FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Nanuck, T AF Nanuck, Tracy TI The Relationship between Polymorphisms in a Truncated Progesterone Receptor (PR-M) and Clinical Response to 17 alpha-Hydroxyprogesterone Caproate for the Treatment of Recurrent Spontaneous Preterm Birth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Nanuck, Tracy] MFMU Network, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 SU S MA 174 BP 119A EP 119A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800175 ER PT J AU Nowicki, BJ Pawelczyk, E Soloff, MS Izban, MG Nowicki, S AF Nowicki, Bogdan J. Pawelczyk, Edyta Soloff, Melvyn S. Izban, Michael G. Nowicki, Stella TI Role of Supra-Physiologic Concentrations of Progesterone in Down-Regulation of TLR4: Implication for Progesterone Treatment in PTL SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Nowicki, Bogdan J.; Izban, Michael G.; Nowicki, Stella] Meharry Med Coll, Nashville, TN 37208 USA. [Soloff, Melvyn S.] Univ Texas Med Branch, Galveston, TX USA. [Pawelczyk, Edyta] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 178 BP 120A EP 120A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800179 ER PT J AU Hsu, R Romero, R Kim, JS Mittal, P Kim, MJ Gotsch, F Kusanovic, JP Hassan, SS Kim, CJ AF Hsu, Robert Romero, Roberto Kim, Jung-Sun Mittal, Pooja Kim, Mi Jeong Gotsch, Francesca Kusanovic, Juan Pedro Hassan, Sonia S. Kim, Chong Jai TI Compartmentalized Expression of Granulocyte Chemotactic Protein-2/CXCL6 in the Human Amnion: A Unique Strategy for Differential Function of a Chemokine in the Placenta. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Hsu, Robert; Romero, Roberto; Kim, Jung-Sun; Mittal, Pooja; Kim, Mi Jeong; Gotsch, Francesca; Kusanovic, Juan Pedro; Hassan, Sonia S.; Kim, Chong Jai] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Kim, Jung-Sun; Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Mittal, Pooja; Kusanovic, Juan Pedro; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 316 BP 160A EP 160A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800317 ER PT J AU Kim, MJ Romero, R Kim, CJ Tarca, AL Chhauy, S LaJeunesse, C Lee, DC Draghici, S Gotsch, F Kusanovic, JP Hassan, SS Kim, JS AF Kim, Mi Jeong Romero, Roberto Kim, Chong Jai Tarca, Adi L. Chhauy, Sovantha LaJeunesse, Christopher Lee, Deug-Chan Draghici, Sorin Gotsch, Francesca Kusanovic, Juan Pedro Hassan, Sonia S. Kim, Jung-Sun TI Villitis of Unknown Etiology: A Unique Lesion in Human Biology Bridging Transplant Rejection (Maternal) and Graft-Versus-Host Disease (Fetal) - Evidence from Placental Villous Transcriptome Analysis. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Kim, Mi Jeong; Romero, Roberto; Kim, Chong Jai; Tarca, Adi L.; Chhauy, Sovantha; LaJeunesse, Christopher; Lee, Deug-Chan; Gotsch, Francesca; Kusanovic, Juan Pedro; Hassan, Sonia S.; Kim, Jung-Sun] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Kim, Chong Jai; Kim, Jung-Sun] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Tarca, Adi L.; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Kusanovic, Juan Pedro; Hassan, Sonia S.; Kim, Jung-Sun] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. RI Draghici, Sorin/B-3074-2013 OI Draghici, Sorin/0000-0002-0786-8377 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 322 BP 161A EP 161A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800323 ER PT J AU Kim, SK Romero, R Mazaki-Tovi, S Kusanovic, JP Erez, O Vaisbuch, E Than, NG Chaiworapongsa, T Dong, Z Mittal, P Pacora, P Gotsch, F Carletti, A Yeo, L Hassan, SS AF Kim, Sun Kwon Romero, Roberto Mazaki-Tovi, Shali Kusanovic, Juan Pedro Erez, Offer Vaisbuch, Edi Than, Nandor G. Chaiworapongsa, Tinnakorn Dong, Zhong Mittal, Pooja Pacora, Percy Gotsch, Francesca Carletti, Angela Yeo, Lami Hassan, Sonia S. TI A Role for Placental Adipokines in Intrauterine Inflammation. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Kim, Sun Kwon; Romero, Roberto; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Erez, Offer; Vaisbuch, Edi; Than, Nandor G.; Chaiworapongsa, Tinnakorn; Dong, Zhong; Mittal, Pooja; Pacora, Percy; Gotsch, Francesca; Carletti, Angela; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto; Mazaki-Tovi, Shali; Chaiworapongsa, Tinnakorn; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kusanovic, Juan Pedro; Erez, Offer; Vaisbuch, Edi; Mittal, Pooja] Wayne State Univ, Dept OB GYN, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 321 BP 161A EP 161A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800322 ER PT J AU Nhan-Chang, CL Romero, R Wildtnan, D Erez, O Kusanovic, JP Tarca, A Hacia, JG Mazaki-Tovi, S Vaisbuch, E Kim, CJ Chaiworapongsa, T Mittal, P Yco, L Hassan, SS AF Nhan-Chang, Chia-Ling Romero, Roberto Wildtnan, Derek Erez, Offer Kusanovic, Juan P. Tarca, Adi Hacia, Joseph G. Mazaki-Tovi, Shali Vaisbuch, Edi Kim, C. J. Chaiworapongsa, Tinnakorn Mittal, Pooja Yco, Lami Hassan, Sonia S. TI Placenta DNA Methylation in Term and Preterm Labor SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Nhan-Chang, Chia-Ling; Romero, Roberto; Wildtnan, Derek; Erez, Offer; Kusanovic, Juan P.; Tarca, Adi; Mazaki-Tovi, Shali; Vaisbuch, Edi; Kim, C. J.; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Yco, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Nhan-Chang, Chia-Ling; Wildtnan, Derek; Erez, Offer; Kusanovic, Juan P.; Mazaki-Tovi, Shali; Vaisbuch, Edi; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Yco, Lami; Hassan, Sonia S.] Wayne State Univ, Dept OB GYN, Detroit, MI USA. [Hacia, Joseph G.] Univ So Calif, Inst Med Genet, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 330 BP 163A EP 164A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800331 ER PT J AU Erez, O Romero, R Vaisbuch, E Kusanovic, JP Mazaki-Tovic, S Gotsch, F Mittal, P Edwin, SS Nhan-Chang, CL Than, NG Kim, CJ Kim, SK Yeo, L Mazor, M Hassan, SS AF Erez, Offer Romero, Roberto Vaisbuch, Edi Kusanovic, Juan Pedro Mazaki-Tovic, Shali Gotsch, Francesca Mittal, Pooja Edwin, Samuel S. Nhan-Chang, Chia-Ling Than, Nandor G. Kim, Chong Jai Kim, Sun Kwon Yeo, Lami Mazor, Moshe Hassan, Sonia S. TI The Pattern and Magnitude of "In-Vivo Thrombin Generation" Is Different in Women with Preeclampsia and in Those with SGA Fetuses without Preeclampsia SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecological-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Erez, Offer; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Mazaki-Tovic, Shali; Gotsch, Francesca; Mittal, Pooja; Edwin, Samuel S.; Nhan-Chang, Chia-Ling; Than, Nandor G.; Kim, Chong Jai; Kim, Sun Kwon; Yeo, Lami; Hassan, Sonia S.] DHHS, Perinatol Res Branch, NICHD, NIH, Detroit, MI USA. [Erez, Offer; Vaisbuch, Edi; Kusanovic, Juan Pedro; Mazaki-Tovic, Shali; Mittal, Pooja; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Mazor, Moshe] Ben Gurion Univ Negev, Dept Obstet Gynecol, Beer Sheva, Israel. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 SU S MA 350 BP 170A EP 170A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800351 ER PT J AU Erez, O Romero, R Vaishuch, E Kusanovic, JP Mazaki-Tovi, S Gotsch, F Mittal, P Dong, Z Than, NG Kim, CJ Nhan-Chang, CL Kim, SK Yeo, L Mazor, M Hassan, SS AF Erez, Offer Romero, Roberto Vaishuch, Edi Kusanovic, Juan Pedro Mazaki-Tovi, Shali Gotsch, Francesca Mittal, Pooja Dong, Zhong Than, Nandor G. Kim, Chong Jai Nhan-Chang, Chia-Ling Kim, Sun Kwon Yeo, Lami Mazor, Moshe Hassan, Sonia S. TI The Activity of the Natural Initiator of Coagulation-Tissue Factor, but Not That of Its Pathway Inhibitor, Is Elevated in Women with Preeclampsia and SGA: A Potential Explanation for the Excessive Thrombin Generation in These Syndromes SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecological-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Erez, Offer; Romero, Roberto; Vaishuch, Edi; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Gotsch, Francesca; Mittal, Pooja; Dong, Zhong; Than, Nandor G.; Kim, Chong Jai; Nhan-Chang, Chia-Ling; Kim, Sun Kwon; Yeo, Lami; Hassan, Sonia S.] DHHS, Perinatol Res Branch, NICHD, NIH, Detroit, MI USA. [Erez, Offer; Vaishuch, Edi; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Mittal, Pooja; Nhan-Chang, Chia-Ling; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Mazor, Moshe] Ben Gurion Univ Negev, Dept Obstet & Gynecol, Beer Sheva, Israel. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 SU S MA 351 BP 170A EP 170A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800352 ER PT J AU Mazaki-Tovi, S Vaisbuch, E Kusanovic, JP Erez, O Mittal, P Chaiworapongsa, T Than, NG Kim, SK Chang, CLN Jodicke, C Pacora, P Gotsch, F Yeo, L Dong, Z Hassan, SS Romero, R AF Mazaki-Tovi, Shali Vaisbuch, Edi Kusanovic, Juan Pedro Erez, Offer Mittal, Pooja Chaiworapongsa, Tinnakorn Than, Nandor G. Kim, Sun Kwon Chang, Chia-Ling Nhan Jodicke, Cristiano Pacora, Percy Gotsch, Francesca Yeo, Lami Dong, Zhong Hassan, Sonia S. Romero, Roberto TI "Adipose Tissue Failure" as a Putative Mechanism for Preeclampsia-Does a Perturbation of Adiponectin Multimers Homeostasis Have a Role in the Pathophysiology of Preeclampsia? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Mazaki-Tovi, Shali; Vaisbuch, Edi; Kusanovic, Juan Pedro; Erez, Offer; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Than, Nandor G.; Kim, Sun Kwon; Chang, Chia-Ling Nhan; Jodicke, Cristiano; Pacora, Percy; Gotsch, Francesca; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Romero, Roberto] DHHS, Perinatol Res Branch, NICHD, NIH, Detroit, MI USA. [Mazaki-Tovi, Shali; Vaisbuch, Edi; Kusanovic, Juan Pedro; Erez, Offer; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Chang, Chia-Ling Nhan; Jodicke, Cristiano; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 365 BP 174A EP 174A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800366 ER PT J AU Kim, MJ Romero, R Gervasi, MT Kim, JS Yoo, W Lee, DC Mittal, P Kusanovic, JP Kim, CJ AF Kim, Mi Jeong Romero, Roberto Gervasi, Maria Teresa Kim, Jung-Sun Yoo, Wonsuk Lee, Deug-Chan Mittal, Pooja Kusanovic, Juan Pedro Kim, Chong Jai TI Molecular Evidence That the Ascending Pathway of Infra-Amniotic Infection Does Not Include a Widespread Choriodecidual Stage: The Need To Revisit a Traditional Paradigm SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Kim, Mi Jeong; Romero, Roberto; Kim, Jung-Sun; Lee, Deug-Chan; Mittal, Pooja; Kusanovic, Juan Pedro; Kim, Chong Jai] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Gervasi, Maria Teresa] Univ Padua, UO Ostetr & Ginecol Azienda Osped, Padua, Italy. [Kim, Jung-Sun; Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Yoo, Wonsuk] Wayne State Univ, Dept Internal Med, Detroit, MI 48202 USA. [Mittal, Pooja; Kusanovic, Juan Pedro] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 468 BP 203A EP 203A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800469 ER PT J AU Kniss, DA Ackerman, WE Li, R Summerfield, T Yu, L Gilati, P Iams, JD Romero, R AF Kniss, Douglas A. Ackerman, William E. Li, Ruth Summerfield, Taryn Yu, Lianbo Gilati, Parul Iams, Jay D. Romero, Roberto TI A Systems Biology Approach to Preterm Parturition: In Vitro Model of Cytokine-Driven Gene Expression Suggests an Inflammatory Signature Dominated by Regulatory Elements Controlled by NF-kappa B SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Kniss, Douglas A.; Ackerman, William E.; Li, Ruth; Summerfield, Taryn; Iams, Jay D.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Yu, Lianbo; Gilati, Parul] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Romero, Roberto] NICHD, Perinatal Res Branch, NIH, Detroit, MI USA. RI Ackerman, William/E-2612-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 469 BP 203A EP 204A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800470 ER PT J AU Kusanovic, JP Romero, R Chaiworapongsa, T Mittal, P Mazaki-Tovi, S Vaisbuch, E Erez, O Gotsch, F Than, NG Edwin, SS Pacora, P Jodicke, C Yeo, L Hassan, SS AF Kusanovic, Juan Pedro Romero, Roberto Chaiworapongsa, Tinnakorn Mittal, Pooja Mazaki-Tovi, Shali Vaisbuch, Edi Erez, Offer Gotsch, Francesca Than, Nandor G. Edwin, Samuel S. Pacora, Percy Jodicke, Cristiano Yeo, Lami Hassan, Sonia S. TI Soluble TREM-1 in Parturition (Term and Preterm) and Intra-Amniotic Infection/Inflammation SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Kusanovic, Juan Pedro; Romero, Roberto; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Mazaki-Tovi, Shali; Vaisbuch, Edi; Erez, Offer; Gotsch, Francesca; Than, Nandor G.; Edwin, Samuel S.; Pacora, Percy; Jodicke, Cristiano; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Mazaki-Tovi, Shali; Vaisbuch, Edi; Erez, Offer; Jodicke, Cristiano; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 470 BP 204A EP 204A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800471 ER PT J AU Vaisbuch, E Mazaki-Tovi, S Kusanovic, JP Erez, O Than, NG Kim, SK Dong, Z Gotsch, F Mittal, P Chaiworapongsa, T Pacora, P Yeo, L Hassan, SS Romero, R AF Vaisbuch, Edi Mazaki-Tovi, Shali Kusanovic, Juan Pedro Erez, Offer Than, Nandor G. Kim, Sun Kwon Dong, Zhong Gotsch, Francesca Mittal, Pooja Chaiworapongsa, Tinnakorn Pacora, Percy Yeo, Lami Hassan, Sonia S. Romero, Roberto TI Beyond a Carrier of Vitamin A: Retinol Binding Protein 4 Is Associated with Intra-Amniotic Infection/Inflammation SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Vaisbuch, Edi; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Erez, Offer; Than, Nandor G.; Kim, Sun Kwon; Dong, Zhong; Gotsch, Francesca; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Pacora, Percy; Yeo, Lami; Hassan, Sonia S.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Vaisbuch, Edi; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Erez, Offer; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 486 BP 208A EP 208A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800487 ER PT J AU Muneyyirci-Delale, O Osei-Tutu, N Parris, R Jiang, XC Dalloul, M Nacharaju, V Fan, YF Cunningham, A Stratton, P AF Muneyyirci-Delale, Ozgul Osei-Tutu, Nanna Parris, Rudolph Jiang, Xian-Cheng Dalloul, Mudar Nacharaju, Vijaya Fan, Yi-Fan Cunningham, Arquita Stratton, Pamela TI Serum Sphingomyelin and Phosphatidylcholine in Women with Symptomatic Endometriosis SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Muneyyirci-Delale, Ozgul; Osei-Tutu, Nanna; Parris, Rudolph; Jiang, Xian-Cheng; Dalloul, Mudar; Nacharaju, Vijaya; Fan, Yi-Fan; Cunningham, Arquita] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Muneyyirci-Delale, Ozgul] Kings Cty Hosp Ctr, Brooklyn, NY USA. [Stratton, Pamela] NICHD, Gynecol Serv, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 489 BP 209A EP 209A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800490 ER PT J AU Stratton, P Yen, RH Sinaii, N Liu, S Wolff, E Shah, J AF Stratton, P. Yen, R-H Sinaii, N. Liu, S. Wolff, E. Shah, J. TI Central Nervous System Sensitization in Women with Chronic Pelvic Pain and Endometriosis SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Stratton, P.; Liu, S.; Wolff, E.] NICHD, RBMB, NIH, Bethesda, MD USA. [Sinaii, N.] NIH, BCES, CC, Bethesda, MD 20892 USA. [Yen, R-H; Shah, J.] NIH, BCES, CC, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 493 BP 210A EP 210A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800494 ER PT J AU Stratton, P Pattaratornkosohn, T Vieira, MR Liu, S Gonzalez, AC Khachikyan, I Idriss, A Battuello, P Karp, B AF Stratton, Pamela Pattaratornkosohn, Tina Vieira, Maria R. Liu, Shannon Gonzalez, Alma C. Khachikyan, Izabella Idriss, Asma Battuello, Patricia Karp, Barbara TI Systematic Review of the Inclusion of Women of Childbearing Potential (WOCBP) in NIH Intramural Clinical Trials: Requirements for Contraception and Pregnancy Testing SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Stratton, Pamela; Liu, Shannon; Gonzalez, Alma C.; Khachikyan, Izabella] NICHD, RBMB, Bethesda, MD USA. [Pattaratornkosohn, Tina; Vieira, Maria R.; Karp, Barbara] USUHS, Bethesda, MD USA. NIAID, Intramural Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 500 BP 212A EP 212A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800501 ER PT J AU Lee, DC Romero, R Kim, JS Chaiworapongsa, T Hong, JS Vaisbuch, E Erez, O Mazaki-Tovi, S Kusanovic, JP Hassan, SS Kim, CJ AF Lee, Deug-Chan Romero, Roberto Kim, Jung-Sun Chaiworapongsa, Tinnakorn Hong, Joon-Seok Vaisbuch, Edi Erez, Offer Mazaki-Tovi, Shali Kusanovic, Juan Pedro Hassan, Sonia S. Kim, Chong Jai TI Amniotic Sequestration of Multimeric Surfactant Protein-A: A Fundamental Difference between Spontaneous Labor at Term in Humans and C57BL/6 Mice SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Lee, Deug-Chan; Romero, Roberto; Kim, Jung-Sun; Chaiworapongsa, Tinnakorn; Vaisbuch, Edi; Erez, Offer; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Hassan, Sonia S.; Kim, Chong Jai] NICHD, Perinantol Res Branch, NIH, DHHS, Detroit, MI USA. [Kim, Jung-Sun; Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Chaiworapongsa, Tinnakorn; Vaisbuch, Edi; Erez, Offer; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Hong, Joon-Seok] Seoul Natl Univ Hosp, Dept Obstet & Gynecol, Seoul 110744, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 510 BP 215A EP 215A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800510 ER PT J AU Owen, CM Malik, M Taboas, J Chen, F Norian, JM Driggers, P Tuan, RS Segars, JH AF Owen, Carter M. Malik, Minnie Taboas, Juan Chen, Faye Norian, John M. Driggers, Paul Tuan, Rocky S. Segars, James H. TI Chronically Elevated Levels of Active Rho Are Associated with Altered Mechanical Sensing in Immortalized Leiomyoma Cells SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Owen, Carter M.; Segars, James H.] NIH, CRTP, Ctr Clin, Bethesda, MD USA. [Owen, Carter M.; Norian, John M.; Segars, James H.] NICHD, Reprod Biol Med Branch, NIH, Bethesda, MD USA. [Malik, Minnie; Driggers, Paul] USUHS, Dept Obstet & Gynecol, Bethesda, MD USA. [Taboas, Juan; Chen, Faye; Tuan, Rocky S.] NIAMS, Cartilage Biol & Orthoped Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 511 BP 215A EP 215A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800511 ER PT J AU Stegmann, BJ Gemmill, J Kino, T Segars, JH Stratton, P AF Stegmann, Barbara J. Gemmill, Julieanne Kino, Tomoshige Segars, James H. Stratton, Pamela TI Identification of Polymorphisms in the Adrenocorticotropin Receptor Promotor in Women with Endometriosis and Chronic Pelvic Pain SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Stegmann, Barbara J.] Univ Iowa, Div Reprod Endocrinol & Infertil, Iowa City, IA USA. [Stegmann, Barbara J.; Gemmill, Julieanne; Kino, Tomoshige; Segars, James H.; Stratton, Pamela] NICHD, RBMB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 512 BP 215A EP 215A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800512 ER PT J AU Sharma, S Venkataramanan, R Caritis, SN Mattison, DR Strom, S AF Sharma, Shringi Venkataramanan, Raman Caritis, Steve N. Mattison, Donald R. Strom, Steve TI Disposition of 17 alpha-Hydroxyprogesterone Caproate (17-OHPC) in Human Fetal SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Caritis, Steve N.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Venkataramanan, Raman; Strom, Steve] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Sharma, Shringi; Venkataramanan, Raman] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Obstetr Fetal Pharmacol Res Units Network, Bethesda, MD USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 516 BP 216A EP 217A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800516 ER PT J AU Caritis, SN Sharma, S Zhang, S Mattison, DR Miodovnik, M Hankins, GDV Hebert, MF Venkataramanan, R AF Caritis, Steve N. Sharma, Shringi Zhang, Shimin Mattison, Donald R. Miodovnik, Menachem Hankins, Gary D. V. Hebert, Mary F. Venkataramanan, Raman TI Placental Transfer of 17-alpha Hydroxyprogesterone Caproate (17-OHPC) SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Caritis, Steve N.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Sharma, Shringi; Zhang, Shimin; Venkataramanan, Raman] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut, Pittsburgh, PA USA. [Miodovnik, Menachem] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Miodovnik, Menachem] Washington Hosp Ctr, Dept Obstet & Gynecol, Washington, DC 20010 USA. [Hankins, Gary D. V.] Univ Texas Med Branch, Dept Pharm, Galveston, TX USA. [Hankins, Gary D. V.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX USA. [Hebert, Mary F.] Univ Washington, Sch Pharm, Dept Obstet & Gynecol, Seattle, WA USA. [Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Obstertr Fetal Pharmacol Res Units Network, Bethesda, MD USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 518 BP 217A EP 217A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800517 ER PT J AU Chaiworapongsa, T Romero, R Tarca, A Gotsch, F Kusanovic, JP Erez, O Vaisbuch, E Mazaki-Tovi, S Mittal, P Dong, Z Kim, CJ Kim, SK Yeo, L Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Tarca, Adi Gotsch, Francesca Kusanovic, Juan Pedro Erez, Offer Vaisbuch, Edi Mazaki-Tovi, Shali Mittal, Pooja Dong, Zhong Kim, Chong Jai Kim, Sun Kwon Yeo, Lami Hassan, Sonia S. TI Spontaneous Preterm Labor and Delivery: Another Anti-Angiogenic State? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Tarca, Adi; Gotsch, Francesca; Kusanovic, Juan Pedro; Erez, Offer; Vaisbuch, Edi; Mazaki-Tovi, Shali; Mittal, Pooja; Dong, Zhong; Kim, Chong Jai; Kim, Sun Kwon; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Erez, Offer; Vaisbuch, Edi; Mazaki-Tovi, Shali; Mittal, Pooja; Dong, Zhong; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Vaisbuch, Edi] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 518 BP 217A EP 217A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800518 ER PT J AU Mazaki-Tovi, S Vaisbuch, E Kusanovic, JP Erez, O Mittal, P Chaiworapongsa, T Than, NG Kim, SK Nhan-Chang, CL Jodicke, C Pacora, P Gotsch, F Yeo, L Dong, Z Hassan, SS Romero, R AF Mazaki-Tovi, Shali Vaisbuch, Edi Kusanovic, Juan Pedro Erez, Offer Mittal, Pooja Chaiworapongsa, Tinnakorn Than, Nandor G. Kim, Sun Kwon Nhan-Chang, Chia-Ling Jodicke, Cristiano Pacora, Percy Gotsch, Francesca Yeo, Lami Dong, Zhong Hassan, Sonia S. Romero, Roberto TI A Role for Adiponectin in Intra-Amniotic Infection SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Mazaki-Tovi, Shali; Vaisbuch, Edi; Kusanovic, Juan Pedro; Erez, Offer; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Than, Nandor G.; Kim, Sun Kwon; Nhan-Chang, Chia-Ling; Jodicke, Cristiano; Pacora, Percy; Gotsch, Francesca; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Romero, Roberto] NICHD NIH DHHS, Perinatol Res Branch, Detroit, MI USA. [Mazaki-Tovi, Shali; Vaisbuch, Edi; Kusanovic, Juan Pedro; Erez, Offer; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Nhan-Chang, Chia-Ling; Jodicke, Cristiano; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 528 BP 220A EP 220A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800528 ER PT J AU Nowicki, S Pawelezyk, E Izban, MG Hart, A Olson, G Nowicki, BJ AF Nowicki, Stella Pawelezyk, Edyta Izban, Michael G. Hart, Audrey Olson, Gayle Nowicki, Bogdan J. TI The Predictive Value of CD55 Expression in Maternal PWBC's on Preterm Delivery SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Nowicki, Stella; Izban, Michael G.; Nowicki, Bogdan J.] Meharry Med Coll, Nashville, TN 37208 USA. [Pawelezyk, Edyta] NIH, Bethesda, MD 20892 USA. [Hart, Audrey; Olson, Gayle] Univ Texas Galveston, Med Branch, Dept Med Obstet & Gyencol, Galveston, TX 77550 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 531 BP 221A EP 221A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609800531 ER PT J AU Vaisbuch, E Romero, R Mazaki-Tovi, S Erez, O Kusanovic, JP Mittal, P Gotsch, F Ward, C Romero, V Chaiworapongsa, T Yeo, L Pacora, P Hassan, SS AF Vaisbuch, Edi Romero, Roberto Mazaki-Tovi, Shali Erez, Offer Kusanovic, Juan Pedro Mittal, Pooja Gotsch, Francesca Ward, Clara Romero, Vivian Chaiworapongsa, Tinnakorn Yeo, Lami Pacora, Percy Hassan, Sonia S. TI The Natural History of Patients with a Sonographic Non-Measurable Cervical Length ("0 mm") in the Second Trimester of Pregnancy SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Erez, Offer; Kusanovic, Juan Pedro; Mittal, Pooja; Gotsch, Francesca; Chaiworapongsa, Tinnakorn; Yeo, Lami; Pacora, Percy; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Vaisbuch, Edi; Mazaki-Tovi, Shali; Erez, Offer; Kusanovic, Juan Pedro; Mittal, Pooja; Ward, Clara; Romero, Vivian; Chaiworapongsa, Tinnakorn; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept OB GYN, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 540 BP 223A EP 223A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801003 ER PT J AU Pacora, P Romero, R Mazaki-Tovi, S Kusanovic, JP Mittal, P Chaiworapongsa, T Vaisbuch, E Erez, O Gotsch, F Than, NG Kim, SK Yeo, L Hassan, SS AF Pacora, Percy Romero, Roberto Mazaki-Tovi, Shali Kusanovic, Juan Pedro Mittal, Pooja Chaiworapongsa, Tinnakorn Vaisbuch, Edi Erez, Offer Gotsch, Francesca Than, Nandor G. Kim, Sun Kwon Yeo, Lami Hassan, Sonia S. TI Adiponectin: A Missing Link between Fetal Death and Altered Metabolic, Inflammatory and Anti-Angiogenic States? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Pacora, Percy; Romero, Roberto; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Vaisbuch, Edi; Erez, Offer; Gotsch, Francesca; Than, Nandor G.; Kim, Sun Kwon; Yeo, Lami; Hassan, Sonia S.] NICHD NIH DHHS, Perinatol Res Branch, Detroit, MI USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Mittal, Pooja; Vaisbuch, Edi; Erez, Offer; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 619 BP 247A EP 247A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801082 ER PT J AU Chaiworapongsa, T Romero, R Gotsch, F Kusanovic, JP Tarca, A Mittal, P Kim, SK Erez, O Vaisbuch, E Mazaki-Tovi, S Kim, CJ Dong, Z Yeo, L Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Gotsch, Francesca Kusanovic, Juan Pedro Tarca, Adi Mittal, Pooja Kim, Sun Kwon Erez, Offer Vaisbuch, Edi Mazaki-Tovi, Shali Kim, Chong Jai Dong, Zhong Yeo, Lami Hassan, Sonia S. TI Acute Pyelonephritis during Pregnancy Changes the Balance of Angiogenic and Anti-Angiogenic Factors in Maternal Plasma SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Gotsch, Francesca; Kusanovic, Juan Pedro; Tarca, Adi; Mittal, Pooja; Kim, Sun Kwon; Erez, Offer; Vaisbuch, Edi; Mazaki-Tovi, Shali; Kim, Chong Jai; Dong, Zhong; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Mittal, Pooja; Erez, Offer; Vaisbuch, Edi; Mazaki-Tovi, Shali; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Tarca, Adi] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 631 BP 251A EP 251A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801094 ER PT J AU Drennan, KJ Linnemann, AK Platts, A Heng, H Armant, DR Krawetz, SA AF Drennan, Kathryn J. Linnemann, Amelia K. Platts, Adrian Heng, Henry Armant, David R. Krawetz, Stephen A. TI Chromatin Structure and Trophoblast Invasion SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Linnemann, Amelia K.; Platts, Adrian; Heng, Henry; Armant, David R.; Krawetz, Stephen A.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Armant, David R.] NICHD, Reprod Biol & Med Branch, NIH, DHHS, Bethesda, MD USA. [Krawetz, Stephen A.] Wayne State Univ, Inst Comp Sci, Detroit, MI USA. RI Platts, Adrian/H-5633-2013 OI Platts, Adrian/0000-0001-9238-9647 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 665 BP 260A EP 260A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801128 ER PT J AU Chaiworapongsa, T Romero, R Tarca, A Kusanovic, JP Gotsch, F Mittal, P Erez, O Vaisbuch, E Mazaki-Tovi, S Dong, Z Kim, CJ Kim, SK Yeo, L Hassan, S AF Chaiworapongsa, Tinnakorn Romero, Roberto Tarca, Adi Kusanovic, Juan Pedro Gotsch, Francesca Mittal, Pooja Erez, Ofter Vaisbuch, Edi Mazaki-Tovi, Shali Dong, Zhong Kim, Chong Jai Kim, Sun Kwon Yeo, Lami Hassan, Sonia TI A Decrease in Maternal Plasma Concentrations of sVEGFR-2 Precedes the Clinical Diagnosis of Preeclampsia SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Tarca, Adi; Kusanovic, Juan Pedro; Gotsch, Francesca; Mittal, Pooja; Erez, Ofter; Vaisbuch, Edi; Mazaki-Tovi, Shali; Dong, Zhong; Kim, Chong Jai; Kim, Sun Kwon; Yeo, Lami; Hassan, Sonia] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Mittal, Pooja; Erez, Ofter; Vaisbuch, Edi; Mazaki-Tovi, Shali; Dong, Zhong; Yeo, Lami; Hassan, Sonia] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Tarca, Adi] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 679 BP 264A EP 264A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801142 ER PT J AU Erez, O Romero, R Vaisbuch, E Kusanovic, JP Mazaki-Tovi, S Golsch, F Mittal, P Kim, SK Dong, Z Kim, CJ Pacora, P Than, NG Yeo, L Mazor, M Hassan, SS AF Erez, Offer Romero, Roberto Vaisbuch, Edi Kusanovic, Juan Pedro Mazaki-Tovi, Shali Golsch, Francesca Mittal, Pooja Kim, Sun Kwon Dong, Zhong Kim, Chong Jai Pacora, Percy Than, Nandor G. Yeo, Lami Mazor, Moshe Hassan, Sonia S. TI A Role for Low Activity of ADAMTS-13 in HELLP Syndrome SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Erez, Offer; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Golsch, Francesca; Mittal, Pooja; Kim, Sun Kwon; Dong, Zhong; Kim, Chong Jai; Pacora, Percy; Than, Nandor G.; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Erez, Offer; Vaisbuch, Edi; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Mittal, Pooja; Kim, Sun Kwon; Dong, Zhong; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Mazor, Moshe] Ben Gurion Univ Beer Sheva, Dept Obstet & Gynecol, Beer Sheva, Israel. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 683 BP 265A EP 265A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801146 ER PT J AU Erez, O Romero, R Vaisbuch, E Kusanovic, JP Mazaki-Tovi, S Gotsch, F Mittal, P Than, NG Dong, Z Kim, CJ Kim, SK Pacora, P Yeo, L Mazor, M Hassan, SS AF Erez, Offer Romero, Roberto Vaisbuch, Edi Kusanovic, Juan Pedro Mazaki-Tovi, Shali Gotsch, Francesca Mittal, Pooja Than, Nandor G. Dong, Zhong Kim, Chong Jai Kim, Sun Kwon Pacora, Percy Yeo, Lami Mazor, Moshe Hassan, Sonia S. TI Preeclampsia Is Characterized by Lower Plasma Concentrations of the von Willebrand Factor Cleavage Protease, ADAMTS-13: A Link between Endothelial Dysfunction and a Specific Deficiency of a Plasma Protease SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Erez, Offer; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Gotsch, Francesca; Mittal, Pooja; Than, Nandor G.; Dong, Zhong; Kim, Chong Jai; Kim, Sun Kwon; Pacora, Percy; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Erez, Offer; Vaisbuch, Edi; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Mittal, Pooja; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Mazor, Moshe] Ben Gurion Univ Negev, Dept Obstet & Gynecol, Beer Sheva, Israel. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 684 BP 266A EP 266A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801147 ER PT J AU Hassan, SS Romero, R Tarca, A Romero, V Ward, C Vaisbuch, E Erez, O Draghici, S Mittal, P Kim, JS Kim, CJ AF Hassan, Sonia S. Romero, Roberto Tarca, Adi Romero, Vivian Ward, Clara Vaisbuch, Edi Erez, Offer Draghici, Sorin Mittal, Pooja Kim, Jung-Sun Kim, C. J. TI Transcriptome Analysis of Human Cervical Ripening: Lack of Differential Expression of Genes Involved in Acute Inflammation and Discovery of Novel Biological Processes and Pathways SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Hassan, Sonia S.; Romero, Roberto; Tarca, Adi; Vaisbuch, Edi; Erez, Offer; Mittal, Pooja; Kim, Jung-Sun; Kim, C. J.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Hassan, Sonia S.; Romero, Vivian; Ward, Clara; Vaisbuch, Edi; Erez, Offer; Mittal, Pooja] Wayne State Univ, Dept OB GYN, Detroit, MI USA. [Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. RI Draghici, Sorin/B-3074-2013 OI Draghici, Sorin/0000-0002-0786-8377 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 771 BP 292A EP 292A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801233 ER PT J AU Moore, RC Matison, D Caritis, SN Condon, JC AF Moore, Robert C. Matison, Don Caritis, Steve N. Condon, Jennifer C. TI Estrogen Responsive Expression of the 46kDa Estrogen Receptor-a Isoform Differs in Term Versus Preterm Human Myometrial Tissue Cultures SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Moore, Robert C.; Caritis, Steve N.; Condon, Jennifer C.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Matison, Don] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, ORWH, Obstet Fetal Pharmacol Res Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 784 BP 295A EP 295A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801246 ER PT J AU Gyamfi, C AF Gyamfi, Cynthia TI The MFMU Cesarean Registry: The Effect of Antenatal Corticosteroids on Respiratory Morbidity in Singletons after Late Preterm Birth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Gyamfi, Cynthia] Eunice Kennedy Shriver NICHD, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 827 BP 308A EP 308A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801289 ER PT J AU Horton, AL AF Horton, Amianda L. TI The Role of Family History in Identifying Factor V Leiden Carriers during Pregnancy SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Horton, Amianda L.] Eunice Kennedy Shriver NICHD, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 830 BP 309A EP 309A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801292 ER PT J AU Kim, SK Romero, R Kusanovic, JP Erez, O Vaisbuch, E Mazaki-Tovi, S Gotsch, F Mittal, P Chiaworapongsa, T Pacora, P Yeo, L Hassan, SS AF Kim, Sun Kwon Romero, Roberto Kusanovic, Juan Pedro Erez, Offer Vaisbuch, Ech Mazaki-Tovi, Shali Gotsch, Francesca Mittal, Pocja Chiaworapongsa, Tinnakorn Pacora, Percy Yeo, Lami Hassan, Sonia S. TI The Prognosis of Pregnancy Conceived Despite the Presence of an Intrauterine Device (IUD) SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Kim, Sun Kwon; Romero, Roberto; Kusanovic, Juan Pedro; Erez, Offer; Vaisbuch, Ech; Mazaki-Tovi, Shali; Gotsch, Francesca; Mittal, Pocja; Chiaworapongsa, Tinnakorn; Pacora, Percy; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto; Mazaki-Tovi, Shali; Mittal, Pocja; Chiaworapongsa, Tinnakorn; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kusanovic, Juan Pedro; Erez, Offer; Vaisbuch, Ech] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 841 BP 312A EP 313A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801303 ER PT J AU Kim, SK Romero, R Chaiworapongsa, T Kusanovic, JP Mazaki-Tovi, S Mittal, P Erez, O Vaisbuch, E Gotsch, F Pacora, P Yeo, L Hassan, SS AF Kim, Sun Kwon Romero, Roberto Chaiworapongsa, Tinnakorn Kusanovic, Juan Pedro Mazaki-Tovi, Shah Mittal, Pooja Erez, Offer Vaisbuch, Edi Gotsch, Francesca Pacora, Percy Yeo, Lami Hassan, Sonia S. TI Immunophenotype and Metabolic Evidence of Activation in Fetal, but Not Maternal, Monocytes and Granulocytes in the Fetal Inflammatory Response Syndrome. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 56th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 17-21, 2009 CL Glasgow, SCOTLAND SP Soc Gynecol Invest C1 [Kim, Sun Kwon; Romero, Roberto; Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Mazaki-Tovi, Shah; Mittal, Pooja; Erez, Offer; Vaisbuch, Edi; Gotsch, Francesca; Pacora, Percy; Yeo, Lami; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn; Mazaki-Tovi, Shah; Vaisbuch, Edi; Yeo, Lami] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Kusanovic, Juan Pedro; Mittal, Pooja; Erez, Offer] Wayne State Univ, Dept OB GYN, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2009 VL 16 IS 3 MA 981 BP 353A EP 353A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 410WU UT WOS:000263609801443 ER PT J AU Dunton, GF Tscherne, J Rodriguez, D AF Dunton, Genevieve Fridlund Tscherne, James Rodriguez, Daniel TI Factorial Validity and Gender Invariance of the Physical Activity Enjoyment Scale (PACES) in Older Adolescents SO RESEARCH QUARTERLY FOR EXERCISE AND SPORT LA English DT Article DE confirmatory factor analysis; structural equation modeling ID SELF-DETERMINATION THEORY; FIT; LIFE C1 [Tscherne, James; Rodriguez, Daniel] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Dunton, Genevieve Fridlund] Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. RP Rodriguez, D (reprint author), Univ Penn, Dept Psychiat, 3535 Market St,Suite 4100, Philadelphia, PA 19104 USA. EM drodrig2@mail.med.upenn.edu NR 21 TC 6 Z9 6 U1 1 U2 6 PU AMER ALLIANCE HEALTH PHYS EDUC REC & DANCE PI RESTON PA 1900 ASSOCIATION DRIVE, RESTON, VA 22091 USA SN 0270-1367 J9 RES Q EXERCISE SPORT JI Res. Q. Exerc. Sport PD MAR PY 2009 VL 80 IS 1 BP 117 EP 121 PG 5 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 427JM UT WOS:000264775600012 PM 19408473 ER PT J AU McGlashan, T Addington, J Cadenhead, KS Cannon, TD Cornblatt, BA Heinssen, R Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW AF McGlashan, Thomas Addington, J. Cadenhead, K. S. Cannon, T. D. Cornblatt, B. A. Heinssen, R. Perkins, D. O. Seidman, L. J. Tsuang, M. T. Walker, E. F. Woods, S. W. TI A NEW DIAGNOSTIC CLASS: THE PRODROMAL RISK SYNDROME FOR FIRST PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [McGlashan, Thomas; Woods, S. W.] Yale Univ, Branford, CT USA. [Addington, J.] Univ Toronto, Toronto, ON, Canada. [Cadenhead, K. S.; Tsuang, M. T.] UCSD, San Diego, CA USA. [Cannon, T. D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Cornblatt, B. A.] Zucker Hillside Hosp, Long Isl City, NY USA. [Heinssen, R.] NIMH, Schizophrenia Spectrum Disorders Res Program, Bethesda, MD 20892 USA. [Perkins, D. O.] Univ N Carolina, Chapel Hill, NC USA. [Seidman, L. J.; Tsuang, M. T.] Harvard Univ, Sch Med, Boston, MA USA. [Walker, E. F.] Emory Univ, Atlanta, GA 30322 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 5 EP 5 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700015 ER PT J AU Boggs, DL Kelly, DL Linthicum, J Liu, F McMahon, RP Gorelick, DA AF Boggs, Douglas Lee Kelly, D. L. Linthicum, J. Liu, F. McMahon, R. P. Gorelick, D. A. TI THE PATTERN OF CANNABIS USE AND WITHDRAWAL SYMPTOMS IN PEOPLE WITH SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Boggs, Douglas Lee; Kelly, D. L.; Linthicum, J.; Liu, F.; McMahon, R. P.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Gorelick, D. A.] Natl Inst Drug Abuse, Off Sci Director, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RI McMahon, Robert/C-5462-2009; Boggs, Douglas/C-7515-2009; Boggs, Douglas/F-5429-2010 NR 1 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 21 EP 21 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700066 ER PT J AU Eastwood, SL Hodgkinson, CA Harrison, PJ AF Eastwood, Sharon L. Hodgkinson, C. A. Harrison, P. J. TI DISC-1 PROTEINS ENCODED BY LEU607PHE ALLELES SHOW A DIFFERENTIAL SUB-CELLULAR LOCALISATION AND DIFFERENTIALLY MODULATE NEUROTRANSMITTER RELEASE SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Eastwood, Sharon L.; Harrison, P. J.] Univ Oxford, Dept Psychiat, Oxford, England. [Hodgkinson, C. A.] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 96 EP 97 PG 2 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700283 ER PT J AU Mayilyan, KR Vakkalanka, R Kolachana, B Weinberger, DR AF Mayilyan, Karine R. Vakkalanka, R. Kolachana, B. Weinberger, D. R. TI POLYMORPHIC VARIANTS OF THE TNXB ASSOCIATED WITH COGNITION AND SCHIZOPHRENIA SUSCEPTIBILITY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Mayilyan, Karine R.; Vakkalanka, R.; Kolachana, B.; Weinberger, D. R.] NIMH, CBDB Genes Cognit & Psychosis Program, IRP, NIH, Bethesda, MD 20892 USA. [Mayilyan, Karine R.] Armenian Natl Acad Sci, Inst Mol Biol, Yerevan, Armenia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 99 EP 99 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700292 ER PT J AU Lencz, T Robinson, DG Xu, K Napolitano, B Sevy, S Gunduz-Bruce, H Kane, JM Goldman, D Malhotra, AK AF Lencz, Todd Robinson, D. G. Xu, K. Napolitano, B. Sevy, S. Gunduz-Bruce, H. Kane, J. M. Goldman, D. Malhotra, A. K. TI DRD2 VARIATION AND WEIGHT GAIN IN FIRST EPISODE SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Lencz, Todd; Robinson, D. G.; Sevy, S.; Kane, J. M.; Malhotra, A. K.] Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY 06520 USA. [Lencz, Todd; Robinson, D. G.; Napolitano, B.; Kane, J. M.; Malhotra, A. K.] Feinstein Inst Med Res, Ctr Translat Psychiat, Manhasset, NY USA. [Xu, K.; Goldman, D.] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Gunduz-Bruce, H.] Yale Univ, Dept Psychiat, New Haven, CT USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 107 EP 107 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700311 ER PT J AU Weickert, T AF Weickert, Thomas TI PROBABILISTIC CATEGORY LEARNING DEFICITS EXIST IN A SUBSET OF UN AFFECTED SIBLINGS OF PATIENTS WITH SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Weickert, Thomas] Univ New S Wales, Sch Psychiat, Randwick, NSW, Australia. [Weickert, Thomas] NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 108 EP 108 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700315 ER PT J AU Toulopoulou, T Goldberg, T Weinberger, DR Rijsdijk, F Faraone, S Tsuang, M Stahl, D Picchioni, M Sham, P Cherney, S Murray, R Seidman, L AF Toulopoulou, Timothea Goldberg, T. Weinberger, D. R. Rijsdijk, F. Faraone, S. Tsuang, M. Stahl, D. Picchioni, M. Sham, P. Cherney, S. Murray, R. Seidman, L. TI ARE INTELLIGENCE AND MEMORY GOOD ENDOPHENOTYPES FOR SCHIZOPHRENIA? GENETIC MODELS IN A HARVARD, IOP, AND NIH COLLABORATION SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Toulopoulou, Timothea; Rijsdijk, F.; Stahl, D.; Picchioni, M.; Murray, R.] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Goldberg, T.] Zucker Hillside Hosp, New York, NY USA. [Weinberger, D. R.] NIMH, Bethesda, MD 20892 USA. [Faraone, S.] SUNY Upstate Med Univ, New York, NY USA. [Tsuang, M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Sham, P.; Cherney, S.] