeffery K. TI Contemporary Avian Influenza A Virus Subtype H1, H6, H7, H10, and H15 Hemagglutinin Genes Encode a Mammalian Virulence Factor Similar to the 1918 Pandemic Virus H1 Hemagglutinin SO MBIO LA English DT Article ID EPITHELIAL-CELLS; AMINO-ACID; HOST-RANGE; MICE; ADAPTATION; INFECTION; EMERGENCE; EVOLUTION; OUTBREAK; PROTEIN AB Zoonotic avian influenza virus infections may lead to epidemics or pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its H1 hemagglutinin was identified as a key mammalian virulence factor. A chimeric 1918 virus expressing a contemporary avian H1 hemagglutinin, however, displayed murine pathogenicity indistinguishable from that of the 1918 virus. Here, isogenic chimeric avian influenza viruses were constructed on an avian influenza virus backbone, differing only by hemagglutinin subtype expressed. Viruses expressing the avian H1, H6, H7, H10, and H15 subtypes were pathogenic in mice and cytopathic in normal human bronchial epithelial cells, in contrast to H2-, H3-, H5-, H9-, H11-, H13-, H14-, and H16-expressing viruses. Mouse pathogenicity was associated with pulmonary macrophage and neutrophil recruitment. These data suggest that avian influenza virus hemagglutinins H1, H6, H7, H10, and H15 contain inherent mammalian virulence factors and likely share a key virulence property of the 1918 virus. Consequently, zoonotic infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals. IMPORTANCE Influenza viruses from birds can cause outbreaks in humans and may contribute to the development of pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its main surface protein, an H1 subtype hemagglutinin, was identified as a key mammalian virulence factor. In a previous study, a 1918 virus expressing an avian H1 gene was as virulent in mice as the reconstructed 1918 virus. Here, a set of avian influenza viruses was constructed, differing only by hemagglutinin subtype. Viruses with the avian H1, H6, H7, H10, and H15 subtypes caused severe disease in mice and damaged human lung cells. Consequently, infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals, and therefore surveillance for human infections with these subtypes may be important in controlling future outbreaks. C1 [Qi, Li; Pujanauski, Lindsey M.; Davis, A. Sally; Schwartzman, Louis M.; Chertow, Daniel S.; Kash, John C.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Chertow, Daniel S.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Baxter, David; Scherler, Kelsey; Walters, Kathie-Anne] Inst Syst Biol, Seattle, WA USA. [Hartshorn, Kevan L.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Slemons, Richard D.] Ohio State Univ, Dept Vet Prevent Med, Columbus, OH 43210 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov OI Pujanandez, Lindsey/0000-0002-2982-3700 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Defense Threat Reduction Agency [HDTRA1-13-C-0055] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. K.-A.W. was supported by Defense Threat Reduction Agency contract HDTRA1-13-C-0055. NR 63 TC 5 Z9 6 U1 2 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2014 VL 5 IS 6 AR e02116-14 DI 10.1128/mBio.02116-14 PG 14 WC Microbiology SC Microbiology GA AX7CE UT WOS:000347073600043 PM 25406382 ER PT J AU Milot, E Morissette-Thomas, V Li, Q Fried, LP Ferrucci, L Cohen, AA AF Milot, Emmanuel Morissette-Thomas, V. Li, Qing Fried, Linda P. Ferrucci, Luigi Cohen, Alan A. TI Trajectories of physiological dysregulation predicts mortality and health outcomes in a consistent manner across three populations SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Diseases; Longitudinal trajectories; Mahalanobis distance; Mortality; Physiological dysregulation ID ALLOSTATIC LOAD; SYSTEMS BIOLOGY; OLDER-ADULTS; TIME-SCALE; FRAILTY; AGE; LONGEVITY; EVOLUTION; DECLINE; STRESS AB Mechanistic and evolutionary perspectives both agree that aging involves multiple integrated biochemical networks in the organism. In particular, the homeostatic physiological dysregulation (PD) hypothesis contends that aging is caused by the progressive breakdown of key regulatory processes. However, nothing is yet known about the specifics of how PD changes with age and affects health. Using a recently validated measure of PD involving the calculation of a multivariate distance (D-M) from biomarker data, we show that PD trajectories predict mortality, frailty, and chronic diseases (cancer, cardiovascular diseases, and diabetes). Specifically, relative risks of outcomes associated with individual slopes in (i.e. rate of) dysregulation range 1.20-1.40 per unit slope. We confirm the results by replicating the analysis using two suites of biomarkers selected with markedly different criteria and, for mortality, in three longitudinal cohort-based studies. Overall, the consistence of effect sizes (direction and magnitude) across data sets, biomarker suites and outcomes suggests that the positive relationship between D-M and health outcomes is a general phenomenon found across human populations. Therefore, the study of dysregulation trajectories should allow important insights into aging physiology and provide clinically meaningful predictors of outcomes. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Milot, Emmanuel] Univ Quebec Trois Rivieres, Dept Chem Biochem & Phys, Trois Rivieres, PQ G9A 5H7, Canada. [Morissette-Thomas, V.; Li, Qing; Cohen, Alan A.] Univ Sherbrooke, Dept Family Med, Grp Rech PRIMUS, PRIMUS Res Grp,CHUS Fleurimont, Sherbrooke, PQ J1H 5N4, Canada. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, Longitudinal Studies Sect, NIH, Baltimore, MD 21225 USA. RP Cohen, AA (reprint author), Univ Sherbrooke, Dept Family Med, Grp Rech PRIMUS, PRIMUS Res Grp,CHUS Fleurimont, 3001 12e Ave North, Sherbrooke, PQ J1H 5N4, Canada. EM alan.cohen@usherbrooke.ca FU Centre de recherche sur le vieillissement; CIHR [110789, 120305, 119485]; NSERC [402079-2011]; Intramural Research Program of the National Institute on Aging; FRQ-S FX The authors thank Veronique Legault for assistance in data preparation. EM was supported by a Centre de recherche sur le vieillissement (Sherbrooke) postdoctoral fellowship. AAC is a member of the FRQ-S-supported Centre de recherche sur le vieillissement and Centre de recherche Etienne Le-Bel, and is a funded Research Scholar of the FRQ-S. This research was supported by CIHR grant nos. 110789, 120305, 119485 and by NSERC Discovery Grant no. 402079-2011. This research was supported by the Intramural Research Program of the National Institute on Aging (LF) NR 39 TC 8 Z9 8 U1 0 U2 9 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 NOV-DEC PY 2014 VL 141 BP 56 EP 63 DI 10.1016/j.mad.2014.10.001 PG 8 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA AX8BK UT WOS:000347135400008 PM 25454986 ER PT J AU Johnson, TL Hinnebusch, BJ Boegler, KA Graham, CB MacMillan, K Montenieri, JA Bearden, SW Gage, KL Eisen, RJ AF Johnson, Tammi L. Hinnebusch, B. Joseph Boegler, Karen A. Graham, Christine B. MacMillan, Katherine Montenieri, John A. Bearden, Scott W. Gage, Kenneth L. Eisen, Rebecca J. TI Yersinia murine toxin is not required for early-phase transmission of Yersinia pestis by Oropsylla montana (Siphonaptera: Ceratophyllidae) or Xenopsylla cheopis (Siphonaptera: Pulicidae) SO MICROBIOLOGY-SGM LA English DT Article ID PLAGUE EPIZOOTICS; PRAIRIE DOGS; PIGMENTATION PHENOTYPE; VECTOR COMPETENCE; BIOFILM FORMATION; FLEAS; EXPRESSION; EFFICIENCY; DYNAMICS; LOCUS AB Plague, caused by Yersinia pestis, is characterized by quiescent periods punctuated by rapidly spreading epizootics. The classical 'blocked flea' paradigm, by which a blockage forms in the flea's proventriculus on average 1-2 weeks post-infection (p.i.), forces starving fleas to take multiple blood meals, thus increasing opportunities for transmission. Recently, the importance of early-phase transmission (EPT), which occurs prior to blockage formation, has been emphasized during epizootics. Whilst the physiological and molecular mechanisms of blocked flea transmission are well characterized, the pathogen vector interactions have not been elucidated for EPT. Within the blocked flea model, Yersinia murine toxin (Ymt) has been shown to be important for facilitating colonization of the midgut within the flea. One proposed mechanism of EPT is the regurgitation of infectious material from the flea midgut during feeding. Such a mechanism would require bacteria to colonize and survive for at least brief periods in the midgut, a process that is mediated by Ymt. Two key bridging vectors of Y. pestis to humans, Oropsylla montana (Siphonaptera: Ceratophyllidae) or Xenopsylla cheopis (Siphonaptera: Pulicidae), were used in our study to test this hypothesis. Fleas were infected with a mutant strain of Y. pestis containing a non-functional ymt that was shown previously to be incapable of colonizing the midgut and were then allowed to feed on SKH-1 mice 3 days p.i. Our results show that Ymt was not required for EPT by either flea species. C1 [Johnson, Tammi L.; Boegler, Karen A.; Graham, Christine B.; MacMillan, Katherine; Montenieri, John A.; Bearden, Scott W.; Gage, Kenneth L.; Eisen, Rebecca J.] Ctr Dis Control & Prevent, Bacterial Dis Branch, Div Vector Borne Dis, Natl Ctr Emerging & Zoonot Infect Dis, Ft Collins, CO 80521 USA. [Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Johnson, TL (reprint author), Ctr Dis Control & Prevent, Bacterial Dis Branch, Div Vector Borne Dis, Natl Ctr Emerging & Zoonot Infect Dis, Ft Collins, CO 80521 USA. EM uzj6@cdc.gov FU Intramural CDC HHS [CC999999] NR 37 TC 6 Z9 7 U1 2 U2 9 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD NOV PY 2014 VL 160 BP 2517 EP 2525 DI 10.1099/mic.0.082123-0 PN 11 PG 9 WC Microbiology SC Microbiology GA AX6GN UT WOS:000347021200017 PM 25187626 ER PT J AU Sudha, G Nussinov, R Srinivasan, N AF Sudha, Govindarajan Nussinov, Ruth Srinivasan, Narayanaswamy TI An overview of recent advances in structural bioinformatics of protein-protein interactions and a guide to their principles SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE Protein-protein complexes; Structure; Evolution; Interaction; Function; Conformation ID SINGLE NUCLEOTIDE POLYMORPHISMS; HOT-SPOTS; DRUG DISCOVERY; COMPUTATIONAL DESIGN; POSTTRANSLATIONAL MODIFICATIONS; CONFORMATIONAL SELECTION; INTERACTION INTERFACES; QUATERNARY STRUCTURE; DISORDERED PROTEINS; INTRINSIC DISORDER AB Rich data bearing on the structural and evolutionary principles of protein protein interactions are paving the way to a better understanding of the regulation of function in the cell. This is particularly the case when these interactions are considered in the framework of key pathways. Knowledge of the interactions may provide insights into the mechanisms of crucial 'driver' mutations in oncogenesis. They also provide the foundation toward the design of protein protein interfaces and inhibitors that can abrogate their formation or enhance them. The main features to learn from known 3-D structures of protein protein complexes and the extensive literature which analyzes them computationally and experimentally include the interaction details which permit undertaking structure-based drug discovery, the evolution of complexes and their interactions, the consequences of alterations such as post-translational modifications, ligand binding, disease causing mutations, host pathogen interactions, oligomerization, aggregation and the roles of disorder, dynamics, allostery and more to the protein and the cell. This review highlights some of the recent advances in these areas, including design, inhibition and prediction of protein protein complexes. The field is broad, and much work has been carried out in these areas, making it challenging to cover it in its entirety. Much of this is due to the fast increase in the number of molecules whose structures have been determined experimentally and the vast increase in computational power. Here we provide a concise overview. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Sudha, Govindarajan; Srinivasan, Narayanaswamy] Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Srinivasan, N (reprint author), Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. EM gsudha@mbu.iisc.ernet.in; nussinor@helix.nih.gov; ns@mbu.iisc.ernet.in FU Department of Biotechnology, India; Department of Biotechnology, Government of India; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research FX We thank lab members for discussions and suggestions. We also thank Prof. Tom Blundell and Dr. Harry Jubb for their critical comments and suggestions. G.S is supported by a fellowship from the Department of Biotechnology, India. This research is supported by the Department of Biotechnology, Government of India. 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, under contract HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. 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 172 TC 18 Z9 18 U1 10 U2 70 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD NOV-DEC PY 2014 VL 116 IS 2-3 BP 141 EP 150 DI 10.1016/j.pbiomolbio.2014.07.004 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AX5GJ UT WOS:000346954400007 PM 25077409 ER PT J AU Nussinov, R Jang, H AF Nussinov, Ruth Jang, Hyunbum TI Dynamic multiprotein assemblies shape the spatial structure of cell signaling SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE Cell organization; Cell signaling; Signal transduction; Cell structure; Signaling modules; Diffusion ID 14-3-3 PROTEINS INTERACT; HISTONE DEACETYLASE 4; INSULIN-RECEPTOR; CYCLE PROGRESSION; POPULATION SHIFT; RAS NANOCLUSTERS; BINDING CASCADES; FOLDING FUNNELS; DRUG DISCOVERY; DNA-DAMAGE AB Cell signaling underlies critical cellular decisions. Coordination, efficiency as well as fail-safe mechanisms are key elements. How the cell ensures that these hallmarks are at play are important questions. Cell signaling is often viewed as taking place through discrete and cross-talking pathways; oftentimes these are modularized to emphasize distinct functions. While simple, convenient and clear, such models largely neglect the spatial structure of cell signaling; they also convey inter-modular (or inter-protein) spatial separation that may not exist. Here our thesis is that cell signaling is shaped by a network of multiprotein assemblies. While pre-organized, the assemblies and network are loose and dynamic. They contain transiently-associated multiprotein complexes which are often mediated by scaffolding proteins. They are also typically anchored in the membrane, and their continuum may span the cell. IQGAP1 scaffolding protein which binds proteins including Raf, calmodulin, Mek, Erk, actin, and tens more, with actin shaping B-cell (and likely other) membrane-anchored nanoclusters and allosterically polymerizing in dynamic cytoskeleton formation, and Raf anchoring in the membrane along with Ras, provides a striking example. The multivalent network of dynamic proteins and lipids, with specific interactions forming and breaking, can be viewed as endowing gel-like properties. Collectively, this reasons that efficient, productive and reliable cell signaling takes place primarily through transient, preorganized and cooperative protein protein interactions spanning the cell rather than stochastic, diffusion-controlled processes. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Nussinov, Ruth; Jang, Hyunbum] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM NussinoR@helix.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number 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. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 113 TC 11 Z9 12 U1 3 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD NOV-DEC PY 2014 VL 116 IS 2-3 BP 158 EP 164 DI 10.1016/j.pbiomolbio.2014.07.002 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AX5GJ UT WOS:000346954400009 PM 25046855 ER PT J AU Goncearenco, A Shoemaker, BA Zhang, DC Sarychey, A Panchenko, AR AF Goncearenco, Alexander Shoemaker, Benjamin A. Zhang, Dachuan Sarychey, Alexey Panchenko, Anna R. TI Coverage of protein domain families with structural protein-protein interactions: Current progress and future trends SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE Protein-protein interactions; Protein binding sites; Coverage of protein families; PPI; Structural genomics ID COMPREHENSIVE DATABASE; BINDING-SITES; DATA-BANK; INTERFACES; SUPERFAMILIES; EVOLUTIONARY; STABILITY; COMPLEXES; SERVER; PFAM AB Protein interactions have evolved into highly precise and regulated networks adding an immense layer of complexity to cellular systems. The most accurate atomistic description of protein binding sites can be obtained directly from structures of protein complexes. The availability of structurally characterized protein interfaces significantly improves our understanding of interactomes, and the progress in structural characterization of protein protein interactions (PPIs) can be measured by calculating the structural coverage of protein domain families. We analyze the coverage of protein domain families (defined according to COD and Pfam databases) by structures, structural protein protein complexes and unique protein binding sites. Structural PPI coverage of currently available protein families is about 30% without any signs of saturation in coverage growth dynamics. Given the current growth rates of domain databases and structural PPI deposition, complete domain coverage with PPIs is not expected in the near future. As a result of this study we identify families without any protein protein interaction evidence (listed on a supporting website http://www.ncbi.nlm.nih.gov/Structurefibis/coverage/) and propose them as potential targets for structural studies with a focus on protein interactions. Published by Elsevier Ltd. C1 [Goncearenco, Alexander; Shoemaker, Benjamin A.; Zhang, Dachuan; Sarychey, Alexey; Panchenko, Anna R.] Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov RI Goncearenco, Alexander/M-3946-2015 OI Goncearenco, Alexander/0000-0002-9738-7146 FU National Library of Medicine at the U.S. National Institutes of Health FX We thank Thomas Madej and Christopher Lanczycki for help with the MMDB database. This work was supported by the Intramural Research Program of the National Library of Medicine at the U.S. National Institutes of Health. NR 40 TC 4 Z9 4 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD NOV-DEC PY 2014 VL 116 IS 2-3 BP 187 EP 193 DI 10.1016/j.pbiomolbio.2014.05.005 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AX5GJ UT WOS:000346954400012 PM 24931138 ER PT J AU Elahi, D Galiatsatos, P Rabiee, A Salas-Carrillo, R Vakilipour, A Carlson, OD Angeli, FS Shannon, RP Egan, JM Andersen, DK AF Elahi, Darinsh Galiatsatos, Panagis Rabiee, Atoosa Salas-Carrillo, Rocio Vakilipour, Amin Carlson, Olga D. Angeli, Franca S. Shannon, Richard P. Egan, Josephine M. Andersen, Dana K. TI Mechanisms of type 2 diabetes resolution after Roux-en-Y gastric bypass SO SURGERY FOR OBESITY AND RELATED DISEASES LA English DT Article DE Standardized test meal; Hyperinsulinemic-euglycemic clamp; Hyperglycemic clamp; RYGB; Type 2 diabetes mellitus ID GLUCAGON-LIKE PEPTIDE-1; BARIATRIC SURGERY; INSULIN SENSITIVITY; WEIGHT-LOSS; OBESE SUBJECTS; UNITED-STATES; GUT HORMONES; GLUCOSE; SECRETION; MELLITUS AB Background: Bariatric surgery is the most effective treatment for the reduction of weight and resolution of type 2 diabetes mellitus (T2 DM). The objective of this study was to longitudinally assess hormonal and tissue responses after RYGB. Methods: Eight patients (5 with T2 DM) were studied before and after RYGB. A standardized test meal (STM) was administered before and at 1, 3, 6, 9, 12, and 15 months. Separately, a 2-hour hyperinsulinemic-euglycemic clamp (E-clamp) and a 2-hour hyperglycemic clamp (H-clamp) were performed before and at 1, 3, 6, and 12 months. Glucagon-like peptide-1 (GLP-1) was infused during the last hour of the H-clamp. Body composition was assessed with DXA methodology. Results: Enrollment body mass index was 49 +/- 3 kg/m(2) (X +/- SE). STM glucose and insulin responses were normalized by 3 and 6 months. GLP-1 level increased dramatically at 1, 3, and 6 months, normalizing by 12 and 15 months. Insulin sensitivity (M of E-clamp) increased progressively at 3-12 months as fat mass decreased. The insulin response to glucose alone fell progressively over 12 months but the glucose clearance/metabolism (M of H-clamp) did not change significantly until 12 months. In response to GLP-1 infusion, insulin levels fell progressively throughout the 12 months. Conclusion: The early hypersecretion of GLP-1 leads to hyperinsulinemia and early normalization of glucose levels. The GLP-1 response normalizes within 1 year after surgery. Enhanced peripheral tissue sensitivity to insulin starts at 3 months and is associated with fat mass loss. beta-cell sensitivity improves at 12 months and after the loss of approximate to 33% of excess weight. There is a tightly controlled feedback loop between peripheral tissue sensitivity and beta-cell and L-cell (GLP-1) responses. (C) 2014 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved. C1 [Elahi, Darinsh; Vakilipour, Amin; Angeli, Franca S.; Shannon, Richard P.] Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. [Galiatsatos, Panagis] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Rabiee, Atoosa; Andersen, Dana K.] Johns Hopkins Univ, Sch Med, Dept Surg, Johns Hopkins Bayview Med Ctr, Baltimore, MD 21205 USA. [Salas-Carrillo, Rocio] Lawrence Hosp, Dept Med, New York, NY USA. [Carlson, Olga D.] NIA, Diabet Sect, Clin Lab Invest, NIH, Baltimore, MD USA. RP Elahi, D (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. EM dariush.elahi@iconplc.com FU National Institute on Aging FX The study was supported by intradepartmental funds from the participating universities and by the intramural program of National Institute on Aging. NR 53 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-7289 EI 1878-7533 J9 SURG OBES RELAT DIS JI Surg. Obes. Relat. Dis. PD NOV-DEC PY 2014 VL 10 IS 6 BP 1028 EP 1039 DI 10.1016/j.soard.2014.07.011 PG 12 WC Surgery SC Surgery GA AX4HY UT WOS:000346895200003 PM 25443077 ER PT J AU Andersen, DK AF Andersen, Dana K. TI Hypoglycemia after gastric bypass: an old problem resurfaces SO SURGERY FOR OBESITY AND RELATED DISEASES LA English DT Editorial Material ID HYPERINSULINEMIC HYPOGLYCEMIA; SURGERY; GLUCOSE C1 Natl Inst Diabet & Digest & Kidney Dis, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Andersen, DK (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-7289 EI 1878-7533 J9 SURG OBES RELAT DIS JI Surg. Obes. Relat. Dis. PD NOV-DEC PY 2014 VL 10 IS 6 BP 1054 EP 1055 PG 2 WC Surgery SC Surgery GA AX4HY UT WOS:000346895200007 PM 25042284 ER PT J AU Le, KY Dastgheyb, S Ho, TV Otto, M AF Le, Katherine Y. Dastgheyb, Sana Ho, Trung V. Otto, Michael TI Molecular determinants of staphylococcal biofilm dispersal and structuring SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Review DE Staphylococcus aureus; Staphylococcus epidermidis; biofilm; phenol-soluble modulins; medical devices ID PHENOL-SOLUBLE MODULINS; QUORUM-SENSING CONTROL; IN-VIVO; AUREUS; EPIDERMIDIS; INFECTIONS; VIRULENCE; SYSTEM; MATURATION; PEPTIDE AB Staphylococci are frequently implicated in human infections, and continue to pose a therapeutic dilemma due to their ability to form deeply seated microbial communities, known as biofilms, on the surfaces of implanted medical devices and host tissues. Biofilm development has been proposed to occur in three stages: (1) attachment, (2) proliferation/structuring, and (3) detachment/dispersal. Although research within the last several decades has implicated multiple molecules in the roles as effectors of staphylococcal biofilm proliferation/structuring and detachment/dispersal, to date, only phenol soluble modulins (PSMs) have been consistently demonstrated to serve in this role under both in vitro and in vivo settings. PSMs are regulated directly through a density-dependent manner by the accessory gene regulator (Agr) system. They disrupt the non-covalent forces holding the biofilm extracellular matrix together, which is necessary for the formation of channels, a process essential for the delivery of nutrients to deeper biofilm layers, and for dispersal/dissemination of clusters of biofilm to distal organs in acute infection. Given their relevance in both acute and chronic biofilm-associated infections, the Agr system and the psm genes hold promise as potential therapeutic targets. C1 [Le, Katherine Y.; Dastgheyb, Sana; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Le, Katherine Y.] Mayo Clin, Coll Med, Dept Med, Div Hosp Internal Med, Rochester, MN USA. [Dastgheyb, Sana] Thomas Jefferson Univ, Sch Med, Dept Orthoped Surg, Philadelphia, PA 19107 USA. [Ho, Trung V.] Uniformed Serv Univ Hlth & Sci, Sch Med, Bethesda, MD USA. RP Otto, M (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike,Bldg 33 1W10,33 North Dr, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Dastgheyb, Sana/0000-0001-8275-1614; Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health. NR 51 TC 4 Z9 4 U1 2 U2 28 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD NOV PY 2014 VL 4 DI 10.3389/fcimb.2014.00167 PG 7 WC Immunology; Microbiology SC Immunology; Microbiology GA AX3KD UT WOS:000346837300011 ER PT J AU Zhang, WG Giancaspro, G Adams, KM Neal-Kababick, J Hildreth, J Li, A Roman, MC Betz, JM AF Zhang, Weiguo Giancaspro, Gabriel Adams, Kristie M. Neal-Kababick, James Hildreth, Jana Li, Aishan Roman, Mark C. Betz, Joseph M. TI Electrophoretie Separation of Alginic Sodium Diester and Sodium Hexametaphosphate in Chondroitin Sulfate that Interfere with the Cetylpyridinium Chloride Titration Assay SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; SUPPLEMENTS; VALIDATION AB The most commonly used chondroitin sulfate (CS) assay method is cetylpyridinium chloride (CPC) titration. Cellulose acetate membrane electrophoresis (CAME) is the technique used for detection of impurities in the U.S. Pharmacopeia's CS monograph. Because CPC titration is a relatively nonspecific quantitative technique, the apparent amount of CS as determined by CPC titration alone may not reflect the true amount of CS due to possible interference with the CPC assay by impurities that contain CPC titratable functional groups. When CAME is used in conjunction with CPC titration, certain non-CS and adulterants can be visualized and estimated, and a true value for CS can be assigned once the presence of these non-CS impurities has been ruled out. This study examines conjunct application of CPC and CAME in ascertaining CS assay and purity in the presence of certain adulterants. These include propylene glycol alginate sulfate sodium, known in commerce as alginic sodium diester (ASD), and Zero One (Z1), a water-soluble agent newly reported in the CS marketplace and subsequently identified as sodium hexametaphosphate. ASD, Z1, and CS are similar in physical appearance and solubility in water and ethanol. They are also titratable anions and form ionic pairs with CPC, therefore interfering with the CPC titration assay for CS. CAME separates these adulterants from each other and from CS by differences in their electrophoretic mobility. CAME is able to detect these impurities in CS at levels as low as 0.66% by weight. Although it is recommended that a method for detecting impurities (e.g., CAME) be used in combination with relatively nonspecific assay methods such as CPC titration, this is seldom done in practice. Assay results for CS derived from CPC titration may, therefore, be misleading, leaving the CS supply chain vulnerable to adulteration. In this study, the authors investigated ASD and Z1 adulteration of CS and developed an electrophoretic separation of these adulterants in CS and procedures to isolate ASD from CS matrixes containing these adulterants. The authors describe in this paper utilization of an orthogonal approach to establish the identity of Z1 as sodium hexametaphosphate and to confirm the identity of ASD, including ethanol fractionation, FTIR spectroscopy, differential scanning calorimetry, and NMR spectroscopy. The authors suggest that CAME is a cost-effective and easy to use method for detecting certain impurities in CS raw ingredients and recommend that CPC and CAME be used in combination by QC laboratories as a means of effectively deterring the practice of adulterating CS raw materials with the known adulterants ASD and Z1 and/or other non-chondroitin substances that can be separated from CS by CAME and that exhibit CPC titration behavior similar to CS. C1 [Zhang, Weiguo; Hildreth, Jana] Synutra Res Lab, Rockville, MD 20850 USA. [Giancaspro, Gabriel; Adams, Kristie M.] US Pharmacopeial Convent Inc, Rockville, MD 20852 USA. [Neal-Kababick, James] Flora Res Labs, Grants Pass, OR 97526 USA. [Li, Aishan] Meitek Technol Qingdao Co Ltd, Jiaonan City, Qingdao, Peoples R China. [Roman, Mark C.] Tampa Bay Analyt Res, Clearwater, FL 33760 USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Zhang, WG (reprint author), Synutra Res Lab, 2275 Res Blvd, Rockville, MD 20850 USA. EM wzhang@synutrapure.com NR 22 TC 0 Z9 0 U1 3 U2 6 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD NOV-DEC PY 2014 VL 97 IS 6 BP 1503 EP 1513 DI 10.5740/jaoacint.14-167 PG 11 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA AX3DF UT WOS:000346820000002 ER PT J AU Marx, SJ AF Marx, Stephen J. TI Uncoupling of Secretion From Growth in Some Hormone Secretory Tissues SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; CALCIUM-SENSING RECEPTOR; ALDOSTERONE-PRODUCING ADENOMAS; NEONATAL SEVERE HYPERPARATHYROIDISM; PERSISTENT HYPERINSULINEMIC HYPOGLYCEMIA; EXTRACELLULAR CA2+-SENSING RECEPTOR; BETA-CELL PROLIFERATION; TERM-FOLLOW-UP; CONGENITAL HYPERINSULINISM; BENIGN HYPERCALCEMIA AB Context: Most syndromes with benign primary excess of a hormone show positive coupling of hormone secretion to size or proliferation in the affected hormone secretory tissue. Syndromes that lack this coupling seem rare and have not been examined for unifying features among each other. Evidence Acquisition: Selected clinical and basic features were analyzed from original reports and reviews. We examined indices of excess secretion of a hormone and indices of size of secretory tissue within the following three syndromes, each suggestive of uncoupling between these two indices: familial hypocalciuric hypercalcemia, congenital diazoxide-resistant hyperinsulinism, and congenital primary hyperaldosteronism type III (with G151E mutation of the KCNJ5 gene). Evidence Synthesis: Some unifying features among the three syndromes were different from features present among common tumors secreting the same hormone. The unifying and distinguishing features included: 1) expression of hormone excess as early as the first days of life; 2) normal size of tissue that oversecretes a hormone; 3) diffuse histologic expression in the hormonal tissue; 4) resistance to treatment by subtotal ablation of the hormone-secreting tissue; 5) causation by a germline mutation; 6) low potential of the same mutation to cause a tumor by somatic mutation; and 7) expression of the mutated molecule in a pathway between sensing of a serum metabolite and secretion of hormone regulating that metabolite. Conclusion: Some shared clinical and basic features of uncoupling of secretion from size in a hormonal tissue characterize three uncommon states of hormone excess. These features differ importantly from features of common hormonal neoplasm of that tissue. C1 [Marx, Stephen J.] Natl Inst Diabet & Digest & Kidney Dis, Genet & Endocrinol Sect, NIH, Bethesda, MD 20892 USA. RP Marx, SJ (reprint author), NIH, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM marxs@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases intramural program. NR 80 TC 2 Z9 2 U1 0 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 NOV PY 2014 VL 99 IS 11 BP 4051 EP 4059 DI 10.1210/jc.2014-2113 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AX1ZN UT WOS:000346743100017 PM 25004249 ER PT J AU Boyce, AM Kelly, MH Brillante, BA Kushner, H Wientroub, S Riminucci, M Bianco, P Robey, PG Collins, MT AF Boyce, Alison M. Kelly, Marilyn H. Brillante, Beth A. Kushner, Harvey Wientroub, Shlomo Riminucci, Mara Bianco, Paolo Robey, Pamela G. Collins, Michael T. TI A Randomized, Double Blind, Placebo-Controlled Trial of Alendronate Treatment for Fibrous Dysplasia of Bone SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MCCUNE-ALBRIGHT-SYNDROME; STIMULATORY G-PROTEIN; INTRAVENOUS PAMIDRONATE; OSTEOGENESIS IMPERFECTA; MINERAL DENSITY; BISPHOSPHONATE TREATMENT; ACTIVATING MUTATIONS; BIOCHEMICAL MARKERS; THERAPY; CHILDREN AB Context: Fibrous dysplasia (FD) is a rare skeletal disorder, resulting in deformity, fracture, functional impairment, and pain. Bisphosphonates have been advocated as a potential treatment. Objective: To determine the efficacy of alendronate for treatment of FD. Design: Two-year randomized,double-blind, placebo-controlled trial. Setting: Clinical research center. Patients: Forty subjects with polyostotic FD (24 adults, 16 children). Subjects were randomized and stratified by age. Interventions: Study drug was administered over a 24 month period in 6 month cycles (6 months on, 6 months off). Alendronate dosing was stratified: 40 mg daily for subjects > 50 kg, 20 mg for 30-50 kg, 10 mg for 20-30 kg. Main Outcome Measures: Primary endpoints were bone turnover markers, including serum osteocalcin, and urinary NTX-telopeptides. Secondary endpoints included areal bone mineral density (aBMD), pain, skeletal disease burden score, and functional parameters including the 9-min walk test and manual muscle testing. Results: Clinical data was collected on 35 subjects who completed the study. There was a decline in NTX-telopeptides in the alendronate group (P = .006), but no significant difference in osteocalcin between groups. The alendronate group had an increase in areal BMD in normal bone at the lumbar spine (P = .006), and in predetermined regions of FD (P <.001). There were no significant differences in pain scores, skeletal disease burden scores, or functional parameters between the groups. Conclusions: Alendronate treatment led to a reduction in the bone resorption marker NTX-telopeptides, and improvement in aBMD, but no significant effect on serum osteocalcin, pain, or functional parameters. C1 [Boyce, Alison M.; Kelly, Marilyn H.; Brillante, Beth A.; Robey, Pamela G.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Boyce, Alison M.] Childrens Natl Hlth Syst, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Boyce, Alison M.] Childrens Natl Hlth Syst, Bone Hlth Program, Div Orthopaed & Sports Med, Washington, DC 20010 USA. [Kushner, Harvey] BioMed Comp Res Inst, Philadelphia, PA 19115 USA. [Wientroub, Shlomo] Tel Aviv Univ, Dana Childrens Hosp, Tel Aviv Sourasky Med Ctr, Dept Pediat Orthoped,Sackler Fac Med, IL-64239 Tel Aviv, Israel. [Riminucci, Mara; Bianco, Paolo] Univ Roma La Sapienza, Dept Mol Med, I-00185 Rome, Italy. RP Collins, MT (reprint author), NIH, 30 Convent Dr,Bldg 30,Room 228,MSC 4320, Bethesda, MD 20910 USA. EM mcollins@mail.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU National Institute of Dental and Craniofacial Research; National Institutes of Health [GGP09227]; Bone Health Program, Division of Orthopaedics and Sports Medicine, Children's National Health System; Fondazione Telethon FX This research was supported by the intramural research program of the National Institute of Dental and Craniofacial Research, National Institutes of Health (M.H.K., B.A.B., P.G.B., M.T.C.), Telethon Grant No. GGP09227 (P.B.), the Bone Health Program, Division of Orthopaedics and Sports Medicine, Children's National Health System (A.M.B.).Study drug and placebo were provided by Merck. NR 39 TC 13 Z9 14 U1 1 U2 7 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 NOV PY 2014 VL 99 IS 11 BP 4133 EP 4140 DI 10.1210/jc.2014-1371 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AX1ZN UT WOS:000346743100029 PM 25033066 ER PT J AU Mulligan, TS Weinstein, BM AF Mulligan, Timothy S. Weinstein, Brant M. TI Emerging from the PAC: Studying zebrafish lymphatic development SO MICROVASCULAR RESEARCH LA English DT Article DE Lymphatic vessels; Endothelial cells; Lymphatic specification; Zebrafish; Development; Lymphangiogenesis; Parachordal ID ENDOTHELIAL-GROWTH-FACTOR; EMBRYONIC LYMPHANGIOGENESIS; VASCULAR DEVELOPMENT; NETWORK FORMATION; CELL FATE; FACTOR-C; TRANSCRIPTION FACTOR; VESSEL DEVELOPMENT; COUP-TFII; IN-VIVO AB Recently the zebrafish has emerged as a promising vertebrate model of lymphatic vasculature development. The establishment of numerous transgenic lines that label the lymphatic endothelium in the zebrafish has allowed the fine examination of the developmental timing and the anatomy of their lymphatic vasculature. Although many questions remain, studying lymphatic development in the zebrafish has resulted in the identification and characterization of novel and established mediators of lymphatic development and lymphangiogenesis. Here, we review the main stages involved in the development of the lymphatic vasculature in the zebrafish from its origins in the embryonic veins to the formation of the primary lymphatic vessels and highlight some of the key molecules necessary for these stages. Published by Elsevier Inc. C1 [Mulligan, Timothy S.; Weinstein, Brant M.] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Mulligan, TS (reprint author), NICHHD, Program Genom Differentiat, NIH, Bldg 6B,Room 309,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Timothy.Mulligan@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH FX The authors would like to thank Jen Anderson for critical reading and suggestions. This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH. NR 52 TC 6 Z9 6 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0026-2862 EI 1095-9319 J9 MICROVASC RES JI Microvasc. Res. PD NOV PY 2014 VL 96 SI SI BP 23 EP 30 DI 10.1016/j.mvr.2014.06.001 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AX4IB UT WOS:000346895500005 PM 24928500 ER PT J AU Guinney, J Dienstmann, R Ferte, C Friend, S McCormick, F AF Guinney, Justin Dienstmann, Rodrigo Ferte, Charles Friend, Stephen McCormick, Frank TI Social Interactomes for Enabling Research Communities SO CANCER DISCOVERY LA English DT Editorial Material ID K-RAS AB Data-driven analyses of scientific abstracts with web apps such as "abstract interactomes" provide a new visualization tool for the biomedical research community to interactively navigate a rich assembly of investigators and identify common research topics. Alternative conference formats such as "social interactomes," with structured, albeit informal, discussions among attendees, are able to engage fellows and top investigators, facilitate the exchange of ideas, and encourage data sharing and future collaborations. (C) 2014 AACR. C1 [Guinney, Justin; Dienstmann, Rodrigo; Friend, Stephen] Fred Hutchinson Canc Res Ctr, Sage Bionetworks, Seattle, WA 98104 USA. [Ferte, Charles] Inst Gustave Roussy, Dept Med Oncol, Villejuif, France. [Ferte, Charles] Inst Gustave Roussy, Dept Biostat & Epidemiol, Villejuif, France. [Ferte, Charles] Inst Gustave Roussy, Dept Innovat Therapeut & Early Drug Dev, Villejuif, France. [Ferte, Charles] Univ Paris 11, Inst Gustave Roussy, INSERM, U981, Villejuif, France. [McCormick, Frank] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [McCormick, Frank] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [McCormick, Frank] Univ Calif San Francisco, Dept Cell & Mol Pharmacol, San Francisco, CA 94143 USA. RP Guinney, J (reprint author), 1100 Fairview Ave North, Seattle, WA 98109 USA. EM justin.guinney@sagebase.org; mccormic@cc.ucsf.edu NR 5 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD NOV PY 2014 VL 4 IS 11 BP 1265 EP 1268 DI 10.1158/2159-8290.CD-14-0774 PG 4 WC Oncology SC Oncology GA AW8GY UT WOS:000346500700021 PM 25367949 ER PT J AU Hettmer, S Li, ZZ Billin, AN Barr, FG Cornelison, DDW Ehrlich, AR Guttridge, DC Hayes-Jordan, A Helman, LJ Houghton, PJ Khan, J Langenau, DM Linardic, CM Pal, R Partridge, TA Pavlath, GK Rota, R Schafer, BW Shipley, J Stillman, B Wexler, LH Wagers, AJ Keller, C AF Hettmer, Simone Li, Zhizhong Billin, Andrew N. Barr, Frederic G. Cornelison, D. D. W. Ehrlich, Alan R. Guttridge, Denis C. Hayes-Jordan, Andrea Helman, Lee J. Houghton, Peter J. Khan, Javed Langenau, David M. Linardic, Corinne M. Pal, Ranadip Partridge, Terence A. Pavlath, Grace K. Rota, Rossella Schaefer, Beat W. Shipley, Janet Stillman, Bruce Wexler, Leonard H. Wagers, Amy J. Keller, Charles TI Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID CHILDRENS ONCOLOGY GROUP; SOFT-TISSUE SARCOMAS; EMBRYONAL RHABDOMYOSARCOMA; PEDIATRIC RHABDOMYOSARCOMA; ALVEOLAR RHABDOMYOSARCOMA; PHASE-2 TRIAL; CANCER; CELLS; CHEMOTHERAPY; CHILDHOOD AB Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in <30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusion-positive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry. C1 [Hettmer, Simone] Univ Hosp Berlin, Charite, D-10439 Berlin, Germany. [Li, Zhizhong] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Li, Zhizhong] Novartis Inst Biomed Res, San Diego, CA 92121 USA. [Billin, Andrew N.] GlaxoSmithKline, Durham, NC 27709 USA. [Barr, Frederic G.; Helman, Lee J.; Khan, Javed] NCI, Bethesda, MD 20892 USA. [Cornelison, D. D. W.] Univ Missouri, Columbia, MO 65211 USA. [Ehrlich, Alan R.] Focus Rhabdo, New York, NY USA. [Guttridge, Denis C.] Ohio State Univ, Columbus, OH 43210 USA. [Hayes-Jordan, Andrea] Univ Texas Houston, Sch Med, Houston, TX 77030 USA. [Houghton, Peter J.] Nationwide Childrens Res Inst, Columbus, OH 43205 USA. [Langenau, David M.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Linardic, Corinne M.] Duke Univ, Sch Med, Durham, NC 27710 USA. [Pal, Ranadip] Texas Tech Univ, Dept Elect & Comp Engn, Lubbock, TX 79409 USA. [Partridge, Terence A.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Pavlath, Grace K.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Rota, Rossella] Osped Pediat Bambino Gesu, Dept Oncohematol, I-00165 Rome, Italy. [Schaefer, Beat W.] Univ Childrens Hosp, CH-8032 Zurich, Switzerland. [Shipley, Janet] Inst Canc Res, Sutton SM2 5NG, Surrey, England. [Stillman, Bruce] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Wexler, Leonard H.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Wagers, Amy J.] Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Wagers, Amy J.] Joslin Diabet Ctr, Cambridge, MA 02138 USA. [Keller, Charles] Oregon Hlth & Sci Univ, Pediat Canc Biol Program, Dept Pediat, Pape Family Pediat Res Inst, Portland, OR 97239 USA. [Keller, Charles] Childrens Canc Therapy Dev Inst, Ft Collins, CO 80524 USA. RP Wagers, AJ (reprint author), Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM amy_wagers@harvard.edu; charles@cc-TDI.org RI Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; Billin, Andrew/0000-0001-7752-0934; Rota, Rossella/0000-0002-9408-7711 FU Michelle Paternoster Foundation for Sarcoma Research; Christina Renna Foundation Inc.; Friends of T.J. Foundation FX The authors are grateful to the Michelle Paternoster Foundation for Sarcoma Research, the Christina Renna Foundation Inc., and the Friends of T.J. Foundation for lending their voice and financial support, and to the staff at the Banbury Center at Cold Spring Harbor Laboratory, NY for their interest and for hosting the RMS meeting in May 2014. NR 41 TC 9 Z9 9 U1 0 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD NOV PY 2014 VL 4 IS 11 AR a025650 DI 10.1101/cshperspect.a025650 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW8OQ UT WOS:000346522200001 PM 25368019 ER PT J AU McClure, EA Sonne, SC Winhusen, T Carroll, KM Ghitza, UE McRae-Clark, AL Matthews, AG Sharma, G Van Veldhuisen, P Vandrey, RG Levin, FR Weiss, RD Lindblad, R Allen, C Mooney, LJ Haynes, L Brigham, GS Sparenborg, S Hasson, AL Gray, KM AF McClure, Erin A. Sonne, Susan C. Winhusen, Theresa Carroll, Kathleen M. Ghitza, Udi E. McRae-Clark, Aimee L. Matthews, Abigail G. Sharma, Gaurav Van Veldhuisen, Paul Vandrey, Ryan G. Levin, Frances R. Weiss, Roger D. Lindblad, Robert Allen, Colleen Mooney, Larissa J. Haynes, Louise Brigham, Gregory S. Sparenborg, Steve Hasson, Albert L. Gray, Kevin M. TI Achieving Cannabis Cessation - Evaluating N-acetylcysteine Treatment (ACCENT): Design and implementation of a multi-site, randomized controlled study in the National Institute on Drug Abuse Clinical Trials Network SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE N-acetylcysteine; Cannabis; Marljuana; Pharmacotherapy; Randomized trials; Clinical study design ID PLACEBO-CONTROLLED TRIAL; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; MARIJUANA CRAVING QUESTIONNAIRE; SUBSTANCE USE DISORDERS; NUCLEUS-ACCUMBENS CORE; CONTINGENCY MANAGEMENT; DOUBLE-BLIND; COCAINE DEPENDENCE; PHARMACOLOGICAL-TREATMENT; SYNAPTIC-TRANSMISSION AB Despite recent advances in behavioral interventions for cannabis use disorders, effect sizes remain modest, and few individuals achieve long-term abstinence. One strategy to enhance outcomes is the addition of pharmacotherapy to complement behavioral treatment, but to date no efficacious medications targeting cannabis use disorders in adults through large, randomized controlled trials have been identified. The National Institute on Drug Abuse Clinical Trials Network (NIDA CTN) is currently conducting a study to test the efficacy of N-acetylcysteine (NAC) versus placebo (PBO), added to contingency management, for cannabis cessation in adults (ages 18-50). This study was designed to replicate positive findings from a study in cannabis-dependent adolescents that found greater odds of abstinence with NAC compared to PBO. This paper describes the design and implementation of an ongoing 12-week, intent-to-treat, double-blind, randomized, placebo-controlled study with one follow-up visit four weeks post-treatment. Approximately 300 treatment-seeking cannabis-dependent adults will be randomized to NAC or PBO across six study sites in the United States. The primary objective of this 12-week study is to evaluate the efficacy of twice-daily orally-administered NAC (1200 mg) versus matched PBO, added to contingency management, on cannabis abstinence. NAC is among the first medications to demonstrate increased odds of abstinence in a randomized controlled study among cannabis users in any age group. The current study will assess the cannabis cessation efficacy of NAC combined with a behavioral intervention in adults, providing a novel and timely contribution to the evidence base for the treatment of cannabis use disorders. (C) 2014 Elsevier Inc. All rights reserved. C1 [McClure, Erin A.; Sonne, Susan C.; McRae-Clark, Aimee L.; Haynes, Louise; Gray, Kevin M.] Med Univ S Carolina, Coll Med, Charleston, SC 29425 USA. [Winhusen, Theresa; Brigham, Gregory S.] Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, Addict Sci Div, Cincinnati, OH 45229 USA. [Carroll, Kathleen M.] Yale Univ, Sch Med, West Haven, CT 06516 USA. [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Matthews, Abigail G.; Sharma, Gaurav; Van Veldhuisen, Paul; Lindblad, Robert; Allen, Colleen] EMMES Corp, Rockville, MD 20850 USA. [Vandrey, Ryan G.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21224 USA. [Levin, Frances R.] Columbia Univ, New York State Psychiat Inst, New York, NY 10032 USA. [Weiss, Roger D.] McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02478 USA. [Weiss, Roger D.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Mooney, Larissa J.; Hasson, Albert L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90025 USA. RP McClure, EA (reprint author), Med Univ S Carolina, Clin Neurosci Div, 125 Doughty St,Suite 190,MSC 861, Charleston, SC 29425 USA. EM mccluree@musc.edu OI Winhusen, Theresa/0000-0002-3364-0739; Brigham, Gregory/0000-0003-1150-4493 FU National Institute on Drug Abuse National Drug Clinical Trials Network [U10DA013727, U10DA15831]; NIDA [K24DA022288, U10DA013045, U10DA013034, U10DA013732, U10DA013714, N01DA92217, N01DA102221] FX This work was supported by the National Institute on Drug Abuse National Drug Clinical Trials Network Grants U10DA013727 (Kathleen T. Brady), U10DA15831 (Kathleen M. Carroll and Roger D. Weiss), NIDA K24DA022288 (Roger D. Weiss), U10DA013045 (Walter Ling), U10DA013034 (Maxine L. Stitzer and Robert P. Schwartz), U10DA013732 (Theresa Winhusen), U10DA013714 (James L Sorensen and Dennis McCarty); and NIDA Contracts N01DA92217 and N01DA102221 (The EMMES Corporation). The authors would like to thank the staff at the study sites and the regional research and training programs of the NIDA CTN who participated in the development and implementation of this study. Special thanks to Ashley Morrill, Ricardo Cantu, Sarah Brewer, and Christine Horne for their hard work and dedication to the implementation of the ACCENT study. The opinions in this manuscript are those of the authors and do not represent the official position of the U.S. government. NR 106 TC 13 Z9 14 U1 5 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2014 VL 39 IS 2 BP 211 EP 223 DI 10.1016/j.cct.2014.08.011 PG 13 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AW8XJ UT WOS:000346542400005 PM 25179587 ER PT J AU Schrama, D Groesser, L Ugurel, S Hafner, C Pastrana, DV Buck, CB Cerroni, L Theiler, A Becker, JC AF Schrama, David Groesser, Leopold Ugurel, Selma Hafner, Christian Pastrana, Diana V. Buck, Christopher B. Cerroni, Lorenzo Theiler, Anna Becker, Juergen C. TI Presence of Human Polyomavirus 6 in Mutation-Specific BRAF Inhibitor-Induced Epithelial Proliferations SO JAMA DERMATOLOGY LA English DT Article ID MERKEL CELL POLYOMAVIRUS; SPINULOSA-ASSOCIATED POLYOMAVIRUS; METASTATIC MELANOMA; RAF INHIBITORS; HUMAN-PAPILLOMAVIRUS; CARCINOMA; DABRAFENIB; VEMURAFENIB; GROWTH; TUMORS AB IMPORTANCE A frequent adverse effect of mutation-specific BRAF inhibitor therapy is the induction of epithelial proliferations including cutaneous squamous cell carcinomas. To date, the only factor identified contributing to their development is the activation of the mitogen-activated signal transduction cascade by mutations in the RAS genes. However, these mutations explain only 60% of the tumors; hence, it is important to identify what is causing the remaining tumors. OBJECTIVE To test for the presence of human papillomaviruses (HPVs) and the recently identified human polyomaviruses (HPyVs), Merkel cell polyomavirus (MCPyV), and trichodysplasia spinulosa-associated polyomavirus (TSPyV), as well as HPyV-6, HPyV-7, HPyV-9, and HPyV-10, in epithelial proliferations occurring after BRAF inhibitor therapy to determine whether these oncogenic viruses may contribute to BRAF inhibitor-induced skin tumors. DESIGN, SETTING, AND PARTICIPANTS Retrospective study at a university hospital in Austria of epithelial proliferations that developed in patients with melanoma after initiation of treatment with the BRAF inhibitor vemurafenib. Samples were analyzed for (1) presence of the most frequently observed RAS mutations by SNaPshot technology, (2) detection of the viruses by real-time polymerase chain reaction, and (3) presence of capsid proteins of the most abundantly detected virus by immunohistochemical analysis. MAIN OUTCOMES AND MEASURES RAS mutational status, as well as HPV and HPyV presence, in BRAF inhibitor-induced epithelial proliferations. RESULTS Eighteen biopsy samples from 6 patients were retrieved from our hospital's archive. We identified RAS mutations in 10 (62%) of the 16 samples with clear results. DNA of HPyV-9, HPyV-10, and TSPyV were virtually absent in the samples. MCPyV DNA was present in 13 of 18 samples, and HPV, HPyV-6, and HPyV-7 DNA were present in all samples. In general, the amount of DNA encoding the latter viruses was rather low, with the exception of HPyV-6 in several samples of 1 individual patient. Notably, the relevance of the presence of HPyV-6 in the epithelial proliferation was underlined by immunohistochemical detection of the core protein VP1 of HPyV-6. CONCLUSIONS AND RELEVANCE The presence of both high HPyV-6 DNA load and VP1 protein suggests that polyomaviruses may contribute to the epithelial proliferations observed in patients receiving BRAF inhibitor therapy, albeit the relative impact as compared with that of RAS mutations appears circumstantial. C1 [Schrama, David; Cerroni, Lorenzo; Theiler, Anna; Becker, Juergen C.] Med Univ Graz, Dept Dermatol, A-8010 Graz, Austria. [Schrama, David; Ugurel, Selma] Univ Hosp Wurzburg, Dept Dermatol, Wurzburg, Germany. [Groesser, Leopold; Hafner, Christian] Univ Hosp Regensburg, Dept Dermatol, Regensburg, Germany. [Pastrana, Diana V.; Buck, Christopher B.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Schrama, D (reprint author), Med Univ Graz, Dept Dermatol, Auenbruggerpl 8, A-8010 Graz, Austria. EM david.schrama@medunigraz.at OI Buck, Christopher/0000-0003-3165-8094 FU Austrian Science Fund FWF [W1241]; PhD program DK-MOLIN - Austrian Science Fund FWF [W1241] FX This study was supported in part by Austrian Science Fund FWF (grant W1241). Ms Theiler and Dr Becker were supported by the PhD program DK-MOLIN funded by the Austrian Science Fund FWF (grant W1241). NR 42 TC 17 Z9 17 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD NOV PY 2014 VL 150 IS 11 BP 1180 EP 1186 DI 10.1001/jamadermatol.2014.1116 PG 7 WC Dermatology SC Dermatology GA AW4EP UT WOS:000346234300010 PM 24943872 ER PT J AU Dinney, CPN Hansel, D McConkey, D Shipley, W Hagan, M Dreicer, R Lerner, S Czerniak, B Waldman, F Groshen, S True, LD Petricoin, E Theodorescu, D Hruszkewycz, A Bajorin, D AF Dinney, Colin P. N. Hansel, Donna McConkey, David Shipley, William Hagan, Michael Dreicer, Robert Lerner, Seth Czerniak, Bogdan Waldman, Fred Groshen, Susan True, Lawrence D. Petricoin, Emanuel Theodorescu, Dan Hruszkewycz, Andrew Bajorin, Dean TI Novel neoadjuvant therapy paradigms for bladder cancer: Results from the National Cancer Center Institute Forum SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Review DE Bladder cancer; Neoadjuvant chemotherapy; Radiation ID COMBINED-MODALITY THERAPY; LONG-TERM OUTCOMES; CELL LUNG-CANCER; RADICAL CYSTECTOMY; BREAST-CANCER; PROTEIN MICROARRAYS; DRUG DISCOVERY; CHEMOTHERAPY; RADIOTHERAPY; EXPRESSION AB Objective: To bridge gaps in translational science and develop the concepts for 2 novel biomarker-driven clinical trials: one in the presurgical setting and the other in the setting of bladder preservation with chemoradiation. Methods and materials: The National Cancer Institute sponsored a forum, "Novel Neoadjuvant Therapy for Bladder Cancer," which brought leading clinical and laboratory-based scientists together with the advocacy community. Results: The group designed a neoadjuvant clinical trial to compare the clinical efficacy of the two frontline chemotherapy regimens (gemcitabine plus cisplatin versus MVAC) and the ability of a gene expression profiling-based algorithm (CoXEN) to predict complete pathological response. The trial was recently opened under the leadership of the Southwest Oncology Group (SWOG, S1314), receiving support for the biomarker studies from the NCI's BISQFP resource. A second clinical trial was planned that will examine the relationship between expression of the DNA repair protein MRE11 and complete response in patients treated with concurrent 5-fiurouracil/mitomycin C plus radiation. Conclusion: The meeting provided a unique opportunity to launch a collective effort to establish molecular-based therapies for muscle-invasive urothelial cancer. The goal is to use this framework to develop comparable trials with immunotherapy in non-muscle invasive cancers and to exploit the neoadjuvant platform to develop targeted therapy in muscle-invasive disease. (C) 2014 Elsevier Inc. All rights reserved. C1 [Dinney, Colin P. N.; McConkey, David] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Hansel, Donna] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Shipley, William] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Hagan, Michael] Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA USA. [Dreicer, Robert] Cleveland Clin, Dept Solid Tumor Oncol, Cleveland, OH 44106 USA. [Lerner, Seth] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. [Czerniak, Bogdan] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Waldman, Fred] Quest Diagnost, San Juan Capistrano, CA USA. [Groshen, Susan] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [True, Lawrence D.] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. [Petricoin, Emanuel] George Mason Univ, Ctr Appl Prote & Mol Med, Fairfax, VA 22030 USA. [Theodorescu, Dan] Univ Colorado, Dept Urol Surg, Denver, CO 80202 USA. [Hruszkewycz, Andrew] NCI, Bethesda, MD 20892 USA. [Bajorin, Dean] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, New York, NY 10021 USA. RP Dinney, CPN (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. EM cdinney@mdanderson.org FU National Cancer Institute of the National Institutes of Health; SPORE in Genitourinary Cancer at The University of Texas MD Anderson Cancer Center [P50 CA91846]; Clinical and Translational Science Center at the Weill Medical College of Cornell University [UL1-RR024996] FX This Workshop was supported by resources from the National Cancer Institute of the National Institutes of Health. Dr. Colin Dinney wishes to acknowledge grant support from the SPORE in Genitourinary Cancer at The University of Texas MD Anderson Cancer Center (P50 CA91846). Dr. Dean Bajorin wishes to acknowledge support from the Clinical and Translational Science Center at the Weill Medical College of Cornell University (UL1-RR024996). NR 60 TC 10 Z9 10 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD NOV PY 2014 VL 32 IS 8 BP 1108 EP 1115 DI 10.1016/j.urolonc.2013.10.021 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AX0EZ UT WOS:000346627300004 PM 25443274 ER PT J AU Abu-Eid, R Samara, RN Ozbun, L Abdalla, MY Berzofsky, JA Friedman, KM Mkrtichyan, M Khleif, SN AF Abu-Eid, Rasha Samara, Raed N. Ozbun, Laurent Abdalla, Maher Y. Berzofsky, Jay A. Friedman, Kevin M. Mkrtichyan, Mikayel Khleif, Samir N. TI Selective Inhibition of Regulatory T Cells by Targeting the PI3K-Akt Pathway SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID METASTATIC MELANOMA; TRANSFER IMMUNOTHERAPY; ADOPTIVE TRANSFER; MAMMALIAN TARGET; TUMOR-ANTIGEN; RAPAMYCIN; SURVIVAL; CANCER; DEPLETION; AKT AB Despite the strides that immunotherapy has made in mediating tumor regression, the clinical effects are often transient, and therefore more durable responses are still needed. The temporary nature of the therapy-induced immune response can be attributed to tumor immune evasion mechanisms, mainly the effect of suppressive immune cells and, in particular, regulatory T cells (Treg). Although the depletion of Tregs has been shown to be effective in enhancing immune responses, selective depletion of these suppressive cells without affecting other immune cells has not been very successful, and new agents are sought. We found that PI3K-Akt pathway inhibitors selectively inhibit Tregs with minimal effect on conventional T cells (Tconv). Our results clearly show selective in vitro inhibition of activation (as represented by a decrease in downstream signaling) and proliferation of Tregs in comparison with Tconvs when treated with different Akt and PI3K inhibitors. This effect has been observed in both human and murine CD4 T cells. In vivo treatment with these inhibitors resulted in a significant and selective reduction in Tregs in both naive and tumor-bearing mice. Furthermore, these PI3K-Akt inhibitors led to a significant therapeutic antitumor effect, which was shown to be Treg dependent. Here, we report the use of PI3K-Akt pathway inhibitors as potent agents for the selective depletion of suppressive Tregs. Weshow that these inhibitors are able to enhance the antitumor immune response and are therefore promising clinical reagents for Treg depletion. (C) 2014 AACR. C1 [Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N.] Georgia Regents Univ, Ctr Canc, Augusta, GA 30912 USA. [Samara, Raed N.; Ozbun, Laurent; Abdalla, Maher Y.; Berzofsky, Jay A.] NCI, NIH, Bethesda, MD 20892 USA. [Friedman, Kevin M.] Bluebird Bio, Cambridge, MA USA. RP Khleif, SN (reprint author), Georgia Regents Univ, Ctr Canc, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. EM SKhleif@gru.edu FU Intramural NIH HHS [ZIA BC010755-07] NR 50 TC 15 Z9 18 U1 0 U2 7 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 NOV PY 2014 VL 2 IS 11 BP 1080 EP 1089 DI 10.1158/2326-6066.CIR-14-0095 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA AW2QY UT WOS:000346134900007 PM 25080445 ER PT J AU Farsaci, B Donahue, RN Coplin, MA Grenga, I Lepone, LM Molinolo, AA Hodge, JW AF Farsaci, Benedetto Donahue, Renee N. Coplin, Michael A. Grenga, Italia Lepone, Lauren M. Molinolo, Alfredo A. Hodge, James W. TI Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; HUMAN CARCINOEMBRYONIC ANTIGEN; IFN-GAMMA; T-CELLS; IMMUNOTHERAPY; EXPRESSION; SUNITINIB; DIFFERENTIATION; CANCER; MICE AB This study investigated the effects on the tumor microenvironment (TME) of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in two murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using three endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the TME, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can, thus, have a dramatic impact on the effectiveness of cancer immunotherapy. (C) 2014 AACR. C1 [Farsaci, Benedetto; Donahue, Renee N.; Coplin, Michael A.; Grenga, Italia; Lepone, Lauren M.; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Molinolo, Alfredo A.] NIDCD, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bldg 10 Ctr Dr,Room 8B13, 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, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 44 TC 12 Z9 12 U1 3 U2 10 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 NOV PY 2014 VL 2 IS 11 BP 1090 EP 1102 DI 10.1158/2326-6066.CIR-14-0076 PG 13 WC Oncology; Immunology SC Oncology; Immunology GA AW2QY UT WOS:000346134900008 PM 25092771 ER PT J AU Rallabhandi, SK AF Rallabhandi, Sriram K. TI Application of Adjoint Methodology to Supersonic Aircraft Design Using Reversed Equivalent Areas SO JOURNAL OF AIRCRAFT LA English DT Article; Proceedings Paper CT 31st AIAA Applied Aerodynamics Conference CY JUN 24-27, 2013 CL San Diego, CA SP AIAA ID UNSTEADY TURBULENT FLOWS; SONIC-BOOM MINIMIZATION; UNSTRUCTURED GRIDS; PREDICTION AB This paper presents an approach to shape an aircraft to equivalent-area-based objectives using the discrete adjoint approach. Equivalent areas can be obtained either using reversed the augmented Burgers equation or direct conversion of off-body pressures into equivalent areas. Formal coupling with computational fluid dynamics allows computation of sensitivities of equivalent-area objectives with respect to aircraft shape parameters. The exactness of the adjoint sensitivities is verified against derivatives obtained using the complex step approach. This methodology has the benefit of using designer-friendly equivalent areas in the shape design of low-boom aircraft. Shape optimization results with equivalent-area cost functionals are discussed and further refined using ground loudness-based objectives. C1 NIA, Hampton, VA 23666 USA. RP Rallabhandi, SK (reprint author), NIA, Hampton, VA 23666 USA. NR 33 TC 0 Z9 0 U1 2 U2 9 PU AMER INST AERONAUTICS ASTRONAUTICS PI RESTON PA 1801 ALEXANDER BELL DRIVE, STE 500, RESTON, VA 22091-4344 USA SN 0021-8669 EI 1533-3868 J9 J AIRCRAFT JI J. Aircr. PD NOV-DEC PY 2014 VL 51 IS 6 BP 1873 EP 1882 DI 10.2514/1.C032518 PG 10 WC Engineering, Aerospace SC Engineering GA AW0KJ UT WOS:000345980800016 ER PT J AU Appel, N Acri, J McCann, D AF Appel, Nathan Acri, Jane McCann, David TI Specialized preclinical safety pharmacology studies for stimulant abuse therapeutics SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Meeting Abstract C1 [Appel, Nathan; Acri, Jane; McCann, David] NIDA, 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 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD NOV-DEC PY 2014 VL 70 IS 3 MA 0159 BP 357 EP 357 DI 10.1016/j.vascn.2014.03.164 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AW2AW UT WOS:000346091500173 ER PT J AU Pollack, MM Holubkov, R Funai, T Clark, A Berger, JT Meert, K Newth, CJL Shanley, T Moler, F Carcillo, J Berg, RA Dalton, H Wessel, DL Harrison, RE Doctor, A Dean, JM Jenkins, TL AF Pollack, Murray M. Holubkov, Richard Funai, Tomohiko Clark, Amy Berger, John T. Meert, Kathleen Newth, Christopher J. L. Shanley, Thomas Moler, Frank Carcillo, Joseph Berg, Robert A. Dalton, Heidi Wessel, David L. Harrison, Rick E. Doctor, Allan Dean, J. Michael Jenkins, Tammara L. CA Eunice Kennedy Shriver Natl Inst TI Pediatric Intensive Care Outcomes: Development of New Morbidities During Pediatric Critical Care SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE critical care; functional status; functional status score; intensive care; morbidity; outcome prediction; pediatric critical care; pediatric intensive care; pediatrics ID QUALITY-OF-LIFE; FUNCTIONAL STATUS SCALE; BRAIN-INJURY; CHILDREN; VALIDITY; ILLNESS; UNIT; FEASIBILITY; RELIABILITY; PERFORMANCE AB Objective: To investigate significant new morbidities associated with pediatric critical care. Design: Randomly selected, prospective cohort. Setting: PICU patients from eight medical and cardiac PICUs. Patients: This was a randomly selected, prospective cohort of PICU patients from eight medical and cardiac PICUs. Measurements and Main Results: The main outcomes measures were hospital discharge functional status measured by Functional Status Scale scores and new morbidity defined as an increase in the Functional Status Scale of more than or equal to 3. Of the 5,017 patients, there were 242 new morbidities (4.8%), 99 PICU deaths (2.0%), and 120 hospital deaths (2.4%). Both morbidity and mortality rates differed (p < 0.001) among the sites. The worst functional status profile was on PICU discharge and improved on hospital discharge. On hospital discharge, the good category decreased from a baseline of 72% to 63%, mild abnormality increased from 10% to 15%, moderate abnormality status increased from 13% to 14%, severe status increased from 4% to 5%, and very severe was unchanged at 1%. The highest new morbidity rates were in the neurological diagnoses (7.3%), acquired cardiovascular disease (5.9%), cancer (5.3%), and congenital cardiovascular disease (4.9%). New morbidities occurred in all ages with more in those under 12 months. New morbidities involved all Functional Status Scale domains with the highest proportions involving respiratory, motor, and feeding dysfunction. Conclusions: The prevalence of new morbidity was 4.8%, twice the mortality rate, and occurred in essentially all types of patients, in relatively equal proportions, and involved all aspects of function. Compared with historical data, it is possible that pediatric critical care has exchanged improved mortality rates for increased morbidity rates. C1 [Pollack, Murray M.; Dalton, Heidi] Phoenix Childrens Hosp, Dept Child Hlth, Phoenix, AZ 85006 USA. [Pollack, Murray M.; Dalton, Heidi] Univ Arizona, Coll Med Phoenix, Phoenix, AZ USA. [Holubkov, Richard; Funai, Tomohiko; Clark, Amy; Dean, J. Michael] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Berger, John T.; Wessel, David L.] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Meert, Kathleen] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Dept Anesthesiol & Crit Care Med, Los Angeles, CA 90027 USA. [Shanley, Thomas; Moler, Frank] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15213 USA. [Berg, Robert A.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Harrison, Rick E.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Biochem, St Louis, MO 63110 USA. [Jenkins, Tammara L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Trauma & Crit Illness Branch, NIH, Bethesda, MD USA. RP Pollack, MM (reprint author), Phoenix Childrens Hosp, Dept Child Hlth, Phoenix, AZ 85006 USA. EM mpollack@childrensnational.org OI Doctor, Allan/0000-0002-6096-6400 FU NICHD NIH HHS [U01HD049934, U10 HD049981, U10 HD049983, U10 HD050012, U10 HD050096, U10 HD063106, U10 HD063108, U01 HD049934, U10 HD063114, U10HD049981, U10HD049983, U10HD050012, U10HD050096, U10HD063106, U10HD063108, U10HD063114, UG1 HD049981, UG1 HD049983, UG1 HD050096, UG1 HD063108] NR 31 TC 21 Z9 21 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1529-7535 EI 1947-3893 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD NOV PY 2014 VL 15 IS 9 BP 821 EP 827 DI 10.1097/PCC.0000000000000250 PG 7 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA AW6TB UT WOS:000346400100009 PM 25226501 ER PT J AU Fernandez-Duenas, V Gomez-Soler, M Lopez-Cano, M Taura, JJ Ledent, C Watanabe, M Jacobson, KA Vilardaga, JP Ciruela, F AF Fernandez-Duenas, Victor Gomez-Soler, Maricel Lopez-Cano, Marc Taura, Jaume J. Ledent, Catherine Watanabe, Masahiko Jacobson, Kenneth A. Vilardaga, Jean-Pierre Ciruela, Francisco TI Uncovering Caffeine's Adenosine A(2A) Receptor Inverse Agonism in Experimental Parkinsonism SO ACS CHEMICAL BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; LIGAND EFFICACY; DRUG DISCOVERY; MICE LACKING; DISEASE; ANTAGONISTS; ACTIVATION; SYMPTOMS; LESION; MOTOR AB Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinsons disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A(2A) receptor (A(2A)R) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A(2A)R agonist, of the receptors activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A(2A)R inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design C1 [Fernandez-Duenas, Victor; Gomez-Soler, Maricel; Lopez-Cano, Marc; Taura, Jaume J.; Ciruela, Francisco] Univ Barcelona, IDIBELL, Fac Med, Unitat Farmacol,Dept Patol & Terapeut Expt, Barcelona 08907, Spain. [Ledent, Catherine] Univ Libre Bruxelles, IRIBHM, Brussels, Belgium. [Watanabe, Masahiko] Hokkaido Univ, Sch Med, Dept Anat, Sapporo, Hokkaido 060, Japan. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Vilardaga, Jean-Pierre] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab Prot Coupled Receptor Biol G, Pittsburgh, PA 15261 USA. RP Vilardaga, JP (reprint author), Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab Prot Coupled Receptor Biol G, Pittsburgh, PA 15261 USA. EM jpv@pitt.edu; fciruela@ub.edu RI Jacobson, Kenneth/A-1530-2009; WATANABE, Masahiko/A-4055-2012 OI Jacobson, Kenneth/0000-0001-8104-1493; FU Ministerio de Economia y Competitividad [SAF2011-24779, CSD2008-00005, PCIN-2013-019-C03-03]; ICREA Academia, Catalan Institution for Research and Advanced Studies; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) [R01 DK087688]; NIDDK Intramural Research Program FX This work was supported by grants SAF2011-24779, Consolider-Ingenio CSD2008-00005, and PCIN-2013-019-C03-03 from Ministerio de Economia y Competitividad and ICREA Academia-2010 from the Catalan Institution for Research and Advanced Studies (to FC), by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under Award number R01 DK087688 (to J.P.V.), and by NIDDK Intramural Research Program (to K.A.J.). V.F.-D., M.G.-S. and P.C. belong to the "Neuropharmacology and Pain" accredited research group (Generalitat de Catalunya, 2014 SGR 1251). We thank E. Castano and B. Torrejon from the Scientific and Technical Services (SCT) group at the Bellvitge Campus of the University of Barcelona for their technical assistance. NR 23 TC 7 Z9 7 U1 1 U2 16 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 NOV PY 2014 VL 9 IS 11 BP 2496 EP 2501 DI 10.1021/cb5005383 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU4AK UT WOS:000345551300008 PM 25268872 ER PT J AU Inglese, J Dranchak, P Moran, JJ Jang, SW Srinivasan, R Santiago, Y Zhang, L Guha, R Martinez, N MacArthur, R Cost, GJ Svaren, J AF Inglese, James Dranchak, Patricia Moran, John J. Jang, Sung-Wook Srinivasan, Rajini Santiago, Yolanda Zhang, Lei Guha, Rajarshi Martinez, Natalia MacArthur, Ryan Cost, Gregory J. Svaren, John TI Genome Editing-Enabled HIS Assays Expand Drug Target Pathways for Charcot-Marie-Tooth Disease SO ACS CHEMICAL BIOLOGY LA English DT Article ID PERIPHERAL NERVOUS-SYSTEM; ASCORBIC-ACID TREATMENT; MOUSE MODEL; LUCIFERASE REPORTER; MYELIN FORMATION; TRANSGENIC MICE; SCHWANN-CELLS; GENE-DOSAGE; PMP22 GENE; IN-VIVO AB Copy number variation resulting in excess PMP22 protein causes the peripheral neuropathy CharcotMarieTooth disease, type 1A. To broadly interrogate chemically sensitive transcriptional pathways controlling PMP22 protein levels, we used the targeting precision of TALEN-mediated genome editing to embed reporters within the genetic locus harboring the Peripheral Myelin Protein 22 (Pmp22) gene. Using a Schwann cell line with constitutively high endogenous levels of Pmp22, we obtained allelic insertion of secreted bioluminescent reporters with sufficient signal to enable a 1536-well assay. Our findings from the quantitative high-throughput screening (qHTS) of several thousand drugs and clinically investigated compounds using this assay design both overlapped and expanded results from a previous assay using a randomly inserted reporter gene controlled by a single regulatory element of the Pmp22 gene. A key difference was the identification of a kinase-controlled inhibitory pathway of Pmp22 transcription revealed by the activity of the Protein kinase C (PKC)-modulator bryostatin. C1 [Inglese, James; Dranchak, Patricia; Jang, Sung-Wook; Guha, Rajarshi; Martinez, Natalia; MacArthur, Ryan] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Inglese, James] NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. [Moran, John J.; Srinivasan, Rajini; Svaren, John] Univ Wisconsin, Dept Comparat Biosci, Madison, WI 53705 USA. [Moran, John J.; Srinivasan, Rajini; Svaren, John] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Santiago, Yolanda; Zhang, Lei; Cost, Gregory J.] Sangamo BioSci, Richmond, CA 94804 USA. RP Inglese, J (reprint author), NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM jinglese@mail.nih.gov; jpsvaren@wisc.edu FU NCATS; Charcot-Marie-Tooth Association; National Institutes of Health/NINDS [R21 NS73726, HD03352] FX From NCATS we thank P. Shinn and S. Michael for management of compound libraries and robotic screening support, respectively, and M. Mendez and B. Wright for constructive comments to the manuscript; from UW, E. Lau for assistance in cell culture, and the UWCCC Flow Laboratory for assistance flow sorting; and from Sangamo BioSciences the Technology and Production groups for nuclease design and assembly and E. Rebar, F. Urnov, and P. Gregory for comments to the manuscript. This work was supported by the intramural program of NCATS and the Charcot-Marie-Tooth Association (J.I.), grants from the National Institutes of Health/NINDS (R21 NS73726) (J.S.), and P30 core grant HD03352. NR 44 TC 8 Z9 8 U1 1 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 NOV PY 2014 VL 9 IS 11 BP 2594 EP 2602 DI 10.1021/cb5005492 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU4AK UT WOS:000345551300019 PM 25188731 ER PT J AU Tran, TA Wichterman-Kouznetsova, J Varghese, D Huang, RL Huang, WW Becker, M Austin, CP Inglese, J Johnson, RL Martinez, ED AF Tram Anh Tran Wichterman-Kouznetsova, Jennifer Varghese, Diana Huang, Ruili Huang, Wenwei Becker, Matthias Austin, Christopher P. Inglese, James Johnson, Ronald L. Martinez, Elisabeth D. TI Identification of Small Molecule Modulators of Gene Transcription with Anticancer Activity SO ACS CHEMICAL BIOLOGY LA English DT Article ID HIGH-THROUGHPUT SCREEN; EPIGENETIC-MODULATORS; MICROPLATE CYTOMETRY; HISTONE DEMETHYLASE; CELL LYMPHOMA; INHIBITOR; CANCER; METHYLTRANSFERASE; EXPRESSION; CMV AB Epigenetic regulation of gene expression is essential in many biological processes, and its deregulation contributes to pathology including tumor formation. We used an image-based cell assay that measures the induction of a silenced GFP-estrogen receptor reporter to identify novel classes of small molecules involved in the regulation of gene expression. Using this Locus Derepression assay, we queried 283,122 compounds by quantitative high-throughput screening evaluating compounds at multiple concentrations. After confirmation and independent validation, the Locus Derepression assay identified 19 small molecules as new actives that induce the GFP message over 2-fold. Viability assays demonstrated that 17 of these actives have anti-proliferative activity, and two of them show selectivity for cancer versus patient-matched normal cells and cause unique changes in gene expression patterns in cancer cells by altering histone marks. Hence, these compounds represent chemical tools for understanding the molecular mechanisms of epigenetic control of transcription and for modulating cell growth pathways. C1 [Tram Anh Tran; Varghese, Diana; Martinez, Elisabeth D.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Martinez, Elisabeth D.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Wichterman-Kouznetsova, Jennifer; Huang, Ruili; Huang, Wenwei; Austin, Christopher P.; Inglese, James; Johnson, Ronald L.] NIH, Chem Genom Ctr, NCATS, Rockville, MD 20850 USA. [Becker, Matthias] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Martinez, ED (reprint author), Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. EM elisabeth.martinez@utsouthwestern.edu FU NCI [R01CA12526901]; NCI (University of Texas SPORE in Lung Cancer) [P50-CA70907]; Doctor's Cancer Foundation; NIH, National Cancer Institute, Center for Cancer Research; NCI Cancer Center Support Grant [1P30 CA142543-01]; NIH Roadmap for Medical Research FX This project was partly funded by the NCI (R01CA12526901 to E.D.M. and by the University of Texas SPORE in Lung Cancer P50-CA70907 to J.D.M, subaward to E.D.M.) and by the Doctor's Cancer Foundation (Nolan Miller Lung Cancer grant to E.D.M.). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors would like to acknowledge the assistance of the Genomics Shared Resource at the Harold C. Simmons Cancer Center, which is supported in part by NCI Cancer Center Support Grant 1P30 CA142543-01. We also acknowledge the support of the NIH Roadmap for Medical Research. We are grateful to L. Girard for the use of Matrix and DIVISA software. NR 37 TC 2 Z9 2 U1 1 U2 15 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 NOV PY 2014 VL 9 IS 11 BP 2603 EP 2611 DI 10.1021/cb500532x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU4AK UT WOS:000345551300020 PM 25188650 ER PT J AU Witkiewitz, K Falk, DE Kranzler, HR Litten, RZ Hallgren, KA O'Malley, SS Anton, RF AF Witkiewitz, Katie Falk, Daniel E. Kranzler, Henry R. Litten, Raye Z. Hallgren, Kevin A. O'Malley, Stephanie S. Anton, Raymond F. CA Alcohol Clinical Trials Initiative TI Methods to Analyze Treatment Effects in the Presence of Missing Data for a Continuous Heavy Drinking Outcome Measure When Participants Drop Out from Treatment in Alcohol Clinical Trials SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Missing data; Alcohol Use Disorder; Relapse; Treatment; Clinical Trials; Continuous Outcome Measure ID COMBINED PHARMACOTHERAPIES; BEHAVIORAL INTERVENTIONS; DOUBLE-BLIND; DEPENDENCE; EFFICACY; SMOKING; COMBINE; IMPACT AB BackgroundAttrition is common in alcohol clinical trials and the resultant loss of data represents an important methodological problem. In the absence of a simulation study, the drinking outcomes among those who are lost to follow-up are not known. Individuals who drop out of treatment and continue to provide drinking data, however, may be a reasonable proxy group for making inferences about the drinking outcomes of those lost to follow-up. MethodsWe used data from the COMBINE study, a multisite, randomized clinical trial, to examine drinking during the 4months of treatment among individuals who dropped out of treatment but continued to provide drinking data (i.e., treatment dropouts; n=185). First, we estimated the observed treatment effect size for naltrexone versus placebo in a sample that included both treatment completers (n=961) and treatment dropouts (n=185; total N=1,146), as well as the observed treatment effect size among just those who dropped out of treatment (n=185). In both the total sample (N=1,146) and the dropout sample (n=185), we then deleted the drinking data after treatment dropout from those 185 individuals to simulate missing data. Using the deleted data sets, we then estimated the effect of naltrexone on the continuous outcome percent heavy drinking days using 6 methods to handle missing data (last observation carried forward, baseline observation carried forward, placebo mean imputation, missing=heavy drinking days, multiple imputation (MI), and full information maximum likelihood [FIML]). ResultsMI and FIML produced effect size estimates that were most similar to the true effects observed in the full data set in all analyses, while missing=heavy drinking days performed the worst. ConclusionsAlthough missing drinking data should be avoided whenever possible, MI and FIML yield the best estimates of the treatment effect for a continuous outcome measure of heavy drinking when there is dropout in an alcohol clinical trial. C1 [Witkiewitz, Katie; Hallgren, Kevin A.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Falk, Daniel E.; Litten, Raye Z.] NIAAA, Bethesda, MD USA. [Kranzler, Henry R.] Univ Penn, Perelman Sch Med, Ctr Studies Addict, Dept Psychiat, Philadelphia, PA 19104 USA. [Kranzler, Henry R.] Philadelphia VAMC, VISN MIRECC 4, Philadelphia, PA USA. [O'Malley, Stephanie S.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Anton, Raymond F.] Med Univ S Carolina, Dept Psychiat, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. RP Witkiewitz, K (reprint author), Univ New Mexico, Dept Psychol, 1 Univ New Mexico,MSC03 2220, Albuquerque, NM 87131 USA. EM katiew@unm.edu FU National Institute on Alcohol Abuse and Alcoholism [1R01 AA022328-01] FX This research was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (1R01 AA022328-01, Witkiewitz (PI)). NR 30 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD NOV PY 2014 VL 38 IS 11 BP 2826 EP 2834 DI 10.1111/acer.12543 PG 9 WC Substance Abuse SC Substance Abuse GA AU5AW UT WOS:000345620400017 PM 25421518 ER PT J AU Shamanna, RA Singh, DK Lu, HM Mirey, G Keijzers, G Salles, B Croteau, DL Bohr, VA AF Shamanna, Raghavendra A. Singh, Dharmendra Kumar Lu, Huiming Mirey, Gladys Keijzers, Guido Salles, Bernard Croteau, Deborah L. Bohr, Vilhelm A. TI RECQ helicase RECQL4 participates in non-homologous end joining and interacts with the Ku complex SO CARCINOGENESIS LA English DT Article ID ROTHMUND-THOMSON-SYNDROME; DOUBLE-STRAND BREAKS; WERNER PROTEIN; DNA-REPAIR; FUNCTIONAL INTERACTION; HOMOLOGOUS RECOMBINATION; UNWINDING ACTIVITIES; GENOMIC STABILITY; IN-VITRO; ROLES AB RECQL4, a member of the RecQ helicase family, is a multifunctional participant in DNA metabolism. RECQL4 protein participates in several functions both in the nucleus and in the cytoplasm of the cell, and mutations in human RECQL4 are associated with three genetic disorders: Rothmund-Thomson, RAPADILINO and Baller-Cerold syndromes. We previously reported that RECQL4 is recruited to laser-induced DNA double-strand breaks (DSB). Here, we have characterized the functional roles of RECQL4 in the non-homologous end joining (NHEJ) pathway of DSB repair. In an in vitro NHEJ assay that depends on the activity of DNA-dependent protein kinase (DNA-PK), extracts from RECQL4 knockdown cells display reduced end-joining activity on DNA substrates with cohesive and non-cohesive ends. Depletion of RECQL4 also reduced the end joining activity on a CFP reporter plasmid in vivo. Knockdown of RECQL4 increased the sensitivity of cells to gamma-irradiation and resulted in accumulation of 53BP1 foci after irradiation, indicating defects in the processing of DSB. We find that RECQL4 interacts with the Ku70/Ku80 heterodimer, part of the DNA-PK complex, via its N-terminal domain. Further, RECQL4 stimulates higher order DNA binding of Ku70/Ku80 to a blunt end DNA substrate. Taken together, these results implicate that RECQL4 participates in the NHEJ pathway of DSB repair via a functional interaction with the Ku70/Ku80 complex. This is the first study to provide both in vitro and in vivo evidence for a role of a RecQ helicase in NHEJ. C1 [Shamanna, Raghavendra A.; Singh, Dharmendra Kumar; Lu, Huiming; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Mirey, Gladys; Salles, Bernard] Univ Toulouse, Res Ctr Food Toxicol, INRA, Toxalim,UMR1331, F-31027 Toulouse, France. [Keijzers, Guido] Univ Copenhagen, Dept Cellular & Mol Med, Ctr Hlth Aging, DK-2200 Copenhagen, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Mirey, Gladys/0000-0002-0095-1864 FU Intramural Program of the National Institute on Aging, National Institutes of Health, USA [ZIA AG000726] FX Intramural Program of the National Institute on Aging (ZIA AG000726), National Institutes of Health, USA. NR 59 TC 6 Z9 6 U1 2 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2014 VL 35 IS 11 BP 2415 EP 2424 DI 10.1093/carcin/bgu137 PG 10 WC Oncology SC Oncology GA AU8GY UT WOS:000345835800003 PM 24942867 ER PT J AU Mashimo, M Kato, J Moss, J AF Mashimo, Masato Kato, Jiro Moss, Joel TI Structure and function of the ARH family of ADP-ribosyl-acceptor hydrolases SO DNA REPAIR LA English DT Article DE ADP-ribosylation; ADP-ribose-acceptor hydrolase; Tumorigenesis; Cholera toxin; Parthanatos; ARH ID APOPTOSIS-INDUCING FACTOR; 39-KDA POLY(ADP-RIBOSE) GLYCOHYDROLASE; POLYMERASE-1-DEPENDENT CELL-DEATH; RIBOSYLARGININE HYDROLASE; DNA-DAMAGE; SUBSTRATE-SPECIFICITY; MITOCHONDRIAL MATRIX; CALORIE RESTRICTION; TURKEY ERYTHROCYTES; RIBOSYLHYDROLASE 3 AB ADP-ribosylation is a post-translational protein modification, in which ADP-ribose is transferred from nicotinamide adenine dinucleotide (NAD(+)) to specific acceptors, thereby altering their activities. The ADPribose transfer reactions are divided into mono-and poly-(ADP-ribosyl)ation. Cellular ADP-ribosylation levels are tightly regulated by enzymes that transfer ADP-ribose to acceptor proteins (e.g., ADP-ribosyltransferases, poly-(ADP-ribose) polymerases (PARP)) and those that cleave the linkage between ADP-ribose and acceptor (e.g., ADP-ribosyl-acceptor hydrolases (ARH), poly-(ADP-ribose) glycohydrolases (PARG)), thereby constituting an ADP-ribosylation cycle. This review summarizes current findings related to the ARH family of proteins. This family comprises three members (ARH1-3) with similar size (39 kDa) and amino acid sequence. ARH1 catalyzes the hydrolysis of the N-glycosidic bond of mono-(ADP-ribosyl)ated arginine. ARH3 hydrolyzes poly-(ADP-ribose) (PAR) and O-acetyl-ADP-ribose. The different substrate specificities of ARH1 and ARH3 contribute to their unique roles in the cell. Based on a phenotype analysis of ARH1(-/-)and ARH3(-/-)mice, ARH1 is involved in the action by bacterial toxins as well as in tumorigenesis. ARH3 participates in the degradation of PAR that is synthesized by PARP1 in response to oxidative stress-induced DNA damage; this hydrolytic reaction suppresses PAR-mediated cell death, a pathway termed parthanatos. (C) 2014 Published by Elsevier B.V. C1 [Mashimo, Masato; Kato, Jiro; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NIH, Room 6D05,Bldg 10,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute FX This study was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. NR 102 TC 8 Z9 8 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD NOV PY 2014 VL 23 SI SI BP 88 EP 94 DI 10.1016/j.dnarep.2014.03.005 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AU8BJ UT WOS:000345821400012 PM 24746921 ER PT J AU Cheng, TJ Pans, YM Hao, M Wang, YL Bryant, SH AF Cheng, Tiejun Pans, Yongmei Hao, Ming Wang, Yanli Bryant, Stephen H. TI PubChem applications in drug discovery: a bibliometric analysis SO DRUG DISCOVERY TODAY LA English DT Review ID SMALL-MOLECULE; BIOASSAY DATA; INHIBITORS; IDENTIFICATION; DATABASE; TOOL; VISUALIZATION; METABONOMICS; DATASETS; ONTOLOGY AB A bibliometric analysis of Pub Chem applications is presented by reviewing 1132 research articles. The massive volume of chemical structure and bioactivity data in Pub Chem and its online services have been used globally in various fields including chemical biology, medicinal chemistry and informatics research. Pub Chem supports drug discovery in many aspects such as lead identification and optimization, compound-target profiling, polypharmacology studies and unknown chemical identity elucidation. Pub Chem has also become a valuable resource for developing secondary databases, informatics tools and web services. The growing Pub Chem resource with its public availability offers support and great opportunities for the interrogation of pharmacological mechanisms and the genetic basis of diseases, which are vital for drug innovation and repurposing. C1 [Cheng, Tiejun; Pans, Yongmei; Hao, Ming; 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, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Cheng, Tiejun/A-5344-2010 OI Cheng, Tiejun/0000-0002-4486-3356 FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported (in part) by the Intramural Research Program of the NIH, National Library of Medicine. NR 59 TC 8 Z9 9 U1 0 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 EI 1878-5832 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD NOV PY 2014 VL 19 IS 11 BP 1751 EP 1756 DI 10.1016/j.drudis.2014.08.008 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU6QH UT WOS:000345726600010 PM 25168772 ER PT J AU van der Marel, J van Baars, R Rodriguez, A Quint, WGV van de Sandt, MM Berkhof, J Schiffman, M Torne, A Ordi, J Jenkins, D Verheijen, RHM Helmerhorst, TJM ter Harmsel, B Wentzensen, N Del Pino, M AF van der Marel, J. van Baars, R. Rodriguez, A. Quint, W. G. V. van de Sandt, M. M. Berkhof, J. Schiffman, M. Torne, A. Ordi, J. Jenkins, D. Verheijen, R. H. M. Helmerhorst, Th. J. M. ter Harmsel, B. Wentzensen, N. Del Pino, M. TI The increased detection of cervical intraepithelial neoplasia when using a second biopsy at colposcopy SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Cervical intraepithelial neoplasia; Colposcopy; Biopsy; Human papillomavirus ID HIGH-RISK HPV; ENDOCERVICAL CURETTAGE; DIRECTED BIOPSY; GRADE 2; WOMEN; ABNORMALITIES; POPULATION; DIAGNOSIS; CYTOLOGY; CANCER AB Objective. It has been suggested that colposcopy can miss a significant percentage of high-grade cervical intraepithelial neoplasia (CIN2 +). Improved disease ascertainment was evaluated by taking multiple lesion-directed biopsies. Methods. In a cross-sectional multicenter study in the Netherlands and Spain, 610 women referred to colposcopy following abnormal cervical cytology results were included. Multiple directed biopsies were collected from lesions and ranked according to impression. A non-directed biopsy of normal-appearing tissue was added if fewer than four biopsies were collected. We evaluated the additional CIN2 + yield for one and two directed biopsies. Colposcopic images were reviewed for quality control. Results. In women with at least two lesion-directed biopsies the yield for CIN2 + increased from 51.7% (95%CI; 45.7-57.7) for one directed biopsy to 60.4% (95%CI; 54.4-662, p < 0.001) for two biopsies. The highest CIN2 + yield was observed in women who were HPV16-positive, had high-grade squamous intraepithelial lesion (HSIL) cytology, and high-grade colposcopy impression. The yield increased from 83.1% (95%CI; 71.5-90.5) with one directed biopsy to 93.2% (95%CI; 83.8-97.3) with two directed biopsies. Only 4.5% additional CIN2 + were detected in biopsies not targeting abnormal areas on the cervix. Conclusions. A second lesion-directed biopsy is associated with a significant increase in CIN2 + detection. Performing a second lesion-directed biopsy and using a low threshold for abnormality of any acetowhitening should become the standard clinical practice of colposcopy. (C) 2014 Elsevier Inc. All rights reserved. C1 [van der Marel, J.; van Baars, R.; Quint, W. G. V.; van de Sandt, M. M.; Jenkins, D.] DDL Diagnost Lab, Dept Res & Dev, NL-2288 ER Rijswijk, Netherlands. [Rodriguez, A.; Del Pino, M.] Hosp Clin Inst Invest Biomed August Pi & Sunyer I, Inst Clin Gynecol Obstet & Neonatol, Barcelona, Spain. [Berkhof, J.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands. [Schiffman, M.; Wentzensen, N.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ordi, J.] Hosp Clin Barcelona, Dept Pathol, CRESIB, Barcelona, Spain. [Verheijen, R. H. M.] Univ Med Ctr Utrecht, Div Woman & Baby Gynaecol Oncol, NL-3508 GA Utrecht, Netherlands. [Helmerhorst, Th. J. M.] Erasmus Univ, Med Ctr, Dept Obstet & Gynaecol, NL-3000 CA Rotterdam, Netherlands. [ter Harmsel, B.] Roosevelt Klin, Dept Gynaecol, NL-2321 CT Leiden, Netherlands. RP van der Marel, J (reprint author), DDL Diagnost Lab, Visseringlaan 25, NL-2288 ER Rijswijk, Netherlands. EM jacolien.van.der.marel@DDL.nl FU Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) Foundation, The Netherlands FX This research was funded by the Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) Foundation, The Netherlands. The sponsor had no involvement in study design, data interpretation, writing of the manuscript, and decision to submit the manuscript for publication. NR 33 TC 4 Z9 4 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD NOV PY 2014 VL 135 IS 2 BP 201 EP 207 DI 10.1016/j.ygyno.2014.08.040 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AU4TW UT WOS:000345605200006 PM 25204846 ER PT J AU Trabert, B Pinto, L Hartge, P Kemp, T Black, A Sherman, ME Brinton, LA Pfeiffer, RM Shiels, MS Chaturvedi, AK Hildesheim, A Wentzensen, N AF Trabert, Britton Pinto, Ligia Hartge, Patricia Kemp, Troy Black, Amanda Sherman, Mark E. Brinton, Louise A. Pfeiffer, Ruth M. Shiels, Meredith S. Chaturvedi, Anil K. Hildesheim, Allan Wentzensen, Nicolas TI Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Nested-case-control study; Pre-diagnostic; Inflammation; Circulating inflammation markers; Cytokines ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; ENDOTHELIAL GROWTH-FACTOR; LOW-GRADE INFLAMMATION; MENSTRUAL-CYCLE; PLASMA-LEVELS; FACTOR-ALPHA; CYTOKINES; INTERLEUKIN-8 AB Objective. Pro-inflammatory mechanisms may explain the increased ovarian cancer risk linked to more lifetime ovulations, endometriosis, and exposure to talc and asbestos, as well as decreased risk with non-steroidal anti-inflammatory drugs. Limited data are available to estimate ovarian cancer risk associated with levels of circulating inflammatory markers. Methods. We conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Pre-diagnostic serum levels of 46 inflammation-related biomarkers (11 with a priori hypotheses; 35 agnostic) were measured in 149 incident ovarian cancer cases and 149 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression and adjusted for identified covariates. Results. Increased ovarian cancer risk was associated with elevated levels of C-reactive protein (CRP) [tertile (T)3 vs. T1: OR (95% CI) 2.04(1.06-3.93), p-trend = 0.03], interleukin (1)-1 alpha [detectable vs. undetectable: 2.23 (1.14-4.34)] and tumor necrosis factor alpha (TNF-alpha) [T3 vs. T1: 2.21 (1.06-4.63), p-trend = 0.04]. Elevated IL-8 was non-significantly associated with risk [T3 vs. T1: 1.86 (0.96-3.61), p-trend = 0.05]. In analyses restricted to serous ovarian cancer (n = 83), the associations with CRP and IL-8 remained or strengthened [CRP T3 vs. T1: 3.96 (1.14-11.14), p-trend = 0.008; IL-8 T3 vs. T1: 3.05 (1.09-8.51), p-trend = 0.03]. Elevated levels of CRP and TNE-alpha remained positively associated with ovarian cancer risk in analysis restricted to specimens collected at least 5 years before diagnosis (n = 56). Conclusion. These results suggest that CRP, IL-1 alpha, IL-8, and TNE-alpha are associated with increased risk of subsequently developing ovarian cancer. Published by Elsevier Inc. C1 [Trabert, Britton; Pinto, Ligia; Hartge, Patricia; Black, Amanda; Brinton, Louise A.; Pfeiffer, Ruth M.; Shiels, Meredith S.; Chaturvedi, Anil K.; Hildesheim, Allan; Wentzensen, Nicolas] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pinto, Ligia; Kemp, Troy] NCI, Dept Hlth & Human Serv, Frederick Natl Lab Canc Res, HPV Immunol Lab,NIH, Frederick, MD USA. [Sherman, Mark E.] NCI, Dept Hlth & Human Serv, Canc Prevent Div, Bethesda, MD 20892 USA. RP Trabert, B (reprint author), 9609 Med Ctr Dr,Room 7E-228, Bethesda, MD 20892 USA. EM britton.trabert@nih.gov RI Hildesheim, Allan/B-9760-2015; Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015; Chaturvedi, Anil/J-2024-2015 OI Hildesheim, Allan/0000-0003-0257-2363; Brinton, Louise/0000-0003-3853-8562; Chaturvedi, Anil/0000-0003-2696-8899 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. NR 51 TC 18 Z9 20 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD NOV PY 2014 VL 135 IS 2 BP 297 EP 304 DI 10.1016/j.ygyno.2014.08.025 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AU4TW UT WOS:000345605200022 PM 25158036 ER PT J AU Bogenschutz, MP Donovan, DM Mandler, RN Perl, HI Forcehimes, AA Crandall, C Lindblad, R Oden, NL Sharma, G Metsch, L Lyons, MS McCormack, R Konstantopoulos, WM Douaihy, A AF Bogenschutz, Michael P. Donovan, Dennis M. Mandler, Raul N. Perl, Harold I. Forcehimes, Alyssa A. Crandall, Cameron Lindblad, Robert Oden, Neal L. Sharma, Gaurav Metsch, Lisa Lyons, Michael S. McCormack, Ryan Konstantopoulos, Wendy Macias Douaihy, Antoine TI Brief Intervention for Patients With Problematic Drug Use Presenting in Emergency Departments A Randomized Clinical Trial SO JAMA INTERNAL MEDICINE LA English DT Article ID SCREENING-TEST; TRAUMA CENTER; ALCOHOL; DISORDERS; MISUSE; RISK; CARE AB IMPORTANCE Medical treatment settings such as emergency departments (EDs) present important opportunities to address problematic substance use. Currently, EDs do not typically intervene beyond acute medical stabilization. OBJECTIVE To contrast the effects of a brief intervention with telephone boosters (BI-B) with those of screening, assessment, and referral to treatment (SAR) and minimal screening only (MSO) among drug-using ED patients. DESIGN, SETTING, AND PARTICIPANTS Between October 2010 and February 2012, 1285 adult ED patients from 6 US academic hospitals, who scored 3 or greater on the 10-item Drug Abuse Screening Test (indicating moderate to severe problems related to drug use) and who were currently using drugs, were randomized to MSO (n = 431), SAR (n = 427), or BI-B (n = 427). Follow-up assessments were conducted at 3, 6, and 12 months by blinded interviewers. INTERVENTIONS Following screening, MSO participants received only an informational pamphlet. The SAR participants received assessment plus referral to addiction treatment if indicated, and the BI-B participants received assessment and referral as in SAR, plus a manual-guided counseling session based on motivational interviewing principles and up to 2 "booster" sessions by telephone during the month following the ED visit. MAIN OUTCOMES AND MEASURES Outcomes evaluated at follow-up visits included self-reported days using the patient-defined primary problem drug, days using any drug, days of heavy drinking, and drug use based on analysis of hair samples. The primary outcome was self-reported days of use of the patient-defined primary problem drug during the 30-day period preceding the 3-month follow-up. RESULTS Follow-up rates were 89%, 86%, and 81% at 3, 6, and 12 months, respectively. For the primary outcome, estimated differences in number of days of use (95% CI) were as follows: MSO vs BI-B, 0.72 (-0.80 to 2.24), P (adjusted) = .57; SAR vs BI-B, 0.70 (-0.83 to 2.23), P (adjusted) = .57; SAR vs MSO, -0.02 (-1.53 to 1.50), P (adjusted) = .98. There were no significant differences between groups in self-reported days using the primary drug, days using any drug, or heavy drinking days at 3, 6, or 12 months. At the 3-month follow-up, participants in the SAR group had a higher rate of hair samples positive for their primary drug of abuse (265 of 280 [95%]) than did participants in the MSO group (253 of 287 [88%]) or the BI-B group (244 of 275 [89%]). Hair analysis differences between groups at other time points were not significant. CONCLUSIONS AND RELEVANCE In this sample of drug users seeking emergency medical treatment, a relatively robust brief intervention did not improve substance use outcomes. More work is needed to determine how drug use disorders may be addressed effectively in the ED. C1 [Bogenschutz, Michael P.; Forcehimes, Alyssa A.] Univ New Mexico, Hlth Sci Ctr, Dept Psychiat, Albuquerque, NM 87131 USA. [Bogenschutz, Michael P.; Forcehimes, Alyssa A.] Univ New Mexico, Ctr Alcoholism Substance Abuse & Addict, Albuquerque, NM 87131 USA. [Donovan, Dennis M.] Univ Washington, Alcohol & Drug Abuse Inst, Seattle, WA 98195 USA. [Donovan, Dennis M.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Mandler, Raul N.; Perl, Harold I.] NIDA, Bethesda, MD 20892 USA. [Crandall, Cameron] Univ New Mexico, Hlth Sci Ctr, Dept Emergency Med, Albuquerque, NM 87131 USA. [Lindblad, Robert; Oden, Neal L.; Sharma, Gaurav] EMMES Corp, Rockville, MD USA. [Metsch, Lisa] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Lyons, Michael S.] Univ Cincinnati, Coll Med, Dept Emergency Med, Cincinnati, OH USA. [McCormack, Ryan] NYU, Sch Med, Dept Emergency Med, New York, NY USA. [Konstantopoulos, Wendy Macias] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Konstantopoulos, Wendy Macias] Harvard Univ, Sch Med, Boston, MA USA. [Douaihy, Antoine] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Bogenschutz, MP (reprint author), Univ New Mexico, Hlth Sci Ctr, Ctr Psychiat Res, Dept Psychiat, MSC11 6035,1 Univ New Mexico, Albuquerque, NM 87131 USA. EM mbogenschutz@salud.unm.edu OI Bogenschutz, Michael/0000-0003-4530-3470; McCormack, Ryan/0000-0002-7210-4736 FU EMMES Corporation [NIDA: HHSN271200900034C]; [U10DA015833]; [U10DA013714]; [U10DA013720]; [U10DA013732]; [U10DA013046]; [U10DA015831]; [U10DA020036]; [U10DA013035] FX The study was supported by the following grants from NIDA: HHSN271200900034C (EMMES Corporation); U10DA015833 (Principal Investigator [PI], Michael P. Bogenschutz); U10DA013714 (PI, Dennis M. Donovan); U10DA013720 (PIs, Jose Szapocznik, PhD, and Lisa Metsch); U10DA013732 (PI, Theresa Winhusen); U10DA013046 (PI, John Rotrosen); U10DA015831 (PIs, Roger D. Weiss and Kathleen M. Carroll, PhD); U10DA020036 (PI, Dennis C. Daley); and U10DA013035 (PIs, John Rotrosen and Edward V. Nunes). NR 28 TC 26 Z9 26 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD NOV PY 2014 VL 174 IS 11 BP 1736 EP 1745 DI 10.1001/jamainternmed.2014.4052 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AU9KA UT WOS:000345909900010 PM 25179753 ER PT J AU McDonald, CJ Callaghan, FM Weissman, A Goodwin, RM Mundkur, M Kuhn, T AF McDonald, Clement J. Callaghan, Fiona M. Weissman, Arlene Goodwin, Rebecca M. Mundkur, Mallika Kuhn, Thomson TI Use of Internist's Free Time by Ambulatory Care Electronic Medical Record Systems SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [McDonald, Clement J.; Callaghan, Fiona M.; Goodwin, Rebecca M.; Mundkur, Mallika] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. [Weissman, Arlene; Kuhn, Thomson] Amer Coll Physicians, Washington, DC USA. RP McDonald, CJ (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, 8600 Rockville Pike,MSC 3828,Bldg 38A,Room 7N707, Bethesda, MD 20894 USA. EM clemmcdonald@nlm.nih.gov FU Intramural NIH HHS NR 4 TC 10 Z9 10 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD NOV PY 2014 VL 174 IS 11 BP 1860 EP 1863 DI 10.1001/jamainternmed.2014.4506 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AU9KA UT WOS:000345909900039 PM 25200944 ER PT J AU Alfano, CM Smith, T de Moor, JS Glasgow, RE Khoury, MJ Hawkins, NA Stein, KD Rechis, R Parry, C Leach, CR Padgett, L Rowland, JH AF Alfano, Catherine M. Smith, Tenbroeck de Moor, Janet S. Glasgow, Russell E. Khoury, Muin J. Hawkins, Nikki A. Stein, Kevin D. Rechis, Ruth Parry, Carla Leach, Corinne R. Padgett, Lynne Rowland, Julia H. TI An Action Plan for Translating Cancer Survivorship Research Into Care SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID UNITED-STATES; HEALTH; INTEGRATION; SCIENCE; COLLABORATION; EPIDEMIOLOGY; POPULATION; ISSUES; POLICY AB To meet the complex needs of a growing number of cancer survivors, it is essential to accelerate the translation of survivorship research into evidence-based interventions and, as appropriate, recommendations for care that may be implemented in a wide variety of settings. Current progress in translating research into care is stymied, with results of many studies un- or underutilized. To better understand this problem and identify strategies to encourage the translation of survivorship research findings into practice, four agencies (American Cancer Society, Centers for Disease Control and Prevention, LIVE STRONG Foundation, National Cancer Institute) hosted a meeting in June, 2012, titled: "Biennial Cancer Survivorship Research Conference: Translating Science to Care." Meeting participants concluded that accelerating science into care will require a coordinated, collaborative effort by individuals from diverse settings, including researchers and clinicians, survivors and families, public health professionals, and policy makers. This commentary describes an approach stemming from that meeting to facilitate translating research into care by changing the process of conducting research-improving communication, collaboration, evaluation, and feedback through true and ongoing partnerships. We apply the T0-T4 translational process model to survivorship research and provide illustrations of its use. The resultant framework is intended to orient stakeholders to the role of their work in the translational process and facilitate the transdisciplinary collaboration needed to translate basic discoveries into best practices regarding clinical care, self-care/management, and community programs for cancer survivors. Finally, we discuss barriers to implementing translational survivorship science identified at the meeting, along with future directions to accelerate this process. C1 [Alfano, Catherine M.; Parry, Carla; Padgett, Lynne] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [de Moor, Janet S.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Glasgow, Russell E.] NCI, Implementat Sci Team, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Smith, Tenbroeck; Stein, Kevin D.; Leach, Corinne R.] Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30329 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Hawkins, Nikki A.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. [Rechis, Ruth] LIVESTRONG Fdn, Austin, TX USA. RP Alfano, CM (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 9609 Med Ctr Dr MSC 9764, Bethesda, MD 20892 USA. EM catherine.alfano@nih.gov NR 31 TC 8 Z9 8 U1 0 U2 8 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 NOV PY 2014 VL 106 IS 11 AR dju287 DI 10.1093/jnci/dju287 PG 9 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500008 ER PT J AU Gail, MH You, WC Li, WQ AF Gail, Mitchell H. You, Wei-Cheng Li, Wen-Qing TI Pluripotent Stem Cell miRNAs and Metastasis in Invasive Breast Cancer Response SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID GASTRIC-CANCER; HELICOBACTER-PYLORI; TRIAL C1 [Gail, Mitchell H.; Li, Wen-Qing] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [You, Wei-Cheng; Li, Wen-Qing] Peking Univ, Canc Hosp & Inst, Dept Canc Epidemiol, Key Lab Carcinogenesis & Translat Res, Beijing 100142, Peoples R China. [Li, Wen-Qing] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. [Li, Wen-Qing] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 7E138, Rockville, MD 20850 USA. EM gailm@mail.nih.gov; weichengyou@yahoo.com NR 7 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD NOV PY 2014 VL 106 IS 11 AR dju348 DI 10.1093/jnci/dju348 PG 1 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500034 ER PT J AU Garcia-Closas, M Gunsoy, NB Chatterjee, N AF Garcia-Closas, Montserrat Gunsoy, Necdet Burak Chatterjee, Nilanjan TI Combined Associations of Genetic and Environmental Risk Factors: Implications for Prevention of Breast Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID METAANALYSIS; VARIANTS; DENSITY; DISEASE; WOMEN; SUSCEPTIBILITY; POLYMORPHISMS; POPULATION; CONSORTIUM; SMOKING AB Genome-wide association studies (GWAS) have identified hundreds of genetic susceptibility loci for cancers and other complex diseases. However, the public health and clinical relevance of these discoveries is unclear. Evaluating the combined associations of genetic and environmental risk factors, particularly those that can be modified, will be critical in assessing the utility of genetic information for risk stratified prevention. In this commentary, using breast cancer as a model, we show that genetic information in combination with other risk factors can provide levels of risk stratification that could be useful for individual decision-making or population-based prevention programs. Our projections are theoretical and rely on a number of assumptions, including multiplicative models for the combined associations of the different risk factors, which need confirmation. Thus, analyses of epidemiological studies with high-quality risk factor information, as well as prevention trials, are needed to empirically assess the impact of genetics in risk stratified prevention. C1 [Garcia-Closas, Montserrat; Gunsoy, Necdet Burak] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Garcia-Closas, Montserrat; Gunsoy, Necdet Burak] Inst Canc Res, Breakthrough Breast Canc Ctr, Sutton, Surrey, England. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Chatterjee, N (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NCI Shady Grove, Rm 7E146, Rockville, MD 20852 USA. EM chattern@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650 NR 33 TC 8 Z9 9 U1 1 U2 13 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 NOV PY 2014 VL 106 IS 11 AR dju305 DI 10.1093/jnci/dju305 PG 6 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500021 ER PT J AU Gierada, DS Pinsky, P Nath, H Chiles, C Duan, FH Aberle, DR AF Gierada, David S. Pinsky, Paul Nath, Hrudaya Chiles, Caroline Duan, Fenghai Aberle, Denise R. TI Projected Outcomes Using Different Nodule Sizes to Define a Positive CT Lung Cancer Screening Examination SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COMPUTED-TOMOGRAPHY; TRIAL; SCANS AB Background Computed tomography (CT) screening for lung cancer has been associated with a high frequency of false positive results because of the high prevalence of indeterminate but usually benign small pulmonary nodules. The acceptability of reducing false-positive rates and diagnostic evaluations by increasing the nodule size threshold for a positive screen depends on the projected balance between benefits and risks. Methods We examined data from the National Lung Screening Trial (NLST) to estimate screening CT performance and outcomes for scans with nodules above the 4 mm NLST threshold used to classify a CT screen as positive. Outcomes assessed included screening results, subsequent diagnostic tests performed, lung cancer histology and stage distribution, and lung cancer mortality. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the different nodule size thresholds. All statistical tests were two-sided. Results In 64% of positive screens (11 598/18 141), the largest nodule was 7 mm or less in greatest transverse diameter. By increasing the threshold, the percentages of lung cancer diagnoses that would have been missed or delayed and false positives that would have been avoided progressively increased, for example from 1.0% and 15.8% at a 5 mm threshold to 10.5% and 65.8% at an 8 mm threshold, respectively. The projected reductions in postscreening follow-up CT scans and invasive procedures also increased as the threshold was raised. Differences across nodules sizes for lung cancer histology and stage distribution were small but statistically significant. There were no differences across nodule sizes in survival or mortality. Conclusion Raising the nodule size threshold for a positive screen would substantially reduce false-positive CT screenings and medical resource utilization with a variable impact on screening outcomes. C1 [Gierada, David S.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Pinsky, Paul] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Nath, Hrudaya] Univ Alabama Birmingham, Birmingham, AL USA. [Chiles, Caroline] Wake Forest Univ, Hlth Sci Ctr, Winston Salem, NC 27109 USA. [Duan, Fenghai] Brown Univ, Sch Publ Hlth, Ctr Stat Sci, Providence, RI 02912 USA. [Duan, Fenghai] Brown Univ, Sch Publ Hlth, Dept Biostat, Providence, RI 02912 USA. [Aberle, Denise R.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Gierada, DS (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, 510 S Kingshighway Blvd,Campus Box 8131, St Louis, MO 63110 USA. EM gieradad@wustl.edu OI Aberle, Denise/0000-0002-8858-3401 FU National Institutes of Health [U01-CA-80098, CA79778, N01-CN-25511, N01-CN-25512, N01-CN-25513, N01-CN-25514, N01-CN-25515, N01-CN-25516, N01-CN-25518, N01-CN-25522, N01-CN-25524, N01-CN-75022, N01-CN-25476, N02-CN-63300] FX The National Lung Screening Trial was supported by National Institutes of Health grants U01-CA-80098 and CA79778 and contracts N01-CN-25511, N01-CN-25512, N01-CN-25513, N01-CN-25514, N01-CN-25515, N01-CN-25516, N01-CN-25518, N01-CN-25522, N01-CN-25524, N01-CN-75022, N01-CN-25476, and N02-CN-63300 NR 20 TC 7 Z9 7 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD NOV PY 2014 VL 106 IS 11 AR dju284 DI 10.1093/jnci/dju284 PG 7 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500007 ER PT J AU Potosky, AL Harlan, LC Albritton, K Cress, RD Friedman, DL Hamilton, AS Kato, I Keegan, THM Keel, G Schwartz, SM Seibel, NL Shnorhavorian, M West, MM Wu, XC AF Potosky, Arnold L. Harlan, Linda C. Albritton, Karen Cress, Rosemary D. Friedman, Debra L. Hamilton, Ann S. Kato, Ikuko Keegan, Theresa H. M. Keel, Gretchen Schwartz, Stephen M. Seibel, Nita L. Shnorhavorian, Margarett West, Michele M. Wu, Xiao-Cheng CA AYA HOPE Study Collaborative Grp TI Use of Appropriate Initial Treatment Among Adolescents and Young Adults With Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE LYMPHOCYTIC-LEUKEMIA; CHILDRENS ONCOLOGY GROUP; HODGKIN LYMPHOMA; CLINICAL-TRIALS; HYPER-CVAD; GROUP-B; RISK; CHEMOTHERAPY; RADIOTHERAPY AB Background There has been little improvement in the survival of adolescent and young adult (AYA) cancer patients aged 15 to 39 years relative to other age groups, raising the question of whether such patients receive appropriate initial treatment. Methods We examined receipt of initial cancer treatment for a population-based sample of 504 AYAs diagnosed in 20072008 with acute lymphoblastic leukemia (ALL), Hodgkin's or non-Hodgkin's lymphoma, germ cell cancer, or sarcoma. Registry data, patient surveys, and detailed medical record reviews were used to evaluate the association of patient demographic, socioeconomic, and health care setting characteristics with receipt of appropriate initial treatment, which was defined by clinical specialists in AYA oncology based on adult guidelines and published literature available before 2009 and analyzed with multivariable logistic regression. All statistical tests were two-sided. Results Approximately 75% of AYA cancer patients in our sample received appropriate treatment, 68% after excluding stage I male germ cell patients who all received appropriate treatment. After this exclusion, appropriate treatment ranged from 79% of sarcoma patients to 56% of ALL patients. Cancer type (P < .01) and clinical trial participation (P =.04) were statistically significantly associated with appropriate treatment in multivariable analyses. Patients enrolled in clinical trials were more likely to receive appropriate therapy relative to those not enrolled (78% vs 67%, adjusted odds ratio = 2.6, 95% confidence interval = 1.1 to 6.4). Conclusions Except for those with early stage male germ cell tumors, approximately 30% (or 3 in 10) AYA cancer patients did not receive appropriate therapy. Further investigation is required to understand the reasons for this potential shortfall in care delivery. C1 [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Harlan, Linda C.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Albritton, Karen] Cook Childrens Med Ctr, Ft Worth, TX USA. [Albritton, Karen] Univ North Texas Hlth Sci Ctr, Ft Worth, TX USA. [Cress, Rosemary D.] Canc Registry Greater Calif, Inst Publ Hlth, Sacramento, CA USA. [Friedman, Debra L.] Monroe Carell Jr Childrens Hosp, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Hamilton, Ann S.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Kato, Ikuko] Wayne State Univ, Dept Oncol, Detroit, MI USA. [Kato, Ikuko] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Keel, Gretchen] Informat Management Serv Inc, Silver Spring, MD USA. [Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Seibel, Nita L.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Shnorhavorian, Margarett] Univ Washington, Seattle Childrens Hosp, Div Pediat Urol, Dept Urol, Seattle, WA 98195 USA. [West, Michele M.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Wu, Xiao-Cheng] Louisiana State Univ, New Orleans, LA USA. RP Potosky, AL (reprint author), Georgetown Univ, Med Ctr, Harris Bldg,Suite 4100,3300 Whitehaven St NW, Washington, DC 20007 USA. EM alp49@georgetown.edu FU National Cancer Institute at the National Institutes of Health [HHSN261201300004I, HHSN261201300005I, HHSN261201300011I, HHSN261201300012I, HHSN261201300014I, HHSN261201300016I, HHSN261201300020I, P30CA051008] FX This work was supported by the National Cancer Institute at the National Institutes of Health (HHSN261201300004I, HHSN261201300005I, HHSN261201300011I, HHSN261201300012I, HHSN261201300014I, HHSN261201300016I, HHSN261201300020I, and P30CA051008). 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 45 TC 5 Z9 5 U1 0 U2 1 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 NOV PY 2014 VL 106 IS 11 AR dju300 DI 10.1093/jnci/dju300 PG 9 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500016 ER PT J AU Shiels, MS Katki, HA Freedman, ND Purdue, MP Wentzensen, N Trabert, B Kitahara, CM Furr, M Li, Y Kemp, TJ Goedert, JJ Chang, CM Engels, EA Caporaso, NE Pinto, LA Hildesheim, A Chaturvedi, AK AF Shiels, Meredith S. Katki, Hormuzd A. Freedman, Neal D. Purdue, Mark P. Wentzensen, Nicolas Trabert, Britton Kitahara, Cari M. Furr, Michael Li, Yan Kemp, Troy J. Goedert, James J. Chang, Cindy M. Engels, Eric A. Caporaso, Neil E. Pinto, Ligia A. Hildesheim, Allan Chaturvedi, Anil K. TI Cigarette Smoking and Variations in Systemic Immune and Inflammation Markers SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTOR; LUNG-CANCER; BIOMARKERS; ACTIVATION; MORTALITY; EXPOSURE; PROSTATE; TOBACCO; SMOKERS; TRIAL AB Background A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease. Methods Levels of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models. Results Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin [IL]-15, IL-1RA, IL-1 beta, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval [CI] = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1 beta, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking. Conclusions Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time. C1 [Shiels, Meredith S.; Katki, Hormuzd A.; Freedman, Neal D.; Purdue, Mark P.; Wentzensen, Nicolas; Trabert, Britton; Kitahara, Cari M.; Goedert, James J.; Engels, Eric A.; Caporaso, Neil E.; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Furr, Michael] Informat Management Serv Inc, Rockville, MD USA. [Li, Yan] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Kemp, Troy J.; Pinto, Ligia A.] Leidos Biomed Res Inc, Frederick, MD USA. [Chang, Cindy M.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Shiels, MS (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E-218 MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; Hildesheim, Allan/B-9760-2015; Freedman, Neal/B-9741-2015; Purdue, Mark/C-9228-2016; Trabert, Britton/F-8051-2015; Chaturvedi, Anil/J-2024-2015; Kitahara, Cari/R-8267-2016 OI Hildesheim, Allan/0000-0003-0257-2363; Freedman, Neal/0000-0003-0074-1098; Purdue, Mark/0000-0003-1177-3108; Chaturvedi, Anil/0000-0003-2696-8899; FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 27 TC 16 Z9 16 U1 1 U2 7 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 NOV PY 2014 VL 106 IS 11 AR dju294 DI 10.1093/jnci/dju294 PG 8 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500012 ER PT J AU Thrift, AP Shaheen, NJ Gammon, MD Bernstein, L Reid, BJ Onstad, L Risch, HA Liu, G Bird, NC Wu, AH Corley, DA Romero, Y Chanock, SJ Chow, WH Casson, AG Levine, DM Zhang, R Ek, WE MacGregor, S Ye, WM Hardie, LJ Vaughan, TL Whiteman, DC AF Thrift, Aaron P. Shaheen, Nicholas J. Gammon, Marilie D. Bernstein, Leslie Reid, Brian J. Onstad, Lynn Risch, Harvey A. Liu, Geoffrey Bird, Nigel C. Wu, Anna H. Corley, Douglas A. Romero, Yvonne Chanock, Stephen J. Chow, Wong-Ho Casson, Alan G. Levine, David M. Zhang, Rui Ek, Weronica E. MacGregor, Stuart Ye, Weimin Hardie, Laura J. Vaughan, Thomas L. Whiteman, David C. TI Obesity and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus: A Mendelian Randomization Study SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BODY-MASS INDEX; INTERNATIONAL BEACON CONSORTIUM; GASTRIC CARDIA; INSTRUMENTAL VARIABLES; GENETIC EPIDEMIOLOGY; ABDOMINAL OBESITY; POOLED ANALYSIS; REFLUX DISEASE; METAANALYSIS; HEIGHT AB Background Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding. Methods We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided. Results The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1 kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses. Conclusions People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses. C1 [Thrift, Aaron P.; Onstad, Lynn; Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Reid, Brian J.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Thrift, Aaron P.; Whiteman, David C.] QIMR Berghofer Med Res Inst, Canc Control Grp, Brisbane, Qld, Australia. [Shaheen, Nicholas J.] Univ N Carolina, UNC Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Bernstein, Leslie] Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Bernstein, Leslie] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Liu, Geoffrey] Univ Toronto, Ontario Canc Inst, Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON M5S 1A1, Canada. [Bird, Nigel C.] Univ Sheffield, Sch Med, Dept Oncol, Sheffield, S Yorkshire, England. [Wu, Anna H.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Corley, Douglas A.] Kaiser Permanente, Div Res, Oakland, CA USA. [Corley, Douglas A.] Kaiser Permanente, Oakland Med Ctr, Oakland, CA USA. [Romero, Yvonne] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chow, Wong-Ho] Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Casson, Alan G.] Univ Saskatchewan, Dept Surg, Saskatoon, SK, Canada. [Levine, David M.; Zhang, Rui] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hardie, Laura J.] Univ Leeds, Div Epidemiol, Leeds, W Yorkshire, England. RP Thrift, AP (reprint author), Fred Hutchinson Canc Res Ctr, Program Epidemiol, POB 19024,M4-B874, Seattle, WA 98109 USA. EM athrift@fhcrc.org RI Macgregor, Stuart/C-6442-2009; Liu, Geoffrey/N-4421-2016; OI Macgregor, Stuart/0000-0001-6731-8142; Whiteman, David/0000-0003-2563-9559 FU National Institutes of Health [R01CA136725, P30 DK034987, NIDDK 02956]; European Association for Cancer Research; University of Queensland; National Health and Medical Research Council of Australia; Alan B. Brown Chair in Molecular Genomics; CCO Chair in Experimental Therapeutics Study; CCO Chair in Population Study; Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program; Fraternal Order of the Eagles; Australian National Health and Medical Research Council Career Development Award; Swedish Ministry of Higher Education; National Institutes of Health Career Development Award [K05CA124911]; Australian Research Council [FT0990987] FX This work was primarily funded by National Institutes of Health (R01CA136725). The funders of the study had no role in the design, analysis, or interpretation of the data, nor in writing or publication decisions related to this article.; APT is supported by Travel Fellowships from the European Association for Cancer Research and the University of Queensland and an Early Career Fellowship from the National Health and Medical Research Council of Australia. NJS is supported by a grant (P30 DK034987) from the National Institutes of Health. GL was supported by the Alan B. Brown Chair in Molecular Genomics and by the CCO Chair in Experimental Therapeutics and Population Studies. YR is supported by a grant from the National Institutes of Health (NIDDK 02956), the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program, and the Fraternal Order of the Eagles. SM is supported by an Australian National Health and Medical Research Council Career Development Award and the Swedish Ministry of Higher Education. TLV is supported by National Institutes of Health Career Development Award K05CA124911. DCW is supported by a Future Fellowship (FT0990987) from the Australian Research Council. NR 42 TC 17 Z9 17 U1 2 U2 6 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 NOV PY 2014 VL 106 IS 11 AR dju252 DI 10.1093/jnci/dju252 PG 8 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500001 ER PT J AU Wong, P Houghton, P Kirsch, DG Finkelstein, SE Monjazeb, AM Xu-Welliver, M Dicker, AP Ahmed, M Vikram, B Teicher, BA Coleman, CN Machtay, M Curran, WJ Wang, D AF Wong, Philip Houghton, Peter Kirsch, David G. Finkelstein, Steven E. Monjazeb, Arta M. Xu-Welliver, Meng Dicker, Adam P. Ahmed, Mansoor Vikram, Bhadrasain Teicher, Beverly A. Coleman, C. Norman Machtay, Mitchell Curran, Walter J. Wang, Dian TI Combining Targeted Agents With Modern Radiotherapy in Soft Tissue Sarcomas SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID RENAL-CELL CARCINOMA; PHASE-II TRIAL; METASTATIC COLORECTAL-CANCER; REFRACTORY SOLID TUMORS; PRECLINICAL TESTING PROGRAM; MOLECULE MDM2 ANTAGONISTS; CHILDRENS ONCOLOGY GROUP; BODY RADIATION-THERAPY; ADVANCED BREAST-CANCER; DEPENDENT KINASE 4/6 AB Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes. C1 [Wong, Philip] Ctr Hosp Univ Montreal, Dept Radiat Oncol, Montreal, PQ, Canada. [Houghton, Peter] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. [Finkelstein, Steven E.] 21st Century Oncol Translat Res Consortium TRC He, Scottsdale, AZ USA. [Monjazeb, Arta M.] Univ Calif Davis, Ctr Comprehens Canc, Dept Radiat Oncol, Sacramento, CA 95817 USA. [Xu-Welliver, Meng] Ohio State Univ, Dept Radiat Oncol, Columbus, OH 43210 USA. [Dicker, Adam P.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Ahmed, Mansoor; Coleman, C. Norman] NCI, Radiotherapy Dev Branch, Bethesda, MD 20892 USA. [Ahmed, Mansoor; Coleman, C. Norman] NCI, Mol Radiat Therapeut Branch, Radiat Res Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Vikram, Bhadrasain] NCI, Clin Radiat Oncol Branch, Bethesda, MD 20892 USA. [Teicher, Beverly A.] NCI, Mol Pharmacol Branch, Bethesda, MD 20892 USA. [Machtay, Mitchell] Univ Hosp Case Med Ctr, Dept Radiat Oncol, Cleveland, OH USA. [Curran, Walter J.] Emory Univ, Winship Canc Inst, Woodruff Hlth Sci Ctr, Atlanta, GA 30322 USA. [Wang, Dian] Rush Univ, Med Ctr, Dept Radiat Oncol, Chicago, IL 60612 USA. RP Wang, D (reprint author), Rush Univ, Med Ctr, Dept Radiat Oncol, 500 S Paulina,Ste 013, Chicago, IL 60612 USA. EM dian_wang@rush.edu FU Radiation Therapy Oncology Group (National Cancer Institute) [U10 CA21661-36]; Radiation Therapy Oncology Foundation; NRG Oncology [U10 CA180868] FX This work was supported by the Radiation Therapy Oncology Group (National Cancer Institute grant number U10 CA21661-36), the Radiation Therapy Oncology Foundation, and NRG Oncology (U10 CA180868). NR 177 TC 4 Z9 4 U1 6 U2 12 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 NOV PY 2014 VL 106 IS 11 AR dju329 DI 10.1093/jnci/dju329 PG 15 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500029 ER PT J AU Hazzard, KC Watkins-Chow, DE Garrett, LJ AF Hazzard, Karen C. Watkins-Chow, Dawn E. Garrett, Lisa J. TI Method of Euthanasia Influences the Oocyte Fertilization Rate with Fresh Mouse Sperm SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID INVITRO FERTILIZATION; BETA-CYCLODEXTRIN; MEIOTIC SPINDLE; CARBON-DIOXIDE; RECOVERY; MICE; CRYOPRESERVATION; SPERMATOZOA; GLUTATHIONE; AGENTS AB In vitro fertilization (IVF) is used to produce mouse embryos for a variety of reasons. We evaluated the effect of the method of euthanasia on the fertilization rate in 2 different IVF protocols. Oocytes collected from C57BL/6J female mice euthanized by CO2 inhalation or cervical dislocation were used in IVF with fresh sperm from either wild-type or genetically engineered C57BL/6J. Compared with CO2 inhalation, cervical dislocation improved the resulting rate of fertilization by 18% in an IVF method using Cook media and by 13% in an IVF method using methyl-B cyclodextrin and reduced glutathione. The lower fertilization rate due to euthanasia by CO2 inhalation was accompanied by changes in blood pH and body temperature despite efforts to minimize temperature drops. In our hands, euthanasia by cervical dislocation improved fertilization rates and consequently reduced the number of egg-donor mice required. C1 [Hazzard, Karen C.; Garrett, Lisa J.] NHGRI, Embryon Stem Cell & Transgen Mouse Core, Bethesda, MD 20892 USA. [Watkins-Chow, Dawn E.] NHGRI, Genet Dis Res Branch, Mouse Embryol Sect, Bethesda, MD 20892 USA. RP Hazzard, KC (reprint author), NHGRI, Embryon Stem Cell & Transgen Mouse Core, Bethesda, MD 20892 USA. EM KHazzard@nhgri.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, NIH FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, NIH. NR 25 TC 1 Z9 1 U1 1 U2 9 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD NOV PY 2014 VL 53 IS 6 BP 641 EP 646 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA AU8AA UT WOS:000345818000002 PM 25650969 ER PT J AU Kim, H Xu, HX Yao, Q Li, WZ Huang, Q Outeda, P Cebotaru, V Chiaravalli, M Boletta, A Piontek, K Germino, GG Weinman, EJ Watnick, T Qian, F AF Kim, Hyunho Xu, Hangxue Yao, Qin Li, Weizhe Huang, Qiong Outeda, Patricia Cebotaru, Valeriu Chiaravalli, Marco Boletta, Alessandra Piontek, Klaus Germino, Gregory G. Weinman, Edward J. Watnick, Terry Qian, Feng TI Ciliary membrane proteins traffic through the Golgi via a Rabep1/GGA1/Arl3-dependent mechanism SO NATURE COMMUNICATIONS LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; RECEPTOR PROTEOLYTIC SITE; PRIMARY CILIUM; INTRAFLAGELLAR TRANSPORT; CYST FORMATION; KIDNEY-DISEASE-1 GENE; INTRACELLULAR CALCIUM; DIFFUSION BARRIER; CELLS; PKD1 AB Primary cilia contain specific receptors and channel proteins that sense the extracellular milieu. Defective ciliary function causes ciliopathies such as autosomal dominant polycystic kidney disease (ADPKD). However, little is known about how large ciliary transmembrane proteins traffic to the cilia. Polycystin-1 (PC1) and -2 (PC2), the two ADPKD gene products, are large transmembrane proteins that co-localize to cilia where they act to control proper tubular diameter. Here we describe that PC1 and PC2 must interact and form a complex to reach the trans-Golgi network (TGN) for subsequent ciliary targeting. PC1 must also be proteolytically cleaved at a GPS site for this to occur. Using yeast two-hybrid screening coupled with a candidate approach, we identify a Rabep1/GGA1/Arl3-dependent ciliary targeting mechanism, whereby Rabep1 couples the polycystin complex to a GGA1/Arl3-based ciliary trafficking module at the TGN. This study provides novel insights into the ciliary trafficking mechanism of membrane proteins. C1 [Kim, Hyunho; Xu, Hangxue; Yao, Qin; Li, Weizhe; Huang, Qiong; Outeda, Patricia; Weinman, Edward J.; Watnick, Terry; Qian, Feng] Univ Maryland, Sch Med, Div Nephrol, Dept Med, Baltimore, MD 21201 USA. [Cebotaru, Valeriu; Piontek, Klaus] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Chiaravalli, Marco; Boletta, Alessandra] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Germino, Gregory G.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Qian, F (reprint author), Univ Maryland, Sch Med, Div Nephrol, Dept Med, Baltimore, MD 21201 USA. EM fqian@medicine.umaryland.edu FU National Institutes of Health [R01 DK062199]; National Kidney Foundation of Maryland; Korea Research Foundation Grant - Korean Government [KRF-2008-357-E00030]; National Kidney Foundation of Maryland [R01DK076017, R01DK DK095036, R37DK48006]; NIDDK Intramural Program [1ZIADK075042, DK55881]; Research Service, Department of Veterans Affairs FX We Dr Owen Woodward for reading and commenting on the manuscript. This work was supported by grants from the National Institutes of Health R01 DK062199, National Kidney Foundation of Maryland to F.Q., the Korea Research Foundation Grant funded by the Korean Government (KRF-2008-357-E00030), the National Kidney Foundation of Maryland to H.K., R01DK076017, R01DK DK095036 to T.W., R37DK48006 and the NIDDK Intramural Program 1ZIADK075042 to G.G.G., and DK55881 and the Research Service, Department of Veterans Affairs to E.J.W. These studies utilized resources provided by the NIDDK sponsored Baltimore Polycystic Kidney Disease Research and Clinical Core Center, P30DK090868. We thank members of the Baltimore PKD Center for insightful discussions. NR 70 TC 14 Z9 14 U1 1 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 NOV PY 2014 VL 5 AR 5482 DI 10.1038/ncomms6482 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU9KF UT WOS:000345910500010 PM 25405894 ER PT J AU Landon, AL Muniandy, PA Shetty, AC Lehrmann, E Volpon, L Houng, S Zhang, YQ Dai, BJ Peroutka, R Mazan-Mamczarz, K Steinhardt, J Mahurkar, A Becker, KG Borden, KL Gartenhaus, RB AF Landon, Ari L. Muniandy, Parameswary A. Shetty, Amol C. Lehrmann, Elin Volpon, Laurent Houng, Simone Zhang, Yongqing Dai, Bojie Peroutka, Raymond Mazan-Mamczarz, Krystyna Steinhardt, James Mahurkar, Anup Becker, Kevin G. Borden, Katherine L. Gartenhaus, Ronald B. TI MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL SO NATURE COMMUNICATIONS LA English DT Article ID CAP-DEPENDENT TRANSLATION; ACUTE MYELOID-LEUKEMIA; INITIATION-FACTOR 4E; NF-KAPPA-B; CELL LYMPHOMA; CANCER-CELLS; C-MYC; GENE-EXPRESSION; KINASES MNK1; PATHWAY AB The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) and show a distinct distribution of MNK1 and MNK2 in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL. Despite displaying a differential distribution in GCB and ABC, both MNKs functionally complement each other to sustain cell survival. MNK inhibition ablates eIF4E1 phosphorylation and concurrently enhances eIF4E3 expression. Loss of MNK protein itself downregulates total eIF4E1 protein level by reducing eIF4E1 mRNA polysomal loading without affecting total mRNA level or stability. Enhanced eIF4E3 expression marginally suppresses eIF4E1-driven translation but exhibits a unique translatome that unveils a novel role for eIF4E3 in translation initiation. We propose that MNKs can modulate oncogenic translation by regulating eIF4E1-eIF4E3 levels and activity in DLBCL. C1 [Landon, Ari L.; Muniandy, Parameswary A.; Houng, Simone; Dai, Bojie; Peroutka, Raymond; Mazan-Mamczarz, Krystyna; Steinhardt, James; Gartenhaus, Ronald B.] Univ Maryland, Dept Med, Marlene Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Muniandy, Parameswary A.; Houng, Simone; Dai, Bojie; Gartenhaus, Ronald B.] Vet Adm Med Ctr, Baltimore, MD 21201 USA. [Shetty, Amol C.; Mahurkar, Anup] Univ Maryland, Inst Genome Sci, Sch Med, Baltimore, MD 21201 USA. [Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Volpon, Laurent; Borden, Katherine L.] Univ Montreal, Inst Res Immunol & Canc, Dept Pathol & Cell Biol, Montreal, PQ H3T 1J4, Canada. RP Gartenhaus, RB (reprint author), Univ Maryland, Dept Med, Marlene Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. EM rgartenhaus@som.umaryland.edu FU Department of Veterans Affairs; National Institutes of Health [R01AA017972, R01CA164311]; Intramural Research Program of the NIH, National Institute on Aging FX We are thankful to Dr Hermann Gram from the Novartis Institutes for BioMedical Research, Switzerland, Dr Hans-Guido Wendel from the Memorial Sloan Kettering Cancer Center, NY and Dr Ari Melnick from Weill Cornell, NY, for generously sharing important reagents. We thank Stephanie Landon for helpful discussions. This work was supported in part by a Merit Review Award from the Department of Veterans Affairs (R.B.G.), R01AA017972 (R.B.G.) and R01CA164311 (R.B.G.) from the National Institutes of Health. This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging (Y.Z., E.L. and K.G.B.). NR 44 TC 13 Z9 13 U1 0 U2 8 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 NOV PY 2014 VL 5 AR 5413 DI 10.1038/ncomms6413 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5CN UT WOS:000345624800034 PM 25403230 ER PT J AU Matthies, D Zhou, WC Klyszejko, AL Anselmi, C Yildiz, O Brandt, K Muller, V Faraldo-Gomez, JD Meier, T AF Matthies, Doreen Zhou, Wenchang Klyszejko, Adriana L. Anselmi, Claudio Yildiz, Oezkan Brandt, Karsten Mueller, Volker Faraldo-Goemez, Jose D. Meier, Thomas TI High-resolution structure and mechanism of an F/V-hybrid rotor ring in a Na+-coupled ATP synthase SO NATURE COMMUNICATIONS LA English DT Article ID ESSENTIAL ARGININE RESIDUE; ESCHERICHIA-COLI; C-RING; SACCHAROMYCES-CEREVISIAE; MOLECULAR ARCHITECTURE; ILYOBACTER-TARTARICUS; ACETOBACTERIUM-WOODII; PROTON TRANSLOCATION; INTERMEDIATE STEP; F0F1-ATP SYNTHASE AB All rotary ATPases catalyse the interconversion of ATP and ADP-P-i through a mechanism that is coupled to the transmembrane flow of H+ or Na+. Physiologically, however, F/A-type enzymes specialize in ATP synthesis driven by downhill ion diffusion, while eukaryotic V-type ATPases function as ion pumps. To begin to rationalize the molecular basis for this functional differentiation, we solved the crystal structure of the Na+-driven membrane rotor of the Acetobacterium woodii ATP synthase, at 2.1 angstrom resolution. Unlike known structures, this rotor ring is a 9: 1 heteromer of F- and V-type c-subunits and therefore features a hybrid configuration of ion-binding sites along its circumference. Molecular and kinetic simulations are used to dissect the mechanisms of Na+ recognition and rotation of this c-ring, and to explain the functional implications of the V-type c-subunit. These structural and mechanistic insights indicate an evolutionary path between synthases and pumps involving adaptations in the rotor ring. C1 [Matthies, Doreen; Klyszejko, Adriana L.; Yildiz, Oezkan; Meier, Thomas] Max Planck Inst Biophys, Dept Biol Struct, D-60438 Frankfurt, Germany. [Zhou, Wenchang; Anselmi, Claudio; Faraldo-Goemez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bethesda, MD 20892 USA. [Brandt, Karsten; Mueller, Volker] Goethe Univ Frankfurt, Inst Mol Biosci, Dept Mol Microbiol & Bioenerget, D-60438 Frankfurt, Germany. [Faraldo-Goemez, Jose D.; Meier, Thomas] Cluster Excellence Macromol Complexes, D-60438 Frankfurt, Germany. RP Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 5635FL, Bethesda, MD 20892 USA. EM jose.faraldo@nih.gov; thomas.meier@biophys.mpg.de RI Anselmi, Claudio/D-6244-2012; Faraldo-Gomez, Jose/H-7127-2016; OI Anselmi, Claudio/0000-0002-3017-5085; zhou, wenchang/0000-0003-0397-1032 FU Collaborative Research Center (SFB) [807]; German Research Foundation (DFG); Cluster of Excellence 'Macromolecular Complexes'; Division of Intramural Research at NHLBI/NIH FX We thank Vanessa Leone for sharing unpublished experimental data and models of the a/c complex, Janet Vonck for advice on single-particle analysis and Fabrizio Marinelli for useful discussions. We also thank the staff of the Swiss Light Source (PXII) and the European Synchrotron Radiation Facility for their continuous support.This research was supported with funds from the Collaborative Research Center (SFB) 807 of the German Research Foundation (DFG) (T.M.and V.M.), the Cluster of Excellence 'Macromolecular Complexes' (DFG Project EXC 115) (T.M.) and the Division of Intramural Research at NHLBI/NIH (J.D.F.- G.). NR 64 TC 22 Z9 22 U1 2 U2 23 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 NOV PY 2014 VL 5 AR 5286 DI 10.1038/ncomms6286 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU6BB UT WOS:000345685900001 PM 25381992 ER PT J AU Qi, J Zhang, SL Wang, HL Wang, HK Buendia, JDA Hoffman, AF Lupica, CR Seal, RP Morales, M AF Qi, Jia Zhang, Shiliang Wang, Hui-Ling Wang, Huikun Buendia, Jose de Jesus Aceves Hoffman, Alexander F. Lupica, Carl R. Seal, Rebecca P. Morales, Marisela TI A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons SO NATURE COMMUNICATIONS LA English DT Article ID CONDITIONED PLACE PREFERENCE; VESICULAR GLUTAMATE; SELF-STIMULATION; PARA-CHLOROPHENYLALANINE; INTRACRANIAL REWARD; SEROTONERGIC SYSTEM; AXON TERMINALS; GABA NEURONS; RAT-BRAIN; NUCLEUS AB Electrical stimulation of the dorsal raphe (DR) and ventral tegmental area (VTA) activates the fibres of the same reward pathway but the phenotype of this pathway and the direction of the reward-relevant fibres have not been determined. Here we report rewarding effects following activation of a DR-originating pathway consisting of vesicular glutamate transporter 3 (VGluT3) containing neurons that form asymmetric synapses onto VTA dopamine neurons that project to nucleus accumbens. Optogenetic VTA activation of this projection elicits AMPA-mediated synaptic excitatory currents in VTA mesoaccumbens dopaminergic neurons and causes dopamine release in nucleus accumbens. Activation also reinforces instrumental behaviour and establishes conditioned place preferences. These findings indicate that the DR-VGluT3 pathway to VTA utilizes glutamate as a neurotransmitter and is a substrate linking the DR-one of the most sensitive reward sites in the brain-to VTA dopaminergic neurons. C1 [Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Buendia, Jose de Jesus Aceves; Morales, Marisela] NIDA, Neuronal Networks Sect, NIH, Baltimore, MD 21287 USA. [Wang, Hui-Ling; Hoffman, Alexander F.; Lupica, Carl R.] NIDA, Electrophysiol Res Sect, NIH, Baltimore, MD USA. [Seal, Rebecca P.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA USA. RP Morales, M (reprint author), NIDA, Neuronal Networks Sect, NIH, Baltimore, MD 21287 USA. EM mmorales@intra.nida.nih.gov RI Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU Intramural Research Program of the National Institute on Drug Abuse (IRP/NIDA/NIH) FX The Intramural Research Program of the National Institute on Drug Abuse (IRP/NIDA/NIH) supported this work. We thank Eduardo D. Gigante for technical assistance. We thank Roy A. Wise and M. Flavia Barbano for critical reading and helpful discussions. NR 58 TC 34 Z9 35 U1 1 U2 10 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 NOV PY 2014 VL 5 AR 5390 DI 10.1038/ncomms6390 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5CN UT WOS:000345624800011 PM 25388237 ER PT J AU Shi, XM Zhang, ZL Zhan, XM Cao, M Satoh, T Akira, S Shpargel, K Magnuson, T Li, QT Wang, RF Wang, CC Ge, K Wu, J AF Shi, Xuanming Zhang, Zilai Zhan, Xiaoming Cao, Mou Satoh, Takashi Akira, Shizuo Shpargel, Karl Magnuson, Terry Li, Qingtian Wang, Rongfu Wang, Chaochen Ge, Kai Wu, Jiang TI An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth SO NATURE COMMUNICATIONS LA English DT Article ID EMBRYONIC STEM-CELLS; SONIC HEDGEHOG; DEMETHYLASE JMJD3; CEREBELLUM DEVELOPMENT; NEURAL DEVELOPMENT; SPINAL-CORD; POLYCOMB; GENOME; DIFFERENTIATION; EXPRESSION AB The Sonic hedgehog (Shh) signalling pathway plays important roles during development and in cancer. Here we report a Shh-induced epigenetic switch that cooperates with Gli to control transcription outcomes. Before induction, poised Shh target genes are marked by a bivalent chromatin domain containing a repressive histone H3K27me3 mark and an active H3K4me3 mark. Shh activation induces a local switch of epigenetic cofactors from the H3K27 methyltransferase polycomb repressive complex 2 (PRC2) to an H3K27me3 demethylase Jmjd3/Kdm6b-centred coactivator complex. We also find that non-enzymatic activities of Jmjd3 are important and that Jmjd3 recruits the Set1/MLL H3K4 methyltransferase complexes in a Shh-dependent manner to resolve the bivalent domain. In vivo, changes of the bivalent domain accompanied Shh-activated cerebellar progenitor proliferation. Overall, our results reveal a regulatory mechanism that underlies the activation of Shh target genes and provides insight into the causes of various diseases and cancers exhibiting altered Shh signalling. C1 [Shi, Xuanming; Zhang, Zilai; Zhan, Xiaoming; Cao, Mou; Wu, Jiang] Univ Texas SW Med Ctr Dallas, Dept Physiol & Dev Biol, Dallas, TX 75390 USA. [Satoh, Takashi; Akira, Shizuo] Osaka Univ, RIMD, World Premier Inst, Lab Host Def,Immunol Frontier Res Ctr, Osaka, Japan. [Satoh, Takashi; Akira, Shizuo] Osaka Univ, Dept Host Def, RIMD, Osaka, Japan. [Shpargel, Karl; Magnuson, Terry] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA. [Li, Qingtian; Wang, Rongfu] Methodist Hosp, Res Inst, Ctr Inflammat & Epigenet, Houston, TX 77030 USA. [Wang, Chaochen; Ge, Kai] NIDDK, NIH, Bethesda, MD 20892 USA. RP Wu, J (reprint author), Univ Texas SW Med Ctr Dallas, Dept Physiol & Dev Biol, Dallas, TX 75390 USA. EM jiang9.wu@utsouthwestern.edu RI Shi, Xuanming/I-8559-2014; Akira, Shizuo/C-3134-2009; OI Ge, Kai/0000-0002-7442-5138 FU March of Dimes Foundation; American Cancer Society; NIH [R21MH102820]; Department of Defense Visionary postdoc fellowship FX We thank Qiu Wang and Yu Chen for technical support, Dr Chao Xing for RNA-seq analyses and Dr Jin Jiang for reagents and critical discussion. This work was supported by grants from March of Dimes Foundation (J.W.), American Cancer Society (J.W.), NIH (R21MH102820, J.W.) and Department of Defense Visionary postdoc fellowship (X.S.). NR 70 TC 17 Z9 17 U1 0 U2 13 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 NOV PY 2014 VL 5 AR 5425 DI 10.1038/ncomms6425 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5CO UT WOS:000345625000005 PM 25370275 ER PT J AU Grunseich, C Kats, IR Bott, LC Rinaldi, C Kokkinis, A Fox, D Chen, KL Schindler, AB Mankodi, AK Shrader, JA Schwartz, DP Lehky, TJ Liu, CY Fischbeck, KH AF Grunseich, Christopher Kats, Ilona R. Bott, Laura C. Rinaldi, Carlo Kokkinis, Angela Fox, Derrick Chen, Ke-lian Schindler, Alice B. Mankodi, Ami K. Shrader, Joseph A. Schwartz, Daniel P. Lehky, Tanya J. Liu, Chia-Ying Fischbeck, Kenneth H. TI Early onset and novel features in a spinal and bulbar muscular atrophy patient with a 68 CAG repeat SO NEUROMUSCULAR DISORDERS LA English DT Article DE Motor neuron disease; Spinal bulbar muscular atrophy; Kennedy's disease; Androgen receptor; Genetics ID ANDROGEN RECEPTOR GENE; NERVE-FIBER DENSITY; EXPANDED POLYGLUTAMINE; KENNEDY-DISEASE; INCLUSIONS; EXPRESSION; PROTEIN; LENGTH AB Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Patients with SBMA have weakness, atrophy, and fasciculations in the bulbar and extremity muscles. Individuals with CAG repeat lengths greater than 62 have not previously been reported. We evaluated a 29 year old SBMA patient with 68 CAGs who had unusually early onset and findings not seen in others with the disease. Analysis of the androgen receptor gene confirmed the repeat length of 68 CAGs in both peripheral blood and fibroblasts. Evaluation of muscle and sensory function showed deficits typical of SBMA, and in addition the patient had manifestations of autonomic dysfunction and abnormal sexual development. These findings extend the known phenotype associated with SBMA and shed new insight into the effects of the mutated androgen receptor. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Grunseich, Christopher; Kats, Ilona R.; Bott, Laura C.; Rinaldi, Carlo; Kokkinis, Angela; Fox, Derrick; Chen, Ke-lian; Schindler, Alice B.; Mankodi, Ami K.; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Bott, Laura C.] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. [Shrader, Joseph A.