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Toulopoulou, Timothea; Seidman, L.] Harvard Univ, Sch Med, Boston, MA USA. RI Cherny, Stacey/B-3315-2008; Stahl, Daniel/B-9713-2011; Rijsdijk, Fruhling/B-4191-2011 OI Cherny, Stacey/0000-0002-0269-3352; Stahl, Daniel/0000-0001-7987-6619; NR 1 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 110 EP 110 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700320 ER PT J AU Weinberger, DR AF Weinberger, Daniel R. TI KCNH2 AND DOPAMINE RELATED CORTICAL EFFICIENCY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Weinberger, Daniel R.] NIMH, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 117 EP 117 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700342 ER PT J AU Kelly, DL Myers, CS Feldman, S Abrams, MT Shim, JC McMahon, RP Chen, S AF Kelly, Deanna L. Myers, C. S. Feldman, S. Abrams, M. T. Shim, J. C. McMahon, R. P. Chen, S. TI THE EFFECTS OF SUBSTANCE USE ON BREAST CANCER AND OSTEOPOROSIS SCREENING IN WOMEN WITH SCHIZOPHRENIA: A REVIEW OF CONTINUOUSLY COVERED MEDICAID BENEFICIARIES SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Kelly, Deanna L.; Feldman, S.; McMahon, R. P.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Myers, C. S.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD USA. [Abrams, M. T.; Chen, S.] Univ Maryland Baltimore Cty, CHPDM, Baltimore, MD 21228 USA. [Shim, J. C.] Inje Univ, Dept Psychiat, Pusan, South Korea. RI McMahon, Robert/C-5462-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 128 EP 129 PG 2 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700372 ER PT J AU Hyde, TM Mathew, SV Ali, T Lipska, BK Law, AJ Metitiri, OE Weinberger, DR Kleinman, JE AF Hyde, Thomas Michael Mathew, S. V. Ali, T. Lipska, B. K. Law, A. J. Metitiri, O. E. Weinberger, D. R. Kleinman, J. E. TI CATION CHLORIDE COTRANSPORTERS: EXPRESSION PATTERNS IN DEVELOPMENT AND SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Hyde, Thomas Michael; Mathew, S. V.; Ali, T.; Lipska, B. K.; Law, A. J.; Metitiri, O. E.; Weinberger, D. R.; Kleinman, J. E.] NIMH, Clin Brain Disorders Branch, GCAP, IRP,NIH, Bethesda, MD 20892 USA. RI Law, Amanda/G-6372-2012 NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 150 EP 151 PG 2 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700434 ER PT J AU Lipska, BK Nakata, K AF Lipska, Barbara K. Nakata, K. TI CHARACTERIZATION AND GENETIC ASSOCIATION OF NOVEL SPLICE VARIANTS OF DISRUPTED-IN-SCHIZOPHRENIA-1 (DISC1) IN HUMAN BRAIN SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Lipska, Barbara K.; Nakata, K.] NIMH, CBDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 151 EP 151 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700436 ER PT J AU Weinberger, DR AF Weinberger, Daniel R. TI A PRIMATE AND BRAIN SPECIFIC ISOFORM OF KCNH2 IS AN ETIOLOGIC AND PATHOPHYSIOLOGIC COMPONENT OF SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Weinberger, Daniel R.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 151 EP 151 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700435 ER PT J AU Waltz, JA Schweitzer, JB Gold, JM Rose, EJ Kurup, PK Salmeron, BJ Ross, TJ McClure, SM Stein, EA AF Waltz, James A. Schweitzer, J. B. Gold, J. M. Rose, E. J. Kurup, P. K. Salmeron, B. J. Ross, T. J. McClure, S. M. Stein, E. A. TI NEURAL CORRELATES OF THE SUBJECTIVE EXPERIENCE OF REWARD IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Waltz, James A.; Gold, J. M.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Schweitzer, J. B.] Univ Calif Davis, Dept Psychiat, Sch Med, Sacramento, CA 95817 USA. [Rose, E. J.; Kurup, P. K.; Salmeron, B. J.; Ross, T. J.; Stein, E. A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, Baltimore, MD USA. [McClure, S. M.] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. RI Salmeron, Betty Jo/M-1793-2016 OI Salmeron, Betty Jo/0000-0003-1699-9333 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 171 EP 171 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700493 ER PT J AU Tan, HYY Chen, Q Nicodemus, KK Straub, RE Kolachana, B Meyer-Lindenberg, A Sei, Y Mattay, VS Callicott, JH Weinberger, DR AF Tan, Hao-Yang Y. Chen, Q. Nicodemus, K. K. Straub, R. E. Kolachana, B. Meyer-Lindenberg, A. Sei, Y. Mattay, V. S. Callicott, J. H. Weinberger, D. R. TI PREFRONTAL BRAIN SYSTEMS IN SCHIZOPHRENIA AND PUTATIVE INTERACTING DOPAMINERGIC GENE MECHANISMS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Tan, Hao-Yang Y.; Chen, Q.; Nicodemus, K. K.; Straub, R. E.; Kolachana, B.; Meyer-Lindenberg, A.; Sei, Y.; Mattay, V. S.; Callicott, J. H.; Weinberger, D. R.] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 183 EP 184 PG 2 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700529 ER PT J AU Weinberger, DR AF Weinberger, Daniel R. TI FUNCTIONAL MAPPING OF EFFECTS IN BRAIN OF SUSCEPTIBILITY GENES SHARED BY SCHIZOPHRENIA AND BIPOLAR DISORDER SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Weinberger, Daniel R.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 190 EP 190 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700548 ER PT J AU Callicott, JH Prust, MJ Huffaker, SJ Tan, HY Kolachana, B Egan, MF Weinberger, DR AF Callicott, Joseph H. Prust, M. J. Huffaker, S. J. Tan, H. Y. Kolachana, B. Egan, M. F. Weinberger, D. R. TI ALLELIC VARIATION IN KCNH2 IS ASSOCIATED WITH DORSOLATERAL PREFRONTAL CORTEX ACTIVATION DURING WORKING MEMORY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Callicott, Joseph H.; Prust, M. J.; Huffaker, S. J.; Tan, H. Y.; Kolachana, B.; Egan, M. F.; Weinberger, D. R.] NIMH, CBDB, GCAP, DIRP,NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 194 EP 194 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700561 ER PT J AU Gogtay, N AF Gogtay, Nitin TI PROGRESSIVE GM AND WM ABNORMALITIES IN CHILDHOOD-ONSET SCHIZOPHRENIA(COS) SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Gogtay, Nitin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 215 EP 215 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700619 ER PT J AU Law, AJ AF Law, Amanda Jayne TI CHARACTERIZATION OF A UNIQUE, DEVELOPMENTALLY REGULATED SPLICE VARIANT OF HUMAN NRG1 TYPE IV. IMPLICATIONS FOR SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Law, Amanda Jayne] Univ Oxford, Dept Psychiat, Oxford, England. [Law, Amanda Jayne] NIMH, CBDB, Bethesda, MD 20892 USA. RI Law, Amanda/G-6372-2012 NR 2 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 232 EP 232 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700669 ER PT J AU Apud, JA Rasetti, R Stankevich, B Skjei, K Magalona, S Mattay, VS Weinberger, DR AF Apud, Jose Antonio Rasetti, R. Stankevich, B. Skjei, K. Magalona, S. Mattay, V. S. Weinberger, D. R. TI TOLCAPONE IMPROVES EFFICIENCY IN CORTICAL AREAS UNDERLYING WORKING MEMORY IN PATIENTS WITH SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Apud, Jose Antonio; Rasetti, R.; Stankevich, B.; Skjei, K.; Magalona, S.; Mattay, V. S.; Weinberger, D. R.] NIMH, CBDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 243 EP 243 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700700 ER PT J AU Longenecker, J Kohn, P Liu, S Zoltick, B Weinberger, D Elvevaag, B AF Longenecker, Julia Kohn, P. Liu, S. Zoltick, B. Weinberger, D. Elvevaag, B. TI A DATA-DRIVEN METHOD TO ILLUSTRATE MECHANISMS UNDERLYING VERBAL RECALL AND ITS APPLICATION TO SCHIZOPHRENIA RESEARCH SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Longenecker, Julia; Kohn, P.; Liu, S.; Zoltick, B.; Weinberger, D.; Elvevaag, B.] NIH, CBDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 275 EP 275 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700795 ER PT J AU Riley, W AF Riley, William TI PERSPECTIVES ON THE ADHERENCE CHALLENGE: REPORT FROM AN NIMH-SPONSORED MEETING ON ADHERENCE METHODOLOGY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Riley, William] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 305 EP 305 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700887 ER PT J AU Cornblatt, B Lencz, T Addington, J Cadenhead, K Walker, E Baskir, L Seidman, L Cannon, T Perkins, D Woods, S Tsuang, M McGlashan, T Heinssen, R AF Cornblatt, Barbara Lencz, T. Addington, J. Cadenhead, K. Walker, E. Baskir, L. Seidman, L. Cannon, T. Perkins, D. Woods, S. Tsuang, M. McGlashan, T. Heinssen, R. TI SOCIAL AND ROLE FUNCTIONING: CRITICAL OUTCOME DOMAINS INDEPENDENT OF PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Cornblatt, Barbara; Lencz, T.; Baskir, L.] Zucker Hillside Hosp, Glen Oaks, NY USA. [Addington, J.] Univ Calgary, Calgary, AB, Canada. [Cadenhead, K.; Tsuang, M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Walker, E.] Emory Univ, Atlanta, GA 30322 USA. [Seidman, L.] Harvard Univ, Boston, MA 02115 USA. [Cannon, T.] Univ Calif Los Angeles, Los Angeles, CA USA. [Perkins, D.] Univ N Carolina, Chapel Hill, NC USA. [Woods, S.; McGlashan, T.] Yale Univ, New Haven, CT USA. [Heinssen, R.] NIMH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 319 EP 319 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700927 ER PT J AU Addington, J Perkins, D Woods, S Cadenhead, K Cannon, T Cornblatt, B Seidman, L Walker, E McGlashan, T Tsuang, M Heinssen, R AF Addington, Jean Perkins, D. Woods, S. Cadenhead, K. Cannon, T. Cornblatt, B. Seidman, L. Walker, E. McGlashan, T. Tsuang, M. Heinssen, R. TI FUNCTIONAL IMPAIRMENT: THE HALLMARK OF RISK FOR PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Addington, Jean] Univ Calgary, Calgary, AB, Canada. [Perkins, D.] UNC, Chapel Hill, NC USA. [Woods, S.; McGlashan, T.] Yale Univ, New Haven, CT USA. [Seidman, L.] Harvard Univ, Boston, MA 02115 USA. [Cornblatt, B.] Zucker Hillside Hosp, New York, NY USA. [Walker, E.] Emory Univ, Atlanta, GA 30322 USA. [Cannon, T.] Univ Calif Los Angeles, Los Angeles, CA USA. [Cadenhead, K.; Tsuang, M.] UCSD, San Diego, CA USA. [Heinssen, R.] NIMH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 324 EP 325 PG 2 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700944 ER PT J AU Robinson, DG Napolitano, B Patel, RC Sevy, SM Gunduz-Bruce, H Soto-Perello, JM Mendelowitz, A Khadivi, A Miller, R McCormack, J Lesser, ML Schooler, NR Kane, JM AF Robinson, Delbert Gail Napolitano, B. Patel, R. C. Sevy, S. M. Gunduz-Bruce, H. Soto-Perello, J. M. Mendelowitz, A. Khadivi, A. Miller, R. McCormack, J. Lesser, M. L. Schooler, N. R. Kane, J. M. TI COMPARISON OF OLANZAPINE AND RISPERIDONE TREATMENT FOR FIRST EPISODE SCHIZOPHRENIA: THREE YEAR FUNCTIONAL OUTCOMES SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 12th International Congress on Schizophrenia Research CY MAR 28-APR 01, 2009 CL San Diego, CA C1 [Robinson, Delbert Gail; Napolitano, B.; Sevy, S. M.; Mendelowitz, A.; McCormack, J.; Kane, J. M.] Zucker Hillside Hosp, Glen Oaks, NY USA. [Robinson, Delbert Gail; Napolitano, B.; Lesser, M. L.; Kane, J. M.] Feinstein Inst Med Res, Ctr Translat Psychiat, Manhasset, NY USA. [Patel, R. C.; Soto-Perello, J. M.; Khadivi, A.] Bronx Lebanon Hosp Ctr, Bronx, NY 10456 USA. [Patel, R. C.; Sevy, S. M.; Mendelowitz, A.; Khadivi, A.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Gunduz-Bruce, H.] Yale Univ, Sch Med, New Haven, CT USA. [Miller, R.] NIMH, Bethesda, MD 20892 USA. [Lesser, M. L.] Weill Cornell Med Coll, New York, NY USA. [Schooler, N. R.] Georgetown Univ, Sch Med, Washington, DC USA. [Schooler, N. R.] Vet Affairs Med Ctr, MIRECC, Washington, DC 20422 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2009 VL 35 BP 327 EP 327 PG 1 WC Psychiatry SC Psychiatry GA 415VP UT WOS:000263964700950 ER PT J AU Resnik, DB AF Resnik, David B. TI What is "Dual Use" Research? A Response to Miller and Selgelid SO SCIENCE AND ENGINEERING ETHICS LA English DT Letter C1 NIEHS, NIH, Greenville, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Res Triangle Pk,Mail Drop NH 06,Box 12233, Greenville, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-03, ZIA ES102646-02] NR 6 TC 5 Z9 5 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1353-3452 J9 SCI ENG ETHICS JI Sci. Eng. Ethics PD MAR PY 2009 VL 15 IS 1 BP 3 EP 5 DI 10.1007/s11948-008-9104-3 PG 3 WC Ethics; Engineering, Multidisciplinary; History & Philosophy Of Science; Multidisciplinary Sciences; Philosophy SC Social Sciences - Other Topics; Engineering; History & Philosophy of Science; Science & Technology - Other Topics; Philosophy GA 404VL UT WOS:000263181000002 PM 19005779 ER PT J AU Anderson, LB Dandurova, H Falk, JE Yeganova, L AF Anderson, Lowell Bruce Dandurova, Helena Falk, James E. Yeganova, Lana TI Relationships between Borda voting and Zermelo ranking SO SOCIAL CHOICE AND WELFARE LA English DT Article ID MATHEMATICIANS GUIDE; POPULAR SPORTS; TOURNAMENTS; SCHEMES; CHOICE; RULE AB There are many situations wherein a group of individuals (e.g., voters, experts, sports writers) must produce an ordered list of 'best' alternatives selected from a given group of alternatives (e.g., candidates, proposals, sports teams). Two long established mechanisms that have been used for this task are 'Zermelo's Ranking Method' (1929) and 'Borda's Voting Scheme' (1781). The main purpose of this paper is to point out that they are, under certain common circumstances, identical. We then show that Zermelo's Method can be used in situations that Borda's Method is not designed to handle. C1 [Falk, James E.] George Washington Univ, Sch Engn & Appl Sci, Washington, DC 20052 USA. [Anderson, Lowell Bruce] Inst Defense Analyses, Alexandria, VA 22311 USA. [Dandurova, Helena] Sci Applicat Int Corp, Washington, DC 20024 USA. [Yeganova, Lana] Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Falk, JE (reprint author), George Washington Univ, Sch Engn & Appl Sci, Washington, DC 20052 USA. EM landerso@ida.org; dandurovay@saic.org; falk@gwu.edu; yeganova@ncbi.nlm.nih.gov NR 26 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0176-1714 J9 SOC CHOICE WELFARE JI Soc Choice Welf. PD MAR PY 2009 VL 32 IS 3 BP 355 EP 365 DI 10.1007/s00355-008-0327-7 PG 11 WC Economics; Social Sciences, Mathematical Methods SC Business & Economics; Mathematical Methods In Social Sciences GA 399FV UT WOS:000262786700002 ER PT J AU Mur, M Bandettini, PA Kriegeskorte, N AF Mur, Marieke Bandettini, Peter A. Kriegeskorte, Nikolaus TI Revealing representational content with pattern-information fMRIan introductory guide SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article ID VENTRAL TEMPORAL CORTEX; EVENT-RELATED FMRI; HUMAN BRAIN; VISUAL-CORTEX; BOLD SIGNALS; ADAPTATION; ACTIVATION; OBJECTS; FACES; RECOGNITION AB Conventional statistical analysis methods for functional magnetic resonance imaging (fMRI) data are very successful at detecting brain regions that are activated as a whole during specific mental activities. The overall activation of a region is usually taken to indicate involvement of the region in the task. However, such activation analysis does not consider the multivoxel patterns of activity within a brain region. These patterns of activity, which are thought to reflect neuronal population codes, can be investigated by pattern-information analysis. In this framework, a regions multivariate pattern information is taken to indicate representational content. This tutorial introduction motivates pattern-information analysis, explains its underlying assumptions, introduces the most widespread methods in an intuitive way, and outlines the basic sequence of analysis steps. C1 [Mur, Marieke] Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, NL-6229 ER Maastricht, Netherlands. [Mur, Marieke; Bandettini, Peter A.; Kriegeskorte, Nikolaus] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Bandettini, Peter A.] NIMH, Funct Magnet Resonance Imaging Facil, NIH, Bethesda, MD 20892 USA. RP Mur, M (reprint author), Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, Univ Singel 40, NL-6229 ER Maastricht, Netherlands. EM mariekemur@gmail.com OI Kriegeskorte, Nikolaus/0000-0001-7433-9005 FU NIH; NIMH FX This research was supported by the Intramural Research Program of the NIH, NIMH. NR 42 TC 144 Z9 147 U1 1 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD MAR PY 2009 VL 4 IS 1 BP 101 EP 109 DI 10.1093/scan/nsn044 PG 9 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 421ZY UT WOS:000264398000011 PM 19151374 ER PT J AU Saczynski, JS Sigurdsson, S Jonsdottir, MK Eiriksdottir, G Jonsson, PV Garcia, ME Kjartansson, O Lopez, O van Buchem, MA Gudnason, V Launer, LJ AF Saczynski, Jane S. Sigurdsson, Sigurdur Jonsdottir, Maria K. Eiriksdottir, Gudny Jonsson, Palmi V. Garcia, Melissa E. Kjartansson, Olafur Lopez, Oscar van Buchem, Mark A. Gudnason, Vilmunder Launer, Lenore J. TI Cerebral Infarcts and Cognitive Performance Importance of Location and Number of Infarcts SO STROKE LA English DT Article DE cognition; epidemiology; MRI ID WHITE-MATTER LESIONS; RISK; PREVALENCE; DEMENTIA; CIRCUITS; DISEASE; MRI; AGE AB Background and Purpose-Cerebral infarcts increase the risk for cognitive impairment. The relevance of location and number of infarcts with respect to cognitive function is less clear. Methods-We studied the cross-sectional association between number and location of infarcts and cognitive performance in 4030 nondemented participants of the Age Gene/Environment Susceptibility-Reykjavik Study. Composite scores for memory, processing speed, and executive function were created from a neuropsychological battery. Subcortical, cortical, and cerebellar infarcts were identified on brain MRI. We performed linear regression analyses adjusted for demographic and vascular risk factors, depression, white matter lesions, and atrophy. Results-Compared to participants with no infarcts, those with infarcts in multiple locations (n = 287, 7%) had slower processing speed (beta = -0.19; P < 0.001) and poorer memory (beta = -0.16; P < 0.001) and executive function (beta = -0.12; P = 0.003). Compared to no infarcts, the presence of either subcortical infarcts only (n = 275; beta = -0.12; P = 0.016) or cortical infarcts only (n = 215; beta = -0.17; P < 0.001) was associated with poorer memory performance. Compared to no infarcts, a combination of cortical and subcortical infarcts (n = 45) was associated with slower processing speed (beta = -0.38; P < 0.001) and poorer executive function (beta = -0.22; P < 0.02), whereas a combination of cerebellar and subcortical infarcts (n = 89) was associated with slower processing speed (beta = -0.15; P < 0.04). Infarcts in all 3 locations was associated with slower processing speed (beta = -0.33; P < 0.002). Conclusions-Having infarcts in >1 location is associated with poor performance in memory, processing speed, and executive function, independent of cardiovascular comorbidities, white matter lesions, and brain atrophy, suggesting that both the number and the distribution of infarcts jointly contribute to cognitive impairment. (Stroke. 2009; 40: 677-682.) C1 [Saczynski, Jane S.] Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA 01605 USA. [Saczynski, Jane S.] Univ Massachusetts, Meyers Primary Care Inst, Worcester, MA 01605 USA. [Saczynski, Jane S.; Garcia, Melissa E.; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Sigurdsson, Sigurdur; Jonsdottir, Maria K.; Eiriksdottir, Gudny; Jonsson, Palmi V.; Kjartansson, Olafur; Gudnason, Vilmunder] Iceland Heart Assoc, Kopavogur, Iceland. [Lopez, Oscar] Univ Pittsburgh, Pittsburgh, PA USA. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. RP Saczynski, JS (reprint author), Univ Massachusetts, Sch Med, Div Geriatr Med, Biotech 4,Suite 315,377 Plantat St, Worcester, MA 01605 USA. EM jane.saczynski@umassmed.edu RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 FU National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program; National Eye Institute; National Institute on Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute FX This study was funded by National Institutes of Health contract N01-AG-12100, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Components of the study were also supported by the National Eye Institute, the National Institute on Deafness and Other Communication Disorders, and the National Heart, Lung, and Blood Institute. NR 27 TC 51 Z9 61 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2009 VL 40 IS 3 BP 677 EP 682 DI 10.1161/STROKEAHA.108.530212 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 410PN UT WOS:000263590200017 PM 19131654 ER PT J AU Launer, LJ AF Launer, Lenore J. TI Diabetes: Vascular or Neurodegenerative An Epidemiologic Perspective SO STROKE LA English DT Editorial Material DE diabetes; vascular dementia ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; POPULATION-BASED COHORT; COGNITIVE DECLINE; BLOOD-PRESSURE; ALZHEIMERS-DISEASE; APOE EPSILON-4; RISK-FACTORS; ELDERLY-MEN; DEMENTIA; MELLITUS C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Launer, LJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [N01 HC05102]; NIA NIH HHS [N01-AG-12100, U01 AG019349, R01 AG0-17155 S1] NR 36 TC 17 Z9 19 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2009 VL 40 IS 3 BP S53 EP S55 DI 10.1161/STROKEAHA.108.533075 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 410QW UT WOS:000263594200016 PM 19064803 ER PT J AU Courcoutsakis, N Patronas, N Filie, AC Carney, JA Moraitis, A Stratakis, CA AF Courcoutsakis, Nickolas Patronas, Nickolas Filie, Armando C. Carney, J. Aidan Moraitis, Andreas Stratakis, Constantine A. TI Ectopic Thymus Presenting as a Thyroid Nodule in a Patient with the Carney Complex SO THYROID LA English DT Article ID SPOTTY SKIN PIGMENTATION; ENDOCRINE OVERACTIVITY; INTRATHYROIDAL THYMUS; REGULATORY SUBUNIT; I-ALPHA; MYXOMAS; SCHWANNOMAS; DISEASE; GENE; LENTIGINOSES AB Ectopic thymic tissue within the thyroid gland is rare. Patients with a complex of myxomas, spotty skin pigmentation, and endocrine overactivity, collectively known as Carney complex (CNC), have a predisposition towards the development of thyroid abnormalities, but there are no reports of thymic defects in CNC. We present the case of a 12-year-old boy with CNC and a growing thyroid nodule. The patient had the c. 682 C > T (Arg228X) pathogenic PRKAR1A mutation. Hemithyroidectomy for a Hurthle cell adenoma led to the confirmation of distinct intrathyroidal ectopic thymic tissue. Thymic abnormalities have not been previously reported in CNC. C1 [Courcoutsakis, Nickolas; Moraitis, Andreas; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Courcoutsakis, Nickolas] Demokritus Univ Thrace, Dept Radiol, Alexandroupolis, Greece. [Courcoutsakis, Nickolas] NIH, Dept Diagnost Radiol, Clin Res Ctr, Bethesda, MD USA. [Patronas, Nickolas] NCI, Clin Res Ctr, Dept Diagnost Radiol, Bethesda, MD USA. [Filie, Armando C.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Carney, J. Aidan] Mayo Clin, Dept Lab Med, Rochester, MN USA. RP Stratakis, CA (reprint author), NICHD, Program Dev Endocrinol & Genet, NIH, Bldg 10,CRC,Rm 1-3330 E Labs 10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); NIH [Z01-HD-000642-04] FX We thank the patient and his family for their participation in this and related studies of the 95-CH-0059 protocol. The latter and the experiments described in this report were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH intramural project Z01-HD-000642-04 (to Dr. C. A. Stratakis). NR 22 TC 9 Z9 11 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD MAR PY 2009 VL 19 IS 3 BP 293 EP 296 DI 10.1089/thy.2008.0404 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 415DF UT WOS:000263913800013 PM 19265501 ER PT J AU Krensky, AM Clayberger, C AF Krensky, A. M. Clayberger, C. TI Biology and clinical relevance of granulysin SO TISSUE ANTIGENS LA English DT Review DE antibiotics; cytolytic T lymphocytes; granulysin; immunotherapeutics; natural killer cells ID CYTOLYTIC T-CELLS; SERUM GRANULYSIN; MYCOBACTERIUM-TUBERCULOSIS; CRYPTOCOCCUS-NEOFORMANS; ANTIMICROBIAL ACTIVITY; REQUIRES GRANULYSIN; HOST-DEFENSE; NK CELLS; IN-VITRO; EXPRESSION AB Granulysin is a cytolytic and proinflammatory molecule first identified by a screen for genes expressed 'late' (3-5 days) after activation of human peripheral blood mononuclear cells. Granulysin is present in cytolytic granules of cytotoxic T lymphocytes and natural killer cells. Granulysin is made in a 15-kDa form that is cleaved into a 9-kDa form at both the amino and the carboxy termini. The 15-kDa form is constitutively secreted, and its function remains poorly understood. The 9-kDa form is released by receptor-mediated granule exocytosis. Nine kiloDalton granulysin is broadly cytolytic against tumors and microbes, including gram-positive and gram-negative bacteria, fungi/yeast and parasites. It kills the causative agents of both tuberculosis and malaria. Granulysin is also a chemoattractant for T lymphocytes, monocytes and other inflammatory cells and activates the expression of a number of cytokines, including regulated upon activation T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1 alpha, interleukin (IL)-10, IL-1, IL-6 and interferon (IFN)-alpha. Granulysin is implicated in a myriad of diseases including infection, cancer, transplantation, autoimmunity, skin and reproductive maladies. Small synthetic forms of granulysin are being developed as novel antibiotics. Studies of the full-length forms may give rise to new diagnostics and therapeutics for use in a wide variety of diseases. C1 [Krensky, A. M.; Clayberger, C.] NCI, Lab Cellular & Mol Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Krensky, AM (reprint author), NCI, Lab Cellular & Mol Biol, Natl Inst Hlth, 37 Convent Dr,MSC 4256,Bldg 37,Room 2016, Bethesda, MD 20892 USA. EM krenskya@mail.nih.gov RI Krensky, Alan/F-7956-2011 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work was supported by the Intramural Program of the National Institutes of Health, National Cancer Institute and the Center for Cancer Research. NR 50 TC 62 Z9 68 U1 3 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD MAR PY 2009 VL 73 IS 3 BP 193 EP 198 DI 10.1111/j.1399-0039.2008.01218.x PG 6 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 409RC UT WOS:000263522500001 PM 19254247 ER PT J AU Ross, PK Woods, CG Bradford, BU Kosyk, S Gatti, DM Cunningham, ML Rusyn, I AF Ross, Pamela K. Woods, Courtney G. Bradford, Blair U. Kosyk, Sana Gatti, Daniel M. Cunningham, Michael L. Rusyn, Ivan TI Time-course comparison of xenobiotic activators of CAR and PPAR alpha in mouse liver SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Kupffer cells; PPAR alpha; Toxicogenomics; Microarrays ID CONSTITUTIVE ANDROSTANE RECEPTOR; GENE-EXPRESSION; ACTIVE/ANDROSTANE RECEPTOR; METABOLIZING-ENZYMES; PHENYTOIN INDUCTION; TUMOR PROMOTION; RISK-ASSESSMENT; X RECEPTOR; MICE; WY-14,643 AB Constitutive androstane receptor (CAR) and peroxisome proliferator activated receptor (PPAR)a are transcription factors known to be primary mediators of liver effects, including carcinogenesis, by phenobarbital-like compounds and peroxisome proliferators, respectively, in rodents. Many similarities exist in the phenotypes elicited by these two classes of agents in rodent liver, and we hypothesized that the initial transcriptional responses to the xenobiotic activators of CAR and PPAR alpha will exhibit distinct patterns, but at later time-points these biological pathways will converge. In order to capture the global transcriptional changes that result from activation of these nuclear receptors over a time-course in the mouse liver, microarray technology was used. First, differences in basal expression of liver genes between C57BI/6J wildtype and Car-null mice were examined and 14 significantly differentially expressed genes were identified. Next, mice were treated with phenobarbital (100 mg/kg by gavage for 24 h, or 0.085% w/w diet for 7 or 28 days), and liver gene expression changes with regards to both time and treatment were identified. While several pathways related to cellular proliferation and metabolism were affected by phenobarbital in wildtype mice, no significant changes in gene expression were found over time in the Car-nulls. Next, we determined commonalities and differences in the temporal response to phenobarbital and WY-14,643, a prototypical activator of PPAR alpha. Gene expression signatures from livers of wild-type mice C57BI6/J mice treated with PB or WY-14,643 were compared. Similar pathways were affected by both compounds; however, considerable time-related differences were present. This study establishes common gene expression fingerprints of exposure to activators of CAR and PPAR alpha in rodent liver and demonstrates that despite similar phenotypic changes, molecular pathways differ between classes of chemical carcinogens. (C) 2008 Elsevier Inc. All rights reserved. C1 [Ross, Pamela K.; Bradford, Blair U.; Kosyk, Sana; Gatti, Daniel M.; Rusyn, Ivan] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Woods, Courtney G.] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Woods, Courtney G.] ExxonMobil Biomed Sci, Annandale, NJ USA. [Cunningham, Michael L.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Rusyn, I (reprint author), Univ N Carolina, Dept Environm Sci & Engn, 0031 Michael Hooker Res Ctr,CB 7431, Chapel Hill, NC 27599 USA. EM iir@unc.edu RI Rusyn, Ivan/S-2426-2016 FU NIH [ES12686, ES10126, ES11391]; EPA [RD832720, RD833825]; National Institute of Environmental Health Sciences FX We thank Drs. Fred Wright, David Threadgill and Chang Fan, and Ms. Alison Hege with the University of North Carolina-Chapel Hill for valuable assistance with data analysis and interpretation. We wish to thank Mr. Jeffrey Davis at ILS, Research Triangle Park, NC for preparing the diet used in this study. Financial support for these studies was provided, in part, by grants from NIH (ES12686, ES10126 and ES11391) and EPA (RD832720 and RD833825), and by the Intramural Research program of the National Institute of Environmental Health Sciences. The content of the manuscript does not reflect the views and policies of the EPA. NR 37 TC 17 Z9 19 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 1 PY 2009 VL 235 IS 2 BP 199 EP 207 DI 10.1016/j.taap.2008.12.011 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 416GX UT WOS:000263994900008 PM 19136022 ER PT J AU Quillen, K Yau, YY Leitman, SF AF Quillen, Karen Yau, Yu Ying Leitman, Susan F. TI The determinants of granulocyte yield in 1198 granulocyte concentrates collected from unrelated volunteer donors mobilized with dexamethasone and granulocyte-colony-stimulating factor: a 13-year experience SO TRANSFUSION LA English DT Article ID G-CSF; PLUS DEXAMETHASONE; PERIPHERAL-BLOOD; GROWTH-FACTORS; TRANSFUSIONS; INFECTIONS; STEM; NEUTROPHILS AB The combination of granulocyte-colony-stimulating factor (G-CSF [filgrastim]) and dexamethasone (G-CSF/dex) is an effective granulocyte mobilization regimen, but the variables that affect donor neutrophil response and granulocyte collection yield are not well characterized. A computerized database containing records of 1198 granulocyte collections from 137 unrelated volunteer apheresis donors during a 13-year period was retrospectively analyzed. Donors were categorized by age, sex, and cumulative number of granulocyte donations. Complete blood counts at baseline and after G-CSF/dex stimulation were recorded. The outcome variables include the preprocedure absolute neutrophil count (preANC), which reflects G-CSF/dex stimulation, and the granulocyte product yield per liter processed (BagGranYield/L). Higher baseline ANC and platelet (PLT) counts were significantly associated with higher preANC while a larger number of prior granulocytapheresis procedures was associated with lower preANC. Total filgrastim dose (used in weight-based dosing) did not significantly impact preANC or the granulocyte yield; weight-based dosing at 5 mu g per kg and a uniform 480-mu g dose produced equivalent preANC. PreANC and weight were the key determinants of granulocyte yield (BagGranYield/L). Apheresis donors with higher baseline PLT counts and ANCs have higher ANCs after G-CSF/dex stimulation; donor age, weight, and sex do not have a significant impact. A uniform G-CSF dose of 480 mu g is as effective as weight-based dosing at 5 mu g per kg. Donor ANC monitoring should be considered after serial granulocytapheresis procedures. C1 [Quillen, Karen; Yau, Yu Ying; Leitman, Susan F.] NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Quillen, K (reprint author), 88 E Newton St,H-3600, Boston, MA 02118 USA. EM kq@bu.edu OI Quillen, Karen/0000-0002-4243-0864 FU Intramural NIH HHS [ZIA CL002124-01] NR 15 TC 13 Z9 13 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAR PY 2009 VL 49 IS 3 BP 421 EP 426 DI 10.1111/j.1537-2995.2008.01997.x PG 6 WC Hematology SC Hematology GA 407KL UT WOS:000263361900006 PM 19040597 ER PT J AU Raat, NJH Hilarius, PM Johannes, T de Korte, D Ince, C Verhoeven, AJ AF Raat, Nicolaas J. H. Hilarius, Petra M. Johannes, Tanja de Korte, Dirk Ince, Can Verhoeven, Arthur J. TI Rejuvenation of stored human red blood cells reverses the renal microvascular oxygenation deficit in an isovolemic transfusion model in rats SO TRANSFUSION LA English DT Article ID CRITICALLY-ILL PATIENTS; TISSUE OXYGENATION; STORAGE TIME; ANEMIA; RBCS; AGE; FAILURE; CRIT AB Storage of red blood cells (RBCs) results in various biochemical changes, including a decrease in cellular adenosine triphosphate and 2,3-diphosphoglycerate acid. Previously it was shown that stored human RBCs show a deficit in the oxygenation of the microcirculation in the gut of anesthetized rats. In this study, the effect of RBCs on rat kidney oxygenation and the effect of rejuvenation of stored RBCs on their ability to deliver oxygen were investigated. Washed RBCs, derived from leukoreduced RBCs stored in saline-adenine-glucose-mannitol, were tested in an isovolemic transfusion model in rats after hemodilution until 30 percent hematocrit (Hct). The cells were derived from RBCs stored for up 3 days or from RBCs stored for 5 to 6 weeks with or without incubation in Rejuvesol to rejuvenate the cells. Renal microvascular oxygen concentrations (mu PO(2)) were determined by Pd-porphyrin phosphorescence lifetime measurements. Isovolemic transfusion exchange of 5- to 6-week-stored RBCs resulted in a significantly larger decrease in renal mu PO(2) than RBCs stored for up to 3 days: 16.1 +/- 2.3 mmHg versus 7.1 +/- 1.5 mmHg, respectively (n = 5). Rejuvenation of stored RBCs completely prevented this deficit in kidney oxygenation. The differences in oxygen delivery were not due to different recoveries of the human RBCs in the rat circulation. This study shows that the storage-induced deficit of human RBCs to oxygenate the rat kidney microcirculation at reduced Hct is completely reversible. Prevention of metabolic changes during storage is therefore a valid approach to prevent this deficit. C1 [Verhoeven, Arthur J.] Sanquin Res, Dept Blood Cell Res, NL-1066 CX Amsterdam, Netherlands. Univ Amsterdam, Acad Med Ctr, Dept Physiol, NL-1105 AZ Amsterdam, Netherlands. NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RP Verhoeven, AJ (reprint author), Sanquin Res, Dept Blood Cell Res, Plesmanlaan 125, NL-1066 CX Amsterdam, Netherlands. EM a.verhoeven@sanquin.nl NR 33 TC 19 Z9 20 U1 3 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAR PY 2009 VL 49 IS 3 BP 427 EP 434 DI 10.1111/j.1537-2995.2008.02002.x PG 8 WC Hematology SC Hematology GA 407KL UT WOS:000263361900007 PM 19040497 ER PT J AU Halverson, GR Tossas, E Velliquette, RW Lobo, C Reid, ME Frame, T Castilho, L Lee, AH Storry, JR Grodecka, M Wasniowska, K Duk, M Lisowska, E AF Halverson, Gregory R. Tossas, Edith Velliquette, Randall W. Lobo, Cheryl Reid, Marion E. Frame, Tom Castilho, Lilian Lee, Agnes H. Storry, Jill R. Grodecka, Magdalena Wasniowska, Kazimiera Duk, Maria Lisowska, Elwira TI Murine monoclonal anti-s and other anti-glycophorin B antibodies resulting from immunizations with a GPB.s peptide SO TRANSFUSION LA English DT Article ID HUMAN-ERYTHROCYTE-MEMBRANE; PLASMODIUM-FALCIPARUM; ANTIGENIC PROPERTIES; BLOOD; GLYCOPROTEINS; RECEPTOR AB The blood group antigens S and s are defined by amino acids Met or Thr at position 29, respectively, on glycophorin B (GPB). Commercial anti-s reagents are expensive to produce because of the scarcity of human anti-s serum. Our aim was to develop hybridoma cell lines that secrete reagent-grade anti-s monoclonal antibodies (MoAbs) to supplement the supply of human anti-s reagents. Mice were immunized with the GPB(s) peptide sequence TKSTISSQTNGETGQLVHRF. Hybridomas were produced by fusing mouse splenocytes with mouse myeloma cells (X63.Ag8.653). Screening for antibody production was done on microtiter plates by hemagglutination. Characterization of the MoAbs was done by hemagglutination, immunoblotting, and epitope mapping. Eight immunoglobulin G MoAbs were identified. Five antibodies are specific by hemagglutination for s and two MoAbs, when diluted, are anti-S-like, but additional analyses shows a broad range of reactivity for GPB. Typing red blood cells (RBCs) for s from 35 donors was concordant with molecular analyses as were tests on RBCs with a positive direct antiglobulin test (DAT) from 15 patients. The anti-s MoAbs are most reactive with peptides containing the (31)QLVHRF(36) motif, with (29)Thr. By Pepscan analyses, the anti-S-like MoAbs reacted within the same regions as did anti-s, but independently of (29)Met. One antibody was defined serologically as anti-U; however, its epitope was identified as (21)ISSQT(25), a sequence common for both GPA and GPB. In addition to their value as typing reagents, these MoAbs can be used to phenotype RBCs with a positive DAT without pre-test chemical modification. C1 [Halverson, Gregory R.] New York Blood Ctr, Lab Immunochem, New York, NY 10065 USA. Immucor Gamma, Norcross, GA USA. Univ Estadual Campinas, Hemoctr, Campinas, SP, Brazil. NIH, Reference Lab, Bethesda, MD 20892 USA. Univ Lund Hosp, Ctr Blood, S-22185 Lund, Sweden. Polish Acad Sci, Ludw Hirszfeld Inst Immunol & Expt Therapy, Wroclaw, Poland. RP Halverson, GR (reprint author), New York Blood Ctr, Lab Immunochem, New York, NY 10065 USA. EM ghalverson@nybloodcenter.org NR 45 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAR PY 2009 VL 49 IS 3 BP 485 EP 494 DI 10.1111/j.1537-2995.2008.02004.x PG 10 WC Hematology SC Hematology GA 407KL UT WOS:000263361900015 PM 19040495 ER PT J AU Quillen, K Byrne, P Yau, YY Leitman, SF AF Quillen, Karen Byrne, Phyllis Yau, Yu Ying Leitman, Susan F. TI Ten-year follow-up of unrelated volunteer granulocyte donors who have received multiple cycles of granulocyte-colony-stimulating factor and dexamethasone SO TRANSFUSION LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ADVERSE DRUG EVENTS; STEM-CELL DONORS; G-CSF; HEALTHY-INDIVIDUALS; PERIPHERAL-BLOOD; MYELODYSPLASTIC SYNDROME; SAFETY CONSIDERATIONS; BREAST-CANCER; TRANSFUSIONS AB The combination of granulocyte-colony-stimulating factor (G-CSF) and dexamethasone is an effective granulocyte mobilization regimen. The short-term side effects of G-CSF are well studied, but the potential long-term effects of repeated G-CSF stimulation in unrelated volunteer granulocyte donors have not been reported. Donors who had received G-CSF three or more times for granulocytapheresis between 1994 and 2002 were identified and attempts were made to contact them if they were no longer active donors. They were matched with control platelet (PLT) donors for sex, age, and approximate number of cytapheresis donations. A health history was obtained and complete blood counts (CBCs) and C-reactive protein (CRP) determined where feasible. Ninety-two granulocyte donors were identified, and 83 of them were contacted. They contributed to 1120 granulocyte concentrates, or a mean of 13.5 granulocytapheresis procedures per donor (and a mean of 87.5 plateletpheresis procedures per donor). There was no difference in CBCs between the granulocyte donors and the control PLT donors. There was no difference in CRP between the two groups, and no difference in pre- and post-G-CSF CRP in a subset of 22 granulocyte donors. Predefined health events included malignancies, coronary artery disease, and thrombosis. At a median 10-year follow-up, there were seven such events in the granulocyte donors and five in the PLT donors. Although the number of granulocyte donors studied is small and continued surveillance of healthy individuals after G-CSF is prudent, our data suggest that G-CSF/dexamethasone stimulation appears to be safe. C1 [Quillen, Karen; Byrne, Phyllis; Yau, Yu Ying; Leitman, Susan F.] NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Quillen, K (reprint author), 88 E Newton St,H-3600, Boston, MA 02118 USA. EM kq@bu.edu OI Quillen, Karen/0000-0002-4243-0864 FU Intramural NIH HHS [ZIA CL002124-01] NR 27 TC 15 Z9 15 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAR PY 2009 VL 49 IS 3 BP 513 EP 518 DI 10.1111/j.1537-2995.2008.01983.x PG 6 WC Hematology SC Hematology GA 407KL UT WOS:000263361900018 PM 19243544 ER PT J AU Tawab, A Fan, Y Read, EJ Kurlander, RJ AF Tawab, Abdul Fan, Yong Read, Elizabeth J. Kurlander, Roger J. TI Effect of ex vivo culture duration on phenotype and cytokine production by mature dendritic cells derived from peripheral blood monocytes SO TRANSFUSION LA English DT Article ID CD8(+) T-CELLS; CANCER-IMMUNOTHERAPY; IN-VITRO; CD14(+) MONOCYTES; IFN-GAMMA; GENERATION; ANTIGEN; INDUCTION; INJECTION; IMMATURE AB To generate clinical-grade dendritic cells (DCs) ex vivo for immunotherapy trials, peripheral blood monocytes are typically cultured in granulocyte-macrophage-colony-stimulating factor (GM-CSF) and interleukin (IL)-4 and then matured using one or more agents. Duration of the initial DC culture is one important variable that has not been systematically evaluated for its effect on the characteristics of the final mature DC product. DCs were generated from elutriated peripheral blood monocytes by incubation in medium containing 2000 units per mL each of GM-CSF and IL-4 for 3 to 7 days, followed by maturation with lipopolysaccharide and interferon-gamma (IFN-gamma). DC yield, viability, flow cytometric phenotype, and cytokine production were evaluated. The percentage yield and viability of mature DCs were similar after GM-CSF/IL-4 culture for 3 or 7 days. In either case, mature DCs expressed abundant CD80, CD86, CD83, and CCR7, but 3-day DCs expressed these antigens in a more consistent and homogeneous manner. Mature 3-day DCs produced much more IL-12 and less IL-10 after restimulation with CD40L-LTK than 7-day DCs. The former were also more effective in presenting immunogenic peptides to CD8 T cells. Analogous changes in cytokine production were observed in mature DCs prepared using lower concentrations of GM-CSF/IL-4 or when the alternative maturation cocktails poly(I:C)/IFN-gamma and soluble CD40L/IFN-gamma were used. Extended initial culture of DCs in GM-CSF/IL-4 does not affect yield or viability of subsequently matured DCs, but can adversely affect their ability to homogeneously express high levels of functionally important surface molecules such as CD83 and CCR7 and to produce IL-12. C1 [Kurlander, Roger J.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kurlander, RJ (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10,Room 2C373,10 Ctr Dr, Bethesda, MD 20892 USA. EM rkurlander@mail.cc.nih.gov FU Intramural NIH HHS [Z01 CL008087-02] NR 42 TC 13 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAR PY 2009 VL 49 IS 3 BP 536 EP 547 DI 10.1111/j.1537-2995.2008.02020.x PG 12 WC Hematology SC Hematology GA 407KL UT WOS:000263361900022 PM 19243546 ER PT J AU Krueger, F Barbey, AK Grafman, J AF Krueger, Frank Barbey, Aron K. Grafman, Jordan TI The medial prefrontal cortex mediates social event knowledge SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID PERCEPTUAL SYMBOL SYSTEMS; NEURAL BASIS; COGNITIVE NEUROSCIENCE; ORBITOFRONTAL CORTEX; FRONTAL-CORTEX; BEHAVIOR; MEMORY; DAMAGE; SELF; REPRESENTATIONS AB Accumulating evidence from social neuroscience demonstrates that the medial prefrontal cortex (mPFC) is a crucial component of the neural systems mediating social event knowledge. Here, we present an integrative theory of the cognitive and neural bases of social event knowledge. The structural and temporal representation binding (STRing) theory assumes that the mPFC represents abstract dynamic summary representations in the form of event simulators (elators). Elators give rise to social event knowledge via binding with regions in the posterior cerebral cortex and limbic structures. We propose a segregation of elator functions along the dorsoventral mPFC axis and review neuroscience evidence to support the specificity of elators as the underlying structures for the development of event, person and self schemata. C1 [Krueger, Frank; Barbey, Aron K.; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Krueger, F (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM krugerf@ninds.nih.gov; grafmanj@ninds.nih.gov RI Barbey, Aron/L-7312-2015; OI Barbey, Aron/0000-0002-6092-0912; Grafman, Jordan H./0000-0001-8645-4457 FU Intramural Research Program of the National Institutes of Health/National Institute Neurological Disorders and Stroke/Cognitive Neuroscience Section FX The authors are grateful to Giovanna Zarnboni for her help with the illustrations. This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute for Neurological Disorders and Stroke/Cognitive Neuroscience Section. NR 70 TC 72 Z9 73 U1 5 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD MAR PY 2009 VL 13 IS 3 BP 103 EP 109 DI 10.1016/j.tics.2008.12.005 PG 7 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 425EA UT WOS:000264618600003 PM 19223228 ER PT J AU Varnai, P Hunyady, L Balla, T AF Varnai, Peter Hunyady, Laszlo Balla, Tamas TI STIM and Orai: the long-awaited constituents of store-operated calcium entry SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID STROMAL INTERACTION MOLECULE-1; LIGHT-CHAIN KINASE; INTRACELLULAR CA2+ STORES; CA2+-SELECTIVE ARC CHANNELS; PLASMA MEMBRANE JUNCTIONS; T-CELL-ACTIVATION; CRAC CHANNEL; ENDOPLASMIC-RETICULUM; 2-AMINOETHOXYDIPHENYL BORATE; ENDOTHELIAL-CELLS AB Rapid changes in cytosolic Ca(2+) concentrations [Ca(2+)](i) are the most commonly used signals in biology to regulate a whole host of cellular functions including contraction, secretion and gene activation. A widely utilized form of Ca(2+) influx is termed store-operated Ca(2+) entry (SOCE) owing to its control by the Ca(2+) content of the endoplasmic reticulum (ER). The underlying molecular mechanism of SOCE has eluded identification until recently when two groups of proteins, the ER Ca(2+) sensors stromal interaction molecule (STIM) 1 and STIM2 and the plasma-membrane channels Orai1, Orai2 and Orai3, have been identified. These landmark discoveries have enabled impressive progress in clarifying how these proteins work in concert and what developmental and cellular processes require their participation most. As we begin to better understand the biology of the STIM and Orai proteins, the attention to the pharmacological tools to influence their functions quickly follow suit. Here, we briefly summarize recent developments in this exciting area of Ca(2+) signaling. C1 [Varnai, Peter; Hunyady, Laszlo] Semmelweis Univ, Fac Med, Dept Physiol, H-1088 Budapest, Hungary. [Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Varnai, P (reprint author), Semmelweis Univ, Fac Med, Dept Physiol, Puskin U 9, H-1088 Budapest, Hungary. EM peter.varnai@eok.sote.hu; ballat@mail.nih.gov OI Balla, Tamas/0000-0002-9077-3335 FU Hungarian Scientific Research Fund [OTKA NF-68563]; Medical Research Council [ETT 440/2006]; National Institute of Child Health and Human Development of the National Institutes of Health FX P.V. is a Bolyai Fellow of the Hungarian Academy of Science (www.mta.hu) and was supported by the Hungarian Scientific Research Fund (OTKA NF-68563; www.otka.hu) and the Medical Research Council (ETT 440/2006; www.ett.hu). The research of T.B. was supported by the Intramural Research Program of the National Institute of Child Health and Human Development of the National Institutes of Health (www.nichd.nih.gov). NR 113 TC 92 Z9 97 U1 2 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD MAR PY 2009 VL 30 IS 3 BP 118 EP 128 DI 10.1016/j.tips.2008.11.005 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 426BC UT WOS:000264681400003 PM 19187978 ER PT J AU Wu, DW Chen, RM Zhou, QF Shung, KK Lin, DM Chan, HLW AF Wu, D. W. Chen, R. M. Zhou, Q. F. Shung, K. K. Lin, D. M. Chan, H. L. W. TI Lead-free KNLNT piezoelectric ceramics for high-frequency ultrasonic transducer application SO ULTRASONICS LA English DT Article DE Piezoelectric materials; Lead-free; High-frequency; Ultrasound transducer ID FREE PIEZOCERAMICS AB This paper presents the latest development of a lead-free piezoelectric ceramic and its application to transducers suitable for high-frequency ultrasonic imaging. A lead-free piezoelectric ceramic with formula of (K(0.5)Na(0.5))(0.97)Li(0.03)(Nb(0.9) Ta(0.1))O(3) (abbreviated as KNLNT-0.03/0.10) was fabricated and characterized. The material was found to have a clamped dielectric constant epsilon(S)(33)/epsilon(0) = 890, piezoelectric coefficient d(33) = 245 pC/N, electromechanical coupling factor k(t) = 0.42 and Curie temperature T(c) > 300 degrees C. High-frequency (40 MHz) ultrasound transducers were successfully fabricated with the lead-free material. A representative lead-free transducer had a bandwidth of 45%, two-way insertion loss of -18 dB. This performance is comparable to reported performances of popular lead-based transducers. The comparison results suggest that the lead-free piezoelectric material may serve as an alternative to lead-based piezoelectric materials for high-frequency ultrasonic transducer applications. Published by Elsevier B. V. C1 [Wu, D. W.; Chen, R. M.; Zhou, Q. F.; Shung, K. K.] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Wu, D. W.; Chen, R. M.; Zhou, Q. F.; Shung, K. K.] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Lin, D. M.; Chan, H. L. W.] Hong Kong Polytech Univ, Dept Appl Phys, Kowloon, Hong Kong, Peoples R China. [Lin, D. M.; Chan, H. L. W.] Hong Kong Polytech Univ, Mat Res Ctr, Kowloon, Hong Kong, Peoples R China. RP Wu, DW (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM daweiwu@usc.edu RI CHAN, Helen Lai Wa/B-5633-2014; wu, dawei/D-3158-2014; Lin, Dunmin/D-6765-2012 OI CHAN, Helen Lai Wa/0000-0002-8508-3049; Lin, Dunmin/0000-0002-2245-6717 FU NIH [P41-EB2182]; Hong Kong Polytechnic University [1-BBZ3, 1-BB95] FX This work has been partially supported by NIH Grant. No. P41-EB2182. The authors would like to thank Dr. Changhong Hu and Mr. Jay Williams their aid with ultrasound imaging and the transducer fabrication process. Financial support from the PolyU Internal Grants (1-BBZ3 and 1-BB95) to authors from the Hong Kong Polytechnic University is also acknowledged. NR 14 TC 12 Z9 17 U1 5 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0041-624X J9 ULTRASONICS JI Ultrasonics PD MAR PY 2009 VL 49 IS 3 BP 395 EP 398 DI 10.1016/j.ultras.2008.11.003 PG 4 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 412JT UT WOS:000263721800015 PM 19121835 ER PT J AU Buldakov, MA Hassan, MA Zhao, QL Feril, LB Kudo, N Kondo, T Litvyakov, NV Bolshakov, MA Rostov, VV Cherdyntseva, NV Riesz, P AF Buldakov, Mikhail A. Hassan, Mariame A. Zhao, Qing-Li Feril, Loreto B., Jr. Kudo, Nobuki Kondo, Takashi Litvyakov, Nikolai V. Bolshakov, Mikhail A. Rostov, Vladislav V. Cherdyntseva, Nadejda V. Riesz, Peter TI Influence of changing pulse repetition frequency on chemical and biological effects induced by low-intensity ultrasound in vitro SO ULTRASONICS SONOCHEMISTRY LA English DT Article DE Pulse repetition frequency (PRF); Modulation; Low-intensity ultrasound; Free radicals; Sucrose hydrolysis; Apoptosis ID AQUEOUS-SOLUTIONS; MALIGNANT-CELLS; STANDING-WAVE; CANCER-CELLS; TRANSFECTION; MANIPULATION; RADIATION; THERAPY AB This study was undertaken to examine ultrasound (US) mechanisms and their impact on chemical and biological effects in vitro as a function of changing pulse repetition frequency (PRF) from 0.5 to 100 Hz using a 1 MHz-generator at low-intensities and 50% duty factor (DF). The presence of inertial cavitation was detected by electron paramagnetic resonance (EPR) spin-trapping of hydroxyl radicals resulting from sonolysis of water. Non-cavitational effects were evaluated by studying the extent of sucrose hydrolysis measured by UV spectrophotometry. Biological effects were assessed by measuring the extent of cell killing and apoptosis induction in U937 cells using Trypan blue dye exclusion test and flow cytometry, respectively. The results indicate significant PRF dependence with respect to hydroxyl radical formation, cell killing and apoptosis induction. The lowest free radical formation and cell killing and the highest cell viability were found at 5 Hz (100 ms pulse duration). On the other hand, no correlation was found between sucrose hydrolysis and PRF. To our knowledge, this is the first report to be devoted to study the impact of low PRFs at low-intensities on US-induced chemical and biological effects and the mechanisms involved. This study has introduced the role of "US streaming" (convection); a forgotten factor in optimization studies, and explored its importance in comparison to standing waves. (c) 2008 Published by Elsevier B.V. C1 [Buldakov, Mikhail A.; Hassan, Mariame A.; Zhao, Qing-Li; Kondo, Takashi] Toyama Univ, Dept Radiol Sci, Grad Sch Med & Pharmaceut Sci, Toyama 9300194, Japan. [Buldakov, Mikhail A.; Litvyakov, Nikolai V.; Cherdyntseva, Nadejda V.] Russian Acad Med Sci, Siberian Dept, Canc Res Inst, Tomsk Sci Ctr, Tomsk 634009, Russia. [Buldakov, Mikhail A.; Litvyakov, Nikolai V.; Bolshakov, Mikhail A.] Tomsk VV Kuibyshev State Univ, Dept Physiol, Tomsk 634050, Russia. [Bolshakov, Mikhail A.; Rostov, Vladislav V.] Russian Acad Sci, Inst High Current Elect, Siberian Dept, Tomsk 634055, Russia. [Feril, Loreto B., Jr.] Fukuoka Univ, Sch Med, Dept Anat, Fukuoka 8140180, Japan. [Kudo, Nobuki] Hokkaido Univ, Lab Biomed Instrumentat & Measurements, Grad Sch Informat Sci & Technol, Sapporo, Hokkaido 0600814, Japan. [Riesz, Peter] NCI, NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Kondo, T (reprint author), Toyama Univ, Dept Radiol Sci, Grad Sch Med & Pharmaceut Sci, Sugitani 2630, Toyama 9300194, Japan. EM kondot@med.u-toyama.ac.jp RI Buldakov, Mikhail/C-7922-2012; Cherdyntseva, Nadezhda/C-7943-2012; Bolshakov, Mikhail/N-7627-2014; Litviakov, Nikolai/C-3263-2012; Rostov, Vladislav/O-6708-2014; Kudo, Nobuki/D-6742-2012; Vladislav, Rostov/A-2031-2012 OI Cherdyntseva, Nadezhda/0000-0003-1526-9013; Litviakov, Nikolai/0000-0002-0714-8927; FU Japan Society of Ultrasonics in Medicine FX This Study was in part supported by the Research and Development Committee Program of the Japan Society of Ultrasonics in Medicine. NR 31 TC 29 Z9 29 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1350-4177 J9 ULTRASON SONOCHEM JI Ultrason. Sonochem. PD MAR PY 2009 VL 16 IS 3 BP 392 EP 397 DI 10.1016/j.ultsonch.2008.10.006 PG 6 WC Acoustics; Chemistry, Multidisciplinary SC Acoustics; Chemistry GA 399DX UT WOS:000262781700019 PM 19022698 ER PT J AU O'Neill, BE Vo, H Angstadt, M Li, KPC Quinn, T Frenkel, V AF O'Neill, Brian E. Vo, Howard Angstadt, Mary Li, King P. C. Quinn, Tim Frenkel, Victor TI PULSED HIGH INTENSITY FOCUSED ULTRASOUND MEDIATED NANOPARTICLE DELIVERY: MECHANISMS AND EFFICACY IN MURINE MUSCLE SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE Pulsed-high intensity focused ultrasound; Nanoparticle delivery; Hyperthermia; Cavitation; Radiation force ID IN-VIVO; MODEL; TUMOR; HYPERTHERMIA; THROMBOLYSIS; CAVITATION; THERAPY; BRAIN; VITRO; BEAM AB High intensity focused ultrasound (HIFU) is generally thought to interact with biological tissues in two ways: hyperthermia (heat) and acoustic cavitation. Pulsed mode HIFU has recently been demonstrated to increase the efficacy of a variety of drug therapies. Generally, it is presumed that the treatment acts to temporarily increase the permeability of the tissue to the therapeutic agent, however, the precise mechanism remains in dispute. In this article, we present evidence precluding hyperthermia as a principal mechanism for enhancing delivery, using a quantitative analysis of systemically administered fluorescent nanoparticles delivered to muscle in the calves of mice. Comparisons were carried out on the degree of enhancement between an equivalent heat treatment, delivered without ultrasound, and that of the pulsed-HIFU itself. In the murine calf muscle, Pulsed-RIFU treatment resulted in a significant increase in distribution of 200 nm particles (p < 0.016, n = 6), while the equivalent thermal (lose showed no significant increase. Additional studies using this tissue/agent model also demonstrated that the pulsed HIFU enhancing effects persist for more than 24 h, which is longer than that of hyperthermia and acoustic cavitation, and offers the possibility of a novel third mechanism for mediating delivery. (E-mail: vfrenkel@cc.nih.gov) Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. C1 [O'Neill, Brian E.; Vo, Howard; Angstadt, Mary; Li, King P. C.; Frenkel, Victor] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [O'Neill, Brian E.; Quinn, Tim] Natl Inst Stand & Technol, Div Mat Reliabil, Boulder, CO 80303 USA. RP Frenkel, V (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, Bldg 10,Room 1N306A,10 Ctr Dr, Bethesda, MD 20892 USA. EM vfrenkel@cc.nih.gov FU National Institutes of Health FX The authors thank Dr. Matthew R. Dreher for thoughtfully providing insights into the complexities of drug delivery, some of which are addressed in this manuscript and Dr. Bradford J. Wood for support of this work. We also thank Ms. Hilary Hancock for editing the manuscript and providing helpful editorial suggestions. The work was done under the auspices of the Research Associateship Program of the National Academies of Sciences, and was supported in part by the intra-mural research program of the Clinical Center, National Institutes of Health. NR 30 TC 53 Z9 56 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-5629 J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD MAR PY 2009 VL 35 IS 3 BP 416 EP 424 DI 10.1016/j.ultrasmedbio.2008.09.021 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 413RW UT WOS:000263811200009 PM 19081668 ER PT J AU Yeo, L Romero, R AF Yeo, Lami Romero, Roberto TI Sonographic evaluation in the second stage of labor to improve the assessment of labor progress and its outcome SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Editorial Material ID FETAL HEAD POSITION; TRANSVAGINAL DIGITAL EXAMINATION; TRANSABDOMINAL ULTRASOUND ASSESSMENT; PRESENTING PART; CERVICAL DILATATION; OPERATIVE DELIVERY; CESAREAN DELIVERY; TRANSLABIAL ULTRASOUND; INTRAPARTUM SONOGRAPHY; NEONATAL MORBIDITY C1 [Yeo, Lami] Eunice Kennedy Shriver NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. Eunice Kennedy Shriver NICHHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Wayne State Univ, Detroit, MI USA. RP Yeo, L (reprint author), Eunice Kennedy Shriver NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. EM prbchiefstaff@med.wayne.edu FU Intramural NIH HHS [ZIA HD002401-18] NR 56 TC 30 Z9 31 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD MAR PY 2009 VL 33 IS 3 BP 253 EP 258 DI 10.1002/uog.6336 PG 6 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 451XZ UT WOS:000266505500001 PM 19247999 ER PT J AU Rosner, I Bratslavsky, G Pinto, PA Linehan, WM AF Rosner, Inger Bratslavsky, Gennady Pinto, Peter A. Linehan, W. Marston TI The clinical implications of the genetics of renal cell carcinoma SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Renal cell carcinoma; Gene; VHL; BHD; HPRC; HLRCC ID VONHIPPEL-LINDAU DISEASE; TUMOR-SUPPRESSOR GENE; HOGG-DUBE-SYNDROME; GERMLINE MUTATIONS; FUMARATE-HYDRATASE; MET PROTOONCOGENE; HEREDITARY LEIOMYOMATOSIS; SPONTANEOUS PNEUMOTHORAX; KIDNEY TUMORS; CANCER AB Over the last several decades, the advances in molecular genetics have elucidated kidney cancer gene pathways. Kidney cancer is a heterogeneous disorder. Each specific type of kidney cancer has its own histologic features, gene, and clinical course. Insight into the genetic basis of kidney cancer has been learned largely from the study of the familial or hereditary forms of kidney cancer. Extirpative surgery is currently the treatment of choice for kidney cancer that is confined to the kidney. Treatment for advanced or metastatic kidney cancer is a formidable challenge with the traditional therapies currently available. However, investigation of the Mendelian single-gene syndromes, like von Hippel Lindau (VHL: VHL gene), hereditary papillary renal carcinoma (HPRC: c-Met gene), Birt-Hogg-Dube (BHD: BHD gene), and hereditary leiomyomatosis renal cell cancer (HLRCC: fumarate hydratase gene) provides an opportunity to develop pathway specific therapies. Advances in molecular therapeutics offer novel treatment options for patients with advanced disease. Published by Elsevier Inc. C1 [Rosner, Inger; Bratslavsky, Gennady; Pinto, Peter A.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM linehanm@mail.nih.gov FU Intramural NIH HHS [Z01 SC006659-25] NR 54 TC 35 Z9 36 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD MAR-APR PY 2009 VL 27 IS 2 BP 131 EP 136 DI 10.1016/j.urolonc.2008.11.001 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 424OL UT WOS:000264575900014 PM 19285230 ER PT J AU Le Nouen, C Munir, S Losq, S Winter, CC McCarty, T Stephany, DA Holmes, KL Bukreyev, A Rabin, RL Collins, PL Buchholz, UJ AF Le Nouen, Cyril Munir, Shirin Losq, Stephanie Winter, Christine C. McCarty, Thomas Stephany, David A. Holmes, Kevin L. Bukreyev, Alexander Rabin, Ronald L. Collins, Peter L. Buchholz, Ursula J. TI Infection and maturation of monocyte-derived human dendritic cells by human respiratory syncytial virus, human metapneumovirus, and human parainfluenza virus type 3 SO VIROLOGY LA English DT Article DE Metapneumovirus; Pneumovirus; Paramyxovirus; Monocyte derived dendritic cells; Cytokine; Maturation marker ID CD4 T-CELLS; IN-VITRO; INFLUENZA-VIRUS; YOUNG-CHILDREN; TRACT DISEASE; RIG-I; EXPRESSION; CD38; CD83; DIFFERENTIATION AB Human respiratory syncytial virus (HRSV), human metapneumovirus (HMPV), and human parainfluenza virus type 3 (HPIV3) are common, important respiratory pathogens, but HRSV has a substantially greater impact with regard to acute disease, long-term effects oil airway function, and frequency of re-infection. It has been reported to strongly interfere with the functioning of dendritic cells (DC). We compared HRSV to HMPV and HPIV3 with regard to their effects on human monocyte-derived immature DC (IDC). Side-by-side analysis distinguished between common effects versus those specific to individual viruses. The use of GFP-expressing viruses yielded clear identification of robustly infected cells and provided the means to distinguish between direct effects of robust viral gene expression versus bystander effects. All three viruses infected inefficiently based oil GFP expression, with considerable donor-to donor-variability. The GFP-negative cells exhibited low, abortive levels of viral RNA synthesis. The three viruses induced low-to-moderate levels of DC maturation and cytokine/chemokine responses, increasing slightly in the order HRSV, HMPV, and HPIV3. Infection at the individual cell level was relatively benign, such that in general GFP-positive cells were neither more nor less able to mature compared to GFP-negative bystanders, and cells were responsive to a secondary treatment with lipopolysaccharide, indicating that the ability to mature was not impaired. However, there was a single exception, namely that HPIV3 Clown-regulated CD38 expression at the RNA level. Maturation by these viruses was anti-apoptotic. Inefficient infection of IDC and sub-optimal maturation might result in reduced immune responses, but these effects would be common to all three viruses rather than specific to HRSV. Published by Elsevier Inc. C1 [Le Nouen, Cyril; Munir, Shirin; Losq, Stephanie; Winter, Christine C.; McCarty, Thomas; Bukreyev, Alexander; Collins, Peter L.; Buchholz, Ursula J.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Stephany, David A.; Holmes, Kevin L.] NIAID, Flow Cytometry Sect, NIH, Bethesda, MD 20892 USA. [Rabin, Ronald L.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Buchholz, UJ (reprint author), Bldg 50,Room 6505,50 S Dr MSC 8007, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 62 TC 35 Z9 35 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2009 VL 385 IS 1 BP 169 EP 182 DI 10.1016/j.virol.2008.11.043 PG 14 WC Virology SC Virology GA 416EW UT WOS:000263989400021 PM 19128816 ER PT J AU Groseth, A Charton, JE Sauerborn, M Feldmann, F Jones, SM Hoenen, T Feldmann, H AF Groseth, A. Charton, J. E. Sauerborn, M. Feldmann, F. Jones, S. M. Hoenen, T. Feldmann, H. TI The Ebola virus ribonucleoprotein complex: A novel VP30-L interaction identified SO VIRUS RESEARCH LA English DT Article DE Ebola virus; Polymerase; VP30; Protein-protein interaction; Ribonucleoprotein complex ID MARBURG-VIRUS; NUCLEOCAPSID PROTEINS; RNA-POLYMERASE; TRANSCRIPTION; REPLICATION; NUCLEOPROTEIN; RESCUE; SYSTEM; CDNA AB The ribonucleoprotein (RNP) complex of Ebola virus (EBOV) is known to be a multiprotein/RNA structure, however, knowledge is rather limited regarding the actual protein-protein interactions involved in its formation. Here we show that singularly expressed VP35 and VP30 are present throughout the cytoplasm, while NP forms prominent cytoplasmic inclusions and L forms smaller perinuclear inclusions. We could demonstrate the existence of NP-VP35, NP-VP30 and VP35-L interactions, similar to those described for Marburg virus (MARV) based on the redistribution of protein partners into NP and L inclusion bodies. Significantly, a novel VP30-L interaction was also identified and found to form as part of an NP-VP30-L bridge structure, similar to that formed by VP35. The identification of these interactions allows a preliminary model of the EBOV RNP complex structure to be proposed, and may provide insight into filovirus transcriptional regulation. Published by Elsevier B.V. C1 [Groseth, A.; Charton, J. E.; Sauerborn, M.; Feldmann, F.; Jones, S. M.; Hoenen, T.; Feldmann, H.] Publ Hlth Agcy Canada, Natl Microbiol Lab, Natl Lab Zoonot Dis & Special Pathogens, Winnipeg, MB R3E 3R2, Canada. [Groseth, A.; Feldmann, H.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0W3, Canada. [Charton, J. E.] Univ Tubingen, Intrefak Inst Biochem, D-72076 Tubingen, Germany. [Sauerborn, M.; Hoenen, T.] Univ Marburg, Inst Virol, D-35043 Marburg, Germany. [Jones, S. M.] Univ Manitoba, Dept Immunol, Winnipeg, MB R3E 0W3, Canada. RP Feldmann, H (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM groseth@staff.uni-marburg.de; enno.charton@med.uni-tuebingen.de; m.s.sauerborn@uu.nl; friederike-feldmann@phac-aspc.gc.ca; steven-jones@phac-aspc.gc.ca; hoenen@staff.uni-marburg.de; feldmannh@niaid.nih.gov OI Hoenen, Thomas/0000-0002-5829-6305 FU Canadian Institutes of Health Research [MOP-43921]; Natural Sciences and Engineering Research Council of Canada; German Academic Exchange Service; German Chemical Industry Association; Public Health Agency of Canada FX The authors are grateful to Victoria Wahl-Jensen, for assistance with various immunofluorescence protocols, and to Hideki Ebihara for valuable discussion. This work was supported by a grant of the Canadian Institutes of Health Research (MOP-43921, awarded to H.F.), and scholarships of the Natural Sciences and Engineering Research Council of Canada (A.G.), the German Academic Exchange Service (M.S.) and the German Chemical Industry Association (T.H.), as well as by funding from the Public Health Agency of Canada. NR 23 TC 24 Z9 26 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD MAR PY 2009 VL 140 IS 1-2 BP 8 EP 14 DI 10.1016/j.virusres.2008.10.017 PG 7 WC Virology SC Virology GA 425PW UT WOS:000264650600002 PM 19041915 ER PT J AU Buxton, DB AF Buxton, Denis B. TI Current status of nanotechnology approaches for cardiovascular disease: a personal perspective SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID ASSEMBLING PEPTIDE NANOFIBERS; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS; DELIVERY; CELLS; CARDIOTOXICITY; CONSTRUCTS; TOPOGRAPHY; SCAFFOLD; THERAPY AB Nanotechnology is poised to have an increasing impact on cardiovascular health in coming years. Diagnostically, multiplexed point-of-care devices will enable rapid genotyping and biomarker measurement to optimize and tailor therapies for the individual patient. Nanoparticle-based molecular imaging agents will take advantage of targeted agents to provide increased insight into disease pathways rather then simply providing structural and functional information. Drug delivery will be impacted by targeting of nanoparticle-encapsulated drugs to the site of action, increasing the effective concentration and decreasing systemic dosage and side effects. Controlled and tailored release of drugs from polymers will improve control of pharmacokinetics and bioavailability. The application of nanotechnology to tissue engineering will facilitate the fabrication of better tissue implants in vitro, and provide scaffolds to promote regeneration in vivo taking advantage of the body's own repair mechanisms. Medical devices will benefit from the development of nanostructured surfaces and coatings to provide better control of thrombogenicity and infection. Taken together, these new technologies have enormous potential for improving the diagnosis and treatment of cardiovascular diseases. (C) 2009 John Wiley & Sons, Inc. WIREs Nanomed Nanobiotechnol 2009 1 149-155 C1 NHLBI, Bethesda, MD 20892 USA. RP Buxton, DB (reprint author), NHLBI, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM db225a@nih.gov OI Buxton, Denis/0000-0003-3077-6435 NR 25 TC 12 Z9 12 U1 2 U2 14 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1939-5116 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD MAR-APR PY 2009 VL 1 IS 2 BP 149 EP 155 DI 10.1002/wnan.008 PG 7 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 585PR UT WOS:000276839400001 PM 20049786 ER PT J AU Grice, E Segre, J Liechty, K AF Grice, Elizabeth Segre, Julia Liechty, Kenneth TI DIVERSITY PROFILE OF THE DIABETIC WOUND MICROBIOME SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Grice, Elizabeth; Segre, Julia] NHGRI, NIH, NISC Comparat Sequencing Program, Bethesda, MD 20892 USA. [Liechty, Kenneth] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2009 VL 17 IS 2 BP A25 EP A25 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 418ZJ UT WOS:000264188600077 ER PT J AU Hammerman, SB Carson, P Panuncialman, J Herring, D Falanga, V AF Hammerman, Scott B. Carson, Polly Panuncialman, Jaymie Herring, Daniel Falanga, Vincent TI COMPRESSION REGIMEN FOR VENOUS LEG ULCER PATIENTS REQUIRING FREQUENT DRESSING CHANGES SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Falanga, Vincent] NIH, Ctr Biomed Res Excellence, Roger Williams Med Ctr, Providence, RI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2009 VL 17 IS 2 BP A47 EP A47 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 418ZJ UT WOS:000264188600164 ER PT J AU Kobrin, K Kwak, T Yufit, T Falanga, V AF Kobrin, Kendra Kwak, Taehee Yufit, Tatyana Falanga, Vincent TI MEDIA CONDITIONED BY METASTATIC MELANOMA CELLS ENHANCES IN VITRO FIBROBLAST MIGRATION SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Falanga, Vincent] NIH, Ctr Biomed Res Excellence, Roger Williams Med Ctr, Providence, RI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2009 VL 17 IS 2 BP A49 EP A49 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 418ZJ UT WOS:000264188600172 ER PT J AU Kwak, T Yufit, T Carson, P Michalowska, A Kim, SJ Falanga, V AF Kwak, Taehee Yufit, Tatyana Carson, Polly Michalowska, Aleksandra Kim, Seong-Jin Falanga, Vincent TI SPECIFIC GENES ARE EXPRESSED WHEN LIVING BILAYERED SKIN CONSTRUCT (BSC) IS ACTIVATED IN VITRO SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Michalowska, Aleksandra] NIH, Bethesda, MD 20892 USA. [Kim, Seong-Jin] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Falanga, Vincent] NIH, Ctr Biomed Res Excellence, Roger Williams Med Ctr, Providence, RI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2009 VL 17 IS 2 BP A16 EP A16 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 418ZJ UT WOS:000264188600042 ER PT J AU Yufit, T Carson, P Kwak, T Fiore, D Falanga, V AF Yufit, Tatyana Carson, Polly Kwak, Taehee Fiore, David Falanga, Vincent TI ESTABLISHMENT OF A GOOD MANUFACTURING PRACTICE (GMP) FACILITY FOR TISSUE REPAIR SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Falanga, Vincent] NIH, Ctr Biomed Res Excellence, Roger Williams Med Ctr, Providence, RI USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2009 VL 17 IS 2 BP A21 EP A21 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 418ZJ UT WOS:000264188600060 ER PT J AU Ghysels, A Van Neck, D Brooks, BR Van Speybroeck, V Waroquier, M AF Ghysels, A. Van Neck, D. Brooks, B. R. Van Speybroeck, V. Waroquier, M. TI Normal modes for large molecules with arbitrary link constraints in the mobile block Hessian approach SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE macromolecules; molecular configurations; polymers; proteins; vibrational states ID CLUSTER CALCULATIONS; VIBRATIONAL ANALYSIS; METHOXY ADSORPTION; FERMI RESONANCES; AL(111) SURFACE; WATER; RAMAN; MACROMOLECULES; SPECTROSCOPY; CA2+-ATPASE AB In a previous paper [Ghysels , J. Chem. Phys. 126, 224102 (2007)] the mobile block Hessian (MBH) approach was presented. The method was designed to accurately compute vibrational modes of partially optimized molecular structures. The key concept was the introduction of several blocks of atoms, which can move as rigid bodies with respect to a local, fully optimized subsystem. The choice of the blocks was restricted in the sense that none of them could be connected, and also linear blocks were not taken into consideration. In this paper an extended version of the MBH method is presented that is generally applicable and allows blocks to be adjoined by one or two common atoms. This extension to all possible block partitions of the molecule provides a structural flexibility varying from very rigid to extremely relaxed. The general MBH method is very well suited to study selected normal modes of large macromolecules (such as proteins and polymers) because the number of degrees of freedom can be greatly reduced while still keeping the essential motions of the molecular system. The reduction in the number of degrees of freedom due to the block linkages is imposed here directly using a constraint method, in contrast to restraint methods where stiff harmonic couplings are introduced to restrain the relative motion of the blocks. The computational cost of this constraint method is less than that of an implementation using a restraint method. This is illustrated for the alpha-helix conformation of an alanine-20-polypeptide. C1 [Brooks, B. R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Ghysels, A.; Van Neck, D.; Van Speybroeck, V.; Waroquier, M.] Univ Ghent, Ctr Mol Modeling, B-9000 Ghent, Belgium. RP Waroquier, M (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM michel.waroquier@ugent.be RI Ghysels, An/M-9095-2015 FU Scientific Research-Flanders (FWO); Ghent University (BOF) FX A.G. is Aspirant of the Fund for Scientific Research-Flanders (FWO). This work is supported by the Fund for Scientific Research-Flanders (FWO) and by the Research Board of Ghent University (BOF). NR 27 TC 15 Z9 16 U1 0 U2 9 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD FEB 28 PY 2009 VL 130 IS 8 AR 084107 DI 10.1063/1.3071261 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 413PE UT WOS:000263804200012 PM 19256597 ER PT J AU Albert, PS AF Albert, Paul S. TI Estimating diagnostic accuracy of multiple binary tests with an imperfect reference standard SO STATISTICS IN MEDICINE LA English DT Article DE diagnostic error; imperfect tests; latent class models; misclassification; predictive values; prevalence; sensitivity; specificity; diagnostic accuracy ID DISCREPANT ANALYSIS; TEST SENSITIVITY; GOLD STANDARD; SCREENING-TEST; SPECIFICITY; BIAS; DISEASE; MODELS; ROBUSTNESS; EFFICACY AB The goal in diagnostic medicine is often to estimate the diagnostic accuracy of multiple experimental tests relative to a gold standard reference. When a gold standard reference is not available, investigators commonly use an imperfect reference standard. This paper proposes methodology for estimating the diagnostic accuracy of multiple binary tests with an imperfect reference standard when information about the diagnostic accuracy of the imperfect test is available front external data sources. We propose alternative joint models for characterizing the dependence between the experimental tests and discuss the use of these models for estimating individual-test sensitivity and specificity as well as prevalence and multivariate post-test probabilities (predictive values). We show using analytical and simulation techniques that, as long as the sensitivity and specificity of the imperfect test are high, inferences on diagnostic accuracy are robust to misspecification of the joint model. The methodology is demonstrated with a study examining the diagnostic accuracy of various HIV-antibody tests for HIV. Published in 2008 by John Wiley & Sons, Ltd. C1 Natl Canc Inst, Div Canc Treatment & Diag, Biometr Res Branch, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), Natl Canc Inst, Div Canc Treatment & Diag, Biometr Res Branch, Bethesda, MD 20892 USA. EM albertp@ctep.nci.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 36 TC 15 Z9 15 U1 0 U2 5 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2009 VL 28 IS 5 BP 780 EP 797 DI 10.1002/sim.3514 PG 18 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 410ND UT WOS:000263583500004 PM 19101935 ER PT J AU Sako, K Fukuhara, S Minami, T Hamakubo, T Song, HH Kodama, T Fukamizu, A Gutkind, JS Koh, GY Mochizuki, N AF Sako, Keisuke Fukuhara, Shigetomo Minami, Takashi Hamakubo, Takao Song, Haihua Kodama, Tatsuhiko Fukamizu, Akiyoshi Gutkind, J. Silvio Koh, Gou Young Mochizuki, Naoki TI Angiopoietin-1 Induces Kruppel-like Factor 2 Expression through a Phosphoinositide 3-Kinase/AKT-dependent Activation of Myocyte Enhancer Factor 2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; TRANSCRIPTION FACTOR MEF2C; CELL-CELL CONTACT; C-JUN PROMOTER; GENE-EXPRESSION; MUSCLE DIFFERENTIATION; INDEPENDENT PATHWAY; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; ADULT VASCULATURE AB Angiopoietin-1 (Ang1) regulates both vascular quiescence and angiogenesis through the receptor tyrosine kinase Tie2. We and another group have recently shown that Ang1 and Tie2 form distinct signaling complexes at cell-cell and cell-matrix contacts and further demonstrated that the former selectively induces expression of Kruppel-like factor 2 (KLF2), a transcription factor involved in vascular quiescence. Here, we investigated the mechanism of how Ang1/Tie2 signal induces KLF2 expression to clarify the role of KLF2 in Ang1/Tie2 signal-mediated vascular quiescence. Ang1 stimulated KLF2 promoter driven reporter gene expression in endothelial cells, whereas it failed when a myocyte enhancer factor 2 (MEF2)-binding site of KLF2 promoter was mutated. Depletion of MEF2 by siRNAs abolished Ang1-induced KLF2 expression, indicating the requirement of MEF2 in KLF2 induction by Ang1. Constitutive active phosphoinositide 3-kinase (PI3K)and AKT increased the MEF2-dependent reporter gene expression by enhancing its transcriptional activity and stimulated the KLF2 promoter activity cooperatively with MEF2. Consistently, inhibition of either PI3K or AKT and depletion of AKT abrogated Ang1-induced KLF2 expression. In addition, we confirmed the dispensability of extracellular signal-regulated kinase 5 (ERK5) for Ang1-induced KLF2 expression. Furthermore, depletion of KLF2 resulted in the loss of the inhibitory effect of Ang1 on vascular endothelial growth factor (VEGF)-mediated expression of vascular cell adhesion molecule-1 in endothelial cells and VEGF-mediated monocyte adhesion to endothelial cells. Collectively, these findings indicate that Ang1/Tie2 signal stimulates transcriptional activity of MEF2 through a PI3K/AKT pathway to induce KLF2 expression, which may counteract VEGF-mediated inflammatory responses. C1 [Sako, Keisuke; Fukuhara, Shigetomo; Mochizuki, Naoki] Natl Cardiovasc Ctr, Res Inst, Dept Struct Anal, Osaka 5658565, Japan. [Minami, Takashi; Hamakubo, Takao; Song, Haihua; Kodama, Tatsuhiko] Univ Tokyo, Adv Sci & Technol Res Ctr, Lab Syst Biol & Med, Meguro Ku, Tokyo 1538904, Japan. [Fukamizu, Akiyoshi] Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 3058577, Japan. [Gutkind, J. Silvio] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Koh, Gou Young] Korea Adv Inst Sci & Technol, Biomed Res Ctr, Taejon 305701, South Korea. [Koh, Gou Young] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. RP Fukuhara, S (reprint author), Natl Cardiovasc Ctr, Res Inst, Dept Struct Anal, 5-7-1 Fujishirodai, Osaka 5658565, Japan. EM fuku@ri.ncvc.go.jp RI Koh, Gou Young /C-1615-2011; Gutkind, J. Silvio/A-1053-2009; Fukamizu, Akiyoshi/J-5350-2012 OI Fukamizu, Akiyoshi/0000-0002-8786-6020 FU Ministry of Education, Science, Sports and Culture of Japan; Ministry of Health, Labour, and Welfare of Japan; Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation; Naito Foundation; Takeda Science Foundation; Sagawa Foundation for Promotion of Cancer Research; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Kowa Life Science Foundation; Kanae Foundation for the Promotion of Medical Science; Takeda Medical Research Foundation FX This work was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan ( to K. S., S. F., and N. M.); the Ministry of Health, Labour, and Welfare of Japan ( to N. M.); and the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation ( to S. F., T. M., T. K., and N. M.); the Naito Foundation ( to S. F.); Takeda Science Foundation ( to S. F.); the Sagawa Foundation for Promotion of Cancer Research ( to S. F.), Mochida Memorial Foundation for Medical and Pharmaceutical Research ( to S. F.), Kowa Life Science Foundation ( to S. F.), Kanae Foundation for the Promotion of Medical Science ( to S. F.), and Takeda Medical Research Foundation ( to N. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 55 TC 45 Z9 48 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 27 PY 2009 VL 284 IS 9 BP 5592 EP 5601 DI 10.1074/jbc.M806928200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 410EP UT WOS:000263560600022 PM 19106103 ER PT J AU Perkovic, M Schmidt, S Marino, D Russell, RA Stauch, B Hofmann, H Kopietz, F Kloke, BP Zielonka, J Strover, H Hermle, J Lindemann, D Pathak, VK Schneider, G Lochelt, M Cichutek, K Munk, C AF Perkovic, Mario Schmidt, Stanislaw Marino, Daniela Russell, Rebecca A. Stauch, Benjamin Hofmann, Henning Kopietz, Ferdinand Kloke, Bjoern-Philipp Zielonka, Joerg Stroever, Heike Hermle, Johannes Lindemann, Dirk Pathak, Vinay K. Schneider, Gisbert Loechelt, Martin Cichutek, Klaus Muenk, Carsten TI Species-specific Inhibition of APOBEC3C by the Prototype Foamy Virus Protein Bet SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EDITING ENZYME APOBEC3G; TYPE-1 VIF; HIV-1 VIF; ANTIRETROVIRAL DEFENSE; CYTIDINE DEAMINASES; ANTIVIRAL ACTIVITY; LEUKEMIA-VIRUS; MURINE APOBEC3; 2 DISTINCT; SOCS-BOX AB The APOBEC3 cytidine deaminases are part of the intrinsic defense of cells against retroviruses. Lentiviruses and spumaviruses have evolved essential accessory proteins, Vif and Bet, respectively, which counteract the APOBEC3 proteins. We show here that Bet of the Prototype foamy virus inhibits the antiviral APOBEC3C activity by a mechanism distinct to Vif: Bet forms a complex with APOBEC3C without inducing its degradation. Bet abolished APOBEC3C dimerization as shown by co-immunoprecipitation and cross-linking experiments. These findings implicate a physical interaction between Bet and the APOBEC3C. Subsequently, we identified the Bet interaction domain in human APOBEC3C in the predicted APOBEC3C dimerization site. Taken together, these data support the hypothesis that Bet inhibits incorporation of APOBEC3Cs into retroviral particles. Bet likely achieves this by trapping APOBEC3C protein in complexes rendering them unavailable for newly generated viruses due to direct immobilization. C1 [Perkovic, Mario; Schmidt, Stanislaw; Marino, Daniela; Hofmann, Henning; Kopietz, Ferdinand; Kloke, Bjoern-Philipp; Zielonka, Joerg; Stroever, Heike; Hermle, Johannes; Cichutek, Klaus; Muenk, Carsten] Paul Ehrlich Inst, Div Med Biotechnol, D-63225 Langen, Germany. [Russell, Rebecca A.; Pathak, Vinay K.] NCI, HIV Drug Resistance Program, NIH, Ctr Canc Res, Frederick, MD 21702 USA. [Stauch, Benjamin; Schneider, Gisbert] Univ Frankfurt, Inst Organ Chem & Chem Biol, D-60323 Frankfurt, Germany. [Lindemann, Dirk] Tech Univ Dresden, Inst Virol, D-01307 Dresden, Germany. [Loechelt, Martin] German Canc Res Ctr, Res Program Infect & Canc, Dept Genome Modificat & Carcinogenesis, D-69120 Heidelberg, Germany. [Hofmann, Henning; Zielonka, Joerg; Muenk, Carsten] Univ Dusseldorf, Clin Gastroenterol Hepatol & Infectiol, D-40225 Dusseldorf, Germany. RP Munk, C (reprint author), Paul Ehrlich Inst, Div Med Biotechnol, D-63225 Langen, Germany. EM carsten.muenk@med.uni-duesseldorf.de RI Lindemann, Dirk/H-5857-2013; OI Lindemann, Dirk/0000-0002-0320-4223; Stauch, Benjamin/0000-0001-7626-2021 FU National Institutes of Health; DFG [MU1608/3-1] FX This work was supported, in whole or in part, by National Institutes of Health Grant from the Intramural Research Program of NCI, NIH, Center for Cancer Research. This work was also supported by the DFG (Grant MU1608/3-1 to C.M.). NR 62 TC 44 Z9 47 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 27 PY 2009 VL 284 IS 9 BP 5819 EP 5826 DI 10.1074/jbc.M808853200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 410EP UT WOS:000263560600045 PM 19074429 ER PT J AU Yang, YW Wang, XX Hawkins, CA Chen, K Vaynberg, J Mao, X Tu, YZ Zuo, XB Wang, JB Wang, YX Wu, CY Tjandra, N Qin, J AF Yang, Yanwu Wang, Xiaoxia Hawkins, Cheryl A. Chen, Kan Vaynberg, Julia Mao, Xian Tu, Yizeng Zuo, Xiaobing Wang, Jinbu Wang, Yun-xing Wu, Chuanyue Tjandra, Nico Qin, Jun TI Structural Basis of Focal Adhesion Localization of LIM-only Adaptor PINCH by Integrin-linked Kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; RESIDUAL DIPOLAR COUPLINGS; CELL-SHAPE MODULATION; KAPPA-B COMPLEX; ANKYRIN REPEAT; MOLECULAR DISSECTION; ILK; MATRIX; SURVIVAL; DOMAIN AB The LIM-only adaptor PINCH (the particularly interesting cysteine- and histidine-rich protein) plays a pivotal role in the assembly of focal adhesions (FAs), supramolecular complexes that transmit mechanical and biochemical information between extracellular matrix and actin cytoskeleton, regulating diverse cell adhesive processes such as cell migration, cell spreading, and survival. A key step for the PINCH function is its localization to FAs, which depends critically on the tight binding of PINCH to integrin-linked kinase (ILK). Here we report the solution NMR structure of the core ILK.PINCH complex (28 kDa, K(D) similar to 68 nM) involving the N-terminal ankyrin repeat domain (ARD) of ILK and the first LIM domain (LIM1) of PINCH. We show that the ILK ARD exhibits five sequentially stacked ankyrin repeat units, which provide a large concave surface to grip the two contiguous zinc fingers of the PINCH LIM1. The highly electrostatic interface is evolutionally conserved but differs drastically from those of known ARD and LIM bound to other types of protein domains. Consistently mutation of a hot spot in LIM1, which is not conserved in other LIM domains, disrupted the PINCH binding to ILK and abolished the PINCH targeting to FAs. These data provide atomic insight into a novel modular recognition and demonstrate how PINCH is specifically recruited by ILK to mediate the FA assembly and cell-extracellular matrix communication. C1 [Yang, Yanwu; Wang, Xiaoxia; Vaynberg, Julia; Qin, Jun] Cleveland Clin, Dept Mol Cardiol, Lerner Res Inst, Cleveland, OH 44195 USA. [Yang, Yanwu; Qin, Jun] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44102 USA. [Hawkins, Cheryl A.; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Chen, Kan; Tu, Yizeng; Wu, Chuanyue] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA. [Zuo, Xiaobing; Wang, Jinbu; Wang, Yun-xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. [Mao, Xian; Qin, Jun] Cleveland Ctr Struct Biol, Cleveland, OH 44102 USA. RP Qin, J (reprint author), Cleveland Clin, Dept Mol Cardiol, Lerner Res Inst, NB20,9500 Euclid Ave, Cleveland, OH 44195 USA. EM qinj@ccf.org RI Qin, Jun/D-5559-2009; Zuo, Xiaobing/F-1469-2010 FU National Institutes of Health [HL58758, GM62823, DK54639, GM65188]; NHLBI; NCI; American Heart Association [0530067N] FX This work was supported, in whole or in part, by National Institutes of Health Grants HL58758 and GM62823 (to J.Q.) and DK54639 and GM65188 (to C. W.) and by the National Institutes of Health intramural research program of the NHLBI (to N.T.) and NCI (to Y.-X.W.). This work was also supported by American Heart Association Grant 0530067N (to Y.Y.). NR 39 TC 19 Z9 21 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 27 PY 2009 VL 284 IS 9 BP 5836 EP 5844 DI 10.1074/jbc.M805319200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 410EP UT WOS:000263560600047 PM 19117955 ER PT J AU Fomenko, DE Novoselov, SV Natarajan, SK Lee, BC Koc, A Carlson, BA Lee, TH Kim, HY Hatfield, DL Gladyshev, VN AF Fomenko, Dmitri E. Novoselov, Sergey V. Natarajan, Sathish Kumar Lee, Byung Cheon Koc, Ahmet Carlson, Bradley A. Lee, Tae-Hyung Kim, Hwa-Young Hatfield, Dolph L. Gladyshev, Vadim N. TI MsrB1 (Methionine-R-sulfoxide Reductase 1) Knock-out Mice ROLES OF MsrB1 IN REDOX REGULATION AND IDENTIFICATION OF A NOVEL SELENOPROTEIN FORM SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN OXIDATION; LIFE-SPAN; A MSRA; MOUSE; SELENIUM; CELLS; MITOCHONDRIAL; MAMMALS; STRESS; DAMAGE AB Protein oxidation has been linked to accelerated aging and is a contributing factor to many diseases. Methionine residues are particularly susceptible to oxidation, but the resulting mixture of methionine R-sulfoxide (Met-RO) and methionine S-sulfoxide (Met-SO) can be repaired by thioredoxin-dependent enzymes MsrB and MsrA, respectively. Here, we describe a knock-out mouse deficient in selenoprotein MsrB1, the main mammalian MsrB located in the cytosol and nucleus. In these mice, in addition to the deletion of 14-kDa MsrB1, a 5-kDa selenoprotein form was specifically removed. Further studies revealed that the 5-kDa protein occurred in both mouse tissues and human HEK 293 cells; was down-regulated by MsrB1 small interfering RNA, selenium deficiency, and selenocysteine tRNA mutations; and was immunoprecipitated and recognized by MsrB1 antibodies. Specific labeling with (75)Se and mass spectrometry analyses revealed that the 5-kDa selenoprotein corresponded to the C-terminal sequence of MsrB1. The MsrB1 knock-out mice lacked both 5-and 14-kDa MsrB1 forms and showed reduced MsrB activity, with the strongest effect seen in liver and kidney. In addition, MsrA activity was decreased by MsrB1 deficiency. Liver and kidney of the MsrB1 knock-out mice also showed increased levels of malondialdehyde, protein carbonyls, protein methionine sulfoxide, and oxidized glutathione as well as reduced levels of free and protein thiols, whereas these parameters were little changed in other organs examined. Overall, this study established an important contribution of MsrB1 to the redox control in mouse liver and kidney and identified a novel form of this protein. C1 [Fomenko, Dmitri E.; Novoselov, Sergey V.; Natarajan, Sathish Kumar; Lee, Byung Cheon; Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Fomenko, Dmitri E.; Novoselov, Sergey V.; Natarajan, Sathish Kumar; Lee, Byung Cheon; Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Koc, Ahmet] Izmir Inst Technol, Dept Mol Biol & Genet, TR-35430 Izmir, Turkey. [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, CCR,NIH, Bethesda, MD 20892 USA. [Lee, Tae-Hyung; Kim, Hwa-Young] Yeungnam Univ, Coll Med, Dept Biochem & Mol Biol, Aging Associated Vasc Dis Res Ctr, Taegu 705717, South Korea. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. EM vgladyshev1@unl.edu RI Gladyshev, Vadim/A-9894-2013; OI Novoselov, Sergey/0000-0003-0104-6492 FU National Institutes of Health [AG021518, RR017675]; Korea Science and Engineering Foundation [R13-2005-005-01004-0] FX This work was supported, in whole or in part, by National Institutes of Health Grant AG021518 (to V.N.G.) and the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health (to D.L.H.). The Nebraska Redox Biology Center is supported by National Institutes of Health Grant RR017675.This work was also supported by Korea Science and Engineering Foundation Grant R13-2005-005-01004-0 (to H.Y.K.). The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact. NR 27 TC 54 Z9 54 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 27 PY 2009 VL 284 IS 9 BP 5986 EP 5993 DI 10.1074/jbc.M805770200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 410EP UT WOS:000263560600062 PM 18990697 ER PT J AU Ronacher, K Hadley, K Avenant, C Stubsrud, E Simons, SS Louw, A Hapgood, JP AF Ronacher, Katharina Hadley, Katie Avenant, Chanel Stubsrud, Elisabeth Simons, S. Stoney, Jr. Louw, Ann Hapgood, Janet P. TI Ligand-selective transactivation and transrepression via the glucocorticoid receptor: Role of cofactor interaction SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Glucocorticoid receptor; Cofactor; Transactivation; Transrepression ID THYROID-HORMONE RECEPTOR; PARTIAL AGONIST ACTIVITY; NF-KAPPA-B; ANDROGEN RECEPTOR; BINDING DOMAIN; ANTAGONIST COMPLEXES; INDUCTION PROPERTIES; NUCLEAR RECEPTOR; TRANSCRIPTIONAL ACTIVITY; PROGESTERONE-RECEPTORS AB The mechanisms that determine ligand-selective transcriptional responses by the glucocorticoid receptor (GR) are not fully understood. Using a wide panel of GR ligands, we investigated the relationships between the potency and maximal response for transactivation via a glucocorticoid response element (GRE) and transrepression via both nuclear factor KB (NF kappa B) and activator protein-1 (AP-1) sites, relative binding affinity for the GR, as well as interaction with both coactivators and corepressors. The results showed ligand-selective differences in potency and efficacy for each promoter, as well as for a particular ligand between the three promoters. Ligand potency correlated with relative affinity for the GR for agonists and partial agonists in transactivation but not for transrepression. Maximal response was unrelated to relative affinity of ligand for GR for both transactivation and transrepression. A good and significant correlation between full length coactivator binding in two-hybrid assays and efficacy as well as potency of different receptor-steroid complexes for both transactivation and transrepression supports a major role for coactivator recruitment in determination of ligand-selective transcriptional activity. Furthermore, ligand-selective GR binding to GRIP-1, as determined by both two-hybrid and DNA pull down assays. correlated positively with ligand-selective efficacy for transactivation of both a synthetic GRE reporter with expressed GR as well as of an endogenous gene via endogenous GR. The receptor interacting domain of the corepressor SMRT exhibited strong interaction with both agonists and partial agonists, similar to the results for coactivators, suggesting a possible role for SMRT in activation of transcription. However, there was no correlation between ligand affinity for the GR and cofactor interaction. These results provide strong quantitative biochemical support for a model in which GR-mediated ligand-selective differential interaction with GRIP-1. SRC-1 A. NCoR and SMRT is a major determinant of ligand-selective and promoter-specific differences in potency and efficacy, for both transactivation and transrepression. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Hadley, Katie; Avenant, Chanel; Hapgood, Janet P.] Univ Cape Town, Dept Mol & Cell Biol, ZA-7700 Rondebosch, South Africa. [Ronacher, Katharina; Stubsrud, Elisabeth; Louw, Ann; Hapgood, Janet P.] Univ Stellenbosch, Dept Biochem, ZA-7602 Matieland, South Africa. [Simons, S. Stoney, Jr.] NIDDK CEB, Steroid Hormontes Sect, NIH, Bethesda, MD 20892 USA. RP Hapgood, JP (reprint author), Univ Cape Town, Dept Mol & Cell Biol, ZA-7700 Rondebosch, South Africa. EM Janet.Hapgood@uct.ac.za RI Louw, Ann/A-7620-2012; Ronacher, Katharina/N-9603-2016 OI Louw, Ann/0000-0002-1021-6732; Ronacher, Katharina/0000-0002-6371-1462 FU Medical Research Council [415794]; National Research Foundation [GUN2054145] FX This work was funded by Medical Research Council (grant number 415794) and National Research Foundation Grants (grant number GUN2054145) in South Africa to J.H. Thanks are given to the Fulbright Foundation, the Ernest Oppenheimer Memorial Trust and Stellenbosch University for sabbatical funding to j.H., and the Claude Harris Leon Foundation for postdoctoral funding to K.R. The ABCD assay work and the sabbatical support to J.H. were funded in part by the Intramural Research Program of the National Institutes of Health, NIDDK. NR 56 TC 60 Z9 66 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 27 PY 2009 VL 299 IS 2 BP 219 EP 231 DI 10.1016/j.mce.2008.10.008 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 411PU UT WOS:000263662500011 PM 19007848 ER PT J AU Wang, Y Reddy, B Thompson, J Wang, HB Noma, K Yates, JR Jia, ST AF Wang, Yu Reddy, Bharat Thompson, James Wang, Hengbin Noma, Ken-ichi Yates, John R., III Jia, Songtao TI Regulation of Set9-Mediated H4K20 Methylation by a PWWP Domain Protein SO MOLECULAR CELL LA English DT Article ID DOUBLE-STRAND BREAKS; HISTONE METHYLTRANSFERASE ACTIVITY; DNA-DAMAGE CHECKPOINT; LYSINE METHYLATION; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; UBIQUITIN LIGASE; GENE-EXPRESSION; CHROMATIN; H3 AB Methylation of histone H4 lysine 20 (H4K20me) is essential for recruiting checkpoint proteins 53BP1/Crb2 to DNA lesions and subsequent activation of a DNA-damage checkpoint. In fission yeast, Set9 (spKMT5) catalyzes mono-, di-, and trimethylation of H4K20. However, the mechanisms that regulate Set9 function are poorly understood. Here, we identified a PWWP domain protein Pdp1 as a Set9-associated factor. Pdp1 binds to histones and is required for Set9 chromatin localization. Yeast cells without Pdp1 were deficient in all three states of H4K20me, sensitive to genotoxic treatments, and impaired in Crb2 recruitment. The PWWP domain of Pdp1 binds to H4K20me, and mutations within the PWWP domain that abrogated this interaction in vitro reduced both the association of Set9 with chromatin and the extent of H4K20me in vivo. These results demonstrate that the PWWP domain is a new methyl-lysine recognition motif that plays important roles in epigenetic regulation. C1 [Wang, Yu; Reddy, Bharat; Jia, Songtao] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Thompson, James; Yates, John R., III] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Wang, Hengbin] Univ Alabama, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. [Noma, Ken-ichi] NCI, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. RP Jia, ST (reprint author), Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. EM jia@biology.columbia.edu FU Basal O'Connor Starter Scholar; March of Dimes foundation; NIH [R01 GM085145]; National Center for Research Resources; National Institutes of Health [P41 RR 11823] FX We thank S. Kallgren, M. Natalia, and V. Ringgold for assistance with strain construction. We thank S. Grewal for providing strains and plasmids. set9J, Set9-Myc, and Set9-Flag strains used in this study were constructed in the Grewal laboratory. We thank N. Walworth, S. Sanders, S. Marcus, P. Silver, F. Chang, and M. Bedford for strains and plasmids; A. Verreault and M. Yanagida for antibodies; A. Courey and B. Strahl for nucleosomes; Y. Shi for histone pepticles; L. Tong and C. Wang for help with structural analysis; R. Rothstein, J. Barlow, and J. Sable for help with microscopy; L. Tong and Y. Bai for help with gel filtration analysis; and J. Hunt and B. Ergel for help with pepticle interaction assays. We thank J. Manley, C. Prives, L. Chasin, S. Grewal, and S. Kallgren for critical reading of the manuscript. This work is supported by a Basal O'Connor Starter Scholar Award from the March of Dimes foundation and NIH grant R01 GM085145 to S.J. and by the National Center for Research Resources of the National Institutes of Health by a grant to T.N.D (P41 RR 11823). NR 58 TC 58 Z9 61 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 27 PY 2009 VL 33 IS 4 BP 428 EP 437 DI 10.1016/j.molcel.2009.02.002 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 413RS UT WOS:000263810800005 PM 19250904 ER PT J AU Stasevich, TJ Tao, CG Cullen, WG Williams, ED Einstein, TL AF Stasevich, T. J. Tao, Chenggang Cullen, William G. Williams, Ellen D. Einstein, T. L. TI Impurity Decoration for Crystal Shape Control: C-60 on Ag(111) SO PHYSICAL REVIEW LETTERS LA English DT Article ID EQUILIBRIUM SHAPES; GROWTH; FLUCTUATIONS; MORPHOLOGY; ANISOTROPY; SURFACES AB The decoration of hexagonal Ag/Ag(111) monolayer islands by chains of C-60, observed via STM at 300 K, dramatically changes the nanocrystalline shape and fluctuations of the islands. We tune coverage so that a single chain of C-60 fully decorates each Ag island boundary, forming a closed circular "necklace." We model the C-60-induced rounding in terms of competing energetic and entropic effects. We thereby characterize the decorated-step fluctuations and estimate the C-60-Ag and C-60-C-60 attractions to be similar to 0.13 and similar to 0.03 eV, respectively. Generalizations of our model show that decorating molecules of both circular and rectangular surface-projected symmetry will similarly lower the energy of fully kinked boundaries, leading to corner rounding and reorientations by 30 degrees on (111) surfaces and 45 degrees on (100) surfaces. C1 [Stasevich, T. J.; Tao, Chenggang; Cullen, William G.; Williams, Ellen D.; Einstein, T. L.] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Stasevich, T. J.] NCI, Fluorescence Imaging Facil, LRBGE, NIH, Bethesda, MD 20892 USA. [Tao, Chenggang] Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA. RP Stasevich, TJ (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. OI Einstein, Theodore L./0000-0001-6031-4923 FU NSF-MRSEC [DMR 05-20471] FX Work at U. Maryland supported by the NSF-MRSEC under Grant No. DMR 05-20471. T. J. Stasevich thanks Madhav Ranganathan for helpful discussions. NR 27 TC 7 Z9 7 U1 0 U2 13 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD FEB 27 PY 2009 VL 102 IS 8 AR 085501 DI 10.1103/PhysRevLett.102.085501 PG 4 WC Physics, Multidisciplinary SC Physics GA 413TU UT WOS:000263816200030 PM 19257751 ER PT J AU Caporaso, N Gu, FY Chatterjee, N Jin, SC Yu, K Yeager, M Chen, C Jacobs, K Wheeler, W Landi, MT Ziegler, RG Hunter, DJ Chanock, S Hankinson, S Kraft, P Bergen, AW AF Caporaso, Neil Gu, Fangyi Chatterjee, Nilanjan Jin Sheng-Chih Yu, Kai Yeager, Meredith Chen, Constance Jacobs, Kevin Wheeler, William Landi, Maria Teresa Ziegler, Regina G. Hunter, David J. Chanock, Stephen Hankinson, Susan Kraft, Peter Bergen, Andrew W. TI Genome-Wide and Candidate Gene Association Study of Cigarette Smoking Behaviors SO PLOS ONE LA English DT Article AB The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, <= 10 versus >10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10(-7)) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10(-5) for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10(-3)), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4x10(-5)), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up. C1 [Caporaso, Neil; Chatterjee, Nilanjan; Yu, Kai; Yeager, Meredith; Landi, Maria Teresa; Ziegler, Regina G.; Hunter, David J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gu, Fangyi; Chen, Constance; Hunter, David J.; Hankinson, Susan; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA USA. [Jin Sheng-Chih] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21218 USA. [Chanock, Stephen] Brigham and Womens Hosp, Channing Lab, Boston, MA USA. [Yeager, Meredith; Jacobs, Kevin; Hunter, David J.] NCI, NIH, Advanced Technol Ctr, Core Genotyping Facil, Gaithersburg, MD USA. [Jacobs, Kevin] BioInformed LLC, Gaithersburg, MD USA. [Wheeler, William] Informat Management Serv, Inc, Rockville, MD USA. [Bergen, Andrew W.] SRI Int, Ctr Hlth Sci, Mol Genet Program, Menlo Pk, CA USA. RP Caporaso, N (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM caporaso@nih.gov RI Gu, Fangyi/I-5957-2014; OI Bergen, Andrew/0000-0002-1237-7644 FU National Cancer Institute [P01 CA087969, U01 DA020830]; Intramural Research Program of the NIH FX NHS (PK, FG, SH, CC, DHH) is supported by National Cancer Institute grant P01 CA087969. This research was supported also supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. AWB was supported by the Intramural Research Program of the National Cancer Institute and is supported by U01 DA020830. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 89 TC 157 Z9 159 U1 5 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 27 PY 2009 VL 4 IS 2 AR e4653 DI 10.1371/journal.pone.0004653 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437LA UT WOS:000265487800032 PM 19247474 ER PT J AU Hugonnet, JE Tremblay, LW Boshoff, HI Barry, CE Blanchard, JS AF Hugonnet, Jean-Emmanuel Tremblay, Lee W. Boshoff, Helena I. Barry, Clifton E., III Blanchard, John S. TI Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant Mycobacterium tuberculosis SO SCIENCE LA English DT Article ID BETA-LACTAM ANTIBIOTICS; PERSISTENCE; INHIBITION; ACID AB beta-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded blaC gene product. The carbapenem class of beta-lactams are very poor substrates for BlaC, allowing us to determine the three-dimensional structure of the covalent BlaC-meropenem covalent complex at 1.8 angstrom resolution. When meropenem was combined with the beta-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [minimum inhibitory concentration (MIC(meropenem)) less than 1 microgram per milliliter], and sterilization of aerobically grown cultures was observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the "persistent" state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. Meropenem and clavulanate are Food and Drug Administration-approved drugs and could potentially be used to treat patients with currently untreatable disease. C1 [Hugonnet, Jean-Emmanuel; Tremblay, Lee W.; Blanchard, John S.] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA. [Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Stn, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Blanchard, JS (reprint author), Albert Einstein Coll Med, Dept Biochem, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM blanchar@aecom.yu.edu RI Barry, III, Clifton/H-3839-2012; HUGONNET, Jean-Emmanuel/H-3581-2014 FU NIH [AI33696]; National Institute of Allergy and Infectious Diseases; Bill and Melinda Gates Foundation; Wellcome Trust FX The authors wish to thank J. Chan and E. Russel for help in the Wayne model studies and H. Xiao for assistance in mass spectrometry. This work was supported partially by the NIH (AI33696 to J.S.B.); in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases; and in part by a grant from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative. A provisional U.S. patent application was filed on 27 May 2008 related to this work. Structure coordinates have been deposited as Protein Data Bank identification code 3DWZ. NR 19 TC 232 Z9 235 U1 5 U2 39 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 27 PY 2009 VL 323 IS 5918 BP 1215 EP 1218 DI 10.1126/science.1167498 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411XT UT WOS:000263687600039 PM 19251630 ER PT J AU Yutin, N Wolf, MY Wolf, YI Koonin, EV AF Yutin, Natalya Wolf, Maxim Y. Wolf, Yuri I. Koonin, Eugene V. TI The origins of phagocytosis and eukaryogenesis SO BIOLOGY DIRECT LA English DT Review ID RECEPTOR-MEDIATED PHAGOCYTOSIS; ALDRICH-SYNDROME PROTEIN; NUCLEAR-PORE-COMPLEX; RHO-FAMILY GTPASES; FC-GAMMA-R; ARP2/3 COMPLEX; PHAGOSOME MATURATION; ENTAMOEBA-HISTOLYTICA; EUKARYOTIC EVOLUTION; ACTIN CYTOSKELETON AB Background: Phagocytosis, that is, engulfment of large particles by eukaryotic cells, is found in diverse organisms and is often thought to be central to the very origin of the eukaryotic cell, in particular, for the acquisition of bacterial endosymbionts including the ancestor of the mitochondrion. Results: Comparisons of the sets of proteins implicated in phagocytosis in different eukaryotes reveal extreme diversity, with very few highly conserved components that typically do not possess readily identifiable prokaryotic homologs. Nevertheless, phylogenetic analysis of those proteins for which such homologs do exist yields clues to the possible origin of phagocytosis. The central finding is that a subset of archaea encode actins that are not only monophyletic with eukaryotic actins but also share unique structural features with actin-related proteins (Arp) 2 and 3. All phagocytic processes are strictly dependent on remodeling of the actin cytoskeleton and the formation of branched filaments for which Arp2/3 are responsible. The presence of common structural features in Arp2/3 and the archaeal actins suggests that the common ancestors of the archaeal and eukaryotic actins were capable of forming branched filaments, like modern Arp2/3. The Rho family GTPases that are ubiquitous regulators of phagocytosis in eukaryotes appear to be of bacterial origin, so assuming that the host of the mitochondrial endosymbiont was an archaeon, the genes for these GTPases come via horizontal gene transfer from the endosymbiont or in an earlier event. Conclusion: The present findings suggest a hypothetical scenario of eukaryogenesis under which the archaeal ancestor of eukaryotes had no cell wall (like modern Thermoplasma) but had an actin-based cytoskeleton including branched actin filaments that allowed this organism to produce actin-supported membrane protrusions. These protrusions would facilitate accidental, occasional engulfment of bacteria, one of which eventually became the mitochondrion. The acquisition of the endosymbiont triggered eukaryogenesis, in particular, the emergence of the endomembrane system that eventually led to the evolution of modern-type phagocytosis, independently in several eukaryotic lineages. Reviewers: This article was reviewed by Simonetta Gribaldo, Gaspar Jekely, and Pierre Pontarotti. For the full reviews, please go to the Reviewers' Reports section. C1 [Yutin, Natalya; Wolf, Maxim Y.; Wolf, Yuri I.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM yutin@ncbi.nlm.nih.gov; nskwolf@gmail.com; wolf@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov FU Department of Health and Human Services intramural program (NIH, National Library of Medicine) FX We thank Dr. Tomoyoshi Nozaki for help with the access to E. histolytica protein database. The authors' research is supported by the Department of Health and Human Services intramural program (NIH, National Library of Medicine). NR 148 TC 70 Z9 70 U1 1 U2 40 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD FEB 26 PY 2009 VL 4 AR 9 DI 10.1186/1745-6150-4-9 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 415TN UT WOS:000263958300001 PM 19245710 ER PT J AU Colt, JS Rothman, N Severson, RK Hartge, P Cerhan, JR Chatterjee, N Cozen, W Morton, LM De Roos, AJ Davis, S Chanock, S Wang, SS AF Colt, Joanne S. Rothman, Nathaniel Severson, Richard K. Hartge, Patricia Cerhan, James R. Chatterjee, Nilanjan Cozen, Wendy Morton, Lindsay M. De Roos, Anneclaire J. Davis, Scott Chanock, Stephen Wang, Sophia S. TI Organochlorine exposure, immune gene variation, and risk of non-Hodgkin lymphoma SO BLOOD LA English DT Article ID POLYCHLORINATED-BIPHENYLS; PERINATAL EXPOSURE; CANCER MORTALITY; CARPET DUST; DIOXINS; POLYMORPHISMS; INTERLEUKIN-10; PCBS; IL10; 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN AB Organochlorine exposure was linked to non-Hodgkin lymphoma (NHL) risk. To determine whether this relation is modified by immune gene variation, we genotyped 61 polymorphisms in 36 immune genes in 1172 NHL cases and 982 controls from the National Cancer Institute Surveillance, Epidemiology, and End Results (NCI-SEER) study. We examined 3 exposures with elevated risk in this study: PCB180 (plasma, dust measurements), the toxic equivalency quotient (an integrated functional measure of several organochlorines) in plasma, and alpha-chlordane (dust measurements, selfreported termiticide use). Plasma (100 cases, 100 controls) and dust (682 cases, 513 controls) levels were treated as natural log-transformed continuous variables. Unconditional logistic regression was used to calculate beta coefficients and odds ratios, stratified by genotype. Associations between all 3 exposures and NHL risk were limited to the same genotypes for IFNG (C-1615T) TT and IL4 (5'-UTR, Ex1-168C>T) CC. Associations between PCB180 in plasma and dust and NHL risk were limited to the same genotypes for IL16 (3'-UTR, Ex22+871A>G) AA, IL8 (T-251A) TT, and IL10 (A-1082G) AG/GG. This shows that the relation between organochlorine exposure and NHL risk may be modified by particular variants in immune genes and provides one of the first examples of a potential gene-environment interaction for NHL. (Blood. 2009; 113: 1899-1905) C1 [Colt, Joanne S.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Severson, Richard K.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med, Detroit, MI USA. [Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN USA. [Cozen, Wendy] Univ So Calif, Los Angeles, CA USA. [De Roos, Anneclaire J.; Davis, Scott] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [De Roos, Anneclaire J.; Davis, Scott] Univ Washington, Seattle, WA 98195 USA. [Chanock, Stephen] Natl Canc Inst, Core Genotyping Facil, Gaithersburg, MD USA. RP Colt, JS (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, 6120 Execut Blvd,Room 8112, Bethesda, MD 20892 USA. EM coltj@mail.nih.gov RI Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Cerhan, James/0000-0002-7482-178X FU National Institutes of Health [N01-CN-67008, N01-CN-67010, N01-PC-67009, N01-PC-65064]; NCI-Southwest Research Institute [N02-CP-19 114]; NCI-CDC [Y1-CP-8028-02] FX This work was supported by the Intramural Research Program of the National Institutes of Health at the NCI and by contracts with the NCI (NCI-SEER contracts N01-CN-67008, N01-CN-67010, N01-PC-67009, and N01-PC-65064; NCI-Southwest Research Institute contract N02-CP-19 114; and NCI-CDC interagency agreement Y1-CP-8028-02). NR 39 TC 21 Z9 21 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 26 PY 2009 VL 113 IS 9 BP 1899 EP 1905 DI 10.1182/blood-2008-04-153858 PG 7 WC Hematology SC Hematology GA 412KM UT WOS:000263723700006 PM 19066394 ER PT J AU Salzer, U Bacchelli, C Buckridge, S Pan-Hammarstrom, Q Jennings, S Lougaris, V Bergbreiter, A Hagena, T Birmelin, J Plebani, A Webster, ADB Peter, HH Suez, D Chapel, H McLean-Tooke, A Spickett, GP Anover-Sombke, S Ochs, HD Urschel, S Belohradsky, BH Ugrinovic, S Kumararatne, DS Lawrence, TC Holm, AM Franco, JL Schulze, I Schneider, P Gertz, EM Schaffer, AA Hammarstrom, L Thrasher, AJ Gaspar, HB Grimbacher, B AF Salzer, Ulrich Bacchelli, Chiara Buckridge, Sylvie Pan-Hammarstrom, Qiang Jennings, Stephanie Lougaris, Vassilis Bergbreiter, Astrid Hagena, Tina Birmelin, Jennifer Plebani, Alessandro Webster, A. David B. Peter, Hans-Hartmut Suez, Daniel Chapel, Helen McLean-Tooke, Andrew Spickett, Gavin P. Anover-Sombke, Stephanie Ochs, Hans D. Urschel, Simon Belohradsky, Bernd H. Ugrinovic, Sanja Kumararatne, Dinakantha S. Lawrence, Tatiana C. Holm, Are M. Franco, Jose L. Schulze, Ilka Schneider, Pascal Gertz, E. Michael Schaffer, Alejandro A. Hammarstrom, Lennart Thrasher, Adrian J. Gaspar, H. Bobby Grimbacher, Bodo TI Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes SO BLOOD LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; IGA DEFICIENCY; B-CELL; BAFF-R; ENCODING TACI; T-CELL; APRIL; RECEPTOR; EXPRESSION; BINDING AB TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n = 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n = 41; 82%) of the patients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P < .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P = .019), benign lymphoproliferation (P < .001), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation. (Blood. 2009; 113: 1967-1976) C1 [Salzer, Ulrich; Jennings, Stephanie; Bergbreiter, Astrid; Hagena, Tina; Peter, Hans-Hartmut] Univ Hosp Freiburg, Dept Rheumatol & Clin Immunol, Freiburg, Germany. [Bacchelli, Chiara; Buckridge, Sylvie; Thrasher, Adrian J.; Gaspar, H. Bobby] Inst Child Hlth, Mol Immunol Unit, London, England. [Pan-Hammarstrom, Qiang; Hammarstrom, Lennart] Karolinska Univ Hosp Huddinge, Karolinska Inst, Div Clin Immunol, Stockholm, Sweden. [Lougaris, Vassilis; Plebani, Alessandro] Univ Brescia, Pediat Clin, Brescia, Italy. [Lougaris, Vassilis; Plebani, Alessandro] Spedali Civil Brescia, Ist Med Mol Angelo Nocivelli, I-25125 Brescia, Italy. [Birmelin, Jennifer; Webster, A. David B.; Grimbacher, Bodo] Royal Free Hosp, Dept Immunol & Mol Pathol, London NW3 2QG, England. [Birmelin, Jennifer; Webster, A. David B.; Grimbacher, Bodo] UCL, London, England. [Suez, Daniel] Allergy Asthma & Immunol Clin, Irving, TX USA. [Chapel, Helen] Oxford Radcliffe Hosp, Nuffield Dept Med, Oxford, England. [McLean-Tooke, Andrew; Spickett, Gavin P.] Royal Victoria Infirm, Dept Immunol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Anover-Sombke, Stephanie; Ochs, Hans D.] Univ Washington, Reg Med Ctr, Seattle, WA 98195 USA. [Anover-Sombke, Stephanie; Ochs, Hans D.] Childrens Hosp, Seattle, WA USA. [Urschel, Simon; Belohradsky, Bernd H.] Univ Munich, Div Infect Dis & Immunol, Univ Childrens Hosp, Munich, Germany. [Ugrinovic, Sanja; Kumararatne, Dinakantha S.] Addenbrookes Hosp, Dept Clin Immunol, Cambridge, England. [Lawrence, Tatiana C.] Univ Fed Sao Paulo, Dept Pediat, Sao Paulo, Brazil. [Holm, Are M.] Univ Oslo, Natl Hosp, Internal Med Res Inst, Oslo, Norway. [Franco, Jose L.] Univ Antioquia, Grp Immunodeficiencias Primarias, Medellin, Colombia. [Schulze, Ilka] Charite Humboldt Univ, Dept Paediat Pneumol & Immunol, Berlin, Germany. [Schneider, Pascal] Univ Lausanne, Dept Biochem, Lausanne, Switzerland. [Gertz, E. Michael; Schaffer, Alejandro A.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, US Dept HHS, Bethesda, MD 20894 USA. RP Grimbacher, B (reprint author), Royal Free Hosp, Dept Immunol & Mol Pathol, Pond St, London NW3 2QG, England. EM bgrimbac@medsch.ucl.ac.uk RI Plebani, Alessandro/C-8593-2011; Schaffer, Alejandro/F-2902-2012; OI Gertz, E. Michael/0000-0001-8390-4387; Schneider, Pascal/0000-0003-0677-9409 FU Deutsche Forschungsgemeinschaft (Bonn, Germany) [GR1617/3, SFB620/C2, SFB620/Z1, SFB620/C1]; European Commission (Brussels, Belgium) [SP23-CT-2005-006411, MEXT-CT-2006-042316, HEALTH-F2-2008-201549]; National Institutes of Health/National Institute of Allergy and Infectious Diseases [NO1-A130070]; Primary Immunodeficiency Association (PIA; London, United Kingdom); Medical Research Council (MRC; London, United Kingdom); The Wellcome Trust (London, United Kingdom); Swedish Research Council (Stockholm, Sweden); Fondazione C. Golgi (Brescia, Italy) [PRIN2006]; Swiss National Science Foundation (Bern, Switzerland); Grant Colciencias (Bogota, Colombia) [1115-05-16784]; NIH [HD 37091]; Jeffrey Modell Foundation (New York, NY); Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This work was supported by grants from the Deutsche Forschungsgemeinschaft (Bonn, Germany) GR1617/3 (B. G.), SFB620/C2 (B. G., U. S.), SFB620/Z1 (H.-H. P.), and SFB620/C1 (H.-H. P.); from the European Commission (Brussels, Belgium) SP23-CT-2005-006411 (H. C., B. G.), MEXT-CT-2006-042316 (B. G.), and HEALTH-F2-2008-201549 (U. S.); from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID; Bethesda, MD)/USIDnet no. NO1-A130070 (B. G.); from the Primary Immunodeficiency Association (PIA; London, United Kingdom), Medical Research Council (MRC; London, United Kingdom), and The Wellcome Trust (London, United Kingdom; C. B., S. B., H. B. G., A. J. T., H. C.); from the Swedish Research Council (Stockholm, Sweden; Q. P.-H., L. H.); from the Fondazione C. Golgi (Brescia, Italy), and PRIN2006 (Rome, Italy; A. P.); from the Swiss National Science Foundation (Bern, Switzerland; P. S.); from the Grant Colciencias (Bogota, Colombia) 1115-05-16784 (J. L. F.); from the NIH (grant HD 37091 to H. D. O., H. C.), and from the Jeffrey Modell Foundation (New York, NY; H. D. O., H. C.). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine (NLM; E. M. G., A. A. S.). NR 38 TC 112 Z9 114 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 26 PY 2009 VL 113 IS 9 BP 1967 EP 1976 DI 10.1182/blood-2008-02-141937 PG 10 WC Hematology SC Hematology GA 412KM UT WOS:000263723700014 PM 18981294 ER PT J AU Bonder, CS Sun, WY Matthews, T Cassano, C Li, XC Ramshaw, HS Pitson, SM Lopez, AF Coates, PT Proia, RL Vadas, MA Gamble, JR AF Bonder, Claudine S. Sun, Wai Y. Matthews, Tyson Cassano, Carlos Li, Xiaochun Ramshaw, Hayley S. Pitson, Stuart M. Lopez, Angel F. Coates, P. Toby Proia, Richard L. Vadas, Mathew A. Gamble, Jennifer R. TI Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation SO BLOOD LA English DT Article ID EMBRYONIC STEM-CELLS; BONE-MARROW-CELLS; ISCHEMIA/REPERFUSION INJURY; HEMATOPOIETIC STEM; PRECURSOR CELLS; ACTIVATION; FTY720; ANGIOGENESIS; MOBILIZATION; SPHINGOSINE-1-PHOSPHATE AB Circulating endothelial progenitor cells (EPCs) are incorporated into foci of neovascularization where they undergo differentiation to mature endothelial cells (ECs). We show here that the enzyme sphingosine kinase-1 (SK-1) regulates the rate and direction of EPC differentiation without effect on the hematopoietic compartment. EPCs have high levels of SK-1 activity, which diminishes with differentiation and is, at least partially, responsible for maintaining their EPC phenotype. EPCs from SK-1 knockout mice form more adherent EC units and acquire a mature EC phenotype more rapidly. Conversely, EPCs from mice overexpressing SK-1 in the EC compartment are retarded in their differentiation. Exogenous regulation of SK-1 levels in normal EPCs, by genetic and pharmacologic means, including the immunomodulating drug FTY720, recapitulates these effects on EC differentiation. SK-1 knockout mice have higher levels of circulating EPCs, an exaggerated response to erythropoietin-induced EPC mobilization, and, in a mouse model of kidney ischemia reperfusion injury, exhibit a recovery similar to that of ischemic mice administered exogenous EPCs. Thus, SK-1 is a critical player in EPC differentiation into EC pointing to the potential utility of SK-1 modifying agents in the specific manipulation of endothelial development and repair. (Blood. 2009; 113: 2108-2117) C1 [Bonder, Claudine S.] Inst Med & Vet Sci, Hanson Inst, Div Human Immunol, Vasc Biol & Cell Trafficking Lab, Adelaide, SA 5000, Australia. Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Matthews, Tyson; Coates, P. Toby] Queen Elizabeth Hosp, Dept Med, Transplantat Immunol Lab, Adelaide, SA, Australia. [Cassano, Carlos; Vadas, Mathew A.; Gamble, Jennifer R.] Centenary Inst, Sydney, NSW, Australia. [Proia, Richard L.] NIH, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. [Gamble, Jennifer R.] Univ Sydney, Med Fdn, Sydney, NSW 2006, Australia. RP Bonder, CS (reprint author), Inst Med & Vet Sci, Hanson Inst, Div Human Immunol, Vasc Biol & Cell Trafficking Lab, POB 14,Rundle Mall, Adelaide, SA 5000, Australia. EM claudine.bonder@imvs.sa.gov.au; j.gamble@centenary.org.au RI Lopez, Angel/E-2260-2011; Proia, Richard/A-7908-2012; Ramshaw, Hayley/F-3828-2013; OI Ramshaw, Hayley/0000-0001-9909-282X FU National Health & Medical Research Council of Australia [430907, 349332]; Peter Nelson Leukemia Research Fund Senior Research Fellowship; Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; University of Sydney (Sydney, Australia) FX This work was supported in part by grants from National Health & Medical Research Council of Australia with a Peter Doherty Fellowship (C. S. B.), Project Grant 430907 (C. S. B.), Program Grant 349332 (J.R.G., M. A. V., A. F. L.), a Peter Nelson Leukemia Research Fund Senior Research Fellowship (H. S. R.), and by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R. L. P.). J.R.G. is a Medical Foundation Fellow at the University of Sydney (Sydney, Australia). NR 63 TC 23 Z9 24 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 26 PY 2009 VL 113 IS 9 BP 2108 EP 2117 DI 10.1182/blood-2008-07-166942 PG 10 WC Hematology SC Hematology GA 412KM UT WOS:000263723700031 PM 19109558 ER PT J AU Peach, ML Tan, N Choyke, SJ Giubellino, A Athauda, G Burke, TR Nicklaus, MC Bottaro, DP AF Peach, Megan L. Tan, Nelly Choyke, Sarah J. Giubellino, Alessio Athauda, Gagani Burke, Terrence R., Jr. Nicklaus, Marc C. Bottaro, Donald P. TI Directed Discovery of Agents Targeting the Met Tyrosine Kinase Domain by Virtual Screening SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SMALL-MOLECULE INHIBITOR; C-MET; THERAPEUTIC INHIBITION; SELECTIVE INHIBITORS; CRYSTAL-STRUCTURE; CELL-GROWTH; RECEPTOR; CANCER; MUTATIONS; VALIDATION AB Hepatocyte growth factor (HGF) is an important regulator of normal development and homeostasis, and dysregulated signaling through the HGF receptor, Met, contributes to tumorigenesis, tumor progression, and metastasis in numerous human malignancies. The development of selective small-molecule inhibitors of oncogenic tyrosine Kinases (TK) has led to well-tolerated, targeted therapies for a growing number of cancer types. To identify selective Met TK inhibitors, we used a high-throughput virtual screen of the 13.5 million compound ChemNavigator database to find compounds most likely to bind to the Met ATP binding site and to form several critical interactions with binding site residues predicted to stabilize the kinase domain in its inactive conformation. Subsequent biological screening of 70 in silico hit structures using cell-free and intact cell assays identified three active compounds with micromolar IC(50) values. The predicted binding modes and target selectivity of these compounds are discussed and compared to other known Met TK inhibitors. C1 [Tan, Nelly; Choyke, Sarah J.; Giubellino, Alessio; Athauda, Gagani; Bottaro, Donald P.