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Schwartz, Daniel P.; Lehky, Tanya J.] NINDS, Electromyog Sect, NIH, Bethesda, MD 20892 USA. [Liu, Chia-Ying] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Grunseich, C (reprint author), NIH, 2A-1010,35 Convent Dr, Bethesda, MD 20892 USA. EM christopher.grunseich@nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 21 TC 12 Z9 12 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD NOV PY 2014 VL 24 IS 11 BP 978 EP 981 DI 10.1016/j.nmd.2014.06.441 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AU6TC UT WOS:000345733600005 PM 25047668 ER PT J AU Dorsey, SG Schiffman, R Redeker, NS Heitkemper, M McCloskey, DJ Weglicki, LS Grady, PA AF Dorsey, Susan G. Schiffman, Rachel Redeker, Nancy S. Heitkemper, Margaret McCloskey, Donna Jo Weglicki, Linda S. Grady, Patricia A. CA NINR Ctr Directors TI National Institute of Nursing Research Centers of Excellence: A logic model for sustainability, leveraging resources, and collaboration to accelerate cross-disciplinary science SO NURSING OUTLOOK LA English DT Article DE National Institute of Nursing Research Centers of Excellence; Logic model; Cross-disciplinary collaboration ID TEAM SCIENCE AB The National Institute. of Nursing Research (NINR) Centers of Excellence program is a catalyst enabling institutions to develop infrastructure and administrative support for creating cross-disciplinary teams that bring multiple strategies and expertise to bear on common areas of science. Centers are increasingly collaborative with campus partners and reflect an integrated team approach to advance science and promote the development of scientists in these areas. The purpose of this paper is to present the NINR Logic Model for Center Sustainability. The components of the logic model were derived from the presentations and robust discussions at the 2013 NINR center directors' meeting focused on best practices for leveraging resources and collaboration as methods to promote center sustainability. Collaboration through development and implementation of cross-disciplinary research teams is critical to accelerate the generation of new knowledge for solving fundamental health problems. Sustainability of centers as a long-term outcome beyond the initial funding can be enhanced by thoughtful planning of inputs, activities, and leveraging resources across multiple levels. C1 [Dorsey, Susan G.] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. [Schiffman, Rachel] Univ Wisconsin, Coll Nursing, Milwaukee, WI 53201 USA. [Redeker, Nancy S.] Yale Univ, Sch Nursing, New Haven, CT 06536 USA. [Heitkemper, Margaret] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [McCloskey, Donna Jo; Weglicki, Linda S.; Grady, Patricia A.] NINR, NIH, Bethesda, MD 20892 USA. RP Dorsey, SG (reprint author), Univ Maryland, Sch Nursing, Room 727A,655 West Lombard St, Baltimore, MD 21201 USA. EM sdorsey@son.umaryland.edu RI Redeker, Nancy/Q-8252-2016; OI Redeker, Nancy/0000-0001-7817-2708; Dorsey, Susan/0000-0001-7648-1312; Greenspan, Joel/0000-0003-4062-9797 FU NINR NIH HHS [P30NR011400, P20 NR010674, P20 NR014126, P20NR010674, P20NR014126, P30 NR011396, P30 NR011400, P30 NR014129, P30 NR014139, P30NR011396, P30NR014129] NR 17 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD NOV-DEC PY 2014 VL 62 IS 6 BP 384 EP 393 DI 10.1016/j.outlook.2014.06.003 PG 10 WC Nursing SC Nursing GA AU7ZX UT WOS:000345817700003 PM 25085328 ER PT J AU Engler, MB Austin, JK Grady, P AF Engler, Mary B. Austin, Joan K. Grady, Patricia TI The National Institute of Nursing Research Graduate Partnerships Program (NINR-GPP): An opportunity for PhD students SO NURSING OUTLOOK LA English DT Article DE Dissertation research; Mentoring; Nursing; PhD training ID SHORTAGE; FACULTY AB The Institutional Graduate Partnerships Program (GPP) offered by the National Institute of Nursing Research (NINR) provides an exceptional opportunity for students who are enrolled in any PhD program in nursing across the nation to complete dissertation research on the premier research campus of the National Institutes of Health, Bethesda, MD. The goal of this doctoral fellowship program, which is up to 3 years in length, is to train promising doctoral students in basic and clinical research. This knowledge and skill set is necessary for the next generation of nurse scientists to ultimately conduct translational research. In this article, the authors describe the program, eligibility requirements, application procedures, and selection criteria for NINR-supported GPP nursing students. Also provided are tips for interested students and outcomes of current and former NINR-supported GPP students (NINR-GPP). C1 [Engler, Mary B.] NINR, NIH, Div Intramural Res, Bethesda, MD 20892 USA. [Austin, Joan K.] Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. [Grady, Patricia] NINR, Bethesda, MD 20892 USA. RP Engler, MB (reprint author), NINR, NIH, Div Intramural Res, 1 Cloister Court,Rm 253,MSC 4733, Bethesda, MD 20892 USA. EM mary.engler@nih.gov NR 6 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD NOV-DEC PY 2014 VL 62 IS 6 BP 469 EP 474 DI 10.1016/j.outlook.2014.08.009 PG 6 WC Nursing SC Nursing GA AU7ZX UT WOS:000345817700011 PM 25261387 ER PT J AU Zhang, XX Chen, L Liu, JL Ito, Y He, J Sun, WJ AF Zhang, Xin-xin Chen, Lin Liu, Jian-li Ito, Yoichiro He, Jiao Sun, Wen-ji TI Neuroprotection of Total Steroid Saponins from Dioscorea zingiberensis against Transient Focal Cerebral Ischemia-Reperfusion Injury in Rats via Anti-Inflammatory and Antiapoptotic Effects SO PLANTA MEDICA LA English DT Article DE Dioscorea zingiberensis; Dioscoreaceae; cerebral ischemia-reperfusion; middle cerebral artery occlusion (MCAO); total steroid saponins; anti-inflammatory; anti-apoptotic ID CELL-DEATH; ARTERY OCCLUSION; APOPTOSIS; DIOSCIN; IDENTIFICATION; PATHWAY; INHIBITION; ACTIVATION; PROTEASE; WRIGHT AB Total steroid saponins isolated from Dioscorea zingiberensis have shown a variety of beneficial bioactivities. However, there are no reports about their neuroprotective effects, until now. Therefore, in the present study, we explored the neuroprotective effects of the total steroid saponins from D. zingiberensis on rats against transient focal cerebral ischemia-reperfusion and their underlying mechanisms. Healthy adult Sprague-Dawley rats were randomly assigned to six groups. After pretreatment with D. zingiberensis total steroid saponins intragastrically for six days, the rats were subjected to an ischemia injury by surgery on the middle cerebral artery occlusion for 90min. Compared to the ischemia-reperfusion group, the D. zingiberensis total steroid saponin group of rats, especially those given a 30-mg/kg dose, showed not only a marked reduction in neurological deficit scores, cerebral infarct volume, and brain edema, but also an increase in neuron survival (Nissl bodies) in the hippocampal cornuammons 1 and cortex hemisphere of the ipsilateral ischemia. At the same time, the inflammatory cytokines in serum induced by the middle cerebral artery occlusion were significantly decreased by the preadministration of D. zingiberensis total steroid saponins. Furthermore, the increase of caspase-3 was evidently reduced in the hippocampal cornuammons 1 and cortex of the hemisphere injured brain. Finally, the downregulating antiapoptotic Bcl-2 and upregulating proapoptotic Bax proteins were obviously suppressed. Taken together, the current findings suggest that D. zingiberensis total steroid saponins played a potential neuroprotective role against a severe injury induced by transient focal cerebral ischemic reperfusion in a rat experimental model, and this role may be mediated by its anti-inflammatory and antiapoptotic actions. C1 [Zhang, Xin-xin; Chen, Lin; Liu, Jian-li; He, Jiao; Sun, Wen-ji] NW Univ Xian, Biomed Key Lab Shaanxi Prov, Xian 710069, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Sun, WJ (reprint author), NW Univ Xian, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd0, Xian 710069, Peoples R China. EM itoy@nhlbi.nih.gov; cxbml@nwu.edu.cn NR 32 TC 0 Z9 0 U1 1 U2 10 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD NOV PY 2014 VL 80 IS 17 BP 1597 EP 1604 DI 10.1055/s-0034-1383181 PG 8 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AU6HL UT WOS:000345704400004 PM 25340467 ER PT J AU Zahn, R Garrido, G Moll, J Grafman, J AF Zahn, Roland Garrido, Griselda Moll, Jorge Grafman, Jordan TI Individual differences in posterior cortical volume correlate with proneness to pride and gratitude SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE social cognition; emotion; neuroanatomy; individual differences; moral emotion ID VOXEL-BASED MORPHOMETRY; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; NEURAL BASIS; PREFRONTAL CORTEX; MORAL COGNITION; TEMPORAL POLE; BRAIN; NETWORKS; DAMAGE AB Proneness to specific moral sentiments (e.g. pride, gratitude, guilt, indignation) has been linked with individual variations in functional MRI (fMRI) response within anterior brain regions whose lesion leads to inappropriate behaviour. However, the role of structural anatomical differences in rendering individuals prone to particular moral sentiments relative to others is unknown. Here, we investigated grey matter volumes (VBM8) and proneness to specific moral sentiments on a well-controlled experimental task in healthy individuals. Individuals with smaller cuneus, and precuneus volumes were more pride-prone, whereas those with larger right inferior temporal volumes experienced gratitude more readily. Although the primary analysis detected no associations with guilt- or indignation-proneness, subgenual cingulate fMRI responses to guilt were negatively correlated with grey matter volumes in the left superior temporal sulcus and anterior dorsolateral prefrontal cortices (right > left). This shows that individual variations in functional activations within critical areas for moral sentiments were not due to grey matter volume differences in the same areas. Grey matter volume differences between healthy individuals may nevertheless play an important role by affecting posterior cortical brain systems that are non-critical but supportive for the experience of specific moral sentiments. This may be of particular relevance when their experience depends on visuo-spatial elaboration. C1 [Zahn, Roland; Moll, Jorge; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Zahn, Roland] Kings Coll London, Inst Psychiat, Dept Psychol Med, London SE5 8AF, England. [Garrido, Griselda; Moll, Jorge] Inst DOr, Cognit & Behav Neurosci Unit, BR-22280080 Rio De Janeiro, RJ, Brazil. [Garrido, Griselda] Univ Western Australia, Western Australian Ctr Hlth & Ageing M573, Med Res Ctr, Perth, WA 6009, Australia. [Grafman, Jordan] Rehabil Inst Chicago, Chicago, IL 60611 USA. [Grafman, Jordan] Northwestern Univ, Dept Phys Med & Rehabil, Chicago, IL 60611 USA. RP Grafman, J (reprint author), Rehabil Inst Chicago, 345 E Super St, Chicago, IL 60611 USA. EM jgrafman@ric.org RI Zahn, Roland/C-4665-2008 OI Zahn, Roland/0000-0002-8447-1453 FU NINDS; German Academy of Natural Scientists Leopoldina Fellowship - Federal Ministry of Education and Research [BMBF-LPD 9901/8-122]; MRC clinician scientist fellowship [G0902304]; LABS-D'Or Hospital Network, Rio de Janeiro, Brazil FX This study was supported by NINDS intramural funding to J.G. and a German Academy of Natural Scientists Leopoldina Fellowship funded by the Federal Ministry of Education and Research (BMBF-LPD 9901/8-122) to R.Z. R.Z. was funded in part by an MRC clinician scientist fellowship (G0902304). J.M. was supported by the LABS-D'Or Hospital Network, Rio de Janeiro, Brazil. The authors thank Eric Wassermann for performing neurological exams. They also thank Shane McKie for imaging analysis advice. NR 67 TC 7 Z9 7 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD NOV PY 2014 VL 9 IS 11 BP 1676 EP 1683 DI 10.1093/scan/nst158 PG 8 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AU8LA UT WOS:000345846800005 PM 24106333 ER PT J AU Silk, JS Siegle, GJ Lee, KH Nelson, EE Stroud, LR Dahl, RE AF Silk, Jennifer S. Siegle, Greg J. Lee, Kyung Hwa Nelson, Eric E. Stroud, Laura R. Dahl, Ronald E. TI Increased neural response to peer rejection associated with adolescent depression and pubertal development SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE depression; neuroimaging; social exclusion; rejection; adolescence ID PROCESSING SOCIAL EXCLUSION; VIRTUAL-REALITY EXPOSURE; PREFRONTAL CORTEX; MOOD DISORDERS; NEUROSCIENCE PERSPECTIVE; PSYCHIATRIC-DISORDERS; ANXIOUS ADOLESCENTS; INCREASED AMYGDALA; ANTERIOR INSULA; BRAIN AB Sensitivity to social evaluation has been proposed as a potential marker or risk factor for depression, and has also been theorized to increase with pubertal maturation. This study utilized an ecologically valid paradigm to test the hypothesis that adolescents with major depressive disorder (MDD) would show altered reactivity to peer rejection and acceptance relative to healthy controls in a network of ventral brain regions implicated in affective processing of social information. A total of 48 adolescents (ages 11-17), including 21 with a current diagnosis of MDD and 27 age- and gender-matched controls, received rigged acceptance and rejection feedback from fictitious peers during a simulated online peer interaction during functional neuroimaging. MDD youth showed increased activation to rejection relative to controls in the bilateral amygdala, subgenual anterior cingulate, left anterior insula and left nucleus accumbens. MDD and healthy youth did not differ in response to acceptance. Youth more advanced in pubertal maturation also showed increased reactivity to rejection in the bilateral amygdala/parahippocampal gyrus and the caudate/subgenual anterior cingulate, and these effects remained significant when controlling for chronological age. Findings suggest that increased reactivity to peer rejection is a normative developmental process associated with pubertal development, but is particularly enhanced among youth with depression. C1 [Silk, Jennifer S.; Siegle, Greg J.; Lee, Kyung Hwa] Univ Pittsburgh, Dept Psychiat, Sch Med, Pittsburgh, PA 15260 USA. [Silk, Jennifer S.; Siegle, Greg J.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Nelson, Eric E.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20895 USA. [Stroud, Laura R.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02903 USA. [Dahl, Ronald E.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. RP Silk, JS (reprint author), Univ Pittsburgh, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15260 USA. EM silkj@upmc.edu OI Nelson, Eric/0000-0002-3376-2453; Silk, Jennifer/0000-0002-8638-4337 FU National Institute of Drug Abuse [R21DA024144]; Clinical and Translational Science Institute at the University of Pittsburgh (NIH/NCRR/CTSA) [UL1 RR024153]; National Institute of Mental Health intramural research program FX This research was supported by National Institute of Drug Abuse grant R21DA024144 (J.S.S./R.E.D., PI's), the Clinical and Translational Science Institute at the University of Pittsburgh (NIH/NCRR/CTSA Grant UL1 RR024153) and the National Institute of Mental Health intramural research program. The authors are grateful to Daniel Pine, MD for his input and assistance on this project; Marcie Walker, Katie Burkhouse and Karen Garelik for their assistance in data acquisition; Harvey Iwamoto for task related computer programming; and Ruth Stroud and Jennifer Sears for assistance with photography. They also thank the participants and their families. NR 90 TC 27 Z9 27 U1 8 U2 34 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD NOV PY 2014 VL 9 IS 11 BP 1798 EP 1807 DI 10.1093/scan/nst175 PG 10 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AU8LA UT WOS:000345846800019 PM 24273075 ER PT J AU Zane, L Sharma, V Misteli, T AF Zane, Linda Sharma, Vivek Misteli, Tom TI Common features of chromatin in aging and cancer: cause or coincidence? SO TRENDS IN CELL BIOLOGY LA English DT Review ID LONG NONCODING RNA; GLOBAL HISTONE MODIFICATIONS; H4 LYSINE-20 TRIMETHYLATION; CPG ISLAND HYPERMETHYLATION; SQUAMOUS-CELL CARCINOMA; STRAND BREAK REPAIR; DNA-DAMAGE; GENE-EXPRESSION; LIFE-SPAN; GENOMIC INSTABILITY AB Age is a major risk factor for cancer. Alterations in DNA methylation, histone modifications, chromatin structure, and epigenetic regulatory mechanisms are prominent hallmarks of both the aging process and cancer. Intriguingly - or possibly coincidentally - several chromatin features are common between aging and cancer. Here we ask whether, and if so how, aging-associated chromatin modifications contribute to tumor susceptibility and tumorigenesis. C1 [Zane, Linda; Sharma, Vivek; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU National Institutes of Health (NIH) Khorana Nirenberg Fellowship; NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX V.S. is supported by a National Institutes of Health (NIH) Khorana Nirenberg Fellowship. Work in the Misteli laboratory is supported by the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research. NR 141 TC 15 Z9 15 U1 3 U2 19 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD NOV PY 2014 VL 24 IS 11 BP 686 EP 694 DI 10.1016/j.tcb.2014.07.001 PG 9 WC Cell Biology SC Cell Biology GA AU9YQ UT WOS:000345948300010 PM 25103681 ER PT J AU Warren, TK Trefry, JC Marko, ST Chance, TB Wells, JB Pratt, WD Johnson, JC Mucker, EM Norris, SL Chappell, M Dye, JM Honko, AN AF Warren, Travis K. Trefry, John C. Marko, Shannon T. Chance, Taylor B. Wells, Jay B. Pratt, William D. Johnson, Joshua C. Mucker, Eric M. Norris, Sarah L. Chappell, Mark Dye, John M. Honko, Anna N. TI Euthanasia Assessment in Ebola Virus Infected Nonhuman Primates SO VIRUSES-BASEL LA English DT Article DE filovirus; nonhuman primate; viral hemorrhagic fever; euthanasia; clinical pathology; Ebola virus ID POSTEXPOSURE PROTECTION; HEMORRHAGIC-FEVER; RHESUS-MONKEYS; DISEASE; CHALLENGE AB Multiple products are being developed for use against filoviral infections. Efficacy for these products will likely be demonstrated in nonhuman primate models of filoviral disease to satisfy licensure requirements under the Animal Rule, or to supplement human data. Typically, the endpoint for efficacy assessment will be survival following challenge; however, there exists no standardized approach for assessing the health or euthanasia criteria for filovirus-exposed nonhuman primates. Consideration of objective criteria is important to (a) ensure test subjects are euthanized without unnecessary distress; (b) enhance the likelihood that animals exhibiting mild or moderate signs of disease are not prematurely euthanized; (c) minimize the occurrence of spontaneous deaths and loss of end-stage samples; (d) enhance the reproducibility of experiments between different researchers; and (e) provide a defensible rationale for euthanasia decisions that withstands regulatory scrutiny. Historic records were compiled for 58 surviving and non-surviving monkeys exposed to Ebola virus at the US Army Medical Research Institute of Infectious Diseases. Clinical pathology parameters were statistically analyzed and those exhibiting predicative value for survival are reported. These findings may be useful for standardization of objective euthanasia assessments in rhesus monkeys exposed to Ebola virus and may serve as a useful approach for other standardization efforts. C1 [Warren, Travis K.; Trefry, John C.; Marko, Shannon T.; Chance, Taylor B.; Wells, Jay B.; Pratt, William D.; Johnson, Joshua C.; Mucker, Eric M.; Norris, Sarah L.; Chappell, Mark; Dye, John M.; Honko, Anna N.] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Marko, Shannon T.] Madigan Army Med Ctr, Tacoma, WA 98431 USA. [Johnson, Joshua C.; Honko, Anna N.] NIAID, Integrated Res Facil, Ft Detrick, MD 21702 USA. [Chappell, Mark] Armed Forces Radiobiol Res Inst, Bethesda, MD 20889 USA. RP Warren, TK (reprint author), US Army, Med Res Inst Infect Dis, 1425 Porter St, Ft Detrick, MD 21702 USA. EM travis.k.warren.ctr@mail.mil; john.c.trefry.ctr@mail.mil; shannon.t.marko.mil@mail.mil; taylor.b.chance.mil@mail.mil; jay.b.wells.ctr@mail.mil; william.d.pratt4.civ@mail.mil; joshua.johnson@nih.gov; eric.m.mucker.ctr@mail.mil; sarah.l.norris2.civ@mail.mil; mark.chappell@usuhs.edu; john.m.dye1.civ@mail.mil; anna.honko@nih.gov OI Johnson, Joshua/0000-0002-5677-3841; Honko, Anna/0000-0001-9165-148X FU Defense Threat Reduction Agency FX Financial contributions for this work were provided in part by the Defense Threat Reduction Agency. The authors acknowledge the contributions of the numerous individuals who participated in the historic nonhuman primate evaluations described in this report. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. Research was conducted under an IACUC approved protocol in compliance with the Animal Welfare Act, PHS Policy, and other Federal statutes and regulations relating to animals and experiments involving animals. The facility where this research was conducted is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, 2011. NR 22 TC 6 Z9 6 U1 0 U2 11 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD NOV PY 2014 VL 6 IS 11 BP 4666 EP 4682 DI 10.3390/v6114666 PG 17 WC Virology SC Virology GA AU4FL UT WOS:000345565200031 PM 25421892 ER PT J AU Kuhn, JH Andersen, KG Baize, S Bao, YM Bavari, S Berthet, N Blinkova, O Brister, JR Clawson, AN Fair, J Gabriel, M Garry, RF Gire, SK Goba, A Gonzalez, JP Gunther, S Happi, CT Jahrling, PB Kapetshi, J Kobinger, G Kugelman, JR Leroy, EM Maganga, GD Mbala, PK Moses, LM Muyembe-Tamfum, JJ N'Faly, M Nichol, ST Omilabu, SA Palacios, G Park, DJ Paweska, JT Radoshitzky, SR Rossi, CA Sabeti, PC Schieffelin, JS Schoepp, RJ Sealfon, R Swanepoel, R Towner, JS Wada, J Wauquier, N Yozwiak, NL Formenty, P AF Kuhn, Jens H. Andersen, Kristian G. Baize, Sylvain Bao, Yiming Bavari, Sina Berthet, Nicolas Blinkova, Olga Brister, J. Rodney Clawson, Anna N. Fair, Joseph Gabriel, Martin Garry, Robert F. Gire, Stephen K. Goba, Augustine Gonzalez, Jean-Paul Guenther, Stephan Happi, Christian T. Jahrling, Peter B. Kapetshi, Jimmy Kobinger, Gary Kugelman, Jeffrey R. Leroy, Eric M. Maganga, Gael Darren Mbala, Placide K. Moses, Lina M. Muyembe-Tamfum, Jean-Jacques N'Faly, Magassouba Nichol, Stuart T. Omilabu, Sunday A. Palacios, Gustavo Park, Daniel J. Paweska, Janusz T. Radoshitzky, Sheli R. Rossi, Cynthia A. Sabeti, Pardis C. Schieffelin, John S. Schoepp, Randal J. Sealfon, Rachel Swanepoel, Robert Towner, Jonathan S. Wada, Jiro Wauquier, Nadia Yozwiak, Nathan L. Formenty, Pierre TI Nomenclature- and Database-Compatible Names for the Two Ebola Virus Variants that Emerged in Guinea and the Democratic Republic of the Congo in 2014 SO VIRUSES-BASEL LA English DT Article DE Ebola; Ebola virus; ebolavirus; filovirid; Filoviridae; filovirus; genome annotation; Lomela; Lokolia; Makona; mononegavirad; Mononegavirales; mononegavirus; virus classification; virus isolate; virus nomenclature; virus strain; virus taxonomy; virus variant ID INTERNATIONAL COMMITTEE; TAXONOMIC PROPOSALS; FAMILY FILOVIRIDAE; RATIFICATION VOTE AB In 2014, Ebola virus (EBOV) was identified as the etiological agent of a large and still expanding outbreak of Ebola virus disease (EVD) in West Africa and a much more confined EVD outbreak in Middle Africa. Epidemiological and evolutionary analyses confirmed that all cases of both outbreaks are connected to a single introduction each of EBOV into human populations and that both outbreaks are not directly connected. Coding-complete genomic sequence analyses of isolates revealed that the two outbreaks were caused by two novel EBOV variants, and initial clinical observations suggest that neither of them should be considered strains. Here we present consensus decisions on naming for both variants (West Africa: "Makona", Middle Africa: "Lomela") and provide database-compatible full, shortened, and abbreviated names that are in line with recently established filovirus sub-species nomenclatures. C1 [Kuhn, Jens H.; Clawson, Anna N.; Jahrling, Peter B.; Wada, Jiro] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Andersen, Kristian G.; Gire, Stephen K.; Sabeti, Pardis C.; Yozwiak, Nathan L.] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. [Baize, Sylvain] Inst Pasteur, Unite Biol Infect Virales Emergentes, Lyon, France. [Baize, Sylvain] Univ Lyon 1, CNRS, Ecole Normale Super Lyon, CIRI,INSERM,U1111,UMR5308, F-69365 Lyon, France. [Bao, Yiming; Blinkova, Olga; Brister, J. Rodney] NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Bavari, Sina; Kugelman, Jeffrey R.; Palacios, Gustavo; Radoshitzky, Sheli R.; Rossi, Cynthia A.; Schoepp, Randal J.] US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Berthet, Nicolas; Leroy, Eric M.; Maganga, Gael Darren] Ctr Int Rech Med Franceville, Franceville, Gabon. [Fair, Joseph] Fdn Merieux, Washington, DC 20036 USA. [Gabriel, Martin; Guenther, Stephan] WHO, Bernhard Nocht Inst Trop Med, Collaborating Ctr Arbovirus & Hemorrhag Fever Ref, D-20259 Hamburg, Germany. [Gabriel, Martin; Guenther, Stephan] German Ctr Infect Res DZIF, D-20259 Hamburg, Germany. [Garry, Robert F.; Moses, Lina M.; Schieffelin, John S.] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Goba, Augustine] Kenema Govt Hosp, Kenema, Sierra Leone. [Gonzalez, Jean-Paul; Wauquier, Nadia] Metabiota Inc, San Francisco, CA 94104 USA. [Happi, Christian T.] Redeemers Univ, Coll Nat Sci, Dept Biol Sci, Mowe, Ogun State, Nigeria. [Happi, Christian T.] Redeemers Univ, African Ctr Excellence Genom Infect Dis, Mowe, Ogun State, Nigeria. [Kobinger, Gary] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB R3E 3R2, Canada. [N'Faly, Magassouba] Univ Gamal Abdel Nasser de Conakry, Lab Fievres Hemorrag Guinee, Hop Natl Donka, Serv Malad Infect & Trop, Conakry, Guinea. [Nichol, Stuart T.; Towner, Jonathan S.] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Div High Consequence Pathogens & Pathol, Viral Special Pathogens Branch, Atlanta, GA 30333 USA. [Omilabu, Sunday A.] Univ Lagos, Coll Med, Dept Med Microbiol & Parasitol, Lagos, Nigeria. [Park, Daniel J.] Broad Inst, Cambridge, MA 02142 USA. [Paweska, Janusz T.] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Ctr Emerging & Zoonot Dis, ZA-2192 Sandringham Johannesburg, Gauteng, South Africa. [Sealfon, Rachel] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Swanepoel, Robert] Univ Pretoria, Zoonoses Res Unit, ZA-0028 Pretoria, South Africa. [Formenty, Pierre] WHO, CH-1211 Geneva, Switzerland. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov; kandersen@oeb.harvard.edu; sylvain.baize@inserm.fr; bao@ncbi.nlm.nih.gov; sina.bavari.civ@mail.mil; nicolas.berthet@pasteur.fr; olga.blinkova@nih.gov; jamesbr@ncbi.nlm.nih.gov; anna@logosconsulting.us; joseph.fair@fondation-merieux.org; gabriel@bni-hamburg.de; rfgarry@tulane.edu; sgire@oeb.harvard.edu; augstgoba@yahoo.com; jpgonzalez@metabiota.com; guenther@bni.uni-hamburg.de; happic@run.edu.ng; jahrlingp@niaid.nih.gov; jimmy_kap@hotmail.com; gary.kobinger@phac-aspc.gc.ca; jeffrey.r.kugelman.mil@mail.mil; eric.leroy@ird.fr; gael_maganga@yahoo.fr; mbalaplacide@gmail.com; lmoses2@tulane.edu; muyembejj@gmail.com; cmagassouba01@gmail.com; stn1@cdc.gov; omilabusa@yahoo.com; gustavo.f.palacios.ctr@us.army.mil; dpark@broadinstitute.org; januszp@nicd.ac.za; sheli.r.radoshitzky.ctr@mail.mil; cynthia.a.rossi.civ@mail.mil; pardis@broadinstitute.org; jschieff@tulane.edu; randal.j.schoepp.civ@mail.mil; sealfon@gmail.com; bobswanepoel@gmail.com; jit8@cdc.gov; wadaj@niaid.nih.gov; nadia.wauquier@gmail.com; nyozwiak@broadinstitute.org; formentyp@who.int RI Berthet, Nicolas/J-9373-2012; Kuhn, Jens H./B-7615-2011; Palacios, Gustavo/I-7773-2015; LEROY, Eric/I-4347-2016 OI Kuhn, Jens H./0000-0002-7800-6045; Palacios, Gustavo/0000-0001-5062-1938; LEROY, Eric/0000-0003-0022-0890 FU Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; Intramural Research Program of the NIH, National Library of Medicine FX We thank Laura Bollinger (IRF-Frederick) for carefully editing the manuscript. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services (DHHS) or of the institutions and companies affiliated with the authors. This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. J.W. performed this work as an employee of Battelle Memorial Institute. Subcontractors to Battelle Memorial Institute who performed this work are: J.H.K., an employee of Tunnell Government Services, Inc. This research was further supported in part by the Intramural Research Program of the NIH, National Library of Medicine (Y.B., O.B., and J.R.B.). NR 22 TC 39 Z9 41 U1 3 U2 29 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD NOV PY 2014 VL 6 IS 11 BP 4760 EP 4799 DI 10.3390/v6114760 PG 40 WC Virology SC Virology GA AU4FL UT WOS:000345565200035 PM 25421896 ER PT J AU Su, LJ Fiehn, O Maruvada, P Moore, SC O'Keefe, SJ Wishart, DS Zanetti, KA AF Su, L. Joseph Fiehn, Oliver Maruvada, Padma Moore, Steven C. O'Keefe, Stephen J. Wishart, David S. Zanetti, Krista A. TI The Use of Metabolomics in Population-Based Research SO ADVANCES IN NUTRITION LA English DT Editorial Material AB The NIH has made a significant commitment through the NIH Common Fund's Metabolomics Program to build infrastructure and capacity for metabolomics research, which should accelerate the field. Given this investment, it is the ideal time to start planning strategies to capitalize on the infrastructure being established. An obvious gap in the literature relates to the effective use of metabolomics in large-population studies. Although published reports from population-based studies are beginning to emerge, the number to date remains relatively small. Yet, there is great potential for using metabolomics in population-based studies to evaluate the effects of nutritional, pharmaceutical, and environmental exposures (the "exposome"); conduct risk assessments; predict disease development; and diagnose diseases. Currently, the majority of the metabolomics studies in human populations are in nutrition or nutrition-related fields. This symposium provided a timely venue to highlight the current state-of-science on the use of metabolomics in population-based research. This session provided a forum at which investigators with extensive experience in performing research within large initiatives, multi-investigator grants, and epidemiology consortia could stimulate discussion and ideas for population-based metabolomics research and, in turn, improve knowledge to help devise effective methods of health research. C1 [Su, L. Joseph; Zanetti, Krista A.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Moore, Steven C.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Fiehn, Oliver] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. [Fiehn, Oliver] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Maruvada, Padma] NIDDK, Div Digest Dis & Nutr, Bethesda, MD USA. [O'Keefe, Stephen J.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Wishart, David S.] Univ Alberta, Dept Biol Sci & Comp Sci, Edmonton, AB, Canada. RP Su, LJ (reprint author), NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. EM sulj@mail.nih.gov RI Moore, Steven/D-8760-2016; OI Moore, Steven/0000-0002-8169-1661; Wishart, David S/0000-0002-3207-2434 FU Breast Cancer Research Stamp Fund; Intramural Research Program of the National Cancer Institute, NIH, U.S. Department of Health and Human Services; NIH [U24 DK097154, R01 CA135379]; NIH Research Biomedical Research Centre based at Imperial College Healthcare NHS Trust; NIH Research Biomedical Research Centre based at Imperial College London; [R37CA70867]; [R01CA082729] FX Supported, in part, by the Breast Cancer Research Stamp Fund, awarded through competitive peer review and the Intramural Research Program of the National Cancer Institute, NIH, U.S. Department of Health and Human Services. The Shanghai Women's Health Study was supported primarily by R37CA70867, and the Shanghai Men's Health Study was supported by R01CA082729. O. F. received funding from NIH grant U24 DK097154 S J. O. is supported by NIH grant R01 CA135379 and the NIH Research Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London (Jeremy Nicholson). NR 11 TC 5 Z9 5 U1 2 U2 38 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD NOV PY 2014 VL 5 IS 6 BP 785 EP 788 DI 10.3945/an.114006494 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AU3WU UT WOS:000345542300011 PM 25398741 ER PT J AU Bilgel, M An, Y Lang, A Prince, J Ferrucci, L Jedynak, B Resnick, SM AF Bilgel, Murat An, Yang Lang, Andrew Prince, Jerry Ferrucci, Luigi Jedynak, Bruno Resnick, Susan M. TI Trajectories of Alzheimer disease-related cognitive measures in a longitudinal sample SO ALZHEIMERS & DEMENTIA LA English DT Article DE Disease progression score; California verbal learning test; Alzheimer's disease; Memory ID VERBAL-LEARNING TEST; NEUROPSYCHOLOGICAL TESTS; MEMORY IMPAIRMENT; PREDICTION; CONVERSION; DIAGNOSIS; AD AB Background: The delineation of the relative temporal trajectories of specific cognitive measures associated with Alzheimer's disease (AD) is important for evaluating preclinical markers and monitoring disease progression. Methods: We characterized the temporal trajectories of measures of verbal episodic memory, short-term visual memory, and mental status using data from 895 participants in the Baltimore Longitudinal Study of Aging. Results: The California Verbal Learning Test (CVLT) immediate recall was the first measure to decline, followed by CVLT delayed recall. However, further along the disease progression scale, CVLT delayed recall and visual memory changed more rapidly than CVLT immediate recall. Conclusions: Our findings reconcile reports of early changes in immediate recall with greater reliance on delayed recall performance in clinical settings. Moreover, the utility of cognitive markers in evaluating AD progression depends on the stage of cognitive decline, suggesting that optimal end-points in therapeutic trials may vary across different stages of the disease process. Published by Elsevier Inc. on behalf of The Alzheimer's Association. C1 [Bilgel, Murat; An, Yang; Ferrucci, Luigi; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Bilgel, Murat; Prince, Jerry] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. [Lang, Andrew; Prince, Jerry] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21205 USA. [Jedynak, Bruno] Johns Hopkins Univ, Dept Appl Math & Stat, Baltimore, MD 21205 USA. RP Bilgel, M (reprint author), NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 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 by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 21 TC 11 Z9 11 U1 1 U2 8 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 NOV PY 2014 VL 10 IS 6 BP 735 EP 742 DI 10.1016/j.jalz.2014.04.520 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AU0KD UT WOS:000345310800018 PM 25035155 ER PT J AU Cuthbert, BN AF Cuthbert, Bruce N. TI Response to Lilienfield SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Research Domain Criteria; RDoC; Intermediate phenotypes; Endophenotypes; Psychopathology AB The article by Lillienfeld in this issue comprises a thoughtful critique of the Research Domain Criteria (RDoC) project initiated by the National Institute of Mental Health, and includes four specific theoretical and methodological challenges along with recommendations to address each one. In this commentary, I briefly consider each of the four challenges in turn, noting points of agreement and also clarifying selected points from the NIMH RDoC perspective. Overall, Lillienfeld's paper represents a valuable contribution to the RDoC literature as research conducted with the new framework continues to accelerate. Published by Elsevier Ltd. C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Cuthbert, BN (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM bcuthber@mail.nih.gov NR 7 TC 4 Z9 5 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 EI 1873-622X J9 BEHAV RES THER JI Behav. Res. Ther. PD NOV PY 2014 VL 62 SI SI BP 140 EP 142 DI 10.1016/j.brat.2014.08.001 PG 3 WC Psychology, Clinical SC Psychology GA AU2TS UT WOS:000345471000014 PM 25294624 ER PT J AU Henriksson, R Backman, CM Harvey, BK Kadyrova, H Bazov, I Shippenberg, TS Bakalkin, G AF Henriksson, Richard Baeckman, Cristina M. Harvey, Brandon K. Kadyrova, Helena Bazov, Igor Shippenberg, Toni S. Bakalkin, Georgy TI PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE PDYN; REST; NRSF; MIR-9; SH-SY5Y cell; Prefrontal cortex ID HUMAN CHRONIC-ALCOHOLICS; IN-VIVO; BINDING-SITES; EXPRESSION; DISEASE; PROTEIN; CELLS; POLYMORPHISMS; DEPENDENCE; REPRESSOR AB The dynorphin kappa-opioid receptor system is implicated in mental health and brain/mental disorders. However, despite accumulating evidence that PDYN and/or dynorphin peptide expression is altered in the brain of individuals with brain/mental disorders, little is known about transcriptional control of PDYN in humans. In the present study, we show that PDYN is targeted by the transcription factor REST in human neuroblastoma SH-SY5Y cells and that that interfering with REST activity increases PDYN expression in these cells. We also show that REST binding to PDYN is reduced in the adult human brain compared to SH-SY5Y cells, which coincides with higher PDYN expression. This may be related to MIR-9 mediated down-regulation of REST as suggested by a strong inverse correlation between REST and MIR-9 expression. Our results suggest that REST represses PDYN expression in SH-SY5Y cells and the adult human brain and may have implications for mental health and brain/mental disorders. (C) 2014 Elsevier B.V. All rights reserved. C1 [Henriksson, Richard; Shippenberg, Toni S.] NIDA, Integrat Neurosci Sect, Integrat Neurosci Res Branch, IRP,NIH, Baltimore, MD 21224 USA. [Henriksson, Richard] Karolinska Inst, Dept Clin Neurosci, S-17176 Stockholm, Sweden. [Henriksson, Richard; Kadyrova, Helena; Bazov, Igor; Bakalkin, Georgy] Uppsala Univ, Uppsala Biomed Ctr, Dept Pharmaceut Biosci, S-75124 Uppsala, Sweden. [Baeckman, Cristina M.] NIDA, Cellular Neurophysiol Sect, Cellular Neurobiol Res Branch, IRP,NIH, Baltimore, MD 21224 USA. [Harvey, Brandon K.] NIDA, Neural Protect & Regenerat Sect, Mol Neuropsychiat Res Branch, IRP,NIH, Baltimore, MD 21224 USA. RP Henriksson, R (reprint author), Uppsala Biomed Ctr, Box 591,Husargatan 3, S-75124 Uppsala, Sweden. EM richard.henriksson@farmbio.uu.se OI Bakalkin, Georgy/0000-0002-8074-9833 FU Intramural Research Program, National Institute on Drug Abuse; Department of Clinical Neuroscience, Karolinska Institutet; Swedish research councils Forskningsradet for halsa, arbetsliv och valfard, FORMAS, VINNOVA and Vetenskapsradet FX This study is dedicated to Toni S. Shippenberg, a devoted mentor and outstanding scientist. Thanks to: 1) doctors Noel Buckley, Elena Cattaneo, Johan Franck, Therese Garrick, Clive Harper, Donna Sheedy, Ranjan Sen, Tatiana Yakovleva and Chiara Zuccato for sharing their expertise; 2) doctors David J. Anderson, Elisa Caffarelli, William J. Freed, Gail Mandel, Raja Jothi, Michael J. Pazin, Igor Ponomarev, Romano Regazzi, Peisu Zhang and Keji Zhao for sharing their material and/or data; and 3) our colleagues Doug Howard, Vanaja Jaligam, Olga Kononenko, Mumtaz M. H. Taqi, Patricia Precht, Daniil Sarkisyan, Lufei Shan, Hiroyuki Watanabe, Andrea Wurster and Katie Zuchowski for their invaluable help. This work was supported by the: 1) Intramural Research Program, National Institute on Drug Abuse; 2) Department of Clinical Neuroscience, Karolinska Institutet; and 3) Swedish research councils Forskningsradet for halsa, arbetsliv och valfard, FORMAS, VINNOVA and Vetenskapsradet. NR 37 TC 3 Z9 3 U1 1 U2 2 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 NOV PY 2014 VL 1839 IS 11 BP 1226 EP 1232 DI 10.1016/j.bbagrm.2014.09.001 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AU3CM UT WOS:000345490400018 PM 25220237 ER PT J AU Hijioka, M Ito, T Igarashi, H Fujimori, N Lee, L Nakamura, T Jensen, RT Takayanagi, R AF Hijioka, Masayuki Ito, Tetsuhide Igarashi, Hisato Fujimori, Nao Lee, Lingaku Nakamura, Taichi Jensen, Robert T. Takayanagi, Ryoichi TI Serum chromogranin A is a useful marker for Japanese patients with pancreatic neuroendocrine tumors SO CANCER SCIENCE LA English DT Article DE Chromogranin A; Japan; pancreatic cancer; pancreatic neuroendocrine tumors; proton pump inhibitors ID NEURON-SPECIFIC ENOLASE; ENDOCRINE NEOPLASIA TYPE-1; ETHNIC-DIFFERENCES; PLASMA; CARCINOMA; DIAGNOSIS; DISEASE; UTILITY; CANCER; DISCONTINUATION AB Although chromogranin A (CGA) is a useful marker for pancreatic neuroendocrine tumors (pNET) in the West, its usefulness in Japanese populations is unclear. To assess this, we evaluated the serum CGA levels in 189 patients with various pancreatic diseases, including proven pNET (n=69), pancreatic cancer (PC) (n=50), chronic pancreatitis (CP) (n=50) and autoimmune pancreatitis (AIP) (n=20), and 112 normal controls (controls) using an ELISA kit. The mean CGA level of patients with pNET was significantly higher than any of the other groups (407.8 +/- 984.6ng/mL [pNET] vs 91.8 +/- 101.8ng/mL [PC], 93.6 +/- 57.5ng/mL [CP], 69.9 +/- 52.4ng/mL [AIP] and 62.5 +/- 48.3ng/mL [controls]). Limiting the analysis to patients not using proton pump inhibitors (PPI), the CGA level of patients with PC or CP was not significantly different compared with the controls. Discriminant analysis revealed that the best cut-off value of CGA to distinguish patients with pNET from the controls was 78.7ng/mL, with a sensitivity and specificity of 53.6% and 78.6%, respectively. In patients with pNET, significant factors associating with elevated CGA levels were tumor classification, tumor size, and the presence of liver metastases in univariate analysis as well as PPI use and the presence of liver metastases in multivariate analysis. We show that CGA is a useful marker for diagnosing pNET in Japanese populations and for distinguishing patients with pNET from patients with other pancreatic diseases. The increased use of CGA in Japan will likely be a helpful tool in managing these patients, as found in the West. C1 [Hijioka, Masayuki; Ito, Tetsuhide; Igarashi, Hisato; Fujimori, Nao; Lee, Lingaku; Nakamura, Taichi; Takayanagi, Ryoichi] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioreguratory Sci, Fukuoka 8128582, Japan. [Nakamura, Taichi; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP Ito, T (reprint author), Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioreguratory Sci, 3-1-1 Maidashi, Fukuoka 8128582, Japan. EM itopapa@intmed3.med.kyushu-u.ac.jp RI U-ID, Kyushu/C-5291-2016 NR 52 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1347-9032 EI 1349-7006 J9 CANCER SCI JI Cancer Sci. PD NOV PY 2014 VL 105 IS 11 BP 1464 EP 1471 DI 10.1111/cas.12533 PG 8 WC Oncology SC Oncology GA AU1HL UT WOS:000345371600012 PM 25220535 ER PT J AU Keijzers, G Maynard, S Shamanna, RA Rasmussen, LJ Croteau, DL Bohr, VA AF Keijzers, Guido Maynard, Scott Shamanna, Raghavendra A. Rasmussen, Lene Juel Croteau, Deborah L. Bohr, Vilhelm A. TI The role of RecQ helicases in non-homologous end-joining SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Alternative end-joining; Ku70/80; microhomology-mediated end-joining; non-homologous end-joining; RecQ helicases; telomere ID DOUBLE-STRAND BREAKS; ROTHMUND-THOMSON-SYNDROME; DEPENDENT PROTEIN-KINASE; WERNER-SYNDROME PROTEIN; CLASS-SWITCH RECOMBINATION; BASE EXCISION-REPAIR; BLOOMS-SYNDROME PROTEIN; OXIDATIVE DNA-DAMAGE; RNA-POLYMERASE-II; SYNDROME GENE-PRODUCT AB DNA double-strand breaks are highly toxic DNA lesions that cause genomic instability, if not efficiently repaired. RecQ helicases are a family of highly conserved proteins that maintain genomic stability through their important roles in several DNA repair pathways, including DNA double-strand break repair. Double-strand breaks can be repaired by homologous recombination (HR) using sister chromatids as templates to facilitate precise DNA repair, or by an HR-independent mechanism known as non-homologous end-joining (NHEJ) (error-prone). NHEJ is a non-templated DNA repair process, in which DNA termini are directly ligated. Canonical NHEJ requires DNA-PKcs and Ku70/80, while alternative NHEJ pathways are DNA-PKcs and Ku70/80 independent. This review discusses the role of RecQ helicases in NHEJ, alternative (or back-up) NHEJ (B-NHEJ) and microhomology-mediated end-joining (MMEJ) in V(D)J recombination, class switch recombination and telomere maintenance. C1 [Keijzers, Guido; Maynard, Scott; Rasmussen, Lene Juel; Bohr, Vilhelm A.] Univ Copenhagen, Dept Cellular & Mol Med, Ctr Hlth Aging, Copenhagen, Denmark. [Shamanna, Raghavendra A.; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Intramural Research Program of the NIH, National Institute on Aging; Nordea Foundation FX This work was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, as well as a grant from the Nordea Foundation. NR 179 TC 7 Z9 7 U1 2 U2 14 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-9238 EI 1549-7798 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD NOV-DEC PY 2014 VL 49 IS 6 BP 463 EP 472 DI 10.3109/10409238.2014.942450 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU3FM UT WOS:000345497900002 PM 25048400 ER PT J AU Enoch, MA Rosser, AA Zhou, Z Mash, DC Yuan, Q Goldman, D AF Enoch, M. -A. Rosser, A. A. Zhou, Z. Mash, D. C. Yuan, Q. Goldman, D. TI Expression of glutamatergic genes in healthy humans across 16 brain regions; altered expression in the hippocampus after chronic exposure to alcohol or cocaine SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Alcoholism; GABAB1 receptor subunit; GABBR1; GRIA4; GRIK3; GRIN2B; GRIN2D; GRM3; GRM4; NMDA receptors; RNA-Seq ID GABA(B) RECEPTORS; NMDA; ETHANOL; DEPENDENCE; ADDICTION; POLYMORPHISM; HOMEOSTASIS; BEHAVIOR; TARGETS; CONTEXT AB We analyzed global patterns of expression in genes related to glutamatergic neurotransmission (glutamatergic genes) in healthy human adult brain before determining the effects of chronic alcohol and cocaine exposure on gene expression in the hippocampus. RNA-Seq data from BrainSpan' was obtained across 16 brain regions from nine control adults. We also generated RNA-Seq data from postmortem hippocampus from eight alcoholics, eight cocaine addicts and eight controls. Expression analyses were undertaken of 28 genes encoding glutamate ionotropic (AMPA, kainate, NMDA) and metabotropic receptor subunits, together with glutamate transporters. The expression of each gene was fairly consistent across the brain with the exception of the cerebellum, the thalamic mediodorsal nucleus and the striatum. GRIN1, encoding the essential NMDA subunit, had the highest expression across all brain regions. Six factors accounted for 84% of the variance in global gene expression. GRIN2B (encoding GluN2B), was up-regulated in both alcoholics and cocaine addicts (FDR corrected P=0.008). Alcoholics showed up-regulation of three genes relative to controls and cocaine addicts: GRIA4 (encoding GluA4), GRIK3 (GluR7) and GRM4 (mGluR4). Expression of both GRM3 (mGluR3) and GRIN2D (GluN2D) was up-regulated in alcoholics and down-regulated in cocaine addicts relative to controls. Glutamatergic genes are moderately to highly expressed throughout the brain. Six factors explain nearly all the variance in global gene expression. At least in the hippocampus, chronic alcohol use largely up-regulates glutamatergic genes. The NMDA GluN2B receptor subunit might be implicated in a common pathway to addiction, possibly in conjunction with the GABAB1 receptor subunit. C1 [Enoch, M. -A.; Rosser, A. A.; Zhou, Z.; Yuan, Q.; Goldman, D.] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Mash, D. C.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. RP Enoch, MA (reprint author), NIAAA, NIH, DICBR, LNG, 5625 Fishers Lane,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH [ZIA AA000306-08]; US PHS Grant from The National Institution on Drug Abuse [DA06227] FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH (ZIA AA000306-08) and by US PHS Grant from The National Institution on Drug Abuse DA06227 for the annotated human postmortem specimens from the University of Miami Brain Endowment BankTM. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. None of the authors have any potential conflicts of interest. NR 37 TC 14 Z9 14 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD NOV PY 2014 VL 13 IS 8 BP 758 EP 768 DI 10.1111/gbb.12179 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AU3MO UT WOS:000345517700004 PM 25262781 ER PT J AU Lenroot, RK Blumenthal, JD Wallace, GL Clasen, LS Lee, NR Giedd, JN AF Lenroot, R. K. Blumenthal, J. D. Wallace, G. L. Clasen, L. S. Lee, N. R. Giedd, J. N. TI A case-control study of brain structure and behavioral characteristics in 47,XXX syndrome SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Trisomy X syndrome; XXX; sex chromosome aneuploidy; magnetic resonance imaging; brain; children; adolescents; X chromosome ID SEX-CHROMOSOME ABNORMALITIES; X-LINKED GENES; KLINEFELTER-SYNDROME; SOCIAL BRAIN; TRISOMY-X; MRI DATA; CHILDREN; INACTIVATION; INDIVIDUALS; VARIABILITY AB Trisomy X, the presence of an extra X chromosome in females (47,XXX), is a relatively common but under-recognized chromosomal disorder associated with characteristic cognitive and behavioral features of varying severity. The objective of this study was to determine whether there were neuroanatomical differences in girls with Trisomy X that could relate to cognitive and behavioral differences characteristic of the disorder during childhood and adolescence. MRI scans were obtained on 35 girls with Trisomy X (mean age 11.4, SD 5.5) and 70 age- and sex-matched healthy controls. Cognitive and behavioral testing was also performed. Trisomy X girls underwent a semi-structured psychiatric interview. Regional brain volumes and cortical thickness were compared between the two groups. Total brain volume was significantly decreased in subjects with Trisomy X, as were all regional volumes with the exception of parietal gray matter. Differences in cortical thickness had a mixed pattern. The subjects with Trisomy X had thicker cortex in bilateral medial prefrontal cortex and right medial temporal lobe, but decreased cortical thickness in both lateral temporal lobes. The most common psychiatric disorders present in this sample of Trisomy X girls included anxiety disorders (40%), attention-deficit disorder (17%) and depressive disorders (11%). The most strongly affected brain regions are consistent with phenotypic characteristics such as language delay, poor executive function and heightened anxiety previously described in population-based studies of Trisomy X and also found in our sample. C1 [Lenroot, R. K.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Lenroot, R. K.] Neurosci Res Australia, Sydney, NSW, Australia. [Blumenthal, J. D.; Wallace, G. L.; Clasen, L. S.; Lee, N. R.; Giedd, J. N.] NIMH, Child Psychiat Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Blumenthal, JD (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 4C110,MSC-1367,10 Ctr Dr, Bethesda, MD 20892 USA. EM jb364e@nih.gov RI Giedd, Jay/J-9644-2015; Lee, Nancy/M-7492-2016; OI Giedd, Jay/0000-0003-2002-8978; Lee, Nancy/0000-0002-6663-0713; Wallace, Gregory/0000-0003-0329-5054 FU Intramural Research Program of the NIMH [protocol 89-M-0006, NCT00001246] FX This research was supported by the Intramural Research Program of the NIMH (protocol 89-M-0006; NCT00001246). We thank the families who participated in this research and the Trisomy X support group (groups.yahoo.com/neo/groups/trisomyx/info), American Association for Klinefelter Syndrome Information and Support (aaksis.org), and Klinefelter Syndrome and Associates (genetic.org) for assisting us in the recruitment of participants. The authors have no financial relationships relevant to this article to disclose. The authors have no conflicts of interest to disclose. R.K.L. and J.D.B. conceptualized and designed the study, coordinated and supervised data collection, carried out the analyses, drafted and revised the initial manuscript, and approved the final manuscript as submitted. G.L.W., L.S.C., N.R.L. and J.N.G. selected the data collection instruments, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. NR 48 TC 2 Z9 2 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD NOV PY 2014 VL 13 IS 8 BP 841 EP 849 DI 10.1111/gbb.12180 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AU3MO UT WOS:000345517700013 PM 25287572 ER PT J AU Chandler, RJ LaFave, MC Varshney, GK Elkahloun, AG Burgess, SM Venditti, CP AF Chandler, R. J. LaFave, M. C. Varshney, G. K. Elkahloun, A. G. Burgess, S. M. Venditti, C. P. TI Genotoxicity after adeno-associated virus (AAV) gene therapy is dependent upon dose, treatment age and enhancer-promoter selection SO HUMAN GENE THERAPY LA English DT Meeting Abstract CT ESGCT and NVGCT Collaborative Congress CY OCT 23-26, 2014 CL The Hague, NETHERLANDS SP European Soc Gene & Cell Therapy, Netherlands Soc Gene & Cell Therapy C1 [Chandler, R. J.; LaFave, M. C.; Varshney, G. K.; Elkahloun, A. G.; Burgess, S. M.; Venditti, C. P.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD NOV 1 PY 2014 VL 25 IS 11 MA P129 BP A97 EP A97 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AT2OR UT WOS:000344774700295 ER PT J AU Witt, CM Withers, SR Grant, S Lauer, MS Tunis, S Berman, BM AF Witt, Claudia M. Withers, Shelly Rafferty Grant, Suzanne Lauer, Michael S. Tunis, Sean Berman, Brian M. TI What Can Comparative Effectiveness Research Contribute to Integrative Health in International Perspective? SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Editorial Material ID PRAGMATIC RANDOMIZED-TRIAL; ACUPUNCTURE; HEADACHE; POLICY; PAIN AB The interest in Comparative Effectiveness Research (CER) in the international community is growing. A panel titled "What Can Comparative Effectiveness Research Contribute to Integrative Health in International Perspective?" took place at the 3rd International Research Congress on Integrative Medicine and Health in Portland, Oregon, in 2012. The presentations at this panel highlighted different perspectives on CER, including the funders' and the stakeholders' perspectives from the United States, as well as experiences with economic evaluations from Australia and pragmatic trials in Europe. The funders' perspective emphasized the need for innovation and controlling costs in large-scale studies. The stakeholder's perspective stressed the need to gather the input of stakeholders in shaping the framework for more informative, more decision-maker-driven research. Several examples of cost-effectiveness analyses were offered from Australia. The importance of balancing rigor and pragmatism was also discussed in a presentation of the efficacy-effectiveness continuum. A wide-ranging discussion explored additional questions concerning the translation of evidence into practice; the effect of pragmatic trials on funding or policy; evidentiary distinctions between and among pragmatic trials and traditional randomized clinical trials; and the multiple roles of stakeholders, particularly in generating new information and knowledge. The presentations and discussions showed that more development of methods is needed. This includes developments on study design and statistical approaches, as well as methods for stakeholder involvement and mechanisms to bring these results into practice. C1 [Witt, Claudia M.] Univ Zurich Hosp, Inst Complementary & Integrat Med, CH-8091 Zurich, Switzerland. [Witt, Claudia M.] Charite, Inst Social Med Epidemiol & Hlth Econ, D-13353 Berlin, Germany. [Withers, Shelly Rafferty; Berman, Brian M.] Inst Integrat Hlth, Baltimore, MD USA. [Grant, Suzanne] Univ Western Sydney, Ctr Complementary Med Res, Sydney, NSW, Australia. [Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Tunis, Sean] Ctr Med Technol Policy, Baltimore, MD USA. [Berman, Brian M.] Univ Maryland, Sch Med, Ctr Integrat Med, Baltimore, MD 21201 USA. RP Witt, CM (reprint author), Univ Zurich Hosp, Inst Complementary & Integrat Med, Ramistr 100, CH-8091 Zurich, Switzerland. EM claudia.witt@uzh.ch OI Rafferty Withers, Shelly/0000-0003-2833-9471 NR 22 TC 1 Z9 1 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 EI 1557-7708 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD NOV 1 PY 2014 VL 20 IS 11 BP 874 EP 880 DI 10.1089/acm.2014.0073 PG 7 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA AU6AM UT WOS:000345684500010 PM 25372702 ER PT J AU Ibrahim, WG El Khouli, RH Abd-Elmoniem, KZ Matta, JR McAreavey, D Gharib, AM AF Ibrahim, Wael G. El Khouli, Riham H. Abd-Elmoniem, Khaled Z. Matta, Jatin Raj McAreavey, Dorothea Gharib, Ahmed M. TI Optimization of Free-Breathing Whole-Heart 3-Dimensional Cardiac Magnetic Resonance Imaging at 3 Tesla to Identify Coronary Vein Anatomy and to Compare With Multidetector Computed Tomography SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE coronary veins; multidetector computed tomography; circulation; magnetic resonance imaging; imaging ID TRANSVENOUS MITRAL ANNULOPLASTY; VENOUS SYSTEM; RESYNCHRONIZATION THERAPY; NONINVASIVE VISUALIZATION; MR-ANGIOGRAPHY; ARTERY-DISEASE; CONTRAST; FAILURE; SINUS; VENOGRAPHY AB Objective: This study optimizes use of 3-T magnetic resonance imaging (MRI) to delineate coronary venous anatomy and compares 3-TMRI with multidetector computed tomography (MDCT) measurements. Methods: The study population included 37 consecutive subjects (22 men, 19-71 years old). Whole-heart contrast-enhanced MRI images at 3 Twere acquired using segmented k-space gradient echo with inversion recovery prepared technique. The MDCT images were obtained using nonionic iodinated contrast. Results: The coronary sinus and great cardiac, posterior interventricular, and anterior interventricular veins were visualized in 100% of cases by both MRI and MDCT. Detection of the posterior vein of the left ventricle and the left marginal vein by MRI was 97% and 81%, respectively. Bland-Altman plots showed agreement in ostial diameter measured by both modalities with correlation coefficients ranging from 0.5 to 0.76. Vein length and distances also agreed closely. Conclusions: Free-breathing whole-heart 3-dimensional MRI at 3 T provides high-spatial-resolution images and could offer an alternative imaging technique instead of MDCT scans. C1 [Ibrahim, Wael G.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [El Khouli, Riham H.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Abd-Elmoniem, Khaled Z.; Matta, Jatin Raj; Gharib, Ahmed M.] NIDDK, Bethesda, MD 20892 USA. [McAreavey, Dorothea] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Gharib, AM (reprint author), 10 Ctr Dr,CRC Room 3-5340, Bethesda, MD 20892 USA. EM agharib@mail.nih.gov RI Gharib, Ahmed/O-2629-2016; Abd-Elmoniem, Khaled/B-9289-2008 OI Gharib, Ahmed/0000-0002-2476-481X; Abd-Elmoniem, Khaled/0000-0002-1001-1702 FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Biomedical Imaging and Bioengineering; National Institutes of Health Clinical Center FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Biomedical Imaging and Bioengineering, and National Institutes of Health Clinical Center. NR 37 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 EI 1532-3145 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD NOV-DEC PY 2014 VL 38 IS 6 BP 941 EP 948 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AU2EW UT WOS:000345430200020 PM 24983436 ER PT J AU Sunassee, SN Ransom, T Henrich, CJ Beutler, JA Covell, DG McMahon, JB Gustafson, KR AF Sunassee, Suthananda N. Ransom, Tanya Henrich, Curtis J. Beutler, John A. Covell, David G. McMahon, James B. Gustafson, Kirk R. TI Steroidal Alkaloids from the Marine Sponge Corticium niger That Inhibit Growth of Human Colon Carcinoma Cells SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID ADJUVANT THERAPY; CANCER; SIMPLEX AB Bioinformatic analysis of data from the NCI-60 cell cytotoxicity screen revealed a subset of extracts that showed selective cytotoxic activity toward human colon carcinoma cell lines. Bioassay-guided fractionation of a colon cancer selective extract from a Philippines collection of the marine sponge Corticium niger provided two new steroidal alkaloids, plakinamines N (1) and O (2), along with two known compounds of the plakinamine class (3, 4). The structures of these compounds were elucidated by interpretation of combined MS and NMR spectroscopic data. Plakinamines N (1), O (2), and J (4) were tested for antiproliferative activity in the NCI-60 screen, and they showed enhanced inhibitory effects against all of the colon cell lines with mean GI(50) values of 11.5, 2.4, and 1.4 mu M, respectively. C1 [Sunassee, Suthananda N.; Ransom, Tanya; Henrich, Curtis J.; Beutler, John A.; McMahon, James B.; Gustafson, Kirk R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Henrich, Curtis J.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Basic Sci Program, Frederick, MD 21702 USA. [Covell, David G.] NCI, Screening Technol Branch, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Gustafson, KR (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM gustafki@mail.nih.gov OI Sunassee, Suthananda/0000-0002-5014-7110 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HH5N261200800001E] FX We thank D. Newman (NCI) for organizing and documenting the collection, along with the Natural Products Support Group at NCI-Frederick for extraction, and S. Tarasov and M. Dyba (Biophysics Resource Core, Structural Biophysics Laboratory, CCR) and H. Bokesch (MTL) for assistance with highresolution mass spectrometry. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project was also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HH5N261200800001E. 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. NR 32 TC 5 Z9 5 U1 1 U2 17 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 NOV PY 2014 VL 77 IS 11 BP 2475 EP 2480 DI 10.1021/np500556t PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA AU2UE UT WOS:000345472100021 PM 25338277 ER PT J AU Zlott, D Farley, J Guidotti, M AF Zlott, Dan Farley, Joel Guidotti, Marti TI Era of specialty pharmaceuticals expands opportunities for pharmacists SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT Editorial Material ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; BLOCKADE C1 [Zlott, Dan] NCI, Surg & Immunotherapy Programs, NIH, Bethesda, MD 20892 USA. RP Zlott, D (reprint author), NCI, Surg & Immunotherapy Programs, NIH, Bethesda, MD 20892 USA. EM zlottd@cc.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 EI 1544-3450 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD NOV-DEC PY 2014 VL 54 IS 6 BP 578 EP 579 DI 10.1331/JAPhA.2014.14540 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU4SF UT WOS:000345601100003 PM 25379979 ER PT J AU Gormally, MV Dexheimer, TS Marsico, G Sanders, DA Lowe, C Matak-Vinkovic, D Michael, S Jadhav, A Rai, G Maloney, DJ Simeonov, A Balasubramanian, S AF Gormally, Michael V. Dexheimer, Thomas S. Marsico, Giovanni Sanders, Deborah A. Lowe, Christopher Matak-Vinkovic, Dijana Michael, Sam Jadhav, Ajit Rai, Ganesha Maloney, David J. Simeonov, Anton Balasubramanian, Shankar TI Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition SO NATURE COMMUNICATIONS LA English DT Article ID BREAST-CANCER CELLS; FORKHEAD BOX M1; PROTEASOME INHIBITORS; EXPRESSION; PROLIFERATION; THIOSTREPTON; RECOGNITION; THERAPY; TARGETS; DNA AB The transcription factor FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA-binding domain (DBD) and activates proliferation- and differentiation-associated genes. Aberrant overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers. Here-from a high-throughput screen applied to a library of 54,211 small molecules-we identify novel small molecule inhibitors of FOXM1 that block DNA binding. One of the identified compounds, FDI-6 (NCGC00099374), is characterized in depth and is shown to bind directly to FOXM1 protein, to displace FOXM1 from genomic targets in MCF-7 breast cancer cells, and induce concomitant transcriptional downregulation. Global transcript profiling of MCF-7 cells by RNA-seq shows that FDI-6 specifically downregulates FOXM1-activated genes with FOXM1 occupancy confirmed by ChIP-PCR. This small molecule-mediated effect is selective for FOXM1-controlled genes with no effect on genes regulated by homologous forkhead family factors. C1 [Balasubramanian, Shankar] Univ Cambridge, Univ Chem Lab, Dept Chem, Cambridge CB2 1EW, England. [Gormally, Michael V.; Lowe, Christopher; Matak-Vinkovic, Dijana; Balasubramanian, Shankar] Univ Cambridge, Univ Chem Lab, Dept Chem, Cambridge CB2 1EW, England. [Gormally, Michael V.; Marsico, Giovanni; Sanders, Deborah A.; Balasubramanian, Shankar] Cambridge Inst, Li Ka Shing Ctr, Canc Res UK, Cambridge CB2 0RE, England. [Gormally, Michael V.; Dexheimer, Thomas S.; Michael, Sam; Jadhav, Ajit; Rai, Ganesha; Maloney, David J.; Simeonov, Anton] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Balasubramanian, S (reprint author), Univ Cambridge, Univ Chem Lab, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM sb10031@cam.ac.uk OI Gormally, Michael/0000-0002-0414-4234 FU Churchill Scholarship; NIH OxCam Fellowship; Wellcome Trust Senior Investigator Award; Cancer Research UK; National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the National Institutes of Health Common Fund [U54MH084681] FX We thank Dr Neil M. Bell for advice and assistance in protein purification. M.V.G. is supported by a Churchill Scholarship and an NIH OxCam Fellowship. The Balasubramanian lab is supported by a Wellcome Trust Senior Investigator Award and core funding from Cancer Research UK. T.S.D., M.G., G.R., A.S., A.J. and D.J.M. were supported by the intramural research programme of the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the National Institutes of Health Common Fund (grant U54MH084681). NR 59 TC 19 Z9 19 U1 2 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 NOV PY 2014 VL 5 AR 5165 DI 10.1038/ncomms6165 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5BO UT WOS:000345622300001 PM 25387393 ER PT J AU Kim, A Hartman, IZ Poore, B Boronina, T Cole, RN Song, N Ciudad, MT Caspi, RR Jaraquemada, D Sadegh-Nasseri, S AF Kim, AeRyon Hartman, Isamu Z. Poore, Brad Boronina, Tatiana Cole, Robert N. Song, Nianbin Teresa Ciudad, M. Caspi, Rachel R. Jaraquemada, Dolores Sadegh-Nasseri, Scheherazade TI Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources SO NATURE COMMUNICATIONS LA English DT Article ID MHC CLASS-II; MYELIN BASIC-PROTEIN; T-CELL EPITOPES; COMPLEX CLASS-II; HLA-DM; HISTOCOMPATIBILITY MOLECULES; LYSOSOMAL PROTEOLYSIS; MULTIPLE-SCLEROSIS; PEPTIDE COMPLEXES; CRYSTAL-STRUCTURE AB Immunodominant epitopes are few selected epitopes from complex antigens that initiate T-cell responses. Here to provide further insights into this process, we use a reductionist cell-free antigen-processing system composed of defined components. We use the system to characterize steps in antigen processing of pathogen-derived proteins or autoantigens and we find distinct paths for peptide processing and selection. Autoantigen-derived immunodominant epitopes are resistant to digestion by cathepsins, whereas pathogen-derived epitopes are sensitive. Sensitivity to cathepsins enforces capture of pathogen-derived epitopes by major histocompatibility complex class II (MHC class II) before processing, and resistance to HLA-DM-mediated-dissociation preserves the longevity of those epitopes. We show that immunodominance is established by higher relative abundance of the selected epitopes, which survive cathepsin digestion either by binding to MHC class II and resisting DM-mediated- dissociation, or being chemically resistant to cathepsins degradation. Non-dominant epitopes are sensitive to both DM and cathepsins and are destroyed. C1 [Kim, AeRyon; Poore, Brad; Sadegh-Nasseri, Scheherazade] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Hartman, Isamu Z.; Song, Nianbin; Sadegh-Nasseri, Scheherazade] Johns Hopkins Univ, Sch Med, Grad Program Immunol, Baltimore, MD 21205 USA. [Boronina, Tatiana; Cole, Robert N.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Mass Spectrometry & Prote Facil, Baltimore, MD 21205 USA. [Teresa Ciudad, M.; Jaraquemada, Dolores] Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Dept Cell Biol Physiol & Immunol, Cellular Immunol Lab, E-08193 Barcelona, Spain. [Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Sadegh-Nasseri, S (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. EM ssadegh@jhmi.edu OI Sadegh-Nasseri, Scheherazade/0000-0002-8127-1720; Caspi, Rachel/0000-0002-7140-7671 FU NIAID [R01AI063764, R21 AI101987]; NIGM [GM053549]; Johns Hopkins Malaria Research Institute; Johns Hopkins University Rheumatology T32; Graduate Immunology T32 Fellowship; National Science Foundation; Spanish Ministry of Science [SAF2009-10622]; F.P.I. fellowship [BES2001-03963] FX S.S.-N. and A.K. wish to dedicate this paper to the memory of late Eli Sercarz who proposed the 'determinant capture' theory. We thank Drs Emil Unanue and Lawrence Stern for reading of the manuscript and discussions and the gift of anti DR Ab, Champ2. This work was supported by grants from NIAID (R01AI063764, R21 AI101987) and NIGM (GM053549), a pilot grant from Johns Hopkins Malaria Research Institute to S.S.-N., a Johns Hopkins University Rheumatology T32, a Graduate Immunology T32 Fellowship to A.K. and a National Science Foundation predoctoral student award to I.Z.H. M.T.C. and D.J. were supported by a grant, SAF2009-10622 from the Spanish Ministry of Science to D.J. and the F.P.I. fellowship BES2001-03963 to M.T.C. We wish to thank our colleagues in the Department of Pathology, Drs Hui Zhang and Punit Sha for peptide sequence identification shown in Supplementary Figures 5-8 and Dr Daniela Cihakova, JHU Pathology Department, for the gift of myosin peptide, and Mary J Mattapallil for uveitis peptide. BEI resources provided influenza recombinant proteins and NIAID Tetramer Facility for DR3 and DR4 monomers, Dr Dennis Zaller, MERCK, provided the original HLA-DR1 Tg mice. NR 63 TC 8 Z9 8 U1 0 U2 5 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 NOV PY 2014 VL 5 AR 5369 DI 10.1038/ncomms6369 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5KJ UT WOS:000345645400001 PM 25413013 ER PT J AU Yoon, JH De, S Srikantan, S Abdelmohsen, K Grammatikakis, I Kim, J Kim, KM Noh, JH White, EJF Martindale, JL Yang, XL Kang, MJ Wood, WH Noren Hooten, N Evans, MK Becker, KG Tripathi, V Prasanth, KV Wilson, GM Tuschl, T Ingolia, NT Hafner, M Gorospe, M AF Yoon, Je-Hyun De, Supriyo Srikantan, Subramanya Abdelmohsen, Kotb Grammatikakis, Ioannis Kim, Jiyoung Kim, Kyoung Mi Noh, Ji Heon White, Elizabeth J. F. Martindale, Jennifer L. Yang, Xiaoling Kang, Min-Ju Wood, William H. Noren Hooten, Nicole Evans, Michele K. Becker, Kevin G. Tripathi, Vidisha Prasanth, Kannanganattu V. Wilson, Gerald M. Tuschl, Thomas Ingolia, Nicholas T. Hafner, Markus Gorospe, Myriam TI PAR-CLIP analysis uncovers AUF1 impact on target RNA fate and genome integrity SO NATURE COMMUNICATIONS LA English DT Article ID MESSENGER-RNA; BINDING-PROTEIN; POSTTRANSCRIPTIONAL REGULATION; TELOMERE MAINTENANCE; WIDE IDENTIFICATION; IN-VITRO; STABILITY; TRANSLATION; DECAY; HUR AB Post-transcriptional gene regulation is robustly regulated by RNA-binding proteins (RBPs). Here we describe the collection of RNAs regulated by AUF1 (AU-binding factor 1), an RBP linked to cancer, inflammation and aging. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis reveals that AUF1 primarily recognizes U-/GU-rich sequences in mRNAs and noncoding RNAs and influences target transcript fate in three main directions. First, AUF1 lowers the steady-state levels of numerous target RNAs, including long noncoding RNA NEAT1, in turn affecting the organization of nuclear paraspeckles. Second, AUF1 does not change the abundance of many target RNAs, but ribosome profiling reveals that AUF1 promotes the translation of numerous mRNAs in this group. Third, AUF1 unexpectedly enhances the steady-state levels of several target mRNAs encoding DNA-maintenance proteins. Through its actions on target RNAs, AUF1 preserves genomic integrity, in agreement with the AUF1-elicited prevention of premature cellular senescence. C1 [Yoon, Je-Hyun; De, Supriyo; Srikantan, Subramanya; Abdelmohsen, Kotb; Grammatikakis, Ioannis; Kim, Jiyoung; Kim, Kyoung Mi; Noh, Ji Heon; Martindale, Jennifer L.; Yang, Xiaoling; Kang, Min-Ju; Wood, William H.; Becker, Kevin G.; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [White, Elizabeth J. F.; Wilson, Gerald M.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Noren Hooten, Nicole; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Tripathi, Vidisha; Prasanth, Kannanganattu V.] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL 61801 USA. [Tuschl, Thomas; Hafner, Markus] Rockefeller Univ, Howard Hughes Med Inst, Lab RNA Mol Biol, New York, NY 10065 USA. [Ingolia, Nicholas T.] Carnegie Inst Sci, Dept Embryol, Baltimore, MD 21218 USA. [Hafner, Markus] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Yoon, JH (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM yoonjehyun@gmail.com; GorospeM@grc.nia.nih.gov OI Hafner, Markus/0000-0002-4336-6518; De, Supriyo/0000-0002-2075-7655 FU American Heart Association [11PRE6900008]; NIH [R01 CA102428, R01 GM088252]; Charles H. Revson Foundation; NIAMS-IRP; NIH; Howard Hughes Medical Institute (HHMI); Starr Cancer Foundation; Ruth L. Kirschstein National Research Service Award [GM080853]; Searle Scholars Program FX We thank R.J. Schneider (NY University), H.Y. Chang (Stanford University), J.L. Rinn (Broad Institute), J.T. Lee and H. Sunwoo (Harvard Medical School), T. Hirose (National Institute of Advanced Industrial Science and Technology, Japan) and N. Mukherjee (Max Delbruck Center for Molecular Medicine, Germany) for providing reagents and information. J.-H.Y., S.S., S.D., I.G., M.-J.K., W.H.W., K.G.B., K.A., J.K., K.M.K., J.H.N., J.L. M., X.Y., N.N.H., M.K.E. and M.G. were supported by the NIA-IRP, NIH. E.J.F.W. and G.M.W. were supported by American Heart Association Grant 11PRE6900008 and NIH R01 CA102428. V.T. and K.V.P. were supported by NIH R01 GM088252. M.H. was supported by the Charles H. Revson Foundation and the NIAMS-IRP, NIH, and T.T. was supported by Howard Hughes Medical Institute (HHMI), the Starr Cancer Foundation and NIH. N.T.I. was supported by a Ruth L. Kirschstein National Research Service Award (GM080853) and the Searle Scholars Program. NR 54 TC 26 Z9 27 U1 0 U2 7 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 NOV PY 2014 VL 5 AR 5248 DI 10.1038/ncomms6248 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5NL UT WOS:000345653700001 PM 25366541 ER PT J AU Simmons, K Ortiz, R Kossowsky, J Krummenacher, P Grillon, C Pine, D Colloca, L AF Simmons, Kanesha Ortiz, Robin Kossowsky, Joe Krummenacher, Peter Grillon, Christian Pine, Daniel Colloca, Luana TI Pain and placebo in pediatrics: A comprehensive review of laboratory and clinical findings SO PAIN LA English DT Review DE Age; Analgesia; Children; Clinical applications; Conditioning; Development; Expectations ID DEFICIT HYPERACTIVITY DISORDER; RANDOMIZED CONTROLLED-TRIAL; AUTISM SPECTRUM DISORDERS; DOUBLE-BLIND; DOSE REDUCTION; CHILDREN; ADOLESCENTS; ANALGESIA; EFFICACY; RESPONSES AB Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet almost all research investigating the mechanisms and implications of the placebo analgesia are based on adult research. After highlighting crucial aspects that need to be considered in studying pain modulation in children, this comprehensive review examines studies related to pain modulation with an emphasis on factors such as age, neural development and pain measures. We critically discuss psychological mechanisms underlying placebo effects, including (1) verbally induced expectations, (2) conditioning and learning mechanisms, and (3) child-parent-physician interactions. Taken together, research suggests that placebo mechanisms can affect therapeutic outcomes and potentially be exploited clinically to improve clinical outcomes in pediatric population. Recommendations for further investigating the mechanistic bases and harnessing placebo effects for supportive therapeutic applications are given. Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 [Simmons, Kanesha; Ortiz, Robin; Grillon, Christian; Pine, Daniel; Colloca, Luana] NIMH, Bethesda, MD 20892 USA. [Kossowsky, Joe] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Kossowsky, Joe; Krummenacher, Peter] Univ Basel, Dept Psychol Clin Psychol & Psychotherapy, Basel, Switzerland. [Krummenacher, Peter] Univ Zurich, Coll Helveticum, Zurich, Switzerland. [Krummenacher, Peter] ETH, Zurich, Switzerland. [Colloca, Luana] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Colloca, Luana] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. RP Colloca, L (reprint author), NIH, Ctr Clin, 10 Ctr Dr,10-1C154, Bethesda, MD 20892 USA. EM luana.colloca@nih.gov OI Colloca, Luana/0000-0002-6503-4709 FU Intramural Program of the National Center for Complementary and Alternative Medicine; Intramural Program of the National Institute of Mental Health; Clinical Center at the National Institutes of Health; Swiss National Science Foundation [P2BSP1_148628] FX This research was supported by the Intramural Program of the National Center for Complementary and Alternative Medicine, the Intramural Program of the National Institute of Mental Health and the Clinical Center at the National Institutes of Health. JK was supported by a Swiss National Science Foundation grant project (P2BSP1_148628). The authors are grateful to Franklin G. Miller for helpful comments and discussion. NR 81 TC 5 Z9 5 U1 3 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2014 VL 155 IS 11 BP 2229 EP 2235 DI 10.1016/j.pain.2014.08.036 PG 7 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA AU1YM UT WOS:000345413400005 PM 25180010 ER PT J AU Srivanitchapoom, P Pandey, S Hallett, M AF Srivanitchapoom, Prachaya Pandey, Sanjay Hallett, Mark TI Drooling in Parkinson's disease: A review SO PARKINSONISM & RELATED DISORDERS LA English DT Review DE Drooling; Sialorrhea; Parkinson's disease; Botulinum toxin ID BOTULINUM-TOXIN-A; AMYOTROPHIC-LATERAL-SCLEROSIS; DOUBLE-BLIND; NONMOTOR SYMPTOMS; QUANTITATIVE ASSESSMENT; SALIVARY SECRETION; SILENT ASPIRATION; RAT MODEL; SIALORRHEA; DYSPHAGIA AB Parkinson's disease (PD) is a neurodegenerative disease causing both motor and non-motor symptoms. Drooling, an excessive pooling and spillover of saliva out of the oral cavity, is one of the non-motor symptoms in PD patients that produces various negative physical and psychosocial consequences for patients and their caregivers. At present, the pathophysiology of drooling in PD is not completely certain; however, impaired intra-oral salivary clearance is likely the major contributor. There are neither standard diagnostic criteria nor standard severity assessment tools for evaluating drooling in PD. In accordance with the possible pathophysiology, dopaminergic agents have been used to improve salivary clearance; however, these agents are not completely effective in controlling drooling. Various pharmacological and non-pharmacological treatment options have been studied. Local injection with botulinum toxin sero-types A and B into major salivary glands is most effective to reduce drooling. Future research to explore the exact pathophysiology and develop standard diagnostic criteria and standard severity assessment tools are needed to formulate specific treatment options and improve patient care. Published by Elsevier Ltd. C1 [Srivanitchapoom, Prachaya] Mahidol Univ, Div Neurol, Dept Med, Fac Med,Siriraj Hosp, Bangkok 10700, Thailand. [Srivanitchapoom, Prachaya; Pandey, Sanjay; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Pandey, Sanjay] Govind Ballabh Pant Hosp, New Delhi 110002, India. RP Hallett, M (reprint author), 10 Ctr Dr MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov OI Hallett, Mark/0000-0002-3180-6811 FU NINDS Intramural Program FX NINDS Intramural Program. NR 71 TC 26 Z9 27 U1 2 U2 10 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 NOV PY 2014 VL 20 IS 11 BP 1109 EP 1118 DI 10.1016/j.parkreldis.2014.08.013 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AU2ZN UT WOS:000345483000001 PM 25200111 ER PT J AU King, HE Wetzell, B Rice, KC Riley, AL AF King, Heather E. Wetzell, Bradley Rice, Kenner C. Riley, Anthony L. TI 3,4-Methylenedioxypyrovalerone (MDPV)-induced conditioned taste avoidance in the F344/N and LEW rat strains SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE F344 and LEW rats; Strain differences; MDPV; Conditioned taste avoidance; Hyperthermia ID PSYCHOACTIVE BATH SALTS; SPRAGUE-DAWLEY RATS; FISCHER RATS; LITHIUM-CHLORIDE; INDUCED PLACE; BASAL LEVELS; COCAINE; AVERSIONS; DOPAMINE; MORPHINE AB The inbred Fischer (F344) and Lewis (LEW) rats, while originally developed as animal models for cancer and tissue transplantation research, have since been used to study genetic differences in a variety of physiological and behavioral endpoints. In this context, LEW rats show greater sensitivity to the aversive effects of cocaine as compared to F344 rats in a conditioned taste avoidance procedure. Like cocaine, 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") acts as a dopamine transport blocker and possesses aversive properties, making it a good candidate for assessing whether the aforementioned strain differences with cocaine would generalize to drugs with similar biochemical action. Accordingly, male F344 and LEW rats were exposed to a novel saccharin solution followed by injections of one of four doses of MDPV in a taste avoidance procedure. Over the four saccharin/MDPV pairings during conditioning, core body temperatures were also assessed. Similar to previous research, MDPV induced robust dose-dependent taste avoidance, although no effect of strain was observed. MDPV also produced hyperthermia that was independent of strain and unrelated to the conditioned taste avoidance. These findings argue for a complex influence of multiple (and likely interacting) monoaminergic systems mediating MDPV-induced taste avoidance in the two strains and suggest different mechanisms of avoidance learning for cocaine and MDPV. (C) 2014 Published by Elsevier Inc. C1 [King, Heather E.; Wetzell, Bradley; Riley, Anthony L.] Amer Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. RP King, HE (reprint author), Amer Univ, Dept Psychol, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. EM hk9905a@american.edu RI Wetzell, B Bradley/J-6802-2013 OI Wetzell, B Bradley/0000-0002-2723-5542 FU Mellon Foundation; National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism, NIH, US Department of Health and Human Services FX This research was supported by a grant from the Mellon Foundation to ALR. A portion of this research was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism, NIH, US Department of Health and Human Services. Requests for reprints should be sent to: Heather King, Psychopharmacology Laboratory, Department of Psychology, American University, Washington, DC 20016, United States. NR 61 TC 7 Z9 7 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD NOV PY 2014 VL 126 BP 163 EP 169 DI 10.1016/j.pbb.2014.09.021 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA AU2TU UT WOS:000345471200022 PM 25284129 ER PT J AU Williams, KA Lee, M Hu, Y Andreas, J Patel, SJ Zhang, SY Chines, P Elkahloun, A Chandrasekharappa, S Gutkind, JS Molinolo, AA Crawford, NPS AF Williams, Kendra A. Lee, Minnkyong Hu, Ying Andreas, Jonathan Patel, Shashank J. Zhang, Suiyuan Chines, Peter Elkahloun, Abdel Chandrasekharappa, Settara Gutkind, J. Silvio Molinolo, Alfredo A. Crawford, Nigel P. S. TI A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; TRANSGENIC ADENOCARCINOMA; TRAMP MODEL; RNA-SEQ; NEUROENDOCRINE CARCINOMA; HISTOLOGICAL VARIANTS; SEMINAL-VESICLES; TUMOR; FIBROBLASTS; PROGRESSION AB Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP) 8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer. C1 [Williams, Kendra A.; Lee, Minnkyong; Andreas, Jonathan; Patel, Shashank J.; Crawford, Nigel P. S.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Hu, Ying] NCI, Ctr Biomed Informat & Informat Technol, NIH, Rockville, MD USA. [Zhang, Suiyuan] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Chines, Peter] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel; Chandrasekharappa, Settara] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Gutkind, J. Silvio; Molinolo, Alfredo A.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Williams, KA (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM crawforn@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported [in part] by the Intramural Research Program of the National Human Genome Research Institute, 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 49 TC 9 Z9 10 U1 1 U2 4 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 NOV PY 2014 VL 10 IS 11 AR e1004809 DI 10.1371/journal.pgen.1004809 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA AU2NL UT WOS:000345455200044 PM 25411967 ER PT J AU George, PJ Kumar, NP Sridhar, R Hanna, LE Nair, D Banurekha, VV Nutman, TB Babu, S AF George, Parakkal Jovvian Kumar, Nathella Pavan Sridhar, Rathinam Hanna, Luke E. Nair, Dina Banurekha, Vaithilingam V. Nutman, Thomas B. Babu, Subash TI Coincident Helminth Infection Modulates Systemic Inflammation and Immune Activation in Active Pulmonary Tuberculosis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID MATRIX METALLOPROTEINASES; DISEASE; MECHANISMS; FILARIAL; PERSPECTIVE; BIOMARKERS; INHIBITORS; TOLERANCE; PATHOGENS; CYTOKINES AB Background: Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity) in TB is not known. Methodology: We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB) with co-incidental Strongyloides stercoralis (Ss) infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB) with or without Ss infection. Principal Findings: Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection. Conclusions: Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease. C1 [George, Parakkal Jovvian; Kumar, Nathella Pavan; Babu, Subash] NIRT, Natl Inst Hlth, Int Ctr Excellence Res, Madras, Tamil Nadu, India. [Sridhar, Rathinam] Govt Stanley Med Hosp, Madras, Tamil Nadu, India. [Hanna, Luke E.; Nair, Dina; Banurekha, Vaithilingam V.] Natl Inst Res TB, Madras, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP George, PJ (reprint author), NIRT, Natl Inst Hlth, Int Ctr Excellence Res, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, NIAID, NIH FX This work was funded by the Division of Intramural Research, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 2 Z9 2 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2014 VL 8 IS 11 AR e3289 DI 10.1371/journal.pntd.0003289 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AU3LF UT WOS:000345514000026 PM 25375117 ER PT J AU Findley, K Grice, EA AF Findley, Keisha Grice, Elizabeth A. TI The Skin Microbiome: A Focus on Pathogens and Their Association with Skin Disease SO PLOS PATHOGENS LA English DT Article ID ATOPIC-DERMATITIS; STAPHYLOCOCCUS-AUREUS; SEBORRHEIC DERMATITIS; DIVERSITY; CHILDREN; SHIFTS; ACNE C1 [Findley, Keisha] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Grice, Elizabeth A.] Univ Penn, Dept Dermatol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Grice, EA (reprint author), Univ Penn, Dept Dermatol, Perelman Sch Med, Philadelphia, PA 19104 USA. EM egrice@mail.med.upenn.edu FU NIAMS NIH HHS [R00 AR060873] NR 26 TC 12 Z9 12 U1 3 U2 38 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 NOV PY 2014 VL 10 IS 11 AR e1004436 DI 10.1371/journal.ppat.1004436 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AU3LX UT WOS:000345515800005 PM 25393405 ER PT J AU Pise-Masison, CA de Castro-Amarante, MF Enose-Akahata, Y Buchmann, RC Fenizia, C Parks, RW Edwards, D Fiocchi, M Alcantara, LC Bialuk, I Graham, J Walser, JC McKinnon, K Galvao-Castro, B Gessain, A Venzon, D Jacobson, S Franchini, G AF Pise-Masison, Cynthia A. de Castro-Amarante, Maria Fernanda Enose-Akahata, Yoshimi Buchmann, R. Cody Fenizia, Claudio Parks, Robyn Washington Edwards, Dustin Fiocchi, Martina Alcantara, Luiz Carlos, Jr. Bialuk, Izabela Graham, Jhanelle Walser, Jean-Claude McKinnon, Katherine Galvao-Castro, Bernardo Gessain, Antoine Venzon, David Jacobson, Steven Franchini, Genoveffa TI Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence SO PLOS PATHOGENS LA English DT Article ID T-CELL LEUKEMIA/LYMPHOMA; PROVIRAL DNA LOAD; I HEAVY-CHAIN; TYPE-1 P12(I); DENDRITIC CELLS; INFECTED-CELLS; NUCLEAR FACTOR; PROTEIN; TRANSMISSION; ACTIVATION AB HTLV-1 orf-I is linked to immune evasion, viral replication and persistence. Examining the orf-I sequence of 160 HTLV-1-infected individuals; we found polymorphism of orf-I that alters the relative amounts of p12 and its cleavage product p8. Three groups were identified on the basis of p12 and p8 expression: predominantly p12, predominantly p8 and balanced expression of p12 and p8. We found a significant association between balanced expression of p12 and p8 with high viral DNA loads, a correlate of disease development. To determine the individual roles of p12 and p8 in viral persistence, we constructed infectious molecular clones expressing p12 and p8 (D26), predominantly p12 (G29S) or predominantly p8 (N26). As we previously showed, cells expressing N26 had a higher level of virus transmission in vitro. However, when inoculated into Rhesus macaques, cells producing N26 virus caused only a partial seroconversion in 3 of 4 animals and only 1 of those animals was HTLV-1 DNA positive by PCR. None of the animals exposed to G29S virus seroconverted or had detectable viral DNA. In contrast, 3 of 4 animals exposed to D26 virus seroconverted and were HTLV-1 positive by PCR. In vitro studies in THP-1 cells suggested that expression of p8 was sufficient for productive infection of monocytes. Since orf-I plays a role in T-cell activation and recognition; we compared the CTL response elicited by CD4(+) T-cells infected with the different HTLV-1 clones. Although supernatant p19 levels and viral DNA loads for all four infected lines were similar, a significant difference in Tax-specific HLA. A2-restricted killing was observed. Cells infected with Orf-I-knockout virus (12KO), G29S or N26 were killed by CTLs, whereas cells infected with D26 virus were resistant to CTL killing. These results indicate that efficient viral persistence and spread require the combined functions of p12 and p8. C1 [Pise-Masison, Cynthia A.; de Castro-Amarante, Maria Fernanda; Buchmann, R. Cody; Fenizia, Claudio; Parks, Robyn Washington; Edwards, Dustin; Fiocchi, Martina; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. [Enose-Akahata, Yoshimi; Graham, Jhanelle; Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Alcantara, Luiz Carlos, Jr.; Galvao-Castro, Bernardo] Oswaldo Cruz Fdn Salvador, Salvador, BA, Brazil. [Bialuk, Izabela] Med Univ Bialystok, Dept Gen & Expt Pathol, Bialystok, Poland. [Walser, Jean-Claude] Univ Basel, Genet Divers Ctr, Basel, Switzerland. [McKinnon, Katherine] NCI, Vaccine Branch Flow Cytometry Core Lab, NIH, Bethesda, MD 20892 USA. [Gessain, Antoine] Inst Pasteur, Dept Virol, Unite Epidemiol & Physiopathol Virus Oncogenes, Paris, France. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU Intramural Program at the National Cancer Institute, National Institutes of Health, Bethesda, MD FX This work was supported by the Intramural Program at the National Cancer Institute, National Institutes of Health, Bethesda, MD. 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 7 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2014 VL 10 IS 11 AR e1004454 DI 10.1371/journal.ppat.1004454 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AU3LX UT WOS:000345515800010 PM 25375128 ER PT J AU Simon, SL Preston, DL Linet, MS Miller, JS Sigurdson, AJ Alexander, BH Kwon, D Yoder, RC Bhatti, P Little, MP Rajaraman, P Melo, D Drozdovitch, V Weinstock, RM Doody, MM AF Simon, Steven L. Preston, Dale L. Linet, Martha S. Miller, Jeremy S. Sigurdson, Alice J. Alexander, Bruce H. Kwon, Deukwoo Yoder, R. Craig Bhatti, Parveen Little, Mark P. Rajaraman, Preetha Melo, Dunstana Drozdovitch, Vladimir Weinstock, Robert M. Doody, Michele M. TI Radiation Organ Doses Received in a Nationwide Cohort of US Radiologic Technologists: Methods and Findings SO RADIATION RESEARCH LA English DT Article ID UNITED-STATES; DIAGNOSTIC-RADIOLOGY; CANCER INCIDENCE; LUNG-CANCER; PERSONNEL; EXPOSURE; WORKERS; RISK; CALIBRATION; REGRESSION AB In this article, we describe recent methodological enhancements and findings from the dose reconstruction component of a study of health risks among U.S. radiologic technologists. An earlier version of the dosimetry published in 2006 used physical and statistical models, literature-reported exposure measurements for the years before 1960, and archival personnel monitoring badge data from cohort members through 1984. The data and models previously described were used to estimate annual occupational radiation doses for 90,000 radiological technologists, incorporating information about each individual's employment practices based on a baseline survey conducted in the mid-1980s. The dosimetry methods presented here, while using many of the same methods as before, now estimate 2.23 million annual badge doses (personal dose equivalent) for the years 1916-1997 for 110,374 technologists, but with numerous methodological improvements. Every technologist's annual dose is estimated as a probability density function to reflect uncertainty about the true dose. Multiple realizations of the entire cohort distribution were derived to account for shared uncertainties and possible biases in the input data and assumptions used. Major improvements in the dosimetry methods from the earlier version include: A substantial increase in the number of cohort member annual badge dose measurements; Additional information on individual apron usage obtained from surveys conducted in the mid-1990s and mid-2000s; Refined modeling to develop lognormal annual badge dose probability density functions using censored data regression models; Refinements of cohort-based annual badge probability density functions to reflect individual work patterns and practices reported on questionnaires and to more accurately assess minimum detection limits; and Extensive refinements in organ dose conversion coefficients to account for uncertainties in radiographic machine settings for the radiographic techniques employed. For organ dose estimation, we rely on well-researched assumptions about critical exposure-related variables and their changes over the decades, including the peak kilovoltage and filtration typically used in conducting radiographic examinations, and the usual body location for wearing radiation monitoring badges, the latter based on both literature and national recommendations. We have derived organ dose conversion coefficients based on air-kerma weighting of photon fluences from published X-ray spectra and derived energy-dependent transmission factors for protective lead aprons of different thicknesses. Findings are presented on estimated organ doses for 12 organs and tissues: red bone marrow, female breast, thyroid, brain, lung, heart, colon, ovary, testes, skin of trunk, skin of head and neck and arms, and lens of the eye. (C) 2014 by Radiation Research Society C1 [Simon, Steven L.; Linet, Martha S.; Sigurdson, Alice J.; Kwon, Deukwoo; Bhatti, Parveen; Little, Mark P.; Rajaraman, Preetha; Melo, Dunstana; Drozdovitch, Vladimir; Doody, Michele M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Preston, Dale L.] HiroSoft Int, Eureka, CA USA. [Miller, Jeremy S.] Informat Management Serv Inc, Silver Spring, MD USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. [Yoder, R. Craig] Landauer Inc, Glenwood, IL USA. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov OI Little, Mark/0000-0003-0980-7567 FU Intramural Research Program of the Division of Cancer Genetics and Epidemiology, National Cancer Institute, National Institutes of Health FX The authors thank the following individuals for their invaluable contributions: Diane Kampa, Allison Iwan and Rick Hoffbeck from the University of Minnesota; William Harris from the U.S. Army Dosimetry Center, Paul Blake and John Crapo from the Naval Dosimetry Center, Craig Refoscoe from the U.S. Air Force Radiation Dosimetry Laboratory, Jim Robb from Landauer, Inc., Marilyn Stovall and Susan Smith from the University of Texas MD Anderson Cancer Center; Verma Walker from the NIH Library; and Norma Kim from Research Triangle Institute. The authors are especially grateful to Andre Bouville, Ethel Gilbert, Kiyohiko Mabuchi, Rochelle Curtis, Amy Berrington de Gonzalez, Jay Lubin, Elaine Ron (deceased), Charles Land and Trish Stewart from the National Cancer Institute for thoroughly reviewing the dosimetry system and for providing advice on dose assessment and statistical methods. This work was funded by the Intramural Research Program of the Division of Cancer Genetics and Epidemiology, National Cancer Institute, National Institutes of Health. NR 42 TC 9 Z9 9 U1 1 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 NOV PY 2014 VL 182 IS 5 BP 507 EP 528 DI 10.1667/RR13542.1 PG 22 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AU4TL UT WOS:000345604200005 PM 25361400 ER PT J AU Brown, J AF Brown, Jeremy TI National Institutes of Health Support for Individual Mentored Career Development Grants in Emergency Medicine SO ACADEMIC EMERGENCY MEDICINE LA English DT Article AB ObjectivesIndividual mentored career (K) awards made by the National Institutes of Health (NIH) are an important way for medical researchers to develop their research skills. This study determined the number of individual mentored (K) awards awarded to emergency medicine (EM) faculty over a 6-year period and compared it with six other specialties. MethodsThe NIH database of both submitted and funded K01, K08, and K23 applications was queried and crossed with the departmental affiliation of the principal investigator. The results were further analyzed with data from the Association of American Medical Colleges to determine the relationship between the number of awards and the size of the teaching and research faculty. ResultsFrom 2008 to 2013, there were a total of 45 career development submissions from principal investigators affiliated with departments of EM. Of these, 27 (60%) were successful. This success rate is the third lowest of the seven specialties in this analysis. Emergency physicians submit relatively few grants compared to the size of their faculty, and the funding rate, $1,959 per EM resident, was the second lowest of the six specialties examined. ConclusionsAlthough success rates are reasonable, EM investigators submit very few individual mentored career development applications. They should take greater advantage of this mechanism to further their research training. Resumen ObjetivosLas becas a la carrera profesional individual supervisada Individual mentored career (K) realizados por los National Institutes of Health (NIH) son una via importante para que los investigadores medicos desarrollen sus habilidades en investigacion. Este estudio determino el numero de becas a la carrera profesional individual supervisada otorgados a las facultades de Medicina de Urgencias y Emergencias (MUE) en un periodo de 6 anos y se comparo con otras seis especialidades. MetodologiaSe consulto en la base de datos de los NIH tanto de las solicitudes K01, K08 y K23 presentadas y otorgadas y se cruzaron con la filiacion del servicio del investigador principal. Los resultados se analizaron posteriormente con los datos de la Association of American Medical Colleges para determinar la relacion entre el numero de becas y el tamano de la facultad en investigacion y formacion. ResultadosDesde 2008 a 2013, hubo un total de 45 solicitudes de desarrollo de la carrera profesional de investigadores principales con filiacion en un Servicio de MUE. De estas, 27 (60%) fueron otorgadas. Este porcentaje de exito es el tercero mas bajo de las siete especialidades de este analisis. Los urgenciologos solicitan relativamente pocas becas en comparacion con el tamano de sus universidades y el porcentaje de financiacion, 1.959 dolares por residente de MUE, es el segundo mas bajo de las seis especialidades evaluadas. ConclusionesAunque los porcentajes de exito son razonables, los investigadores de MUE solicitan pocas becas para el desarrollo de la carrera profesional individual supervisada y deberian aprovechar mas este mecanismo para su futura formacion en investigacion. C1 NIH, Off Emergency Care Res, Bethesda, MD 20892 USA. RP Brown, J (reprint author), NIH, Off Emergency Care Res, Bldg 10, Bethesda, MD 20892 USA. EM Jeremy.brown@nih.gov NR 9 TC 3 Z9 3 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD NOV PY 2014 VL 21 IS 11 BP 1269 EP 1273 DI 10.1111/acem.12517 PG 5 WC Emergency Medicine SC Emergency Medicine GA AT9GZ UT WOS:000345237300012 PM 25377405 ER PT J AU Zimmermann, SC Rais, R Alt, J Burzynski, C Slusher, BS Tsukamoto, T AF Zimmermann, Sarah C. Rais, Rana Alt, Jesse Burzynski, Caitlin Slusher, Barbara S. Tsukamoto, Takashi TI Structure-Metabolism Relationships in the Glucuronidation of D-Amino Acid Oxidase Inhibitors SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE glucronidation; D-amino acid oxidase (DAAO); drug metabolism ID IN-VITRO; DISCOVERY; PHARMACOKINETICS; SCHIZOPHRENIA; DERIVATIVES; SERIES; SAR AB Representative D-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing a-hydroxycarbonyl moiety exhibited nearly complete glucuronidation within 30 min. The one exception was 6-[2-(3,5-difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one 10, which exhibited some degree of resistance to glucuronidation by liver microsomes from mice, rats, and humans. C1 [Zimmermann, Sarah C.; Rais, Rana; Alt, Jesse; Slusher, Barbara S.; Tsukamoto, Takashi] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21205 USA. [Zimmermann, Sarah C.; Rais, Rana; Alt, Jesse; Slusher, Barbara S.; Tsukamoto, Takashi] Johns Hopkins Univ, Brain Sci Inst, Baltimore, MD 21205 USA. [Burzynski, Caitlin] NIDA, Intramural Res Program, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Baltimore, MD 21224 USA. RP Tsukamoto, T (reprint author), Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21205 USA. EM ttsukamoto@jhmi.edu FU National Institutes of Health [R01MH091387] FX This work was supported by National Institutes of Health (R01MH091387 to T.T. and a postbaccalaureate fellowship to C.B.). NR 16 TC 2 Z9 2 U1 3 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD NOV PY 2014 VL 5 IS 11 BP 1251 EP 1253 DI 10.1021/ml500335z PG 3 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AT5IM UT WOS:000344977100018 PM 25408840 ER PT J AU Leiss, V Flockerzie, K Novakovic, A Rath, M Schonsiegel, A Birnbaumer, L Schurmann, A Harteneck, C Nurnberg, B AF Leiss, Veronika Flockerzie, Katarina Novakovic, Ana Rath, Michaela Schonsiegel, Annika Birnbaumer, Lutz Schurmann, Annette Harteneck, Christian Nurnberg, Bernd TI Insulin secretion stimulated by L-arginine and its metabolite L-ornithine depends on G alpha(i2) SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE G alpha(i2); insulin secretion; beta-cell; L-arginine; GPCR ID PANCREATIC BETA-CELLS; PROTEIN-COUPLED RECEPTORS; IN-VIVO; SIGNAL-TRANSDUCTION; GPRC6A; MICE; RELEASE; ALPHA; ISLETS; EXPRESSION AB Bordetella pertussis toxin (PTx), also known as islet-activating protein, induces insulin secretion by ADP-ribosylation of inhibitory G proteins. PTx-induced insulin secretion may result either from inactivation of G alpha(o) proteins or from combined inactivation of G alpha(o), G alpha(i1), G alpha(i2), and G alpha(i3) isoforms. However, the specific role of G alpha(i2) in pancreatic beta-cells still remains unknown. In global (G alpha(-/-)(i2)) and beta-cell-specific (G alpha(beta cko)(i2)) gene-targeted G alpha(i2) mouse models, we studied glucose homeostasis and islet functions. Insulin secretion experiments and intracellular Ca2+ measurements were used to characterize G alpha(i2) function in vitro. G alpha(-/-)(i2) and G alpha(beta cko)(i2) mice showed an unexpected metabolic phenotype, i.e., significantly lower plasma insulin levels upon intraperitoneal glucose challenge in G alpha(-/-)(i2) and G alpha(beta cko)(i2) mice, whereas plasma glucose concentrations were unchanged in G alpha(-/-)(i2) but significantly increased in G alpha(beta cko)(i2) mice. These findings indicate a novel albeit unexpected role for G alpha(i2) in the expression, turnover, and/or release of insulin from islets. Detection of insulin secretion in isolated islets did not show differences in response to high (16 mM) glucose concentrations between control and beta-cell-specific G alpha(i2)-deficient mice. In contrast, the two-to threefold increase in insulin secretion evoked by L-arginine or L-ornithine (in the presence of 16 mM glucose) was significantly reduced in islets lacking G alpha(i2). In accord with a reduced level of insulin secretion, intracellular calcium concentrations induced by the agonistic amino acid L-arginine did not reach control levels in beta-cells. The presented analysis of gene-targeted mice provides novel insights in the role of beta-cell G alpha(i2) showing that amino acid-induced insulin-release depends on G alpha(i2). C1 [Leiss, Veronika; Flockerzie, Katarina; Novakovic, Ana; Schonsiegel, Annika; Harteneck, Christian; Nurnberg, Bernd] Univ Tubingen, Eberhard Karls Univ Hosp & Clin, Inst Expt & Clin Pharmacol & Toxicol, Dept Pharmacol & Expt Therapy, Tubingen, Germany. [Leiss, Veronika; Flockerzie, Katarina; Novakovic, Ana; Schonsiegel, Annika; Harteneck, Christian; Nurnberg, Bernd] Univ Tubingen, Interfac Ctr Pharmacogenom & Drug Res, Tubingen, Germany. [Rath, Michaela; Schurmann, Annette] German Inst Human Nutr, Dept Expt Diabetol, Potsdam, Nuthetal, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Dept Hlth & Human Serv, NIH, Durham, NC USA. RP Nurnberg, B (reprint author), Eberhard Karls Univ Hosp & Clin, Inst Expt & Clin Pharmacol & Toxicol, Dept Pharmacol & Expt Therapy, Wilhelmstr 56, D-72074 Tubingen, Germany. EM bernd.nuernberg@uni-tuebingen.de FU Deutsche Forschungsgemeinschaft (DFG) [GRK 1302]; Intramural Program of the National Institutes of Health [Z01 ES-101684]; German Ministry of Education and Research (BMBF: DZD) [01GI0922] FX This work was supported by the Deutsche Forschungsgemeinschaft (DFG) with grants to B. Nurnberg and V. Leiss, and GRK 1302 to B. Nurnberg, by the Intramural Program of the National Institutes of Health to L. Birnbaumer (Project Z01 ES-101684), and by the German Ministry of Education and Research (BMBF: DZD, 01GI0922) to A. Schurmann. NR 42 TC 2 Z9 2 U1 0 U2 5 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 NOV 1 PY 2014 VL 307 IS 9 BP E800 EP E812 DI 10.1152/ajpendo.00337.2014 PG 13 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA AT5NK UT WOS:000344989400008 PM 25205820 ER PT J AU Phillips, SM Glasgow, RE Bello, G Ory, MG Glenn, BA Sheinfeld-Gorin, SN Sabo, RT Heurtin-Roberts, S Johnson, SB Krist, AH AF Phillips, Siobhan M. Glasgow, Russell E. Bello, Ghalib Ory, Marcia G. Glenn, Beth A. Sheinfeld-Gorin, Sherri N. Sabo, Roy T. Heurtin-Roberts, Suzanne Johnson, Sallie Beth Krist, Alex H. CA MOHR Study Grp TI Frequency and Prioritization of Patient Health Risks from a Structured Health Risk Assessment SO ANNALS OF FAMILY MEDICINE LA English DT Article DE primary care; health risk appraisal; patient-centered care ID QUALITY-OF-LIFE; SCREENING-TEST; PRIMARY-CARE; BEHAVIOR; POPULATION; PREVENTION; SEVERITY; VALIDITY; PHQ-9 AB PURPOSE To describe the frequency and patient-reported readiness to change, desire to discuss, and perceived importance of 13 health risk factors in a diverse range of primary care practices. METHODS Patients (n = 1,707) in 9 primary care practices in the My Own Health Report (MOHR) trial reported general, behavioral, and psychosocial risk factors (body mass index [BMI], health status, diet, physical activity, sleep, drug use, stress, anxiety or worry, and depression). We classified responses as "at risk" or "healthy" for each factor, and patients indicated their readiness to change and/or desire to discuss identified risk factors with providers. Patients also selected 1 of the factors they were ready to change as most important. We then calculated frequencies within and across these factors and examined variation by patient characteristics and across practices. RESULTS On average, patients had 5.8 (SD = 2.12; range, 0-13) unhealthy behaviors and mental health risk factors. About 55% of patients had more than 6 risk factors. On average, patients wanted to change 1.2 and discuss 0.7 risks. The most common risks were inadequate fruit/vegetable consumption (84.5%) and overweight/obesity (79.6%). Patients were most ready to change BMI (33.3%) and depression (30.7%), and most wanted to discuss depression (41.9%) and anxiety or worry (35.2%). Overall, patients rated health status as most important. CONCLUSIONS Implementing routine comprehensive health risk assessments in primary care will likely identify a high number of behavioral and psychosocial health risks. By soliciting patient priorities, providers and patients can better manage counseling and behavior change. C1 [Phillips, Siobhan M.; Glasgow, Russell E.; Heurtin-Roberts, Suzanne] NCI, Implementat Sci Team, Div Canc Control & Populat Sci, Rockville, MD USA. [Phillips, Siobhan M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Glasgow, Russell E.] Univ Colorado, Colorado Hlth Outcomes Program, Aurora, CO USA. [Bello, Ghalib; Sabo, Roy T.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA USA. [Ory, Marcia G.] Texas A&M Univ, Hlth Sci Ctr, Hlth Promot & Community Hlth Sci, Round Rock, TX USA. [Glenn, Beth A.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Sheinfeld-Gorin, Sherri N.] NCI, Leidos Biomed Res Inc, Div Canc Control & Populat Sci, Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Johnson, Sallie Beth] Carilion Clin, Dept Family & Community Med, Roanoke, VA USA. [Johnson, Sallie Beth] Virginia Tech, Dept Human Nutr Food & Excercise, Blacksburg, VA USA. [Krist, Alex H.] Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, Richmond, VA USA. RP Phillips, SM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. EM smphillips@northwestern.edu FU National Cancer Institute; Agency for Healthcare Research and Quality; Office of Behavioral and Social Sciences Research; National Center for Advancing Translational Sciences [ULTR00058] FX Funding for the MOHR project was provided by the National Cancer Institute, Agency for Healthcare Research and Quality, Office of Behavioral and Social Sciences Research, and National Center for Advancing Translational Sciences (CTSA Grant Number ULTR00058). The opinions expressed in this manuscript are those of the authors and do not necessarily reflect those of the funders. NR 37 TC 6 Z9 6 U1 0 U2 5 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 EI 1544-1717 J9 ANN FAM MED JI Ann. Fam. Med. PD NOV-DEC PY 2014 VL 12 IS 6 BP 505 EP 513 DI 10.1370/afm.1717 PG 9 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AT5DE UT WOS:000344962900005 PM 25384812 ER PT J AU Krist, AH Phillips, SM Sabo, RT Balasubramanian, BA Heurtin-Roberts, S Ory, MG Johnson, SB Sheinfeld-Gorin, SN Estabrooks, PA Ritzwoller, DP Glasgow, RE AF Krist, Alex H. Phillips, Siobhan M. Sabo, Roy T. Balasubramanian, Bijal A. Heurtin-Roberts, Suzanne Ory, Marcia G. Johnson, Sallie Beth Sheinfeld-Gorin, Sherri N. Estabrooks, Paul A. Ritzwoller, Debra P. Glasgow, Russell E. CA MOHR Study Grp TI Adoption, Reach, Implementation, and Maintenance of a Behavioral and Mental Health Assessment in Primary Care SO ANNALS OF FAMILY MEDICINE LA English DT Article DE health risk appraisal; primary health care; patient reported measures; health behavior; mental health; pragmatic clinical trial ID RE-AIM FRAMEWORK; FORCE RECOMMENDATION STATEMENT; RISK APPRAISAL; SCREENING-TEST; INTERVENTIONS; IMPACT; PROMOTION; DELIVERY; VALIDITY; OUTCOMES AB PURPOSE Guidelines recommend screening patients for unhealthy behaviors and mental health concerns. Health risk assessments can systematically identify patient needs and trigger care. This study seeks to evaluate whether primary care practices can routinely implement such assessments into routine care. METHODS As part of a cluster-randomized pragmatic trial, 9 diverse primary care practices implemented My Own Health Report (MOHR)-an electronic or paper-based health behavior and mental health assessment and feedback system paired with counseling and goal setting. We observed how practices integrated MOHR into their workflows, what additional practice staff time it required, and what percentage of patients completed a MOHR assessment (Reach). RESULTS Most practices approached (60%) agreed to adopt MOHR. How they implemented MOHR depended on practice resources, informatics capacity, and patient characteristics. Three practices mailed patients invitations to complete MOHR on the Web, 1 called patients and completed MOHR over the telephone, 1 had patients complete MOHR on paper in the office, and 4 had staff help patients complete MOHR on the Web in the office. Overall, 3,591 patients were approached and 1,782 completed MOHR (Reach = 49.6%). Reach varied by implementation strategy with higher reach when MOHR was completed by staff than by patients (71.2% vs 30.2%, P < .001). No practices were able to sustain the complete MOHR assessment without adaptations after study completion. Fielding MOHR increased staff and clinician time an average of 28 minutes per visit. CONCLUSIONS Primary care practices can implement health behavior and mental health assessments, but counseling patients effectively requires effort. Practices will need more support to implement and sustain assessments. C1 [Krist, Alex H.] Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, Richmond, VA USA. [Phillips, Siobhan M.] NCI, Div Canc Control & Populat Sci, Implementat Sci Team, Rockville, MD USA. [Sabo, Roy T.] Virginia Commonwealth Univ, Dept Family Med & Populat Hlth, Dept Biostat, Richmond, VA USA. [Balasubramanian, Bijal A.] Univ Texas Dallas, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Dallas, TX 75230 USA. [Heurtin-Roberts, Suzanne] NCI, Div Canc Control & Populat Sci, Implementat Sci Team, Rockville, MD USA. [Ory, Marcia G.] Texas A&M Hlth Sci Ctr, Sch Publ Hlth, Dept Hlth Promot & Community Hlth Sci, College Stn, TX USA. [Johnson, Sallie Beth; Estabrooks, Paul A.] Caril Clin, Dept Family & Community Med, Roanoke, VA USA. [Sheinfeld-Gorin, Sherri N.] NCI, Herbert Irving Comprehens Canc Ctr, Div Canc Control & Populat Sci, New York Phys Canc NYPAC,Leidos Biomed Res Inc, New York, NY USA. [Estabrooks, Paul A.] Virginia Tech, Dept Human Nutr Foods & Exercise, Blacksburg, VA USA. [Ritzwoller, Debra P.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Glasgow, Russell E.] Univ Colorado, Sch Med, Dept Family Med, Denver, CO USA. RP Krist, AH (reprint author), POB 980101, Richmond, VA 23298 USA. EM ahkrist@vcu.edu FU National Cancer Institute; Agency for Healthcare Research and Quality; Office of Behavioral and Social Sciences Research; National Center for Advancing Translational Sciences [ULTR00058] FX Funding for the MOHR project was provided by the National Cancer Institute, Agency for Healthcare Research and Quality, Office of Behavioral and Social Sciences Research, and National Center for Advancing Translational Sciences (CTSA Grant Number ULTR00058). The opinions expressed in this manuscript are those of the authors and do not necessarily reflect those of the funders. NR 48 TC 7 Z9 7 U1 0 U2 5 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 EI 1544-1717 J9 ANN FAM MED JI Ann. Fam. Med. PD NOV-DEC PY 2014 VL 12 IS 6 BP 525 EP 533 DI 10.1370/afm.1710 PG 9 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AT5DE UT WOS:000344962900007 PM 25384814 ER PT J AU Koh, DH Nam, JM Graubard, BI Chen, YC Locke, SJ Friesen, MC AF Koh, Dong-Hee Nam, Jun-Mo Graubard, Barry I. Chen, Yu-Cheng Locke, Sarah J. Friesen, Melissa C. TI Evaluating Temporal Trends from Occupational Lead Exposure Data Reported in the Published Literature Using Meta-Regression SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE exposure; lead; meta-analysis; meta-regression; temporal trend ID RADIATOR REPAIR WORKERS; LONG-TERM TRENDS; COMPREHENSIVE EVALUATION; BLOOD LEAD; METAANALYSIS; SHANGHAI; BENZENE; MODELS; MATRIX; COHORT AB Objectives: The published literature provides useful exposure measurements that can aid retrospective exposure assessment efforts, but the analysis of this data is challenging as it is usually reported as means, ranges, and measures of variability. We used mixed-effects meta-analysis regression models, which are commonly used to summarize health risks from multiple studies, to predict temporal trends of blood and air lead concentrations in multiple US industries from the published data while accounting for within-and between-study variability in exposure. Methods: We extracted the geometric mean (GM), geometric standard deviation (GSD), and number of measurements from journal articles reporting blood and personal air measurements from US worksites. When not reported, we derived the GM and GSD from other summary measures. Only industries with measurements in >= 2 time points and spanning >= 10 years were included in our analyses. Meta-regression models were developed separately for each industry and sample type. Each model used the log-transformed GM as the dependent variable and calendar year as the independent variable. It also incorporated a random intercept that weighted each study by a combination of the between-and within-study variances. The within-study variances were calculated as the squared log-transformed GSD divided by the number of measurements. Maximum likelihood estimation was used to obtain the regression parameters and between-study variances. Results: The blood measurement models predicted statistically significant declining trends of 2-11% per year in 8 of the 13 industries. The air measurement models predicted a statistically significant declining trend (3% per year) in only one of the seven industries; an increasing trend (7% per year) was also observed for one industry. Of the five industries that met our inclusion criteria for both air and blood, the exposure declines per year tended to be slightly greater based on blood measurements than on air measurements. Conclusions: Meta-analysis provides a useful tool for synthesizing occupational exposure data to examine exposure trends that can aid future retrospective exposure assessment. Data remained too sparse to account for other exposure predictors, such as job category or sampling strategy, but this limitation may be overcome by using additional data sources. C1 [Koh, Dong-Hee; Nam, Jun-Mo; Graubard, Barry I.; Locke, Sarah J.; Friesen, Melissa C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chen, Yu-Cheng] Natl Hlth Res Inst, Natl Environm Hlth Res Ctr, Taipei 11503, Taiwan. [Koh, Dong-Hee] Natl Canc Ctr, Natl Canc Control Inst, Goyang 410769, South Korea. RP Friesen, MC (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr Room 6E608 MSC 9771, Bethesda, MD 20892 USA. EM friesenmc@mail.nih.gov RI Friesen, Melissa/A-5362-2009 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health [Z01 CP10122-19] FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (Z01 CP10122-19). NR 29 TC 5 Z9 5 U1 0 U2 9 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 NOV PY 2014 VL 58 IS 9 BP 1111 EP 1125 DI 10.1093/annhyg/meu061 PG 15 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA AU0DN UT WOS:000345293800003 PM 25193938 ER PT J AU Huynh, T Ramachandran, G Banerjee, S Monteiro, J Stenzel, M Sandler, DP Engel, LS Kwok, RK Blair, A Stewart, PA AF Tran Huynh Ramachandran, Gurumurthy Banerjee, Sudipto Monteiro, Joao Stenzel, Mark Sandler, Dale P. Engel, Lawrence S. Kwok, Richard K. Blair, Aaron Stewart, Patricia A. TI Comparison of Methods for Analyzing Left-Censored Occupational Exposure Data SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE exposure assessment; left-censored data; the GuLF STUDY ID DETECTION LIMITS AB The National Institute for Environmental Health Sciences (NIEHS) is conducting an epidemiologic study (GuLF STUDY) to investigate the health of the workers and volunteers who participated from April to December of 2010 in the response and cleanup of the oil release after the Deepwater Horizon explosion in the Gulf of Mexico. The exposure assessment component of the study involves analyzing thousands of personal monitoring measurements that were collected during this effort. A substantial portion of these data has values reported by the analytic laboratories to be below the limits of detection (LOD). A simulation study was conducted to evaluate three established methods for analyzing data with censored observations to estimate the arithmetic mean (AM), geometric mean (GM), geometric standard deviation (GSD), and the 95th percentile (X-0.95) of the exposure distribution: the maximum likelihood (ML) estimation, the beta-substitution, and the Kaplan-Meier (K-M) methods. Each method was challenged with computer-generated exposure datasets drawn from lognormal and mixed lognormal distributions with sample sizes (N) varying from 5 to 100, GSDs ranging from 2 to 5, and censoring levels ranging from 10 to 90%, with single and multiple LODs. Using relative bias and relative root mean squared error (rMSE) as the evaluation metrics, the beta-substitution method generally performed as well or better than the ML and K-M methods in most simulated lognormal and mixed lognormal distribution conditions. The ML method was suitable for large sample sizes (N >= 30) up to 80% censoring for lognormal distributions with small variability (GSD = 2-3). The K-M method generally provided accurate estimates of the AM when the censoring was <50% for lognormal and mixed distributions. The accuracy and precision of all methods decreased under high variability (GSD = 4 and 5) and small to moderate sample sizes (N < 20) but the beta-substitution was still the best of the three methods. When using the ML method, practitioners are cautioned to be aware of different ways of estimating the AM as they could lead to biased interpretation. A limitation of the beta-substitution method is the absence of a confidence interval for the estimate. More research is needed to develop methods that could improve the estimation accuracy for small sample sizes and high percent censored data and also provide uncertainty intervals. C1 [Tran Huynh; Ramachandran, Gurumurthy; Banerjee, Sudipto; Monteiro, Joao] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN 55455 USA. [Stenzel, Mark] Exposure Assessment Applicat LLC, Arlington, VA 22707 USA. [Sandler, Dale P.; Engel, Lawrence S.; Kwok, Richard K.] NIEHS, Res Triangle Pk, NC 27709 USA. [Engel, Lawrence S.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Blair, Aaron] NCI, Bethesda, MD 20892 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA 22707 USA. RP Ramachandran, G (reprint author), Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN 55455 USA. EM ramac002@umn.edu RI Kwok, Richard/B-6907-2017; OI Kwok, Richard/0000-0002-6794-8360; Sandler, Dale/0000-0002-6776-0018; Engel, Lawrence/0000-0001-9268-4830 FU NIH, National Institute of Environmental Health Sciences [ZO1 ES 102945] FX Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZO1 ES 102945). NR 29 TC 5 Z9 5 U1 3 U2 17 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 NOV PY 2014 VL 58 IS 9 BP 1126 EP 1142 DI 10.1093/annhyg/meu067 PG 17 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA AU0DN UT WOS:000345293800004 PM 25261453 ER PT J AU Debelenko, LV Agarwal, S Du, Q Yan, WS Erickson, HS Abu-Asab, M Raffeld, MA Libutti, SK Marx, SJ Emmert-Buck, MR AF Debelenko, Larisa V. Agarwal, Sunita Du, Qiang Yan, Wusheng Erickson, Heidi S. Abu-Asab, Mones Raffeld, Mark A. Libutti, Steven K. Marx, Stephen J. Emmert-Buck, Michael R. TI Menin Immunoreactivity in Secretory Granules of Human Pancreatic Islet Cells SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY LA English DT Article DE endocrine tumor; menin localization; human tissue; immunohistochemical analysis ID ENDOCRINE NEOPLASIA TYPE-1; PRIMARY HYPERPARATHYROIDISM; PROLIFERATION RATES; SOMATIC MUTATION; GENE-EXPRESSION; PROTEIN; TUMORS; IDENTIFICATION; TRANSCRIPTION; LOCALIZATION AB The protein product of the Multiple Endocrine Neoplasia Type I (MEN1) gene is thought to be involved in predominantly nuclear functions; however, immunohistochemical (IHC) analysis data on cellular localization are conflicting. To further investigate menin expression, we analyzed human pancreas (an MEN1 target organ) using IHC analyses and 6 antibodies raised against full-length menin or its peptides. In 10 normal pancreas specimens, 2 independently raised antibodies showed unexpected cytoplasmic immunoreactivity in peripheral cells in each islet examined (over 100 total across all 10 patients). The staining exhibited a distinct punctate pattern and subsequent immunoelectron microscopy indicated the target antigen was in secretory granules. Exocrine pancreas and pancreatic stroma were not immunoreactive. In MEN1 patients, unaffected islets stained similar to those in normal samples but with a more peripheral location of positive cells, whereas hyperplastic islets and tumorlets showed increased and diffuse cytoplasmic staining, respectively. Endocrine tumors from MEN1 patients were negative for menin, consistent with a 2-hit loss of a tumor suppressor gene. Secretory granule localization of menin in a subset of islet cells suggests a function of the protein unique to a target organ of familial endocrine neoplasia, although the IHC data must be interpreted with some caution because of the possibility of antibody cross-reaction. The identity, cellular trafficking, and role of this putative secretory granule-form of menin warrant additional investigation. C1 [Debelenko, Larisa V.] Wayne State Univ, Childrens Hosp Michigan, Sch Med, Dept Pathol, Detroit, MI USA. NIDDK, Metab Dis Branch, NCI, Bethesda, MD 20892 USA. [Du, Qiang; Yan, Wusheng; Erickson, Heidi S.; Emmert-Buck, Michael R.] NCI, Pathogenet Unit, Lab Pathol, Bethesda, MD 20892 USA. [Raffeld, Mark A.] NCI, Lab Pathol, Bethesda, MD 20892 USA. [Abu-Asab, Mones] NEI, Histopathol Core, NIH, Bethesda, MD 20892 USA. [Libutti, Steven K.] Montefiore Med Ctr, Bronx, NY 10467 USA. [Libutti, Steven K.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Emmert-Buck, MR (reprint author), NCI, Ctr Canc Res, Pathogenet Unit, Pathol Lab, Room 2N208,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM buckm@mail.nih.gov OI Agarwal, Sunita/0000-0002-7557-3191 FU NIH (National Cancer Institute, Center for Cancer Research), Bethesda, MD; NIH (National Institute for Diabetes, Digestive and Kidney Disease), Bethesda, MD FX Supported (in part) by the Intramural Research Program of the NIH (National Cancer Institute, Center for Cancer Research; National Institute for Diabetes, Digestive and Kidney Disease), Bethesda, MD. NR 47 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1541-2016 EI 1533-4058 J9 APPL IMMUNOHISTO M M JI Appl. Immunohistochem. PD NOV-DEC PY 2014 VL 22 IS 10 BP 748 EP 755 DI 10.1097/PAI.0000000000000046 PG 8 WC Anatomy & Morphology; Medical Laboratory Technology; Pathology SC Anatomy & Morphology; Medical Laboratory Technology; Pathology GA AU0UZ UT WOS:000345341500007 PM 25153502 ER PT J AU Polonsky, TS Liu, K Tian, L Carr, J Carroll, TJ Berry, J Criqui, MH Ferrucci, L Guralnik, JM Kibbe, MR Kramer, CM Li, FY Xu, DX Zhao, XH Yuan, C McDermott, MM AF Polonsky, Tamar S. Liu, Kiang Tian, Lu Carr, James Carroll, Timothy J. Berry, Jarett Criqui, Michael H. Ferrucci, Luigi Guralnik, Jack M. Kibbe, Melina R. Kramer, Christopher M. Li, Feiyu Xu, Dongxiang Zhao, Xihao Yuan, Chun McDermott, Mary M. TI High-risk plaque in the superficial femoral artery of people with peripheral artery disease: Prevalence and associated clinical characteristics SO ATHEROSCLEROSIS LA English DT Article DE Atherosclerosis; Magnetic resonance imaging; Peripheral vascular disease; Plaque ID ANKLE-BRACHIAL INDEX; ACUTE CORONARY SYNDROME; RICH NECROTIC CORE; CAROTID PLAQUE; INTRAPLAQUE HEMORRHAGE; IN-VIVO; VULNERABLE PLAQUE; ATHEROSCLEROTIC PLAQUE; CEREBROVASCULAR EVENTS; LEG CIRCULATION AB Objective: We used magnetic resonance imaging (MRI) to study the prevalence and associated clinical characteristics of high-risk plaque (defined as presence of lipid-rich necrotic core [LRNC] and intraplaque hemorrhage) in the superficial femoral arteries (SFA) among people with peripheral artery disease (PAD). Background: The prevalence and clinical characteristics associated with high-risk plaque in the SFA are unknown. Methods: Three-hundred-three participants with PAD underwent MRI of the proximal SFA using a 1.5 T S platform. Twelve contiguous 2.5 mm cross-sectional images were obtained. Results: LRNC was present in 68 (22.4%) participants. Only one had intra-plaque hemorrhage. After adjusting for age and sex, smoking prevalence was higher among adults with LRNC than among those without LRNC (35.9% vs. 21.4%, p = 0.02). Among participants with vs. without LRNC there were no differences in mean percent lumen area (31% vs. 33%, p = 0.42), normalized mean wall area (0.71 vs. 0.70, p = 0.67) or maximum wall area (0.96 vs. 0.92, p = 0.54) in the SFA. Among participants with LRNC, cross-sectional images containing LRNC had a smaller percent lumen area (33% +/- 1% vs. 39% +/- 1%, p < 0.001), greater normalized mean wall thickness (0.25 +/- 0.01 vs. 0.22 +/- 0.01, p < 0.001), and greater normalized maximum wall thickness (0.41 +/- 0.01 vs. 0.31 +/- 0.01, p < 0.001), compared to cross-sectional images without LRNC. Conclusions: Fewer than 25% of adults with PAD had high-risk plaque in the proximal SFA using MRI. Smoking was the only clinical characteristic associated with presence of LRNC. Further study is needed to determine the prognostic significance of LRNC in the SFA. Clinical trial registrationdURL: http://www.clinicaltrials.gov.Unique identifier: NCT00520312. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Polonsky, Tamar S.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Liu, Kiang; McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Tian, Lu] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Carr, James; Carroll, Timothy J.] Northwestern Univ, Dept Biomed Engn & Radiol, Chicago, IL 60611 USA. [Berry, Jarett] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Ferrucci, Luigi] NIA, Lab Clin Epidemiol, Bethesda, MD 20892 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Kibbe, Melina R.] Northwestern Univ, Feinberg Sch Med, Div Vasc Surg, Chicago, IL 60611 USA. [Kramer, Christopher M.] Univ Virginia Hlth Syst, Dept Radiol & Med, Charlottesville, VA USA. [Li, Feiyu; Xu, Dongxiang; Zhao, Xihao; Yuan, Chun] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [McDermott, Mary M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. RP Polonsky, TS (reprint author), 5841 S Maryland Ave,MC 6080, Chicago, IL 60637 USA. EM tpolonsky@medicine.bsd.uchicago.edu; kiangliu@northwestern.edu; lutian@stanford.edu; jcarr@northwestern.edu; t-carroll@northwestern.edu; Jarett.Berry@UTSouthwestern.edu; mcriqui@ucsd.edu; FerrucciLu@grc.nia.nih.gov; JGuralnik@epi.umaryland.edu; mkibbe@nmh.org; ckramer@virginia.edu; redwindowlfy@yahoo.com.cn; xdx@uw.edu; xihao.zhao@gmail.com; cyuan@u.washington.edu; mdm608@northwestern.edu RI Carroll, Timothy/B-6934-2009 FU National Heart Lung and Blood Institute [R01-HL083064, R01-HL109244, 5T32-HL069771]; Intramural Research Program of the National Institute on Aging; Jesse Brown VA Medical Center FX Supported by the National Heart Lung and Blood Institute (R01-HL083064 and R01-HL109244), the Intramural Research Program of the National Institute on Aging, and the Jesse Brown VA Medical Center. Dr. Polonsky was supported by a training grant in Cardiovascular Epidemiology and Prevention from the National Heart Lung and Blood Institute (5T32-HL069771). The sources of funding had no role in the collection, analysis or interpretation of data. NR 41 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD NOV PY 2014 VL 237 IS 1 BP 169 EP 176 DI 10.1016/j.atherosclerosis.2014.08.034 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT5WT UT WOS:000345011300028 PM 25240112 ER PT J AU Simpson, EA Buchin, Z Werner, K Worrell, R Jakobsen, KV AF Simpson, Elizabeth A. Buchin, Zachary Werner, Katie Worrell, Rey Jakobsen, Krisztina V. TI Finding faces among faces: human faces are located more quickly and accurately than other primate and mammal faces SO ATTENTION PERCEPTION & PSYCHOPHYSICS LA English DT Article DE Face detection; Visual attention; Visual search; Search efficiency; Animal faces ID VISUAL-SEARCH; COLOR; PERCEPTION; POP; OWN AB We tested the specificity of human face search efficiency by examining whether there is a broad window of detection for various face-like stimuli-human and animal faces-or whether own-species faces receive greater attentional allocation. We assessed the strength of the own-species face detection bias by testing whether human faces are located more efficiently than other animal faces, when presented among various other species' faces, in heterogeneous 16-, 36-, and 64-item arrays. Across all array sizes, we found that, controlling for distractor type, human faces were located faster and more accurately than primate and mammal faces, and that, controlling for target type, searches were faster when distractors were human faces compared to animal faces, revealing more efficient processing of human faces regardless of their role as targets or distractors (Experiment 1). Critically, these effects remained when searches were for specific species' faces (human, chimpanzee, otter), ruling out a category-level explanation (Experiment 2). Together, these results suggest that human faces may be processed more efficiently than animal faces, both when task-relevant (targets) and task-irrelevant (distractors), even in direct competition with other faces. These results suggest that there is not a broad window of detection for all face-like patterns but that human adults process own-species' faces more efficiently than other species' faces. Such own-species search efficiencies may arise through experience with own-species faces throughout development or may be privileged early in development, due to the evolutionary importance of conspecifics' faces. C1 [Simpson, Elizabeth A.] Univ Parma, I-43100 Parma, Italy. [Simpson, Elizabeth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dickerson, MD 20842 USA. [Buchin, Zachary; Werner, Katie; Worrell, Rey; Jakobsen, Krisztina V.] James Madison Univ, Harrisonburg, VA 22807 USA. RP Simpson, EA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 16701 Elmer Sch Rd, Dickerson, MD 20842 USA. EM elizabethannsimpson@gmail.com OI Buchin, Zachary/0000-0003-3059-0411; Simpson, Elizabeth/0000-0003-2715-2533 FU National Institutes of Health, NICHD [P01HD064653-01]; Alvin V., Jr. and Nancy C. Baird Professorship FX The authors thank Janet Frick and the research assistants at the University of Georgia for help with stimulus preparation, and the research assistants at James Madison University for testing participants. This research was supported by the National Institutes of Health, NICHD P01HD064653-01 (EAS), and by the Alvin V., Jr. and Nancy C. Baird Professorship (KVJ). Portions of this data were presented at the Association for Psychological Science's 24th Annual Convention. NR 24 TC 3 Z9 3 U1 0 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1943-3921 EI 1943-393X J9 ATTEN PERCEPT PSYCHO JI Atten. Percept. Psychophys. PD NOV PY 2014 VL 76 IS 8 BP 2175 EP 2183 DI 10.3758/s13414-014-0744-x PG 9 WC Psychology; Psychology, Experimental SC Psychology GA AT6UH UT WOS:000345074200001 PM 25113852 ER PT J AU Winuthayanon, W Hewitt, SC Korach, KS AF Winuthayanon, Wipawee Hewitt, Sylvia C. Korach, Kenneth S. TI Uterine Epithelial Cell Estrogen Receptor Alpha-Dependent and -Independent Genomic Profiles That Underlie Estrogen Responses in Mice SO BIOLOGY OF REPRODUCTION LA English DT Article DE epithelium; estradiol/estradiol receptor; proliferation; stroma; uterus ID MESSENGER-RIBONUCLEIC-ACID; LEUKEMIA INHIBITORY FACTOR; MOUSE UTERUS; GENE-EXPRESSION; INDIAN HEDGEHOG; CROSS-TALK; ER-ALPHA; IN-VIVO; GROWTH; PROLIFERATION AB Estrogens exert their activity through estrogen receptor alpha (ERalpha) to stimulate hypertrophy and hyperplasia in the uterus. A uterine epithelial ERalpha conditional knockout mouse model (Wnt7a(Cre+); Esr1(f/f) or cKO) demonstrated that ERalpha in the epithelial cells was dispensable for an initial uterine proliferative response to 17beta-estradiol (E-2) but required for subsequent uterine biological responses. This study aimed to characterize the differential gene expression patterns induced by E-2 in the presence or absence of epithelial ERalpha. RNA microarray analysis revealed that approximately 20% of the genes differentially expressed at 2 h were epithelial ERalpha independent, as they were preserved in the cKO uteri. This indicates that early uterine transcripts mediated by stromal ERalpha are sufficient to promote initial proliferative responses. However, more than 90% of the differentially expressed transcripts at 24 h were not regulated in the cKO, indicating that the majority of later transcriptional regulation required epithelial ERalpha, especially those involved in mitosis. This shows that loss of regulation of these later transcripts results in blunted subsequent uterine growth after 3 days of E-2 treatment. Additionally, progesterone's ability to inhibit E-2-induced epithelial cell proliferation was impaired, consistent with a uterine receptivity defect that contributes to cKO infertility. These transcriptional profiles correlate with our previously observed biological responses, in which the initial proliferative response is independent of epithelial ERalpha and thus dependent on stromal ERalpha, yet epithelial ERalpha is essential for subsequent tissue responsiveness. C1 [Winuthayanon, Wipawee; Hewitt, Sylvia C.; Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU NIH, National Institute of Environmental Health Sciences [Z01ES70065] FX Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to K. S. K. (Z01ES70065). NR 40 TC 6 Z9 6 U1 0 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD NOV 1 PY 2014 VL 91 IS 5 AR 110 DI 10.1095/biolreprod.114.120170 PG 10 WC Reproductive Biology SC Reproductive Biology GA AT4UC UT WOS:000344937300012 PM 25210133 ER PT J AU Qian, WJ Park, JE Lim, D Lai, CC Kelley, JA Park, SY Lee, KW Yaffe, MB Lee, KS Burke, TR AF Qian, Wen-Jian Park, Jung-Eun Lim, Dan Lai, Christopher C. Kelley, James A. Park, Suk-Youl Lee, Ki Won Yaffe, Michael B. Lee, Kyung S. Burke, Terrence R., Jr. TI Mono-Anionic Phosphopeptides Produced by Unexpected Histidine Alkylation Exhibit High Plk1 Polo-Box Domain-Binding Affinities and Enhanced Antiproliferative Effects in HeLa Cells SO BIOPOLYMERS LA English DT Article DE Plk1; polo kinase; polo-box domain; crystal structure; cationic dialkyl histidine; intramolecular charge masking; phosphopeptides ID SMALL-MOLECULE INHIBITOR; KINASE 1 PLK1; CANCER-THERAPY; PEPTIDE; POLO-LIKE-KINASE-1; POSITION; PRODRUGS; TARGET; PHOSPHOTHREONINE; FRAGMENTATION AB Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides provide starting points for developing PBD-directed inhibitors, to date the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising, in part, from the di-anionic nature of the phosphoryl group or its mimetics. In our current article we report the unanticipated on-resin N()-alkylation of histidine residues already bearing a N()- alkyl group. This resulted in cationic imidazolium-containing pThr peptides, several of which exhibit single-digit nanomolar PBD-binding affinities in extracellular assays and improved antimitotic efficacies in intact cells. We enhanced the cellular efficacies of these peptides further by applying bio-reversible pivaloyloxymethyl (POM) phosphoryl protection. New structural insights presented in our current study, including the potential utility of intramolecular charge masking, may be useful for the further development of PBD-binding peptides and peptide mimetics. (c) 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 444-455, 2014. C1 [Qian, Wen-Jian; Lai, Christopher C.; Kelley, James A.; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lim, Dan; Yaffe, Michael B.] MIT, Dept Biol & Biol Engn, Ctr Canc Res, Cambridge, MA 02139 USA. [Park, Suk-Youl; Lee, Ki Won] Seoul Natl Univ, Adv Inst Convergence Technol, Suwon 443270, South Korea. [Lee, Ki Won] Seoul Natl Univ, World Class Univ Biomodulat Major, Seoul 151742, South Korea. [Lee, Ki Won] Seoul Natl Univ, Dept Agr Biotechnol, Seoul 151742, South Korea. RP Burke, TR (reprint author), NCI, NIH, Bldg 376 Boyles St, Frederick, MD 21702 USA. EM kyunglee@mail.nih.gov; tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU National Institutes of Health [ES015339, GM104047]; Intramural Research Program of the NIH; Center for Cancer Research; NCI-Frederick; National Cancer Institute; NCI Director's Innovation Career Development Award FX Contract grant sponsor: National Institutes of Health; Contract grant numbers: ES015339, GM104047; Contract grant sponsors: Intramural Research Program of the NIH; Center for Cancer Research; NCI-Frederick and the National Cancer Institute; NCI Director's Innovation Career Development Award NR 54 TC 9 Z9 9 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD NOV PY 2014 VL 102 IS 6 BP 444 EP 455 DI 10.1002/bip.22569 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AU1EX UT WOS:000345364900004 PM 25283071 ER PT J AU Jung, M Ranpura, VN Dunbar, CE Tisdale, JF Fitzhugh, CD Hsieh, MM AF Jung, M. Ranpura, V. N. Dunbar, C. E. Tisdale, J. F. Fitzhugh, C. D. Hsieh, M. M. TI Angioedema in patients treated with sirolimus and ACE inhibitor post hematopoietic SCT SO BONE MARROW TRANSPLANTATION LA English DT Letter ID ANGIOTENSIN-CONVERTING ENZYME; MAMMALIAN TARGET; RAPAMYCIN C1 [Jung, M.; Dunbar, C. E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Ranpura, V. N.] Washington Hosp Ctr, Dept Hematol & Oncol, Washington, DC 20010 USA. [Tisdale, J. F.; Fitzhugh, C. D.; Hsieh, M. M.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Jung, M (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM matthewhs@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL006007-06] NR 10 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD NOV PY 2014 VL 49 IS 11 BP 1448 EP 1449 DI 10.1038/bmt.2014.162 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA AT4RC UT WOS:000344927400021 PM 25068425 ER PT J AU Gage, JC Katki, HA Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Behrens, C Sharma, A Zhao, FH Cuzick, J Yang, ZH Kinney, WK AF Gage, Julia C. Katki, Hormuzd A. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Behrens, Catherine Sharma, Abha Zhao, Fang-Hui Cuzick, Jack Yang, Zi Hua Kinney, Walter K. TI The Low Risk of Precancer After A Screening Result of Human Papillomavirus-Negative/Atypical Squamous Cells of Undetermined Significance Papanicolaou and Implications for Clinical Management SO CANCER CYTOPATHOLOGY LA English DT Article DE human papillomavirus (HPV); cervical intraepithelial neoplasia (CIN); cytology; atypical squamous cells of undetermined significance (ASC-US) ID TERM-FOLLOW-UP; CERVICAL-CANCER; 5-YEAR RISKS; WOMEN; CYTOLOGY; HPV; GUIDELINES; IMPLEMENTATION; PROVINCE; TRIAL AB BACKGROUNDDifferent US practice guidelines have conflicting recommendations for when women should return after a screening result of human papillomavirus (HPV)-negative with an equivocal Papanicolaou (Pap) result of atypical squamous cells of undetermined significance (ASC-US) (ie, return in either 3 or 5 years). One way to determine management is to compare the risk of precancer/cancer after an HPV-negative/ASC-US result with the risks after other negative screening results. For example, if the risk after an HPV-negative/ASC-US result was similar to the risk after a negative Pap test, a 3-year return would be preferred because guidelines agree that women with negative Pap test results should return in 3 years. Alternatively, if the risk after an HPV-negative/ASC-US result is similar to that after a cotest-negative result (HPV negative/Pap test negative), a 5-year return would be preferred because guidelines agree that women testing cotest negative should return in 5 years. METHODSThe authors compared risks of cervical intraepithelial neoplasia of grade 3 or higher (CIN3+) and cervical cancer among women aged 30 years to 64 years at Kaiser Permanente Northern California with the following test results from 2003 through 2012: 17,191 women testing HPV negative/ASC-US; 980,268 women testing Pap test negative (regardless of HPV result); and 892,882 women testing cotest negative. RESULTSThe 5-year CIN3+ and cancer risks after an HPV-negative/ASC-US result were closer to the risks after a negative Pap test result (CIN3+: 0.48% vs 0.31% [P =.0019]; and cancer: 0.043% vs 0.031% [P =.4]) than after a negative cotest (CIN3+: 0.48% vs 0.11% [P<.0001]; and cancer: 0.043% vs 0.014% [P =.016]). CONCLUSIONSWomen testing HPV negative/ASC-US were found to have precancer/cancer risks that were more closely aligned with women with negative Pap test results, suggesting that women testing HPV negative/ASC-US should be managed similarly to women testing negative on Pap tests with a 3-year return for screening. Cancer (Cancer Cytopathol) 2014;122:842-850. (c) 2014 American Cancer Society. C1 [Gage, Julia C.; Katki, Hormuzd A.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente No Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Behrens, Catherine; Sharma, Abha] Roche Mol Syst, Pleasanton, CA USA. [Zhao, Fang-Hui] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Epidemiol, Beijing 100730, Peoples R China. [Zhao, Fang-Hui] Peking Union Med Coll, Beijing 100021, Peoples R China. [Cuzick, Jack; Yang, Zi Hua] Queen Mary Univ London, Wolfson Inst Prevent Med, Ctr Canc Prevent, London, England. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Gage, JC (reprint author), NCI, Clin Genet Branch, DCEG, NIH, 9609 Med Ctr Dr,MSC 9772, Bethesda, MD 20892 USA. EM gagej@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; OI Cheung, Li/0000-0003-1625-4331 NR 25 TC 11 Z9 12 U1 0 U2 1 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 NOV PY 2014 VL 122 IS 11 BP 842 EP 850 DI 10.1002/cncy.21463 PG 9 WC Oncology; Pathology SC Oncology; Pathology GA AT9DO UT WOS:000345228400009 PM 25045058 ER PT J AU Cheng, I Le, GM Noone, AM Gali, K Patel, M Haile, RW Wakelee, HA Gomez, SL AF Cheng, Iona Le, Gem M. Noone, Anne-Michelle Gali, Kathleen Patel, Manali Haile, Robert W. Wakelee, Heather A. Gomez, Scarlett L. TI Lung Cancer Incidence Trends by Histology Type among Asian American, Native Hawaiian, and Pacific Islander Populations in the United States, 1990-2010 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SMOKING-BEHAVIOR; NEVER-SMOKERS; RATES; RISK; ADENOCARCINOMA; ACCULTURATION; EPIDEMIOLOGY; ETHNICITY; SUSCEPTIBILITY; TUBERCULOSIS AB Background: Lung cancer is one of the leading cancer sites diagnosed among Asian Americans, Pacific Islanders, and Native Hawaiians (AANHPI). To better understand the patterns of lung cancer incidence among AANHPIs, we examined the incidence trends of five histologic cell types of lung cancer across ten AANHPI populations in comparison with non-Hispanic Whites. Methods: Lung cancer incidence data from 1990 through 2010 were obtained from 13 U.S. population-based cancer registries. Age-adjusted histologic cell-type-specific incidence rates and 95% confidence intervals were calculated. Joinpoint regression models and annual percentage change (APC) statistics were used to characterize the magnitude and direction of trends. Results: From 1990 through 2010, incidence rates of adenocarcinoma increased significantly for Filipino and Korean women with a 2.6% and 3.0% annual percentage increase, respectively. More recently, a significant rise in the incidence of adenocarcinoma was observed for Chinese men (1996-2010; APC = 1.3%). Squamous cell carcinoma (SCC) increased 2.4% per year among Japanese women. For SCC, small cell lung carcinoma, large cell and other specified carcinoma, and unspecified types, stable or decreasing trends were observed in most AANHPI groups and non-Hispanic Whites. Conclusions: AANHPIs demonstrate a range in the burden of lung cancer across histologies and specific populations. Impact: These findings illustrate the importance of disaggregating AANHPIs into their specific populations. The rise in incidence of adenocarcinoma and SCC among certain AANHPIs demonstrates the need for research into non-tobacco associated risk factors for these populations and targeted efforts for tobacco prevention. (C)2014 AACR. C1 [Cheng, Iona; Le, Gem M.; Gomez, Scarlett L.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Cheng, Iona; Le, Gem M.; Haile, Robert W.; Wakelee, Heather A.; Gomez, Scarlett L.] Stanford Canc Inst, Stanford, CA USA. [Le, Gem M.; Patel, Manali; Gomez, Scarlett L.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA. [Noone, Anne-Michelle] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Gali, Kathleen] Univ Calif Merced, Sch Social Sci Humanities & Arts, Social Cognit Sci Grad Grp, Merced, CA USA. [Patel, Manali; Haile, Robert W.; Wakelee, Heather A.] Stanford Univ, Dept Med, Sch Med, Div Oncol, Stanford, CA 94305 USA. RP Cheng, I (reprint author), Canc Prevent Inst Calif, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA. EM iona.cheng@cpic.org FU Stanford Cancer Institute; California Department of Health Services, statewide cancer reporting program [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] FX This work was supported by the Stanford Cancer Institute (to S. Glaser). 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. NR 55 TC 8 Z9 9 U1 4 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2250 EP 2265 DI 10.1158/1055-9965.EPI-14-0493 PG 16 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600007 PM 25368400 ER PT J AU Nguyen, AB Chawla, N Noone, AM Srinivasan, S AF Nguyen, Anh Bao Chawla, Neetu Noone, Anne-Michelle Srinivasan, Shobha TI Disaggregated Data and Beyond: Future Queries in Cancer Control Research SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID RURAL-URBAN DISPARITIES; HEALTH DISPARITIES; UNITED-STATES; MULTILEVEL INTERVENTIONS; PACIFIC ISLANDERS; SICK INDIVIDUALS; INCIDENCE TRENDS; LIFE EXPECTANCY; MODEL MINORITY; ALL-CAUSE AB The goal of health equity requires the collection and reporting of disaggregated data in underrepresented populations such as Asian American (AA) and Native Hawaiian and Other Pacific Islander (NHOPI) communities. A recent Department of Health and Human Services report outlines the necessity for disaggregated data, which would offer communities, providers, and planners better tools to address health problems. In a recent collaboration, the National Cancer Institute (NCI) and several registries published a series of articles tracking cancer incidence data on AA and NHOPI communities using data from the NCI's Surveillance, Epidemiology, and End Results (SEER) program. The findings indicate a need for concentrated focus and planning for the next stages of cancer prevention and control for AA and NHOPI subpopulations. In this article, we provide (i) the context for the perpetuation of the model minority myth as well as historical and sociocultural factors that have shaped health and disease for AA and NHOPI subgroups; (ii) potential strategies for research and public health policy for AA and NHOPI groups using subpopulation-based approaches while addressing challenges and limitations; and (iii) a portfolio analysis of currently funded projects within the NCI/DCCPS to identify gaps and areas of potential research. (C)2014 AACR. C1 [Nguyen, Anh Bao; Chawla, Neetu; Noone, Anne-Michelle; Srinivasan, Shobha] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. RP Nguyen, AB (reprint author), NCI, 9609 Med Ctr Dr 3E638, Rockville, MD 20850 USA. EM Anh.Nguyen3@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 49 TC 7 Z9 7 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2266 EP 2272 DI 10.1158/1055-9965.EPI-14-0387 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600008 PM 25368401 ER PT J AU Sivaram, S Sanchez, MA Rimer, BK Samet, JM Glasgow, RE AF Sivaram, Sudha Sanchez, Michael A. Rimer, Barbara K. Samet, Jonathan M. Glasgow, Russell E. TI Implementation Science in Cancer Prevention and Control: A Framework for Research and Programs in Low- and Middle-Income Countries SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID TO-CHILD-TRANSMISSION; CERVICAL-CANCER; COST-EFFECTIVENESS; TOBACCO SMOKING; HIGH COVERAGE; BREAST; INDIA; HEALTH; POLICY; HIV AB Implementation science is a set of tools, principles, and methodologies that can be used to bring scientific evidence into action, improve health care quality and delivery, and improve public health. As the burden of cancer increases in low- and middle-income countries, it is important to plan cancer control programs that are both evidence based and delivered in ways that are feasible, cost-effective, contextually appropriate, and sustainable. This review presents a framework for using implementation science for cancer control planning and implementation and discusses potential areas of focus for research and programs in low- and middle-income countries interested in integrating research into practice and policy. (C)2014 AACR. C1 [Sivaram, Sudha] NCI, Ctr Global Hlth, Rockville, MD 20850 USA. [Sanchez, Michael A.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Rimer, Barbara K.] UNC Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Samet, Jonathan M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Samet, Jonathan M.] Univ So Calif, Keck Sch Med, Inst Global Hlth, Los Angeles, CA 90033 USA. [Glasgow, Russell E.] Univ Colorado, Sch Med, Dept Family Med, Aurora, CO USA. RP Sivaram, S (reprint author), NCI, Ctr Global Hlth, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM sudha.sivaram@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 82 TC 3 Z9 3 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2273 EP 2284 DI 10.1158/1055-9965.EPI-14-0472 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600009 PM 25178984 ER PT J AU Rosenberg, PS Check, DP Anderson, WF AF Rosenberg, Philip S. Check, David P. Anderson, William F. TI A Web Tool for Age-Period-Cohort Analysis of Cancer Incidence and Mortality Rates SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CHRONIC DISEASE RATES; UNITED-STATES; BIRTH COHORT; ETIOLOGIC HETEROGENEITY; EUROPEAN COUNTRIES; TESTICULAR CANCER; TEMPORAL VARIATION; COLORECTAL-CANCER; INCIDENCE TRENDS; DEATH RATES AB Background: Age-period-cohort (APC) analysis can inform registry-based studies of cancer incidence and mortality, but concerns about statistical identifiability and interpretability, as well as the learning curves of statistical software packages, have limited its uptake. Methods: We implemented a panel of easy-to-interpret estimable APC functions and corresponding Wald tests in R code that can be accessed through a user-friendly Web tool. Results: Input data for the Web tool consist of age-specific numbers of events and person-years over time, in the form of a rate matrix of paired columns. Output functions include model-based estimators of cross-sectional and longitudinal age-specific rates, period and cohort rate ratios that incorporate the overall annual percentage change (net drift), and estimators of the age-specific annual percentage change (local drifts). The Web tool includes built-in examples for teaching and demonstration. User data can be input from a Microsoft Excel worksheet or by uploading a comma-separated-value file. Model outputs can be saved in a variety of formats, including R and Excel. Conclusions: APC methodology can now be carried out through a freely available user-friendly Web tool. The tool can be accessed at http://analysistools.nci.nih.gov/apc/. Impact: The Web tool can help cancer surveillance researchers make important discoveries about emerging cancer trends and patterns. (C) 2014 AACR. C1 [Rosenberg, Philip S.; Check, David P.; Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. RP Rosenberg, PS (reprint author), NCI, Biostat Branch, 9609 Med Ctr Dr,Room 7-E-130 MSC 9780, Bethesda, MD 20892 USA. EM rosenbep@mail.nih.gov RI Check, David/J-7184-2015 OI Check, David/0000-0003-3887-0493 FU Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics FX This research was supported entirely by the Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics. NR 52 TC 13 Z9 14 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2296 EP 2302 DI 10.1158/1055-9965.EPI-14-0300 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600011 PM 25146089 ER PT J AU Gierach, GL Geller, BM Shepherd, JA Patel, DA Vacek, PM Weaver, DL Chicoine, RE Pfeiffer, RM Fan, B Mahmoudzadeh, AP Wang, J Johnson, JM Herschorn, SD Brinton, LA Sherman, ME AF Gierach, Gretchen L. Geller, Berta M. Shepherd, John A. Patel, Deesha A. Vacek, Pamela M. Weaver, Donald L. Chicoine, Rachael E. Pfeiffer, Ruth M. Fan, Bo Mahmoudzadeh, Amir Pasha Wang, Jeff Johnson, Jason M. Herschorn, Sally D. Brinton, Louise A. Sherman, Mark E. TI Comparison of Mammographic Density Assessed as Volumes and Areas among Women Undergoing Diagnostic Image-Guided Breast Biopsy SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FIELD DIGITAL MAMMOGRAMS; X-RAY ABSORPTIOMETRY; CANCER RISK-FACTORS; FIBROGLANDULAR TISSUE; TUMOR LOCATION; UNITED-STATES; FORM; ASSOCIATION; LATERALITY AB Background: Mammographic density (MD), the area of non-fatty-appearing tissue divided by total breast area, is a strong breast cancer risk factor. Most MD analyses have used visual categorizations or computer-assisted quantification, which ignore breast thickness. We explored MD volume and area, using a volumetric approach previously validated as predictive of breast cancer risk, in relation to risk factors among women undergoing breast biopsy. Methods: Among 413 primarily white women, ages 40 to 65 years, undergoing diagnostic breast biopsies between 2007 and 2010 at an academic facility in Vermont, MD volume (cm(3)) was quantified in craniocaudal views of the breast contralateral to the biopsy target using a density phantom, whereas MD area (cm(2)) was measured on the same digital mammograms using thresholding software. Risk factor associations with continuous MD measurements were evaluated using linear regression. Results: Percent MD volume and area were correlated (r = 0.81) and strongly and inversely associated with age, body mass index (BMI), and menopause. Both measures were inversely associated with smoking and positively associated with breast biopsy history. Absolute MD measures were correlated (r = 0.46) and inversely related to age and menopause. Whereas absolute dense area was inversely associated with BMI, absolute dense volume was positively associated. Conclusions: Volume and area MD measures exhibit some overlap in risk factor associations, but divergence as well, particularly for BMI. Impact: Findings suggest that volume and area density measures differ in subsets of women; notably, among obese women, absolute density was higher with volumetric methods, suggesting that breast cancer risk assessments may vary for these techniques. (C) 2014 AACR. C1 [Gierach, Gretchen L.; Patel, Deesha A.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Geller, Berta M.; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael E.; Johnson, Jason M.; Herschorn, Sally D.] Univ Vermont, Burlington, VT USA. [Shepherd, John A.; Fan, Bo; Mahmoudzadeh, Amir Pasha; Wang, Jeff] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Gierach, GL (reprint author), NCI, NIH, 9609 Med Ctr Dr,Rm 7-E108, Bethesda, MD 20892 USA. EM gierachg@mail.nih.gov RI Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016; OI Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522; Mahmoudzadeh, Amir Pasha/0000-0003-4322-5325 FU Intramural Research Program of the NIH, National Cancer Institute; Breast Cancer Research Stamp Funds; NCI [U01CA70013, 1R21CA157254] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, and Breast Cancer Research Stamp Funds. Cooperative agreements U01CA70013 (to B.M. Geller, P.M. Vacek, D.L. Weaver, R.E. Chicoine, and S.D. Herschorn) and 1R21CA157254 (to J.A. Shepherd, B. Fan, and A.P. Mahmoudzadeh) from the NCI funded some of the data collection and image analysis for this study. NR 44 TC 11 Z9 11 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2338 EP 2348 DI 10.1158/1055-9965.EPI-14-0257 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600016 PM 25139935 ER PT J AU Huang, B Gao, YT Shu, XO Wen, WQ Yang, G Li, GL Courtney, R Ji, BT Li, HL Purdue, MP Zheng, W Cai, QY AF Huang, Bo Gao, Yu-Tang Shu, Xiao-Ou Wen, Wanqing Yang, Gong Li, Guoliang Courtney, Regina Ji, Bu-Tian Li, Hong-Lan Purdue, Mark P. Zheng, Wei Cai, Qiuyin TI Association of Leukocyte Mitochondrial DNA Copy Number with Colorectal Cancer Risk: Results from the Shanghai Women's Health Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID COACTIVATOR; BIOGENESIS; DEPLETION; DISEASES; NUCLEAR; STRESS; GENOME; MOUSE; LUNG AB Background: Mitochondria play an important role in cellular energy metabolism, free radical production, and apoptosis, and thus may be involved in cancer development. Methods: We evaluated mitochondrial DNA (mtDNA) copy number in peripheral leukocytes in relation to colorectal cancer risk in a case-control study of 444 colorectal cancer cases and 1,423 controls nested in the Shanghai Women's Health Study, a population-based, prospective cohort study. Relative mtDNA copy number was determined by a quantitative real-time PCR assay using peripheral leukocyte DNA samples collected at the time of study enrollment, before cancer diagnosis. Results: We found that baseline mtDNA copy number was lower among women who subsequently developed colorectal cancer [geometric mean, 0.277; 95% confidence interval (CI), 0.269-0.285] than among women who remained cancer-free (geometric mean, 0.288; 95% CI, 0.284-0.293; P = 0.0153). Multivariate adjusted ORs were 1.26 (95% CI, 0.93-1.70) and 1.44 (95% CI, 1.06-1.94) for the middle and lower tertiles of mtDNA copy number, respectively, compared with the upper tertile (highest mtDNA copy number; P-trend = 0.0204). The association varied little by the interval between blood collection and cancer diagnosis. Conclusions: Our data suggest that mtDNA copy number measured in peripheral leukocytes may be a potential biomarker useful for colorectal cancer risk assessment. Impact: If confirmed, mtDNA copy number measured in peripheral leukocytes may be a biomarker useful for colorectal cancer risk assessment. (C) 2014 AACR. C1 [Huang, Bo; Shu, Xiao-Ou; Wen, Wanqing; Yang, Gong; Li, Guoliang; Courtney, Regina; Zheng, Wei; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37232 USA. [Huang, Bo; Shu, Xiao-Ou; Wen, Wanqing; Yang, Gong; Li, Guoliang; Courtney, Regina; Zheng, Wei; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Dept Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37232 USA. [Huang, Bo; Shu, Xiao-Ou; Wen, Wanqing; Yang, Gong; Li, Guoliang; Courtney, Regina; Zheng, Wei; Cai, Qiuyin] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Huang, Bo] Guilin Med Univ, Sch Publ Hlth, Guilin, Guangxi, Peoples R China. [Gao, Yu-Tang; Li, Hong-Lan] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Ji, Bu-Tian; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Cai, QY (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, B-2104 Med Ctr North,1161 21st Ave South, Nashville, TN 37232 USA. EM qiuyin.cai@vanderbilt.edu RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU U.S. National Institutes of Health (NIH) [R37 CA070867]; Vanderbilt-Ingram Cancer Center; NIH [P30 CA068485] FX This study was supported by grant number R37 CA070867 (to W. Zheng) from the U.S. National Institutes of Health (NIH). Sample preparation and mtDNA copy-number assays were performed at the Survey and Biospecimen Shared Resource, which is supported in part by the Vanderbilt-Ingram Cancer Center and NIH grant number P30 CA068485 (to Q. Cai). NR 38 TC 5 Z9 5 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2357 EP 2365 DI 10.1158/1055-9965.EPI-14-0297 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600018 PM 25139937 ER PT J AU Black, A Pinsky, PF Grubb, RL Falk, RT Hsing, AW Chu, LS Meyer, T Veenstra, TD Xu, X Yu, K Ziegler, RG Brinton, LA Hoover, RN Cook, MB AF Black, Amanda Pinsky, Paul F. Grubb, Robert L., III Falk, Roni T. Hsing, Ann W. Chu, Lisa Meyer, Tamra Veenstra, Timothy D. Xu, Xia Yu, Kai Ziegler, Regina G. Brinton, Louise A. Hoover, Robert N. Cook, Michael B. TI Sex Steroid Hormone Metabolism in Relation to Risk of Aggressive Prostate Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID URINARY ESTROGEN METABOLITES; BREAST-CANCER; MASS-SPECTROMETRY; SCREENING TRIAL; UNITED-STATES; SERUM; MEN; METAANALYSIS; AMERICANS; ETIOLOGY AB Background: The combined action of androgens and estrogens-specifically their balance-may play a role in prostate carcinogenesis, but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer. Methods: In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort, we measured serum estrone, estradiol, and 13 estrogen metabolites, in the 2-, 4-, or 16-hydroxylation pathways, using an LC/MS-MS assay. Cases (n = 195) were non-Hispanic white men ages 55 to 70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason >= 7). Controls (n = 195) were non-Hispanic white men without prostate cancer who were frequency matched to cases by age and year at blood draw, and time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate ORs and 95% confidence intervals (95% CI). Results: Risk of aggressive prostate cancer was strongly inversely associated with estradiol: testosterone ratio (OR4th quartile vs. (1st) = 0.27; 95% CI, 0.12-0.59, P-trend = 0.003) and positively associated with 2: 16 alpha-hydroxyestrone ratio (OR4(th quartile) vs. (1st) = 2.44; 95% CI, 1.34-4.45, P-trend = 0.001). Individual estrogen metabolites were unrelated to risk. Conclusions: Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer. Impact: Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions. (C) 2014 AACR. C1 [Black, Amanda; Falk, Roni T.; Yu, Kai; Ziegler, Regina G.; Brinton, Louise A.; Hoover, Robert N.; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD 20850 USA. [Pinsky, Paul F.] NCI, Canc Prevent Div, NIH, US Dept HHS, Rockville, MD 20850 USA. [Grubb, Robert L., III] Washington Univ, St Louis, MO USA. [Hsing, Ann W.; Chu, Lisa] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann W.; Chu, Lisa] Stanford Canc Inst, Palo Alto, CA USA. [Meyer, Tamra] US Army Med Command, Pharmacovigilance Ctr, Falls Church, VA USA. [Veenstra, Timothy D.] C2N Diagnost, St Louis, MO USA. [Xu, Xia] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc Res Technol Program, Frederick, MD USA. RP Black, A (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 9609 Med Ctr Dr,Suite 7-E582,MSC 9773, Rockville, MD 20850 USA. EM blacka@mail.nih.gov RI Brinton, Louise/G-7486-2015; Cook, Michael/A-5641-2009 OI Brinton, Louise/0000-0003-3853-8562; Cook, Michael/0000-0002-0533-7302 FU Intramural Research Program of the National Cancer Institute, NIH; Leidos Biomedical Research, Inc. [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the National Cancer Institute, NIH. This work was performed, in part, under contract HHSN261200800001E with Leidos Biomedical Research, Inc. NR 37 TC 9 Z9 10 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2374 EP 2382 DI 10.1158/1055-9965.EPI-14-0700 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600020 PM 25178985 ER PT J AU Etemadi, A O'Doherty, MG Freedman, ND Hollenbeck, AR Dawsey, SM Abnet, CC AF Etemadi, Arash O'Doherty, Mark G. Freedman, Neal D. Hollenbeck, Albert R. Dawsey, Sanford M. Abnet, Christian C. TI A Prospective Cohort Study of Body Size and Risk of Head and Neck Cancers in the NIH-AARP Diet and Health Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MASS INDEX; CIGARETTE-SMOKING; NATIONAL INSTITUTES; INHANCE CONSORTIUM; POOLED ANALYSIS; UNITED-STATES; ORAL-CAVITY; EPIDEMIOLOGY; STATISTICS; ALCOHOL AB Background: The association between body size and head and neck cancers (HNCA) is unclear, partly because of the biases in case-control studies. Methods: In the prospective NIH-AARP cohort study, 218,854 participants (132,288 men and 86,566 women), aged 50 to 71 years, were cancer free at baseline (1995 and 1996), and had valid anthropometric data. Cox proportional hazards regression was used to examine the associations between body size and HNCA, adjusted for current and past smoking habits, alcohol intake, education, race, and fruit and vegetable consumption, and reported as HR and 95% confidence intervals (CI). Results: Until December 31, 2006, 779 incident HNCAs occurred: 342 in the oral cavity, 120 in the oro- and hypopharynx, 265 in the larynx, 12 in the nasopharynx, and 40 at overlapping sites. There was an inverse association between HNCA and body mass index, which was almost exclusively among current smokers (HR = 0.76 per each 5 U increase; 95% CI, 0.63-0.93), and diminished as initial years of follow-up were excluded. We observed a direct association with waist-to-hip ratio (HR = 1.16 per 0.1 U increase; 95% CI, 1.03-1.31), particularly for cancers of the oral cavity (HR, 1.40; 95% CI, 1.17-1.67). Height was also directly associated with total HNCAs (P = 0.02), and oro- and hypopharyngeal cancers (P < 0.01). Conclusions: The risk of HNCAs was associated inversely with leanness among current smokers, and directly with abdominal obesity and height. Impact: Our study provides evidence that the association between leanness and risk of HNCAs may be due to effect modification by smoking. (C)2014 AACR. C1 [Etemadi, Arash; Freedman, Neal D.; Dawsey, Sanford M.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Etemadi, Arash] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. [O'Doherty, Mark G.] Queens Univ, UKCRC Ctr Excellence Publ Hlth, Belfast, Antrim, North Ireland. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Etemadi, A (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM arash.etemadi@nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Etemadi, Arash/C-1386-2016 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Etemadi, Arash/0000-0002-3458-1072 NR 31 TC 3 Z9 3 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2422 EP 2429 DI 10.1158/1055-9965.EPI-14-0709-T PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600025 PM 25172872 ER PT J AU Parks, CG Miller, FW Satoh, M Chan, EKL Andrushchenko, Z Birnbaum, LS Jusko, TA Kissling, GE Patel, MD Rose, KM Weinberg, C Zeldin, DC Sandler, DP AF Parks, Christine G. Miller, Frederick W. Satoh, Minoru Chan, Edward K. L. Andrushchenko, Zhanna Birnbaum, Linda S. Jusko, Todd A. Kissling, Grace E. Patel, Mehul D. Rose, Kathryn M. Weinberg, Clarice Zeldin, Darryl C. Sandler, Dale P. TI Reproductive and Hormonal Risk Factors for Antinuclear Antibodies (ANA) in a Representative Sample of US Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; BREAST-CANCER; AUTOIMMUNE-DISEASE; RHEUMATOID-ARTHRITIS; HEALTHY-INDIVIDUALS; UNITED-STATES; IMMUNE-SYSTEM; ADULT-ONSET; VITAMIN-D; AUTOANTIBODIES AB Background: Autoantibodies are of growing interest in cancer research as potential biomarkers; yet, the determinants of autoimmunity are not well understood. Antinuclear antibodies (ANA) are common in the general population and are more prevalent in women and older adults. Here, we examined the relationship of ANA with reproductive and hormonal factors in a representative sample of U.S. women. Methods: We analyzed data on reproductive history and exogenous hormone use in relation to serum ANA in 2,037 females ages 12 years and older from the National Health and Nutrition Examination Survey (NHANES; 1999-2004). Estimated ANA prevalences were adjusted for sampling weights. Prevalence ORs (POR) and 95% confidence intervals (CI) were adjusted for age, race, and poverty-income ratio, and models were stratified by menopause status. Results: In premenopausal women ages 20 years and older, ANA prevalence was associated with parity (P < 0.001; parous vs. nulliparous POR -2.0; 95% CI, 1.2-3.4), but in parous women, ANAdid not vary by number of births, age at first birth, years since last birth, or breastfeeding. In postmenopausal women, ANA prevalence was associated with an older age at menarche (P = 0.019; age 16-20 vs. 10-12 years POR = 3.0; 95% CI, 1.6-5.9), but not with parity. Oral contraceptives and estrogen therapy were not associated with a higher ANA prevalence. Conclusions: Childbearing (having had one or more births) may explain age-associated elevations in ANA prevalence seen in premenopausal women. Impact: These findings highlight the importance of considering reproductive history in studies of autoimmunity and cancer in women. (C)2014 AACR. C1 [Parks, Christine G.; Birnbaum, Linda S.; Kissling, Grace E.; Weinberg, Clarice; Zeldin, Darryl C.; Sandler, Dale P.] NIEHS, NIH, Res Triangle Pk, NC 27599 USA. [Miller, Frederick W.] NIEHS, NIH, Bethesda, MD USA. [Satoh, Minoru] Univ Occupat & Environm Hlth, Kitakyushu, Fukuoka 807, Japan. [Chan, Edward K. L.] Univ Florida, Gainesville, FL USA. [Andrushchenko, Zhanna; Rose, Kathryn M.] Social & Sci Syst, Res Triangle Pk, NC USA. [Jusko, Todd A.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Patel, Mehul D.] Univ N Carolina, Chapel Hill, NC USA. RP Parks, CG (reprint author), NIEHS, Epidemiol Branch, A3-05,POB 12233, Res Triangle Pk, NC 27599 USA. EM Parks1@mail.nih.gov OI Miller, Frederick/0000-0003-2831-9593; Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU Intramural Program of the NIH, National Institute of Environmental Health Sciences [Z01ES-044005, Z01ES-101074]; NIH [K12 ES019852, P30 ES001247] FX This work was supported by the Intramural Program of the NIH, National Institute of Environmental Health Sciences (Z01ES-044005 and Z01ES-101074), and NIH grant K12 ES019852 and P30 ES001247 (to T.A. Jusko). NR 66 TC 4 Z9 4 U1 2 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2492 EP 2502 DI 10.1158/1055-9965.EPI-14-0429 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600033 PM 25086100 ER PT J AU Park, SL Caberto, CP Lin, Y Goodloe, RJ Dumitrescu, L Love, SA Matise, TC Hindorff, LA Fowke, JH Schumacher, FR Beebe-Dimmer, J Chen, C Hou, LF Thomas, F Deelman, E Han, Y Peters, U North, KE Heiss, G Crawford, DC Haiman, CA Wilkens, LR Bush, WS Kooperberg, C Cheng, I Le Marchand, L AF Park, S. Lani Caberto, Christian P. Lin, Yi Goodloe, Robert J. Dumitrescu, Logan Love, Shelly-Ann Matise, Tara C. Hindorff, Lucia A. Fowke, Jay H. Schumacher, Fredrick R. Beebe-Dimmer, Jennifer Chen, Chu Hou, Lifang Thomas, Fridtjof Deelman, Ewa Han, Ying Peters, Ulrike North, Kari E. Heiss, Gerardo Crawford, Dana C. Haiman, Christopher A. Wilkens, Lynne R. Bush, William S. Kooperberg, Charles Cheng, Iona Le Marchand, Loic TI Association of Cancer Susceptibility Variants with Risk of Multiple Primary Cancers: The Population Architecture using Genomics and Epidemiology Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CAUSE-SPECIFIC MORTALITY; URINARY-BLADDER CANCER; BASAL-CELL CARCINOMA; WIDE ASSOCIATION; BREAST-CANCER; PROSTATE-CANCER; LUNG-CANCER; COMMON VARIANTS AB Background: Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). Methods: As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. Results: A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P <= 0.046). These associations did not show significant heterogeneity by smoking status (P-heterogeneity >= 0.53). Conclusions: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. Impact: These findings may help to identify genetic regions associated with IMPC risk. (C)2014 AACR. C1 [Park, S. Lani; Schumacher, Fredrick R.; Han, Ying; Haiman, Christopher A.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Caberto, Christian P.; Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Lin, Yi; Chen, Chu; Peters, Ulrike; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Goodloe, Robert J.; Dumitrescu, Logan] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Dumitrescu, Logan] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Love, Shelly-Ann; North, Kari E.; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Matise, Tara C.] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Fowke, Jay H.] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Nashville, TN 37235 USA. [Beebe-Dimmer, Jennifer] Wayne State Univ, Sch Med, Detroit, MI USA. [Beebe-Dimmer, Jennifer] Karmanos Canc Inst, Detroit, MI USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc, Dept Prevent Med, Chicago, IL 60611 USA. [Thomas, Fridtjof] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Deelman, Ewa] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, CA USA. [Crawford, Dana C.; Bush, William S.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Inst Computat Biol, Cleveland, OH 44106 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. RP Park, SL (reprint author), Univ So Calif, Dept Prevent Med, Keck Sch Med, 1450 Biggy St,NRT 1509G, Los Angeles, CA 90033 USA. EM sungship@usc.edu OI Bush, William/0000-0002-9729-6519 FU NHGRI - CALiCo [U01HG004803]; NHGRI - EAGLE [U01HG004798]; NHGRI - MEC [U01HG004802]; NHGRI -WHI [U01HG004790]; NHGRI - Coordinating Center [U01HG004801]; NHGRI [U01HG004803, U01HG004798, U01HG004801]; NHGRI PAGE program [U01HG004802, U01HG004790]; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; NIH [P30 CA014089]; National Heart, Lung, and Blood Institute; U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 3211832119, 32122, 42107-26, 42129-32, 44221] FX (a) The PAGE program is funded by the NHGRI, supported by U01HG004803 (CALiCo; awarded to K.E. North and G. Heiss), U01HG004798 (EAGLE; awarded to D.C. Crawford), U01HG004802 (MEC; awarded to L. Le Marchand), U01HG004790 (WHI; awarded to C. Kooperberg), and U01HG004801 (Coordinating Center; awarded to T.C. Matise), and their respective NHGRI American Recovery and Reinvestment Act of 2009 (ARRA) supplements.; (b) The data and materials included in this report result from a collaboration between the following studies:; S.L. Park, C.P. Caberto, I. Cheng, L. Le Marchand, C.A. Haiman, L.R. Wilkens, F.R. Schumacher, and Y. Han are affiliated with the MEC study. The MEC study characterization of epidemiologic architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). This work is also supported, in part, by NIH grant P30 CA014089 to the Norris Comprehensive Cancer Center (S.L. Park).; J. Beebe-Dimmer, C. Chen, L. Hou, C. Kooperberg, Y. Lin, U. Peters, and F. Thomas are affiliated with the WHI study. Funding support for the "Epidemiology of putative genetic variants: The Women's Health Initiative" study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 3211832119, 32122, 42107-26, 42129-32, and 44221.; W.S. Bush, D.C. Crawford, L. Dumitrescu, J.H. Fowke, and R.J. Goodloe are affiliated with EAGLE study, which is supported by NHGRI U01HG004798.; G. Heiss, S. Love, and K.E. North are affiliated with the CALiCo consortium, which is supported by NHGRI U01HG004803.; E. Deelman and T.C. Matise are affiliated with Coordinating Center, which is supported by the NHGRI U01HG004801. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. L.A. Hindorff is an epidemiology and program director in the Division of Genomic Medicine at the NHGRI. She is the project scientist for the PAGE study. NR 100 TC 7 Z9 7 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2568 EP 2578 DI 10.1158/1055-9965.EPI-14-0129 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600041 PM 25139936 ER PT J AU Sklavos, MM Zhou, CK Pinto, LA Cook, MB AF Sklavos, Martha M. Zhou, Cindy Ke Pinto, Ligia A. Cook, Michael B. TI Prediagnostic Circulating Anti-Mullerian Hormone Concentrations Are Not Associated with Prostate Cancer Risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SCREENING TRIAL; OVARIAN; MEN; PROGRESSION; GROWTH; CELLS; LUNG AB Despite considerable research, the pathogenesis of prostate cancer remains poorly understood. Meanwhile, PSA testing has shifted prostate cancer case populations for study to include a greater proportion of asymptomatic and indolent disease. Thus, efforts to identify prostate cancer biomarkers-particularly for aggressive disease-are required to elucidate pathogenesis and aid screening efficacy. Current evidence suggests that decreased circulating concentrations of the testis-derived, TGF beta family peptide hormone-anti-Mullerian hormone (AMH)-may be associated with prostate cancer pathogenesis. To test this hypothesis, we measured AMH concentrations in prediagnostic (cohort baseline) sera using the Beckman Coulter AMH Gen II ELISA in 1,000 cases and 1,000 controls nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Controls were frequency matched to cases on age at entry, enrollment year, and years of follow-up. Unconditional logistic regression models, adjusted for age at randomization, were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). We found that prediagnostic serologic AMH concentrations were not significantly associated with total (ORQ4 (vs. Q1) = 1.15; 95% CI, 0.89-1.48; P-trend = 0.13), aggressive (ORQ4 vs. Q1 = 1.14; 95% CI, 0.80-1.63; P-trend = 0.51), or nonaggressive (ORQ4 vs. Q1 = 1.22; 95% CI, 0.91-1.63; P-trend = 0.07) prostate cancer risks. Different definitions of aggressive disease did not meaningfully alter these results. Despite in vitro studies linking AMH to prostate cancer, this first analysis of prediagnostic, circulating AMH concentrations in men provides no evidence for an association with prostate cancer risk. (C)2014 AACR. C1 [Sklavos, Martha M.; Pinto, Ligia A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Human Papillomavirus Immunol Lab, Frederick, MD USA. [Zhou, Cindy Ke; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zhou, Cindy Ke] George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. RP Cook, MB (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 7E106, Bethesda, MD 20892 USA. EM michael.cook@nih.gov RI Zhou, Cindy /H-2165-2015; Cook, Michael/A-5641-2009 OI Zhou, Cindy /0000-0003-4814-4305; Cook, Michael/0000-0002-0533-7302 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Department of Health and Human Services; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, and funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. NR 20 TC 1 Z9 1 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2597 EP 2602 DI 10.1158/1055-9965.EPI-14-0803 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600044 PM 25159294 ER PT J AU Schully, SD Rogers, SD Lam, TK Chang, CQ Clyne, M Cyr, J Watson, D Khoury, MJ AF Schully, Sheri D. Rogers, Scott D. Lam, Tram Kim Chang, Christine Q. Clyne, Mindy Cyr, Jean Watson, Daniel Khoury, Muin J. TI The Cancer Genomics and Epidemiology Navigator: An NCI Online Tool to Enhance Cancer Epidemiology Research SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 [Schully, Sheri D.; Rogers, Scott D.; Lam, Tram Kim; Khoury, Muin J.] Epidemiol & Genom Res Program, Bethesda, MD USA. [Chang, Christine Q.] NHGRI, Bethesda, MD 20892 USA. [Clyne, Mindy] Kelly Serv, Troy, MI USA. [Cyr, Jean; Watson, Daniel] Informat Management Serv Inc, Rockville, MD USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. RP Schully, SD (reprint author), NCI, NIH, 9609 Med Ctr Dr 4E106, Bethesda, MD 20850 USA. EM schullys@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 3 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2610 EP 2611 DI 10.1158/1055-9965.EPI-14-0902 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600049 PM 25368405 ER PT J AU Pinto, BM Demark-Wahnefried, W Rowland, JH Aziz, NM AF Pinto, Bernardine M. Demark-Wahnefried, Wendy Rowland, Julia H. Aziz, Noreen M. TI Accelerometer Determined Lifestyle Behaviors Over Time-Letter SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter ID CANCER C1 [Pinto, Bernardine M.] Brown Univ, Miriam Hosp, Ctr Behav & Prevent Med, Providence, RI USA. [Pinto, Bernardine M.] Brown Univ, W Alpert Sch Med, Providence, RI 02912 USA. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH DHHS, Bethesda, MD 20892 USA. [Aziz, Noreen M.] NINR, NIH DHHS, Bethesda, MD 20892 USA. RP Pinto, BM (reprint author), Ctr Behav & Prevent Med, 164 Summit Ave, Providence, RI 02906 USA. EM bpinto@lifespan.org FU NCI NIH HHS [R01 CA132854] NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD NOV PY 2014 VL 23 IS 11 BP 2612 EP 2612 DI 10.1158/1055-9965.EPI-14-0916 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9YL UT WOS:000345279600050 PM 25368406 ER PT J AU Ngu, JMC Teng, G Meijndert, HC Mewhort, HE Turnbull, JD Stetler-Stevenson, WG Fedak, PWM AF Ngu, Janet M. C. Teng, Guoqi Meijndert, Hans Christopher Mewhort, Holly E. Turnbull, Jeannine D. Stetler-Stevenson, William G. Fedak, Paul W. M. TI Human cardiac fibroblast extracellular matrix remodeling: dual effects of tissue inhibitor of metalloproteinase-2 SO CARDIOVASCULAR PATHOLOGY LA English DT Article DE TIMP-2; Extracellular matrix; Cardiac fibroblasts; Remodelling; Human cells ID COLLAGEN GEL CONTRACTION; MUSCLE ACTIN EXPRESSION; HUMAN-SKIN FIBROBLASTS; MYOFIBROBLAST DIFFERENTIATION; 3-DIMENSIONAL COLLAGEN; ENDOTHELIAL-CELLS; IN-VIVO; TIMP-2; ACTIVATION; MECHANISM AB Objective: Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinases (MMPs) that attenuates maladaptive cardiac remodeling in ischemic heart failure. We examined the effects of TIMP-2 on human cardiac fibroblast activation and extracellular matrix (ECM) remodeling. Methods: Human cardiac fibroblasts within a three-dimensional collagen matrix were assessed for phenotype conversion, ECM architecture and key molecular regulators of ECM remodeling after differential exposure to TIMP-2 and Ala+TIMP-2 (a modified TIMP-2 analogue devoid of MMP inhibitory activity). Results: TIMP-2 induced opposite effects on human cardiac fibroblast activation and ECM remodeling depending on concentration. TIMP-2 activated fibroblasts into contractile myofibroblasts that remodeled ECM. At higher concentrations (> 10 nM), TIMP-2 inhibited fibroblast activation and prevented ECM remodeling. As compared to profibrotic cytokine transforming growth factor (TGF)-beta1, TIMP-2 activated fibroblasts and remodeled ECM without a net accumulation of matrix elements. TIMP-2 increased total protease activity as compared to TGF-beta1. Ala+TIMP-2 exposure revealed that the actions of TIMP-2 on cardiac fibroblast activation are independent of its effects on MMP inhibition. In the presence of GM6001, a broad-spectrum MMP inhibitor, TIMP-2-mediated ECM contraction was completely abolished, indicating that TIMP-2-mediated fibroblast activation is MMP dependent. Conclusion: TIMP-2 functions in a contextual fashion such that the effect on cardiac fibroblasts depends on the tissue microenvironment. These observations highlight potential clinical challenges in using TIMP-2 as a therapeutic strategy to attenuate postinjury cardiac remodeling. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ngu, Janet M. C.; Teng, Guoqi; Meijndert, Hans Christopher; Mewhort, Holly E.; Turnbull, Jeannine D.; Fedak, Paul W. M.] Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Cardiac Sci, Sect Cardiac Surg, Calgary, AB, Canada. [Stetler-Stevenson, William G.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Fedak, PWM (reprint author), C880,1403-29 St NW, Calgary, AB T2N 2T9, Canada. EM paul.fedak@gmail.com RI Stetler-Stevenson, William/H-6956-2012; OI Stetler-Stevenson, William/0000-0002-5500-5808; , Paul/0000-0003-0658-9381 FU Heart and Stroke Foundation of Alberta; NWT; Nunavut; AIHS; NCI Center for Cancer Research Intramural Research Program Grant [ZIA-SC009179-22] FX This work was supported by the Heart and Stroke Foundation of Alberta, NWT, and Nunavut. P. W. M. F. is a clinical investigator for Alberta Innovates-Health Solutions (AIHS). H. E. M. receives salary support from the AIHS. W.G.S.-S. was funded by the NCI Center for Cancer Research Intramural Research Program Grant (ZIA-SC009179-22). The authors have no conflicts of interest to disclose. NR 34 TC 5 Z9 5 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-8807 EI 1879-1336 J9 CARDIOVASC PATHOL JI Cardiovasc. Pathol. PD NOV-DEC PY 2014 VL 23 IS 6 BP 335 EP 343 DI 10.1016/j.carpath.2014.06.003 PG 9 WC Cardiac & Cardiovascular Systems; Pathology SC Cardiovascular System & Cardiology; Pathology GA AT4XC UT WOS:000344944400003 PM 25060386 ER PT J AU Aslibekyan, S Dashti, HS Tanaka, T Sha, J Ferrucci, L Zhi, DG Bandinelli, S Borecki, IB Absher, DM Arnett, DK Ordovas, JM AF Aslibekyan, Stella Dashti, Hassan S. Tanaka, Toshiko Sha, Jin Ferrucci, Luigi Zhi, Degui Bandinelli, Stefania Borecki, Ingrid B. Absher, Devin M. Arnett, Donna K. Ordovas, Jose M. TI PRKCZ methylation is associated with sunlight exposure in a North American but not a Mediterranean population SO CHRONOBIOLOGY INTERNATIONAL LA English DT Article DE Epigenetics; methylation; protein kinase C; sunlight ID LIPID-LOWERING DRUGS; DIET NETWORK; WIDE ASSOCIATION; GENETICS; CLOCK; CELLS; LIGHT AB Sunlight exposure has been shown to alter DNA methylation patterns across several human cell-types, including T-lymphocytes. Since epigenetic changes establish gene expression profiles, changes in DNA methylation induced by sunlight exposure warrant investigation. The purpose of this study was to assess the effects of sunlight exposure on CD4+ T-cell methylation patterns on an epigenome-wide scale in a North American population of European origin (n = 991). In addition, we investigated the genetic contribution to epigenetic variation (methylQTL). We used linear regression to test the associations between methylation scores at 461 281 cytosine-phosphate- guanine (CpG) sites and sunlight exposure, followed by a genome-wide association analysis (methylQTL) to test for associations between methylation at the top CpG locus and common genetic variants, assuming an additive genetic model. We observed an epigenome-wide significant association between sunlight exposure and methylation status at cg26930596 (p = 9.2 x 10(-8)), a CpG site located in protein kinase C zeta (PRKCZ), a gene previously shown to be entrained by light. MethylQTL analysis resulted in significant associations between cg26930596 and two intergenic single nucleotide polymorphisms on chromosome 3, rs4574216 (p = 1.5 x 10(-10)) and rs4405858 (p = 1.9 x 10(-9)). These common genetic variants reside downstream of WWTR1, a transcriptional co-activator of PRKCZ. Associations observed in the North American population, however, did not replicate in an independent Mediterranean cohort. Our preliminary results support the role of sunlight exposure in epigenetic processes, and lay the groundwork for future studies of the molecular link between sunlight and physiologic processes such as tumorigenesis and metabolism. C1 [Aslibekyan, Stella; Sha, Jin; Arnett, Donna K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Dashti, Hassan S.; Ordovas, Jose M.] Tufts Univ, Jean Mayer US Dept Agr Human Nutr, Res Ctr Aging, Boston, MA 02111 USA. [Tanaka, Toshiko; Ferrucci, Luigi] Harbor Hosp, Natl Inst Aging, Translat Gerontol Branch, Baltimore, MD USA. [Zhi, Degui] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Borecki, Ingrid B.] Washington Univ, Div Stat Genom, St Louis, MO USA. [Absher, Devin M.] Hudson Alpha Inst Biotechnol, Huntsville, AL USA. [Ordovas, Jose M.] CNIC, Dept Epidemiol, Madrid, Spain. [Ordovas, Jose M.] Inst Madrilen Estudios Avanzados Alimentacio IMDE, Madrid, Spain. RP Aslibekyan, S (reprint author), Univ Alabama Birmingham, Dept Epidemiol, RPHB 230J, Birmingham, AL 35294 USA. EM stella7@gmail.com FU National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) [U01HL072524-04]; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336] FX The work on the GOLDN study has been funded by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI), grant U01HL072524-04. The InCHIANTI study baseline (1998-2000) was supported as a "targeted project'' (ICS110.1/RF97.71) by the Italian Ministry of Health and, in part, by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). NR 36 TC 1 Z9 1 U1 1 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0742-0528 EI 1525-6073 J9 CHRONOBIOL INT JI Chronobiol. Int. PD NOV PY 2014 VL 31 IS 9 BP 1034 EP 1040 DI 10.3109/07420528.2014.944266 PG 7 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA AT9HC UT WOS:000345237600010 PM 25075435 ER PT J AU Captur, G Lopes, LR Mohun, TJ Patel, V Li, CM Bassett, P Finocchiaro, G Ferreira, VM Esteban, MT Muthurangu, V Sherrid, MV Day, SM Canter, CE McKenna, WJ Seidman, CE Bluemke, DA Elliott, PM Ho, CY Moon, JC AF Captur, Gabriella Lopes, Luis R. Mohun, Timothy J. Patel, Vimal Li, Chunming Bassett, Paul Finocchiaro, Gherardo Ferreira, Vanessa M. Esteban, Maite Tome Muthurangu, Vivek Sherrid, Mark V. Day, Sharlene M. Canter, Charles E. McKenna, William J. Seidman, Christine E. Bluemke, David A. Elliott, Perry M. Ho, Carolyn Y. Moon, James C. TI Prediction of Sarcomere Mutations in Subclinical Hypertrophic Cardiomyopathy SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE cardiomyopathy, hypertrophic; genetics; magnetic resonance imaging ID CARDIOVASCULAR MAGNETIC-RESONANCE; LEFT-VENTRICULAR HYPERTROPHY; MYOCARDIAL CRYPTS; DIAGNOSTIC-CRITERIA; DIASTOLIC FUNCTION; FRACTAL ANALYSIS; TASK-FORCE; CARRIERS; ABNORMALITIES; DIVERTICULA AB Background-Sarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]). Methods and Results-A multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29 +/- 13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for >= 1 crypt, beta=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for >= 2 crypts, beta=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (beta=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (beta=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (beta=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045). Conclusions-The subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study. C1 [Captur, Gabriella; Lopes, Luis R.; Patel, Vimal; Muthurangu, Vivek; McKenna, William J.; Elliott, Perry M.; Moon, James C.] UCL, Dept Cardiovasc Sci, London, England. [Bassett, Paul] UCL, Biostat Joint Res Off, London, England. [Captur, Gabriella; Lopes, Luis R.; Patel, Vimal; Esteban, Maite Tome; McKenna, William J.; Elliott, Perry M.; Moon, James C.] Barts Heart Ctr, Dept Inherited Cardiovasc Dis, London, England. [Captur, Gabriella; Finocchiaro, Gherardo; Esteban, Maite Tome; McKenna, William J.; Moon, James C.] Barts Heart Ctr, Cardiac Imaging Dept, London, England. [Mohun, Timothy J.] MRC Natl Inst Med Res, Dept Dev Biol, Mill Hill, England. [Li, Chunming] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Ferreira, Vanessa M.] Univ Oxford, John Radcliffe Hosp, Ctr Clin Magnet Resonance Res OCMR, Radcliffe Dept Med,Div Cardiovasc Med, Oxford OX3 9DU, England. [Muthurangu, Vivek] Great Ormond St Hosp Sick Children, Dept Cardiovasc Imaging, London WC1N 3JH, England. [Sherrid, Mark V.] Icahn Sch Med Mt Sinai, Mt Sinai Roosevelt Hosp, Dept Cardiol, New York, NY 10029 USA. [Day, Sharlene M.] Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA. [Canter, Charles E.] Washington Univ, Sch Med, Dept Pediat Cardiol, St Louis, MO USA. [Seidman, Christine E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Bluemke, David A.] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. [Ho, Carolyn Y.] Brigham & Womens Hosp, Cardiovasc Dept, Boston, MA 02115 USA. RP Moon, JC (reprint author), Heart Hosp, Imaging Ctr, 16-18 Westmoreland St, London, England. EM j.moon@ucl.ac.uk RI McKenna, William/C-3243-2008; OI McKenna, William/0000-0001-7994-2460; Ho, Carolyn/0000-0002-7334-7924; Ferreira, Vanessa/0000-0002-0046-7634; Lopes, Luis/0000-0002-6408-4667; Bluemke, David/0000-0002-8323-8086; moon, james/0000-0001-8071-1491; Sherrid, Mark/0000-0003-4972-7780 FU University College London Institute of Life Sciences' Charlotte and Yule Bogue Research Fellowship; European Union Science and Technology Research and Innovation Program (European Social Fund under the Operational Programme II - 5th Call of the Strategic Educational Pathways Scholarship, STEPS) National Institutes of Health Intramural Research Program; Gulbenkian Doctoral Programme for Advanced Medical Education; Fundacao Calouste Gulbenkian; Fundacao Champalimaud; Ministerio da Saude; Fundacao para a Ciencia e Tecnologia, Portugal; National Institute for Health Research University College London Hospitals Biomedical Research Center; National Heart, Lung, and Blood Institute at the National Institutes of Health FX This work was funded by: University College London Institute of Life Sciences' Charlotte and Yule Bogue Research Fellowship; European Union Science and Technology Research and Innovation Program (European Social Fund under the Operational Programme II - 5th Call of the Strategic Educational Pathways Scholarship, STEPS) National Institutes of Health Intramural Research Program; and Gulbenkian Doctoral Programme for Advanced Medical Education, sponsored by Fundacao Calouste Gulbenkian, Fundacao Champalimaud, Ministerio da Saude and Fundacao para a Ciencia e Tecnologia, Portugal, and supported by National Institute for Health Research University College London Hospitals Biomedical Research Center and National Heart, Lung, and Blood Institute at the National Institutes of Health. NR 36 TC 18 Z9 19 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD NOV PY 2014 VL 7 IS 6 BP 863 EP + DI 10.1161/CIRCIMAGING.114.002411 PG 22 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AU0CA UT WOS:000345289500005 PM 25228707 ER PT J AU Nesbitt, T Doctorvaladan, S Southard, JA Singh, S Fekete, A Marie, K Moser, DK Pelter, MM Robinson, S Wilson, MD Cooper, L Dracup, K AF Nesbitt, Thomas Doctorvaladan, Sahar Southard, Jeffrey A. Singh, Satinder Fekete, Anne Marie, Kate Moser, Debra K. Pelter, Michelle M. Robinson, Susan Wilson, Machelle D. Cooper, Lawton Dracup, Kathleen TI Correlates of Quality of Life in Rural Patients With Heart Failure SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; quality of life; rural population ID HEALTH; PREDICTORS; CARE; HOSPITALIZATION; MORTALITY; READMISSION; POPULATION; OUTCOMES; DISEASE AB Background-There is abundant research indicating poor physical, psychological, and social functioning of patients with chronic heart failure (HF), a reality that can lead to poor health-related quality of life (QoL). Little is known about the experience of rural patients with HF. Methods and Results-This study was part of a randomized clinical trial titled Rural Education to Improve Outcomes in Heart Failure (REMOTE-HF) designed to test an education and counseling intervention to improve self-care in patients with HF. We evaluated 612 rural patients. Multiple validated questionnaires were administered to assess patient perceptions of health and health literacy. Baseline factors were collected and compared with baseline QoL measures only. Patients' health-related QoL was assessed using the Minnesota Living with Heart Failure scale. The data were analyzed using a general linear model to test the association of various patient characteristics with QoL in rural patients with HF. Patients were 65.8 (+12.9) years of age. The majority were men (58.7%), married (56.4%), and had completed a high-school education (80.9%). Factors associated with reduced QoL among this population include geographic location, younger age, male sex, higher New York Heart Association class, worse HF knowledge, poorer perceived control, and symptoms of depression or anxiety. The data provided no evidence of an association between left ventricular ejection fraction and QoL. Conclusions-This study of rural patients with HF confirms previously identified factors associated with perceptions of QoL. However, further study is warranted with an urban control group. C1 [Nesbitt, Thomas] Univ Calif Davis, Sch Med, Strateg Technol & Alliances, Davis, CA 95616 USA. [Doctorvaladan, Sahar] Univ Calif Davis, Sch Med, Davis, CA 95616 USA. [Southard, Jeffrey A.] Univ Calif Davis, Div Cardiovasc Med, Davis, CA 95616 USA. [Singh, Satinder] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Fekete, Anne] Univ Calif Davis, Clin Translat Sci Ctr, Davis, CA 95616 USA. [Marie, Kate] Univ Calif Davis, Ctr Hlth & Technol, Davis, CA 95616 USA. [Wilson, Machelle D.] Univ Calif Davis, Sch Med, Div Biostat, Davis, CA 95616 USA. [Moser, Debra K.] Univ Kentucky, Ctr Biobehav Res Self Management Cardiopulm Dis, Coll Nursing, Lexington, KY 40506 USA. [Pelter, Michelle M.] Univ Nevada, Orvis Sch Nursing, Reno, NV 89557 USA. [Robinson, Susan; Dracup, Kathleen] Univ Calif San Francisco, Dept Physiol Nursing, Sch Nursing, San Francisco, CA USA. [Cooper, Lawton] NHLBI, Bethesda, MD 20892 USA. RP Southard, JA (reprint author), Univ Calif Davis, Davis Med Ctr, Div Cardiovasc Med, 4860 Y St,Suite 2820, Sacramento, CA 95817 USA. EM jeffrey.southard@ucdmc.ucdavis.edu OI Wilson, Machelle/0000-0003-1734-2755 FU National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000002]; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Nursing Research [5R01HL83176-5] FX The project described was supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant No. UL1 TR000002 (www.ClincalTrials.gov-NCT00415545). This study was funded by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Nursing Research: 5R01HL83176-5. NR 41 TC 4 Z9 5 U1 2 U2 7 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 NOV PY 2014 VL 7 IS 6 BP 882 EP 887 DI 10.1161/CIRCHEARTFAILURE.113.000577 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU0BS UT WOS:000345288800004 PM 25146960 ER PT J AU Yamamizu, K Schlessinger, D Ko, MSH AF Yamamizu, Kohei Schlessinger, David Ko, Minoru S. H. TI SOX9 accelerates ESC differentiation to three germ layer lineages by repressing SOX2 expression through P21 (WAF1/CIP1) SO DEVELOPMENT LA English DT Article DE Embryonic stem cells; Sox9; Sox2; Cdkn1a; (P21/WAF1/CIP1) ID EMBRYONIC STEM-CELLS; TRANSCRIPTION FACTOR SOX9; AUTOSOMAL SEX REVERSAL; SRY-RELATED GENE; SELF-RENEWAL; DEFINED FACTORS; CAMPOMELIC DYSPLASIA; DIRECT CONVERSION; UP-REGULATION; GENOME-WIDE AB Upon removal of culture conditions that maintain an undifferentiated state, mouse embryonic stem cells (ESCs) differentiate into various cell types. Differentiation can be facilitated by forced expression of certain transcription factors (TFs), each of which can generally specify a particular developmental lineage. We previously established 137 mouse ESC lines, each of which carried a doxycycline-controllable TF. Among them, Sox9 has unique capacity: its forced expression accelerates differentiation of mouse ESCs into cells of all three germ layers. With the additional use of specific culture conditions, overexpression of Sox9 facilitated the generation of endothelial cells, hepatocytes and neurons from ESCs. Furthermore, Sox9 action increases formation of p21 (WAF1/CIP1), which then binds to the SRR2 enhancer of pluripotency marker Sox2 and inhibits its expression. Knockdown of p21 abolishes inhibition of Sox2 and Sox9-accelerated differentiation, and reduction of Sox2 2 days after the beginning of ESC differentiation can comparably accelerate mouse ESC formation of cells of three germ layers. These data implicate the involvement of the p21-Sox2 pathway in the mechanism of accelerated ESC differentiation by Sox9 overexpression. The molecular cascade could be among the first steps to program ESC differentiation. C1 [Yamamizu, Kohei; Schlessinger, David; Ko, Minoru S. H.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Ko, Minoru S. H.] Keio Univ, Dept Syst Med, Sakaguchi Lab, Sch Med, Tokyo 1608582, Japan. RP Ko, MSH (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM kom@z7.keio.jp OI Ko, Minoru/0000-0002-3530-3015 FU Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging; Japan Science and Technology Agency (JST), CREST program; Research Center Network for Realization of Regenerative Medicine program; Kanae Foundation (Japan); Uehara Memorial Foundation (Japan); Naito Foundation (Japan); Japan Society for Promotion of Science (JSPS) FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging. This research was also supported in part by the Japan Science and Technology Agency (JST), CREST program and Research Center Network for Realization of Regenerative Medicine program. K.Y. was supported by the postdoctoral fellowships from the Kanae Foundation (Japan), Uehara Memorial Foundation (Japan), Naito Foundation (Japan) and the Japan Society for Promotion of Science (JSPS). Deposited in PMC for release after 12 months. NR 68 TC 2 Z9 2 U1 0 U2 4 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 NOV PY 2014 VL 141 IS 22 BP 4254 EP 4266 DI 10.1242/dev.115436 PG 13 WC Developmental Biology SC Developmental Biology GA AT6DN UT WOS:000345029400006 PM 25371362 ER PT J AU Chalamalasetty, RB Garriock, RJ Dunty, WC Kennedy, MW Jailwala, P Si, H Yamaguchi, TP AF Chalamalasetty, Ravindra B. Garriock, Robert J. Dunty, William C., Jr. Kennedy, Mark W. Jailwala, Parthav Si, Han Yamaguchi, Terry P. TI Mesogenin 1 is a master regulator of paraxial presomitic mesoderm differentiation SO DEVELOPMENT LA English DT Article DE bHLH transcription factor; Paraxial mesoderm; PSM; Differentiation; EMT; Motility; Wnt; Embryonic stem cell; Somite; Mouse ID EPITHELIAL-MESENCHYMAL TRANSITIONS; TRANSCRIPTION FACTOR SNAIL; BETA-CATENIN GENE; MOUSE EMBRYO; STEM-CELLS; TUMOR-CELLS; EXPRESSION; TBX6; SEGMENTATION; PROGENITORS AB Neuromesodermal (NM) stem cells generate neural and paraxial presomitic mesoderm (PSM) cells, which are the respective progenitors of the spinal cord and musculoskeleton of the trunk and tail. The Wnt-regulated basic helix-loop-helix (bHLH) transcription factor mesogenin 1 (Msgn1) has been implicated as a cooperative regulator working in concert with T-box genes to control PSM formation in zebrafish, although the mechanism is unknown. We show here that, in mice, Msgn1 alone controls PSM differentiation by directly activating the transcriptional programs that define PSM identity, epithelial-mesenchymal transition, motility and segmentation. Forced expression of Msgn1 in NM stem cells in vivo reduced the contribution of their progeny to the neural tube, and dramatically expanded the unsegmented mesenchymal PSM while blocking somitogenesis and notochord differentiation. Expression of Msgn1 was sufficient to partially rescue PSM differentiation in Wnt3a(-/-) embryos, demonstrating that Msgn1 functions downstream of Wnt3a as the master regulator of PSM differentiation. Our data provide new insights into how cell fate decisions are imposed by the expression of a single transcriptional regulator. C1 [Chalamalasetty, Ravindra B.; Garriock, Robert J.; Dunty, William C., Jr.; Kennedy, Mark W.; Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Jailwala, Parthav; Si, Han] FNLCR, Leidos Biomed Res, CCRIFX Bioinformat Core, Frederick, MD 21702 USA. RP Yamaguchi, TP (reprint author), NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM yamagute@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Deposited in PMC for release after 12 months. NR 52 TC 15 Z9 15 U1 1 U2 10 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 NOV PY 2014 VL 141 IS 22 BP 4285 EP 4297 DI 10.1242/dev.110908 PG 13 WC Developmental Biology SC Developmental Biology GA AT6DN UT WOS:000345029400009 PM 25371364 ER PT J AU Sankineni, S Wood, BJ Rais-Bahrami, S Diaz, AW Hoang, AN Pinto, PA Choyke, PL AF Sankineni, Sandeep Wood, Bradford J. Rais-Bahrami, Soroush Diaz, Annerleim Walton Hoang, Anthony N. Pinto, Peter A. Choyke, Peter L. TI Image-guided focal therapy for prostate cancer SO DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY LA English DT Review ID INTENSITY FOCUSED ULTRASOUND; STEREOTACTIC BODY RADIOTHERAPY; PHYSICIAN PRACTICE PATTERNS; ASSOCIATION GALLUP SURVEY; CRYOSURGICAL ABLATION; LASER; EXPERIENCE; OUTCOMES; SYSTEM; MRI AB The adoption of routine prostate specific antigen screening has led to the discovery of many small and low-grade prostate cancers which have a low probability of causing mortality. These cancers, however, are often treated with radical therapies resulting in long-term side effects. There has been increasing interest in minimally invasive focal therapies to treat these tumors. While imaging modalities have improved rapidly over the past decade, similar advances in image-guided therapy are now starting to emerge-potentially achieving equivalent oncologic efficacy while avoiding the side effects of conventional radical surgery. The purpose of this article is to review the existing literature regarding the basis of various focal therapy techniques such as cryotherapy, microwave, laser, and high intensity focused ultrasound, and to discuss the results of recent clinical trials that demonstrate early outcomes in patients with prostate cancer. C1 [Sankineni, Sandeep; Wood, Bradford J.; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] Ctr Clin, NIH, Bethesda, MD USA. [Rais-Bahrami, Soroush; Diaz, Annerleim Walton; Hoang, Anthony N.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov OI Rais-Bahrami, Soroush/0000-0001-9466-9925 NR 52 TC 10 Z9 10 U1 0 U2 9 PU AVES PI SISLI PA BUYUKDERE CAD 105-9, MECIDIYEKOY, SISLI, ISTANBUL 34394, TURKEY SN 1305-3825 EI 1305-3612 J9 DIAGN INTERV RADIOL JI Diagn. Interv. Radiol. PD NOV PY 2014 VL 20 IS 6 BP 492 EP 497 DI 10.5152/dir.2014.14134 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT6CW UT WOS:000345027600008 PM 25205025 ER PT J AU Castaneto, MS Gorelick, DA Desrosiers, NA Hartman, RL Pirard, S Huestis, MA AF Castaneto, Marisol S. Gorelick, David A. Desrosiers, Nathalie A. Hartman, Rebecca L. Pirard, Sandrine Huestis, Marilyn A. TI Synthetic cannabinoids: Epidemiology, pharmacodynamics, and clinical implications SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE Synthetic cannabinoids; Designer drug; Epidemiology; Pharmacodynamics; CB1/CB2 agonists; Spice ID RECEPTOR AGONIST WIN-55,212-2; CANNABIMIMETIC INDOLES; CASE SERIES; DRUG DISCRIMINATION; CB2 RECEPTORS; WIN 55,212-2; LONG-TERM; ENDOCANNABINOID SYSTEM; INCREASED SENSITIVITY; SIGNAL-TRANSDUCTION AB Background: Synthetic cannabinoids (SC) are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system or as potential therapeutics. Clandestine laboratories subsequently utilized published data to develop SC variations marketed as abusable designer drugs. In the early 2000s, SC became popular as "legal highs" under brand names such as Spice and K2, in part due to their ability to escape detection by standard cannabinoid screening tests. The majority of SC detected in herbal products have greater binding affinity to the cannabinoid CB1 receptor than does Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive compound in the cannabis plant, and greater affinity at the CB1 than the CB2 receptor. In vitro and animal in vivo studies show SC pharmacological effects 2-100 times more potent than THC, including analgesic, anti-seizure, weight-loss, anti-inflammatory, and anti-cancer growth effects. SC produce physiological and psychoactive effects similar to THC, but with greater intensity, resulting in medical and psychiatric emergencies. Human adverse effects include nausea and vomiting, shortness of breath or depressed breathing, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Long-term or residual effects are unknown. Due to these public health consequences, many SC are classified as controlled substances. However, frequent structural modification by clandestine laboratories results in a stream of novel SC that may not be legally controlled or detectable by routine laboratory tests. Methods: We present here a comprehensive review, based on a systematic electronic literature search, of SC epidemiology and pharmacology and their clinical implications. Published by Elsevier Ireland Ltd. C1 [Castaneto, Marisol S.; Desrosiers, Nathalie A.; Hartman, Rebecca L.; Pirard, Sandrine; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Castaneto, Marisol S.; Desrosiers, Nathalie A.; Hartman, Rebecca L.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Gorelick, David A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, IRP, NIH, Biomed Res Ctr, 251 Bayview Blvd Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Department of Defense Counter Narcotics Program; Chemistry and Drug Metabolism Section, IRP, National Institute on Drug Abuse, NIH FX This work was funded by an interagency agreement between the Department of Defense Counter Narcotics Program and Chemistry and Drug Metabolism Section, IRP, National Institute on Drug Abuse, NIH. NR 228 TC 85 Z9 86 U1 12 U2 86 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD NOV 1 PY 2014 VL 144 BP 12 EP 41 DI 10.1016/j.drugalcdep.2014.08.005 PG 30 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AT8SE UT WOS:000345201500002 PM 25220897 ER PT J AU Yu, P Bamford, RN Waldmann, TA AF Yu, Ping Bamford, Richard N. Waldmann, Thomas A. TI IL-15-dependent CD8(+)CD122(+) T cells ameliorate experimental autoimmune encephalomyelitis by modulating IL-17 production by CD4(+) T cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD8(+)CD122(+) T cells; Experimental autoimmune encephalomyelitis; Interleukin-15; Interleukin-17; Multiple sclerosis ID REMITTING MULTIPLE-SCLEROSIS; MESSENGER-RNA EXPRESSION; NATURAL-KILLER-CELLS; RECEPTOR-BETA-CHAIN; TRANSGENIC MICE; RHEUMATOID-ARTHRITIS; HUMANIZED MIK-BETA-1; MONOCLONAL-ANTIBODY; MONONUCLEAR-CELLS; CUTTING EDGE AB Interleukin-15 (IL-15) is an inflammatory cytokine whose role in autoimmune diseases has not been fully elucidated. Th17 cells have been shown to play critical roles in experimental autoimmune encephalomyelitis (EAE) models. In this study, we demonstrate that blockade of IL-15 signaling by TM-1 mAb treatment aggravated EAE severity. The key mechanism was not NK-cell depletion but depletion of CD8(+)CD122(+) T cells. Adoptive transfer of exogenous CD8(+)CD122(+) T cells to TM-1-treated mice rescued animals from severe disease. Moreover, transfer of preactivated CD8(+)CD122(+) T cells prevented EAE development and significantly reduced IL-17 secretion. Naive effector CD4(+)CD25(-) T cells cultured with either CD8(+)CD122(+) T cells from wild-type mice or IL-15 transgenic mice displayed lower frequencies of IL-17A production with lower amounts of IL-17 in the supernatants when compared with production by effector CD4(+)CD25(-) T cells cultured alone. Addition of a neutralizing antibody to IL-10 led to recovery of IL-17A production in Th17 cultures. Furthermore, coculture of CD8(+)CD122(+) T cells with effector CD4(+) T cells inhibited their proliferation significantly, suggesting a regulatory function for IL-15 dependent CD8(+)CD122(+) T cells. Taken together, these observations suggest that IL-15, acting through CD8(+)CD122(+) T cells, has a negative regulatory role in reducing IL-17 production and Th17-mediated EAE inflammation. C1 [Yu, Ping; Waldmann, Thomas A.] NCI, Ctr Canc Res, Lymphoid Malignancies Branch, Bethesda, MD 20892 USA. [Bamford, Richard N.] Transponics, Jacobus, PA USA. RP Waldmann, TA (reprint author), NCI, Ctr Canc Res, Lymphoid Malignancies Branch, Bethesda, MD 20892 USA. EM tawald@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, NCI, NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. NR 50 TC 6 Z9 7 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 NOV PY 2014 VL 44 IS 11 BP 3330 EP 3341 DI 10.1002/eji.201444675 PG 12 WC Immunology SC Immunology GA AT9CG UT WOS:000345225000018 PM 25142300 ER PT J AU Chen, SL Lee, SY Chang, YH Chen, PS Lee, IH Wang, TY Chen, KC Yang, YK Hong, JS Lu, RB AF Chen, Shiou-Lan Lee, Sheng-Yu Chang, Yun-Hsuan Chen, Po-See Lee, I-Hui Wang, Tzu-Yun Chen, Kao-Ching Yang, Yen-Kuang Hong, Jau-Shyong Lu, Ru-Band TI Therapeutic effects of add-on low-dose dextromethorphan plus valproic acid in bipolar disorder SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Bipolar disorder; Cytokine; BDNF; HDRS; YMRS ID NEUROTROPHIC FACTOR; DOPAMINERGIC-NEURONS; II DISORDER; BRAIN; BDNF; 3-HYDROXYMORPHINAN; INFLAMMATION; DEPRESSION; DISEASE; BARRIER AB Changes in inflammatory cytokines and dysfunction of the neurotrophic system are thought to be involved in the pathology of bipolar disorder (BP). We investigated whether inflammatory and neurotrophic factors were changed in BP. We also investigated whether treating BP with valproic acid (VPA) plus low-dose (30 or 60 mg/day) dextromethorphan (DM) is more effective than treating it with VPA only, and whether DM affects plasma cytokines and brain derived neurotrophic factor (BDNF) levels. In a 12-week, randomized, double-blind study, patients were randomly assigned to the VPA+DM30, VPA+DM60, or VPA+Placebo groups. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate symptom severity, and ELISA to analyze plasma cytokine and BDNF levels. We recruited 309 patients with BP and 123 healthy controls. Before treatment, patients with BP had significantly higher plasma cytokine and lower plasma BDNF levels than did healthy controls. After treatment, HDRS and YMRS scores in each group showed significant improvement. Plasma cytokine levels tended to decline in all groups. Changes in plasma BDNF levels were significantly greater in the VPA+DM60 group than in the VPA+Placebo group. Conclusion: patients with BP have a certain degree of systemic inflammation and BDNF dysfunction. Treatment with VPA plus DM (60 mg/day) provided patients with BP significantly more neurotrophic benefit than did VPA treatment alone. (C) 2014 Elsevier B.V. and ECNP. All rights reserved. C1 [Chen, Shiou-Lan; Lee, I-Hui] Kaohsiung Med Univ, Sch Med, Dept Neurol, Kaohsiung, Taiwan. [Chang, Yun-Hsuan; Chen, Po-See; Wang, Tzu-Yun; Chen, Kao-Ching; Yang, Yen-Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Dept Psychiat, Tainan 70428, Taiwan. [Chang, Yun-Hsuan; Chen, Po-See; Wang, Tzu-Yun; Chen, Kao-Ching; Yang, Yen-Kuang; Lu, Ru-Band] Natl Cheng Kung Univ Hosp, Coll Med, Dept Psychiat, Tainan 70428, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Inst Allied Hlth Sci, Tainan 70428, Taiwan. [Lee, I-Hui; Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Inst Behav Sci, Tainan 70428, Taiwan. [Chang, Yun-Hsuan; Yang, Yen-Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70428, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan. [Lee, Sheng-Yu] Kaohsiung Vet Gen Hosp, Dept Psychiat, Kaohsiung, Taiwan. [Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Coll Med & Hosp, Dept Psychiat, 138 Sheng Li Rd, Tainan 70428, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3, NSC 99-2627-B-006-015, NSC100-2314-B-075B-010-MY3]; National Cheng Kung University Project to promote academic excellence and develop a World Class Research Center FX This work was supported in part by Grant NSC98-2314-B-006-022-MY3 (to RBL), Grant NSC 99-2627-B-006-015 (to RBL), NSC100-2314-B-075B-010-MY3 (to SYL) from the Taiwan National Science Council; and by a Grant from the National Cheng Kung University Project to promote academic excellence and develop a World Class Research Center. NR 34 TC 10 Z9 10 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD NOV PY 2014 VL 24 IS 11 BP 1753 EP 1759 DI 10.1016/j.euroneuro.2014.09.001 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT8UB UT WOS:000345206200005 PM 25262178 ER PT J AU Golani, I Tadmor, H Buonanno, A Kremer, I Shamir, A AF Golani, Idit Tadmor, Hagar Buonanno, Andres Kremer, Ilana Shamir, Alon TI Disruption of the ErbB signaling in adolescence increases striatal dopamine levels and affects learning and hedonic-like behavior in the adult mouse SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Neuregulin; ErbB receptor; Schizophrenia; Cognition; Animal behavior; Dopaminergic system ID EPIDERMAL-GROWTH-FACTOR; RISK GENE NEUREGULIN-1; WORKING-MEMORY; D2 RECEPTORS; SCHIZOPHRENIA; BRAIN; MICE; COGNITION; MUTANT; AGE AB The ErbB signaling pathway has been genetically and functionally implicated in schizophrenia. Numerous findings support the dysregulation of Neuregulin (NRG) and epidermal growth factor (EGF) signaling in schizophrenia. However, it is unclear whether alterations of these pathways in the adult brain or during development are involved in the pathophysiology of schizophrenia. Herein we characterized the behavioral profile and molecular changes resulting from pharmacologically blocking the ErbB signaling pathway during a critical period in the development of decision making, planning, judgments, emotions, social cognition and cognitive skills, namely adolescence. We demonstrate that chronic administration of the pan-ErbB kinase inhibitor JNJ-28871063 (JNJ) to adolescent mice elevated striatal dopamine levels and reduced preference for sucrose without affecting locomotor activity and exploratory behavior. In adulthood, adolescent JNJ-treated mice continue to consume less sucrose and needed significantly more correct-response trials to reach the learning criterion during the discrimination phase of the T-maze reversal learning task than their saline-injected controls. In addition, JNJ mice exhibited deficit in reference memory but not in working memory as measured in the radial arm maze. Inhibition of the pathway during adolescence did not affect exploratory behavior and locomotor activity in the open field, social interaction, social memory, and reversal learning in adult mice. Our data suggest that alteration of ErbB signaling during adolescence resulted in changes in the dopaminergic systems that emerge in pathological learning and hedonic behavior in adulthood, and pinpoints the possible role of the pathway in the development of cognitive skills and motivated behavior. (C) 2014 Elsevier B.V. and ECNP. All rights reserved. C1 [Golani, Idit] ORT Braude Coll, Dept Biotechnol Engn, Karmiel, Israel. [Tadmor, Hagar; Kremer, Ilana; Shamir, Alon] Mazra Mental Hlth Ctr, Psychobiol Res Lab, Akko, Israel. [Tadmor, Hagar] Bar Ilan Univ, Fac Med Galilee, Safed, Israel. [Buonanno, Andres] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurobiol Sect, Bethesda, MD USA. [Kremer, Ilana; Shamir, Alon] Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Haifa, Israel. RP Shamir, A (reprint author), Technion Israel Inst Technol DN Oshrat, Mazra Mental Hlth Ctr, Psychobiol Res Lab, IL-25201 Akko, Israel. EM alons@mazra.health.gov.il FU National Institute of Psychobiology Young Investigator Research [218-12-13]; Technion V.P.R. Fund for Medical Research [1011359]; Ort Bruda College FX This work was supported by the National Institute of Psychobiology Young Investigator Research (218-12-13) Grant to A.S. and by the Technion V.P.R. Fund for Medical Research (1011359; A.S.). We are also grateful for the financial support from Ort Bruda College (I.G.). NR 50 TC 3 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD NOV PY 2014 VL 24 IS 11 BP 1808 EP 1818 DI 10.1016/j.euroneuro.2014.09.011 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT8UB UT WOS:000345206200012 PM 25451700 ER PT J AU Otto, M AF Otto, Michael TI Physical stress and bacterial colonization SO FEMS MICROBIOLOGY REVIEWS LA English DT Review DE adhesion; Staphylococcus; Streptococcus; Pseudomonas aeruginosa; Escherichia coli; Helicobacter pylori ID POLYSACCHARIDE INTERCELLULAR ADHESIN; GRAM-POSITIVE BACTERIA; STAPHYLOCOCCUS-EPIDERMIDIS STRAINS; ACCUMULATION-ASSOCIATED PROTEIN; UROPATHOGENIC ESCHERICHIA-COLI; FIBRINOGEN-BINDING-PROTEIN; URINARY-TRACT-INFECTION; CLUMPING FACTOR-B; HELICOBACTER-PYLORI; BIOFILM FORMATION AB Bacterial surface colonizers are subject to a variety of physical stresses. During the colonization of human epithelia such as on the skin or the intestinal mucosa, bacteria mainly have to withstand the mechanical stress of being removed by fluid flow, scraping, or epithelial turnover. To that end, they express a series of molecules to establish firm attachment to the epithelial surface, such as fibrillar protrusions (pili) and surface-anchored proteins that bind to human matrix proteins. In addition, some bacteria - in particular gut and urinary tract pathogens - use internalization by epithelial cells and other methods such as directed inhibition of epithelial turnover to ascertain continued association with the epithelial layer. Furthermore, many bacteria produce multilayered agglomerations called biofilms with a sticky extracellular matrix, providing additional protection from removal. This review will give an overview over the mechanisms human bacterial colonizers have to withstand physical stresses with a focus on bacterial adhesion. C1 NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 33 North Dr,Bldg 33 1W10, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH). The author wishes to thank Dr. Hwang-Soo Joo for the help of chemical structures presented in Fig. 5. NR 179 TC 15 Z9 15 U1 4 U2 50 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0168-6445 EI 1574-6976 J9 FEMS MICROBIOL REV JI Fems Microbiol. Rev. PD NOV PY 2014 VL 38 IS 6 SI SI BP 1250 EP 1270 DI 10.1111/1574-6976.12088 PG 21 WC Microbiology SC Microbiology GA AT6UT UT WOS:000345075600008 PM 25212723 ER PT J AU Ganini, D Mason, RP AF Ganini, Douglas Mason, Ronald P. TI Absence of an effect of vitamin E on protein and lipid radical formation during lipoperoxidation of LDL by lipoxygenase SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Free radicals; LDL oxidation; DMPO; Immuno-spin trapping; Copper; Lipoxidase; Lipoxygenase; Lipoperoxidation; Atherosclerosis; Vitamin E ID LOW-DENSITY-LIPOPROTEIN; HUMAN ATHEROSCLEROTIC PLAQUES; ALPHA-TOCOPHEROL; OXIDATIVE MODIFICATION; SCAVENGER RECEPTOR; NITRIC-OXIDE; OXIDIZED PHOSPHOLIPIDS; CARDIOVASCULAR EVENTS; PEROXYL RADICALS; APOLIPOPROTEIN-B AB Low-density lipoprotein (LDL) oxidation is the primary event in atherosclerosis, and LDL lipoperoxidation leads to modifications in apolipoprotein B-100 (apo B-100) and lipids. Intermediate species of lipoperoxidation are known to be able to generate amino acid-centered radicals. Thus, we hypothesized that lipoperoxidation intermediates induce protein-derived free radical formation during LDL oxidation. Using DMPO and immuno-spin trapping, we detected the formation of protein free radicals on LDL incubated with Cu2+ or the soybean lipoxidase (LPOx)/phospholipase A(2) (PLA(2)). With low concentrations of DMPO (1 mM), Cu2+ dose-dependently induced oxidation of LDL and easily detected apo B-100 radicals. Protein radical formation in LDL incubated with Cu2+ showed maximum yields after 30 min. In contrast, the yields of apo B-100 radicals formed by LPOx/PLA(2) followed a typical enzyme-catalyzed kinetics that was unaffected by DMPO concentrations of up to 50 mM. Furthermore, when we analyzed the effect of antioxidants on protein radical formation during LDL oxidation, we found that ascorbate, urate, and Trolox dose-dependently reduced apo B-100 free radical formation in LDL exposed to Cu2+. In contrast, Trolox was the only antioxidant that even partially protected LDL from LPOx/PLA(2). We also examined the kinetics of lipid radical formation and protein radical formation induced by Cu2+ or LPOx/PLA(2) for LDL supplemented with alpha-tocopherol. In contrast to the potent antioxidant effect of alpha-tocopherol on the delay of LDL oxidation induced by Cu2+, when we used the oxidizing system LPOx/PLA(2), no significant protection was detected. The lack of protection of alpha-tocopherol on the apo B-100 and lipid free radical formation by LPOx may explain the failure of vitamin E as a cardiovascular protective agent for humans. Published by Elsevier Inc. C1 [Ganini, Douglas; Mason, Ronald P.] NIEHS, Free Radical Metab Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Ganini, D (reprint author), NIEHS, Free Radical Metab Sect, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM ganinidasilvad@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences, NIH FX The authors gratefully acknowledge Dr. Thomas Eling, Dr. Ann Motten, Mary Mason, and Jean Corbett for their valuable help in the preparation and revision of the manuscript. We also acknowledge Jean Corbett for her valuable technical assistance. This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. NR 69 TC 4 Z9 4 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV PY 2014 VL 76 BP 61 EP 68 DI 10.1016/j.freeradbiomed.2014.07.031 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AT9NW UT WOS:000345254800007 PM 25091900 ER PT J AU Tomlinson, M Bornstein, MH Marlow, M Swartz, L AF Tomlinson, Mark Bornstein, Marc H. Marlow, Marguerite Swartz, Leslie TI IMBALANCES IN THE KNOWLEDGE ABOUT INFANT MENTAL HEALTH IN RICH AND POOR COUNTRIES: TOO LITTLE PROGRESS IN BRIDGING THE GAP SO INFANT MENTAL HEALTH JOURNAL LA English DT Article ID MIDDLE-INCOME COUNTRIES; CHILD-DEVELOPMENT; INTERVENTION; DIVIDE AB The vast majority of infants are born in poor countries, but most of our knowledge about infants and children has emerged from high-income countries. In 2003, M. Tomlinson and L. Swartz conducted a survey of articles on infancy between 1996 and 2001 from major international journals, reporting that a meager 5% of articles emanated from parts of the world other than North America, Europe, or Australasia. In this article, we conducted a similar review of articles on infancy published between 2002 and 2012 to assess whether the status of cross-national research has changed in the subsequent decade. Results indicate that despite slight improvements in research output from the rest of world, only 2.3% of articles published in 11 years included data from low- and middle-income countries-where 90% of the world's infants live. These discrepancies are indicative of the progress still needed to bridge the so-called 10/90 gap (S. Saxena, G. Paraje, P. Sharan, G. Karam, & R. Sadana, 2006) in infant mental health research. Cross-national collaboration is urgently required to ensure expansion of research production in low-resource settings. C1 [Tomlinson, Mark; Marlow, Marguerite; Swartz, Leslie] Univ Stellenbosch, ZA-7602 Stellenbosch, South Africa. [Bornstein, Marc H.] NIMH, Bethesda, MD USA. RP Tomlinson, M (reprint author), Univ Stellenbosch, Dept Psychol, Private Bag X1, ZA-7602 Stellenbosch, South Africa. EM markt@sun.ac.za OI Swartz, Leslie/0000-0003-1741-5897 FU NIAAA NIH HHS [R24 AA022919] NR 22 TC 8 Z9 8 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0163-9641 EI 1097-0355 J9 INFANT MENT HEALTH J JI Infant Ment. Health J. PD NOV-DEC PY 2014 VL 35 IS 6 BP 624 EP 629 DI 10.1002/imhj.21462 PG 6 WC Psychology, Developmental SC Psychology GA AU0DT UT WOS:000345294500010 PM 25798511 ER PT J AU Lheureux, S Ledermann, J Kaye, S Gourley, C Friedlander, M Bowtell, D De Greve, J DeFazio, A Frommer, R De Bono, JS Audeh, MW Kohn, E Alsop, K Scott, C Matulonis, U Kaufman, B Burger, B Robertson, J Ho, T Oza, A AF Lheureux, S. Ledermann, J. Kaye, S. Gourley, C. Friedlander, M. Bowtell, D. De Greve, J. DeFazio, A. Frommer, R. De Bono, J. S. Audeh, M. W. Kohn, E. Alsop, K. Scott, C. Matulonis, U. Kaufman, B. Burger, B. Robertson, J. Ho, T. Oza, A. TI A PILOT INTEGRATED ANALYSIS OF LONG-TERM BENEFIT OF OLAPARIB IN OVARIAN CANCER: RESULTS OF FEASIBILITY TESTING. SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Meeting Abstract C1 [Lheureux, S.; Oza, A.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Ledermann, J.] UCL Canc Inst, London, England. [Kaye, S.; De Bono, J. S.] Royal Marsden Hosp, Sutton, Surrey, England. [Gourley, C.] Edinburgh Canc Res UK Ctr, Edinburgh, Midlothian, Scotland. [Friedlander, M.] Prince Wales Hosp, Sydney, NSW, Australia. [Bowtell, D.; Alsop, K.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [De Greve, J.] Univ Hosp Brussels, Familial Canc Clin, Brussels, Belgium. [De Greve, J.] Univ Hosp Brussels, Brussels, Belgium. [DeFazio, A.] Univ Sydney, Westmead Inst Canc Res, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Frommer, R.] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Audeh, M. W.] Samuel Oschin Comprehens Canc Inst, Los Angeles, CA USA. [Kohn, E.] NCI, NIH, Bethesda, MD 20892 USA. [Scott, C.] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Matulonis, U.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kaufman, B.] Chaim Sheba Med Ctr, Breast Canc Unit, IL-52621 Tel Hashomer, Israel. [Burger, B.] AstraZeneca, Stat, Wilmington, NC USA. [Robertson, J.] AstraZeneca, Med Oncol, Macclesfield, Cheshire, England. [Ho, T.] AstraZeneca, Med Oncol, Wilmington, NC USA. RI De Greve, Jacques/J-4939-2012 OI De Greve, Jacques/0000-0002-2389-0742 NR 0 TC 0 Z9 0 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD NOV PY 2014 VL 24 IS 9 SU 4 MA IGCSM-0468 BP 141 EP 142 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AT5EP UT WOS:000344966500119 ER PT J AU Kim, B Cho, H Kim, JH Hewitt, S AF Kim, B. Cho, H. Kim, J. H. Hewitt, S. TI PROGNOSTIC SIGNIFICANCE OF CANCER STEM CELL MARKERS IN CERVICAL CANCER SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Meeting Abstract C1 [Kim, B.] Hallym Univ, Kangdong Sacred Heart Hosp, Seoul, South Korea. [Cho, H.; Kim, J. H.] Yonsei Univ, Coll Med, Gangnam Severance Hosp, Seoul, South Korea. [Hewitt, S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD NOV PY 2014 VL 24 IS 9 SU 4 MA IGCSM-0779 BP 988 EP 989 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AT5EP UT WOS:000344966501284 ER PT J AU Lederman, RJ Chen, MY Rogers, T Wang, DD Paone, G Guerrero, M O'Neill, WW Greenbaum, AB AF Lederman, Robert J. Chen, Marcus Y. Rogers, Toby Wang, Dee Dee Paone, Gaetano Guerrero, Mayra O'Neill, William W. Greenbaum, Adam B. TI Planning Transcaval Access Using CT for Large Transcatheter Implants SO JACC-CARDIOVASCULAR IMAGING LA English DT Editorial Material DE cardiac catheterization; extra-anatomic procedures; medical devices; transcatheter valve replacement; vascular access and closure C1 [Lederman, Robert J.; Chen, Marcus Y.; Rogers, Toby] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Wang, Dee Dee; Paone, Gaetano; Guerrero, Mayra; O'Neill, William W.; Greenbaum, Adam B.] Henry Ford Hlth Syst, Inst Struct Heart Dis, Div Cardiol, Detroit, MI USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC 1538, Bethesda, MD 20892 USA. EM lederman@nih.gov OI Rogers, Toby/0000-0002-6043-3137; lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [ZIA HL006040-04]; NHLBI NIH HHS [Z01 HL005062, Z01-HL006040] NR 1 TC 4 Z9 4 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD NOV PY 2014 VL 7 IS 11 BP 1167 EP 1171 DI 10.1016/j.jcmg.2014.05.015 PG 5 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AT9NS UT WOS:000345254500014 PM 25459598 ER PT J AU Resnick, SM AF Resnick, Susan M. TI Preclinical Biomarkers in Alzheimer Disease A Sum Greater Than the Parts SO JAMA NEUROLOGY LA English DT Editorial Material ID HYPOTHETICAL MODEL; DYNAMIC BIOMARKERS; DEMENTIA C1 NIA, Lab Behav Neurosci, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Resnick, SM (reprint author), NIA, Lab Behav Neurosci, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM resnicks@mail.nih.gov NR 10 TC 3 Z9 3 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD NOV PY 2014 VL 71 IS 11 BP 1357 EP 1358 DI 10.1001/jamaneurol.2014.2462 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AT7WN UT WOS:000345145300004 PM 25221849 ER PT J AU Sharma, S Zhou, XB Thibault, DM Himes, BE Liu, A Szefler, SJ Strunk, R Castro, M Hansel, NN Diette, GB Vonakis, BM Adkinson, NF Avila, L Soto-Quiros, M Barraza-Villareal, A Lemanske, RF Solway, J Krishnan, J White, SR Cheadle, C Berger, AE Fan, JS Boorgula, MP Nicolae, D Gilliland, F Barnes, K London, SJ Martinez, F Ober, C Celedon, JC Carey, VJ Weiss, ST Raby, BA AF Sharma, Sunita Zhou, Xiaobo Thibault, Derek M. Himes, Blanca E. Liu, Andy Szefler, Stanley J. Strunk, Robert Castro, Mario Hansel, Nadia N. Diette, Gregory B. Vonakis, Becky M. Adkinson, N. Franklin, Jr. Avila, Lydiana Soto-Quiros, Manuel Barraza-Villareal, Albino Lemanske, Robert F., Jr. Solway, Julian Krishnan, Jerry White, Steven R. Cheadle, Chris Berger, Alan E. Fan, Jinshui Boorgula, Meher Preethi Nicolae, Dan Gilliland, Frank Barnes, Kathleen London, Stephanie J. Martinez, Fernando Ober, Carole Celedon, Juan C. Carey, Vincent J. Weiss, Scott T. Raby, Benjamin A. TI A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; CD4(+) lymphocytes; regulatory variants; expression quantitative trait locus; haplotype; integrative genomics ID CHILDHOOD ASTHMA; ASSOCIATION; DISEASE; CELLS; POLYMORPHISMS; INFLAMMATION; CLUSTER; OBESITY; ACID AB Background: Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective: We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4(+) lymphocytes for association with asthma. Methods: eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results: Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 x 10(-8)). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P = .002), N-acetyl-alpha-D-galactosaminidase (NAGA; P = .0002), and Factor XIII, A1 (F13A1; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4(+) lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions: Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma. C1 [Sharma, Sunita; Zhou, Xiaobo; Thibault, Derek M.; Himes, Blanca E.; Carey, Vincent J.; Weiss, Scott T.; Raby, Benjamin A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Sharma, Sunita; Zhou, Xiaobo; Thibault, Derek M.; Himes, Blanca E.; Carey, Vincent J.; Weiss, Scott T.; Raby, Benjamin A.] Harvard Univ, Sch Med, Boston, MA USA. [Sharma, Sunita; Zhou, Xiaobo; Raby, Benjamin A.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Liu, Andy; Szefler, Stanley J.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Strunk, Robert; Castro, Mario] Washington Univ, Sch Med, Dept Pediat, Div Allergy Immunol & Pulm Med, St Louis, MO USA. [Hansel, Nadia N.; Diette, Gregory B.; Vonakis, Becky M.; Adkinson, N. Franklin, Jr.; Cheadle, Chris; Berger, Alan E.; Fan, Jinshui; Boorgula, Meher Preethi; Barnes, Kathleen] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Avila, Lydiana; Soto-Quiros, Manuel] Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica. [Barraza-Villareal, Albino] Hosp Infantil Mexico Dr Federico Gomez, Natl Inst Publ Hlth Mexico, Mexico City, DF, Mexico. [Lemanske, Robert F., Jr.] Univ Wisconsin, Dept Med, Div Allergy & Immunol, Madison, WI USA. [Solway, Julian; White, Steven R.] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Nicolae, Dan; Ober, Carole] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Krishnan, Jerry] Univ Illinois Hosp & Hlth Sci Syst, Dept Med, Chicago, IL USA. [Gilliland, Frank] Univ So Calif, Dept Med, Div Environm & Occupat Hlth, Los Angeles, CA USA. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Martinez, Fernando] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Celedon, Juan C.] Univ Pittsburgh, Childrens Hosp Pittsburgh UPMC, Dept Pediat, Div Pulm Med Allergy & Immunol, Pittsburgh, PA 15260 USA. RP Sharma, S (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM sunita.sharma@channing.harvard.edu OI London, Stephanie/0000-0003-4911-5290 FU National Heart, Lung, and Blood Institute/ National Institutes of Health (NIH/NHLBI) [R01 HL086601, RC2 HL101543]; NIH and National Center for Research Resources [1 UL1 RR025780]; NIH [K99 HL105663, P01ES011627]; NIH/NHLBI [K08 HL096833]; Division of Intramural Research, National Institute of Environmental Health Sciences, NIH; [R37 HL066289]; [U01 HL075419]; [U01 HL65899]; [P01 HL083069] FX Supported by R01 HL086601, RC2 HL101543, R37 HL066289, and K08 HL096833. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham andWomen's Hospital under appropriate CAMP policies and human subject protections. This work is supported by grants R01 HL086601 and RC2 HL101543 from the National Heart, Lung, and Blood Institute/ National Institutes of Health (NIH/NHLBI). The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, and P01 HL083069 and through the Colorado CTSA grant 1 UL1 RR025780 from the NIH and National Center for Research Resources. B. E. H. was supported by NIH K99 HL105663. S. S. receives additional support from K08 HL096833 from NIH/NHLBI. Additional support was provided by NIH P01ES011627 (PI: F. Gilliland). Supported in part by the Division of Intramural Research, National Institute of Environmental Health Sciences, NIH. NR 46 TC 14 Z9 14 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2014 VL 134 IS 5 BP 1153 EP 1162 DI 10.1016/j.jaci.2014.04.011 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA AT4UN UT WOS:000344938900021 PM 24934276 ER PT J AU Simhadri, VR Mariano, JL Zenarruzabeitia, O Seroogy, CM Holland, SM Kuehn, HS Rosenzweig, SD Borrego, F AF Simhadri, Venkateswara R. Mariano, John L. Zenarruzabeitia, Olatz Seroogy, Christine M. Holland, Steven M. Kuehn, Hye Sun Rosenzweig, Sergio D. Borrego, Francisco TI Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID NK CELLS; MEMORY C1 [Simhadri, Venkateswara R.; Mariano, John L.; Borrego, Francisco] Food & Drug Adm, Ctr Drug Evaluat & Res, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Bethesda, MD 20993 USA. [Zenarruzabeitia, Olatz; Borrego, Francisco] BioCruces Hlth Res Inst, Baracaldo, Spain. [Seroogy, Christine M.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.] NIAID, Primary Immuno Deficiency Clin, NIH, Bethesda, MD 20892 USA. [Kuehn, Hye Sun] Ctr Clin, Serv Immunol, Dept Lab Med, NIH, Bethesda, MD USA. [Borrego, Francisco] Basque Fdn Sci, Ikerbasque, Bilbao, Spain. RP Simhadri, VR (reprint author), Food & Drug Adm, Ctr Drug Evaluat & Res, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Bethesda, MD 20993 USA. EM francisco.borregorabasco@osakidetza.net FU Intramural NIH HHS [Z99 CL999999] NR 10 TC 5 Z9 5 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2014 VL 134 IS 5 BP 1190 EP 1193 DI 10.1016/j.jaci.2014.06.006 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA AT4UN UT WOS:000344938900026 PM 25065718 ER PT J AU Funakoshi, Y Chou, MM Kanaho, Y Donaldson, JG AF Funakoshi, Yuji Chou, Margaret M. Kanaho, Yasunori Donaldson, Julie G. TI TRE17/USP6 regulates ubiquitylation and trafficking of cargo proteins that enter cells by clathrin-independent endocytosis SO JOURNAL OF CELL SCIENCE LA English DT Article DE TRE17; USP6; Ubiquitin; Cargo sorting; Ubiquitin-specific protease; Lysosome ID ANEURYSMAL BONE-CYST; 6 USP6 ONCOGENE; NF-KAPPA-B; ENDOSOMAL TRAFFICKING; UBIQUITINATION; CANCER; ACTIVATION; RECEPTOR; FUSION; DEGRADATION AB Plasma membrane proteins that enter cells by clathrin-independent endocytosis (CIE) are sorted either to lysosomes for degradation or recycled back to the plasma membrane. Expression of some MARCH E3 ubiquitin ligases promotes trafficking of CIE cargo proteins to lysosomes by ubiquitylating the proteins. Here, we show that co-expression of the ubiquitin-specific protease TRE17/USP6 counteracts the MARCH-dependent targeting of CIE cargo proteins, but not that of transferrin receptor, to lysosomes, leading to recovery of the stability and cell surface level of the proteins. The ubiquitylation of CIE cargo proteins by MARCH8 was reversed by TRE17, suggesting that TRE17 leads to deubiquitylation of CIE cargo proteins. The effects of TRE17 were dependent on its deubiquitylating activity and expression of TRE17 alone led to a stabilization of surface major histocompatibility complex class I (MHCI) molecules, a CIE cargo, suggesting that deubiquitylation of endogenous CIE cargo proteins promotes their stability. This study demonstrates that cycles of ubiquitylation and deubiquitylation can determine whether CIE cargo proteins are degraded or recycled. C1 [Funakoshi, Yuji; Donaldson, Julie G.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20891 USA. [Funakoshi, Yuji; Kanaho, Yasunori] Univ Tsukuba, Dept Physiol Chem, Fac Med, Tsukuba, Ibaraki 3058575, Japan. [Funakoshi, Yuji; Kanaho, Yasunori] Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058575, Japan. [Chou, Margaret M.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20891 USA. EM donaldsonj@helix.nih.gov FU Intramural Research Program in the National Heart, Lung and Blood Institute at the National Institutes of Health [HL006060]; National Cancer Institute [CA126452]; Ministry of Education, Science, Sports and Culture of Japan [26440044] FX This work was supported by the Intramural Research Program in the National Heart, Lung and Blood Institute at the National Institutes of Health [grant number HL006060] to J.G.D.; and by a grant from the National Cancer Institute [grant number CA126452] to M.M.C. This work was also supported by the Institutional Program for Young Researcher Overseas Visits and the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from the Ministry of Education, Science, Sports and Culture of Japan to Y.F. and a research grant [grant number 26440044] from the Ministry of Education, Science, Sports and Culture of Japan to Y.K. Deposited in PMC for release after 12 months. NR 40 TC 3 Z9 3 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD NOV 1 PY 2014 VL 127 IS 21 BP 4750 EP 4761 DI 10.1242/jcs.156786 PG 12 WC Cell Biology SC Cell Biology GA AT3QK UT WOS:000344848700019 PM 25179595 ER PT J AU Best, RB Zheng, WW Mittal, J AF Best, Robert B. Zheng, Wenwei Mittal, Jeetain TI Balanced Protein-Water Interactions Improve Properties of Disordered Proteins and Non-Specific Protein Association SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; VILLIN HEADPIECE SUBDOMAIN; POLARIZABLE FORCE-FIELDS; HYDRATION FREE-ENERGIES; SOLVATION FREE-ENERGIES; N-15 NMR RELAXATION; SIDE-CHAIN ANALOGS; FOLDING SIMULATIONS; BETA-HAIRPIN; UNFOLDED PROTEINS AB Some frequently encountered deficiencies in all-atom molecular simulations, such as nonspecific proteinprotein interactions being too strong, and unfolded or disordered states being too collapsed, suggest that proteins are insufficiently well solvated in simulations using current state-of-the-art force fields. To address these issues, we make the simplest possible change, by modifying the short-range proteinwater pair interactions, and leaving all the waterwater and proteinprotein parameters unchanged. We find that a modest strengthening of proteinwater interactions is sufficient to recover the correct dimensions of intrinsically disordered or unfolded proteins, as determined by direct comparison with small-angle X-ray scattering (SAXS) and Forster resonance energy transfer (FRET) data. The modification also results in more realistic protein-protein affinities, and average solvation free energies of model compounds which are more consistent with experiment. Most importantly, we show that this scaling is small enough not to affect adversely the stability of the folded state, with only a modest effect on the stability of model peptides forming a-helix and Beta-sheet structures. The proposed adjustment opens the way to more accurate atomistic simulations of proteins, particularly for intrinsically disordered proteins, proteinprotein association, and crowded cellular environments. C1 [Best, Robert B.; Zheng, Wenwei] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Mittal, Jeetain] Lehigh Univ, Dept Chem & Biomol Engn, Bethlehem, PA 18015 USA. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov; jeetain@lehigh.edu RI Zheng, Wenwei/M-5031-2015; Best, Robert/H-7588-2016 OI Zheng, Wenwei/0000-0002-9603-009X; Best, Robert/0000-0002-7893-3543 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Insitutes of Health; National Science Foundation [CBET-1120399, TG-MCB-120014] FX We thank Magnus Kjaergaard and Birthe Kragelund for kindly making available the original SAXS data for ACTR, and Kresten Lindorff-Larsen for helpful comments on the manuscript. W. Z. and R. B. B. are supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Insitutes of Health. This work was supported in part by the National Science Foundation grant CBET-1120399 (J.M.). 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 use of the high-performance computing capabilities of the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (TG-MCB-120014), is also gratefully acknowledged. NR 99 TC 62 Z9 62 U1 8 U2 64 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD NOV PY 2014 VL 10 IS 11 BP 5113 EP 5124 DI 10.1021/ct500569b PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA AT4JI UT WOS:000344905300033 PM 25400522 ER PT J AU Bhattacharya, S Lee, S Grisshammer, R Tate, CG Vaidehi, N AF Bhattacharya, Supriyo Lee, Sangbae Grisshammer, Reinhard Tate, Christopher G. Vaidehi, Nagarajan TI Rapid Computational Prediction of Thermostabilizing Mutations for G Protein-Coupled Receptors SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID ADENOSINE A(2A) RECEPTOR; BIOMOLECULAR SIMULATION PROGRAM; PARTICLE MESH EWALD; NEUROTENSIN RECEPTOR; BETA(1)-ADRENERGIC RECEPTOR; CONFORMATIONAL STATES; STRUCTURAL INSIGHTS; MOLECULAR-DYNAMICS; GPCR; STABILIZATION AB G protein-coupled receptors (GPCRs) are highly dynamic and often denature when extracted in detergents. Deriving thermostable mutants has been a successful strategy to stabilize GPCRs in detergents, but this process is experimentally tedious. We have developed a computational method to predict the position of the thermostabilizing mutations for a given GPCR sequence. We have validated the method against experimentally measured thermostability data for single mutants of the beta(1)-adrenergic receptor (beta(1)AR), adenosine A2A receptor (A(2A)R) and neurotensin receptor 1 (NTSR1). To make these predictions we started from homology models of these receptors of varying accuracies and generated an ensemble of conformations by sampling the rigid body degrees of freedom of transmembrane helices. Then, an all-atom force field function was used to calculate the enthalpy gain, known as the "stability score" upon mutation of every residue, in these receptor structures, to alanine. For all three receptors, beta(1)AR, A(2A)R, and NTSR1, we observed that mutations of hydrophobic residues in the transmembrane domain to alanine that have high stability scores correlate with high experimental thermostability. The prediction using the stability score improves when using an ensemble of receptor conformations compared to a single structure, showing that receptor flexibility is important. We also find that our previously developed LITiCon method for generating conformation ensembles is similar in performance to predictions using ensembles obtained from microseconds of molecular dynamics simulations (which is computationally hundred times slower than LITiCon). We improved the thermostability prediction by including other properties such as residue-based stress and the extent of allosteric communication by each residue in the stability score. Our method is the first step toward a computational method for rapid prediction of thermostable mutants of GPCRs. C1 [Bhattacharya, Supriyo; Lee, Sangbae; Vaidehi, Nagarajan] City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, Duarte, CA 91010 USA. [Grisshammer, Reinhard] Natl Inst Neurol Disorders & Stroke, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Tate, Christopher G.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. RP Vaidehi, N (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, 1500 East Duarte Rd, Duarte, CA 91010 USA. EM NVaidehi@coh.org RI Grisshammer, Reinhard/C-3089-2015; OI Tate, Christopher/0000-0002-2008-9183 FU NIH [RO1GM097261]; Medical Research Council [MRC U105197215]; National Institute of Neurological Disorders and Stroke, The National Institutes of Health FX Funding for this work was provided by NIH-RO1GM097261 to N.V. We thank Dr. Jean Chin (NIGMS) for her support and encouragement. C.G.T. is funded by the Medical Research Council (MRC U105197215) and the research of RG is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, The National Institutes of Health. NR 40 TC 11 Z9 11 U1 4 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD NOV PY 2014 VL 10 IS 11 BP 5149 EP 5160 DI 10.1021/ct500616v PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA AT4JI UT WOS:000344905300036 PM 25400524 ER PT J AU Mottl, AK Pajewski, N Fonseca, V Ismail-Beigi, F Chew, E Ambrosius, WT Greven, C Schubart, U Buse, J AF Mottl, Amy K. Pajewski, Nicholas Fonseca, Vivian Ismail-Beigi, Faramarz Chew, Emily Ambrosius, Walter T. Greven, Craig Schubart, Ulrich Buse, John TI The degree of retinopathy is equally predictive for renal and macrovascular outcomes in the ACCORD Trial SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Retinopathy; Nephropathy; Macrovascular; Albuminuria; Microvascular ID TYPE-2 DIABETES-MELLITUS; CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; CARDIOVASCULAR EVENTS; RISK-FACTORS; COMPETING RISKS; ASSOCIATION; MICROALBUMINURIA AB Aims: Diabetic retinopathy (DR) is associated with a higher risk of renal and cardiovascular events. We sought to compare the risk for renal versus cardiovascular (CV) outcomes, stratified by retinopathy severity. Methods: ACCORD was a randomized trial of people with type 2 diabetes, at high-risk for CV disease. A subgroup (n = 3,369 from 71 clinics) had stereoscopic fundus photographs graded centrally. Participants were stratified at baseline to moderate/severe DR or no/mild DR and were monitored for renal and CV outcomes at follow-up visits over 4 years. The composite renal outcome was composed of serum creatinine doubling, macroalbuminuria, or end-stage renal disease. The composite CV outcome was the ACCORD trial primary outcome. Competing risk techniques were used to estimate the relative risk (RR) of renal versus CV composite outcomes within each DR stratum. Results: The hazards ratio for doubling of serum creatinine and incident CV event in the moderate/severe DR versus no/mild DR strata were: 2.31 (95% CI: 1.25-4.26) and 1.98 (95% CI: 1.49-2.62), respectively. The RR of the two composite outcomes was highly similar in the no/mild DR stratum (adjusted RR at 4 years for CV versus renal events = 0.96, 95% CI: 0.72-1.28) and the moderate/severe DR stratum (adjusted RR = 0.92, 95% CI: 0.64-1.31). Conclusions: Thus, in people with type 2 diabetes at high risk for cardiovascular disease, incident CV versus renal events was similar, irrespective of the severity of the DR. Further evaluation of the specificity of DR for microvascular versus macrovascular events in other populations is warranted. (C) 2014 Elsevier Inc. All rights reserved. C1 [Mottl, Amy K.] Univ N Carolina, Sch Med, Div Nephrol & Hypertens, Chapel Hill, NC 27599 USA. [Pajewski, Nicholas; Ambrosius, Walter T.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Fonseca, Vivian] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Ismail-Beigi, Faramarz] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Ismail-Beigi, Faramarz] Cleveland VA Med Ctr, Cleveland, OH USA. [Chew, Emily] NEI, NIH, Bethesda, MD 20892 USA. [Greven, Craig] Wake Forest Sch Med, Dept Ophthalmol, Winston Salem, NC USA. [Schubart, Ulrich] North Bronx Healthcare Network, Bronx, NY USA. [Schubart, Ulrich] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Buse, John] Univ N Carolina, Sch Med, Div Endocrinol, Chapel Hill, NC USA. RP Mottl, AK (reprint author), Univ N Carolina, Sch Med, UNC Kidney Ctr, CB 7155, Chapel Hill, NC 27599 USA. EM amy_mottl@med.unc.edu OI Mottl, Amy/0000-0002-4258-1726 FU National Institute of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health [K23DK093804]; NHLBI ACCORDion; PAR, NCATS CTSA FX Research reported in this publication was supported by the National Institute of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number K23DK093804 and NHLBI ACCORDion and PAR, NCATS CTSA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 39 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD NOV-DEC PY 2014 VL 28 IS 6 BP 874 EP 879 DI 10.1016/j.jdiacomp.2014.07.001 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT5KD UT WOS:000344981200022 PM 25123755 ER PT J AU Rozzi, SJ Borelli, G Ryan, K Steiner, JP Reglodi, D Mocchetti, I Avdoshina, V AF Rozzi, Summer J. Borelli, Giulia Ryan, Kerry Steiner, Joseph P. Reglodi, Dora Mocchetti, Italo Avdoshina, Valeriya TI PACAP27 is Protective Against Tat-Induced Neurotoxicity SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE DNA damage; Oxidative stress; Mitochondria; CCL5; HIV; gp120 ID CYCLASE-ACTIVATING POLYPEPTIDE; HIV-1 TAT; OXIDATIVE STRESS; CELL-DEATH; MITOCHONDRIAL HYPERPOLARIZATION; NEURODEGENERATIVE DISEASES; NEUROCOGNITIVE DISORDERS; RECEPTOR ACTIVATION; SIGNALING PATHWAYS; CORTICAL-NEURONS AB Human immunodeficiency virus type-1 (HIV) infection of the central nervous system promotes neuronal injury and apoptosis that culminate in HIV-associated neurocognitive disorders (HAND). Viral proteins, such as transactivator of transcription (Tat), have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanism remains unclear. To determine the effects of Tat, rat cortical neurons were exposed to nanomolar concentrations of Tat for various time points. Within a few hours, Tat induced the production of reactive oxygen species (ROS), and other indices of mitochondrial destabilization. In addition, we observed a significant induction of DNA double-strand breaks (DSBs) by Tat. We next investigated the neuroprotective activity of the pituitary adenylate cyclase-activating polypeptide 27 (PACAP27) against these cardinal features of Tat-induced neurodegeneration. PACAP27 (100 nM) inhibited all Tat-mediated toxic effects including DNA DSBs. Importantly, PACAP27 prevented the induction of neuronal loss induced by Tat. The neuroprotective effect of PACAP27 is correlated with its ability to release the anti-apoptotic chemokine CCL5. Our data support a mechanism of Tat neurotoxicity in which Tat induces mitochondrial destabilization, thus increasing the release of ROS, which causes DNA DSBs leading to cell death. PACAP27, through CCL5, mitigates the effects of Tat-induced neuronal dysfunction, suggesting that PACAP27 could be a new strategy for an adjunct therapy against HIV-associated neurocognitive disorders. C1 [Rozzi, Summer J.; Mocchetti, Italo] Georgetown Univ, Interdisciplinary Program Neurosci, Washington, DC USA. [Rozzi, Summer J.; Borelli, Giulia; Mocchetti, Italo; Avdoshina, Valeriya] Georgetown Univ, Lab Preclin Neurobiol, Dept Neurosci, Washington, DC 20057 USA. [Ryan, Kerry] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Steiner, Joseph P.] NINDS, NIH, Bethesda, MD 20892 USA. [Reglodi, Dora] Univ Pecs, Dept Anat, PTE MTA Lendulet PACAP Res Team, Pecs, Hungary. RP Mocchetti, I (reprint author), Georgetown Univ, Lab Preclin Neurobiol, Dept Neurosci, Washington, DC 20057 USA. EM moccheti@georgetown.edu FU HHS [T32 NS041218, NS079172, NS074916]; Arimura Foundation, PTE-MTA "Lendulet" Program [OTKAK104984 NAP, TAMOP4.2.2.A-11/1/KONV-2012-0024] FX This work was partly supported in part by HHS grant T32 NS041218 to SR and NS079172 and NS074916 to IM. PACAP synthesis was supported by OTKAK104984 NAP, TAMOP4.2.2.A-11/1/KONV-2012-0024, Arimura Foundation, PTE-MTA "Lendulet" Program. NR 51 TC 4 Z9 4 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD NOV PY 2014 VL 54 IS 3 BP 485 EP 493 DI 10.1007/s12031-014-0273-z PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AT3ZN UT WOS:000344875700022 PM 24696163 ER PT J AU Lee, JS AF Lee, Janice S. TI In Search of the Highest Quality: Levels of Evidence in Oral and Maxillofacial Surgery SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID EVIDENCE-BASED MEDICINE; FIBROUS DYSPLASIA; CONTROLLED-TRIALS; OSTEONECROSIS; JAWS; JOURNALS C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Lee, JS (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 10 Ctr Dr,Room 5-2531,MSC 1470, Bethesda, MD 20892 USA. EM Janice.lee@nih.gov NR 20 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 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD NOV PY 2014 VL 72 IS 11 BP 2102 EP 2104 DI 10.1016/j.joms.2014.06.464 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AT9CE UT WOS:000345224800009 PM 25438269 ER PT J AU Korzeniewski, SJ Soto-Rivera, CL Fichorova, RN Allred, EN Kuban, KCK O'Shea, TM Paneth, N Agus, M Dammann, O Leviton, A AF Korzeniewski, Steven J. Soto-Rivera, Carmen L. Fichorova, Raina N. Allred, Elizabeth N. Kuban, Karl C. K. O'Shea, T. Michael Paneth, Nigel Agus, Michael Dammann, Olaf Leviton, Alan CA ELGAN Study Investigators TI Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage? SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE cerebral palsy; inflammation; microcephaly; thyroid-stimulating hormone ID LOW-BIRTH-WEIGHT; SERUM THYROID-HORMONES; C-REACTIVE PROTEIN; TRANSIENT HYPOTHYROXINEMIA; CONGENITAL HYPOTHYROIDISM; NONTHYROIDAL ILLNESS; PREMATURE-INFANTS; GESTATIONAL-AGE; SEVERITY; CHILDREN AB Background: We sought to disentangle the contributions of hyperthyrotropinemia (an indicator of thyroid dysfunction) (HTT) and intermittent or sustained systemic inflammation (ISSI) to structural and functional indicators of brain damage. Methods: We measured the concentrations of thyroid-stimulating hormone (TSH) on day 14 and of 25 inflammation-related proteins in blood collected during the first 2 postnatal weeks from 786 infants born before the 28th week of gestation who were not considered to have hypothyroidism. We defined hyperthyrotropinemia (HTT) as a TSH concentration in the highest quartile for gestational age on postnatal day 14 and ISSI was defined as a concentration in the top quartile for gestational age of a specific inflammation-related protein on 2 separate days a week apart during the first 2 postnatal weeks. We first assessed the risk of brain damage indicators by comparing 1) neonates who had HTT to those without (regardless of ISSI) and 2) neonates with HTT only, ISSI only, or HTT+ISSI to those who were exposed to neither HTT nor ISSI. Results: In univariable models that compared those with HTT to those without, HTT was not significantly associated with any indicator of brain damage. In models that compared HTT only, ISSI only, and HTT+ISSI to those with neither, children with ISSI only or with HTT+ISSI were at significantly higher risk of ventriculomegaly [ odds ratios (ORs) 2-6], whereas those with HTT only were at significantly reduced risk of a hypoechoic lesion (ORs 0.2-0.4). Children with HTT only had a higher risk of quadriparesis and those with ISSI alone had a higher risk of hemiparesis (ORs 1.6-2.4). Elevated risk of a very low mental development score was associated with both ISSI only and HTT+ISSI, whereas a very low motor development score and microcephaly were associated with HTT+ISSI. Conclusions: The association of HTT with increased or decreased risk of indicators of brain damage depends on the presence or absence of ISSI. C1 [Korzeniewski, Steven J.] Hutzel Womens Hosp, Detroit, MI 48201 USA. [Korzeniewski, Steven J.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Korzeniewski, Steven J.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Korzeniewski, Steven J.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Soto-Rivera, Carmen L.; Agus, Michael] Harvard Univ, Boston Childrens Hosp, Sch Med, Div Endocrinol, Boston, MA 02115 USA. [Fichorova, Raina N.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Fichorova, Raina N.; Allred, Elizabeth N.; Leviton, Alan] Harvard Univ, Sch Med, Boston, MA USA. [Allred, Elizabeth N.; Leviton, Alan] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Kuban, Karl C. K.] Boston Med Ctr, Dept Pediat, Boston, MA USA. [Kuban, Karl C. K.] Boston Univ, Boston, MA 02215 USA. [O'Shea, T. Michael] Wake Forest Univ, Dept Pediat, Winston Salem, NC USA. [Paneth, Nigel] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Dammann, Olaf] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Dammann, Olaf] Hannover Med Sch, Neuroepidemiol Unit, Hannover, Germany. RP Korzeniewski, SJ (reprint author), Hutzel Womens Hosp, 4 Brush Off 4817,3990 John R, Detroit, MI 48201 USA. EM sKorzeni@med.wayne.edu FU National Institute of Neurological Disorders and Stroke [5U01NS040069-05, 2R01NS040069-06A2]; National Eye Institute [1-R01-EY021820-01]; National Institute of Child Health and Human Development [5P30HD018655-28] FX This study was supported by the National Institute of Neurological Disorders and Stroke (5U01NS040069-05; 2R01NS040069-06A2), the National Eye Institute (1-R01-EY021820-01), and the National Institute of Child Health and Human Development (5P30HD018655-28). NR 38 TC 2 Z9 2 U1 1 U2 3 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X EI 2191-0251 J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD NOV PY 2014 VL 27 IS 11-12 BP 1077 EP 1088 DI 10.1515/jpem-2014-0059 PG 12 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA AT6BE UT WOS:000345022900009 PM 24897395 ER PT J AU Huibregtse, KE Wolfgram, P Winer, KK Connor, EL AF Huibregtse, Kelly Egan Wolfgram, Peter Winer, Karen K. Connor, Ellen L. TI Polyglandular autoimmune syndrome type I - a novel AIRE mutation in a North American patient SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE AIRE gene; autoimmune polyglandular syndrome; mucocutaneous candidiasis ID CANDIDIASIS-ECTODERMAL-DYSTROPHY; DISEASE; GENE; COMMON; THERAPY AB Autoimmune polyglandular syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autoimmune disease that results from autosomal recessive mutations of the human autoimmune regulatory (AIRE) gene. We present the case of a 17-year-old North American girl of primarily Norwegian descent with a novel AIRE gene mutation causing APS-1. In addition to the classic triad of chronic candidiasis, hypoparathyoidism and autoimmune adrenocortical insufficiency, she also has vitiligo, intestinal malabsorption, autoimmune hepatitis, autoimmune hypothyroidism, myositis, myalgias, chronic fatigue, and failure to thrive. Genetic testing revealed heterozygosity for c.20_115de196 and c.967_979del13 mutations in the AIRE gene. The AIRE gene c.20_115de196 mutation has not been previously reported. C1 [Huibregtse, Kelly Egan] Univ Calif San Francisco, Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94143 USA. [Wolfgram, Peter] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Winer, Karen K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Connor, Ellen L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Div Pediat Endocrinol, Madison, WI USA. RP Huibregtse, KE (reprint author), Parnassus Ave, San Francisco, CA USA. EM huibregtse@ucsf.edu OI Connor, Ellen/0000-0002-9667-7002 FU NIDDK NIH HHS [T32 DK077586] NR 20 TC 2 Z9 3 U1 1 U2 2 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X EI 2191-0251 J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD NOV PY 2014 VL 27 IS 11-12 BP 1257 EP 1260 DI 10.1515/jpem-2013-0328 PG 4 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA AT6BE UT WOS:000345022900038 PM 24945421 ER PT J AU Lane, C AF Lane, Clifford TI Mechanisms underlying abnormalities of immune activation/coagulation in HIV infection SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Meeting Abstract C1 [Lane, Clifford] NIAID, Clin & Mol Retrovirol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2014 VL 17 SU 3 MA KL2 BP 1 EP 1 DI 10.7448/IAS.17.4.19477 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AT5CR UT WOS:000344961700003 ER PT J AU Shaikh, QN Memon, AA Kamal, AK AF Shaikh, Quratulain Nauman Memon, Adeel Ali Kamal, Ayeesha Kamran TI Association of hypertension with stroke recurrence may depend on ischaemic stroke subtype SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material ID INFARCTION C1 [Shaikh, Quratulain Nauman; Memon, Adeel Ali; Kamal, Ayeesha Kamran] Aga Khan Univ, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Res Team, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Res Team, Karachi, Pakistan. EM ayeesha.kamal@aku.edu OI Shaikh, Quratulain/0000-0001-6106-2713 NR 2 TC 0 Z9 1 U1 0 U2 1 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD NOV PY 2014 VL 64 IS 11 BP 1327 EP 1328 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AT6ND UT WOS:000345055000028 PM 25831660 ER PT J AU Nathan, M Sleeper, LA Ohye, RG Frommelt, PC Caldarone, CA Tweddell, JS Lu, MM Pearson, GD Gaynor, JW Pizarro, C Williams, IA Colan, SD Dunbar-Masterson, C Gruber, PJ Hill, K Hirsch-Romano, J Jacobs, JP Kaltman, JR Kumar, SR Morales, D Bradley, SM Kanter, K Newburger, JW AF Nathan, Meena Sleeper, Lynn A. Ohye, Richard G. Frommelt, Peter C. Caldarone, Christopher A. Tweddell, James S. Lu, Minmin Pearson, Gail D. Gaynor, J. William Pizarro, Christian Williams, Ismee A. Colan, Steven D. Dunbar-Masterson, Carolyn Gruber, Peter J. Hill, Kevin Hirsch-Romano, Jennifer Jacobs, Jeffrey P. Kaltman, Jonathan R. Kumar, S. Ram Morales, David Bradley, Scott M. Kanter, Kirk Newburger, Jane W. CA Pediat Heart Network Investigators TI Technical performance score is associated with outcomes after the Norwood procedure SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID VENTRICLE RECONSTRUCTION TRIAL; CONGENITAL HEART-DISEASE; SINGLE-VENTRICLE; CARDIAC-SURGERY; ADVERSE EVENTS; RISK-FACTORS; PATIENT OUTCOMES; LATE MORTALITY; INFANTS; MULTICENTER AB Objectives: The technical performance score (TPS) has been reported in a single center study to predict the outcomes after congenital cardiac surgery. We sought to determine the association of the TPS with outcomes in patients undergoing the Norwood procedure in the Single Ventricle Reconstruction trial. Methods: We calculated the TPS (class 1, optimal; class 2, adequate; class 3, inadequate) according to the predischarge echocardiograms analyzed in a core laboratory and unplanned reinterventions that occurred before discharge from the Norwood hospitalization. Multivariable regression examined the association of the TPS with interval to first extubation, Norwood length of stay, death or transplantation, unplanned postdischarge reinterventions, and neurodevelopment at 14 months old. Results: Of 549 patients undergoing a Norwood procedure, 356 (65%) had an echocardiogram adequate to assess atrial septal restriction or arch obstruction or an unplanned reintervention, enabling calculation of the TPS. On multivariable regression, adjusting for preoperative variables, a better TPS was an independent predictor of a shorter interval to first extubation (P = .019), better transplant-free survival before Norwood discharge (P < .001; odds ratio, 9.1 for inadequate vs optimal), shorter hospital length of stay (P < .001), fewer unplanned reinterventions between Norwood discharge and stage II (P = .004), and a higher Bayley II psychomotor development index at 14 months (P = .031). The TPS was not associated with transplant-free survival after Norwood discharge, unplanned reinterventions after stage II, or the Bayley II mental development index at 14 months. Conclusions: TPS is an independent predictor of important outcomes after Norwood and could serve as a tool for quality improvement. C1 [Nathan, Meena; Colan, Steven D.; Dunbar-Masterson, Carolyn; Newburger, Jane W.] Harvard Univ, Boston Childrens Hosp, Boston, MA 02215 USA. [Nathan, Meena; Colan, Steven D.; Dunbar-Masterson, Carolyn; Newburger, Jane W.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Sleeper, Lynn A.] Cytel Inc, Cambridge, MA USA. [Ohye, Richard G.; Hirsch-Romano, Jennifer] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Frommelt, Peter C.; Tweddell, James S.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Frommelt, Peter C.; Tweddell, James S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Caldarone, Christopher A.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Lu, Minmin; Colan, Steven D.] New England Res Inst, Watertown, MA 02172 USA. [Pearson, Gail D.; Kaltman, Jonathan R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Gaynor, J. William] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Gaynor, J. William] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Pizarro, Christian] Nemours Cardiac Ctr, Wilmington, DE USA. [Williams, Ismee A.] Morgan Stanley Childrens Hosp NewYork Presbyteria, New York, NY USA. [Gruber, Peter J.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Hill, Kevin] Duke Univ, Chapel Hill, NC USA. [Jacobs, Jeffrey P.] Johns Hopkins All Childrens Heart Inst, St Petersburg, FL USA. [Kumar, S. Ram] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Morales, David] Cincinnati Childrens Med Ctr, Cincinnati, OH USA. [Bradley, Scott M.] Med Univ S Carolina, Charleston, SC 29425 USA. [Kanter, Kirk] Emory Univ, Atlanta, GA 30322 USA. RP Nathan, M (reprint author), Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Cardiac Surg, 300 Longwood Ave, Boston, MA 02215 USA. EM meena.nathan@cardio.chboston.org FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, HL085057, HL109737, HL109781] FX This work was supported by the National Heart, Lung, and Blood Institute (grants HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, HL085057, HL109737, and HL109781). This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health. NR 32 TC 12 Z9 12 U1 1 U2 2 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 NOV PY 2014 VL 148 IS 5 BP 2208 EP 2214 DI 10.1016/j.jtcvs.2014.05.076 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA AT7QM UT WOS:000345132600093 PM 25037617 ER PT J AU Herman, SEM Niemann, CU Farooqui, M Jones, J Mustafa, RZ Lipsky, A Saba, N Martyr, S Soto, S Valdez, J Gyamfi, JA Maric, I Calvo, KR Pedersen, LB Geisler, CH Liu, D Marti, GE Aue, G Wiestner, A AF Herman, S. E. M. Niemann, C. U. Farooqui, M. Jones, J. Mustafa, R. Z. Lipsky, A. Saba, N. Martyr, S. Soto, S. Valdez, J. Gyamfi, J. A. Maric, I. Calvo, K. R. Pedersen, L. B. Geisler, C. H. Liu, D. Marti, G. E. Aue, G. Wiestner, A. TI Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study SO LEUKEMIA LA English DT Article ID B-CELL-RECEPTOR; KINASE INHIBITOR IBRUTINIB; BRUTONS TYROSINE KINASE; TUMOR PROLIFERATION; THERAPEUTIC TARGET; ANTIGEN RECEPTORS; IN-VIVO; LYMPHOMA; PCI-32765; BTK AB Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. Here we report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes (LNs), spleen and bone marrow, assessed phenotypic changes of circulating cells and measured whole-blood viscosity. With just one dose of ibrutinib, the average increase in ALC was 66%, and in >40% of patients the ALC peaked within 24 h of initiating treatment. Circulating CLL cells on day 2 showed increased Ki67 and CD38 expression, indicating an efflux of tumor cells from the tissue compartments into the blood. The kinetics and degree of the treatment-induced lymphocytosis was highly variable; interestingly, in patients with a high baseline ALC the relative increase was mild and resolution rapid. After two cycles of treatment the disease burden in the LN, bone marrow and spleen decreased irrespective of the relative change in ALC. Whole-blood viscosity was dependent on both ALC and hemoglobin. No adverse events were attributed to the lymphocytosis. C1 [Herman, S. E. M.; Niemann, C. U.; Farooqui, M.; Jones, J.; Mustafa, R. Z.; Lipsky, A.; Saba, N.; Martyr, S.; Soto, S.; Valdez, J.; Gyamfi, J. A.; Liu, D.; Marti, G. E.; Aue, G.; Wiestner, A.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Jones, J.] NIH, Med Res Scholars Program, Bethesda, MD 20892 USA. [Maric, I.; Calvo, K. R.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Pedersen, L. B.; Geisler, C. H.] Copenhagen Univ Hosp, Rigshosp, Dept Hematol, Copenhagen, Denmark. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 8c104,CRC 3-5140 10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov RI Niemann, Carsten/P-3497-2015; OI Niemann, Carsten/0000-0001-9880-5242; Calvo, Katherine/0000-0002-0771-4191 FU Intramural Research Program of NHLBI, NIH; Danish Cancer Society; NIH Medical Research Scholars Program; NIH FX We thank our patients for participating and donating samples to make this research possible. We thank Ajunae Wells for assistance in the clinic and Stephanie Housel, Adrian Byrnes and Allison Wise for protocol support. We acknowledge Pharmacyclics for providing study drug. This work was supported by the Intramural Research Program of NHLBI, NIH. CUN was supported by The Danish Cancer Society. JJ was supported by the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Leona M and Harry B Helmsley Charitable Trust and the Howard Hughes Medical Institute, as well as other private donors (http://www.fnih.org/work/programs-development/medical-research-scholars -program). NR 51 TC 43 Z9 44 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD NOV PY 2014 VL 28 IS 11 BP 2188 EP 2196 DI 10.1038/leu.2014.122 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA AT4UY UT WOS:000344940300008 PM 24699307 ER PT J AU Nicolae, A Xi, L Pittaluga, S Abdullaev, Z Pack, SD Chen, J Waldmann, TA Jaffe, ES Raffeld, M AF Nicolae, A. Xi, L. Pittaluga, S. Abdullaev, Z. Pack, S. D. Chen, J. Waldmann, T. A. Jaffe, E. S. Raffeld, M. TI Frequent STAT5B mutations in gamma delta hepatosplenic T-cell lymphomas SO LEUKEMIA LA English DT Letter ID GRANULAR LYMPHOCYTIC-LEUKEMIA C1 [Nicolae, A.; Pittaluga, S.; Jaffe, E. S.] Ctr Canc Res, Natl Canc Inst, Hematopathol Sect, Bethesda, MD 20892 USA. [Xi, L.; Raffeld, M.] Ctr Canc Res, Natl Canc Inst, Mol Diagnost Unit, Bethesda, MD USA. [Abdullaev, Z.; Pack, S. D.] Ctr Canc Res, Natl Canc Inst, Pathol Lab, Chromosome Biol Unit, Bethesda, MD USA. [Chen, J.; Waldmann, T. A.] Ctr Canc Res, Natl Canc Inst, Lymphoid Malignancies Branch, Bethesda, MD USA. RP Nicolae, A (reprint author), Ctr Canc Res, Natl Canc Inst, Hematopathol Sect, Bethesda, MD 20892 USA. EM mraff@mail.nih.gov FU Intramural NIH HHS NR 16 TC 31 Z9 31 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD NOV PY 2014 VL 28 IS 11 BP 2244 EP 2248 DI 10.1038/leu.2014.200 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA AT4UY UT WOS:000344940300016 PM 24947020 ER PT J AU Alewine, C Xiang, LM Yamori, T Niederfellner, G Bosslet, K Pastan, I AF Alewine, Christine Xiang, Laiman Yamori, Takao Niederfellner, Gerhard Bosslet, Klaus Pastan, Ira TI Efficacy of RG7787, a Next-Generation Mesothelin-Targeted Immunotoxin, against Triple-Negative Breast and Gastric Cancers SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PHASE-I TRIAL; RECOMBINANT IMMUNOTOXIN; PANCREATIC-CANCER; OVARIAN-CANCER; CELL-LINES; EXPRESSION; SS1P; TAXOL; ADENOCARCINOMAS; ANTIGENICITY AB The RG7787 mesothelin-targeted recombinant immunotoxin (RIT) consists of an antibody fragment targeting mesothelin (MSLN) fused to a 24- kD fragment of Pseudomonas exotoxin A for cell killing. Compared with prior RITs, RG7787 has improved properties for clinical development including decreased nonspecific toxicity and immunogenicity and resistance to degradation by lysosomal proteases. MSLN is a cell surface glycoprotein highly expressed by many solid tumor malignancies. New reports have demonstrated that MSLN is expressed by a significant percentage of triple-negative breast and gastric cancer clinical specimens. Here, panels of triple-negative breast and gastric cancer cell lines were tested for surface MSLN expression, and for sensitivity to RG7787 in vitro and in animal models. RG7787 produced > 95% cell killing of the HCC70 and SUM149 breast cancer cell lines in vitro with IC50 < 100 pmol/L. RG7787 was also effective against gastric cancer cell lines MKN28, MKN45, and MKN74 in vitro, with subnanomolar IC50s. In a nude mouse model, RG7787 treatment (2.5 mg/kg i.v. qod x 3-4) resulted in a statistically significant 41% decrease in volumes of HCC70 x enograft tumors (P < 0.0001) and an 18% decrease in MKN28 tumors (P < 0.0001). Pretreatment with paclitaxel (50 mg/kg i.p.) enhanced efficacy, producing 88% and 70% reduction in tumor volumes for HCC70 and MKN28, respectively, a statistically significant improvement over paclitaxel alone (P < 0.0001 for both). RG7787 merits clinical testing for triple-negative breast and gastric cancers. (C) 2014 AACR. C1 [Alewine, Christine; Xiang, Laiman; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD USA. [Yamori, Takao] Pharmaceut & Med Device Agcy, Ctr Prod Evaluat, Tokyo, Japan. [Niederfellner, Gerhard; Bosslet, Klaus] F Hoffmann La Roche & Cie AG, Pharmaceut Res & Early Dev pRED, Discovery Oncol, Penzberg, Germany. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5106, Bethesda, MD 20814 USA. EM pastani@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute and Roche Pharmaceuticals [2791]; National Cancer Institute; Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by a Cooperative Research and Development Agreement (# 2791) between the National Cancer Institute and Roche Pharmaceuticals. NR 30 TC 22 Z9 22 U1 0 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2014 VL 13 IS 11 BP 2653 EP 2661 DI 10.1158/1535-7163.MCT-14-0132 PG 9 WC Oncology SC Oncology GA AT5BB UT WOS:000344957600016 PM 25239937 ER PT J AU Adams, DR Yuan, HJ Holyoak, T Arajs, KH Hakimi, P Markello, TC Wolfe, LA Vilboux, T Burton, BK Fajardo, KF Grahame, G Holloman, C Sincan, M Smith, ACM Wells, GA Huang, Y Vega, H Snyder, JP Golas, GA Tifft, CJ Boerkoel, CF Hanson, RW Traynelis, SF Kerr, DS Gahl, WA AF Adams, David R. Yuan, Hongjie Holyoak, Todd Arajs, Katrina H. Hakimi, Parvin Markello, Thomas C. Wolfe, Lynne A. Vilboux, Thierry Burton, Barbara K. Fajardo, Karin Fuentes Grahame, George Holloman, Conisha Sincan, Murat Smith, Ann C. M. Wells, Gordon A. Huang, Yan Vega, Hugo Snyder, James P. Golas, Gretchen A. Tifft, Cynthia J. Boerkoel, Cornelius F. Hanson, Richard W. Traynelis, Stephen F. Kerr, Douglas S. Gahl, William A. TI Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Hypoglycemia; Lactic acidemia; Dysmorphism; Developmental delay; Protein structure-function; Multiple genetic disorders ID DE-NOVO MUTATIONS; LOOP LID DOMAIN; PHOSPHOENOLPYRUVATE CARBOXYKINASE; UNDIAGNOSED DISEASES; INTELLECTUAL DISABILITY; STRUCTURE VALIDATION; ZINC INHIBITION; SUBUNIT; PROGRAM; EXPRESSION AB The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAII gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases. (C) 2014 Elsevier Inc. All rights reserved. C1 [Adams, David R.; Markello, Thomas C.; Wolfe, Lynne A.; Fajardo, Karin Fuentes; Sincan, Murat; Smith, Ann C. M.; Huang, Yan; Vega, Hugo; Golas, Gretchen A.; Tifft, Cynthia J.; Boerkoel, Cornelius F.; Gahl, William A.] Off Director, Undiagnosed Dis Program, NIH, Bethesda, MD 20817 USA. [Adams, David R.; Vilboux, Thierry; Gahl, William A.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Yuan, Hongjie; Traynelis, Stephen F.] Emory Univ, Rollins Res Ctr, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. [Holyoak, Todd; Arajs, Katrina H.] Univ Waterloo, Dept Biol, Waterloo, ON N2L 3G1, Canada. [Burton, Barbara K.] Northwestern Univ, Ann & Robert H Lurie Childrens Hosp, Chicago, IL 60611 USA. [Burton, Barbara K.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Hakimi, Parvin; Hanson, Richard W.; Kerr, Douglas S.] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. [Hakimi, Parvin; Kerr, Douglas S.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Grahame, George; Kerr, Douglas S.] Univ Hosp Case Med Ctr, Ctr Inherited Disorders Energy Metab, Cleveland, OH USA. [Holloman, Conisha] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Wells, Gordon A.; Snyder, James P.] Emory Univ, Dept Chem, Atlanta, GA 30322 USA. [Wells, Gordon A.] Univ Stellenbosch, Dept Biochem, ZA-7600 Stellenbosch, South Africa. RP Adams, DR (reprint author), Off Director, Undiagnosed Dis Program, NIH, Bethesda, MD 20817 USA. EM david.adams@nih.gov OI Wells, Gordon/0000-0003-2328-5208 FU Intramural Research Program of the National Human Genome Research Institute [NS036654]; NIH Undiagnosed Diseases Program [HSN268201300162P]; Center for Inherited Disorders of Energy Metabolism; Allison Foundation [116491]; National Center for Research Resources [P20 RR17708]; Natural Sciences and Engineering Research Council of Canada FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, by grant NS036654 (S.F.T.); by the NIH Undiagnosed Diseases Program (HSN268201300162P, H.Y.); the Center for Inherited Disorders of Energy Metabolism (D.S.K); the Allison Foundation, grant 116491 (R.W.H.); the National Center for Research Resources Grant P20 RR17708 and the Natural Sciences and Engineering Research Council of Canada (T.H.). Professor Richard W. Hanson died the same day that this article was originally submitted; he had spent most of his illustrious career studying regulation of PEPCK-C. NR 52 TC 13 Z9 14 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2014 VL 113 IS 3 BP 161 EP 170 DI 10.1016/j.ymgme.2014.04.001 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AT3ON UT WOS:000344844000003 PM 24863970 ER PT J AU Das, S Chigurupati, S Dowding, J Munusamy, P Baer, DR McGinnis, JF Mattson, MP Self, W Seal, S AF Das, Soumen Chigurupati, Srinivasulu Dowding, Janet Munusamy, Prabhakaran Baer, Donald R. McGinnis, James F. Mattson, Mark P. Self, William Seal, Sudipta TI Therapeutic potential of nanoceria in regenerative medicine SO MRS BULLETIN LA English DT Article ID CERIUM OXIDE NANOPARTICLES; OXIDATIVE STRESS; CEO2 NANOPARTICLES; NEURONAL SURVIVAL; CELLS; RADIATION; PROTECT; MICE; NANOSTRUCTURES; PROLIFERATION AB Tissue engineering and regenerative medicine aim to achieve functional restoration of tissue or cells damaged through disease, aging, or trauma. Advancement of tissue engineering requires innovation in the field of three-dimensional scaffolding and functionalization with bioactive molecules. Nanotechnology offers advanced materials with patterned nano-morphologies for cell growth and different molecular substrates that can support cell survival and functions. Cerium oxide nanoparticles (nanoceria) can control intracellular as well as extracellular reactive oxygen and nitrogen species. Recent findings suggest that nanoceria can enhance long-term cell survival, enable cell migration and proliferation, and promote stem cell differentiation. Moreover, the self-regenerative property of nanoceria permits a small dose to remain catalytically active for an extended time. This review summarizes the possibilities and applications of nanoceria in the field of tissue engineering and regenerative medicine. C1 [Das, Soumen] Univ Cent Florida, Nanosci Technol Ctr, Adv Mat Proc Anal Ctr, Orlando, FL 32816 USA. [Chigurupati, Srinivasulu] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. [Dowding, Janet] Univ Cent Florida, Burnett Sch Biomed Sci, Orlando, FL 32816 USA. [Munusamy, Prabhakaran; Baer, Donald R.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [McGinnis, James F.] Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, Norman, OK 73019 USA. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Self, William] Univ Cent Florida, Burnett Sch Biomed Sci, Orlando, FL 32816 USA. [Seal, Sudipta] Univ Cent Florida, Adv Mat Proc & Anal Ctr, Nanosci & Technol Ctr, Coll Med, Orlando, FL 32816 USA. RP Das, S (reprint author), Univ Cent Florida, Nanosci Technol Ctr, Adv Mat Proc Anal Ctr, Orlando, FL 32816 USA. EM soumen.das@ucf.edu; srinivasulu.chigurupati@fda.hhs.gov; jdowding42q@gmail.com; prabhakaran.munusamy@pnnl.gov; don.baer@pnnl.gov; James-McGinnis@ouhsc.edu; MattsonM@grc.nia.nih.gov; william.self@ucf.edu; Sudipta.Seal@ucf.edu RI Baer, Donald/J-6191-2013; Self, William/A-6704-2008 OI Baer, Donald/0000-0003-0875-5961; FU National Institute on Aging; NIH NEI [COBRE-P20 RR017703, P30-EY 12190, R21EY018306, R01EY18724, R01EY022111]; National Science Foundation [CBET-0708172]; NIEHS Center [U19 ES019544]; US Department of Energy, Biological and Environmental Research and located at PNNL FX This work was supported, in part, by the intramural research program of the National Institute on Aging. The work by J.F.M. was supported by NIH NEI Grant COBRE-P20 RR017703, P30-EY 12190, R21EY018306, R01EY18724, R01EY022111; National Science Foundation: CBET-0708172; and Research to Prevent Blindness. D.R.B. was supported by the NIEHS Center Grant U19 ES019544. Part of this work was performed using EMSL, a national scientific user facility sponsored by the US Department of Energy, Biological and Environmental Research and located at PNNL. S.S. and W.S. acknowledge NSF and NIH for various aspects of nano-biotechnology research. NR 50 TC 5 Z9 5 U1 3 U2 20 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0883-7694 EI 1938-1425 J9 MRS BULL JI MRS Bull. PD NOV PY 2014 VL 39 IS 11 BP 976 EP 983 DI 10.1557/mrs.2014.221 PG 8 WC Materials Science, Multidisciplinary; Physics, Applied SC Materials Science; Physics GA AT7ML UT WOS:000345121300017 ER PT J AU Guo, WS Yang, WT Wang, Y Sun, XL Liu, ZY Zhang, BB Chang, J Chen, XY AF Guo, Weisheng Yang, Weitao Wang, Yu Sun, Xiaolian Liu, Zhongyun Zhang, Bingbo Chang, Jin Chen, Xiaoyuan TI Color-tunable Gd-Zn-Cu-In-S/ZnS quantum dots for dual modality magnetic resonance and fluorescence imaging SO NANO RESEARCH LA English DT Article DE CuInS2 quantum dot; magnetic resonance imaging; photoluminescence; multimodality imaging; gadolinium doped ID IRON-OXIDE NANOPARTICLES; ONE-POT SYNTHESIS; CONTRAST AGENTS; SEMICONDUCTOR NANOCRYSTALS; HIGH RELAXIVITY; PHOTOLUMINESCENCE; PROBES; MRI AB Inorganic nanoparticles have been introduced into biological systems as useful probes for in vitro diagnosis and in vivo imaging, due to their relatively small size and exceptional physical and chemical properties. A new kind of colortunable Gd-Zn-Cu-In-S/ZnS (GZCIS/ZnS) quantum dots (QDs) with stable crystal structure has been successfully synthesized and utilized for magnetic resonance (MR) and fluorescence dual modality imaging. This strategy allows successful fabrication of GZCIS/ZnS QDs by incorporating Gd into ZCIS/ZnS QDs to achieve great MR enhancement without compromising the fluorescence properties of the initial ZCIS/ZnS QDs. The as-prepared GZCIS/ZnS QDs show high T (1) MR contrast as well as "color-tunable" photoluminescence (PL) in the range of 550-725 nm by adjusting the Zn/Cu feeding ratio with high PL quantum yield (QY). The GZCIS/ZnS QDs were transferred into water via a bovine serum albumin (BSA) coating strategy. The resulting Cd-free GZCIS/ZnS QDs reveal negligible cytotoxicity on both HeLa and A549 cells. Both fluorescence and MR imaging studies were successfully performed in vitro and in vivo. The results demonstrated that GZCIS/ZnS QDs could be a dual-modal contrast agent to simultaneously produce strong MR contrast enhancement as well as fluorescence emission for in vivo imaging. C1 [Guo, Weisheng; Yang, Weitao; Liu, Zhongyun; Chang, Jin] Tianjin Univ, Sch Mat Sci & Engn, Inst Nanobiotechnol, Tianjin 300072, Peoples R China. [Guo, Weisheng; Yang, Weitao; Liu, Zhongyun; Chang, Jin] Tianjin Key Lab Composites & Funct Mat, Tianjin 300072, Peoples R China. [Guo, Weisheng; Sun, Xiaolian; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Zhang, Bingbo] Tongji Univ, Sch Med, Inst Biomed Engn & Nano Sci, Shanghai East Hosp, Shanghai 200120, Peoples R China. [Wang, Yu] Southeast Univ, Sch Med, Zhongda Hosp, Dept Radiol,Jiangsu Key Lab Mol Imaging & Funct I, Nanjing 210009, Peoples R China. RP Zhang, BB (reprint author), Tongji Univ, Sch Med, Inst Biomed Engn & Nano Sci, Shanghai East Hosp, Shanghai 200120, Peoples R China. EM bingbozhang@tongji.edu.cn; jinchang@tju.edu.cn; shawn.chen@nih.gov OI Zhang, Bingbo/0000-0002-0981-7071 FU National High Technology Program of China [2012AA022603]; National Natural Science Foundation of China [51373117, 81171372, 81371596, 81371618]; Tianjin Nature Science Foundation [13JCZDJC33200]; Ministry of Education of China [20120032110027]; China Scholarship Council (CSC) FX The authors gratefully acknowledge the National High Technology Program of China (No. 2012AA022603), the National Natural Science Foundation of China (Nos. 51373117, 81171372, 81371596, and 81371618), the Key Project of Tianjin Nature Science Foundation (No. 13JCZDJC33200), the Doctoral Fund of Ministry of Education of China (No. 20120032110027), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. W.G. was funded in part by the China Scholarship Council (CSC). NR 40 TC 18 Z9 19 U1 7 U2 99 PU TSINGHUA UNIV PRESS PI BEIJING PA TSINGHUA UNIV, RM A703, XUEYAN BLDG, BEIJING, 10084, PEOPLES R CHINA SN 1998-0124 EI 1998-0000 J9 NANO RES JI Nano Res. PD NOV PY 2014 VL 7 IS 11 BP 1581 EP 1591 DI 10.1007/s12274-014-0518-8 PG 11 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA AU0WL UT WOS:000345342800002 PM 25485043 ER PT J AU Turkbey, B Choyke, PL AF Turkbey, Baris Choyke, Peter L. TI DECADE IN REVIEW-IMAGING A decade in image-guided prostate biopsy SO NATURE REVIEWS UROLOGY LA English DT Editorial Material ID CANCER-DETECTION; ULTRASOUND FUSION AB The prostate is still largely assessed by random biopsy, but developments in prostate MRI and fusion with transrectal ultrasonography (TRUS) have made targeted biopsy of the prostate a reality. MRI/TRUS techniques promise to address the issues of overdiagnosis and underdiagnosis in prostate cancer. C1 [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM pchoyke@mail.nih.gov NR 10 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4812 EI 1759-4820 J9 NAT REV UROL JI Nat. Rev. Urol. PD NOV PY 2014 VL 11 IS 11 BP 611 EP 612 DI 10.1038/nrurol.2014.273 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AT4XY UT WOS:000344946900003 PM 25311679 ER PT J AU Linehan, WM Ricketts, CJ AF Linehan, W. Marston Ricketts, Christopher J. TI DECADE IN REVIEW-KIDNEY CANCER Discoveries, therapies and opportunities SO NATURE REVIEWS UROLOGY LA English DT Editorial Material ID RENAL-CELL CARCINOMA; FUMARATE AB Several advances in kidney cancer have occurred over the past decade, including the discovery of mutations in chromatin remodelling genes and genomic heterogeneity in clear cell renal cell carcinoma (ccRCC). Altered metabolic patterns in ccRCC and papillary RCC have become apparent, and new drugs for ccRCC have been approved. C1 [Linehan, W. Marston; Ricketts, Christopher J.