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Peach, Megan L.] SAIC Frederick Inc, Basic Res Program, NCI Frederick, Frederick, MD 21702 USA. [Burke, Terrence R., Jr.; Nicklaus, Marc C.] NCI, Med Chem Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 10 Ctr Dr MSC 1107,Bldg 10,CRC,Room 1-3961, Bethesda, MD 20892 USA. EM bottarod@mail.nih.gov RI Bottaro, Donald/F-8550-2010; Nicklaus, Marc/N-4183-2014; Burke, Terrence/N-2601-2014; OI Bottaro, Donald/0000-0002-5057-5334; Nicklaus, Marc/0000-0002-4775-7030; Giubellino, Alessio/0000-0002-5352-0662 FU NIH; National Cancer Institute; Center for Cancer Research; National Institutes of Health [N01-CO12400]; [PHA665752] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO12400. We thank Dr. James Christensen and Pfizer for the generous gift of PHA665752. NR 40 TC 26 Z9 26 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 26 PY 2009 VL 52 IS 4 BP 943 EP 951 DI 10.1021/jm800791f PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 409UB UT WOS:000263530200008 PM 19199650 ER PT J AU Cai, Q Sheng, ZH AF Cai, Qian Sheng, Zu-Hang TI Moving or Stopping Mitochondria: Miro as a Traffic Cop by Sensing Calcium SO NEURON LA English DT Editorial Material ID KINESIN HEAVY-CHAIN; AXONAL-TRANSPORT; MOTILITY; SYNAPSES; MILTON; DYNEIN AB Mitochondrial transport in neurons and their spatial distribution among synapses are directly correlated with synaptic activity. One paper in this issue of Neuron (MacAskill et al.) and two papers recently published in Cell (Wang and Schwarz) and PNAS (Saotome et al.) provide compelling evidence that Miro serves as a calcium sensor that controls mitochondrial mobility. C1 [Cai, Qian; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, NIH, Bldg 35,Room 3B203,35 Convent Dr, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002946-12, Z01 NS003029-01, ]; NIA NIH HHS [R00 AG033658] NR 16 TC 26 Z9 26 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 26 PY 2009 VL 61 IS 4 BP 493 EP 496 DI 10.1016/j.neuron.2009.02.003 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 413TV UT WOS:000263816300002 PM 19249268 ER PT J AU Sacks, FM Bray, GA Carey, VJ Smith, SR Ryan, DH Anton, SD McManus, K Champagne, CM Bishop, LM Laranjo, N Leboff, MS Rood, JC de Jonge, L Greenway, FL Loria, CM Obarzanek, E Williamson, DA AF Sacks, Frank M. Bray, George A. Carey, Vincent J. Smith, Steven R. Ryan, Donna H. Anton, Stephen D. McManus, Katherine Champagne, Catherine M. Bishop, Louise M. Laranjo, Nancy Leboff, Meryl S. Rood, Jennifer C. de Jonge, Lilian Greenway, Frank L. Loria, Catherine M. Obarzanek, Eva Williamson, Donald A. TI Comparison of Weight-Loss Diets with Different Compositions of Fat, Protein, and Carbohydrates. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR RISK-FACTORS; MONOUNSATURATED FAT; BODY-COMPOSITION; HEART-DISEASE; GLYCEMIC LOAD; VEGAN DIET; OBESITY; WOMEN; MAINTENANCE AB Background: The possible advantage for weight loss of a diet that emphasizes protein, fat, or carbohydrates has not been established, and there are few studies that extend beyond 1 year. Methods: We randomly assigned 811 overweight adults to one of four diets; the targeted percentages of energy derived from fat, protein, and carbohydrates in the four diets were 20, 15, and 65%; 20, 25, and 55%; 40, 15, and 45%; and 40, 25, and 35%. The diets consisted of similar foods and met guidelines for cardiovascular health. The participants were offered group and individual instructional sessions for 2 years. The primary outcome was the change in body weight after 2 years in two-by-two factorial comparisons of low fat versus high fat and average protein versus high protein and in the comparison of highest and lowest carbohydrate content. Results: At 6 months, participants assigned to each diet had lost an average of 6 kg, which represented 7% of their initial weight; they began to regain weight after 12 months. By 2 years, weight loss remained similar in those who were assigned to a diet with 15% protein and those assigned to a diet with 25% protein (3.0 and 3.6 kg, respectively); in those assigned to a diet with 20% fat and those assigned to a diet with 40% fat (3.3 kg for both groups); and in those assigned to a diet with 65% carbohydrates and those assigned to a diet with 35% carbohydrates (2.9 and 3.4 kg, respectively) (P>0.20 for all comparisons). Among the 80% of participants who completed the trial, the average weight loss was 4 kg; 14 to 15% of the participants had a reduction of at least 10% of their initial body weight. Satiety, hunger, satisfaction with the diet, and attendance at group sessions were similar for all diets; attendance was strongly associated with weight loss (0.2 kg per session attended). The diets improved lipid-related risk factors and fasting insulin levels. Conclusions: Reduced-calorie diets result in clinically meaningful weight loss regardless of which macronutrients they emphasize. (ClinicalTrials.gov number, NCT00072995.) N Engl J Med 2009;360:859-73. C1 [Sacks, Frank M.; Bishop, Louise M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sacks, Frank M.; Carey, Vincent J.; Laranjo, Nancy] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Leboff, Meryl S.] Brigham & Womens Hosp, Dept Med, Div Endocrine, Boston, MA USA. [McManus, Katherine] Harvard Univ, Sch Med, Boston, MA USA. [McManus, Katherine] Brigham & Womens Hosp, Dept Nutr, Boston, MA 02115 USA. [Bray, George A.; Smith, Steven R.; Ryan, Donna H.; Anton, Stephen D.; Champagne, Catherine M.; Rood, Jennifer C.; de Jonge, Lilian; Greenway, Frank L.; Williamson, Donald A.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Loria, Catherine M.; Obarzanek, Eva] NHLBI, Bethesda, MD 20892 USA. RP Sacks, FM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RI Biguzzi, Felipe/E-4724-2015; OI de Jonge, Lilian/0000-0001-5900-0695 FU National Heart, Lung, and Blood Institute [HL073286]; General Clinical Research Center, National Institutes of Health [RR-02635]; Anian; Bristol-Myers Squibb; Clarus Health; Encore Pharmaceutical; Leptos Biomedical; MDRNA; Nuovo Nordisk; General Nutrition Corporation; Catalyst; Jenny Craig; Orexigen; Lithera; Basic Research; BAROnova; Lazard; Biologene FX Supported by grants from the National Heart, Lung, and Blood Institute (HL073286) and the General Clinical Research Center, National Institutes of Health (RR-02635). Dr. Greenway reports receiving consulting fees from or serving on a paid advisory board for Anian, Bristol-Myers Squibb, Clarus Health, Encore Pharmaceutical, Leptos Biomedical, MDRNA, Nuovo Nordisk, General Nutrition Corporation, Catalyst, Jenny Craig, Orexigen, Lithera, and Basic Research, receiving lecture fees from BAROnova, Lazard, and Biologene, and owning equity in Lithera. No other potential conflict of interest relevant to this article was reported. NR 44 TC 688 Z9 702 U1 23 U2 201 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 26 PY 2009 VL 360 IS 9 BP 859 EP 873 DI 10.1056/NEJMoa0804748 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 411CD UT WOS:000263624700004 PM 19246357 ER PT J AU Tsujimoto, S Genovesio, A Wise, SP AF Tsujimoto, Satoshi Genovesio, Aldo Wise, Steven P. TI Monkey Orbitofrontal Cortex Encodes Response Choices Near Feedback Time SO JOURNAL OF NEUROSCIENCE LA English DT Article DE decision; feedback; monitoring; evaluation; frontal lobe; prefrontal cortex ID MEDIAL PREFRONTAL CORTEX; MIXED-STRATEGY GAME; DECISION-MAKING; REWARD PREFERENCE; NEURONAL-ACTIVITY; ECONOMIC VALUE; SPATIAL GOALS; REPRESENTATION; RATS; PERFORMANCE AB The primate prefrontal cortex contributes to stimulus-guided behavior, but the functional specializations among its areas remain uncertain. To better understand such specializations, we contrasted neuronal activity in the dorsolateral prefrontal cortex (PFdl) and the orbital prefrontal cortex (PFo). The task required rhesus monkeys to use a visual cue to choose a saccade target. Some cues instructed the monkeys to repeat their most recent response; others instructed them to change it. Responses were followed by feedback: fluid reward if correct, visual feedback if incorrect. Previous studies, using different tasks, have reported that PFo neurons did not encode responses. We found PFo did encode responses in this task, but only near feedback time, after the response had been completed. PFdl differed from PFo in several respects. As reported previously, some PFdl neurons encoded responses from the previous trial and others encoded planned responses. PFo neurons did not have these properties. After feedback, PFdl encoded rewarded responses better than unrewarded ones and thus combined response and outcome information. PFo, in contrast, encoded the responses chosen, rewarded or not. These findings suggest that PFdl and PFo contribute differently to response knowledge, with PFo using an outcome-independent signal to monitor current responses at feedback time. C1 [Tsujimoto, Satoshi] Kobe Univ, Grad Sch Human Dev & Environm, Dept Hlth Promot & Educ, Dev Cognit Neurosci Lab,Nada Ku, Kobe, Hyogo 6578501, Japan. [Tsujimoto, Satoshi; Genovesio, Aldo; Wise, Steven P.] NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. [Genovesio, Aldo] Univ Roma La Sapienza, Dept Physiol & Pharmacol, I-00185 Rome, Italy. RP Tsujimoto, S (reprint author), Kobe Univ, Grad Sch Human Dev & Environm, Dept Hlth Promot & Educ, Dev Cognit Neurosci Lab,Nada Ku, 3-11 Tsurukabuto, Kobe, Hyogo 6578501, Japan. RI Tsujimoto, Satoshi/B-8223-2011 FU Division of Intramural Research of the National Institute of Mental Health [Z01MH-01092]; Japan Society for the Promotion of Science FX This work was supported by the Division of Intramural Research of the National Institute of Mental Health (Z01MH-01092). S. T. was supported by a Research Fellowship from the Japan Society for the Promotion of Science. We thank Dr. Andrew R. Mitz for engineering support, James Fellows for assistance in animal training, and Ping Yu for preparing the histological material. We also thank Dr. Paul Cisek for constructive comments and suggestions. NR 31 TC 44 Z9 44 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 25 PY 2009 VL 29 IS 8 BP 2569 EP 2574 DI 10.1523/JNEUROSCI.5777-08.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 412IX UT WOS:000263719600026 PM 19244532 ER PT J AU Hamouda, ABH Stasevich, TJ Pimpinelli, A Einstein, TL AF Hamouda, Ajmi B. H. Stasevich, T. J. Pimpinelli, Alberto Einstein, T. L. TI Effects of impurities on surface morphology: some examples SO JOURNAL OF PHYSICS-CONDENSED MATTER LA English DT Article ID TERRACE-WIDTH DISTRIBUTIONS; MANY-BODY PROBLEM; THIN-FILM GROWTH; ONE DIMENSION; STATISTICAL THEORY; VICINAL SURFACES; COMPLEX SYSTEMS; BROWNIAN-MOTION; ENERGY LEVELS; EPITAXIAL-GROWTH AB Small amounts of impurities are known to have remarkably great influence on surface morphology. We discuss three examples that arise in our research. First, we consider impurities codeposited during epitaxial growth, paying particular attention to Cu(100). After many layers of growth, the impurities can dramatically alter the surface morphology, changing the wavelength of the meandering instability and producing small square-base pyramids. Second, we consider the decoration of both island and vacancy island edges on Ag(111) with C-60. We use this system as a prototype to model how edge decoration with impurities can have a striking effect on the shape of the island as well as the dynamics of edge fluctuations. Finally, we show that about one per cent of pentacene quinone impurities alters the size of the critical nucleus in submonolayer pentacene deposition. This provides a platform on which to discuss our recent work characterizing the capture-zone distribution associated with the islands in terms of the generalized Wigner distribution, a simple one-parameter expression in which the characteristic exponent is the size of the smallest stable island. C1 [Hamouda, Ajmi B. H.; Stasevich, T. J.; Pimpinelli, Alberto; Einstein, T. L.] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Hamouda, Ajmi B. H.; Pimpinelli, Alberto] Univ Clermont Ferrand, NRS, LASMEA, UMR 6602, F-63177 Aubiere, France. [Stasevich, T. J.] NCI, Fluorescence Imaging Facil, LRBGE, NIH, Bethesda, MD 20892 USA. RP Hamouda, ABH (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. EM hammouda@umd.edu; stasevicht@mail.nih.gov; alpimpin@univ-bpclermont.fr; einstein@umd.edu RI Pimpinelli, Alberto/A-7928-2008; OI Pimpinelli, Alberto/0000-0002-3237-9807; Einstein, Theodore L./0000-0001-6031-4923 FU NSF-MRSEC [DMR 05-20471]; Center for Nanophysics and Advanced Materials (CNAM); DOE CMSN [DEFG0205ER46227] FX Work at U. of Maryland was supported by the NSF-MRSEC, Grant DMR 05-20471, with ancillary support from the Center for Nanophysics and Advanced Materials (CNAM) and DOE CMSN grant DEFG0205ER46227. We benefited greatly from our interactions with Ellen D Williams, John D Weeks, and Raymond J Phaneuf, and their groups, especially Brad Conrad and Chenggang Tao, and with Rajesh Sathiyanarayanan. ABHH and AP thank P E Hoggan and the late H- J Ernst for helpful exchanges. We are particularly grateful to B R Conrad and E D Williams for permission to use two unpublished figures from his dissertation research. NR 73 TC 7 Z9 7 U1 0 U2 9 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0953-8984 EI 1361-648X J9 J PHYS-CONDENS MAT JI J. Phys.-Condes. Matter PD FEB 25 PY 2009 VL 21 IS 8 AR 084215 DI 10.1088/0953-8984/21/8/084215 PG 10 WC Physics, Condensed Matter SC Physics GA 400VL UT WOS:000262897400016 ER PT J AU Hayashi, T Gray, CS Chan, M Tawatao, RI Ronacher, L McGargill, MA Datta, SK Carson, DA Corr, M AF Hayashi, Tomoko Gray, Christine S. Chan, Michael Tawatao, Rommel I. Ronacher, Lisa McGargill, Maureen A. Datta, Sandip K. Carson, Dennis A. Corr, Maripat TI Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE arthritis; encephalomyelitis; synthetic agonist ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ENDOTOXIN TOLERANCE; MYD88-INDEPENDENT PATHWAYS; MULTIPLE-SCLEROSIS; UP-REGULATION; IRAK-M; ACTIVATION; IMMUNITY; CELLS; TLR7 AB Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases. C1 [Hayashi, Tomoko; Gray, Christine S.; Chan, Michael; Tawatao, Rommel I.; Carson, Dennis A.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Ronacher, Lisa; Corr, Maripat] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [McGargill, Maureen A.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. [Datta, Sandip K.] NIAID, NIH, Bethesda, MD 20892 USA. RP Carson, DA (reprint author), Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. EM dcarson@ucsd.edu; mpcorr@ucsd.edu OI Datta, Sandip/0000-0003-0243-7815 FU National Institutes of Health [5 U01 AI056453, CA119335]; National Institute of Allergy and Infectious Diseases; Arthritis Foundation FX This work was funded in part by National Institutes of Health Grants 5 U01 AI056453 and CA119335, the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and the Arthritis Foundation. NR 39 TC 42 Z9 46 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2009 VL 106 IS 8 BP 2764 EP 2769 DI 10.1073/pnas.0813037106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411ME UT WOS:000263652900054 PM 19188597 ER PT J AU Miyagi, E Andrew, AJ Kao, S Strebel, K AF Miyagi, Eri Andrew, Amy J. Kao, Sandra Strebel, Klaus TI Vpu enhances HIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CD317; host restriction; tetherin; virus assembly ID INTEGRAL MEMBRANE-PROTEIN; TYPE-1 VPU; MOLECULAR-CLONING; PARTICLE RELEASE; INHIBITS HIV-1; IDENTIFICATION; MACROPHAGES; EXPRESSION; GENE; GAG AB HIV-1 Vpu enhances the release of virions from infected cells. Recent work identified Bst-2/CD317/tetherin as a host factor whose inhibitory activity on viral release is counteracted by Vpu. A current working model proposes that Bst-2 inhibits virus release by tethering viral particles to the cell surface. Here, we analyzed endogenous Bst-2 with respect to its effect on virus release from HeLa cells, T cells, and macrophages. We noted significant cell type-dependent variation in Bst-2 expression. Vpu caused a reduction in Bst-2 expression in transfected HeLa cells and long-term infected macrophages. However, Vpu expression did not result in cell surface down-modulation of Bst-2 or a reduction in intracellular Bst-2 expression in CEMx174 or H9 cells, yet virus replication in these cells was Vpu-responsive. Surprisingly, Bst-2 was undetectable in cell-free virions that were recovered from the surface of HeLa cells by physical shearing, suggesting that a tethering model may not explain all of the functional properties of Bst-2. Taken together we conclude that enhancement of virus release by Vpu does not, at least in CEMx174 and H9 cells, require cell surface down-modulation or intracellular depletion of Bst-2, nor does it entail exclusion of Bst-2 from viral particles. C1 [Miyagi, Eri; Andrew, Amy J.; Kao, Sandra; Strebel, Klaus] NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bldg 4,Room 310,4 Ctr Dr MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU National Institutes of Health Intramural AIDS Targeted Antiviral Program; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX We thank Mohammad Khan, Ritu Goila-Gaur, Robert Walker, and Ronald Willey for helpful discussion and critical comments. We thank Jason Brenchley for help with cell sorting, Bernard Lafont for help with FACS, and Kathleen Clouse and Linda Tiffany ( Center for Drug Evaluation and Research, Beltsville, MD) for providing monocyte-derived macrophages. IFN alpha-2c was a generous gift from Kathryn C. Zoon ( National Institute of Allergy and Infectious Diseases, Bethesda, MD). This work was supported by a grant from the National Institutes of Health Intramural AIDS Targeted Antiviral Program ( to K. S.) and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 42 TC 162 Z9 166 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2009 VL 106 IS 8 BP 2868 EP 2873 DI 10.1073/pnas.0813223106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411ME UT WOS:000263652900072 PM 19196977 ER PT J AU Christen, WG Glynn, RJ Chew, EY Albert, CM Manson, JE AF Christen, William G. Glynn, Robert J. Chew, Emily Y. Albert, Christine M. Manson, Joann E. TI Folic Acid, Pyridoxine, and Cyanocobalamin Combination Treatment and Age-Related Macular Degeneration in Women The Women's Antioxidant and Folic Acid Cardiovascular Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID SUBFOVEAL CHOROIDAL NEOVASCULARIZATION; ACUTE MYOCARDIAL-INFARCTION; ENDOTHELIAL FUNCTION; PLASMA HOMOCYSTEINE; PHOTODYNAMIC THERAPY; SECONDARY PREVENTION; CIGARETTE-SMOKING; RANDOMIZED-TRIAL; CLINICAL-TRIAL; BETA-CAROTENE AB Background: Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of age-related macular degeneration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are lacking. Our objective was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)) therapy. Methods: We conducted a randomized, double-blind, placebo-controlled trial including 5442 female health care professionals 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. A total of 5205 of these women did not have a diagnosis of AMD at baseline and were included in this analysis. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) or placebo. Our main outcome measures included total AMD, defined as a self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity of 20/30 or worse attributable to this condition. Results: After an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group (relative risk, 0.66; 95% confidence interval, 0.47-0.93 [P=.02]). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (relative risk, 0.59; 95% confidence interval, 0.36-0.95 [P=.03]). Conclusions: These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD. Trial Registration: clinical trials. gov Identifier NCT00000161 C1 [Christen, William G.; Glynn, Robert J.; Albert, Christine M.; Manson, Joann E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med,Dept Med, Boston, MA 02215 USA. [Albert, Christine M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Cardiovasc Med, Boston, MA 02215 USA. [Glynn, Robert J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Manson, Joann E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. RP Christen, WG (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med,Dept Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. EM wchristen@rics.bwh.harvard.edu FU Intramural NIH HHS [Z99 EY999999]; NEI NIH HHS [EY 06633, R01 EY006633-11, R01 EY006633-12, R01 EY006633-13, R01 EY006633-14]; NHLBI NIH HHS [HL 46959, R01 HL046959, R01 HL046959-07, R01 HL046959-08, R01 HL046959-09, R01 HL046959-10, R01 HL046959-11, R01 HL046959-12, R01 HL046959-13]; NIDDK NIH HHS [P30 DK040561, P30 DK040561-13] NR 70 TC 64 Z9 67 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 23 PY 2009 VL 169 IS 4 BP 335 EP 341 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 410SW UT WOS:000263599600002 PM 19237716 ER PT J AU Chiao, EY Engels, EA Kramer, JR Pietz, K Henderson, L Giordano, TP Landgren, O AF Chiao, Elizabeth Y. Engels, Eric A. Kramer, Jennifer R. Pietz, Kenneth Henderson, Louise Giordano, Thomas P. Landgren, Ola TI Risk of Immune Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia Among 120 908 US Veterans With Hepatitis C Virus Infection SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HCV-ASSOCIATED THROMBOCYTOPENIA; ALPHA-INTERFERON TREATMENT; CHRONIC LIVER-DISEASE; UNITED-STATES; EXTRAHEPATIC MANIFESTATIONS; HEPATOCELLULAR-CARCINOMA; PREVALENCE; THERAPY; ERADICATION; EXPERIENCE AB Background: There is emerging evidence that hepatitis C virus (HCV) infection play a role in the etiology of immune thrombocytopenia purpura (ITP) and autoimmune hemolytic anemia (AIHA), both of which are severe autoimmune cytopenias. Methods: To determine if HCV infection increases the risk for ITP and AIHA, we calculated the incidence rates of ITP and AIHA among 120 691 HCV-infected and 454 905 matched HCV-uninfected US veterans who received diagnoses during the period 1997 to 2004. After excluding individuals with a prior diagnosis of a lymphoproliferative disease, human immunodeficiency virus, or cirrhosis, we fitted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of risks. Results: We found 296 ITP and 90 AIHA cases. Among HCV-infected vs HCV-uninfected persons, the overall incidence rates of ITP were 30.2 and 18.5 per 100 000 person-years, and for AIHA they were 11.4 and 5.0 per 100 000 person-years, respectively. Hepatitis C virus was associated with elevated risks for ITP (HR, 1.8; 95% CI, 1.4-2.3) and AIHA (HR, 2.8; 95% CI, 1.8-4.2). The ITP incidence was increased among both untreated and treated HCV-infected persons (HR, 1.7; 95%, CI, 1.3-2.2 and HR, 2.4; 95% CI, 1.5-3.7, respectively), whereas AIHA incidence was elevated only among treated HCV-infected persons (HR, 11.6; 95% CI, 7.0-19.3). Conclusions: Individuals infected with HCV are at an increased risk for ITP, whereas the development of AIHA seems to be associated with HCV treatment. It may be beneficial to test individuals newly diagnosed as having ITP for HCV infection. C1 [Chiao, Elizabeth Y.; Kramer, Jennifer R.; Pietz, Kenneth; Henderson, Louise; Giordano, Thomas P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Chiao, Elizabeth Y.; Kramer, Jennifer R.; Pietz, Kenneth; Henderson, Louise; Giordano, Thomas P.] Michael E DeBakey VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Hlth Serv Res & Dev Serv, Houston, TX 77030 USA. [Engels, Eric A.; Landgren, Ola] NCI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Chiao, EY (reprint author), Baylor Coll Med, Dept Med, 2002 Holcombe Rd, Houston, TX 77030 USA. EM echiao@bcm.edu FU Intramural Program of the National Cancer Institute; National Institutes of Health; Houston VA Health Services Research and Development Center of Excellence (HFP 90-020); National Cancer Institute; National Institutes of Health [K23CA124318]; Health Services Research and Development Service FX This material is based on work supported by the Intramural Program of the National Cancer Institute, National Institutes of Health, and in part by the Houston VA Health Services Research and Development Center of Excellence (HFP 90-020). Dr Chiao received support from the National Cancer Institute, National Institutes of Health, grant K23CA124318. Dr Kramer received support from the Health Services Research and Development Service, , grant MRP05315. Dr Giordano received support from the NatioOffice of Research and Development, Department of Veterans Affairsnal Institute of Mental Health, National Institutes of Health, grant K23MH67505. NR 44 TC 20 Z9 22 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 23 PY 2009 VL 169 IS 4 BP 357 EP 363 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 410SW UT WOS:000263599600005 PM 19237719 ER PT J AU Park, Y Leitzmann, MF Subar, AF Hollenbeck, A Schatzkin, A AF Park, Yikyung Leitzmann, Michael F. Subar, Amy F. Hollenbeck, Albert Schatzkin, Arthur TI Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID NON-HODGKINS-LYMPHOMA; RETIRED-PERSONS DIET; GROWTH-FACTOR I; VITAMIN-D; PROSTATE-CANCER; BREAST-CANCER; COLORECTAL-CANCER; ESOPHAGEAL CANCER; UNITED-STATES; AMERICAN-ASSOCIATION AB Background: Dairy food and calcium intakes have been hypothesized to play roles that differ among individual cancer sites, but the evidence has been limited and inconsistent. Moreover, their effect on cancer in total is unclear. Methods: Dairy food and calcium intakes in relation to total cancer as well as cancer at individual sites were examined in the National Institutes of Health (NIH)-AARP ( formerly known as the American Association of Retired Persons) Diet and Health Study. Intakes of dairy food and calcium from foods and supplements were assessed with a food frequency questionnaire. Incident cancer cases were identified through linkage with state cancer registries. A Cox proportional hazard model was used to estimate relative risks and 2-sided 95% confidence intervals (CIs). Results: During an average of 7 years of follow-up, we identified 36 965 and 16 605 cancer cases in men and women, respectively. Calcium intake was not related to total cancer in men but was nonlinearly associated with total cancer in women: the risk decreased up to approximately 1300 mg/d, above which no further risk reduction was observed. In both men and women, dairy food and calcium intakes were inversely associated with cancers of the digestive system (multivariate relative risk for the highest quintile of total calcium vs the lowest, 0.84; 95% CI, 0.77-0.92 in men, and 0.77; 95% CI, 0.69-0.91 in women). Decreased risk was particularly pronounced with colorectal cancer. Supplemental calcium intake was also inversely associated with colorectal cancer risk. Conclusion: Our study suggests that calcium intake is associated with a lower risk of total cancer and cancers of the digestive system, especially colorectal cancer. C1 [Park, Yikyung] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20852 USA. [Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20852 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Park, Y (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 6120 Execut Blvd, Bethesda, MD 20852 USA. EM parkyik@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Cancer Institute; National Institutes of Health FX d The study was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 59 TC 78 Z9 78 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 23 PY 2009 VL 169 IS 4 BP 391 EP 401 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 410SW UT WOS:000263599600010 PM 19237724 ER PT J AU Doyle, AD Wang, FW Matsumoto, K Yamada, KM AF Doyle, Andrew D. Wang, Francis W. Matsumoto, Kazue Yamada, Kenneth M. TI One-dimensional topography underlies three-dimensional fibrillar cell migration SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SELECTIVE STABILIZATION; FIBROBLAST MOVEMENT; FOCAL ADHESIONS; MATRIX; 3D; MICROTUBULES; ATTACHMENT; LOCOMOTION; ACTOMYOSIN; SUBSTRATE AB Current concepts of cell migration were established in regular two-dimensional (2D) cell culture, but the roles of topography are poorly understood for cells migrating in an oriented 3D fibrillar extracellular matrix (ECM). We use a novel micropatterning technique termed microphotopatterning (mu PP) to identify functions for 1D fibrillar patterns in 3D cell migration. In striking contrast to 2D, cell migration in both 1D and 3D is rapid, uniaxial, independent of ECM ligand density, and dependent on myosin II contractility and microtubules (MTs). 1D and 3D migration are also characterized by an anterior MT bundle with a posterior centrosome. We propose that cells migrate rapidly through 3D fibrillar matrices by a 1D migratory mechanism not mimicked by 2D matrices. C1 [Doyle, Andrew D.; Matsumoto, Kazue; Yamada, Kenneth M.] Natl Inst Dental & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Wang, Francis W.] Natl Inst Stand & Technol, Div Polymers, Mat Sci & Engn Lab, Gaithersburg, MD 20899 USA. RP Doyle, AD (reprint author), Natl Inst Dental & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM adoyle@mail.nih.gov; kyamada@mail.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 FU National Institute of Dental; National Institutes of Health FX Support was provided by the intramural research program of the National Institute of Dental and Craniofacial Research at the National Institutes of Health. NR 26 TC 323 Z9 325 U1 3 U2 53 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD FEB 23 PY 2009 VL 184 IS 4 BP 481 EP 490 DI 10.1083/jcb.200810041 PG 10 WC Cell Biology SC Cell Biology GA 416OY UT WOS:000264016600004 PM 19221195 ER PT J AU Lehmann, T Hume, JCC Licht, M Burns, CS Wollenberg, K Simard, F Ribeiro, JMC AF Lehmann, Tovi Hume, Jen C. C. Licht, Monica Burns, Christopher S. Wollenberg, Kurt Simard, Fred Ribeiro, Jose M. C. TI Molecular Evolution of Immune Genes in the Malaria Mosquito Anopheles gambiae SO PLOS ONE LA English DT Article AB Background: As pathogens that circumvent the host immune response are favoured by selection, so are host alleles that reduce parasite load. Such evolutionary processes leave their signature on the genes involved. Deciphering modes of selection operating on immune genes might reveal the nature of host-pathogen interactions and factors that govern susceptibility in host populations. Such understanding would have important public health implications. Methodology/Findings: We analyzed polymorphisms in four mosquito immune genes (SP14D1, GNBP, defensin, and gambicin) to decipher selection effects, presumably mediated by pathogens. Using samples of Anopheles arabiensis, An. quadriannulatus and four An. gambiae populations, as well as published sequences from other Culicidae, we contrasted patterns of polymorphisms between different functional units of the same gene within and between populations. Our results revealed selection signatures operating on different time scales. At the most recent time scale, within-population diversity revealed purifying selection. Between populations and between species variation revealed reduced differentiation (GNBP and gambicin) at coding vs. noncoding-regions, consistent with balancing selection. McDonald-Kreitman tests between An. quadriannulatus and both sibling species revealed higher fixation rate of synonymous than nonsynonymous substitutions (GNBP) in accordance with frequency dependent balancing selection. At the longest time scale (>100 my), PAML analysis using distant Culicid taxa revealed positive selection at one codon in gambicin. Patterns of genetic variation were independent of exposure to human pathogens. Significance and Conclusions: Purifying selection is the most common form of selection operating on immune genes as it was detected on a contemporary time scale on all genes. Selection for "hypervariability" was not detected, but negative balancing selection, detected at a recent evolutionary time scale between sibling species may be rather common. Detection of positive selection at the deepest evolutionary time scale suggests that it occurs infrequently, possibly in association with speciation events. Our results provided no evidence to support the hypothesis that selection was mediated by pathogens that are transmitted to humans. C1 [Lehmann, Tovi; Licht, Monica; Burns, Christopher S.] Ctr Dis Control & Prevent, Entomol Branch, Div Parasit Dis, Chamblee, GA USA. [Lehmann, Tovi; Licht, Monica; Burns, Christopher S.] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Lehmann, Tovi; Hume, Jen C. C.; Burns, Christopher S.; Ribeiro, Jose M. C.] NIAID, NIH, Lab Malaria & Vector Res, Rockville, MD USA. [Wollenberg, Kurt] NIAID, NIH, Office Cyber Infrastructure & Computat Biol, Bioinformat & Computat Biosci Branch, Bethesda, MD USA. [Simard, Fred] Org lutte Contre grandes Endemies Afrique Cent, LabInst Rech Dev, RU 016, Yaounde, Cameroon. RP Lehmann, T (reprint author), Ctr Dis Control & Prevent, Entomol Branch, Div Parasit Dis, Chamblee, GA USA. EM TLehmann@niaid.nih.gov RI SIMARD, Frederic/J-9489-2016; OI SIMARD, Frederic/0000-0002-2871-5329; Ribeiro, Jose/0000-0002-9107-0818 FU UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR); Entomology Branch, Division of Parasitic Diseases, Centers for Disease Control and Prevention; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This research was supported in part by the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Entomology Branch, Division of Parasitic Diseases, Centers for Disease Control and Prevention, and by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 31 Z9 32 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 23 PY 2009 VL 4 IS 2 AR e4549 DI 10.1371/journal.pone.0004549 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437KU UT WOS:000265487200005 PM 19234606 ER PT J AU Roy, SW AF Roy, Scott William TI Phylogenomics: Gene Duplication, Unrecognized Paralogy and Outgroup Choice SO PLOS ONE LA English DT Article AB Comparative genomics has revealed the ubiquity of gene and genome duplication and subsequent gene loss. In the case of gene duplication and subsequent loss, gene trees can differ from species trees, thus frequent gene duplication poses a challenge for reconstruction of species relationships. Here I address the case of multi-gene sets of putative orthologs that include some unrecognized paralogs due to ancestral gene duplication, and ask how outgroups should best be chosen to reduce the degree of non-species tree (NST) signal. Consideration of expected internal branch lengths supports several conclusions: (i) when a single outgroup is used, the degree of NST signal arising from gene duplication is either independent of outgroup choice, or is minimized by use of a maximally closely related post-duplication (MCRPD) outgroup; (ii) when two outgroups are used, NST signal is minimized by using one MCRPD outgroup, while the position of the second outgroup is of lesser importance; and (iii) when two outgroups are used, the ability to detect gene trees that are inconsistent with known aspects of the species tree is maximized by use of one MCRPD, and is either independent of the position of the second outgroup, or is maximized for a more distantly related second outgroup. Overall, these results generalize the utility of closely-related outgroups for phylogenetic analysis. C1 [Roy, Scott William] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Roy, SW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM royscott@ncbi.nlm.nih.gov FU National Library of Medicine Internal Research Training Award FX National Library of Medicine Internal Research Training Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 7 Z9 7 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 23 PY 2009 VL 4 IS 2 AR e4568 DI 10.1371/journal.pone.0004568 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437KU UT WOS:000265487200019 PM 19234600 ER PT J AU Roy, SW AF Roy, Scott William TI Probing Evolutionary Repeatability: Neutral and Double Changes and the Predictability of Evolutionary Adaptation SO PLOS ONE LA English DT Article AB Background: The question of how organisms adapt is among the most fundamental in evolutionary biology. Two recent studies investigated the evolution of Escherichia coli in response to challenge with the antibiotic cefotaxime. Studying five mutations in the beta-lactamase gene that together confer significant antibiotic resistance, the authors showed a complex fitness landscape that greatly constrained the identity and order of intermediates leading from the initial wildtype genotype to the final resistant genotype. Out of 18 billion possible orders of single mutations leading from non-resistant to fully-resistant form, they found that only 27 (1.5x10(-7)%) pathways were characterized by consistently increasing resistance, thus only a tiny fraction of possible paths are accessible by positive selection. I further explore these data in several ways. Principal Findings: Allowing neutral changes (those that do not affect resistance) increases the number of accessible pathways considerably, from 27 to 629. Allowing multiple simultaneous mutations also greatly increases the number of accessible pathways. Allowing a single case of double mutation to occur along a pathway increases the number of pathways from 27 to 259, and allowing arbitrarily many pairs of simultaneous changes increases the number of possible pathways by more than 100 fold, to 4800. I introduce the metric 'repeatability,' the probability that two random trials will proceed via the exact same pathway. In general, I find that while the total number of accessible pathways is dramatically affected by allowing neutral or double mutations, the overall evolutionary repeatability is generally much less affected. Conclusions: These results probe the conceivable pathways available to evolution. Even when many of the assumptions of the analysis of Weinreich et al. (2006) are relaxed, I find that evolution to more highly cefotaxime resistant beta-lactamase proteins is still highly repeatable. C1 [Roy, Scott William] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Roy, SW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM royscott@ncbi.nlm.nih.gov FU National Institutes of Health Intramural Research Program FX National Institutes of Health Intramural Research Program NR 9 TC 5 Z9 5 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 23 PY 2009 VL 4 IS 2 AR e4500 DI 10.1371/journal.pone.0004500 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437KU UT WOS:000265487200002 PM 19234610 ER PT J AU Fontana, G Savona, G Rodriguez, B Dersch, CM Rothman, RB Prisinzano, TE AF Fontana, Gianfranco Savona, Giuseppe Rodriguez, Benjamin Dersch, Christina M. Rothman, Richard B. Prisinzano, Thomas E. TI Synthetic studies on neoclerodane diterpenes from Salvia splendens: oxidative modifications of ring A SO TETRAHEDRON LA English DT Article DE Salvia splendens; Opioid receptors; Neoclerodane diterpenes; Semisynthetic derivatives ID SALVINORIN-A ANALOGS; CLERODANE DITERPENOIDS; C(2) AB Salvinorin A (1), a neoclerodane diterpene from the hallucinogenic mint Salvia divinorum, is the only known naturally occurring non-nitrogenous and specific K-opioid agonist. Some oxidative modifications of the A ring in the congeners of 1 isolated from Salvia splendens salviarin, splenolide B, splendidin, and in the non-natural 8-epi-salviarin gave new derivatives, some of which were tested as agonists at opioid receptors. However, none of these compounds was active. The presence of the C-18. C-19 lactone could be at the origin of the observed lack of binding affinity. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Fontana, Gianfranco; Savona, Giuseppe] Univ Palermo, Dept Chim Organ E Paterno, I-90128 Palermo, Italy. [Rodriguez, Benjamin] CSIC, Inst Quim Organ, E-28006 Madrid, Spain. [Dersch, Christina M.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, IRP, NIH,DHHS, Baltimore, MD 21224 USA. [Prisinzano, Thomas E.] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. RP Savona, G (reprint author), Univ Palermo, Dept Chim Organ E Paterno, Parco Orleans 2, I-90128 Palermo, Italy. EM giussav@unipa.it; iqor107@iqog.csic.es RI Prisinzano, Thomas/B-7877-2010 FU Spanish 'Comision Interministerial de Ciencia y Tecnologia' (CICYT) [CTQ2006-15279-C02-02]; Italian 'Universita degli Studi di Palermo' ['Ex 60%-2005']; National Institute on Drug Abuse [R01DA018151]; NIH; DHHS FX This work was supported in part by funds from the Spanish 'Comision Interministerial de Ciencia y Tecnologia' (CICYT), grant No. CTQ2006-15279-C02-02, and from the Italian 'Universita degli Studi di Palermo', grant 'Ex 60%-2005', and R01DA018151 (to TEP) from the National Institute on Drug Abuse. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. Portions of this work were also supported by the Intramural Research Program, National Institute on Drug Abuse (NIDA), NIH, DHHS (RBR and CMD). NR 8 TC 3 Z9 4 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD FEB 21 PY 2009 VL 65 IS 8 BP 1708 EP 1715 DI 10.1016/j.tet.2008.12.009 PG 8 WC Chemistry, Organic SC Chemistry GA 406DU UT WOS:000263276000023 PM 21544261 ER PT J AU Yamada, A Suzuki, D Miyazono, A Oshima, K Kamiya, A Zhao, BH Takami, M Donnelly, RP Itabe, H Yamamoto, M Kimura, S Kamijo, R AF Yamada, Atsushi Suzuki, Dai Miyazono, Agasa Oshima, Kumiko Kamiya, Akihide Zhao, Baohong Takami, Masamichi Donnelly, Raymond P. Itabe, Hiroyuki Yamamoto, Matsuo Kimura, Shioko Kamijo, Ryutaro TI IFN-gamma down-regulates Secretoglobin 3A1 gene expression SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE SCGB3A1; Uteroglobin-related protein 2; IFN-gamma ID JAK-STAT PATHWAY; INTERFERON-GAMMA; EPITHELIAL-CELLS; INDUCTION; RECEPTOR; UGRP2; MOUSE; RESPONSES; PROTEINS; SCGB3A1 AB STAT1 mediates Interferon (IFN)-dependent positive and negative regulation of inflammatory gene expression in lung. In this Study, we examined the effect of IFN-gamma on the expression of SCGB3A1 which is thought to play crucial roles in inflammation and epithelial cell differentiation in lung. We found that expression of SCGB3A1 was down-regulated by IFN-gamma in a time- and dose-dependent manner in the murine transformed Clara Cells (mtCC) line. IFN-gamma induced the phosphorylation of STAT1, which binds to a STAT-binding element (SBE) in the SCGB3A1 gene promoter, leading to decreased transcriptional activation of this gene. (C) 2009 Elsevier Inc. All rights reserved, C1 [Yamada, Atsushi; Suzuki, Dai; Miyazono, Agasa; Zhao, Baohong; Takami, Masamichi; Kamijo, Ryutaro] Showa Univ, Sch Dent, Dept Biochem, Shinagawa Ku, Tokyo 1428555, Japan. [Yamada, Atsushi; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Miyazono, Agasa; Yamamoto, Matsuo] Showa Univ, Sch Dent, Dept Periodontol, Tokyo 1458515, Japan. [Oshima, Kumiko; Itabe, Hiroyuki] Showa Univ, Sch Pharm, Dept Biol & Chem, Shinagawa Ku, Tokyo 1428555, Japan. [Kamiya, Akihide] Univ Tokyo, Inst Med Sci, Ctr Stem Cell & Regenerat Med, Div Stem Cell Therapy,Minato Ku, Tokyo 1088639, Japan. [Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Yamada, A (reprint author), Showa Univ, Sch Dent, Dept Biochem, Shinagawa Ku, 1-5-8 Hatanodai, Tokyo 1428555, Japan. EM yamadaa@dent.showa-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Science FX We would like to thank Dr. J. Francesco DeMayo for providing mtCC cells. This work was supported in part by the 'High-Tech Research Center' Project for Private Universities matching fund subsidy from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid for Scientific research from the Japan Society for the Promotion of Science. NR 23 TC 4 Z9 4 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 20 PY 2009 VL 379 IS 4 BP 964 EP 968 DI 10.1016/j.bbrc.2008.12.187 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 407AT UT WOS:000263336700032 PM 19135978 ER PT J AU Stockwin, LH Yu, SX Stotler, H Hollingshead, MG Newton, DL AF Stockwin, Luke H. Yu, Sherry X. Stotler, Howard Hollingshead, Melinda G. Newton, Dianne L. TI ARC (NSC 188491) has identical activity to Sangivamycin (NSC 65346) including inhibition of both P-TEFb and PKC SO BMC CANCER LA English DT Article ID PROTEIN-KINASE-C; NUCLEOSIDE ANALOGS; TUMOR-CELLS; TOYOCAMYCIN; ANTIBIOTICS; FLUDARABINE; LEUKEMIA; AGENTS AB Background: The nucleoside analog, ARC (NSC 188491) is a recently characterized transcriptional inhibitor that selectively kills cancer cells and has the ability to perturb angiogenesis in vitro. In this study, the mechanism of action of ARC was further investigated by comparing in vitro and in vivo activity with other anti-neoplastic purines. Methods: Structure-based homology searches were used to identify those compounds with similarity to ARC. Comparator compounds were then evaluated alongside ARC in the context of viability, cell cycle and apoptosis assays to establish any similarities. Following this, biological overlap was explored in detail using gene-expression analysis and kinase inhibition assays. Results: Results demonstrated that sangivamycin, an extensively characterized pro-apoptotic nucleoside isolated from Streptomyces, had identical activity to ARC in terms of 1) cytotoxicity assays, 2) ability to induce a G(2)/M block, 3) inhibitory effects on RNA/DNA/protein synthesis, 4) transcriptomic response to treatment, 5) inhibition of protein kinase C, 6) inhibition of positive transcription elongation factor b (P-TEFb), 7) inhibition of VEGF secretion, and 8) activity within hollow fiber assays. Extending ARC activity to PKC inhibition provides a molecular basis for ARC cancer selectivity and anti-angiogenic effects. Furthermore, functional overlap between ARC and sangivamycin suggests that development of ARC may benefit from a retrospective of previous sangivamycin clinical trials. However, ARC was found to be inactive in several xenograft models, likely a consequence of rapid serum clearance. Conclusion: Overall, these data expand on the biological properties of ARC but suggest additional studies are required before it can be considered a clinical trials candidate. C1 [Stockwin, Luke H.; Yu, Sherry X.; Stotler, Howard; Newton, Dianne L.] NCI, Dev Therapeut Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Hollingshead, Melinda G.] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Newton, DL (reprint author), NCI, Dev Therapeut Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM Stockwin@ncifcrf.gov; xiaoxiayu@ncifcrf.gov; lstotler@ncifcrf.gov; hollingm@mail.nih.gov; dnewton@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [NO1-CO-12400] 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 No. NO1-CO-12400. 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 NR 30 TC 14 Z9 14 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD FEB 20 PY 2009 VL 9 AR 63 DI 10.1186/1471-2407-9-63 PG 13 WC Oncology SC Oncology GA 417HN UT WOS:000264067200002 PM 19232100 ER PT J AU Cam, HP Chen, ES Grewal, SIS AF Cam, Hugh P. Chen, Ee Sin Grewal, Shiv I. S. TI Transcriptional Scaffolds for Heterochromatin Assembly SO CELL LA English DT Article ID RNA; CHROMATIN; COMPLEX; GENES; ROLES AB Heterochromatin is dynamically regulated during the cell cycle and in response to developmental signals. Recent findings from diverse systems suggest an extensive role for transcription in the assembly of heterochromatin, highlighting the emerging theme that transcription and noncoding RNAs can provide the initial scaffold for the formation of heterochromatin, which serves as a versatile recruiting platform for diverse factors involved in many cellular processes. C1 [Cam, Hugh P.; Chen, Ee Sin; Grewal, Shiv I. S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Grewal, SIS (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov FU Intramural NIH HHS NR 20 TC 47 Z9 48 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 20 PY 2009 VL 136 IS 4 BP 610 EP 614 DI 10.1016/j.cell.2009.02.004 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 411XX UT WOS:000263688200013 PM 19239883 ER PT J AU Waters, LS Storz, G AF Waters, Lauren S. Storz, Gisela TI Regulatory RNAs in Bacteria SO CELL LA English DT Review ID SMALL NONCODING RNAS; PROVIDES ACQUIRED-RESISTANCE; OUTER-MEMBRANE PROTEINS; SOS-INDUCED TOXIN; ESCHERICHIA-COLI; MESSENGER-RNA; GENE-EXPRESSION; SOLUBLE-RNA; VIBRIO-CHOLERAE; ANTISENSE RNAS AB Bacteria possess numerous and diverse means of gene regulation using RNA molecules, including mRNA leaders that affect expression in cis, small RNAs that bind to proteins or base pair with target RNAs, and CRISPR RNAs that inhibit the uptake of foreign DNA. Although examples of RNA regulators have been known for decades in bacteria, we are only now coming to a full appreciation of their importance and prevalence. Here, we review the known mechanisms and roles of regulatory RNAs, highlight emerging themes, and discuss remaining questions. C1 [Waters, Lauren S.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM storz@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 FU Intramural Research Program of NICHD; PRAT program of NIGMS FX We appreciate the comments from many colleagues. This work was supported by the Intramural Research Program of NICHD and a fellowship from the PRAT program of NIGMS ( L. S. W.). NR 119 TC 717 Z9 744 U1 23 U2 286 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 20 PY 2009 VL 136 IS 4 BP 615 EP 628 DI 10.1016/j.cell.2009.01.043 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 411XX UT WOS:000263688200014 PM 19239884 ER PT J AU Sonenberg, N Hinnebusch, AG AF Sonenberg, Nahum Hinnebusch, Alan G. TI Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets SO CELL LA English DT Review ID MESSENGER-RNA TRANSLATION; CAP-INDEPENDENT TRANSLATION; TERM SYNAPTIC PLASTICITY; 40S RIBOSOMAL-SUBUNIT; START CODON SELECTION; DIET-INDUCED OBESITY; CAENORHABDITIS-ELEGANS; PROTEIN-SYNTHESIS; INHIBITS TRANSLATION; BINDING-PROTEIN AB Translational control in eukaryotic cells is critical for gene regulation during nutrient deprivation and stress, development and differentiation, nervous system function, aging, and disease. We describe recent advances in our understanding of the molecular structures and biochemical functions of the translation initiation machinery and summarize key strategies that mediate general or gene-specific translational control, particularly in mammalian systems. C1 [Sonenberg, Nahum] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada. [Sonenberg, Nahum] McGill Univ, Goodman Canc Ctr, Montreal, PQ H3G 1Y6, Canada. [Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Sonenberg, N (reprint author), McGill Univ, Dept Biochem, 3655 Drummond St, Montreal, PQ H3G 1Y6, Canada. EM nahum.sonenberg@mcgill.ca; alanh@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; Canadian Institutes of Health Research; The National Cancer Institute of Canada; Howard Hughes Medical Institute; National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Institutes of Health ( A. G. H.) and the Canadian Institutes of Health Research, The National Cancer Institute of Canada, the Howard Hughes Medical Institute, and the National Institutes of Health ( N. S.). NR 143 TC 1142 Z9 1161 U1 18 U2 165 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 20 PY 2009 VL 136 IS 4 BP 731 EP 745 DI 10.1016/j.cell.2009.01.042 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 411XX UT WOS:000263688200022 PM 19239892 ER PT J AU Brown, JR Yang, F Sinha, A Ramakrishnan, B Tor, Y Qasba, PK Esko, JD AF Brown, Jillian R. Yang, Feng Sinha, Anjana Ramakrishnan, Boopathy Tor, Yitzhak Qasba, Pradman K. Esko, Jeffrey D. TI Deoxygenated Disaccharide Analogs as Specific Inhibitors of beta 1-4-Galactosyltransferase 1 and Selectin-mediated Tumor Metastasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIALYL-LEWIS-X; CRYSTAL-STRUCTURE; ACCEPTOR SPECIFICITY; LACTOSE SYNTHASE; CELL-ADHESION; UDP-GAL; BETA-1,4-GALACTOSYLTRANSFERASE; GLYCOSYLATION; COMPLEX; MICE AB The disaccharide peracetylated GlcNAc beta 1-3Gal beta-O-naphthalenemethanol (disaccharide 1) diminishes the formation of the glycan sialyl Lewis X (Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)Glc-NAc; sLe(X)) in tumor cells. Previous studies showed that the mechanism of action of disaccharide 1 involves three steps: (i) deacetylation by carboxyesterases, (ii) action as a biosynthetic intermediate for downstream enzymes involved in sLe(X) assembly, and (iii) generation of several glycans related to sLe(X). In this report, we show that GlcNAc beta 1-3Gal beta-O-naphthalenemethanol binds to the acceptor site of human beta 1-4-galactosyltransferase much like the acceptor trisaccharide, GlcNAc beta 1-2Man beta 1-6Man, which is present on N-linked glycans. The 4'-deoxy analog, in which the acceptor hydroxyl group was replaced by -H, did not act as a substrate but instead acted as a competitive inhibitor of the enzyme. The acetylated form of this compound inhibited sLe(X) formation in U937 monocytic leukemia cells, suggesting that it had inhibitory activity in vivo as well. A series of synthetic acetylated analogs of 1 containing -H, -F, -N(3), -NH(2), or -OCH(3) instead of the hydroxyl groups at C-3'- and C-4'-positions of the terminal N-acetylglucosamine residue also blocked sLe(X) formation in cells. The reduction of sLe(X) by the 4'-deoxy analog also diminished experimental tumor metastasis by Lewis lung carcinoma in vivo. These data suggest that nonsubstrate disaccharides have therapeutic potential through their ability to bind to glycosyltransferases in vivo and to alter glycan-dependent pathologic processes. C1 [Brown, Jillian R.; Yang, Feng; Sinha, Anjana; Esko, Jeffrey D.] Univ Calif San Diego, Dept Cellular & Mol Med, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA. [Tor, Yitzhak] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Ramakrishnan, Boopathy] Nanobiol Program, Struct Glycobiol Sect, Frederick, MD 21702 USA. [Ramakrishnan, Boopathy] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Esko, JD (reprint author), Univ Calif San Diego, Dept Cellular & Mol Med, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA. EM jesko@ucsd.edu FU National Institutes of Health [CA46462, CA112278, N01-CO-12400]; Intramural Research Program of the National Institutes of Health; NCI, Center for Cancer Research FX This work was supported, in whole or in part, by National Institutes of Health Grants CA46462 and CA112278 (to J. D. E.) and by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. The crystallographic part of this project has been funded, in whole or in part, with federal funds from NCI, National Institutes of Health, under Contract N01-CO-12400. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 36 TC 23 Z9 25 U1 0 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 20 PY 2009 VL 284 IS 8 BP 4952 EP 4959 DI 10.1074/jbc.M805782200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 408DY UT WOS:000263416600025 PM 19106107 ER PT J AU Sargent, D Sobrero, A Grothey, A O'Connell, MJ Buyse, M Andre, T Zheng, Y Green, E Labianca, R O'Callaghan, C Seitz, JF Francini, G Haller, D Yothers, G Goldberg, R de Gramont, A AF Sargent, Daniel Sobrero, Alberto Grothey, Axel O'Connell, Michael J. Buyse, Marc Andre, Thierry Zheng, Yan Green, Erin Labianca, Roberto O'Callaghan, Chris Seitz, Jean Francois Francini, Guido Haller, Daniel Yothers, Greg Goldberg, Richard de Gramont, Aimery TI Evidence for Cure by Adjuvant Therapy in Colon Cancer: Observations Based on Individual Patient Data From 20,898 Patients on 18 Randomized Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FLUOROURACIL; CHEMOTHERAPY; LEUCOVORIN; BREAST; OXALIPLATIN; LEVAMISOLE; CARCINOMA; DISEASE AB Purpose Limited data are available on the time course of treatment failures (recurrence and/or death), the nature and duration of adjuvant treatment benefit, and long-term recurrence rates in patients with resected stage II and III colon cancer. Methods The data set assembled by the Adjuvant Colon Cancer Endpoints Group, a collection of individual patient data from 18 trials and more than 20,800 patients testing fluorouracil-based adjuvant therapy in patients with stage II or III colon cancer, was analyzed. Results A significant overall survival (OS) benefit of adjuvant therapy was consistent over the 8-year follow-up period. The risk of recurrence in patients treated with adjuvant chemotherapy never exceeds that of control patients, signifying that adjuvant therapy cures some patients, as opposed to delaying recurrence. After 5 years, recurrence rates were less than 1.5% per year, and after 8 years, they were less than 0.5% per year. Significant disease-free survival (DFS) benefit from adjuvant chemotherapy was observed in the first 2 years. After 2 years, DFS rates in treated and control patients were not significantly different, and after 4 years, no trend toward benefit was demonstrated. This benefit was primarily driven by patients with stage III disease. Conclusion Adjuvant chemotherapy provides significant DFS benefit, primarily by reducing the recurrence rate, within the first 2 years of adjuvant therapy with some benefit in years 3 to 4, translating into long-term OS benefit. This reflects the curative role of chemotherapy in the adjuvant setting. After 5 years, recurrence rates in patients treated on clinical trials are low, and after 8 years, they are minimal; thus, long-term follow-up for recurrence is of little value. C1 Mayo Clin, Div Biostat & Med Oncol, Rochester, MN 55905 USA. Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. Operat Off & Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Univ N Carolina, Chapel Hill, NC USA. Osped San Martino Genova, Genoa, Italy. Univ Siena, I-53100 Siena, Italy. Osped Riuniti Bergamo, I-24100 Bergamo, Italy. Int Inst Drug Dev, Louvain, Belgium. Hop La Pitie Salpetriere, Paris, France. Univ Mediterranean, Marseille, France. Hop St Antoine, F-75571 Paris, France. Queens Univ, Natl Canc Inst, Canada Clin Trials Grp, Kingston, ON, Canada. RP Sargent, D (reprint author), Mayo Clin, Div Biomed Stat & Informat, 200 1st St SW, Rochester, MN 55905 USA. EM sargent.daniel@mayo.edu RI Labianca, Roberto/N-1847-2016; OI Labianca, Roberto/0000-0001-7149-822X; Yothers, Greg/0000-0002-7965-7333; Sargent, Daniel/0000-0002-2684-4741 FU National Cancer Institute [CA 25224, CA 12027, CA 69974, CA 37377, CA 69651] FX Supported by National Cancer Institute Grants No. CA 25224, CA 12027, CA 69974, CA 37377, and CA 69651. NR 20 TC 183 Z9 191 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2009 VL 27 IS 6 BP 872 EP 877 DI 10.1200/JCO.2008.19.5362 PG 6 WC Oncology SC Oncology GA 409NR UT WOS:000263513000007 PM 19124803 ER PT J AU Bellizzi, KM Rowland, JH Arora, NK Hamilton, AS Miller, MF Aziz, NM AF Bellizzi, Keith M. Rowland, Julia H. Arora, Neeraj K. Hamilton, Ann S. Miller, Melissa Farmer Aziz, Noreen M. TI Physical Activity and Quality of Life in Adult Survivors of Non-Hodgkin's Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PROSTATE-CANCER SURVIVORS; HIGH-DOSE CHEMOTHERAPY; TRANSTHEORETICAL MODEL; PUBLIC-HEALTH; EXERCISE; BREAST; BEHAVIORS; METAANALYSIS; PREVALENCE AB Purpose To examine the prevalence and correlates of physical activity in adult survivors of aggressive non-Hodgkin's Lymphoma (NHL) and to explore the association between physical activity level and health-related quality of life (HRQOL). Patients and Methods Physical activity and HRQOL data from 319 survivors of NHL (mean age, 59.8 years, standard deviation, +/- 14.8) who were diagnosed in Los Angeles County approximately 2 to 5 years before the study was analyzed. Results One quarter of survivors of NHL met public health guidelines of 150 minutes or more of moderate to vigorous exercise per week. More than half (53%) reported some activity but less than 150 minutes per week, whereas 20% reported no physical activity. Females, those with lower perceived health competence, and individuals with more comorbid limitations were at increased risk for inactivity. Individuals who met public health guidelines reported better HRQOL than those who were sedentary. Interestingly, our findings suggest a significant positive association between HRQOL and those who get at least some exercise. Conclusion The effort to promote physical activity among cancer survivors, who are at risk for poor quality of life as a result of treatment, is of great importance to the health of this growing population. As NHL, similar to other cancers, becomes a disease that people live with as opposed to one that people die as a result of, oncologists and primary care physicians will be increasingly challenged to provide evidence-based guidance for the long-term management of the patient's health. Consideration should be given to how clinicians frame exercise-promoting messages to cancer survivors, especially to those who are sedentary. C1 [Bellizzi, Keith M.] Univ Connecticut, Dept Human Dev & Family Studies, Storrs, CT 06269 USA. Off Canc Survivorship, Bethesda, MD USA. Canc Prevent Fellowship Program, Bethesda, MD USA. NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. RP Bellizzi, KM (reprint author), Univ Connecticut, Dept Human Dev & Family Studies, 348 Mansfield Rd,Unit 2058, Storrs, CT 06269 USA. EM Keith.M.Bellizzi@Uconn.edu FU California Department of Health Services [103885]; National Cancer Institute Surveillance, Epidemiology, and End Results Program [N01-PC-35139, N02-PC-15105]; Centers for Disease Control and Prevention [U55/CCR921930-02] FX Supported in part by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; by National Cancer Institute Surveillance, Epidemiology, and End Results Program Contract No. N01-PC-35139 awarded to the University of Southern California and Contract No. N02-PC-15105 awarded to the Public Health Institute; and by Centers for Disease Control and Prevention National Program of Cancer Registries Agreement No. U55/CCR921930-02 awarded to the Public Health Institute. NR 52 TC 40 Z9 40 U1 1 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2009 VL 27 IS 6 BP 960 EP 966 DI 10.1200/JCO.2008.17.5026 PG 7 WC Oncology SC Oncology GA 409NR UT WOS:000263513000020 PM 19139438 ER PT J AU Chaturvedi, AK Kleinerman, RA Hildesheim, A Gilbert, ES Storm, H Lynch, CF Hall, P Langmark, F Pukkala, E Kaijser, M Andersson, M Fossa, SD Joensuu, H Travis, LB Engels, EA AF Chaturvedi, Anil K. Kleinerman, Ruth A. Hildesheim, Allan Gilbert, Ethel S. Storm, Hans Lynch, Charles F. Hall, Per Langmark, Froydis Pukkala, Eero Kaijser, Magnus Andersson, Michael Fossa, Sophie D. Joensuu, Heikki Travis, Lois B. Engels, Eric A. TI Second Cancers After Squamous Cell Carcinoma and Adenocarcinoma of the Cervix SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS; UTERINE CERVIX; LUNG-CANCER; UNITED-STATES; RISK-FACTORS; INTERNATIONAL COLLABORATION; INCIDENCE TRENDS; TOBACCO SMOKING; WOMEN; INFECTIONS AB Purpose Although cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) are both caused by human papillomavirus (HPV) infection, they differ in cofactors such as cigarette smoking. We assessed whether these cofactor differences translate into differences in second cancer risk. Patients and Methods We assessed second cancer risk among 85,109 cervical SCC and 10,280 AC survivors reported to population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States. Risks compared to the general population were assessed using standardized incidence ratios (SIR). Results Overall cancer risk was significantly increased among both cervical SCC survivors (n = 10,559 second cancers; SIR, 1.31; 95% CI, 1.29 to 1.34) and AC survivors (n = 920 second cancers; SIR, 1.29; 95% CI, 1.22 to 1.38). Risks of HPV-related and radiation-related cancers were increased to a similar extent among cervical SCC and AC survivors. Although significantly increased in both groups when compared with the general population, risk of smoking-related cancers was significantly higher among cervical SCC than AC survivors (P = .015; SIR for cervical SCC = 2.07 v AC = 1.78). This difference was limited to lung cancer (SIR for cervical SCC = 2.69 v AC = 2.18; P = .026). The increased lung cancer risk among cervical AC survivors was observed for both lung SCC and lung AC. SIRs for second cancers of the colon, soft tissue, melanoma, and non-Hodgkin's lymphoma were significantly higher among cervical AC than SCC survivors. Conclusion The second cancer profiles among cervical SCC and AC survivors mirror the similarities and differences in cofactors for these two histologies. Because smoking is not a cofactor for cervical AC, the increased lung cancer risk suggests a role for additional factors. C1 NCI, Div Canc Epidemiol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Iowa, Iowa City, IA USA. Danish Canc Soc, Copenhagen, Denmark. Karolinska Inst, Stockholm, Sweden. Canc Registry Norway, Oslo, Norway. Univ Helsinki, Cent Hosp, Helsinki, Finland. Finnish Canc Registry, FIN-00170 Helsinki, Finland. RP Chaturvedi, AK (reprint author), Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7072, Rockville, MD 20852 USA. EM chaturva@mail.nih.gov RI Hildesheim, Allan/B-9760-2015; Chaturvedi, Anil/J-2024-2015; OI Hildesheim, Allan/0000-0003-0257-2363; Chaturvedi, Anil/0000-0003-2696-8899; Storm, Hans/0000-0001-7223-8198; Kleinerman, Ruth/0000-0001-7415-2478; Joensuu, Heikki/0000-0003-0281-2507 FU Intramural Research Program; National Cancer Institute; National Institutes of Health FX Supported by the Intramural Research Program, National Cancer Institute, National Institutes of Health. NR 37 TC 32 Z9 34 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2009 VL 27 IS 6 BP 967 EP 973 DI 10.1200/JCO.2008.18.4549 PG 7 WC Oncology SC Oncology GA 409NR UT WOS:000263513000021 PM 19114696 ER PT J AU Zon, RT Goss, E Vogel, VG Chlebowski, RT Jatoi, I Robson, ME Wollins, DS Garber, JE Brown, P Kramer, BS AF Zon, Robin T. Goss, Elizabeth Vogel, Victor G. Chlebowski, Rowan T. Jatoi, Ismail Robson, Mark E. Wollins, Dana S. Garber, Judy E. Brown, Powel Kramer, Barnett S. TI American Society of Clinical Oncology Policy Statement: The Role of the Oncologist in Cancer Prevention and Risk Assessment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; INVASIVE BREAST-CANCER; BILATERAL PROPHYLACTIC MASTECTOMY; UPPER AERODIGESTIVE TRACT; BRCA2 MUTATION CARRIERS; 2ND PRIMARY TUMORS; COLORECTAL-CANCER; TEACHABLE MOMENT; PROSTATE-CANCER; HEPATOCELLULAR-CARCINOMA AB Oncologists have a critical opportunity to utilize risk assessment and cancer prevention strategies to interrupt the initiation or progression of cancer in cancer survivors and individuals at high risk of developing cancer. Expanding knowledge about the natural history and prognosis of cancers positions oncologists to advise patients regarding the risk of second malignancies and treatment-related cancers. In addition, as recognized experts in the full spectrum of cancer care, oncologists are afforded opportunities for involvement in community-based cancer prevention activities. Although oncologists are currently providing many cancer prevention and risk assessment services to their patients, economic barriers exist, including inadequate or lack of insurance, that may compromise uniform patient access to these services. Additionally, insufficient reimbursement for existing and developing interventions may discourage patient access to these services. The American Society of Clinical Oncology (ASCO), the medical society representing cancer specialists involved in patient care and clinical research, is committed to supporting oncologists in their wide-ranging involvement in cancer prevention. This statement on risk assessment and prevention counseling, although not intended to be a comprehensive overview of cancer prevention describes the current role of oncologists in risk assessment and prevention; provides examples of risk assessment and prevention activities that should be offered by oncologists; identifies potential opportunities for coordination between oncologists and primary care physicians in prevention education and coordination of care for cancer survivors; describes ASCO's involvement in education and training of oncologists regarding prevention; and proposes improvement in the payment environment to encourage patient access to these services. C1 [Wollins, Dana S.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. Turner & Goss LLP, Washington, DC USA. Michiana Hematol Oncol, South Bend, IN USA. Univ Pittsburgh, Inst Canc, Magee UPCI Breast Canc Prevent Program, Pittsburgh, PA USA. Harbor UCLA Med Ctr, Div Hematol & Med Oncol, Torrance, CA 90509 USA. Natl Naval Med Ctr, Breast Care Ctr, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Wollins, DS (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM dana.wollins@asco.org OI Robson, Mark/0000-0002-3109-1692 NR 76 TC 29 Z9 29 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2009 VL 27 IS 6 BP 986 EP 993 DI 10.1200/JCO.2008.16.3691 PG 8 WC Oncology SC Oncology GA 409NR UT WOS:000263513000023 PM 19075281 ER PT J AU Sapp, M Day, PM AF Sapp, Martin Day, Patricia M. TI Structure, attachment and entry of polyoma- and papillomaviruses SO VIROLOGY LA English DT Review DE Receptor; Conformational change; Endocytosis; Intracellular transport ID MINOR CAPSID PROTEIN; HEPARAN-SULFATE PROTEOGLYCANS; VIRUS-LIKE PARTICLES; MAJOR HISTOCOMPATIBILITY PROTEINS; AMINO-ACID-RESIDUES; CELL-SURFACE; JC-VIRUS; ENDOPLASMIC-RETICULUM; MURINE POLYOMAVIRUS; HUMAN KERATINOCYTES AB Polyoma- (PY) and Papillomavirus (PV) virions have remarkable structural equivalence although no discernable sequence similarities among the capsid proteins can be detected. Their similarities include the overall surface organization, the presence of 72 capsomeres composed of five molecules of the major capsid proteins, VP1 and L1, respectively, the structure of the core segment of capsomeres with classical antiparallel "jelly roll" beta strands as the major feature, and the linkage of neighboring capsomeres by invading C-terminal arms. Differences include the size of surface exposed loops that contain the dominant neutralizing epitopes, the details of the intercapsomeric interactions, and the presence of 2 or I minor capsid proteins, respectively. These differences may affect the dramatic differences observed in receptor binding and internalization pathways utilized by these viruses, but as detailed later even structural differences cannot completely explain receptor and pathway usage. In recent years, technical advances aiding the study of entry processes have allowed the identification of novel endocytic compartments and an appreciation of the links between endocytic pathways that were previously thought to be completely separable. This review is intended to highlight recent advances in our understanding of virus receptor interactions and their consequences for endocytosis and intracellular trafficking. (C) 2009 Elsevier Inc. All rights reserved. C1 [Sapp, Martin] Louisiana State Univ, Hlth Sci Ctr, Feist Weiller Canc Ctr, Dept Microbiol & Immunol, Shreveport, LA 71130 USA. [Day, Patricia M.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Sapp, M (reprint author), Louisiana State Univ, Hlth Sci Ctr, Feist Weiller Canc Ctr, Dept Microbiol & Immunol, Shreveport, LA 71130 USA. EM msapp1@lsuhsc.edu NR 112 TC 45 Z9 48 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 20 PY 2009 VL 384 IS 2 BP 400 EP 409 DI 10.1016/j.virol.2008.12.022 PG 10 WC Virology SC Virology GA 409TG UT WOS:000263528100019 PM 19157477 ER PT J AU Landgren, O AF Landgren, Ola TI A role for ionizing radiation in myelomagenesis? SO BLOOD LA English DT Editorial Material ID ATOMIC-BOMB SURVIVORS; MULTIPLE-MYELOMA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; RISK; LEUKEMIA C1 NIH, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NIH, Bethesda, MD 20892 USA. NR 12 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 19 PY 2009 VL 113 IS 8 BP 1616 EP 1617 DI 10.1182/blood-2008-11-186957 PG 4 WC Hematology SC Hematology GA 410GS UT WOS:000263566100002 PM 19228928 ER PT J AU Dobrovolsky, VN Shaddock, JG Mittelstaedt, RA Manjanatha, MG Miura, D Uchikawa, M Mattison, DR Morris, SM AF Dobrovolsky, Vasily N. Shaddock, Joseph G. Mittelstaedt, Roberta A. Manjanatha, Mugimane G. Miura, Daishiro Uchikawa, Makoto Mattison, Donald R. Morris, Suzanne M. TI Evaluation of Macaca mulatta as a model for genotoxicity studies SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Rhesus monkey; Mutation; ENU; HPRT; PIG-A; Cloning; Flow cytometry; Lymphocytes; Erythrocytes ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; ETHYL-N-NITROSOUREA; DNA-SEQUENCE ANALYSIS; MONKEY T-LYMPHOCYTES; IN-VIVO; PERIPHERAL-BLOOD; CYNOMOLGUS MONKEY; MONOCLONAL-ANTIBODIES; MOLECULAR ANALYSIS; ANCHORED PROTEINS AB We have investigated the use of peripheral blood from the nonhuman primate (NHP) rhesus monkey (Macaca mulatta) as a model system for mutation detection. The rhesus monkey is metabolically closer to humans than most common laboratory animals, and therefore may be a relevant model for hazard identification and human risk assessment. To validate the model, conditions were determined for in vitro selection and expansion of 6-thioguanine-resistant (6-TGr) HPRT mutant and proaerolysin-resistant (ProAERr) PIG-A mutant lymphocytes from peripheral blood obtained by routine venipuncture. Also, flow cytometric methods were developed for the rapid detection of PIG-A mutant erythrocytes. The flow cytometric analysis of PIG-A mutant erythrocytes was based on enumerating cells deficient in surface markers attached to the cellular membrane via glycosylphosphatidyl inositol (GPI) anchors. Mutant cells were enumerated over an extended period of time in peripheral blood of male monkeys receiving daily doses of the electrolyte replenisher Prang (TM) (a common carrier for oral delivery of drugs in NHPs), and in the blood of one male monkey treated with a single i.p. dose of 50 mg/kg of N-ethyl-N-nitrosourea at similar to 2 years of age and another similar injection at approximately 3.5 years of age. The spontaneous PIG-A and HPRT T-cell mutant frequency (MF) was low in animals receiving Prang (0-8 x 10(-6)), and treatment with ENU resulted in a clearly detectable increase in the frequency of ProAERr and 6-TGr lymphocytes (up to similar to 28 x 10(-6) and similar to 30 x 10(-6), respectively). Also, the ENU-treated animal had higher frequency of GPI-deficient erythrocytes (46.5 x 10(-6) in the treated animal vs. 7.8 +/- 4.2 x 10(-6) in control animals). our results indicate that the rhesus monkey can be a valuable model for the identification of agents that may impact upon human health as mutagens and that the PIG-A gene can be a useful target for detection of mutation in both white and red blood cells. Published by Elsevier B.V. C1 [Dobrovolsky, Vasily N.; Shaddock, Joseph G.; Mittelstaedt, Roberta A.; Manjanatha, Mugimane G.; Miura, Daishiro; Morris, Suzanne M.] US FDA, Natl Ctr Toxicol Res, Div Genet & Reprod Toxicol, Jefferson, AR 72079 USA. [Miura, Daishiro] Teijin Pharma Ltd, Tokyo, Japan. [Uchikawa, Makoto] Tokyo Blood Ctr, Tokyo, Japan. [Mattison, Donald R.] NICHD, US NIH, Bethesda, MD 20852 USA. RP Dobrovolsky, VN (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Reprod Toxicol, 3900 NCTR Rd,HFT-120, Jefferson, AR 72079 USA. EM vasily.dobrovolsky@fda.hhs.gov RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 FU NICHD FX We would like to thank the following people for their important contributions to the study. We thank Dr. R. Albertini for providing human T-cell growth factor supplement, Dr. Patrick O'Neill for providing HPRT-deficient human lymphoblastoid TK6 cell line. Special thanks to employees of animal care facility for multiple blood samplings of experimental animals. Also we thank Drs. Charlotte Hotchkiss and Jeff Carraway for administering ENU and monitoring health of monkey colony at NCTR. This work was partially supported by the NICHD through the U.S. Congressional Best Pharmaceuticals for Children Act of 2002. The views presented in this article do not necessary reflect those of the U.S. Food and Drug Administration. NR 37 TC 19 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD FEB 19 PY 2009 VL 673 IS 1 BP 21 EP 28 DI 10.1016/j.mrgentox.2008.11.006 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 412TZ UT WOS:000263748400005 PM 19073277 ER PT J AU Morris, SA Dobrovolsky, VN Shaddock, JG Mittelstaedt, RA Bishop, ME Manjanatha, MG Shelton, SD Doerge, DR Twaddle, NC Chen, JJ Lin, CJ Paule, MG Slikker, W Hotchkiss, CE Petibone, D Tucker, JD Mattison, DR AF Morris, Suzanne A. Dobrovolsky, Vasily N. Shaddock, Joseph G. Mittelstaedt, Roberta A. Bishop, Michelle E. Manjanatha, Mugimane G. Shelton, Sharon D. Doerge, Daniel R. Twaddle, Nathan C. Chen, James J. Lin, Chien-Ju Paule, Merle G. Slikker, William, Jr. Hotchkiss, Charlotte E. Petibone, Dayton Tucker, James D. Mattison, Donald R. TI The genetic toxicology of methylphenidate hydrochloride in non-human primates SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Methylphenidate; Non-human primates; Chromosome aberrations; Micronuclei; HPRT mutations ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; FLOW-CYTOMETRIC ANALYSIS; DNA-SEQUENCE ANALYSIS; PERIPHERAL-BLOOD; IN-VIVO; CALORIE RESTRICTION; CHROMOSOMAL DAMAGE; MACACA-MULATTA; LYMPHOCYTES; CHILDREN AB The studies presented in this work were designed to evaluate the genetic toxicity of methylphenidate hydrochloride (MPH) in non-human primates (NHP) using a long-term, chronic dosing regimen. Thus, approximately two-year old, male rhesus monkeys of Indian origin were orally exposed to MPH diluted in the electrolyte replenisher, Prang (R), five days per week over a 20-month period. There were 10 animals per dose group and the doses were (1) control, Prang only, (2) low, 0.15 mg/kg of MPH twice per day increased to 2.5 mg/kg twice per day and (3) high, 1.5 mg/kg of MPH twice per day increased to 12.5 mg/kg twice per day. Blood samples were obtained from each animal to determine the base-line serum levels of MPH and the major metabolite of MPH in NHP, ritalinic acid (RA). In addition, the base-line frequency of micronucleated erythrocytes (MN-RETs) by flow cytometry, HPRT mutants by a lymphocyte cloning assay, and chromosome aberrations by FISH painting were determined from peripheral blood samples. Once dosing began, the serum levels of MPH and its major metabolite, RA, were determined monthly. The MN-RET frequency and health parameters (CBC, serum chemistries) were also determined monthly. HPRT mutant and chromosome aberration frequencies were measured every three months. CBC values and serum chemistries. with the exception of alanine amino transferase, were within normal limits over the course of drug exposure. The final plasma levels of MPH were similar to those produced by the pediatric dose of 0.3 mu g/ml. No significant increases in the frequencies of MN-RETs, HPRT mutants, or chromosome aberrations were detected in the treated animals compared to the control animals over the 20-month exposure period. Published by Elsevier B.V. C1 [Morris, Suzanne A.; Dobrovolsky, Vasily N.; Shaddock, Joseph G.; Mittelstaedt, Roberta A.; Bishop, Michelle E.; Manjanatha, Mugimane G.; Shelton, Sharon D.] US FDA, Div Genet & Reprod Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Doerge, Daniel R.; Twaddle, Nathan C.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chen, James J.; Lin, Chien-Ju] US FDA, Div Personalized Med & Nutr, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Paule, Merle G.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Slikker, William, Jr.] US FDA, Off Director, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Hotchkiss, Charlotte E.] Washington Natl Primate Res Ctr, Seattle, WA USA. [Petibone, Dayton; Tucker, James D.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Mattison, Donald R.] Eunice Kennedy Shriver Natl Ctr Child Hlth & Dev, Bethesda, MD USA. RP Morris, SA (reprint author), US FDA, Div Genet & Reprod Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM suzanne.morris@fda.hhs.gov RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 FU National Center for Toxicological Research/FDA; Best Pharmaceuticals for Children Act/Eunice M. Kennedy Shriver National Institute for Child Health and Development/NIH; NCTR/FDA; Wayne State University FX Funding: These studies were supported by an Inter-Agency Agreement between the National Center for Toxicological Research/FDA and the Best Pharmaceuticals for Children Act/Eunice M. Kennedy Shriver National Institute for Child Health and Development/NIH. The studies were also supported by a contract between the NCTR/FDA and Wayne State University. NR 34 TC 18 Z9 18 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD FEB 19 PY 2009 VL 673 IS 1 BP 59 EP 66 DI 10.1016/j.mrgentox.2008.12.001 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 412TZ UT WOS:000263748400010 PM 19135169 ER PT J AU Lee, T Hillis, D Nabel, E AF Lee, Thomas Hillis, David Nabel, Elizabeth TI Perspective Roundtable: CABG vs. Stenting: Clinical Implications of the SYNTAX Trial. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Hillis, David] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Nabel, Elizabeth] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 19 PY 2009 VL 360 IS 8 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 408CN UT WOS:000263411300004 ER PT J AU Lin, L Amin, R Gallicano, GI Glasgow, E Jogunoori, W Jessup, JM Zasloff, M Marshall, JL Shetty, K Johnson, L Mishra, L He, AR AF Lin, L. Amin, R. Gallicano, G. I. Glasgow, E. Jogunoori, W. Jessup, J. M. Zasloff, M. Marshall, J. L. Shetty, K. Johnson, L. Mishra, L. He, A. R. TI The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling SO ONCOGENE LA English DT Article DE IL6; stem cell; TGF-beta; STAT3; beta 2SP; hepatocellular carcinoma ID LIVER STEM-CELLS; SERINE PHOSPHORYLATION; STEM/PROGENITOR CELLS; GENE-EXPRESSION; CARCINOMA CELLS; MICE; ACTIVATION; PATHWAY; CHEMORESISTANCE; CD133(+) AB Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, with few effective therapeutic options for advanced disease. At least 40% of HCCs are clonal, potentially arising from STAT3+, NANOG+ and OCT3/4+ liver progenitor/stem cell transformation, along with inactivation of transforming growth factor-beta (TGF-beta) signaling. Here we report significantly greater signal transducer and activator of transcription 3 (STAT3) and tyrosine phosphorylated STAT3 in human HCC tissues (P<0.0030 and P<0.0455, respectively) than in human normal liver. Further, in HCC cells with loss of response to TGF-b, NSC 74859, a STAT3-specific inhibitor, markedly suppresses growth. In contrast, CD133(+) status did not affect the response to STAT3 inhibition: both CD133(+) Huh-7 cells and CD133(-) Huh-7 cells are equally sensitive to NSC 74859 treatment and STAT3 inhibition, with an IC(50) of 100 mu M. Thus, the TGF-beta/beta2 spectrin (beta 2SP) pathway may reflect a more functional 'stem/progenitor' state than CD133. Furthermore, NSC 74859 treatment of Huh-7 xenografts in nude mice significantly retarded tumor growth, with an effective dose of only 5 mg/kg. Moreover, NSC 74859 inhibited tyrosine phosphorylation of STAT3 in HCC cells in vivo. We conclude that inhibiting interleukin 6 (IL6)/STAT3 in HCCs with inactivation of the TGF-beta/beta 2SP pathway is an effective approach in management of HCCs. Thus, IL6/STAT3, a major signaling pathway in HCC stem cell renewal and proliferation, can provide a novel approach to the treatment of specific HCCs. C1 [Lin, L.; Glasgow, E.; Marshall, J. L.; He, A. R.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Med & Oncol, Washington, DC 20007 USA. [Lin, L.; Amin, R.; Glasgow, E.; Jogunoori, W.; Zasloff, M.; Shetty, K.; Johnson, L.; Mishra, L.; He, A. R.] Georgetown Univ, Dept Surg, Washington, DC 20007 USA. [Gallicano, G. I.] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. [Jessup, J. M.] NCI, Canc Diag Program, Rockville, MD USA. [Shetty, K.; Johnson, L.] Georgetown Univ, Inst Transplant Surg, Dept Surg, Washington, DC USA. [Mishra, L.] Dept Vet Affairs Med Ctr, Washington, DC USA. RP He, AR (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Med & Oncol, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM lm229@georgetown.edu; aiwu.r.he@gunet.georgetown.edu FU NCI NIH HHS [R01 CA042857, P01 CA130821, P30 CA051008, P30 CA51008-13, R01 CA042857-18A1, R01 CA106614, R01 CA106614-01A2, R01 CA106614A, R01 CA4285718A]; NIDDK NIH HHS [R01 DK056111, R01 DK056111-01, R01 DK56111] NR 45 TC 121 Z9 126 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 19 PY 2009 VL 28 IS 7 BP 961 EP 972 DI 10.1038/onc.2008.448 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 408TH UT WOS:000263457400003 PM 19137011 ER PT J AU Schiewer, MJ Morey, LM Burd, CJ Liu, Y Merry, DE Ho, SM Knudsen, KE AF Schiewer, M. J. Morey, L. M. Burd, C. J. Liu, Y. Merry, D. E. Ho, S-M Knudsen, K. E. TI Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer SO ONCOGENE LA English DT Article DE androgen receptor; testosterone; prostatic adenocarcinoma; cell cycle ID ANDROGEN-RECEPTOR REGULATION; D-DEPENDENT KINASE; INDEPENDENT MECHANISM; CELL-PROLIFERATION; ESTROGEN-RECEPTOR; GENE-EXPRESSION; CARCINOMA-CELLS; CO-REPRESSOR; DNA-BINDING; ACTIVATION AB Regulation of the androgen receptor (AR) is critical to prostate cancer (PCa) development; therefore, AR is the first line therapeutic target for disseminated tumors. Cell cycle-dependent accumulation of cyclin D1 negatively modulates the transcriptional regulation of AR through discrete, CDK4-independent mechanisms. The transcriptional corepressor function of cyclin D1 resides within a defined motif termed repressor domain (RD), and it was hypothesized that this motif could be utilized as a platform to develop new strategies for blocking AR function. Here, we demonstrate that expression of the RD peptide is sufficient to disrupt AR transcriptional activation of multiple, prostate-specific AR target genes. Importantly, these actions are sufficient to specifically inhibit S-phase progression in AR-positive PCa cells, but not in AR-negative cells or tested AR-positive cells of other lineages. As expected, impaired cell cycle progression resulted in a suppression of cell doubling. Additionally, cell death was observed in AR-positive cells that maintain androgen dependence and in a subset of castrate-resistant PCa cells, dependent on Akt activation status. Lastly, the ability of RD to cooperate with existing hormone therapies was examined, which revealed that RD enhanced the cellular response to an AR antagonist. Together, these data demonstrate that RD is sufficient to disrupt AR-dependent transcriptional and proliferative responses in PCa, and can enhance efficacy of AR antagonists, thus establishing the impetus for development of RD-based mimetics. C1 [Merry, D. E.; Knudsen, K. E.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Schiewer, M. J.; Knudsen, K. E.] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA. [Morey, L. M.; Ho, S-M] Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Burd, C. J.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Liu, Y.; Merry, D. E.] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Ho, S-M] Univ Cincinnati, Coll Med, Cter Environm Genet, Cincinnati, OH USA. [Ho, S-M] Univ Cincinnati, Coll Med, UC Barrett Canc Ctr, Cincinnati, OH USA. [Knudsen, K. E.] Thomas Jefferson Univ, Dept Urol, Philadelphia, PA 19107 USA. RP Knudsen, KE (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, Bluemle Life Sci Bldg,233 S 10th St,Room 1008A, Philadelphia, PA 19107 USA. EM karen.knudsen@kimmelcancercenter.org OI Burd, Craig/0000-0002-6899-6751 FU NIH [CA099996, CA116777, CA015776, CA062269, CA112532]; [T32-CA117846] FX We thank the K Knudsen lab for critical input, especially SM Godoy Tundidor; S Schwemberger, S Fox and M Faradaugh for technical assistance, and the E Knudsen laboratory for commentary. This work was supported by NIH grants CA099996 and CA116777 (to KEK); CA015776, CA062269, CA112532 (to SMH). LMM was supported by training grant T32-CA117846. NR 78 TC 15 Z9 15 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 19 PY 2009 VL 28 IS 7 BP 1016 EP 1027 DI 10.1038/onc.2008.446 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 408TH UT WOS:000263457400008 PM 19079343 ER PT J AU Martin, DN Boersma, BJ Yi, M Reimers, M Howe, TM Yfantis, HG Tsai, YC Williams, EH Lee, DH Stephens, RM Weissman, AM Ambs, S AF Martin, Damali N. Boersma, Brenda J. Yi, Ming Reimers, Mark Howe, Tiffany M. Yfantis, Harry G. Tsai, Yien Che Williams, Erica H. Lee, Dong H. Stephens, Robert M. Weissman, Allan M. Ambs, Stefan TI Differences in the Tumor Microenvironment between African-American and European-American Breast Cancer Patients SO PLOS ONE LA English DT Article AB Background: African-American breast cancer patients experience higher mortality rates than European-American patients despite having a lower incidence of the disease. We tested the hypothesis that intrinsic differences in the tumor biology may contribute to this cancer health disparity. Methods and Results: Using laser capture microdissection, we examined genome-wide mRNA expression specific to tumor epithelium and tumor stroma in 18 African-American and 17 European-American patients. Numerous genes were differentially expressed between these two patient groups and a two-gene signature in the tumor epithelium distinguished between them. To identify the biological processes in tumors that are different by race/ethnicity, Gene Ontology and disease association analyses were performed. Several biological processes were identified which may contribute to enhanced disease aggressiveness in African-American patients, including angiogenesis and chemotaxis. African-American tumors also contained a prominent interferon signature. The role of angiogenesis in the tumor biology of African-Americans was further investigated by examining the extent of vascularization and macrophage infiltration in an expanded set of 248 breast tumors. Immunohistochemistry revealed that microvessel density and macrophage infiltration is higher in tumors of African-Americans than in tumors of European-Americans. Lastly, using an in silico approach, we explored the potential of tailored treatment options for African-American patients based on their gene expression profile. This exploratory approach generated lists of therapeutics that may have specific antagonistic activity against tumors of African-American patients, e. g., sirolimus, resveratrol, and chlorpromazine in estrogen receptor-negative tumors. Conclusions: The gene expression profiles of breast tumors indicate that differences in tumor biology may exist between African-American and European-American patients beyond the knowledge of current markers. Notably, pathways related to tumor angiogenesis and chemotaxis could be functionally different in these two patient groups. RP Martin, DN (reprint author), NCI, Human Carcinogenesis Lab, CCR, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov RI Boersma, Brenda/A-9270-2009; OI Boersma, Brenda/0000-0002-8992-2735; Tsai, Yien Che/0000-0001-9624-1092 FU Intramural NIH HHS NR 55 TC 65 Z9 67 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 19 PY 2009 VL 4 IS 2 AR e4531 DI 10.1371/journal.pone.0004531 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437KI UT WOS:000265486000008 PM 19225562 ER PT J AU Young, JE Garden, GA Martinez, RA Tanaka, F Sandoval, CM Smith, AC Sopher, BL Lin, A Fischbeck, KH Ellerby, LM Morrison, RS Taylor, JP La Spada, AR AF Young, Jessica E. Garden, Gwenn A. Martinez, Refugio A. Tanaka, Fumiaki Sandoval, C. Miguel Smith, Annette C. Sopher, Bryce L. Lin, Amy Fischbeck, Kenneth H. Ellerby, Lisa M. Morrison, Richard S. Taylor, J. Paul La Spada, Albert R. TI Polyglutamine-Expanded Androgen Receptor Truncation Fragments Activate a Bax-Dependent Apoptotic Cascade Mediated by DP5/Hrk SO JOURNAL OF NEUROSCIENCE LA English DT Article DE polyglutamine; spinal and bulbar muscular atrophy; truncation; apoptosis; Bax; DP5 ID BULBAR MUSCULAR-ATROPHY; TRANSGENIC MOUSE MODEL; AMYOTROPHIC-LATERAL-SCLEROSIS; ENDOPLASMIC-RETICULUM STRESS; NEURONAL CELL-DEATH; BCL-2 FAMILY-MEMBER; UP-REGULATING BAX; INTRANUCLEAR INCLUSIONS; ER STRESS; NEURODEGENERATIVE DISEASES AB Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by a polyglutamine (polyQ) repeat expansion in the androgen receptor (AR). PolyQ-AR neurotoxicity may involve generation of an N-terminal truncation fragment, as such peptides occur in SBMA patients and mouse models. To elucidate the basis of SBMA, we expressed N-terminal truncated AR in motor neuron-derived cells and primary cortical neurons. Accumulation of polyQ-AR truncation fragments in the cytosol resulted in neurodegeneration and apoptotic, caspase-dependent cell death. Using primary neurons from mice transgenic or deficient for apoptosis-related genes, we determined that polyQ-AR apoptotic activation is fully dependent on Bax. Jun N-terminal kinase (JNK) was required for apoptotic pathway activation through phosphorylation of c-Jun. Expression of polyQ-AR in DP5/Hrk null neurons yielded significant protection against apoptotic activation, but absence of Bim did not provide protection, apparently due to compensatory upregulation of DP5/Hrk or other BH3-only proteins. Misfolded AR protein in the cytosol thus initiates a cascade of events beginning with JNK and culminating in Bax-dependent, intrinsic pathway activation, mediated in part by DP5/Hrk. As apoptotic mediators are candidates for toxic fragment generation and other cellular processes linked to neuron dysfunction, delineation of the apoptotic activation pathway induced by polyQ-expanded AR may shed light on the pathogenic cascade in SBMA and other motor neuron diseases. C1 [La Spada, Albert R.] Univ Washington, Med Ctr, Dept Lab Med, Seattle, WA 98195 USA. [Garden, Gwenn A.; La Spada, Albert R.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Morrison, Richard S.] Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA. [La Spada, Albert R.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Garden, Gwenn A.; Morrison, Richard S.; La Spada, Albert R.] Univ Washington, Ctr Neurogenet & Neurotherapeut, Seattle, WA 98195 USA. [Tanaka, Fumiaki; Sandoval, C. Miguel; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Lin, Amy; Ellerby, Lisa M.] Buck Inst Age Res, Novato, CA 94945 USA. [Taylor, J. Paul] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. RP Young, JE (reprint author), Univ Washington, Med Ctr, Dept Lab Med, Box 357110,Room NW 120, Seattle, WA 98195 USA. EM laspada@u.washington.edu FU National Institutes of Health [NS41648, NS35533, NS40251A, NS53825]; National Institute of Neurological Disorders and Stroke funds; Muscular Dystrophy Association FX This work was supported by National Institutes of Health Grants NS41648 (A. R. L.), NS35533 (R. S. M.), NS40251A (L. M. E.), and NS53825 (J.P.T.); intramural National Institute of Neurological Disorders and Stroke funds (K. H. F.); and grants from the Muscular Dystrophy Association (A. R. L., J.P.T., and L. M. E.). We thank S. Finkbeiner, R. Youle, S. Gutkind, C. Duckett, E. Johnson, and G. Nunez for providing reagents or mice. NR 80 TC 39 Z9 39 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 18 PY 2009 VL 29 IS 7 BP 1987 EP 1997 DI 10.1523/JNEUROSCI.4072-08.2009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 410EA UT WOS:000263558900004 PM 19228953 ER PT J AU Li, J Li, LK Ma, JF Wei, LH Niyazi, M Li, CQ Xu, AD Wang, JB Liang, H Belinson, J Qiao, YL AF Li, Jing Li, Lian-Kun Ma, Jun-Fei Wei, Li-Hui Niyazi, Mayinuer Li, Chang-Qing Xu, Ai-Di Wang, Jian-Bin Liang, Hao Belinson, Jerome Qiao, You-Lin TI Knowledge and attitudes about human papillomavirus (HPV) and HPV vaccines among women living in metropolitan and rural regions of China SO VACCINE LA English DT Article DE Human papillomavirus (HPV) vaccines; Knowledge; Acceptability ID CERVICAL-CANCER; VACCINATION; ACCEPTANCE; AWARENESS; TRENDS AB Infection with the human papillomavirus (HPV) is one of the most common sexually transmitted infections and causes Virtually all cervical cancer globally. The recent development of two safe and clinically effective vaccines against HPV is a promising step towards lowering cervical cancer rates in the future. What Chinese women think about HPV and the vaccines remains unknown. We undertook a population-based Survey, which was embedded in a cervical cancer screening project and was designed to assess women's knowledge about HPV and their acceptability to the vaccines. We found that only 15.0% of women in our study reported to have ever heard of HPV, and this knowledge differs by rural (9.3%) and metropolitan areas (21.6%) and also by education. Most (84.6%) participants were willing to be vaccinated if HPV vaccine became available to them. The present Study documents ways in which women learn about HPV and indicates the potential barriers and success of introducing HPV vaccine to China. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Li, Jing; Wang, Jian-Bin; Liang, Hao; Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Dept Canc Epidemiol, Beijing 100021, Peoples R China. [Li, Jing] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Lian-Kun] Liaoning Prov Tumor Hosp, Shenyang, Peoples R China. [Niyazi, Mayinuer] Xinjiang Uygur Autonomous Reg Hosp, Dept OB GYN, Urumqi 830001, Peoples R China. [Xu, Ai-Di] Hongkou Dist Women & Childrens Hosp, Shanghai 200082, Peoples R China. [Belinson, Jerome] Cleveland Clin Fdn, Dept OB GYN, Cleveland, OH 44195 USA. RP Qiao, YL (reprint author), Chinese Acad Med Sci, Inst Canc, Dept Canc Epidemiol, Beijing 100021, Peoples R China. EM qiaoy@cicams.ac.cn RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 FU Cleveland Clinic Foundation (CCF); National Cancer Institute; NIH; DHHS FX We thank the Cancer Foundation of China (CFC) and the Cancer Institute of the Chinese Academy of Medical Sciences (CICAMS) with providing their expertise in the development of the study. We also thank the local health workers from Beijing, Shanghai, Shenyang, Shanxi (Xiangyuan), Xinjiang (Hetian), and Henan (Xinmi) for inviting women to participate in the Study and assisting us complete the project successfully. The authors thank Dr. Philip Castle (U.S. National Cancer Institute, NIH, DHHS) for his help with the data analysis and manuscript preparation. Dr. Jing Li was supported by the Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS and the Short Term Scientist Exchange Program (STSEP) from the National Institute of Health (NIH). NR 24 TC 61 Z9 64 U1 1 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 18 PY 2009 VL 27 IS 8 BP 1210 EP 1215 DI 10.1016/j.vaccine.2008.12.020 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 412GH UT WOS:000263712200009 PM 19135493 ER PT J AU Jenkins, LMM Yamaguchi, H Hayashi, R Cherry, S Tropea, JE Miller, M Wlodawer, A Appella, E Mazur, SJ AF Jenkins, Lisa M. Miller Yamaguchi, Hiroshi Hayashi, Ryo Cherry, Scott Tropea, Joseph E. Miller, Maria Wlodawer, Alexander Appella, Ettore Mazur, Sharlyn J. TI Two Distinct Motifs within the p53 Transactivation Domain Bind to the Taz2 Domain of p300 and Are Differentially Affected by Phosphorylation SO BIOCHEMISTRY LA English DT Article ID TRANSCRIPTIONAL ACTIVATION DOMAIN; TERMINAL DOMAIN; UV DAMAGE; PROTEIN; MDM2; ACETYLATION; CBP/P300; COMPLEX; RECRUITMENT; CBP AB The tumor suppressor p53 functions as a transcriptional activator for many genes, including several key genes involved in cell cycle arrest and apoptosis. Following DNA damage-induced stress, p53 undergoes extensive posttranslational modification, resulting in increased stability and activity. Two critical cofactors for p53-mediated transactivation are the histone acetyltransferase paralogues CREB-binding protein (CBP) and p300. The N-terminal transactivation domain of p53 interacts with several domains of CBP/p300, including the Taz2 domain. Here, we report the effects of specific p53 phosphorylations on its interaction with the Taz2 domain of p300. Using a competitive fluorescence anisotropy assay, we determined that monophosphorylation of p53 at Ser(15) or Thr(18) increased the affinity of p53(1-39) for Taz2, and diphosphorylations at Ser(15) and Ser(37) or Thr(18) and Ser(20) further increased the affinity. In addition, we identified a second binding site for Taz2 within p53 residues 35-59. This second site bound Taz2 with a similar affinity as the first site, but the binding was unaffected by phosphorylation. Thus, p53 posttranslational modification modulates only one of the two binding sites for p300 Taz2. Further investigation of Taz2 binding to p53(1-39) or p53(35-59) by isothermal titration calorimetry indicated that upon complex formation, the change in heat capacity at constant pressure, Delta C(p), was negative for both sites, suggesting the importance of hydrophobic interactions. However, the more negative value of Delta C(p) for Taz2 binding to the first (-330 cal/(mol.K)) compared to the second site (-234 cal/(mol.K)) suggests that the importance of nonpolar and polar interactions differs between the two sites. C1 [Jenkins, Lisa M. Miller; Yamaguchi, Hiroshi; Hayashi, Ryo; Appella, Ettore; Mazur, Sharlyn J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Cherry, Scott; Tropea, Joseph E.; Miller, Maria; Wlodawer, Alexander] NCI, Macromol Crystallog lab, Frederick, MD 21702 USA. RP Mazur, SJ (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM mazurs@mail.nih.gov RI Miller, Maria/I-1636-2013 OI Miller, Maria/0000-0003-0252-5348 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Center Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Center Research. NR 51 TC 32 Z9 32 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 17 PY 2009 VL 48 IS 6 BP 1244 EP 1255 DI 10.1021/bi801716h PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 405LN UT WOS:000263226400011 PM 19166313 ER PT J AU Mohan, S Kourentzi, K Schick, KA Uehara, C Lipschultz, CA Acchione, M DeSantis, ME Smith-Gill, SJ Willson, RC AF Mohan, S. Kourentzi, Katerina Schick, Kari A. Uehara, Christian Lipschultz, Claudia A. Acchione, Mauro DeSantis, Morgan E. Smith-Gill, Sandra J. Willson, Richard C. TI Association Energetics of Cross-Reactive and Specific Antibodies SO BIOCHEMISTRY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; EGG-WHITE LYSOZYME; MONOCLONAL-ANTIBODIES; ANTILYSOZYME ANTIBODY; BINDING-SITES; CHICKEN LYSOZYME; AVIAN LYSOZYME; FAB COMPLEX; ANTIGEN; HYHEL-10 AB HyHEL-8, HyHEL-10, and HyHEL-26 (HH8, HH10, and HH26, respectively) are murine monoclonal IgG(1), antibodies which share over 90% variable-region amino acid sequence identity and recognize identical structurally characterized epitopes on hen egg white lysozyme (HEL). Previous immunochemical and surface plasmon resonance-based studies have shown that these antibodies differ widely in their tolerance of mutations in the epitope. While HH8 is the most cross-reactive, HH26 is rigidified by a more extensive network of intramolecular salt links and is highly specific, with both association and dissociation rates strongly affected by epitope mutations. HH10 is of intermediate specificity, and epitope mutations produce changes primarily in the dissociation rate. Calorimetric characterization of the association energetics of these three antibodies with the native antigen HEL and with Japanese quail egg white lysozyme (JQL), a naturally occurring avian variant, shows that the energetics of interaction correlate with cross-reactivity and specificity. These results suggest that the greater cross-reactivity of HH8 may be mediated by a combination of conformational flexibility and less specific intermolecular interactions. Thermodynamic calculations suggest that upon association HH8 incurs the largest configurational entropic penalty and also the smallest loss of enthalpic driving force with variant antigen. Much smaller structural perturbations are expected in the formation of the less flexible HH26 complex, and the large loss of enthalpic driving force observed with variant antigen reflects its specificity. The observed thermodynamic parameters correlate well with the observed functional behavior of the antibodies and illustrate fundamental differences in thermodynamic characteristics between cross-reactive and specific molecular recognition. C1 [Mohan, S.; Kourentzi, Katerina; Schick, Kari A.; Uehara, Christian; Willson, Richard C.] Univ Houston, Dept Chem & Biomol Engn, Houston, TX 77204 USA. [Willson, Richard C.] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Lipschultz, Claudia A.; Acchione, Mauro; DeSantis, Morgan E.; Smith-Gill, Sandra J.] NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Willson, RC (reprint author), Univ Houston, Dept Chem & Biomol Engn, Houston, TX 77204 USA. EM Willson@uh.edu FU Welch Foundation [E-1264]; Alliance for Nanohealth; NIH; National Cancer Institute,; Center for Cancer Research FX This research was supported by the Welch Foundation (E-1264) and the Alliance for Nanohealth, NIH, and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 44 TC 19 Z9 19 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 17 PY 2009 VL 48 IS 6 BP 1390 EP 1398 DI 10.1021/bi801901d PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 405LN UT WOS:000263226400026 PM 19166328 ER PT J AU Fu, LZ Das, B Mathew, S Shi, YB AF Fu, Liezhen Das, Biswajit Mathew, Smita Shi, Yun-Bo TI Genome-wide identification of Xenopus matrix metalloproteinases: conservation and unique duplications in amphibians SO BMC GENOMICS LA English DT Article ID THYROID-HORMONE REGULATION; EXTRACELLULAR-MATRIX; GENE-EXPRESSION; MATRIX-METALLOPROTEINASE-9 GENES; POSTEMBRYONIC DEVELOPMENT; EMBRYONIC-DEVELOPMENT; ANURAN METAMORPHOSIS; FROG METAMORPHOSIS; CYSTEINE SWITCH; TAIL RESORPTION AB Background: Matrix metalloproteinases (MMPs) are members of the superfamily of Zn(2+) dependent extracellular or membrane-bound endopeptidases which have been implicated to play critical roles in vertebrate development and human pathogenesis. A number of MMP genes have been found to be upregulated in some or all organs during frog metamorphosis, suggesting that different MMPs may have different functions in various organs/tissues. The recent advances in EST (expressed sequence tag) sequencing and the completion of the genome of Xenopus (X.) tropicalis prompted us to systematically analyze the existence of MMPs in the Xenopus genome. Results: We examined X. laevis and X. tropicalis ESTs and genomic sequences for MMPs and obtained likely homologs for 20 out of the 25 MMPs known in higher vertebrates. Four of the five missing MMPs, i.e. MMPs 8, 10, 12 and 27, were all encoded on human Chromosome II and the other missing MMP, MMP22 (a chicken MMP), was also absent in human genome. In addition, we identified several novel MMPs which appears to be derived from unique duplications over evolution, are present in the genomes of both Xenopus species. Conclusion: We identified the homologs of most of the mammalian MMPs in Xenopus and discovered a number of novel MMPs. Our results suggest that MMP genes undergo dynamic changes over evolution. It will be of interest in the future to investigate whether MMP expression and functions during vertebrate development are conserved. The sequence information reported here should facilitate such an endeavor in the near future. C1 [Fu, Liezhen; Das, Biswajit; Mathew, Smita; Shi, Yun-Bo] NICHD, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, Sect Mol Morphogenesis, PCRM, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. EM fuliez@helix.nih.gov; dasbiswa@mail.nih.gov; mathewsm@mail.nih.gov; shi@helix.nih.gov FU NICHD; NIH FX This research was supported by the Intramural Research Program of NICHD, NIH. NR 71 TC 14 Z9 14 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 17 PY 2009 VL 10 AR 81 DI 10.1186/1471-2164-10-81 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 430HX UT WOS:000264981300001 PM 19222855 ER PT J AU Gutkind, JS Offermanns, S AF Gutkind, J. Silvio Offermanns, Stefan TI A New Gq-Initiated MAPK Signaling Pathway in the Heart SO DEVELOPMENTAL CELL LA English DT Editorial Material ID CARDIAC-HYPERTROPHY; MYOCARDIAL HYPERTROPHY AB Pathological cardiac hypertrophy involves auto/paracrine mediators acting through G(q/11)-coupled receptors. A novel signaling route stimulated by beta gamma-subunits of G(q/11) results in the autophosphorylation of ERK1/2 on a new site and the nuclear retention of ERK1/2, thereby activating hypertrophic gene programs. C1 [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Offermanns, Stefan] Univ Heidelberg, Inst Pharmacol, D-69120 Heidelberg, Germany. [Offermanns, Stefan] Max Planck Inst Heart & Lung Res, Dept Pharmacol, D-61231 Bad Nauheim, Germany. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM gutkind@dir.nidcr.nih.gov RI Gutkind, J. Silvio/A-1053-2009 NR 9 TC 10 Z9 10 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD FEB 17 PY 2009 VL 16 IS 2 BP 163 EP 164 DI 10.1016/j.devcel.2009.01.021 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 410PI UT WOS:000263589700005 PM 19217418 ER PT J AU Dejana, E Tournier-Lasserve, E Weinstein, BM AF Dejana, Elisabetta Tournier-Lasserve, Elisabeth Weinstein, Brant M. TI The Control of Vascular Integrity by Endothelial Cell Junctions: Molecular Basis and Pathological Implications SO DEVELOPMENTAL CELL LA English DT Review ID CEREBRAL CAVERNOUS MALFORMATIONS; HEREDITARY HEMORRHAGIC TELANGIECTASIA; BLOOD-BRAIN-BARRIER; RECEPTOR-LIKE KINASE-1; VE-CADHERIN; TIGHT JUNCTIONS; ARTERIOVENOUS-MALFORMATIONS; CARDIOVASCULAR DEVELOPMENT; ADHERENS JUNCTIONS; KEY ROLE AB Human pathologies such as vascular malformations, hemorrhagic stroke, and edema have been associated with defects in the organization of endothelial cell junctions. Understanding the molecular basis of these diseases requires different integrated approaches which include basic cell biology, clinical studies, and studies in animal models such as mice and zebrafish. In this review we discuss recent findings derived from these approaches and their possible integration in a common picture. C1 [Dejana, Elisabetta] IFOM, FIRC Inst Mol Oncol, Milan, Italy. [Dejana, Elisabetta] Univ Milan, Sch Sci, Milan, Italy. [Tournier-Lasserve, Elisabeth] INSERM, UMR S 740, F-75010 Paris, France. [Tournier-Lasserve, Elisabeth] Univ Paris 07, Fac Med, Site Labs, F-75010 Paris, France. [Weinstein, Brant M.] NICHD, Sect Vertebrate Organogenesis, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Dejana, E (reprint author), IFOM, FIRC Inst Mol Oncol, Via Adamello 16, Milan, Italy. EM elisabetta.dejana@ifom-ieo-campus.it FU Fondation Leducq Transatlantic Network of Excellence; Associazione Italiana per la Ricerca sul Cancro; Association for International Cancer Research UK; European Community [LSHG-CT-2004-503573, NoE MAIN 502935, NoE EVGN 503254]; Istituto Superiore di Sanita; Italian Ministry of Health; MIUR [2006058482_002]; NIH (NICHD) FX This work was supported by the Fondation Leducq Transatlantic Network of Excellence, Associazione Italiana per la Ricerca sul Cancro, Association for International Cancer Research UK, the European Community (integrated Project Contract No LSHG-CT-2004-503573; NoE MAIN 502935; NoE EVGN 503254; EUSTROKE and OPTISTEM Networks), and Istituto Superiore di Sanita', Italian Ministry of Health, MIUR (COFIN prot: 2006058482_002). B.M.W. was supported by the Intramural Research Program of the NIH (NICHD). NR 103 TC 315 Z9 326 U1 4 U2 36 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD FEB 17 PY 2009 VL 16 IS 2 BP 209 EP 221 DI 10.1016/j.devcel.2009.01.004 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 410PI UT WOS:000263589700010 PM 19217423 ER PT J AU Koh, E Bandle, RW Roberts, DD Stracke, ML Clair, T AF Koh, Eunjin Bandle, Russell W. Roberts, David D. Stracke, Mary L. Clair, Timothy TI Novel point mutations attenuate autotaxin activity SO LIPIDS IN HEALTH AND DISEASE LA English DT Article ID HUMAN-MELANOMA CELLS; LYSOPHOSPHATIDIC ACID; LYSOPHOSPHOLIPASE-D; NUCLEOTIDE PYROPHOSPHATASES/PHOSPHODIESTERASES; MOTILITY; PHOSPHODIESTERASE; IDENTIFICATION; EXPRESSION; SUBSTRATE; MOTOGEN AB Background: The secreted enzyme autotaxin (ATX) stimulates tumor cell migration, tumorigenesis, angiogenesis, and metastasis. ATX hydrolyzes nucleotides, but its hydrolysis of lysophospholipids to produce lysophosphatidic acid (LPA) accounts for its biological activities. ATX has been identified only as a constitutively active enzyme, and regulation of its activity is largely unexplored. In spite of its presence in plasma along with abundant putative substrate LPC, the product LPA is found in plasma at unexpectedly low concentrations. It is plausible that the LPA-producing activity of ATX is regulated by its expression and by access to substrate(s). For this reason studying the interaction of enzyme with substrate is paramount to understanding the regulation of LPA production. Results: In this study we determine ATX hydrolytic activities toward several artificial and natural substrates. Two novel point mutations near the enzyme active site (H226Q and H434Q) confer attenuated activity toward all substrates tested. The Vmax for LPC compounds depends upon chain length and saturation; but this order does not differ among wild type and mutants. However the mutant forms show disproportionately low activity toward two artificial substrates, pNpTMP and FS-3. The mutant forms did not significantly stimulate migration responses at concentrations that produced a maximum response for WT-ATX, but this defect could be rescued by inclusion of exogenous LPC. Conclusion: H226Q-ATX and H434Q-ATX are the first point mutations of ATX/NPP2 demonstrated to differentially impair substrate hydrolysis, with hydrolysis of artificial substrates being disproportionately lower than that of LPC. This implies that H226 and H434 are important for substrate interaction. Assays that rely on hydrolyses of artificial substrates (FS-3 and pNpTMP), or that rely on hydrolysis of cell-derived substrate, might fail to detect certain mutated forms of ATX that are nonetheless capable of producing LPA in the presence of sufficient exogenous substrate. H420Q-ATX could not be differentiated from WT-ATX, indicating that histidine at position 420 is not required for any of the activities of ATX tested in this study. C1 [Koh, Eunjin; Bandle, Russell W.; Roberts, David D.; Stracke, Mary L.; Clair, Timothy] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Koh, Eunjin] Univ Virginia, Sch Med, Dept Cell Biol, Charlottesville, VA 22908 USA. RP Clair, T (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM ek4a@virginia.edu; bandler@mail.nih.gov; droberts@helix.nih.gov; stracke@helix.nih.gov; timclair@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 3 Z9 3 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD FEB 17 PY 2009 VL 8 AR 4 DI 10.1186/1476-511X-8-4 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 419BQ UT WOS:000264194500001 PM 19222837 ER PT J AU Roux, KJ Crisp, ML Liu, Q Kim, D Kozlov, S Stewart, CL Burke, B AF Roux, Kyle J. Crisp, Melissa L. Liu, Qian Kim, Daein Kozlov, Serguei Stewart, Colin L. Burke, Brian TI Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE centrosome; LINC complex; nuclear envelope ID SPECTRIN SUPERFAMILY; DOMAIN PROTEINS; LAMIN-A; ENVELOPE; MIGRATION; LOCALIZATION; MICROTUBULES; CYTOSKELETON; EXPRESSION; DROSOPHILA AB Nucleocytoplasmic coupling is mediated by outer nuclear membrane (ONM) nesprin proteins and inner nuclear membrane Sun proteins. Interactions spanning the perinuclear space create nesprin-Sun complexes connecting the cytoskeleton to nuclear components. A search for proteins displaying a conserved C-terminal sequence present in nesprins 1-3 identified nesprin 4 (Nesp4), a new member of this family. Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. Expression of Nesp4 is associated with dramatic changes in cellular organization involving relocation of the centrosome and Golgi apparatus relative to the nucleus. These effects can be accounted for entirely by Nesp4's kinesin-binding function. The implication is that Nesp4 may contribute to microtubule-dependent nuclear positioning. C1 [Roux, Kyle J.; Crisp, Melissa L.; Liu, Qian; Kim, Daein; Burke, Brian] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. [Stewart, Colin L.] 8A Biomed Grove, Med Biol Inst, Immunos, Singapore 138648, Singapore. [Kozlov, Serguei] SAIC Frederick Inc, Natl Canc Inst, Ctr Adv Preclin Res, Ft Detrick, MD 21702 USA. [Kozlov, Serguei] SAIC Frederick Inc, Natl Canc Inst, Mouse Canc Genet Program, Ft Detrick, MD 21702 USA. RP Burke, B (reprint author), Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. EM kroux@ufl.edu RI Kim, Dae In /G-7291-2012 FU National Institutes of Health FX We thank Kristen Verhey for kinesin cDNA constructs and very helpful advice and Arnoud Sonnenberg and Catherine Shanahan for antibodies and cDNAs. This work was supported by a grant from the National Institutes of Health. NR 47 TC 163 Z9 169 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2009 VL 106 IS 7 BP 2194 EP 2199 DI 10.1073/pnas.0808602106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 409OQ UT WOS:000263516100023 PM 19164528 ER PT J AU Wang, Q Mora-Jensen, H Weniger, MA Perez-Galan, P Wolford, C Hai, T Ron, D Chen, WP Trenkle, W Wiestner, A Ye, YH AF Wang, Qiuyan Mora-Jensen, Helena Weniger, Marc A. Perez-Galan, Patricia Wolford, Chris Hai, Tsonwin Ron, David Chen, Weiping Trenkle, William Wiestner, Adrian Ye, Yihong TI ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bortezomib; cancer therapy; ER stress/UPR; histone H2A; ubiquitin ID ENDOPLASMIC-RETICULUM; PROTEASOME INHIBITORS; INDUCED APOPTOSIS; MULTIPLE-MYELOMA; GENE-EXPRESSION; MESSENGER-RNA; UBIQUITINATION; BORTEZOMIB; PATHWAYS; LYMPHOMA AB The ubiquitin-proteasome system has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks endoplasmic reticulum (ER)associated protein degradation, has antitumor and biologic activities similar to bortezomib and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the up-regulation of the Bcl-2 homology3 (BH3)-only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes. First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anticancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death. C1 [Mora-Jensen, Helena; Weniger, Marc A.; Perez-Galan, Patricia; Wiestner, Adrian] NHLBI, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wang, Qiuyan; Ye, Yihong] NIDDKD, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wolford, Chris; Hai, Tsonwin] Ohio State Univ, Ctr Mol Neurobiol, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. [Ron, David] NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY 10016 USA. [Chen, Weiping] NIDDKD, Genom Core Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Trenkle, William] NIDDKD, Chem Biol Core Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov; yihongy@mail.nih.gov RI Hai, Tsonwin/H-4480-2011; Hai, Tsonwin/E-3185-2011 OI Hai, Tsonwin/0000-0003-4510-0315; Hai, Tsonwin/0000-0003-4510-0315 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Research Program of the National Heart, Lung, and Blood Institute; National Institutes of Health [DK47119, ES08681, CA118306, DK064938] FX We thank H. Wang(University of Alabama, Birmingham, AL), L. Staudt (National Cancer Institute, Bethesda, MD), H. Puthalakath, and A. Strasser (The Walter and Eliza Hall Institute of Medical Research, Melbourne), R. Prywes (Columbia University, New York), F. Urano (University of Massachusetts, Worcester, MA), and S. Fang (University of Maryland, Baltimore) for reagents; G. Felsenfeld (National Institute of Diabetes and Digestive and Kidney Diseases), C. Jin (National Institute of Diabetes and Digestive and Kidney Diseases), Z. Wang, and G. Wei (National Heart, Lung, and Blood Institute) for helpful discussions; F. Gibellini, and C. Chapman for help with cell culture; and M. Krause, M. Gellert, G. Felsenfeld, and A. Shaffer (National Cancer Institute) for critical reading of the manuscript. The research is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, and the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health, and by National Institutes of Health grants DK47119 and ES08681 to D. Ron, and CA118306 and DK064938 to T. Hai. NR 36 TC 143 Z9 144 U1 2 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2009 VL 106 IS 7 BP 2200 EP 2205 DI 10.1073/pnas.0807611106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 409OQ UT WOS:000263516100024 PM 19164757 ER PT J AU Hong, SK Dawid, IB AF Hong, Sung-Kook Dawid, Igor B. TI FGF-dependent left-right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ciliogenesis; Kupffer's vesicle; laterality ID LEFT-RIGHT AXIS; FIBROBLAST-GROWTH-FACTOR; BARDET-BIEDL-SYNDROME; MOTOR PROTEIN; NODAL FLOW; GENE; SPECIFICATION; VERTEBRATES; EMBRYO; HEART AB Establishment of left-right asymmetry in vertebrates requires nodal, Wnt-PCP and FGF signaling and involves ciliogenesis in a laterality organ. Effector genes through which FGF signaling affects laterality have not been described. We isolated the zebrafish ier2 and fibp1 genes as FGF target genes and show that their protein products interact. Knock down of these factors interferes with establishment of organ laterality and causes defective cilia formation in Kupffer's Vesicle, the zebrafish laterality organ. Cilia are also lost after suppression of FGF8, but can be rescued by injection of ier2 and fibp1 mRNA. We conclude that Ier2 and Fibp1 mediate FGF signaling in ciliogenesis in Kupffer's Vesicle and in the establishment of laterality in the zebrafish embryo. C1 [Hong, Sung-Kook; Dawid, Igor B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM idawid@mail.nih.gov FU Intramural Research Program of the National Institute of Child Health; Human Development, National Institutes of Health FX We thank J. M. Gonzales for fish care, M. Tsang for sharing clones, and K. Tanegashima and H. Zhao for help in microarray experiment. This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health. NR 44 TC 54 Z9 58 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2009 VL 106 IS 7 BP 2230 EP 2235 DI 10.1073/pnas.0812880106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 409OQ UT WOS:000263516100029 PM 19164561 ER PT J AU Kim, SI Bultman, SJ Kiefer, CM Dean, A Bresnick, EH AF Kim, Shin-Il Bultman, Scott J. Kiefer, Christine M. Dean, Ann Bresnick, Emery H. TI BRG1 requirement for long-range interaction of a locus control region with a downstream promoter SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromatin; erythroid; GATA-1; globin; transcription ID BETA-GLOBIN LOCUS; TRANSCRIPTION FACTOR GATA-1; CHROMATIN DOMAIN ACTIVATION; HISTONE ACETYLATION PATTERN; RNA-POLYMERASE-II; ERYTHROID-DIFFERENTIATION; BINDING-PROTEIN; INTERGENIC TRANSCRIPTION; FACTOR COMPLEXES; SWI/SNF COMPLEX AB The dynamic packaging of DNA into chromatin is a fundamental step in the control of diverse nuclear processes. Whereas certain transcription factors and chromosomal components promote the formation of higher-order chromatin loops, the co-regulator machinery mediating loop assembly and disassembly is unknown. Using mice bearing a hypomorphic allele of the BRG1 chromatin remodeler, we demonstrate that the Brg1 mutation abrogated a cell type-specific loop between the beta-globin locus control region and the downstream beta major promoter, despite trans-acting factor occupancy at both sites. By contrast, distinct loops were insensitive to the Brg1 mutation. Molecular analysis with a conditional allele of GATA-1, a key regulator of hematopoiesis, in a novel cell-based system provided additional evidence that BRG1 functions early in chromatin domain activation to mediate looping. Although the paradigm in which chromatin remodelers induce nucleosome structural transitions is well established, our results demonstrating an essential role of BRG1 in the genesis of specific chromatin loops expands the repertoire of their functions. C1 [Kim, Shin-Il; Bresnick, Emery H.