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr,MSC 1107,CRC Room 1W-5940, Bethesda, MD 20892 USA. EM wml@nih.gov FU Intramural NIH HHS [Z01 BC011023-01]; NCI NIH HHS [Z01 BC011028-01, Z01 BC011038-01] NR 10 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4812 EI 1759-4820 J9 NAT REV UROL JI Nat. Rev. Urol. PD NOV PY 2014 VL 11 IS 11 BP 614 EP 615 DI 10.1038/nrurol.2014.262 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AT4XY UT WOS:000344946900005 PM 25287783 ER PT J AU Albersen, M Cartwright, R Choyke, P Goldenberg, SL Goldman, H Lawrentschuk, N Linehan, WM Murphy, D Nagler, H Scardino, P Shortliffe, L Stenzl, A Theodorescu, D AF Albersen, Maarten Cartwright, Rufus Choyke, Peter Goldenberg, S. Larry Goldman, Howard Lawrentschuk, Nathan Linehan, W. Marston Murphy, Declan Nagler, Harris Scardino, Peter Shortliffe, Linda Stenzl, Arnulf Theodorescu, Dan TI Looking forward, looking back-10-years in urology SO NATURE REVIEWS UROLOGY LA English DT Editorial Material ID RISK PROSTATE-CANCER; RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; MITOXANTRONE; PREDNISONE; SURVIVAL; UPDATE; MEN AB When Nature Reviews Urology launched in 2004, the field of urology was vastly different to that which we work in today, and the past 10 years have seen the field change immensely. As a specialty on the forefront of cutting-edge innovation, urologists are often the first to embrace new technologies and ideas. In this Viewpoint, members of the Nature Reviews Urology advisory board were asked what they thought was the most important change, issue or innovation in urology in the past 10 years, and what they expected to be the most important in the next decade. Here are their opinions. C1 [Albersen, Maarten] Univ Hosp Leuven, Dept Urol, B-3000 Leuven, Belgium. [Cartwright, Rufus] Hammersmith Hosp, Univ London Imperial Coll Sci Technol & Med, Inst Reprod & Dev Biol, London W12 0NN, England. [Choyke, Peter] NCI, Mol Imaging Program, NIH, Bethesda, MD USA. [Goldenberg, S. Larry] Univ British Columbia, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada. [Goldman, Howard] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44195 USA. [Lawrentschuk, Nathan] Univ Melbourne, Dept Surg, Heidelberg, Vic 3084, Australia. [Lawrentschuk, Nathan] Austin Hosp, Ludwig Inst Canc Res, Heidelberg, Vic 3084, Australia. [Linehan, W. Marston] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Murphy, Declan] Peter MacCallum Canc Ctr, Div Canc Surg, East Melbourne, Vic 3003, Australia. [Nagler, Harris] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Scardino, Peter] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Shortliffe, Linda] Dept Urol, Stanford, CA 94305 USA. [Stenzl, Arnulf] Univ Clin Urol, Dept Urol, D-72076 Tubingen, Germany. [Theodorescu, Dan] Univ Colorado, Ctr Comprehens Canc, Aurora, CO 80045 USA. RP Albersen, M (reprint author), Nat Reviews Urol Editorial Off, London, England. EM nruro@nature.com OI Lawrentschuk, Nathan/0000-0001-8553-5618 FU Medical Research Council [G1100377] NR 25 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4812 EI 1759-4820 J9 NAT REV UROL JI Nat. Rev. Urol. PD NOV PY 2014 VL 11 IS 11 BP 649 EP 655 DI 10.1038/nrurol.2014.263 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AT4XY UT WOS:000344946900011 PM 25348169 ER PT J AU Kadipasaoglu, CM Baboyan, VG Conner, CR Chen, G Saad, ZS Tandon, N AF Kadipasaoglu, C. M. Baboyan, V. G. Conner, C. R. Chen, G. Saad, Z. S. Tandon, N. TI Surface-based mixed effects multilevel analysis of grouped human electrocorticography SO NEUROIMAGE LA English DT Article DE Subdural electrodes; High gamma-band activity; Surface-based normalization; Mixed effects multilevel analysis (MEMA); Fusiform face area; Occipital face area ID FUSIFORM FACE AREA; CORTICAL SURFACE; INTRACRANIAL EEG; BRAIN ACTIVITY; GAMMA ACTIVITY; BOLD-FMRI; COORDINATE SYSTEM; CORTEX; LOCALIZATION; OSCILLATIONS AB Electrocorticography (ECoG) in humans yields data with unmatched spatio-temporal resolution that provides novel insights into cognitive operations. However, the broader application of ECoG has been confounded by difficulties in accurately depicting individual data and performing statistically valid population-level analyses. To overcome these limitations, we developed methods for accurately registering ECoG data to individual cortical topology. We integrated this technique with surface-based co-registration and a mixed-effects multilevel analysis (MEMA) to control for variable cortical surface anatomy and sparse coverage across patients, as well as intra-and inter-subject variability. We applied this surface-based MEMA (SB-MEMA) technique to a face-recognition task dataset (n = 22). Compared against existing techniques, SB-MEMA yielded results much more consistent with individual data and with meta-analyses of face-specific activation studies. We anticipate that SB-MEMA will greatly expand the role of ECoG in studies of human cognition, and will enable the generation of population-level brain activity maps and accurate multimodal comparisons. (C) 2014 Elsevier Inc. All rights reserved. C1 [Kadipasaoglu, C. M.; Baboyan, V. G.; Conner, C. R.; Tandon, N.] Univ Texas Houston, Med Sch Houston, Vivian Smith Dept Neurosurg, Houston, TX 77030 USA. [Tandon, N.] Mem Hermann Hosp, Texas Med Ctr, Houston, TX 77030 USA. [Chen, G.; Saad, Z. S.] NIMH, Sci & Stat Comp Core, NIH, DHHS, Bethesda, MD 20892 USA. RP Tandon, N (reprint author), UT Houston Med Sch, 6431 Fannin St Suite G-500, Houston, TX 77030 USA. EM nitin.tandon@uth.tmc.edu OI Conner, Christopher R/0000-0003-0176-9025; Kadipasaoglu, Cihan/0000-0001-5390-372X; Tandon, Nitin/0000-0002-2752-2365 FU Center for Clinical and Translational Sciences, National Institutes of Health Clinical and Translational Award from the National Center for Research Resources [KL2 RR0224149]; Vivian Smith Foundation for Neurologic Research; Memorial Hermann Foundation FX We would like to thank Vips Patel, the nurses, EEG technicians, and Drs. Jeremy Slater, Giridhar Kalamangalam and Omotola Hope at Memorial Hermann. This work was supported by the Center for Clinical and Translational Sciences, National Institutes of Health Clinical and Translational Award KL2 RR0224149 from the National Center for Research Resources, the Vivian Smith Foundation for Neurologic Research and the Memorial Hermann Foundation. NR 70 TC 8 Z9 8 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV 1 PY 2014 VL 101 BP 215 EP 224 DI 10.1016/j.neuroimage.2014.07.006 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AT4SJ UT WOS:000344931800020 PM 25019677 ER PT J AU Xiao, NZ Jenkins, TM Nehus, E Inge, TH Michalsky, MP Harmon, CM Helmrath, MA Brandt, ML Courcoulas, A Moxey-Mims, M Mitsnefes, MM AF Xiao, Nianzhou Jenkins, Todd M. Nehus, Edward Inge, Thomas H. Michalsky, Marc P. Harmon, Carroll M. Helmrath, Michael A. Brandt, Mary L. Courcoulas, Anita Moxey-Mims, Marva Mitsnefes, Mark M. CA Teen-LABS Consortium TI Kidney Function in Severely Obese Adolescents Undergoing Bariatric Surgery SO OBESITY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; BODY-MASS INDEX; INSULIN-RESISTANCE; CYSTATIN-C; RENAL-FUNCTION; RISK-FACTORS; MICROALBUMINURIA; CHILDREN; ASSOCIATION; HYPERFILTRATION AB ObjectiveDetermine objective measures of kidney function and analyze factors associated with kidney dysfunction in severely obese adolescents undergoing weight loss surgery were described. MethodsCross-sectional data from 242 adolescent participants in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study before weight loss surgery were analyzed. Kidney status was assessed by measuring urine albumin creatinine ratio to determine microalbuminuria and by calculating serum cystatin C-based estimated glomerular filtration rate (eGFR) to assess kidney function. ResultsMean age and median body mass index (BMI) were 17.1 years and 50.5 kg/m(2), respectively; 76% were females and 65% were non-Hispanic white race. Fourteen percent of the cohort had microalbuminuria, and 3% had macroalbuminuria; 3% had eGFR<60 ml/min/1.73 m(2), and 7.1% had eGFR>150 ml/min/1.73 m(2). In adjusted analyses, female gender and increasing ferritin levels were significantly associated with the presence of microalbuminuria/macroalbuminuria. Increasing BMI and homeostasis model assessment of insulin resistance values were significantly associated with lower eGFR. ConclusionsA significant number of severely obese adolescents undergoing weight loss surgery have evidence of early kidney dysfunction. Longitudinal studies following weight loss surgery in these individuals are needed to determine whether these kidney abnormalities are reversible following weight loss therapy. C1 [Xiao, Nianzhou; Jenkins, Todd M.; Nehus, Edward; Inge, Thomas H.; Helmrath, Michael A.; Mitsnefes, Mark M.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Michalsky, Marc P.] Nationwide Childrens Hosp, Columbus, OH USA. [Harmon, Carroll M.] SUNY Buffalo, Buffalo, NY 14260 USA. [Brandt, Mary L.] Texas Childrens Hosp, Houston, TX 77030 USA. [Courcoulas, Anita] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD 20892 USA. RP Mitsnefes, MM (reprint author), Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. EM mark.mitsnefes@cchmc.org OI michalsky, marc/0000-0002-7119-3634 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK072493, UM1DK072493, UM1DK095710]; Cincinnati Children's Hospital Medical Center [UL1 TR000077-04]; Nationwide Children's Hospital [UL1RR025755]; Texas Children's Hospital/Baylor College of Medicine [M01-RR00188]; University of Pittsburgh [UL1 RR024153, UL1TR000005]; University of Alabama at Birmingham [UL1 TR000165] FX This research was supported by grants (U01DK072493, UM1DK072493, and UM1DK095710) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), grant (UL1 TR000077-04) from the Cincinnati Children's Hospital Medical Center, grant (UL1RR025755) from the Nationwide Children's Hospital, grant (M01-RR00188) from the Texas Children's Hospital/Baylor College of Medicine, grants (UL1 RR024153 and UL1TR000005) from the University of Pittsburgh, and grant (UL1 TR000165) from the University of Alabama at Birmingham. NR 40 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD NOV PY 2014 VL 22 IS 11 BP 2319 EP 2325 DI 10.1002/oby.20870 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AT3QR UT WOS:000344849400006 PM 25376399 ER PT J AU Votruba, SB Thearle, MS Piaggi, P Knowler, WC Hanson, RL Krakoff, J AF Votruba, Susanne B. Thearle, Marie S. Piaggi, Paolo Knowler, William C. Hanson, Robert L. Krakoff, Jonathan TI Weight Maintenance from Young Adult Weight Predicts Better Health Outcomes SO OBESITY LA English DT Article ID BODY-MASS INDEX; PIMA-INDIANS; DEVELOPMENTAL TRAJECTORIES; SOCIOECONOMIC POSITION; RESPIRATORY CHAMBER; ENERGY-EXPENDITURE; SAS PROCEDURE; LIFE-COURSE; FOLLOW-UP; OVERWEIGHT AB ObjectiveDefining groups of individuals within a larger population with similar patterns of weight change over time may provide insight into influences of weight stability or gain. MethodsLatent class growth modeling was used to define subgroups of weight change in adult members of the Gila River Indian Community participating in at least four non-diabetic health exams including OGTTs (N=1,157, 762F/395M; 78.419.0 kg). In a separate study, 152 individuals had 24-h EE measured in a respiratory chamber. ResultsEight groups with baseline weights of 54.6 +/- 7.3 (n=124), 64.2 +/- 7.7 (n=267), 73.6 +/- 7.8 (n=298), 86.1 +/- 10.2 (n=194), 95.5 +/- 6.7 (n=90), 97.9 +/- 10.4 (n=92), 110.9 +/- 11.9 (n=61), and 122.1 +/- 13.6 (n=31) kg (P<0.001) were delineated. Group 5, (initial weight=95.5 +/- 6.7 kg) maintained a comparatively stable weight over time (+3.3 +/- 10.3 kg, +3.8 +/- 11.2% of initial weight; median follow-up time: 13.1 years). All other groups gained weight over time (+29.9 +/- 21.1% of initial weight; median follow-up time: 16.3 years). Higher starting weight defined weight gain in most groups, but higher 2 h glucose predicted membership in the lower weight trajectories. The weight stable group had higher rates of impaired glucose regulation at baseline and higher 24-h EE. ConclusionsWeight in young adulthood defined weight gain trajectory underscoring the importance of intervening early to prevent weight gain. C1 [Votruba, Susanne B.; Thearle, Marie S.; Krakoff, Jonathan] NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, Phoenix, AZ 85014 USA. [Piaggi, Paolo] NIDDK, Diabet Mol Genet Sect, NIH, DHHS, Phoenix, AZ USA. [Knowler, William C.; Hanson, Robert L.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, DHHS, Phoenix, AZ USA. RP Votruba, SB (reprint author), NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, Phoenix, AZ 85014 USA. EM votrubas@mail.nih.gov OI Piaggi, Paolo/0000-0003-2774-9161 FU Intramural Research Program of the NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 33 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD NOV PY 2014 VL 22 IS 11 BP 2361 EP 2369 DI 10.1002/oby.20854 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AT3QR UT WOS:000344849400013 PM 25131650 ER PT J AU Jensen, ET Longnecker, MP AF Jensen, Elizabeth T. Longnecker, Matthew P. TI Pharmacologic Sex Hormones in Pregnancy in Relation to Offspring Obesity SO OBESITY LA English DT Article DE obesogens; ethinyl estradiol or mestranol; diethylstilbestrol; fetal origins of disease ID ENDOCRINE DISRUPTING CHEMICALS; ORAL-CONTRACEPTIVE HISTORIES; ADIPOCYTE DIFFERENTIATION; PERINATAL EXPOSURE; BISPHENOL-A; US WOMEN; IN-UTERO; DIETHYLSTILBESTROL; COHORT; ADIPOGENESIS AB ObjectiveTo assess the association between in utero exposure to either diethylstilbestrol (DES) or an oral contraceptive in pregnancy and offspring obesity. MethodsUsing data from the Collaborative Perinatal Project (1959-1974), a multicenter prospective study of pregnant women and their offspring, we examined overweight or obesity among 34,419 children with height and weight data at age 7 years. Generalized linear models to estimate the adjusted odds ratio (aOR) for overweight or obesity (85th percentile) or obesity (95th percentile) in the offspring according to exposure during different months of pregnancy were used. ResultsOral contraceptive use during pregnancy was positively associated with offspring overweight or obesity and obesity. The magnitude of association was strongest in the first 2 months of pregnancy for obesity (aOR 2.0, 95% CI: 1.1, 3.7). DES use was also associated with offspring overweight or obesity and obesity, with the association being strongest for exposure beginning between months 3 and 5 (e.g., for exposure beginning in months 3-4, the aOR for obesity was 2.8, 95% CI: 1.3, 6.3). ConclusionsPharmacologic sex hormone use in pregnancy may be associated with childhood obesity. Whether contemporary, lower dose oral contraceptive formulations are similarly associated with increased risk of childhood obesity is unclear. C1 [Jensen, Elizabeth T.; Longnecker, Matthew P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Jensen, ET (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM elizabeth.jensen@nih.gov RI Jensen, Elizabeth/L-1466-2016; OI Longnecker, Matthew/0000-0001-6073-5322 FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). NR 40 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD NOV PY 2014 VL 22 IS 11 BP 2406 EP 2412 DI 10.1002/oby.20778 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AT3QR UT WOS:000344849400018 PM 24760473 ER PT J AU Reis, JP Allen, N Gibbs, BB Gidding, SS Lee, JM Lewis, CE Lima, J Lloyd-Jones, D Loria, CM Powell-Wiley, TM Sharma, S Wei, G Liu, K AF Reis, Jared P. Allen, Norrina Gibbs, Bethany B. Gidding, Samuel S. Lee, Joyce M. Lewis, Cora E. Lima, Joao Lloyd-Jones, Donald Loria, Catherine M. Powell-Wiley, Tiffany M. Sharma, Shishir Wei, Gina Liu, Kiang TI Association of the Degree of Adiposity and Duration of Obesity with Measures of Cardiac Structure and Function: The CARDIA Study SO OBESITY LA English DT Article ID LEFT-VENTRICULAR MASS; HEART-FAILURE; BODY-MASS; SYSTOLIC FUNCTION; BLOOD-PRESSURE; HYPERTROPHY; HYPERTENSION; GEOMETRY; WEIGHT; IMPACT AB ObjectiveExamine whether there are independent influences of a greater degree of adiposity and longer duration of obesity on cardiac structure and function. MethodsParticipants of CARDIA were 18-30 years when they underwent a baseline examination in 1985-86. Seven follow-up examinations were conducted every 2-5 years. ResultsAmong 2,547 participants who underwent an echocardiogram at the year 25 examination and were not obese at baseline, 34.4 and 35.5% were overall (BMI30 kg m(-2)) and abdominally obese (waist circumference: men: >102 cm; women: >88 cm) at year 25, respectively. A greater degree of overall and abdominal adiposity at year 25 were each associated with a greater left ventricular (LV) mass (P<0.001), LV volume (P<0.001), LV mass-to-volume ratio (P<0.001), left atrial dimension (P<0.001), and ejection fraction (P<0.05) after adjustment for duration of obesity and other risk factors. In contrast, a longer duration of overall obesity was associated with a greater LV mass (P=0.003) and a trend for a lower ejection fraction (P=0.07). ConclusionsA greater degree of adiposity is strongly associated with concentric LV remodeling in midlife, while the cumulative effects of a longer duration of overall obesity during young adulthood contribute to concentric remodeling predominantly by increasing LV mass. C1 [Reis, Jared P.; Loria, Catherine M.; Wei, Gina] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Allen, Norrina; Lloyd-Jones, Donald; Sharma, Shishir; Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Gibbs, Bethany B.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Gidding, Samuel S.] Alfred I DuPont Hosp Children, Nemours Cardiac Ctr, Wilmington, DC USA. [Lee, Joyce M.] Univ Michigan, Div Gen Pediat, Ann Arbor, MI 48109 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Lima, Joao] Johns Hopkins Univ, Sch Med, Dept Cardiol, Baltimore, MD USA. [Lima, Joao] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. RP Reis, JP (reprint author), NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. EM reisjp@mail.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). NR 37 TC 8 Z9 8 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD NOV PY 2014 VL 22 IS 11 BP 2434 EP 2440 DI 10.1002/oby.20865 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AT3QR UT WOS:000344849400022 PM 25124342 ER PT J AU Abraham, TM Massaro, JM Hoffmann, U Yanovski, JA Fox, CS AF Abraham, Tobin M. Massaro, Joseph M. Hoffmann, Udo Yanovski, Jack A. Fox, Caroline S. TI Metabolic Characterization of Adults with Binge Eating in the General Population: The Framingham Heart Study SO OBESITY LA English DT Article ID DIABETES-MELLITUS; OBESE-PATIENTS; ALL-CAUSE; DISORDER; WOMEN; FAT; PREVALENCE; MORTALITY; PATHOGENESIS; ADIPONECTIN AB ObjectiveTo describe the metabolic profile of individuals with objective binge eating (OBE) and to evaluate whether associations between OBE and metabolic risk factors are mediated by body mass index (BMI). MethodsParticipants from the Framingham Heart Study, Third Generation and Omni 2 cohorts (n=3,551, 53.1% women, mean age 46.4 years) were screened for binge eating. Multivariable-adjusted regression models to examine the associations of OBE with metabolic risk factors were used. ResultsThe prevalence of OBE was 4.8% in women and 4.9% in men. Compared to non-binge eating, OBE was associated with higher odds of hypertension (OR 1.85, 95% CI 1.32-2.60), hypertriglyceridemia (OR 1.42, 95% CI 1.01-2.01), low HDL (OR 1.70, 95% CI 1.18-2.44), insulin resistance (OR 3.18, 95% CI 2.25-4.50) and metabolic syndrome (OR 2.75, 95% CI 1.94-3.90). Fasting glucose was 7.2 mg dl(-1) higher in those with OBE (P=0.0001). Individuals with OBE had more visceral, subcutaneous and liver fat. Most of these associations were attenuated with adjustment for BMI, with the exception of fasting glucose. ConclusionsBinge eating is associated with a high burden of metabolic risk factors. Much of the associated risk appears to be mediated by BMI, with the exception of fasting glucose. C1 [Abraham, Tobin M.; Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol Hypertens & Diabet, Boston, MA 02115 USA. [Abraham, Tobin M.; Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Yanovski, Jack A.] NICHHD, Sect Growth & Obes, Bethesda, MD 20892 USA. [Abraham, Tobin M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Abraham, Tobin M.; Fox, Caroline S.] NHLBI, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), Brigham & Womens Hosp, Dept Endocrinol Hypertens & Diabet, 75 Francis St, Boston, MA 02115 USA. EM foxca@nhlbi.nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU National Heart, Lung and Blood Institute [N01-HC-25195]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Division of Intramural Research, the National Heart, Lung, and Blood Institute FX The Framingham Heart Study of the National Heart, Lung and Blood Institute is supported by contract N01-HC-25195. Dr. Yanovski is supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, and Dr. Fox is supported by the Division of Intramural Research, the National Heart, Lung, and Blood Institute. NR 34 TC 9 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD NOV PY 2014 VL 22 IS 11 BP 2441 EP 2449 DI 10.1002/oby.20867 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AT3QR UT WOS:000344849400023 PM 25136837 ER PT J AU Tronnes, H Wilcox, AJ Markestad, T Tollanes, MC Lie, RT Moster, D AF Tronnes, Havard Wilcox, Allen J. Markestad, Trond Tollanes, Mette Christophersen Lie, Rolv Terje Moster, Dag TI Associations of Maternal Atopic Diseases with Adverse Pregnancy Outcomes: a National Cohort Study SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE Atopy; asthma; atopic dermatitis; allergic rhinoconjunctivitis; hay fever; pregnancy outcome; preterm birth; stillbirth; neonatal death; population register ID BIRTH OUTCOMES; PRETERM BIRTH; RISK-FACTORS; WOMEN; ASTHMA; PSORIASIS; MALFORMATIONS; METAANALYSIS; DELIVERY; MOTHERS AB BackgroundMaternal asthma has been associated with adverse pregnancy outcomes. Little is known about the influence of other atopic diseases on pregnancy outcomes. We assessed how various maternal atopic diseases might affect preterm birth, stillbirth, and neonatal death. MethodsBy linking Norwegian national registries, we acquired information on maternal health, socio-demographic factors, pregnancy, birth, and neonatal outcome on all births in Norway from 1967 to 2003. ResultsA total of 1974226 births were included. Of these, 1.8% had a record of maternal asthma, 3.4% of maternal atopic dermatitis, and 0.4% of maternal allergic rhinoconjunctivitis. Overall rates of preterm birth, stillbirth, and neonatal death were 6.0%, 0.6%, and 0.5%, respectively. After adjustments for possible confounders, maternal asthma was associated with increased risk of preterm birth (relative risk (RR), 1.15, [95% confidence interval (CI) 1.10, 1.21]). In contrast, maternal atopic dermatitis was associated with decreased risk of preterm birth (RR 0.90, [95% CI 0.86, 0.93]), stillbirth (RR 0.70, [95% CI 0.62, 0.79]), and neonatal death (RR 0.76, [95% CI 0.65, 0.90]). Similarly, maternal allergic rhinoconjunctivitis was associated with decreased risk of preterm birth (RR 0.84, [95% CI 0.76, 0.94]) and stillbirth (RR 0.40, [95% CI 0.25, 0.66]). ConclusionsWe confirmed the previously reported association of maternal asthma with increased risk for preterm birth. Unexpectedly, maternal atopic dermatitis and allergic rhinoconjunctivitis were associated with decreased risk of preterm birth and stillbirth. Mechanisms for these protective associations are unclear, and our findings require confirmation in further studies. C1 [Tronnes, Havard; Tollanes, Mette Christophersen; Lie, Rolv Terje; Moster, Dag] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Markestad, Trond] Univ Bergen, Dept Clin Med, Bergen, Norway. [Tronnes, Havard; Markestad, Trond; Moster, Dag] Haukeland Hosp, Dept Pediat, NO-5021 Bergen, Norway. [Lie, Rolv Terje; Moster, Dag] Norwegian Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. [Wilcox, Allen J.] NIEHS, Epidemiol Branch, NIH, Durham, NC USA. RP Tronnes, H (reprint author), Haukeland Hosp, Dept Pediat, Jonas Lies Vei 65, NO-5021 Bergen, Norway. EM havard.tronnes@igs.uib.no OI Wilcox, Allen/0000-0002-3376-1311 FU Western Norwegian Regional Health Authority; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX The study was funded by the Western Norwegian Regional Health Authority and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors declare no conflicts of interest. NR 29 TC 1 Z9 1 U1 0 U2 3 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 NOV PY 2014 VL 28 IS 6 BP 489 EP 497 DI 10.1111/ppe.12154 PG 9 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA AT9EY UT WOS:000345231900006 PM 25359226 ER PT J AU Kaplan, RM AF Kaplan, Robert M. TI Behavior change and reducing health disparities SO PREVENTIVE MEDICINE LA English DT Article DE Behavioral; Outcomes research; Social determinants of health; Educational attainment ID EDUCATIONAL-ATTAINMENT; ADULT MORTALITY; LIFE EXPECTANCY; UNITED-STATES; FOLLOW-UP; CANCER; HEART; RISK; PREVENTION; GRADIENT AB The mission of the National Institutes of Health," ... is science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability". A wide range of factors contribute to longer life and to less illness. Although estimates vary, most analyses suggest that only about 10% of the variation in health outcome is attributable to medical care. Further, medical care is most effective in addressing and preventing infectious disease and acute illnesses. Recent large randomized clinical trials often fail to demonstrate that medical care lengthens life expectancy. International comparisons suggest that life expectancy in the United States is increasing, but the rate of increase is falling behind that of other wealthy countries. Strategies for improving health outcomes include better dissemination and implementation of proven evidence-based interventions. Further, reduction of services that use resources but do not offer health benefits must be considered. The final section of this paper reviews evidence relevant to factors outside the health care system that may enhance life expectancy and reduce illness and the disability. The relationship between educational attainment and life expectancy is used as a case example. The potential of behavioral and social interventions for increasing life expectancy may be orders of magnitude greater than traditional medial interventions. However, considerably more research is necessary in order to provide persuasive evidence for the benefits of these programs. Published by Elsevier Inc. C1 Off Behav & Social Sci Res, NIH, Bethesda, MD 20892 USA. RP Kaplan, RM (reprint author), Off Behav & Social Sci Res, NIH, Bldg 31,B1c 19, Bethesda, MD 20892 USA. EM rmkaplan@ucla.edu NR 38 TC 8 Z9 8 U1 3 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD NOV PY 2014 VL 68 SI SI BP 5 EP 10 DI 10.1016/j.ypmed.2014.04.014 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AT8QU UT WOS:000345198100002 PM 24780526 ER PT J AU Buist, DSM Anderson, ML Smith, RA Carney, PA Miglioretti, DL Monsees, BS Sickles, EA Taplin, SH Geller, BM Yankaskas, BC Onega, TL AF Buist, Diana S. M. Anderson, Melissa L. Smith, Robert A. Carney, Patricia A. Miglioretti, Diana L. Monsees, Barbara S. Sickles, Edward A. Taplin, Stephen H. Geller, Berta M. Yankaskas, Bonnie C. Onega, Tracy L. TI Effect of Radiologists' Diagnostic Work-up Volume on Interpretive Performance SO RADIOLOGY LA English DT Article ID COMPUTER-AIDED DETECTION; CANCER SURVEILLANCE CONSORTIUM; SCREENING MAMMOGRAPHY; TRIAL; ATTITUDES; ACCURACY; FEEDBACK; OUTCOMES AB Purpose: To examine radiologists' screening performance in relation to the number of diagnostic work-ups performed after abnormal findings are discovered at screening mammography by the same radiologist or by different radiologists. Materials and Methods: In an institutional review board-approved HIPAA-compliant study, the authors linked 651 671 screening mammograms interpreted from 2002 to 2006 by 96 radiologists in the Breast Cancer Surveillance Consortium to cancer registries (standard of reference) to evaluate the performance of screening mammography (sensitivity, false-positive rate [FPR], and cancer detection rate [CDR]). Logistic regression was used to assess the association between the volume of recalled screening mammograms ("own" mammograms, where the radiologist who interpreted the diagnostic image was the same radiologist who had interpreted the screening image, and "any" mammograms, where the radiologist who interpreted the diagnostic image may or may not have been the radiologist who interpreted the screening image) and screening performance and whether the association between total annual volume and performance differed according to the volume of diagnostic work-up. Results: Annually, 38% of radiologists performed the diagnostic work-up for 25 or fewer of their own recalled screening mammograms, 24% performed the work-up for 0-50, and 39% performed the work-up for more than 50. For the work-up of recalled screening mammograms from any radiologist, 24% of radiologists performed the work-up for 0-50 mammograms, 32% performed the work-up for 51-125, and 44% performed the work-up for more than 125. With increasing numbers of radiologist work-ups for their own recalled mammograms, the sensitivity (P = .039), FPR (P = .004), and CDR (P < .001) of screening mammography increased, yielding a stepped increase in women recalled per cancer detected from 17.4 for 25 or fewer mammograms to 24.6 for more than 50 mammograms. Increases in work-ups for any radiologist yielded significant increases in FPR (P = .011) and CDR (P = .001) and a nonsignificant increase in sensitivity (P = .15). Radiologists with a lower annual volume of any work-ups had consistently lower FPR, sensitivity, and CDR at all annual interpretive volumes. Conclusion: These findings support the hypothesis that radiologists may improve their screening performance by performing the diagnostic work-up for their own recalled screening mammograms and directly receiving feedback afforded by means of the outcomes associated with their initial decision to recall. Arranging for radiologists to work up a minimum number of their own recalled cases could improve screening performance but would need systems to facilitate this workflow. (C) RSNA, 2014 C1 [Buist, Diana S. M.; Anderson, Melissa L.; Miglioretti, Diana L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Smith, Robert A.] Amer Canc Soc, Canc Control Sci Dept, Atlanta, GA 30329 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Miglioretti, Diana L.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Monsees, Barbara S.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Sickles, Edward A.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, Behav Res Program, Rockville, MD USA. [Geller, Berta M.] Univ Vermont, Coll Med, Dept Family Med, Burlington, VT USA. [Yankaskas, Bonnie C.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Onega, Tracy L.] Geisel Sch Med Dartmouth, Norris Cotton Canc Ctr, Dartmouth Inst Hlth Policy & Clin Practice, Dept Community & Family Med, Lebanon, NH USA. RP Buist, DSM (reprint author), Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM buist.d@ghc.org FU American Cancer Society; Longaberger Company's Horizon of Hope Campaign [SIRSG-07-271, SIRSG-07-272, SIRSG-07-273, SIRSG-07-274, SIRSG-07-275, SIRGS-06-281, SIRSG-09-270, SIRSG-09-271]; Breast Cancer Stamp Fund FX This work was supported by the American Cancer Society, made possible by a generous donation from the Longaberger Company's Horizon of Hope Campaign (SIRSG-07-271, SIRSG-07-272, SIRSG-07-273, SIRSG-07-274, SIRSG-07-275, SIRGS-06-281, SIRSG-09-270, SIRSG-09-271) and the Breast Cancer Stamp Fund. NR 36 TC 6 Z9 6 U1 0 U2 1 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 NOV PY 2014 VL 273 IS 2 BP 351 EP 364 DI 10.1148/radiol.14132806 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT6SS UT WOS:000345069800007 PM 24960110 ER PT J AU Johnstone, EB Louis, GMB Parsons, PJ Steuerwald, AJ Palmer, CD Chen, Z Sun, LP Hammoud, AO Dorais, J Peterson, CM AF Johnstone, Erica B. Louis, Germaine M. Buck Parsons, Patrick J. Steuerwald, Amy J. Palmer, Christopher D. Chen, Zhen Sun, Liping Hammoud, Ahmad O. Dorais, Jessie Peterson, C. Matthew TI Increased urinary cobalt and whole blood concentrations of cadmium and lead in women with uterine leiomyomata: Findings from the ENDO Study SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Cadmium; Fibroids; Lead; Leiomyoma; Mercury; Metals; Trace elements; Toxic exposures ID PLASMA-MASS SPECTROMETRY; ESTROGEN-RECEPTOR-ALPHA; NEW-YORK-CITY; TRACE-ELEMENTS; PREMENOPAUSAL WOMEN; MERCURY; ENDOMETRIOSIS; EXPOSURE; MYOMAS; METALS AB Multiple trace elements have estrogen receptor activity, but the association of these elements with uterine leiomyoma has not been defined. A cohort of 473 women aged 18-44 undergoing surgery for benign gynecologic indications provided whole blood and urine specimens for trace element analysis, which was performed by inductively coupled plasma mass spectrometry. Twenty elements were analyzed in blood and 3 in urine. The surgeon documented whether fibroids were present. Geometric mean concentrations were compared between women with and without fibroids, and logistic regression models were generated to assess the impact of the concentration of each trace element on the odds of fibroids. In multivariate regressions, odds of a fibroid diagnosis were higher with increased whole blood cadmium (AOR 1.44, 95% CI 1.02, 2.04) and lead (AOR 1.31 95% CI 1.02, 1.69), and urine cobalt (AOR 1.31, 95% CI 1.02, 1.70). Urinary cadmium and lead were not related to fibroid diagnosis. Increased exposure to trace elements may contribute to fibroid growth, and fibroids may serve as a reservoir for these elements. Differences between urinary and whole blood findings merit further investigation, as urinary cadmium has been considered a superior marker of exposure. (C) 2014 Elsevier Inc. All rights reserved. C1 [Johnstone, Erica B.; Hammoud, Ahmad O.; Dorais, Jessie; Peterson, C. Matthew] Univ Utah, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertility, Salt Lake City, UT 84108 USA. [Louis, Germaine M. Buck; Chen, Zhen; Sun, Liping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Parsons, Patrick J.; Steuerwald, Amy J.; Palmer, Christopher D.] SUNY Albany, New York State Dept Hlth, Wadsworth Ctr, Lab Inorgan & Nucl Chem, Albany, NY 12201 USA. [Parsons, Patrick J.; Steuerwald, Amy J.; Palmer, Christopher D.] SUNY Albany, Dept Environm Hlth Sci, Albany, NY 12201 USA. RP Johnstone, EB (reprint author), Univ Utah, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertility, 50 North 1900 East,Ste 2B200, Salt Lake City, UT 84108 USA. EM erica.johnstone@hsc.utah.edu OI Peterson, C. Matthew/0000-0002-4644-602X; Parsons, Patrick/0000-0001-9133-875X; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health [HHSN267200603427C, NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02] FX Funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (Contracts HHSN267200603427C, NO1-DK-6-3428; NO1-DK-6-3427; 10001406-02). NR 45 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD NOV PY 2014 VL 49 BP 27 EP 32 DI 10.1016/j.reprotox.2014.06.007 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA AT9PC UT WOS:000345257900003 PM 24994689 ER PT J AU Jackson, J Eaton, W Cascella, N Fasano, A Santora, D Sullivan, K Feldman, S Raley, H McMahon, RP Carpenter, WT Demyanovich, H Kelly, DL AF Jackson, Jessica Eaton, William Cascella, Nicola Fasano, Alessio Santora, Debby Sullivan, Kelli Feldman, Stephanie Raley, Heather McMahon, Robert P. Carpenter, William T., Jr. Demyanovich, Haley Kelly, Deanna L. TI Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Gluten; Celiac disease; Schizophrenia; Gliadin; Gluten sensitivity ID DANISH NATIONAL REGISTERS; CELIAC-DISEASE; FREE DIET; AUTOIMMUNE-DISEASES; ANTIBODIES; DEPRESSION; ATAXIA; INDIVIDUALS; PREVALENCE; GLIADIN AB The relationship between gluten sensitivity and schizophrenia has been of increasing interest and novel mechanisms explaining this relationship continue to be described. Our study in 100 people with schizophrenia compared to 100 matched controls replicates a higher prevalence of gluten sensitivity and higher mean antigliadin IgG antibody levels schizophrenia (2.9 +/- 7.7 vs. 1.3 +/- 1.3, p = 0.046, controlled for age). Additionally, we examined symptoms within the schizophrenia group and found that while positive symptoms are significantly lower in people who have elevated antigliadin antibodies (AGA; 4.11 +/- 1.36 vs. 6.39 +/- 2.99, p = 0.020), no robust clinical profile differentiates between positive and negative antibody groups. Thus, identifying people in schizophrenia who may benefit from a gluten-free diet remains possible by blood test only. (C) 2014 Published by Elsevier B.V. C1 [Jackson, Jessica] Temple Univ, Sch Med, Philadelphia, PA 19140 USA. [Eaton, William] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Cascella, Nicola] Sheppard Pratt Hosp, Neuropsychiat Program, Baltimore, MD 21285 USA. [Fasano, Alessio] Massachusetts Gen Hosp Children, Boston, MA 02114 USA. [Fasano, Alessio] Massachusetts Gen Hosp East, Charlestown, MA 02129 USA. [Santora, Debby] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Sullivan, Kelli; Feldman, Stephanie; McMahon, Robert P.; Carpenter, William T., Jr.; Demyanovich, Haley; Kelly, Deanna L.] Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Sch Med, Catonsville, MD 21228 USA. [Raley, Heather] NIDA, Baltimore, MD 21223 USA. RP Kelly, DL (reprint author), Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. EM dkelly@mprc.umaryland.edu FU NIMH [R34MH100776] FX This study was supported in part by NIMH R34MH100776 (PIs Eaton and Kelly). The funding source had no role in the design, results and dissemination of the findings. NR 33 TC 9 Z9 9 U1 4 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD NOV PY 2014 VL 159 IS 2-3 BP 539 EP 542 DI 10.1016/j.schres.2014.09.023 PG 4 WC Psychiatry SC Psychiatry GA AT9DX UT WOS:000345229200045 PM 25311778 ER PT J AU Reardon, ES Schrump, DS AF Reardon, Emily S. Schrump, David S. TI Extended Resections of Non-small Cell Lung Cancers Invading the Aorta, Pulmonary Artery, Left Atrium, or Esophagus: Can They Be Justified? SO THORACIC SURGERY CLINICS LA English DT Article DE Non-small cell lung cancer; T4; Aorta; Pulmonary artery; Left atrium; Esophagus; Extended resection ID RANDOMIZED CONTROLLED-TRIAL; FORTHCOMING 7TH EDITION; SUPERIOR VENA-CAVA; LONG-TERM SURVIVAL; CARDIOPULMONARY BYPASS; TNM CLASSIFICATION; SURGICAL RESECTION; STAGING PROJECT; THORACIC AORTA; GREAT-VESSELS AB Historically, extended resections for T4 non-small cell lung cancers that invade adjacent organs have been associated with significant morbidity and mortality, and poor long-term survival. However, notable improvements in imaging, surgical techniques, and perioperative care during the past several decades have resulted in an increase in survival for highly selected patients. This article provides a critical review of the existing statistical evidence regarding the utility of resections of T4 tumors invading the aorta, pulmonary artery, left atrium, and esophagus. C1 [Reardon, Emily S.; Schrump, David S.] NCI, Thorac Surg Sect, Thorac & GI Oncol Branch, CCR,NIH, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, CCR, Thorac & GI Oncol Branch, Bldg 10,4-3942 10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM david.schrump@nih.gov NR 43 TC 3 Z9 3 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1547-4127 J9 THORAC SURG CLIN JI Thorac. Surg. Clin. PD NOV PY 2014 VL 24 IS 4 BP 457 EP + DI 10.1016/j.thorsurg.2014.07.012 PG 9 WC Respiratory System; Surgery SC Respiratory System; Surgery GA AT8LN UT WOS:000345184900013 PM 25441139 ER PT J AU Atwood, BK Lovinger, DM Mathur, BN AF Atwood, Brady K. Lovinger, David M. Mathur, Brian N. TI Presynaptic long-term depression mediated by G(i/o)-coupled receptors SO TRENDS IN NEUROSCIENCES LA English DT Review DE long-term synaptic plasticity; G(i/o)-GPCR; synaptic inhibition; presynaptic plasticity; neurotransmitter release; vesicle release machinery; plasticity mechanisms ID BETA-GAMMA-SUBUNITS; UNDERLYING CANNABINOID INHIBITION; EXCITATORY SYNAPTIC-TRANSMISSION; METABOTROPIC GLUTAMATE RECEPTORS; CELL-DEPENDENT PLASTICITY; CEREBELLAR PURKINJE-CELLS; MIDBRAIN DOPAMINE NEURONS; MOSSY FIBER-CA3 SYNAPSE; GTP-BINDING PROTEINS; RAT DENTATE GYRUS AB Long-term depression (LTD) of the efficacy of synaptic transmission is now recognized as an important mechanism for the regulation of information storage and the control of actions, as well as for synapse, neuron, and circuit development. Studies of LTD mechanisms have focused mainly on postsynaptic AMPA-type glutamate receptor trafficking. However, the focus has now expanded to include presynaptically expressed plasticity, the predominant form being initiated by presynaptically expressed G(i/o)-coupled metabotropic receptor (G(i/o)-GPCR) activation. Several forms of LTD involving activation of different presynaptic G(i/o)-GPCRs as a 'common pathway' are described. We review here the literature on presynaptic G(i/o)-GPCR-mediated LTD, discuss known mechanisms, gaps in our knowledge, and evaluate whether all G(i/o)-GPCRs are capable of inducing presynaptic LTD. C1 [Atwood, Brady K.; Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, US NIH, Rockville, MD 20852 USA. [Mathur, Brian N.] Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA. RP Mathur, BN (reprint author), Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA. EM bmathur@som.umaryland.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the US National Institutes of Health (NIH) [K22 AA021414]; Division of Intramural Clinical and Biological Research of the NIAAA/NIH FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the US National Institutes of Health (NIH) (grant K22 AA021414 to B.N.M.) and by the Division of Intramural Clinical and Biological Research of the NIAAA/NIH (B.K.A. and D.M.L.). NR 107 TC 14 Z9 14 U1 1 U2 16 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD NOV PY 2014 VL 37 IS 11 BP 663 EP 673 DI 10.1016/j.tins.2014.07.010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AT9PE UT WOS:000345258100007 PM 25160683 ER PT J AU Jarlenski, M McManus, J Diener-West, M Schwarz, EB Yeung, E Bennett, WL AF Jarlenski, Marian McManus, Jenny Diener-West, Marie Schwarz, Eleanor Bimla Yeung, Edwina Bennett, Wendy L. TI Association between Support from a Health Professional and Breastfeeding Knowledge and Practices Among Obese Women: Evidence from the Infant Practices Study II SO WOMENS HEALTH ISSUES LA English DT Article ID UNITED-STATES; DURATION; CARE; LACTATION; WEIGHT; TRIAL AB Background: Obese women are less likely to initiate and continue breastfeeding. We described barriers to breastfeeding and examined the association between support from a health professional and breastfeeding knowledge and practices, by prepregnancy obesity status. Methods: Using data from the Infant Feeding Practices Study II, a cohort of U. S. women (N = 2,997), we performed descriptive statistics to describe barriers to breastfeeding by prepregnancy obesity status. We conducted multivariable regression to examine the association of breastfeeding support from a physician or nonphysician health professional with knowledge of the recommended duration of breastfeeding, breastfeeding initiation, and breastfeeding duration, and whether breastfeeding support had different associations with outcomes by prepregnancy obesity status. Average marginal effects were calculated from regression models to interpret results as percentage-point changes. Findings: Believing that formula was as good as breast milk was the most commonly cited reason for not initiating breastfeeding, and milk supply concerns were cited as reasons for not continuing breastfeeding. Physician breastfeeding support was associated with a 9.4 percentage-point increase (p < .05) in breastfeeding knowledge among obese women, although no increase was observed among nonobese women. Breastfeeding support from a physician or nonphysician health professional was associated with a significantly increased probability of breastfeeding initiation (8.5 and 12.5 percentage points, respectively) and breastfeeding for 6 months (12.5 and 8.4 percentage points, respectively), without differential associations by prepregnancy obesity. Conclusions: Support for exclusive breastfeeding is an important predictor of breastfeeding initiation and duration among obese and nonobese women. Health educational interventions tailored to obese women might improve their breastfeeding initiation and continuation. Copyright (C) 2014 by the Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Jarlenski, Marian] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA USA. [McManus, Jenny] Sexual Hlth Innovat, New York, NY USA. [Diener-West, Marie] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Schwarz, Eleanor Bimla] Calif State Univ Sacramento, Davis Sch Med, Dept Internal Med, Sacramento, CA 95819 USA. [Yeung, Edwina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Bennett, Wendy L.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Bennett, Wendy L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. RP Jarlenski, M (reprint author), 130 DeSoto St,A647, Pittsburgh, PA 15261 USA. EM mpj@pitt.edu RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Jarlenski, Marian/0000-0001-6907-5447; Schwarz, Eleanor Bimla/0000-0002-9912-8236 FU Intramural NIH HHS NR 31 TC 4 Z9 4 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD NOV-DEC PY 2014 VL 24 IS 6 BP 641 EP 648 DI 10.1016/j.whi.2014.08.002 PG 8 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA AT8BD UT WOS:000345157900010 PM 25239780 ER PT J AU Moon, AF Gaudu, P Pedersen, LC AF Moon, Andrea F. Gaudu, Philippe Pedersen, Lars C. TI Structural characterization of the virulence factor nuclease A from Streptococcus agalactiae SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; ACTIVE-SITE; PROTEIN CRYSTALLIZATION; STRUCTURE REFINEMENT; CHEMICAL RESCUE; PNEUMONIAE; MODEL; ENDA; ENDONUCLEASE; INFECTIONS AB The group B pathogen Streptococcus agalactiae commonly populates the human gut and urogenital tract, and is a major cause of infection-based mortality in neonatal infants and in elderly or immunocompromised adults. Nuclease A (GBS_NucA), a secreted DNA/RNA nuclease, serves as a virulence factor for S. agalactiae, facilitating bacterial evasion of the human innate immune response. GBS_NucA efficiently degrades the DNA matrix component of neutrophil extracellular traps (NETs), which attempt to kill and clear invading bacteria during the early stages of infection. In order to better understand the mechanisms of DNA substrate binding and catalysis of GBS_NucA, the high-resolution structure of a catalytically inactive mutant (H148G) was solved by X-ray crystallography. Several mutants on the surface of GBS_NucA which might influence DNA substrate binding and catalysis were generated and evaluated using an imidazole chemical rescue technique. While several of these mutants severely inhibited nuclease activity, two mutants (K146R and Q183A) exhibited significantly increased activity. These structural and biochemical studies have greatly increased our understanding of the mechanism of action of GBS_NucA in bacterial virulence and may serve as a foundation for the structure-based drug design of antibacterial compounds targeted to S. agalactiae. C1 [Moon, Andrea F.; Pedersen, Lars C.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Gaudu, Philippe] INRA, Micalis UMR1319, Jouy En Josas, France. [Gaudu, Philippe] AgroParisTech, UMR Micalis, Jouy En Josas, France. RP Pedersen, LC (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM pederse2@niehs.nih.gov FU Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health (NIH) [1ZIA ES102645-03]; Institut National de la Recherche Agronomique; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We thank R. London and B. Freudenthal for critical reading of the manuscript. This research was supported by the Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health (NIH) Grant 1ZIA ES102645-03 (LCP) and by the Institut National de la Recherche Agronomique (PG). Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences Contract W-31-109-Eng-38. NR 49 TC 4 Z9 4 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0907-4449 EI 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD NOV PY 2014 VL 70 BP 2937 EP 2949 DI 10.1107/S1399004714019725 PN 11 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA AT2UM UT WOS:000344792000015 PM 25372684 ER PT J AU Morley, KC Baillie, A Leung, S Addolorato, G Leggio, L Haber, PS AF Morley, K. C. Baillie, A. Leung, S. Addolorato, G. Leggio, L. Haber, P. S. TI Baclofen for the Treatment of Alcohol Dependence and Possible Role of Comorbid Anxiety SO ALCOHOL AND ALCOHOLISM LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; GABA(B) RECEPTOR; DRINKING; EFFICACY; SAFETY; DETOXIFICATION; VALIDATION; ABSTINENCE AB Aim: To conduct a double-blind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence. Methods: Out of 69 participants consecutively screened, 42 alcohol-dependent patients were randomized to receive placebo, baclofen 30 mg/day or baclofen 60 mg/day for 12 weeks. All subjects were offered BRENDA, a structured psychosocial therapy for alcohol dependence that seeks to improve motivation for change, enhance strategies to prevent relapse and encourage compliance with treatment. Results: Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. There were no statistically significant advantages to treatment on time to first heavy drinking day (relapse) (P = 0.08), nor time to first drink (lapse) (P = 0.18). A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). Both doses of baclofen were well tolerated. There were no serious adverse events. Conclusions: In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fully-powered studies is required. C1 [Morley, K. C.; Haber, P. S.] Univ Sydney, Discipline Addict Med, NHMRC Ctr Res Excellence Mental Hlth & Subst Use, Sydney, NSW 2006, Australia. [Baillie, A.] Macquarie Univ, Dept Psychol, NHMRC Ctr Res Excellence Mental Hlth & Subst Use, Sydney, NSW 2109, Australia. [Leung, S.] Univ Sydney, Cent Clin Sch, Sydney, NSW 2006, Australia. [Addolorato, G.] Univ Cattolica Sacro Cuore, Inst Internal Med, Rome, Italy. [Leggio, L.] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Leggio, L.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Leggio, L.] Brown Univ, Dept Behav & Social Sci, Providence, RI 02912 USA. [Haber, P. S.] Royal Prince Alfred Hosp, Drug Hlth Serv, Sydney, NSW, Australia. RP Morley, KC (reprint author), Univ Sydney, Discipline Addict Med, Sydney, NSW 2006, Australia. EM kirsten.morley@sydney.edu.au RI Leggio, Lorenzo/M-2972-2016 FU New South Wales Health Drug and Alcohol grant FX This trial was funded by a New South Wales Health Drug and Alcohol grant (PH, AB, KM). NR 41 TC 10 Z9 10 U1 4 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 EI 1464-3502 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD NOV-DEC PY 2014 VL 49 IS 6 BP 654 EP 660 DI 10.1093/alcalc/agu062 PG 7 WC Substance Abuse SC Substance Abuse GA AT0BJ UT WOS:000344601500008 PM 25246489 ER PT J AU Perin, EC Murphy, M Cooke, JP Moye, L Henry, TD Bettencourt, J Gahremanpour, A Leeper, N Anderson, RD Hiatt, WR Lima, JA Venkatesh, B Sayre, SL Vojvodic, RW Taylor, DA Ebert, RF Hirsch, AT AF Perin, Emerson C. Murphy, Michael Cooke, John P. Moye, Lem Henry, Timothy D. Bettencourt, Judy Gahremanpour, Amir Leeper, Nicholas Anderson, R. David Hiatt, William R. Lima, Joao A. Venkatesh, Bharath Sayre, Shelly L. Vojvodic, Rachel W. Taylor, Doris A. Ebert, Ray F. Hirsch, Alan T. CA Cardiovasc Cell Therapy Res Networ TI Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells SO AMERICAN HEART JOURNAL LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; CRITICAL LIMB ISCHEMIA; RESEARCH NETWORK CCTRN; ALDEHYDE DEHYDROGENASE-ACTIVITY; BLOOD MONONUCLEAR-CELLS; BONE-MARROW-CELLS; AUTOLOGOUS TRANSPLANTATION; THERAPY; REVASCULARIZATION; ANGIOGENESIS AB Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in patients with PAD, have limitations. Cells identified using cytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network to assess the safety and efficacy of autologous bone marrow-derived ALDH(br) cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index less than 0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary end points are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance imaging at 6 months compared with baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based end points that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDH(br) cells in patients with claudication and provide valuable insight into the utility of advanced magnetic resonance imaging end points. C1 [Perin, Emerson C.; Gahremanpour, Amir; Taylor, Doris A.] Texas Heart Inst, Houston, TX 77025 USA. [Murphy, Michael] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Cooke, John P.] Houston Methodist Res Inst, Houston, TX USA. [Moye, Lem; Bettencourt, Judy; Sayre, Shelly L.; Vojvodic, Rachel W.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Henry, Timothy D.] Cedars Sinai Heart Inst, Los Angeles, CA USA. [Leeper, Nicholas] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Anderson, R. David] Univ Florida, Sch Med, Gainesville, FL USA. [Hiatt, William R.] Univ Colorado, Sch Med, Denver, CO USA. [Lima, Joao A.; Venkatesh, Bharath] Johns Hopkins Univ, Baltimore, MD USA. [Ebert, Ray F.] NHLBI, Bethesda, MD 20892 USA. [Hirsch, Alan T.] Univ Minnesota, Sch Med, Div Cardiovasc, Lillehei Heart Inst, Minneapolis, MN 55455 USA. RP Moye, L (reprint author), 1200 Pressler,E-1009, Houston, TX 77030 USA. EM lemmoye@msn.com RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Cooke, John/0000-0003-0033-9138 FU NHLBI [UM1 HL087318-07] FX Funding for the CCTRN was provided by the NHLBI under cooperative agreement UM1 HL087318-07. NR 29 TC 3 Z9 3 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD NOV PY 2014 VL 168 IS 5 BP 667 EP 673 DI 10.1016/j.ahj.2014.07.021 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS7KE UT WOS:000344434300008 PM 25440794 ER PT J AU Ballester, LY Cowen, EW Lee, CCR AF Ballester, Leomar Y. Cowen, Edward W. Lee, Chyi-Chia Richard TI Adult T-Cell Leukemia-Lymphoma Associated With Follicular Mucinosis SO AMERICAN JOURNAL OF DERMATOPATHOLOGY LA English DT Article DE ATLL; follicular mucinosis; HTLV-1; T-cell lymphoma; mycosis fungoides ID MYCOSIS-FUNGOIDES AB Follicular mucinosis is frequently associated with follicular mycosis fungoides, but its association with adult T-cell leukemia-lymphoma (ATLL) is extremely rare. We report a case of a 50-year-old female patient with a history of ATLL, after multiple treatments, with residual/recurrent skin tumors in the forehead and legs. Biopsy of a skin tumor from the forehead revealed a perifollicular and intra-follicular atypical lymphoid infiltrate with abundant mucin deposition. Immunohistochemical stains showed that the atypical cells were positive for CD3, CD4, and CD25. Reverse transcription polymerase chain reaction performed on the tissue sections confirmed the presence of human T-cell leukemia virus in the biopsies of skin tumors. To our knowledge, this is only the third reported case of a follicular mucinosis in the setting of ATLL. C1 [Ballester, Leomar Y.; Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, CCR (reprint author), NCI, Pathol Lab, Ctr Canc Res, Bldg 10,Room 2B50, Bethesda, MD 20892 USA. EM leechy@mail.nih.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0193-1091 EI 1533-0311 J9 AM J DERMATOPATH JI Am. J. Dermatopathol. PD NOV PY 2014 VL 36 IS 11 BP 901 EP 903 PG 3 WC Dermatology SC Dermatology GA AT0DG UT WOS:000344606600011 PM 24614206 ER PT J AU Brubaker, L Nager, CW Richter, HE Weidner, AC Hsu, Y Wai, CY Paraiso, M Nolen, TL Wallace, D Meikle, S AF Brubaker, Linda Nager, Charles W. Richter, Holly E. Weidner, Alison C. Hsu, Yvonne Wai, Clifford Y. Paraiso, Marie Nolen, Tracy L. Wallace, Dennis Meikle, Susan CA NICHD Pelvic Floor Disorders Netwo TI Effectiveness of blinding: sham suprapubic incisions in a randomized trial of retropubic midurethral sling in women undergoing vaginal prolapse surgery SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE pelvic organ prolapse; sham incision; stress urinary incontinence; surgical trial ID STRESS URINARY-INCONTINENCE; CONSENT; REPAIR; TAPE AB OBJECTIVE: This planned secondary analysis of the Outcomes Following Vaginal Prolapse Repairs and Midurethral Sling trial assessed whether treatment knowledge differed between randomized groups at 12 months and whether treatment success was affected by treatment perception. STUDY DESIGN: Sham suprapubic tension-free vaginal tape (TVT) incisions were made in the Outcomes Following Vaginal Prolapse Repairs and Midurethral Sling trial participants randomized to no-TVT. Primary surgical outcomes and maintenance of blinding was assessed at 12 months. Knowledge of treatment assignment was compared between groups, and the relationship with treatment success rates was assessed. RESULTS: Prior to the 12 month postoperative visit, only 4% of treated participants (13 of 336) formally reported unmasking. At 12 months, 94% of the randomized participants (315 of 336) provided treatment knowledge data. Sixteen TVT participants (10%) reported treatment knowledge; most (n = 15, 94%) were correct; 17 of the sham participants (11%) reported treatment knowledge; half (n = 8, 47%) were correct. Similar proportions of unmasked participants who reported no treatment knowledge correctly guessed/perceived treatment assignment (sham, 46 [33%] vs TVT, 44 [33%]). We did not detect significant differences in treatment success rates based on perception within and across received treatment groups (perceived sham vs TVT overall [P = .76]). Of those receiving TVT, more participants perceiving TVT had treatment success compared with those who perceived sham (84% vs 74%; P = .29). Among sham participants, more participants perceiving sham had success compared with those who perceived receiving TVT (65% vs 56%; P = .42). CONCLUSION: Sham surgical incisions effectively mask TVT randomization. These findings may help to inform future surgical trial designs. C1 [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Stritch Sch Med, Dept Urol, Chicago, IL 60611 USA. [Nager, Charles W.] Univ Calif San Diego, Sch Med, Dept Reprod Med, San Diego, CA 92103 USA. [Richter, Holly E.] Univ Alabama Birmingham, Sch Med, Dept Obstet & Gynecol, Birmingham, AL USA. [Weidner, Alison C.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Hsu, Yvonne] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Wai, Clifford Y.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Paraiso, Marie] Cleveland Clin, Ob Gyn & Womens Hlth Inst, Cleveland, OH 44106 USA. [Nolen, Tracy L.; Wallace, Dennis] RTI Int, Res Triangle Pk, NC USA. [Meikle, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Brubaker, L (reprint author), Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. EM LBrubaker@lumc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [2U01HD41249, 2U10 HD41250, 2U10 HD41261, 2U10 HD41267, 1U10 HD54136, 1U10 HD54214, 1U10 HD54215, 1U10 HD54241, U01HD069031]; National Institutes of Health Office of Research on Women's Health FX This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (2U01HD41249, 2U10 HD41250, 2U10 HD41261, 2U10 HD41267, 1U10 HD54136, 1U10 HD54214, 1U10 HD54215, 1U10 HD54241, and U01HD069031) and the National Institutes of Health Office of Research on Women's Health. NR 10 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2014 VL 211 IS 5 AR 554.e1 DI 10.1016/j.ajog.2014.07.009 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AS7ZN UT WOS:000344470500040 PM 25019487 ER PT J AU Konstantopoulos, WLM Dreifuss, JA McDermott, KA Parry, BA Howell, ML Mandler, RN Fitzmaurice, GM Bogenschutz, MP Weiss, RD AF Konstantopoulos, Wendy L. Macias Dreifuss, Jessica A. McDermott, Katherine A. Parry, Blair Alden Howell, Melissa L. Mandler, Raul N. Fitzmaurice, Garrett M. Bogenschutz, Michael P. Weiss, Roger D. TI Identifying Patients With Problematic Drug Use in the Emergency Department: Results of a Multisite Study SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID SUBSTANCE USE; BRIEF INTERVENTION; MARIJUANA USE; ILLICIT DRUG; PRIMARY-CARE; ALCOHOL; RISK; CONSEQUENCES; DRINKERS; SERVICES AB Study objective: Drug-related emergency department (ED) visits have steadily increased, with substance users relying heavily on the ED for medical care. The present study aims to identify clinical correlates of problematic drug use that would facilitate identification of ED patients in need of substance use treatment. Methods: Using previously validated tests, 15,224 adult ED patients across 6 academic institutions were prescreened for drug use as part of a large randomized prospective trial. Data for 3,240 participants who reported drug use in the past 30 days were included. Self-reported variables related to demographics, substance use, and ED visit were examined to determine their correlative value for problematic drug use. Results: Of the 3,240 patients, 2,084 (64.3%) met criteria for problematic drug use (Drug Abuse Screening Test score >= 3). Age greater than or equal to 30 years, tobacco smoking, daily or binge alcohol drinking, daily drug use, primary noncannabis drug use, resource-intense ED triage level, and perceived drug-relatedness of ED visit were highly correlated with problematic drug use. Among primary cannabis users, correlates of problematic drug use were age younger than 30 years, tobacco smoking, binge drinking, daily drug use, and perceived relatedness of the ED visit to drug use. Conclusion: Clinical correlates of drug use problems may assist the identification of ED patients who would benefit from comprehensive screening, intervention, and referral to treatment. A clinical decision rule is proposed. The correlation between problematic drug use and resource-intense ED triage levels suggests that ED-based efforts to reduce the unmet need for substance use treatment may help decrease overall health care costs. C1 [Konstantopoulos, Wendy L. Macias; Parry, Blair Alden; Howell, Melissa L.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Dreifuss, Jessica A.; Weiss, Roger D.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Konstantopoulos, Wendy L. Macias; Dreifuss, Jessica A.; Weiss, Roger D.] Harvard Univ, Sch Med, Boston, MA USA. [Dreifuss, Jessica A.] McLean Hosp, Behav Hlth Partial Program, Belmont, MA 02178 USA. [McDermott, Katherine A.; Weiss, Roger D.] McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02178 USA. [Mandler, Raul N.] NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. [Fitzmaurice, Garrett M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Bogenschutz, Michael P.] Univ New Mexico, Hlth Sci Ctr, Dept Psychiat, Albuquerque, NM 87131 USA. RP Konstantopoulos, WLM (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM wmacias@mgh.harvard.edu OI Bogenschutz, Michael/0000-0003-4530-3470 FU National Institute on Drug Abuse through McLean Hospital [5U10DA015]; National Institute on Drug Abuse [U10 DA01583, K24 DA022288, U10 DA020036, U10 DA13720, U10 DA13035, U10 DA15831, U10 DA13732, U10 DA15833] FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). Dr. Macias Konstantopoulos reports receiving grants from the National Institute on Drug Abuse through McLean Hospital during the conduct of the study. Ms. Parry reports receiving salary support from grants from the National Institute on Drug Abuse (grant #5U10DA015) through McLean Hospital during the conduct of the study. Dr. Mandler, an employee of the National Institute on Drug Abuse, reviewed and approved the article as a part of his authorship role. His role in the project is through the National Institute on Drug Abuse Clinical Trials Network (U10-DA13720). The National Institute on Drug Abuse appointed members and coordinated meetings of the data and safety monitoring board. Dr. Bogenschutz reports receiving grants from the National Institute on Drug Abuse during the conduct of the study. Dr. Weiss reports receiving grants from the National Institute on Drug Abuse during the conduct of the study. This secondary analysis was completed with financial support from the National Institute on Drug Abuse, grants U10 DA01583, K24 DA022288, U10 DA020036, U10 DA13720, U10 DA13035, U10 DA15831, U10 DA13732, and U10 DA15833. NR 38 TC 9 Z9 9 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD NOV PY 2014 VL 64 IS 5 BP 516 EP 525 DI 10.1016/j.annemergmed.2014.05.012 PG 10 WC Emergency Medicine SC Emergency Medicine GA AS7LX UT WOS:000344438600014 ER PT J AU Abola, MV Prasad, V Jena, AB AF Abola, M. V. Prasad, V. Jena, A. B. TI Association between treatment toxicity and outcomes in oncology clinical trials SO ANNALS OF ONCOLOGY LA English DT Article DE treatment toxicity; clinical trials ID CHEMOTHERAPY-INDUCED NEUTROPENIA; CELL LUNG-CANCER; BREAST-CANCER; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIALS; PROGNOSTIC-FACTOR; POOLED ANALYSIS; SURVIVAL; EFFICACY; CARCINOMA AB Whether treatment toxicity predicts outcomes in oncology is unknown. We analyzed treatment toxicity and outcomes in phase III oncology RCTs and examined whether treatments with relatively greater toxicity had relatively greater progression-free or overall survival (PFS or OS). Across trials, treatments with relatively greater toxicity (compared to controls) had relatively greater PFS but not OS.Whether or not toxicity predicts clinical outcomes has long been a question regarding cancer treatments. While prior studies have focused on specific cancers, therapies, and toxicities, no comprehensive evidence exists on whether treatment toxicity predicts favorable outcomes. We abstracted treatment toxicity and clinical outcome data from a sample of phase III oncology randomized clinical trials (n = 99 trials). We investigated whether treatments with relatively greater toxicity compared with their controls had relatively higher, lower, or equivocal rates of clinical efficacy, measured by progression-free survival (PFS) and overall survival (OS). Several toxicities were assessed (all grades, grades III/IV, cutaneous rash, gastrointestinal toxicity, and myelosuppression). Toxicity and efficacy were greater among treatments than controls (e.g. 3.5 instances of all-grade toxicity per patient in treatment arms versus 2.8 instances in controls, P < 0.001; mean PFS of 9.1 months across treatment arms versus 7.1 months across controls, P < 0.001; mean OS of 18.6 months across treatment arms versus 16.9 months across controls, P < 0.001). Across trials, greater relative treatment toxicity was strongly associated with greater PFS in treatments versus controls (P < 0.001), but not OS (P = 0.44). Although higher relative rates of myelosuppression and cutaneous rash among treatments were not associated with greater treatment efficacy, greater relative gastrointestinal toxicity among treatments was associated with greater relative PFS compared with controls (P = 0.007). Across trials, treatments with relatively greater all-grade toxicity compared with controls are associated with relatively greater PFS but not OS. C1 [Abola, M. V.] Case Western Reserve Univ, Dept Family Med, Sch Med, Cleveland, OH 44106 USA. [Prasad, V.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Jena, A. B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, A. B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu RI Abola, Matthew/F-4869-2015; OI Abola, Matthew/0000-0001-8084-3515; Prasad, Vinay/0000-0002-6110-8221 FU Office of the Director, National Institutes of Health (NIH Early Independence Award) [1DP5OD017897-01] FX Support was provided by the Office of the Director, National Institutes of Health (NIH Early Independence Award, 1DP5OD017897-01, ABJ). NR 21 TC 1 Z9 1 U1 0 U2 2 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 NOV PY 2014 VL 25 IS 11 BP 2284 EP 2289 DI 10.1093/annonc/mdu444 PG 6 WC Oncology SC Oncology GA AT0SC UT WOS:000344644200027 PM 25193993 ER PT J AU Kaplan, RM Sun, QK Naunheim, KS Ries, AL AF Kaplan, Robert M. Sun, Qiankun Naunheim, Keith S. Ries, Andrew L. TI Long-Term Follow-Up of High-Risk Patients in the National Emphysema Treatment Trial SO ANNALS OF THORACIC SURGERY LA English DT Article ID VOLUME-REDUCTION SURGERY; WELL-BEING SCALE; RANDOMIZED-TRIAL; QUALITY AB Background. The National Emphysema Treatment Trial (NETT) was a randomized clinical trial designed to compare lung volume reduction surgery (LVRS) with maximal medical care for patients with severe emphysema. The trial was halted early for a subgroup of patients with severe lung disease. We report longer term follow-up for this high-risk subgroup. Methods. In a randomized clinical trial, patients with moderate to severe emphysema were assigned to LVRS plus maximal medical care or to maximal medical care alone and followed prospectively for vital status over 15 years. We focus on 140 high-risk patients. Quality of life data were available through 6 years of follow-up and were assessed using the University of California, San Diego Shortness of Breath Questionnaire and the Self-Administered Quality of Well-Being Scale. Results. Through the first 3 years of follow-up, surgical patients in the high-risk subgroup had a significantly higher probability of death. However, the mortality curves crossed and there was a trend favoring surgical treatment through the remainder of the follow-up. The log-rank test suggested that the 2 groups were not significantly different (p = 0.95) in survival. Quality of life data suggested an advantage of LVRS through the first 5 years of follow-up (p < 0.01). The combined quality-adjusted survival model favored the medical group for the first few years of follow-up and favored the LVRS group after 4 years. Conclusions. The NETT was stopped early for high-risk patients with severe lung disease. Longer term follow-up suggests that surgical patients in this high-risk subgroup ultimately achieved comparable outcomes. The high risk of death within 30 days of the surgery may discourage use of the procedure for high-risk patients despite the potential for better long-term outcomes. (C) 2014 by The Society of Thoracic Surgeons C1 NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. St Louis Univ, Sch Med, Dept Surg, St Louis, MO USA. Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. RP Kaplan, RM (reprint author), Off Director, Agcy Healthcare Res & Qual, 240 Gaither Rd, Rockville, MD 20850 USA. EM rmkaplan@ucla.edu FU National Heart, Lung, and Blood Institute [N01HR76101, N01HR76102, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119]; Center for Medicare and Medicaid Services (formerly the Health Care Financing Administration); Agency for Healthcare Research and Quality FX Supported by contracts with the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119), the Center for Medicare and Medicaid Services (formerly the Health Care Financing Administration), and the Agency for Healthcare Research and Quality. ClinicalTrials.gov Identifier: NCT00000606. NR 10 TC 4 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD NOV PY 2014 VL 98 IS 5 BP 1782 EP 1789 DI 10.1016/j.athoracsur.2014.06.031 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA AT2EZ UT WOS:000344746600064 PM 25201722 ER PT J AU Sathaye, S Zhang, HX Sonmez, C Schneider, JP MacDermaid, CM Von Bargen, CD Saven, JG Pochan, DJ AF Sathaye, Sameer Zhang, Huixi Sonmez, Cem Schneider, Joel P. MacDermaid, Christopher M. Von Bargen, Christopher D. Saven, Jeffery G. Pochan, Darrin J. TI Engineering Complementary Hydrophobic Interactions to Control beta-Hairpin Peptide Self-Assembly, Network Branching, and Hydrogel Properties SO BIOMACROMOLECULES LA English DT Article ID AMYLOID-FORMING PEPTIDES; DE-NOVO DESIGN; MOLECULAR-DYNAMICS; LACTOGLOBULIN GELS; REVERSIBLE HYDROGELS; PROTEIN; AGGREGATION; SIMULATIONS; LOCK; ASSOCIATION AB The MAX1 beta-hairpin peptide (VKVKVKVK-(VPPT)-P-D-KVKVKVKV-NH2) has been shown to form nanofibrils having a cross-section of two folded peptides forming a hydrophobic, valine-rich core, and the polymerized fibril exhibits primarily beta-sheet hydrogen bonding.(1-7) These nanofibrils form hydrogel networks through fibril entanglements as well as fibril branching.(8) Fibrillar branching in MAX1 hydrogel networks provide the ability to flow under applied shear stress and immediately reform a hydrogel solid on cessation of shear. New beta-hairpins were designed to limit branching during nanofibril growth because of steric specificity in the assembled fibril hydrophobic core. The nonturn valines of MAX1 were substituted by 2-naphthylalanine (Nal) and alanine (A) residues, with much larger and smaller side chain volumes, respectively, to obtain LNK1 (Nal)K(Nal)KAKAK-(VPPT)-P-D-KAKAK(Nal)K(Nal)-NH2. LNK1 was targeted to self-associate with a specific lock and key complementary packing in the hydrophobic core in order to accommodate the Nal and Ala residue side chains. The experimentally observable manifestation of reduced fibrillar branching in the LNK1 peptide is the lack of solid hydrogel formation after shear in stark contrast to the MAX1 branched fibril system. Molecular dynamics simulations provide a molecular picture of interpeptide interactions within the assembly that is consistent with the branching propensity of MAX1 vs LNK1 and in agreement with experimental observations. C1 [Sathaye, Sameer; Pochan, Darrin J.] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. [Sathaye, Sameer; Pochan, Darrin J.] Univ Delaware, Delaware Biotechnol Inst, Newark, DE 19716 USA. [Zhang, Huixi; MacDermaid, Christopher M.; Von Bargen, Christopher D.; Saven, Jeffery G.] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Sonmez, Cem] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Sonmez, Cem; Schneider, Joel P.] NCI, Chem Biol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Pochan, DJ (reprint author), Univ Delaware, Dept Mat Sci & Engn, 201 DuPont Hall, Newark, DE 19716 USA. EM pochan@udel.edu RI Sonmez, Cem/C-2730-2015 OI Sonmez, Cem/0000-0002-6071-641X FU NSF [DMR 12-34161]; Penn Laboratory for Research on the Structure of Matter [NSF DMR 11-20901] FX The authors acknowledge support from NSF DMR 12-34161. J.G.S. acknowledges additional support from the Penn Laboratory for Research on the Structure of Matter (NSF DMR 11-20901) and thanks the Penn Nano/Bio Interface Center for Infrastructural Support (NSF DMR 08-32802). D.J.P. and S.S. would like to acknowledge cooperative agreement 70NANB12H239 from NIST, U.S. Department of Commerce and the UD-NIST Center for Neutron Science. The statements, findings, conclusions and recommendations are those of the author(s) and do not necessarily reflect the view of NIST or the U.S. Department of Commerce. NR 60 TC 10 Z9 10 U1 5 U2 92 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 EI 1526-4602 J9 BIOMACROMOLECULES JI Biomacromolecules PD NOV PY 2014 VL 15 IS 11 BP 3891 EP 3900 DI 10.1021/bm500874t PG 10 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA AT1WI UT WOS:000344721400003 PM 25251904 ER PT J AU Umar, A AF Umar, Asad TI Cancer Immunoprevention: A New Approach to Intercept Cancer Early SO CANCER PREVENTION RESEARCH LA English DT Article ID ADAPTIVE IMMUNITY; VACCINE DELIVERY; PREVENTION; ANTIGENS; IMMUNOTHERAPY; EFFICACY; INNATE; CELLS AB Cancer immunoprevention refers to the modulation of the host immune response to control the initiation or development of cancer. The significant role of host immunity in early tumorigenesis has only recently been confirmed, as a better understanding of the mechanisms, molecules and cells involved in tumor immunology have been elucidated over the past two decades. Of utmost importance, preclinical and clinical evidences have demonstrated that early neoplastic cells (transformed cells that initiate cancer formation) express antigens that allow the immune system to distinguish them from normal cells. Furthermore, recognition of the aberrant cell by the immune cells activates a complex interaction of mutual modulation between the immune cells, the tumor and the tumor microenvironment that may result not only in inhibition but also promotion of cancer. The deepening understanding of cancer-related immunologic processes, properties, and components has spawned exploration of more rational, mechanism-based immunologic strategies (using vaccines, antibodies, and immune modulators) for cancer prevention. This introduction to the Cancer Prevention Research immunoprevention series will attempt to review the basics of the immune response modulation as a basis for potential application to cancer immunoprevention strategies with an emphasis on vaccines. Recognizing the fast-paced research inimmune response modulation, the series will cover current understandings and future directions of cancer immunoprevention research. (C) 2014 AACR. C1 [Umar, Asad] NCI, Gastrointestinal & Other Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Umar, A (reprint author), NCI, 9609 Med Ctr Dr,5E226, Rockville, MD 20850 USA. EM Asad.Umar@nih.gov NR 25 TC 2 Z9 2 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2014 VL 7 IS 11 BP 1067 EP 1071 DI 10.1158/1940-6207.CAPR-14-0213 PG 5 WC Oncology SC Oncology GA AT5PP UT WOS:000344994900001 PM 25237055 ER PT J AU Pan, J Zhang, Q Liu, Q Komas, SM Kalyanaraman, B Lubet, RA Wang, Y You, M AF Pan, Jing Zhang, Qi Liu, Qian Komas, Steven M. Kalyanaraman, Balaraman Lubet, Ronald A. Wang, Yian You, Ming TI Honokiol Inhibits Lung Tumorigenesis through Inhibition of Mitochondrial Function SO CANCER PREVENTION RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; CANCER CHEMOPREVENTION; MAGNOLIA-OFFICINALIS; BREAST-CANCER; CYCLE ARREST; MICE; PIOGLITAZONE; APOPTOSIS; PROGRESS; PROMISE AB Honokiol is an important bioactive compound found in the bark of Magnolia tree. It is a non-adipogenic PPAR gamma agonist and capable of inhibiting the growth of a variety of tumor types both in vitro and in xenograft models. However, to fully appreciate the potential chemopreventive activity of honokiol, a less artificial model system is required. To that end, this study examined the chemopreventive efficacy of honokiol in an initiation model of lung squamous cell carcinoma (SCC). This model system uses the carcinogen N-nitroso-trischloroethylurea (NTCU), which is applied topically, reliably triggering the development of SCC within 24 to 26 weeks. Administration of honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol-treated group (P = 0.01) while protecting normal bronchial histology (present in 20.5% of bronchial in control group and 38.5% of bronchial in honokiol-treated group. P = 0.004). P63 staining at the SCC site confirmed the lung SCCs phenotype. In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G(1)-S cell-cycle checkpoint, while also leading to increased apoptosis. Our study showed that interfering with mitochondrial respiration is a novel mechanism by which honokiol changed redox status in the mitochondria, triggered apoptosis, and finally leads to the inhibition of lung SCC. This novel mechanism of targeting mitochondrial suggests honokiol as a potential lung SCC chemopreventive agent. (C) 2014 AACR. C1 [Pan, Jing; Zhang, Qi; Liu, Qian; Wang, Yian; You, Ming] Med Coll Wisconsin, Ctr Canc, Milwaukee, WI 53226 USA. [Pan, Jing; Zhang, Qi; Liu, Qian; Wang, Yian; You, Ming] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA. [Komas, Steven M.; Kalyanaraman, Balaraman] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. [Lubet, Ronald A.] NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Med Coll Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM myou@mcw.edu FU [R01CA139959] FX This work was supported by R01CA139959. NR 38 TC 8 Z9 9 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2014 VL 7 IS 11 BP 1149 EP 1159 DI 10.1158/1940-6207.CAPR-14-0091 PG 11 WC Oncology SC Oncology GA AT5PP UT WOS:000344994900009 PM 25245764 ER PT J AU Wei, F Yang, D Tewary, P Li, YN Li, S Chen, X Howard, OMZ Bustin, M Oppenheim, JJ AF Wei, Feng Yang, De Tewary, Poonam Li, Yana Li, Sandra Chen, Xin Howard, O. M. Zack Bustin, Michael Oppenheim, Joost J. TI The Alarmin HMGN1 Contributes to Antitumor Immunity and Is a Potent Immunoadjuvant SO CANCER RESEARCH LA English DT Article ID EOSINOPHIL-DERIVED NEUROTOXIN; DENDRITIC CELL MATURATION; CHROMOSOMAL-PROTEIN HMGN1; CANCER-IMMUNOTHERAPY; ANTIMICROBIAL-PEPTIDE; ADAPTIVE IMMUNITY; RESPONSES; RECEPTOR; ACTS; ANTIGEN AB Alarmins are endogenous mediators that are elicited rapidly in response to danger signals, enhancing innate and adaptive immune responses by promoting the recruitment and maturation of antigen-presenting cells (APC). The nucleosome-binding protein HMGN1 is a potent alarmin that binds TLR4 and induces antigen-specific Th1 immune responses, but its contributions to antitumor immunity have not been explored. We found that ovalbumin (OVA)-expressing EG7 mouse thymoma cells grew much faster in Hmgn1-deficient mice than littermate-matched controls. Tumor-bearing Hmgn1(-/-) mice generated fewer OVA-specific CD8 cells in the spleen than EG7-bearing Hmgn1(+/+) mice, suggesting that HMGN1 supported T cell-mediated antitumor immunity. In addition, EG7 tumors expressing HMGN1 grew more slowly than control EG7 tumors, suggesting greater resistance to HMGN1-expressing tumors. This resistance relied on T cell-mediated immunity because it was abolished by in vivo depletion of CD4(+) and CD8(+) T cells. Moreover, mice vaccinated with a DNA vector expressing an HMGN1-gp100 fusion protein manifested gp100-specific, Th1-polarized immune responses, acquiring resistance to challenge with mouse B16F1 melanoma. Overall, our findings show that HMGN1 contributes to antitumor immunity and it may offer an effective adjuvant to heighten responses to cancer vaccines. (C) 2014 AACR. C1 [Wei, Feng; Yang, De; Tewary, Poonam; Li, Yana; Li, Sandra; Chen, Xin; Howard, O. M. Zack; Oppenheim, Joost J.] Frederick Natl Lab Canc Res, Ctr Canc Res, Canc & Inflammat Program, Mol Immunoregulat Lab, Frederick, MD USA. [Wei, Feng] Tianjin Med Univ, Canc Inst & Hosp, Dept Immunol, Tianjin, Peoples R China. [Yang, De] Tianjin Med Univ, Res Ctr Basic Med Sci, Tianjin, Peoples R China. [Yang, De; Tewary, Poonam; Chen, Xin] Frederick Natl Lab, Leidos Biomed Res Inc, Basic Res Program, Frederick, MD USA. [Bustin, Michael] NCI, Lab Metab, NIH, Frederick, MD 21702 USA. RP Yang, D (reprint author), NCI, 1050 Boyles St, Frederick, MD 21702 USA. EM dyang@mail.nih.gov RI Wei, Feng/E-2806-2015; Bustin, Michael/G-6155-2015; OI Wei, Feng/0000-0002-4797-449X; Chen, Xin/0000-0002-2628-4027 FU Frederick National Laboratory, NIH [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Laboratory, Center for Cancer Research; National Natural Science Foundation of China [30901376]; National Key Basic Research Program of China (973 grant) [2012CB932503] FX This project has been funded, in part, with Federal funds from the Frederick National Laboratory, NIH, under contract no. HHSN261200800001E and by the Intramural Research Program of NIH, Frederick National Laboratory, Center for Cancer Research. This project has also been funded, in part, by grants from the National Natural Science Foundation of China (grant no. 30901376) and the National Key Basic Research Program of China (973 grant 2012CB932503). NR 43 TC 9 Z9 9 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 1 PY 2014 VL 74 IS 21 BP 5989 EP 5998 DI 10.1158/0008-5472.CAN-13-2042 PG 10 WC Oncology SC Oncology GA AT2IF UT WOS:000344756800007 PM 25205103 ER PT J AU Bae, EJ Sato, M Kim, RJ Kwak, MK Naka, K Gim, J Kadota, M Tang, BW Flanders, KC Kim, TA Leem, SH Park, T Liu, F Wakefield, LM Kim, SJ Ooshima, A AF Bae, Eunjin Sato, Misako Kim, Ran-Ju Kwak, Mi-Kyung Naka, Kazuhito Gim, Jungsoo Kadota, Mitsutaka Tang, Binwu Flanders, Kathleen C. Kim, Tae-Aug Leem, Sun-Hee Park, Taesung Liu, Fang Wakefield, Lalage M. Kim, Seong-Jin Ooshima, Akira TI Definition of Smad3 Phosphorylation Events That Affect Malignant and Metastatic Behaviors in Breast Cancer Cells SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; EPITHELIAL-MESENCHYMAL TRANSITION; TGF-BETA; STEM-CELLS; LINKER PHOSPHORYLATION; INHIBITION; CONTEXT; CARCINOGENESIS; IDENTIFICATION; REPRESSION AB Smad3, a major intracellular mediator of TGF beta signaling, functions as both a positive and negative regulator in carcinogenesis. In response to TGF beta, the TGF beta receptor phosphorylates serine residues at the Smad3 C-tail. Cancer cells often contain high levels of the MAPK and CDK activities, which can lead to the Smad3 linker region becoming highly phosphorylated. Here, we report, for the first time, that mutation of the Smad3 linker phosphorylation sites markedly inhibited primary tumor growth, but significantly increased lung metastasis of breast cancer cell lines. In contrast, mutation of the Smad3 C-tail phosphorylation sites had the opposite effect. We show that mutation of the Smad3 linker phosphorylation sites greatly intensifies all TGF beta-induced responses, including growth arrest, apoptosis, reduction in the size of putative cancer stem cell population, epithelial-mesenchymal transition, and invasive activity. Moreover, all TGF beta responses were completely lost on mutation of the Smad3 C-tail phosphorylation sites. Our results demonstrate a critical role of the counterbalance between the Smad3 C-tail and linker phosphorylation in tumorigenesis and metastasis. Our findings have important implications for therapeutic intervention of breast cancer. (C) 2014 AACR. C1 [Bae, Eunjin; Kim, Ran-Ju; Kwak, Mi-Kyung; Kim, Tae-Aug; Kim, Seong-Jin; Ooshima, Akira] CHA Univ, CHA Canc Res Inst, Seoul, South Korea. [Sato, Misako; Tang, Binwu; Flanders, Kathleen C.; Wakefield, Lalage M.; Ooshima, Akira] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Naka, Kazuhito] Kanazawa Univ, Canc Res Inst, Kanazawa, Ishikawa 920, Japan. [Gim, Jungsoo; Park, Taesung] Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea. [Kadota, Mitsutaka] RIKEN Ctr Dev Biol, Genome Resource & Anal Unit, Kobe, Hyogo, Japan. [Leem, Sun-Hee] Dong A Univ, Dept Biol & Biomed Sci, Pusan, South Korea. [Park, Taesung] Seoul Natl Univ, Dept Stat, Seoul, South Korea. [Liu, Fang] Rutgers State Univ, Ctr Adv Biotechnol & Med, Susan Lehman Cullman Lab Canc Res, Dept Chem Biol,Ernest Mario Sch Pharm, Piscataway, NJ 08854 USA. RP Ooshima, A (reprint author), CHA Canc Inst, 605 Yeoksam Dong, Seoul 135081, South Korea. EM kimsj@cha.ac.kr; aooshima@cha.ac.kr FU National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [NRF-2012M3A9C4048735] FX This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2012M3A9C4048735). NR 41 TC 7 Z9 7 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 1 PY 2014 VL 74 IS 21 BP 6139 EP 6149 DI 10.1158/0008-5472.CAN-14-0803 PG 11 WC Oncology SC Oncology GA AT2IF UT WOS:000344756800020 PM 25205100 ER PT J AU Gomez-Lopez, N StLouis, D Lehr, MA Sanchez-Rodriguez, EN Arenas-Hernandez, M AF Gomez-Lopez, Nardhy StLouis, Derek Lehr, Marcus A. Sanchez-Rodriguez, Elly N. Arenas-Hernandez, Marcia TI Immune cells in term and preterm labor SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE B cells; cytotoxic T cells; dendritic cells; macrophages; mast cells; neutrophils; NKT cells; parturition; preterm delivery; regulatory T cells; T cells ID REGULATORY T-CELLS; INVARIANT NKT CELLS; HUMAN FETAL MEMBRANES; TUMOR-NECROSIS-FACTOR; MAST-CELLS; DENDRITIC CELLS; PREMATURE RUPTURE; HUMAN PARTURITION; PERIPHERAL-BLOOD; HUMAN-PREGNANCY AB Labor resembles an inflammatory response that includes secretion of cytokines/chemokines by resident and infiltrating immune cells into reproductive tissues and the maternal/fetal interface. Untimely activation of these inflammatory pathways leads to preterm labor, which can result in preterm birth. Preterm birth is a major determinant of neonatal mortality and morbidity; therefore, the elucidation of the process of labor at a cellular and molecular level is essential for understanding the pathophysiology of preterm labor. Here, we summarize the role of innate and adaptive immune cells in the physiological or pathological activation of labor. We review published literature regarding the role of innate and adaptive immune cells in the cervix, myometrium, fetal membranes, decidua and the fetus in late pregnancy and labor at term and preterm. Accumulating evidence suggests that innate immune cells (neutrophils, macrophages and mast cells) mediate the process of labor by releasing pro-inflammatory factors such as cytokines, chemokines and matrix metalloproteinases. Adaptive immune cells (T-cell subsets and B cells) participate in the maintenance of fetomaternal tolerance during pregnancy, and an alteration in their function or abundance may lead to labor at term or preterm. Also, immune cells that bridge the innate and adaptive immune systems (natural killer T (NKT) cells and dendritic cells (DCs)) seem to participate in the pathophysiology of preterm labor. In conclusion, a balance between innate and adaptive immune cells is required in order to sustain pregnancy; an alteration of this balance will lead to labor at term or preterm. C1 [Gomez-Lopez, Nardhy; StLouis, Derek; Lehr, Marcus A.; Sanchez-Rodriguez, Elly N.; Arenas-Hernandez, Marcia] Wayne State Univ, Dept Obstet & Gynecol & Immunol & Microbiol, Detroit, MI 48201 USA. [Gomez-Lopez, Nardhy] Wayne State Univ, NICHD, NIH, Sch Med,Perinatol Res Branch, Detroit, MI 48201 USA. RP Gomez-Lopez, N (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Perinatol Res Branch, Detroit, MI 48201 USA. EM nardhy.gomez-lopez@wayne.edu FU Wayne State University Research Initiative in Maternal, Perinatal and Child Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD/NIH); Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver NICHD/NIH FX The Gomez-Lopez Laboratory is funded by Wayne State University Research Initiative in Maternal, Perinatal and Child Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD/NIH). This laboratory is also supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver NICHD/NIH. NR 146 TC 44 Z9 45 U1 4 U2 25 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD NOV PY 2014 VL 11 IS 6 SI SI BP 571 EP 581 DI 10.1038/cmi.2014.46 PG 11 WC Immunology SC Immunology GA AT5NW UT WOS:000344990500008 PM 24954221 ER PT J AU Dunsmoor, JE Kragel, PA Martin, A Labar, KS AF Dunsmoor, Joseph E. Kragel, Philip A. Martin, Alex LaBar, Kevin S. TI Aversive Learning Modulates Cortical Representations of Object Categories SO CEREBRAL CORTEX LA English DT Article DE anxiety; categories and concepts; fear conditioning; functional magnetic resonance imaging; generalization ID FEAR-RELEVANT STIMULI; CONDITIONED FEAR; HUMAN AMYGDALA; CONCEPTUAL KNOWLEDGE; AUDITORY-CORTEX; HUMAN BRAIN; NEURAL BASIS; MEMORY; EXTINCTION; ACQUISITION AB Experimental studies of conditioned learning reveal activity changes in the amygdala and unimodal sensory cortex underlying fear acquisition to simple stimuli. However, real-world fears typically involve complex stimuli represented at the category level. A consequence of category-level representations of threat is that aversive experiences with particular category members may lead one to infer that related exemplars likewise pose a threat, despite variations in physical form. Here, we examined the effect of category-level representations of threat on human brain activation using 2 superordinate categories (animals and tools) as conditioned stimuli. Hemodynamic activity in the amygdala and category-selective cortex was modulated by the reinforcement contingency, leading to widespread fear of different exemplars from the reinforced category. Multivariate representational similarity analyses revealed that activity patterns in the amygdala and object-selective cortex were more similar among exemplars from the threat versus safe category. Learning to fear animate objects was additionally characterized by enhanced functional coupling between the amygdala and fusiform gyrus. Finally, hippocampal activity co-varied with object typicality and amygdala activation early during training. These findings provide novel evidence that aversive learning can modulate category-level representations of object concepts, thereby enabling individuals to express fear to a range of related stimuli. C1 [Dunsmoor, Joseph E.; Kragel, Philip A.; LaBar, Kevin S.] Duke Univ, Ctr Cognit Neurosci, Dept Psychol & Neurosci, Durham, NC 27708 USA. [Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Labar, KS (reprint author), Duke Univ, Ctr Cognit Neurosci, Dept Psychol & Neurosci, Durham, NC 27708 USA. EM klabar@duke.edu OI Kragel, Philip/0000-0001-9463-6381 FU NSF [0745919]; NIH [R01 DA027802, F31 MH090682] FX This work was supported by NSF grant 0745919 and NIH grants R01 DA027802 and F31 MH090682. NR 63 TC 18 Z9 18 U1 5 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD NOV PY 2014 VL 24 IS 11 BP 2859 EP 2872 DI 10.1093/cercor/bht138 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AT0SX UT WOS:000344646200005 PM 23709642 ER PT J AU Scherf, KS Thomas, C Doyle, J Behrmann, M AF Scherf, K. Suzanne Thomas, Cibu Doyle, Jaime Behrmann, Marlene TI Emerging Structure-Function Relations in the Developing Face Processing System SO CEREBRAL CORTEX LA English DT Article DE adolescent; child; development; DTI; fMRI; IFOF; ILF; visual processing ID WHITE-MATTER DEVELOPMENT; DIFFUSION-TENSOR MRI; HUMAN BRAIN; VISUAL-CORTEX; NEURAL SYSTEMS; CONGENITAL PROSOPAGNOSIA; DIFFERENTIAL DEVELOPMENT; EFFECTIVE CONNECTIVITY; DEVELOPMENTAL-CHANGES; AXONAL PROJECTIONS AB To evaluate emerging structure-function relations in a neural circuit that mediates complex behavior, we investigated age-related differences among cortical regions that support face recognition behavior and the fiber tracts through which they transmit and receive signals using functional neuroimaging and diffusion tensor imaging. In a large sample of human participants (aged 6-23 years), we derived the microstructural and volumetric properties of the inferior longitudinal fasciculus (ILF), the inferior fronto-occipital fasciculus, and control tracts, using independently defined anatomical markers. We also determined the functional characteristics of core face- and place-selective regions that are distributed along the trajectory of the pathways of interest. We observed disproportionately large age-related differences in the volume, fractional anisotropy, and mean and radial, but not axial, diffusivities of the ILF. Critically, these differences in the structural properties of the ILF were tightly and specifically linked with an age-related increase in the size of a key face-selective functional region, the fusiform face area. This dynamic association between emerging structural and functional architecture in the developing brain may provide important clues about the mechanisms by which neural circuits become organized and optimized in the human cortex. C1 [Scherf, K. Suzanne] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Thomas, Cibu] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Thomas, Cibu] Univ Hlth Sci, Ctr Neurosci & Regenerat Med Uniformed Serv, Bethesda, MD 20892 USA. [Doyle, Jaime; Behrmann, Marlene] Carnegie Mellon Univ, Dept Psychol, Pittsburgh, PA 15213 USA. [Behrmann, Marlene] Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA. RP Scherf, KS (reprint author), Penn State Univ, Dept Psychol, 111 Moore Hall, University Pk, PA 16802 USA. EM suzyscherf@psu.edu OI Scherf, Suzy/0000-0002-0696-6362; Behrmann, Marlene/0000-0002-3814-1015 FU Pennsylvania Department of Health SAP grant [4100047862]; NICHD/NIDCD [P01/U19]; National Alliance for Autism Research; NSF Science of Learning Center grant, "Temporal Dynamics of Learning Center"; NSF grant [BCS0923763] FX The research reported in this paper was supported by Pennsylvania Department of Health SAP grant 4100047862 (M.B., K.S.S.), NICHD/NIDCD P01/U19 (M.B., PI-Nancy Minshew), a post-doctoral fellowship from the National Alliance for Autism Research to Suzy Scherf and Beatriz Luna, an NSF Science of Learning Center grant, "Temporal Dynamics of Learning Center" (PI: Gary Cottrell, Co-I: M.B.), and a NSF grant (BCS0923763) to M.B. NR 100 TC 8 Z9 8 U1 1 U2 19 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD NOV PY 2014 VL 24 IS 11 BP 2964 EP 2980 DI 10.1093/cercor/bht152 PG 17 WC Neurosciences SC Neurosciences & Neurology GA AT0SX UT WOS:000344646200014 ER PT J AU Liu, ZM de Zwart, JA Chang, C Duan, Q van Gelderen, P Duyn, JH AF Liu, Zhongming de Zwart, Jacco A. Chang, Catie Duan, Qi van Gelderen, Peter Duyn, Jeff H. TI Neuroelectrical Decomposition of Spontaneous Brain Activity Measured with Functional Magnetic Resonance Imaging SO CEREBRAL CORTEX LA English DT Article DE band-limited power; functional networks; resting state; spectral clustering; subspace analysis ID RESTING-STATE NETWORKS; DEFAULT MODE; BOLD SIGNAL; NEURONAL OSCILLATIONS; ACTIVITY FLUCTUATIONS; CONNECTIVITY MRI; ALPHA-RHYTHM; FMRI; CORTEX; EEG AB Spontaneous activity in the human brain occurs in complex spatiotemporal patterns that may reflect functionally specialized neural networks. Here, we propose a subspace analysis method to elucidate large-scale networks by the joint analysis of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data. The new approach is based on the notion that the neuroelectrical activity underlying the fMRI signal may have EEG spectral features that report on regional neuronal dynamics and interregional interactions. Applying this approach to resting healthy adults, we indeed found characteristic spectral signatures in the EEG correlates of spontaneous fMRI signals at individual brain regions as well as the temporal synchronization among widely distributed regions. These spectral signatures not only allowed us to parcel the brain into clusters that resembled the brain's established functional subdivision, but also offered important clues for disentangling the involvement of individual regions in fMRI network activity. C1 [Liu, Zhongming; de Zwart, Jacco A.; Chang, Catie; Duan, Qi; van Gelderen, Peter; Duyn, Jeff H.] NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20982 USA. RP Liu, ZM (reprint author), NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bldg 10,Room B1D 723,9000 Rockville Pike,MSC 1065, Bethesda, MD 20982 USA. EM liuz5@mail.nih.gov RI Duan, Qi/J-7916-2016 OI Duan, Qi/0000-0002-2407-6611 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 60 TC 3 Z9 3 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD NOV PY 2014 VL 24 IS 11 BP 3080 EP 3089 DI 10.1093/cercor/bht164 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AT0SX UT WOS:000344646200024 PM 23796947 ER PT J AU Frey, SE Peiperl, L McElrath, MJ Kalams, S Goepfert, PA Keefer, MC Baden, LR Lally, MA Mayer, K Blattner, WA Harro, CD Hammer, SM Gorse, GJ Hural, J Tomaras, GD Levy, Y Gilbert, P deCamp, A Russell, ND Elizaga, M Allen, M Corey, L AF Frey, Sharon E. Peiperl, Laurence McElrath, M. Juliana Kalams, Spyros Goepfert, Paul A. Keefer, Michael C. Baden, Lindsey R. Lally, Michelle A. Mayer, Kenneth Blattner, William A. Harro, Clayton D. Hammer, Scott M. Gorse, Geoffrey J. Hural, John Tomaras, Georgia D. Levy, Yves Gilbert, Peter deCamp, Allan Russell, Nina D. Elizaga, Marnie Allen, Mary Corey, Lawrence TI Phase I/II Randomized Trial of Safety and Immunogenicity of LIPO-5 Alone, ALVAC-HIV (vCP1452) Alone, and ALVAC-HIV (vCP1452) Prime/LIPO-5 Boost in Healthy, HIV-1-Uninfected Adult Participants SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; VIRUS TYPE-1 VACCINE; IMMUNODEFICIENCY-VIRUS; CANARYPOX VACCINE; CELL RESPONSES; LIPOPEPTIDE VACCINE; IMMUNE-RESPONSES; IN-VIVO; RECOMBINANT VACCINES; SERONEGATIVE ADULTS AB Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 mu g), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 mu g). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P <= 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452) + LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452) + LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited. C1 [Frey, Sharon E.; Gorse, Geoffrey J.] St Louis Univ, Dept Internal Med, St Louis, MO 63103 USA. [Peiperl, Laurence] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [McElrath, M. Juliana; Corey, Lawrence] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [McElrath, M. Juliana; Corey, Lawrence] Univ Washington, Seattle, WA 98195 USA. [Kalams, Spyros] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Goepfert, Paul A.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Keefer, Michael C.] Univ Rochester, Sch Med & Dent, Dept Med, Univ Med, Rochester, NY 14642 USA. [Baden, Lindsey R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lally, Michelle A.] Brown Univ, Alpert Med Sch, Dept Med, Providence, RI 02912 USA. [Mayer, Kenneth] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Fenway Inst, Boston, MA 02215 USA. [Blattner, William A.] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Harro, Clayton D.] Johns Hopkins Univ, Ctr Immunizat Res, Baltimore, MD USA. [Hammer, Scott M.] Columbia Univ, Med Ctr, Dept Med, New York, NY USA. [Hural, John; Elizaga, Marnie] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Tomaras, Georgia D.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Levy, Yves] Univ Paris Est, INSERM, Fac Med, Vaccine Res Inst,U955,Equipe 16, Creteil, France. [Gilbert, Peter; deCamp, Allan] Fred Hutchinson Canc Res Ctr, SCHARP Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Russell, Nina D.] Bill & Melinda Gates Fdn, Seattle, WA USA. [Allen, Mary] NIAID, NIH, Bethesda, MD 20892 USA. RP Frey, SE (reprint author), St Louis Univ, Dept Internal Med, St Louis, MO 63103 USA. EM freyse@slu.edu RI Lally, Michelle/I-4865-2016; Tomaras, Georgia/J-5041-2016 OI Lally, Michelle/0000-0003-0716-4668; FU National Institutes of Health [5-U01 AI-46703 (HVTN SDMC), 5-U01 AI-46747 (HVTN Core), 5-U01-AI-47976, 5-U01-AI-47980, 5-U01-AI-48017]; DHHS/CDC [U62CCU222414]; Agence Nationale de Recherche sur le SIDA et les Hepatites, Paris; Sanofi Pasteur, Swiftwater, PA; NIAID; [5-U01-AI-46747]; [5-U01-AI-48022]; [5-U01-AI-47996]; [5-U01-AI-48021]; [5-U01-AI-47985]; [5-U01-AI-48001]; [5-U01-AI-48023]; [5U01AI46725]; [UM1 AI069481-06]; [UM1 AI069439]; [UL1TR000445]; [UMAI068618-07]; [AI-069470]; [RR-024156] FX The research was supported by National Institutes of Health grants 5-U01 AI-46703 (HVTN SDMC), 5-U01 AI-46747 (HVTN Core), 5-U01-AI-47976, 5-U01-AI-47980, 5-U01-AI-48017, 5-U01-AI-46747, 5-U01-AI-48022, 5-U01-AI-47996, 5-U01-AI-48021, 5-U01-AI-47985, 5-U01-AI-48001, 5-U01-AI-48023, and 5U01AI46725, UM1 AI069481-06, UM1 AI069439, UL1TR000445, UMAI068618-07, AI-069470, and RR-024156, by DHHS/CDC number U62CCU222414, by the Agence Nationale de Recherche sur le SIDA et les Hepatites, Paris, and by Sanofi Pasteur, Swiftwater, PA.; Mary Allen is employed by NIAID, the study sponsor. Several coauthors are current recipients of NIAID funding, and the publication is a result of activities funded by NIAID. Mary Allen was not involved in the process of funding these awards or in their administration or scientific aspects and, in accordance with NIAID policies, is deferred from decisions regarding funding of coauthors for a requisite period. NR 45 TC 2 Z9 2 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD NOV PY 2014 VL 21 IS 11 BP 1589 EP 1599 DI 10.1128/CVI.00450-14 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0UX UT WOS:000344651200017 PM 25253665 ER PT J AU Thomas, A Rajan, A Szabo, E Tomita, Y Carter, CA Scepura, B Lopez-Chavez, A Lee, MJ Redon, CE Frosch, A Peer, CJ Chen, Y Piekarz, R Steinberg, SM Trepel, JB Figg, WD Schrump, DS Giaccone, G AF Thomas, Anish Rajan, Arun Szabo, Eva Tomita, Yusuke Carter, Corey A. Scepura, Barbara Lopez-Chavez, Ariel Lee, Min-Jung Redon, Christophe E. Frosch, Ari Peer, Cody J. Chen, Yuanbin Piekarz, Richard Steinberg, Seth M. Trepel, Jane B. Figg, William D. Schrump, David S. Giaccone, Giuseppe TI A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin, and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical and Translational Study SO CLINICAL CANCER RESEARCH LA English DT Article ID DEACETYLASE INHIBITOR BELINOSTAT; REGULATORY T-CELLS; HISTONE DEACETYLASE; SOLID TUMORS; HISTOLOGIC CLASSIFICATION; INVASIVE THYMOMA; HDAC INHIBITORS; EXPRESSION; DNA; CHEMOTHERAPY AB Purpose: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed. Experimental Design: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. Results: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m(2) belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m(2) with chemotherapy (P, 50 mg/m(2) on day 2; A, 25 mg/m(2) on days 2 and 3; C, 500 mg/m(2) on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%-50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhaustedCD8(+) T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3(+) CD8(+) T cells were larger in responders than nonresponders (P = 0.049). Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3(+) CD8(+) T cells warrant further study. (C) 2014 AACR. C1 [Thomas, Anish; Rajan, Arun; Tomita, Yusuke; Scepura, Barbara; Lopez-Chavez, Ariel; Lee, Min-Jung; Frosch, Ari; Peer, Cody J.; Chen, Yuanbin; Trepel, Jane B.; Figg, William D.; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Szabo, Eva] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Carter, Corey A.] Walter Reed Natl Mil Med Ctr, Dept Hematol & Oncol, Bethesda, MD 20892 USA. [Redon, Christophe E.] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Piekarz, Richard] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Schrump, David S.] NCI, Thorac Surg Sect, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), Georgetown Univ, Lombardi Canc Ctr, Res Bldg Room W503,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM gg496@georgetown.edu RI Figg Sr, William/M-2411-2016; Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 41 TC 23 Z9 24 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2014 VL 20 IS 21 BP 5392 EP 5402 DI 10.1158/1078-0432.CCR-14-0968 PG 11 WC Oncology SC Oncology GA AT2IU UT WOS:000344759100009 PM 25189481 ER PT J AU Mattoo, AR Zhang, JY Espinoza, LA Jessup, JM AF Mattoo, Abid R. Zhang, Jingyu Espinoza, Luis A. Jessup, J. Milburn TI Inhibition of NANOG/NANOGP8 Downregulates MCL-1 in Colorectal Cancer Cells and Enhances the Therapeutic Efficacy of BH3 Mimetics SO CLINICAL CANCER RESEARCH LA English DT Article ID BCL-2 FAMILY-MEMBERS; EMBRYONIC STEM-CELLS; SELF-RENEWAL; NANOG; RESISTANCE; APOPTOSIS; LEUKEMIA; ABT-737; LINES; DEATH AB Purpose: High levels of BCL-2 family members in colorectal carcinoma cause resistance to treatment. Inhibition of NANOG or its paralog NANOGP8 reduces the proliferation, stemness, and tumorigenicity of colorectal carcinoma cells. Our hypothesis was that inhibition of NANOG/NANOGP8 enhances the cytotoxic effect of BH3 mimetics targeting BCL-2 family members in colorectal carcinoma cells through reducing expression of MCL-1, a prosurvival BCL-2 protein. Experimental Design: Lentiviral vector (LV) shRNA to NANOG (shNG-1) or NANOGP8 (shNp8-1) transduced colorectal carcinoma cells that were also exposed to the BH3 mimetics ABT-737 or ABT-199 in vivo in colorectal carcinoma xenografts and in vitro where proliferation, protein and gene expression, and apoptosis were measured. Results: Clone A and CX-1 were sensitive to ABT-737 and ABT-199 at IC50s of 2 to 9 mu mol/L but LS174T was resistant with IC50s of 18 to 30 mu mol/L. Resistance was associated with high MCL-1 expression in LS174T. LVshNG-1 or LVshNp8-1 decreased MCL-1 expression, increased apoptosis, and decreased replating efficiency in colorectal carcinoma cells treated with either ABT-737 or ABT-199 compared with the effects of either BH3 mimetic alone. Inhibition or overexpression of MCL-1 alone replicated the effects of LVshNG-1 or LVshNp8-1 in increasing or decreasing the apoptosis caused with the BH3 mimetic. The combination therapy inhibited the growth of LS174T xenografts in vivo compared with untreated controls or treatment with only LV shRNA or ABT-737. Conclusions: Inhibition of NANOGP8 or NANOGenhances the cytotoxicity of BH3 mimetics that target BCL-2 family members. Gene therapy targeting the NANOGs may increase the efficacy of BH3 mimetics in colorectal carcinoma. (C) 2014 AACR. C1 [Mattoo, Abid R.; Zhang, Jingyu; Espinoza, Luis A.; Jessup, J. Milburn] NCI, Lab Expt Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. [Jessup, J. Milburn] NCI, Canc Diag Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Jessup, JM (reprint author), NCI, 9609 Med Ctr Dr,Room 4W410, Bethesda, MD 20892 USA. EM jessupj@mail.nih.gov OI MATTOO, ABID/0000-0002-4947-0113 FU Center for Cancer Research of the NCI [ZIA BC 011199]; Department of Defense [W81XWH-11-1-0327] FX The authors thank Dr. Snorri Thorgeirsson for helpful comments about improving the manuscript, the valuable advice and support of Drs. Elizabeth Conner and Valentina Factor as well as the outstanding support of the Geneva Foundation, Tacoma, WA, the support provided by the Center for Cancer Research of the NCI for Project ZIA BC 011199, and by the Department of Defense for Grant Number W81XWH-11-1-0327. NR 40 TC 8 Z9 10 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2014 VL 20 IS 21 BP 5446 EP 5455 DI 10.1158/1078-0432.CCR-14-1134 PG 10 WC Oncology SC Oncology GA AT2IU UT WOS:000344759100014 PM 25208882 ER PT J AU Remaley, AT Shamburek, RD Amar, M AF Remaley, Alan T. Shamburek, Robert D. Amar, Marcelo TI The New ACC/AHA Cardiovascular Risk Guidelines: Impact and Controversies SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Remaley, Alan T.; Shamburek, Robert D.; Amar, Marcelo] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov FU Intramural NIH HHS NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD NOV PY 2014 VL 60 IS 11 BP 1365 EP 1367 DI 10.1373/clinchem.2014.224964 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AT2QW UT WOS:000344780100004 PM 24914045 ER PT J AU Vaught, J Abayomi, A Peakman, T Watson, P Matzke, L Moore, H AF Vaught, Jim Abayomi, Akin Peakman, Tim Watson, Peter Matzke, Lise Moore, Helen TI Critical Issues in International Biobanking SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Vaught, Jim] Int Soc Biol & Environm Repositories, Rockville, MD USA. [Abayomi, Akin] Univ Stellenbosch, Div Haematol, Cape Town, South Africa. [Peakman, Tim] UK Biobank, Stockport, Lancs, England. [Watson, Peter] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Watson, Peter] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada. [Matzke, Lise] Univ British Columbia, Dept Pathol & Lab Med, Off Biobank Educ & Res, Vancouver, BC, Canada. [Matzke, Lise] Deeley Res Ctr, Victoria, BC, Canada. [Moore, Helen] US NCI, Biorepositories & Biospecimen Res Branch, Canc Diag Program, Bethesda, MD USA. RP Vaught, J (reprint author), 9609 Med Ctr Dr Rockville, Rockville, MD 20852 USA. EM vaughtj@mail.nih.gov NR 1 TC 6 Z9 6 U1 0 U2 3 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD NOV PY 2014 VL 60 IS 11 BP 1368 EP 1374 DI 10.1373/clinchem.2014.224469 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AT2QW UT WOS:000344780100005 PM 25098414 ER PT J AU Gopal, DM Larson, MG Januzzi, JL Cheng, SS Ghorbani, A Wollert, KC Kempf, T D'Agostino, RB Polak, JF Ramachandran, VS Wang, TJ Ho, JE AF Gopal, Deepa M. Larson, Martin G. Januzzi, James L. Cheng, Susan Ghorbani, Anahita Wollert, Kai C. Kempf, Tibor D'Agostino, Ralph B. Polak, Joseph F. Ramachandran, Vasan S. Wang, Thomas J. Ho, Jennifer E. TI Biomarkers of Cardiovascular Stress and Subclinical Atherosclerosis in the Community SO CLINICAL CHEMISTRY LA English DT Article ID GROWTH-DIFFERENTIATION FACTOR-15; INTIMA-MEDIA THICKNESS; ACUTE CORONARY SYNDROME; CHRONIC KIDNEY-DISEASE; CAROTID-ARTERY INTIMA; MYOCARDIAL-INFARCTION; OLDER-ADULTS; RISK-FACTORS; INHIBITORY CYTOKINE-1; NATRIURETIC PEPTIDE AB BACKGROUND: Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described. METHODS: We measured plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995-1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT >1.5 mm), and mean common carotid artery IMT. We carried out multivariable regressions for carotid measurements vs biomarkers using linear and logistic models; P < 0.0056 was deemed statistically significant. RESULTS: Maximal ICA IMT was significantly associated with plasma GDF-15 [beta-estimate 0.04 per 1-U increase in log(GDF-15), SE 0.01, P < 0.0001]. Similarly, the odds of having carotid plaque increased 33% [odds ratio 1.33 per 1-U increase in log(GDF-15), 95% CI 1.20-1.48, P < 0.0001]. In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the 3 biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together. CONCLUSIONS: Increased GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted. (C) 2014 American Association for Clinical Chemistry C1 [Gopal, Deepa M.; Cheng, Susan] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp,Div Cardiol, Boston, MA USA. [Larson, Martin G.; Cheng, Susan; D'Agostino, Ralph B.; Ramachandran, Vasan S.; Wang, Thomas J.; Ho, Jennifer E.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Larson, Martin G.; Cheng, Susan; D'Agostino, Ralph B.; Ramachandran, Vasan S.; Wang, Thomas J.; Ho, Jennifer E.] Boston Univ, Sch Med, Framingham, MA USA. [Larson, Martin G.; D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Januzzi, James L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. [Ghorbani, Anahita] Mt Auburn Hosp, Dept Med, Boston, MA USA. [Wollert, Kai C.; Kempf, Tibor] Hannover Med Sch, Dept Cardiol & Angiol, Div Mol & Translat Cardiol, Hannover, Germany. [Polak, Joseph F.] Tufts Med Ctr, Dept Radiol, Boston, MA USA. [Ramachandran, Vasan S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ho, Jennifer E.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Wang, Thomas J.] Vanderbilt Univ, Div Med, Div Cardiovasc Med, Nashville, TN 37235 USA. RP Ho, JE (reprint author), Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, 88 East Newton St,C-818, Boston, MA 02118 USA. EM jennifer.ho@bmc.org OI Gopal, Deepa/0000-0003-3534-9360; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; NIH [R00-HL107642, K23-HL116780]; Ellison Foundation; Roche Diagnostics; German Ministry of Education and Research (BMBF, Bio-ChancePlus); National Heart, Lung, and Blood Institute; Boston University School of Medicine Department of Medicine Career Investment Award; Singulex; Critical Diagnostics FX Funded by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195); GDF assays were provided by Roche Diagnostics, Inc. J. Januzzi, Siemens, Thermo Fisher, Singulex, Roche, Critical Diagnostics, the De-Sanctis Clinical Scholar Endowment; S. Cheng, NIH grant R00-HL107642, the Ellison Foundation; K.C. Wollert, Roche Diagnostics, the German Ministry of Education and Research (BMBF, Bio-ChancePlus); R.B. D'Agostino, funded on the Framingham contract by National Heart, Lung, and Blood Institute; T.J. Wang, Singulex, Critical Diagnostics; J.E. Ho, NIH grant K23-HL116780, Boston University School of Medicine Department of Medicine Career Investment Award. NR 40 TC 8 Z9 9 U1 1 U2 7 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD NOV PY 2014 VL 60 IS 11 BP 1402 EP 1408 DI 10.1373/clinchem.2014.227116 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AT2QW UT WOS:000344780100012 PM 25237063 ER PT J AU Acosta, AM Chavez, CB Flores, JT Olotegui, MP Pinedo, SR Trigoso, DR Vasquez, AO Ahmed, I Alam, D Ali, A Bhutta, ZA Qureshi, S Shakoor', S Soofi, S Turab, A Yousafzai, AK Zaidi, AKM Bodhidatta, L Mason, CJ Babji, S Bose, A John, S Kang, G Kurien, B Muliyil, J Raghava, M Ramachandran, A Rose, A Pan, W Ambikapathi, R Carreon, D Charu, V Dabo, L Doan, V Graham, J Hoest, C Knobler, S Lang, D McCormick, B McGrath, M Miller, M Mohale, A Nayyar, G Psaki, S Rasmussen, Z Richard, S Seidman, J Wang, V Blank, R Gottlieb, M Tountas, K Amour, C Mduma, E Ahmed, T Ahmed, AMS Dinesh, M Tofail, F Haque, R Hossain, I Islam, M Mahfuz, M Chandyo, RK Shrestha, PS Shrestha, R Ulak, M Black, R Caulfield, L Checkley, W Chen, P Kosek, M Lee, G Yori, PP Murray-Kolb, L Schaefer, B Pendergast, L Abreu, C Bind, A Costa, H Di Moura, A Filho, JQ Leite, A Lima, A Lima, N Lima, I Maciel, B Moraes, M Mota, F Oria, R Quetz, J Soares, A Svensen, E Tor, S Patil, C Bessong, P Mahopo, C Mapula, A Nesamvuni, C Nyathi, E Samie, A Barrett, L Gratz, J Guerrant, R Houpt, E Olmsted, L Petri, W Platts-Mills, J Scharf, R Shrestha, B Shrestha, SK AF Acosta, Angel Mendez Chavez, Cesar Banda Flores, Julian Torres Olotegui, Maribel Paredes Pinedo, Silvia Rengifo Trigoso, Dixner Rengifo Vasquez, Angel Orbe Ahmed, Imran Alam, Didar Ali, Asad Bhutta, Zulfiqar A. Qureshi, Shahida Shakoor', Sadia Soofi, Sajid Turab, Ali Yousafzai, Aisha K. Zaidi, Anita K. M. Bodhidatta, Ladaporn Mason, Carl J. Babji, Sudhir Bose, Anuradha John, Sushil Kang, Gagandeep Kurien, Beena Muliyil, Jayaprakash Raghava, Mohan Ramachandran, Anup Rose, Anuradha Pan, William Ambikapathi, Ramya Carreon, Danny Charu, Vivek Dabo, Leyfou Doan, Viyada Graham, Jhanelle Hoest, Christel Knobler, Stacey Lang, Dennis McCormick, Benjamin McGrath, Monica Miller, Mark Mohale, Archana Nayyar, Gaurvika Psaki, Stephanie Rasmussen, Zeba Richard, Stephanie Seidman, Jessica Wang, Vivian Blank, Rebecca Gottlieb, Michael Tountas, Karen Amour, Caroline Mduma, Estomih Ahmed, Tahmeed Ahmed, A. M. Shamsir Dinesh, Mondol Tofail, Fahmida Haque, Rashidul Hossain, Iqbal Islam, Munirul Mahfuz, Mustafa Chandyo, Ram Krishna Shrestha, Prakash Sunder Shrestha, Rita Ulak, Manjeswori Black, Robert Caulfield, Laura Checkley, William Chen, Ping Kosek, Margaret Lee, Gwenyth Yori, Pablo Penataro Murray-Kolb, Laura Schaefer, Barbara Pendergast, Laura Abreu, Claudia Bind, Alexandre Costa, Hilda Di Moura, Alessandra Filho, Jose Quirino Leite, Alvaro Lima, Aldo Lima, Noelia Lima, Ila Maciel, Bruna Moraes, Milena Mota, Francisco Oria, Reinaldo Quetz, Josiane Soares, Alberto Svensen, Erling Tor, Strand Patil, Crystal Bessong, Pascal Mahopo, Cloupas Mapula, Angelina Nesamvuni, Cebisa Nyathi, Emanuel Samie, Amidou Barrett, Leah Gratz, Jean Guerrant, Richard Houpt, Eric Olmsted, Liz Petri, William Platts-Mills, James Scharf, Rebecca Shrestha, Binob Shrestha, Sanjaya Kumar CA MAL-ED Network Investigators TI The MAL-ED Study: A Multinational and Multidisciplinary Approach to Understand the Relationship Between Enteric Pathogens, Malnutrition, Gut Physiology, Physical Growth, Cognitive Development, and Immune Responses in Infants and Children Up to 2 Years of Age in Resource-Poor Environments SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE MAL-ED; diarrhea; malnutrition ID BODY PROTEIN-METABOLISM; DEVELOPING-COUNTRIES; RISK-FACTORS; INTESTINAL PERMEABILITY; CHILDHOOD DIARRHEA; NUTRITIONAL-STATUS; PERUVIAN CHILDREN; YOUNG-CHILDREN; CROHNS-DISEASE; LINEAR GROWTH AB Highly prevalent conditions with multiple and complex underlying etiologies are a challenge to public health. Undernutrition, for example, affects 20% of children in the developing world. The cause and consequence of poor nutrition are multifaceted. Undernutrition has been associated with half of all deaths worldwide in children aged <5 years; in addition, its pernicious long-term effects in early childhood have been associated with cognitive and physical growth deficits across multiple generations and have been thought to suppress immunity to further infections and to reduce the efficacy of childhood vaccines. The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED) Study, led by the Fogarty International Center of the National Institutes of Health and the Foundation for the National Institutes of Health, has been established at sites in 8 countries with historically high incidence of diarrheal disease and undernutrition. Central to the study is the hypothesis that enteropathogen infection contributes to undernutrition by causing intestinal inflammation and/or by altering intestinal barrier and absorptive function. It is further postulated that this leads to growth faltering and deficits in cognitive development. The effects of repeated enteric infection and undernutrition on the immune response to childhood vaccines is also being examined in the study. MAL-ED uses a prospective longitudinal design that offers a unique opportunity to directly address a complex system of exposures and health outcomes in the community-rather than the relatively rarer circumstances that lead to hospitalization-during the critical period of development of the first 2 years of life. Among the factors being evaluated are enteric infections (with or without diarrhea) and other illness indicators, micronutrient levels, diet, socioeconomic status, gut function, and the environment. MAL-ED aims to describe these factors, their interrelationships, and their overall impact on health outcomes in unprecedented detail, and to make individual, site-specific, and generalized recommendations regarding the nature and timing of possible interventions aimed at improving child health and development in these resource-poor settings. C1 [Acosta, Angel Mendez; Chavez, Cesar Banda; Flores, Julian Torres; Olotegui, Maribel Paredes; Pinedo, Silvia Rengifo; Trigoso, Dixner Rengifo; Vasquez, Angel Orbe; MAL-ED Network Investigators] AB PRISMA, Iquitos, Peru. [Ahmed, Imran; Alam, Didar; Ali, Asad; Bhutta, Zulfiqar A.; Qureshi, Shahida; Shakoor', Sadia; Soofi, Sajid; Turab, Ali; Yousafzai, Aisha K.; Zaidi, Anita K. M.] Aga Khan Univ, Naushahro Feroze, Pakistan. [Bodhidatta, Ladaporn; Mason, Carl J.] AFRIMS, Bangkok, Thailand. [Babji, Sudhir; Bose, Anuradha; John, Sushil; Kang, Gagandeep; Kurien, Beena; Muliyil, Jayaprakash; Raghava, Mohan; Ramachandran, Anup; Rose, Anuradha] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Pan, William] Duke Univ, Durham, NC USA. [Ambikapathi, Ramya; Carreon, Danny; Charu, Vivek; Dabo, Leyfou; Doan, Viyada; Graham, Jhanelle; Hoest, Christel; Knobler, Stacey; Lang, Dennis; McCormick, Benjamin; McGrath, Monica; Miller, Mark; Mohale, Archana; Nayyar, Gaurvika; Psaki, Stephanie; Rasmussen, Zeba; Richard, Stephanie; Seidman, Jessica; Wang, Vivian] NIH, FIC, Bethesda, MD 20892 USA. [Blank, Rebecca; Gottlieb, Michael; Tountas, Karen] FNIH, Bethesda, MD USA. [Amour, Caroline; Mduma, Estomih; Svensen, Erling] Haydom Lutheran Hosp, Haydom, Tanzania. [Ahmed, Tahmeed; Ahmed, A. M. Shamsir; Dinesh, Mondol; Tofail, Fahmida; Haque, Rashidul; Hossain, Iqbal; Islam, Munirul; Mahfuz, Mustafa] ICDDR B, Dhaka, Bangladesh. [Chandyo, Ram Krishna; Shrestha, Prakash Sunder; Shrestha, Rita; Ulak, Manjeswori] Tribuhvan Univ, IOM, Kathmandu, Nepal. [Black, Robert; Caulfield, Laura; Checkley, William; Chen, Ping; Kosek, Margaret; Lee, Gwenyth; Yori, Pablo Penataro] JHU, Baltimore, MD USA. [Murray-Kolb, Laura; Schaefer, Barbara] Penn State Univ, University Pk, PA 16802 USA. [Pendergast, Laura] Temple Univ, Philadelphia, PA 19122 USA. [Abreu, Claudia; Bind, Alexandre; Costa, Hilda; Di Moura, Alessandra; Filho, Jose Quirino; Leite, Alvaro; Lima, Aldo; Lima, Noelia; Lima, Ila; Maciel, Bruna; Moraes, Milena; Mota, Francisco; Oria, Reinaldo; Quetz, Josiane; Soares, Alberto] Univ Fed Ceara, Fortaleza, Ceara, Brazil. [Svensen, Erling; Tor, Strand] Univ Bergen, N-5020 Bergen, Norway. [Patil, Crystal] Univ Illinois, Urbana, IL 61801 USA. [Bessong, Pascal; Mahopo, Cloupas; Mapula, Angelina; Nesamvuni, Cebisa; Nyathi, Emanuel; Samie, Amidou] Univ Venda, Thohoyandou, South Africa. [Barrett, Leah; Gratz, Jean; Guerrant, Richard; Houpt, Eric; Olmsted, Liz; Petri, William; Platts-Mills, James; Scharf, Rebecca] UVA, Charlottesville, VA USA. [Shrestha, Binob; Shrestha, Sanjaya Kumar] Walter Reed AFRIMS Res Unit, Kathmandu, Nepal. RP Miller, M (reprint author), Fogarty Int Ctr, 16 Ctr Dr,MSC 6705, Bethesda, MD 20892 USA. EM millemar@mail.nih.gov RI Strand, Tor/D-9836-2016 OI Strand, Tor/0000-0002-4038-151X FU Bill & Melinda Gates Foundation; Foundation for the NIH; National Institutes of Health, Fogarty International Center FX The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the NIH, and the National Institutes of Health, Fogarty International Center. NR 93 TC 3 Z9 4 U1 6 U2 29 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 NOV 1 PY 2014 VL 59 SU 4 BP S193 EP S206 DI 10.1093/cid/ciu653 PG 14 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400001 ER PT J AU Caulfield, LE Bose, A Chandyo, RK Nesamvuni, C de Moraes, ML Turab, A Patil, C Mahfuz, M Ambikapathi, R Ahmed, T AF Caulfield, Laura E. Bose, Anuradha Chandyo, Ram Krishna Nesamvuni, Cebisa de Moraes, Milena Lima Turab, Ali Patil, Crystal Mahfuz, Mustafa Ambikapathi, Ramya Ahmed, Tahmeed CA MAL-ED Network Investigators TI Infant Feeding Practices, Dietary Adequacy, and Micronutrient Status Measures in the MAL-ED Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE dietary intake; infant feeding; MAL-ED; micronutrients ID CHILD-DEVELOPMENT; IRON INTERVENTIONS; VITAMIN-A; DEFICIENCY; UNDERNUTRITION; VALIDATION; INDICATORS AB The overall goal of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study is to evaluate the roles of repeated enteric infection and poor dietary intakes on the development of malnutrition, poor cognitive development, and diminished immune response. The use of 8 distinct sites for data collection from Latin America, sub-Saharan Africa, and South Asia allow for an examination of these relationships across different environmental contexts. Key to testing study hypotheses is the collection of appropriate data to characterize the dietary intakes and nutritional status of study children from birth through 24 months of age. The focus of the current article is on the collection of data to describe the nature and adequacy of infant feeding, energy and nutrient intakes, and the chosen indicators to capture micronutrient status in children over time. C1 [Caulfield, Laura E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. [Bose, Anuradha] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Chandyo, Ram Krishna] Univ Bergen, Ctr Int Hlth, N-5020 Bergen, Norway. [Chandyo, Ram Krishna] Tribhuvan Univ, Inst Med, Dept Child Hlth, Kathmandu, Nepal. [Nesamvuni, Cebisa] Univ Venda, Sch Hlth Sci, Dept Nutr, Thohoyandou, South Africa. [de Moraes, Milena Lima] Univ Estadual Ceara, Dept Nutr, Fortaleza, Ceara, Brazil. [Turab, Ali] Aga Khan Univ, Dept Paediat & Child Hlth, Karachi, Pakistan. [Patil, Crystal] Univ Illinois, Dept Anthropol, Chicago, IL USA. [Mahfuz, Mustafa; Ahmed, Tahmeed] Icddr B, Dhaka, Bangladesh. [Ambikapathi, Ramya] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Caulfield, LE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, 615 N Wolfe St,W2041, Baltimore, MD 21205 USA. EM lcaulfie@jhsph.edu RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; Mohan, Venkata Raghava/0000-0001-5787-7223; Kang, Gagandeep/0000-0002-3656-564X; Lima de Moraes, Milena/0000-0003-1222-8400 FU Bill & Melinda Gates Foundation; Foundation for the National Institutes of Health; National Institutes of Health/Fogarty International Center FX The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the National Institutes of Health/Fogarty International Center. NR 41 TC 6 Z9 7 U1 2 U2 12 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 NOV 1 PY 2014 VL 59 SU 4 BP S248 EP S254 DI 10.1093/cid/ciu421 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400008 PM 25305294 ER PT J AU Hoest, C Seidman, JC Pan, W Ambikapathi, R Kang, G Kosek, M Knobler, S Mason, CJ Miller, M AF Hoest, Christel Seidman, Jessica C. Pan, William Ambikapathi, Ramya Kang, Gagandeep Kosek, Margaret Knobler, Stacey Mason, Carl J. Miller, Mark CA MAL-ED Network Investigators TI Evaluating Associations Between Vaccine Response and Malnutrition, Gut Function, and Enteric Infections in the MAL-ED Cohort Study: Methods and Challenges SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE vaccines; malnutrition; enteric infections; gut function; MAL-ED ID ORAL ROTAVIRUS VACCINES; ANTIBODY-RESPONSES; POLIO VACCINATION; IMMUNE-SYSTEM; BREAST-MILK; MEASLES; CHILDREN; PROTECTION; COUNTRIES AB Most vaccine assessments have occurred in well-nourished populations of higher socioeconomic status. However, vaccines are often used in populations with high incidences of malnutrition and infections, in whom the effectiveness of some vaccines is inferior for unknown reasons. The degree and extent of vaccine underperformance have not been systematically studied for most vaccines across differing epidemiologic settings. This paper outlines the methods used and challenges associated with measuring immunological responses to oral vaccines against poliovirus and rotavirus, and parenteral vaccines against pertussis, tetanus, and measles in an observational study that monitored daily illness, monthly growth, intestinal inflammation and permeability, pathogen burden, dietary intake, and micronutrient status in children in 8 countries. This evaluation of vaccine response in the context of low- and middle-income countries is intended to address the gaps in knowledge of the heterogeneity in vaccine response in diverse epidemiological settings and the interplay between infections, nutrition, and immune response. C1 [Hoest, Christel; Seidman, Jessica C.; Ambikapathi, Ramya; Knobler, Stacey; Miller, Mark] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pan, William] Duke Univ, Dept Environm Sci & Policy, Durham, NC USA. [Pan, William] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Kang, Gagandeep] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Kosek, Margaret] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Mason, Carl J.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. RP Miller, M (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. EM millemar@mail.nih.gov RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; Mohan, Venkata Raghava/0000-0001-5787-7223; Kang, Gagandeep/0000-0002-3656-564X; Lima de Moraes, Milena/0000-0003-1222-8400 FU Bill & Melinda Gates Foundation; Foundation for the National Institutes of Health; National Institutes of Health, Fogarty International Center FX The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the National Institutes of Health, Fogarty International Center. NR 44 TC 7 Z9 7 U1 2 U2 10 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 NOV 1 PY 2014 VL 59 SU 4 BP S273 EP S279 DI 10.1093/cid/ciu611 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400011 PM 25305297 ER PT J AU Houpt, E Gratz, J Kosek, M Zaidi, AKM Qureshi, S Kang, G Babji, S Mason, C Bodhidatta, L Samie, A Bessong, P Barrett, L Lima, A Havt, A Haque, R Mondal, D Taniuchi, M Stroup, S McGrath, M Lang, D AF Houpt, Eric Gratz, Jean Kosek, Margaret Zaidi, Anita K. M. Qureshi, Shahida Kang, Gagandeep Babji, Sudhir Mason, Carl Bodhidatta, Ladaporn Samie, Amidou Bessong, Pascal Barrett, Leah Lima, Aldo Havt, Alexandre Haque, Rashidul Mondal, Dinesh Taniuchi, Mami Stroup, Suzanne McGrath, Monica Lang, Dennis CA MAL-ED Network Investigators TI Microbiologic Methods Utilized in the MAL-ED Cohort Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE culture; ELISA; enteropathogen; microscopy; PCR ID DIARRHEAGENIC ESCHERICHIA-COLI; HELICOBACTER-PYLORI INFECTION; DEVELOPING-COUNTRIES; INTESTINAL PERMEABILITY; YOUNG-CHILDREN; ENZYME-IMMUNOASSAY; HELMINTH INFECTION; COGNITIVE FUNCTION; GROWTH IMPAIRMENT; PERUVIAN CHILDREN AB A central hypothesis of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study is that enteropathogens contribute to growth faltering. To examine this question, the MAL-ED network of investigators set out to achieve 3 goals: (1) develop harmonized protocols to test for a diverse range of enteropathogens, (2) provide quality-assured and comparable results from 8 global sites, and (3) achieve maximum laboratory throughput and minimum cost. This paper describes the rationale for the microbiologic assays chosen and methodologies used to accomplish the 3 goals. C1 [Houpt, Eric; Gratz, Jean; Barrett, Leah; Taniuchi, Mami; Stroup, Suzanne] Univ Virginia, Charlottesville, VA 22908 USA. [Kosek, Margaret] Johns Hopkins Univ, Baltimore, MD USA. [Zaidi, Anita K. M.; Qureshi, Shahida] Aga Khan Univ, Naushahro Feroze, Pakistan. [Kang, Gagandeep; Babji, Sudhir] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Mason, Carl; Bodhidatta, Ladaporn] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Samie, Amidou; Bessong, Pascal] Univ Venda, Thohoyandou, South Africa. [Lima, Aldo; Havt, Alexandre] Univ Fed Ceara, Fortaleza, Ceara, Brazil. [Haque, Rashidul; Mondal, Dinesh] Icddr B, Dhaka, Bangladesh. [McGrath, Monica; Lang, Dennis] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lang, Dennis] Fdn Natl Inst Hlth, Bethesda, MD USA. RP Houpt, E (reprint author), Univ Virginia, Div Infect Dis & Int Hlth, 345 Crispell Dr,MR6 Bldg 1716, Charlottesville, VA 22908 USA. EM erh6k@virginia.edu RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; Mohan, Venkata Raghava/0000-0001-5787-7223 FU Bill & Melinda Gates Foundation; Foundation for the National Institutes of Health; National Institutes of Health, Fogarty International Center FX The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation; the Foundation for the National Institutes of Health; and the National Institutes of Health, Fogarty International Center. NR 42 TC 13 Z9 14 U1 1 U2 9 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 NOV 1 PY 2014 VL 59 SU 4 BP S225 EP S232 DI 10.1093/cid/ciu413 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400005 PM 25305291 ER PT J AU Kosek, M Guerrant, RL Kang, G Bhutta, Z Yori, PP Gratz, J Gottlieb, M Lang, D Lee, G Haque, R Mason, CJ Ahmed, T Lima, A Petri, WA Houpt, E Olortegui, MP Seidman, JC Mduma, E Samie, A Babji, S AF Kosek, Margaret Guerrant, Richard L. Kang, Gagandeep Bhutta, Zulfiqar Penataro Yori, Pablo Gratz, Jean Gottlieb, Michael Lang, Dennis Lee, Gwenyth Haque, Rashidul Mason, Carl J. Ahmed, Tahmeed Lima, Aldo Petri, William A. Houpt, Eric Paredes Olortegui, Maribel Seidman, Jessica C. Mduma, Estomih Samie, Amidou Babji, Sudhir CA MAL-ED Network Investigators TI Assessment of Environmental Enteropathy in the MAL-ED Cohort Study: Theoretical and Analytic Framework SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE environmental enteropathy; infant growth failure; intestinal infections; lactulose mannitol test; tropical enteropathy ID INTESTINAL PERMEABILITY PROBES; AUTOMATED ENZYMATIC ASSAYS; CHILD UNDERNUTRITION; BARRIER FUNCTION; GAMBIAN INFANTS; CHOLERA VACCINE; GROWTH; LACTULOSE; MANNITOL; MALNUTRITION AB Individuals in the developing world live in conditions of intense exposure to enteric pathogens due to suboptimal water and sanitation. These environmental conditions lead to alterations in intestinal structure, function, and local and systemic immune activation that are collectively referred to as environmental enteropathy EE). This condition, although poorly defined, is likely to be exacerbated by undernutrition as well as being responsible for permanent growth deficits acquired in early childhood, vaccine failure, and loss of human potential. This article addresses the underlying theoretical and analytical frameworks informing the methodology proposed by the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development MAL-ED) cohort study to define and quantify the burden of disease caused by EE within a multisite cohort. Additionally, we will discuss efforts to improve, standardize, and harmonize laboratory practices within the MAL-ED Network. These efforts will address current limitations in the understanding of EE and its burden on children in the developing world. C1 [Kosek, Margaret; Penataro Yori, Pablo; Lee, Gwenyth; Paredes Olortegui, Maribel] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Kosek, Margaret; Penataro Yori, Pablo; Lee, Gwenyth; Paredes Olortegui, Maribel] Asociac Benef PRISMA, Iquitos, Peru. [Guerrant, Richard L.; Gratz, Jean; Petri, William A.; Houpt, Eric] Univ Virginia, Ctr Global Hlth, Charlottesville, VA USA. [Kang, Gagandeep; Babji, Sudhir] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Bhutta, Zulfiqar] Aga Khan Univ, Dept Pediat & Child Hlth, Karachi, Pakistan. [Gottlieb, Michael; Lang, Dennis] Fdn Natl Inst Hlth, Bethesda, MD USA. [Lang, Dennis; Seidman, Jessica C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Haque, Rashidul; Ahmed, Tahmeed] Iccdr B, Ctr Vaccine Sci, Dhaka, Bangladesh. [Mason, Carl J.] Walter Reed Armed Forces Res Inst Med Sci, Res Unit, Bangkok, Thailand. [Lima, Aldo] Univ Fed Ceara, Fortaleza, Ceara, Brazil. [Mduma, Estomih] Haydom Lutheran Hosp, Manraya, Tanzania. [Samie, Amidou] Univ Venda, Thohoyandou, Limpopo Provinc, South Africa. RP Kosek, M (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, 615 N Wolfe St E5545, Baltimore, MD 21205 USA. EM mkosek@jhsph.edu RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; Mohan, Venkata Raghava/0000-0001-5787-7223; Kang, Gagandeep/0000-0002-3656-564X FU Bill & Melinda Gates Foundation; Foundation for the National Institutes of Health; National Institutes of Health, Fogarty International Center FX The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the National Institutes of Health, Fogarty International Center. NR 44 TC 25 Z9 26 U1 1 U2 17 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 NOV 1 PY 2014 VL 59 SU 4 BP S239 EP S247 DI 10.1093/cid/ciu457 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400007 PM 25305293 ER PT J AU Murray-Kolb, LE Rasmussen, ZA Scharf, RJ Rasheed, MA Svensen, E Seidman, JC Tofail, F Koshy, B Shrestha, R Maphula, A Vasquez, AO da Costa, HP Yousafzai, AK Oria, RB Roshan, R Bayyo, EB Kosek, M Shrestha, S Schaefer, BA Bessong, P Ahmed, T Lang, D AF Murray-Kolb, Laura E. Rasmussen, Zeba A. Scharf, Rebecca J. Rasheed, Muneera A. Svensen, Erling Seidman, Jessica C. Tofail, Fahmida Koshy, Beena Shrestha, Rita Maphula, Angelina Orbe Vasquez, Angel da Costa, Hilda P. Yousafzai, Aisha K. Oria, Reinaldo B. Roshan, Reeba Bayyo, Eliwasa B. Kosek, Margaret Shrestha, Sanjaya Schaefer, Barbara A. Bessong, Pascal Ahmed, Tahmeed Lang, Dennis CA MAL-ED Network Investigators TI The MAL-ED Cohort Study: Methods and Lessons Learned When Assessing Early Child Development and Caregiving Mediators in Infants and Young Children in 8 Low- and Middle-Income Countries SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE child; cognitive development; infant; low- and middle-income countries; methods ID POSTNATAL DEPRESSION; ZINC SUPPLEMENTATION; IRON-DEFICIENCY; BEHAVIOR QUESTIONNAIRE; COGNITIVE-DEVELOPMENT; PROGRESSIVE MATRICES; LANGUAGE-DEVELOPMENT; MATERNAL DEPRESSION; SCHOOL-ACHIEVEMENT; TEST SELECTION AB More epidemiological data are needed on risk and protective factors for child development. In The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study, we assessed child development in a harmonious manner across 8 sites in Bangladesh, Brazil, India, Nepal, Pakistan, Peru, South Africa, and Tanzania. From birth to 24 months, development and language acquisition were assessed via the Bayley Scales of Infant and Toddler Development and a modified MacArthur Communicative Development Inventory. Other measures were infant temperament, the child's environment, maternal psychological adjustment, and maternal reasoning abilities. We developed standard operating procedures and used multiple techniques to ensure appropriate adaptation and quality assurance across the sites. Test adaptation required significant time and human resources but is essential for data quality; funders should support this step in future studies. At the end of this study, we will have a portfolio of culturally adapted instruments for child development studies with examination of psychometric properties of each tool used. C1 [Murray-Kolb, Laura E.; Schaefer, Barbara A.] Penn State Univ, University Pk, PA 16802 USA. [Rasmussen, Zeba A.; Seidman, Jessica C.; Lang, Dennis] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Scharf, Rebecca J.] Univ Virginia, Charlottesville, VA USA. [Rasheed, Muneera A.; Yousafzai, Aisha K.] Aga Khan Univ, Karachi, Pakistan. [Svensen, Erling] Univ Bergen, N-5020 Bergen, Norway. [Svensen, Erling; Bayyo, Eliwasa B.] Haydom Lutheran Hosp, Haydom, Tanzania. [Tofail, Fahmida] Icddr B, Dhaka, Bangladesh. [Koshy, Beena; Roshan, Reeba; Ahmed, Tahmeed] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Shrestha, Rita; Shrestha, Sanjaya] Inst Med, Kathmandu, Nepal. [Maphula, Angelina; Bessong, Pascal] Univ Venda, Thohoyandou, South Africa. [Orbe Vasquez, Angel; Kosek, Margaret] Asociac Benef PRISMA, Iquitos, Peru. [Orbe Vasquez, Angel; Kosek, Margaret] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [da Costa, Hilda P.; Oria, Reinaldo B.] Univ Fed Ceara, Fortaleza, Ceara, Brazil. [Lang, Dennis] Fdn Natl Inst Hlth, Bethesda, MD USA. RP Murray-Kolb, LE (reprint author), Penn State Univ, 219 Chandlee Lab, University Pk, PA 16802 USA. EM lem118@psu.edu RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; Mohan, Venkata Raghava/0000-0001-5787-7223; Bessong, Pascal/0000-0003-0561-272X; Kang, Gagandeep/0000-0002-3656-564X FU Bill & Melinda Gates Foundation; Foundation for the National Institutes of Health; National Institutes of Health, Fogarty International Center FX The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the National Institutes of Health, Fogarty International Center. NR 75 TC 8 Z9 8 U1 6 U2 13 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 NOV 1 PY 2014 VL 59 SU 4 BP S261 EP S272 DI 10.1093/cid/ciu437 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400010 PM 25305296 ER PT J AU Platts-Mills, JA McCormick, BJJ Kosek, M Pan, WK Checkley, W Houpt, ER AF Platts-Mills, James A. McCormick, Benjamin J. J. Kosek, Margaret Pan, William K. Checkley, William Houpt, Eric R. CA MAL-ED Network Investigators TI Methods of Analysis of Enteropathogen Infection in the MAL-ED Cohort Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE birth cohort study; enteropathogens; diarrhea etiology; growth; MAL-ED ID GLOBAL ENTERIC MULTICENTER; POLYMERASE-CHAIN-REACTION; MULTIPLE RISK-FACTORS; DEVELOPING-COUNTRIES; DIARRHEAL DISEASE; PERUVIAN CHILDREN; CAMPYLOBACTER INFECTIONS; SYSTEMATIC ANALYSIS; INTESTINAL DISEASE; YOUNG-CHILDREN AB Studies of diarrheal etiology in low- and middle-income countries have typically focused on children presenting with severe symptoms to health centers and thus are best equipped to describe the pathogens capable of leading to severe diarrheal disease. The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study was designed to evaluate, via intensive community surveillance, the hypothesis that repeated exposure to enteropathogens has a detrimental effect on growth, vaccine response, and cognitive development, which are the primary outcome measures for this study. In the setting of multiple outcomes of interest, a longitudinal cohort design was chosen. Because many or even the majority of enteric infections are asymptomatic, the collection of asymptomatic surveillance stools was a critical element. However, capturing diarrheal stools additionally allowed for the determination of the principle causes of diarrhea at the community level as well as for a comparison between those enteropathogens associated with diarrhea and those that are associated with poor growth, diminished vaccine response, and impaired cognitive development. Here, we discuss the analytical methods proposed for the MAL-ED study to determine the principal causes of diarrhea at the community level and describe the complex interplay between recurrent exposure to enteropathogens and these critical long-term outcomes. C1 [Platts-Mills, James A.; Houpt, Eric R.] Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. [McCormick, Benjamin J. J.; Checkley, William] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Kosek, Margaret; Checkley, William] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Kosek, Margaret] Asociac Benef PRISMA, Iquitos, Peru. [Pan, William K.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. RP Houpt, ER (reprint author), Univ Virginia, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. EM erh6k@virginia.edu RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; Mohan, Venkata Raghava/0000-0001-5787-7223 FU Bill & Melinda Gates Foundation; Foundation for the NIH; NIH Fogarty International Center FX The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation; the Foundation for the NIH; and the NIH Fogarty International Center. NR 48 TC 9 Z9 9 U1 2 U2 10 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 NOV 1 PY 2014 VL 59 SU 4 BP S233 EP S238 DI 10.1093/cid/ciu408 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400006 PM 25305292 ER PT J AU Richard, SA McCormick, BJJ Miller, MA Caulfield, LE Checkley, W AF Richard, Stephanie A. McCormick, Benjamin J. J. Miller, Mark A. Caulfield, Laura E. Checkley, William CA MAL-ED Network Investigators TI Modeling Environmental Influences on Child Growth in the MAL-ED Cohort Study: Opportunities and Challenges SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE diarrhea; growth; MAL-ED; malnutrition; stunting ID HEAD CIRCUMFERENCE; ETHNIC-DIFFERENCES; LONGITUDINAL DATA; LINEAR GROWTH; CATCH-UP; DIARRHEA; WEIGHT; LENGTH; UNDERNUTRITION; PATTERNS AB Although genetics, maternal undernutrition and low birth weight status certainly play a role in child growth, dietary insufficiency and infectious diseases are key risk factors for linear growth faltering during early childhood. A primary goal of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study is to identify specific risk factors associated with growth faltering during the first 2 years of life; however, growth in early childhood is challenging to characterize because growth may be inherently nonlinear with age. In this manuscript, we describe some methods for analyzing longitudinal growth to evaluate both short- and long-term associations between risk factors and growth trajectories over the first 2 years of life across 8 resource-limited settings using harmonized protocols. We expect there will be enough variability within and between sites in the prevalence of risk factors and burden of linear growth faltering to allow us to distinguish some of the key pathways to linear growth faltering in the MAL-ED study. C1 [Richard, Stephanie A.; McCormick, Benjamin J. J.; Miller, Mark A.; Checkley, William] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Caulfield, Laura E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Program Human Nutr, Baltimore, MD USA. [Checkley, William] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Program Global Dis Epidemiol & Control, Baltimore, MD USA. RP Richard, SA (reprint author), Fogarty Int Ctr, Bldg 16,Rm 202,16 Ctr Dr, Bethesda, MD 20892 USA. EM richardst@mail.nih.gov RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; Mohan, Venkata Raghava/0000-0001-5787-7223 FU Bill & Melinda Gates Foundation; Foundation for the National Institutes of Health; National Institutes of Health, Fogarty International Center FX The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the National Institutes of Health, Fogarty International Center. M. M. was supported by the National Institutes of Health, Fogarty International Center. NR 37 TC 10 Z9 10 U1 0 U2 4 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 NOV 1 PY 2014 VL 59 SU 4 BP S255 EP S260 DI 10.1093/cid/ciu436 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400009 PM 25305295 ER PT J AU Richard, SA Barrett, LJ Guerrant, RL Checkley, W Miller, MA AF Richard, Stephanie A. Barrett, Leah J. Guerrant, Richard L. Checkley, William Miller, Mark A. CA MAL-ED Network Investigators TI Disease Surveillance Methods Used in the 8-Site MAL-ED Cohort Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE diarrhea; infectious disease; MAL-ED; respiratory infection; surveillance ID EARLY-CHILDHOOD DIARRHEA; CATCH-UP GROWTH; PERUVIAN CHILDREN; RURAL BANGLADESH; DEVELOPING-COUNTRIES; LINEAR GROWTH; WEIGHT-GAIN; MALNUTRITION; ASSOCIATION; INFECTION AB Describing the early life associations between infectious disease episodes and growth, cognitive development, and vaccine response in the first 2 years of life is one of the primary goals of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. To collect high-resolution data during a critical early period of development, field staff visit each study participant at their house twice weekly from birth to 2 years of age to collect daily reported illness and treatment data from caregivers. Detailed infectious disease histories will not only allow us to relate the overall burden of infectious disease with the primary outcomes of the study, but will also allow us to describe the ages at which infectious diseases have the greatest effect on child health. In addition, twice-weekly visits allow for sample collection when diarrhea episodes are identified. This article describes the methods used to collect illness and treatment history data and discusses the a priori definitions of diarrhea and acute lower respiratory illness episodes. C1 [Richard, Stephanie A.; Checkley, William; Miller, Mark A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Barrett, Leah J.; Guerrant, Richard L.] Univ Virginia, Sch Med, Ctr Global Hlth, Charlottesville, VA 22908 USA. [Checkley, William] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Program Global Dis Epidemiol & Control, Baltimore, MD USA. RP Richard, SA (reprint author), Fogarty Int Ctr, Bldg16,Rm 202,16 Ctr Dr, Bethesda, MD 20892 USA. EM richardst@mail.nih.gov RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; Mohan, Venkata Raghava/0000-0001-5787-7223 FU Bill & Melinda Gates Foundation; Foundation for the National Institutes of Health; National Institutes of Health, Fogarty International Center FX The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the National Institutes of Health, Fogarty International Center. M. M. was supported by the National Institutes of Health, Fogarty International Center. NR 38 TC 11 Z9 11 U1 0 U2 4 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 NOV 1 PY 2014 VL 59 SU 4 BP S220 EP S224 DI 10.1093/cid/ciu435 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TJ UT WOS:000344647400004 PM 25305290 ER PT J AU Cashion, AK Hathaway, DK Stanfill, A Thomas, F Ziebarth, JD Cui, Y Cowan, PA Eason, J AF Cashion, A. K. Hathaway, D. K. Stanfill, A. Thomas, F. Ziebarth, J. D. Cui, Y. Cowan, P. A. Eason, J. TI Pre-transplant predictors of one yr weight gain after kidney transplantation SO CLINICAL TRANSPLANTATION LA English DT Article DE activity; Bayesian network modeling; diet; kidney transplant; obesity; weight gain ID RENAL-TRANSPLANTATION; CARDIOVASCULAR RISK; RECIPIENTS; OBESITY AB Clinically useful predictors of weight gain could be used to reduce the epidemic of post-kidney transplant obesity and resulting co-morbidities. The purpose of this study was to identify predictors of weight gain at 12 months following kidney transplant in a cohort of 96 recipients. Demographic, clinical, and environmental data were obtained at transplant and 12 months. Descriptive, correlational, and Bayesian network analysis were used to identify predictors. For the 52 (55.9%) recipients who gained weight, the average amount gained was 9.18 +/- 6.59kg. From the 15 baseline factors that met inclusion criteria, Bayesian network modeling identified four baseline predictors for weight gain: younger age, higher carbohydrate consumption, higher trunk fat percentage, and higher perception of mental health quality of life. Three are modifiable through either pre- or immediate post-transplant clinical intervention programs. C1 [Cashion, A. K.] NIH, Natl Inst Nursing Res, Bethesda, MD 20892 USA. [Cashion, A. K.; Hathaway, D. K.; Stanfill, A.; Thomas, F.; Ziebarth, J. D.; Cui, Y.; Cowan, P. A.; Eason, J.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Eason, J.] Methodist Univ Hosp, Transplant Inst, Memphis, TN USA. RP Cashion, AK (reprint author), 3 Ctr Dr,Bldg 3,RM 5E28, Bethesda, MD 20892 USA. EM Ann.cashion@nih.gov FU National Institutes of Health/National Institute of Nursing Research [R01NR009270, 3R01NR009270-03S2] FX The authors would like to acknowledge the National Institutes of Health/National Institute of Nursing Research for funding R01NR009270 and 3R01NR009270-03S2. Our research associates Robin Bloodworth and Deborah Gibson were instrumental in recruiting and retaining our subjects and managing our database. NR 25 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-0063 EI 1399-0012 J9 CLIN TRANSPLANT JI Clin. Transplant. PD NOV PY 2014 VL 28 IS 11 BP 1271 EP 1278 DI 10.1111/ctr.12456 PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA AT3SX UT WOS:000344854900008 PM 25159302 ER PT J AU Nair, AK Muller, YL McLean, NA Abdussamad, M Piaggi, P Kobes, S Weil, EJ Curtis, JM Nelson, RG Knowler, WC Hanson, RL Baier, LJ AF Nair, Anup K. Muller, Yunhua Li McLean, Nellie A. Abdussamad, Maryam Piaggi, Paolo Kobes, Sayuko Weil, E. Jennifer Curtis, Jeffrey M. Nelson, Robert G. Knowler, William C. Hanson, Robert L. Baier, Leslie J. TI Variants associated with type 2 diabetes identified by the transethnic meta-analysis study: assessment in American Indians and evidence for a new signal in LPP SO DIABETOLOGIA LA English DT Article DE American Indians; ARL15; FAF1; GWAS; LPP; MPHOSPH9; POU5F1-TCF19; SSR1-RREB1; Trans-ancestry meta-analysis; Type 2 diabetes ID PIMA-INDIANS; SUSCEPTIBILITY AB Aim/hypothesis A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians. Methods Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed. Previous genome-wide association study (GWAS) data from these individuals were used to screen for additional type 2 diabetes signals at these loci. A variant independent of the trans-ancestry meta-analysis was identified within LPP, and its replication was assessed in an additional 3,106 urban American Indians. Results SNP rs6813195 near to TMEM154 was nominally associated with type 2 diabetes (p=0.01, OR 1.12 [95% CI 1.03, 1.22]) and adiposity: the type 2 diabetes risk allele was associated with a lower percentage body fat (beta=-1.451%, p=4.8 x 10(-4)). Another SNP, rs3130501 near to POU5F1TCF19, was associated with BMI (beta=-0.012, p=0.004), type 2 diabetes adjusted for BMI (p=0.02, OR 1.11 [95% CI 1.02, 1.22]), 2 h glucose concentrations (beta=0.080 mmol/l, p=0.02) and insulin resistance estimated by homeostatic model (beta=0.039, p=0.009). The independent variant identified at the LPP locus in our American Indian GWAS for type 2 diabetes was replicated in the additional samples (all American Indian meta-analysis, p=8.9 x 10(-6), OR 1.29 [95% CI 1.15, 1.45]). Conclusions/interpretation For two of the seven newly identified variants, there was nominal evidence for association with type 2 diabetes and related traits in American Indians. Identification of an independent variant at the LPP locus suggests the existence of more than one type 2 diabetes signal at this locus. C1 [Nair, Anup K.; Muller, Yunhua Li; McLean, Nellie A.; Abdussamad, Maryam; Piaggi, Paolo; Kobes, Sayuko; Weil, E. Jennifer; Curtis, Jeffrey M.; Nelson, Robert G.; Knowler, William C.; Hanson, Robert L.; Baier, Leslie J.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85004 USA. RP Baier, LJ (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, 445 North 5th St, Phoenix, AZ 85004 USA. EM lbaier@phx.niddk.nih.gov OI Piaggi, Paolo/0000-0003-2774-9161 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX The study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 10 TC 2 Z9 2 U1 3 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD NOV PY 2014 VL 57 IS 11 BP 2334 EP 2338 DI 10.1007/s00125-014-3351-4 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT0MN UT WOS:000344630300010 PM 25112377 ER PT J AU Kim, KS Egan, JM Jang, HJ AF Kim, Ki-Suk Egan, Josephine M. Jang, Hyeung-Jin TI Denatonium induces secretion of glucagon-like peptide-1 through activation of bitter taste receptor pathways (vol 57, pg 2117, 2014) SO DIABETOLOGIA LA English DT Correction C1 [Kim, Ki-Suk; Jang, Hyeung-Jin] Kyung Hee Univ, Coll Korean Med, Dept Biochem, Seoul 130701, South Korea. [Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. RP Jang, HJ (reprint author), Kyung Hee Univ, Coll Korean Med, Dept Biochem, Seoul 130701, South Korea. EM hjjang@khu.ac.kr NR 1 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD NOV PY 2014 VL 57 IS 11 BP 2428 EP 2428 DI 10.1007/s00125-014-3363-0 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT0MN UT WOS:000344630300023 ER PT J AU Finnegan, LP AF Finnegan, Loretta P. TI NEONATAL OPIOID ABSTINENCE SYNDROME-2014 SO DRUG AND ALCOHOL REVIEW LA English DT Meeting Abstract C1 [Finnegan, Loretta P.] Finnegan Consulting LLC, Avalon, NJ USA. [Finnegan, Loretta P.] NIH, Off Res Womens Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM finnegal337@aol.com NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0959-5236 EI 1465-3362 J9 DRUG ALCOHOL REV JI Drug Alcohol Rev. PD NOV PY 2014 VL 33 SU S1 SI SI BP 2 EP 2 PG 1 WC Substance Abuse SC Substance Abuse GA AT4NA UT WOS:000344914800007 ER PT J AU Sadath, A Muralidhar, D Varambally, S AF Sadath, Anvar Muralidhar, D. Varambally, Shivarama TI Caregivers experience in first episode psychosis: a qualitative study SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Meeting Abstract C1 [Sadath, Anvar; Muralidhar, D.; Varambally, Shivarama] Natl Inst Mental Hlth & Neurosci, Philadelphia, IN USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-7885 EI 1751-7893 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD NOV PY 2014 VL 8 SU 1 SI SI MA B34 BP 106 EP 106 PG 1 WC Psychiatry SC Psychiatry GA AT2SM UT WOS:000344785700392 ER PT J AU Kim, SN Jo, HJ Lee, TY Jang, JH Kwon, JS AF Kim, Sung Nyun Jo, Hang Joon Lee, Tae Young Jang, Joon Hwan Kwon, Jun Soo TI Functional interhemispheric asymmetry of resting state brain controlling anatomical asymmetry in schizophrenia SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Meeting Abstract C1 [Kim, Sung Nyun; Jang, Joon Hwan; Kwon, Jun Soo] Seoul Natl Univ Hosp, Seoul 110744, South Korea. [Jo, Hang Joon] NIMH, Bethesda, MD 20892 USA. [Lee, Tae Young; Kwon, Jun Soo] SNU MRC, Inst Human Behav Med, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-7885 EI 1751-7893 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD NOV PY 2014 VL 8 SU 1 SI SI MA B54 BP 112 EP 112 PG 1 WC Psychiatry SC Psychiatry GA AT2SM UT WOS:000344785700412 ER PT J AU Sahu, T Boisson, B Lacroix, C Bischoff, E Richier, Q Formaglio, P Thiberge, S Dobrescu, I Menard, R Baldacci, P AF Sahu, Tejram Boisson, Bertrand Lacroix, Celine Bischoff, Emmanuel Richier, Quentin Formaglio, Pauline Thiberge, Sabine Dobrescu, Irina Menard, Robert Baldacci, Patricia TI ZIPCO, a putative metal ion transporter, is crucial for Plasmodium liver-stage development SO EMBO MOLECULAR MEDICINE LA English DT Article DE iron; liver stage; Plasmodium; transporter; ZIP ID MAMMALIAN ZINC TRANSPORTERS; MALARIA PARASITES; IRON TRANSPORTER; HOST-CELL; FALCIPARUM; BERGHEI; DESFERRIOXAMINE; LEISHMANIA; INFECTION; CHILDREN AB The malaria parasite, Plasmodium, requires iron for growth, but how it imports iron remains unknown. We characterize here a protein that belongs to the ZIP (Zrt-, Irt-like Protein) family of metal ion transport proteins and have named ZIP domain-containing protein (ZIPCO). Inactivation of the ZIPCO-encoding gene in Plasmodium berghei, while not affecting the parasite's ability to multiply in mouse blood and to infect mosquitoes, greatly impairs its capacity to develop inside hepatocytes. Iron/zinc supplementation and depletion experiments suggest that ZIPCO is required for parasite utilization of iron and possibly zinc, consistent with its predicted function as a metal transporter. This is the first report of a ZIP protein having a crucial role in Plasmodium liver-stage development, as well as the first metal ion transporter identified in Plasmodium pre-erythrocytic stages. Because of the drastic dependence on iron of Plasmodium growth, ZIPCO and related proteins might constitute attractive drug targets to fight against malaria. ZIPCO is a novel Plasmodium berghei ZIP family protein, which might be involved in the transport of iron and possibly zinc. Parasites lacking ZIPCO present a normal blood phase but display a major developmental block in the host liver, which can be rescued by iron and zinc supplementation. ZIPCO is a newly identified Plasmodium protein belonging to the ZRT, IRT-like Protein (ZIP) family.Plasmodium berghei parasites lacking ZIPCO have no defect during the blood phase of malaria but display a major developmental block in the host liver. The growth defect is rescued by iron and zinc supplementation. This is first time that a ZIP protein has been shown to be important for the Plasmodium life cycle. C1 [Sahu, Tejram; Boisson, Bertrand; Lacroix, Celine; Richier, Quentin; Formaglio, Pauline; Thiberge, Sabine; Dobrescu, Irina; Menard, Robert; Baldacci, Patricia] Inst Pasteur, Unite Biol & Genet Paludisme, Paris 15, France. [Sahu, Tejram] NIAID, Lab Malaria Immunol & Vaccinol, Rockville, MD USA. [Boisson, Bertrand] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA. [Lacroix, Celine] Inst Biol & Chim Prot, Lyon 07, France. [Bischoff, Emmanuel] Inst Pasteur, Plateforme Puces ADN Genopole, Paris 15, France. RP Baldacci, P (reprint author), Inst Pasteur, Unite Biol & Genet Paludisme, Paris 15, France. EM patricia.baldacci@pasteur.fr RI Bischoff, Emmanuel/F-1197-2011; OI Bischoff, Emmanuel/0000-0003-4655-4247; Sahu, Tejram/0000-0002-0912-7660 FU HHMI grant; Fonds dedies 'Combattre les maladies Parasitaires' - Ministere de la Recherche; Sanofi-Aventis; Institut Pasteur; Howard Hughes Medical Institute; European Commission (FP6 BioMalPar Network of Excellence) FX The team of the 'Centre de Production et d'Infection des Anopheles' (Institut Pasteur) are thanked for mosquito rearing. J. Pham and other members of the laboratory are thanked for helping with mosquito infections. We are extremely grateful to Dr. J-C. Barale for providing the protein extracts of P. berghei SUB1-HA merozoites prior to publication and the anti MSP1 antibody. Dr. G. Badis-Breard, L. Decourty and Dr. C. Saveanu are thanked for their advice and help with attempts to express ZIPCO in yeast. TS was supported by an HHMI grant awarded to RM. BB was supported by the Fonds dedies 'Combattre les maladies Parasitaires' financed by the Ministere de la Recherche and Sanofi-Aventis. This work was supported by funds from the Institut Pasteur, the Howard Hughes Medical Institute and the European Commission (FP6 BioMalPar Network of Excellence). NR 49 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-4676 EI 1757-4684 J9 EMBO MOL MED JI EMBO Mol. Med. PD NOV PY 2014 VL 6 IS 11 BP 1387 EP 1397 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS9HZ UT WOS:000344555200003 PM 25257508 ER PT J AU Jin, QH Zhuang, LA Lai, BB Wang, CC Li, WQ Dolan, B Lu, Y Wang, ZB Zhao, KJ Peng, WQ Dent, SYR Ge, K AF Jin, Qihuang Zhuang, Lenan Lai, Binbin Wang, Chaochen Li, Wenqian Dolan, Brian Lu, Yue Wang, Zhibin Zhao, Keji Peng, Weiqun Dent, Sharon Y. R. Ge, Kai TI Gcn5 and PCAF negatively regulate interferon-beta production through HAT-independent inhibition of TBK1 SO EMBO REPORTS LA English DT Article DE Gcn5; PCAF; H3K9ac; innate immune signaling; interferon-; TBK1 ID TRANSCRIPTION FACTOR; HISTONE ACETYLATION; ANTIVIRAL RESPONSE; ACTIVATION; GENE; IMMUNITY; DISTINCT; ALPHA AB Viral infection triggers innate immune signaling, which in turn induces interferon- (IFN-) production to establish innate antiviral immunity. Previous studies showed that Gcn5 (Kat2a), a histone acetyltransferase (HAT) with partial functional redundancy with PCAF (Kat2b), and Gcn5/PCAF-mediated histone H3K9 acetylation (H3K9ac) are enriched on the active IFNB gene promoter. However, whether Gcn5/PCAF and H3K9ac regulate IFN- production is unknown. Here, we show that Gcn5/PCAF-mediated H3K9ac correlates well with, but is surprisingly dispensable for, the expression of endogenous IFNB and the vast majority of active genes in fibroblasts. Instead, Gcn5/PCAF repress IFN- production and innate antiviral immunity in several cell types in a HAT-independent and non-transcriptional manner: by inhibiting the innate immune signaling kinase TBK1 in the cytoplasm. Our results thus identify Gcn5 and PCAF as negative regulators of IFN- production and innate immune signaling. C1 [Jin, Qihuang; Zhuang, Lenan; Lai, Binbin; Wang, Chaochen; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. [Jin, Qihuang; Li, Wenqian; Lu, Yue; Dent, Sharon Y. R.] Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Dept Mol Carcinogenesis, Smithville, TX 78957 USA. [Dolan, Brian] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Wang, Zhibin; Zhao, Keji] NHLBI, Syst Biol Ctr, Bethesda, MD USA. [Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. RP Dent, SYR (reprint author), Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Dept Mol Carcinogenesis, Smithville, TX 78957 USA. EM sroth@mdanderson.org; kaig@niddk.nih.gov OI Li, Wenqian/0000-0001-6663-9809 FU NIDDK, NIH; NIH [RO1GM067718] FX We thank Kate Fitzgerald for Gal4-IRF3, pcDNA3-TBK1, and IFN beta-Luc plasmids, Rongtuan Lin and John Hiscott for Gal4-IRF3(5D) and GST-IRF3(380-427aa) plasmids, Jonathan Ashwell for VSV-GFP, Sarah Park for proof-reading the manuscript. This work was supported by the Intramural Research Program of the NIDDK, NIH to KG, and by NIH RO1GM067718 to SYRD. RNA-Seq was made possible by CPRIT (#RP120348). NR 24 TC 6 Z9 6 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD NOV PY 2014 VL 15 IS 11 BP 1192 EP 1201 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AT2WR UT WOS:000344795500015 PM 25269644 ER PT J AU Elliott, KC Resnik, DB AF Elliott, Kevin C. Resnik, David B. TI Transparency of Values in Science: Elliott and Resnik Respond SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 [Elliott, Kevin C.] Michigan State Univ, E Lansing, MI 48824 USA. [Resnik, David B.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Elliott, KC (reprint author), Michigan State Univ, E Lansing, MI 48824 USA. EM kce@msu.edu NR 7 TC 0 Z9 0 U1 1 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2014 VL 122 IS 11 BP A291 EP A292 DI 10.1289/ehp.1408936R PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AT2IZ UT WOS:000344759500003 PM 25360598 ER PT J AU Mahabir, S Baer, DJ Pfeiffer, RM Li, Y Watkins, BA Taylor, PR AF Mahabir, S. Baer, D. J. Pfeiffer, R. M. Li, Y. Watkins, B. A. Taylor, P. R. TI Low to moderate alcohol consumption on serum vitamin D and other indicators of bone health in postmenopausal women in a controlled feeding study SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID OBESITY AB The objective of this study was to evaluate the effect of 8 weeks of no alcohol, low (1 drink or 15 g/day) and moderate (2 drinks or 30 g/day) alcohol consumption on markers of bone health: fasting serum 25-hydroxy vitamin D (25(OH)D), osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), urine deoxypyridinoline (DPD) and helical peptide (HP) in postmenopausal women (n=51). Compared with no alcohol, 1 or 2 drinks/day for 8 weeks had no significant impact on any of the bone markers. Within each alcohol group, obese women had significantly lower serum 25(OH)D and higher DPD concentrations than normal weight women. Season significantly affected the concentrations of serum 25(OH)D, but there was oo significant interaction between alcohol and season on serum 25(OH)D concentrations. Low or moderate alcohol consumption for 8 weeks had no significant impact on markers of bone health in postmenopausal women. C1 [Mahabir, S.] NCI, Div Canc Control & Populat Sci, Modifiable Risk Factors Branch, Epidemiol & Genom Res Program, Bethesda, MD 20892 USA. [Mahabir, S.; Taylor, P. R.] NCI, DCEG, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Baer, D. J.] USDA, Agr Res Serv, Beltsville, MD 20705 USA. [Pfeiffer, R. M.] NCI, DCEG, Biostat Branch, Bethesda, MD 20892 USA. [Li, Y.; Watkins, B. A.] Univ Connecticut, Dept Nutr Sci, Storrs, CT USA. RP Mahabir, S (reprint author), NCI, Div Canc Control & Populat Sci, Modifiable Risk Factors Branch, Epidemiol & Genom Res Program, 9609 Med Ctr Dr,Room 4E548, Rockville, MD 20892 USA. EM mahabir@mail.nih.gov FU NIH; National Cancer Institute Interagency [Y1-5C-8012]; Intramural Research Program FX This study was supported by NIH and the National Cancer Institute Interagency agreement Y1-5C-8012 and the Intramural Research Program. NR 6 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD NOV PY 2014 VL 68 IS 11 BP 1267 EP 1270 DI 10.1038/ejcn.2014.191 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AT1UQ UT WOS:000344719700020 PM 25226824 ER PT J AU Esber, GR Holland, PC AF Esber, Guillem R. Holland, Peter C. TI The basolateral amygdala is necessary for negative prediction errors to enhance cue salience, but not to produce conditioned inhibition SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE associative learning; basolateral amygdala; conditioned inhibition; prediction error; salience; unblocking ID LESIONS DISRUPT INCREMENTS; POSTERIOR PARIETAL CORTEX; CENTRAL NUCLEUS LESIONS; UNBLOCKING; ASSOCIABILITY; BLOCKING; STIMULI; EVENT; DISCRIMINATIONS; DECREMENTS AB Behavioral evidence shows that prediction errors (PEs) not only drive associative learning, but also enhance the salience of predictive cues, making them better able to capture attention when they are next encountered. Research from our laboratory suggests that this latter consequence of PEs depends on a neural circuit that includes the amygdala. Lesions of the basolateral complex of the amygdala (BLA), for instance, selectively disrupt enhancements in cue processing that are normally induced by positive PEs without compromising simple excitatory learning. This result is consistent with electrophysiological evidence showing that BLA neurons track positive PEs. Interestingly, the same neurons also seem to track negative PEs, suggesting the possibility that the BLA might also use these errors to drive enhancements in cue processing. Here, we examined the role of the BLA in the processing (Experiment 1) and utilization (Experiment 2) of negative PEs in increasing cue salience in an unblocking procedure. Using FOS expression as an index of neural activity, Experiment 1 confirmed that BLA neurons track negative PEs with reinforcement downshifts. This tracking was evident both when these errors were generated by decreasing the concentration of a sucrose reinforcer (which encourages the development of conditioned inhibition) and when they were generated by decreasing the number of sucrose reinforcers (which encourages excitatory learning - unblocking - and allows the detection of enhancements in cue processing). Experiment 2 demonstrated that BLA lesions abolished enhancements in cue processing while sparing inhibitory learning. These results suggest a general role of the BLA in utilizing PEs, whatever their sign, for boosting cue processing. C1 [Esber, Guillem R.] NIDA, Intramural Res Program, Baltimore, MD USA. [Holland, Peter C.] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. RP Holland, PC (reprint author), Johns Hopkins Univ, Dept Psychol & Brain Sci, 200E Ames Hall,3400 North Charles St, Baltimore, MD 21218 USA. EM pch@jhu.edu FU NIH [MH53667] FX We thank David Mehler, Bayan Adileh, Melanie Hsu and Weidong Hu for their assistance in conducting these experiments. Funding was provided by NIH grant MH53667. NR 36 TC 6 Z9 7 U1 0 U2 1 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 NOV PY 2014 VL 40 IS 9 BP 3328 EP 3337 DI 10.1111/ejn.12695 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AS9WT UT WOS:000344590000005 PM 25135841 ER PT J AU Becker, CM Laufer, MR Stratton, P Hummelshoj, L Missmer, SA Zondervan, KT Adamson, GD AF Becker, Christian M. Laufer, Marc R. Stratton, Pamela Hummelshoj, Lone Missmer, Stacey A. Zondervan, Krina T. Adamson, G. David CA WERF EPHect Working Grp TI World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research SO FERTILITY AND STERILITY LA English DT Article DE Endometriosis; standardization; harmonization; phenotyping; laparoscopy; EPHect SSF ID DEEP ENDOMETRIOSIS; ADHESION FORMATION; PERITONEAL-FLUID; CONTROLLED-TRIAL; FERTILITY INDEX; ESHRE GUIDELINE; STAGING SYSTEM; SURGERY; BIOMARKERS; DISEASE AB Objective: To standardize the recording of surgical phenotypic information on endometriosis and related sample collections obtained at laparoscopy, allowing large-scale collaborative research into the condition. Design: An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries. Setting: Two workshops were conducted in 2013, bringing together 54 clinical, academic, and industry leaders in endometriosis research and management worldwide. Patient(s): None. Intervention(s): A postsurgical scoring sheet containing general and gynecological patient and procedural information, extent of disease, the location and type of endometriotic lesion, and any other findings was developed during several rounds of review. Comments and any systematic surgical data collection tools used in the reviewers' centers were incorporated. Main Outcome Measure(s): The development of a standard recommended (SSF) and minimum required (MSF) form to collect data on the surgical phenotype of endometriosis. Result(s): SSF and MSF include detailed descriptions of lesions, modes of procedures and sample collection, comorbidities, and potential residual disease at the end of surgery, along with previously published instruments such as the revised American Society for Reproductive Medicine and Endometriosis Fertility Index classification tools for comparison and validation. Conclusion(s): This is the first multicenter, international collaboration between academic centers and industry addressing standardization of phenotypic data collection for a specific disease. The Endometriosis Phenome and Biobanking Harmonisation Project SSF and MSF are essential tools to increase our understanding of the pathogenesis of endometriosis by allowing large-scale collaborative research into the condition. (C) 2014 by American Society for Reproductive Medicine. C1 [Becker, Christian M.; Zondervan, Krina T.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Oxford, England. [Becker, Christian M.; Zondervan, Krina T.] Univ Oxford, Endometriosis CaRe Ctr Oxford, Oxford, England. [Laufer, Marc R.] Boston Childrens Hosp, Dept Surg, Div Gynecol, Boston, MA USA. [Laufer, Marc R.; Missmer, Stacey A.] Harvard Univ, Sch Med, Boston, MA USA. [Laufer, Marc R.; Missmer, Stacey A.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Laufer, Marc R.; Missmer, Stacey A.] Boston Childrens Hosp, Boston Ctr Endometriosis, Boston, MA USA. [Laufer, Marc R.; Missmer, Stacey A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Intramural Program, NIH, Bethesda, MD USA. [Hummelshoj, Lone] World Endometriosis Res Fdn, London, England. [Missmer, Stacey A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Zondervan, Krina T.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Zondervan, Krina T.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Adamson, G. David] Palo Alto Med Fdn Fertil Phys Nothern Calif, Palo Alto, CA USA. RP Becker, CM (reprint author), John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Oxford OX3 9DU, England. EM christian.becker@obs-gyn.ox.ac.uk RI Salumets, Andres/J-2278-2015; Renner, Stefan/F-1158-2014; OI Salumets, Andres/0000-0002-1251-8160; Renner, Stefan/0000-0003-2057-1268; Horne, Andrew/0000-0002-9656-493X; Zondervan, Krina/0000-0002-0275-9905; Rogers, Peter/0000-0002-7399-8997; Forman, Axel/0000-0003-1369-1296; Nyegaard, Mette/0000-0003-4973-8543 FU Bayer Healthcare; Roche Diagnostics; Auxogyn; Ferring Pharmaceuticals; Merck Serono Merck; Besins; Pharmaplex; Astellas; World Endometriosis Research Foundation through grants from AbbVie Inc; Bayer Pharma AG; Roche Diagnostics International Ltd.; Wellcome Trust [WT085235/Z/08/Z]; J. Willard and Alice S. Marriott Foundation contribution; National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development grant [HD57210]; Intramural Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD008769-11]; Oxford Partnership Comprehensive Biomedical Research Centre; Department of Health's National Institute for Health Research Biomedical Research Centres Scheme; Puerto Rico Science and Technology Trust [2013-000032]; MRC [MR/K011480/1]; Ernst Schering Foundation; Elsa Neumann Stipendium des Landes Berlin; Endometriosis Association; Eunice Kennedy Shriver National Institute of Child Health and Human Development Specialized Cooperative Centers Program in Reproduction and Infertility Research [U54HD 055764] FX C.M.B. receives research grants from Bayer Healthcare and consultancy fees from Roche Diagnostics. M.R.L. has nothing to disclose. P.S. has nothing to disclose. L.H. has been remunerated by WERF for project management. S.A.M. is a non-remunerated board member of WERF. K.T.Z. is a member of scientific advisory boards for AbbVie Inc, Bayer HealthCare, and Roche Diagnostics and receives an honorarium for lectures from Bayer HealthCare. G.D.A. is the CEO of Advanced Reproductive Care, Inc.; receives research funds from Auxogyn; holds a consultancy for Bayer Healthcare, Glycotope, and Ziva, and is a non-remunerated board member of WERF.; The WERF EPHect Working Group (not listed in the author list): C.A. is on the Actavis advisory board and the Bayer Healthcare advisory board and is a speaker for Johnson and Johnson. R.A. has nothing to disclose. M.A.B. has nothing to disclose. G.M.B.L. has nothing to disclose. C.C.-J. has nothing to disclose. K.C. is employed by AbbVie Inc and holds stock in this company. T.M.D. receives research and travel grants from Ferring Pharmaceuticals and Merck Serono Merck, Besins, and Pharmaplex, and consultancy fees from Astellas, Bayer Healthcare, Proteomika, Roche Diagnostics, and Teva. A. F. has nothing to disclose. T.F. is employed by Bayer Healthcare. A.T.F has nothing to disclose. I.F. has nothing to disclose. A. F. has nothing to disclose. I.F. has nothing to disclose. L.C.G. is an academic associate with Quest Diagnostics, and is a non-remunerated board member of WERF. M.G. has nothing to disclose. P. G. has nothing to disclose. S.-W.G. has nothing to disclose. T.H. has nothing to disclose. D.H. has nothing to disclose. A.W.H. has nothing to disclose. M.L.H. has nothing to disclose. M.G.I. has nothing to disclose. L. K. receives speaker fees from Bayer Healthcare and consultancy fees from Roche Diagnostics. K.M. is employed by Bayer Healthcare. S.M. has nothing to disclose. G. W. M. has nothing to disclose. A. N. receives consulting fees from Merck Serono and MSD. M.N. has nothing to disclose. K.G.O. has nothing to disclose. C. A. P. is a consultant for Bayer Healthcare and is a non-remunerated board member of WERF. N.R. has nothing to disclose. S.P. R. receives consultancy fees from Roche Diagnostics, Gedeon Richter, and Ethicon and an honorarium for lectures from Jenapharm. J.R. is employed by Roche Diagnostics GmbH. S.R. is employed by Bayer Healthcare. P.A.R. has nothing to disclose. L. R. is a non-remunerated board member of WERF. A. S. has nothing to disclose. E. S. receives honoraria from Ethicon and Gedeon Richter for providing training to health care professionals. T.S. has nothing to disclose. K.L.S.-T. has nothing to disclose. S.S.T. has nothing to disclose. U.-H.W.-T. is employed by Roche Diagnostics GmbH. P.V. holds a consultancy for Roche Diagnostics. K.V. receives honoraria and travel expenses for lectures from Bayer Healthcare. A.F.V. has nothing to disclose. P.P.Y. is a consultant for Lumenis. P.Y. has nothing to disclose.; This work was funded by the World Endometriosis Research Foundation through grants from AbbVie Inc, Bayer Pharma AG, and Roche Diagnostics International Ltd. K.T.Z. is supported by a Wellcome Trust Career Development Fellowship (grant no. WT085235/Z/08/Z); S.A.M. and A.F.V. are supported, in part, by the J. Willard and Alice S. Marriott Foundation contribution to the Boston Center for Endometriosis, and S.A.M by a National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development grant (grant no. HD57210); P.S. is supported by the Intramural Program of the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant no. HD008769-11); C.M.B. was supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health's National Institute for Health Research Biomedical Research Centres Scheme; I.F. is supported by the Puerto Rico Science and Technology Trust (grant no. 2013-000032); N.R. was supported by an MRC grant (grant no. MR/K011480/1); M.G.I. holds a scholarship from the Ernst Schering Foundation and an Elsa Neumann Stipendium des Landes Berlin; K.V. is supported by an National Institute for Health Research Academic Clinical Lecturer Award; A.W.H. is supported by grants from the Chief Scientist Office Scotland, Wellbeing of Women, and Health Technology Assessment; K.G.O. is supported by a grant from the Endometriosis Association; L.C.G. acknowledges funding support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Specialized Cooperative Centers Program in Reproduction and Infertility Research (grant no. U54HD 055764). NR 47 TC 23 Z9 23 U1 5 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2014 VL 102 IS 5 DI 10.1016/j.fertnstert.2014.07.709 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AT1JE UT WOS:000344688400002 PM 25150390 ER PT J AU Vitonis, AF Vincent, K Rahmioglu, N Fassbender, A Louis, GMB Hummelshoj, L Giudice, LC Stratton, P Adamson, GD Becker, CM Zondervan, KT Missmer, SA AF Vitonis, Allison F. Vincent, Katy Rahmioglu, Nilufer Fassbender, Amelie Louis, Germaine M. Buck Hummelshoj, Lone Giudice, Linda C. Stratton, Pamela Adamson, G. David Becker, Christian M. Zondervan, Krina T. Missmer, Stacey A. CA WERF EPHect Working Grp TI World Endometriosis Research Foundation Endometriosis Phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research SO FERTILITY AND STERILITY LA English DT Article DE Endometriosis; EPHect EPQ; pelvic pain; questionnaire; standardization; symptoms ID DEEP INFILTRATING ENDOMETRIOSIS; SELF-REPORTED WEIGHT; CHRONIC PELVIC PAIN; RED HAIR COLOR; BODY-SIZE; PROSPECTIVE COHORT; DEPRESSION SCALE; HOSPITAL ANXIETY; CANCER-RISK; WOMEN AB Objective: To harmonize the collection of nonsurgical clinical and epidemiologic data relevant to endometriosis research, allowing large-scale collaboration. Design: An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries on five continents. Setting: In 2013, two workshops followed by global consultation, bringing together 54 leaders in endometriosis research. Patients: None. Intervention(s): Development of a self-administered endometriosis patient questionnaire (EPQ), based on [1] systematic comparison of questionnaires from eight centers that collect data from endometriosis cases (and controls/comparison women) on a medium to large scale (publication on >100 cases); [2] literature evidence; and [3] several global consultation rounds. Main Outcome Measure(s): Standard recommended and minimum required questionnaires to capture detailed clinical and covariate data. Result(s): The standard recommended (EPHect EPQ-S) and minimum required (EPHect EPQ-M) questionnaires contain questions on pelvic pain, subfertility and menstrual/reproductive history, hormone/medication use, medical history, and personal information. Conclusion(s): The EPQ captures the basic set of patient characteristics and exposures considered by the WERF EPHect Working Group to be most critical for the advancement of endometriosis research, but is also relevant to other female conditions with similar risk factors and/or symptomatology. The instruments will be reviewed based on feedback from investigators, and-after a first review after 1 year-triannually through systematic follow-up surveys. Updated versions will be made available through http://endometriosisfoundation. org/ephect. (C) 2014 by American Society for Reproductive Medicine. C1 [Vitonis, Allison F.; Missmer, Stacey A.] Brigham & Womens Hosp, ObGyn Epidemiol Ctr, Boston, MA 02115 USA. [Vitonis, Allison F.; Missmer, Stacey A.] Harvard Univ, Sch Med, Boston, MA USA. [Vitonis, Allison F.; Missmer, Stacey A.] Boston Childrens Hosp, Boston Ctr Endometriosis, Boston, MA USA. [Vitonis, Allison F.; Missmer, Stacey A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Vincent, Katy; Becker, Christian M.; Zondervan, Krina T.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Oxford, England. [Rahmioglu, Nilufer; Zondervan, Krina T.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Fassbender, Amelie] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium. [Fassbender, Amelie] Leuven Univ, Univ Hosp Leuven, Fertil Ctr, Dept Obstet & Gynecol, Leuven, Belgium. [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Hummelshoj, Lone; Giudice, Linda C.; Adamson, G. David] WERF, London, England. [Giudice, Linda C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Intramural Program, NIH, Bethesda, MD USA. [Adamson, G. David] Palo Alto Med Fdn Fertil Phys Northern Calif, Palo Alto, CA USA. [Becker, Christian M.; Zondervan, Krina T.] Univ Oxford, Endometriosis CaRe Ctr Oxford, Oxford, England. [Missmer, Stacey A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Missmer, Stacey A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Missmer, SA (reprint author), Brigham & Womens Hosp, ObGyn Epidemiol Ctr, 221 Longwood Ave, Boston, MA 02115 USA. EM stacey.missmer@channing.harvard.edu RI Salumets, Andres/J-2278-2015; Renner, Stefan/F-1158-2014; OI Zondervan, Krina/0000-0002-0275-9905; Rogers, Peter/0000-0002-7399-8997; Forman, Axel/0000-0003-1369-1296; Nyegaard, Mette/0000-0003-4973-8543; Buck Louis, Germaine/0000-0002-1774-4490; Salumets, Andres/0000-0002-1251-8160; Renner, Stefan/0000-0003-2057-1268; Horne, Andrew/0000-0002-9656-493X FU Auxogyn; Bayer Healthcare; Roche Diagnostics; Ferring Pharmaceuticals; Merck Serono Merck; Besins; Pharmaplex; Astellas; Proteomika; Teva; Merck Serono; MSD; Gedeon-Richter; Ethicon; World Endometriosis Research Foundation; AbbVie; Bayer Pharma AG; Roche Diagnostics International Ltd.; Wellcome Trust [WT085235/Z/08/Z]; J. Willard and Alice S. Marriott Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD57210]; Intramural Program of the NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development; MRC [MR/K011480/1]; Oxford Partnership Comprehensive Biomedical Research Centre; Department of Health's NIHR Biomedical Research Centres Scheme; Puerto Rico Science and Technology Trust [2013-000032]; Ernst Schering Foundation; Elsa Neumann Stipendium des Landes Berlin; NIHR Academic Clinical Lecturer Award; Chief Scientist Office Scotland, Wellbeing of Women; HTA; Endometriosis Association; Eunice Kennedy Shriver National Institute of Child Health and Human Development Specialized Cooperative Centers Program in Reproduction and Infertility Research [U54HD 055764] FX A.F.V. has nothing to disclose. K.V. has received honoraria and travel expenses for lectures from Bayer Healthcare. N.R. has nothing to disclose. A.F. has nothing to disclose. G.M.B.L. has nothing to disclose. L.H. reports remuneration by WERF for project management. L.C.G. is an academic associate with Quest Diagnostics and is a non-remunerated Board member of WERF. P.S. has nothing to disclose. G.D.A. is CEO of Advanced Reproductive Care Inc., and has received research funds from Auxogyn, and consultancy for Bayer Healthcare, Glycotope, and Ziva, and is a non-remunerated Board member of WERF. C.M.B. has received research grants from Bayer Healthcare and consultancy fees from Roche Diagnostics. K.T.Z. is a member of scientific advisory boards for AbbVie Inc., Bayer HealthCare, and Roche Diagnostics, and has received honorarium for lectures from Bayer HealthCare. S.A.M. is a non-remunerated board member of WERF.; The other participants of the WERF EPHect Working Group make the following disclosures: C.A. is on the advisory boards of Actavis and Bayer Healthcare and the speakers bureau for Johnson & Johnson. K.C. is employed by AbbVie and holds stock in this company. T.M.D'H. has received research and travel grants from Ferring Pharmaceuticals and Merck Serono Merck, Besins, and Pharmaplex, and consultancy fees from Astellas, Bayer Healthcare, Proteomika, Roche Diagnostics, and Teva. A.F. has nothing to disclose. I.F. has nothing to disclose. T.F. is employed by Bayer Healthcare. M.G. has nothing to disclose. P.G. has nothing to disclose. S.-W.G. has nothing to disclose. T.H. has nothing to disclose. D. H. has nothing to disclose. A.W.H. has nothing to disclose. M.L.H. has nothing to disclose. M.G.I. has nothing to disclose. M.R.L. has nothing to disclose. L.K. has received speaker fees from Bayer Healthcare and consultancy fees from Roche Diagnostics. K.M. is employed by Bayer Healthcare; S.M. has nothing to disclose. G.W.M. has nothing to disclose. M.N. has nothing to disclose. A.N. has received consulting fees from Merck Serono and MSD. K.G.O. has nothing to disclose. C.A.P is a consultant for Bayer Healthcare and is a non-remunerated Board member of WERF. P.A.R. has nothing to disclose. L. R is a non-remunerated Board member of WERF. S.P.R. has received consultancy fees from Roche Diagnostics, Gedeon-Richter, and Ethicon, and honorarium for lectures from Jenapharm. J.R. is employed by Roche Diagnostics GmbH. S.R. is employed by Bayer Healthcare. A.S. has nothing to disclose. T.S. has nothing to disclose. K.L.S.-T. has nothing to disclose. E.S. has received honoraria from Ethicon and Gedeon-Richter for providing training to healthcare professionals. U.-H.W.-T. is employed by Roche Diagnostics GmbH. S.S.T. has nothing to disclose. P.V. has a consultancy for Roche Diagnostics. P.P.Y. is a consultant for Lumenis. P.Y. has nothing to disclose.; This work was funded by the World Endometriosis Research Foundation through grants from AbbVie, Bayer Pharma AG, and Roche Diagnostics International Ltd.; a Wellcome Trust Career Development Fellowship (grant no. WT085235/Z/08/Z, to K.T.Z.); in part by the J. Willard and Alice S. Marriott Foundation contribution to the Boston Center for Endometriosis (S.A.M. and A.F.V.), and a Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant (grant no. HD57210, to S.A.M.); the Intramural Program of the NIH and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (to G.M.B.L. and P.S.); an MRC grant (grant no. MR/K011480/1, to N.R.); the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health's NIHR Biomedical Research Centres Scheme (to C.M.B.); the Puerto Rico Science and Technology Trust (grant no. 2013-000032, to I.F.); a scholarship from the Ernst Schering Foundation and an Elsa Neumann Stipendium des Landes Berlin (to M.G.I.); an NIHR Academic Clinical Lecturer Award (to K.V.); grants from the Chief Scientist Office Scotland, Wellbeing of Women, and HTA (to A.W.H.); a grant from the Endometriosis Association (to K.G.O.); and the Eunice Kennedy Shriver National Institute of Child Health and Human Development Specialized Cooperative Centers Program in Reproduction and Infertility Research (grant no. U54HD 055764, to L.C.G.). NR 77 TC 21 Z9 22 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2014 VL 102 IS 5 DI 10.1016/j.fertnstert.2014.07.1244 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AT1JE UT WOS:000344688400003 PM 25256930 ER PT J AU Korf, BR Berry, AB Limson, M Marian, AJ Murray, MF O'Rourke, PP Passamani, ER Relling, MV Tooker, J Tsongalis, GJ Rodriguez, LL AF Korf, Bruce R. Berry, Anna B. Limson, Melvin Marian, Ali J. Murray, Michael F. O'Rourke, P. Pearl Passamani, Eugene R. Relling, Mary V. Tooker, John Tsongalis, Gregory J. Rodriguez, Laura L. TI Framework for development of physician competencies in genomic medicine: report of the Competencies Working Group of the Inter-Society Coordinating Committee for Physician Education in Genomics SO GENETICS IN MEDICINE LA English DT Article DE competencies; education; genomic medicine; genomics AB Completion of the Human Genome Project, in conjunction with dramatic reductions in the cost of DNA sequencing and advances in translational research, is gradually ushering genomic discoveries and technologies into the practice of medicine. The rapid pace of these advances is opening up a gap between the knowledge available about the clinical relevance of genomic information and the ability of clinicians to include such information in their medical practices. This educational gap threatens to be rate limiting to the clinical adoption of genomics in medicine. Solutions will require not only a better understanding of the clinical implications of genetic discoveries but also training in genomics at all levels of professional development, including for individuals in formal training and others who long ago completed such training. The National Human Genome Research Institute has convened the Inter-Society Coordinating Committee for Physician Education in Genomics (ISCC) to develop and share best practices in the use of genomics in medicine. The ISCC has developed a. framework for development of genomics practice competencies that may serve as a starting point for formulation of competencies for physicians in various medical disciplines. C1 [Korf, Bruce R.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35233 USA. [Berry, Anna B.] Swedish Canc Inst, CellNetix Pathol & Labs, Seattle, WA USA. [Berry, Anna B.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Limson, Melvin] Assoc Mol Pathol, Bethesda, MD USA. [Marian, Ali J.] Univ Texas Hlth Sci Ctr Houston, Ctr Cardiovasc Genet, Houston, TX 77030 USA. [Murray, Michael F.] Genom Med Inst, Geisinger Hlth Syst, Danville, PA USA. [O'Rourke, P. Pearl] Partners HealthCare Syst, Boston, MA USA. [Passamani, Eugene R.; Rodriguez, Laura L.] NHGRI, Bethesda, MD 20892 USA. [Relling, Mary V.] St Jude Chlldrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN USA. [Tooker, John] Amer Coll Physicians, Philadelphia, PA USA. [Tsongalis, Gregory J.] Amer Assoc Clin Chem, Washington, DC USA. [Tsongalis, Gregory J.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med Dartmouth, Dept Pathol, Lebanon, NH 03766 USA. [Tsongalis, Gregory J.] Norris Cotton Canc Ctr, Lebanon, NH USA. RP Korf, BR (reprint author), Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35233 USA. EM bkorf@uab.edu NR 10 TC 28 Z9 29 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD NOV PY 2014 VL 16 IS 11 BP 804 EP 809 DI 10.1038/gim.2014.35 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AT1XW UT WOS:000344725200002 PM 24763287 ER PT J AU Abramowitz, LK Hanover, JA AF Abramowitz, Lara K. Hanover, John A. TI Tissue-specific expression of the short O-linked N-acetylglucosamine transferase isoform modulates UDP-GlcNAc levels by balancing hydrolysis and utilization SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Abramowitz, Lara K.; Hanover, John A.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 176 BP 1150 EP 1151 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300184 ER PT J AU Olivier-Vanstichelen, S Hanover, J AF Olivier-Vanstichelen, Stephanie Hanover, John TI X-inactivation normalizes O-GlcNAc Transferase levels and generates an O-GlcNAc-depleted Barr body SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Olivier-Vanstichelen, Stephanie; Hanover, John] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 188 BP 1155 EP 1155 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300196 ER PT J AU Akan, I Harwood, K Love, D Hanover, J AF Akan, Ilhan Harwood, Katryn Love, Dona Hanover, John TI O-GlcNAcase is a critical epigenetic regulator of nutrient-responsive Drosophila oogenesis SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Akan, Ilhan; Harwood, Katryn; Love, Dona; Hanover, John] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 240 BP 1173 EP 1174 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300246 ER PT J AU Bond, M Fukushige, T Krause, M Hanover, J AF Bond, Michelle Fukushige, Tetsu Krause, Michael Hanover, John TI Fidelity in developmental patterning requires O-GlcNAc transferase SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Bond, Michelle; Fukushige, Tetsu; Krause, Michael; Hanover, John] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 256 BP 1179 EP 1180 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300262 ER PT J AU Inamori, K Willer, T Hara, Y Venzke, D Anderson, ME Clarke, NF Guicheney, P Bonnemann, CG Moore, SA Campbell, KP AF Inamori, Kei-ichiro Willer, Tobias Hara, Yuji Venzke, David Anderson, Mary E. Clarke, Nigel F. Guicheney, Pascale Boennemann, Carsten G. Moore, Steven A. Campbell, Kevin P. TI Endogenous glucuronyltransferase activity of LARGE or LARGE2 required for functional modification of alpha-dystroglycan in cells and tissues SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Inamori, Kei-ichiro; Willer, Tobias; Hara, Yuji; Venzke, David; Anderson, Mary E.; Campbell, Kevin P.] Univ Iowa, Howard Hughes Med Inst, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. [Inamori, Kei-ichiro] Tohoku Pharmaceut Univ, Inst Mol Biomembrane & Glycobiol, Sendai, Miyagi, Japan. [Clarke, Nigel F.] Univ Sydney, Inst Neurosci & Muscle Res, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [Guicheney, Pascale] INSERM, Inst Cardiometab & Nutr, U1166, Paris, France. [Guicheney, Pascale] Univ Paris 04, Paris, France. [Boennemann, Carsten G.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Moore, Steven A.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 262 BP 1181 EP 1182 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300268 ER PT J AU Harwood, K Hanover, J AF Harwood, Katryn Hanover, John TI The Enzymes of the O-GlcNAc Cycling: Writers AND Readers of the Histone Code? SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Harwood, Katryn; Hanover, John] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 265 BP 1182 EP 1183 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300271 ER PT J AU St Amand, MM Shiloach, J Hanover, JA AF St Amand, Melissa M. Shiloach, Joseph Hanover, John A. TI Generation of Immortalized MEF cell lines to study O-GlcNAc Metabolism and Neurodegeneration SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [St Amand, Melissa M.; Shiloach, Joseph] NIDDK, Biotechnol Core, NIH, Bethesda, MD 20892 USA. [Hanover, John A.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 266 BP 1183 EP 1183 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300272 ER PT J AU Tian, E Stevens, S Guan, Y Anderson, S Springer, D Starost, M Patel, V Ten Hagen, K Tabak, L AF Tian, E. Stevens, Sharon Guan, Yu Anderson, Stasia Springer, Danielle Starost, Matthew Patel, Vyomesh Ten Hagen, Kelly Tabak, Lawrence TI Galnt1 is required for normal heart valve development and cardiac function SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Tian, E.; Stevens, Sharon; Guan, Yu; Ten Hagen, Kelly; Tabak, Lawrence] NIDCR, NIH, Bethesda, MD USA. [Anderson, Stasia; Springer, Danielle] NHLBI, NIH, Bethesda, MD USA. [Starost, Matthew] NIH, DVR, Bethesda, MD USA. [Patel, Vyomesh] Sime Darby Med Ctr, CRIF, Selangor, Malaysia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 305 BP 1197 EP 1197 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300311 ER PT J AU Hanover, J Abramowitz, L Bond, M Zirzow, A Cheng, C Carolyn, B Gharib, A Olivier-Van Stichelen, S Love, D AF Hanover, John Abramowitz, Lara Bond, Michelle Zirzow, Amanda Cheng, Clara Carolyn, Bondy Gharib, Ahmed Olivier-Van Stichelen, Stephanie Love, Dona TI OGT Isoform expression is an X-linked trait predictive of Disease susceptibility SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Hanover, John; Abramowitz, Lara; Bond, Michelle; Olivier-Van Stichelen, Stephanie; Love, Dona] NIDDK, NIH, Bethesda, MD 20892 USA. [Zirzow, Amanda] Georgetown Univ, Washington, DC 20057 USA. [Cheng, Clara; Carolyn, Bondy] NICHD, NIH, Bethesda, MD USA. [Gharib, Ahmed] NIBIB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 320 BP 1202 EP 1203 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300326 ER PT J AU Malicdan, MCV Bodine, S Tanawattanacharoen, V Yokoyama, T Leoyklang, P Zerfas, PM Rosenberg, A Shrivastav, S Murakami, T Okamoto, K Kopp, JB Gahl, WA Huizing, M AF Malicdan, May Christine V. Bodine, Steven Tanawattanacharoen, Veeraya Yokoyama, Tadafumi Leoyklang, Petcharat Zerfas, Patricia M. Rosenberg, Avi Shrivastav, Shashi Murakami, Taichi Okamoto, Koji Kopp, Jeffrey B. Gahl, William A. Huizing, Marjan TI Oral N-acetylmannosamine reverses glomerular hyposialyation and ameliorates proteinuria in a mouse model of nephrotic syndrome SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Malicdan, May Christine V.; Bodine, Steven; Yokoyama, Tadafumi; Leoyklang, Petcharat; Rosenberg, Avi; Huizing, Marjan] NIH, Natl Human Genome Res Inst, Med Genet Branch, Bethesda, MD USA. [Malicdan, May Christine V.] NIH, Bethesda, MD USA. [Tanawattanacharoen, Veeraya; Shrivastav, Shashi; Murakami, Taichi; Okamoto, Koji; Kopp, Jeffrey B.] NIH, Natl Inst Diabet & Digest & Kidney Dis, Kidney Dis Sect, Bethesda, MD USA. [Zerfas, Patricia M.] NIH, Off Director, Off Res Serv, Bethesda, MD USA. [Gahl, William A.] NIH, Off Director, Common Fund, NIH Undiagnosed Dis Program, Bethesda, MD USA. [Gahl, William A.] NHGRI, NIH, Off Clin Director, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 355 BP 1215 EP 1215 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300361 ER PT J AU Maglic, D Petcharat, L Chaiyasap, P Bishop, K Sood, R Zerfas, PM Gahl, WA Huizing, M Malicdan, MC AF Maglic, Dino Petcharat, Leoyklang Chaiyasap, Pongsathorn Bishop, Kevin Sood, Raman Zerfas, Patricia M. Gahl, William A. Huizing, Marjan Malicdan, May Christine TI Gne defects in zebrafish lead to impairment of sialylation and myopathy SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Maglic, Dino; Petcharat, Leoyklang; Chaiyasap, Pongsathorn; Huizing, Marjan; Malicdan, May Christine] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Bishop, Kevin; Sood, Raman] NHGRI, Zebrafish Core Facil, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Zerfas, Patricia M.] NIH, Off Res Serv, Off Director, Bethesda, MD 20892 USA. [Gahl, William A.] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20892 USA. [Malicdan, May Christine] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Malicdan, May Christine] NIH, NIH Undiagnosed Dis Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 358 BP 1216 EP 1216 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300364 ER PT J AU Huizing, M Leoyklang, P Yardeni, T Celeste, F Ciccone, C Li, XL Jian, R Carrillo-Carrasco, N He, M Gahl, WA Malicdan, MCV AF Huizing, Marjan Leoyklang, Petcharat Yardeni, Tal Celeste, Frank Ciccone, Carla Li, Xueli Jian, Rong Carrillo-Carrasco, Nuria He, Miao Gahl, William A. Malicdan, May Christine V. TI Sialylation of Thomsen-Friedenreich antigen is a noninvasive blood-based biomarker for GNE myopathy SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Huizing, Marjan; Leoyklang, Petcharat; Yardeni, Tal; Ciccone, Carla; Gahl, William A.; Malicdan, May Christine V.] NHGRI, Med Genet Branch, NIH, Bethesda, MD USA. [Yardeni, Tal] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Celeste, Frank; Carrillo-Carrasco, Nuria] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD USA. [Li, Xueli; Jian, Rong; He, Miao] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Li, Xueli; Jian, Rong; He, Miao] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD USA. RI Carrillo-Carrasco, Nuria/B-9034-2009 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 360 BP 1217 EP 1217 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300366 ER PT J AU Stratakis, CA Bertherat, J AF Stratakis, C. A. Bertherat, J. TI PDE 2013, Paris, France: Another Exciting Workshop for Cyclic AMP, Protein Kinase A, and Phosphodiesterases SO HORMONE AND METABOLIC RESEARCH LA English DT Editorial Material ID ADRENOCORTICAL DISEASE; TUMORS; MEDICINE; GNAS C1 [Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Bertherat, J.] Hop Cochin, AP HP, Dept Endocrinol, F-75014 Paris, France. [Bertherat, J.] Univ Paris 05, CNRS 8104, INSERM U1016, Inst Cochin, Paris, France. RP Bertherat, J (reprint author), Hop Cochin, Serv Endocrinol, 27 Rue Fg St Jacques, F-75014 Paris, France. EM jerome.bertherat@cch.aphp.fr NR 28 TC 0 Z9 0 U1 0 U2 2 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 NOV PY 2014 VL 46 IS 12 BP 825 EP 826 DI 10.1055/s-0034-1394418 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT2CJ UT WOS:000344738500001 PM 25398031 ER PT J AU Weinstein, LS AF Weinstein, L. S. TI Role of G(s)alpha in Central Regulation of Energy and Glucose Metabolism SO HORMONE AND METABOLIC RESEARCH LA English DT Review DE genomic imprinting; obesity; pseudohypoparathyroidism; Albright hereditary osteodystrophy ID PSEUDOHYPOPARATHYROIDISM TYPE 1A; GS-ALPHA GENE; ALBRIGHT HEREDITARY OSTEODYSTROPHY; INCREASED INSULIN SENSITIVITY; RECEPTOR-DEFICIENT MICE; MELANOCORTIN-4 RECEPTOR; ADIPOSE-TISSUE; KNOCKOUT MICE; TARGETED DISRUPTION; PATERNAL DELETION AB GNAS is a complex imprinted locus with multiple oppositely imprinted gene products, including the G protein alpha-subunit G(s)alpha that is expressed primarily from the maternal allele in some tissues and the G(s)alpha isoform XL alpha s that is expressed only from the paternal allele. Maternal G(s)alpha mutations in mice and in patients with Albright hereditary osteodystrophy lead to obesity, insulin resistance, and hyperlipidemia. Studies in mice show that these effects are primarily due to G(s)alpha imprinting in the central nervous system and that G(s)alpha deficiency in one or more regions of the central nervous system lead to reduced sympathetic nervous system and energy expenditure without affecting food intake. Loss of G(s)alpha in the central nervous system appears to lead to these effects primarily through impairment of melanocortin signaling. Loss of XL alpha s in mice leads to opposite effects on energy and glucose metabolism. C1 NIDDK, Signal Transduct Sect, NIH, Bethesda, MD 20892 USA. RP Weinstein, LS (reprint author), NIDDK, Signal Transduct Sect, NIH, Bldg 10 Rm 8C101, Bethesda, MD 20892 USA. EM leew@mail.nih.gov OI Weinstein, Lee/0000-0002-1899-5152 NR 47 TC 4 Z9 5 U1 3 U2 3 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 NOV PY 2014 VL 46 IS 12 BP 841 EP 844 DI 10.1055/s-0034-1387798 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT2CJ UT WOS:000344738500004 PM 25232907 ER PT J AU Szarek, E Stratakis, CA AF Szarek, E. Stratakis, C. A. TI Phosphodiesterases and Adrenal Cushing in Mice and Humans SO HORMONE AND METABOLIC RESEARCH LA English DT Review DE PDE2A; PDE8B; PDE11A; Cushing syndrome; cAMP; bilateral adrenal hyperplasia ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; NODULAR ADRENOCORTICAL DISEASE; TISSUE-SPECIFIC EXPRESSION; MOLECULAR-CLONING; SPLICE VARIANTS; 11A PDE11A; GLOMERULOSA CELLS; GENE ORGANIZATION; CARNEY COMPLEX; PROTEIN-KINASE AB The majority of benign adrenal cortex lesions leading to Cushing syndrome are associated to one or another abnormality of the cAMP/cGMP-phosphodiesterase signaling pathway. Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP/cGMP levels. These second messengers play important regulatory roles in controlling steroidogenesis in the adrenal. Disruption of PDEs has been associated with a number of adrenal diseases. Specifically, genetic mutations have been associated with benign adrenal lesions, leading to Cushing syndrome and/or related adrenal hyperplasias. A Genome Wide Association study, in 2006, led to the identification of mutations in 2 PDE genes: PDE8B and PDE11A; mutations in these 2 genes modulate steroidogenesis. Further human studies have identified PDE2 as also directly regulating steroidogenesis. PDE2 decreases aldosterone production. This review focuses on the most recent knowledge we have gained on PDEs and their association with adrenal steroidogenesis and altered function, through analysis of patient cohorts and what we have learned from mouse studies. C1 [Szarek, E.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, SEGEN PDEGEN, NIH, Bldg 10 CRC,Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS [ZIA HD008920-03] NR 83 TC 2 Z9 2 U1 2 U2 5 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 NOV PY 2014 VL 46 IS 12 BP 863 EP 868 DI 10.1055/s-0034-1389916 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT2CJ UT WOS:000344738500007 PM 25232906 ER PT J AU Basso, F Rocchetti, F Rodriguez, S Nesterova, M Cormier, F Stratakis, CA Ragazzon, B Bertherat, J Rizk-Rabin, M AF Basso, F. Rocchetti, F. Rodriguez, S. Nesterova, M. Cormier, F. Stratakis, C. A. Ragazzon, B. Bertherat, J. Rizk-Rabin, M. TI Comparison of the Effects of PRKAR1A and PRKAR2B Depletion on Signaling Pathways, Cell Growth, and Cell Cycle Control of Adrenocortical Cells SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE PKA R1A; R2B; apoptosis; NF-kappa B; cyclins; cdks ID PROTEIN-KINASE-A; REGULATORY SUBUNIT; CUSHINGS-SYNDROME; TUMORS; PROLIFERATION; EXPRESSION; MUTATIONS; DISRUPTION; ACTIVATION AB The cyclic AMP/protein kinase A signaling cascade is one of the main pathways involved in the pathogenesis of adrenocortical tumors. The PKA R1A and R2B proteins are the most abundant regulatory subunits in endocrine tissues. Inactivating mutations of PRKAR1A are associated with Carney complex and a subset of sporadic tumors and the abundance of R2B protein is low in a subset of secreting adrenocortical adenomas. We previously showed that PRKAR1A and PRKAR2B inactivation have anti-apoptotic effects on the adrenocortical carcinoma cell line H295R. The aim of this study was to compare the effects of PRKAR1A and PRKAR2B depletion on cell proliferation, apoptosis, cell signaling pathways, and cell cycle regulation. We found that PRKAR2B depletion is compensated by an upregulation of R1A protein, whereas PRKAR1A depletion has no effect on the production of R2B. The depletion of either PRKAR1A or PRKAR2B promotes the expression of Bcl-xL and resistance to apoptosis; and is associated with a high percentage of cells in S and G2 phase, activates PKA and MEK/ERK pathways, and impairs the expression of IkB leading to activate the NF-kappa B pathway. However, we observed differences in the regulation of cyclins. The depletion of PRKAR1A leads to the accumulation of cyclin D1 and p27kip, whereas the depletion of PRKAR2B promotes the accumulation of cyclin A, B, cdk1, cdc2, and p21Cip. In conclusion, although the depletion of PRKAR1A and PRKAR2B in adrenocortical cells has similar effects on cell proliferation and apoptosis; loss of these PKA subunits differentially affects cyclin expression. Supporting Information for this article is available online at http://www.thieme-connect.de/products C1 [Basso, F.; Rocchetti, F.; Rodriguez, S.; Cormier, F.; Ragazzon, B.; Bertherat, J.; Rizk-Rabin, M.] Univ Paris 05, Sorbonne Paris Cite, Fac Med, INSERM,U1016,CNRS,UMR 8104,Inst Cochin, Paris, France. [Nesterova, M.; Stratakis, C. A.] NICHHD, NIH, Bethesda, MD 20892 USA. [Bertherat, J.] Hop Cochin, Dept Endocrinol, Ctr Rare Adrenal Dis, F-75674 Paris, France. RP Rizk-Rabin, M (reprint author), Inst Cochin Genet Mol, Fac Cochin, Dept Endocrinol Metab & Diabet, 24 Rue Fbg St Jacques, F-75014 Paris, France. EM Marthe.rizk@inserm.fr RI Ragazzon, Bruno/E-6541-2017 OI Ragazzon, Bruno/0000-0001-9476-4973 FU INSERM Conny-Maeva Charitable; NICHD, NIH, Bethesda, MD, USA; [259735] FX We thank the members of the FACS Core Facility of Institute Cochin for their cooperation. This study was supported by grants from INSERM the Conny-Maeva Charitable, and the funding of the Seventh Framework Program (FP7/2007-2013) under grant agreement 259735. This work was also supported in part by the intramural program, NICHD, NIH, Bethesda, MD, USA. NR 21 TC 5 Z9 5 U1 0 U2 5 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 NOV PY 2014 VL 46 IS 12 BP 883 EP 888 DI 10.1055/s-0034-1389951 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT2CJ UT WOS:000344738500010 PM 25268545 ER PT J AU Berthon, A Stratakis, CA AF Berthon, A. Stratakis, C. A. TI From beta-Catenin to ARM-Repeat Proteins in Adrenocortical Disorders SO HORMONE AND METABOLIC RESEARCH LA English DT Review DE adrenocortical tumor; macronodular adrenal hyperplasia; APC; ARMC5; beta-catenin ID MACRONODULAR ADRENAL-HYPERPLASIA; FAMILIAL ADENOMATOUS POLYPOSIS; ALDOSTERONE-PRODUCING ADENOMA; WNT SIGNALING PATHWAY; WNT/BETA-CATENIN; ARMADILLO-REPEAT; CORTICAL TUMORS; MUTATIONS; CARCINOMA; CANCER AB Armadillo-containing proteins (ACPs) are a large family of evolutionary conserved proteins, characterized by the tandem repeat copy of a 42 amino acids motif, which forms a 3 dimensional protein-protein interaction domain. This permits ACPs to interact with plenty of partners and consequently, most of these proteins have several independent cellular roles. Perhaps the most well-known protein of this family is beta-catenin, which is crucial in the regulation of development and adult tissue homeostasis through its 2 independent functions, acting in cellular adhesion in addition to being a transcriptional co-activator. APCs have important functions in many tissues, but here we summarize the adrenocortical role of 2 well-described ACPs, beta-catenin (CTNNB1), Adenomatous Polyposis Coli (APC), and discuss the possible role in the adrenal cortex of the most recently discovered, Armadillo-repeat containing 5 (ARMC5). C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,NIH Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (NIH) FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (NIH). NR 61 TC 7 Z9 7 U1 1 U2 2 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 NOV PY 2014 VL 46 IS 12 BP 889 EP 896 DI 10.1055/s-0034-1389993 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT2CJ UT WOS:000344738500011 PM 25295421 ER PT J AU London, E Lodish, M Keil, M Lyssikatos, C Sierra, MD Nesterova, M Stratakis, CA AF London, E. Lodish, M. Keil, M. Lyssikatos, C. Sierra, M. de la Luz Nesterova, M. Stratakis, C. A. TI Not All Glucocorticoid-Induced Obesity is the Same: Differences in Adiposity Among Various Diagnostic Groups of Cushing Syndrome SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE body mass index; bilateral adrenocortical hyperplasia; adipose tissue; protein kinase A; pediatric ID PROTEIN-KINASE-A; NODULAR ADRENOCORTICAL DISEASE; RII-BETA-SUBUNIT; MACRONODULAR ADRENAL-HYPERPLASIA; CARNEY COMPLEX; TARGETED DISRUPTION; REGULATORY SUBUNIT; MUTATIONS; TUMORS; MICE AB The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias (BAHs), which are often associated with ACTH-independent Cushing syndrome (CS). Although CS is invariably associated with obesity and is frequently associated with PKA signaling defects, we recently reported that its different forms appear to also present with variable weight gain and adiposity. The present study was aimed at characterizing further the phenotypic and molecular differences in periadrenal adipose tissue (PAT) among patients with subtypes of CS, by anthropometric/biochemical analyses and quantification of PKA expression and activity in BAHs in comparison to a non-CS group with aldosterone producing adenomas (APAs). Glucocorticoid levels, serum parameters, and BMI were analyzed among a larger patient cohort including those with different forms of CS, APAs, and Cushing disease. Abdominal CT scans were available for a small subset of patients examined for fat distribution. PAT collected during adrenalectomy was assayed for PKA activity, cAMP, and PKA expression. BMI and BMI z-score were lower in adults with PPNAD with PRKAR1A mutations and in pediatric patients with PPNAD with and without PRKAR1A mutations, respectively. Patients with PPNAD had higher cAMP levels in PAT and different fat distribution. Thus, PKA activity in PAT differed between CS diagnostic groups. Increased cAMP and PKA activity may have contributed to phenotypic differences among subtypes of CS. In agreement with the known roles of cAMP signaling in the regulation of adiposity, patients with PPNAD were less obese than other patients with CS. Supporting Information for this article is available online at http://www.thieme-connect.de/products C1 [London, E.; Lodish, M.; Keil, M.; Lyssikatos, C.; Sierra, M. de la Luz; Nesterova, M.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Stratakis, C. A.] NIH, Interinst Pediat Endocrinol Training Program, Bethesda, MD 20892 USA. RP London, E (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,CRC,East Labs, Room 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM londonec@mail.nih.gov FU NICHD FX This work was supported by the NICHD intramural research program. NR 31 TC 5 Z9 6 U1 0 U2 3 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 NOV PY 2014 VL 46 IS 12 BP 897 EP 903 DI 10.1055/s-0034-1389956 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT2CJ UT WOS:000344738500012 PM 25295416 ER PT J AU Upson, K Sathyanarayana, S De Roos, AJ Koch, HM Scholes, D Holt, VL AF Upson, Kristen Sathyanarayana, Sheela De Roos, Anneclaire J. Koch, Holger M. Scholes, Delia Holt, Victoria L. TI A population-based case-control study of urinary bisphenol A concentrations and risk of endometriosis SO HUMAN REPRODUCTION LA English DT Article DE Bisphenol A; endometriosis; epidemiology; environmental health; population-based case-control study ID ENDOCRINE DISRUPTORS; PRENATAL EXPOSURE; DETECTION LIMITS; US POPULATION; WOMEN; HEALTH; EPIDEMIOLOGY; ASSOCIATION; PREVALENCE; HISTORY AB Is bisphenol A (BPA) exposure associated with the risk of endometriosis, an estrogen-driven disease of women of reproductive age? Our study suggests that increased urinary BPA is associated with an increased risk of non-ovarian pelvic endometriosis, but not ovarian endometriosis. BPA, a high-volume chemical used in the polymer industry, has been the focus of public and scientific concern given its demonstrated estrogenic effects in vivo and in vitro and widespread human exposure. Prior studies of BPA and endometriosis have yielded inconsistent results and were limited by the participant sampling framework, small sample size or use of serum (which has very low/transient concentrations) instead of urine to measure BPA concentrations. We used data from the Women's Risk of Endometriosis study, a population-based case-control study of endometriosis, conducted among female enrollees of a large healthcare system in the US Pacific Northwest. Cases were women with incident, surgically confirmed endometriosis diagnosed between 1996 and 2001 and controls were women randomly selected from the defined population that gave rise to the cases, without a current or prior diagnosis of endometriosis. Total urinary BPA concentrations were measured in 143 cases and 287 population-based controls using single, spot urine samples collected after disease diagnosis in cases. Total urinary BPA concentration (free and conjugated species) was quantified using a high-performance liquid chromatography-mass spectrometry method. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression, adjusting for urinary creatinine concentrations, age and reference year. We also evaluated the association by disease subtypes, ovarian and non-ovarian pelvic endometriosis, that may be etiologically distinct. We did not observe a statistically significant association between total urinary BPA concentrations and endometriosis overall. We did observe statistically significant positive associations when evaluating total urinary BPA concentrations in relation to non-ovarian pelvic endometriosis (second versus lowest quartile: OR 3.0; 95% CI: 1.2, 7.3; third versus lowest quartile: OR 3.0; 95% CI: 1.1, 7.6), but not in relation to ovarian endometriosis. Given the short elimination half-life of BPA, our study was limited by the timing of collection of the single urine sample, that occurred after case diagnosis. Thus, our BPA measurements may not accurately represent the participants' levels during the etiologically relevant time period for endometriosis development. In addition, since it was not feasible in this population-based study to surgically confirm the absence of disease, it is possible that some controls may have had undiagnosed endometriosis. By using population-based data, it is more likely that the controls represented the underlying frequency of BPA exposure in contrast to prior studies that used for comparison control women undergoing surgical evaluation, where the indication for surgery may be associated with BPA exposure. The significant associations observed in this study suggest that BPA may affect the normal dynamic structural changes of hormonally responsive endometrial tissue during the menstrual cycle, promoting the establishment and persistence of refluxed endometrial tissue in cases with non-ovarian pelvic endometriosis. Further research is warranted to confirm our novel findings in endometriosis subtypes that may be etiologically distinct. This work was supported by the National Institutes of Health, National Institute of Environmental Health Sciences (grant number R03 ES019976), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number R01 HD033792); US Environmental Protection Agency, Science to Achieve Results (STAR) (grant number R82943-01-0) and National Institute of Nursing Research (grant number F31NR013092) to KU for training support. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, National Institute of Nursing Research or the National Institutes of Health. The authors have no actual or potential competing financial interests. Not applicable. C1 [Upson, Kristen; Scholes, Delia; Holt, Victoria L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Upson, Kristen; Holt, Victoria L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Upson, Kristen] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Sathyanarayana, Sheela] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Sathyanarayana, Sheela] Univ Washington, Sch Publ Hlth, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Sathyanarayana, Sheela] Seattle Childrens Res Inst, Seattle, WA USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Koch, Holger M.] Inst Ruhr Univ Bochum IPA, German Social Accid Insurance, Inst Prevent & Occupat Med, Bochum, Germany. [Scholes, Delia] Grp Hlth Res Inst, Seattle, WA USA. RP Upson, K (reprint author), Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. EM kristen.upson@nih.gov RI Koch, Holger/B-3277-2011; Upson, Kristen/D-4504-2017 OI Koch, Holger/0000-0002-8328-2837; Upson, Kristen/0000-0001-9598-8776 FU National Institutes of Health, National Institute of Environmental Health Sciences [R03 ES019976]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01 HD033792]; US Environmental Protection Agency, Science to Achieve Results (STAR) [R82943-01-0]; National Institute of Nursing Research [F31NR013092]; National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported by the National Institutes of Health, National Institute of Environmental Health Sciences (grant number R03 ES019976), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number R01 HD033792); US Environmental Protection Agency, Science to Achieve Results (STAR) (grant number R82943-01-0) and National Institute of Nursing Research (grant number F31NR013092) to K. U. for training support. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, National Institute of Nursing Research or the National Institutes of Health. NR 49 TC 12 Z9 12 U1 7 U2 32 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD NOV PY 2014 VL 29 IS 11 BP 2457 EP 2464 DI 10.1093/humrep/deu227 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AT1EJ UT WOS:000344675700014 PM 25205760 ER PT J AU Sapra, KJ McLain, AC Maisog, JM Sundaram, R Louis, GMB AF Sapra, K. J. McLain, A. C. Maisog, J. M. Sundaram, R. Louis, G. M. Buck TI Successive time to pregnancy among women experiencing pregnancy loss SO HUMAN REPRODUCTION LA English DT Article DE time-to-pregnancy; spontaneous abortion; pregnancy loss ID SPONTANEOUS-ABORTION; 1ST PREGNANCY; DECREASED FERTILITY; ALCOHOL-CONSUMPTION; PROSPECTIVE COHORT; TO-PREGNANCY; LIFE-STYLE; FETAL LOSS; FECUNDABILITY; COUPLES AB Is time to pregnancy (TTP) similar across successive pregnancy attempts among women experiencing pregnancy loss? TTP after a loss may be longer compared with TTP before a loss. Two pregnancy cohort studies have reported that TTP is similar across pregnancy attempts in fertile women. However, this has not been investigated among women experiencing pregnancy losses. Data for this analysis come from the Longitudinal Investigation of Fertility and the Environment Study, a population-based, preconception cohort of couples attempting pregnancy. During 2005-2009, recruitment was targeted to 16 counties in Michigan and Texas with reported exposures to persistent environmental chemicals. A total of 501 couples were recruited and followed for up to 12 months of pregnancy attempts allowing for continued participation of women with pregnancy losses until censoring. We assessed TTP among 70 couples recruited upon discontinuing contraception for purposes of becoming pregnant and experiencing a parts per thousand yen1 prospectively observed pregnancy losses during 12 months of trying. There were 61 couples who contributed two pregnancy attempts and 9 who contributed three. Women were instructed in the use of urine-based home fertility monitors to time intercourse relative to ovulation and recorded their bleeding patterns in daily journals. TTP was defined as the number of menstrual cycles taken to achieve pregnancy. Women were also instructed in the use of home digital pregnancy tests and asked to begin pregnancy testing on the day of expected menses. Women recorded the results of their pregnancy tests in a daily journal with a single positive pregnancy test result indicating an hCG-confirmed pregnancy. Pregnancy losses were ascertained from a subsequent recorded negative pregnancy test or clinically confirmed loss. We estimated fecundability odds ratios (FORs) comparing subsequent to first TTP using discrete Cox models with robust standard errors, accounting for cycles off contraception before study entry and adjusting for maternal age, body mass index, reproductive history and time-varying cigarette, alcohol and caffeine usage while trying. The mean female age was 30.3 +/- 4.3 years; 21% had a prior pregnancy loss before study entry. Of the second and third attempts, 59 and 43%, respectively, were longer compared with the first attempt. FORs < 1 suggest reduced fecundability or a longer TTP when comparing the second with the first attempt (0.42, 95% confidence interval (CI): 0.28, 0.65), and similarly for the third relative to the first attempt (0.64, 95% CI: 0.18, 2.36). TTP in the second attempt was a median of 1 cycle longer (interquartile range: 0, 3 cycles) compared with TTP in the first attempt. As this is the first study to investigate successive TTP exclusively among women experiencing pregnancy loss, our findings await corroboration since most losses occurred early in gestation. As such, the generalizability of our findings for all pregnancy losses awaits further research. We also had limited power to detect a reduction in fecundability for the third compared with first pregnancy attempt. Unlike fertile women, TTP in women experiencing early pregnancy losses may trend towards longer subsequent attempts. If the findings are corroborated, women experiencing losses may benefit from counselling regarding trying times. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355, N01-HD-3-3356 and NOH-HD-3-3358). K.J.S. was supported by an Intramural Research Training Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research. The authors have no conflicts of interest to declare. C1 [Sapra, K. J.; Sundaram, R.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [McLain, A. C.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Maisog, J. M.] Glotech Inc, Rockville, MD USA. RP Sapra, KJ (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 saprakj@mail.nih.gov OI Sapra, Katherine/0000-0001-5659-6489; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355, N01-HD-3-3356 and NOH-HD-3-3358). K.J.S. was supported by an Intramural Research Training Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research. NR 46 TC 5 Z9 5 U1 3 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD NOV PY 2014 VL 29 IS 11 BP 2553 EP 2559 DI 10.1093/humrep/deu216 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AT1EJ UT WOS:000344675700025 PM 25164026 ER PT J AU Ilkhanoff, L Arking, DE Lemaitre, RN Alonso, A Chen, LY Durda, P Hesselson, SE Kerr, KF Magnani, JW Marcus, GM Schnabel, RB Smith, JG Soliman, EZ Reiner, AP Sotoodehnia, N AF Ilkhanoff, Leonard Arking, Dan E. Lemaitre, Rozenn N. Alonso, Alvaro Chen, Lin Y. Durda, Peter Hesselson, Stephanie E. Kerr, Kathleen F. Magnani, Jared W. Marcus, Gregory M. Schnabel, Renate B. Smith, J. Gustav Soliman, Elsayed Z. Reiner, Alexander P. Sotoodehnia, Nona CA Candidate-Gene Assoc Resource CARE Cardiac Arrest Blood Study CABS TI A Common SCN5A Variant Is Associated with PR Interval and Atrial Fibrillation Among African Americans SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE atrial fibrillation; electrocardiogram; genetics; PR interval; sudden death ID GENOME-WIDE ASSOCIATION; SODIUM-CHANNEL VARIANT; ATHEROSCLEROSIS RISK; CARDIAC-ARRHYTHMIA; HEART; BLACKS; COHORT; CONDUCTION; ANCESTRY; S1103Y AB rs7629265 and AF Risk ObjectiveWe examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans. BackgroundThe SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored. MethodsUsing genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS). ResultsMeta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration ( = -4.1 milliseconds; P = 2.2x10(-6)), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 x 10(-4)). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29). ConclusionThe common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population. C1 [Ilkhanoff, Leonard] Northwestern Univ, Dept Med, Div Cardiol, Sect Electrophysiol, Chicago, IL 60611 USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Lemaitre, Rozenn N.; Sotoodehnia, Nona] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Chen, Lin Y.] Univ Minnesota, Sch Med, Dept Med, Cardiac Arrhythmia Ctr,Cardiovasc Div, Minneapolis, MN 55455 USA. [Durda, Peter] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Hesselson, Stephanie E.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Hesselson, Stephanie E.] Garvan Inst Med Res, Diabet & Obes Div, Sydney, NSW, Australia. [Kerr, Kathleen F.] Univ Washington, Dept Biostat, Sch Publ Hlth, Seattle, WA 98195 USA. [Magnani, Jared W.; Schnabel, Renate B.] Boston Univ, Framingham, MA USA. [Magnani, Jared W.; Schnabel, Renate B.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Marcus, Gregory M.] Univ Calif San Francisco, Div Cardiol, Electrophysiol Sect, San Francisco, CA USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Smith, J. Gustav] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Smith, J. Gustav] Lund Univ, Fac Med, Dept Cardiol, Lund, Sweden. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alexander P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Dept Med, Seattle, WA 98195 USA. RP Sotoodehnia, N (reprint author), Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. EM nsotoo@u.washington.edu RI Alonso, Alvaro/A-4917-2010; Kerr, Kathleen/A-2893-2013 OI Alonso, Alvaro/0000-0002-2225-8323; FU John L. Locke Charitable Trust; Sandra Daugherty Foundation; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; University of Virginia [R01-HL-071205]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; [R01 HL111089]; [R01 HL092111-01]; [R01 HL088456]; [R01 HL116747]; [R01 HL091244]; [1RO1HL092577]; [1RC1HL101056]; [1RO1HL102214]; [N01-HC25195] FX Cardiac Arrest Blood Study (CABS): The CABS research was supported by R01 HL111089, R01 HL092111-01, R01 HL088456, R01 HL116747, R01 HL091244, the John L. Locke Charitable Trust, and the Sandra Daugherty Foundation. Atherosclerosis Risk in Communities (ARIC): The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. Cleveland Family Study (CFS): Case Western Reserve University (NIH HL 46380, M01RR00080); Jackson Heart Study (JHS): Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172); Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington (N01-HC-95159), Regents of the University of California (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 (subcontract to R01-HL-071205). Framingham Health Study (FHS): This FHS research was supported by 1RO1HL092577; 1RC1HL101056; 1RO1HL102214; N01-HC25195. Cardiovascular Health Study (CHS): This CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. NR 27 TC 5 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 EI 1540-8167 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD NOV PY 2014 VL 25 IS 11 BP 1150 EP 1157 DI 10.1111/jce.12483 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS7ZL UT WOS:000344470300002 PM 25065297 ER PT J AU O'Connell, E Rosen, LB LaRue, RW Fabre, V Melia, MT Auwaerter, PG Holland, SM Browne, SK AF O'Connell, Elise Rosen, Lindsey B. LaRue, Richard W. Fabre, Valeria Melia, Michael T. Auwaerter, Paul G. Holland, Steven M. Browne, Sarah K. TI The First US Domestic Report of Disseminated Mycobacterium avium Complex and Anti-Interferon-gamma Autoantibodies SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Anticytokine autoantibodies; interferon-gamma (IFN gamma); nontuberculous mycobacteria; intracranial infection ID IFN-GAMMA; INFECTION; ANTIBODIES; IMMUNODEFICIENCY; AUTOIMMUNITY; DISEASE; PATIENT; LARYNX; HIV AB Anti-interferon-gamma (IFN gamma) autoantibodies have been associated with disseminated mycobacterial infections, mostly in patients from Southeast Asia. We studied an American-born, Caucasian female with M. avium complex infection of the subglottic mucosa and brain for underlying etiologies of infection. Plasma was screened for anticytokine autoantibodies using a Luminex-based approach. The ability of patient plasma to block IFN gamma-induced STAT1 phosphorylation in normal blood cells was evaluated by flow cytometry with intracellular staining. Plasma inhibition of IFN gamma production and IFN gamma-induced cytokines in normal and patient blood cells washed of autologous plasma was also evaluated. Patient plasma contained high-titer IgG anti-IFN gamma autoantibodies, primarily of the IgG(1) subclass. Patient but not control plasma prevented IFN gamma-induced STAT1 phosphorylation and expression of the IFN gamma-inducible cytokines tumor necrosis factor (TNF) alpha and interleukin (IL)-12 in normal blood cells. Patient blood cells washed free of autologous plasma demonstrated normal IFN gamma production and response. Disseminated nontuberculous mycobacterial infections should always prompt immune evaluation. This first case of disseminated nontuberculous mycobacterial infection and anti-IFN gamma autoantibodies in an American-born Caucasian suggests that anti-cytokine autoantibodies are not racially or regionally restricted. C1 [O'Connell, Elise] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Rosen, Lindsey B.; Holland, Steven M.; Browne, Sarah K.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [LaRue, Richard W.; Fabre, Valeria; Melia, Michael T.; Auwaerter, Paul G.] Johns Hopkins, Div Infect Dis, Bethesda, MD 20892 USA. RP Browne, SK (reprint author), NIAID, Lab Clin Infect Dis, NIH, CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM brownesa@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Johns Hopkins Hospital. NR 25 TC 10 Z9 10 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD NOV PY 2014 VL 34 IS 8 BP 928 EP 932 DI 10.1007/s10875-014-0073-9 PG 5 WC Immunology SC Immunology GA AT2QU UT WOS:000344780000007 PM 25149293 ER PT J AU Wilson, EMP Singh, A Hullsiek, KH Gibson, D Henry, WK Lichtenstein, K Onen, NF Kojic, E Patel, P Brooks, JT Sereti, I Baker, JV AF Wilson, Eleanor M. P. Singh, Amrit Hullsiek, Katherine Huppler Gibson, Dave Henry, W. Keith Lichtenstein, Ken Oenen, Nur F. Kojic, Erna Patel, Pragna Brooks, John T. Sereti, Irini Baker, Jason V. CA Understand Nat Hist HIV AIDS Era TI Monocyte-Activation Phenotypes Are Associated With Biomarkers of Inflammation and Coagulation in Chronic HIV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE monocytes; HIV; immune activation; IL-6; D-dimer; C-reactive protein ID ACUTE MYOCARDIAL-INFARCTION; T-CELL-ACTIVATION; ANTIRETROVIRAL THERAPY; SOLUBLE CD163; CARDIOVASCULAR-DISEASE; GENERAL-POPULATION; PREDICT MORTALITY; IMMUNE ACTIVATION; RISK-FACTORS; AIDS AB Background. Soluble biomarkers of inflammation predict non-AIDS related morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. Exploring associations between plasma biomarkers and cellular phenotypes may identify sources of excess inflammation. Methods. Plasma biomarkers (interleukin 6 [IL-6] level, D-dimer level, high-sensitivity C-reactive protein [hsCRP] level, soluble CD14 [sCD14] level, and soluble CD163 [sCD163] level) were measured from cryopreserved samples from the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study). We performed immunophenotyping of peripheral blood mononuclear cells for markers of T-cell and monocyte activation, maturation, and migration. We evaluated associations between cellular phenotypes and soluble biomarkers by Spearman rank correlation and multivariate linear regression. Results. Participants' (n = 670) median age was 41 years, 88% were prescribed antiretroviral therapy, 72% had a plasma HIV RNA load of <400 copies/mL, and the median CD4(+) T-lymphocyte count was 471 cells/mu L. After adjustment, CD14(++)CD16(+) monocytes were associated with higher levels of IL-6, hsCRP, and sCD163; associations with IL-6 and hsCRP persisted in persons with suppressed HIV replication. While CCR5(+) monocytes positively associated with D-dimer levels, CCR2(+) monocytes were inversely associated with hsCRP levels. Conclusions. Plasma inflammatory biomarkers that predict morbidity and mortality were strongly associated with monocyte activation and migration, modestly associated with T-cell maturation, and not associated with CD8(+) T-cell activation phenotypes. These findings suggest that strategies to control monocyte activation warrant further investigation. C1 [Wilson, Eleanor M. P.; Singh, Amrit; Sereti, Irini] NIAID, NIH, Bethesda, MD 20892 USA. [Hullsiek, Katherine Huppler] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Henry, W. Keith; Baker, Jason V.] Univ Minnesota, Dept Med, Minneapolis, MN USA. [Baker, Jason V.] Hennepin Cty Med Ctr, Div Infect Dis, Minneapolis, MN 55415 USA. [Gibson, Dave; Henry, W. Keith; Oenen, Nur F.] Washington Univ Sch Med, St Louis, MO USA. [Lichtenstein, Ken] Natl Jewish Hlth, Denver, CO USA. [Kojic, Erna] Miriam Hosp, Providence, RI 02906 USA. [Patel, Pragna; Brooks, John T.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. RP Baker, JV (reprint author), 701 Pk Ave MC G5, Minneapolis, MN 55415 USA. EM baker459@umn.edu OI Wilson, Eleanor/0000-0002-4855-514X FU Centers for Disease Control and Prevention [200 2002 00610, 200 2002 00611, 200 2002-00612, 200-2002-00613, 200-2007-23633, 200-2007-23634, 200-2007-23635, 200-2007-23636]; National Institutes of Health [1KL2RR033182-01]; National Institute of Allergy and Infectious Diseases FX This work was supported by the Centers for Disease Control and Prevention (contracts 200 2002 00610, 200 2002 00611, 200 2002-00612, 200-2002-00613, 200-2007-23633, 200-2007-23634, 200-2007-23635, and 200-2007-23636), the National Institutes of Health (grant 1KL2RR033182-01), and the National Institute of Allergy and Infectious Diseases (intramural program funds to E. M. P. W., A. S., and I. S.). NR 41 TC 28 Z9 28 U1 0 U2 5 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 NOV 1 PY 2014 VL 210 IS 9 BP 1396 EP 1406 DI 10.1093/infdis/jiu275 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0ER UT WOS:000344610600007 PM 24813472 ER PT J AU Wahl, SM AF Wahl, Sharon M. TI Memorial: Nancy McCartney-Francis, 1950-2014 SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Letter DE TGF-beta; SLPI; Leishmania major; leukocyte; macrophage; pathogen C1 [Wahl, Sharon M.] Natl Inst Dent & Craniofacial Res, Cellular Immunol Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. RP Wahl, SM (reprint author), NIDCR, NIH, 30 Convent Dr,Bldg 30,Room 106, Bethesda, MD 20892 USA. EM smwahl@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD NOV PY 2014 VL 96 IS 5 BP 667 EP 668 DI 10.1189/jlb.4LT0614-301 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AT2JC UT WOS:000344759800001 PM 25360038 ER PT J AU McCartney-Francis, N Jin, WW Belkaid, Y McGrady, G Wahl, SM AF McCartney-Francis, Nancy Jin, Wenwen Belkaid, Yasmine McGrady, George Wahl, Sharon M. TI Aberrant host defense against Leishmania major in the absence of SLPI SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE parasite; IFN-gamma; macrophage polarization; SOCS; NO ID LEUKOCYTE PROTEASE INHIBITOR; SECRETORY LEUCOPROTEASE INHIBITOR; MARROW-DERIVED MACROPHAGES; NITRIC-OXIDE SYNTHASE; L-ARGININE METABOLISM; ARGINASE-I INDUCTION; NF-KAPPA-B; ALTERNATIVE ACTIVATION; INTRACELLULAR PATHOGENS; CUTANEOUS LEISHMANIASIS AB SLPI, a potent epithelial and myeloid-derived serine protease inhibitor with antimicrobial and anti-inflammatory functions, is induced by the intracellular parasite Leishmania major, and increased SLPI expression is evident within lesions that follow L. major infection. In contrast to self-resolving infection in C57Bl/6 WT mice, Slpi(--) mice launch a strong Th1 response to L. major, yet fail to control infection and develop destructive, nonhealing lesions with systemic spread of parasites. Because SLPI is both produced by murine macrophages and antagonizes their function, we examined the contribution of macrophage polarization to the defective host response in the absence of SLPI. Slpi(-/-) and Slpi(-/-) macrophages were first primed with either IFN gamma or IL-4 to generate classically activated M1 or alternatively activated M2 macrophages. After infection with L. major, Slpi(-/-) M1 macrophages expressed elevated iNOS RNA, whereas arginase was more highly expressed in WT than Slpi(-/-) M2 macrophages. After in vivo infection, we found that both IFN gamma and iNOS were persistently overexpressed in chronic lesions in Slpi(-/-) mice, but surprisingly, IL-4 and arginase concomitantly remained elevated. Moreover, overexpression of the negative regulators SOCS1 and IL-27 provided insight into the failure of IFN gamma to clear L. major from the dermal lesions. Notably, adenoviral delivery of SLPI to L. major-infected Slpi(-/-) mice significantly limited the progression of infection. These studies suggest that convergence of M1 and M2 macrophage responses may influence the outcome of innate host defense against intracellular parasites and that SLPI is critical for coordinating resistance to chronic leishmaniasis. C1 [McCartney-Francis, Nancy; Jin, Wenwen; McGrady, George; Wahl, Sharon M.] NIDCR, Cellular Immunol Sect, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, Parasit Dis Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Wahl, SM (reprint author), NIDCR, NIH, 30 Convent Dr,Bldg 30,Room 106, Bethesda, MD 20892 USA. EM smwahl@mail.nih.gov FU Intramural Research Program of the U.S. National Institutes of Health, National Institute of Dental and Craniofacial Research FX This research was supported in part by the Intramural Research Program of the U.S. National Institutes of Health, National Institute of Dental and Craniofacial Research. The authors thank Drs. A. Molinolo and Azita Adli, NIDCR, NIH, for expertise in immunopathology and immunohistochemistry, and Dr. D. Sacks, NIAID, NIH, for Leishmania parasites, and Dr. D. Chou, NIAID, NIH, for assistance with SLPI leishmanicidal assays. NR 69 TC 2 Z9 2 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD NOV PY 2014 VL 96 IS 5 BP 917 EP 929 DI 10.1189/jlb.4A0612-295RR PG 13 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AT2JC UT WOS:000344759800026 PM 25030421 ER PT J AU Gatwood, J Gibson, TB Chernew, ME Farr, AM Vogtmann, E Fendrick, AM AF Gatwood, Justin Gibson, Teresa B. Chernew, Michael E. Farr, Amanda M. Vogtmann, Emily Fendrick, A. Mark TI Price Elasticity and Medication Use: Cost Sharing Across Multiple Clinical Conditions SO JOURNAL OF MANAGED CARE PHARMACY LA English DT Article ID PRESCRIPTION DRUGS; COPAYMENTS; HEALTH; IMPACT AB BACKGROUND: To address the impact that out-of-pocket prices may have on medication use, it is vital to understand how the demand for medications may be affected when patients are faced with changes in the price to acquire treatment and how price responsiveness differs across medication classes. OBJECTIVE: To examine the impact of cost-sharing changes on the demand for 8 classes of prescription medications. METHODS: This was a retrospective database analysis of 11,550,363 commercially insured enrollees within the 2005-2009 Market Scan Database. Patient cost sharing, expressed as a price index for each medication class, was the main explanatory variable to examine the price elasticity of demand. Negative binomial fixed effect models were estimated to examine medication fills. The elasticity estimates reflect how use changes over time as a function of changes in copayments. RESULTS: Model estimates revealed that price elasticity of demand ranged from -0.015 to -0.157 within the 8 categories of medications (P<0.01 for 7 of 8 categories). The price elasticity of demand for smoking deterrents was largest (-0.157, P<0.0001), while demand for antiplatelet agents was not responsive to price (P>0.05). CONCLUSIONS: The price elasticity of demand varied considerably by medication class, suggesting that the influence of cost sharing on medication use may be related to characteristics inherent to each medication class or underlying condition. Copyright (C) 2014, Academy of Managed Care Pharmacy. All rights reserved. C1 [Gatwood, Justin] Univ Tennessee, Coll Pharm, Memphis, TN 38103 USA. [Gibson, Teresa B.; Farr, Amanda M.] Truven Hlth Analyt, Ann Arbor, MI USA. [Vogtmann, Emily] NCI, Bethesda, MD 20892 USA. [Chernew, Michael E.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Fendrick, A. Mark] Univ Michigan, Sch Med, Ann Arbor, MI USA. RP Gatwood, J (reprint author), Univ Tennessee, Coll Pharm, 881 Madison Ave, Memphis, TN 38103 USA. EM jgatwood@uthsc.edu FU Pfizer, Inc. FX This project was funded by Pfizer, Inc. All opinions expressed are those of the authors. NR 14 TC 2 Z9 2 U1 0 U2 1 PU ACAD MANAGED CARE PHARMACY PI ALEXANDRIA PA 100 N PITT ST, 400, ALEXANDRIA, VA 22314-3134 USA SN 1083-4087 J9 J MANAGE CARE PHARM JI J. Manag. Care Pharm. PD NOV PY 2014 VL 20 IS 11 BP 1102 EP 1107 PG 6 WC Health Care Sciences & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA AS8RF UT WOS:000344515200004 PM 25351971 ER PT J AU Korzeniewski, SJ Romero, R Cortez, J Pappas, A Schwartz, AG Kim, CJ Kim, JS Kim, YM Yoon, BH Chaiworapongsa, T Hassan, SS AF Korzeniewski, Steven J. Romero, Roberto Cortez, Josepf Pappas, Athina Schwartz, Alyse G. Kim, Chong Jai Kim, Jung-Sun Kim, Yeon Mee Yoon, Bo Hyun Chaiworapongsa, Tinnakorn Hassan, Sonia S. TI A "multi-hit" model of neonatal white matter injury: cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE FIRS; infection; ventricular enlargement; ventriculomegaly ID EXTREMELY PRETERM INFANTS; DEVELOPING RAT-BRAIN; LOW-BIRTH-WEIGHT; SEVERE INTRAVENTRICULAR HEMORRHAGE; BACTERIAL-ENDOTOXIN SENSITIZES; RESPIRATORY-DISTRESS-SYNDROME; POLYMERASE-CHAIN-REACTION; NECROSIS-FACTOR-ALPHA; INTENSIVE-CARE-UNIT; SYSTEMIC INFLAMMATION AB Objective: We sought to determine whether cumulative evidence of perinatal inflammation was associated with increased risk in a "multi-hit" model of neonatal white matter injury (WMI). Methods: This retrospective cohort study included very preterm (gestational ages at delivery <32 weeks) live-born singleton neonates delivered at Hutzel Women's Hospital, Detroit, MI, from 2006 to 2011. Four pathologists blinded to clinical diagnoses and outcomes performed histological examinations according to standardized protocols. Neurosonography was obtained per routine clinical care. The primary indicator of WMI was ventriculomegaly (VE). Neonatal inflammation-initiating illnesses included bacteremia, surgical necrotizing enterocolitis, other infections, and those requiring mechanical ventilation. Results: A total of 425 live-born singleton neonates delivered before the 32nd week of gestation were included. Newborns delivered of pregnancies affected by chronic chorioamnionitis who had histologic evidence of an acute fetal inflammatory response were at increased risk of VE, unlike those without funisitis, relative to referent newborns without either condition, adjusting for gestational age [odds ratio (OR) 4.7; 95% confidence interval (CI) -1.4-15.8 vs. OR 1.3; 95% CI 0.7-2.6]. Similarly, newborns with funisitis who developed neonatal inflammation-initiating illness were at increased risk of VE, unlike those who did not develop such illness, compared to the referent group without either condition [OR 3.6 (95% CI 1.58.3) vs. OR 1.7 (95% CI 0.5-5.5)]. The greater the number of these three types of inflammation documented, the higher the risk of VE (P < 0.0001). Conclusion: Chronic placental inflammation, acute fetal inflammation, and neonatal inflammation-initiating illness seem to interact in contributing risk information and/or directly damaging the developing brain of newborns delivered very preterm. C1 [Korzeniewski, Steven J.; Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, D Med Sci Perinatol Res Branch, NICHD,DHHS,NIH, Detroit, MI 48201 USA. [Korzeniewski, Steven J.; Romero, Roberto; Cortez, Josepf; Pappas, Athina; Schwartz, Alyse G.; Kim, Chong Jai; Chaiworapongsa, Tinnakorn; 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. [Korzeniewski, Steven J.; Romero, Roberto; Cortez, Josepf; Pappas, Athina; Schwartz, Alyse G.; Kim, Chong Jai; Chaiworapongsa, Tinnakorn; 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. [Korzeniewski, Steven J.; Schwartz, Alyse G.; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet Gynecol, Detroit, MI USA. [Korzeniewski, Steven J.; Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Cortez, Josepf; Pappas, Athina] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Kim, Chong Jai] Seoul Natl Univ, Bundang Hosp, Dept Obstet & Gynecol, Gyeonggi Do, South Korea. [Kim, Jung-Sun] Sungkyunkwan Univ, Sch Med, Dept Pathol, Seoul, South Korea. [Kim, Yeon Mee] Inje Univ, Haeundae Paik Hosp, Coll Med, Dept Pathol, Gimhae, South Korea. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Korzeniewski, SJ (reprint author), Wayne State Univ, Hutzel Womens Hosp, D Med Sci Perinatol Res Branch, NICHD,DHHS,NIH, 3990 John R,Box 4, Detroit, MI 48201 USA. EM skorzeni@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, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HHSN275201300006C] FX 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, National Institutes of Health, Department of Health and Human Services (NICHD/NIH), and, in part, with federal funds from NICHD, NIH under contract no. HHSN275201300006C. NR 96 TC 16 Z9 18 U1 0 U2 8 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD NOV PY 2014 VL 42 IS 6 BP 731 EP 743 DI 10.1515/jpm-2014-0250 PG 13 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AT4WM UT WOS:000344942500010 PM 25205706 ER PT J AU Han, MHJ Hu, ZH Chen, CY Chen, Y Gucek, M Li, Z Markey, SP AF Han, Meng-Hsuan J. Hu, Zhonghua Chen, Cai Yun Chen, Yong Gucek, Marjan Li, Zheng Markey, Sanford P. TI Dysbindin-Associated Proteome in the P2 Synaptosome Fraction of Mouse Brain SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Dysbindin; schizophrenia; synaptosome; protein complex; protein-protein interaction; BAC transgenesis; proteasome; mass spectrometry ID ORGANELLES COMPLEX 1; PREFRONTAL CORTEX; STATISTICAL-MODEL; NEGATIVE SYMPTOMS; ANALYSIS REVEALS; CANDIDATE GENES; SANDY MICE; SCHIZOPHRENIA; DTNBP1; EXPRESSION AB The gene DTNBP1 encodes the protein dysbindin and is among the most promising and highly investigated schizophrenia-risk genes. Accumulating evidence suggests that dysbindin plays an important role in the regulation of neuroplasticity. Dysbindin was reported to be a stable component of BLOC-1 complex in the cytosol. However, little is known about the endogenous dysbindin-containing complex in the brain synaptosome. In this study, we investigated the associated proteome of dysbindin in the P2 synaptosome fraction of mouse brain. Our data suggest that dysbindin has three isoforms associating with different complexes in the P2 fraction of mouse brain. To facilitate immunopurification, BAC transgenic mice expressing a tagged dysbindin were generated, and 47 putative dysbindin-associated proteins, including all components of BLOC-1, were identified by mass spectrometry in the dysbindin-containing complex purified from P2. The interactions of several selected candidates, including WDR11, FAM91A1, snapin, muted, pallidin, and two proteasome subunits, PSMD9 and PSMA4, were verified by coimmunoprecipitation. The specific proteasomal activity is significantly reduced in the P2 fraction of the brains of the dysbindin-null mutant (sandy) mice. Our data suggest that dysbindin is functionally interrelated to the ubiquitin-proteasome system and offer a molecular repertoire for future study of dysbindin functional networks in brain. C1 [Han, Meng-Hsuan J.; Hu, Zhonghua; Chen, Cai Yun; Li, Zheng; Markey, Sanford P.] NIMH, Bethesda, MD 20892 USA. [Han, Meng-Hsuan J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Chen, Yong; Gucek, Marjan] NHLBI, Bethesda, MD 20892 USA. RP Markey, SP (reprint author), NIMH, Bethesda, MD 20892 USA. EM sanford.markey@nih.gov RI Li, Zheng/I-8016-2014; Hu, Zhonghua/J-1169-2016 OI Li, Zheng/0000-0002-2978-2531; Hu, Zhonghua/0000-0002-0117-7081 FU National Institute of Mental Health [1ZIAMH000274-35, 1ZIAMH00279-27, 1ZIAMH002881] FX Our sincere thanks to Jim Makusky, Ronald Finnegan (scientific applications and virtual machine services), Dr. Brian Martin, Dr. Michael Strader, Dr. Adele Blackler, Dr. Jeff Kowalak, Dr. Yan Leng, Dr. Song Jiao, and Dr. Jie-Min Jia at NIMH for technical support, advice, and assistance. This research was supported by the Intramural Research Program of the National Institute of Mental Health, project nos. 1ZIAMH000274-35, 1ZIAMH00279-27, and 1ZIAMH002881. NR 66 TC 5 Z9 5 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD NOV PY 2014 VL 13 IS 11 BP 4567 EP 4580 DI 10.1021/pr500656z PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AT0PA UT WOS:000344636500009 PM 25198678 ER PT J AU Moore, RA Sturdevant, DE Chesebro, B Priola, SA AF Moore, Roger A. Sturdevant, Dan E. Chesebro, Bruce Priola, Suzette A. TI Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE LC-MS/MS; proteomics; prion disease; transmissible spongiform encephalopathies; glycosylphosphatidylinositol; amyloid; cerebral amyloid angiopathy; Alzheimers disease ID CREUTZFELDT-JAKOB-DISEASE; INFECTED MOUSE BRAINS; FALSE-DISCOVERY RATE; QUANTITATIVE PROTEOMICS; SECONDARY STRUCTURE; SHOTGUN PROTEOMICS; MASS-SPECTROMETRY; SCRAPIE AGENT; CELL-DEATH; PROTEIN AB Prion diseases are a heterogeneous group of neurodegenerative disorders affecting various mammals including humans. Prion diseases are characterized by a misfolding of the host-encoded prion protein (PrP(C)) into a pathological isoform termed PrP(Sc). In wild-type mice, PrP(C) is attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and PrP(Sc) typically accumulates in diffuse nonamyloid deposits with gray matter spongiosis. By contrast, when mice lacking the GPI anchor are infected with the same prion inoculum, PrP(Sc) accumulates in dense perivascular amyloid plaques with little or no gray matter spongiosis. In order to evaluate whether different host biochemical pathways were implicated in these two phenotypically distinct prion disease models, we utilized a proteomics approach. In both models, infected mice displayed evidence of a neuroinflammatory response and complement activation. Proteins involved in cell death and calcium homeostasis were also identified in both phenotypes. However, mitochondrial pathways of apoptosis were implicated only in the nonamyloid form, whereas metal binding and synaptic vesicle transport were more disrupted in the amyloid phenotype. Thus, following infection with a single prion strain, PrP(C) anchoring to the plasma membrane correlated not only with the type of PrP(Sc) deposition but also with unique biochemical pathways associated with pathogenesis. C1 [Moore, Roger A.; Chesebro, Bruce; Priola, Suzette A.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. [Sturdevant, Dan E.] NIAID, Rocky Mt Labs, Res Technol Branch, Hamilton, MT 59840 USA. RP Moore, RA (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM rmoore@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Disease FX The authors wish to acknowledge Dr. Michael Klingeborn and Kimberly Meade-White for technical assistance and Drs. Karin Peterson, Jay Carroll, and Katherine Taylor for critical review of the manuscript. The authors also thank Anita Mora and Austin Athman for help with the figures. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease. NR 83 TC 6 Z9 6 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD NOV PY 2014 VL 13 IS 11 BP 4620 EP 4634 DI 10.1021/pr500329w PG 15 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AT0PA UT WOS:000344636500013 PM 25140793 ER PT J AU Sjoelund, V Smelkinson, M Nita-Lazar, A AF Sjoelund, Virginie Smelkinson, Margery Nita-Lazar, Aleksandra TI Phosphoproteome Profiling of the Macrophage Response to Different Toll-Like Receptor Ligands Identifies Differences in Global Phosphorylation Dynamics SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE toll-like receptors; phosphoproteomics; macrophage; innate immunity; SILAC; TLR2; TLR4; TLR7 ID NF-KAPPA-B; ACTIN CYTOSKELETON; INFLAMMATORY RESPONSES; SIGNALING NETWORKS; MOUSE-LIVER; RHO GTPASES; CROSS-TALK; LPS; PROTEOMICS; REVEALS AB Toll-like receptors (TLRs) are among the first sensors that detect infection and drive immune response. Macrophages encountering a pathogen are usually stimulated not by one TLR, but by a combination of TLRs engaged by distinct microbe ligands. To understand the integrated signaling under complex conditions, we investigated the differences in the phosphoprotein signaling cascades triggered by TLR2, TLR4, and TLR7 ligands using a single responding cell population. We performed a global, quantitative, early poststimulation kinetic analysis of the mouse macrophage phosphoproteome using stable isotope labeling with amino acids coupled to phosphopeptide enrichment and high-resolution mass spectrometry. For each TLR ligand, we found marked elevation of phosphorylation of cytoskeleton components, GTPases of the Rho family, and phospholipase C signaling pathway proteins. Phosphorylation of proteins involved in phagocytosis was only seen in response to TLR2 and TLR4 but not to TLR7 activation. Changes in the phosphorylation of proteins involved in endocytosis were delayed in response to TLR2 as compared to TLR4 ligands. These findings reveal that the phosphoproteomic response to stimulation of distinct TLRs varies both in the major modification targets and the phosphorylation dynamics. These results advance the understanding of how macrophages sense and respond to a diverse set of TLR stimuli. C1 [Sjoelund, Virginie; Nita-Lazar, Aleksandra] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Smelkinson, Margery] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Nita-Lazar, A (reprint author), NIAID, Cellular Networks Prote Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. EM nitalazarau@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Owen Schwartz at Biological Imaging Section (NIAID/NIH) for help with the imaging. We also thank lain Fraser and Nathan Manes for advice and discussions, Art Nuccio for technical assistance and Jack Bennink, Marijke Koppenol-Raab, and Jessica Mann for helpful comments on the manuscript. We are also grateful to Ronald N. Germain for his support and advice during the conduct of this study and for help with preparation of the manuscript. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 65 TC 5 Z9 5 U1 2 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD NOV PY 2014 VL 13 IS 11 BP 5185 EP 5197 DI 10.1021/pr5002466 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AT0PA UT WOS:000344636500060 PM 24941444 ER PT J AU Cotrim, AP Alevizos, I AF Cotrim, Ana P. Alevizos, Ilias TI Human and Viral microRNA Expression in Sjogren Syndrome SO JOURNAL OF RHEUMATOLOGY LA English DT Editorial Material ID MONONUCLEAR-CELLS; RESPONSES; PROFILES; LYMPHOMA; MIR-146A C1 [Cotrim, Ana P.; Alevizos, Ilias] NIDCR, Mol Physiol & Therapeut Branch, SS & Salivary Gland Dysfunct Unit, NIH, Bethesda, MD USA. RP Alevizos, I (reprint author), Natl Inst Dent & Craniofacial Res, SS & Salivary Dysfunct Unit, 10 Ctr Dr,Bldg 10,Rm 1N110, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 17 TC 0 Z9 0 U1 1 U2 7 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD NOV PY 2014 VL 41 IS 11 BP 2102 EP 2103 DI 10.3899/jrheum.141068 PG 2 WC Rheumatology SC Rheumatology GA AT0AI UT WOS:000344598900005 PM 25362707 ER PT J AU Rose, S Toloza, S Bautista-Molano, W Helliwell, PS AF Rose, Shawn Toloza, Sergio Bautista-Molano, Wilson Helliwell, Philip S. CA GRAPPA Dactylitis Study Grp TI Comprehensive Treatment of Dactylitis in Psoriatic Arthritis SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE PSORIATIC ARTHRITIS; DACTYLITIS; TREATMENT; SYSTEMATIC REVIEW ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; MONOCLONAL-ANTIBODY; CLINICAL-RESPONSE; IMPACT-2 TRIAL; OPEN-LABEL; EFFICACY; SAFETY; INFLIXIMAB; THERAPY AB Dactylitis, a hallmark clinical feature of psoriatic arthritis (PsA) and other spondyloarthropathies, may also be a severity marker for PsA and psoriasis. Traditionally, clinicians have used nonsteroidal antiinflammatory drugs and local corticosteroid injections to treat dactylitis, although conventional disease-modifying antirheumatic drugs are also used. We performed a systematic literature review to determine the most efficacious current treatment options for dactylitis in PsA. Effect sizes were greatest for the biologic agents ustekinumab, certolizumab, and infliximab, suggesting that therapy with one of these agents should be initiated in patients with dactylitis. However, the limited data highlight the need for randomized, placebo-controlled trials, with dactylitis as a primary outcome, to determine a valid, reliable, and responsive clinical outcome measure for PsA patients with dactylitis. C1 US Natl Inst Hlth, Bethesda, MD USA. [Toloza, Sergio] Minist Hlth, San Fernando Del Valle D, Argentina. [Bautista-Molano, Wilson] UMNG, Cent Mil Hosp, Fac Med, Dept Rheumatol, Bogota, Colombia. [Helliwell, Philip S.] Univ Leeds, Leeds, W Yorkshire, England. [Helliwell, Philip S.] Bradford Hosp NHS Fdn Trust, Bradford, W Yorkshire, England. RP Helliwell, PS (reprint author), Univ Leeds, Inst Mol Med, Sect Musculoskeletal Dis, Chapel Allerton Hosp, 2nd Floor,Harehills Lane, Leeds LS7 4SA, W Yorkshire, England. EM p.helliwell@leeds.ac.uk OI Queiro, Ruben/0000-0002-8418-7145 NR 32 TC 14 Z9 14 U1 0 U2 4 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD NOV PY 2014 VL 41 IS 11 BP 2295 EP 2300 DI 10.3899/jrheum.140879 PG 6 WC Rheumatology SC Rheumatology GA AT0AI UT WOS:000344598900032 PM 25362714 ER PT J AU Millen, BE Wolongevicz, DM de Jesus, JM Nonas, CA Lichtenstein, AH AF Millen, Barbara E. Wolongevicz, Dolores M. de Jesus, Janet M. Nonas, Cathy A. Lichtenstein, Alice H. TI 2013 American Heart Association/American College of Cardiology Guideline on Lifestyle Management to Reduce Cardiovascular Risk: Practice Opportunities for Registered Dietitian Nutritionists SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Editorial Material DE Cardiovascular disease; Cardiovascular disease risk reduction guidelines; Lifestyle guidelines; Dietary guidelines; Comprehensive lifestyle intervention ID RANDOMIZED-CONTROLLED-TRIALS; RESTING BLOOD-PRESSURE; DIETARY FATTY-ACIDS; DASH-SODIUM TRIAL; AEROBIC EXERCISE; DISEASE RISK; SERUM-LIPIDS; MEDITERRANEAN DIET; SUBGROUP ANALYSIS; PHYSICAL-ACTIVITY C1 [Millen, Barbara E.] Millennium Prevent Inc, Boston Nutr Fdn Inc, Westwood, MA 02090 USA. [Millen, Barbara E.] Boston Univ, Sch Med, Dept Family Med, Program Grad Med Nutr Sci, Boston, MA 02118 USA. [Wolongevicz, Dolores M.] Millennium Prevent Inc, Westwood, MA 02090 USA. [de Jesus, Janet M.] NHLBI, CTRIS, NIH, Bethesda, MD USA. [Nonas, Cathy A.] Bur Chron Dis Prevent & Tobacco Control, New York City Dept Hlth & Mental Hyg, Queens, NY USA. [Lichtenstein, Alice H.] Tufts Univ, Boston, MA 02111 USA. RP Wolongevicz, DM (reprint author), Millennium Prevent Inc, POB 311, Westwood, MA 02090 USA. EM dwolongevicz@millenniumprevention.com NR 67 TC 4 Z9 4 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD NOV PY 2014 VL 114 IS 11 BP 1723 EP 1729 DI 10.1016/j.jand.2014.07.037 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AS8CE UT WOS:000344477100005 PM 25439080 ER PT J AU Ternpero, M AF Tempero, Margaret TI Bringing Science to Clinical Practice SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] Univ Calif San Francisco, Pancreas Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect CONC, Bethesda, MD 20892 USA. [Tempero, Margaret] NCI, Board Sci Counselors Subcomm, Bethesda, MD 20892 USA. [Tempero, Margaret] Mayo Clin, Rochester, MN USA. [Tempero, Margaret] UAB Minnesota, Birmingham, AL USA. [Tempero, Margaret] Univ Arizona, GI SPORE, Tucson, AZ 85721 USA. [Tempero, Margaret] Lustgarten Fdn, Bethpage, NY USA. [Tempero, Margaret] Pancreat Canc Act Network, Manhattan Beach, CA USA. [Tempero, Margaret] Alberta Canada Canc Board, Calgary, AB, Canada. [Tempero, Margaret] EORTC, Brussels, Belgium. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE USA. [Tempero, Margaret] Univ Calif San Francisco, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA 94143 USA. RP Ternpero, M (reprint author), Univ Calif San Francisco, Pancreas Ctr, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2014 VL 12 IS 11 BP 1495 EP 1495 PG 1 WC Oncology SC Oncology GA AS8RP UT WOS:000344516200001 ER PT J AU Hultcrantz, M Pfeiffer, RM Bjorkholm, M Goldin, LR Turesson, I Schulman, S Landgren, O Kristinsson, SY AF Hultcrantz, M. Pfeiffer, R. M. Bjorkholm, M. Goldin, L. R. Turesson, I. Schulman, S. Landgren, O. Kristinsson, S. Y. TI Elevated risk of venous but not arterial thrombosis in Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE embolism and thrombosis; lymphoma; B cell; thrombosis; venous thrombosis; Waldenstrom macroglobulinemia ID RETINAL VEIN OCCLUSION; L265P SOMATIC MUTATION; MULTIPLE-MYELOMA; MONOCLONAL GAMMOPATHY; MYD88 L265P; LYMPHOPROLIFERATIVE MALIGNANCIES; UNDETERMINED SIGNIFICANCE; HYPERVISCOSITY SYNDROME; PLUS DEXAMETHASONE; MACROGLOBULINEMIA AB BackgroundMany malignancies, including multiple myeloma and its precursor, monoclonal gammopathy of unknown significant, are associated with an elevated risk of thromboembolism. There is limited information on the risk of thrombosis in patients with Waldenstrom macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). ObjectivesTo assess the risk of venous and arterial thrombosis in WM/LPL patients in a large population-based cohort study in Sweden. Patients/methodsA total of 2190 patients with WM/LPL and 8086 matched controls were identified through Swedish registers between 1987 and 2005. Information on occurrence of venous and arterial thrombosis after the diagnosis of WM/LPL was obtained through the centralized Swedish Patient Register, with follow-up to 2006. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsPatients with WM/LPL had a significantly increased risk of venous thrombosis and the highest risk was observed during the first year following diagnosis (HR=4.0, 95% CI 2.5-6.4). The risk was significantly elevated 5 (HR=2.3, 95% CI 1.7-3.0) and 10years after diagnosis (HR=2.0, 95% CI 1.6-2.5). There was no increased risk of arterial thrombosis during any period of follow-up time (10-year HR=1.0, 95% CI 0.9-1.1). ConclusionsVenous thrombosis is a significant cause of morbidity in patients with WM/LPL. The potential role of thromboprophylaxis in WM/LPL, especially during the first year after diagnosis and in patients treated with thrombogenic agents, needs to be assessed to further improve outcome in WM/LPL patients. C1 [Hultcrantz, M.; Bjorkholm, M.; Schulman, S.] Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden. [Hultcrantz, M.; Bjorkholm, M.; Schulman, S.] Karolinska Inst, Stockholm, Sweden. [Pfeiffer, R. M.; Goldin, L. R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Turesson, I.] Skane Univ Hosp, Dept Hematol & Coagulat disorders, Malmo, Sweden. [Schulman, S.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Landgren, O.] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, New York, NY 10021 USA. Univ Iceland, Fac Med, Reykjavik, Iceland. [Kristinsson, S. Y.] Landspitali Natl Univ Hosp, Dept Hematol, Reykjavik, Iceland. RP Hultcrantz, M (reprint author), Karolinska Univ, Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. EM malin.hultcrantz@ki.se RI Kristinsson, Sigurdur /M-2910-2015; OI Kristinsson, Sigurdur /0000-0002-4964-7476; Schulman, Sam/0000-0002-8512-9043 NR 30 TC 1 Z9 1 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD NOV PY 2014 VL 12 IS 11 BP 1816 EP 1821 DI 10.1111/jth.12724 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AT1IN UT WOS:000344686700007 PM 25196979 ER PT J AU Ahmed, M Solbiati, L Brace, CL Breen, DJ Callstrom, MR Charboneau, JW Chen, MH Choi, BI de Baere, T Dodd, GD Gervais, DA Gianfelice, D Gillams, AR Lee, FT Leen, E Lencioni, R Littrup, PJ Livraghi, T Lu, DS McGahan, JP Meloni, MF Nikolic, B Pereira, PL Liang, P Rhim, H Rose, SC Salem, R Sofocleous, CT Solomon, SB Soulen, MC Tanaka, M Vogl, TJ Wood, BJ Goldberg, SN AF Ahmed, Muneeb Solbiati, Luigi Brace, Christopher L. Breen, David J. Callstrom, Matthew R. Charboneau, J. William Chen, Min-Hua Choi, Byung Ihn de Baere, Thierry Dodd, Gerald D., III Gervais, Debra A. Gianfelice, David Gillams, Alice R. Lee, Fred T., Jr. Leen, Edward Lencioni, Riccardo Littrup, Peter J. Livraghi, Tito Lu, David S. McGahan, John P. Meloni, Maria Franca Nikolic, Boris Pereira, Philippe L. Liang, Ping Rhim, Hyunchul Rose, Steven C. Salem, Riad Sofocleous, Constantinos T. Solomon, Stephen B. Soulen, Michael C. Tanaka, Masatoshi Vogl, Thomas J. Wood, Bradford J. Goldberg, S. Nahum CA Int Working Grp Image-Guided Tumor TI Image-Guided Tumor Ablation: Standardization of Terminology and Reporting Criteria-A 10-Year Update SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID PERCUTANEOUS RADIOFREQUENCY ABLATION; RENAL-CELL CARCINOMA; VIVO PORCINE LIVER; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; IRREVERSIBLE ELECTROPORATION ABLATION; CONTRAST-ENHANCED ULTRASOUND; INTERNALLY COOLED ELECTRODES; LONG-TERM SURVIVAL; QUALITY-OF-LIFE; HEPATOCELLULAR-CARCINOMA AB Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. C1 [Ahmed, Muneeb] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Solbiati, Luigi] Osped Generale, Dept Radiol, Busto Arsizio, Italy. [Brace, Christopher L.] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Brace, Christopher L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biomed Engn, Madison, WI USA. [Brace, Christopher L.] Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Breen, David J.] Southampton Univ Hosp, Dept Radiol, Southampton, Hants, England. [Callstrom, Matthew R.; Charboneau, J. William] Mayo Clin, Dept Radiol, Rochester, MN USA. [Chen, Min-Hua] Peking Univ, Sch Oncol, Dept Ultrasound, Beijing 100871, Peoples R China. [Choi, Byung Ihn] Seoul Natl Univ Hosp, Dept Radiol, Seoul 110744, South Korea. [de Baere, Thierry] Inst Cancerol Gustave Roussy, Dept Imaging, Villejuif, France. [Dodd, Gerald D., III] Univ Colorado Anschutz Med Campus, Sch Med, Dept Radiol, Aurora, CO USA. Rhode Isl Hosp, Dept Diagnost Fladiol, Providence, RI USA. [Gervais, Debra A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Gianfelice, David] Univ Hlth Network, Laval, PQ, Canada. [Gillams, Alice R.] London Clin, Dept Imaging, London, England. [Lee, Fred T., Jr.] Univ Wisconsin Hosp & Clin, Dept Radiol, Madison, WI 53792 USA. [Leen, Edward] Royal Infirm, Dept Radiol, Glasgow G31 2ER, Lanark, Scotland. [Lencioni, Riccardo] Univ Pisa, Pisa Univ Hosp, Cisanello Hosp, Dept Diagnost Imaging & Intervent, Pisa, Italy. [Lencioni, Riccardo] Univ Pisa, Sch Med, I-56100 Pisa, Italy. [Littrup, Peter J.] Wayne State Univ, Karmonos Canc Inst, Dept Radiol, Detroit, MI USA. [Lu, David S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. [McGahan, John P.] Univ Calif Davis, Med Ctr, Ctr Ambulatory Care, Dept Radiol, Sacramento, CA 95817 USA. [Meloni, Maria Franca] Osped Valduce, Dept Radiol, Como, Italy. [Nikolic, Boris] Albert Einstein Med Ctr, Dept Radiol, Philadelphia, PA 19141 USA. [Pereira, Philippe L.] Heidelberg Univ, Acad Hosp, Clin Radiol Minimally Invas Therapies & Nucl Med, Heilbronn, Germany. [Liang, Ping] Chinese Peoples Liberat Army Gen Hosp, Dept Intervent Ultrasound, Beijing, Peoples R China. [Rhim, Hyunchul] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Diagnost Radiol, Seoul, South Korea. [Rose, Steven C.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Salem, Riad] Northwestern Univ, Dept Radiol, Chicago, IL USA. [Sofocleous, Constantinos T.; Solomon, Stephen B.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Soulen, Michael C.] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Tanaka, Masatoshi] Yokokura Hosp, Dept Hepatol, Miyama, Japan. [Vogl, Thomas J.] Goethe Univ Frankfurt, Univ Hosp Frankfurt, Inst Diagnost & Intervent Radiol, D-60054 Frankfurt, Germany. [Wood, Bradford J.] NIH, Bethesda, MD 20892 USA. [Goldberg, S. Nahum] Hadassah Hebrew Univ, Med Ctr, Dept Radiol ImageGuided Therapy, Jerusalem, Israel. [Goldberg, S. Nahum] Hadassah Hebrew Univ, Med Ctr, Intervent Oncol Unit, Jerusalem, Israel. RP Ahmed, M (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 1 Deaconess Rd,WCC-308B, Boston, MA 02215 USA. EM mahmed@bidmc.harvard.edu OI Dupuy, Damian/0000-0003-0524-5982 FU NeuWave Medical; University of Wisconsin; Galil Medical; Siemens Medical; GE Medical; Thermedical; Samsung Electronics; Terumo; HS-Medical; Boston-Scientific; BSD Medical; Covidien; Covidien/Valleylab; Endocare; Ethicon Endo-Surgery; Philips; Celon Olympus; Siemens Medical Solutions; GE Healthcare; AngioDyamics; Guerbet LLC; BTG; Merit Medical; Sirtex; Cooperative Research and Development Agreement (CRADA) Philips Healthcare; CRADA Biocompatibles BTG; CRADA Perfint; CRADA Celsion; CRADA Invivo; AngioDynamics; Cosman Medical FX M.A. No relevant conflicts of interest to disclose. L.S. No relevant conflicts of interest to disclose. C.L.B. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received consultancy fees from NeuWave Medical, author and institution received payment for patents (planned, pending, or issued) from University of Wisconsin and NeuWave Medical, received payment for stock/stock options from NeuWave Medical Other relationships: none to disclose. D.J.B. Financial activities related to the present article: paid for occasional proctoring by Galli Medical. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. M.R.C. Financial activities related to the present article: none to disclose. Financial activities not related to the present article. received grants from Galil Medical, Siemens Medical, GE Medical, Thermedical. Other relationships: none to disclose. J.W.C. No relevant conflicts of interest to disclose. M.H.C. No relevant conflicts of interest to disclose. B.I.C. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution received a research grant from Samsung Electronics. Other relationships: none to disclose. T.d.B. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received personal fees from Terumo, a grant from HS-Medical, and payment for travel to a meeting from Boston-Scientific. Other relationships: none to disclose. G.D.D. No relevant conflicts of interest to disclose. D.E.D. Financial activities related to the present article. none to disclose. Financial activities not related to the present article: paid for board membership by BSD Medical, received consultancy fees from BSD Medical and Covidien, received grants or has grants pending from NeuWave Medical, received payment for lectures including service on speakers bureaus from BSD Medical, was paid royalties by Springer Verlag and UpToDate, received stock or stock options from BSD Medical. Other relationships: none to disclose. D.A.G. Financial activities related to the present article: none to disclose. Financial activities not related to the present article. received a research grant from Covidien/Valleylab. Other relationships: none to disclose. D.G. No relevant conflicts of interest to disclose. A.R.G. Financial activities related to the present article: received consulting fee or honorarium from Covidien, received fees for participatient in review activities such as data monitoring boards, statistical analysis, end point committees, and the like from Covidien Financial activities not related to the present article: was paid for board membership, consultancy, and lectures including service on speakers bureaus by Covidien Other relationships: none to disclose. F.T.L. Financial activities related to the present article: received payment from NeuWave Medical. Financial activities not related to the present article: received royalties from Covidien, is a stockholder and on the Board of Directors for NeuWave Medical, has a patent on the Switching Controller with royalties paid from Covidien, has multiple patents on heat-based thermal therapies for microwave ablation systems licensed to NeuWave Medical. Other relationships: none to disclose. E.L. No relevant conflicts of interest to disclose. R.L. No relevant conflicts of interest to disclose. P.J.L.; No relevant conflicts of interest to disclose T.L. No relevant conflicts of interest to disclose. D.S.L. Financial activities related to the present article. none to disclose. Financial activities not related to the present article: institution received grants or has grants pending from Endocare and Ethicon Endo-Surgery, received payment for lectures including service on speakers bureaus from Philips. Other relationships: none to disclose. J.P.M. No relevant conflicts of interest to disclose. M.F.M. No relevant conflicts of interest to disclose. B.N. No relevant conflicts of interest to disclose. P.L.P. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received a grant from Celon Olympus; fees for conferences from Siemens Medical Solutions; consultant's honoraries from Terumo Europe, Terumo Germany, and Microsulis; materials from AngioDynamics. Other relationships: none to disclose. P.L. No relevant conflicts of interest to disclose. H.R. No relevant conflicts of interest to disclose. S.C.R. No relevant conflicts of interest to disclose. R.S. No relevant conflicts of interest to disclose. C.T.S. No relevant conflicts of interest to disclose. S.B.S. Financial activities related to the present article: institution received a grant from GE Healthcare, author received consulting fee or honorarium from AngioDyamics, Covidien, and GE Healthcare. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. M.C.S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author received consultancy fees from Guerbet LLC, BTG, Merit Medical; institution received grants or has grants pending from Guerbet LLC and BTG; author received payment for lectures including service on speakers bureaus from Sirtex; author received royalties from Cambridge University Press. Other relationships: none to disclose. M.T. No relevant conflicts of interest to disclose. T.J.V. No relevant conflicts of interest to disclose. B.J.W. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution received grants or has grants pending from Cooperative Research and Development Agreement (CRADA) Philips Healthcare, CRADA Biocompatibles BTG, CRADA Perfint, CRADA Celsion, CRADA Invivo; the National Institutes of Health has intellectual property in the field. Other relationships: none to disclose. S.N.G. Financial activities related to the present article. institution received a grant for sponsored research from AngioDynamics; author received consulting fee or honorarium from AngioDynamics. Financial activities not related to the present article: author received consultancy fees from Cosman Medical and institution received grants or has grants pending from Cosman Medical. Other relationships: none to disclose. NR 99 TC 58 Z9 58 U1 5 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD NOV PY 2014 VL 25 IS 11 BP 1691 EP 1705 DI 10.1016/j.jvir.2014.08.027 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AT1UZ UT WOS:000344720500005 PM 25442132 ER PT J AU Pereyra, F Heckerman, D Carlson, JM Kadie, C Soghoian, DZ Karel, D Goldenthal, A Davis, OB DeZiel, CE Lin, TH Peng, J Piechocka, A Carrington, M Walker, BD AF Pereyra, Florencia Heckerman, David Carlson, Jonathan M. Kadie, Carl Soghoian, Damien Z. Karel, Daniel Goldenthal, Ariel Davis, Oliver B. DeZiel, Charles E. Lin, Tienho Peng, Jian Piechocka, Alicja Carrington, Mary Walker, Bruce D. TI HIV Control Is Mediated in Part by CD8(+) T-Cell Targeting of Specific Epitopes SO JOURNAL OF VIROLOGY LA English DT Article ID HLA CLASS-I; VIRAL LOAD; DISCORDANT ASSOCIATIONS; INFECTED INDIVIDUALS; LYMPHOCYTE EPITOPES; DISEASE PROGRESSION; CRYSTAL-STRUCTURE; VIRUS CONTROL; CTL EPITOPES; ESCAPE AB We investigated the hypothesis that the correlation between the class I HLA types of an individual and whether that individual spontaneously controls HIV-1 is mediated by the targeting of specific epitopes by CD8(+) T cells. By measuring gamma interferon enzyme-linked immunosorbent spot (ELISPOT) assay responses to a panel of 257 optimally defined epitopes in 341 untreated HIV-infected persons, including persons who spontaneously control viremia, we found that the correlation between HLA types and control is mediated by the targeting of specific epitopes. Moreover, we performed a graphical model-based analysis that suggested that the targeting of specific epitopes is a cause of such control-that is, some epitopes are protective rather than merely associated with control-and identified eight epitopes that are significantly protective. In addition, we use an in silico analysis to identify protein regions where mutations are likely to affect the stability of a protein, and we found that the protective epitopes identified by the ELISPOT analysis correspond almost perfectly to such regions. This in silico analysis thus suggests a possible mechanism for control and could be used to identify protective epitopes that are not often targeted in natural infection but that may be potentially useful in a vaccine. Our analyses thus argue for the inclusion (and exclusion) of specific epitopes in an HIV vaccine. IMPORTANCE Some individuals naturally control HIV replication in the absence of antiretroviral therapy, and this ability to control is strongly correlated with the HLA class I alleles that they express. Here, in a large-scale experimental study, we provide evidence that this correlation is mediated largely by the targeting of specific CD8(+) T-cell epitopes, and we identify eight epitopes that are likely to cause control. In addition, we provide an in silico analysis indicating that control occurs because mutations within these epitopes change the stability of the protein structures. This in silico analysis also identified additional epitopes that are not typically targeted in natural infection but may lead to control when included in a vaccine, provided that other epitopes that would otherwise distract the immune system from targeting them are excluded from the vaccine. C1 [Pereyra, Florencia; Soghoian, Damien Z.; Karel, Daniel; Goldenthal, Ariel; Davis, Oliver B.; Piechocka, Alicja; Carrington, Mary; Walker, Bruce D.] MIT & Harvard, MGH, Ragon Inst, Boston, MA 02142 USA. [Pereyra, Florencia] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Heckerman, David; Carlson, Jonathan M.; DeZiel, Charles E.; Lin, Tienho; Peng, Jian] Microsoft Res, Los Angeles, CA USA. [Kadie, Carl] Microsoft Res, Redmond, WA USA. [Carrington, Mary] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Walker, BD (reprint author), MIT & Harvard, MGH, Ragon Inst, Boston, MA 02142 USA. EM bwalker@partners.org FU International HIV Controllers Study (IHCS) - Bill and Melinda Gates Foundation; AIDS Healthcare Foundation; Harvard University Center for AIDS Research (CFAR), NIH [P30 AI060354]; NIAID; NCI; NICHD; NHLBI; NIDA; NIMH; NIA; FIC; OAR; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research; Mark and Lisa Schwartz Foundation FX This study was supported in part by the International HIV Controllers Study (IHCS), funded by the Bill and Melinda Gates Foundation (F.P. and B.D.W.), the AIDS Healthcare Foundation (F.P.), and the Harvard University Center for AIDS Research (CFAR), an NIH-funded Center for AIDS Research (P30 AI060354), which is supported by the following NIH CoFunding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR. Members of IHCS can be found at http://ragoninstitute.org/hivcontrollers/health-professionals/study-memb ers/the-international-hiv-controllers-study-members/. We also gratefully acknowledge support from the Mark and Lisa Schwartz Foundation. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. NR 88 TC 19 Z9 19 U1 0 U2 3 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 NOV PY 2014 VL 88 IS 22 BP 12937 EP 12948 DI 10.1128/JVI.01004-14 PG 12 WC Virology SC Virology GA AT3CG UT WOS:000344812500002 PM 25165115 ER PT J AU Matsuda, K Dang, Q Brown, CR Keele, BF Wu, F Ourmanov, I Goeken, R Whitted, S Riddick, NE Buckler-White, A Hirsch, VM AF Matsuda, Kenta Dang, Que Brown, Charles R. Keele, Brandon F. Wu, Fan Ourmanov, Ilnour Goeken, Robert Whitted, Sonya Riddick, Nadeene E. Buckler-White, Alicia Hirsch, Vanessa M. TI Characterization of Simian Immunodeficiency Virus (SIV) That Induces SIV Encephalitis in Rhesus Macaques with High Frequency: Role of TRIM5 and Major Histocompatibility Complex Genotypes and Early Entry to the Brain SO JOURNAL OF VIROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; AIDS DEMENTIA COMPLEX; I MOLECULE MAMU-A-ASTERISK-01; ACTIVE ANTIRETROVIRAL THERAPY; INFECTED MACAQUES; HIV-1 INFECTION; T-CELLS; REPLICATION; CLONES; NEUROPATHOLOGY AB Although nonhuman primate models of neuro-AIDS have made tremendous contributions to our understanding of disease progression in the central nervous system (CNS) of human immunodeficiency virus type 1 (HIV-1)-infected individuals, each model holds advantages and limitations. In this study, in vivo passage of SIV smE543 was conducted to obtain a viral isolate that can induce neuropathology in rhesus macaques. After a series of four in vivo passages in rhesus macaques, we have successfully isolated SIV sm804E. SIV sm804E shows efficient replication in peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) in vitro and induces neuro-AIDS in high frequencies in vivo. Analysis of the acute phase of infection revealed that SIV sm804E establishes infection in the CNS during the early phase of the infection, which was not observed in the animals infected with the parental SIV smE543-3. Comprehensive analysis of disease progression in the animals used in the study suggested that host major histocompatibility complex class I (MHC-I) and TRIM5 alpha genotypes influence the disease progression in the CNS. Taken together, our findings show that we have successfully isolated a new strain of simian immunodeficiency virus (SIV) that is capable of establishing infection in the CNS at early stage of infection and causes neuropathology in infected rhesus macaques at a high frequency (83%) using a single inoculum, when animals with restrictive MHC-I or TRIM5 alpha genotypes are excluded. SIV sm804E has the potential to augment some of the limitations of existing nonhuman primate neuro-AIDS models. IMPORTANCE Human immunodeficiency virus (HIV) is associated with a high frequency of neurologic complications due to infection of the central nervous system (CNS). Although the use of antiviral treatment has reduced the incidence of severe complications, milder disease of the CNS continues to be a significant problem. Animal models to study development of neurologic disease are needed. This article describes the development of a novel virus isolate that induces neurologic disease in a high proportion of rhesus macaques infected without the need for prior immunomodulation as is required for some other models. C1 [Matsuda, Kenta; Wu, Fan; Ourmanov, Ilnour; Goeken, Robert; Whitted, Sonya; Riddick, Nadeene E.; Buckler-White, Alicia; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Dang, Que] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Brown, Charles R.] MedImmune LLC, Gaithersburg, MD USA. [Keele, Brandon F.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. RP Hirsch, VM (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM vhirsch@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported with federal funds from the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and contract no. HHSN261200800001E from the National Cancer Institute, NIH. NR 42 TC 7 Z9 7 U1 0 U2 3 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 NOV PY 2014 VL 88 IS 22 BP 13201 EP 13211 DI 10.1128/JVI.01996-14 PG 11 WC Virology SC Virology GA AT3CG UT WOS:000344812500022 PM 25187546 ER PT J AU Bailey, AL Lauck, M Sibley, SD Pecotte, J Rice, K Weny, G Tumukunde, A Hyeroba, D Greene, J Correll, M Gleicher, M Friedrich, TC Jahrling, PB Kuhn, JH Goldberg, TL Rogers, J O'Connor, DH AF Bailey, Adam L. Lauck, Michael Sibley, Samuel D. Pecotte, Jerilyn Rice, Karen Weny, Geoffrey Tumukunde, Alex Hyeroba, David Greene, Justin Correll, Michael Gleicher, Michael Friedrich, Thomas C. Jahrling, Peter B. Kuhn, Jens H. Goldberg, Tony L. Rogers, Jeffrey O'Connor, David H. TI Two Novel Simian Arteriviruses in Captive and Wild Baboons (Papio spp.) SO JOURNAL OF VIROLOGY LA English DT Article ID HEMORRHAGIC-FEVER VIRUS; EBOLA-VIRUS; MONKEYS; INFECTION; ALIGNMENT; DISEASE; OUTBREAK AB Since the 1960s, simian hemorrhagic fever virus ( SHFV; Nidovirales, Arteriviridae) has caused highly fatal outbreaks of viral hemorrhagic fever in captive Asian macaque colonies. However, the source(s) of these outbreaks and the natural reservoir(s) of this virus remain obscure. Here we report the identification of two novel, highly divergent simian arteriviruses related to SHFV, Mikumi yellow baboon virus 1 (MYBV-1) and Southwest baboon virus 1 (SWBV-1), in wild and captive baboons, respectively, and demonstrate the recent transmission of SWBV-1 among captive baboons. These findings extend our knowledge of the genetic and geographic diversity of the simian arteriviruses, identify baboons as a natural host of these viruses, and provide further evidence that baboons may have played a role in previous outbreaks of simian hemorrhagic fever in macaques, as has long been suspected. This knowledge should aid in the prevention of disease outbreaks in captive macaques and supports the growing body of evidence that suggests that simian arterivirus infections are common in Old World monkeys of many different species throughout Africa. IMPORTANCE Historically, the emergence of primate viruses both in humans and in other primate species has caused devastating outbreaks of disease. One strategy for preventing the emergence of novel primate pathogens is to identify microbes with the potential for cross-species transmission in their natural state within reservoir species from which they might emerge. Here, we detail the discovery and characterization of two related simian members of the Arteriviridae family that have a history of disease emergence and host switching. Our results expand the phylogenetic and geographic range of the simian arteriviruses and define baboons as a natural host for these viruses. Our findings also identify a potential threat to captive macaque colonies by showing that simian arteriviruses are actively circulating in captive baboons. C1 [Bailey, Adam L.; Lauck, Michael; Greene, Justin; O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Bailey, Adam L.; Lauck, Michael; Greene, Justin; Friedrich, Thomas C.; Goldberg, Tony L.; Rogers, Jeffrey; O'Connor, David H.] Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Sibley, Samuel D.; Friedrich, Thomas C.; Goldberg, Tony L.] Univ Wisconsin, Dept Pathobiol Sci, Madison, WI 53706 USA. [Pecotte, Jerilyn; Rice, Karen] Southwest Natl Primate Res Ctr, San Antonio, TX USA. [Weny, Geoffrey; Tumukunde, Alex; Hyeroba, David] Makerere Univ, Kampala, Uganda. [Correll, Michael; Gleicher, Michael] Univ Wisconsin, Dept Comp Sci, Madison, WI 53706 USA. [Jahrling, Peter B.; Kuhn, Jens H.] Natl Inst Allergy & Infect Dis, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Rogers, Jeffrey] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP O'Connor, DH (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. EM doconnor@primate.wisc.edu RI Kuhn, Jens H./B-7615-2011; OI Kuhn, Jens H./0000-0002-7800-6045; Sibley, Samuel/0000-0002-6754-3187; o'connor, david/0000-0003-2139-470X FU NIH, National Institutes of Health (NIH)-NSF Ecology of Infectious Diseases program [TW009237]; United Kingdom Economic and Social Research Council; Wisconsin Partnership Program through the Wisconsin Center for Infectious Diseases; NIH [R01 AI077376-01]; Office of Research Infrastructure Programs (ORIP) [P51 RR000167]; Research Facilities Improvement Program [RR15459-01, RR020141-01]; National Center for Research Resources [P51 RR013986]; Office of Research Infrastructure Programs/OD [P51 OD011133]; NSF [BNS8303506, ISS-1162037]; University of Wisconsin's Medical Scientist Training Program (MSTP) [T32GM008692]; National Research Service Award (NRSA) through the Cell and Molecular Pathology (CMP) training program at the University of Wisconsin [T32 GM081061]; Battelle's prime; NIAID [HHSN272200700016I]; University of Wisconsin, Department of Pathology and Laboratory Medicine; WNPRC FX This work was funded by NIH grant TW009237 as part of the joint National Institutes of Health (NIH)-NSF Ecology of Infectious Diseases program and the United Kingdom Economic and Social Research Council and by the Wisconsin Partnership Program through the Wisconsin Center for Infectious Diseases and the NIH (R01 AI077376-01). This publication was made possible in part by a grant (P51 RR000167) from the Office of Research Infrastructure Programs (ORIP), a component of the NIH, to the Wisconsin National Primate Research Center (WNPRC), University of Wisconsin-Madison. This research was conducted in part at a facility constructed with support from the Research Facilities Improvement Program (grant numbers RR15459-01 and RR020141-01). This project used SNPRC biological materials funded by the National Center for Research Resources (P51 RR013986) and is currently supported by the Office of Research Infrastructure Programs/OD (P51 OD011133). The collection of blood samples from Mikumi baboons was approved by the appropriate Tanzanian government authorities and funded by NSF grant BNS8303506 to Jane Phillips-Conroy (Washington University). A.L.B. performed this work with support from the University of Wisconsin's Medical Scientist Training Program (MSTP; grant T32GM008692) and a National Research Service Award (NRSA) through the Cell and Molecular Pathology (CMP) training program at the University of Wisconsin (T32 GM081061). J.H.K. performed this work as an employee of Tunnell Government Services, Inc., a subcontractor under Battelle's prime contract with NIAID, under contract no. HHSN272200700016I. The development of the Layercake data visualization tool was made possible in part by NSF award ISS-1162037. We thank the University of Wisconsin, Department of Pathology and Laboratory Medicine, and the WNPRC for funding. NR 34 TC 12 Z9 12 U1 1 U2 14 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 NOV PY 2014 VL 88 IS 22 BP 13231 EP 13239 DI 10.1128/JVI.02203-14 PG 9 WC Virology SC Virology GA AT3CG UT WOS:000344812500025 PM 25187550 ER PT J AU Kennedy, AR Crucian, B Huff, JL Klein, SL Morens, D Murasko, D Nickerson, CA Sonnenfeld, G AF Kennedy, Ann R. Crucian, Brian Huff, Janice L. Klein, Sabra L. Morens, David Murasko, Donna Nickerson, Cheryl A. Sonnenfeld, Gerald TI Effects of Sex and Gender on Adaptation to Space: Immune System SO JOURNAL OF WOMENS HEALTH LA English DT Review ID MICROBIAL CHARACTERIZATION; SPACEFLIGHT; REACTIVATION; ASTRONAUTS; RESPONSES; STATION; DISEASE AB This review is focused on sex and gender effects on immunological alterations occurring during space flight. Sex differences in immune function and the outcome of inflammatory, infectious, and autoimmune diseases are well documented. The work of the Immunology Workgroup identified numerous reasons why there could be sex and/or gender differences observed during and after spaceflight, but thus far, there has been very little investigation in this area of research. In most cases, this is due to either a low total number of subjects or the minimal number of female flight crew members available for these studies. Thus, the availability of a sufficient number of female subjects to enable statistical analysis of the data has been a limiting factor. As the inclusion of female crew members has increased in the recent past, such studies should be possible in the future. It is very difficult to obtain immunologic and infectious data in small animals that can be usefully extrapolated to humans undergoing spaceflight. Thus, it is recommended by the Immunology Workgroup that a greater emphasis be placed on studying astronauts themselves, with a focus on long-term evaluations of specific, known infectious risks. C1 [Kennedy, Ann R.] Univ Penn, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Crucian, Brian] NASA, Lyndon B Johnson Space Ctr, Human Hlth & Performance Directorate, Houston, TX 77058 USA. [Huff, Janice L.] Univ Space Res Assoc, Div Space Life Sci, Houston, TX USA. [Klein, Sabra L.] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Morens, David] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. [Murasko, Donna] Drexel Univ, Coll Arts & Sci, Dept Biol, Philadelphia, PA 19104 USA. [Nickerson, Cheryl A.] Arizona State Univ, Biodesign Inst, Tempe, AZ USA. [Sonnenfeld, Gerald] Clemson Univ, Sch Hlth Res, Dept Biol Sci, Greenville, SC USA. [Sonnenfeld, Gerald] Greenville Hlth Syst, Greenville, SC USA. RP Kennedy, AR (reprint author), Univ Penn, Perelman Sch Med, Dept Radiat Oncol, 195 John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM akennedy@mail.med.upenn.edu NR 24 TC 5 Z9 5 U1 1 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD NOV 1 PY 2014 VL 23 IS 11 BP 956 EP 958 DI 10.1089/jwh.2014.4913 PG 3 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AT3XO UT WOS:000344868200012 PM 25401940 ER PT J AU Reschke, MF Cohen, HS Cerisano, JM Clayton, JA Cromwell, R Danielson, RW Hwang, EY Tingen, C Allen, JR Tomko, DL AF Reschke, Millard F. Cohen, Helen S. Cerisano, Jody M. Clayton, Janine A. Cromwell, Ronita Danielson, Richard W. Hwang, Emma Y. Tingen, Candace Allen, John R. Tomko, David L. TI Effects of Sex and Gender on Adaptation to Space: Neurosensory Systems SO JOURNAL OF WOMENS HEALTH LA English DT Review ID PRODUCT OTOACOUSTIC EMISSIONS; EMOTIONALLY INFLUENCED MEMORY; HEARING-LOSS; SELF-ORIENTATION; AGE; EPIDEMIOLOGY; POPULATION; VERTIGO AB Sex and gender differences have long been a research topic of interest, yet few studies have explored the specific differences in neurological responses between men and women during and after spaceflight. Knowledge in this field is limited due to the significant disproportion of sexes enrolled in the astronaut corps. Research indicates that general neurological and sensory differences exist between the sexes, such as those in laterality of amygdala activity, sensitivity and discrimination in vision processing, and neuronal cell death (apoptosis) pathways. In spaceflight, sex differences may include a higher incidence of entry and space motion sickness and of post-flight vestibular instability in female as opposed to male astronauts who flew on both short- and long-duration missions. Hearing and auditory function in crewmembers shows the expected hearing threshold differences between men and women, in which female astronauts exhibit better hearing thresholds. Longitudinal observations of hearing thresholds for crewmembers yield normal age-related decrements; however, no evidence of sex-related differences from spaceflight has been observed. The impact of sex and gender differences should be studied by making spaceflight accessible and flying more women into space. Only in this way will we know if increasingly longer-duration missions cause significantly different neurophysiological responses in men and women. C1 [Reschke, Millard F.] NASA, Dept Neurosci, Lyndon B Johnson Space Ctr, Houston, TX 77058 USA. [Cohen, Helen S.; Danielson, Richard W.] Baylor Coll Med, Dept Otolaryngol Head & Neck Surg, Houston, TX 77030 USA. [Cerisano, Jody M.; Hwang, Emma Y.] Wyle Sci Technol & Engn Grp, Houston, TX USA. [Clayton, Janine A.] NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. [Tingen, Candace] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Cromwell, Ronita] Univ Space Res Assoc, Houston, TX USA. [Allen, John R.] Natl Aeronaut & Space Adm NASA Headquarters, Human Explorat & Operat Mission Directorate, Washington, DC USA. [Tomko, David L.] Natl Aeronaut & Space Adm NASA Headquarters, Space Life & Phys Sci Res Div, Washington, DC USA. RP Reschke, MF (reprint author), NASA, Dept Neurosci, Lyndon B Johnson Space Ctr, 2101 NASA Pkwy, Houston, TX 77058 USA. EM millard.f.reschke@nasa.gov NR 32 TC 5 Z9 5 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD NOV 1 PY 2014 VL 23 IS 11 BP 959 EP 962 DI 10.1089/jwh.2014.4908 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AT3XO UT WOS:000344868200013 PM 25401941 ER PT J AU Ronca, AE Baker, ES Bavendam, TG Beck, KD Miller, VM Tash, JS Jenkins, M AF Ronca, April E. Baker, Ellen S. Bavendam, Tamara G. Beck, Kevin D. Miller, Virginia M. Tash, Joseph S. Jenkins, Marjorie TI Effects of Sex and Gender on Adaptations to Space: Reproductive Health SO JOURNAL OF WOMENS HEALTH LA English DT Review ID PSYCHOSOCIAL STRESS; SLEEP-DEPRIVATION; URINARY RETENTION; GONADAL-STEROIDS; MALE RATS; ESTRADIOL; TESTOSTERONE; CONTRACEPTION; SPACEFLIGHT; OXYTOCIN AB In this report, sex/gender research relevant to reproduction on Earth, in conjunction with the extant human and animal observations in space, was used to identify knowledge gaps and prioritize recommendations for future sex- and gender-specific surveillance and monitoring of male and female astronauts. With overall increased durations of contemporary space missions, a deeper understanding of sex/gender effects on reproduction-related responses and adaptations to the space environment is warranted to minimize risks and insure healthy aging of the men and women who travel into space. C1 [Ronca, April E.] NASA, Space Biosci Res Branch, Ames Res Ctr, Mountain View, CA 94035 USA. [Ronca, April E.] Wake Forest Sch Med, Dept Obstet & Gynecol, Winston Salem, NC USA. [Ronca, April E.] Wake Forest Sch Med, Dept Neurobiol & Anat, Winston Salem, NC USA. [Ronca, April E.] Wake Forest Sch Med, Dept Mol Med & Translat Sci, Winston Salem, NC USA. [Baker, Ellen S.] NASA, Lyndon B Johnson Space Ctr, Houston, TX 77058 USA. [Bavendam, Tamara G.] NIDDK, NIH, Bethesda, MD USA. [Beck, Kevin D.] Rutgers New Jersey Med Sch, Dept Neurol & Neurosci, Newark, NJ USA. [Miller, Virginia M.] Mayo Clin, Coll Med, Dept Physiol, Rochester, MN USA. [Miller, Virginia M.] Mayo Clin, Coll Med, Dept Surg, Rochester, MN USA. [Tash, Joseph S.] Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol, Kansas City, KS 66103 USA. [Tash, Joseph S.] Univ Kansas, Med Ctr, Dept Urol, Kansas City, KS 66103 USA. [Tash, Joseph S.] Univ Kansas, Med Ctr, Interdisciplinary Ctr Male Contracept Res & Drug, Kansas City, KS 66103 USA. [Jenkins, Marjorie] Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Laura W Bush Inst Womens Hlth, Amarillo, TX USA. [Jenkins, Marjorie] Texas Tech Univ, Hlth Sci Ctr, Rush Endowed Chair Excellence Gynecol Oncol, Amarillo, TX USA. RP Ronca, AE (reprint author), NASA, Space Biosci Res Branch, Ames Res Ctr, MS 236-7, Mountain View, CA 94035 USA. EM aronca@wakehealth.edu NR 69 TC 5 Z9 5 U1 1 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD NOV 1 PY 2014 VL 23 IS 11 BP 967 EP 974 DI 10.1089/jwh.2014.4915 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AT3XO UT WOS:000344868200015 PM 25401943 ER PT J AU Rosano, C Rosso, AL Studenski, SA AF Rosano, Caterina Rosso, Andrea L. Studenski, Stephanie A. TI Aging, Brain, and Mobility: Progress and Opportunities SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material C1 [Rosano, Caterina; Rosso, Andrea L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Studenski, Stephanie A.] NIA, Translat Gerontol Branch, Longitudinal Studies Sect, Bethesda, MD 20892 USA. RP Rosano, C (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, 130 N Bellefield Ave, Pittsburgh, PA 15213 USA. EM rosanoc@edc.pitt.edu OI Rosso, Andrea/0000-0001-5890-9856; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU NIA NIH HHS [P30 AG024827, T32 AG000181] NR 8 TC 4 Z9 4 U1 2 U2 3 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 NOV PY 2014 VL 69 IS 11 BP 1373 EP 1374 DI 10.1093/gerona/glu159 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AT0YU UT WOS:000344660900008 PM 25199913 ER PT J AU Diniz, BS Teixeira, AL Machado-Vieira, R Talib, LL Radanovic, M Gattaz, WF Forlenza, OV AF Diniz, Breno S. Teixeira, Antonio L. Machado-Vieira, Rodrigo Talib, Leda L. Radanovic, Marcia Gattaz, Wagner F. Forlenza, Orestes V. TI Reduced Cerebrospinal Fluid Levels of Brain-Derived Neurotrophic Factor Is Associated With Cognitive Impairment in Late-Life Major Depression SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Alzheimer's disease; Amyloid-beta(42); BDNF; Cerebrospinal fluid; Cognition; Late-life depression ID ANTIDEPRESSANT-FREE PATIENTS; ALZHEIMERS-DISEASE; DEMENTIA; BIOMARKERS; METAANALYSIS; COHORT; STATE; RISK AB Objectives. Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in neurodegenerative cascades. The aim of the present study is to determine the concentrations of brain-derived neurotrophic factor (BDNF), amyloid-beta(42), total Tau, and phosphorylated Tau in the cerebrospinal fluid (CSF) of patients with LLD and cognitive impairment compared to healthy older adults. Method. We included 25 antidepressant-free patients with LLD (10 with mild cognitive impairment [LLD + MCI] and 15 with no cognitive decline [LLD + NCD]) and 25 healthy older adults as a comparison group. Depressive symptoms were assessed by the 21-item Hamilton Depression Rating Scale (HDRS-21) and cognitive performance by a comprehensive cognitive battery. Results. Patients with LLD + MCI showed significantly lower CSF BDNF levels compared to LLD + NCD and healthy controls (p = .003). There were no significant differences in Alzheimer's disease-related CSF biomarkers between groups. CSF BDNF concentrations were positively correlated with Cambridge Cognitive Test (CAMCOG) scores (r = .36, p = .02). Discussion. The present study adds to the growing body of evidence that abnormalities in the BDNF system are involved in the pathophysiology of LLD. The reduction of the availability of BDNF in the central nervous system may indicate increased vulnerability to the development of several age-related neuropsychiatric disorders as well as to adverse cognitive outcomes. C1 [Diniz, Breno S.] Univ Fed Minas Gerais, Fac Med, Dept Mental Hlth, Belo Horizonte, MG, Brazil. [Diniz, Breno S.; Machado-Vieira, Rodrigo; Talib, Leda L.; Radanovic, Marcia; Gattaz, Wagner F.; Forlenza, Orestes V.] Univ Sao Paulo, Fac Med, Dept & Inst Psychiat, BR-05508 Sao Paulo, Brazil. [Diniz, Breno S.] Univ Fed Minas Gerais, Natl Inst Sci & Technol Mol Med INCT MM, Belo Horizonte, MG, Brazil. [Teixeira, Antonio L.] Univ Fed Minas Gerais, Fac Med, Dept Internal Med, Belo Horizonte, MG, Brazil. [Machado-Vieira, Rodrigo] NIMH, NIH, Bethesda, MD 20892 USA. RP Diniz, BS (reprint author), Fed Univ Minas Gerais Sch, Fac Med, Dept Mental Hlth, Av Alfredo Balena 190, BR-30130100 Belo Horizonte, MG, Brazil. EM brenosatler@gmail.com RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Diniz, Breno/0000-0003-0653-1905 FU FAPESP [09/52825-8, 02/12633-7]; Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS); FAPEMIG; CNPq; CAPES, Brazil; PRPq-UFMG [01/2013]; CNPq [472138/2013-8] FX This work was supported by grants from FAPESP (09/52825-8 and 02/12633-7), Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS), FAPEMIG, CNPq, and CAPES, Brazil. B. S. Diniz receives intramural research support from the PRPq-UFMG (01/2013) and research grants from CNPq (472138/2013-8). NR 30 TC 14 Z9 14 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5014 EI 1758-5368 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD NOV PY 2014 VL 69 IS 6 BP 845 EP 851 DI 10.1093/geronb/gbu096 PG 7 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA AT1BE UT WOS:000344667300004 PM 25149921 ER PT J AU Chaturvedi, AK AF Chaturvedi, Anil K. TI Global burden of human papillomavirus-positive head and neck cancers SO LANCET ONCOLOGY LA English DT Editorial Material ID ORAL-CAVITY C1 NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. RP Chaturvedi, AK (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. EM chaturva@mail.nih.gov RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 NR 10 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD NOV PY 2014 VL 15 IS 12 BP 1282 EP 1283 DI 10.1016/S1470-2045(14)71029-0 PG 3 WC Oncology SC Oncology GA AS9ER UT WOS:000344546400029 PM 25439682 ER PT J AU Huang, NN Becker, S Boularan, C Kamenyeva, O Vural, A Hwang, IY Shi, CS Kehrl, JH AF Huang, Ning-Na Becker, Steven Boularan, Cedric Kamenyeva, Olena Vural, Ali Hwang, Il-Young Shi, Chong-Shan Kehrl, John H. TI Canonical and Noncanonical G-Protein Signaling Helps Coordinate Actin Dynamics To Promote Macrophage Phagocytosis of Zymosan SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; G-BETA-SUBUNITS; LEUKOTRIENE B-4; ACTIVATION; ALPHA; CHEMOTAXIS; RECEPTOR; EXPRESSION; TOXIN; TRANSDUCTION AB Both chemotaxis and phagocytosis depend upon actin-driven cell protrusions and cell membrane remodeling. While chemoattractant receptors rely upon canonical G-protein signaling to activate downstream effectors, whether such signaling pathways affect phagocytosis is contentious. Here, we report that G alpha(i) nucleotide exchange and signaling helps macrophages coordinate the recognition, capture, and engulfment of zymosan bioparticles. We show that zymosan exposure recruits F-actin, G alpha(i) proteins, and Elmo1 to phagocytic cups and early phagosomes. Zymosan triggered an increase in intracellular Ca2+ that was partially sensitive to G alpha(i) nucleotide exchange inhibition and expression of GTP-bound G alpha(i) recruited Elmo1 to the plasma membrane. Reducing GDP-G alpha(i) nucleotide exchange, decreasing G alpha(i) expression, pharmacologically interrupting G beta gamma signaling, or reducing Elmo1 expression all impaired phagocytosis, while favoring the duration that G alpha(i) remained GTP bound promoted it. Our studies demonstrate that targeting heterotrimeric G-protein signaling offers opportunities to enhance or retard macrophage engulfment of phagocytic targets such as zymosan. C1 [Huang, Ning-Na; Boularan, Cedric; Kamenyeva, Olena; Vural, Ali; Hwang, Il-Young; Shi, Chong-Shan; Kehrl, John H.] NIAID, Immunoregulat Lab, B Cell Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. [Becker, Steven] NIAID, Biol Imaging Facil, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, B Cell Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X FU National Institute of Allergy and Infectious Diseases FX This research was supported by the intramural program of the National Institute of Allergy and Infectious Diseases. NR 46 TC 4 Z9 4 U1 0 U2 11 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 NOV PY 2014 VL 34 IS 22 BP 4186 EP 4199 DI 10.1128/MCB.00325-14 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AT0MP UT WOS:000344630500009 PM 25225330 ER PT J AU McGlothlin, JW Chuckalovcak, JP Janes, DE Edwards, SV Feldman, CR Brodie, ED Pfrender, ME Brodie, ED AF McGlothlin, Joel W. Chuckalovcak, John P. Janes, Daniel E. Edwards, Scott V. Feldman, Chris R. Brodie, Edmund D., Jr. Pfrender, Michael E. Brodie, Edmund D., III TI Parallel Evolution of Tetrodotoxin Resistance in Three Voltage-Gated Sodium Channel Genes in the Garter Snake Thamnophis sirtalis SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE adaptation; coevolution; gene families; molecular evolution; predator-prey interactions; toxins ID BLOOD-BRAIN-BARRIER; ADAPTIVE EVOLUTION; OUTER VESTIBULE; GENOME REVEALS; DANGEROUS PREY; ION CHANNELS; ARMS-RACE; ADAPTATION; VERTEBRATES; SAXITOXIN AB Members of a gene family expressed in a single species often experience common selection pressures. Consequently, the molecular basis of complex adaptations may be expected to involve parallel evolutionary changes in multiple paralogs. Here, we use bacterial artificial chromosome library scans to investigate the evolution of the voltage-gated sodium channel (Na-v) family in the garter snake Thamnophis sirtalis, a predator of highly toxic Taricha newts. Newts possess tetrodotoxin (TTX), which blocks Na-v's, arresting action potentials in nerves and muscle. Some Thamnophis populations have evolved resistance to extremely high levels of TTX. Previous work has identified amino acid sites in the skeletal muscle sodium channel Na(v)1.4 that confer resistance to TTX and vary across populations. We identify parallel evolution of TTX resistance in two additional Na-v paralogs, Na(v)1.6 and 1.7, which are known to be expressed in the peripheral nervous system and should thus be exposed to ingested TTX. Each paralog contains at least one TTX-resistant substitution identical to a substitution previously identified in Na(v)1.4. These sites are fixed across populations, suggesting that the resistant peripheral nerves antedate resistant muscle. In contrast, three sodium channels expressed solely in the central nervous system (Na(v)1.1-1.3) showed no evidence of TTX resistance, consistent with protection from toxins by the blood-brain barrier. We also report the exon-intron structure of six Na-v paralogs, the first such analysis for snake genes. Our results demonstrate that the molecular basis of adaptation may be both repeatable across members of a gene family and predictable based on functional considerations. C1 [McGlothlin, Joel W.] Virginia Tech, Dept Biol Sci, Blacksburg, VA 24061 USA. [McGlothlin, Joel W.; Chuckalovcak, John P.; Brodie, Edmund D., III] Univ Virginia, Dept Biol, Charlottesville, VA 22903 USA. [Chuckalovcak, John P.] Biorad Labs, Hercules, CA USA. [Janes, Daniel E.; Edwards, Scott V.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Janes, Daniel E.] NIH, Div Genet & Dev Biol, Bethesda, MD 20892 USA. [Feldman, Chris R.] Univ Nevada, Dept Biol, Reno, NV 89557 USA. [Brodie, Edmund D., Jr.] Utah State Univ, Dept Biol, Logan, UT 84322 USA. [Pfrender, Michael E.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Pfrender, Michael E.] Univ Notre Dame, Environm Change Initiat, Notre Dame, IN 46556 USA. [Brodie, Edmund D., III] Univ Virginia, Mt Lake Biol Stn, Charlottesville, VA 22903 USA. RP McGlothlin, JW (reprint author), Virginia Tech, Dept Biol Sci, Blacksburg, VA 24061 USA. EM joelmcg@vt.edu RI McGlothlin, Joel/B-8222-2008; OI McGlothlin, Joel/0000-0003-3645-6264; Edwards, Scott/0000-0003-2535-6217 FU National Science Foundation [DEB 0922216, DEB 1034686]; Virginia Tech's Open Access Subvention Fund FX The authors thank Michelle Sivilich and Megan Kobiela for assistance in the laboratory, Dan Sloan for advice on molecular techniques, Shana Geffeney and Charles Hanifin for helpful discussions, Nigel Delaney and Yoel Stuart for logistical support in Cambridge, and Angela Hornsby, Marjorie Matocq, and Kendra Sewall for comments on the manuscript. This material is based upon work supported by the National Science Foundation (grant numbers DEB 0922216 to E. D. B. III and DEB 1034686 to M. E. P.). Publication of this article was supported by Virginia Tech's Open Access Subvention Fund. NR 85 TC 9 Z9 9 U1 11 U2 76 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD NOV PY 2014 VL 31 IS 11 BP 2836 EP 2846 DI 10.1093/molbev/msu237 PG 11 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA AT0JO UT WOS:000344622800002 PM 25135948 ER PT J AU Sheeley, DM AF Sheeley, Douglas M. TI The Proteomics of Networks and Pathways: A Movie Is Worth A Thousand Pictures SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Editorial Material C1 Natl Inst Gen Med Sci, Div Biomed Technol Bioinformat & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Sheeley, DM (reprint author), Natl Inst Gen Med Sci, Div Biomed Technol Bioinformat & Computat Biol, NIH, 45 Ctr Dr, Bethesda, MD 20892 USA. EM dms@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD NOV PY 2014 VL 13 IS 11 SI SI BP 2801 EP 2802 DI 10.1074/mcp.M114.045104 PG 2 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AT4SA UT WOS:000344930500001 PM 25368409 ER PT J AU Lang, LX Ma, Y Kiesewetter, DO Chen, XY AF Lang, Lixin Ma, Ying Kiesewetter, Dale O. Chen, Xiaoyuan TI Stability Analysis of Glutamic Acid Linked Peptides Coupled to NOTA through Different Chemical Linkages SO MOLECULAR PHARMACEUTICS LA English DT Article DE peptide; glutamate linker; thiourea; hydrolysis; Edman degradation ID ASPARAGINYL RESIDUES; DEAMIDATION; DEGRADATION; PATHWAYS; MICE; PET AB Glutamic acid is a commonly used linker to form dimeric peptides with enhanced binding affinity than their corresponding monomeric counterparts. We have previously labeled NOTA-Bn-NCS-PEG(3)-E[c(RGDyK)](2) (NOTA-PRGD2) [1] with [F-18]AlF and Ga-68 for imaging tumor angiogenesis. The p-SCN-Bn-NOTA was attached to E[c(RGDyK)](2) [2] through a mini-PEG with a thiourea linkage, and the product [1] was stable at radiolabeling condition of 100 degrees C and pH 4.0 acetate buffer. However, when the same p-SCN-Bn-NOTA was directly attached to the a-amine of E[c(RGDfK)](2) [3], the product NOTA-Bn-NCS-E[c(RGDfK)](2) [4] became unstable under similar conditions and the release of monomeric c(RGDfK) [5] was observed. The purpose of this work was to use HPLC and LC-MS to monitor the decomposition of glutamic acid linked dimeric peptides and their NOTA derivatives. A c(RGDyK) [6] and bombesin (BBN) [7] heterodimer c(RGDyK)-E-BBN [8], and a dimeric bombesin E(BBN)(2) [9], both with a glutamic acid as the linker, along with a model compound PhSCN-E[c(RGDfK)] [10] were also studied. All the compounds were dissolved in 0.5 M pH 4.0 acetate buffer at the concentration of 1 mg/mL, and 0.1 mL of each sample was heated at 100 degrees C for 10 min and the more stable compounds were heated for another 30 min. The samples at both time points were analyzed with analytical HPLC to monitor the decomposition of the heated samples. The samples with decomposition were further analyzed by LC-MS to determine the mass of products from the decomposition for possible structure elucidation. After 10 min heating, the obvious release of c(RGDfK) [5] was observed for NOTA-Bn-NCS-E[c(RGDfK)](2) [4] and Ph-SCN-E[c(RGDfK)] [10]. Little or no release of monomers was observed for the remaining samples at this time point. After further heating, the release of monomers was clearly observed for E[c(RGDyK)](2) [2], E[c(RGDfK)](2) [3], c(RGDyK)-E-BBN [8], and E(BBN)(2) [9]. No decomposition or little decomposition was observed for NOTA-Bn-NCS-PEG3-E[c(RGDyK)](2) [1], PEG3-E[c(RGDyK)](2) [11], NOTA-E[c(RGDyK)](2) [12], and NOTA-PEG3-E[c(RGDyK)](2) [13]. The glutamic acid linked dimeric peptides with a free a-amine are labile due to the neighboring amine participation in the hydrolysis. The stability of peptides could be increased by converting the free amine into amide. The instability of thiourea derivatives formed from a-amine was caused by participation of thiol group derived from thiourea. C1 [Lang, Lixin; Ma, Ying; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, 31 Ctr Dr,Bldg 31,1C22, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 15 TC 3 Z9 3 U1 2 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV PY 2014 VL 11 IS 11 BP 3867 EP 3874 DI 10.1021/mp400706q PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AS5JP UT WOS:000344307700010 PM 24533430 ER PT J AU Yue, XY Yan, XF Wu, CX Niu, G Ma, Y Jacobson, O Shen, BZ Kiesewetter, DO Chen, XY AF Yue, Xuyi Yan, Xuefeng Wu, Chenxi Niu, Gang Ma, Ying Jacobson, Orit Shen, Baozhong Kiesewetter, Dale O. Chen, Xiaoyuan TI One-Pot Two-Step Radiosynthesis of a New F-18-Labeled Thiol Reactive Prosthetic Group and Its Conjugate for Insulinoma Imaging SO MOLECULAR PHARMACEUTICS LA English DT Article DE fluorine-18; thiol reactive prosthetic group; insulinoma imaging ID POSITRON-EMISSION-TOMOGRAPHY; GLUCAGON-LIKE PEPTIDE-1; IN-VIVO; (ALF)-F-18 CHELATION; BUILDING-BLOCKS; N-SUCCINIMIDYL; F-18; PROTEINS; PET; REAGENT AB N-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-6-fluoronicotinamide ([F-18]FNEM), a novel prosthetic agent that is thiol-specific, was synthesized using a one-pot two-step strategy: (1) F-18 incorporation by a nucleophilic displacement of trimethylammonium substrate under mild conditions; (2) amidation of the resulting 6-[F-18]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester with N-(2-aminoethyl)maleimide trifluoroacetate salt. The radiosynthesis of the maleimide tracer was completed in 75 min from [F-18]fluoride with 26 +/- 5% decay uncorrected radiochemical yield, and specific activity of 19-88 GBq/mu mol (decay uncorrected). The in vitro cell uptake, in vivo biodistribution, and positron emission tomography (PET) imaging properties of its conjugation product with [Cys(40)]-exendin-4 were described. [F-18]FNEM-Cys(40)-exendin-4 showed specific targeting of glucagon-like peptide 1 receptor (GLP-1R) positive insulinomas and comparable imaging results to our recently reported [F-18]FPenM-Cys(40)exendin-4. C1 [Yue, Xuyi; Yan, Xuefeng; Wu, Chenxi; Niu, Gang; Ma, Ying; Jacobson, Orit; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD 20892 USA. [Yan, Xuefeng; Shen, Baozhong] Harbin Med Univ, Hosp 4, Dept Radiol, Harbin 150001, Heilongjiang, Peoples R China. [Wu, Chenxi] Chinese Acad Med Sci, PUMCH, Dept Nucl Med, Beijing 100730, Peoples R China. [Wu, Chenxi] Peking Union Med Coll, CAMS, Beijing 100021, Peoples R China. [Wu, Chenxi] PUMC, Beijing, Peoples R China. RP Shen, BZ (reprint author), Harbin Med Univ, Hosp 4, Dept Radiol, Harbin 150001, Heilongjiang, Peoples R China. EM shenbzh@vip.sina.com; dale.kiesewetter@nih.gov; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the intramural research program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. The authors acknowledge the NIH Warren Grant Magnuson Clinical Center's PET Department for radioisotope production. NR 60 TC 9 Z9 10 U1 3 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV PY 2014 VL 11 IS 11 BP 3875 EP 3884 DI 10.1021/mp5001857 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AS5JP UT WOS:000344307700011 PM 24798315 ER PT J AU Li, DL Zhao, XB Zhang, LW Li, F Ji, N Gao, ZX Wang, JS Kang, P Liu, ZF Shi, JY Chen, XY Zhu, ZH AF Li, Deling Zhao, Xiaobin Zhang, Liwei Li, Fang Ji, Nan Gao, Zhixian Wang, Jisheng Kang, Peng Liu, Zhaofei Shi, Jiyun Chen, Xiaoyuan Zhu, Zhaohui TI Ga-68-PRGD2 PET/CT in the Evaluation of Glioma: A Prospective Study SO MOLECULAR PHARMACEUTICS LA English DT Article DE integrin alpha(v)beta(3); glioma; Ga-68; PET/CT ID INTEGRIN ALPHA(V)BETA(3) EXPRESSION; BRAIN-TUMORS; PHASE-II; CILENGITIDE; GLIOBLASTOMA; GRADE; ALPHA-V-BETA-3; THERAPY; GROWTH; CELLS AB Integrin alpha(v)beta 3 is overexpressed in both neovasculature and glioma cells. We aimed to evaluate (68)gallium-BNOTA-PRGD(2) (Ga-68-PRGD2) as a new reagent for noninvasive integrin alpha(v)beta(3) imaging in glioma patients. With informed consent, 12 patients with suspicious brain glioma, as diagnosed by enhanced magnetic resonance imaging (MRI) scanning, were enrolled to undergo Ga-68-PRGD2 PET/CT and F-18-FDG PET/CT scans before surgery. The preoperative images were compared and correlated with the pathologically determined WHO grade. Next, the expression of integrin alpha(v)beta(3), CD34, and Ki-67 were determined by immunohistochemical staining of the resected brain tumor tissue. Our findings demonstrated that Ga-68-PRGD2 specifically accumulated in the brain tumors that were rich of integrin alpha(v)beta(3) and other neovasculature markers, but not in the brain parenchyma other than the choroid plexus. Therefore, Ga-68-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than F-18-FDG PET/CT. The maximum standardized uptake values (SUVmax) of Ga-68-PRGD2, rather than those of F-18-FDG, were significantly correlated with the glioma grading. The maximum tumor-to-brain ratios (TBRmax) of both tracers were significantly correlated with glioma grading, whereas Ga-68-PRGD2 seemed to be more superior to F-18-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, Ga-68-PRGD2 PET/CT showed different accumulation patterns for HGG of WHO grades III and IV. This is the first noninvasive integrin imaging study, to the best of our knowledge, conducted in preoperative patients with different grades of glioma, and it preliminarily indicated the effectiveness of this novel method for evaluating glioma grading and demarcation. C1 [Li, Deling; Zhang, Liwei; Ji, Nan; Gao, Zhixian; Wang, Jisheng; Kang, Peng] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurosurg, Beijing, Peoples R China. [Li, Deling; Zhang, Liwei; Ji, Nan; Gao, Zhixian; Wang, Jisheng; Kang, Peng] China Natl Clin Res Ctr Neurol Dis, NCRC ND, Beijing, Peoples R China. [Li, Deling; Zhang, Liwei; Ji, Nan; Gao, Zhixian; Wang, Jisheng; Kang, Peng] Beijing Key Lab Brian Tumor, Beijing, Peoples R China. [Zhao, Xiaobin; Li, Fang; Zhu, Zhaohui] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Nucl Med, Beijing 100730, Peoples R China. [Zhao, Xiaobin; Li, Fang; Zhu, Zhaohui] Peking Union Med Coll, Beijing 100021, Peoples R China. [Liu, Zhaofei; Shi, Jiyun] Peking Univ, Med Isotopes Res Ctr, Beijing 100871, Peoples R China. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Zhu, ZH (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Nucl Med, Beijing 100730, Peoples R China. EM shawn.chen@nih.gov; zhuzhh@pumch.cn FU National Key Scientific Instrument and Equipment Development Project [2011YQ17006710]; Major State Basic Research Development Program of China (973 Program) [2013CB733802, 2014CB744503]; National Natural Science Foundation of China [81171370, 81271614, 81371596]; Capital Special Project for Featured Clinical Application [Z121107001012119]; Beijing Key Laboratory of Brian Tumor Project; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported, in part, by National Key Scientific Instrument and Equipment Development Project (2011YQ17006710), Major State Basic Research Development Program of China (973 Program) (Grant Nos. 2013CB733802 and 2014CB744503), the National Natural Science Foundation of China projects (81171370, 81271614, and 81371596), the Capital Special Project for Featured Clinical Application (Z121107001012119), a Beijing Key Laboratory of Brian Tumor Project, and the Intramural Research Program (IRP), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). The authors are grateful to Guijun Jia, Ming Ni, Lin Qiao, and the other related staff at Beijing Tiantan Hospital, who helped in performing this study and collecting the data. Also we thank Junmei Wang, Yun Cui, and Peng Zhang for immunohistochemical analysis. NR 31 TC 7 Z9 7 U1 4 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV PY 2014 VL 11 IS 11 BP 3923 EP 3929 DI 10.1021/mp5003224 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AS5JP UT WOS:000344307700016 PM 25093246 ER PT J AU Kuo, F Histed, S Xu, BY Bhadrasetty, V Szajek, LP Williams, MR Wong, K Wu, HT Lane, K Coble, V Vasalatiy, O Griffiths, GL Paik, CH Elbuluk, O Szot, C Chaudhary, A St Croix, B Choyke, P Jagoda, EM AF Kuo, Frank Histed, Stephanie Xu, Biying Bhadrasetty, Veerendra Szajek, Lawrence P. Williams, Mark R. Wong, Karen Wu, Haitao Lane, Kelly Coble, Vincent Vasalatiy, Olga Griffiths, Gary L. Paik, Chang H. Elbuluk, Osama Szot, Christopher Chaudhary, Amit St Croix, Brad Choyke, Peter Jagoda, Elaine M. TI Immuno-PET Imaging of Tumor Endothelial Marker 8 (TEM8) SO MOLECULAR PHARMACEUTICS LA English DT Article DE immuno-PET imaging; TEM8; anti-TEM8 antibodies; L2; [Zr-89]-df-L2mAb; angiogenesis ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; MONOCLONAL-ANTIBODIES; PATHOLOGICAL ANGIOGENESIS; BREAST-CANCER; GROWTH; RECEPTOR; EXPRESSION; MICE; CONJUGATION AB Tumor endothelial marker 8 (TEM8) is a cell surface receptor that is highly expressed in a variety of human tumors and promotes tumor angiogenesis and cell growth. Antibodies targeting TEM8 block tumor angiogenesis in a manner distinct from the VEGF receptor pathway. Development of a TEM8 imaging agent could aid in patient selection for specific antiangiogenic therapies and for response monitoring. In these studies, L2, a therapeutic anti-TEM8 monoclonal IgG antibody (L2mAb), was labeled with Zr-89 and evaluated in vitro and in vivo in TEM8 expressing cells and mouse xenografts (NCI-H460, DLD-1) as a potential TEM8 immuno-PET imaging agent. Zr-89-df-L2mAb was synthesized using a desferioxamine-L2mAb conjugate (df-L2mAb); (125)I-L2mAb was labeled directly. In vitro binding studies were performed using human derived cell lines with high, moderate, and low/undetectable TEM8 expression. Zr-89-df-L2mAb in vitro autoradiography studies and CD31 IHC staining were performed with cryosections from human tumor xenografts (NCI-H460, DLD-1, MKN-45, U87-MG, T-47D, and A-431). Confirmatory TEM8 Western blots were performed with the same tumor types and cells. Zr-89-df-L2mAb biodistribution and PET imaging studies were performed in NCI-H460 and DLD-1 xenografts in nude mice. (125)I-L2mAb and Zr-89-df-L2mAb exhibited specific and high affinity binding to TEM8 that was consistent with TEM8 expression levels. In NCI-H460 and DLD-1 mouse xenografts nontarget tissue uptake of Zr-89-df-L2mAb was similar; the liver and spleen exhibited the highest uptake at all time points. Zr-89-L2mAb was highly retained in NCI-H460 tumors with <10% losses from day 1 to day 3 with the highest tumor to muscle ratios (T:M) occurring at day 3. DLD-1 tumors exhibited similar pharmacokinetics, but tumor uptake and T:M ratios were reduced similar to 2-fold in comparison to NCI-H460 at all time points. NCI-H460 and DLD-1 tumors were easily visualized in PET imaging studies despite low in vitro TEM8 expression in DLD-1 cells indicating that in vivo expression might be higher in DLD-1 tumors. From in vitro autoradiography studies Zr-89-df-L2mAb specific binding was found in 6 tumor types (U87-MG, NCI-H460, T-47D MKN-45, A-431, and DLD-1) which highly correlated to vessel density (CD31 IHC). Westerns blots confirmed the presence of TEM8 in the 6 tumor types but found undetectable TEM8 levels in DLD-1 and MKN-45 cells. This data would indicate that TEM8 is associated with the tumor vasculature rather than the tumor tissue, thus explaining the increased TEM8 expression in DLD-1 tumors compared to DLD-1 cell cultures. Zr-89-df-L2mAb specifically targeted TEM8 in vitro and in vivo although the in vitro expression was not necessarily predictive of in vivo expression which seemed to be associated with the tumor vasculature. In mouse models, Zr-89-df-L2mAb tumor uptakes and T:M ratios were sufficient for visualization during PET imaging. These results would suggest that a TEM8 targeted PET imaging agent, such as Zr-89-df-L2mAb, may have potential clinical, diagnostic, and prognostic applications by providing a quantitative measure of tumor angiogenesis and patient selection for future TEM8 directed therapies. C1 [Kuo, Frank; Histed, Stephanie; Bhadrasetty, Veerendra; Williams, Mark R.; Wong, Karen; Elbuluk, Osama; Choyke, Peter; Jagoda, Elaine M.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Xu, Biying; Wu, Haitao; Lane, Kelly; Coble, Vincent; Vasalatiy, Olga] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20892 USA. [Szajek, Lawrence P.] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. [Paik, Chang H.] NIH, Div Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. [Griffiths, Gary L.] Leidos Biomed Res Inc, Clin Res Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Szot, Christopher; Chaudhary, Amit; St Croix, Brad] NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Jagoda, EM (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr BLG10 RM B3B69, Bethesda, MD 20892 USA. EM ejagoda@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors would like to thank Xiaoyan M. Zhang, Saurabh Saha, Tony Fleming, and others at Novartis Institutes for BioMedical Research for help in developing the L2 anti-TEM8 antibody. The authors would like to acknowledge Dr. Miriam R. Anver, Donna Butcher, and Rebecca Oden of the Pathology/Histotechnology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, for providing the CD31 PECAM-1 staining and microvessel quantatitation results. 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. NR 49 TC 6 Z9 6 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV PY 2014 VL 11 IS 11 BP 3996 EP 4006 DI 10.1021/mp500056d PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AS5JP UT WOS:000344307700025 PM 24984190 ER PT J AU Yue, XY Wang, Z Zhu, L Wang, Y Qian, CQ Ma, Y Kiesewetter, DO Niu, G Chen, XY AF Yue, Xuyi Wang, Zhe Zhu, Lei Wang, Yu Qian, Chunqi Ma, Ying Kiesewetter, Dale O. Niu, Gang Chen, Xiaoyuan TI Novel F-19 Activatable Probe for the Detection of Matrix Metalloprotease-2 Activity by MRI/MRS SO MOLECULAR PHARMACEUTICS LA English DT Article ID IRON-OXIDE NANOPARTICLES; IN-VIVO; PERFLUOROCARBON NANOPARTICLES; PROTEASE ACTIVITY; MMP ACTIVITY; MRI PROBES; MECHANISM; CANCER; BLOOD; NANOPROBES AB Matrix metalloproteases (MMPs) have been found to be highly expressed in a variety of malignant tumor tissues. Noninvasive visualization of MMP activity may play an important role in the diagnosis of MMP associated diseases. Here we report the design and synthesis of a set of fluorine-19 dendron-based magnetic resonance imaging (MRI) probes for real-time imaging of MMP-2 activity. The probes have the following features: (a) symmetrical fluorine atoms; (b) the number of fluorine atoms can be increased through facile chemical modification; (c) readily accessible peptide sequence as the MMP-2 substrate; (d) activatable (19)F signal (off/on mode) via paramagnetic metal ion incorporation. Following optimization for water solubility, one of the probes was selected to evaluate MMP-2 activity by (19)F magnetic resonance spectroscopy (MRS). Our results showed that the fluorine signal increased by 8.5-fold in the presence of MMP-2. The specific cleavage site was verified by mass spectrometry. The selected probe was further applied to detect secreted MMP-2 activity of living SCC7 squamous cell carcinoma cells. The fluorine signal was increased by 4.8-fold by MRS analysis after 24 h incubation with SCC7 cells. This type of fluorine probe can be applied to evaluate other enzyme activities by simply tuning the substrate structures. This symmetrical fluorine dendron-based probe design extends the scope of the existing (19)F MRI agents and provides a simple but robust method for real-time (19)F MRI application. C1 [Yue, Xuyi; Wang, Zhe; Zhu, Lei; Wang, Yu; Ma, Ying; Kiesewetter, Dale O.; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Yue, Xuyi; Zhu, Lei] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Peoples R China. [Yue, Xuyi; Zhu, Lei] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Peoples R China. [Wang, Yu] Southeast Univ, Sch Med, Zhongda Hosp, Jiangsu Key Lab Mol & Funct Imaging,Dept Radiol, Nanjing 210009, Jiangsu, Peoples R China. [Qian, Chunqi] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Kiesewetter, DO (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM dkiesewetter@mail.nih.gov; shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; National Science Foundation of China (NSFC) [81301256] FX This work was supported by the intramural research program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, and the National Science Foundation of China (NSFC) (81301256). NR 46 TC 6 Z9 6 U1 17 U2 72 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV PY 2014 VL 11 IS 11 BP 4208 EP 4217 DI 10.1021/mp500443x PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AS5JP UT WOS:000344307700045 PM 25271556 ER PT J AU Dong, J Beard, JD Umbach, DM Park, Y Huang, XM Blair, A Kamel, F Chen, HL AF Dong, Jing Beard, John D. Umbach, David M. Park, YikYung Huang, Xuemei Blair, Aaron Kamel, Freya Chen, Honglei TI Dietary Fat Intake and Risk for Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE dietary fat intake; Parkinson's disease; cohort study ID FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; MARGINAL STRUCTURAL MODELS; RETIRED-PERSONS DIET; NIH-AARP DIET; DOCOSAHEXAENOIC ACID; NATIONAL-INSTITUTES; OXIDATIVE STRESS; BRAIN; SURVIVAL AB Previous epidemiological studies have generated inconsistent results regarding the associations between dietary fat intakes and risk for Parkinson's disease (PD). We therefore prospectively examined these associations in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. A 124-item food frequency questionnaire was administered at baseline in1995 to 1996, and PD diagnosis was self-reported at the follow-up survey in 2004 to 2006. A total of 1,087 cases with a PD diagnosis between 2000 and 2006 and 299,617 controls were included in the analyses. Overall, intakes of fats and other macronutrients were not associated with PD risk. However, we found a weak positive association between n-6 polyunsaturated fatty acids (PUFA) and the risk for PD. After adjusting for potential confounders, the odds ratio (OR) and 95% confidence interval (CI) between extreme quintiles of n-6 PUFA intake was 1.23 (95% CI=1.02-1.49, P for trend=0.02). A similar association was observed for the intake of linoleic acid. Results were similar among men and among women. Our study suggests that fat intake in general is not related to the risk for PD. The weak positive association between intake of n-6 PUFA and PD risk needs further investigation. (c) 2014 International Parkinson and Movement Disorder Society C1 [Dong, Jing; Beard, John D.; Kamel, Freya; Chen, Honglei] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Beard, John D.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Park, YikYung; Blair, Aaron] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. RP Dong, J (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM dongj4@mail.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Chen, Honglei/0000-0003-3446-7779; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [Z01-ES-101986]; National Cancer Institute [Z01-CP010196-02]; National Institute for Occupational Safety and Health [T42OH00867302] FX This study was supported by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES-101986) and the National Cancer Institute (Z01-CP010196-02), and Award Number T42OH00867302 from the National Institute for Occupational Safety and Health. NR 41 TC 4 Z9 4 U1 2 U2 16 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 NOV PY 2014 VL 29 IS 13 BP 1623 EP 1630 DI 10.1002/mds.26032 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AT0TT UT WOS:000344648400009 PM 25186946 ER PT J AU LaFaver, K Hallett, M AF LaFaver, Kathrin Hallett, Mark TI Functional or Psychogenic: What's the Better Name? SO MOVEMENT DISORDERS LA English DT Letter ID MOVEMENT-DISORDERS C1 [LaFaver, Kathrin] Univ Louisville, Louisville, KY 40292 USA. [Hallett, Mark] NINDS, Bethesda, MD 20892 USA. RP LaFaver, K (reprint author), Univ Louisville Phys, Dept Neurol, Movement Disorder Div, 220 Abraham Flexner Way,Suite 606, Louisville, KY 40202 USA. EM Kathrin.LaFaver@louisville.edu NR 5 TC 3 Z9 3 U1 0 U2 1 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 NOV PY 2014 VL 29 IS 13 BP 1698 EP 1699 DI 10.1002/mds.26035 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AT0TT UT WOS:000344648400023 PM 25242623 ER PT J AU Divi, RL Lindeman, TLE Shockley, ME Keshava, C Weston, A Poirier, MC AF Divi, Rao L. Lindeman, Tracey L. Einem Shockley, Marie E. Keshava, Channa Weston, Ainsley Poirier, Miriam C. TI Correlation between CYP1A1 transcript, protein level, enzyme activity and DNA adduct formation in normal human mammary epithelial cell strains exposed to benzo[a]pyrene SO MUTAGENESIS LA English DT Article ID FED COAL-TAR; BREAST-CANCER; DIOL-EPOXIDE; P450 REDUCTASE; DT-DIAPHORASE; EROD ACTIVITY; RISK; MICE; CYTOCHROME-P450; BIOMARKERS AB The polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BP) is thought to bind covalently to DNA, through metabolism by cytochrome P450 1A1 (CYP1A1) and CYP1B1, and other enzymes, to form r7, t8, t9-trihydroxy-c-10-(N (2) -deoxyguanosyl)-7,8,9,10-tetrahydro-benzo[a]-pyrene (BPdG). Evaluation of RNA expression data, to understand the contribution of different metabolic enzymes to BPdG formation, is typically presented as fold-change observed upon BP exposure, leaving the actual number of RNA transcripts unknown. Here, we have quantified RNA copies/ng cDNA (RNA cpn) for CYP1A1 and CYP1B1, as well as NAD(P)H:quinone oxidoreductase 1 (NQO1), which may reduce formation of BPdG adducts, using primary normal human mammary epithelial cell (NHMEC) strains, and the MCF-7 breast cancer cell line. In unexposed NHMECs, basal RNA cpn values were 58-836 for CYP1A1, 336-5587 for CYP1B1 and 5943-40112 for NQO1. In cells exposed to 4.0 A mu M BP for 12h, RNA cpn values were 251-13234 for CYP1A1, 4133-57078 for CYP1B1 and 4456-55887 for NQO1. There were 3.5 (mean, range 0.2-15.8) BPdG adducts/10(8) nucleotides in the NHMECs (n = 16), and 790 in the MCF-7s. In the NHMECs, BP-induced CYP1A1 RNA cpn was highly associated with BPdG (P = 0.002), but CYP1B1 and NQO1 were not. Western blots of four NHMEC strains, chosen for different levels of BPdG adducts, showed a linear correlation between BPdG and CYP1A1, but not CYP1B1 or NQO1. Ethoxyresorufin-O-deethylase (EROD) activity, which measures CYP1A1 and CYP1B1 together, correlated with BPdG, but NQO1 activity did not. Despite more numerous levels of CYP1B1 and NQO1 RNA cpn in unexposed and BP-exposed NHMECs and MCF-7cells, BPdG formation was only correlated with induction of CYP1A1 RNA cpn. The higher level of BPdG in MCF-7 cells, compared to NHMECs, may have been due to a much increased induction of CYP1A1 and EROD. Overall, BPdG correlation was observed with CYP1A1 protein and CYP1A1/1B1 enzyme activity, but not with CYP1B1 or NQO1 protein, or NQO1 enzyme activity. C1 [Divi, Rao L.; Lindeman, Tracey L. Einem; Shockley, Marie E.; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Ctr Canc Res, NIH, Bethesda, MD 20817 USA. [Keshava, Channa] US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Weston, Ainsley] Ctr Dis Control & Prevent, Div Resp Dis Studies, NIOSH, Morgantown, WV 26505 USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, Ctr Canc Res, NIH, Bethesda, MD 20817 USA. EM poirierm@exchange.nih.gov FU Intramural NIH HHS NR 39 TC 4 Z9 4 U1 3 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 EI 1464-3804 J9 MUTAGENESIS JI Mutagenesis PD NOV PY 2014 VL 29 IS 6 BP 409 EP 417 DI 10.1093/mutage/geu049 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AT0KI UT WOS:000344624700003 PM 25245543 ER PT J AU McLean, MIH El-Omar, EM AF McLean, Main I. H. El-Omar, Emad M. TI Genetics of gastric cancer SO NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY LA English DT Review ID HELICOBACTER-PYLORI INFECTION; COMPARATIVE-GENOMIC-HYBRIDIZATION; CELL ANTIGEN POLYMORPHISMS; SIGNALING PATHWAY GENES; PEUTZ-JEGHERS-SYNDROME; MICROSATELLITE INSTABILITY; CHINESE POPULATION; INTESTINAL-TYPE; WIDE ASSOCIATION; E-CADHERIN AB Gastric cancer remains highly prevalent and accounts for a notable proportion of global cancer mortality. This cancer is also associated with poor survival rates. Understanding the genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing individualized treatment strategies in the future. An inherited component contributes to <3% of gastric cancers; the majority of genetic changes associated with gastric cancer are acquired. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. These aspects are multifaceted and heterogeneous and represent a wide spectrum of several key genetic influences, such as chromosomal instability, microsatellite instability, changes in microRNA profile, somatic gene mutations or functional single nucleotide polymorphisms. These genetic aspects of the pathogenesis of gastric cancer will be addressed in this Review. C1 [McLean, Main I. H.] NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick, MD 21702 USA. [El-Omar, Emad M.] Univ Aberdeen, Inst Med Sci, Div Appl Med, Aberdeen AB51 5ER, Scotland. RP McLean, MIH (reprint author), NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, 1050 Boyles St, Frederick, MD 21702 USA. EM mairi.mclean@nih.gov NR 172 TC 71 Z9 74 U1 6 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5045 EI 1759-5053 J9 NAT REV GASTRO HEPAT JI Nat. Rev. Gastroenterol. Hepatol. PD NOV PY 2014 VL 11 IS 11 BP 664 EP 674 DI 10.1038/nrgastro.2014.143 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AT1XH UT WOS:000344723800009 PM 25134511 ER PT J AU Chew, EY Klein, ML Clemons, TE Agron, E Ratnapriya, R Edwards, AO Fritsche, LG Swaroop, A Abecasis, GR AF Chew, Emily Y. Klein, Michael L. Clemons, Traci E. Agron, Elvira Ratnapriya, Rinki Edwards, Albert O. Fritsche, Lars G. Swaroop, Anand Abecasis, Goncalo R. CA Age-Related Eye Dis Study Res Grp TI No Clinically Significant Association between CFH and ARMS2 Genotypes and Response to Nutritional Supplements AREDS Report Number 38 SO OPHTHALMOLOGY LA English DT Article ID COMPLEMENT FACTOR-H; MACULAR DEGENERATION; INTRAVITREAL BEVACIZUMAB; BLOOD-PRESSURE; EYE DISEASE; VITAMIN-C; AREDS; LOCI; ZINC; PHARMACOGENETICS AB Objective: To determine whether genotypes at 2 major loci associated with late age-related macular degeneration (AMD), complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), influence the relative benefits of Age-Related Eye Disease Study (AREDS) supplements. Design: Unplanned retrospective evaluation of a prospective, randomized, placebo-controlled clinical trial of vitamins and minerals for the treatment of AMD. Subjects: AREDS participants (mean age, 69 years) who were at risk of developing late AMD and who were randomized to the 4 arms of AREDS supplement treatment. Methods: Analyses were performed using the Cox proportional hazards model to predict progression to late AMD (neovascular or central geographic atrophy). Statistical models, adjusted for age, gender, smoking status, and baseline AMD severity, were used to examine the influence of genotypes on the response to therapy with 4 randomly assigned arms of AREDS supplement components: placebo, antioxidants (vitamin C, vitamin E, b-carotene), zinc, or a combination. Main Outcome Measures: The influence of the genotype on the relative treatment response to the randomized components of the AREDS supplement, measured as progression to late AMD. Results: Of the 1237 genotyped AREDS participants of white ethnicity, late AMD developed in 385 (31.1%) during the mean follow-up of 6.6 years. As previously demonstrated, CFH genotype (P = 0.005), ARMS2 (P< 0.0001), and supplement were associated individually with progression to late AMD. An interaction analysis found no evidence that the relative benefits of AREDS supplementation varied by genotype. Analysis of (1) CFH rs1061170 and rs1410996 combined with ARMS2 rs10490924 with the 4 randomly assigned arms of AREDS supplement and (2) analysis of the combination of CFH rs412852 and rs3766405 with ARMS2 c. 372_815del443ins54 with the AREDS components resulted in no interaction (P = 0.06 and P = 0.45, respectively, before multiplicity adjustment). Conclusions: The AREDS supplements reduced the rate of AMD progression across all genotype groups. Furthermore, the genotypes at the CFH and ARMS2 loci did not statistically significantly alter the benefits of AREDS supplements. Genetic testing remains a valuable research tool, but these analyses suggest it provides no benefits in managing nutritional supplementation for patients at risk of late AMD. (C) 2014 by the American Academy of Ophthalmology. C1 [Chew, Emily Y.; Agron, Elvira] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Klein, Michael L.; Edwards, Albert O.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Ratnapriya, Rinki; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Edwards, Albert O.] Oregon Retina LLP, Eugene, OR USA. [Edwards, Albert O.] Univ Oregon, Dept Biol, Eugene, OR 97403 USA. [Fritsche, Lars G.; Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Chew, EY (reprint author), NEI, NIH, Bldg 10,CRC Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute/National Institutes of Health, Bethesda Maryland [HHS-NOI-EY-0-2127] FX Supported by the National Eye Institute/National Institutes of Health, (contract no.: HHS-NOI-EY-0-2127), Bethesda Maryland. The sponsor and funding organization participated in the design and conduct of the study; data collection, management, analysis, and interpretation; and the preparation, review, and approval of the manuscript. The NIH holds a royalty-bearing license issued to Bausch & Lomb for the Age-Related Eye Disease Study Supplement. The Age-Related Eye Disease Study was a clinical trial that was conducted before the required clinical trials registration. NR 25 TC 27 Z9 27 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2014 VL 121 IS 11 BP 2173 EP 2180 DI 10.1016/j.ophtha.2014.05.008 PG 8 WC Ophthalmology SC Ophthalmology GA AS8DM UT WOS:000344480400022 PM 24974817 ER PT J AU Sen, HN Vitale, S Gangaputra, SS Nussenblatt, RB Liesegang, TL Levy-Clarke, GA Rosenbaum, JT Suhler, EB Thorne, JE Foster, CS Jabs, DA Kempen, JH AF Sen, H. Nida Vitale, Susan Gangaputra, Sapna S. Nussenblatt, Robert B. Liesegang, Teresa L. Levy-Clarke, Grace A. Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Kempen, John H. TI Periocular Corticosteroid Injections in Uveitis Effects and Complications SO OPHTHALMOLOGY LA English DT Article ID TRIAMCINOLONE ACETONIDE INJECTIONS; CYSTOID MACULAR EDEMA; INTRAOCULAR-PRESSURE ELEVATION; PERSISTENT GLAUCOMA SECONDARY; SUB-TENON TRIAMCINOLONE; RETINAL VEIN OCCLUSION; NONINFECTIOUS UVEITIS; RISK-FACTORS; POSTERIOR; INFLAMMATION AB Purpose: To evaluate the benefits and complications of periocular depot corticosteroid injections in patients with ocular inflammatory disorders. Design: Multicenter, retrospective cohort study. Participants: A total of 914 patients (1192 eyes) who had received >= 1 periocular corticosteroid injection at 5 tertiary uveitis clinics in the United States. Methods: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained at every visit via medical record review by trained reviewers. Main Outcome Measures: Control of inflammation, improvement of visual acuity (VA) to >= 20/40, improvement of VA loss attributed to macular edema (ME), incident cataract affecting VA, cataract surgery, ocular hypertension, and glaucoma surgery. Results: Among 914 patients (1192 eyes) who received >= 1 periocular injection during follow-up, 286 (31.3%) were classified as having anterior uveitis, 303 (33.3%) as intermediate uveitis, and 324 (35.4%) as posterior or panuveitis. Cumulatively by <= 6 months, 72.7% (95% CI, 69.1-76.3) of the eyes achieved complete control of inflammation and 49.7% (95% CI, 45.5-54.1) showed an improvement in VA from <20/40 to >= 20/40. Among the subset with VA <20/40 attributed to ME, 33.1% (95% CI, 25.2-42.7) improved to >= 20/40. By 12 months, the cumulative incidence of >= 1 visits with an intraocular pressure of >= 24 mmHg and >= 30 mmHg was 34.0% (95% CI, 24.8-45.4) and 15.0% (95% CI, 11.8-19.1) respectively; glaucoma surgery was performed in 2.4% of eyes (95% CI, 1.4-3.9). Within 12 months, among phakic eyes initially >= 20/40, the incidence of a reduction in VA to <20/40 attributed to cataract was 20.2% (95% CI, 15.9-25.6); cataract surgery was performed within 12 months in 13.8% of the initially phakic eyes (95% CI, 11.1-17.2). Conclusions: Periocular injections were effective in treating active intraocular inflammation and in improving reduced VA attributed to ME in a majority of patients. The response pattern was similar across anatomic locations of uveitis. Overall, VA improved in one half of the patients at some point within 6 months. However, cataract and ocular hypertension occurred in a substantial minority. (C) 2014 by the American Academy of Ophthalmology. C1 [Sen, H. Nida; Vitale, Susan; Nussenblatt, Robert B.; Levy-Clarke, Grace A.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Gangaputra, Sapna S.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Liesegang, Teresa L.; Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Levy-Clarke, Grace A.] Tampa Bay Uveitis Ctr, Tampa, FL USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Oregon Hlth & Sci Univ, Vet Affairs Med Ctr, Portland, OR 97201 USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Clin Trials, Dept Epidemiol, Baltimore, MD USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY USA. [Kempen, John H.] Univ Penn, Perelman Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Rm 10N112, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU National Eye Institute [EY014943]; Research to Prevent Blindness (RPB); Paul and Evanina Mackall Foundation; Lois Pope Life Foundation; RPB James S. Adams Special Scholar Award; RPB Harrington Special Scholar Award; Department of Veterans Affairs, United States Government; National Eye Institute FX The authors have made the following disclosures:; Supported primarily by National Eye Institute Grant EY014943 (Dr. Kempen). Additional support was provided by Research to Prevent Blindness (RPB), the Paul and Evanina Mackall Foundation, and the Lois Pope Life Foundation. Dr. Kempen was an RPB James S. Adams Special Scholar Award recipient and Dr. Thorne was an RPB Harrington Special Scholar Award recipient during the conduct of the study. Drs. Jabs and Rosenbaum were RPB Senior Scientific Investigator Award recipients during the conduct of the study. Dr. Suhler is supported in part by the Department of Veterans Affairs, United States Government. Dr. Levy-Clarke was previously supported by and Drs. Sen and Nussenblatt continue to be supported by intramural research program of the National Eye Institute. None of the sponsors had any role in the design and conduct of the report; collection, management, analysis, and interpretation of the data; nor in the preparation, review, and approval of this manuscript. NR 42 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2014 VL 121 IS 11 BP 2275 EP 2286 DI 10.1016/j.ophtha.2014.05.021 PG 12 WC Ophthalmology SC Ophthalmology GA AS8DM UT WOS:000344480400035 PM 25017415 ER PT J AU Pacak, K Chew, EY Pappo, AS Yang, CZ Lorenzo, FR Wilson, MW Aronow, MB Young, JA Popovic, V Zhuang, ZP AF Pacak, Karel Chew, Emily Y. Pappo, Alberto S. Yang, Chunzhang Lorenzo, Felipe R. Wilson, Matthew W. Aronow, Mary Beth Young, James A. Popovic, Vera Zhuang, Zhengping TI Ocular Manifestations of HypoxiaInducible Factor-2 alpha Paraganglioma-Somatostatinoma-Polycythemia Syndrome SO OPHTHALMOLOGY LA English DT Article C1 [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Chew, Emily Y.; Aronow, Mary Beth] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Pappo, Alberto S.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Yang, Chunzhang; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lorenzo, Felipe R.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Wilson, Matthew W.] St Jude Childrens Res Hosp, Dept Surg & Pathol, Memphis, TN 38105 USA. [Wilson, Matthew W.] Univ Tennessee, Hlth Sci Ctr, Dept Ophthalmol, Memphis, TN USA. [Young, James A.] Rocky Mt Canc Ctr, Colorado Springs, CO USA. [Popovic, Vera] Univ Belgrade, Fac Med, Belgrade, Serbia. [Popovic, Vera] Clin Ctr Serbia, Dept Neuroendocrinol, Belgrade, Serbia. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg 10,CRC,Room 1E-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [1ZIAHD008735-14]; National Institute of Neurological Disorders and Stroke; National Eye Institute [ZIE EY000487-05] FX 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 (grant no. 1ZIAHD008735-14), National Institute of Neurological Disorders and Stroke, and the National Eye Institute (grant no. ZIE EY000487-05). NR 5 TC 6 Z9 7 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2014 VL 121 IS 11 BP 2291 EP 2293 PG 4 WC Ophthalmology SC Ophthalmology GA AS8DM UT WOS:000344480400039 PM 25109928 ER PT J AU Josephson, CD Mondoro, TH Ambruso, DR Sanchez, R Sloan, SR Luban, NLC Widness, JA AF Josephson, Cassandra D. Mondoro, Traci Heath Ambruso, Daniel R. Sanchez, Rosa Sloan, Steven R. Luban, Naomi L. C. Widness, John A. TI One size will never fit all: the future of research in pediatric transfusion medicine SO PEDIATRIC RESEARCH LA English DT Review ID BIRTH-WEIGHT INFANTS; RED-BLOOD-CELLS; PATHOGEN REDUCTION TECHNOLOGY; INTENSIVE-CARE-UNIT; NECROTIZING ENTEROCOLITIS; PREMATURE-INFANTS; PLATELET TRANSFUSIONS; INTRAVENTRICULAR HEMORRHAGE; BACTERIAL-CONTAMINATION; ULTRAVIOLET-LIGHT AB There is concern at the National Heart, Lung, and Blood Institute (NHLBI) and among transfusion medicine specialists regarding the small number of investigators and studies in the field of pediatric transfusion medicine (PTM). Accordingly, the objective of this article is to provide a snapshot of the clinical and translational PTM research considered to be of high priority by pediatricians, neonatologists, and transfusion medicine specialists. Included is a targeted review of three research areas of importance: (i) transfusion strategies, (ii) short- and long-term clinical consequences, and (iii) transfusion-transmitted infectious diseases. The recommendations by PTM and transfusion medicine specialists represent opportunities and innovative strategies to execute translational research, observational studies, and clinical trials of high relevance to PTM. With the explosion of new biomedical knowledge and increasingly sophisticated methodologies over the past decade, this is an exciting time to consider transfusion medicine as a paradigm for addressing questions related to fields such as cell biology, immunology, neurodevelopment, outcomes research, and many others. Increased awareness of PTM as an important, fertile field and the promotion of accompanying opportunities will help establish PTM as a viable career option and advance basic and clinical investigation to improve the health and wellbeing of children. C1 [Josephson, Cassandra D.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Josephson, Cassandra D.] Emory Univ, Sch Med, Ctr Transfus & Cellular Therapies, Atlanta, GA USA. [Mondoro, Traci Heath] NHLBI, NIH, Bethesda, MD 20892 USA. [Ambruso, Daniel R.] Bonfils Blood Ctr, Aurora, CO USA. [Sanchez, Rosa] Blood Syst Res Inst, San Francisco, CA USA. [Sloan, Steven R.] Childrens Hosp, Joint Program Transfus Med, Boston, MA 02115 USA. [Luban, Naomi L. C.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Widness, John A.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. RP Josephson, CD (reprint author), Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. EM cjoseph@emory.edu FU National Institutes of Health, Bethesda, MD [K07 HL088921, K07 HL088922, K07 HL088923, K07 HL088968, P01 HL046925, UL1RR024979]; Thrasher Research Fund, Salt Lake City, UT FX We gratefully acknowledge the input, advice, and knowledge gained from many intensive discussions with the following: Raymond P Goodrich (Terumo Corporation), Christopher D Hillyer (New York Blood Center), Heather A Hume (Canadian Blood Services), Haresh Kirpalani (Children's Hospital of Philadelphia), Catherine S Manno (New York University), William Reed (Cellerant Therapeutics), Leslie E Silberstein (Boston Children's Hospital), Martha Sola-Visner (Boston Children's Hospital), Susan Stramer (American Red Cross), and Ronald G Strauss (University of Iowa). K07 HL088921 (S.R.S.), K07 HL088922 (C.D.J.), K07 HL088923 (R.S.R.), K07 HL088968 (D.R.A.), P01 HL046925 (J.A.W.), and UL1RR024979 (J.A.W.); these are all grants from the National Institutes of Health, Bethesda, MD and Thrasher Research Fund, Salt Lake City, UT (J.A.W.). NR 79 TC 5 Z9 5 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD NOV PY 2014 VL 76 IS 5 BP 425 EP 431 DI 10.1038/pr.2014.120 PG 7 WC Pediatrics SC Pediatrics GA AS8QA UT WOS:000344512200002 PM 25119336 ER PT J AU Calderon, MM Chairez, CL Gordon, LA Alfaro, RM Kovacs, JA Penzak, SR AF Calderon, Monica M. Chairez, Cheryl L. Gordon, Lori A. Alfaro, Raul M. Kovacs, Joseph A. Penzak, Scott R. TI Influence of Panax ginseng on the Steady State Pharmacokinetic Profile of Lopinavir-Ritonavir in Healthy Volunteers SO PHARMACOTHERAPY LA English DT Article DE Panax ginseng; lopinavir-ritonavir; pharmacokinetics; complementary and alternative medicine; drug interaction; cytochrome P450; HIV; HIV protease inhibitor; antiretrovirals ID ST-JOHNS-WORT; ALTERNATIVE MEDICINE USE; HIV-INFECTED PATIENTS; DRUG-INTERACTIONS; GINKGO-BILOBA; COMPLEMENTARY; FEXOFENADINE; SUPPLEMENTS; INHIBITION; SAQUINAVIR AB STUDY OBJECTIVE Panax ginseng has been shown in preclinical studies to modulate cytochrome P450 enzymes involved in the metabolism of HIV protease inhibitors. Therefore, the purpose of this study was to determine the influence of P. ginseng on the pharmacokinetics of the HIV protease inhibitor combination lopinavir-ritonavir (LPV-r) in healthy volunteers. DESIGN Single-sequence, open-label, single-center pharmacokinetic investigation. SETTING Government health care facility. SUBJECTS Twelve healthy human volunteers. MEASUREMENTS AND MAIN RESULTS Twelve healthy volunteers received LPV-r (400-100 mg) twice/day for 29.5 days. On day 15 of LPV-r administration, serial blood samples were collected over 12 hours for determination of lopinavir and ritonavir concentrations. On study day 16, subjects began taking P. ginseng 500 mg twice/day, which they continued for 2 weeks in combination with LPV-r. On day 30 of LPV-r administration, serial blood samples were again collected over 12 hours for determination of lopinavir and ritonavir concentrations. Lopinavir and ritonavir pharmacokinetic parameter values were determined using noncompartmental methods, and preadministration and postadministration ginseng values were compared using a Student t test, where p<0.05 was accepted as statistically significant. CONCLUSION Neither lopinavir nor ritonavir steady-state pharmacokinetics were altered by 2 weeks of P. ginseng administration to healthy human volunteers. Thus, a clinically significant interaction between P. ginseng and LPV-r is unlikely to occur in HIV-infected patients who choose to take these agents concurrently. It is also unlikely that P. ginseng will interact with other ritonavir-boosted protease inhibitor combinations, although confirmatory data are necessary. C1 [Calderon, Monica M.; Gordon, Lori A.; Alfaro, Raul M.; Penzak, Scott R.] NIH, Clin Res Ctr, Clin Ctr Pharm Dept, Bethesda, MD 20892 USA. [Chairez, Cheryl L.] NIAID, NIH, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Clin Res Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Penzak, SR (reprint author), UNT Syst Coll Pharm, Dept Pharmacotherapy, 3500 Camp Bowie Blvd, Ft Worth, TX 76107 USA. EM scott.penzak@unthsc.edu NR 35 TC 4 Z9 4 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD NOV PY 2014 VL 34 IS 11 BP 1151 EP 1158 DI 10.1002/phar.1473 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT4RD UT WOS:000344927500007 PM 25142999 ER PT J AU Schneiderman, N Chirinos, DA Aviles-Santa, ML Heiss, G AF Schneiderman, Neil Chirinos, Diana A. Aviles-Santa, M. Larissa Heiss, Gerardo TI Challenges in Preventing Heart Disease in Hispanics: Early Lessons Learned from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Cardiovascular risk factors; Hispanic Community Health Study; Health insurance ID OBSTRUCTIVE SLEEP-APNEA; NUTRITION EXAMINATION SURVEY; UNITED-STATES; METABOLIC SYNDROME; DIVERSE BACKGROUNDS; PERIODONTAL-DISEASE; US POPULATION; CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; NATIONAL-HEALTH AB The challenge of preventing cardiovascular disease (CVD) in US Hispanics depends upon being able to understand and communicate about the diversity within this population in terms of environmental exposures, health behaviors, socio-cultural experiences and genetic background to CVD risk factor profiles and disease burdens. Recent publications from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) launched by the National Institutes of Health (NIH) have begun to accomplish this task. In this article we review some of the HCHS/SOL findings concerning cardiometabolic and other CVD risk factors and relate them to the need for increased access to health care and attention to lifestyle variables including nutrition. A major challenge that needs to be accomplished is to alert our lawmakers, public health officials, health care providers and the Hispanic population at large about how to lighten the CVD risk factor and disease burdens now carried by our Hispanic population. (C) 2014 Elsevier Inc. All rights reserved. C1 [Schneiderman, Neil; Chirinos, Diana A.] Univ Miami, Dept Psychol, Miami, FL 33124 USA. [Schneiderman, Neil; Chirinos, Diana A.] Univ Miami, Behav Med Res Ctr, Miami, FL 33124 USA. [Aviles-Santa, M. Larissa] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Schneiderman, N (reprint author), Univ Miami, Dept Psychol, 5665 Ponce Leon Blvd,FLIPSE Bldg,4th Floor, Coral Gables, FL 33146 USA. EM nschneid@miami.edu FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233]; University of Miami [N01-HC65234]; Albert Einstein College of Medicine [N01-HC65235]; Northwestem University [N01-HC65236]; San Diego State University [N01-HC65237] FX 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), Northwestem University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contributed to the baseline HCHS/SOL funding period 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, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Office of Dietary Supplements. NR 64 TC 8 Z9 9 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD NOV-DEC PY 2014 VL 57 IS 3 BP 253 EP 261 DI 10.1016/j.pcad.2014.08.004 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT1WN UT WOS:000344721900005 PM 25212986 ER PT J AU Meyer, EC Carrion, RE Cornblatt, BA Addington, J Cadenhead, KS Cannon, TD McGlashan, TH Perkins, DO Tsuang, MT Walker, EF Woods, SW Heinssen, R Seidman, LJ AF Meyer, Eric C. Carrion, Ricardo E. Cornblatt, Barbara A. Addington, Jean Cadenhead, Kristin S. Cannon, Tyrone D. McGlashan, Thomas H. Perkins, Diana O. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Heinssen, Robert Seidman, Larry J. CA NAPLS Grp TI The Relationship of Neurocognition and Negative Symptoms to Social and Role Functioning Over Time in Individuals at Clinical High Risk in the First Phase of the North American Prodrome Longitudinal Study SO SCHIZOPHRENIA BULLETIN LA English DT Article DE social and role functioning; neurocognition; negative symptoms; prodrome ID ULTRA-HIGH RISK; 1ST-EPISODE PSYCHOSIS; COGNITIVE DEFICITS; FOLLOW-UP; FAMILY-HISTORY; SCHIZOPHRENIA; PREDICTION; NEUROPSYCHOLOGY; ADOLESCENTS; CHILDREN AB Objectives: Impaired social, role, and neurocognitive functioning are preillness characteristics of people who later develop psychosis. In people with schizophrenia, neurocognition and negative symptoms are associated with functional impairment. We examined the relative contributions of neurocognition and symptoms to social and role functioning over time in clinically high-risk (CHR) individuals and determined if negative symptoms mediated the influence of cognition on functioning. Methods: Social, role, and neurocognitive functioning and positive, negative, and disorganized symptoms were assessed in 167 individuals at CHR for psychosis in the North American Prodrome Longitudinal Study Phase 1 (NAPLS-1), of whom 96 were reassessed at 12 months. Results: Regression analyses indicated that negative symptoms accounted for unique variance in social and role functioning at baseline and follow-up. Composite neurocognition accounted for unique, but modest, variance in social and role functioning at baseline and in role functioning at follow-up. Negative symptoms mediated the relationship between composite neurocognition and social and role functioning across time points. In exploratory analyses, individual tests (IQ estimate, Digit Symbol/Coding, verbal memory) selectively accounted for social and role functioning at baseline and follow-up after accounting for symptoms. When negative symptom items with content overlapping with social and role functioning measures were removed, the relationship between neurocognition and social and role functioning was strengthened. Conclusion: The modest overlap among neurocognition, negative symptoms, and social and role functioning indicates that these domains make substantially separate contributions to CHR individuals. C1 [Meyer, Eric C.] VA VISN 17 Ctr Excellence Res Returning War Vet, Waco, TX USA. [Meyer, Eric C.] Texas A&M Hlth Sci Ctr, Coll Med, Dept Psychiat & Behav Sci, College Stn, TX USA. [Carrion, Ricardo E.; Cornblatt, Barbara A.] Zucker Hillside Hosp, North Shore Long Isl Jewish Hlth Syst NS LIJHS, Div Psychiat Res, Glen Oaks, NY USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA USA. [Cannon, Tyrone D.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Cannon, Tyrone D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Tsuang, Ming T.] UCSD, Ctr Behav Genom, La Jolla, CA USA. [Tsuang, Ming T.] UCSD, Inst Genom Med, La Jolla, CA USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Heinssen, Robert] NIMH, Schizophrenia Spectrum Res Program, Div Adult Translat Res, Bethesda, MD 20892 USA. [Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Seidman, LJ (reprint author), Massachusetts Mental Hlth Ctr, Neuropsychol Lab, Commonwealth Res Ctr, 5th Floor,75 Fenwood Rd, Boston, MA 02115 USA. EM lseidman@bidmc.harvard.edu FU National Institute of Mental Health of the National Institutes of Health [U01 MH081928, U01 MH066134, R01 MH60720, R01 MH065079, R01 MH061523, U01 MH066069, RO1MH062066, U01 MH066160, K05MH01654]; Commonwealth of Massachusetts [SCDMH82101008006] FX National Institute of Mental Health of the National Institutes of Health (U01 MH081928 to L.J.S., U01 MH066134 to J.A., R01 MH60720 to K. S. C., R01 MH065079 to T. D. C., R01 MH061523 to B. A. C., U01 MH066069 to D.O.P., RO1MH062066 to E. F. W., U01 MH066160 to S. W. W., K05MH01654 to T. H. M.), and the Commonwealth of Massachusetts (SCDMH82101008006 to L.J.S.). NR 48 TC 26 Z9 26 U1 2 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD NOV PY 2014 VL 40 IS 6 BP 1452 EP 1461 DI 10.1093/schbul/sbt235 PG 10 WC Psychiatry SC Psychiatry GA AT0FF UT WOS:000344611900029 PM 24550526 ER PT J AU Engle, RE Bukh, J Alter, HJ Emerson, SU Trenbeath, JL Nguyen, HT Brockington, A Mitra, T Purcell, RH AF Engle, Ronald E. Bukh, Jens Alter, Harvey J. Emerson, Suzanne U. Trenbeath, Joni L. Nguyen, Hanh T. Brockington, Alicia Mitra, Tanaji Purcell, Robert H. TI Transfusion-associated hepatitis before the screening of blood for hepatitis risk factors SO TRANSFUSION LA English DT Article ID C VIRUS-INFECTION; NON-B-HEPATITIS; POSTTRANSFUSION HEPATITIS; VIRAL-HEPATITIS; NON-A; ENZYME-IMMUNOASSAY; SERUM HEPATITIS; GAMMA-GLOBULIN; LIVER-DISEASE; ANTIBODY AB BackgroundThe true incidence of transfusion-associated hepatitis (TAH) before blood screening is unknown. Our aims were to reevaluate blood recipients receiving unscreened blood and analyze hepatitis viruses circulating more than 45 years ago. Study Design and MethodsCryopreserved serum samples from 66 patients undergoing open heart surgery in the 1960s were reevaluated with modern diagnostic tests to determine the incidence of TAH and its virologic causes. ResultsIn this heavily transfused population receiving a mean of 20 units per patient of predominantly paid-donor blood, 30 of 66 (45%) developed biochemical evidence of hepatitis; of these, 20 (67%) were infected with hepatitis C virus (HCV) alone, four (13%) with hepatitis B virus (HBV) alone, and six (20%) with both viruses. Among the 36 patients who did not develop hepatitis, four (11%) were newly infected with HCV alone, nine (25%) with HBV alone, and one (3%) with both viruses. Overall, 100% of patients with hepatitis and 39% of those without hepatitis were infected with HBV and/or HCV; one patient was also infected with hepatitis E virus. The donor carrier rate for HBV and/or HCV was estimated to be more than 6%; contemporaneously prepared pooled normal human plasma was also contaminated with multiple hepatitis viruses. ConclusionTAH virus infections were a larger problem than perceived 50 years ago and HCV was the predominant agent transmitted. All hepatitis cases could be attributed to HCV and/or HBV and hence there was no evidence to suggest that an additional hepatitis agent existed undetected in the blood supply. C1 [Engle, Ronald E.; Emerson, Suzanne U.; Nguyen, Hanh T.; Brockington, Alicia; Mitra, Tanaji; Purcell, Robert H.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Alter, Harvey J.; Trenbeath, Joni L.] NIH, Dept Transfus Med, Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Bukh, Jens] Univ Copenhagen, Hvidovre Hosp, Copenhagen Hepatitis Program CO HEP C, Dept Infect Dis, DK-2650 Hvidovre, Denmark. [Bukh, Jens] Univ Copenhagen, Hvidovre Hosp, Clin Res Ctr, DK-2650 Hvidovre, Denmark. [Bukh, Jens] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Fac Hlth & Med Sci, Copenhagen, Denmark. RP Engle, RE (reprint author), NIAID, Infect Dis Lab, 50 South Dr,Room 6345, Bethesda, MD 20892 USA. EM rengle@niaid.nih.gov FU Intramural Research Programs of the Clinical Center Department of Transfusion Medicine; National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Intramural Research Programs of the Clinical Center Department of Transfusion Medicine and the National Institute of Allergy and Infectious Diseases. NR 44 TC 3 Z9 4 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD NOV PY 2014 VL 54 IS 11 BP 2833 EP 2841 DI 10.1111/trf.12682 PG 9 WC Hematology SC Hematology GA AT1FQ UT WOS:000344679200009 PM 24797372 ER PT J AU Zhang, CL Hu, FB Olsen, SF Vaag, A Gore-Langton, R Chavarro, JE Bao, W Yeung, E Bowers, K Grunnet, LG Sherman, S Kiely, M Strom, M Hansen, S Liu, AY Mills, J Fan, RZ AF Zhang, Cuilin Hu, Frank B. Olsen, Sjurdur F. Vaag, Allan Gore-Langton, Robert Chavarro, Jorge E. Bao, Wei Yeung, Edwina Bowers, Katherine Grunnet, Louise G. Sherman, Seth Kiely, Michele Strom, Marin Hansen, Susanne Liu, Aiyi Mills, James Fan, Ruzong CA DWH Study Team TI Rationale, design, and method of the Diabetes & Women's Health study - a study of long-term health implications of glucose intolerance in pregnancy and their determinants SO ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA LA English DT Article DE Diabetes & Women's Health study; gestational diabetes; impaired glucose tolerance; type 2 diabetes; glucose tolerance test; metabolism; pregnancy; genetic factors; environmental factors ID NATIONAL-BIRTH-COHORT; MELLITUS; RISK; PREVALENCE; DIAGNOSIS; VARIANTS AB Women who develop gestational diabetes mellitus or impaired glucose tolerance during pregnancy are at substantially increased risk for type 2 diabetes and comorbidities after pregnancy. Little is known about the role of genetic factors and their interactions with environmental factors in determining the transition from gestational diabetes mellitus to overt type 2 diabetes mellitus. These critical data gaps served as the impetus for this Diabetes & Women's Health study with the overall goal of investigating genetic factors and their interactions with risk factors amenable to clinical or public health interventions in relation to the transition of gestational diabetes mellitus to type 2 diabetes mellitus. To achieve the goal efficiently, we are applying a hybrid design enrolling and collecting data longitudinally from approximately 4000 women with a medical history of gestational diabetes mellitus in two existing prospective cohorts, the Nurses' Health Study II and the Danish National Birth Cohort. Women who had a medical history of gestational diabetes mellitus in one or more of their pregnancies are eligible for the present study. After enrollment, we follow study participants for an additional 2years to collect updated information on major clinical and environmental factors that may predict type 2 diabetes mellitus risk as well as with biospecimens to measure genetic and biochemical markers implicated in glucose metabolism. Newly collected data will be appended to the relevant existing data for the creation of a new database inclusive of genetic, epigenetic and environmental data. Findings from the study are critical for the development of targeted and more effective strategies to prevent type 2 diabetes mellitus and its complications in this high-risk population. C1 [Zhang, Cuilin; Bao, Wei; Yeung, Edwina; Kiely, Michele; Liu, Aiyi; Mills, James; Fan, Ruzong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Hu, Frank B.; Chavarro, Jorge E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MD USA. [Hu, Frank B.; Chavarro, Jorge E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MD USA. [Olsen, Sjurdur F.; Strom, Marin; Hansen, Susanne] Statens Serum Inst, Dept Epidemiol Res, Ctr Fetal Programming, DK-2300 Copenhagen, Denmark. [Vaag, Allan; Grunnet, Louise G.] Univ Copenhagen Hosp, Rigshosp, Dept Endocrinol, DK-2100 Copenhagen, Denmark. [Gore-Langton, Robert; Sherman, Seth] EMMES Corp, Rockville, MD USA. [Chavarro, Jorge E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MD USA. [Chavarro, Jorge E.] Harvard Univ, Sch Med, Boston, MD USA. [Bowers, Katherine] Cincinnati Childrens Hosp, Med Ctr, Dept Pediat, Div Biostat & Epidemiol, Cincinnati, OH USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov RI Bowers, Katherine/N-5226-2015; Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Liu, Aiyi/0000-0002-6618-5082; Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275201000020C]; NIH [R01 CA50385, R01 CA67262, 1UM1CA176726-01]; Danish Research Council [09-067124, 09-075611] FX The study is funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275201000020C). The NHS II cohort is funded by NIH grants R01 CA50385, R01 CA67262, and 1UM1CA176726-01. The DNBC is supported by grants from The Danish Research Council (09-067124 (Center for Fetal Programming) and 09-075611. NR 24 TC 7 Z9 7 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-6349 EI 1600-0412 J9 ACTA OBSTET GYN SCAN JI Acta Obstet. Gynecol. Scand. PD NOV PY 2014 VL 93 IS 11 SI SI BP 1123 EP 1130 DI 10.1111/aogs.12425 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AS4FI UT WOS:000344228200009 PM 24828694 ER PT J AU Shehata, L Simeonov, DR Raams, A Wolfe, L Vanderver, A Li, XL Huang, Y Garner, S Boerkoel, CF Thurm, A Herman, GE Tifft, CJ He, M Jaspers, NGJ Gahl, WA AF Shehata, Laila Simeonov, Dimitre R. Raams, Anja Wolfe, Lynne Vanderver, Adeline Li, Xueli Huang, Yan Garner, Shannon Boerkoel, Cornelius F. Thurm, Audrey Herman, Gail E. Tifft, Cynthia J. He, Miao Jaspers, Nicolaas G. J. Gahl, William A. TI ERCC6 Dysfunction Presenting as Progressive Neurological Decline With Brain Hypomyelination SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE hypomyelination; developmental delay; intellectual disability; Cockayne syndrome group B; deafness; vision loss ID UV-SENSITIVE SYNDROME; TRANSCRIPTION-COUPLED REPAIR; COCKAYNE-SYNDROME; DNA-REPAIR; EPIGENETIC MECHANISMS; EXCISION-REPAIR; GENE; MUTATIONS; PROTEIN; DAMAGE AB Mutations in ERCC6 are associated with growth failure, intellectual disability, neurological dysfunction and deterioration, premature aging, and photosensitivity. We describe siblings with biallelic ERCC6 mutations (NM_000124.2:c. [543+4delA];[2008C>T]) and brain hypomyelination, microcephaly, cognitive decline, and skill regression but without photosensitivity or progeria. DNA repair assays on cultured skin fibroblasts confirmed a defect of transcription-coupled nucleotide excision repair and increased ultraviolet light sensitivity. This report expands the disease spectrum associated with ERCC6 mutations. (c) 2014 Wiley Periodicals, Inc. C1 [Shehata, Laila; Simeonov, Dimitre R.; Wolfe, Lynne; Huang, Yan; Boerkoel, Cornelius F.; Tifft, Cynthia J.; Gahl, William A.] NIH, Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20892 USA. [Shehata, Laila; Simeonov, Dimitre R.; Wolfe, Lynne; Huang, Yan; Boerkoel, Cornelius F.; Tifft, Cynthia J.; Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Raams, Anja; Jaspers, Nicolaas G. J.] Erasmus MC, Dept Genet, Rotterdam, Netherlands. [Vanderver, Adeline; Tifft, Cynthia J.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Vanderver, Adeline] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Li, Xueli; He, Miao] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Li, Xueli; He, Miao] Univ Penn, Philadelphia, PA 19104 USA. [Garner, Shannon; Herman, Gail E.] Nationwide Childrens Hosp, Columbus, OH USA. [Garner, Shannon; Herman, Gail E.] Ohio State Univ, Columbus, OH 43210 USA. [Thurm, Audrey] NIMH, NIH, Bethesda, MD 20892 USA. RP Tifft, CJ (reprint author), NHGRI, NIH, 10 Ctr Dr,MSC 1205,Bldg 10,Room CRC3-2551, Bethesda, MD 20892 USA. EM ctifft@nih.gov FU National Human Genome Research Institute (NIH, Bethesda, Maryland) FX Grant sponsor: Director and the Intramural Research Program of the National Human Genome Research Institute (NIH, Bethesda, Maryland). NR 43 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD NOV PY 2014 VL 164 IS 11 BP 2892 EP 2900 DI 10.1002/ajmg.a.36709 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AS3OB UT WOS:000344187200030 PM 25251875 ER PT J AU Jowsey, SG Jacobs, C Gross, CR Hong, BA Messersmith, EE Gillespie, BW Beebe, TJ Kew, C Matas, A Yusen, RD Hill-Callahan, M Odim, J Taler, SJ AF Jowsey, S. G. Jacobs, C. Gross, C. R. Hong, B. A. Messersmith, E. E. Gillespie, B. W. Beebe, T. J. Kew, C. Matas, A. Yusen, R. D. Hill-Callahan, M. Odim, J. Taler, S. J. CA RELIVE Study Grp TI Emotional Well-Being of Living Kidney Donors: Findings From the RELIVE Study SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Clinical research; practice; health services and outcomes research; kidney transplantation; nephrology; social sciences; depression; donors and donation; donors and donation: donor follow-up; donors and donation: living; kidney transplantation: living donor ID QUALITY-OF-LIFE; HEALTH-STATUS; FOLLOW-UP; 5 DECADES; DONATION; OPTIMISM; DEPRESSION; PESSIMISM; ANXIETY; IMPACT AB Following kidney donation, short-term quality of life outcomes compare favorably to US normative data but long-term effects on mood are not known. In the Renal and Lung Living Donors Evaluation Study (RELIVE), records from donations performed 1963-2005 were reviewed for depression and antidepressant use predonation. Postdonation, in a cross-sectional cohort design 2010-2012, donors completed the Patient Health Questionnaire (PHQ-9) depression screening instrument, the Life Orientation Test-Revised, 36-Item Short Form Health Survey and donation experience questions. Of 6909 eligible donors, 3470 were contacted and 2455 participated (71%). The percent with depressive symptoms (8%; PHQ-9>10) was similar to National Health and Nutrition Examination Survey participants (7%, p=0.30). Predonation psychiatric disorders were more common in unrelated than related donors (p=0.05). Postdonation predictors of depressive symptoms included nonwhite race OR=2.00, p=0.020), younger age at donation (OR=1.33 per 10 years, p=0.002), longer recovery time from donation (OR=1.74, p=0.0009), greater financial burden (OR=1.32, p=0.013) and feeling morally obligated to donate (OR=1.23, p=0.003). While cross-sectional prevalence of depression is comparable to population normative data, some factors identifiable around time of donation, including longer recovery, financial stressors, younger age and moral obligation to donate may identify donors more likely to develop future depression, providing an opportunity for intervention. Using donor records, validated depression surveys, and donation experience questions from 2455 living kidney donors, the investigators find that most donors report emotional well-being years after donation, but for those with subsequent depression symptoms, identified predictors provide an opportunity for intervention. C1 [Jowsey, S. G.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA. [Jowsey, S. G.; Taler, S. J.] Mayo Clin, William J von Liebig Transplant Ctr, Rochester, MN USA. [Jacobs, C.; Gross, C. R.] Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. [Jacobs, C.; Gross, C. R.] Univ Minnesota, Sch Nursing, Minneapolis, MN 55455 USA. [Hong, B. A.; Yusen, R. D.] Washington Univ, Sch Med, St Louis, MO USA. [Messersmith, E. E.; Hill-Callahan, M.] Arbor Res Collaborat Hlth, Ann Arbor, MI USA. [Gillespie, B. W.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Beebe, T. J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Kew, C.] Univ Alabama Birmingham, Div Nephrol, Birmingham, AL USA. [Matas, A.] Univ Minnesota, Sch Med, Dept Surg, Minneapolis, MN 55455 USA. [Odim, J.] NIAID, NIH, Bethesda, MD 20892 USA. [Taler, S. J.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. RP Jowsey, SG (reprint author), Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA. EM jowsey.sheila@mayo.edu FU National Institute of Allergy and Infectious Diseases, Health Resources and Services Administration; National Heart, Lung, and Blood Institute [U01 AI069491, U01 AI069544, U01 AI069550, U01 AI069545] FX This research was performed as a project of the RELIVE, a collaborative clinical research project sponsored by the National Institute of Allergy and Infectious Diseases, Health Resources and Services Administration and National Heart, Lung, and Blood Institute (grant no. U01 AI069491; U01 AI069544; U01 AI069550; U01 AI069545). Dr. Sheila Jowsey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 35 TC 9 Z9 9 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD NOV PY 2014 VL 14 IS 11 BP 2535 EP 2544 DI 10.1111/ajt.12906 PG 10 WC Surgery; Transplantation SC Surgery; Transplantation GA AS3LH UT WOS:000344178800014 PM 25293374 ER PT J AU Madhavan, P Jairath, S Sukumaran, N Sagar, A Molmenti, E Natarajan, B Basu, A Ali, N Bhaskaran, M AF Madhavan, P. Jairath, S. Sukumaran, N. Sagar, A. Molmenti, E. Natarajan, B. Basu, A. Ali, N. Bhaskaran, M. TI Kidney Transplant Access in the Southeast: Middle View SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Letter ID RENAL-TRANSPLANTATION C1 [Madhavan, P.; Jairath, S.; Sukumaran, N.; Molmenti, E.; Basu, A.; Ali, N.; Bhaskaran, M.] North Shore LIJ Hlth Syst, Kidney Transplant Program, Manhasset, NY 11030 USA. [Sagar, A.] Hofstra North Shore LIJ Sch Med, Dept Med, Hempstead, NY USA. [Natarajan, B.] NHLBI, NIH, New York, NY USA. RP Madhavan, P (reprint author), North Shore LIJ Hlth Syst, Kidney Transplant Program, Manhasset, NY 11030 USA. EM madhavan.parvathy@gmail.com NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD NOV PY 2014 VL 14 IS 11 BP 2669 EP 2670 DI 10.1111/ajt.12980 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA AS3LH UT WOS:000344178800033 PM 25219445 ER PT J AU Ranieri, N Tabernero, P Green, MD Verbois, L Herrington, J Sampson, E Satzger, RD Phonlavong, C Thao, K Newton, PN Witkowski, MR AF Ranieri, Nicola Tabernero, Patricia Green, Michael D. Verbois, Leigh Herrington, James Sampson, Eric Satzger, R. Duane Phonlavong, Chindaphone Thao, Khamxay Newton, Paul N. Witkowski, Mark R. TI Evaluation of a New Handheld Instrument for the Detection of Counterfeit Artesunate by Visual Fluorescence Comparison SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID OFFSET RAMAN-SPECTROSCOPY; ANTIMALARIAL TABLETS; FAKE ARTESUNATE; SOUTHEAST-ASIA; DRUGS; QUALITY; AUTHENTICATION; MEDICINES; CAMBODIA; AFRICA AB There is an urgent need for accurate and inexpensive handheld instruments for the evaluation of medicine quality in the field. A blinded evaluation of the diagnostic accuracy of the Counterfeit Detection Device 3 (CD-3), developed by the US Food and Drug Administration Forensic Chemistry Center, was conducted in the Lao People's Democratic Republic. Two hundred three samples of the oral antimalarial artesunate were compared with authentic products using the CD-3 by a trainer and two trainees. The specificity (95% confidence interval [95% CI]), sensitivity (95% CI), positive predictive value (95% CI), and negative predictive value (95% CI) of the CD-3 for detecting counterfeit (falsified) artesunate were 100% (93.8-100%), 98.4% (93.8-99.7%), 100% (96.2-100%), and 97.4% (90.2-99.6%), respectively. Interobserver agreement for 203 samples of artesunate was 100%. The CD-3 holds promise as a relatively inexpensive and easy to use instrument for field evaluation of medicines, potentially empowering drug inspectors, customs agents, and pharmacists. C1 [Ranieri, Nicola; Satzger, R. Duane; Witkowski, Mark R.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. [Tabernero, Patricia; Newton, Paul N.] Mahosot Hosp, Microbiol Lab, Lao Oxford Mahosot Hosp Wellcome Trust Res Unit L, Viangchan, Laos. [Tabernero, Patricia; Newton, Paul N.] Univ Oxford, Nuffield Dept Clin Med, Worldwide Antimalarial Resistance Network WWARN, Oxford, England. [Tabernero, Patricia; Newton, Paul N.] Univ Oxford, Churchill Hosp, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England. [Green, Michael D.; Sampson, Eric] Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Atlanta, GA USA. [Verbois, Leigh; Sampson, Eric] US FDA, Off Int Programs, Off Global Regulatory Operat & Policy, Silver Spring, MD USA. [Herrington, James] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Phonlavong, Chindaphone] Govt Lao Peoples Democrat Republ, BIDI, Minist Hlth, Viangchan, Laos. [Thao, Khamxay] Govern Lao PDR, FDQCC, Minist Hlth, Viangchan, Laos. RP Ranieri, N (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM Nicola.Ranieri@fda.hhs.gov; Patricia.Tabernero@wwarn.org; mdg4@CDC.GOV; Leigh.Verbois@fda.hhs.gov; James.Herrington@nih.gov; ejs1@verizon.net; RD.Satzger@fda.hhs.gov; bfdi_chindaphone@yahoo.com; kham_xay@hotmail.com; paul@tropmedres.ac; Mark.Witkowski@fda.hhs.gov FU US Food and Drug Administration; Wellcome Trust of Great Britain; Institut de Recherche sur l'Asie du Sud-Est Contemporaine through French Ministry of Foreign and European Affairs (FSP [Fonds de Solidarite Prioritaire] Mekong Project); Bill and Melinda Gates Foundation FX This work was supported by the US Food and Drug Administration and the Wellcome Trust of Great Britain. The Antimalarial Quality Scientific Group of the Worldwide Antimalarial Resistance Network is supported by the Institut de Recherche sur l'Asie du Sud-Est Contemporaine through funding from the French Ministry of Foreign and European Affairs (FSP [Fonds de Solidarite Prioritaire] Mekong Project) and the Bill and Melinda Gates Foundation. NR 29 TC 9 Z9 9 U1 3 U2 20 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2014 VL 91 IS 5 BP 920 EP 924 DI 10.4269/ajtmh.13-0644 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AS7PO UT WOS:000344447800013 PM 25266348 ER PT J AU Del Prete, GQ Shoemaker, R Oswald, K Lara, A Trubey, CM Fast, R Schneider, DK Kiser, R Coalter, V Wiles, A Wiles, R Freemire, B Keele, BF Estes, JD Quinones, OA Smedley, J Macallister, R Sanchez, RI Wai, JS Tan, CM Alvord, WG Hazuda, DJ Piatak, M Lifson, JD AF Del Prete, Gregory Q. Shoemaker, Rebecca Oswald, Kelli Lara, Abigail Trubey, Charles M. Fast, Randy Schneider, Douglas K. Kiser, Rebecca Coalter, Vicky Wiles, Adam Wiles, Rodney Freemire, Brandi Keele, Brandon F. Estes, Jacob D. Quinones, Octavio A. Smedley, Jeremy Macallister, Rhonda Sanchez, Rosa I. Wai, John S. Tan, Christopher M. Alvord, W. Gregory Hazuda, Daria J. Piatak, Michael, Jr. Lifson, Jeffrey D. TI Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CD4(+) T-CELLS; HISTONE DEACETYLASE INHIBITORS; SUSTAINED VIRAL SUPPRESSION; SIV-INFECTED MACAQUES; HIV-INFECTION; REVERSE-TRANSCRIPTASE; PLASMA VIREMIA; SYNERGISTIC ACTIVATION; LATENT INFECTION AB Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4(+) T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches. C1 [Del Prete, Gregory Q.; Shoemaker, Rebecca; Oswald, Kelli; Lara, Abigail; Trubey, Charles M.; Fast, Randy; Schneider, Douglas K.; Kiser, Rebecca; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Freemire, Brandi; Keele, Brandon F.; Estes, Jacob D.; Piatak, Michael, Jr.; Lifson, Jeffrey D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Smedley, Jeremy; Macallister, Rhonda] Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Quinones, Octavio A.; Alvord, W. Gregory] Data Management Serv Inc, Stat Consulting, Frederick, MD USA. [Sanchez, Rosa I.; Wai, John S.; Hazuda, Daria J.] Merck Res Labs, West Point, PA USA. RP Lifson, JD (reprint author), Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. EM lifsonj@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. NR 78 TC 20 Z9 20 U1 0 U2 3 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 NOV PY 2014 VL 58 IS 11 BP 6790 EP 6806 DI 10.1128/AAC.03746-14 PG 17 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AS3EF UT WOS:000344158600055 PM 25182644 ER PT J AU Arora, K Ochoa-Montano, B Tsang, PS Blundell, TL Dawes, SS Mizrahi, V Bayliss, T Mackenzie, CJ Cleghorn, LAT Ray, PC Wyatt, PG Uh, E Lee, J Barry, CE Boshoff, HI AF Arora, Kriti Ochoa-Montano, Bernardo Tsang, Patricia S. Blundell, Tom L. Dawes, Stephanie S. Mizrahi, Valerie Bayliss, Tracy Mackenzie, Claire J. Cleghorn, Laura A. T. Ray, Peter C. Wyatt, Paul G. Uh, Eugene Lee, Jinwoo Barry, Clifton E., III Boshoff, Helena I. TI Respiratory Flexibility in Response to Inhibition of Cytochrome c Oxidase in Mycobacterium tuberculosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ATP HOMEOSTASIS AB We report here a series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc(1) complex in Mycobacterium tuberculosis in a strain-dependent manner. Deletion of the cytochrome bd oxidase generated a hypersusceptible mutant in which resistance was acquired by a mutation in qcrB. These results highlight the promiscuity of the bc(1) complex and the risk of targeting energy metabolism with new drugs. C1 [Arora, Kriti; Tsang, Patricia S.; Uh, Eugene; Lee, Jinwoo; Barry, Clifton E., III; Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Ochoa-Montano, Bernardo; Blundell, Tom L.] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England. [Dawes, Stephanie S.; Mizrahi, Valerie] Univ Witwatersrand, Sch Pathol, Johannesburg, South Africa. [Mizrahi, Valerie] Univ Cape Town, Inst Infect Dis & Mol Med, MRC NHLS UCT Mol Mycobacteriol Res Unit, ZA-7700 Rondebosch, South Africa. [Bayliss, Tracy; Mackenzie, Claire J.; Cleghorn, Laura A. T.; Ray, Peter C.; Wyatt, Paul G.] Univ Dundee, James Black Ctr, Coll Life Sci, Drug Discovery Unit, Dundee, Scotland. RP Boshoff, HI (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hboshoff@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 FU NIAID; Foundation for the National Institutes of Health; Bill & Melinda Gates Foundation; South African Medical Research Council FX This work was funded, in part, by the Intramural Research Program of the NIAID and by grants from the Foundation for the National Institutes of Health with support from the Bill & Melinda Gates Foundation (to C.E.B.) and the South African Medical Research Council (to V.M.). NR 19 TC 20 Z9 20 U1 0 U2 10 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 NOV PY 2014 VL 58 IS 11 BP 6962 EP 6965 DI 10.1128/AAC.03486-14 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AS3EF UT WOS:000344158600077 PM 25155596 ER PT J AU Ruhl, S Eidt, A Melzl, H Reischl, U Cisar, JO AF Ruhl, Stefan Eidt, Andreas Melzl, Holger Reischl, Udo Cisar, John O. TI Probing of Microbial Biofilm Communities for Coadhesion Partners SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID CAPNOCYTOPHAGA-OCHRACEA ATCC-33596; STREPTOCOCCUS-SANGUIS H-1; PLATE FLOW CHAMBER; ACTINOMYCES-NAESLUNDII; ORAL MICROBIOME; QUANTITATIVE METHOD; CO-ADHESION; IN-VITRO; COAGGREGATION; BACTERIA AB Investigations of interbacterial adhesion in dental plaque development are currently limited by the lack of a convenient assay to screen the multitude of species present in oral biofilms. To overcome this limitation, we developed a solid-phase fluorescence-based screening method to detect and identify coadhesive partner organisms in mixed-species biofilms. The applicability of this method was demonstrated using coaggregating strains of type 2 fimbrial adhesin-bearing actinomyces and receptor polysaccharide (RPS)-bearing streptococci. Specific adhesin/receptor-mediated coadhesion was detected by overlaying bacterial strains immobilized to a nitrocellulose membrane with a suspended, fluorescein-labeled bacterial partner strain. Coadhesion was comparable regardless of which cell type was labeled and which was immobilized. Formaldehyde treatment of bacteria, either in suspension or immobilized on nitrocellulose, abolished actinomyces type 2 fimbrial adhesin but not streptococcal RPS function, thereby providing a simple method for assigning complementary adhesins and glycan receptors to members of a coadhering pair. The method's broader applicability was shown by overlaying colony lifts of dental plaque biofilm cultures with fluorescein-labeled strains of type 2 fimbriated Actinomyces naeslundii or RPS-bearing Streptococcus oralis. Prominent coadhesion partners included not only streptococci and actinomyces, as expected, but also other bacteria not identified in previous coaggregation studies, such as adhesin- or receptor-bearing strains of Neisseria pharyngitis, Rothia dentocariosa, and Kingella oralis. The ability to comprehensively screen complex microbial communities for coadhesion partners of specific microorganisms opens a new approach in studies of dental plaque and other mixed-species biofilms. C1 [Ruhl, Stefan] SUNY Buffalo, Sch Dent Med, Dept Oral Biol, Buffalo, NY 14260 USA. [Ruhl, Stefan; Eidt, Andreas] Univ Regensburg, Univ Hosp Regensburg, Sch Dent, Dept Operat Dent & Periodontol, D-93053 Regensburg, Germany. [Melzl, Holger; Reischl, Udo] Univ Regensburg, Univ Hosp Regensburg, Inst Clin Microbiol & Hyg, D-93053 Regensburg, Germany. [Cisar, John O.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Ruhl, S (reprint author), SUNY Buffalo, Sch Dent Med, Dept Oral Biol, Buffalo, NY 14260 USA. EM shruhl@buffalo.edu OI Ruhl, Stefan/0000-0003-3888-4908; Melzl, Holger/0000-0002-5220-166X FU DFG [SFB 585/B5]; NIDCR [DE019807]; Intramural Research Program of the NIDCR, National Institutes of Health FX This study was supported by grants DFG SFB 585/B5 (S.R.) and NIDCR DE019807 (S.R.) and by the Intramural Research Program of the NIDCR, National Institutes of Health (J.O.C.). NR 40 TC 4 Z9 4 U1 4 U2 28 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD NOV PY 2014 VL 80 IS 21 BP 6583 EP 6590 DI 10.1128/AEM.01826-14 PG 8 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AS3FA UT WOS:000344160900002 PM 25107971 ER PT J AU Vuillerot, C Meilleur, KG Jain, M Waite, M Wu, TX Linton, M Datsgir, J Donkervoort, S Leach, ME Rutkowski, A Rippert, P Payan, C Iwaz, J Hamroun, D Berard, C Poirot, I Bonnemann, CG AF Vuillerot, Carole Meilleur, Katherine G. Jain, Minal Waite, Melissa Wu, Tianxia Linton, Melody Datsgir, Jahannaz Donkervoort, Sandra Leach, Meganne E. Rutkowski, Anne Rippert, Pascal Payan, Christine Iwaz, Jean Hamroun, Dalil Berard, Carole Poirot, Isabelle Boennemann, Carsten G. TI English Cross-Cultural Translation and Validation of the Neuromuscular Score: A System for Motor Function Classification in Patients With Neuromuscular Diseases SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Activities of daily living; Disability evaluation; Neuromuscular diseases; Rehabilitation ID DUCHENNE MUSCULAR-DYSTROPHY; CHILDREN; SCALE; ATROPHY AB Objective: To develop and validate an English version of the Neuromuscular (NM)-Score, a classification for patients with NM diseases in each of the 3 motor function domains: D1, standing and transfers; D2, axial and proximal motor function; and D3, distal motor function. Design: Validation survey. Setting: Patients seen at a medical research center between June and September 2013. Participants: Consecutive patients (N=42) aged 5 to 19 years with a confirmed or suspected diagnosis of congenital muscular dystrophy. Interventions: Not applicable. Main Outcome Measures: An English version of the NM-Score was developed by a 9-person expert panel that assessed its content validity and semantic equivalence. Its concurrent validity was tested against criterion standards (Brooke Scale, Motor Function Measure [MFM], activity limitations for patients with upper and/or lower limb impairments [ACTIVLIM], Jebsen Test, and myometry measurements). Informant agreement between patient/caregiver (P/C)-reported and medical doctor (MD)-reported NM scores was measured by weighted kappa. Results: Significant correlation coefficients were found between NM scores and criterion standards. The highest correlations were found between NM-score D1 and MFM score D1 (rho =-.944, P<.0001), ACTIVLIM (rho =-.895, P<.0001), and hip abduction strength by myometry (rho =-.811, P<.0001). Informant agreement between P/C-reported and MD-reported NM scores was high for D1 (kappa=.801; 95% confidence interval [CI],.701-.914) but moderate for D2 (kappa=.592; 95% CI,.412-.773) and D3 (kappa =.485; 95% CI,.290-.680). Correlation coefficients between the NM scores and the criterion standards did not significantly differ between P/C-reported and MD-reported NM scores. Conclusions: Patients and physicians completed the English NM-Score easily and accurately. The English version is a reliable and valid instrument that can be used in clinical practice and research to describe the functional abilities of patients with NM diseases. (C) 2014 by the American Congress of Rehabilitation Medicine C1 [Vuillerot, Carole; Wu, Tianxia; Datsgir, Jahannaz; Donkervoort, Sandra; Leach, Meganne E.; Boennemann, Carsten G.] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. [Vuillerot, Carole; Rippert, Pascal; Berard, Carole; Poirot, Isabelle] Hosp Civils Lyon, LEscale, Pediat Phys Med & Rehabil Dept, Bron, France. [Vuillerot, Carole] Univ Lyon, Lyon, France. [Vuillerot, Carole] Equipe Biostat Sante, CNRS, Lab Biometrie & Biol Evolut, UMR 5558, Pierre Benite, France. [Meilleur, Katherine G.; Linton, Melody] NINR, NIH, Bethesda, MD 20892 USA. [Jain, Minal; Waite, Melissa] Mark O Hatfield Clin Res Ctr, NIH, Bethesda, MD USA. [Leach, Meganne E.] Childrens Natl Hlth Syst, Washington, DC USA. [Rutkowski, Anne] Cure Congenital Muscular Dystrophy & Kaiser South, Los Angeles, CA USA. [Rippert, Pascal] Hosp Civils Lyon, Pole Informat Med Evaluat Rech, Lyon, France. [Payan, Christine] Hop La Pitie Salpetriere, AP HP, Dept Clin Pharmacol, Paris, France. [Iwaz, Jean] Hosp Civils Lyon, Serv Biostat, Lyon, France. [Hamroun, Dalil] Univ Montpellier, Ctr Hosp, F-34059 Montpellier, France. RP Vuillerot, C (reprint author), NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA NS003129-03, ZIA NS003129-04] NR 25 TC 0 Z9 0 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD NOV PY 2014 VL 95 IS 11 BP 2064 EP 2070 DI 10.1016/j.apmr.2014.05.003 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA AS3XC UT WOS:000344207500010 PM 24862765 ER PT J AU Vuillerot, C Rippert, P Kinet, V Renders, A Jain, M Waite, M Glanzman, AM Girardot, F Hamroun, D Iwaz, J Ecochard, R Quijano-Roy, S Berard, C Poirot, I Bonnemann, CG AF Vuillerot, Carole Rippert, Pascal Kinet, Virginie Renders, Anne Jain, Minal Waite, Melissa Glanzman, Allan M. Girardot, Francoise Hamroun, Dalil Iwaz, Jean Ecochard, Rene Quijano-Roy, Susana Berard, Carole Poirot, Isabelle Boennemann, Carsten G. CA CDM MFM Study Group TI Rasch Analysis of the Motor Function Measure in Patients With Congenital Muscle Dystrophy and Congenital Myopathy SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Congenital muscular dystrophy; Congenital myopathy; Disability evaluation; Outcome measures; Rehabilitation ID SPINAL MUSCULAR-ATROPHY; NEUROMUSCULAR DISEASES; MEASUREMENT MODEL; OUTCOME MEASURES; SCALE; RESPONSIVENESS AB Objectives: To monitor treatment effects in patients with congenital myopathies and congenital muscular dystrophies, valid outcome measures are necessary. The Motor Function Measure (MFM) was examined for robustness, and changes are proposed for better adequacy. Design: Observational study based on data previously collected from several cohorts. Setting: Nineteen departments of physical medicine or neuromuscular consultation in France, Belgium, and the United States. Participants: Patients (N=289) aged 5 to 77 years. Interventions: None. Main Outcome Measures: A Rasch analysis examined the robustness of the MFM across the disease spectrum. The 3 domains of the scale (standing position and transfers, axial and proximal motor function, and distal motor function) were independently examined with a partial credit model. Results: The original 32-item MFM did not sufficiently fit the Rasch model expectations in either of its domains. Switching from a 4- to a 3-category response scale in 18 items restored response order in 16. Various additional checks suggested the removal of 7 items. The resulting Rasch-scaled Motor Function Measure with 25 items for congenital disorders of the muscle (Rs-MFM25(CDM)) demonstrated a good fit to the Rasch model. Domain 1 was well targeted to the whole severity spectrum close mean locations for items and persons (0 vs 0.316) whereas domains 2 and 3 were better targeted to severe cases. The reliability coefficients of the Rs-MFM25(CDM) suggested sufficient ability for each summed score to distinguish between patient groups (0.9, 0.8, and 0.7 for domains 1, 2, and 3, respectively). A sufficient agreement was found between results of the Rasch analysis and physical therapists' opinions. Conclusions: The Rs-MFM25(CDM) can be considered a clinically relevant linear scale in each of its 3 domains and may be soon reliably used for assessment in congenital disorders of the muscle. (C) 2014 by the American Congress of Rehabilitation Medicine C1 [Vuillerot, Carole; Girardot, Francoise; Berard, Carole; Poirot, Isabelle] Hop Femme Mere Enfant, Hosp Civils Lyon, Serv Med Phys & Readaptat Pediat, Bron, France. [Vuillerot, Carole; Iwaz, Jean; Ecochard, Rene] Univ Lyon, Lyon, France. [Vuillerot, Carole; Iwaz, Jean; Ecochard, Rene] Univ Lyon 1, F-69622 Villeurbanne, France. [Vuillerot, Carole; Iwaz, Jean; Ecochard, Rene] CNRS, Lab Biometrie & Biol Evolut, Equipe Biostat Sante, UMR 5558, Pierre Benite, France. [Vuillerot, Carole; Boennemann, Carsten G.] NINDS, NIH, Bethesda, MD 20892 USA. [Rippert, Pascal] Hosp Civils Lyon, Lyon, France. [Kinet, Virginie; Renders, Anne] Catholic Univ Louvain, Clin Univ St Luc, Ctr Reference Malad Neuromusculaires, B-1200 Brussels, Belgium. [Jain, Minal; Waite, Melissa] Clin Res Ctr, NIH, Bethesda, MD USA. [Glanzman, Allan M.] Childrens Hosp Philadelphia, Phys Therapy Dept, Philadelphia, PA 19104 USA. [Hamroun, Dalil] CHU Montpellier, Hop Arnaud Villeneuve, Montpellier, France. [Iwaz, Jean; Ecochard, Rene] Hosp Civils Lyon, Serv Biostat, Lyon, France. [Quijano-Roy, Susana] Hop Raymond Poincare, Hop Univ Paris Ile de France Ouest, AP HP, Ctr Reference Malad Neuromusculaires GNMH, Garches, France. [Quijano-Roy, Susana] Univ Versailles St Quentin, St Quentin en Yvelines, France. RP Vuillerot, C (reprint author), NINDS, Porter Neurosci Res Ctr, NIH, 10 Ctr Dr,Bldg 10,Rm 12N210, Bethesda, MD 20892 USA. EM carole.vuillerot@gmail.com; carsten.bonnemann@nih.gov FU Intramural NIH HHS [, Z99 NS999999, ZIA NS003129-03, ZIA NS003129-04] NR 26 TC 1 Z9 1 U1 1 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 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD NOV PY 2014 VL 95 IS 11 BP 2086 EP 2095 DI 10.1016/j.apmr.2014.06.005 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA AS3XC UT WOS:000344207500013 PM 24973498 ER PT J AU Waalkes, MP Qu, W Tokar, EJ Kissling, GE Dixon, D AF Waalkes, Michael P. Qu, Wei Tokar, Erik J. Kissling, Grace E. Dixon, Darlene TI Response to letter to the editor by Cohen et al. (2014) "Re: Waalkes et al.: Lung tumors in mice induced by "whole-life" inorganic arsenic exposure at human-relevant doses, Arch Toxicol, 2014" SO ARCHIVES OF TOXICOLOGY LA English DT Letter ID CD1 MICE; POSTNATAL DIETHYLSTILBESTROL; CARCINOGENESIS C1 [Waalkes, Michael P.; Qu, Wei; Tokar, Erik J.; Dixon, Darlene] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102925-04] NR 10 TC 2 Z9 3 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD NOV PY 2014 VL 88 IS 11 BP 2063 EP 2065 DI 10.1007/s00204-014-1369-5 PG 3 WC Toxicology SC Toxicology GA AS1WP UT WOS:000344070300011 PM 25253650 ER PT J AU Hussmann, KL Vandergaast, R Ochsner, SP Huang, AC Gale, M Fredericksen, BL AF Hussmann, Katherine L. Vandergaast, Rianna Ochsner, Susan Park Huang, Albert C. Gale, Michael, Jr. Fredericksen, Brenda L. TI In vitro and in vivo characterization of a West Nile virus MAD78 infectious clone SO ARCHIVES OF VIROLOGY LA English DT Article DE West Nile virus; WNV; Infectious clone; WNV-MAD78; Pathogenicity ID CYCLIZATION SEQUENCES; UNTRANSLATED REGION; RNA REPLICATION; STRAINS; GENOME; VIRULENCE; ELEMENTS AB The viral determinants governing the varied neuropathogenicity of different West Nile virus (WNV) strains are poorly understood. Here, we generated an infectious clone (WNV-MAD(IC)) of the non-pathogenic strain WNV-MAD78 and compared its replication to that of parental WNV-MAD78 and a WNV-MAD78 infectious clone (WNV-MAD(TX-UTRs)) containing the 5' and 3' untranslated regions (UTRs) of the pathogenic strain WNV-TX. All three viruses replicated at similar rates and caused similar lethality in mice. Thus, the infectious clone is indistinguishable from parental virus in replication and neurovirulence, and the UTRs alone do not account for the increased virulence of WNV-TX compared to WNV-MAD78. C1 [Hussmann, Katherine L.; Vandergaast, Rianna; Fredericksen, Brenda L.] Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. [Hussmann, Katherine L.; Vandergaast, Rianna; Ochsner, Susan Park; Fredericksen, Brenda L.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Huang, Albert C.; Gale, Michael, Jr.] Univ Washington, Dept Immunol, Sch Med, Seattle, WA 98195 USA. RP Fredericksen, BL (reprint author), NIAID, Aids Review Branch, NIH, DHHS, Bethesda, MD 20817 USA. EM brenda.fredericksen@nih.gov OI Gale, Michael/0000-0002-6332-7436 FU NIH [AI083397, R01 AI074973, U19 AI083019]; NSF (NSF GFRP) FX Work was supported by NIH grants AI083397 (BLF), R01 AI074973 (MG) and U19 AI083019 (MG). Katherine L. Hussmann was supported by a graduate research fellowship from the NSF (NSF GFRP). NR 17 TC 3 Z9 3 U1 1 U2 2 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD NOV PY 2014 VL 159 IS 11 BP 3113 EP 3118 DI 10.1007/s00705-014-2176-2 PG 6 WC Virology SC Virology GA AS0WF UT WOS:000343995900033 PM 25023336 ER PT J AU Tsao, CW Pencina, KM Massaro, JM Benjamin, EJ Levy, D Vasan, RS Hoffmann, U O'Donnell, CJ Mitchell, GF AF Tsao, Connie W. Pencina, Karol M. Massaro, Joseph M. Benjamin, Emelia J. Levy, Daniel Vasan, Ramachandran S. Hoffmann, Udo O'Donnell, Christopher J. Mitchell, Gary F. TI Cross-Sectional Relations of Arterial Stiffness, Pressure Pulsatility, Wave Reflection, and Arterial Calcification SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE hemodynamics; vascular calcification; vascular stiffness ID ISOLATED SYSTOLIC HYPERTENSION; CORONARY-HEART-DISEASE; AORTIC STIFFNESS; CARDIOVASCULAR EVENTS; OLDER-ADULTS; ATHEROSCLEROSIS; ROTTERDAM; CALCIUM; AGE; ASSOCIATION AB Objective Arterial hemodynamics and vascular calcification are associated with increased risk for cardiovascular disease, but their inter-relations remain unclear. We sought to examine the associations of arterial stiffness, pressure pulsatility, and wave reflection with arterial calcification in individuals free of prevalent cardiovascular disease. Approach and Results Framingham Heart Study Third Generation and Offspring Cohort participants free of cardiovascular disease underwent applanation tonometry to measure arterial stiffness, pressure pulsatility, and wave reflection, including carotid-femoral pulse wave velocity, central pulse pressure, forward wave amplitude, and augmentation index. Participants in each cohort (n=1905, 456 years and n=1015, 65 +/- 9 years, respectively) underwent multidetector computed tomography to assess the presence and quantity of thoracic aortic calcification, abdominal aortic calcification, and coronary artery calcification. In multivariable-adjusted models, both higher carotid-femoral pulse wave velocity and central pulse pressure were associated with greater thoracic aortic calcification and abdominal aortic calcification, whereas higher augmentation index was associated with abdominal aortic calcification. Among the tonometry measures, carotid-femoral pulse wave velocity was the strongest correlate of all calcification measures in multivariable-adjusted models (odds ratio per SD for thoracic aortic calcification, 2.69 [95% confidence interval, 2.17-3.35]; abdominal aortic calcification, 1.47 [95% confidence interval, 1.26-1.73]; and coronary artery calcification, 1.48 [95% confidence interval, 1.28-1.72]; all P<0.001, respectively). We observed stronger relations of carotid-femoral pulse wave velocity, central pulse pressure, and forward wave amplitude with nearly all continuous calcification measures in the younger Third Generation Cohort as compared with the Offspring Cohort. Conclusions In community-dwelling individuals without prevalent cardiovascular disease, abnormal central arterial hemodynamics were positively associated with vascular calcification and were observed at younger ages than previously recognized. The mechanisms of these associations may be bidirectional and deserve further study. C1 [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Dept Med, Boston, MA 02215 USA. [Pencina, Karol M.; Massaro, Joseph M.] Boston Univ, Sch Med, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Cardiol & Preventat Med, Boston, MA 02215 USA. [Levy, Daniel] NHLBI, Bethesda, MD 20892 USA. [Tsao, Connie W.; Benjamin, Emelia J.; Levy, Daniel; Vasan, Ramachandran S.; O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Tsao, Connie W.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Tsao, CW (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave,RW-453, Boston, MA 02215 USA. EM ctsao1@bidmc.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute [N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385]; National Institutes of Health [K23 HL118529]; American Heart Association [13SDG14250015]; Harvard Medical School Fellowship FX The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, and HL107385). Dr Tsao is supported by National Institutes of Health K23 HL118529, the American Heart Association (13SDG14250015), and the Harvard Medical School Fellowship. NR 29 TC 17 Z9 18 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2014 VL 34 IS 11 BP 2495 EP 2500 DI 10.1161/ATVBAHA.114.303916 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AS1QX UT WOS:000344056400018 PM 25169933 ER PT J AU Plotz, PH AF Plotz, Paul H. TI Autoimmunity The History of an Idea SO ARTHRITIS & RHEUMATOLOGY LA English DT Article C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Plotz, PH (reprint author), NIAMSD, NIH, Bldg 50,Room 1503,9000 Rockville Pike, Bethesda, MD 20892 USA. EM plotzp@arb.niams.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD NOV PY 2014 VL 66 IS 11 BP 2915 EP 2920 DI 10.1002/art.38796 PG 6 WC Rheumatology SC Rheumatology GA AS6BI UT WOS:000344349500001 PM 25080146 ER PT J AU Askanase, AD Byron, M Keyes-Elstein, LL Cagnoli, PC McCune, WJ Chatham, WW Contreras, G Daikh, DI Dall'Era, M Wofsy, D Davidson, A Diamond, B Mackay, M Ding, L Gao, W Dooley, MA Fragoso-Loyo, H Sanchez-Guerrero, J Karp, DR Olsen, NJ Jolly, M Kalunian, K Kamen, D Lee, I Levesque, MC Lim, SS Ramos-Remus, C Rovin, BH Sayre, PH Smilek, DE Tosta, P Utset, TO Venuturupalli, S Winchester, R AF Askanase, Anca D. Byron, Margie Keyes-Elstein, Lynette L. Cagnoli, Patricia C. McCune, W. Joseph Chatham, W. Winn Contreras, Gabriel Daikh, David I. Dall'Era, Maria Wofsy, David Davidson, Anne Diamond, Betty Mackay, Meggan Ding, Linna Gao, Wendy Dooley, Mary Anne Fragoso-Loyo, Hilda Sanchez-Guerrero, Jorge Karp, David R. Olsen, Nancy J. Jolly, Meenakshi Kalunian, Kenneth Kamen, Diane Lee, Iris Levesque, Marc C. Lim, S. Sam Ramos-Remus, Cesar Rovin, Brad H. Sayre, Peter H. Smilek, Dawn E. Tosta, Patti Utset, Tammy O. Venuturupalli, Swamy Winchester, Robert CA ACCESS Trial Grp TI Treatment of Lupus Nephritis With Abatacept SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID MYCOPHENOLATE-MOFETIL; INTRAVENOUS CYCLOPHOSPHAMIDE; RHEUMATOID-ARTHRITIS; ERYTHEMATOSUS SLE; RANDOMIZED-TRIAL; MURINE LUPUS; THERAPY; GLOMERULONEPHRITIS; CLASSIFICATION; COSTIMULATION AB Objective. To assess the efficacy and safety of a 24-week course of abatacept in the treatment of active lupus nephritis and to assess the potential of abatacept to induce "clinical tolerance," defined as sustained clinical quiescence of lupus nephritis after discontinuation of immunosuppressive therapy. Methods. Patients with active lupus nephritis (n = 134) were enrolled in a randomized, double-blind phase II add-on trial in which they received either abatacept or placebo in conjunction with the Euro-Lupus Nephritis Trial regimen of low-dose cyclophosphamide (CYC) followed by azathioprine (AZA). The primary efficacy outcome was the frequency of complete response at week 24. Thereafter, patients who met either complete or partial response criteria continued blinded treatment through week 52. During this phase of the study, subjects in the abatacept treatment group in whom a complete response was achieved at week 24 discontinued immunosuppressive therapy other than prednisone (10 mg/day). Results. There were no statistically significant differences between groups with respect to the primary outcome or any of the secondary outcomes, including measures of safety. A complete response was achieved in 33% of the subjects in the treatment group and in 31% of the subjects in the control group at week 24. Fifty percent of the subjects in the treatment group who met complete response criteria and therefore discontinued immunosuppressive therapy at week 24 maintained their complete response status through week 52. Conclusion. The addition of abatacept to a regimen of CYC followed by AZA did not improve the outcome of lupus nephritis at either 24 or 52 weeks. No worrisome safety signals were encountered. C1 [Askanase, Anca D.] NYU, New York, NY USA. [Byron, Margie; Keyes-Elstein, Lynette L.] Rho Inc, Chapel Hill, NC USA. [Cagnoli, Patricia C.; McCune, W. Joseph] Univ Michigan, Ann Arbor, MI 48109 USA. [Chatham, W. Winn] Univ Alabama Birmingham, Birmingham, AL USA. [Contreras, Gabriel] Univ Miami, Coral Gables, FL 33124 USA. [Dall'Era, Maria; Wofsy, David] Univ Calif San Francisco, Div Rheumatol, San Francisco, CA 94143 USA. [Dall'Era, Maria; Wofsy, David] Russell Engleman Rheumatol Res Ctr, San Francisco, CA USA. [Davidson, Anne; Diamond, Betty; Mackay, Meggan] North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Ding, Linna; Gao, Wendy] NIAID, NIH, Bethesda, MD 20892 USA. [Dooley, Mary Anne] Univ N Carolina, Chapel Hill, NC USA. [Dooley, Mary Anne] Thurston Arthrit Res Ctr, Chapel Hill, NC USA. [Fragoso-Loyo, Hilda; Sanchez-Guerrero, Jorge] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Karp, David R.; Olsen, Nancy J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Jolly, Meenakshi] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Kalunian, Kenneth] Univ Calif San Diego, La Jolla, CA 92093 USA. [Kamen, Diane] Med Univ S Carolina, Charleston, SC USA. [Lee, Iris] Temple Univ, Philadelphia, PA 19122 USA. [Levesque, Marc C.] Univ Pittsburgh, Pittsburgh, PA USA. [Lim, S. Sam] Emory Univ, Atlanta, GA 30322 USA. [Ramos-Remus, Cesar] Unidad Invest Enfermedades Cronico Degenerativas, Guadalajara, Jalisco, Mexico. [Rovin, Brad H.] Ohio State Univ, Columbus, OH 43210 USA. [Sayre, Peter H.; Smilek, Dawn E.; Tosta, Patti] NIAID, Immune Tolerance Network, San Francisco, CA USA. [Utset, Tammy O.] Univ Chicago, Chicago, IL 60637 USA. [Venuturupalli, Swamy] Univ Calif Los Angeles, Los Angeles, CA USA. [Venuturupalli, Swamy] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Winchester, Robert] Columbia Univ, New York, NY USA. RP Wofsy, D (reprint author), Univ Calif San Francisco, Div Rheumatol, Box 0633,533 Parnassus Ave, San Francisco, CA 94143 USA. EM wofsyd@medsch.ucsf.edu FU NIH (National Institute of Allergy and Infectious Diseases) [N01-AI-15416, ITN034AI] FX This research was performed as a project of the Immune Tolerance Network, an international research consortium headquartered at the University of California, San Francisco, and funded by the NIH (National Institute of Allergy and Infectious Diseases contract N01-AI-15416, protocol number ITN034AI). NR 34 TC 40 Z9 40 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD NOV PY 2014 VL 66 IS 11 BP 3096 EP 3104 DI 10.1002/art.38790 PG 9 WC Rheumatology SC Rheumatology GA AS6BI UT WOS:000344349500019 ER PT J AU Miloslavsky, EM Specks, U Merkel, PA Seo, P Spiera, R Langford, CA Hoffman, GS Kallenberg, CGM Clair, EWS Tchao, NK Viviano, L Ding, L Ikle, D Villarreal, M Jepson, B Brunetta, P Allen, NB Fervenza, FC Geetha, D Keogh, K Kissin, EY Monach, PA Peikert, T Stegeman, C Ytterberg, SR Stone, JH AF Miloslavsky, E. M. Specks, U. Merkel, P. A. Seo, P. Spiera, R. Langford, C. A. Hoffman, G. S. Kallenberg, C. G. M. Clair, E. W. St. Tchao, N. K. Viviano, L. Ding, L. Ikle, D. Villarreal, M. Jepson, B. Brunetta, P. Allen, N. B. Fervenza, F. C. Geetha, D. Keogh, K. Kissin, E. Y. Monach, P. A. Peikert, T. Stegeman, C. Ytterberg, S. R. Stone, J. H. CA Rituximab ANCA-Associated Vasculit TI Rituximab for the Treatment of Relapses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ACTIVE RHEUMATOID-ARTHRITIS; ANCA-ASSOCIATED VASCULITIS; REMISSION-INDUCTION; WEGENERS-GRANULOMATOSIS; MAINTENANCE THERAPY; RANDOMIZED-TRIAL; RISK-FACTORS; CYCLOPHOSPHAMIDE; EFFICACY AB Objective. Disease relapses are frequent in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. Methods. The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a pre-specified protocol. Investigators remained blinded with regard to the original treatment assignment. Results. Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). Conclusion. Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment. C1 [Miloslavsky, E. M.; Stone, J. H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Specks, U.; Fervenza, F. C.; Keogh, K.; Peikert, T.; Ytterberg, S. R.] Mayo Clin, Rochester, MN USA. [Merkel, P. A.] Univ Penn, Philadelphia, PA 19104 USA. [Seo, P.; Geetha, D.] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, R.] Hosp Special Surg, New York, NY 10021 USA. [Langford, C. A.; Hoffman, G. S.] Cleveland Clin, Cleveland, OH 44106 USA. [Kallenberg, C. G. M.; Stegeman, C.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Kallenberg, C. G. M.; Stegeman, C.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Clair, E. W. St.; Allen, N. B.] Duke Univ, Med Ctr, Durham, NC USA. [Tchao, N. K.] Immune Tolerance Network, San Francisco, CA USA. [Ding, L.] NIAID, NIH, Bethesda, MD 20892 USA. [Ikle, D.; Villarreal, M.; Jepson, B.] Rho, Chapel Hill, NC USA. [Brunetta, P.] Genentech Inc, San Francisco, CA 94080 USA. [Kissin, E. Y.; Monach, P. A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, Yawkey 2C,55 Fruit St, Boston, MA 02114 USA. EM jhstone@mgh.harvard.edu FU NIH [N01-AI-15416, 1 UL1-RR-024150-01, UL1-RR-025005, K23-AR-052820, K24-AR-049185, UL1-RR-025771, M01-RR-00533, K24-AR-02224]; National Institute of Allergy and Infectious Diseases, NIH; Juvenile Diabetes Research Foundation; Genentech (Clinical Immunology Fellowship); Arthritis Foundation FX The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was performed with the support of the Immune Tolerance Network (NIH contract N01-AI-15416, protocol number ITN021AI), an international clinical research consortium headquartered at the University of California San Francisco and supported by the National Institute of Allergy and Infectious Diseases, NIH and the Juvenile Diabetes Research Foundation. Genentech and Biogen Idec provided the study medication and partial funding for the RAVE trial. At the Mayo Clinic, Johns Hopkins University, and Boston University School of Medicine, the RAVE trial was supported by the NIH (Mayo Clinic: National Center for Research Resources Clinical and Translational Science award 1 UL1-RR-024150-01; Johns Hopkins University: National Center for Research Resources Clinical and Translational Science award UL1-RR-025005 and career development awards K23-AR-052820 to Dr. Seo and K24-AR-049185 to Dr. Stone; Boston University: National Center for Research Resources Clinical and Translational Science award UL1-RR-025771, grant M01-RR-00533, and career development award K24-AR-02224 to Dr. Merkel). Dr. Miloslavsky's work was supported by Genentech (Clinical Immunology Fellowship 2012-2013). Dr. Monach's work was supported by the Arthritis Foundation (Arthritis Investigator Award). NR 24 TC 22 Z9 22 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD NOV PY 2014 VL 66 IS 11 BP 3151 EP 3159 DI 10.1002/art.38788 PG 9 WC Rheumatology SC Rheumatology GA AS6BI UT WOS:000344349500025 PM 25047592 ER PT J AU Chang, Z Spong, CY Jesus, AA Davis, MA Plass, N Stone, DL Chapelle, D Hoffmann, P Kastner, DL Barron, K Goldbach-Mansky, RT Stratton, P AF Chang, Zenas Spong, Catherine Y. Jesus, Adriana A. Davis, Michael A. Plass, Nicole Stone, Deborah L. Chapelle, Dawn Hoffmann, Patrycja Kastner, Daniel L. Barron, Karyl Goldbach-Mansky, Raphaela T. Stratton, Pamela TI Anakinra Use During Pregnancy in Patients With Cryopyrin-Associated Periodic Syndromes SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID ARTICULAR SYNDROME; CIAS1 MUTATIONS; BIRTH AB Objective. To describe the pregnancy course and outcome and the use of anakinra, a recombinant selective interleukin-1 receptor blocker, during pregnancy in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Methods. Women with CAPS who were currently enrolled in natural history protocols and had been pregnant were included. Subjects underwent a structured, standardized interview with regard to maternal health, pregnancy, and fetal outcomes. Medical records were reviewed. Results. Nine women (4 with FCAS, 2 with MWS/NOMID overlap, and 3 with NOMID) reported 1-4 pregnancies (a total of 15 pregnancies in women with FCAS, 3 in women with MWS, and 6 in women with NOMID). Six births to women with FCAS and 3 births to women with NOMID or MWS/NOMID overlap occurred while the patients were receiving anakinra. In women who became pregnant while taking anakinra, the anakinra treatment was continued; the prepregnancy dosage was maintained except in the case of 1 woman whose dosage was increased during a pregnancy with twins. No preterm births or serious complications of pregnancy were observed. One fetus of the twin pregnancy had renal agenesis and died in utero. Genetic testing showed that the deceased twin carried the same NLRP3 c.785T>C, p.V262A mutation as the mother. The other twin was healthy and mutation negative. Conclusion. Anakinra was continued during pregnancy in women with CAPS and provided significant, persistent symptom relief while continuing to prevent the long-term sequelae of CAPS. Anakinra was well tolerated. Although a causal relationship between anakinra and renal agenesis seems unlikely, further safety data are needed. C1 [Chang, Zenas; Spong, Catherine Y.; Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Jesus, Adriana A.; Davis, Michael A.; Plass, Nicole; Chapelle, Dawn; Goldbach-Mansky, Raphaela T.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Stone, Deborah L.; Hoffmann, Patrycja; Kastner, Daniel L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Barron, Karyl] NIAID, NIH, Bethesda, MD 20892 USA. RP Goldbach-Mansky, RT (reprint author), NIAMSD, Translat Autoinflammatory Dis Sect, NIH, Bldg 10,Room 6D47B,10 Ctr Dr, Bethesda, MD 20892 USA. EM goldbacr@mail.nih.gov FU NIH through National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program; NIH Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Sobi; Novartis; Regeneron FX Supported by the NIH through the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program, the NIH Clinical Center, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.; Dr. Goldbach-Mansky has received grant support from Sobi, Novartis, and Regeneron for clinical studies. NR 18 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD NOV PY 2014 VL 66 IS 11 BP 3227 EP 3232 DI 10.1002/art.38811 PG 6 WC Rheumatology SC Rheumatology GA AS6BI UT WOS:000344349500033 PM 25223501 ER PT J AU Brotman, MA Deveney, CM Thomas, LA Hinton, KE Yi, JY Pine, DS Leibenluft, E AF Brotman, Melissa A. Deveney, Christen M. Thomas, Laura A. Hinton, Kendra E. Yi, Jennifer Y. Pine, Daniel S. Leibenluft, Ellen TI Parametric modulation of neural activity during face emotion processing in unaffected youth at familial risk for bipolar disorder SO BIPOLAR DISORDERS LA English DT Article DE at risk; bipolar disorder; face emotion; functional magnetic resonance imaging (fMRI); parametric modulation ID FUNCTIONAL NEUROANATOMY; FACIAL EXPRESSIONS; ANTERIOR CINGULATE; LABELING DEFICITS; AMYGDALA ACTIVITY; RATING-SCALE; DEPRESSION; CONNECTIVITY; RELIABILITY; VALIDITY AB ObjectivesBoth patients with pediatric bipolar disorder (BD) and unaffected youth at familial risk (AR) for the illness show impairments in face emotion labeling. Few studies, however, have examined brain regions engaged in AR youth when processing emotional faces. Moreover, studies have yet to explore neural responsiveness to subtle changes in face emotion in AR youth. MethodsSixty-four unrelated youth, including 20 patients with BD, 15 unaffected AR youth, and 29 healthy comparisons (HC), completed functional magnetic resonance imaging. Neutral faces were morphed with angry or happy faces in 25% intervals. In specific phases of the task, youth alternatively made explicit (hostility) or implicit (nose width) ratings of the faces. The slope of blood oxygenated level-dependent activity was calculated across neutral to angry and neutral to happy face stimuli. ResultsBehaviorally, both subjects with BD (p0.001) and AR youth (p0.05) rated faces as less hostile relative to HC. Consistent with this, in response to increasing anger on the face, patients with BD and AR youth showed decreased modulation in the amygdala and inferior frontal gyrus (IFG; BA 46) compared to HC (all p0.05). Amygdala dysfunction was present across both implicit and explicit rating conditions, but IFG modulation deficits were specific to the explicit condition. With increasing happiness, AR youth showed aberrant modulation in the IFG, which was also sensitive to task demands (all p0.05). ConclusionsDecreased amygdala and IFG modulation in patients with BD and AR youth may be pathophysiological risk markers for BD, and may underlie the social cognition and face emotion labeling deficits observed in BD and AR youth. C1 [Brotman, Melissa A.; Deveney, Christen M.; Hinton, Kendra E.; Yi, Jennifer Y.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Deveney, Christen M.] Wellesley Coll, Dept Psychol, Wellesley, MA 02181 USA. [Thomas, Laura A.] Vet Affairs Med Ctr, War Related Illness & Injury Study Ctr, Washington, DC 20422 USA. [Hinton, Kendra E.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. RP Brotman, MA (reprint author), NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Room B1D43C 10 Ctr Dr, Bethesda, MD 20892 USA. EM brotmanm@mail.nih.gov RI Brotman, Melissa/H-7409-2013; OI Thomas, Laura/0000-0002-4106-1358 FU National Institute of Mental Health (NIMH), National Institutes of Health FX Funding for this study was provided by the Intramural Research Program of the National Institute of Mental Health (NIMH), National Institutes of Health. We would like to thank the staff of the Emotion and Development Branch at NIMH and the patients and their parents for their participation. NR 47 TC 9 Z9 9 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD NOV PY 2014 VL 16 IS 7 BP 756 EP 763 DI 10.1111/bdi.12193 PG 8 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AS6KR UT WOS:000344373100010 PM 24617738 ER PT J AU Kreitchmann, R Li, SX Melo, VH Coelho, DF Watts, DH Joao, E Coutinho, CM Alarcon, JO Siberry, GK AF Kreitchmann, R. Li, S. X. Melo, V. H. Fernandes Coelho, D. Watts, D. H. Joao, E. Coutinho, C. M. Alarcon, J. O. Siberry, G. K. TI Predictors of adverse pregnancy outcomes in women infected with HIV in Latin America and the Caribbean: a cohort study SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article DE HIV; Latin America; pregnancy; pregnancy outcomes; prematurity ID ACTIVE ANTIRETROVIRAL THERAPY; LOW-BIRTH-WEIGHT; PRETERM DELIVERY; INCREASED RISK; UNITED-STATES; MATERNAL AGE; FETAL-GROWTH; SOUTH-AFRICA; STILLBIRTH; METAANALYSIS AB ObjectiveTo examine maternal characteristics associated with adverse pregnancy outcomes among women infected with HIV. DesignProspective cohort study. SettingMultiple sites in Latin America and the Caribbean. PopulationWomen infected with HIV enrolled in the Perinatal (2002-2007) and the Longitudinal Study in Latin American Countries (LILAC; 2008-2012) studies of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI). MethodsFrequencies of adverse pregnancy outcomes assessed among pregnancies. Risk factors investigated by logistic regression analysis. Main outcome measuresAdverse pregnancy outcomes, including preterm delivery (PT), low birthweight (LBW), small for gestational age (SGA), stillbirth (SB), and neonatal death. ResultsAmong 1512 women, 1.9% (95% confidence interval, 95% CI, 1.3-2.7) of singleton pregnancies resulted in a stillbirth and 32.9% (95% CI 30.6-35.4) had at least one adverse pregnancy outcome. Of 1483 singleton live births, 19.8% (95% CI 17.8-21.9) were PT, 14.2% (95% CI 12.5-16.1) were LBW, 12.6% (95% CI 10.9-14.4) were SGA, and 0.4% (95%CI 0.2-0.9) of infants died within 28days of birth. Multivariable logistic regression modelling indicated that the following risk factors increased the probability of having one or more adverse pregnancy outcomes: lower maternal body mass index at delivery (odds ratio, OR, 2.2; 95% CI 1.4-3.5), hospitalisation during pregnancy (OR 3.3; 95% CI 2.0-5.3), hypertension during pregnancy (OR 2.7; 95% CI 1.5-4.8), antiretroviral use at conception (OR 1.4; 95% CI 1.0-1.9), and tobacco use during pregnancy (OR 1.7; 95% CI 1.3-2.2). The results of fitting multivariable logistic regression models for PT, LBW, SGA, and SB are also reported. ConclusionsWomen infected with HIV had a relatively high occurrence of adverse pregnancy outcomes, and some maternal risk factors were associated with these adverse pregnancy outcomes. Interventions targeting modifiable risk factors should be evaluated further. C1 [Kreitchmann, R.; Fernandes Coelho, D.] Irmandade Santa Casa de Misericordia Porto Alegre, BR-90460001 Porto Alegre, RS, Brazil. [Li, S. X.] WESTAT Corp, Rockville, MD 20850 USA. [Melo, V. H.] Univ Fed Minas Gerais, Fac Med, Belo Horizonte, MG, Brazil. [Watts, D. H.; Siberry, G. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis MPID Branch, NIH, Bethesda, MD USA. [Joao, E.] Hosp Fed Servidores Estado, Rio De Janeiro, Brazil. [Coutinho, C. M.] Univ Sao Paulo, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, Brazil. [Alarcon, J. O.] Univ Nacl Mayor San Marcos, Trop Med Inst Daniel A Carrion, Lima 14, Peru. RP Kreitchmann, R (reprint author), Irmandade Santa Casa de Misericordia Porto Alegre, Ave Lucas de Oliveira 1937-202, BR-90460001 Porto Alegre, RS, Brazil. EM regis.kr@terra.com.br OI Alarcon, Jorge/0000-0002-0800-2380 FU NICHD [N01-HD-3-3345, HHSN267200800001C, N01-HD-8-0001] FX The study was supported by NICHD contract no. N01-HD-3-3345 (2002 2007) and by NICHD contract no. HHSN267200800001C (NICHD control no. N01-HD-8-0001; 2007-2012). NR 42 TC 4 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 EI 1471-0528 J9 BJOG-INT J OBSTET GY JI BJOG PD NOV PY 2014 VL 121 IS 12 BP 1501 EP 1508 DI 10.1111/1471-0528.12680 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AS6KM UT WOS:000344372600007 PM 24602102 ER PT J AU Hassan, R Sharon, E Thomas, A Zhang, JL Ling, A Miettinen, M Kreitman, RJ Steinberg, SM Hollevoet, K Pastan, I AF Hassan, Raffit Sharon, Elad Thomas, Anish Zhang, Jingli Ling, Alexander Miettinen, Markku Kreitman, Robert J. Steinberg, Seth M. Hollevoet, Kevin Pastan, Ira TI Phase 1 Study of the Antimesothelin Immunotoxin SS1P in Combination With Pemetrexed and Cisplatin for Front-Line Therapy of Pleural Mesothelioma and Correlation of Tumor Response With Serum Mesothelin, Megakaryocyte Potentiating Factor, and Cancer Antigen 125 SO CANCER LA English DT Article DE mesothelin; pleural mesothelioma; SS1P; immunotoxin ID SOLUBLE MESOTHELIN; OVARIAN CANCERS; MARKER; IMMUNOGENICITY; OSTEOPONTIN; TAXOL AB BACKGROUNDThe primary objective of this study was to determine the safety and maximum tolerated dose (MTD) of the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) (a recombinant antimesothelin immunotoxin consisting of a murine antimesothelin variable antibody fragment [Fv] linked to PE38, a truncated portion of Pseudomonas exotoxin A) in combination with pemetrexed and cisplatin in chemotherapy-naive patients with advanced malignant pleural mesothelioma (MPM). Secondary objectives included tumor response, SS1P pharmacokinetics, and serum biomarkers of response. METHODSChemotherapy-naive patients with stage III or IV, unresectable, epithelial or biphasic MPM and normal organ functions were eligible. Pemetrexed (500 mg/m(2) on day 1) and cisplatin (75 mg/m(2) on day 1) were administered every 3 weeks for up to 6 cycles with escalating doses of SS1P administered intravenously on days 1, 3, and 5 during cycles 1 and 2. Tumor response was evaluated every 6 weeks. RESULTSTwenty-four patients received SS1P at 4 dose levels from 25 to 55 mcg/kg. Grade 3 fatigue was dose-limiting in 1 patient at 55 mcg/kg. The MTD of SS1P was established as 45 mcg/kg. Other grade 3 toxicities associated with SS1P included hypoalbuminemia (21%), back pain (13%), and hypotension (8%). Of 20 evaluable patients, 12 (60%) had a partial response, 3 had stable disease, and 5 had progressive disease. Of 13 patients who received the MTD, 10 (77%) had a partial response, 1 had stable disease, and 2 had progressive disease. Objective radiologic responses were associated with significant decreases in serum mesothelin (P=.0030), megakaryocyte potentiating factor (P=.0005), and cancer antigen 125 (P<.0001). CONCLUSIONSSS1P given with pemetrexed and cisplatin is safe and well tolerated and exhibits significant antitumor activity in patients with unresectable, advanced pleural mesothelioma. Serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125 levels correlated with objective tumor responses. Cancer 2014;120:3311-3319. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. In this first clinical evaluation of the combination of an immunotoxin with chemotherapy, SS1P, an antimesothelin immunotoxin, was combined with pemetrexed and cisplatin in chemotherapy-naive patients who had advanced malignant pleural mesothelioma. The results from this phase 1 trial demonstrate that SS1P and chemotherapy can be safely combined with no overlapping toxicity. In addition, the objective tumor response rate for the combination is higher than expected with chemotherapy alone and provides a strong rationale for a randomized trial to confirm this finding. C1 [Hassan, Raffit; Thomas, Anish; Kreitman, Robert J.; Hollevoet, Kevin; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sharon, Elad] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Ling, Alexander] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Miettinen, Markku] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 27 TC 43 Z9 43 U1 2 U2 7 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 NOV 1 PY 2014 VL 120 IS 21 BP 3311 EP 3319 DI 10.1002/cncr.28875 PG 9 WC Oncology SC Oncology GA AS3FZ UT WOS:000344164100010 PM 24989332 ER PT J AU Figg, WD Monga, M Headlee, D Shah, A Chau, CH Peer, C Messman, R Elsayed, YA Murgo, AJ Melillo, G Ryan, QC Kalnitskiy, M Senderowicz, AM Hollingshead, M Arbuck, SG Sausville, EA AF Figg, William D. Monga, Manish Headlee, Donna Shah, Avni Chau, Cindy H. Peer, Cody Messman, Richard Elsayed, Yusri A. Murgo, Anthony J. Melillo, Giovanni Ryan, Qin C. Kalnitskiy, Mikhail Senderowicz, Adrian M. Hollingshead, Melinda Arbuck, Susan G. Sausville, Edward A. TI A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Perifosine; Loading dose; Maintenance dose; Drug development; Phase I ID RELAPSED/REFRACTORY MULTIPLE-MYELOMA; RADIATION-INDUCED APOPTOSIS; ALKYL-LYSOPHOSPHOLIPIDS; MILTEFOSINE HEXADECYLPHOSPHOCHOLINE; COLORECTAL-CANCER; BREAST-CANCER; ETHER LIPIDS; SOLID TUMORS; CELLS; TRIAL AB To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations. Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized. Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 A mu g/mL. Four patients had stable disease ranging from 167 to 735 days. Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect. C1 [Figg, William D.; Monga, Manish; Headlee, Donna; Shah, Avni; Chau, Cindy H.; Peer, Cody; Elsayed, Yusri A.; Ryan, Qin C.; Kalnitskiy, Mikhail] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Messman, Richard; Hollingshead, Melinda; Sausville, Edward A.] NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. [Murgo, Anthony J.; Arbuck, Susan G.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Melillo, Giovanni] Sci Applicat Int Corp, Frederick, MD USA. [Senderowicz, Adrian M.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Oncol Branch, Bldg 10 Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov; esausville@umm.edu RI Figg Sr, William/M-2411-2016 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We thank the nursing staff of National Cancer Institute and the fellows of the Medical Oncology Branch at National Cancer Institute for their care of our patients; Cancer Therapy and Evaluation Program for sponsoring the trial; Eunhee W. Woo ( deceased, and to whose memory we dedicate this paper), Suoping Zhai, Kyung Hwang and Nicola Smith for their assistance in conducting this study; and Victoria Giffi for editorial assistance. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. This is a US Government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US Government. NR 37 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD NOV PY 2014 VL 74 IS 5 BP 955 EP 967 DI 10.1007/s00280-014-2569-7 PG 13 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AS5QF UT WOS:000344324200008 PM 25183650 ER PT J AU Balbus, JM Greenblatt, JB Chari, R Millstein, D Ebi, KL AF Balbus, John M. Greenblatt, Jeffery B. Chari, Ramya Millstein, Dev Ebi, Kristie L. TI A wedge-based approach to estimating health co-benefits of climate change mitigation activities in the United States SO CLIMATIC CHANGE LA English DT Article AB While it has been recognized that actions reducing greenhouse gas (GHG) emissions can have significant positive and negative impacts on human health through reductions in ambient fine particulate matter (PM2.5) concentrations, these impacts are rarely taken into account when analyzing specific policies. This study presents a new framework for estimating the change in health outcomes resulting from implementation of specific carbon dioxide (CO2) reduction activities, allowing comparison of different sectors and options for climate mitigation activities. Our estimates suggest that in the year 2020, the reductions in adverse health outcomes from lessened exposure to PM2.5 would yield economic benefits in the range of $6 to $30 billion (in 2008 USD), depending on the specific activity. This equates to between $40 and $198 per metric ton of CO2 in health benefits. Specific climate interventions will vary in the health co-benefits they provide as well as in potential harms that may result from their implementation. Rigorous assessment of these health impacts is essential for guiding policy decisions as efforts to reduce GHG emissions increase in scope and intensity. C1 [Balbus, John M.] NIEHS, Bethesda, MD 20892 USA. [Greenblatt, Jeffery B.; Millstein, Dev] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [Chari, Ramya] RAND Corp, Santa Monica, CA USA. [Ebi, Kristie L.] Univ Washington, Seattle, WA 98195 USA. RP Balbus, JM (reprint author), NIEHS, 31 Ctr Dr,Room B1C02, Bethesda, MD 20892 USA. EM john.balbus@nih.gov FU U.S. Department of Energy [DE-AC02-05CH11231] FX This research was supported in part by Laboratory Directed Research and Development funding at the Lawrence Berkeley National Laboratory (LBNL), which is operated for U.S. Department of Energy under Contract Grant No. DE-AC02-05CH11231. NR 19 TC 2 Z9 2 U1 3 U2 20 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-0009 EI 1573-1480 J9 CLIMATIC CHANGE JI Clim. Change PD NOV PY 2014 VL 127 IS 2 BP 199 EP 210 DI 10.1007/s10584-014-1262-5 PG 12 WC Environmental Sciences; Meteorology & Atmospheric Sciences SC Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA AS6QG UT WOS:000344387000004 ER PT J AU Lerner, I Bentin, S Shriki, O AF Lerner, Itamar Bentin, Shlomo Shriki, Oren TI Integrating the Automatic and the Controlled: Strategies in Semantic Priming in an Attractor Network With Latching Dynamics SO COGNITIVE SCIENCE LA English DT Article DE Word recognition; Semantic priming; Neural networks; Distributed representations; Latching dynamics; Controlled processes; Expectancy; Semantic matching ID VISUAL WORD RECOGNITION; SPREADING ACTIVATION; LEXICAL DECISION; GENERATED EXPECTANCIES; RELATEDNESS PROPORTION; MODEL; MEMORY; PRONUNCIATION; FACILITATION; ASSOCIATION AB Semantic priming has long been recognized to reflect, along with automatic semantic mechanisms, the contribution of controlled strategies. However, previous theories of controlled priming were mostly qualitative, lacking common grounds with modern mathematical models of automatic priming based on neural networks. Recently, we introduced a novel attractor network model of automatic semantic priming with latching dynamics. Here, we extend this work to show how the same model can also account for important findings regarding controlled processes. Assuming the rate of semantic transitions in the network can be adapted using simple reinforcement learning, we show how basic findings attributed to controlled processes in priming can be achieved, including their dependency on stimulus onset asynchrony and relatedness proportion and their unique effect on associative, category-exemplar, mediated and backward prime-target relations. We discuss how our mechanism relates to the classic expectancy theory and how it can be further extended in future developments of the model. C1 [Lerner, Itamar; Bentin, Shlomo] Hebrew Univ Jerusalem, Interdisciplinary Ctr Neural Computat, IL-91905 Jerusalem, Israel. [Bentin, Shlomo] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [Shriki, Oren] NIMH, Sect Crit Brain Dynam, Bethesda, MD USA. RP Lerner, I (reprint author), Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. EM itamar.lerner@gmail.com OI Shriki, Oren/0000-0003-1129-4799 FU Intramural NIH HHS NR 56 TC 1 Z9 1 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-0213 EI 1551-6709 J9 COGNITIVE SCI JI Cogn. Sci. PD NOV-DEC PY 2014 VL 38 IS 8 BP 1562 EP 1603 DI 10.1111/cogs.12133 PG 42 WC Psychology, Experimental SC Psychology GA AS6CY UT WOS:000344353500002 PM 24890261 ER PT J AU McCoy, JP AF McCoy, J. Philip, Jr. TI Untitled SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; FLOW-CYTOMETRY; HEALTHY-SUBJECTS; EXPRESSION; ANTICOAGULANTS; DIAGNOSIS; LYMPHOMAS; DISEASE; ZAP-70; MARKER C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP McCoy, JP (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mccoyjp@mail.nih.gov NR 20 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 EI 1552-4957 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2014 VL 86 IS 6 BP 371 EP 372 DI 10.1002/cyto.b.21186 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AS6UM UT WOS:000344397600001 PM 25336149 ER PT J AU Lindell, SG Yuan, QP Zhou, ZF Goldman, D Thompson, RC Lopez, JF Suomi, SJ Higley, JD Barr, CS AF Lindell, Stephen G. Yuan, Qiaoping Zhou, Zhifeng Goldman, David Thompson, Robert C. Lopez, Juan F. Suomi, Stephen J. Higley, J. Dee Barr, Christina S. TI The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: Potential roles in genetic selection and Gene x Environment interactions (vol 24, pg 1391, 2012) SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Correction C1 [Lindell, Stephen G.; Yuan, Qiaoping; Zhou, Zhifeng; Goldman, David; Barr, Christina S.] NIAAA, NIH, Bethesda, MD 20892 USA. [Thompson, Robert C.; Lopez, Juan F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Suomi, Stephen J.] NICHD, NIH, Bethesda, MD USA. [Higley, J. Dee] Brigham Young Univ, Provo, UT 84602 USA. RP Barr, CS (reprint author), NIAA, Sect Comparat Behav Genom, Neurogenet Lab, DICBR,NIH, 5625 Fishers Lane,Room 3S-32, Rockville, MD 20852 USA. EM cbarr@mail.nih.gov NR 1 TC 0 Z9 0 U1 1 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD NOV PY 2014 VL 26 IS 4 BP 1181 EP 1181 DI 10.1017/S0954579414000583 PN 1 PG 1 WC Psychology, Developmental SC Psychology GA AS2XY UT WOS:000344140900020 ER PT J AU Paukner, A Simpson, EA Ferrari, PF Mrozek, T Suomi, SJ AF Paukner, Annika Simpson, Elizabeth A. Ferrari, Pier F. Mrozek, Timothy Suomi, Stephen J. TI Neonatal imitation predicts how infants engage with faces SO DEVELOPMENTAL SCIENCE LA English DT Article ID RHESUS-MONKEYS; ATTENTION; AUTISM; PRECURSORS; SYNCHRONY; OUTCOMES; SPEECH; SKILLS; MOUTH; RISK AB In human infants, neonatal imitation and preferences for eyes are both associated with later social and communicative skills, yet the relationship between these abilities remains unexplored. Here we investigated whether neonatal imitation predicts facial viewing patterns in infant rhesus macaques. We first assessed infant macaques for lipsmacking (a core affiliative gesture) and tongue protrusion imitation in the first week of life. When infants were 10-28days old, we presented them with an animated macaque avatar displaying a still face followed by lipsmacking or tongue protrusion movements. Using eye tracking technology, we found that macaque infants generally looked equally at the eyes and mouth during gesture presentation, but only lipsmacking-imitators showed significantly more looking at the eyes of the neutral still face. These results suggest that neonatal imitation performance may be an early measure of social attention biases and might potentially facilitate the identification of infants at risk for atypical social development. C1 [Paukner, Annika; Simpson, Elizabeth A.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Dept Hlth & Human Serv, Poolesville, MD USA. [Simpson, Elizabeth A.; Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Mrozek, Timothy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Comp Support Serv, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Paukner, A (reprint author), NIH Anim Ctr, POB 529, Poolesville, MD 20837 USA. EM pauknera@mail.nih.gov OI Simpson, Elizabeth/0000-0003-2715-2533 FU Intramural NIH HHS [Z99 HD999999]; NICHD NIH HHS [P01 HD064653, P01HD064653] NR 37 TC 8 Z9 8 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1363-755X EI 1467-7687 J9 DEVELOPMENTAL SCI JI Dev. Sci. PD NOV PY 2014 VL 17 IS 6 BP 833 EP 840 DI 10.1111/desc.12207 PG 8 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA AS5XX UT WOS:000344340900005 PM 24995706 ER PT J AU Chowell, G Simonsen, L Flores, J Miller, MA Viboud, C AF Chowell, Gerardo Simonsen, Lone Flores, Jose Miller, Mark A. Viboud, Cecile TI Death Patterns during the 1918 Influenza Pandemic in Chile SO EMERGING INFECTIOUS DISEASES LA English DT Article ID MORTALITY IMPACT; WAVE; CITY; AGE; TRANSMISSIBILITY; BURDEN; EUROPE; BRAZIL; SEX AB Scarce information about the epidemiology of historical influenza pandemics in South America prevents complete understanding of pandemic patterns throughout the continent and across different climatic zones. To fill gaps with regard to spatiotemporal patterns of deaths associated with the 1918 influenza pandemic in Chile, we reviewed archival records. We found evidence that multiple pandemic waves at various times of the year and of varying intensities occurred during 1918-1921 and that influenza-related excess deaths peaked during July-August 1919. Pandemic-associated mortality rates were elevated for all age groups, including for adults >= 50 years of age; elevation from baseline was highest for young adults. Overall, the rate of excess deaths from the pandemic was estimated at 0.94% in Chile, similar to rates reported elsewhere in Latin America, but rates varied approximate to 10-fold across provinces. Patterns of death during the pandemic were affected by variation in host-specific susceptibility, population density, baseline death rate, and climate. C1 [Chowell, Gerardo] Arizona State Univ, Tempe, AZ 85282 USA. [Chowell, Gerardo; Miller, Mark A.; Viboud, Cecile] NIH, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Washington, DC USA. [Flores, Jose] Univ S Dakota, Vermillion, SD 57069 USA. [Flores, Jose] Univ Chile, Santiago, Chile. RP Chowell, G (reprint author), Arizona State Univ, Box 872402, Tempe, AZ 85282 USA. EM gchowell@asu.edu OI Simonsen, Lone/0000-0003-1535-8526 FU RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science & Technology Directorate, Department of Homeland Security; Office of Global Affairs, International Influenza Unit, in the Office of the Secretary of the US Department of Health and Human Services FX This research was conducted in the context of the Multinational Influenza Seasonal Mortality Study, an ongoing international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). Funding for this project comes in part (L.S.) from the RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science & Technology Directorate, Department of Homeland Security, and from the Office of Global Affairs, International Influenza Unit, in the Office of the Secretary of the US Department of Health and Human Services. NR 40 TC 3 Z9 3 U1 0 U2 4 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD NOV PY 2014 VL 20 IS 11 BP 1803 EP 1811 DI 10.3201/eid2011.130632 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AS0KO UT WOS:000343966300003 PM 25341056 ER PT J AU Di Martino, B Di Profio, F Ceci, C Di Felice, E Green, KY Bok, K De Grazia, S Giammanco, GM Massirio, I Lorusso, E Buonavoglia, C Marsilio, F Martella, V AF Di Martino, Barbara Di Profio, Federica Ceci, Chiara Di Felice, Elisabetta Green, Kim Y. Bok, Karin De Grazia, Simona Giammanco, Giovanni M. Massirio, Ivano Lorusso, Eleonora Buonavoglia, Canio Marsilio, Fulvio Martella, Vito TI Seroprevalence of Norovirus Genogroup IV Antibodies among Humans, Italy, 2010-2011 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID NORWALK-LIKE VIRUSES; CAPSID PROTEIN; HUMAN CALICIVIRUSES; IMMUNE-RESPONSES; PREVALENCE; STRAIN; SEROEPIDEMIOLOGY; GASTROENTERITIS; PATHOGENESIS; INFECTIONS AB Noroviruses (NoVs) of genogroup IV (GIV) (Alphatron-like) cause infections in humans and in carnivorous animals such as dogs and cats. We screened an age-stratified collection of serum samples from 535 humans in Italy, using virus-like particles of genotypes GIV.1, circulating in humans, and GIV.2, identified in animals, in ELISA, in order to investigate the prevalence of GIV NoV-specific IgG antibodies. Antibodies specific for both genotypes were detected, ranging from a prevalence of 6.6% to 44.8% for GIV.1 and from 6.8% to 15.1% for GIV.2 among different age groups. These data are consistent with a higher prevalence of GIV.1 strains in the human population. Analysis of antibodies against GIV.2 suggests zoonotic transmission of animal No Vs, likely attributable to interaction between humans and domestic pets. This finding, and recent documentation of human C1 [Di Martino, Barbara; Di Profio, Federica; Ceci, Chiara; Di Felice, Elisabetta; Marsilio, Fulvio] Univ Teramo, Teramo, Italy. [Green, Kim Y.; Bok, Karin] NIH, Bethesda, MD 20892 USA. [De Grazia, Simona; Giammanco, Giovanni M.] Univ Palermo, Palermo, Italy. [Massirio, Ivano] Azienda USL Reggio Emilia, Reggio Emilia, Italy. [Lorusso, Eleonora; Buonavoglia, Canio; Martella, Vito] Univ Aldo Moro Bari, Valenzano, Italy. RP Di Martino, B (reprint author), Fac Vet Med Teramo, Piazza Aldo Moro 45, I-64100 Teramo, Italy. EM bdimartino@unite.it RI Giammanco, Giovanni/G-4000-2012; Martella, Vito/K-3146-2016; OI Giammanco, Giovanni/0000-0002-7874-6289; Martella, Vito/0000-0002-5740-6947; Di Felice, Elisabetta/0000-0002-8320-6340 FU University of Teramo, Italy; Italian Ministry of University and Research; National Institute of Infectious Diseases, National Institutes of Health, US FX This study was supported by grants from the University of Teramo, Italy, and from the Italian Ministry of University and Research, and was also partially funded by the intramural research program of the National Institute of Infectious Diseases, National Institutes of Health, US. NR 37 TC 4 Z9 4 U1 0 U2 5 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD NOV PY 2014 VL 20 IS 11 BP 1828 EP 1832 DI 10.3201/eid2011.131601 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AS0KO UT WOS:000343966300006 PM 25340375 ER PT J AU Boikos, SA Stratakis, CA AF Boikos, Sosipatros A. Stratakis, Constantine A. TI The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations SO ENDOCRINE LA English DT Review DE SDH-deficient GIST; BRAF; NF1; Paraganglioma; Chondroma ID SUCCINATE-DEHYDROGENASE SUBUNIT; MEDULLARY-THYROID CARCINOMA; GIST FOLLOWING FAILURE; MULTICENTER PHASE-II; V600E BRAF MUTATIONS; CARNEY TRIAD; GERMLINE MUTATION; NEUROFIBROMATOSIS TYPE-1; PULMONARY CHONDROMA; DEFICIENT GISTS AB About 10-15 % of adult gastrointestinal stromal tumors (GISTs) and 85 % of pediatric GISTs do not have mutations in the KIT or PDGFRA genes and are generally classified as KIT/PDGFRA wild type (WT). Recent studies have shown that this group of KIT/PDGFRA WT GISTs is quite heterogeneous in terms of clinical phenotype, genetic etiology, and molecular pathways. Succinate dehydrogenase subunit (SDH)-deficient GISTs, which include tumors that are part of multiple endocrine neoplasia syndromes, are the newest group of KIT/PDGFRA WT GIST to be molecularly elucidated. This review aims to describe the different genetic subgroups of KIT/PDGFRA WT GIST, with a special focus on the SDH-deficient GIST. C1 [Boikos, Sosipatros A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21287 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Boikos, SA (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21287 USA. EM sboikos1@jhmi.edu FU Intramural NIH HHS [ZIA HD008920-03] NR 69 TC 8 Z9 8 U1 1 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD NOV PY 2014 VL 47 IS 2 BP 401 EP 408 DI 10.1007/s12020-014-0346-3 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS2DF UT WOS:000344088900010 PM 25027296 ER PT J AU Bendtsen, KM Jensen, MB May, A Rasmussen, LJ Trusina, A Bohr, VA Jensen, MH AF Bendtsen, Kristian Moss Jensen, Martin Borch May, Alfred Rasmussen, Lene Juel Trusina, Ala Bohr, Vilhelm A. Jensen, Mogens H. TI Dynamics of the DNA repair proteins WRN and BLM in the nucleoplasm and nucleoli SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Article DE DNA damage; FRAP; Diffusion; DNA repair; WRN; BLM ID QUANTITATIVE FLUORESCENCE RECOVERY; WERNER-SYNDROME PROTEIN; RIBOSOMAL-RNA; LIVING CELLS; HELICASE; TRANSCRIPTION; MODEL AB We have investigated the mobility of two EGFP-tagged DNA repair proteins, WRN and BLM. In particular, we focused on the dynamics in two locations, the nucleoli and the nucleoplasm. We found that both WRN and BLM use a "DNA-scanning" mechanism, with rapid binding-unbinding to DNA resulting in effective diffusion. In the nucleoplasm WRN and BLM have effective diffusion coefficients of 1.62 and 1.34 mu m(2)/s, respectively. Likewise, the dynamics in the nucleoli are also best described by effective diffusion, but with diffusion coefficients a factor of ten lower than in the nucleoplasm. From this large reduction in diffusion coefficient we were able to classify WRN and BLM as DNA damage scanners. In addition to WRN and BLM we also classified other DNA damage proteins and found they all fall into one of two categories. Either they are scanners, similar to WRN and BLM, with very low diffusion coefficients, suggesting a scanning mechanism, or they are almost freely diffusing, suggesting that they interact with DNA only after initiation of a DNA damage response. C1 [Bendtsen, Kristian Moss; Trusina, Ala; Jensen, Mogens H.] Univ Copenhagen, Niels Bohr Inst, CMOL, DK-2100 Copenhagen, Denmark. [Jensen, Martin Borch; Rasmussen, Lene Juel; Bohr, Vilhelm A.] Univ Copenhagen, Dept Cellular & Mol Med, Ctr Healthy Aging, DK-2200 Copenhagen, Denmark. [May, Alfred; Bohr, Vilhelm A.] NIA, Baltimore, MD 21224 USA. RP Bendtsen, KM (reprint author), Univ Copenhagen, Niels Bohr Inst, CMOL, DK-2100 Copenhagen, Denmark. EM kmoss@nbi.dk OI Trusina, Ala/0000-0003-1945-454X FU Danish Council for Independent research (DFF); CMOL through the Danish National Research Foundation; Center for Healthy Aging; Danish Ministry of Science; National Institute of Aging, National Institutes of Health, USA FX We would like to thank members of Center for Models of Life and the Bohr Laboratory for discussions. AT is supported by a Steno fellowship granted by the Danish Council for Independent research (DFF), KMB is supported by CMOL through the Danish National Research Foundation (DG), and MBJ is supported by the Center for Healthy Aging and an Elite Research Scholarship from the Danish Ministry of Science. This work was supported by funds from the intramural program of the National Institute of Aging, National Institutes of Health, USA. NR 24 TC 2 Z9 3 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD NOV PY 2014 VL 43 IS 10-11 BP 509 EP 516 DI 10.1007/s00249-014-0981-x PG 8 WC Biophysics SC Biophysics GA AS6QY UT WOS:000344388700006 PM 25119658 ER PT J AU Badu, SR Melnik, R Paliy, M Prabhakar, S Sebetci, A Shapiro, B AF Badu, S. R. Melnik, R. Paliy, M. Prabhakar, S. Sebetci, A. Shapiro, B. A. TI Modeling of RNA nanotubes using molecular dynamics simulation SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Article DE RNA nanocluster; Nanotube; Drug delivery; Cancer therapy; Bionanotechnology ID COLE1 PLASMID REPLICATION; NANOPARTICLES; DELIVERY; COMPLEX; BINDING; THERAPEUTICS; PRNA AB In this study, we construct novel RNA nanoclusters, RNA nanotubes made of several nanorings up to the size of 20 nm, utilizing the molecular dynamics simulation, and study their structural properties [i.e., the root mean square deviation, the radius of gyration and the radial distribution function (RDF)] in physiological solutions that can be used for drug delivery into the human body. The patterns of energy and temperature variations of the systems are also discussed. Furthermore, we study the concentration of ions around the tube as a function of time at a particular temperature. We have found that when the temperature increases, the number of ions increases within a certain distance of the tube. We report that the number of ions within this distance around the tubes decreases in quenched runs. This indicates that some ions evaporate with decrease in temperature, as has been observed in the case of the nanoring. RDF plots also demonstrate a similar trend with temperature, as was found in the case of RNA nanorings. C1 [Badu, S. R.; Melnik, R.; Prabhakar, S.] Wilfrid Laurier Univ, M2Net Lab, MS2Discovery Interdisciplinary Res Inst, Waterloo, ON N3L 3V6, Canada. [Paliy, M.] Univ Western Ontario, Dept Mech & Mat Engn, Dept Chem, London, ON N6A 5B9, Canada. [Sebetci, A.] Mevlana Univ, Dept Mech Engn, TR-42003 Konya, Turkey. [Shapiro, B. A.] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 20892 USA. RP Badu, SR (reprint author), Wilfrid Laurier Univ, M2Net Lab, MS2Discovery Interdisciplinary Res Inst, 75 Univ Ave, Waterloo, ON N3L 3V6, Canada. EM sbadu@wlu.ca FU NSERC; CRC Program; TUBITAK FX Authors are grateful to the NSERC and CRC Program for their support and Shared Hierarchical Academic Research Computing Network (SHARCNET: www.sharcnet.ca) for providing the computational facilities. RM and AS acknowledge TUBITAK support. Finally, we would like to thank Dr. P. J. Douglas Roberts for helping with technical SHARCNET computational aspects. NR 30 TC 6 Z9 6 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD NOV PY 2014 VL 43 IS 10-11 BP 555 EP 564 DI 10.1007/s00249-014-0985-6 PG 10 WC Biophysics SC Biophysics GA AS6QY UT WOS:000344388700009 PM 25208764 ER PT J AU Wolkow, N Li, YF Maminishkis, A Song, Y Alekseev, O Iacovelli, J Song, DL Lee, JC Dunaief, JL AF Wolkow, Natalie Li, Yafeng Maminishkis, Arvydas Song, Ying Alekseev, Oleg Iacovelli, Jared Song, Delu Lee, Jennifer C. Dunaief, Joshua L. TI Iron upregulates melanogenesis in cultured retinal pigment epithelial cells SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE Iron; Retinal pigment epithelium; Human fetal retinal pigment epithelial cells; ARPE-19 cells; Melanosome; MITF; LEF 1 ID TRANSCRIPTION FACTOR; MELANIN; EYE; HEMOCHROMATOSIS; DEGENERATION; MORPHOLOGY; INDUCTION; MEMBRANE; PROTEINS; MUTATION AB The purpose of our studies was to examine the relationship between iron and melanogenesis in retinal pigment epithelial cells, as prior observations had suggested that iron may promote melanogenesis. This relationship has potential clinical importance, as both iron overload and hyperpigmentation are associated with age-related macular degeneration (AMD). Human fetal retinal pigment epithelial cells and ARPE-19 cells were treated with iron in the form of ferric ammonium citrate, after which quantitative RTPCR and electron microscopy were performed. Melanogenesis genes tyrosinase, tyrosinase-related protein 1, Hermansky-Pudlak Syndrome 3, premelanosome protein and dopachrome tautomerase were upregulated, as was the melanogenesis-controlling transcription factor, microphthalmia-associated transcription factor (MITF). Iron-treated cells had increased pigmentation and melanosome number. Multiple transcription factors upstream of MITF were upregulated by iron. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Wolkow, Natalie; Li, Yafeng; Song, Ying; Alekseev, Oleg; Iacovelli, Jared; Song, Delu; Lee, Jennifer C.; Dunaief, Joshua L.] Univ Penn, Perelman Sch Med, FM Kirby Ctr Mol Ophthalmol, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Maminishkis, Arvydas] NEI, Sect Epithelial & Retinal Physiol & Dis, MSC 1861, NIH, Bethesda, MD 20892 USA. RP Dunaief, JL (reprint author), Univ Penn, Perelman Sch Med, FM Kirby Ctr Mol Ophthalmol, Scheie Eye Inst, 305 Stellar Chance Labs,422 Curie Blvd, Philadelphia, PA 19104 USA. EM jdunaief@mail.med.upenn.edu FU NIH/NEI [R01 EY015240]; FM Kirby Foundation; Research to Prevent Blindness; Paul and Evanina Bell MacKall Foundation Trust FX We thank Sheldon S. Miller, PhD for generously providing us with human fetal RPE cells. We thank Raymond Meade, MS of the Penn Electron Microscopy Resource Laboratory for exceptional technical assistance. Funding was provided by NIH/NEI R01 EY015240, Research to Prevent Blindness, the FM Kirby Foundation, a gift in honor of Dr. Lee F. Mauger, and the Paul and Evanina Bell MacKall Foundation Trust. NR 45 TC 4 Z9 4 U1 0 U2 10 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 NOV PY 2014 VL 128 BP 92 EP 101 DI 10.1016/j.exer.2014.09.010 PG 10 WC Ophthalmology SC Ophthalmology GA AS5LL UT WOS:000344312300012 PM 25277027 ER PT J AU Rodriguez, IR Clark, ME Lee, JW Curcio, CA AF Rodriguez, Ignacio R. Clark, Mark E. Lee, Jung Wha Curcio, Christine A. TI 7-ketocholesterol accumulates in ocular tissues as a consequence of aging and is present in high levels in drusen SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE 7-Ketocholesterol; Monkey; Retina; Drusen; Aging; Human; Cholesterol; Age-related macular degeneration ID AGE-RELATED MACULOPATHY; RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; BASAL DEPOSITS; CHOLESTEROL; INFLAMMATION; EYES; PREVALENCE; MEMBRANE AB We analyzed by LCMS lipid extracts of lens, retina (MNR) and RPE/Choroid (MPEC) from macaque monkeys 2-25 yr in age to determine their content of 7-ketocholesterol (7KCh) as function of age. In addition we also analyzed drusen capped with retinal pigment epithelium (RPE), RPE, and neural retina from human donors age 72-95 yr. The lowest 7KCh levels were found in monkey lens (<0.5-3.5 pmol 7KCh per nmol Ch), the second highest in MNR (1-15 pmol/nmol), and the highest in MPEC (1 to >60 pmol/nmol). Despite individual variability all three tissues demonstrated a strong age-related increase. In older human donors 7KCh levels were significantly higher. The levels in human neural retina ranged from 8 to 20 pmol/nmol, similar to the oldest monkeys, but 7-KCh levels in RPE ranged from 200 to 17,000 pmol/nmol, and in RPE-capped drusen from 200 to 2000 pmol/nmol, levels that would be lethal in most cultured cell systems. Most of the 7KCh is sequestered and not readily available to the surrounding tissue, based on published histochemical evidence that extracellular cholesterol (Ch) and cholesteryl fatty acid esters (CEs) are highly concentrated in Bruch's membrane and drusen. However, adjacent tissues, especially RPE but also choriocapillaris endothelium, could be chronically inflamed and in peril of receiving a lethal exposure. Implications for initiation and progression of age-related macular degeneration are discussed. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Rodriguez, Ignacio R.; Lee, Jung Wha] NEI, Lab Retinal Cell & Mol Biol, Mech Retinal Dis Sect, NIH, Bethesda, MD USA. [Clark, Mark E.; Curcio, Christine A.] Univ Alabama Birmingham, Sch Med, Dept Ophthalmol, Birmingham, AL 35294 USA. RP Curcio, CA (reprint author), Univ Alabama Birmingham, EyeSight Fdn, Sch Med, Dept Ophthalmol,Alabama Vision Res Labs, 1670 Univ Blvd Room 360, Birmingham, AL 35294 USA. EM curcio@uab.edu FU National Eye Institute Intramural Research program; NIH [EY06109]; Arnold and Mabel Beckman Initiative for Macular Research; Research to Prevent Blindness, Inc.; EyeSight Foundation of Alabama FX National Eye Institute Intramural Research program (IRR); NIH grant EY06109, Arnold and Mabel Beckman Initiative for Macular Research (D. Stambolian MD PhD; co-PI), unrestricted funds to the UAB Department of Ophthalmology from Research to Prevent Blindness, Inc., and from EyeSight Foundation of Alabama (CAC). NR 27 TC 11 Z9 11 U1 0 U2 5 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 NOV PY 2014 VL 128 BP 151 EP 155 DI 10.1016/j.exer.2014.09.009 PG 5 WC Ophthalmology SC Ophthalmology GA AS5LL UT WOS:000344312300019 PM 25261634 ER PT J AU Yasgar, A Simeonov, A AF Yasgar, Adam Simeonov, Anton TI Current approaches for the discovery of drugs that deter substance and drug abuse SO EXPERT OPINION ON DRUG DISCOVERY LA English DT Review DE addiction; combination therapy; drug abuse; drugs of abuse; high-throughput screening; receptor agonist; substance abuse ID MUSCARINIC ACETYLCHOLINE-RECEPTOR; NEGATIVE ALLOSTERIC MODULATORS; ZEBRAFISH MODELS; 5-HT2C RECEPTOR; SELECTIVE ANTAGONISTS; EPIGENETIC MECHANISMS; TRANSGENIC ZEBRAFISH; EFFECTIVE VACCINES; SCREENING ASSAY; ANIMAL-MODELS AB Introduction: Much has been presented and debated on the topic of drug abuse and its multidimensional nature, including the role of society and its customs and laws, economical factors, and the magnitude and nature of the burden. Given the complex nature of the receptors and pathways implicated in regulation of the cognitive and behavioral processes associated with addiction, a large number of molecular targets have been interrogated during recent years to discover starting points for development of small-molecule interventions. Areas covered: This review describes recent developments in the field of early drug discovery for drug abuse interventions with an emphasis on the advances published during the 2012 - 2014 period. Expert opinion: Technologically, the processes/platforms utilized in drug abuse drug discovery are nearly identical to those used in the other disease areas. A key complicating factor in drug abuse research is the enormous biological complexity surrounding the brain processes involved and the associated difficulty in finding 'good' targets and achieving exquisite selectivity of treatment agents. While tremendous progress has been made during recent years to use the power of high-throughput technologies to discover proof-of-principle molecules for many new targets, next-generation models will be especially important in this field. Examples include: seeking advantageous drug-drug combinations, the use of automated whole-animal behavioral screening systems, advancing our understanding of the role of epigenetics in drug addiction and the employment of organoid-level 3D test platforms (also referred to as tissue-chip or organs-on-chip). C1 [Yasgar, Adam; Simeonov, Anton] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Simeonov, A (reprint author), NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM asimeono@mail.nih.gov FU National Institutes of Health FX The authors are supported by the National Institutes of Health. 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 118 TC 0 Z9 0 U1 2 U2 26 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1746-0441 EI 1746-045X J9 EXPERT OPIN DRUG DIS JI Expert. Opin. Drug Discov. PD NOV PY 2014 VL 9 IS 11 BP 1319 EP 1331 DI 10.1517/17460441.2014.956721 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AS5TT UT WOS:000344333100008 PM 25251069 ER PT J AU Martin, F Taylor, GP Jacobson, S AF Martin, Fabiola Taylor, Graham P. Jacobson, Steven TI Inflammatory manifestations of HTLV-1 and their therapeutic options SO EXPERT REVIEW OF CLINICAL IMMUNOLOGY LA English DT Review DE arthritis; Graves'; HAID; HAM/TSP; Hashimoto; HAU; HTLV; infective dermatitis; inflammation; keratitis; polymyositis; Sjogren's; thyroiditis; uveitis ID VIRUS-TYPE-I; CELL LYMPHOTROPIC VIRUS; MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; INCLUSION-BODY MYOSITIS; BLOOD MONONUCLEAR-CELLS; REVERSE-TRANSCRIPTASE INHIBITORS; RESEMBLING RHEUMATOID-ARTHRITIS; BRONCHOALVEOLAR LAVAGE FLUID; SYSTEMIC-LUPUS-ERYTHEMATOSUS; POLYMERASE-CHAIN-REACTION AB Human T lymphotropic virus type 1 (HTLV-1) is one of the most intriguing retroviruses infecting humans. Most commonly, infection remains undetected, since it does not cause obvious harm, yet in 4-9% of patients, this infection can be devastating, causing adult T-cell leukemia/lymphoma and/or HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). This review concentrates on all inflammatory aspects of HTLV-1 infection: HAM/TSP, HTLV-1 associated uveitis, HTLV-1 associated conjunctivitis, sicca syndrome and interstitial keratitis, HTLV-1 associated Sjogren's syndrome, Hashimoto's thyroiditis and Graves' disease, HTLV-1 associated pulmonary disease, infective dermatitis associated with HTLV-1, HTLV-1 associated inflammatory myositis and HTLV-1 associated arthritis. With the exception of HAM/TSP treatment, studies of these conditions are sparse and even for HAM/TSP, the level of evidence is limited. While control or elimination of infection remains a goal, most therapy beyond symptomatic management is directed at the immune response to HTLV-1. C1 [Martin, Fabiola] Univ York, Ctr Immunol & Infect, Hull & York Med Sch, Dept Biol, York YO10 5DD, N Yorkshire, England. [Taylor, Graham P.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Infect Dis Sect, London W2 1PG, England. [Jacobson, Steven] NIH, Viral immunol Sect, Bethesda, MD 20892 USA. RP Martin, F (reprint author), Univ York, Ctr Immunol & Infect, Hull & York Med Sch, Dept Biol, York YO10 5DD, N Yorkshire, England. EM fabiola.martin@hyms.ac.uk FU Imperial NIHR Biomedical Research Centre FX GP Taylor is supported by the Imperial NIHR Biomedical Research Centre. P Roberts acted as the authors' medical illustrator and was reimbursed by F Martin's research funds. 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 219 TC 11 Z9 12 U1 0 U2 10 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1744-666X EI 1744-8409 J9 EXPERT REV CLIN IMMU JI Expert Rev. Clin. Immunol. PD NOV PY 2014 VL 10 IS 11 BP 1531 EP 1546 DI 10.1586/1744666X.2014.966690 PG 16 WC Immunology SC Immunology GA AS5OS UT WOS:000344320500012 PM 25340428 ER PT J AU Singh, NS Zarate, CA Moaddel, R Bernier, M Wainer, IW AF Singh, Nagendra S. Zarate, Carlos A., Jr. Moaddel, Ruin Bernier, Michel Wainer, Irving W. TI What is hydroxynorketamine and what can it bring to neurotherapeutics? SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Editorial Material DE depression; D-serine; nicotinic acetylcholine receptors; NMDA receptor; serine racemase ID D-SERINE; MAJOR DEPRESSION; MAMMALIAN TARGET; KETAMINE; METABOLITES; ANTAGONISTS; RACEMASE; NORKETAMINE; ACTIVATION; RAPAMYCIN AB (R,S)-Ketamine was initially developed as an anesthetic agent and its pharmacological properties were determined on the basis of this clinical use. However, pharmacological studies in rat led to the development of the Ketamine Paradigm', whereby (R,S)-ketamine and its N-demethylated metabolite (R,S)-norketamine were deemed the active compounds whereas the other ketamine metabolites were considered inactive. Recent in vivo and in vitro studies with (2S,6S)-hydroxynorketamine, a previously identified inactive' metabolite, have demonstrated that this compound is an active and selective inhibitor of the 7 subtype of the nicotinic acetylcholine receptor and that this activity contributes to the pharmacological responses associated with the antidepressant activity of (R,S)-ketamine. Thus, it appears that it is necessary to reassess the Ketamine Paradigm' in regards to the use of sub-anesthetic doses of (R,S)-ketamine in the treatment of treatment-resistant depression. C1 [Singh, Nagendra S.; Moaddel, Ruin; Wainer, Irving W.] NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Bernier, Michel] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM wainerir@grc.nia.nih.gov RI Singh, Nagendra/K-8966-2015; OI Bernier, Michel/0000-0002-5948-368X FU Intramural NIH HHS NR 27 TC 8 Z9 8 U1 2 U2 7 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD NOV PY 2014 VL 14 IS 11 BP 1239 EP 1242 DI 10.1586/14737175.2014.971760 PG 4 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AS4NR UT WOS:000344253500001 PM 25331415 ER PT J AU Du, J Ma, X Shen, B Huang, Y Birnbaumer, L Yao, XQ AF Du, Juan Ma, Xin Shen, Bing Huang, Yu Birnbaumer, Lutz Yao, Xiaoqiang TI TRPV4, TRPC1, and TRPP2 assemble to form a flow-sensitive heteromeric channel SO FASEB JOURNAL LA English DT Article DE endothelial cells; shear stress; Ca2+; mesenteric artery ID VASCULAR ENDOTHELIAL-CELLS; INDUCED CA2+ INFLUX; CATION CHANNEL; NITRIC-OXIDE; SUBUNITS; EXPRESSION; ARTERIAL; COMPLEX; PKD2 AB Transient receptor potential (TRP) channels, a superfamily of ion channels, can be divided into 7 subfamilies, including TRPV, TRPC, TRPP, and 4 others. Functional TRP channels are tetrameric complexes consisting of 4 pore-forming subunits. The purpose of this study was to explore the heteromerization of TRP subunits crossing different TRP subfamilies. Two-step coimmunoprecipitation (co-IP) and fluorescence resonance energy transfer (FRET) were used to determine the interaction of the different TRP subunits. Patch-clamp and cytosolic Ca2+ measurements were used to determine the functional role of the ion channels in flow conditions. The analysis demonstrated the formation of a heteromeric TRPV4-C1-P2 complex in primary cultured rat mesenteric artery endothelial cells (MAECs) and HEK293 cells that were cotransfected with TRPV4, TRPC1, and TRPP2. In functional experiments, pore-dead mutants for each of these 3 TRP isoforms nearly abolished the flow-induced cation currents and Ca2+ increase, suggesting that all 3 TRPs contribute to the ion permeation pore of the channels. We identified the first heteromeric TRP channels composed of subunits from 3 different TRP subfamilies. Functionally, this heteromeric TRPV4-C1-P2 channel mediates the flow-induced Ca2+ increase in native vascular endothelial cells.Du, J., Ma, X., Shen, B., Huang, Y., Birnbaumer, L., Yao, X. TRPV4, TRPC1, and TRPP2 assemble to form a flow-sensitive heteromeric channel. C1 [Du, Juan; Ma, Xin; Shen, Bing; Huang, Yu; Yao, Xiaoqiang] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China. [Du, Juan; Ma, Xin; Shen, Bing; Huang, Yu; Yao, Xiaoqiang] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Peoples R China. [Du, Juan; Shen, Bing] Anhui Med Univ, Dept Physiol, He Fei, Peoples R China. [Birnbaumer, Lutz] NIEHS, US NIH, Res Triangle Pk, NC 27709 USA. RP Yao, XQ (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China. EM yao2068@cuhk.edu.hk RI Yao, Xiaoqiang /I-5413-2016 OI Yao, Xiaoqiang /0000-0002-0687-8186 FU Hong Kong Research Grants Council [CUHK478011, CUHK478710, T13-706/11, AoE/M-05/12]; U.S. National Institutes of Health [Z01-ES-101684] FX The authors thank J. Li, X. Wang, and J. Guo, (Anhui Medical University), who performed co-IP and immunostaining experiments in the revision phase of the manuscript. This work was supported by grants CUHK478011, CUHK478710, T13-706/11, and AoE/M-05/12 from the Hong Kong Research Grants Council and by the Intramural Research Program of the U.S. National Institutes of Health (project Z01-ES-101684; to L.B.). NR 25 TC 20 Z9 21 U1 1 U2 13 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD NOV PY 2014 VL 28 IS 11 BP 4677 EP 4685 DI 10.1096/fj.14-251652 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AS1OU UT WOS:000344050900009 PM 25114176 ER PT J AU Maddipati, KR Romero, R Chaiworapongsa, T Zhou, SL Xu, ZH Tarca, AL Kusanovic, JP Munoz, H Honn, KV AF Maddipati, Krishna Rao Romero, Roberto Chaiworapongsa, Tinnakorn Zhou, Sen-Lin Xu, Zhonghui Tarca, Adi L. Kusanovic, Juan Pedro Munoz, Hernan Honn, Kenneth V. TI Eicosanomic profiling reveals dominance of the epoxygenase pathway in human amniotic fluid at term in spontaneous labor SO FASEB JOURNAL LA English DT Article DE epoxy fatty acids; hydroxy fatty acids; LC-MS; lipidomics; parturition ID SOLUBLE EPOXIDE HYDROLASE; PLATELET-NEUTROPHIL INTERACTIONS; HUMAN MYOMETRIAL CONTRACTILITY; HUMAN FETAL MEMBRANES; ARACHIDONIC-ACID; HUMAN PARTURITION; EPOXYEICOSATRIENOIC ACIDS; PRETERM LABOR; 5-HYDROXYEICOSATETRAENOIC ACID; PROSTAGLANDIN CONCENTRATIONS AB Lipid mediators play an important role in reproductive biology, especially, in parturition. Enhanced biosynthesis of eicosanoids, such as prostaglandin E-2 (PGE(2)) and PGF(2), precedes the onset of labor as a result of increased expression of inducible cyclooxygenase 2 (COX-2) in placental tissues. Metabolism of arachidonic acid results in bioactive lipid mediators beyond prostaglandins that could significantly influence myometrial activity. Therefore, an unbiased lipidomic approach was used to profile the arachidonic acid metabolome of amniotic fluid. In this study, liquid chromatography-mass spectrometry was used for the first time to quantitate these metabolites in human amniotic fluid by comparing patients at midtrimester, at term but not in labor, and at term and in spontaneous labor. In addition to exposing novel aspects of COX pathway metabolism, this lipidomic study revealed a dramatic increase in epoxygenase- and lipoxygenase-pathway-derived lipid mediators in spontaneous labor with remarkable product selectivity. Despite their recognition as anti-inflammatory lipid mediators and regulators of ion channels, little is known about the epoxygenase pathway in labor. Epoxygenase pathway metabolites are established regulators of vascular homeostasis in cardiovascular and renal physiology. Their presence as the dominant lipid mediators in spontaneous labor at term portends a yet undiscovered physiological function in parturition.Maddipati, K. R., Romero, R., Chaiworapongsa, T., Zhou, S.-L., Xu, Z., Tarca, A. L., Kusanovic, J. P., Munoz, H., Honn, K. V. Eicosanomic profiling reveals dominance of the epoxygenase pathway in human amniotic fluid at term in spontaneous labor. C1 [Maddipati, Krishna Rao; Zhou, Sen-Lin; Honn, Kenneth V.] Wayne State Univ, Sch Med, Dept Pathol, Bioact Lipids Res Program, Detroit, MI 48202 USA. [Maddipati, Krishna Rao; Zhou, Sen-Lin] Wayne State Univ, Sch Med, Lipid Core Facil, Detroit, MI 48202 USA. [Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Xu, Zhonghui; Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Kusanovic, Juan Pedro] Pontificia Univ Catolica Chile, Sch Med, Dept Obstet & Gynecol, Santiago, Chile. [Kusanovic, Juan Pedro] Hosp Dr Sotero del Rio, Santiago, Chile. [Munoz, Hernan] Univ Chile, Santiago, Chile. RP Maddipati, KR (reprint author), Wayne State Univ, Dept Pathol, 435 Chem Bldg,410 W Warren Ave, Detroit, MI 48202 USA. EM maddipati@wayne.edu OI Maddipati, Krishna Rao/0000-0003-1445-791X FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), U.S. Department of Health and Human Services [HSN275201300006C]; National Center for Research Resources/NIH [S10RR027926]; Perinatal Virtual Discovery grant from Wayne State University FX The authors thank Dr. S. Tucker for a careful reading of the manuscript. 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 (NICHD), National Institutes of Health (NIH), U.S. Department of Health and Human Services; and, in part, with federal funds from NICHD/NIH (contract HSN275201300006C). The work was also supported, in part, by a grant from the National Center for Research Resources/NIH (S10RR027926) and a Perinatal Virtual Discovery grant from Wayne State University (to K.R.M.). NR 81 TC 16 Z9 16 U1 2 U2 18 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD NOV PY 2014 VL 28 IS 11 BP 4835 EP 4846 DI 10.1096/fj.14-254383 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AS1OU UT WOS:000344050900021 PM 25059230 ER PT J AU Lujan, SA Clausen, AR Clark, AB MacAlpine, HK MacAlpine, DM Malc, EP Mieczkowski, PA Burkholder, AB Fargo, DC Gordenin, DA Kunkel, TA AF Lujan, Scott A. Clausen, Anders R. Clark, Alan B. MacAlpine, Heather K. MacAlpine, David M. Malc, Ewa P. Mieczkowski, Piotr A. Burkholder, Adam B. Fargo, David C. Gordenin, Dmitry A. Kunkel, Thomas A. TI Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition SO GENOME RESEARCH LA English DT Article ID EUKARYOTIC REPLICATION FORK; STRAND DNA-REPLICATION; MUTATION-RATES; SACCHAROMYCES-CEREVISIAE; WIDE VIEW; DROSOPHILA-MELANOGASTER; CHROMATIN-STRUCTURE; SUBSTITUTION RATES; MAMMALIAN GENOMES; CANCER GENOMES AB Mutational heterogeneity must be taken into account when reconstructing evolutionary histories, calibrating molecular clocks, and predicting links between genes and disease. Selective pressures and various DNA transactions have been invoked to explain the heterogeneous distribution of genetic variation between species, within populations, and in tissue-specific tumors. To examine relationships between such heterogeneity and variations in leading- and lagging-strand replication fidelity and mismatch repair, we accumulated 40,000 spontaneous mutations in eight diploid yeast strains in the absence of selective pressure. We found that replicase error rates vary by fork direction, coding state, nucleosome proximity, and sequence context. Further, error rates and DNA mismatch repair efficiency both vary by mismatch type, responsible polymerase, replication time, and replication origin proximity. Mutation patterns implicate replication infidelity as one driver of variation in somatic and germline evolution, suggest mechanisms of mutual modulation of genome stability and composition, and predict future observations in specific cancers. C1 [Lujan, Scott A.; Clausen, Anders R.; Clark, Alan B.; Gordenin, Dmitry A.; Kunkel, Thomas A.] NIH, Dept Hlth & Human Serv, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Lujan, Scott A.; Clausen, Anders R.; Clark, Alan B.; Kunkel, Thomas A.] NIH, Dept Hlth & Human Serv, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [MacAlpine, Heather K.; MacAlpine, David M.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Malc, Ewa P.; Mieczkowski, Piotr A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA. [Burkholder, Adam B.; Fargo, David C.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIH, Dept Hlth & Human Serv, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Clausen, Anders Ranegaard/0000-0002-5069-0930 FU Division of Intramural Research of the NIH, NIEHS [Z01 ES065070, Z01 ES065073]; NIH [2R01GM052319-16A1, 1R01GM104097] FX We thank Matthew Longley, Shayamal Peddada, Marta Garbacz, and Matthew Young for helpful comments on the manuscript and Tianyuan Wang for computational support. This work was supported by Project Z01 ES065070 to T.A.K. and Z01 ES065073 to Michael A. Resnick (whom we also thank), both from the Division of Intramural Research of the NIH, NIEHS, and by 2R01GM052319-16A1 to P.A.M. and 1R01GM104097 to D.M.M., both from the NIH. NR 88 TC 33 Z9 33 U1 3 U2 20 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD NOV PY 2014 VL 24 IS 11 BP 1751 EP 1764 DI 10.1101/gr.178335.114 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA AS7NG UT WOS:000344442000004 PM 25217194 ER PT J AU Gao, B Xu, MJ AF Gao, Bin Xu, Mingjiang TI Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets? SO GUT LA English DT Editorial Material ID SURVIVAL; LIVER C1 [Gao, Bin; Xu, Mingjiang] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov NR 12 TC 5 Z9 5 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD NOV PY 2014 VL 63 IS 11 BP 1683 EP 1684 DI 10.1136/gutjnl-2013-306603 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AR9YI UT WOS:000343933000002 PM 24515805 ER PT J AU Greten, TF AF Greten, Tim F. TI Myeloid-derived suppressor cells in pancreatic cancer: more than a hidden barrier for antitumour immunity? SO GUT LA English DT Editorial Material ID TUMOR-BEARING MICE; CARCINOMA C1 NCI, Thorac & Gastrointestinal Oncol Branch, Gastrointestinal Malignancy Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, Gastrointestinal Malignancy Sect, Ctr Canc Res, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 14 TC 1 Z9 2 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD NOV PY 2014 VL 63 IS 11 BP 1690 EP + DI 10.1136/gutjnl-2014-306790 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AR9YI UT WOS:000343933000006 PM 24633728 ER PT J AU Fuss, IJ Joshi, B Yang, ZQ Degheidy, H Fichtner-Feigl, S de Souza, H Rieder, F Scaldaferri, F Schirbel, A Scarpa, M West, G Yi, CL Xu, LL Leland, P Yao, M Mannon, P Puri, RK Fiocchi, C Strober, W AF Fuss, Ivan J. Joshi, Bharat Yang, Zhiqiong Degheidy, Heba Fichtner-Feigl, Stefan de Souza, Heitor Rieder, Florian Scaldaferri, Franco Schirbel, Anja Scarpa, Melania West, Gail Yi, Chuli Xu, Lili Leland, Pamela Yao, Michael Mannon, Peter Puri, Raj K. Fiocchi, Claudio Strober, Warren TI IL-13R alpha 2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis SO GUT LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; T-CELLS; CROHNS-DISEASE; INTERLEUKIN-13; RECEPTOR; AUTOIMMUNITY; FIBROSIS; GLIOMA AB Objective Previous studies have shown that ulcerative colitis (UC) is associated with the presence of lamina propria non-invariant (Type II) NKT cells producing IL-13 and mediating epithelial cell cytotoxicity. Here we sought to define the antigen(s) stimulating the NKT cells and to quantitate these cells in the UC lamina propria. Design Detection of Type II NKT cells in UC lamina propria mononuclear cells (LPMC) with lyso-sulfatide loaded tetramer and quantum dot-based flow cytometry and staining. Culture of UC LPMCs with lyso-sulfatide glycolipid to determine sulfatide induction of epithelial cell cytotoxicity, IL-13 production and IL-13R alpha 2 expression. Blinded quantum dot-based phenotypic analysis to assess UC LPMC expression of IL-13R alpha 2, CD161 and IL-13. Results Approximately 36% of UC LPMC were lysosulfatide tetramer positive, whereas few, if any, control LPMCs were positive. When tested, the positive cells were also CD3 and IL-13R alpha 2 positive. Culture of UC LPMC with lyso-sulfatide glycolipid showed that sulfatide stimulates UC LPMC production of IL-13 and induces UC CD161 LPMC-mediated cytotoxicity of activated epithelial cells; additionally, lyso-sulfatide induces enhanced expression of IL-13R alpha 2. Finally, blinded phenotypic analysis of UC LP MC using multicolour quantum dot-staining technology showed that approximately 60% of the LPMC bear both IL-13R alpha 2 and CD161 and most of these cells also produce IL-13. Conclusions These studies show that UC lamina propria is replete with Type II NKT cells responsive to lyso-sulfatide glycolipid and bearing IL-13R alpha 2. Since lyso-sulfatide is a self-antigen, these data suggest that an autoimmune response is involved in UC pathogenesis. C1 [Fuss, Ivan J.; Yang, Zhiqiong; Yi, Chuli; Xu, Lili; Yao, Michael; Mannon, Peter; Strober, Warren] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Joshi, Bharat; Degheidy, Heba; Leland, Pamela; Puri, Raj K.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Fichtner-Feigl, Stefan] Univ Regensburg, Dept Surg, D-93053 Regensburg, Germany. [de Souza, Heitor; Rieder, Florian; Scaldaferri, Franco; Schirbel, Anja; Scarpa, Melania; West, Gail; Fiocchi, Claudio] Cleveland Clin Fdn, Dept Pathobiol, Cleveland, OH 44195 USA. RP Fuss, IJ (reprint author), NIH, Mucosal Immun Sect, LHD, 10 Ctr Dr,CRC Bldg,Room 5W-3864, Bethesda, MD 20892 USA. EM ifuss@niaid.nih.gov RI Scarpa, Melania/J-6912-2016 OI Scarpa, Melania/0000-0002-7055-635X FU NIAID, National Institutes of Health FX This work was supported by the Intramural Research Program of NIAID, National Institutes of Health. NR 21 TC 20 Z9 20 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD NOV PY 2014 VL 63 IS 11 BP 1728 EP + DI 10.1136/gutjnl-2013-305671 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AR9YI UT WOS:000343933000013 PM 24515806 ER PT J AU Wang, XF Korangy, F AF Wang, Xiao-Fan Korangy, Firouzeh TI Intrahepatic Landscape of Regulatory T-Cell Subsets in Chronically HCV-Infected Patients With Cirrhosis and HCC SO HEPATOLOGY LA English DT Editorial Material ID HEPATOCELLULAR-CARCINOMA; MECHANISMS C1 [Wang, Xiao-Fan] Duke Univ, Med Ctr, Durham, NC USA. [Korangy, Firouzeh] NCI, Gastrointestinal Malignancy Sect, Thorac & GI Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Korangy, F (reprint author), NIH, Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM korangyf@mail.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 1 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 NOV PY 2014 VL 60 IS 5 BP 1461 EP 1462 DI 10.1002/hep.27271 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6CM UT WOS:000344352400002 PM 24954163 ER PT J AU Wang, H Gao, B AF Wang, Hua Gao, Bin TI MicroRNAs Control Hepatocarcinogenesis by Regulating Hepatocyte Nuclear Factor 4 alpha-Inflammatory Signal Feedback Loops SO HEPATOLOGY LA English DT Editorial Material ID NF-KAPPA-B; HEPATOCELLULAR-CARCINOMA; DELETION C1 [Wang, Hua; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Wang, Hua] Anhui Med Univ, Inst Liver Dis, Hefei, Anhui, Peoples R China. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov FU Intramural NIH HHS [Z99 AA999999, ZIA AA000368-12, ZIA AA000369-12] NR 16 TC 2 Z9 2 U1 0 U2 1 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 NOV PY 2014 VL 60 IS 5 BP 1466 EP 1468 DI 10.1002/hep.27287 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6CM UT WOS:000344352400004 PM 24996014 ER PT J AU Ulahannan, SV Duffy, AG McNeel, TS Kish, JK Dickie, LA Rahma, OE McGlynn, KA Greten, TF Altekruse, SF AF Ulahannan, Susanna V. Duffy, Austin G. McNeel, Timothy S. Kish, Jonathan K. Dickie, Lois A. Rahma, Osama E. McGlynn, Katherine A. Greten, Tim F. Altekruse, Sean F. TI Earlier Presentation and Application of Curative Treatments in Hepatocellular Carcinoma SO HEPATOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; RADIOFREQUENCY ABLATION; SURGICAL RESECTION; UNITED-STATES; SURVEILLANCE; CIRRHOSIS; SURVIVAL; CHEMOEMBOLIZATION; METAANALYSIS; RATES AB The purpose of the study was to assess the use of curative therapies for hepatocellular carcinoma (HCC) in the population. HCC treatment patterns were examined in Surveillance, Epidemiology, and End Results (SEER) 18 registries (28% of U.S.). Joinpoint regression analyses were performed to assess 2000-2010 incidence trends by tumor size, count, and receipt of potentially curative treatments (transplantation, resection, and ablation). SEER-Medicare data enabled evaluation of treatment patterns including receipt of sorafenib or transarterial chemoembolization (TACE) by HCC-associated comorbidities. Diagnoses of tumors <= 5.0 cm in diameter significantly increased during 2000-2010, surpassing diagnosis of larger tumors. Overall, 23% of cases received potentially curative treatment. Joinpoint models indicated incidence rates of treatment with curative intent increased 17.6% per year during 2000-2005, then declined by -2.9% per year during 2005-2010 (P < 0.001). Among HCC cases with a single tumor <= 5.0 cm and no extension beyond the liver, use of ablative therapy significantly increased during 2000-2010. Use of invasive surgery for single tumors, regardless of size, significantly increased during the initial years of the decade, then plateaued. The group most likely to receive curative treatment in the SEER-Medicare cases was patients with one, small tumor confined to the liver (657 of 1,597 cases, 41%), with no difference in treatment by hepatic comorbidity status (P = 0.24). A higher proportion of cases with reported liver-associated comorbidities were, however, diagnosed with tumors <= 5.0 cm in diameter (1,745 0f 2,464, 71%) compared to patients with no reported comorbidities (996 of 2,596, 38%, P < 0.001). Conclusion: Although more HCC patients were diagnosed with early disease over time, the use of curative treatments in this patient group has recently plateaued. Efforts to identify and treat more eligible candidates for curative therapy could be beneficial. C1 [Ulahannan, Susanna V.; Duffy, Austin G.; Rahma, Osama E.; Greten, Tim F.] NCI, Gastrointestinal Malignancies Sect, Thorac & GI Oncol Branch, Bethesda, MD 20892 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Calverton, MD USA. [Kish, Jonathan K.; Dickie, Lois A.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Greten, TF (reprint author), NCI, 9000 Rockville Pike,Bldg 10 Room 12N226, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015; Ulahannan, Susanna/H-6525-2016 OI Greten, Tim/0000-0002-0806-2535; Ulahannan, Susanna/0000-0002-7234-2283 FU NIH, National Cancer Institute, National Cancer Institute FX Supported by the Intramural Research Program of the NIH, National Cancer Institute, National Cancer Institute contracts with SEER registries. NR 26 TC 19 Z9 20 U1 1 U2 4 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 NOV PY 2014 VL 60 IS 5 BP 1637 EP 1644 DI 10.1002/hep.27288 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6CM UT WOS:000344352400022 PM 24996116 ER PT J AU Yamashita, T Kitao, A Matsui, O Hayashi, T Nio, K Kondo, M Ohno, N Miyati, T Okada, H Yamashita, T Mizukoshi, E Honda, M Nakanuma, Y Takamura, H Ohta, T Nakamoto, Y Yamamoto, M Takayama, T Arii, S Wang, XW Kaneko, S AF Yamashita, Taro Kitao, Azusa Matsui, Osamu Hayashi, Takehiro Nio, Kouki Kondo, Mitsumasa Ohno, Naoki Miyati, Tosiaki Okada, Hikari Yamashita, Tatsuya Mizukoshi, Eishiro Honda, Masao Nakanuma, Yasuni Takamura, Hiroyuki Ohta, Tetsuo Nakamoto, Yasunari Yamamoto, Masakazu Takayama, Tadatoshi Arii, Shigeki Wang, XinWei Kaneko, Shuichi TI Gd-EOB-DTPA-Enhanced Magnetic Resonance Imaging and Alpha-Fetoprotein Predict Prognosis of Early-Stage Hepatocellular Carcinoma SO HEPATOLOGY LA English DT Article ID NUCLEAR FACTOR 4-ALPHA; CANCER STEM-CELLS; FORKHEAD BOX M1B; TRANSCRIPTION FACTOR; LIVER-CANCER; SIGNAL INTENSITY; EXPRESSION; FOXM1; FEATURES; THERAPY AB The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here we report that Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in combination with serum alpha-fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd-EOB-DTPA uptake in the hepatobiliary phase was observed in similar to 15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the upregulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd-EOB-DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd-EOB-DTPA uptake in vivo. HCC classification based on EOB-MRI and serum AFP levels predicted overall survival in a single-institution cohort (n = 70), and its prognostic utility was validated independently in a multi-institution cohort of early-stage HCCs (n = 109). Conclusion: This noninvasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging practices to improve management algorithms, especially in the early stage of disease. C1 [Yamashita, Taro] Kanazawa Univ, Grad Sch Med Sci, Dept Gen Med, Kanazawa, Ishikawa 9208641, Japan. [Yamashita, Taro; Hayashi, Takehiro; Nio, Kouki; Kondo, Mitsumasa; Okada, Hikari; Yamashita, Tatsuya; Mizukoshi, Eishiro; Honda, Masao; Kaneko, Shuichi] Kanazawa Univ, Grad Sch Med Sci, Dept Gastroenterol, Kanazawa, Ishikawa 9208641, Japan. [Kitao, Azusa; Matsui, Osamu] Kanazawa Univ, Grad Sch Med Sci, Dept Radiol, Kanazawa, Ishikawa 9208641, Japan. [Ohno, Naoki; Miyati, Tosiaki] Kanazawa Univ, Fac Hlth Sci, Inst Med Pharmaceut & Hlth Sci, Kanazawa, Ishikawa 9208641, Japan. [Nakanuma, Yasuni] Kanazawa Univ, Grad Sch Med Sci, Dept Pathol, Kanazawa, Ishikawa 9208641, Japan. [Takamura, Hiroyuki; Ohta, Tetsuo] Kanazawa Univ, Grad Sch Med Sci, Dept Surg Gastroenterol, Kanazawa, Ishikawa 9208641, Japan. [Nakamoto, Yasunari] Univ Fukui, Sch Med, Dept Internal Med 2, Fukui 910, Japan. [Yamamoto, Masakazu] Tokyo Womens Med Univ, Inst Gastroenterol, Dept Surg, Tokyo, Japan. [Takayama, Tadatoshi] Nihon Univ, Sch Med, Dept Digest Surg, Tokyo, Japan. [Arii, Shigeki] Tokyo Med & Dent Univ, Dept Hepatobiliary Pancreat Surg, Tokyo, Japan. [Wang, XinWei] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yamashita, T (reprint author), Kanazawa Univ, Grad Sch Med Sci, Dept Gastroenterol Gen Med, 13-1 Takara Machi, Kanazawa, Ishikawa 9208641, Japan. EM taroy@m-kanazawa.jp RI Wang, Xin/B-6162-2009 FU Health and Labor Sciences Research Grants for "Development of novel molecular markers and imaging modalities for earlier diagnosis of hepatocellular carcinoma"; Ministry of Education, Culture, Sports, Science, and Technology of Japan; National Cancer Center Research and Development Fund [23-B-5]; Center for Cancer Research, US National Cancer Institute [Z01 BC 010313] FX Supported by Health and Labor Sciences Research Grants for "Development of novel molecular markers and imaging modalities for earlier diagnosis of hepatocellular carcinoma," Grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the National Cancer Center Research and Development Fund (23-B-5), and the Intramural Research Program Grant (Z01 BC 010313) of the Center for Cancer Research, US National Cancer Institute. NR 37 TC 21 Z9 22 U1 2 U2 16 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 NOV PY 2014 VL 60 IS 5 BP 1674 EP 1685 DI 10.1002/hep.27093 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6CM UT WOS:000344352400025 PM 24700365 ER PT J AU Proctor, WR Chakraborty, M Fullerton, AM Korrapati, MC Ryan, PM Semple, K Morrison, JC Berkson, JD Chea, LS Yang, Q Li, AP Spolski, R West, EE Rochman, Y Leonard, WJ Bourdi, M Pohl, LR AF Proctor, William R. Chakraborty, Mala Fullerton, Aaron M. Korrapati, Midhun C. Ryan, Pauline M. Semple, Kenrick Morrison, Jeffrey C. Berkson, Julia D. Chea, Lynette S. Yang, Qian Li, Albert P. Spolski, Rosanne West, Erin E. Rochman, Yrina Leonard, Warren J. Bourdi, Mohammed Pohl, Lance R. TI Thymic Stromal Lymphopoietin and Interleukin-4 Mediate the Pathogenesis of Halothane-Induced Liver Injury in Mice SO HEPATOLOGY LA English DT Article ID T-CELLS; EOSINOPHILIC INFILTRATION; TH2 CYTOKINE; HEPATITIS-C; INFLAMMATION; EXPRESSION; MODEL; IL-4; INDUCTION; NECROSIS AB Liver eosinophilia has been associated with incidences of drug-induced liver injury (DILI) for more than 50 years, although its role in this disease has remained largely unknown. In this regard, it was recently shown that eosinophils played a pathogenic role in a mouse model of halothane-induced liver injury (HILI). However, the signaling events that drove hepatic expression of eosinophil-associated chemokines, eotaxins, eosinophil infiltration, and subsequent HILI were unclear. We now provide evidence implicating hepatic epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) and type 2 immunity, in particular, interleukin-4 (IL-4) production, in mediating hepatic eosinophilia and injury during HILI. TSLP was constitutively expressed by mouse hepatocytes and increased during HILI. Moreover, the severity of HILI was reduced in mice deficient in either the TSLP receptor (TSLPR) or IL-4 and was accompanied by decreases in serum levels of eotaxins and hepatic eosinophilia. Similarly, concanavalin A-induced liver injury, where type 2 cytokines and eosinophils play a significant role in its pathogenesis, was also reduced in TSLPR-deficient mice. Studies in vitro revealed that mouse and human hepatocytes produce TSLP and eotaxins in response to treatment with combinations of IL-4 and proinflammatory cytokines IL-1 beta and tumor necrosis factor alpha. Conclusion: This report provides the first evidence implicating roles for hepatic TSLP signaling, type 2 immunity, and eosinophilia in mediating liver injury caused by a drug. C1 [Proctor, William R.; Chakraborty, Mala; Fullerton, Aaron M.; Korrapati, Midhun C.; Ryan, Pauline M.; Semple, Kenrick; Morrison, Jeffrey C.; Berkson, Julia D.; Chea, Lynette S.; Bourdi, Mohammed; Pohl, Lance R.] NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Yang, Qian; Li, Albert P.] Vitro ADMET Labs, Columbia, MD USA. [Spolski, Rosanne; West, Erin E.; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Rochman, Yrina] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. RP Pohl, LR (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bldg 10,Room 8N110,10 Ctr Dr, Bethesda, MD 20892 USA. EM pohll@nih.gov FU National Institutes of Health; National Heart, Lung and Blood Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Heart, Lung and Blood Institute. NR 35 TC 6 Z9 6 U1 0 U2 1 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 NOV PY 2014 VL 60 IS 5 BP 1741 EP 1752 DI 10.1002/hep.27169 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6CM UT WOS:000344352400031 PM 24723460 ER PT J AU Hato, T Goyal, L Greten, TF Duda, DG Zhu, AX AF Hato, Tai Goyal, Lipika Greten, Tim F. Duda, Dan G. Zhu, Andrew X. TI Immune Checkpoint Blockade in Hepatocellular Carcinoma: Current Progress and Future Directions SO HEPATOLOGY LA English DT Review ID REGULATORY T-CELLS; PERCUTANEOUS ETHANOL INJECTION; SUPPRESSOR-CELLS; POSTOPERATIVE RECURRENCE; CTLA-4 BLOCKADE; LIVER; RESPONSES; PD-1; RECEPTOR; MOLECULES AB Immune checkpoint blockade has recently emerged as a promising therapeutic approach for various malignancies including hepatocellular carcinoma (HCC). Preclinical and clinical studies have shown the potential benefit of modulating the immunogenicity of HCC. In addition, recent advances in tumor immunology have broadened our understanding of the complex mechanism of immune evasion. In this review we summarize the current knowledge on HCC immunology and discuss the potential of immune checkpoint blockade as a novel HCC therapy from the basic, translational, and clinical perspectives. C1 [Hato, Tai; Duda, Dan G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Goyal, Lipika; Zhu, Andrew X.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. [Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. RP Duda, DG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. EM GDUDA@PARTNERS.ORG; AZHU@PARTNERS.ORG RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU National Institutes of Health [P01-CA080124, R01-CA159258, R21-CA139168]; National Cancer Institute/Proton Beam Federal Share Program award; American Cancer Society [120733-RSG-11-073-01-TBG]; Astellas Foundation for Research on Metabolic Disorders, Japan FX Supported by National Institutes of Health grants P01-CA080124, R01-CA159258, and R21-CA139168, a National Cancer Institute/Proton Beam Federal Share Program award, and the American Cancer Society grant 120733-RSG-11-073-01-TBG (to D. G. D.); and a Postdoctoral Fellowship from Astellas Foundation for Research on Metabolic Disorders, Japan (to T.H.). NR 62 TC 23 Z9 26 U1 3 U2 18 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 NOV PY 2014 VL 60 IS 5 BP 1776 EP 1782 DI 10.1002/hep.27246 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6CM UT WOS:000344352400034 PM 24912948 ER PT J AU Walia, V Prickett, TD Kim, JS Gartner, JJ Lin, JC Zhou, M Rosenberg, SA Elble, RC Solomon, DA Waldman, T Samuels, Y AF Walia, Vijay Prickett, Todd D. Kim, Jung-Sik Gartner, Jared J. Lin, Jimmy C. Zhou, Ming Rosenberg, Steven A. Elble, Randolph C. Solomon, David A. Waldman, Todd Samuels, Yardena TI Mutational and Functional Analysis of the Tumor-Suppressor PTPRD in Human Melanoma SO HUMAN MUTATION LA English DT Article DE desmoplakin; cell migration; somatic mutations; desmosomes ID LUNG ADENOCARCINOMA; COLORECTAL CANCERS; BREAST-CANCER; TYROSINE; DESMOSOMES; SUBSTRATE; KINASE; CELLS; IDENTIFICATION; GLIOBLASTOMA AB Protein tyrosine phosphatases (PTPs) tightly regulate tyrosine phosphorylation essential for cell growth, adhesion, migration, and survival. We performed a mutational analysis of the PTP gene family in cutaneous metastatic melanoma and identified 23 phosphatase genes harboring somatic mutations. Among these, receptor-type tyrosine-protein phosphatase delta (PTPRD) was one of the most highly mutated genes, harboring 17 somatic mutations in 79 samples, a prevalence of 21.5%. Functional evaluation of six PTPRD mutations revealed enhanced anchorage-dependent and anchorage-independent growth. Interestingly, melanoma cells expressing mutant PTPRD were significantly more migratory than cells expressing wild-type PTPRD or vector alone, indicating a novel gain-of-function associated with mutant PTPRD. To understand the molecular mechanisms of PTPRD mutations, we searched for its binding partners by converting the active PTPRD enzyme into a "substrate trap" form. Using mass spectrometry and coimmunoprecipitation, we report desmoplakin, a desmosomal protein that is implicated in cell-cell adhesion, as a novel PTPRD substrate. Further analysis showed reduced phosphatase activity of mutant PTPRD against desmoplakin. Our findings identify an essential signaling cascade that is disrupted in melanoma. Moreover, because PTPRD is also mutated in glioblastomas and adenocarcinoma of the colon and lung, our data might be applicable to a large number of human cancers. (C) 2014 Wiley Periodicals, Inc. C1 [Walia, Vijay; Prickett, Todd D.; Gartner, Jared J.; Lin, Jimmy C.; Samuels, Yardena] NHGRI, NIH, Bethesda, MD 20892 USA. [Kim, Jung-Sik; Solomon, David A.; Waldman, Todd] Georgetown Univ, Sch Med, Lombardi Canc Ctr, Dept Oncol, Washington, DC USA. [Zhou, Ming] Leidos Frederick Natl Lab Canc Res, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. [Rosenberg, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Elble, Randolph C.] So Illinois Univ, Springfield, IL USA. [Solomon, David A.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 St Rehovot, Israel. RP Samuels, Y (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, Wolfson Bldg,Room 534,POB 26,234 Herzl, IL-76100 St Rehovot, Israel. EM Yardena.samuels@weizmann.ac.il FU Intramural Research Programs of the National Human Genome Research Institute; National Cancer Institute; National Institutes of Health; The Harry J. Lloyd Charitable Trust; Gideon Hamburger; Israel Science Foundation [877/13]; ERC [St. G-335377]; [5R01CA115699] FX Contract grant sponsors: 5R01CA115699; Intramural Research Programs of the National Human Genome Research Institute; National Cancer Institute; National Institutes of Health; The Harry J. Lloyd Charitable Trust; Gideon Hamburger; Israel Science Foundation grant numbers 877/13; ERC (St. G-335377). NR 28 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2014 VL 35 IS 11 BP 1301 EP 1310 DI 10.1002/humu.22630 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AS6JM UT WOS:000344369900006 PM 25113440 ER PT J AU Flynn, EK Kamat, A Lach, FP Donovan, FX Kimble, DC Narisu, N Sanborn, E Boulad, F Davies, SM Gillio, AP Harris, RE MacMillan, ML Wagner, JE Smogorzewska, A Auerbach, AD Ostrander, EA Chandrasekharappa, SC AF Flynn, Elizabeth K. Kamat, Aparna Lach, Francis P. Donovan, Frank X. Kimble, Danielle C. Narisu, Narisu Sanborn, Erica Boulad, Farid Davies, Stella M. Gillio, Alfred P., III Harris, Richard E. MacMillan, Margaret L. Wagner, John E. Smogorzewska, Agata Auerbach, Arleen D. Ostrander, Elaine A. Chandrasekharappa, Settara C. TI Comprehensive Analysis of Pathogenic Deletion Variants in Fanconi Anemia Genes SO HUMAN MUTATION LA English DT Article DE Fanconi anemia; arrayCGH; FANCA; FANCB; FANCC; FANCD2 ID HAPLOTYPE RECONSTRUCTION; MUTATION; POPULATION; MECHANISM; ELEMENTS; REARRANGEMENTS; RECOMBINATION; UNDERLIES; FREQUENCY; DIAGNOSIS AB Fanconi anemia (FA) is a rare recessive disease resulting from mutations in one of at least 16 different genes. Mutation types and phenotypic manifestations of FA are highly heterogeneous and influence the clinical management of the disease. We analyzed 202 FA families for large deletions, using high-resolution comparative genome hybridization arrays, single-nucleotide polymorphism arrays, and DNA sequencing. We found pathogenic deletions in 88 FANCA, seven FANCC, two FANCD2, and one FANCB families. We find 35% of FA families carry large deletions, accounting for 18% of all FA pathogenic variants. Cloning and sequencing across the deletion breakpoints revealed that 52 FANCA deletion ends, and one FANCC deletion end extended beyond the gene boundaries, potentially affecting neighboring genes with phenotypic consequences. Seventy-five percent of the FANCA deletions are Alu-Alu mediated, predominantly by AluY elements, and appear to be caused by nonallelic homologous recombination. Individual Alu hotspots were identified. Defining the haplotypes of four FANCA deletions shared by multiple families revealed that three share a common ancestry. Knowing the exact molecular changes that lead to the disease may be critical for a better understanding of the FA phenotype, and to gain insight into the mechanisms driving these pathogenic deletion variants. (C) 2014 Wiley Periodicals, Inc. C1 [Flynn, Elizabeth K.; Kamat, Aparna; Kimble, Danielle C.; Ostrander, Elaine A.; Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Lach, Francis P.; Sanborn, Erica; Smogorzewska, Agata] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA. [Donovan, Frank X.; Narisu, Narisu] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Boulad, Farid] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Davies, Stella M.; Harris, Richard E.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Gillio, Alfred P., III] Hackensack UMC, Hackensack, NJ 07601 USA. [MacMillan, Margaret L.; Wagner, John E.] Univ Minnesota, Minneapolis, MN 55455 USA. [Auerbach, Arleen D.] Rockefeller Univ, Human Genet & Hematol Program, New York, NY 10065 USA. RP Chandrasekharappa, SC (reprint author), NHGRI, Canc Genet Branch, NIH, 50 South Dr,Bldg 50,Room 5232, Bethesda, MD 20892 USA. EM auerbac@mail.rockefeller.edu; chandra@mail.nih.gov OI Auerbach, Arleen/0000-0002-6911-8379; Ostrander, Elaine/0000-0001-6075-9738 FU NIH [R01 HL120922]; NCATS [UL1 TR000043]; NIH CTSA program; NHGRI Intramural Research Program, NIH; Anderson Cancer Center at the Rockefeller University, Burroughs Wellcome Fund Career Award for Medical Scientists; Fanconi Anemia Research Fund FX Contract grant sponsors: Grant R01 HL120922 from NIH, Grant #UL1 TR000043 from NCATS, NIH CTSA program, and NHGRI Intramural Research Program, NIH; Anderson Cancer Center at the Rockefeller University, Burroughs Wellcome Fund Career Award for Medical Scientists; Fanconi Anemia Research Fund. NR 37 TC 8 Z9 8 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2014 VL 35 IS 11 BP 1342 EP 1353 DI 10.1002/humu.22680 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AS6JM UT WOS:000344369900010 PM 25168418 ER PT J AU Hendriks, G Morolli, B Calleja, FMGR Plomp, A Mesman, RLS Meijers, M Sharan, SK Vreeswijk, MPG Vrieling, H AF Hendriks, Giel Morolli, Bruno Calleja, Fabienne M. G. R. Plomp, Anouk Mesman, Romy L. S. Meijers, Matty Sharan, Shyam K. Vreeswijk, Maaike P. G. Vrieling, Harry TI An Efficient Pipeline for the Generation and Functional Analysis of Human BRCA2 Variants of Uncertain Significance SO HUMAN MUTATION LA English DT Article DE BRCA2; VUS; functional testing; BAC recombineering; positive-negative selection ID GENETIC SUSCEPTIBILITY; BREAST-CANCER; ASSAY; MUTATIONS; CLASSIFICATION; MODEL AB The implementation of next-generation sequence analysis of disease-related genes has resulted in an increasing number of genetic variants with an unknown clinical significance. The functional analysis of these so-called "variants of uncertain significance" (VUS) is hampered by the tedious and time-consuming procedures required to generate and test specific sequence variants in genomic DNA. Here, we describe an efficient pipeline for the generation of gene variants in a full-length human gene, BRCA2, using a bacterial artificial chromosome. This method permits the rapid generation of intronic and exonic variants in a complete gene through the use of an exon-replacement strategy based on simple site-directed mutagenesis and an effective positive-negative selection system in E. coli. The functionality of variants can then be assessed through the use of functional assays, such as complementation of gene-deficient mouse-embryonic stem (mES) cells in the case of human BRCA2. Our methodology builds upon an earlier protocol and, through the introduction of a series of major innovations, now represents a practical proposition for the rapid analysis of BRCA2 variants and a blueprint for the analysis of other genes using similar approaches. This method enables rapid generation and reliable classification of VUS in disease-related genes, allowing informed clinical decision-making. (C) 2014 Wiley Periodicals, Inc. C1 [Hendriks, Giel; Morolli, Bruno; Calleja, Fabienne M. G. R.; Plomp, Anouk; Mesman, Romy L. S.; Meijers, Matty; Vreeswijk, Maaike P. G.; Vrieling, Harry] Leiden Univ, Med Ctr, Dept Toxicogenet, NL-2300 RC Leiden, Netherlands. [Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Vreeswijk, Maaike P. G.] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. RP Vrieling, H (reprint author), Leiden Univ, Med Ctr, Dept Toxicogenet, Postal Zone S4-P,POB 9600, NL-2300 RC Leiden, Netherlands. EM h.vrieling@lumc.nl FU Dutch Cancer Society KWF [UL2012-5649] FX Contract grant sponsors: Dutch Cancer Society KWF (UL2012-5649). NR 18 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2014 VL 35 IS 11 BP 1382 EP 1391 DI 10.1002/humu.22678 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AS6JM UT WOS:000344369900014 PM 25146914 ER PT J AU Vannucci, A Tanofsky-Kraff, M Ranzenhofer, LM Kelly, NR Hannallah, LM Pickworth, CK Grygorenko, MV Brady, SM Condarco, TA Kozlosky, M Demidowich, AP Yanovski, SZ Shomaker, LB Yanovski, JA AF Vannucci, Anna Tanofsky-Kraff, Marian Ranzenhofer, Lisa M. Kelly, Nichole R. Hannallah, Louise M. Pickworth, C. Katie Grygorenko, Mariya V. Brady, Sheila M. Condarco, Tania A. Kozlosky, Merel Demidowich, Andrew P. Yanovski, Susan Z. Shomaker, Lauren B. Yanovski, Jack A. TI Puberty and the Manifestations of Loss of Control Eating in Children and Adolescents SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE loss of control eating; binge eating; puberty; body image; weight and shape concern; eating disorders ID OVERWEIGHT CHILDREN; ENERGY-INTAKE; DISORDER EXAMINATION; YOUNG ADULTHOOD; SCHOOL-CHILDREN; RISK-FACTORS; BODY-FAT; BEHAVIORS; OBESITY; GIRLS AB Objective: We investigated the manifestations of pediatric loss of control (LOC) eating at different stages of pubertal development. Method: Participants were a nonclinical sample of 468 youth (8-17 years). Physical examination determined pubertal stage. LOC eating and disordered eating attitudes were assessed with the Eating Disorder Examination. In a randomized crossover design, a subset (n = 244) ate ad libitum from two test meals designed to capture normal and LOC eating. Results: There were no differences in the prevalence rates or frequency of reported LOC eating episodes across pubertal stages (ps >= 0.50). There were, however, puberty by LOC eating interactions in disordered eating attitudes and palatable food consumption (ps <= .05), even after adjusting for age and body composition. LOC eating was associated with elevated global disordered eating attitudes, weight concern, and shape concern in post-pubertal youth (ps <= .001), but not pre-pubertal youth (ps >= .49). In late-puberty, youth with LOC eating consumed less energy from protein p < .001) and more from carbohydrate (p = .003) and snack-type foods (p = .02) than those without LOC eating, whereas endorsement of LOC eating in pre- or early-to-mid-puberty was not associated with differences in eating behavior (ps >= 0.20). Conclusions: Findings suggest that puberty may be a critical risk period, when LOC eating behaviors in boys and girls may become accompanied by greater weight and shape concerns and more obesogenic food consumption patterns. Interventions for LOC eating during pre-puberty should be evaluated to determine if they are particularly beneficial for the prevention of exacerbated eating disorder psychopathology and adverse weight outcomes. (C) 2014 Wiley Periodicals, Inc. C1 [Vannucci, Anna; Tanofsky-Kraff, Marian; Ranzenhofer, Lisa M.; Kelly, Nichole R.; Hannallah, Louise M.; Shomaker, Lauren B.] USUHS, Dept Med & Clin Psychol, DoD, Bethesda, MD 20814 USA. [Vannucci, Anna; Tanofsky-Kraff, Marian; Ranzenhofer, Lisa M.; Kelly, Nichole R.; Hannallah, Louise M.; Pickworth, C. Katie; Grygorenko, Mariya V.; Brady, Sheila M.; Condarco, Tania A.; Demidowich, Andrew P.; Yanovski, Susan Z.; Shomaker, Lauren B.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20814 USA. [Kozlosky, Merel] NIH, Dept Nutr, Ctr Clin, DHHS, Bethesda, MD 20814 USA. [Yanovski, Susan Z.] Natl Inst Diabet & Digest & Kidney Dis NIDDK, Div Digest Dis & Nutr, NIH, DHHS, Bethesda, MD 20814 USA. RP Yanovski, JA (reprint author), NICHD, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,Hatfield Clin Res Ctr, 10 Ctr Dr,Room 1E-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU USUHS [R072IC]; Intramural Research Program, NIH [1ZIAHD000641]; Bench to Bedside Program [F31MH095348]; Office of Behavioral and Social Sciences Research (OBSSR) of the NIH; NICHD FX Supported by R072IC from USUHS; by 1ZIAHD000641 from Intramural Research Program, NIH; by F31MH095348 from Bench to Bedside Program and the Office of Behavioral and Social Sciences Research (OBSSR) of the NIH; and from the NICHD. NR 59 TC 4 Z9 6 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD NOV PY 2014 VL 47 IS 7 SI SI BP 738 EP 747 DI 10.1002/eat.22305 PG 10 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA AS6CO UT WOS:000344352600009 PM 24888295 ER PT J AU Clarke, DF Acosta, EP Rizk, ML Bryson, YJ Spector, SA Mofenson, LM Handelsman, E Teppler, H Welebob, C Persaud, D Cababasay, MP Wang, JJ Mirochnick, M AF Clarke, Diana F. Acosta, Edward P. Rizk, Matthew L. Bryson, Yvonne J. Spector, Stephen A. Mofenson, Lynne M. Handelsman, Edward Teppler, Hedy Welebob, Carolee Persaud, Deborah Cababasay, Mae P. Wang, JiaJia Mirochnick, Mark CA Int Maternal Pediat Adolescent TI Raltegravir Pharmacokinetics in Neonates Following Maternal Dosing SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE raltegravir pharmacokinetics; neonates ID TRANSPLACENTAL TRANSFER; BILIRUBIN; REGIMENS; MOTHER; PLASMA AB International Maternal Pediatric Adolescent AIDS Clinical Trials P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-infected pregnant women receiving raltegravir-based antiretroviral therapy. Twenty-two mother-infant pairs were enrolled; evaluable pharmacokinetic data were available from 19 mother-infant pairs. Raltegravir readily crossed the placenta, with a median cord blood/maternal delivery plasma raltegravir concentration ratio of 1.48 (range, 0.32-4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t(1/2) 26.6 (range, 9.3-184) hours]. Prolonged raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive raltegravir concentrations must be avoided in the neonate because raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Subtherapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must also be avoided. Two ongoing International Maternal Pediatric Adolescent AIDS Clinical Trials studies are further investigating the pharmacology of raltegravir in neonates. C1 [Clarke, Diana F.] Boston Med Ctr, Sect Pediat Infect Dis, Boston, MA USA. [Acosta, Edward P.] Univ Alabama Birmingham, Div Clin Pharmacol, Birmingham, AL 35294 USA. [Rizk, Matthew L.; Teppler, Hedy; Welebob, Carolee] Merck & Co Inc, Whitehouse Stn, NJ USA. [Bryson, Yvonne J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat Infect Dis, Los Angeles, CA 90095 USA. [Spector, Stephen A.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Spector, Stephen A.] Rady Childrens Hosp San Diego, La Jolla, CA USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Handelsman, Edward] NIH, Div AIDS, Bethesda, MD 20892 USA. [Persaud, Deborah] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Cababasay, Mae P.; Wang, JiaJia] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Mirochnick, Mark] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. RP Clarke, DF (reprint author), Boston Univ, Sch Med, Boston Med Ctr, Sect Pediat Infect Dis,Dept Pediat, 670 Albany St,6th Floor, Boston, MA 02118 USA. EM diana.clarke@bmc.org FU International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT); National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID [1 U01 AI068616]; IMPAACT Group; NICHD [N01-DK-9-001/HHSN267200800001C] FX Supported by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT). Overall support for IMPAACT was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632); and the Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID cooperative agreement #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number: N01-DK-9-001/HHSN267200800001C). NR 15 TC 8 Z9 8 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV 1 PY 2014 VL 67 IS 3 BP 310 EP 315 DI 10.1097/QAI.0000000000000316 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AS6GC UT WOS:000344361400015 PM 25162819 ER PT J AU Sturke, R Harmston, C Simonds, RJ Mofenson, LM Siberry, GK Watts, DH McIntyre, J Anand, N Guay, L Castor, D Brouwers, P Nagel, JD AF Sturke, Rachel Harmston, Christine Simonds, R. J. Mofenson, Lynne M. Siberry, George K. Watts, D. Heather McIntyre, James Anand, Nalini Guay, Laura Castor, Delivette Brouwers, Pim Nagel, Joan D. TI A Multi-Disciplinary Approach to Implementation Science: The NIH-PEPFAR PMTCT Implementation Science Alliance SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; AIDS; PMTCT; implementation science; PEPFAR ID TO-CHILD TRANSMISSION; HIV AB In resource-limited countries, interventions to prevent mother-to-child HIV transmission (PMTCT) have not yet realized their full potential health impact, illustrating the common gap between the scientific proof of an intervention's efficacy and effectiveness and its successful implementation at scale into routine health services. For PMTCT, this gap results, in part, from inadequate adaptation of PMTCT interventions to the realities of the implementation environment, including client and health care worker behaviors and preferences, health care policies and systems, and infrastructure and resource constraints. Elimination of mother-to-child HIV transmission can only be achieved through understanding of key implementation barriers and successful adaptation of scientifically proven interventions to the local environment. Central to such efforts is implementation science (IS), which aims to investigate and address major bottlenecks that impede effective implementation and to test new approaches to identifying, understanding, and overcoming barriers to the adoption, adaptation, integration, scale-up, and sustainability of evidence-based interventions. Advancing IS will require deliberate and strategic efforts to facilitate collaboration, communication, and relationship-building among researchers, implementers, and policy-makers. To speed the translation of effective PMTCT interventions into practice and advance IS more broadly, the US National Institutes of Health, in collaboration with the President's Emergency Plan for AIDS Relief launched the National Institutes of Health/President's Emergency Plan for AIDS Relief PMTCT IS Alliance, comprised of IS researchers, PMTCT program implementers, and policy-makers as an innovative platform for interaction and coordination. C1 [Sturke, Rachel; Harmston, Christine; Anand, Nalini] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonds, R. J.; Guay, Laura] Elizabeth Glaser Pediat AIDS Fdn, Washington, DC USA. [Mofenson, Lynne M.; Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Watts, D. Heather; Castor, Delivette] US Dept State, Off US Global AIDS Coordinator, Washington, DC 20520 USA. [McIntyre, James] Anova Hlth Inst, Johannesburg, South Africa. [Brouwers, Pim] NIMH, NIH, Bethesda, MD 20892 USA. [Nagel, Joan D.] NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. RP Sturke, R (reprint author), NIH, Div Int Sci Policy Planning & Evaluat, Fogarty Int Ctr, 16 Ctr Dr,MSC 6705, Bethesda, MD 20892 USA. EM rachel.sturke@nih.gov NR 6 TC 13 Z9 13 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV 1 PY 2014 VL 67 SU 2 BP S163 EP S167 DI 10.1097/QAI.0000000000000323 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AS5ZO UT WOS:000344345100011 PM 25310124 ER PT J AU Brooks-Russell, A Simons-Morton, B Ehsani, J AF Brooks-Russell, Ashley Simons-Morton, Bruce Ehsani, Johnathon TI Parents Are the Key to Improving Teen Driving Safety SO JOURNAL OF ADOLESCENT HEALTH LA English DT Editorial Material ID NOVICE DRIVERS; CRASHES; INVOLVEMENT C1 [Brooks-Russell, Ashley] Univ Colorado Denver, Colorado Sch Publ Hlth, Aurora, CO 80045 USA. [Simons-Morton, Bruce; Ehsani, Johnathon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, NIH, Bethesda, MD USA. RP Brooks-Russell, A (reprint author), Univ Colorado Denver, Colorado Sch Publ Hlth, Aurora, CO 80045 USA. OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 12 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD NOV PY 2014 VL 55 IS 5 BP 600 EP 601 DI 10.1016/j.jadohealth.2014.08.008 PG 2 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA AS4IA UT WOS:000344236300003 PM 25344032 ER PT J AU Saggio, I Remoli, C Spica, E Cersosimo, S Sacchetti, B Robey, PG Holmbeck, K Cumano, A Boyde, A Bianco, P Riminucci, M AF Saggio, Isabella Remoli, Cristina Spica, Emanuela Cersosimo, Stefania Sacchetti, Benedetto Robey, Pamela G. Holmbeck, Kenn Cumano, Ana Boyde, Alan Bianco, Paolo Riminucci, Mara TI Constitutive Expression of Gs alpha(R201C) in Mice Produces a Heritable, Direct Replica of Human Fibrous Dysplasia Bone Pathology and Demonstrates Its Natural History SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE FIBROUS DYSPLASIA; GS-ALPHA; GNAS; GENETIC SKELETAL DISEASES; MOUSE MODELS ID MCCUNE-ALBRIGHT-SYNDROME; STIMULATORY G-PROTEIN; EMBRYONIC STEM-CELLS; ACTIVE GS-ALPHA; ACTIVATING MUTATIONS; PAMIDRONATE TREATMENT; SKELETAL PROGENITORS; COUPLED RECEPTOR; TRABECULAR BONE; GNAS1 GENE AB Fibrous dysplasia of bone (FD) is a crippling skeletal disease associated with postzygotic mutations (R201C, R201H) of the gene encoding the subunit of the stimulatory G protein, Gs. By causing a characteristic structural subversion of bone and bone marrow, the disease results in deformity, hypomineralization, and fracture of the affected bones, with severe morbidity arising in childhood or adolescence. Lack of inheritance of the disease in humans is thought to reflect embryonic lethality of germline-transmitted activating Gs mutations, which would only survive through somatic mosaicism. We have generated multiple lines of mice that express Gs(R201C) constitutively and develop an inherited, histopathologically exact replica of human FD. Robust transgene expression in neonatal and embryonic tissues and embryonic stem (ES) cells were associated with normal development of skeletal tissues and differentiation of skeletal cells. As in humans, FD lesions in mice developed only in the postnatal life; a defined spatial and temporal pattern characterized the onset and progression of lesions across the skeleton. In individual bones, lesions developed through a sequence of three distinct histopathological stages: a primary modeling phase defined by endosteal/medullary excess bone formation and normal resorption; a secondary phase, with excess, inappropriate remodeling; and a tertiary fibrous dysplastic phase, which reproduced a full-blown replica of the human bone pathology in mice of age 1 year. Gs mutations are sufficient to cause FD, and are per se compatible with germline transmission and normal embryonic development in mice. Our novel murine lines constitute the first model of FD. (c) 2014 American Society for Bone and Mineral Research. C1 [Saggio, Isabella] Univ Roma La Sapienza, Dept Biol & Biotechnol C Darwin, I-00161 Rome, Italy. [Saggio, Isabella] IBPM CNR, Rome, Italy. [Remoli, Cristina; Spica, Emanuela; Cersosimo, Stefania; Sacchetti, Benedetto; Bianco, Paolo; Riminucci, Mara] Univ Roma La Sapienza, Dept Mol Med, I-00161 Rome, Italy. [Robey, Pamela G.; Holmbeck, Kenn] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Cumano, Ana] Inst Pasteur, Lymphopoiesis Unit, Paris, France. [Boyde, Alan] Queen Mary Univ, Inst Dent, London, England. RP Bianco, P (reprint author), Univ Roma La Sapienza, Dept Mol Med, Viale Regina Elena 324, I-00161 Rome, Italy. EM paolo.bianco@uniroma1.it RI Robey, Pamela/H-1429-2011; OI Robey, Pamela/0000-0002-5316-5576; saggio, isabella/0000-0002-9497-7415 FU Telethon [GGP09227]; Fondazione Roma; Istituto Pasteur-Fondazione Cenci-Bolognetti; MIUR; EU (PLURIMES); EU FP7 Brainvectors [286071]; Division of Intramural Research, NIDCR, a part of the Intramural Research Program of the NIH, DHHS FX Supported by grants from Telethon (GGP09227) to PB, from Fondazione Roma to PB and MR, from Istituto Pasteur-Fondazione Cenci-Bolognetti to PB, and from MIUR and EU (PLURIMES) to PB. Funding for IS was supported by EU FP7 Brainvectors no. 286071. Funding for PGR and KH was supported by the Division of Intramural Research, NIDCR, a part of the Intramural Research Program of the NIH, DHHS. NR 46 TC 10 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD NOV PY 2014 VL 29 IS 11 BP 2357 EP 2368 DI 10.1002/jbmr.2267 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS4DF UT WOS:000344222800006 PM 24764158 ER PT J AU Gamsjaeger, S Srivastava, AK Wergedal, JE Zwerina, J Klaushofer, K Paschalis, EP Tatakis, DN AF Gamsjaeger, Sonja Srivastava, Apurva K. Wergedal, Jon E. Zwerina, Jochen Klaushofer, Klaus Paschalis, Eleftherios P. Tatakis, Dimitris N. TI Altered Bone Material Properties in HLA-B27 Rats Include Reduced Mineral to Matrix Ratio and Altered Collagen Cross-Links SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE Genetic animal models; Collagen; Matrix mineralization ID INFLAMMATORY-BOWEL-DISEASE; GLYCATION END-PRODUCTS; ILIAC CREST BIOPSIES; X-RAY-SCATTERING; TRANSGENIC RATS; RAMAN MICROSPECTROSCOPY; ANKYLOSING-SPONDYLITIS; PERIODONTAL-DISEASE; BRUCHS MEMBRANE; NONENZYMATIC GLYCATION AB Spondyloarthropathy and inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, are often associated with severe osteopenia/osteoporosis in both children and adults. HLA-B27 transgenic rats present a phenotype that includes severe colitis and severely accelerated alveolar bone loss. The purpose of this study was to evaluate long bone density status, systemic bone metabolic markers, and intrinsic bone material properties in HLA-B27 transgenic (TG) rats, and compare them with those of age- and sex-matched wild-type (WT) animals. The results indicate that in the HLA-B27 rat, an animal susceptible to both alveolar bone loss (ABL) and long bone osteopenia, there is a statistically significant negative correlation between ABL and long bone bone mineral density (BMD), as well as mineral/matrix ratio at active bone-forming trabecular surfaces. The TG animals had a lower mineral/matrix ratio and higher relative proteoglycan and advanced glycation end product (E-N-Carboxymethyl-L-lysine) content and pyridinoline/divalent collagen cross-link ratio compared with WT. These results may provide better understanding of the interrelationship between osteoporosis and oral bone loss, the underlying causes of the inferior bone strength in the HLA-B27 transgenic animals, and could prove to be a useful model in the elucidation of the pathophysiology of spondyloarthropathy and IBD-associated osteopenia/osteoporosis and in the evaluation of pharmacological intervention(s) against such conditions. (c) 2014 American Society for Bone and Mineral Research. C1 [Gamsjaeger, Sonja; Zwerina, Jochen; Klaushofer, Klaus; Paschalis, Eleftherios P.] Hanusch Hosp WGKK, Ludwig Boltzmann Inst Osteol, Vienna, Austria. [Gamsjaeger, Sonja; Zwerina, Jochen; Klaushofer, Klaus; Paschalis, Eleftherios P.] Hanusch Hosp, Dept Med 1, AUVA Trauma Ctr Meidling, Vienna, Austria. [Srivastava, Apurva K.] Leidos Biomed Natl Canc Inst, Lab Human Toxicol & Pharmacol, Appl Dev Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA. [Wergedal, Jon E.] Jerry L Pettis VA Med Ctr, Musculoskeletal Dis Ctr, Loma Linda, CA USA. [Tatakis, Dimitris N.] Ohio State Univ, Coll Dent, Div Periodontol, Columbus, OH 43210 USA. RP Paschalis, EP (reprint author), Hanusch Hosp, Ludwig Boltzmann Inst Osteol, Heinrich Collin Str 30, A-1140 Vienna, Austria. EM eleftherios.paschalis@osteologie.at OI Gamsjaeger, Sonja/0000-0002-9543-6530 FU Allgemeine Unfallversicherungsanstalt (AUVA), research funds of the Austrian workers compensation board; Wiener Gebietskrankenkasse (WGKK), Viennese sickness insurance funds; Division of Periodontology, The Ohio State University FX The authors thank the Jerry L Pettis VA Medical Center for use of their laboratory research facilities. The present study was supported by Allgemeine Unfallversicherungsanstalt (AUVA), research funds of the Austrian workers compensation board; Wiener Gebietskrankenkasse (WGKK), Viennese sickness insurance funds; and the Division of Periodontology, The Ohio State University. NR 71 TC 3 Z9 3 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD NOV PY 2014 VL 29 IS 11 BP 2382 EP 2391 DI 10.1002/jbmr.2268 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS4DF UT WOS:000344222800008 PM 24771481 ER PT J AU Sinha, P Aarnisalo, P Chubb, R Ono, N Fulzele, K Selig, M Saeed, H Chen, M Weinstein, LS Pajevic, PD Kronenberg, HM Wu, JY AF Sinha, Partha Aarnisalo, Piia Chubb, Rhiannon Ono, Noriaki Fulzele, Keertik Selig, Martin Saeed, Hamid Chen, Min Weinstein, Lee S. Pajevic, Paola Divieti Kronenberg, Henry M. Wu, Joy Y. TI Loss of G(s)alpha Early in the Osteoblast Lineage Favors Adipogenic Differentiation of Mesenchymal Progenitors and Committed Osteoblast Precursors SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE OSTEOBLASTS; G(S)A; MESENCHYMAL PROGENITORS; ADIPOCYTES ID HEMATOPOIETIC STEM-CELLS; RECEPTOR-RELATED PROTEIN-5; BONE-MARROW FAT; PARATHYROID-HORMONE; ADIPOCYTE DIFFERENTIATION; PPAR-GAMMA; TARGETED DISRUPTION; ANOREXIA-NERVOSA; TRABECULAR BONE; LEAN PHENOTYPE AB In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit G(s) activates protein kinase A signaling downstream of several G protein-coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of G(s) in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage. (c) 2014 American Society for Bone and Mineral Research C1 [Sinha, Partha; Aarnisalo, Piia; Chubb, Rhiannon; Ono, Noriaki; Fulzele, Keertik; Pajevic, Paola Divieti; Kronenberg, Henry M.; Wu, Joy Y.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Aarnisalo, Piia] Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland. [Aarnisalo, Piia] Univ Helsinki, Cent Hosp, Hosp Dist Helsinki & Uusimaa, Lab Serv HUSLAB, Helsinki, Finland. [Selig, Martin] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Saeed, Hamid; Wu, Joy Y.] Stanford Univ, Sch Med, Div Endocrinol, Stanford, CA 94305 USA. [Chen, Min; Weinstein, Lee S.] NIDDK, Metabol Dis Branch, Bethesda, MD USA. RP Wu, JY (reprint author), Stanford Univ, Sch Med, 300 Pasteur Dr,Room S-025, Stanford, CA 94305 USA. EM jywu1@stanford.edu FU MGH Executive Committee on Research; Harvard Stem Cell Institute; National Institutes of Health [AR054741, AR059942]; Ruth Kirschstein NRSA [DK11794, AR060211]; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program FX This work was supported by the MGH Executive Committee on Research (JYW), the Harvard Stem Cell Institute (JYW), and National Institutes of Health grants AR054741 and AR059942 to JYW; Ruth Kirschstein NRSA to PS; DK11794 to HMK; AR060211 to PDP; and by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (MC and LSW). NR 86 TC 8 Z9 8 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD NOV PY 2014 VL 29 IS 11 BP 2414 EP 2426 DI 10.1002/jbmr.2270 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS4DF UT WOS:000344222800011 PM 24806274 ER PT J AU Yuen, M Sandaradura, SA Dowling, JJ Kostyukova, AS Moroz, N Quinlan, KG Lehtokari, VL Ravenscroft, G Todd, EJ Ceyhan-Birsoy, O Gokhin, DS Maluenda, J Lek, M Nolent, F Pappas, CT Novak, SM D'Amico, A Malfatti, E Thomas, BP Gabriel, SB Gupta, N Daly, MJ Ilkovski, B Houweling, PJ Davidson, AE Swanson, LC Brownstein, CA Gupta, VA Medne, L Shannon, P Martin, N Bick, DP Flisberg, A Holmberg, E Van den Bergh, P Lapunzina, P Waddell, LB Sioboda, DD Bertini, E Chitayat, D Telfer, WR Laquerriere, A Gregorio, CC Ottenheijm, CAC Bonnemann, CG Pelin, K Beggs, AH Hayashi, YK Romero, NB Laing, NG Nishino, I Wallgren-Pettersson, C Melki, J Fowler, VM MacArthur, DG North, KN Clarke, NF AF Yuen, Michaele Sandaradura, Sarah A. Dowling, James J. Kostyukova, Alla S. Moroz, Natalia Quinlan, Kate G. Lehtokari, Vilma-Lotta Ravenscroft, Gianina Todd, Emily J. Ceyhan-Birsoy, Ozge Gokhin, David S. Maluenda, Jerome Lek, Monkol Nolent, Flora Pappas, Christopher T. Novak, Stefanie M. D'Amico, Adele Malfatti, Edoardo Thomas, Brett P. Gabriel, Stacey B. Gupta, Namrata Daly, Mark J. Ilkovski, Biljana Houweling, Peter J. Davidson, Ann E. Swanson, Lindsay C. Brownstein, Catherine A. Gupta, Vandana A. Medne, Livija Shannon, Patrick Martin, Nicole Bick, David P. Flisberg, Anders Holmberg, Eva Van den Bergh, Peter Lapunzina, Pablo Waddell, Leigh B. Sioboda, Darcee D. Bertini, Enrico Chitayat, David Telfer, William R. Laquerriere, Annie Gregorio, Carol C. Ottenheijm, Coen A. C. Boennemann, Carsten G. Pelin, Katarina Beggs, Alan H. Hayashi, Yukiko K. Romero, Norma B. Laing, Nigel G. Nishino, Ichizo Wallgren-Pettersson, Carina Melki, Judith Fowler, Velia M. MacArthur, Daniel G. North, Kathryn N. Clarke, Nigel F. TI Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MUSCLE ALPHA-TROPOMYOSIN; SKELETAL-MUSCLE; POINTED-END; N-TERMINUS; ACTIN; TROPOMODULIN; MUTATIONS; LENGTH; POLYMERIZATION; DEFICIENCY AB Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of Imod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle. C1 [Yuen, Michaele; Sandaradura, Sarah A.; Quinlan, Kate G.; Ilkovski, Biljana; Houweling, Peter J.; Waddell, Leigh B.; North, Kathryn N.; Clarke, Nigel F.] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW, Australia. [Yuen, Michaele; Sandaradura, Sarah A.; Quinlan, Kate G.; Houweling, Peter J.; Waddell, Leigh B.; Clarke, Nigel F.] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Dowling, James J.; Davidson, Ann E.; Telfer, William R.] Univ Michigan, Med Ctr, Dept Pediat, Ann Arbor, MI 48109 USA. [Dowling, James J.; Davidson, Ann E.; Telfer, William R.] Univ Michigan, Med Ctr, Dept Neurol, Ann Arbor, MI 48109 USA. [Dowling, James J.; Davidson, Ann E.] Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada. [Dowling, James J.; Davidson, Ann E.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Kostyukova, Alla S.; Moroz, Natalia] Washington State Univ, Gene & Linda Voiland Sch Chem Engn & Bioengn, Pullman, WA 99164 USA. [Lehtokari, Vilma-Lotta; Wallgren-Pettersson, Carina] Univ Helsinki, Folkhalsan Inst Genet, Haartman Inst, Helsinki, Finland. [Lehtokari, Vilma-Lotta; Wallgren-Pettersson, Carina] Univ Helsinki, Haartman Inst, Dept Med Genet, Helsinki, Finland. [Ravenscroft, Gianina; Todd, Emily J.; Laing, Nigel G.] Univ Western Australia, Western Australia Inst Med Res, Nedlands, WA 6009, Australia. [Ravenscroft, Gianina; Todd, Emily J.; Laing, Nigel G.] Univ Western Australia, Med Res Ctr, Nedlands, WA 6009, Australia. [Ceyhan-Birsoy, Ozge; Swanson, Lindsay C.; Brownstein, Catherine A.; Gupta, Vandana A.; Beggs, Alan H.] Harvard Univ, Boston Childrens Hosp, Sch Med, Div Genet & Genom,Manton Ctr Orphan Dis Res, Boston, MA USA. [Gokhin, David S.; Fowler, Velia M.] Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA 92037 USA. [Maluenda, Jerome; Nolent, Flora; Melki, Judith] INSERM, Unite Mixte Rech 788, F-94275 Le Kremlin Bicetre, France. [Maluenda, Jerome; Nolent, Flora; Melki, Judith] Univ Paris, Le Kremlin Bicetre, France. [Lek, Monkol; Thomas, Brett P.; Daly, Mark J.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; Thomas, Brett P.; Gabriel, Stacey B.; Gupta, Namrata; Daly, Mark J.; MacArthur, Daniel G.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Pappas, Christopher T.; Novak, Stefanie M.; Gregorio, Carol C.] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ USA. [D'Amico, Adele; Bertini, Enrico] Bambino Gesu Pediat Hosp, Lab Mol Med Neuromuscular & Neurodegenerat Dis, Rome, Italy. [Malfatti, Edoardo; Romero, Norma B.] Grp Hosp Univ La Pitie Salpetriere, Inst Myol, Neuromuscular Morphol Unit, Paris, France. [Houweling, Peter J.; North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Medne, Livija] Childrens Hosp Philadelphia, Div Human Genet & Neurol, Philadelphia, PA 19104 USA. [Shannon, Patrick] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5G 1X5, Canada. [Martin, Nicole; Chitayat, David] Univ Toronto, Mt Sinai Hosp, Dept Obstet & Gynaecol, Prenatal Diag & Med Genet Program, Toronto, ON M5G 1X5, Canada. [Bick, David P.] Med Coll Wisconsin, Dept Pediat, Genet Sect, Milwaukee, WI 53226 USA. [Bick, David P.] Med Coll Wisconsin, Ctr Mol Genet, Milwaukee, WI 53226 USA. [Flisberg, Anders] Sahlgrens Univ Hosp, Dept Neonatol, Gothenburg, Sweden. [Holmberg, Eva] Sahlgrens Univ Hosp, Dept Clin Genet, Gothenburg, Sweden. [Van den Bergh, Peter] St Luc Univ Hosp, Neuromuscular Reference Ctr, Brussels, Belgium. [Lapunzina, Pablo] Hosp Univ La Paz, Inst Invest Sanitaria, Inst Genet Med & Mol, Madrid, Spain. [Lapunzina, Pablo] Univ Autonoma Madrid, Madrid, Spain. [Lapunzina, Pablo] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain. [Sioboda, Darcee D.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Chitayat, David] Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Med Genet, Toronto, ON M5G 1X8, Canada. [Laquerriere, Annie] Univ Rouen, Pathol Lab, Rouen, France. [Laquerriere, Annie] Univ Rouen, NeoVasc Reg INSERM Team ERI28, Rouen, France. [Ottenheijm, Coen A. C.] Vrije Univ Amsterdam, Med Ctr, Inst Cardiovasc Res, Dept Physiol, Amsterdam, Netherlands. [Boennemann, Carsten G.] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. [Pelin, Katarina] Univ Helsinki, Dept Biosci, Helsinki, Finland. [Hayashi, Yukiko K.] Tokyo Med Univ, Dept Neurophysiol, Tokyo 1608402, Japan. [Hayashi, Yukiko K.; Nishino, Ichizo] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Neuromuscular Res, Tokyo, Japan. [Melki, Judith] Ctr Hosp Sud Francilien, Unite Genet Med, Corbel Essonnes, France. [North, Kathryn N.] Univ Melbourne, Dept Paediat, Melbourne, Vic 3010, Australia. RP North, KN (reprint author), Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia. EM kathryn.north@mcri.edu.au RI d'amico, adele/J-9203-2016; North, Kathryn/K-6476-2012; Houweling, Peter/B-4157-2016; OI d'amico, adele/0000-0003-2438-2624; North, Kathryn/0000-0003-0841-8009; Houweling, Peter/0000-0001-6132-2554; Pelin, Katarina/0000-0002-7040-7266 FU National Health and Medical Research Council of Australia [1022707, 1031893, 1035828, 1035955, 0511981, 1002147, 1075451]; Association Francaise contre les Myopathies [15734, DAJ1891]; National Hospital Clinical Research Program [A0M10181]; National Institute of Child Health and Development of the NIH [R01 HD 075802]; Muscular Dystrophy Association (USA) [MDA201302]; AUism Charitable Foundation; National Institute on Aging [AG000114]; University of Sydney Australian Postgraduate Award; International Postgraduate Research Scholarship; University of Western Australia Postgraduate Award; Dubai-Harvard Foundation for Medical Research postdoctoral fellowship; Schlumberger Foundation Faculty; Italian Ministry of Health Ricerca finalizzata [GR-2010-2310981]; NIH [GM081688, K01 AR062601]; Muscular Dystrophy Association (USA); National Human Genome Research Institute of the NIH [U54 HG003067] FX This work was funded by the National Health and Medical Research Council of Australia (1022707 and 1031893 to N.F. Clarke, K.N. North, and N.G. Laing; 1035828 to N.F. Clarke; 1035955 to G. Ravenscroft; 0511981 to K.G. Quinlan; 1002147 to N.G. Laing; and 1075451 to S.A. Sandaradura), the Association Francaise contre les Myopathies (15734 to G. Ravenscroft and N.G. Laing; DAJ1891 to J. Melki), the National Hospital Clinical Research Program (A0M10181 to J. Melki), the National Institute of Child Health and Development of the NIH (R01 HD 075802 to A.H. Beggs), the Muscular Dystrophy Association (USA) (MDA201302 to A.H. Beggs), the AUism Charitable Foundation (to A.H. Beggs), and the National Institute on Aging (AG000114 to D.D. Sloboda). M. Kreissl is supported by a University of Sydney Australian Postgraduate Award and an International Postgraduate Research Scholarship. E.J. Todd is supported by a University of Western Australia Postgraduate Award. O. Ceyhan-Birsoy is supported by a Dubai-Harvard Foundation for Medical Research postdoctoral fellowship and Schlumberger Foundation Faculty for the Future grant. A. D'Amico and E. Bertini are supported by the Italian Ministry of Health Ricerca finalizzata (GR-2010-2310981). A.S. Kostyukova is supported by NIH grant GM081688, and V.A. Gupta is supported by NIH grant K01 AR062601. D.S. Gokhin is supported by a Development Grant from the Muscular Dystrophy Association (USA). Exome sequencing was supported by grants from the National Human Genome Research Institute of the NIH (Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, Lander) and by the Gene Partnership Project of Boston Children's Hospital. The authors would like to thank the study patients and their families, without whose participation this work would not have been possible. We thank F. Muntoni (Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital for Children), C. Lacroix, (Service de Neuropathologie, CHU Bicetre), V. Zupan-Simunek (Service de Neonatologie, Hopital Antoine Beclere), A. Kan and N. Graf (The Children's Hospital at Westmead), and F. Fattori (Bambino Gesu Children's Hospital) for contribution and/or analysis of patient samples; S. Brammah(Concord Hospital) for provision of EM control images; T. Peduto (The Children's Hospital at Westmead) for assistance with analysis of muscle MRI; D.M. Margulies (Boston Children's Hospital) for support of WES through The Gene Partnership; and T. Yu and P. Park (Boston Children's Hospital) for WES pipeline development. We thank S.V. Brooks (University of Michigan) for assistance with experimental work and R. Dominguez (University of Pennsylvania) for providing reagents. NR 37 TC 35 Z9 38 U1 1 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4693 EP 4708 DI 10.1172/JCI75199 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300008 PM 25250574 ER PT J AU Wu, RX Chang, HC Khechaduri, A Chawla, K Tran, M Hai, XM Wagg, C Ghanefar, M Jiang, XH Bayeya, M Gonzalez, F Lopaschuk, G Ardehali, H AF Wu, Rongxue Chang, Hsiang-Chun Khechaduri, Arineh Chawla, Kusum Tran, Minh Hai, Xiaomeng Wagg, Cory Ghanefar, Mohsen Jiang, Xinghang Bayeva, Marina Gonzalez, Frank Lopaschuk, Gary Ardehali, Hossein TI Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID FATTY-ACID OXIDATION; WORKING RAT-HEART; DIABETIC CARDIOMYOPATHY; PPAR-ALPHA; ENERGY-METABOLISM; GENE-EXPRESSION; MICE; OXYGEN; DYSFUNCTION; HOMEOSTASIS AB Patients with type 2 diabetes often present with cardiovascular complications; however, it is not clear how diabetes promotes cardiac dysfunction. In murine models, deletion of the gene encoding aryl hydrocarbon nuclear translocator (ARNT, also known as HIF1 beta) in the liver or pancreas leads to a diabetic phenotype; however, the role of ARNT in cardiac metabolism is unknown. Here, we determined that cardiac-specific deletion of Arnt in adult mice results in rapid development of cardiomyopathy (CM) that is characterized by accumulation of lipid droplets. Compared with hearts from ARNT-expressing mice, ex vivo analysis of ARNT-deficient hearts revealed a 2-fold increase in fatty acid (FA) oxidation as well as a substantial increase in the expression of PPAR alpha and its target genes. Furthermore, deletion of both Arnt and Ppara preserved cardiac function, improved survival, and completely reversed the FA accumulation phenotype, indicating that PPAR alpha mediates the detrimental effects of Arnt deletion in the heart. Finally, we determined that ARNT directly regulates Ppara expression by binding to its promoter and forming a complex with HIF2 alpha. Together, these findings suggest that ARNT is a critical regulator of myocardial FA metabolism and that its deletion leads to CM and an increase in triglyceride accumulation through PPAR alpha. C1 [Wu, Rongxue; Chang, Hsiang-Chun; Khechaduri, Arineh; Chawla, Kusum; Tran, Minh; Hai, Xiaomeng; Ghanefar, Mohsen; Jiang, Xinghang; Bayeva, Marina; Ardehali, Hossein] Northwestern Univ, Sch Med, Dept Med, Div Cardiol, Chicago, IL 60611 USA. [Wagg, Cory; Lopaschuk, Gary] Univ Alberta, Mazankowski Alberta Heart Inst, Cardiovasc Res Ctr, Edmonton, AB, Canada. [Gonzalez, Frank] NCI, Ctr Canc Res, Lab Metab, Bethesda, MD 20892 USA. RP Ardehali, H (reprint author), Tarry 14-733,303 E Chicago Ave, Chicago, IL 60611 USA. EM h-ardehali@northwestern.edu FU NCI [CCSG P30 CA060553]; NIH [K02 HL107448, R01 HL104181, 1PO1 HL108795]; American Heart Association (AHA) [13SDG17270046] FX We would like to thank Konrad Sawicki for careful review of the manuscript. Imaging work was performed at the Northwestern University Cell Imaging Facility, which is supported by NCI grant CCSG P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center. H. Ardehali is supported by NIH grants K02 HL107448, R01 HL104181, and 1PO1 HL108795. R. Wu is supported by American Heart Association (AHA) grant 13SDG17270046. NR 45 TC 8 Z9 8 U1 2 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4795 EP 4806 DI 10.1172/JCI76737 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300016 PM 25329697 ER PT J AU Xiang, YQ Yang, PY Proia, RL Hla, T AF Xiang, Yuquan Yang, Peiying Proia, Richard L. Hla, Timothy TI Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID LYMPHOCYTE EGRESS; ENDOTHELIAL-CELLS; SPHINGOSINE-1-PHOSPHATE; ANGIOGENESIS; RECEPTOR; GENE; MICE; MUTATIONS; BLOOD AB Transport of oxygen by red blood cells (rbc) is critical for life and embryogenesis. Here, we determined that provision of the lipid mediator sphingosine 1-phosphate (S1P) to the systemic circulation is an essential function of rbc in embryogenesis. Mice with rbc-specific deletion of sphingosine kinases 1 and 2 (Sphk1 and Sphk2) showed embryonic lethality between E11.5 and E12.5 due to defects in vascular development. Administration of an S1P(1) receptor agonist to pregnant dams rescued early embryonic lethality. Even though rbc-specific Sphk1 Sphk2-KO embryos were anemic, the erythropoietic capacity of hematopoietic stem cells (HSCs) was not impaired, suggesting that rbc can develop in the absence of sphingosine kinase activity. Indeed, transplantation of HSCs deficient for Sphk1 and Sphk2 into adult mice produced rbc that lacked S1P and attenuated plasma S1P levels in recipients. However, in adult animals, both rbc and endothelium contributed to plasma SW. Together, these findings demonstrate that rbc are essential for embryogenesis by supplying the lysophospholipid S1P, which regulates embryonic vascular development via its receptors. C1 [Xiang, Yuquan; Hla, Timothy] Cornell Univ, Weill Cornell Med Coll, Dept Pathol & Lab Med, Ctr Vasc Biol, New York, NY 10065 USA. [Yang, Peiying] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Proia, Richard L.] Natl Inst Diabet & Digest & Kidney Dis, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Hla, T (reprint author), Cornell Univ, Weill Med Coll, 1300 York Ave,Box 69,Room A607E, New York, NY 10065 USA. EM tih2002@med.cornell.edu RI Hla, Timothy/G-5873-2012 OI Hla, Timothy/0000-0001-8355-4065 FU NIH [HL-067330, HL-089934, CA-077839]; NIDDK, NIH FX We thank Stuart Orkin for advice regarding the Epor-Cre mice; Todd Evans, Ralph Nachman, Stefano Rivella, and S.K. Dey for critical comments; Lee Cohen-Gould for help with transmission electron microscopy experiments; Jason McCormick for FACS experiments; Sushmita Mukherjee for 2-photon microscopy; Ursula Klingmiiller and Ralf H. Adams for the gift of unique mouse strains; and Jacek Bielawski for sphingolipid measurements. This work was supported by NIH grants HL-067330, HL-089934, and CA-077839 (to T. Hla) and intramural grants from the NIDDK, NIH (to R.L. Proia). Sphingolipid measurements were partially supported by Lipidomics Shared Resource, the Hollings Cancer Center, the Medical University of South Carolina (P30 CA138313), and the Lipidomics Core at the SC Lipidomics and Pathobiology COBRE (P20 RR017677). NR 24 TC 5 Z9 5 U1 1 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4823 EP 4828 DI 10.1172/JCI77685 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300018 ER PT J AU Bart, PA Huang, Y Karuna, ST Chappuis, S Gaillard, J Kochar, N Shen, X Allen, MA Ding, S Hural, J Liao, HX Haynes, BF Graham, BS Gilbert, PB McElrath, MJ Montefiori, DC Tomaras, GD Pantaleo, G Frahm, N AF Bart, Pierre-Alexandre Huang, Yunda Karuna, Shelly T. Chappuis, Samuel Gaillard, Julien Kochar, Nidhi Shen, Xiaoying Allen, Mary A. Ding, Song Hural, John Liao, Hua-Xin Haynes, Barton F. Graham, Barney S. Gilbert, Peter B. McElrath, M. Juliana Montefiori, David C. Tomaras, Georgia D. Pantaleo, Giuseppe Frahm, Nicole TI HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID T-CELL RESPONSES; DNA PRIME; NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; HEALTHY-ADULTS; EFFICACY TRIAL; NYVAC-C; VACCINE; ADENOVIRUS; BOOST AB BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5-vectored (rAd5-vectored) vaccine. METHODS. NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5-seronegative subjects were randomized to receive 2 x NYVAC-B followed by 1 x 10(10) PFU rAd5 (NYVAC/Ad5(hi)); 1 x 10(8) PFU rAd5 followed by 2 x NYVAC-B (Ad5(lo)/NYVAC); 1 x 10(9) PFU rAd5 followed by 2 x NYVAC-B (Ad5(med)/NYVAC); 1 x 10(10) PFU rAd5 followed by 2 x NYVAC-B (Ad5(hi)/NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-gamma and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses. RESULTS. CD4(+) T cell response rates ranged from 42.9% to 93.3%. NYVAC/AdS(hi) response rates (P <= 0.01) and magnitudes (P <= 0.03) were significantly lower than those of other groups. CD18(+) T cell response rates ranged from 65.5 % to 85.7%. NYVAC/Ad5(hi) magnitudes were significantly lower than those of other groups (P <= 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/Ad5(hi) and 21.4%, 84.6%, and 100% for Ad5(lo)/NYVAC, Ad5(med)/NYVAC, and Ad5(hi)/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate, responses appeared stronger for Ad5(med)/NYVAC and Ad5(hi)/NYVAC than for NYVAC/AdS5(hi.) CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine-induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies. C1 [Bart, Pierre-Alexandre; Chappuis, Samuel; Gaillard, Julien; Pantaleo, Giuseppe] Univ Lausanne Hosp, Serv Immunol & Allergy, Lausanne, Switzerland. [Bart, Pierre-Alexandre; Ding, Song] EuroVacc Fdn, Lausanne, Switzerland. [Huang, Yunda; Karuna, Shelly T.; Kochar, Nidhi; Hural, John; Gilbert, Peter B.; McElrath, M. Juliana; Frahm, Nicole] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Shen, Xiaoying; Liao, Hua-Xin; Haynes, Barton F.; Montefiori, David C.; Tomaras, Georgia D.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Allen, Mary A.] NIAID, NIH, Bethesda, MD 20892 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [McElrath, M. Juliana; Frahm, Nicole] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [McElrath, M. Juliana] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [McElrath, M. Juliana] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Pantaleo, Giuseppe] Swiss Vaccine Res Inst, Lausanne, Switzerland. [Bart, Pierre-Alexandre; Huang, Yunda; Karuna, Shelly T.; Chappuis, Samuel; Kochar, Nidhi; Hural, John; Gilbert, Peter B.; McElrath, M. Juliana; Montefiori, David C.; Tomaras, Georgia D.; Pantaleo, Giuseppe; Frahm, Nicole] NIAID, HIV Vaccine Trials Network, Bethesda, MD USA. RP Frahm, N (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1100 Fairview Ave N,E4-200, Seattle, WA 98109 USA. EM nfrahm@fhcrc.org RI Tomaras, Georgia/J-5041-2016; Pantaleo, Giuseppe/K-6163-2016 FU NIAID of the NIH [UM1AI068618, AI068635, AI068614, AI069443] FX Research reported in this publication was supported by the NIAID of the NIH under award numbers UM1AI068618, AI068635, AI068614, and AI069443. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 14 Z9 14 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4843 EP 4856 DI 10.1172/JCI75894 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300020 PM 25271627 ER PT J AU Carpentier, A Tesfaye, A Chu, V Nimgaonkar, I Zhang, F Lee, SB Thorgeirsson, SS Feinstone, SM Liang, TJ AF Carpentier, Arnaud Tesfaye, Abeba Chu, Virginia Nimgaonkar, Ila Zhang, Fang Lee, Seung Bum Thorgeirsson, Snorri S. Feinstone, Stephen M. Liang, T. Jake TI Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HEPATITIS-C-VIRUS; HUMAN FIBROBLASTS; IN-VITRO; EFFICIENT DIFFERENTIATION; DIRECTED DIFFERENTIATION; GENETIC-VARIATION; MOUSE-LIVER; LOW-DENSITY; CULTURE; ENDODERM AB The demonstrated ability to differentiate both human embryonic stem cells (hESCs) and patient-derived induced pluripotent stem cells (hiPSCs) into hepatocyte-like cells (HLCs) holds great promise for both regenerative medicine and liver disease research. Here, we determined that, despite an immature phenotype, differentiated HLCs are permissive to hepatitis C virus (HCV) infection and mount an interferon response to HCV infection in vitro. HLCs differentiated from hESCs and hiPSCs could be engrafted in the liver parenchyma of immune-deficient transgenic mice carrying the urokinase-type plasminogen activator gene driven by the major urinary protein promoter. The HLCs were maintained for more than 3 months in the livers of chimeric mice, in which they underwent further maturation and proliferation. These engrafted and expanded human HLCs were permissive to in vivo infection with HCV-positive sera and supported long-term infection of multiple HCV genotypes. Our study demonstrates efficient engraftment and in vivo HCV infection of human stem cell-derived hepatocytes and provides a model to study chronic HCV infection in patient-derived hepatocytes, action of antiviral therapies, and the biology of HCV infection. C1 [Carpentier, Arnaud; Tesfaye, Abeba; Chu, Virginia; Nimgaonkar, Ila; Zhang, Fang; Feinstone, Stephen M.; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Tesfaye, Abeba; Feinstone, Stephen M.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA. [Lee, Seung Bum; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM arnaud.carpentier@nih.gov; jakel@bdg10.niddk.nih.gov FU Intramural Research Program of the NIDDK [Z01 DK54504, DK54505]; NIH Center for Regenerative Medicine; NIH [N01-DK-7-0004/HHSN26700700004C] FX We wish to thank Ronda Sapp, Frank Qisheng Li, Zhensheng Zhang, Zongyi Hu, Emmanuel Thomas, and Chen Du (all from NIDDK); Marian E. Major (FDA); Stephen Strom (Karolinska Institute); Hengli Tang (University of Florida); and the Flow Cytometry Core of National Heart, Lung, and Blood Institute for technical assistance and helpful discussions. This work was supported by the Intramural Research Program of the NIDDK (Z01 DK54504 and DK54505) and the NIH Center for Regenerative Medicine. PHHs were provided by the NIH-funded Liver Tissue Procurement and Cell Distribution System (N01-DK-7-0004/HHSN26700700004C). NR 64 TC 30 Z9 31 U1 0 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4953 EP 4964 DI 10.1172/JCI75456 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300030 PM 25295540 ER PT J AU Lin, YJ Lan, YC Lai, CH Lin, TH Huang, SM Liao, CC Lin, CW Hung, CH Tien, N Liu, X Chien, WK Chen, JH Tsai, FJ AF Lin, Ying-Ju Lan, Yu-Ching Lai, Chih-Ho Lin, Ting-Hsu Huang, Shao-Mei Liao, Chiu-Chu Lin, Cheng-Wen Hung, Chien-Hui Tien, Ni Liu, Xiang Chien, Wen-Kuei Chen, Jin-Hua Tsai, Fuu-Jen TI Association of Promoter Genetic Variants in Interleukin-10 and Kawasaki Disease With Coronary Artery Aneurysms SO JOURNAL OF CLINICAL LABORATORY ANALYSIS LA English DT Article DE Kawasaki disease; coronary artery aneurysms; interleukin-10; genetic polymorphism ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; GAMMA-GLOBULIN; POLYMORPHISMS; IL-10; SUSCEPTIBILITY; POPULATION; CHILDREN AB Background: Kawasaki disease (KD) is an acute, self-limited vasculitis in infants and young children. Interleukin-10 (IL-10) is a potent cytokine that exerts pleiotropic effects on immunoregulation and inflammation. Elevated IL-10 serum levels have been reported in the KD patients. Methods: In this study, we investigated whether IL-10 genetic polymorphisms contribute to coronary artery aneurysm (CAA) development among KD patients in Taiwan. A total of 58 KD patients with CAA and 277 unrelated healthy children matched for sex and age were enrolled for this study. Results: Higher G allele frequencies of IL-10 at - 1082 position were observed in KD patients with CAA compared to the controls (P = 0.016, OR: 2.86, 95% CI, 1.17-6.98). In addition, higher IL-10 GCC haplotype frequencies were also observed in KD patients with CAA (P = 0.016, OR: 2.85, 95% CI, 1.17-6.98). Conclusion: Our data support the possibility that IL-10 gene polymorphisms may be related with CAA development of KD in Taiwanese population. C (C) 2014 Wiley Periodicals, Inc. C1 [Lin, Ying-Ju; Lin, Ting-Hsu; Huang, Shao-Mei; Liao, Chiu-Chu; Tsai, Fuu-Jen] China Med Univ Hosp, Dept Med Res, Taichung, Taiwan. [Lin, Ying-Ju; Tsai, Fuu-Jen] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Lan, Yu-Ching] China Med Univ, Dept Hlth Risk Management, Taichung, Taiwan. [Lai, Chih-Ho] China Med Univ, Sch Med, Dept Microbiol, Taichung, Taiwan. [Lin, Cheng-Wen; Tien, Ni] China Med Univ, Dept Med Lab Sci & Biotechnol, Taichung, Taiwan. [Hung, Chien-Hui] Chang Gung Univ, Grad Inst Clin Med Sci, Chiayi, Taiwan. [Liu, Xiang] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Chien, Wen-Kuei; Chen, Jin-Hua] China Med Univ, Biostat Ctr, Taichung, Taiwan. [Tsai, Fuu-Jen] Asia Univ, Dept Biotechnol, Taichung, Taiwan. RP Tsai, FJ (reprint author), China Med Univ Hosp, Dept Med Res, Taichung, Taiwan. EM d0704@mail.cmuh.org.tw RI Liu, Xiang/F-5731-2014; Tsai, Fuu-Jen/J-4140-2015; Lai, Chih-Ho/M-2433-2013; Lan, Yu-Ching/F-2449-2017 OI Lai, Chih-Ho/0000-0001-9229-818X; Lan, Yu-Ching/0000-0003-4781-6405 FU China Medical University [CMU100-S-01]; China Medical University Hospital [DMR-103-100]; National Science Council [NSC101-2314-B-039-008-MY3] FX Grant sponsor: China Medical University; Grant number: CMU100-S-01; Grant sponsor: China Medical University Hospital; Grant number: DMR-103-100; Grant sponsor: National Science Council; Grant number: NSC101-2314-B-039-008-MY3. NR 21 TC 5 Z9 5 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-8013 EI 1098-2825 J9 J CLIN LAB ANAL JI J. Clin. Lab. Anal. PD NOV PY 2014 VL 28 IS 6 BP 461 EP 464 DI 10.1002/jcla.21710 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AS5ZP UT WOS:000344345200007 PM 24659220 ER PT J AU Cillo, AR Vagratian, D Bedison, MA Anderson, EM Kearney, MF Fyne, E Koontz, D Coffin, JM Piatak, M Mellors, JW AF Cillo, Anthony R. Vagratian, David Bedison, Margaret A. Anderson, Elizabeth M. Kearney, Mary F. Fyne, Elizabeth Koontz, Dianna Coffin, John M. Piatak, Michael, Jr. Mellors, John W. TI Improved Single-Copy Assays for Quantification of Persistent HIV-1 Viremia in Patients on Suppressive Antiretroviral Therapy SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; LOW-LEVEL VIREMIA; REVERSE-TRANSCRIPTASE; PLASMA VIREMIA; INFECTION; TIME; INTENSIFICATION; LYMPHOCYTES; DYNAMICS; MARKERS AB A quantitative real-time PCR (qRT-PCR) assay with single-copy sensitivity targeting HIV-1 gag RNA (the gag single-copy assay [gSCA]) has been used widely to quantify plasma viremia below the limit of detection of clinical assays in patients on effective antiretroviral therapy (ART), but viral RNA in 15 to 30% of samples amplifies inefficiently because of primer/probe mismatches. We sought to develop improved single-copy assays with increased sensitivity by improving nucleic acid recovery, designing qRT-PCR primers and a probe for a highly conserved region of integrase in the HIV-1 pol gene (the integrase single-copy assay [iSCA]), and increasing the plasma volume tested (Mega-iSCA). We evaluated gSCA versus iSCA in paired plasma samples from 10 consecutive patients with viremia of >1,000 copies/ml and 25 consecutive patients on suppressive ART. Three of 10 viremic samples amplified inefficiently with gSCA compared to the Roche Cobas Ampliprep/TaqMan 2.0, whereas all 10 samples amplified efficiently with iSCA. Among 25 samples from patients on suppressive ART, 8 of 12 samples that were negative for HIV-1 RNA by gSCA had detectable HIV-1 RNA by iSCA, and iSCA detected 3-fold or higher HIV-1 RNA levels compared to gSCA in 10 of 25 samples. Large-volume plasma samples (>20 ml) from 7 patients were assayed using Mega-iSCA, and HIV-1 RNA was quantifiable in 6, including 4 of 5 that were negative by standard-volume iSCA. These improved assays with superior sensitivity will be useful for evaluating whether in vivo interventions can reduce plasma viremia and for assessing relationships between residual viremia and other virologic parameters, including the inducible proviral reservoir. C1 [Cillo, Anthony R.; Vagratian, David; Bedison, Margaret A.; Fyne, Elizabeth; Koontz, Dianna; Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Anderson, Elizabeth M.; Kearney, Mary F.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Coffin, John M.] Tufts Univ, Boston, MA 02111 USA. [Piatak, Michael, Jr.] Leidos Biomed Res Inc, Frederick, MD USA. RP Cillo, AR (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. EM arc85@pitt.edu; jwm1@pitt.edu FU Pittsburgh AIDS Research Training Program [5 T32 AI065380-08]; Leidos contracts through the National Cancer Institute [25XS119, 33XS110]; F. M. Kirby Foundation FX This study was supported by the Pittsburgh AIDS Research Training Program 5 T32 AI065380-08 and Leidos contracts 25XS119 and 33XS110 through the National Cancer Institute. J.M.C. was a Research Professor of the American Cancer Society, with support from the F. M. Kirby Foundation. NR 33 TC 16 Z9 16 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD NOV PY 2014 VL 52 IS 11 BP 3944 EP 3951 DI 10.1128/JCM.02060-14 PG 8 WC Microbiology SC Microbiology GA AS3EO UT WOS:000344159500018 PM 25187636 ER PT J AU Deng, XL Zhuo, L Lan, Y Dai, ZX Chen, WS Cai, WP Kovacs, JA Ma, L Tang, XP AF Deng, Xilong Zhuo, Li Lan, Yun Dai, Zhaoxia Chen, Wan-shan Cai, Weiping Kovacs, Joseph A. Ma, Liang Tang, Xiaoping TI Mutational Analysis of Pneumocystis jirovecii Dihydropteroate Synthase and Dihydrofolate Reductase Genes in HIV-Infected Patients in China SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID AIDS PATIENTS; PROPHYLAXIS; PREVALENCE; PNEUMONIA; FAILURE; ABSENCE AB We investigated Pneumocystis jirovecii dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) genes for mutations in 25 Chinese HIV-infected patients with P. jirovecii pneumonia. We identified DHPS mutations in 3 (12%) patients and DHFR mutations in 1 (4%) patient. The prevalence of DHPS and DHFR mutations in China remains low, as it does in other developing countries. C1 [Deng, Xilong] Guangzhou 8 Peoples Hosp, Intens Care Unit, Guangzhou, Guangdong, Peoples R China. [Zhuo, Li; Dai, Zhaoxia; Cai, Weiping; Tang, Xiaoping] Guangzhou 8 Peoples Hosp, Dept Infect Dis, Guangzhou, Guangdong, Peoples R China. [Lan, Yun; Chen, Wan-shan] Guangzhou 8 Peoples Hosp, Dept Lab Med, Guangzhou, Guangdong, Peoples R China. [Deng, Xilong; Kovacs, Joseph A.; Ma, Liang] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Tang, XP (reprint author), Guangzhou 8 Peoples Hosp, Dept Infect Dis, Guangzhou, Guangdong, Peoples R China. EM xtang@21cn.com FU Public Health Bureau of Guangzhou City [2009-YB-089009]; Department of Public Health, Guangdong Province, China [2012513]; Intramural Research Program of the U.S. National Institutes of Health Clinical Center FX This study was supported by the Public Health Bureau of Guangzhou City (grant 2009-YB-089009), the Department of Public Health, Guangdong Province, China (grant 2012513), and the Intramural Research Program of the U.S. National Institutes of Health Clinical Center. NR 14 TC 0 Z9 2 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD NOV PY 2014 VL 52 IS 11 BP 4017 EP 4019 DI 10.1128/JCM.01848-14 PG 3 WC Microbiology SC Microbiology GA AS3EO UT WOS:000344159500029 PM 25122865 ER PT J AU Ligibel, JA Alfano, CM Courneya, KS Demark-Wahnefried, W Burger, RA Chlebowski, RT Fabian, CJ Gucalp, A Hershman, DL Hudson, MM Jones, LW Kakarala, M Ness, KK Merrill, JK Wollins, DS Hudis, CA AF Ligibel, Jennifer A. Alfano, Catherine M. Courneya, Kerry S. Demark-Wahnefried, Wendy Burger, Robert A. Chlebowski, Rowan T. Fabian, Carol J. Gucalp, Ayca Hershman, Dawn L. Hudson, Melissa M. Jones, Lee W. Kakarala, Madhuri Ness, Kirsten K. Merrill, Janette K. Wollins, Dana S. Hudis, Clifford A. TI American Society of Clinical Oncology Position Statement on Obesity and Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-MASS INDEX; LONG-TERM EFFECTIVENESS; BREAST-CANCER; WEIGHT-LOSS; PHYSICAL-ACTIVITY; HEALTH BEHAVIORS; LIFE-STYLE; POSTMENOPAUSAL WOMEN; TEACHABLE MOMENT; RANDOMIZED-TRIAL AB Rates of obesity have increased significantly over the last three decades in the United States and globally. In addition to contributing to heart disease and diabetes, obesity is a major unrecognized risk factor for cancer. Obesity is associated with worsened prognosis after cancer diagnosis and also negatively affects the delivery of systemic therapy, contributes to morbidity of cancer treatment, and may raise the risk of second malignancies and comorbidities. Research shows that the time after a cancer diagnosis can serve as a teachable moment to motivate individuals to adopt risk-reducing behaviors. For this reason, the oncology care team-the providers with whom a patient has the closest relationships in the critical period after a cancer diagnosis-is in a unique position to help patients lose weight and make other healthy lifestyle changes. The American Society of Clinical Oncology is committed to reducing the impact of obesity on cancer and has established a multipronged initiative to accomplish this goal by 1) increasing education and awareness of the evidence linking obesity and cancer; 2) providing tools and resources to help oncology providers address obesity with their patients; 3) building and fostering a robust research agenda to better understand the pathophysiology of energy balance alterations, evaluate the impact of behavior change on cancer outcomes, and determine the best methods to help cancer survivors make effective and useful changes in lifestyle behaviors; and 4) advocating for policy and systems change to address societal factors contributing to obesity and improve access to weight management services for patients with cancer. (C) 2014 by American Society of Clinical Oncology C1 [Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA 02155 USA. [Alfano, Catherine M.] NCI, Bethesda, MD 20892 USA. [Courneya, Kerry S.] Univ Alberta, Edmonton, AB, Canada. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Birmingham, AL USA. [Burger, Robert A.] Univ Penn, Philadelphia, PA 19104 USA. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Fabian, Carol J.] Univ Kansas, Med Ctr, Westwood, KS USA. [Gucalp, Ayca; Jones, Lee W.; Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hershman, Dawn L.] Columbia Univ, Med Ctr, New York, NY USA. [Hudson, Melissa M.; Ness, Kirsten K.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kakarala, Madhuri] Van Andel Inst, Grand Rapids, MI USA. [Merrill, Janette K.; Wollins, Dana S.] Amer Soc Clin Oncol, Alexandria, VA USA. RP Ligibel, JA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02155 USA. EM jligibel@partners.org NR 48 TC 79 Z9 79 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 NOV 1 PY 2014 VL 32 IS 31 BP 3568 EP + DI 10.1200/JCO.2014.58.4680 PG 8 WC Oncology SC Oncology GA AS6MY UT WOS:000344378700019 PM 25273035 ER PT J AU Dhurandhar, NV Dhurandhar, EJ Ingram, DK Vaughan, K Mattison, JA AF Dhurandhar, Nikhil V. Dhurandhar, Emily J. Ingram, Donald K. Vaughan, Kelli Mattison, Julie A. TI Natural infection of human adenovirus 36 in rhesus monkeys is associated with a reduction in fasting glucose SO JOURNAL OF DIABETES LA English DT Letter DE Ad36; Adv36; glycemic; obesity; primates ID GLYCEMIC CONTROL; ADIPOSE-TISSUE; FAT C1 [Dhurandhar, Nikhil V.; Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Dhurandhar, Emily J.] Univ Alabama Birmingham, Dept Hlth Behav, Birmingham, AL USA. [Vaughan, Kelli; Mattison, Julie A.] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Vaughan, Kelli] SoBran Inc, Burtonsville, MD USA. RP Dhurandhar, NV (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM Nikhil.Dhurandhar@PBRC.EDU OI Vaughan, Kelli/0000-0001-5274-582X FU Intramural NIH HHS [ZIA AG000369-06] NR 8 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1753-0393 EI 1753-0407 J9 J DIABETES JI J. Diabetes PD NOV PY 2014 VL 6 IS 6 BP 614 EP 616 DI 10.1111/1753-0407.12178 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6BS UT WOS:000344350500018 PM 24909894 ER PT J AU Raskolnikov, D George, AK Rais-Bahrami, S Turkbey, B Shakir, NA Okoro, C Rothwax, JT Walton-Diaz, A Siddiqui, MM Su, D Stamatakis, L Merino, MJ Wood, BJ Choyke, PL Pinto, PA AF Raskolnikov, Dima George, Arvin K. Rais-Bahrami, Soroush Turkbey, Baris Shakir, Nabeel A. Okoro, Chinonyerem Rothwax, Jason T. Walton-Diaz, Annerleim Siddiqui, M. Minhaj Su, Daniel Stamatakis, Lambros Merino, Maria J. Wood, Bradford J. Choyke, Peter L. Pinto, Peter A. TI Multiparametric Magnetic Resonance Imaging and Image-Guided Biopsy to Detect Seminal Vesicle Invasion by Prostate Cancer SO JOURNAL OF ENDOUROLOGY LA English DT Article ID TRANSRECTAL ULTRASOUND BIOPSY; INCREMENTAL VALUE; ENDORECTAL COIL; 3 TESLA; NOMOGRAM; SURVEILLANCE; DISEASE AB Objectives: To evaluate the correlation between multiparametric prostate MRI (MP-MRI) suspicion for seminal vesicle invasion (SVI) by prostate cancer (PCa) and pathology on MRI/ultrasound (US) fusion-guided biopsy. Patients and Methods: From March 2007 to June 2013, 822 patients underwent MP-MRI at 3 Tesla and MRI/US fusion-guided biopsy. Of these, 25 patients underwent targeted biopsy of the seminal vesicles (SVs). In six patients, bilateral SVI was suspected, resulting in 31 samples. MP-MRI findings that triggered these SV biopsies were scored as low, moderate, or high suspicion for SVI based on the degree of involvement on MRI. Correlative prostate biopsy and radical prostatectomy (RP) pathology were reviewed by a single genitourinary pathologist. Results: At the time of MP-MRI, the median age was 64 years with a median prostate-specific antigen of 10.74ng/mL. Of the 31 SV lesions identified, MP-MRI suspicion scores of low, moderate, and high were assigned to 3, 19, and 9 lesions, respectively. MRI/US fusion-guided biopsy detected SVI in 20/31 (65%) of cases. For the four patients who underwent RP after a preoperative assessment of SVI, biopsy pathology and RP pathology were concordant in all cases. Conclusions: As this technology becomes more available, MP-MRI and MRI/US fusion-guided biopsy may play a role in the preoperative staging for PCa. Future work will determine if improved preoperative staging leads to better surgical outcomes. C1 [Raskolnikov, Dima; George, Arvin K.; Rais-Bahrami, Soroush; Shakir, Nabeel A.; Okoro, Chinonyerem; Rothwax, Jason T.; Walton-Diaz, Annerleim; Siddiqui, M. Minhaj; Su, Daniel; Stamatakis, Lambros; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH Clin Ctr, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Rais-Bahrami, Soroush/0000-0001-9466-9925 FU NIH, National Cancer Institute, Center for Cancer Research; Center for Interventional Oncology; NIH FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and the Center for Interventional Oncology. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field. This research was also made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, Inc., the Doris Duke Charitable Foundation, the Alexandria Real Estate Equities, Inc., Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at http:// fnih.org/work/education-training-0/medical-research-scholars-program. NR 26 TC 21 Z9 21 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 EI 1557-900X J9 J ENDOUROL JI J. Endourol. PD NOV 1 PY 2014 VL 28 IS 11 BP 1283 EP 1289 DI 10.1089/end.2014.0250 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AS0PM UT WOS:000343979900006 PM 25010361 ER PT J AU Jackling, FC Johnson, WE Appleton, BR AF Jackling, Felicity C. Johnson, Warren E. Appleton, Belinda R. TI The Genetic Inheritance of the Blue-eyed White Phenotype in Alpacas (Vicugna pacos) SO JOURNAL OF HEREDITY LA English DT Article DE association; coat color; KIT; pigmentation ID SOUTH-AMERICAN CAMELIDS; 8 MICROSATELLITE MARKERS; MELANOCORTIN 1 RECEPTOR; ROAN COAT COLOR; DOMINANT-WHITE; KIT GENE; POPULATION STRATIFICATION; WAARDENBURG-SYNDROME; SPOTTING LOCUS; LAMA-PACOS AB White-spotting patterns in mammals can be caused by mutations in the gene KIT, whose protein is necessary for the normal migration and survival of melanocytes from the neural crest. The alpaca (Vicugna pacos) blue-eyed white (BEW) phenotype is characterized by 2 blue eyes and a solid white coat over the whole body. Breeders hypothesize that the BEW phenotype in alpacas is caused by the combination of the gene causing gray fleece and a white-spotting gene. We performed an association study using KIT flanking and intragenic markers with 40 unrelated alpacas, of which 17 were BEW. Two microsatellite alleles at KIT-related markers were significantly associated (P < 0.0001) with the BEW phenotype (bew1 and bew2). In a larger cohort of 171 related individuals, we identify an abundance of an allele (bew1) in gray animals and the occurrence of bew2 homozygotes that are solid white with pigmented eyes. Association tests accounting for population structure and familial relatedness are consistent with a proposed model where these alleles are in linkage disequilibrium with a mutation or mutations that contribute to the BEW phenotype and to individual differences in fleece color. C1 [Jackling, Felicity C.; Appleton, Belinda R.] Univ Melbourne, Dept Genet, Melbourne, Vic 3010, Australia. [Johnson, Warren E.] NCI, Lab Genom Divers, NIH, Frederick, MD 21702 USA. RP Jackling, FC (reprint author), Univ Melbourne, Dept Genet, Melbourne, Vic 3010, Australia. EM f.jackling@student.unimelb.edu.au FU University of Melbourne Faculty of Science Research Development Grant; Intramural Research Program of the National Cancer Institute, National Institutes of Health; Australian Postgraduate Award FX University of Melbourne Faculty of Science Research Development Grant; Intramural Research Program of the National Cancer Institute, National Institutes of Health. F.J. is the recipient of an Australian Postgraduate Award. NR 57 TC 2 Z9 2 U1 2 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 EI 1465-7333 J9 J HERED JI J. Hered. PD NOV-DEC PY 2014 VL 105 IS 6 BP 847 EP 857 DI 10.1093/jhered/ess093 PG 11 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA AS6UG UT WOS:000344397000013 PM 23144493 ER PT J AU Avila, F Das, PJ Kutzler, M Owens, E Perelman, P Rubes, J Hornak, M Johnson, WE Raudsepp, T AF Avila, Felipe Das, Pranab J. Kutzler, Michelle Owens, Elaine Perelman, Polina Rubes, Jiri Hornak, Miroslav Johnson, Warren E. Raudsepp, Terje TI Development and Application of Camelid Molecular Cytogenetic Tools SO JOURNAL OF HEREDITY LA English DT Article DE alpaca; BAC library; cytogenetics; FISH; minute chromosome; translocation ID SOUTH-AMERICAN CAMELIDS; IN-SITU HYBRIDIZATION; HUMAN-CHROMOSOMES; PSEUDOAUTOSOMAL REGION; ANCESTRAL KARYOTYPE; TARGET-ENRICHMENT; DOMESTIC-ANIMALS; AUTOSOMAL LOCI; B-CHROMOSOMES; FEMALE LLAMA AB Cytogenetic chromosome maps offer molecular tools for genome analysis and clinical cytogenetics and are of particular importance for species with difficult karyotypes, such as camelids (2n = 74). Building on the available human-camel zoo-fluorescence in situ hybridization (FISH) data, we developed the first cytogenetic map for the alpaca (Lama pacos, LPA) genome by isolating and identifying 151 alpaca bacterial artificial chromosome (BAC) clones corresponding to 44 specific genes. The genes were mapped by FISH to 31 alpaca autosomes and the sex chromosomes; 11 chromosomes had 2 markers, which were ordered by dual-color FISH. The STS gene mapped to Xpter/Ypter, demarcating the pseudoautosomal region, whereas no markers were assigned to chromosomes 14, 21, 22, 28, and 36. The chromosome-specific markers were applied in clinical cytogenetics to identify LPA20, the major histocompatibility complex (MHC)-carrying chromosome, as a part of an autosomal translocation in a sterile male llama (Lama glama, LGL; 2n = 73,XY). FISH with LPAX BACs and LPA36 paints, as well as comparative genomic hybridization, were also used to investigate the origin of the minute chromosome, an abnormally small LPA36 in infertile female alpacas. This collection of cytogenetically mapped markers represents a new tool for camelid clinical cytogenetics and has applications for the improvement of the alpaca genome map and sequence assembly. C1 [Avila, Felipe; Das, Pranab J.; Raudsepp, Terje] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. [Kutzler, Michelle] Oregon State Univ, Dept Anim Sci, Coll Agr Sci, Corvallis, OR 97331 USA. [Owens, Elaine] Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX 77843 USA. [Perelman, Polina; Johnson, Warren E.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Perelman, Polina] Inst Mol & Cellular Biol, Lab Cytogenet Anim, Novosibirsk, Russia. [Rubes, Jiri; Hornak, Miroslav] Vet Res Inst, CS-62132 Brno, Czech Republic. RP Raudsepp, T (reprint author), Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. EM traudsepp@cvm.tamu.edu RI Perelman, Polina/N-8088-2015 OI Perelman, Polina/0000-0002-0982-5100 FU Alpaca Research Foundation; Morris Animal Foundation [(D09LA-004), GA (CR P506/10/0421)]; CEITEC [CZ.1.05/1.1.00/02.0068] FX Alpaca Research Foundation; Morris Animal Foundation (D09LA-004), GA (CR P506/10/0421); CEITEC (CZ.1.05/1.1.00/02.0068). NR 57 TC 4 Z9 4 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 EI 1465-7333 J9 J HERED JI J. Hered. PD NOV-DEC PY 2014 VL 105 IS 6 BP 858 EP 869 DI 10.1093/jhered/ess067 PG 12 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA AS6UG UT WOS:000344397000014 PM 23109720 ER PT J AU Tassi, I Claudio, E Wang, HS Tang, WH Ha, HL Saret, S Ramaswamy, M Siegel, R Siebenlist, U AF Tassi, Ilaria Claudio, Estefania Wang, Hongshan Tang, Wanhu Ha, Hye-lin Saret, Sun Ramaswamy, Madhu Siegel, Richard Siebenlist, Ulrich TI The NF-kappa B Regulator Bcl-3 Governs Dendritic Cell Antigen Presentation Functions in Adaptive Immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AUTOREACTIVE T-CELLS; FAS ENGAGEMENT; DISTINCT ROLES; CUTTING EDGE; LIFE-CYCLE; IN-VIVO; APOPTOSIS; SURVIVAL; ACTIVATION; TOLERANCE AB Bcl-3 is an atypical member of the I kappa B family and modulates gene expression via interaction with p50/NF-kappa B1 or p52/NF-kappa B2 homodimers. We report in the present study that Bcl-3 is required in dendritic cells (DCs) to assure effective priming of CD4 and CD8 T cells. Lack of Bcl-3 in bone marrow-derived DCs blunted their ability to expand and promote effector functions of T cells upon Ag/adjuvant challenge in vitro and after adoptive transfers in vivo. Importantly, the critical role of Bcl-3 for priming of T cells was exposed upon Ag/adjuvant challenge of mice specifically ablated of Bcl-3 in DCs. Furthermore, Bcl-3 in endogenous DCs was necessary for contact hypersensitivity responses. Bcl-3 modestly aided maturation of DCs, but most consequentially, Bcl-3 promoted their survival, partially inhibiting expression of several antiapoptotic genes. Loss of Bcl-3 accelerated apoptosis of bone marrow-derived DCs during Ag presentation to T cells, and DC survival was markedly impaired in the context of inflammatory conditions in mice specifically lacking Bcl-3 in these cells. Conversely, selective overexpression of Bcl-3 in DCs extended their lifespan in vitro and in vivo, correlating with increased capacity to prime T cells. These results expose a previously unidentified function for Bcl-3 in DC survival and the generation of adaptive immunity. C1 [Tassi, Ilaria; Claudio, Estefania; Wang, Hongshan; Tang, Wanhu; Ha, Hye-lin; Saret, Sun; Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Ramaswamy, Madhu; Siegel, Richard] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIH, Bldg 10,Room 11B15A, Bethesda, MD 20892 USA. EM usiebenlist@niaid.nih.gov FU Intramural Research Programs of the National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 40 TC 6 Z9 7 U1 1 U2 9 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 NOV 1 PY 2014 VL 193 IS 9 BP 4303 EP 4311 DI 10.4049/jimmunol.1401505 PG 9 WC Immunology SC Immunology GA AS1ZS UT WOS:000344079500006 PM 25246497 ER PT J AU Mion, F D'Inca, F Danelli, L Toffoletto, B Guarnotta, C Frossi, B Burocchi, A Rigoni, A Gerdes, N Lutgens, E Tripodo, C Colombo, MP Rivera, J Vitale, G Pucillo, CE AF Mion, Francesca D'Inca, Federica Danelli, Luca Toffoletto, Barbara Guarnotta, Carla Frossi, Barbara Burocchi, Alessia Rigoni, Alice Gerdes, Norbert Lutgens, Esther Tripodo, Claudio Colombo, Mario P. Rivera, Juan Vitale, Gaetano Pucillo, Carlo E. TI Mast Cells Control the Expansion and Differentiation of IL-10-Competent B Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID B10 CELLS; ADAPTIVE IMMUNITY; LYMPHOCYTES; ACTIVATION; RESPONSES; AUTOIMMUNITY; INFLAMMATION; MOUSE; EXOSOMES; SIGNALS AB The discovery of B cell subsets with regulatory properties, dependent on IL-10 production, has expanded our view on the mechanisms that control inflammation. Regulatory B cells acquire the ability to produce IL-10 in a stepwise process: first, they become IL-10 competent, a poised state in which B cells are sensitive to trigger signals but do not actually express the IL-10 gene; then, when exposed to appropriate stimuli, they start producing IL-10. Even if the existence of IL-10-competent B cells is now well established, it is not yet known how different immune cell types cross talk with B cells and affect IL-10-competent B cell differentiation and expansion. Mast cells (MCs) contribute to the differentiation and influence the effector functions of various immune cells, including B lymphocytes. In this study, we explored whether MCs could play a role in the expansion of IL-10-competent B cells and addressed the in vivo relevance of MC deficiency on the generation of these cells. We show that MCs can expand IL-10-competent B cells, but they do not directly induce IL-10 production; moreover, the absence of MCs negatively affects IL-10-competent B cell differentiation. Noteworthy, our findings reveal that the CD40L/CD40 axis plays a significant role in MC-driven expansion of IL-10-competent B cells in vitro and highlight the importance of MC CD40L signaling in the colon. C1 [Mion, Francesca; D'Inca, Federica; Danelli, Luca; Toffoletto, Barbara; Frossi, Barbara; Vitale, Gaetano; Pucillo, Carlo E.] Univ Udine, Dept Med & Biol Sci, I-33100 Udine, Italy. [Guarnotta, Carla; Tripodo, Claudio] Univ Palermo, Human Pathol Sect, Dept Hlth Sci, Tumor Immunol Unit, I-90127 Palermo, Italy. [Burocchi, Alessia; Rigoni, Alice; Colombo, Mario P.] Fdn Ist Ricovero & Cura Carattere Scientifico, Unita Immunol Mol, Dipartimento Oncol Sperimentale & Med Mol, Ist Nazl Tumori, I-20133 Milan, Italy. [Gerdes, Norbert; Lutgens, Esther] Univ Munich, Inst Cardiovasc Prevent, D-80336 Munich, Germany. [Lutgens, Esther] Univ Amsterdam, Acad Med Ctr, Dept Med Biochem, Expt Vasc Biol Lab, NL-1105 AZ Amsterdam, Netherlands. [Rivera, Juan] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Pucillo, CE (reprint author), Univ Udine, Dept Med & Biol Sci, Piazzale Massimiliano Kolbe 4, I-33100 Udine, Italy. EM carlo.pucillo@uniud.it RI Lutgens, Esther/E-2919-2010; Gerdes, Norbert/E-2787-2010; Tripodo, Claudio/O-4536-2016; Burocchi, Alessia/C-5512-2017; Rigoni, Alice/C-5532-2017; OI Lutgens, Esther/0000-0002-2609-5744; Gerdes, Norbert/0000-0002-4546-7208; Tripodo, Claudio/0000-0002-0821-6231; Burocchi, Alessia/0000-0001-8269-0460; Rigoni, Alice/0000-0002-4147-1904; Colombo, Mario Paolo/0000-0003-0042-7955; Pucillo, Carlo/0000-0002-4872-6156 FU Ministero della Salute; Associazione Italiana Ricerca sul Cancro; Ministero dell'Istruzione, Universita e Ricerca Grant PRIN; Fondazione Compagnia di San Paolo, Turin; Grant Legge Regionale 26 del Friuli Venezia Giulia; Agenzia Spaziale Italiana (Progetto MoMa); Humboldt Foundation Sofja Kovalevskaja Award; Deutsche Forschungsgemeinschaft [DFG FOR809] FX This work was supported by the Ministero della Salute; the Associazione Italiana Ricerca sul Cancro; Ministero dell'Istruzione, Universita e Ricerca Grant PRIN 2009; the Fondazione Compagnia di San Paolo, Turin; Grant Legge Regionale 26 del Friuli Venezia Giulia; the Agenzia Spaziale Italiana (Progetto MoMa); a Humboldt Foundation Sofja Kovalevskaja Award to E.L.; and Deutsche Forschungsgemeinschaft Grant DFG FOR809 (to E.L. and N.G.). NR 38 TC 5 Z9 5 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2014 VL 193 IS 9 BP 4568 EP 4579 DI 10.4049/jimmunol.1302593 PG 12 WC Immunology SC Immunology GA AS1ZS UT WOS:000344079500031 PM 25267976 ER PT J AU Wang, HS Yan, M Sun, JF Jain, S Yoshimi, R Abolfath, SM Ozato, K Coleman, WG Ng, AP Metcalf, D DiRago, L Nutt, SL Morse, HC AF Wang, Hongsheng Yan, Ming Sun, Jiafang Jain, Shweta Yoshimi, Ryusuke Abolfath, Sanaz Momben Ozato, Keiko Coleman, William G., Jr. Ng, Ashley P. Metcalf, Donald DiRago, Ladina Nutt, Stephen L. Morse, Herbert C., III TI A reporter mouse reveals lineage-specific and heterogeneous expression of IRF8 during lymphoid and myeloid cell differentiation (vol 193, pg 1766, 2014) SO JOURNAL OF IMMUNOLOGY LA English DT Correction C1 [Wang, Hongsheng; Sun, Jiafang; Jain, Shweta; Abolfath, Sanaz Momben; Morse, Herbert C., III] Natl Inst Allergy & Infect Dis, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Yan, Ming; Coleman, William G., Jr.] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Yan, Ming; Coleman, William G., Jr.] Natl Inst Diabet & Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Yoshimi, Ryusuke] Yokohama City Univ, Grad Sch Med, Dept Internal Med & Clin Immunol, Yokohama, Kanagawa 2360004, Japan. [Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Ng, Ashley P.; Metcalf, Donald; DiRago, Ladina; Nutt, Stephen L.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Ng, Ashley P.; Metcalf, Donald; Nutt, Stephen L.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia. RP Wang, HS (reprint author), Natl Inst Allergy & Infect Dis, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NR 1 TC 0 Z9 0 U1 1 U2 5 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 NOV 1 PY 2014 VL 193 IS 9 BP 4749 EP 4749 DI 10.4049/jimmunol.1490036 PG 1 WC Immunology SC Immunology GA AS1ZS UT WOS:000344079500050 ER PT J AU Vernon, HJ Sperati, CJ King, JD Poretti, A Miller, NR Sloan, JL Cameron, AM Myers, D Venditti, CP Valle, D AF Vernon, Hilary J. Sperati, C. John King, Joshua D. Poretti, Andrea Miller, Neil R. Sloan, Jennifer L. Cameron, Andrew M. Myers, Donna Venditti, Charles P. Valle, David TI A detailed analysis of methylmalonic acid kinetics during hemodialysis and after combined liver/kidney transplantation in a patient with mut(0) methylmalonic acidemia SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID LIVER-KIDNEY TRANSPLANTATION; CHRONIC-RENAL-FAILURE; MITOCHONDRIAL DISEASE; PERITONEAL-DIALYSIS; CEREBROSPINAL-FLUID; INBORN ERROR; DEFICIENCY; METABOLISM; MANAGEMENT; MUTATIONS AB End stage kidney disease is a well-known complication of methylmalonic acidemia (MMA), and can be treated by dialysis, kidney transplant, or combined kidney-liver transplant. While liver and/or kidney transplantation in MMA may reduce the risk of metabolic crisis and end-organ disease, it does not fully prevent disease-related complications. We performed detailed metabolite and kinetic analyses in a 28-year-old patient with mut(0) MMA who underwent hemodialysis for 6 months prior to receiving a combined liver/kidney transplant. A single hemodialysis session led to a 54 % reduction in plasma methylmalonic acid and yielded a plasma clearance of 103 ml/min and V(D)0.48 L/kg, which approximates the total body free water space. This was followed by rapid reaccumulation of methylmalonic acid over 24 h to the predialysis concentration in the plasma. Following combined liver/kidney transplantation, the plasma methylmalonic acid was reduced to 3 % of pre-dialysis levels (6,965 +/- 1,638 (SD) mu mol/L and 234 +/- 100 (SD) mu mol/L) but remained >850x higher than the upper limit of normal (0.27 +/- 0.08 (SD) mu mol/L). Despite substantial post-operative metabolic improvement, the patient developed significant neurologic complications including acute worsening of vision in the setting of pre-existing bilateral optic neuropathy, generalized seizures, and a transient, focal leukoencephalopathy. Plasma methylmalonic acid was stable throughout the post-operative course. The biochemical parameters exhibited by this patient further define the whole body metabolism of methylmalonic acid in the setting of dialysis and subsequent combined liver/kidney transplant. C1 [Vernon, Hilary J.; Valle, David] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Sperati, C. John; Myers, Donna] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [King, Joshua D.] Univ Virginia, Dept Med, Charlottesville, VA USA. [King, Joshua D.] Univ Virginia, Dept Emergency Med, Charlottesville, VA USA. [Poretti, Andrea] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Div Pediat Radiol, Sect Pediat Neuroradiol, Baltimore, MD 21205 USA. [Miller, Neil R.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD 21205 USA. [Sloan, Jennifer L.; Venditti, Charles P.] NHGRI, NIH, Bethesda, MD 20892 USA. [Cameron, Andrew M.] Johns Hopkins Univ, Dept Surg, Baltimore, MD 21205 USA. RP Vernon, HJ (reprint author), Johns Hopkins Univ, McKusick Nathans Inst Genet Med, 733 N Broadway,BRB 529, Baltimore, MD 21205 USA. EM hvernon1@jhmi.edu OI Poretti, Andrea/0000-0002-9594-3858 FU NICHD NIH HHS [K08 HD073492] NR 46 TC 6 Z9 7 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 EI 1573-2665 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD NOV PY 2014 VL 37 IS 6 BP 899 EP 907 DI 10.1007/s10545-014-9730-7 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AS5SN UT WOS:000344330000004 PM 24961826 ER PT J AU Beyoglu, D Krausz, KW Martin, J Maurhofer, O Dorow, J Ceglarek, U Gonzalez, FJ Dufour, JF Idle, JR AF Beyoglu, Diren Krausz, Kristopher W. Martin, Juliette Maurhofer, Olivier Dorow, Juliane Ceglarek, Uta Gonzalez, Frank J. Dufour, Jean-Francois Idle, Jeffrey R. TI Disruption of tumor suppressor gene Hint1 leads to remodeling of the lipid metabolic phenotype of mouse liver SO JOURNAL OF LIPID RESEARCH LA English DT Article DE lipidomics; metabolomics; mass spectrometry; carcinogenesis; cholesterol; phospholipids; eicosanoids; proliferation; apoptosis ID PROTEIN-KINASE-C; HEPATOCELLULAR-CARCINOMA; LYSOPHOSPHATIDIC ACID; CERAMIDE SYNTHASES; FATTY-ACIDS; CANCER; EXPRESSION; HEPATOCARCINOGENESIS; METHYLATION; ACTIVATION AB A lipidomic and metabolomic investigation of serum and liver from mice was performed to gain insight into the tumor suppressor gene Hint1. A major reprogramming of lipid homeostasis was found in both serum and liver of Hint1-null (Hint(-/-)) mice, with significant changes in the levels of many lipid molecules, as compared with gender-, age-, and strain-matched WT mice. In the Hint1(-/-) mice, serum total and esterified cholesterol were reduced 2.5-fold, and lysophosphatidylcholines (LPCs) and lysophosphatidic acids were 10-fold elevated in serum, with a corresponding fall in phosphatidylcholines (PCs). In the liver, MUFAs and PUFAs, including arachidonic acid (AA) and its metabolic precursors, were also raised, as was mRNA encoding enzymes involved in AA de novo synthesis. There was also a significant 50% increase in hepatic macrophages in the Hint1(-/-) mice. Several hepatic ceramides and acylcarnitines were decreased in the livers of Hint1(-/-) mice. The changes in serum LPCs and PCs were neither related to hepatic phospholipase A2 activity nor to mRNAs encoding lysophosphatidylcholine acetyltransferases 1-4.jlr The lipidomic phenotype of the Hint1(-/-) mouse revealed decreased inflammatory eicosanoids with elevated proliferative mediators that, combined with decreased ceramide apoptosis signaling molecules, may contribute to the tumor suppressor activity of Hint1 C1 [Beyoglu, Diren; Martin, Juliette; Maurhofer, Olivier; Dufour, Jean-Francois; Idle, Jeffrey R.] Univ Bern, Hepatol Res Grp, Dept Clin Res, CH-3012 Bern, Switzerland. [Krausz, Kristopher W.; Gonzalez, Frank J.; Idle, Jeffrey R.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dorow, Juliane; Ceglarek, Uta] Univ Hosp Leipzig, Inst Lab Med, Leipzig, Germany. RP Idle, JR (reprint author), Univ Bern, Hepatol Res Grp, Dept Clin Res, CH-3012 Bern, Switzerland. EM jeff.idle@ikp.unibe.ch OI Idle, Jeff/0000-0002-6143-1520 FU Imperial Tobacco Limited, UK; National Institutes of Health/National Institute of Allergy and Infectious Diseases [U19 AI067773-08/09/10]; Swiss National Science Foundation [140930]; Bernerische und Schweizerische Krebsliga; Sasella Foundation; Hassan Badawi Foundation Against Liver Cancer; National Cancer Institute Intramural Research Program FX This work was supported by a grant from Imperial Tobacco Limited, UK (D.B., J.R.I.), by National Institutes of Health/National Institute of Allergy and Infectious Diseases grant U19 AI067773-08/09/10 (J.R.I.), by Swiss National Science Foundation grant no. 140930 (J.F.D.), by the Bernerische und Schweizerische Krebsliga, Sasella Foundation and the Hassan Badawi Foundation Against Liver Cancer (J.R.I., J.F.D.), and by the National Cancer Institute Intramural Research Program (K.W.K., F.J.G.) NR 46 TC 3 Z9 3 U1 3 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD NOV PY 2014 VL 55 IS 11 BP 2309 EP 2319 DI 10.1194/jlr.M050682 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AS6EB UT WOS:000344356300011 PM 25193995 ER PT J AU Odia, Y Shih, JH Kreisl, TN Fine, HA AF Odia, Yazmin Shih, Joanna H. Kreisl, Teri N. Fine, Howard A. TI Bevacizumab-related toxicities in the National Cancer Institute malignant glioma trial cohort SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Bevacizumab; Toxicity; Glioma; Glioblastoma ID ENDOTHELIAL GROWTH-FACTOR; NEWLY-DIAGNOSED GLIOBLASTOMA; RENAL-CELL CARCINOMA; PHASE-II TRIAL; RECURSIVE PARTITIONING ANALYSIS; SINGLE-AGENT BEVACIZUMAB; CENTRAL-NERVOUS-SYSTEM; RECURRENT GLIOBLASTOMA; PLUS IRINOTECAN; TARGETED THERAPIES AB Bevacizumab is an antiangiogenic agent approved for recurrent glioblastoma due to high response rates. Prior reviews focused on severe or cardiovascular bevacizumab toxicities. We performed a comprehensive review of toxicities experienced among 210 patients enrolled in 3 phase II bevacizumab trials for recurrent malignant gliomas at the National Cancer Institute. No bevacizumab toxicities were experienced by 20 % patients, 40.2 % on monotherapy versus a parts per thousand currency sign9.5 % on combination therapy. Hypertension and proteinuria occurred in similar to 25 %. Fatigue, hypophosphatemia, aspartate aminotransferase elevation, rashes were common. Low grade headache, hoarseness, myalgias/arthralgias, liver enzyme elevation, azotemia and electrolyte abnormalities were noted. Rare severe toxicities, including thrombosis, hemorrhage, wound complications and colonic perforations, occurred at rates seen in other diseases. Leukopenia and neutropenia occurred solely with combination therapy, while thrombocytopenia occurred in 12.5 % on bevacizumab monotherapy. Thrombocytopenia was generally mild, but severe in (1.4 %) and increased in frequency with prolonged or combination therapy. Bevacizumab-related deaths occurred in 4 (1.9 %) patients, including brain ischemia (n = 1) and sudden unexplained deaths (n = 2). Prior hypertension increased the odds of hypertension by a parts per thousand yen3.4-fold (p < 0.001) and grade 3+ hypertension by a parts per thousand yen11.2 (p < 0.001). Prior hypertension increased the odds of hypophosphatemia by 2.4-fold (p = 0.011), but failed to predict proteinuria or azotemia. Age did not greatly impact toxicity. Hypertension, proteinuria and hypophosphatemia often occurred concurrently, more frequently and severely with prolonged use. Our study shows bevacizumab monotherapy is well tolerated, but toxicity increases with combination therapy. Balancing the risks and benefits of bevacizumab requires understanding the spectrum of bevacizumab toxicities and predisposing factors. C1 [Odia, Yazmin] Columbia Univ Coll Phys & Surg, Div Neurooncol, Neurol Inst New York, New York, NY 10032 USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Kreisl, Teri N.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Fine, Howard A.] NYU, Brain Tumor Ctr, New York, NY USA. [Fine, Howard A.] NYU, Inst Canc, Langone Med Ctr, New York, NY USA. RP Odia, Y (reprint author), Columbia Univ Coll Phys & Surg, Div Neurooncol, Neurol Inst New York, 710 West 168th St,NI 9-017, New York, NY 10032 USA. EM yo2240@cumc.columbia.edu FU Intramural NIH HHS NR 42 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD NOV PY 2014 VL 120 IS 2 BP 431 EP 440 DI 10.1007/s11060-014-1571-6 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS3JD UT WOS:000344172600024 PM 25098701 ER PT J AU Oh, J Seigo, M Saidha, S Sotirchos, E Zackowski, K Chen, M Prince, J Diener-West, M Calabresi, PA Reich, DS AF Oh, Jiwon Seigo, Michaela Saidha, Shiv Sotirchos, Elias Zackowski, Kathy Chen, Min Prince, Jerry Diener-West, Marie Calabresi, Peter A. Reich, Daniel S. TI Spinal Cord Normalization in Multiple Sclerosis SO JOURNAL OF NEUROIMAGING LA English DT Article DE Multiple sclerosis; MRI; spinal cord; atrophy; normalization ID INTRACRANIAL VOLUME; BRAIN ATROPHY; MRI; DISABILITY; AREA AB BACKGROUND Spinal cord (SC) pathology is common in multiple sclerosis (MS), and measures of SC-atrophy are increasingly utilized. Normalization reduces biological variation of structural measurements unrelated to disease, but optimal parameters for SC volume (SCV)normalization remain unclear. Using a variety of normalization factors and clinical measures, we assessed the effect of SCV normalization on detecting group differences and clarifying clinical-radiological correlations in MS. METHODS 3T cervical SC-MRI was performed in 133 MS cases and 11 healthy controls (HC). Clinical assessment included expanded disability status scale (EDSS), MS functional composite (MSFC), quantitative hip-flexion strength ("strength"), and vibration sensation threshold ("vibration"). SCV between C3 and C4 was measured and normalized individually by subject height, SC-length, and intracranial volume (ICV). RESULTS There were group differences in raw-SCV and after normalization by height and length (MS vs. HC; progressive vs. relapsing MS-subtypes, P < .05). There were correlations between clinical measures and raw-SCV (EDSS: r = -.20; MSFC: r = .16; strength: r = .35; vibration: r = -.19). Correlations consistently strengthened with normalization by length (EDSS: r = -.43; MSFC: r = .33; strength: r = .38; vibration: r = -.40), and height (EDSS: r = -.26; MSFC: r = .28; strength: r = .22; vibration: r = -.29), but diminished with normalization by ICV (EDSS: r = -.23; MSFC: r = -.10; strength: r = .23; vibration: r = -.35). In relapsing MS, normalization by length allowed statistical detection of correlations that were not apparent with raw-SCV. CONCLUSIONS SCV-normalization by length improves the ability to detect group differences, strengthens clinical-radiological correlations, and is particularly relevant in settings of subtle disease-related SC-atrophy in MS. SCV-normalization by length may enhance the clinical utility of measures of SC-atrophy. C1 [Oh, Jiwon; Seigo, Michaela; Saidha, Shiv; Sotirchos, Elias; Calabresi, Peter A.; Reich, Daniel S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Zackowski, Kathy] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD 21218 USA. [Zackowski, Kathy] Kennedy Krieger Inst, Motion Anal Lab, Baltimore, MD USA. [Chen, Min; Prince, Jerry] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Prince, Jerry] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. [Diener-West, Marie; Reich, Daniel S.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21218 USA. [Reich, Daniel S.] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. RP Oh, J (reprint author), Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. EM joh20@jhmi.edu RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Sotirchos, Elias/0000-0002-8812-1637 FU Multiple Sclerosis Society of Canada Decker Family Transitional Career Development Award; National Multiple Sclerosis Society [TR 3760-A-3]; Intramural Research Program of the National Institute of Neurological Disorders and Stroke FX Study Funding: Multiple Sclerosis Society of Canada Decker Family Transitional Career Development Award (to J.O.). National Multiple Sclerosis Society (TR 3760-A-3 to P.A.C.). Intramural Research Program of the National Institute of Neurological Disorders and Stroke (to D.S.R.). NR 23 TC 9 Z9 9 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD NOV-DEC PY 2014 VL 24 IS 6 BP 577 EP 584 DI 10.1111/jon.12097 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AS6DJ UT WOS:000344354600007 PM 24593281 ER PT J AU Truog, WE Nelin, LD Das, A Kendrick, DE Bell, EF Carlo, WA Higgins, RD Laptook, AR Sanchez, PJ Shankaran, S Stoll, BJ Van Meurs, KP Walsh, MC AF Truog, W. E. Nelin, L. D. Das, A. Kendrick, D. E. Bell, E. F. Carlo, W. A. Higgins, R. D. Laptook, A. R. Sanchez, P. J. Shankaran, S. Stoll, B. J. Van Meurs, K. P. Walsh, M. C. CA NICHD Neonatal Res Network TI Inhaled nitric oxide usage in preterm infants in the NICHD neonatal research network: inter-site variation and propensity evaluation SO JOURNAL OF PERINATOLOGY LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; PREMATURE-INFANTS; BRONCHOPULMONARY DYSPLASIA; MECHANICAL VENTILATION; OUTCOMES; FAILURE; DEFINITION; NEWBORNS; THERAPY; TRIAL AB OBJECTIVE: The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, a National Institutes of Health consensus development conference cautioned against use of iNO in preterm infants. This study aims (1) to determine the prevalence and variability in use of iNO in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) before and after the consensus conference and (2) separately, to examine associations between iNO use and severe bronchopulmonary dysplasia (BPD) or death. STUDY DESIGN: The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008 to 2011. Infants exposed or not to NO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO. RESULT: A total of 4885 infants were assessed between 2008 and 2011; 128 (2.6%) received iNO before day 7, 140 (2.9%) between day 7 and 28, and 47 (1.0%) at >28 days. Center-specific iNO use during 2008 to 2010 ranged from 21.9 to 0.4%; 12 of 13 sites reduced usage and overall NRN NO usage decreased from 4.6 to 1.6% (P<0.001) in 2011. The use of iNO started between day 7 and day 14 was more prevalent among younger infants with more severe courses in week 1 and associated with increased risk of severe BPD or death (odds ratio 2.24; 95% confidence interval 1.23 to 4.07). CONCLUSION: The variability and total use of iNO decreased in 2011 compared with 2008 to 2010. iNO administration started at day >= 7 was associated with more severe outcomes compared with infants without iNO exposure. C1 [Truog, W. E.] Childrens Mercy Hosp & Clin, Ctr Infant Pulm Disorders, Kansas City, MO USA. [Truog, W. E.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA. [Nelin, L. D.] Ohio State Univ, Sch Med, Dept Pediat, Columbus, OH 43210 USA. [Das, A.; Kendrick, D. E.] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Bell, E. F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Carlo, W. A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Higgins, R. D.] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, NIH, Bethesda, MD USA. [Laptook, A. R.] Brown Univ, Sch Med, Women & Infants Hosp, Dept Pediat, Providence, RI 02912 USA. [Sanchez, P. J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Shankaran, S.] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Stoll, B. J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, B. J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Van Meurs, K. P.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Walsh, M. C.; NICHD Neonatal Res Network] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. RP Truog, WE (reprint author), Univ Missouri, Sch Med, Childrens Mercy Hosp & Clin, Ctr Infant Pulm Disorders, 2401 Gillham Rd, Kansas City, MO 64108 USA. EM wtruog@cmh.edu FU NICHD NIH HHS [U10 HD021364, U10 HD068284, U10 HD027904, U10 HD027880, U10 HD027851, UG1 HD087229] NR 29 TC 7 Z9 7 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 EI 1476-5543 J9 J PERINATOL JI J. Perinatol. PD NOV PY 2014 VL 34 IS 11 BP 842 EP 846 DI 10.1038/jp.2014.105 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AS1NE UT WOS:000344046800009 PM 24901452 ER PT J AU Martini, S Nair, V Keller, BJ Eichinger, F Hawkins, JJ Randolph, A Boger, CA Gadegbeku, CA Fox, CS Cohen, CD Kretzler, M AF Martini, Sebastian Nair, Viji Keller, Benjamin J. Eichinger, Felix Hawkins, Jennifer J. Randolph, Ann Boeger, Carsten A. Gadegbeku, Crystal A. Fox, Caroline S. Cohen, Clemens D. Kretzler, Matthias CA European Renal cDNA Bank C-PROBE Cohort CKDGen Consortium TI Integrative Biology Identifies Shared Transcriptional Networks in CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; CHRONIC-RENAL-FAILURE; HUMAN DIABETIC-NEPHROPATHY; GENE-EXPRESSION; OXIDATIVE STRESS; SIGNALING PATHWAYS; RECEPTOR; CONSEQUENCES; ASSOCIATION; PROGRESSION AB A previous meta-analysis of genome-wide association data by the Cohorts for Heart and Aging Research in Genomic Epidemiology and CKDGen consortia identified 16 loci associated with eGFR. To define how each of these single-nucleotide polymorphisms (SNPs) could affect renal function, we integrated GFR-associated loci with regulatory pathways, producing a molecular map of CKD. In kidney biopsy specimens from 157 European subjects representing nine different CKDs, renal transcript levels for 18 genes in proximity to the SNPs significantly correlated with GFR. These 18 genes were mapped into their biologic context by testing coregulated transcripts for enriched pathways. A network of 97 pathways linked by shared genes was constructed and characterized. Of these pathways, 56 pathways were reported previously to be associated with CKD; 41 pathways without prior association with CKD were ranked on the basis of the number of candidate genes connected to the respective pathways. All pathways aggregated into a network of two main clusters comprising inflammation- and metabolism-related pathways, with the NRF2-mediated oxidative stress response pathway serving as the hub between the two clusters. In all, 78 pathways and 95% of the connections among those pathways were verified in an independent North American biopsy cohort. Disease-specific analyses showed that most pathways are shared between sets of three diseases, with closest interconnection between lupus nephritis, IgA nephritis, and diabetic nephropathy. Taken together, the network integrates candidate genes from genome-wide association studies into their functional context, revealing interactions and defining established and novel biologic mechanisms of renal impairment in renal diseases. C1 [Martini, Sebastian; Nair, Viji; Eichinger, Felix; Hawkins, Jennifer J.; Randolph, Ann; Kretzler, Matthias] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Martini, Sebastian; Nair, Viji; Eichinger, Felix; Hawkins, Jennifer J.; Randolph, Ann; Kretzler, Matthias] Univ Michigan, Dept Nephrol, Ann Arbor, MI 48109 USA. [Martini, Sebastian; Nair, Viji; Eichinger, Felix; Hawkins, Jennifer J.; Randolph, Ann; Kretzler, Matthias] Univ Michigan, Dept Internal Med, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Keller, Benjamin J.] Eastern Michigan Univ, Dept Comp Sci, Ypsilanti, MI 48197 USA. [Boeger, Carsten A.] Univ Hosp Regensburg, Dept Internal Med 2, Regensburg, Germany. [Gadegbeku, Crystal A.] Temple Univ, Sch Med, Dept Med, Sect Nephrol & Kidney Transplantat, Philadelphia, PA 19122 USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Lab Populat & Metab Hlth, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Cohen, Clemens D.] Univ Zurich, Inst Physiol, Zurich, Switzerland. RP Kretzler, M (reprint author), Univ Michigan, Dept Internal Med, Div Nephrol, 1150 West Med Ctr Dr,1560 MSRB 2, Ann Arbor, MI 48109 USA. EM kretzler@umich.edu FU O'Brien Renal Center National Institutes of Health [P30-DK081943-01]; National Institutes of Health [R01-DK079912-01]; National Center for Integrative Bioinformatics National Institutes of Health [U54-DA021519 01A1]; Else Kroner-Fresenius-Stiftung [P48/08//A11/08, 2012_A147] FX This study was supported, in part, by O'Brien Renal Center National Institutes of Health Grant P30-DK081943-01, National Institutes of Health Grant R01-DK079912-01, and National Center for Integrative Bioinformatics National Institutes of Health Grant U54-DA021519 01A1 (to M.K.). C.A.B. was supported by Else Kroner-Fresenius-Stiftung Grants Nr P48/08//A11/08 and 2012_A147. NR 47 TC 21 Z9 21 U1 0 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2014 VL 25 IS 11 BP 2559 EP 2572 DI 10.1681/ASN.2013080906 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA AS1KO UT WOS:000344040300019 PM 24925724 ER PT J AU Kanda, S Tanigawa, S Ohmori, T Taguchi, A Kudo, K Suzuki, Y Sato, Y Hino, S Sander, M Perantoni, AO Sugano, S Nakao, M Nishinakamura, R AF Kanda, Shoichiro Tanigawa, Shunsuke Ohmori, Tomoko Taguchi, Atsuhiro Kudo, Kuniko Suzuki, Yutaka Sato, Yuki Hino, Shinjiro Sander, Maike Perantoni, Alan O. Sugano, Sumio Nakao, Mitsuyoshi Nishinakamura, Ryuichi TI Sall1 Maintains Nephron Progenitors and Nascent Nephrons by Acting as Both an Activator and a Repressor SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID TOWNES-BROCKS-SYNDROME; EMBRYONIC STEM-CELLS; KIDNEY DEVELOPMENT; CAUSATIVE GENE; MAMMALIAN KIDNEY; OKIHIRO-SYNDROME; CRE RECOMBINASE; MURINE HOMOLOG; MOUSE KIDNEY; POPULATION AB The balanced self-renewal and differentiation of nephron progenitors are critical for kidney development and controlled, in part, by the transcription factor Six2, which antagonizes canonical Wnt signaling-mediated differentiation. A nuclear factor, Sall1 is expressed in Six2-positive progenitors as well as differentiating nascent nephrons, and it is essential for kidney formation. However, the molecular functions and targets of Sal 11, especially the functions and targets in the nephron progenitors, remain unknown. Here, we report that Sall1 deletion in Six2-positive nephron progenitors results in severe progenitor depletion and apoptosis of the differentiating nephrons in mice. Analysis of mice with an inducible Sall1 deletion revealed that Sall1 activates genes expressed in progenitors while repressing genes expressed in differentiating nephrons. Sall1 and Six2 co-occupied many progenitor-related gene loci, and Sall1 bound to Six2 biochemically. In contrast, Sal did not bind to the Wnt4 locus suppressed by Six2. Sall1-mediated repression was also independent of its binding to DNA. Thus, Sal 11 maintains nephron progenitors and their derivatives by a unique mechanism, which partly overlaps but is distinct from that of Six2: Sall1 activates progenitor-related genes in Six2-positive nephron progenitors and represses gene expression in Six2-negative differentiating nascent nephrons. C1 [Kanda, Shoichiro; Tanigawa, Shunsuke; Ohmori, Tomoko; Taguchi, Atsuhiro; Kudo, Kuniko; Nishinakamura, Ryuichi] Kumamoto Univ, Inst Mol Embryol & Genet, Dept Kidney Dev, Kumamoto 8600811, Japan. [Hino, Shinjiro; Nakao, Mitsuyoshi] Kumamoto Univ, Inst Mol Embryol & Genet, Dept Med Cell Biol, Kumamoto 8600811, Japan. [Sato, Yuki] Kumamoto Univ, Prior Org Innovat & Excellence, Kumamoto 8600811, Japan. [Suzuki, Yutaka; Sugano, Sumio] Univ Tokyo, Dept Med Genome Sci, Tokyo, Japan. [Sander, Maike] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Sander, Maike] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21701 USA. [Nakao, Mitsuyoshi; Nishinakamura, Ryuichi] Japan Sci & Technol Agcy, CREST, Saitama, Japan. RP Nishinakamura, R (reprint author), Kumamoto Univ, Inst Mol Embryol & Genet, Dept Kidney Dev, 2-2-1 Honjo, Kumamoto 8600811, Japan. EM ryuichi@kumamoto-u.ac.jp RI Sander, Maike/N-6615-2016; OI Sander, Maike/0000-0001-5308-7785; Taguchi, Atsuhiro/0000-0003-1741-2987 FU Ministry of Education, Culture, Sports, Science and Technology, Japan [23390228, 25111725, 221S0002]; National Institutes of Health [R01-DK68471] FX This study was supported by KAKENHI Grants 23390228, 25111725, and 221S0002 from Ministry of Education, Culture, Sports, Science and Technology, Japan. Research in the laboratory of M.S. was supported by National Institutes of Health Grant R01-DK68471. NR 34 TC 14 Z9 14 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2014 VL 25 IS 11 BP 2584 EP 2595 DI 10.1681/ASN.2013080896 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA AS1KO UT WOS:000344040300021 PM 24744442 ER PT J AU McMahon, GM Preis, SR Hwang, SJ Fox, CS AF McMahon, Gearoid M. Preis, Sarah R. Hwang, Shih-Jen Fox, Caroline S. TI Mid-Adulthood Risk Factor Profiles for CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; OBESITY-RELATED GLOMERULOPATHY; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; GENERAL-POPULATION; METABOLIC SYNDROME; LIFETIME RISK; UNITED-STATES; AGE AB Early identification of CKD risk factors may allow risk factor modification and prevention of CKD progression. We investigated the hypothesis that risk factors are present >= 30 years before the diagnosis of CKD in a case-control study using data from the Framingham Offspring Study. Patients with incident CKD (eGFR <= 60 ml/min per 1.73 m(2)) at examination cycles 6, 7, and 8 were age- and sex-matched 1:2 to patients without CKD at baseline (examination 5). CKD risk factors were measured at each examination cycle. Logistic regression models, adjusted for age, sex, and time period, were constructed to compare risk factor profiles at each time point between cases and controls. During follow-up, 441 new cases of CKD were identified and matched to 882 controls (mean age 69.2 years, 52.4% women). Those who ultimately developed CKD were more likely to have hypertension (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.23 to 2.51), obesity (OR, 1.71; 95% Cl, 1.14 to 2.59), and higher triglyceride levels (OR, 1.43; 95% CI, 1.12 to 1.83) 30 years before CKD diagnosis, and were more likely to have hypertension (OR, 1.38; 95% CI, 1.07 to 1.79), higher triglyceride levels (OR, 1.35; 95% CI, 1.11 to 1.64), lower HDLc (OR, 0.89; 95% Cl, 0.81 to 0.97), and diabetes (OR, 2.90; 95% Cl, 1.59 to 5.29)20 years before CKD diagnosis. These findings demonstrate that risk factors for CKD are identifiable >= 30 years before diagnosis and suggest the importance of early risk factor identification in patients at risk for CKD. C1 [McMahon, Gearoid M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [McMahon, Gearoid M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. [McMahon, Gearoid M.; Fox, Caroline S.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Preis, Sarah R.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 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 OI McMahon, Gearoid/0000-0002-7723-2198 FU [N01-HC-25195] FX The National Heart, Lung, and Blood Institute's Framingham Heart Study is supported by contract N01-HC-25195. NR 44 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2014 VL 25 IS 11 BP 2633 EP 2641 DI 10.1681/ASN.2013070750 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AS1KO UT WOS:000344040300026 PM 24970884 ER PT J AU Burotto, M Thomas, A Subramaniam, D Giaccone, G Rajan, A AF Burotto, Mauricio Thomas, Anish Subramaniam, Deepa Giaccone, Giuseppe Rajan, Arun TI Biomarkers in Early-Stage Non-Small-Cell Lung Cancer Current Concepts and Future Directions SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Lung cancer; Biomarkers; Early-stage lung cancer; Predictive; Prognostic ID GROWTH-FACTOR RECEPTOR; K-RAS ONCOGENE; TUMOR-INFILTRATING LYMPHOCYTES; EGFR GENE-MUTATIONS; ADJUVANT CHEMOTHERAPY; POOLED ANALYSIS; DNA-REPAIR; PROGNOSTIC-SIGNIFICANCE; CLINICAL-SIGNIFICANCE; MOLECULAR-ORIGINS AB Advances in molecular biology and bioinformatics have resulted in the identification of a number of potential biomarkers that could be relevant in the management of patients with non-small-cell lung cancer (NSCLC). Although there is an increasing amount of literature related to these biomarkers, major issues need to be resolved including validity and reproducibility of results. Additionally, in order to interpret the existing literature accurately, a clear distinction must be made between the prognostic and predictive value of biomarkers. The practical applicability of biomarker discovery for patients with lung cancer includes the identification of patients with early-stage NSCLC who are most likely to benefit from adjuvant therapy. Information gleaned from biomarkers has the potential to help in evaluating the role of targeted therapies including immunotherapy in the neoadjuvant and adjuvant setting. The role of gene signatures and the use of newer platforms such as RNA, methylation, and protein signatures is being explored in patients with early-stage NSCLC. This review focuses on the applications of biomarker discovery in patients with early-stage NSCLC. C1 [Burotto, Mauricio; Thomas, Anish; Rajan, Arun] NCI, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. [Subramaniam, Deepa; Giaccone, Giuseppe] Georgetown Univ, Lombardi Canc Ctr, Dept Med, Div Hematol Oncol, Washington, DC USA. RP Rajan, A (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, 10 Ctr Dr,10-CRC,Room 4-5330, Bethesda, MD 20892 USA. EM rajana@mail.nih.gov RI Mendez, Pedro /J-8955-2016; Giaccone, Giuseppe/E-8297-2017; OI Mendez, Pedro /0000-0001-6713-7907; Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU National Cancer Institute, National Institutes of Health FX Supported by Intramural Program, National Cancer Institute, National Institutes of Health. NR 82 TC 11 Z9 11 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2014 VL 9 IS 11 BP 1609 EP 1617 DI 10.1097/JTO.0000000000000302 PG 9 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AS6IT UT WOS:000344368100008 PM 25185530 ER PT J AU Tobian, AAR Quinn, TC AF Tobian, Aaron A. R. Quinn, Thomas C. TI Prevention of syphilis: another positive benefit of male circumcision SO LANCET GLOBAL HEALTH LA English DT Editorial Material ID SEXUALLY-TRANSMITTED INFECTIONS; VIRUS TYPE-2 INFECTION; HERPES; HIV; ACQUISITION; UGANDA; RAKAI C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21218 USA. [Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. [Quinn, Thomas C.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21218 USA. EM tquinn@jhmi.edu FU Intramural NIH HHS; NIAID NIH HHS [1K23AI093152-01A1] NR 11 TC 1 Z9 1 U1 0 U2 4 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 NOV PY 2014 VL 2 IS 11 BP E623 EP E624 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AS4ID UT WOS:000344236700005 PM 25442680 ER PT J AU Taylor, RJ Patel, MR Wheless, SA McKinney, KA Stadler, ME Sasaki-Adams, D Ewend, MG Germanwala, AV Zanation, AM AF Taylor, Robert J. Patel, Mihir R. Wheless, Stephen A. McKinney, Kibwei A. Stadler, Michael E. Sasaki-Adams, Deanna Ewend, Matthew G. Germanwala, Anand V. Zanation, Adam M. TI Endoscopic Endonasal Approaches to Infratemporal Fossa Tumors: A Classification System and Case Series SO LARYNGOSCOPE LA English DT Article DE Infratemporal fossa; cranial base surgery; skull base surgery; endoscopic endonasal approach ID SKULL BASE; TRANSPTERYGOID APPROACH; PTERYGOPALATINE FOSSA; EUSTACHIAN-TUBE; CRANIAL BASE; ACCESS; MAXILLOTOMY; SURGERY; SINUSES; ANATOMY AB Objectives/HypothesisTo propose a clinically applicable anatomic classification system describing three progressive endoscopic endonasal approaches (EEAs) to the infratemporal fossa (ITF) and their potential sequelae. Overall feasibility and outcomes of these approaches are presented through a consecutive case series. Study DesignDescription of classification system for EEAs to the ITF and case series. MethodsA classification system of EEAs to ITF tumors was created based on the senior author's clinical experience and cadaveric dissection. A retrospective chart review of 21 child and adult patients with primary ITF tumors treated by these approaches from 2008 to 2012 at a tertiary-care academic medical center was conducted. ResultsThree progressive EEAs to ITF tumors were defined: 1) a transpterygopalatine fossa approach, 2) a transmedial pterygoid plate approach, and 3) a translateral pterygoid plate approach. Twenty-one patients treated with these approaches were identified consecutively, with a mean age of 44.2 years (range, 11-79 years). Tumors primarily involving the pterygopalatine fossa and not the ITF were excluded. Pathology included three advanced juvenile nasopharyngeal angiofibromas, three adenoid cystic carcinomas, two recurrent inverted papillomas, two trigeminal schwannomas, and 11 other diverse skull base pathologies. No intraoperative or postoperative complications occurred, with a mean follow-up of 21.5 months (range, 1-55 months). Expected potential sequelae such as V2/palatal numbness, Eustachian tube dysfunction, and trismus occurred in 10/21 patients. ConclusionsEEAs to ITF tumors are technically feasible with low risk of complications for well-selected patients. The proposed classification system is useful for anticipating potential sequelae for each approach. Level of Evidence4 Laryngoscope, 124:2443-2450, 2014 C1 [Taylor, Robert J.; Patel, Mihir R.; Wheless, Stephen A.; McKinney, Kibwei A.; Stadler, Michael E.; Zanation, Adam M.] Univ N Carolina, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC 27599 USA. [Sasaki-Adams, Deanna; Ewend, Matthew G.; Zanation, Adam M.] Univ N Carolina, Dept Neurosurg, Chapel Hill, NC 27599 USA. [Germanwala, Anand V.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Zanation, AM (reprint author), Univ N Carolina, Dept Otolaryngol Head & Neck Surg, 170 Manning Dr,Phys Off Bldg,Ground Floor,CB 7070, Chapel Hill, NC 27599 USA. EM adam_zanation@med.unc.edu OI Patel, Mihir/0000-0001-6477-9728 FU Doris Duke Charitable Foundation FX This work was supported by grants from the Doris Duke Charitable Foundation to the University of North Carolina-Chapel Hill to fund clinical research fellows Stephen Wheless and Robert Taylor. NR 21 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2014 VL 124 IS 11 BP 2443 EP 2450 DI 10.1002/lary.24638 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AS6OH UT WOS:000344382100010 PM 25513678 ER PT J AU Roschewski, M Dunleavy, K Wilson, WH AF Roschewski, Mark Dunleavy, Kieron Wilson, Wyndham H. TI Moving beyond rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for diffuse large B-cell lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Review DE Lymphoma and Hodgkin disease; molecular genetics; chemotherapeutic approaches ID CHOP-LIKE CHEMOTHERAPY; NON-HODGKINS-LYMPHOMA; DOSE-ADJUSTED EPOCH; SMALL-MOLECULE INHIBITORS; RANDOMIZED PHASE-3 TRIAL; HIGH-RISK PATIENTS; GERMINAL-CENTER; PLUS CYCLOPHOSPHAMIDE; ELDERLY-PATIENTS; KAPPA-B AB Diff use large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). While the de facto treatment standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) is curative in most cases, it is ineffective for a significant proportion of patients, particularly those with intermediate and high-risk disease. Efforts to improve upon the results of R-CHOP have principally explored dose intensification of chemotherapy and resulted in considerable additive toxicity without clear benefit. DLBCL is not a uniform disease, however, and can be dissected into distinct molecular subtypes by gene expression profiling. These subtypes are characterized by distinct oncogenic mechanisms of activation and addictions to aberrant intracellular signaling pathways. Novel therapeutic agents that target these pathway addictions are emerging, and may have specific activity within molecular subtypes of DLBCL. To move beyond R-CHOP for all patients with DLBCL, targeted therapies added to the most effective chemotherapy platforms must be studied within the context of molecularly defined subsets. C1 [Roschewski, Mark; Dunleavy, Kieron; Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wilson, WH (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10 Room 4N115, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov FU intramural research program of the NIH FX All research support comes from the intramural research program of the NIH. NR 107 TC 5 Z9 6 U1 0 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD NOV PY 2014 VL 55 IS 11 BP 2428 EP 2437 DI 10.3109/10428194.2014.883075 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA AS5XD UT WOS:000344339000006 PM 24438195 ER PT J AU Doria-Rose, VP Harlan, LC Stevens, J Little, RF AF Doria-Rose, V. Paul Harlan, Linda C. Stevens, Jennifer Little, Richard F. TI Treatment of de novo acute myeloid leukemia in the United States: a report from the Patterns of Care program SO LEUKEMIA & LYMPHOMA LA English DT Article DE Acute myeloid leukemia; treatment; survival; patterns of care ID PATIENT SURVIVAL; PHASE-III; ADULTS; OUTCOMES; AML; AGE; CHEMOTHERAPY; DECISION; THERAPY; TRENDS AB Few US studies have examined patterns of care (POC) for acute myeloid leukemia (AML) in community settings. We examined treatment and survival in 978 adults with AML sampled from Surveillance, Epidemiology, and End Results (SEER) registries through the POC program. Logistic regression was used to evaluate the association between patient/hospital characteristics and receipt of chemotherapy and allogeneic transplant. Survival was examined using proportional hazards models. Treatment with cytarabine/anthracycline occurred in >80% of patients without acute promeyelocytic leukemia (non-APL) <60, but only about one-third of older non-APL patients. Ultimately, 27% of those <60 received an allogeneic transplant. Thirty-seven percent of those <40 and 4% of those >= 80 were alive at the end of follow-up. About three-quarters of patients with APL received all-trans retinoic acid (ATRA) and either an anthracycline or arsenic trioxide, with 71% surviving. Age and APL diagnosis were the strongest predictors of treatment and survival. Trends in dissemination of novel diagnostic tests and treatments and in survival will be monitored by POC in future years. C1 [Doria-Rose, V. Paul; Harlan, Linda C.; Little, Richard F.] NCI, Bethesda, MD 20892 USA. [Stevens, Jennifer] Informat Management Serv Inc, Silver Spring, MD USA. RP Doria-Rose, VP (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E440, Bethesda, MD 20892 USA. EM doriarop@mail.nih.gov OI Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute [N01-PC-35133, N01-PC-35135, N01-PC-35141, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54403, N01-PC-54404, N01-PC-54405] FX The study was supported by National Cancer Institute contracts N01-PC-35133, N01-PC-35135, N01-PC-35141, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54403, N01-PC-54404 and N01-PC-54405. NR 33 TC 8 Z9 8 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD NOV PY 2014 VL 55 IS 11 BP 2549 EP 2555 DI 10.3109/10428194.2014.885517 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA AS5XD UT WOS:000344339000022 PM 24467221 ER PT J AU Yee, KWL Storring, JM Buckstein, R Wells, RA Xenocostas, A Kovacs, MJ Howson-Jan, K Wang, ES Battista, K Wang, LS Oza, AM Ivy, SP Schuh, AC AF Yee, Karen W. L. Storring, John M. Buckstein, Rena Wells, Richard A. Xenocostas, Anargyros Kovacs, Michael J. Howson-Jan, Kang Wang, Eunice S. Battista, Kristina Wang, Lisa Oza, Amit M. Ivy, S. Percy Schuh, Andre C. TI Sunitinib malate in patients with intermediate-2 or high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia SO LEUKEMIA & LYMPHOMA LA English DT Letter ID ACUTE MYELOID-LEUKEMIA; PROGNOSTIC-SIGNIFICANCE; GROWTH-FACTOR; SU11248; MUTATIONS; DIAGNOSIS C1 [Yee, Karen W. L.; Storring, John M.; Buckstein, Rena; Wells, Richard A.; Xenocostas, Anargyros; Kovacs, Michael J.; Howson-Jan, Kang; Wang, Eunice S.; Battista, Kristina; Wang, Lisa; Oza, Amit M.; Schuh, Andre C.] Princess Margaret Phase II Consortium, Toronto, ON, Canada. [Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Yee, KWL (reprint author), Princess Margaret Hosp, Div Med Oncol & Hematol, 610 Univ Ave,5-218, Toronto, ON M5G 2M9, Canada. EM karen.yee@uhn.ca NR 15 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD NOV PY 2014 VL 55 IS 11 BP 2669 EP 2671 DI 10.3109/10428194.2014.900763 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA AS5XD UT WOS:000344339000045 PM 24611649 ER PT J AU Whitaker, K Young-Hyman, D Vernon, M Wilcox, S AF Whitaker, Kara Young-Hyman, Deborah Vernon, Marlo Wilcox, Sara TI Maternal Stress Predicts Postpartum Weight Retention SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Postpartum; Weight retention; Stress ID LOW-INCOME WOMEN; PSYCHOSOCIAL FACTORS; DEPRESSIVE SYMPTOMS; PARENTING STRESS; YOUNG-CHILDREN; OBESE WOMEN; PREGNANCY; GAIN; MOTHERS; PARENTHOOD AB Postpartum weight retention (PPWR) is a significant contributor to the development of overweight and obesity in women of childbearing age. Stress may be a key mechanism making it more difficult for mothers to lose weight in the year following delivery. The aim of this study was to assess whether specific aspects of parenting stress and life stress influence postpartum weight retention in new mothers. Women in late pregnancy or up to 2 months postpartum (n = 123) were enrolled in the study and followed through the first year postpartum. Linear regression models evaluated the associations of parenting stress (isolation, attachment and depressive symptoms) as well as overall life stress at 2, 6, and 12 months postpartum with PPWR at 6 and 12 months. During the first year postpartum, higher depression and life stress were significantly associated with greater PPWR. As the effect of depression diminished, the effect of life stress became significant. Contrary to hypothesized relationships, fewer problems with attachment and less social isolation were significantly associated with greater PPWR. Higher gestational weight gain and African American race were also significantly associated with greater PPWR at both 6 and 12 months. Different types of stress predict weight retention in first time mothers during the first year postpartum. Understanding the relationships between parenting stress, concurrent life stress and PPWR can enhance the development of future interventions that specifically target self-identified stressors, leading to improved weight related outcomes. C1 [Whitaker, Kara; Wilcox, Sara] Univ S Carolina, Columbia, SC 29208 USA. [Vernon, Marlo] Georgia Regents Univ, Augusta, GA 30912 USA. RP Young-Hyman, D (reprint author), NIH, Off Behav & Social Sci Res, Off Director, 31 Ctr Dr,Bldg 31,Room B1-C19,MSC 2027, Bethesda, MD 20892 USA. EM goodricm@email.sc.edu; deborah.young-hyman@od.nih.gov; mvernon@gru.edu; wilcoxs@mailbox.sc.edu OI Vernon, Marlo/0000-0002-7575-1576 FU NHLBI NIH HHS [R21 HL091284, R21 HL091284A2]; NIGMS NIH HHS [T32 GM081740] NR 56 TC 4 Z9 5 U1 2 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD NOV PY 2014 VL 18 IS 9 BP 2209 EP 2217 DI 10.1007/s10995-014-1470-7 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AR9XE UT WOS:000343929300022 PM 24760321 ER PT J AU Sharma, GVM Ramesh, A Singh, A Srikanth, G Jayaram, V Duscharla, D Jun, JH Ummanni, R Malhotra, SV AF Sharma, Gangavaram V. M. Ramesh, Adepu Singh, Ashita Srikanth, Gourishetty Jayaram, Vankudoth Duscharla, Divya Jun, Jung Ho Ummanni, Ramesh Malhotra, Sanjay V. TI Imidazole derivatives show anticancer potential by inducing apoptosis and cellular senescence SO MEDCHEMCOMM LA English DT Article ID RECEPTOR ANTAGONISTS; PROSTATE-CANCER; INHIBITORS; ANALOGS; KINASE; AGENTS; MIGRATION; PHOSPHODIESTERASE; PHARMACOKINETICS; EFFICACY AB Imidazole-based compounds are attractive targets in the design of novel chemical structures for the discovery of new drugs. In the current study, we have synthesized a series of new 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles by multicomponent reaction (MCR). Vanillin and isovanillin derivatives were reacted with benzil/pyridil and diverse amines and ammonium acetate in acetic acid at 50-110 degrees C for 24 h to afford respective imidazoles in 55-70% yields. The series of molecules were evaluated for anti-cancer potential against the National Cancer Institute's 60 human cancer cell line panel. Preliminary screening highlighted the anticancer potential of 2,2'-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)- 1-isobutyl-1H-imidazole-4,5-diyl) dipyridine (NSC 771432) against different cancer cell types. A549 cells were treated in vitro to determine the mode of action of NSC 771432 on growth of these cells. This compound inhibits anchorage independent growth and cell migration, and induces cell cycle arrest in the G2/M phase. Also, the exposure of A549 cells to NSC 771432 leads to cellular senescence. C1 [Sharma, Gangavaram V. M.; Ramesh, Adepu; Srikanth, Gourishetty; Jayaram, Vankudoth] CSIR, Indian Inst Chem Technol, Organ & Biomol Chem Div, Hyderabad 500007, Andhra Pradesh, India. [Singh, Ashita; Duscharla, Divya; Ummanni, Ramesh] CSIR, Indian Inst Chem Technol, Ctr Chem Biol, Hyderabad 500007, Andhra Pradesh, India. [Jun, Jung Ho; Malhotra, Sanjay V.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Synthet Chem, Frederick, MD 21702 USA. RP Sharma, GVM (reprint author), CSIR, Indian Inst Chem Technol, Organ & Biomol Chem Div, Hyderabad 500007, Andhra Pradesh, India. EM esmvee@iict.res.in; ummanni@iict.res.in; malhotrasa@mail.nih.gov FU CSIR; UGC; CSIR, New Delhi, India [SMILE-CSC-0111, ORIGIN-CSC0108]; National Cancer Institute and National Institutes of Health [HHSN261200800001E] FX G.S., A.R., and V.J. are thankful to the CSIR and UGC for financial support in the form of fellowship. The presented work is supported by the CSIR, New Delhi, India, under the 12th Five Year Plan for "SMILE-CSC-0111 and ORIGIN-CSC0108". S.V.M. would like to acknowledge the support from National Cancer Institute and National Institutes of Health, under Contract no. HHSN261200800001E. NR 35 TC 4 Z9 4 U1 1 U2 9 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-2503 EI 2040-2511 J9 MEDCHEMCOMM JI MedChemComm PD NOV PY 2014 VL 5 IS 11 BP 1751 EP 1760 DI 10.1039/c4md00277f PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AS5OU UT WOS:000344320700019 ER PT J AU Rasch, EK Huynh, M Ho, PS Heuser, A Houtenville, A Chan, L AF Rasch, Elizabeth K. Minh Huynh Ho, Pei-Shu Heuser, Aaron Houtenville, Andrew Chan, Leighton TI First in Line Prioritizing Receipt of Social Security Disability Benefits Based on Likelihood of Death During Adjudication SO MEDICAL CARE LA English DT Article DE (MeSH): survival analysis; disabled persons; government programs ID FUNCTIONAL STATUS; MORTALITY; LIFE AB Background: Given the complexity of the adjudication process and volume of applications to Social Security Administration's (SSA) disability programs, many individuals with serious medical conditions die while awaiting an application decision. Limitations of traditional survival methods called for a new empirical approach to identify conditions resulting in rapid mortality. Objective: To identify health conditions associated with significantly higher mortality than a key reference group among applicants for SSA disability programs. Research Design: We identified mortality patterns and generated a survival surface for a reference group using conditions already designated for expedited processing. We identified conditions associated with significantly higher mortality than the reference group and prioritized them by the expected likelihood of death during the adjudication process. Subjects: Administrative records of 29 million Social Security disability applicants, who applied for benefits from 1996 to 2007, were analyzed. Measures: We computed survival spells from time of onset of disability to death, and from date of application to death. Survival data were organized by entry cohort. Results: In our sample, we observed that approximately 42,000 applicants died before a decision was made on their disability claims. We identified 24 conditions with survival profiles comparable with the reference group. Applicants with these conditions were not likely to survive adjudication. Conclusions: Our approach facilitates ongoing revision of the conditions SSA designates for expedited awards and has applicability to other programs where survival profiles are a consideration. C1 [Rasch, Elizabeth K.; Minh Huynh; Ho, Pei-Shu; Heuser, Aaron; Chan, Leighton] NIH, Epidemiol & Biostat Sect, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Houtenville, Andrew] Univ New Hampshire, Inst Disabil, Durham, NH 03824 USA. RP Rasch, EK (reprint author), NIH, Epidemiol & Biostat Sect, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, 6100 Execut Blvd,Suite 3C01,MSC 7515, Bethesda, MD 20892 USA. EM rasche@cc.nih.gov FU National Institutes of Health; US Social Security Administration FX Supported by the Intramural Research Program of the National Institutes of Health and the US Social Security Administration. NR 27 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD NOV PY 2014 VL 52 IS 11 BP 944 EP 950 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AR9XL UT WOS:000343930300002 PM 25310524 ER PT J AU Liu, L Christodoulou-Vafeiadou, E Rao, JN Zou, TT Xiao, L Chung, HK Yang, H Gorospe, M Kontoyiannis, D Wang, JY AF Liu, Lan Christodoulou-Vafeiadou, Eleni Rao, Jaladanki N. Zou, Tongtong Xiao, Lan Chung, Hee Kyoung Yang, Hong Gorospe, Myriam Kontoyiannis, Dimitris Wang, Jian-Ying TI RNA-binding protein HuR promotes growth of small intestinal mucosa by activating the Wnt signaling pathway SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID EPITHELIAL BARRIER FUNCTION; MESSENGER-RNA; C-MYC; COMPETITIVE-BINDING; POLYAMINE DEPLETION; INDUCED APOPTOSIS; CELL-MIGRATION; TRANSLATION; EXPRESSION; STABILITY AB Inhibition of growth of the intestinal epithelium, a rapidly self-renewing tissue, is commonly found in various critical disorders. The RNA-binding protein HuR is highly expressed in the gut mucosa and modulates the stability and translation of target mRNAs, but its exact biological function in the intestinal epithelium remains unclear. Here, we investigated the role of HuR in intestinal homeostasis using a genetic model and further defined its target mRNAs. Targeted deletion of HuR in intestinal epithelial cells caused significant mucosal atrophy in the small intestine, as indicated by decreased cell proliferation within the crypts and subsequent shrinkages of crypts and villi. In addition, the HuR-deficient intestinal epithelium also displayed decreased regenerative potential of crypt progenitors after exposure to irradiation. HuR deficiency decreased expression of the Wnt coreceptor LDL receptor-related protein 6 (LRP6) in the mucosal tissues. At the molecular level, HuR was found to bind the Lrp6 mRNA via its 3'-untranslated region and enhanced LRP6 expression by stabilizing Lrp6 mRNA and stimulating its translation. These results indicate that HuR is essential for normal mucosal growth in the small intestine by altering Wnt signals through up-regulation of LRP6 expression and highlight a novel role of HuR deficiency in the pathogenesis of intestinal mucosal atrophy under pathological conditions. C1 [Liu, Lan; Rao, Jaladanki N.; Zou, Tongtong; Xiao, Lan; Chung, Hee Kyoung; Yang, Hong; 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. [Liu, Lan; Rao, Jaladanki N.; Zou, Tongtong; Xiao, Lan; Chung, Hee Kyoung; Yang, Hong; Wang, Jian-Ying] Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Christodoulou-Vafeiadou, Eleni; Kontoyiannis, Dimitris] Biomed Sci Res Ctr Alexander Fleming, Vari 16672, Greece. [Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU Merit Review Awards from the U.S. Department of Veterans Affairs; National Institutes of Health Grants [DK57819, DK61972, DK68491]; Association for International Cancer Research Grant [AICR-07-0548]; European Commission INFLACARE [HEALTH-F2-2009-223151]; National Institute on Aging-Intramural Research Program FX This work was supported by Merit Review Awards to J.Y.W. and J.N.R. from the U.S. Department of Veterans Affairs; National Institutes of Health Grants DK57819, DK61972, and DK68491 to J.Y.W.; Association for International Cancer Research Grant AICR-07-0548 and the European Commission INFLACARE (HEALTH-F2-2009-223151 to D. K.; and the National Institute on Aging-Intramural Research Program to M.G. J.Y.W. is a Senior Research Career Scientist, Biomedical Laboratory Research and Development Service, U.S. Department of Veterans Affairs. NR 51 TC 13 Z9 14 U1 1 U2 5 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 NOV 1 PY 2014 VL 25 IS 21 BP 3308 EP + DI 10.1091/mbc.E14-03-0853 PG 24 WC Cell Biology SC Cell Biology GA AS4HY UT WOS:000344236100014 PM 25165135 ER PT J AU Lee, DE Reid, WC Ibrahim, WG Peterson, KL Lentz, MR Maric, D Choyke, PL Jagoda, EM Hammoud, DA AF Lee, Dianne E. Reid, William C. Ibrahim, Wael G. Peterson, Kristin L. Lentz, Margaret R. Maric, Dragan Choyke, Peter L. Jagoda, Elaine M. Hammoud, Dima A. TI Imaging Dopaminergic Dysfunction as a Surrogate Marker of Neuropathology in a Small-Animal Model of HIV SO MOLECULAR IMAGING LA English DT Article ID TRANSGENIC RATS EVIDENCE; F-18 FALLYPRIDE; HUMAN-BRAIN; TEST-RETEST; IN-VITRO; NEUROTOXICITY; RECEPTORS; PET; NEURONS; DEMENTIA AB The dopaminergic system is especially vulnerable to the effects of human immunodeficiency virus (HIV) infection, rendering dopaminergic deficits early surrogate markers of HIV-associated neuropathology. We quantified dopamine D-2/3 receptors in young HIV-1 transgenic (Tg) (n = 6) and age-matched control rats (n = 7) and adult Tg (n = 5) and age-matched control rats (n = 5) using [F-18] fallypride positron emission tomography (PET). Regional uptake was quantified as binding potential (BPND) using the two-tissue reference model with the cerebellum as the reference. Time-activity curves were generated for the ventral striatum, dorsal striatum, thalamus, and cerebellum. Whereas BPND values were significantly lower in the ventral striatum (p < .001) and dorsal striatum (p < .001) in the adult Tg rats compared to controls rats, they were significantly lower only in the dorsal striatum (p = .05) in the young rats. Tg rats had smaller striatal volumes on magnetic resonance imaging. We also found lower expression levels of tyrosine hydroxylase on immunohistochemistry in the Tg animals. Our findings suggest that progressive striatal D-2/3 receptor deficits occur in Tg rats as they age and can be detected using small-animal PET imaging. The effectiveness of various approaches in preventing or halting this dopaminergic loss in the Tg rat can thus be measured preclinically using [F-18] fallypride PET as a molecular imaging biomarker of HIV-associated neuropathology. C1 NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Bethesda, MD 20814 USA. NINDS, Div Intermural Res, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Hammoud, DA (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Room 1C368, Bethesda, MD 20814 USA. EM hammoudd@cc.nih.gov RI Hammoud, Dima/C-2286-2015 FU Center of Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences (RIS), Clinical Center, National Institutes of Health (Intramural Program) FX This work was supported by the Center of Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences (RIS), Clinical Center, National Institutes of Health (Intramural Program). NR 49 TC 4 Z9 4 U1 2 U2 6 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 EI 1536-0121 J9 MOL IMAGING JI Mol. Imaging PD NOV PY 2014 VL 13 DI 10.2310/7290.2014.00031 PG 10 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA AS4AM UT WOS:000344216000003 ER PT J AU Le Guiner, C Montus, M Servais, L Cherel, Y Francois, V Thibaud, JL Wary, C Matot, B Larcher, T Guigand, L Dutilleul, M Domenger, C Allais, M Beuvin, M Moraux, A Le Duff, J Devaux, M Jaulin, N Guilbaud, M Latournerie, V Veron, P Boutin, S Leborgne, C Desgue, D Deschamps, JY Moullec, S Fromes, Y Vulin, A Smith, RH Laroudie, N Barnay-Toutain, F Riviere, C Bucher, S Le, TH Delaunay, N Gasmi, M Kotin, RM Bonne, G Adjali, O Masurier, C Hogrel, JY Carlier, P Moullier, P Voit, T AF Le Guiner, Caroline Montus, Marie Servais, Laurent Cherel, Yan Francois, Virginie Thibaud, Jean-Laurent Wary, Claire Matot, Beatrice Larcher, Thibaut Guigand, Lydie Dutilleul, Maeva Domenger, Claire Allais, Marine Beuvin, Maud Moraux, Amelie Le Duff, Johanne Devaux, Marie Jaulin, Nicolas Guilbaud, Mickael Latournerie, Virginie Veron, Philippe Boutin, Sylvie Leborgne, Christian Desgue, Diana Deschamps, Jack-Yves Moullec, Sophie Fromes, Yves Vulin, Adeline Smith, Richard H. Laroudie, Nicolas Barnay-Toutain, Frederic Riviere, Christel Bucher, Stephanie Thanh-Hoa Le Delaunay, Nicolas Gasmi, Mehdi Kotin, Robert M. Bonne, Gisele Adjali, Oumeya Masurier, Carole Hogrel, Jean-Yves Carlier, Pierre Moullier, Philippe Voit, Thomas TI Forelimb Treatment in a Large Cohort of Dystrophic Dogs Supports Delivery of a Recombinant AAV for Exon Skipping in Duchenne Patients SO MOLECULAR THERAPY LA English DT Article ID RETRIEVER MUSCULAR-DYSTROPHY; PRIMATE SKELETAL-MUSCLE; HEMOPHILIA-B DOGS; GENE-TRANSFER; THERAPEUTIC STRATEGIES; EXPRESSION; RESTORATION; VECTORS; MODELS; SAFETY AB Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by mutations in the dystrophin gene, without curative treatment yet available. Our study provides, for the first time, the overall safety profile and therapeutic dose of a recombinant adeno-associated virus vector, serotype 8 (rAAV8) carrying a modified U7snRNA sequence promoting exon skipping to restore a functional in-frame dystrophin transcript, and injected by locoregional transvenous perfusion of the forelimb. Eighteen Golden Retriever Muscular Dystrophy (GRMD) dogs were exposed to increasing doses of GMP-manufactured vector. Treatment was well tolerated in all, and no acute nor delayed adverse effect, including systemic and immune toxicity was detected. There was a dose relationship for the amount of exon skipping with up to 80% of nnyofibers expressing dystrophin at the highest dose. Similarly, histological, nuclear magnetic resonance pathological indices and strength improvement responded in a dose-dependent manner. The systematic comparison of effects using different independent methods, allowed to define a minimurn threshold of dystrophin expressing fibers (>33% for structural measures and >40% for strength) under which there was no clear-cut therapeutic effect. Altogether, these results support the concept of a phase 1/2 trial of locoregional delivery into upper limbs of nonannbulatory DMD patients. C1 [Le Guiner, Caroline; Francois, Virginie; Domenger, Claire; Allais, Marine; Le Duff, Johanne; Devaux, Marie; Jaulin, Nicolas; Guilbaud, Mickael; Adjali, Oumeya; Moullier, Philippe] Univ Nantes, CHU Nantes, INSERM UMR 1089, Atlantic Gene Therapies, Nantes, France. [Le Guiner, Caroline; Montus, Marie; Latournerie, Virginie; Veron, Philippe; Boutin, Sylvie; Leborgne, Christian; Desgue, Diana; Laroudie, Nicolas; Barnay-Toutain, Frederic; Riviere, Christel; Bucher, Stephanie; Thanh-Hoa Le; Delaunay, Nicolas; Gasmi, Mehdi; Masurier, Carole; Moullier, Philippe] Genethon, Evry, France. [Servais, Laurent] Serv Clin Trials & Databases, Inst Myol, Paris, France. [Cherel, Yan; Larcher, Thibaut; Guigand, Lydie; Dutilleul, Maeva; Deschamps, Jack-Yves] ONIRIS, INRA UMR 703, Atlantic Gene Therapies, Nantes, France. [Thibaud, Jean-Laurent; Wary, Claire; Matot, Beatrice; Carlier, Pierre] Inst Myol, Lab RMN, Paris, France. [Thibaud, Jean-Laurent; Wary, Claire; Matot, Beatrice; Carlier, Pierre] AIM, Paris, France. [Thibaud, Jean-Laurent; Wary, Claire; Matot, Beatrice; Carlier, Pierre] CEA, Paris, France. [Thibaud, Jean-Laurent] Ecole Natl Vet Alfort, UPR Neurobiol, Maisons Alfort, France. [Beuvin, Maud; Bonne, Gisele; Voit, Thomas] Univ Paris 06, Inst Myol, Grp Hosp Pitie Salpetriere, UPMC INSERM UMR 974,CNRS FRE 3617, Paris, France. [Moraux, Amelie; Hogrel, Jean-Yves] Inst Myol, Neuromuscular Physiol & Evaluat Lab, Paris, France. [Deschamps, Jack-Yves; Moullec, Sophie; Fromes, Yves] ONIRIS, Ctr Boisbonne, Atlantic Gene Therapies, Nantes, France. [Vulin, Adeline] Nationwide Childrens Hosp, Ctr Gene Therapy, Res Inst, Columbus, OH USA. [Smith, Richard H.; Kotin, Robert M.] NHLBI, Lab Mol Virol & Gene Therapy, NIH, Bethesda, MD 20892 USA. [Bonne, Gisele] Grp Hosp Pitie Salpetriere, AP HP, UF Cardiogenet & Myogenet, Serv Biochim Metab, F-75634 Paris, France. [Moullier, Philippe] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. RP Voit, T (reprint author), Univ Paris 06, Inst Myol, Grp Hosp Pitie Salpetriere, UPMC INSERM UMR 974,CNRS FRE 3617, Paris, France. EM moullier@ufl.edu; t.voit@institut-myologie.org RI Bonne, Gisele/G-3121-2013 FU AFM-Telethon (Association Francaise contre les Myopathies); ADNA (Advanced Diagnostics for New Therapeutic Approaches); French public agency, Bpifrance FX We thank all the personnel of the Boisbonne Center for Gene Therapy (ONIRIS, Atlantic Gene Therapies, Nantes, France) for the handling and care of the GRMD dog colony. We also thank Peggy Adin-Chabon, Nathalie Lambert, Caroline Burie, Jonathan Lecaille, Julien Blin (Genethon, Evry, France), and Laurence Dubreil (Atlantic Gene Therapies, INRA UMR 703, Nantes, France) for their technical assistance. We thank Karl Rouger (Atlantic Gene Therapies, INRA UMR 703, Nantes, France) for providing GRMD myoblasts used for testing the in vitro functionality of our vectors. We thank Stephane Blot (Veterinary School of Maisons-Alfort, France) for providing anti-dystrophin IgG positive canine sera from immunized GRMD dogs. And we finally thank Fulvio Mavilio (Genethon, Evry, France) for his critical reading of this manuscript. This project was supported by AFM-Telethon (Association Francaise contre les Myopathies) and by ADNA (Advanced Diagnostics for New Therapeutic Approaches), a program dedicated to personalized medicine, coordinated by Institut Merieux and supported by research and innovation aid from the French public agency, Bpifrance. NR 50 TC 31 Z9 31 U1 0 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD NOV PY 2014 VL 22 IS 11 BP 1923 EP 1935 DI 10.1038/mt.2014.751 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AS7IJ UT WOS:000344429800010 PM 25200009 ER PT J AU Watanabe, T Asano, N Meng, G Yamashita, K Arai, Y Sakurai, T Kudo, M Fuss, IJ Kitani, A Shimosegawa, T Chiba, T Strober, W AF Watanabe, T. Asano, N. Meng, G. Yamashita, K. Arai, Y. Sakurai, T. Kudo, M. Fuss, I. J. Kitani, A. Shimosegawa, T. Chiba, T. Strober, W. TI NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6 SO MUCOSAL IMMUNOLOGY LA English DT Article ID TOLL-LIKE-RECEPTOR; CROHNS-DISEASE; BOWEL-DISEASE; DENDRITIC CELLS; PROINFLAMMATORY CYTOKINES; EXPERIMENTAL COLITIS; HOST-DEFENSE; RIP2; HOMEOSTASIS; ACTIVATION AB It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-kappa B activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD. C1 [Watanabe, T.] Kyoto Univ, Grad Sch Med, Ctr Innovat Immunoregulat Technol & Therapeut, Kyoto, Japan. [Watanabe, T.; Asano, N.; Meng, G.; Fuss, I. J.; Kitani, A.; Strober, W.] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Watanabe, T.; Chiba, T.] Kyoto Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Kyoto, Japan. [Asano, N.; Shimosegawa, T.] Tohoku Univ, Grad Sch Med, Div Gastroenterol, Sendai, Miyagi 980, Japan. [Yamashita, K.] Kyoto Univ, Grad Sch Med, Dept Hematol & Oncol, Kyoto, Japan. [Sakurai, T.; Kudo, M.] Kinki Univ, Sch Med, Dept Gastroenterol & Hepatol, Osakasayama, Japan. RP Watanabe, T (reprint author), Kyoto Univ, Grad Sch Med, Ctr Innovat Immunoregulat Technol & Therapeut, Kyoto, Japan. EM tmhrwtnb@kuhp.kyoto-u.ac.jp; wstrober@niaid.nih.gov OI Kudo, Masatoshi/0000-0002-4102-3474 FU Japan Society for the Promotion of Science [25293172, 21229009, 24229005, 24659363]; Japanese Society of Gastroenterology; Special Coordination Funds by the Ministry of Education, Culture, Sports, Science and Technology of Japan; Astellas Pharma in Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program; National Institutes of Health FX This work was supported by Grant-in-Aid for Scientific Research (25293172, 21229009, 24229005, and 24659363) from the Japan Society for the Promotion of Science, the Japanese Society of Gastroenterology, and the Special Coordination Funds by the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Astellas Pharma in Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program, and by the Intramural Research Program of the National Institutes of Health. We thank Ms M. Tosaka and Dr H. Ezoe for their support. NR 43 TC 6 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD NOV PY 2014 VL 7 IS 6 BP 1312 EP 1325 DI 10.1038/mi.2014.19 PG 14 WC Immunology SC Immunology GA AS2ED UT WOS:000344091700004 PM 24670424 ER PT J AU Wood, AR Esko, T Yang, J Vedantam, S Pers, TH Gustafsson, S Chun, AY Estrada, K Luan, J Kutalik, Z Amin, N Buchkovich, ML Croteau-Chonka, DC Day, FR Duan, Y Fall, T Fehrmann, R Ferreira, T Jackson, AU Karjalainen, J Lo, KS Locke, AE Magi, R Mihailov, E Porcu, E Randall, JC Scherag, A Vinkhuyzen, AAE Westra, HJ Winkler, TW Workalemahu, T Zhao, JH Absher, D Albrecht, E Anderson, D Baron, J Beekman, M Demirkan, A Ehret, GB Feenstra, B Feitosa, MF Fischer, K Fraser, RM Goel, A Gong, J Justice, AE Kanoni, S Kleber, ME Kristiansson, K Lim, U Lotay, V Lui, JC Mangino, M Leach, IM Medina-Gomez, C Nalls, MA Nyholt, DR Palmer, CD Pasko, D Pechlivanis, S Prokopenko, I Ried, JS Ripke, S Shungin, D Stancakova, A Strawbridge, RJ Sung, YJ Tanaka, T Teumer, A Trompet, S van der Laan, SW van Setten, J Van Vliet-Ostaptchouk, JV Wang, ZM Yengo, L Zhang, WH Afzal, U Arnlov, J Arscott, GM Bandinelli, S Barrett, A Bellis, C Bennett, AJ Berne, C Bluher, M Bolton, JL Bottcher, Y Boyd, HA Bruinenberg, M Buckley, BM Buyske, S Caspersen, IH Chines, PS Clarke, R Claudi-Boehm, S Cooper, M Daw, EW De Jong, PA Deelen, J Delgado, G Denny, JC Dhonukshe-Rutten, R Dimitriou, M Doney, ASF Dorr, M Eklund, N Eury, E Folkersen, L Garcia, ME Geller, F Giedraitis, V Go, AS Grallert, H Grammer, TB Grassler, J Gronberg, H de Groot, LCPGM Groves, CJ Haessler, J Hall, P Haller, T Hallmans, G Hannemann, A Hartman, CA Hassinen, M Hayward, C Heard-Costa, NL Helmer, Q Hemani, G Henders, AK Hillege, HL Hlatky, MA Hoffmann, W Hoffmann, P Holmen, O Houwing-Duistermaat, JJ Illig, T Isaacs, A James, AL Jeff, J Johansen, B Johansson, A Jolley, J Juliusdottir, T Junttila, J Kho, AN Kinnunen, L Klopp, N Kocher, T Kratzer, W Lichtner, P Lind, L Lindstrom, J Lobbens, S Lorentzon, M Lu, YC Lyssenko, V Magnusson, PKE Mahajan, A Maillard, M McArdle, WL McKenzie, CA McLachlan, S McLaren, PJ Menni, C Merger, S Milani, L Moayyeri, A Monda, KL Morken, MA Muller, G Muller-Nurasyid, M Musk, AW Narisu, N Nauck, M Nolte, IM Nothen, MM Oozageer, L Pilz, S Rayner, NW Renstrom, F Robertson, NR Rose, LM Roussel, R Sanna, S Scharnagl, H Scholtens, S Schumacher, FR Schunkert, H Scott, RA Sehmi, J Seufferlein, T Shin, JX Silventoinen, K Smit, JH Smith, AV Smolonska, J Stanton, AV Stirrups, K Stott, DJ Stringham, HM Sundstrom, J Swertz, MA Syvanen, AC Tayo, BO Thorleifsson, G Tyrer, JP van Dijk, S van Schoor, NM van der Velde, N van Heemst, D van Oort, FVA Vermeulen, SH Verweij, N Vonk, JM Waite, LL Waldenberger, M Wennauer, R Wilkens, LR Willenborg, C Wilsgaard, T Wojczynski, MK Wong, A Wright, AF Zhang, QY Arveiler, D Bakker, SJL Beilby, J Bergman, RN Bergmann, S Biffar, R Blangero, J Boomsma, DI Bornstein, SR Bovet, P Brambilla, P Brown, MJ Campbell, H Caulfield, MJ Chakravarti, A Collins, R Collins, FS Crawford, DC Cupples, LA Danesh, J de Faire, U den Ruijter, HM Erbel, R Erdmann, J Eriksson, JG Farrall, M Ferrannini, E Ferrieres, J Ford, I Forouhi, NG Forrester, T Gansevoort, RT Gejman, PV Gieger, C Golay, A Gottesman, O Gudnason, V Gyllensten, U Haas, DW Hall, AS Harris, TB Hattersley, AT Heath, AC Hengstenberg, C Hicks, AA Hindorff, LA Hingorani, AD Hofman, A Hovingh, GK Humphries, SE Hunt, SC Hypponen, E Jacobs, KB Jarvelin, MR Jousilahti, P Jula, AM Kaprio, J Kastelein, JJP Kayser, M Kee, F Keinanen-Kiukaanniemi, SM Kiemeney, LA Kooner, JS Kooperberg, C Koskinen, S Kovacs, P Kraja, AT Kumari, M Kuusisto, J Lakka, TA Langenberg, C Le Marchand, L Lehtimaki, T Lupoli, S Madden, PAF Mannisto, S Manunta, P Marette, A Matise, TC McKnight, B Meitinger, T Moll, FL Montgomery, GW Morris, AD Morris, AP Murray, JC Nelis, M Ohlsson, C Oldehinkel, AJ Ong, KK Ouwehand, WH Pasterkamp, G Peters, A Pramstaller, PP Price, JF Qi, L Raitakari, OT Rankinen, T Rao, DC Rice, TK Ritchie, M Rudan, I Salomaa, V Samani, NJ Saramies, J Sarzynski, MA Schwarz, PEH Sebert, S Sever, P Shuldiner, AR Sinisalo, J Steinthorsdottir, V Stolk, RP Tardif, JC Tonjes, A Tremblay, A Tremoli, E Virtamo, J Vohl, MC Amouyel, P Asselbergs, FW Assimes, TL Bochud, M Boehm, BO Boerwinkle, E Bottinger, EP Bouchard, C Cauchi, S Chambers, JC Chanock, SJ Cooper, RS de Bakker, PIW Dedoussis, G Ferrucci, L Franks, PW Froguel, P Groop, LC Haiman, CA Hamsten, A Hayes, MG Hui, J Hunter, DJ Hveem, K Jukema, JW Kaplan, RC Kivimaki, M Kuh, D Laakso, M Liu, YM Martin, NG Marz, W Melbye, M Moebus, S Munroe, PB Njolstad, I Oostra, BA Palmer, CNA Pedersen, NL Perola, M Perusse, L Peters, U Powell, JE Power, C Quertermous, T Rauramaa, R Reinmaa, E Ridker, PM Rivadeneira, F Rotter, JI Saaristo, TE Saleheen, D Schlessinger, D Slagboom, PE Snieder, H Spector, TD Strauch, K Stumvoll, M Tuomilehto, J Uusitupa, M van der Harst, P Volzke, H Walker, M Wareham, NJ Watkins, H Wichmann, HE Wilson, JF Zanen, P Deloukas, P Heid, IM Lindgren, CM Mohlke, KL Speliotes, EK Thorsteinsdottir, U Barroso, I Fox, CS North, KE Strachan, DP Beckmann, JS Berndt, SI Boehnke, M Borecki, IB McCarthy, MI Metspalu, A Stefansson, K Uitterlinden, AG van Duijn, CM Franke, L Willer, CJ Price, AL Lettre, G Loos, RJF Weedon, MN Ingelsson, E O'Connell, JR Abecasis, GR Chasman, DI Goddard, ME Visscher, PM Hirschhorn, JN Frayling, TM AF Wood, Andrew R. Esko, Tonu Yang, Jian Vedantam, Sailaja Pers, Tune H. Gustafsson, Stefan Chun, Audrey Y. Estrada, Karol Luan, Jian'an Kutalik, Zoltan Amin, Najaf Buchkovich, Martin L. Croteau-Chonka, Damien C. Day, Felix R. Duan, Yanan Fall, Tove Fehrmann, Rudolf Ferreira, Teresa Jackson, Anne U. Karjalainen, Juha Lo, Ken Sin Locke, Adam E. Maegi, Reedik Mihailov, Evelin Porcu, Eleonora Randall, Joshua C. Scherag, Andre Vinkhuyzen, Anna A. E. Westra, Harm-Jan Winkler, Thomas W. Workalemahu, Tsegaselassie Zhao, Jing Hua Absher, Devin Albrecht, Eva Anderson, Denise Baron, Jeffrey Beekman, Marian Demirkan, Ayse Ehret, Georg B. Feenstra, Bjarke Feitosa, Mary F. Fischer, Krista Fraser, Ross M. Goel, Anuj Gong, Jian Justice, Anne E. Kanoni, Stavroula Kleber, Marcus E. Kristiansson, Kati Lim, Unhee Lotay, Vaneet Lui, Julian C. Mangino, Massimo Leach, Irene Mateo Medina-Gomez, Carolina Nalls, Michael A. Nyholt, Dale R. Palmer, Cameron D. Pasko, Dorota Pechlivanis, Sonali Prokopenko, Inga Ried, Janina S. Ripke, Stephan Shungin, Dmitry Stancakova, Alena Strawbridge, Rona J. Sung, Yun Ju Tanaka, Toshiko Teumer, Alexander Trompet, Stella van der Laan, Sander W. van Setten, Jessica Van Vliet-Ostaptchouk, Jana V. Wang, Zhaoming Yengo, Loic Zhang, Weihua Afzal, Uzma Arnloev, Johan Arscott, Gillian M. Bandinelli, Stefania Barrett, Amy Bellis, Claire Bennett, Amanda J. Berne, Christian Blueher, Matthias Bolton, Jennifer L. Boettcher, Yvonne Boyd, Heather A. Bruinenberg, Marcel Buckley, Brendan M. Buyske, Steven Caspersen, Ida H. Chines, Peter S. Clarke, Robert Claudi-Boehm, Simone Cooper, Matthew Daw, E. Warwick De Jong, Pim A. Deelen, Joris Delgado, Graciela Denny, Josh C. Dhonukshe-Rutten, Rosalie Dimitriou, Maria Doney, Alex S. F. Doerr, Marcus Eklund, Niina Eury, Elodie Folkersen, Lasse Garcia, Melissa E. Geller, Frank Giedraitis, Vilmantas Go, Alan S. Grallert, Harald Grammer, Tanja B. Graessler, Juergen Groenberg, Henrik de Groot, Lisette C. P. G. M. Groves, Christopher J. Haessler, Jeffrey Hall, Per Haller, Toomas Hallmans, Goran Hannemann, Anke Hartman, Catharina A. Hassinen, Maija Hayward, Caroline Heard-Costa, Nancy L. Helmer, Quinta Hemani, Gibran Henders, Anjali K. Hillege, Hans L. Hlatky, Mark A. Hoffmann, Wolfgang Hoffmann, Per Holmen, Oddgeir Houwing-Duistermaat, Jeanine J. Illig, Thomas Isaacs, Aaron James, Alan L. Jeff, Janina Johansen, Bent Johansson, Asa Jolley, Jennifer Juliusdottir, Thorhildur Junttila, Juhani Kho, Abel N. Kinnunen, Leena Klopp, Norman Kocher, Thomas Kratzer, Wolfgang Lichtner, Peter Lind, Lars Lindstroem, Jaana Lobbens, Stephane Lorentzon, Mattias Lu, Yingchang Lyssenko, Valeriya Magnusson, Patrik K. E. Mahajan, Anubha Maillard, Marc McArdle, Wendy L. McKenzie, Colin A. McLachlan, Stela McLaren, Paul J. Menni, Cristina Merger, Sigrun Milani, Lili Moayyeri, Alireza Monda, Keri L. Morken, Mario A. Mueller, Gabriele Mueller-Nurasyid, Martina Musk, Arthur W. Narisu, Narisu Nauck, Matthias Nolte, Ilja M. Noethen, Markus M. Oozageer, Laticia Pilz, Stefan Rayner, Nigel W. Renstrom, Frida Robertson, Neil R. Rose, Lynda M. Roussel, Ronan Sanna, Serena Scharnagl, Hubert Scholtens, Salome Schumacher, Fredrick R. Schunkert, Heribert Scott, Robert A. Sehmi, Joban Seufferlein, Thomas Shin, Jianxin Silventoinen, Karri Smit, Johannes H. Smith, Albert Vernon Smolonska, Joanna Stanton, Alice V. Stirrups, Kathleen Stott, David J. Stringham, Heather M. Sundstrom, Johan Swertz, Morris A. Syvanen, Ann-Christine Tayo, Bamidele O. Thorleifsson, Gudmar Tyrer, Jonathan P. van Dijk, Suzanne van Schoor, Natasja M. van der Velde, Nathalie van Heemst, Diana van Oort, Floor V. A. Vermeulen, Sita H. Verweij, Niek Vonk, Judith M. Waite, Lindsay L. Waldenberger, Melanie Wennauer, Roman Wilkens, Lynne R. Willenborg, Christina Wilsgaard, Tom Wojczynski, Mary K. Wong, Andrew Wright, Alan F. Zhang, Qunyuan Arveiler, Dominique Bakker, Stephan J. L. Beilby, John Bergman, Richard N. Bergmann, Sven Biffar, Reiner Blangero, John Boomsma, Dorret I. Bornstein, Stefan R. Bovet, Pascal Brambilla, Paolo Brown, Morris J. Campbell, Harry Caulfield, Mark J. Chakravarti, Aravinda Collins, Rory Collins, Francis S. Crawford, Dana C. Cupples, L. Adrienne Danesh, John de Faire, Ulf den Ruijter, Hester M. Erbel, Raimund Erdmann, Jeanette Eriksson, Johan G. Farrall, Martin Ferrannini, Ele Ferrieres, Jean Ford, Ian Forouhi, Nita G. Forrester, Terrence Gansevoort, Ron T. Gejman, Pablo V. Gieger, Christian Golay, Alain Gottesman, Omri Gudnason, Vilmundur Gyllensten, Ulf Haas, David W. Hall, Alistair S. Harris, Tamara B. Hattersley, Andrew T. Heath, Andrew C. Hengstenberg, Christian Hicks, Andrew A. Hindorff, Lucia A. Hingorani, Aroon D. Hofman, Albert Hovingh, G. Kees Humphries, Steve E. Hunt, Steven C. Hypponen, Elina Jacobs, Kevin B. Jarvelin, Marjo-Riitta Jousilahti, Pekka Jula, Antti M. Kaprio, Jaakko Kastelein, John J. P. Kayser, Manfred Kee, Frank Keinanen-Kiukaanniemi, Sirkka M. Kiemeney, Lambertus A. Kooner, Jaspal S. Kooperberg, Charles Koskinen, Seppo Kovacs, Peter Kraja, Aldi T. Kumari, Meena Kuusisto, Johanna Lakka, Timo A. Langenberg, Claudia Le Marchand, Loic Lehtimaki, Terho Lupoli, Sara Madden, Pamela A. F. Mannisto, Satu Manunta, Paolo Marette, Andre Matise, Tara C. McKnight, Barbara Meitinger, Thomas Moll, Frans L. Montgomery, Grant W. Morris, Andrew D. Morris, Andrew P. Murray, Jeffrey C. Nelis, Mari Ohlsson, Claes Oldehinkel, Albertine J. Ong, Ken K. Ouwehand, Willem H. Pasterkamp, Gerard Peters, Annette Pramstaller, Peter P. Price, Jackie F. Qi, Lu Raitakari, Olli T. Rankinen, Tuomo Rao, D. C. Rice, Treva K. Ritchie, Marylyn Rudan, Igor Salomaa, Veikko Samani, Nilesh J. Saramies, Jouko Sarzynski, Mark A. Schwarz, Peter E. H. Sebert, Sylvain Sever, Peter Shuldiner, Alan R. Sinisalo, Juha Steinthorsdottir, Valgerdur Stolk, Ronald P. Tardif, Jean-Claude Toenjes, Anke Tremblay, Angelo Tremoli, Elena Virtamo, Jarmo Vohl, Marie-Claude Amouyel, Philippe Asselbergs, Folkert W. Assimes, Themistocles L. Bochud, Murielle Boehm, Bernhard O. Boerwinkle, Eric Bottinger, Erwin P. Bouchard, Claude Cauchi, Stephane Chambers, John C. Chanock, Stephen J. Cooper, Richard S. de Bakker, Paul I. W. Dedoussis, George Ferrucci, Luigi Franks, Paul W. Froguel, Philippe Groop, Leif C. Haiman, Christopher A. Hamsten, Anders Hayes, M. Geoffrey Hui, Jennie Hunter, David J. Hveem, Kristian Jukema, J. Wouter Kaplan, Robert C. Kivimaki, Mika Kuh, Diana Laakso, Markku Liu, Yongmei Martin, Nicholas G. Maerz, Winfried Melbye, Mads Moebus, Susanne Munroe, Patricia B. Njolstad, Inger Oostra, Ben A. Palmer, Colin N. A. Pedersen, Nancy L. Perola, Markus Perusse, Louis Peters, Ulrike Powell, Joseph E. Power, Chris Quertermous, Thomas Rauramaa, Rainer Reinmaa, Eva Ridker, Paul M. Rivadeneira, Fernando Rotter, Jerome I. Saaristo, Timo E. Saleheen, Danish Schlessinger, David Slagboom, P. Eline Snieder, Harold Spector, Tim D. Strauch, Konstantin Stumvoll, Michael Tuomilehto, Jaakko Uusitupa, Matti van der Harst, Pim Voelzke, Henry Walker, Mark Wareham, Nicholas J. Watkins, Hugh Wichmann, H-Erich Wilson, James F. Zanen, Pieter Deloukas, Panos Heid, Iris M. Lindgren, Cecilia M. Mohlke, Karen L. Speliotes, Elizabeth K. Thorsteinsdottir, Unnur Barroso, Ines Fox, Caroline S. North, Kari E. Strachan, David P. Beckmann, Jacques S. Berndt, Sonja I. Boehnke, Michael Borecki, Ingrid B. McCarthy, Mark I. Metspalu, Andres Stefansson, Kari Uitterlinden, Andre G. van Duijn, Cornelia M. Franke, Lude Willer, Cristen J. Price, Alkes L. Lettre, Guillaume Loos, Ruth J. F. Weedon, Michael N. Ingelsson, Erik O'Connell, Jeffrey R. Abecasis, Goncalo R. Chasman, Daniel I. Goddard, Michael E. Visscher, Peter M. Hirschhorn, Joel N. Frayling, Timothy M. CA Elect Med Records & Genom eMERGE C MIGen Consortium PAGE Consortium LifeLines Cohort Study TI Defining the role of common variation in the genomic and biological architecture of adult human height SO NATURE GENETICS LA English DT Article ID GENETIC-VARIATION; COMPLEX TRAITS; HERITABILITY; MUTATIONS; SNPS AB Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated similar to 2,000, similar to 3,700 and similar to 9,500 SNPs explained similar to 21%, similar to 24% and similar to 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants. C1 [Wood, Andrew R.; Pasko, Dorota; Weedon, Michael N.; Frayling, Timothy M.] Univ Exeter, Sch Med, Exeter, Devon, England. [Esko, Tonu; Maegi, Reedik; Mihailov, Evelin; Fischer, Krista; Haller, Toomas; Milani, Lili; Morris, Andrew P.; Nelis, Mari; Perola, Markus; Reinmaa, Eva; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. 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[Bovet, Pascal; Bochud, Murielle] Minist Hlth, Victoria, Seychelles. [Brambilla, Paolo] Univ Milan, Hosp Desio, Dept Hlth Sci, Bicocca, Italy. [Brown, Morris J.] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England. [Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Cupples, L. Adrienne] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [de Faire, Ulf] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden. [den Ruijter, Hester M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Erbel, Raimund] Univ Hosp Essen, West German Heart Ctr, Essen, Germany. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Ferrannini, Ele] Univ Pisa, Dept Internal Med, Pisa, Italy. [Ferrannini, Ele] Univ Pisa, Inst Clin Physiol, Natl Res Council CNR, Pisa, Italy. [Ferrieres, Jean] Toulouse Univ, Rangueil Hosp, Sch Med, Dept Cardiol, Toulouse, France. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Gejman, Pablo V.] Univ Chicago, NorthShore Univ HealthSyst, Evanston, IL USA. [Golay, Alain] Univ Hosp Geneva, Serv Therapeut Educ Diabet Obes & Chron Dis, Geneva, Switzerland. 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[Humphries, Steve E.] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Hunt, Steven C.] Univ Utah, Cardiovasc Genet Div, Dept Internal Med, Salt Lake City, UT USA. [Hypponen, Elina; Hui, Jennie] Univ S Australia, Sch Populat Hlth, Adelaide, SA 5001, Australia. [Hypponen, Elina; Hui, Jennie] Univ S Australia, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia. [Hypponen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Hypponen, Elina; Power, Chris] UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Jarvelin, Marjo-Riitta; O'Connell, Jeffrey R.] Natl Inst Hlth & Welf, Oulu, Finland. [Jarvelin, Marjo-Riitta; O'Connell, Jeffrey R.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Ctr Environm & Hlth, MRC Hlth Protect Agcy HPA, London, England. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. 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[Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester, Leics, England. [Saramies, Jouko] South Carelia Cent Hosp, Lappeenranta, Finland. [Schwarz, Peter E. H.] German Ctr Diabet Res DZD, Paul Langerhans Inst Dresden, Dresden, Germany. [Sever, Peter] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, London, England. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vetrans Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Sinisalo, Juha] Univ Helsinki, Cent Hosp, Heart & Lung Ctr, Dept Med, Helsinki, Finland. [Tardif, Jean-Claude; Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. 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W.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet,Dept Med, Boston, MA 02114 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands. [Groop, Leif C.] Lund Univ, Ctr Diabet, Malmo, Sweden. [Groop, Leif C.] Lund Univ, Diabet & Endocrinol Unit, Dept Clin Sci, Malmo, Sweden. [Hunter, David J.; Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Belfer, NY USA. [Liu, Yongmei] Wake Forest Sch Med, Ctr Human Genet, Div Publ Hlth Sci, Winston Salem, NC USA. [Maerz, Winfried] Synlab Acad, Synlab Serv, Mannheim, Germany. [Oostra, Ben A.] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Rotter, Jerome I.] Univ Calif Los Angeles, Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst Harbor, Torrance, CA 90509 USA. [Saaristo, Timo E.] Finnish Diabet Assoc, Tampere, Finland. [Saaristo, Timo E.] Pirkanmaa Hosp Dist, Tampere, Finland. [Saleheen, Danish] Ctr Noncommun Dis, Karatchi, Pakistan. [Saleheen, Danish] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Schlessinger, David] Natl Inst Aging, Genet Lab, Baltimore, MD USA. [Tuomilehto, Jaakko] Hosp Univ La Paz IdiPAZ, Inst Invest Sanit, Madrid, Spain. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Uusitupa, Matti] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, Kuopio, Finland. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, Munich, Germany. [Walker, Mark; Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-80539 Munich, Germany. [Wichmann, H-Erich] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, Neuherberg, Germany. [Zanen, Pieter] Univ Med Ctr Utrecht, Dept Pulmonol, Utrecht, Netherlands. [Deloukas, Panos] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Barroso, Ines] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England. [Barroso, Ines] NIHR Cambridge, Addenbrookes Hosp, Biomed Res Ctr, Inst Metab Sci, Cambridge, England. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Strachan, David P.] Univ London, Div Populat Hlth Sci & Educ, London, England. [Beckmann, Jacques S.] CHUV Univ Hosp, Serv Med Genet, Lausanne, Switzerland. [McCarthy, Mark I.] Oxford Univ Hosp NHS Trust, Oxford NIHR Biomed Res Ctr, Oxford, England. [Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Melbourne, Vic, Australia. [Goddard, Michael E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic, Australia. RP Visscher, PM (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. 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Eline/0000-0002-2875-4723; Wong, Andrew/0000-0003-2079-4779; Sundstrom, Johan/0000-0003-2247-8454; Hypponen, Elina/0000-0003-3670-9399; Bovet, Pascal/0000-0002-0242-4259; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Nato, Alejandro/0000-0002-8745-9046; Yang, Jian/0000-0003-2001-2474; kinnunen, leena/0000-0001-8739-4812; Bochud, Murielle/0000-0002-5727-0218; de Jong, Pim/0000-0003-4840-6854; Bakker, Stephan/0000-0003-3356-6791; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Montgomery, Grant/0000-0002-4140-8139; Deloukas, Panos/0000-0001-9251-070X; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; de Bakker, Paul/0000-0001-7735-7858; Fehrmann, Rudolf/0000-0002-7516-315X; Darbar, Dawood/0000-0002-4103-5977; Kiemeney, Lambertus/0000-0002-2368-1326; EHRET, Georg/0000-0002-5730-0675; Strawbridge, Rona/0000-0001-8506-3585 FU British Heart Foundation [FS/11/35/28871, FS/12/33/29561, FS/12/8/29377, FS/14/12/30540, PG/07/085/23349, RG/08/008/25291, RG/08/014/24067, RG/09/012/28096, RG/10/12/28456, SP/08/002/24118]; Chief Scientist Office [CZB/4/672, CZB/4/710]; Department of Health [RP-PG-0310-1002]; European Research Council [323195]; Medical Research Council [MC_UU_12015/5, G0500070, G0601463, G1002084, MC_PC_U127561128, MC_U106179471, MC_U106179472, MC_UP_A100_1003, MC_UU_12015/1, MC_UU_12015/2, MC_UU_12019/1, MR/K006584/1, MR/K013351/1, MR/L003120/1, MR/L01629X/1]; NCATS NIH HHS [UL1 TR000124]; NCI NIH HHS [P30 CA015704, P30 CA071789]; NHGRI NIH HHS [U01 HG007419]; NHLBI NIH HHS [R01 HL109946, R01 HL117626, T32 HL007055]; NICHD NIH HHS [P30 HD018655]; NIDDK NIH HHS [P30 DK063491, P30 DK072488, R01 DK072193, R01 DK075787, R01 DK093757, U01 DK062370]; NIGMS NIH HHS [P01 GM099568, P30 GM103341, R01 GM075091, T32 GM080178]; Wellcome Trust [085301, 090532, 098381, 098395] NR 21 TC 296 Z9 299 U1 27 U2 179 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2014 VL 46 IS 11 BP 1173 EP 1186 DI 10.1038/ng.3097 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AS2TI UT WOS:000344131900008 PM 25282103 ER PT J AU Cerhan, JR Berndt, SI Vijai, J Ghesquieres, H McKay, J Wang, SS Wang, ZM Yeager, M Conde, L de Bakker, PIW Nieters, A Cox, D Burdett, L Monnereau, A Flowers, CR De Roos, AJ Brooks-Wilson, AR Lan, Q Severi, G Melbye, M Gu, J Jackson, RD Kane, E Teras, LR Purdue, MP Vajdic, CM Spinelli, JJ Giles, GG 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 Weiner, GJ Veron, AS Zelenika, D Tilly, H Haioun, C Molina, TJ Hjalgrim, H Glimelius, B Adami, HO 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 Kricker, A Turner, J Southey, MC Clavel, J Virtamo, J Weinstein, S Riboli, E Vineis, P Kaaks, R Trichopoulos, D Vermeulen, RCH Boeing, H Tjonneland, A Angelucci, E Di Lollo, S Rais, M Birmann, BM Laden, F Giovannucci, E Kraft, P Huang, JY Ma, BS Ye, YQ Chiu, BCH Sampson, J Liang, LM Park, JH Chung, CC Weisenburger, DD Chatterjee, N Fraumeni, JF Slager, SL Wu, XF de Sanjose, S Smedby, KE Salles, G Skibola, CF Rothman, N Chanock, SJ AF Cerhan, James R. Berndt, Sonja I. Vijai, Joseph Ghesquieres, Herve McKay, James Wang, Sophia S. Wang, Zhaoming Yeager, Meredith Conde, Lucia de Bakker, Paul I. W. Nieters, Alexandra Cox, David Burdett, Laurie Monnereau, Alain Flowers, Christopher R. De Roos, Anneclaire J. Brooks-Wilson, Angela R. Lan, Qing Severi, Gianluca Melbye, Mads Gu, Jian Jackson, Rebecca D. Kane, Eleanor Teras, Lauren R. Purdue, Mark P. Vajdic, Claire M. Spinelli, John J. Giles, Graham G. 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. Weiner, George J. Veron, Amelie S. Zelenika, Diana Tilly, Herve Haioun, Corinne Molina, Thierry Jo Hjalgrim, Henrik Glimelius, Bengt Adami, Hans-Olov 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. Kricker, Anne Turner, Jenny Southey, Melissa C. Clavel, Jacqueline Virtamo, Jarmo Weinstein, Stephanie Riboli, Elio Vineis, Paolo Kaaks, Rudolph Trichopoulos, Dimitrios Vermeulen, Roel C. H. Boeing, Heiner Tjonneland, Anne Angelucci, Emanuele Di Lollo, Simonetta Rais, Marco Birmann, Brenda M. Laden, Francine Giovannucci, Edward Kraft, Peter Huang, Jinyan Ma, Baoshan Ye, Yuanqing Chiu, Brian C. H. Sampson, Joshua Liang, Liming Park, Ju-Hyun Chung, Charles C. Weisenburger, Dennis D. Chatterjee, Nilanjan Fraumeni, Joseph F., Jr. Slager, Susan L. Wu, Xifeng de Sanjose, Silvia Smedby, Karin E. Salles, Gilles Skibola, Christine F. Rothman, Nathaniel Chanock, Stephen J. TI Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma SO NATURE GENETICS LA English DT Article ID NON-HODGKIN-LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; NECROSIS-FACTOR TNF; FOLLICULAR LYMPHOMA; COMMON VARIANTS; RAL GTPASES; RISK; CANCER; TUMORIGENESIS; POPULATION AB Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10(-13) and 3.63 x 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL. C1 [Cerhan, James R.; Slager, Susan L.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Berndt, Sonja I.; Vijai, Joseph; Lan, Qing; Purdue, Mark P.; Albanes, Demetrius; Hartge, Patricia; Morton, Lindsay M.; Weinstein, Stephanie; Sampson, Joshua; Chung, Charles C.; Chatterjee, Nilanjan; Fraumeni, Joseph F., Jr.; Rothman, Nathaniel; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J.; Villano, Danylo J.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Ghesquieres, Herve] Ctr Leon Berard, Dept Hematol, F-69373 Lyon, France. [Ghesquieres, Herve; Salles, Gilles] CNRS, UMR 5239, Lab Biol Mol Cellule, Pierre Benite, France. [McKay, James] Int Agcy Res Canc, Genet Sect, Genet Canc Susceptibil Grp, F-69372 Lyon, France. [Wang, Sophia S.] City Hope Beckman Res Inst, Dept Canc Etiol, Duarte, CA USA. [Wang, Zhaoming; Yeager, Meredith; Burdett, Laurie; De Roos, Anneclaire J.; Hutchinson, Amy] NCI, Div Canc Epidemiol & Genet, Canc Genom Res Lab, Gaithersburg, MD USA. [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. [Conde, Lucia; Riby, Jacques; Smith, Martyn T.; Skibola, Christine F.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet & Epidemiol, Utrecht, Netherlands. [de Bakker, Paul I. W.; Vermeulen, Roel C. H.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Nieters, Alexandra] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [Cox, David; Veron, Amelie S.] Ctr Leon Berard, Canc Res Ctr Lyon, F-69373 Lyon, France. [Monnereau, Alain; Clavel, Jacqueline] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Environm Epidemiol Canc Grp, Villejuif, France. [Monnereau, Alain; Clavel, Jacqueline] Univ Paris 11, UMRS 1018, Villejuif, 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, Seattle, WA 98104 USA. [Brooks-Wilson, Angela R.] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Brooks-Wilson, Angela R.] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Severi, Gianluca; Vineis, Paolo] Human Genet Fdn, Turin, Italy. [Severi, Gianluca; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Severi, Gianluca; Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, 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, Sch Med, Dept Med, Stanford, CA USA. [Gu, Jian; Ye, Yuanqing; Wu, Xifeng] Univ Texas Houston, 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. [Teras, Lauren R.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Vajdic, Claire M.] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia. [Spinelli, John J.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC V5Z 4E6, Canada. [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Kelly, Rachel S.; Bertrand, Kimberly A.; Adami, Hans-Olov; Trichopoulos, Dimitrios; Laden, Francine; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kelly, Rachel S.; Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Ctr Environm & Hlth, MRC,Publ Hlth England, London, England. [Zucca, Mariagrazia] Univ Cagliari, Dept Biomed Sci, Monserrato, Italy. [Bertrand, Kimberly A.; Birmann, Brenda M.; Laden, Francine; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Bertrand, Kimberly A.; Birmann, Brenda M.; Laden, Francine; Giovannucci, Edward] 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, Inst Canc, New York, NY USA. [Lawrence, Charles] Westat Corp, Hlth Studies Sector, Rockville, MD USA. [Zhi, Degui] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 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. [Link, Brian K.; Weiner, George J.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Dogan, Ahmet] Mem Sloan Kettering Canc Ctr, Dept Lab Med & Pathol, New York, NY 10021 USA. [Asmann, Yan W.] Mayo Clin, Div Biomed Stat & Informat, Jacksonville, FL 32224 USA. [Zelenika, Diana] Ctr Natl Genotypage, Evry, France. [Tilly, Herve] Ctr Henri Becquerel, F-76038 Rouen, France. [Haioun, Corinne] CHU Henri Mondor, Dept Hematol, F-94010 Creteil, France. [Molina, Thierry Jo] Univ Paris 05, Sorbonne Paris Cite, Necker Enfants Malades, Dept Pathol, Paris, France. [Glimelius, Bengt] Karolinska Univ Hosp Solna, Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden. [Glimelius, Bengt] Uppsala Univ, Dept Radiol Oncol & Radiat Sci, Uppsala, Sweden. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, 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, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, 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; Clavel, Jacqueline; Kaaks, Rudolph] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Benavente, Yolanda; de Sanjose, Silvia] Bellvitge Biomed Res Inst IDIBELL, Inst Catala Oncol, Canc Epidemiol Res Programme, Unit Infect & Canc UNIC, Barcelona, Spain. [Benavente, Yolanda; de Sanjose, Silvia] Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Barcelona, Spain. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Brennan, Paul] Int Agcy Res Canc, Genet Sect, Grp Genet Epidemiol, F-69372 Lyon, France. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Foretova, Lenka] Masaryk Univ, Brno, Czech Republic. [Maynadie, Marc] Univ Burgundy, Registre Hemopathies Malignes Cote Or, 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, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT USA. [Holford, Theodore R.] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT USA. [Kricker, Anne] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Turner, Jenny] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW 2109, Australia. [Turner, Jenny] Douglass Hanly Moir Pathol, Dept Histopathol, Macquarie Pk, NSW, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Vermeulen, Roel C. H.] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [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, Florence, Italy. [Rais, Marco] Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Monserrato, Italy. [Laden, Francine] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 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. [Ma, Baoshan] Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian, Peoples R China. [Chiu, Brian C. H.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Park, Ju-Hyun] Dongguk Univ Seoul, Seoul, South Korea. [Weisenburger, Dennis D.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Smedby, Karin E.] Karolinska Inst, Dept Med Solna, Stockholm, Sweden. [Salles, Gilles] Hosp Civils Lyon, Dept Hematol, Pierre Benite, France. [Salles, Gilles] Univ Lyon 1, Dept Hematol, Pierre Benite, France. RP Cerhan, JR (reprint author), Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. EM cerhan.james@mayo.edu RI de Sanjose Llongueras, Silvia/H-6339-2014; Cox, David/A-2023-2009; Clavel, Jacqueline/Q-2750-2016; Vermeulen, Roel/F-8037-2011; Flowers, Christopher/F-1953-2010; Monnereau, Alain/L-1249-2014; de Bakker, Paul/B-8730-2009; Morton, Lindsay/B-5234-2015; Albanes, Demetrius/B-9749-2015; Brooks-Wilson, Angela/E-9399-2012; Conde, Lucia/D-9295-2011; Purdue, Mark/C-9228-2016; OI Cox, David/0000-0002-2152-9259; Clavel, Jacqueline/0000-0002-3616-7676; Vermeulen, Roel/0000-0003-4082-8163; Angelucci, Emanuele/0000-0002-6512-6080; Flowers, Christopher/0000-0002-9524-3990; Monnereau, Alain/0000-0002-5056-1397; de Bakker, Paul/0000-0001-7735-7858; Morton, Lindsay/0000-0001-9767-2310; Brooks-Wilson, Angela/0000-0003-1009-6408; Purdue, Mark/0000-0003-1177-3108; Staines, Anthony/0000-0001-9161-1357; Salles, Gilles/0000-0002-9541-8666; Joseph, Vijai/0000-0002-7933-151X; Giles, Graham/0000-0003-4946-9099; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Intramural Program of the US National Institutes of Health/National Cancer Institute FX We thank C. Allmer, E. Angelucci, A. Bigelow, S. Buehler, K. Butterbach, A. Chabrier, J.M. Conners, M. Corines, M. Cornelis, K. Corsano, H. Dykes, L. Ershler, A. Gabbas, R.P. Gallagher, R.D. Gascoyne, P. Hui, L. Irish, L. Jacobus, L. Klareskog, A.S. Lai, J. Lunde, M. McAdams, R. Montalvan, L. Padyukov, M. Rais, T. Rattle, L. Rigacci, K. Snyder, G. Specchia, M. Stagner, G. Thomas, C. Tornow, G. Wood and M. Yang. The overall GWAS project was supported by the Intramural Program of the US National Institutes of Health/National Cancer Institute. A list of support provided to individual studies appears in the Supplementary Note. NR 41 TC 36 Z9 36 U1 3 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2014 VL 46 IS 11 BP 1233 EP 1238 DI 10.1038/ng.3105 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AS2TI UT WOS:000344131900015 PM 25261932 ER PT J AU Kumar, A Wu, YC Christensen, R Chandris, P Gandler, W McCreedy, E Bokinsky, A Colon-Ramos, DA Bao, ZR McAuliffe, M Rondeau, G Shroff, H AF Kumar, Abhishek Wu, Yicong Christensen, Ryan Chandris, Panagiotis Gandler, William McCreedy, Evan Bokinsky, Alexandra Colon-Ramos, Daniel A. Bao, Zhirong McAuliffe, Matthew Rondeau, Gary Shroff, Hari TI Dual-view plane illumination microscopy for rapid and spatially isotropic imaging SO NATURE PROTOCOLS LA English DT Article ID LIGHT-SHEET MICROSCOPY; LIVING CELLS; EMBRYOS; SPECIMENS; DYNAMICS; PLATFORM AB We describe the construction and use of a compact dual-view inverted selective plane illumination microscope (diSPIM) for time-lapse volumetric (4D) imaging of living samples at subcellular resolution. Our protocol enables a biologist with some prior microscopy experience to assemble a diSPIM from commercially available parts, to align optics and test system performance, to prepare samples, and to control hardware and data processing with our software. Unlike existing light sheet microscopy protocols, our method does not require the sample to be embedded in agarose; instead, samples are prepared conventionally on glass coverslips. Tissue culture cells and Caenorhabditis elegans embryos are used as examples in this protocol; successful implementation of the protocol results in isotropic resolution and acquisition speeds up to several volumes per s on these samples. Assembling and verifying diSPSPIM performance takes similar to 6 d, sample preparation and data acquisition take up to 5 d and postprocessing takes 3-8 h, depending on the size of the data. C1 [Kumar, Abhishek; Wu, Yicong; Christensen, Ryan; Chandris, Panagiotis; Shroff, Hari] US Natl Inst Hlth NIH, Sect High Resolut Optic Imaging, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20852 USA. [Kumar, Abhishek; Colon-Ramos, Daniel A.] Yale Univ, Sch Med, Dept Cell Biol, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT 06510 USA. [Gandler, William; McCreedy, Evan; Bokinsky, Alexandra; McAuliffe, Matthew] NIH, Biomed Imaging Res Serv Sect, Ctr Informat Technol, Bethesda, MD 20892 USA. [Bao, Zhirong] Sloan Kettering Inst, Dev Biol Program, New York, NY USA. [Rondeau, Gary] Appl Sci Instrumentat, Eugene, OR USA. RP Kumar, A (reprint author), US Natl Inst Hlth NIH, Sect High Resolut Optic Imaging, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20852 USA. EM abhishk@gmail.com; hari.shroff@nih.gov RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Bao, Zhirong/0000-0002-2201-2745 FU Intramural Research Programs of the NIH National Institute of Biomedical Imaging and Bioengineering; Center for Information Technology; NIH [U01 HD075602, OD016474]; Whitman research award FX We thank V. Kopuri and J. Daniels for their help with instrumentation; M. Anthony for the Solidworks drawings; A. Santella for troubleshooting registration issues with the MIPAV plug-in; and B. Mohler, A. York, H. Eden and J.-Bernard Fiche for their critical feedback on the diSPIM system. We also thank the Research Center for Minority Institutions program and the Institute of Neurobiology at the University of Puerto Rico for providing a meeting and brainstorming platform. This work was partially conducted at the Marine Biological Laboratories at Woods Hole, under a Whitman research award (to D.A.C.-R., Z.B. and H.S.). This work was supported by the Intramural Research Programs of the NIH National Institute of Biomedical Imaging and Bioengineering, the Center for Information Technology and by NIH grants U01 HD075602 and OD016474. The NIH does not endorse or recommend any commercial products, processes or services. The views and opinions of authors expressed here do not necessarily state or reflect those of the U.S. Government, and they may not be used for advertising and product endorsement purposes. Links to internet sites are only for the convenience of readers. The NIH is not responsible for the availability or the content of these external sites, nor does NIH endorse, warrant or guarantee the products, services or information described or offered at these internet sites. NR 24 TC 20 Z9 21 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD NOV PY 2014 VL 9 IS 11 BP 2555 EP 2573 DI 10.1038/nprot.2014.172 PG 19 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AS4LT UT WOS:000344248300003 PM 25299154 ER PT J AU Ileva, LV Bernardo, M Young, MR Riffle, LA Tatum, JL Kalen, JD Choyke, PL AF Ileva, Lilia V. Bernardo, Marcelino Young, Matthew R. Riffle, Lisa A. Tatum, James L. Kalen, Joseph D. Choyke, Peter L. TI In vivo MRI virtual colonography in a mouse model of colon cancer SO NATURE PROTOCOLS LA English DT Article ID MAGNETIC-RESONANCE COLONOGRAPHY; ACUTE LUNG INJURY; PARTIAL LIQUID VENTILATION; CONVENTIONAL COLONOSCOPY; POLYP DETECTION; MIN MICE; INFLAMMATION; CARCINOGENESIS; FEASIBILITY; PROGRESSION AB We have developed a reliable noninvasive method for monitoring colonic tumors and mucosal inflammation in a mouse model of colon cancer using magnetic resonance colonography (MRC). After a mild cleansing enema, the colon is filled with Fluorinert, a perfluorinated liquid that does not produce a proton MR signal. The mouse is placed in a dedicated volume MR receiver coil, and high-resolution images are acquired in three planes. The Fluorinert enema distends the mouse colon, creating an artifact-free black homogeneous background, allowing clear delineation of the inflamed colonic wall and visualization of luminal tumors in various stages of development. A gadolinium-based contrast agent can be administered i.v. to the animal to detect mural inflammation or tumor vascularity. This technique is useful for serial monitoring of the effects of preventive or therapeutic strategies on tumor development without killing the animal or requiring invasive endoscopies. The animal preparation and imaging can be completed in similar to 1.5 h. C1 [Ileva, Lilia V.; Riffle, Lisa A.; Kalen, Joseph D.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Lab Anim Sci Program, Small Anim Imaging Program, Frederick, MD 21701 USA. [Bernardo, Marcelino] Frederick Natl Lab Canc Res, Leidos Biomed Res, Lab Anim Sci Program, Mol Imaging Program, Frederick, MD USA. [Young, Matthew R.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Tatum, James L.] NCI, Canc Imaging Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ileva, LV (reprint author), Frederick Natl Lab Canc Res, Leidos Biomed Res, Lab Anim Sci Program, Small Anim Imaging Program, Frederick, MD 21701 USA. EM ileval@mail.nih.gov FU National Cancer Institute, US National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, US National Institutes of Health, 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 endorsement by the US Government. NR 36 TC 3 Z9 3 U1 3 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD NOV PY 2014 VL 9 IS 11 BP 2682 EP 2692 DI 10.1038/nprot.2014.178 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AS4LT UT WOS:000344248300012 PM 25340441 ER PT J AU Sargent, DJ Korn, EL AF Sargent, Daniel J. Korn, Edward L. TI Shifting paradigms in cancer clinical trial design SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID THERAPY; ISSUES C1 [Sargent, Daniel J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55902 USA. [Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Sargent, DJ (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55902 USA. EM sargent.daniel@mayo.edu NR 10 TC 3 Z9 3 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD NOV PY 2014 VL 11 IS 11 BP 625 EP 626 DI 10.1038/nrclinonc.2014.167 PG 2 WC Oncology SC Oncology GA AS7IC UT WOS:000344429100002 PM 25286977 ER PT J AU Rosenberg, SA AF Rosenberg, Steven A. TI Entering the mainstream of cancer treatment SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID IMMUNOTHERAPY; ANTIBODY; SAFETY; CELLS C1 NCI, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, 10 Ctr Dr MSC 1201, Bethesda, MD 20892 USA. EM sar@nih.gov NR 10 TC 25 Z9 28 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD NOV PY 2014 VL 11 IS 11 BP 630 EP 632 DI 10.1038/nrclinonc.2014.174 PG 3 WC Oncology SC Oncology GA AS7IC UT WOS:000344429100005 PM 25311350 ER PT J AU Fojo, T Giannakakou, P AF Fojo, Tito Giannakakou, Paraskevi TI National Cancer Institute awards-a work in progress SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID PROVOCATIVE QUESTIONS AB Over the past decade, funding for cancer research by the US government and others has stagnated, while the demand for investment has grown because of the increasing cancer incidence worldwide. We discuss how National Cancer Institute funding efforts have developed during this period, and the contemporary and future impact of these measures on cancer research in the USA. C1 [Fojo, Tito] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Giannakakou, Paraskevi] Weill Cornell Med Coll, Weill Cornell Canc Ctr, Dept Med, Div Hematol & Med Oncol, New York, NY 10021 USA. RP Fojo, T (reprint author), NCI, Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD NOV PY 2014 VL 11 IS 11 BP 634 EP 636 DI 10.1038/nrclinonc.2014.173 PG 3 WC Oncology SC Oncology GA AS7IC UT WOS:000344429100007 PM 25311348 ER PT J AU Doroshow, JH Kummar, S AF Doroshow, James H. Kummar, Shivaani TI Translational research in oncology-10 years of progress and future prospects SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID CIRCULATING TUMOR-CELLS; ANTICANCER DRUG DEVELOPMENT; METASTATIC BREAST-CANCER; LUNG-CANCER; EPITHELIAL-CELLS; MOUSE MODELS; T-CELLS; PHARMACODYNAMIC BIOMARKERS; MONOCLONAL-ANTIBODY; EMISSION-TOMOGRAPHY AB International efforts to sequence the genomes of various human cancers have been broadly deployed in drug discovery programmes. Diagnostic tests that predict the value of the molecularly targeted anticancer agents used in such programmes are conceived and validated in parallel with new small-molecule treatments and immunotherapies. This approach has been aided by better preclinical cancer models; an enhanced appreciation of the complex interactions that exist between tumour cells and their microenvironment; the elucidation of interactions between many of the genetic drivers of cancer, including oncogenes and tumour suppressors; and recent insights into the genetic heterogeneity of human tumours made possible by extraordinary improvements in DNA-sequencing techniques. These advances are being employed in the first generation of genomic clinical trials that will examine the feasibility of matching a broad range of systemic therapies to specific molecular tumour characteristics. More-extensive molecular characterization of tumours and their supporting matrices are anticipated to become standard aspects of oncological practice, permitting continuous molecular re-evaluations of human malignancies on a patient-by-patient and treatment-by-treatment basis. We review selected developments in translational cancer biology, diagnostics, and therapeutics that have occurred over the past decade and offer our thoughts on future prospects for the next few years. C1 [Doroshow, James H.; Kummar, Shivaani] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Doroshow, James H.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, NIH, Room 3A-44,Bldg 31,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov NR 144 TC 18 Z9 19 U1 3 U2 38 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD NOV PY 2014 VL 11 IS 11 BP 649 EP 662 DI 10.1038/nrclinonc.2014.158 PG 14 WC Oncology SC Oncology GA AS7IC UT WOS:000344429100009 PM 25286976 ER PT J AU Wholley, D AF Wholley, David TI The Biomarkers Consortium SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material ID PNEUMONIA; APPROVAL; TRIALS; CANCER; SKIN C1 NIH, Res Partnerships Fdn, Bethesda, MD 20892 USA. RP Wholley, D (reprint author), NIH, Res Partnerships Fdn, Bldg 10, Bethesda, MD 20892 USA. EM dwholley@fnih.org NR 5 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD NOV PY 2014 VL 13 IS 11 BP 791 EP 792 DI 10.1038/nrd4439 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AS4AR UT WOS:000344216500006 PM 25359363 ER PT J AU Cox, AD Fesik, SW Kimmelman, AC Luo, J Der, CJ AF Cox, Adrienne D. Fesik, Stephen W. Kimmelman, Alec C. Luo, Ji Der, Channing J. TI Drugging the undruggable RAS: Mission Possible? SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID PANCREATIC TUMOR-GROWTH; ONCOGENIC K-RAS; INDUCED MYELOPROLIFERATIVE DISEASE; SYNTHETIC LETHAL INTERACTIONS; MEDIATED NUCLEOTIDE EXCHANGE; SMALL-MOLECULE INHIBITION; SQUAMOUS-CELL CARCINOMAS; INDUCED LUNG-CANCER; IN-VIVO; FARNESYLTHIOSALICYLIC ACID AB Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches. C1 [Cox, Adrienne D.; Der, Channing J.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Fesik, Stephen W.] Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA. [Kimmelman, Alec C.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Luo, Ji] NCI, Bethesda, MD 20892 USA. RP Der, CJ (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. EM cjder@med.unc.edu FU US National Institutes of Health (NIH) [CA042978, CA179193, CA175747]; Lustgarten Foundation for Pancreatic Cancer Research, USA; Pancreatic Cancer Action Network-American Association for Cancer Research; NIH [DPI OD006933/DP1CA174419, P50A095103-12, RC2CA148375, R01 CA157490]; Lustgarten Foundation for Pancreatic Cancer Research; American Cancer Society Research Scholar Grant [RSG-13-298-01-TBG]; Lustgarten Foundation; US National Cancer Institute Intramural Program FX The work of C.J.D. and A.D.C. is supported by US National Institutes of Health (NIH) grants CA042978, CA179193 and CA175747, and by grants from the Lustgarten Foundation for Pancreatic Cancer Research, USA, and the Pancreatic Cancer Action Network-American Association for Cancer Research. The work of S.W.F. is supported by NIH grants DPI OD006933/DP1CA174419 (NIH Director's Pioneer Award; S.W F.), P50A095103-12 (NCI SPORE in GI Cancer; R. J. Coffey), and RC2CA148375 (NIH ARRA Stimulus Grant; L. J. Marnett), and by the Lustgarten Foundation for Pancreatic Cancer Research. The work of A.C.K. is supported by NIH grant R01 CA157490, American Cancer Society Research Scholar Grant RSG-13-298-01-TBG and by the Lustgarten Foundation. A.C.K. is a consultant for Forma Therapeutics. The work of J.L. is supported by the US National Cancer Institute Intramural Program. NR 230 TC 158 Z9 160 U1 15 U2 94 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD NOV PY 2014 VL 13 IS 11 BP 828 EP 851 DI 10.1038/nrd4389 PG 24 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AS4AR UT WOS:000344216500027 PM 25323927 ER PT J AU Fletcher, BR Hill, GS Long, JM Gallagher, M Shapiro, ML Rapp, PR AF Fletcher, Bonnie R. Hill, Gordon S. Long, Jeffrey M. Gallagher, Michela Shapiro, Matthew L. Rapp, Peter R. TI A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging SO NEUROBIOLOGY OF LEARNING AND MEMORY LA English DT Article DE Immediate-early gene; Memory; Plasticity; Synapse ID LONG-TERM POTENTIATION; EARLY GENE ARC; FRAGILE-X-SYNDROME; MESSENGER-RNA; PROTEIN-EXPRESSION; AMPA RECEPTOR; SPATIAL EXPLORATION; NEURAL PLASTICITY; IMPAIRMENT; SYNAPSES AB Memory decline is a common feature of aging. Expression of the immediate-early gene Arc is necessary for normal long-term memory, and although experience dependent Arc transcription is reportedly reduced in the aged rat hippocampus, it has not been clear whether this effect is an invariant consequence of growing older, or a finding linked specifically to age-related memory impairment. Here we show that experience dependent Arc mRNA expression in the hippocampus fails selectively among aged rats with spatial memory deficits. While these findings are consistent with the possibility that blunted Arc transcription contributes to cognitive aging, we also found increased basal ARC protein levels in the CA1 field of the hippocampus in aged rats with memory impairment, together with a loss of the experience dependent increase observed in young and unimpaired aged rats. Follow-up analysis revealed that increased basal translation and blunted ubiquitin mediated degradation may contribute to increased basal ARC protein levels noted in memory impaired aged rats. These findings indicate that Arc expression is regulated at multiple levels, and that several of these mechanisms are altered in cognitively impaired aged rats. Defining the influence of these alterations on the spatial and temporal fidelity of synapse specific, memory-related plasticity in the aged hippocampus is an important challenge. Published by Elsevier Inc. C1 [Fletcher, Bonnie R.; Hill, Gordon S.; Long, Jeffrey M.; Rapp, Peter R.] NIA, Lab Behav Neurosci, Neurocognit Aging Sect, Baltimore, MD 21224 USA. [Gallagher, Michela] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. [Shapiro, Matthew L.] Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. RP Rapp, PR (reprint author), NIA, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM rappp@mail.nih.gov FU National Institutes of Health [AG09973]; National Institute on Aging FX The authors thank Daniel Rutimann for expert technical assistance, and Dr. Rebecca Haberman and members of the Neurocognitive Aging Section for insightful discussion. This work supported by National Institutes of Health Grant AG09973, and in part by the Intramural Research Program of the National Institute on Aging. NR 69 TC 8 Z9 8 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1074-7427 EI 1095-9564 J9 NEUROBIOL LEARN MEM JI Neurobiol. Learn. Mem. PD NOV PY 2014 VL 115 SI SI BP 58 EP 67 DI 10.1016/j.nlm.2014.08.007 PG 10 WC Behavioral Sciences; Neurosciences; Psychology; Psychology, Multidisciplinary SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AS0FH UT WOS:000343953100009 PM 25151943 ER PT J AU Cantu, J Clifton, RG Roberts, JM Leveno, KJ Myatt, L Reddy, UM Varner, MW Wapner, RJ Thorp, JM Mercer, BM Peaceman, AM Ramin, SM Samuels, P Sciscione, A Saade, G Sorokin, Y AF Cantu, Jessica Clifton, Rebecca G. Roberts, James M. Leveno, Kenneth J. Myatt, Leslie Reddy, Uma M. Varner, Michael W. Wapner, Ronald J. Thorp, John M., Jr. Mercer, Brian M. Peaceman, Alan M. Ramin, Susan M. Samuels, Philip Sciscione, Anthony Saade, George Sorokin, Yoram CA Eunice Kennedy Shriver Natl Inst TI Laboratory Abnormalities in Pregnancy-Associated Hypertension Frequency and Association With Pregnancy Outcomes SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ELEVATED LIVER-ENZYMES; LOW PLATELET COUNT; GESTATIONAL HYPERTENSION; HELLP HEMOLYSIS; PREECLAMPSIA; MANAGEMENT; DIAGNOSIS; WOMEN AB OBJECTIVE: To estimate the frequency of abnormal laboratory test results in pregnancy-associated hypertension and the relationship with pregnancy outcomes. METHODS: This was a secondary analysis of a multicenter trial of vitamin C and E for prevention of pregnancy-associated hypertension in low-risk nulliparous women. Laboratory abnormalities included: platelets less than 100,000/mm(3), aspartate aminotransferase 100 units/L or greater, creatinine 1.5 mg/dL or greater, lactate dehydrogenase 600 units/L or greater, total bilirubin 1.2 mg/dL or greater, or evidence of hemolysis on peripheral smear. Mild pregnancy-associated hypertension was defined as blood pressure 140-159/90-109 mm Hg. Severe pregnancy-associated hypertension was defined as persistent blood pressure 160/110 mm Hg or greater, acute antihypertensive treatment, or any blood pressure elevation associated with clinical signs of end-organ dysfunction (one or more of headache, epigastric pain, blurred vision, pulmonary edema, eclampsia, or oliguria). Pregnancy outcomes were compared across four groups: I, mild hypertension alone; II, mild hypertension+abnormal laboratory values; III, severe pregnancy-associated hypertension alone; and IV, severe pregnancyassociated hypertension+ abnormal laboratory values. RESULTS: Of 9,969 women, 2,752 (27.9%) developed pregnancy-associated hypertension and of these, laboratory abnormalities occurred in 7.3%. Laboratory abnormalities increased with severity of hypertension: mild hypertension alone (4.9%), severe hypertension alone (8.9%), and mild or severe hypertension with clinical signs of end-organ dysfunction (12.2%) (P for trend,. 001). Compared with women with mild hypertension alone, the adjusted odds for the perinatal composite (2-fold to 4.8-fold in Category III-IV), preterm birth (2.1-fold to 7.8-fold in Category II-IV), and other adverse perinatal outcomes increase with disease severity, particularly with laboratory abnormalities and severe clinical signs. CONCLUSION: The frequency of abnormal laboratory values in women with pregnancy-associated hypertension increases with disease severity. Adverse perinatal outcomes increase in the presence of abnormal laboratory values, particularly in those with clinical signs, likely atttributable in part to the decision to deliver early. C1 Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35249 USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Drexel Univ, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. George Washington Univ, Dept Obstet & Gynecol, Biostat Ctr, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Cantu, J (reprint author), Univ Alabama Birmingham, Dept Obstet & Gynecol, Div Maternal Fetal Med, 619 19th St S,176F 10270C, Birmingham, AL 35249 USA. EM jesscantu27@gmail.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, HD36801]; National Heart, Lung, and Blood Institute; National Center for Research Resources [M01 RR00080, UL1 RR024153, UL1 RR024989] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, and HD36801); the National Heart, Lung, and Blood Institute; and the National Center for Research Resources (M01 RR00080, UL1 RR024153, UL1 RR024989). NR 18 TC 1 Z9 1 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD NOV PY 2014 VL 124 IS 5 BP 933 EP 940 DI 10.1097/AOG.0000000000000509 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AS3ES UT WOS:000344159900011 PM 25437721 ER PT J AU Nudelman, Z Friedman, M Barasch, D Nemirovski, A Findler, M Pikovsky, A Gutkind, JS Czerninski, R AF Nudelman, Z. Friedman, M. Barasch, D. Nemirovski, A. Findler, M. Pikovsky, A. Gutkind, J. S. Czerninski, R. TI Levels of sirolimus in saliva and blood following mouthwash application SO ORAL DISEASES LA English DT Article DE rapalogs; local application; oral cancer; safety; mucositis ID RADIATION-INDUCED MUCOSITIS; RELEASE DELIVERY-SYSTEMS; MTOR INHIBITORS; DRUG-DELIVERY; RAPAMYCIN; OPPORTUNITIES; PROTECTS; DISEASES AB ObjectivesSirolimus (rapamycin) is a mammalian target of rapamycin (mTOR) inhibitor with antiproliferative activity. Its systemic administration is currently evaluated for the management of squamous cell carcinoma and various oral disorders. Topical oral application can enhance availability, efficacy and improve safety and compliance. Our objective was to evaluate the release profile and the safety of a sirolimus mouthwash. Subjects and methodsA sirolimus mouthwash (0.05mgml(-1)) was applied to ten healthy male volunteers. Saliva and blood samples were taken after rinsing. Mass spectrometry and chemiluminescent microparticle immunoassay were used to determine saliva and blood levels of sirolimus. A topical oral release profile measurement and safety evaluation were performed. ResultsAfter rinsing with the mouthwash, a classic immediate release profile was noted in the oral cavity. Extremely high initial sirolimus levels rapidly declined over a 4-hour period. Systemic exposure was limited, with a maximum level significantly lower than therapeutic doses, and safety was confirmed. ConclusionsA single rinse with sirolimus mouthwash leads to high transient levels of the drug in the saliva. Although levels were variable, a therapeutic concentration was achieved topically along with minimal systemic absorption. These results broaden the potential clinical use of oral topical rapalogs. C1 [Nudelman, Z.; Friedman, M.; Barasch, D.; Nemirovski, A.] Hebrew Univ Jerusalem, Dept Pharmaceut, Inst Drug Res, Fac Med,Sch Pharm, IL-91905 Jerusalem, Israel. [Findler, M.; Pikovsky, A.; Czerninski, R.] Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Dept Oral Med, Sch Dent Med, IL-91120 Jerusalem, Israel. [Gutkind, J. S.] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Czerninski, R (reprint author), Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Dept Oral Med, Sch Dent Med, POB 12272, IL-91120 Jerusalem, Israel. EM rakefetc@hadassah.org.il FU Israel Cancer Research Fund FX This study was supported by a Project Grant from the Israel Cancer Research Fund. NR 21 TC 2 Z9 2 U1 0 U2 6 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 NOV PY 2014 VL 20 IS 8 BP 768 EP 772 DI 10.1111/odi.12229 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AS6TT UT WOS:000344395800007 PM 24548545 ER PT J AU Bellin, MD Gelrud, A Arreaza-Rubin, G Dunn, TB Humar, A Morgan, KA Naziruddin, B Rastellini, C Rickels, MR Schwarzenberg, SJ Andersen, DK AF Bellin, Melena D. Gelrud, Andres Arreaza-Rubin, Guillermo Dunn, Ty B. Humar, Abhinav Morgan, Katherine A. Naziruddin, Bashoo Rastellini, Cristiana Rickels, Michael R. Schwarzenberg, Sarah J. Andersen, Dana K. TI Total Pancreatectomy With Islet Autotransplantation Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop SO PANCREAS LA English DT Article DE pancreatectomy; islet transplantation; diabetes; chronic pancreatitis; pain; pancreatic exocrine insufficiency ID CELL SECRETORY CAPACITY; AGE-RELATED-CHANGES; LONG-TERM-OUTCOMES; CHRONIC-PANCREATITIS; ENDOSCOPIC TREATMENT; ADULT PANCREAS; TRANSPLANTATION; PAIN; MANAGEMENT; SURGERY AB A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases focused on research gaps and opportunities in total pancreatectomy with islet autotransplantation (TPIAT) for the management of chronic pancreatitis (CP). The session was held on July 23, 2014, and structured into 5 sessions: (1) patient selection, indications, and timing; (2) technical aspects of TPIAT; (3) improving success of islet autotransplantation; (4) improving outcomes after total pancreatectomy; and (5) registry considerations for TPIAT. The current state of knowledge was reviewed; knowledge gaps and research needs were specifically highlighted. Common themes included the need to identify which patients best benefit from and when to intervene with TPIAT, current limitations of the surgical procedure, diabetes remission and the potential for improvement, opportunities to better address pain remission, gastrointestinal complications in this population, and unique features of children with CP considered for TPIAT. The need for a multicenter patient registry that specifically addresses the complexities of CP and total pancreatectomy outcomes as well as postsurgical diabetes outcomes was repeatedly emphasized. C1 [Bellin, Melena D.; Dunn, Ty B.; Schwarzenberg, Sarah J.] Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55454 USA. [Bellin, Melena D.; Dunn, Ty B.; Schwarzenberg, Sarah J.] Univ Minnesota, Sch Med, Dept Surg, Minneapolis, MN 55454 USA. [Gelrud, Andres] Univ Chicago, Pritzker Sch Med, Dept Med, Ctr Endoscop Res & Therapeut, Chicago, IL 60637 USA. [Arreaza-Rubin, Guillermo; Andersen, Dana K.] Natl Inst Diabet & Digest & Kidney Dis, Div Diabet, NIH, Bethesda, MD USA. [Arreaza-Rubin, Guillermo; Andersen, Dana K.] Natl Inst Diabet & Digest & Kidney Dis, Div Endocrinol & Metab, NIH, Bethesda, MD USA. [Arreaza-Rubin, Guillermo; Andersen, Dana K.] Natl Inst Diabet & Digest & Kidney Dis, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. [Humar, Abhinav] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. [Morgan, Katherine A.] Med Univ S Carolina, Dept Surg, Charleston, SC 29425 USA. [Naziruddin, Bashoo] Baylor Simmons Transplant Inst, Dallas, TX USA. [Rastellini, Cristiana] Univ Texas Med Branch, Dept Surg, Galveston, TX 77555 USA. [Rickels, Michael R.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Bellin, MD (reprint author), Univ Minnesota, Childrens Hosp, East Bldg Rm MB 671,2450 Riverside Ave, Minneapolis, MN 55454 USA. EM bell0130@umn.edu OI Dunn, Ty/0000-0002-5941-0659 FU NCATS NIH HHS [UL1 TR000114]; NIDDK NIH HHS [K23 DK084315] NR 71 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1163 EP 1171 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600007 PM 25333399 ER PT J AU Afghani, E Hutfless, SM Sinha, A Khashab, MA Lennon, AM Yadav, D Makary, MA Andersen, DK Kalloo, AN Singh, VK AF Afghani, E. Hutfless, S. M. Sinha, A. Khashab, M. A. Lennon, A. M. Yadav, D. Makary, M. A. Andersen, D. K. Kalloo, A. N. Singh, V. K. TI Hospital Admission Volume Does Not Impact the In-Hospital Mortality of Acute Pancreatitis SO PANCREAS LA English DT Meeting Abstract C1 [Afghani, E.; Hutfless, S. M.; Sinha, A.; Khashab, M. A.; Lennon, A. M.; Kalloo, A. N.; Singh, V. K.] Johns Hopkins Univ Hosp, Div Gastroenterol, Baltimore, MD 21287 USA. [Makary, M. A.] Johns Hopkins Univ Hosp, Dept Surg, Baltimore, MD 21287 USA. [Yadav, D.] Univ Pittsburgh SOM, Div Gastroenterol, Pittsburgh, PA USA. [Andersen, D. K.] Natl Inst Digest & Kidney Dis, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1340 EP 1341 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600038 ER PT J AU Sinha, A Patel, YA Cruise, M Matsukuma, K Zaheer, A Yadav, D Makary, MA Hirose, K Andersen, DK Singh, VK AF Sinha, A. Patel, Y. A. Cruise, M. Matsukuma, K. Zaheer, A. Yadav, D. Makary, M. A. Hirose, K. Andersen, D. K. Singh, V. K. TI Predictors of Post-Operative Pain Relief in Patients With Chronic Pancreatitis Undergoing the Frey or Whipple Procedure SO PANCREAS LA English DT Meeting Abstract C1 [Sinha, A.; Patel, Y. A.; Singh, V. K.] Johns Hopkins Univ Hosp, Div Gastroenterol, Baltimore, MD 21287 USA. [Cruise, M.; Matsukuma, K.] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. [Zaheer, A.] Johns Hopkins Univ Hosp, Dept Radiol, Baltimore, MD 21287 USA. [Makary, M. A.; Hirose, K.] Johns Hopkins Univ Hosp, Dept Surg, Baltimore, MD 21287 USA. [Yadav, D.] Univ Pittsburgh, Div Gastroenterol, Pittsburgh, PA USA. [Andersen, D. K.] NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1409 EP 1409 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600322 ER PT J AU Nozyce, ML Huo, YL Williams, PL Kapetanovic, S Hazra, R Nichols, S Hunter, S Smith, R Seage, GR Sirois, PA AF Nozyce, Molly L. Huo, Yanling Williams, Paige L. Kapetanovic, Suad Hazra, Rohan Nichols, Sharon Hunter, Scott Smith, Renee Seage, George R., III Sirois, Patricia A. CA Pediat HIV-AIDS Cohort Study TI Safety of In Utero and Neonatal Antiretroviral Exposure Cognitive and Academic Outcomes in HIV-exposed, Uninfected Children 5-13 Years of Age SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV; ARV; neurodevelopment; children; cognition; academic achievement ID TO-CHILD TRANSMISSION; UNINFECTED CHILDREN; MITOCHONDRIAL DYSFUNCTION; PERINATAL EXPOSURE; INFECTED WOMEN; DRUGS; NEURODEVELOPMENT; INFANTS; ZIDOVUDINE; COMPROMISE AB Background: Long-term effects of in utero and neonatal antiretroviral (ARV) exposure on cognitive and academic development in HIV-exposed, uninfected school-age children are unknown. Methods: HIV-exposed, uninfected children, ages 5-13 years, in Pediatric HIV/AIDS Cohort Study Surveillance Monitoring for Antiretroviral Treatment Toxicities, a US-based multisite cohort study, completed age-appropriate Wechsler intelligence and academic scales (WPPSI-III, WASI, WIAT-II-A). Associations between cognitive and academic outcomes and in utero ARV exposure by regimen, class and individual ARVs were evaluated, adjusting for potential confounders. Results: Children completing WPPSI-IIIs (n = 350) were 49% male, 74% Black, 25% Hispanic; WASI (n = 337) and WIAT-II-A (n = 415) cohorts were similar. The percentage exposed to combination ARV (cARV) was 84% (WPPSI-III), 64% (WASI) and 67% (WIAT-II-A). Among ARV-exposed children, there were no significant associations between any ARV regimen or class and any cognitive or academic outcome. In addition, in both unadjusted models and after adjustment for caregiver IQ, sociodemographic factors and maternal health and substance use during pregnancy, no individual ARV drug was associated with significantly lower cognitive or academic scores. Factors typically associated with lower cognitive and academic scores in the general population, such as prematurity, small for gestational age, maternal alcohol use and lower maternal cognitive status, were also associated with lower scores in this study. Conclusions: Overall, the safety of prenatal and neonatal ARV use was supported. C1 [Nozyce, Molly L.] Albert Einstein Coll Med, Jacobi Med Ctr, Bronx, NY 10461 USA. [Huo, Yanling; Williams, Paige L.; Seage, George R., III] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Kapetanovic, Suad] NIMH, Bethesda, MD 20892 USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Nichols, Sharon] Univ Calif San Diego, San Diego, CA 92103 USA. [Hunter, Scott] Univ Chicago, Chicago, IL 60637 USA. [Smith, Renee; Sirois, Patricia A.] Univ Illinois, Chicago, IL USA. Tulane Univ, Sch Med, New Orleans, LA 70112 USA. RP Nozyce, ML (reprint author), Albert Einstein Coll Med, Jacobi Med Ctr, Bldg 1-8W16,1400 Pelham Parkway South, Bronx, NY 10461 USA. EM molly.nozyce@nbhn.net RI Hunter, Scott/S-7866-2016 OI Hunter, Scott/0000-0001-7434-2327 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard University School of Public Health [HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3]; Tulane University School of Medicine [HD052104, 3U01HD052104-06S1] FX The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3; Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104, 3U01HD052104-06S1; Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or US Department of Health and Human Services. NR 39 TC 2 Z9 2 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD NOV PY 2014 VL 33 IS 11 BP 1128 EP 1133 DI 10.1097/INF.0000000000000410 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA AS6DH UT WOS:000344354400013 PM 25361407 ER PT J AU Guttmacher, AE Raju, TNK AF Guttmacher, Alan E. Raju, Tonse N. K. TI The Child Is Father of the Man, and Mother of the Woman SO PEDIATRICS LA English DT Editorial Material DE aging; childhood; intrauterine environment; telomere; perinatal period C1 [Guttmacher, Alan E.; Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Guttmacher, AE (reprint author), 31 Ctr Dr,Rm 2A03,MSC 2425, Bethesda, MD 20892 USA. EM guttmach@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2014 VL 134 IS 5 BP E1411 EP E1412 DI 10.1542/peds.2014-2646 PG 2 WC Pediatrics SC Pediatrics GA AS6PU UT WOS:000344385900018 PM 25349322 ER PT J AU Kelleher, J Salas, AA Bhat, R Ambalavanan, N Saha, S Stoll, BJ Bell, EF Walsh, MC Laptook, AR Sanchez, PJ Shankaran, S VanMeurs, KP Hale, EC Newman, NS Ball, MB Das, A Higgins, RD Peralta-Carcelen, M Carlo, WA AF Kelleher, John Salas, Ariel A. Bhat, Ramachandra Ambalavanan, Namasivayam Saha, Shampa Stoll, Barbara J. Bell, Edward F. Walsh, Michele C. Laptook, Abbot R. Sanchez, Pablo J. Shankaran, Seetha VanMeurs, Krisa P. Hale, Ellen C. Newman, Nancy S. Ball, M. Bethany Das, Abhik Higgins, Rosemary D. Peralta-Carcelen, Myriam Carlo, Waldemar A. CA GDB Subcomm Eunice Kennedy Shriver Natl Inst C Neonatal Res Network TI Prophylactic Indomethacin and Intestinal Perforation in Extremely Low Birth Weight Infants SO PEDIATRICS LA English DT Article DE indomethacin; intestinal perforation; necrotizing enterocolitis; neonate ID EXTREMELY PRETERM INFANTS; PATENT DUCTUS-ARTERIOSUS; NECROTIZING ENTEROCOLITIS; NEURODEVELOPMENTAL OUTCOMES; THERAPY; EXPOSURE; DISTINCT; IMPACT; TRIAL; RISK AB OBJECTIVE: Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP. METHODS: This was a cohort study of 15 751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP. RESULTS: Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49-1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37-0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36-0.777, P = .0011). CONCLUSIONS: The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants. C1 [Kelleher, John; Salas, Ariel A.; Bhat, Ramachandra; Ambalavanan, Namasivayam; Hale, Ellen C.; Peralta-Carcelen, Myriam; Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35233 USA. [Saha, Shampa] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Walsh, Michele C.; Newman, Nancy S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Laptook, Abbot R.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Sanchez, Pablo J.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Shankaran, Seetha] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [VanMeurs, Krisa P.; Ball, M. Bethany] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Das, Abhik] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Das, Abhik] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Higgins, Rosemary D.] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. RP Carlo, WA (reprint author), Univ Alabama Birmingham, Women & Infants Ctr, Div Neonatol, 176F Suite 9380,619 20th St Sputh, Birmingham, AL 35233 USA. EM wcarlo@peds.uab.edu OI Ambalavanan, Namasivayam/0000-0003-0731-9092; Salas, Ariel/0000-0002-4676-7747 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development provided grant support for the Neonatal Research Network's Generic Database and Follow-up Studies. NR 30 TC 6 Z9 6 U1 0 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2014 VL 134 IS 5 BP E1369 EP E1377 DI 10.1542/peds.2014-0183 PG 9 WC Pediatrics SC Pediatrics GA AS6PU UT WOS:000344385900013 PM 25349317 ER PT J AU Than, NG Romero, R Xu, Y Erez, O Xu, Z Bhatti, G Leavitt, R Chung, TH El-Azzamy, H LaJeunesse, C Wang, B Balogh, A Szalai, G Land, S Dong, Z Hassan, SS Chaiworapongsa, T Krispin, M Kim, CJ Tarca, AL Papp, Z Bohn, H AF Than, N. G. Romero, R. Xu, Y. Erez, O. Xu, Z. Bhatti, G. Leavitt, R. Chung, T. H. El-Azzamy, H. LaJeunesse, C. Wang, B. Balogh, A. Szalai, G. Land, S. Dong, Z. Hassan, S. S. Chaiworapongsa, T. Krispin, M. Kim, C. J. Tarca, A. L. Papp, Z. Bohn, H. TI Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia SO PLACENTA LA English DT Article DE ALU; AP2; Anthropoid primate; Epigenome; ESRRG; GATA; GCM1; Lectin; LINE; PP13; Pregnancy; Syncytiotrophoblast; TEF5 ID HUMAN CHORIONIC-GONADOTROPIN; DEEP TROPHOBLAST INVASION; MATERNAL-FETAL INTERFACE; FOR-GESTATIONAL-AGE; CELL-LINE BEWO; GENE-EXPRESSION; TRANSCRIPTION FACTORS; VILLOUS TROPHOBLAST; SOLUBLE ENDOGLIN; NORMAL-PREGNANCY AB Introduction: The dysregulation of maternal-fetal immune tolerance is one of the proposed mechanisms leading to preeclampsia. Galectins are key regulator proteins of the immune response in vertebrates and maternal-fetal immune tolerance in eutherian mammals. Previously we found that three genes in a Chr19 cluster encoding for human placental galectin-13 (PP13), galectin-14 and galectin-16 emerged during primate evolution and may confer immune tolerance to the semi-allogeneic fetus. Materials and Methods: This study involved various methodologies for gene and protein expression profiling, genomic DNA methylation analyses, functional assays on differentiating trophoblasts including gene silencing, luciferase reporter and methylation assays. These methods were applied on placental specimens, umbilical cord blood cells, primary trophoblasts and BeWo cells. Genomic DNA sequences were analyzed for transposable elements, transcription factor binding sites and evolutionary conservation. Results and Discussion: The villous trophoblastic expression of Chr19 cluster galectin genes is developmentally regulated by DNA methylation and induced by key transcription factors of villous placental development during trophoblast fusion and differentiation. This latter mechanism arose via the co-option of binding sites for these transcription factors through promoter evolution and the insertion of an anthropoid-specific L1PREC2 transposable element into the 5' untranslated region of an ancestral gene followed by gene duplication events. Among placental Chr19 cluster galectin genes, the expression of LGALS13 and LGALS14 is down-regulated in preterm severe preeclampsia associated with SGA. We reveal that this phenomenon is partly originated from the dysregulated expression of key transcription factors controlling trophoblastic functions and galectin gene expression. In addition, the differential DNA methylation of these genes was also observed in preterm preeclampsia irrespective of SGA. Conclusions: These findings reveal the evolutionary origins of the placental expression of Chr19 cluster galectins. The complex dysregulation of these genes in preeclampsia may alter immune tolerance mechanisms at the maternal-fetal interface. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Than, N. G.; Romero, R.; Xu, Y.; Xu, Z.; Bhatti, G.; El-Azzamy, H.; LaJeunesse, C.; Wang, B.; Balogh, A.; Szalai, G.; Dong, Z.; Hassan, S. S.; Chaiworapongsa, T.; Kim, C. J.; Tarca, A. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Than, N. G.; Romero, R.; Xu, Y.; Xu, Z.; Bhatti, G.; El-Azzamy, H.; LaJeunesse, C.; Wang, B.; Balogh, A.; Szalai, G.; Dong, Z.; Hassan, S. S.; Chaiworapongsa, T.; Kim, C. J.; Tarca, A. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Than, N. G.; Hassan, S. S.; Chaiworapongsa, T.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Than, N. G.; Papp, Z.] Semmelweis Univ, Matern Private Dept, H-1085 Budapest, Hungary. [Than, N. G.] Hungarian Acad Sci, Inst Enzymol, Res Ctr Nat Sci, Budapest, Hungary. [Erez, O.] Ben Gurion Univ Negev, Dept Obstet & Gynecol, IL-84105 Beer Sheva, Israel. [Leavitt, R.; Chung, T. H.; Krispin, M.] Zymo Res Corp, Irvine, CA USA. [Balogh, A.] Eotvos Lorand Univ, Dept Immunol, Budapest, Hungary. [Land, S.; Tarca, A. L.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kim, C. J.] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Bohn, H.] Behringwerke AG, Marburg, Germany. RP Than, NG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM nthan@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 (NICHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS); NICHD [HHSN275201300006C]; European Union [Pregenesys 037244]; Hungarian OTKA-PD grant [104398]; Hungarian Academy of Sciences Momentum Grant [LP2014-7/2014] FX We thank for Sandy Field, Hong Meng, Tara Reinholz, Sivasakthy Sivalogan, Vanessa Topping, Anita Vasudevan, Brad Baker, Po Jen Chiang, Gerardo Rodriguez and Dr. Theodore Price for technical assistance, Dr. Douglas Ruden for helpful discussions, and Sara Tipton for critical reading of the manuscript (all Wayne State University). We thank Professor Andras Falus for inspiring the study design on transcriptional regulation by non-coding genomic regions, Dr. Katalin Eder for assistance in microarray experiments (both Semmelweis University), and Dr. Valerie Reeb (University of Iowa) and Nazeena Alvi (Roche NimbleGen, Inc.) for assistance with MEDIP chip experiments. 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 (NICHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS); and, in part, with Federal funds from the NICHD under Contract No. HHSN275201300006C. Microarray and evolutionary analyses were supported by the European Union FP6 Grant "Pregenesys 037244" (to N.G.T.). Manuscript writing was partly supported by the Hungarian OTKA-PD grant "104398" (to A.B.) and the Hungarian Academy of Sciences Momentum Grant "LP2014-7/2014" (to N.G.T.). NR 91 TC 13 Z9 13 U1 4 U2 17 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD NOV PY 2014 VL 35 IS 11 BP 855 EP 865 DI 10.1016/j.placenta.2014.07.015 PG 11 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA AS7MU UT WOS:000344440900002 PM 25266889 ER PT J AU Tycko, R AF Tycko, Robert TI Physical and structural basis for polymorphism in amyloid fibrils SO PROTEIN SCIENCE LA English DT Review DE amyloid structure; fibril structure; solid state NMR; Alzheimer's disease; prion ID SOLID-STATE NMR; BETA-SHEET STRUCTURE; NUCLEAR-MAGNETIC-RESONANCE; HUMAN PRION PROTEIN; PAIRED HELICAL FILAMENTS; ALPHA-SYNUCLEIN; ALZHEIMERS-DISEASE; CORE STRUCTURE; INTERMOLECULAR ALIGNMENT; ELECTRON-MICROSCOPY AB As our understanding of the molecular structures of amyloid fibrils has matured over the past 15 years, it has become clear that, while amyloid fibrils do have well-defined molecular structures, their molecular structures are not uniquely determined by the amino acid sequences of their constituent peptides and proteins. Self-propagating molecular-level polymorphism is a common phenomenon. This article reviews current information about amyloid fibril structures, variations in molecular structures that underlie amyloid polymorphism, and physical considerations that explain the development and persistence of amyloid polymorphism. Much of this information has been obtained through solid state nuclear magnetic resonance measurements. The biological significance of amyloid polymorphism is also discussed briefly. Although this article focuses primarily on studies of fibrils formed by amyloid- peptides, the same principles apply to many amyloid-forming peptides and proteins. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health FX Work described in this article was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health. NR 112 TC 43 Z9 43 U1 7 U2 63 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD NOV PY 2014 VL 23 IS 11 BP 1528 EP 1539 DI 10.1002/pro.2544 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AS5QX UT WOS:000344325900005 PM 25179159 ER PT J AU Eliezer, D Hadley, DW Koehly, LM AF Eliezer, Dina Hadley, Donald W. Koehly, Laura M. TI Exploring psychological responses to genetic testing for Lynch Syndrome within the family context SO PSYCHO-ONCOLOGY LA English DT Article DE Cancer; Oncology; Genetic testing; Lynch Snydrome; Family; Depression ID NONPOLYPOSIS COLORECTAL-CANCER; IMPACT; SUSCEPTIBILITY; RISK; COMMUNICATION; HEALTH; INDIVIDUALS; DIFFUSION; DISTRESS; CHILDREN AB ObjectiveGenetic testing for hereditary cancer susceptibility syndromes is a family-centered process. Nonetheless, little research has explored how the family context affects psychological responses to genetic testing. We examine how personal test results and the test results of immediate and extended family members shape responses to genetic testing. MethodsIndividuals at risk of carrying a mutation associated with an inherited cancer susceptibility syndrome (Lynch syndrome) received genetic testing. Six months after receiving their results, participants reported on cancer distress, cancer worry, and depressive symptoms. ResultsAmong mutation carriers for Lynch syndrome, the higher the proportion of carriers in their immediate family, the less cancer worry and distress they reported. In contrast, mutation carriers and non-carriers with a high proportion of carriers in their immediate family and mutation carriers with a high proportion of carriers in their extended family were at elevated risk for clinically significant levels of depressive symptoms. ConclusionPersonal test results alone are not highly predictive of psychological outcomes. Instead, the interaction between personal and family test results, or in some cases, family test results alone, predict key psychological outcomes. The current research has important implications for genetic counseling and intervention efforts. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Eliezer, Dina; Hadley, Donald W.; Koehly, Laura M.] NHGRI, Bethesda, MD 20892 USA. RP Koehly, LM (reprint author), NHGRI, Bethesda, MD 20892 USA. EM koehlyl@mail.nih.gov FU Intramural NIH HHS [ZIA HG000059-20]; NHGRI NIH HHS [F32 HG000165] NR 40 TC 1 Z9 1 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD NOV PY 2014 VL 23 IS 11 BP 1292 EP 1299 DI 10.1002/pon.3551 PG 8 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AS4JX UT WOS:000344242500012 PM 24872228 ER EF