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pharmacol, Madison, WI 53706 USA. [Bultman, Scott J.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Kiefer, Christine M.; Dean, Ann] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bresnick, EH (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Pharmacol, Madison, WI 53706 USA. EM ehbresni@wisc.edu FU National Institutes of Health [DK50107]; AHA Predoctoral Fellowship; Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was funded by National Institutes of Health Grant DK50107 ( to E. H. B.), an AHA Predoctoral Fellowship ( S. I. K.), and the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases ( C. M. K. and A. D.). NR 59 TC 77 Z9 83 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2009 VL 106 IS 7 BP 2259 EP 2264 DI 10.1073/pnas.0806420106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 409OQ UT WOS:000263516100034 PM 19171905 ER PT J AU Xia, MH Huang, RL Guo, V Southall, N Cho, MH Inglese, J Austin, CP Nirenberg, M AF Xia, Menghang Huang, Ruili Guo, Vicky Southall, Noel Cho, Ming-Hsuang Inglese, James Austin, Christopher P. Nirenberg, Marshall TI Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE memory enhancer; phosphodiesterase inhibitor; quantitative high-throughput screening ID RUBINSTEIN-TAYBI-SYNDROME; ELEMENT-BINDING PROTEIN; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; PHOSPHORYLATED CREB; GENE-TRANSCRIPTION; MOUSE MODEL; INHIBITOR; DROSOPHILA; MICE; PDE4 AB Many studies have implicated the cAMP Response Element Binding (CREB) protein signaling pathway in long-term memory. To identify small molecule enhancers of CREB activation of gene expression, we screened approximate to 73,000 compounds, each at 7-15 concentrations in a quantitative high-throughput screening (qHTS) format, for activity in cells by assaying CREB mediated beta-lactamase reporter gene expression. We identified 1,800 compounds that potentiated CREB mediated gene expression, with potencies as low as 16 nM, comprising 96 structural series. Mechanisms of action were systematically determined, and compounds that affect phosphodiesterase 4, protein kinase A, and cAMP production were identified, as well as compounds that affect CREB signaling via apparently unidentified mechanisms. qHTS folowed by interrogation of pathway targets is an efficient paradigm for lead generation for chemical genomics and drug development. C1 [Xia, Menghang; Huang, Ruili; Southall, Noel; Cho, Ming-Hsuang; Inglese, James; Austin, Christopher P.] NHLBI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Guo, Vicky; Nirenberg, Marshall] NHLBI, NIH, Lab Biochem Genet, Bethesda, MD 20892 USA. RP Austin, CP (reprint author), NHLBI, NIH, Chem Genom Ctr, Bldg 10, Bethesda, MD 20892 USA. EM austinc@mail.nih.gov; mnirenberg@nih.gov RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; National Human Genome Research Institute; National Heart, Lung, and Blood Institute; National Institutes of Health FX We thank S. Michael, C. Klumpp and Paul Shinn for assistance with automated screening, and Isaac Lichtenstein for assistance in the preparation of the manuscript. This work was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute and National Heart, Lung, and Blood Institute, National Institutes of Health. NR 39 TC 29 Z9 30 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2009 VL 106 IS 7 BP 2412 EP 2417 DI 10.1073/pnas.0813020106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 409OQ UT WOS:000263516100060 PM 19196967 ER PT J AU Yu, MJ Miller, RL Uawithya, P Rinschen, MM Khositseth, S Braucht, DWW Chou, CL Pisitkun, T Nelson, RD Knepper, MA AF Yu, Ming-Jiun Miller, R. Lance Uawithya, Panapat Rinschen, Markus M. Khositseth, Sookkasem Braucht, Drew W. W. Chou, Chung-Lin Pisitkun, Trairak Nelson, Raoul D. Knepper, Mark A. TI Systems-level analysis of cell-specific AQP2 gene expression in renal collecting duct SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aquaporin 2; kidney; microarrays; transcription; vasopressin ID GREEN FLUORESCENT PROTEIN; LC-MS/MS ANALYSIS; WATER CHANNEL; AQUAPORIN-2 GENE; TRANSGENIC MICE; RAT-KIDNEY; PRINCIPAL CELLS; MOUSE KIDNEY; VASOPRESSIN; TRANSCRIPTION AB We used a systems biology-based approach to investigate the basis of cell-specific expression of the water channel aquaporin-2 (AQP2) in the renal collecting duct. Computational analysis of the 5'-flanking region of the AQP2 gene (Genomatix) revealed 2 conserved clusters of putative transcriptional regulator (TR) binding elements (BEs) centered at -513 bp (corresponding to the SF1, NFAT, and FKHD TR families) and -224 bp (corresponding to the AP2, SRF, CREB, GATA, and HOX TR families). Three other conserved motifs corresponded to the ETS, EBOX, and RXR TR families. To identify TRs that potentially bind to these BEs, we carried out mRNA profiling (Affymetrix) in mouse mpkCCDc14 collecting duct cells, revealing expression of 25 TRs that are also expressed in native inner medullary collecting duct. One showed a significant positive correlation with AQP2 mRNA abundance among mpkCCD subclones (Ets1), and 2 showed a significant negative correlation (Elf1 and an orphan nuclear receptor Nr1h2). Transcriptomic profiling in native proximal tubules (PT), medullary thick ascending limbs (MTAL), and IMCDs from kidney identified 14 TRs (including Ets1 and HoxD3) expressed in the IMCD but not PT or MTAL (candidate AQP2 enhancer roles), and 5 TRs (including HoxA5, HoxA9 and HoxA10) expressed in PT and MTAL but not in IMCD (candidate AQP2 repressor roles). In luciferase reporter assays, overexpression of 3 ETS family TRs transactivated the mouse proximal AQP2 promoter. The results implicate ETS family TRs in cell-specific expression of AQP2 and point to HOX, RXR, CREB and GATA family TRs as playing likely additional roles. C1 [Yu, Ming-Jiun; Uawithya, Panapat; Rinschen, Markus M.; Khositseth, Sookkasem; Braucht, Drew W. W.; Chou, Chung-Lin; Pisitkun, Trairak; Knepper, Mark A.] NHLBI, NIH, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. [Miller, R. Lance; Nelson, Raoul D.] Univ Utah, Dept Pediat, Div Nephrol, Salt Lake City, UT 84132 USA. RP Knepper, MA (reprint author), NHLBI, NIH, Kidney & Electrolyte Metab Lab, Bldg 10, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 FU Division of Intramural Research, NHLBI [ZO1-HL001285]; National Institutes of Health [DK053990]; Braun Foundation (Melsungen, Germany); Biomedical Sciences Exchange Program (Hannover, Germany) FX We thank Prof. M. Kretzler (University of Michigan) and Dr. C.-H. Tai (National Cancer Institute) for advice regarding Genomatix software. These studies used the Gene Expression Core Facility (Dr. N. Raghavachari, Director), Light Microscopy Core Facility (Dr. C. Combs, Director), and Flow Cytometry Core Facility (Dr. J. P. McCoy, Director) of the NHLBI. Support: Division of Intramural Research, NHLBI (project ZO1-HL001285, MAK) and National Institutes of Health Grant DK053990 (to R. D. N. and R. L. M.). M. M. R. was supported by the Braun Foundation (Melsungen, Germany) and the Biomedical Sciences Exchange Program (Hannover, Germany). NR 32 TC 54 Z9 55 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2009 VL 106 IS 7 BP 2441 EP 2446 DI 10.1073/pnas.0813002106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 409OQ UT WOS:000263516100065 PM 19190182 ER PT J AU Kino, T VanHook, AM AF Kino, Tomoshige VanHook, Annalisa M. TI Science Signaling Podcast: 17 February 2009 SO SCIENCE SIGNALING LA English DT Editorial Material C1 [Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Natl Inst Hlth, Bethesda, MD 20892 USA. [VanHook, Annalisa M.] Amer Assoc Advancement Sci, Washington, DC 20005 USA. RP Kino, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD FEB 17 PY 2009 VL 2 IS 58 AR pc4 DI 10.1126/scisignal.258pc4 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 567UP UT WOS:000275472400001 ER PT J AU Feng, CG Zheng, LX Lenardo, MJ Sher, A AF Feng, Carl G. Zheng, Lixin Lenardo, Michael J. Sher, Alan TI Interferon-inducible immunity-related GTPase Irgm1 regulates IFN gamma-dependent host defense, lymphocyte survival and autophagy SO AUTOPHAGY LA English DT Article DE autophagy; cell death; IFN gamma; Th1; lymphocyte homeostasis; GTPase; Irgm1 ID CELL-DEATH; INTRACELLULAR PATHOGENS; MICE DEFICIENT; P47 GTPASES; LRG-47; PROLIFERATION; TUBERCULOSIS; RESISTANCE AB IFN gamma is a pleiotropic cytokine that plays a key role in host resistance, yet when not properly regulated can become detrimental to the host. The interferon-inducible Immunity Related GTPase family M member I (Irgm1), previously characterized as an effector molecule required for macrophage microbicidal activity has been shown recently to control IFN gamma-dependent cell survival and host resistance. Irgm1 regulates the expansion/survival of mature effector CD4(+) T lymphocytes by protecting them from IFN gamma-induced autophagic cell death. Importantly, mice deficient in both IFN gamma and Irgm1 were rescued from the lymphocyte depletion and increased mortality that typically occurs in Irgm1(-/-) animals following pathogen exposure. We propose that Irgm1 plays a major role in maintaining T lymphocyte homeostasis during host IFN gamma responses by protecting these cells from autophagy-dependent cell death. C1 [Feng, Carl G.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Zheng, Lixin; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Feng, CG (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Room 6150,Bldg 50,50 South Dr, Bethesda, MD 20892 USA. EM cfeng@niaid.nih.gov FU NIAID; NIH; DHHS FX This research was supported by the Intramural Research Program of NIAID, NIH, DHHS. NR 18 TC 22 Z9 22 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD FEB 16 PY 2009 VL 5 IS 2 BP 232 EP 234 PG 3 WC Cell Biology SC Cell Biology GA 412KO UT WOS:000263723900014 PM 19066452 ER PT J AU Minamimoto, T Hori, Y Kimura, M AF Minamimoto, Takafumi Hori, Yukiko Kimura, Minoru TI Roles of the thalamic CM-PF complex-Basal ganglia circuit in externally driven rebias of action SO BRAIN RESEARCH BULLETIN LA English DT Review DE Centromedian; Parafascicular; Reward; Striatum; Attention; Pain; Thalamus ID SQUIRREL-MONKEY; EFFERENT CONNECTIONS; SUPERIOR COLLICULUS; GLOBUS-PALLIDUS; SUBCORTICAL PROJECTIONS; PARAFASCICULAR COMPLEX; SYNAPTIC ORGANIZATION; STRIATAL INTERNEURONS; RETICULAR-FORMATION; CAUDATE-NUCLEUS AB The centromedian (CM)-parafascicular (PF) nuclear complex in the primate thalamus has reciprocal and specific connections with the basal ganglia. It has been argued that the thalamic CM-PF complex has a role in pain processing and attention. However, the functional relationship of this complex with the basal ganglia, which is considered to have a role in goal-directed movement, has not been well characterized. Here we present a hypothetical view that the thalamic CM-PF complex-basal ganglia circuit plays complementary roles in response bias. The basal ganglia are involved in creating 'reward-based pre-action bias', which facilitates the selection and execution of an action associated with a higher value. In contrast, when an action with a lower value is unexpectedly requested, the CM-PF induces an 'externally driven rebiasing' process in the striatum that aborts the pre-action bias and assists selecting and executing actions appropriate for unexpected situations. This model provides a framework for how the thalamic CM-PF complex and the basal ganglia function together in general for unexpected situations. (C) 2008 Elsevier Inc. All rights reserved. C1 [Minamimoto, Takafumi] Natl Inst Radiol Sci, Mol Imaging Ctr, Dept Mol Neuroimaging, Inage Ku, Chiba 2638555, Japan. [Minamimoto, Takafumi] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Minamimoto, Takafumi; Hori, Yukiko; Kimura, Minoru] Kyoto Prefectural Univ Med, Dept Physiol, Kyoto 6028566, Japan. RP Minamimoto, T (reprint author), Natl Inst Radiol Sci, Mol Imaging Ctr, Dept Mol Neuroimaging, Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan. EM minamoto@nirs.go.jp RI Minamimoto, Takafumi/D-6610-2012 OI Minamimoto, Takafumi/0000-0003-4305-0174 FU JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH FX article. T.M. was partly supported by JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH. NR 50 TC 30 Z9 31 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD FEB 16 PY 2009 VL 78 IS 2-3 BP 75 EP 79 DI 10.1016/j.brainresbull.2008.08.013 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 408JJ UT WOS:000263431000005 PM 18793702 ER PT J AU Zhu, JF Davidson, TS Wei, G Jankovic, D Cui, KR Schones, DE Guo, LY Zhao, KJ Shevach, EM Paul, WE AF Zhu, Jinfang Davidson, Todd S. Wei, Gang Jankovic, Dragana Cui, Kairong Schones, Dustin E. Guo, Liying Zhao, Keji Shevach, Ethan M. Paul, William E. TI Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103(+) inducible regulatory T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TRANSCRIPTIONAL REPRESSOR GFI1; HEMATOPOIETIC STEM-CELLS; ZINC-FINGER PROTEIN; TH2 DIFFERENTIATION; INTERFERON-GAMMA; FACTOR GATA-3; CUTTING EDGE; FACTOR FOXP3; LINEAGE; RESPONSES AB Growth factor independent 1 (Gfi-1), a transcriptional repressor, is transiently induced during T cell activation. Interleukin (IL) 4 further induces Gfi-1, resulting in optimal Th2 cell expansion. We report a second important function of Gfi-1 in CD4 T cells: prevention of alternative differentiation by Th2 cells, and inhibition of differentiation of naive CD4 T cells to either Th17 or inducible regulatory T (iTreg) cells. In Gfi1(-/-) Th2 cells, the Rorc, Il23r, and Cd103 loci showed histone 3 lysine 4 trimethylation modifications that were lacking in wild-type Th2 cells, implying that Gfi-1 is critical for epigenetic regulation of Th17 and iTreg cell-related genes in Th2 cells. Enforced Gfi-1 expression inhibited IL-17 production and iTreg cell differentiation. Furthermore, a key inducer of both Th17 and iTreg cell differentiation, transforming growth factor beta, repressed Gfi-1 expression, implying a reciprocal negative regulation of CD4 T cell fate determination. Chromatin immunoprecipitation showed direct binding of the Gfi-1-lysine-specific demethylase 1 repressive complex to the intergenic region of Il17a/Il17f loci and to intron 1 of Cd103. T cell-specific Gfi1 conditional knockout mice displayed a striking delay in the onset of experimental allergic encephalitis correlated with a dramatic increase of Foxp3(+)CD103(+) CD4 T cells. Thus, Gfi-1 plays a critical role both in enhancing Th2 cell expansion and in repressing induction of Th17 and CD103(+) iTreg cells. C1 [Zhu, Jinfang; Davidson, Todd S.; Guo, Liying; Shevach, Ethan M.; Paul, William E.] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Jankovic, Dragana] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Wei, Gang; Cui, Kairong; Schones, Dustin E.; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. EM jfzhu@niaid.nih.gov RI Wei, Gang/A-3291-2011; Zhu, Jinfang/B-7574-2012 FU Division of Intramural Research; NIAID; Division of Intramural Research, National Heart, Lung, and Blood Institute; National Institutes of Health FX This work is supported by the Division of Intramural Research, NIAID and the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 57 TC 86 Z9 87 U1 0 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 16 PY 2009 VL 206 IS 2 BP 329 EP 341 DI 10.1084/jem.20081666 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VP UT WOS:000266008800008 PM 19188499 ER PT J AU Goldszmid, RS Coppens, I Lev, A Caspar, P Mellman, I Sher, A AF Goldszmid, Romina S. Coppens, Isabelle Lev, Avital Caspar, Pat Mellman, Ira Sher, Alan TI Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CD8(+) T-CELLS; IFN-GAMMA PRODUCTION; ENDOPLASMIC-RETICULUM; MEMBRANE-FRACTION; IN-VITRO; FUSION; IMMUNITY; COMPLEX; MITOCHONDRIA; MACROPHAGES AB Toxoplasma gondii tachyzoites infect host cells by an active invasion process leading to the formation of a specialized compartment, the parasitophorous vacuole (PV). PVs resist fusion with host cell endosomes and lysosomes and are thus distinct from phagosomes. Because the parasite remains sequestered within the PV, it is unclear how T. gondii-derived antigens (Ag's) access the major histocompatibility complex (MHC) class I pathway for presentation to CD8(+) T cells. We demonstrate that recruitment of host endoplasmic reticulum (hER) to the PV in T. gondii-infected dendritic cells (DCs) directly correlates with cross-priming of CD8(+) T cells. Furthermore, we document by immunoelectron microscopy the transfer of hER components into the PV, a process indicative of direct fusion between the two compartments. In strong contrast, no association between hER and phagosomes or Ag presentation activity was observed in DCs containing phagocytosed live or dead parasites. Importantly, cross-presentation of parasite-derived Ag in actively infected cells was blocked when hER retrotranslocation was inhibited, indicating that the hER serves as a conduit for the transport of Ag between the PV and host cytosol. Collectively, these findings demonstrate that pathogen-driven hER-PV interaction can serve as an important mechanism for Ag entry into the MHC class I pathway and CD8(+) T cell cross-priming. C1 [Goldszmid, Romina S.; Caspar, Pat; Sher, Alan] NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Lev, Avital] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Coppens, Isabelle] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Mellman, Ira] Genentech Inc, San Francisco, CA 94080 USA. RP Goldszmid, RS (reprint author), NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM rgoldszmid@niaid.nih.gov; asher@niaid.nih.gov FU Intramural Research Program of the NIAID FX This research was supported by the Intramural Research Program of the NIAID. NR 51 TC 90 Z9 91 U1 1 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 16 PY 2009 VL 206 IS 2 BP 399 EP 410 DI 10.1084/jem.20082108 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VP UT WOS:000266008800013 PM 19153244 ER PT J AU Tomihara, K Soga, T Nomura, M Korach, KS Gustafsson, JA Pfaff, DW Ogawa, S AF Tomihara, Kazuya Soga, Tomoko Nomura, Masayoshi Korach, Kenneth S. Gustafsson, Jan-Ake Pfaff, Donald W. Ogawa, Sonoko TI Effect of ER-beta gene disruption on estrogenic regulation of anxiety in female mice SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Fear; Emotion; Social anxiety; Behavioral tests; Knockout mouse ID ELEVATED PLUS-MAZE; RECEPTOR-BETA; OVARIECTOMIZED RATS; POSTMENOPAUSAL WOMEN; WORKING-MEMORY; MIDBRAIN RAPHE; DEFICIENT MICE; ESTROUS-CYCLE; BEHAVIOR; OXYTOCIN AB It has been shown that long-term estrogen treatment in gonadectomized female mice increases anxiety levels. On the other hand, a recent study has reported that estrogen may down-regulate the levels of anxiety by acting through estrogen receptor (ER) beta. In the present study, we investigated the role of ER-beta in the regulation of anxiety levels in female mice after long-term estrogen treatment. Gonadectomized ER-beta knockout (beta ERKO) female mice and their wild type (beta WT) littermates were implanted several different doses (experiment 1: 2.0 mu g/day, experiment 2: 1.0, 0.4, 0.2 or 0.1 mu g/day) of an estradiol benzoate (EB) or placebo pellet. Ten days after pellet implant, behavioral tests commenced to measure the anxiety levels (experiment 1: light-dark transition test (LDT), experiment 2: LDT, elevated plus maze test (EPM) and social investigation test (SIT)). We found that, at higher-doses, long-term treatment of EB had anxiogenic effects in both beta WT and beta ERKO mice as indicated by a decrease of the time spent in the light side and the number of transitions between two sides during LOT. In contrast, several behavioral measurements indicated that the lower-doses treatment of EB might reduce the anxiety levels possibly through ER-beta. Particularly, the anxiolytic effects of EB in the SIT were more pronounced in beta MT mice than beta ERKO mice. Together, the findings in the present study suggest that estrogen may have both anxiolytic and anxiogenic effects in female mice, and that ER-beta gene disruption did not affect anxiogenic regulation by estrogen in female mice, but partially affected anxiolytic regulation. (C) 2008 Elsevier Inc. All rights reserved. C1 [Tomihara, Kazuya] Kagoshima Univ, Fac Law Econ & Humanities, Dept Psychol, Kagoshima 8900065, Japan. [Tomihara, Kazuya; Soga, Tomoko; Nomura, Masayoshi; Pfaff, Donald W.; Ogawa, Sonoko] Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. [Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Gustafsson, Jan-Ake] Karolinska Inst, Dept Biosci & Nutr, S-14186 Huddinge, Sweden. RP Tomihara, K (reprint author), Kagoshima Univ, Fac Law Econ & Humanities, Dept Psychol, 1-21-30 Korimoto, Kagoshima 8900065, Japan. EM tomihara@leh.kagoshima-u.ac.jp OI Korach, Kenneth/0000-0002-7765-418X FU Ministry of Education, Culture, Sports, Science and Technology of Japan; National Institute of Mental Health [MH-62147] FX This work was supported by the Overseas Research Grant of the Ministry of Education, Culture, Sports, Science and Technology of Japan to K. T. and the National Institute of Mental Health Grants MH-62147 to S. O. We thank Ms. Lee Holmes and Mr. Walter Chan for their assistance. NR 40 TC 39 Z9 41 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD FEB 16 PY 2009 VL 96 IS 2 BP 300 EP 306 DI 10.1016/j.physbeh.2008.10.014 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 408AO UT WOS:000263405600013 PM 18996135 ER PT J AU Hou, SJ Kovac, P AF Hou, Shujie Kovac, Pavol TI Conjugation-Amenable Tetrasaccharide of the Side Chain of the Major Glycoprotein of the Bacillus anthracis Exosporium: A Large-Scale Preparation SO SYNTHESIS-STUTTGART LA English DT Article DE carbohydrates; oligosaccharides; glycosylations; conjugation; amines ID VACCINE; OLIGOSACCHARIDE; GLYCOSIDES; ANTHROSE; BCLA AB A new strategy towards the synthesis of the title tetrasaccharide is described. The novelty within the common (2+2) assembly lies ill the use of a disaccharide glycosyl donor having the fully assembled anthrose as one of the constituent sugar residues. Also, the final deprotection and transformation of the spacer arm into an amine, to form a Structure amenable to conjugation by different conjugation techniques, is a one-pot conversion. Compared to other synthetic approaches, the present synthesis involves fewer chemical manipulations with the assembled tetrasaccharide as well as fewer overall numbers of synthetic steps towards this important antigenic component of a potential conjugate vaccine for anthrax. C1 [Hou, Shujie; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Hou, SJ (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov FU Intramural Research Program of the NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 19 TC 7 Z9 7 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 J9 SYNTHESIS-STUTTGART JI Synthesis PD FEB 16 PY 2009 IS 4 BP 545 EP 550 DI 10.1055/s-0028-1083338 PG 6 WC Chemistry, Organic SC Chemistry GA 417FE UT WOS:000264061100003 ER PT J AU George, SM Mayne, ST Leitzmann, MF Park, Y Schatzkin, A Flood, A Hollenbeck, A Subar, AF AF George, Stephanie Materese Mayne, Susan T. Leitzmann, Michael F. Park, Yikyung Schatzkin, Arthur Flood, Andrew Hollenbeck, Albert Subar, Amy F. TI Dietary Glycemic Index, Glycemic Load, and Risk of Cancer: A Prospective Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diet; glycemic index; neoplasms; prospective studies ID POSTMENOPAUSAL BREAST-CANCER; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; COLORECTAL-CANCER; CARBOHYDRATE INTAKE; PANCREATIC-CANCER; ENDOMETRIAL CANCER; WOMENS HEALTH; CARDIOVASCULAR-DISEASE; NATIONAL-INSTITUTES AB Previous studies have provided limited evidence for a harmful effect of high glycemic index and dietary glycemic load on cancer. The authors analyzed associations among glycemic index, glycemic load, and risk of cancer in women and men in the National Institutes of Health-AARP Diet and Health Study. Published glycemic index values were assigned to 225 foods/food groups. Glycemic load was calculated by multiplying the glycemic index, carbohydrate content, and intake frequency of individual foods reported on a food frequency questionnaire. From 1995 through 2003, the authors identified 15,215 and 33,203 cancer cases in women and men, respectively. Cox proportional hazards models were used to estimate multivariate relative risks and 95% confidence intervals. For women and men, respectively, the relative risks for total cancer for high versus low glycemic index were 1.03 (P(trend) = 0.217) and 1.04 (P(trend) = 0.012) and, for glycemic load, were 0.90 (P(trend) = 0.024) and 0.93 (P(trend) = 0.01). Associations with total cancer held only among the overweight for glycemic index and among those of healthy weight for glycemic load. These findings suggest that glycemic index and glycemic load are not strong predictors of cancer incidence. The direction and small magnitude of associations might be explained by the manner in which high glycemic index and glycemic load track with overall diet and lifestyle patterns. C1 [George, Stephanie Materese; Mayne, Susan T.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [George, Stephanie Materese; Park, Yikyung; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Leitzmann, Michael F.] Univ Regensburg, Inst Epidemiol & Preventat Med, Regensburg, Germany. [Flood, Andrew] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN USA. [Hollenbeck, Albert] AARP, Washington, DC USA. [Subar, Amy F.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Subar, AF (reprint author), 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. EM subara@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Cancer Institute; National Institutes of Health FX This research was supported (in part) by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 67 TC 42 Z9 43 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2009 VL 169 IS 4 BP 462 EP 472 DI 10.1093/aje/kwn347 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 407ZR UT WOS:000263403300010 PM 19095757 ER PT J AU Nabel, EG AF Nabel, Elizabeth G. TI Notes from the NHLBI Director Transitions SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2009 VL 179 IS 4 BP 263 EP 264 DI 10.1164/rccm.200812-1848ED PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 406FL UT WOS:000263280300001 PM 19201927 ER PT J AU Anchordoquy, TJ Molina, MD Kempner, ES AF Anchordoquy, T. J. Molina, M. dC. Kempner, E. S. TI A radiation target method for size determination of supercoiled plasmid DNA SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE DNA; Plasmid; Radiation; Target analysis ID DOUBLE-STRAND BREAKS; IONIZING-RADIATION; COMPLEXES; ELECTRONS; RAYS AB Supercoiled DNA plasmids were exposed in the frozen state to high-energy electrons. Surviving super-coiled molecules were separated from their degradation products (e.g., open circle and linear forms) by agarose gel electrophoresis and subsequently quantified by staining and image analysis. Complex survival Curves were analyzed using radiation target theory, yielding the radiation-sensitive mass of each form. One of the irradiated plasmids was transfected into cells, permitting radiation analysis of gene expression. Loss of this function was associated with a mass much smaller than the entire plasmid molecule, indicating a lack of energy transfer in amounts sufficient to cause structural damage along the DNA polynucleotide. The method of radiation target analysis can be applied to study both structure and function of DNA. (C) Published by Elsevier Inc. C1 [Kempner, E. S.] NIAMSD, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Anchordoquy, T. J.; Molina, M. dC.] Univ Colorado, Hlth Sci Ctr, Sch Pharm, Denver, CO 80262 USA. RP Kempner, ES (reprint author), NIAMSD, Off Sci Director, NIH, Room 1524,Bldg 50, Bethesda, MD 20892 USA. EM eskempner@yahoo.com FU National Institutes of Health through NIBIB [1 R01 EB005476-01]; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal; Skin Diseases of the National Institutes of Health FX The authors thank Dr. Martin Gellert for many helpful discussions. Support for these studies was derived in part from the National Institutes of Health through NIBIB Grant 1 R01 EB005476-01 to T.J.A. and partially from the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 17 TC 5 Z9 5 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD FEB 15 PY 2009 VL 385 IS 2 BP 229 EP 233 DI 10.1016/j.ab.2008.10.049 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 400OI UT WOS:000262877400007 PM 19028447 ER PT J AU Carlson, BA Schweizer, U Perella, C Shrimali, RK Feigenbaum, L Shen, L Speransky, S Floss, T Jeong, SJ Watts, J Hoffmann, V Combs, GF Gladyshev, VN Hatfield, DL AF Carlson, Bradley A. Schweizer, Ulrich Perella, Christine Shrimali, Rajeev K. Feigenbaum, Lionel Shen, Liya Speransky, Svetlana Floss, Thomas Jeong, Soon-Jeong Watts, Jennifer Hoffmann, Victoria Combs, Gerald F., Jr. Gladyshev, Vadim N. Hatfield, Dolph L. TI The selenocysteine tRNA STAF-binding region is essential for adequate selenocysteine tRNA status, selenoprotein expression and early age survival of mice SO BIOCHEMICAL JOURNAL LA English DT Article DE selenium; selenocysteine (Sec) tRNA gene (Trsp); selenoprotein; Sec tRNA gene transcription activating factor (STAF); survival rate; tRNA transcription ID TRANSCRIPTION-ACTIVATING FACTOR; TRNA(SEC) GENE-TRANSCRIPTION; PHOSPHOSERINE TRANSFER-RNA; MOUSE MAMMARY-GLAND; SMALL NUCLEAR-RNA; ZINC-FINGER; TRANSGENIC MICE; POLYMERASE-III; SELENIUM; PROMOTER AB STAF [Sec (selenocysteine) tRNA gene transcription activating factor] is a transcription activating factor for a number of RNA Pol III- and RNA Pol II-dependent genes including the Trsp [Sec tRNA gene], which in turn controls the expression of all selenoproteins. Here, the role of STAF in regulating expression of Sec tRNA and selenoproteins was examined. We generated transgenic mice expressing the Trsp transgene lacking the STAF-binding site and made these mice dependent on the transgene for survival by removing the wild-type Trsp. The level of Sec tRNA was unaffected or slightly elevated in heart and testis, but reduced similar to 60% in liver and kidney, similar to 70% in lung and spleen and similar to 80% in brain and muscle compared with the corresponding organs in control mice. Moreover, the ratio of the two isoforms of Sec tRNA that differ by methylation at position 34 (Um34) was altered significantly, and the Um34-containing form was substantially reduced in all tissues examined. Selenoprotein expression in these animals was most affected in tissues in which the Sec tRNA levels were most severely reduced. Importantly, mice had a neurological phenotype strikingly similar to that of mice in which the selenoprotein P gene had been removed and their life span was substantially reduced. The results indicate that STAF influences selenoprotein expression by enhancing Trsp synthesis in an organ-specific manner and by controlling Sec tRNA modification in each tissue examined. C1 [Carlson, Bradley A.; Shrimali, Rajeev K.; Jeong, Soon-Jeong; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Schweizer, Ulrich] Charite Univ Med Berlin, Neurosci Res Ctr, D-10117 Berlin, Germany. [Perella, Christine; Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. [Shen, Liya; Speransky, Svetlana] NCI, Lab Cellular Carcinogenesis & Tumor Promot & GMCF, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Floss, Thomas] Helmholtz Ctr Munich, Inst Dev Genet, D-85764 Neuherberg, Germany. [Watts, Jennifer; Combs, Gerald F., Jr.] USDA ARS, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58201 USA. [Hoffmann, Victoria] NIH, Diagnost & Res Serv Branch, Off Director, Bethesda, MD 20189 USA. [Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013; Schweizer, Ulrich/E-8105-2013; OI Schweizer, Ulrich/0000-0003-1380-4780 FU Center for Cancer Research; NCI; NIH; Deutsche Forschungsgemeinschaft [SFB665, Scho849/1-21] FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH, to D.L.H., NIH grants to VXG, and Deutsche Forschungsgemeinschaft grants [DFG SFB665, Scho849/1-21 to U.S. NR 47 TC 22 Z9 22 U1 0 U2 4 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD FEB 15 PY 2009 VL 418 BP 61 EP 71 DI 10.1042/BJ20081304 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 407BF UT WOS:000263337900006 PM 18973473 ER PT J AU Zhang, B Li, H Riggins, RB Zhan, M Xuan, J Zhang, Z Hoffman, EP Clarke, R Wang, Y AF Zhang, Bai Li, Huai Riggins, Rebecca B. Zhan, Ming Xuan, Jianhua Zhang, Zhen Hoffman, Eric P. Clarke, Robert Wang, Yue TI Differential dependency network analysis to identify condition-specific topological changes in biological networks SO BIOINFORMATICS LA English DT Article ID EMBRYONIC STEM-CELLS; GENE-EXPRESSION DATA; ESTROGEN-RECEPTOR-ALPHA; BREAST-CANCER; REGULATORY NETWORKS; VARIABLE SELECTION; ANTIESTROGEN RESISTANCE; BAYESIAN NETWORKS; SYSTEMS BIOLOGY; MICROARRAY DATA AB Motivation: Significant efforts have been made to acquire data under different conditions and to construct static networks that can explain various gene regulation mechanisms. However, gene regulatory networks are dynamic and condition-specific; under different conditions, networks exhibit different regulation patterns accompanied by different transcriptional network topologies. Thus, an investigation on the topological changes in transcriptional networks can facilitate the understanding of cell development or provide novel insights into the pathophysiology of certain diseases, and help identify the key genetic players that could serve as biomarkers or drug targets. Results: Here, we report a differential dependency network (DDN) analysis to detect statistically significant topological changes in the transcriptional networks between two biological conditions. We propose a local dependency model to represent the local structures of a network by a set of conditional probabilities. We develop an efficient learning algorithm to learn the local dependency model using the Lasso technique. A permutation test is subsequently performed to estimate the statistical significance of each learned local structure. In testing on a simulation dataset, the proposed algorithm accurately detected all the genes with network topological changes. The method was then applied to the estrogen-dependent T-47D estrogen receptor-positive (ER+) breast cancer cell line datasets and human and mouse embryonic stem cell datasets. In both experiments using real microarray datasets, the proposed method produced biologically meaningful results. We expect DDN to emerge as an important bioinformatics tool in transcriptional network analyses. While we focus specifically on transcriptional networks, the DDN method we introduce here is generally applicable to other biological networks with similar characteristics. C1 [Zhang, Bai; Xuan, Jianhua; Wang, Yue] Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Arlington, VA 22203 USA. [Li, Huai; Zhan, Ming] NIA, Bioinformat Unit, RRB, NIH, Baltimore, MD 21224 USA. [Riggins, Rebecca B.; Clarke, Robert] Georgetown Univ, Dept Oncol Physiol & Biophys, Washington, DC 20057 USA. [Riggins, Rebecca B.; Clarke, Robert] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Zhang, Zhen] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA. [Hoffman, Eric P.] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. RP Wang, Y (reprint author), Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Arlington, VA 22203 USA. RI Clarke, Robert/A-6485-2008 OI Clarke, Robert/0000-0002-9278-0854 FU National Institutes of Health [CA109872, EB000830, CA096483, CA86323, NS29525]; Department of Defense Breast Cancer Research Program [BC030280] FX Funding: National Institutes of Health (CA109872, EB000830, CA096483, CA86323 and NS29525, partial); Department of Defense Breast Cancer Research Program BC030280. IRP/NIA/NIH (to H.L. and M.Z.). NR 59 TC 57 Z9 58 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2009 VL 25 IS 4 BP 526 EP 532 DI 10.1093/bioinformatics/btn660 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 408AS UT WOS:000263406000016 PM 19112081 ER PT J AU Qi, QH Zhao, YD Li, MC Simon, R AF Qi, Qihao Zhao, Yingdong Li, MingChung Simon, Richard TI Non-negative matrix factorization of gene expression profiles: a plug-in for BRB-ArrayTools SO BIOINFORMATICS LA English DT Article AB Non-negative matrix factorization (NMF) is an increasingly used algorithm for the analysis of complex high-dimensional data. BRB-ArrayTools is a widely used software system for the analysis of gene expression data with almost 9000 registered users in over 65 countries. We have developed a NMF analysis plug-in in BRB-ArrayTools for unsupervised sample clustering of microarray gene expression data. Our analysis tool also incorporates an algorithm for Semi-NMF which can handle both positive and negative elements for log-ratio data. Output includes a heat map of sample clusters and differentially expressed genes with extensive biological annotation. For comparison, output also includes the results of K-means clustering. C1 [Zhao, Yingdong; Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Li, MingChung] EMMES Corp, Rockville, MD 20850 USA. [Qi, Qihao] Georgetown Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC 20057 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 13 TC 18 Z9 20 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2009 VL 25 IS 4 BP 545 EP 547 DI 10.1093/bioinformatics/btp009 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 408AS UT WOS:000263406000023 PM 19131367 ER PT J AU Mudunuri, U Che, A Yi, M Stephens, RM AF Mudunuri, Uma Che, Anney Yi, Ming Stephens, Robert M. TI bioDBnet: the biological database network SO BIOINFORMATICS LA English DT Article ID GENOME BROWSER; BIOINFORMATICS; WAREHOUSE; SYSTEM AB bioDBnet is an online web resource that provides interconnected access to many types of biological databases. It has integrated many of the most commonly used biological databases and in its current state has 153 database identifiers (nodes) covering all aspects of biology including genes, proteins, pathways and other biological concepts. bioDBnet offers various ways to work with these databases including conversions, extensive database reports, custom navigation and has various tools to enhance the quality of the results. Importantly, the access to bioDBnet is updated regularly, providing access to the most recent releases of each individual database. C1 [Mudunuri, Uma; Che, Anney; Yi, Ming; Stephens, Robert M.] SAIC Frederick Inc, Adv Technol Program, Adv Biomed Comp Ctr, NCI, Frederick, MD 21702 USA. RP Stephens, RM (reprint author), SAIC Frederick Inc, Adv Technol Program, Adv Biomed Comp Ctr, NCI, Frederick, MD 21702 USA. FU National Cancer Institute; National Institutes of Health [N01-CO-12400] FX National Cancer Institute; National Institutes of Health (contract N01-CO-12400). NR 8 TC 72 Z9 72 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2009 VL 25 IS 4 BP 555 EP 556 DI 10.1093/bioinformatics/btn654 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 408AS UT WOS:000263406000027 PM 19129209 ER PT J AU Goodman, WK Insel, TR AF Goodman, Wayne K. Insel, Thomas R. TI Deep Brain Stimulation in Psychiatry: Concentrating on the Road Ahead SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID OBSESSIVE-COMPULSIVE DISORDER; TRANSCRANIAL MAGNETIC STIMULATION; TREATMENT-RESISTANT DEPRESSION; TOURETTE-SYNDROME; LONG-TERM; MECHANISMS; SURGERY; SAFETY C1 [Goodman, Wayne K.] NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. RP Goodman, WK (reprint author), NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. NR 32 TC 17 Z9 18 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2009 VL 65 IS 4 BP 263 EP 266 DI 10.1016/j.biopsych.2008.12.011 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 405UO UT WOS:000263249900001 PM 19167964 ER PT J AU Salvadore, G Cornwell, BR Colon-Rosario, V Coppola, R Grillon, C Zarate, CA Manji, HK AF Salvadore, Giacomo Cornwell, Brian R. Colon-Rosario, Veronica Coppola, Richard Grillon, Christian Zarate, Carlos A., Jr. Manji, Husseini K. TI Increased Anterior Cingulate Cortical Activity in Response to Fearful Faces: A Neurophysiological Biomarker that Predicts Rapid Antidepressant Response to Ketamine SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anterior cingulate; antidepressant response; ketamine; biomarker; fearful faces; habituation; magnetoencephalography (MEG); major depressive disorder (MDD); predictor ID FUNCTIONAL MAGNETIC-RESONANCE; MOOD-REGULATING CIRCUIT; EVENT-RELATED FMRI; MAJOR DEPRESSION; SLEEP-DEPRIVATION; BRAIN; DISORDER; CORTEX; MEG; MAGNETOENCEPHALOGRAPHY AB Background: Most patients with major depressive disorder (MDD) experience a period of lengthy trial and error when trying to find optimal antidepressant treatment; identifying biomarkers that could predict response to antidepressant treatment would be of enormous benefit. We tested the hypothesis that pretreatment anterior cingulate cortex (ACC) activity could be a putative biomarker of rapid antidepressant response to ketamine, in line with previous findings that investigated the effects of conventional antidepressants. We also investigated patterns of ACC activity to rapid presentation of fearful faces compared with the normal habituation observed in healthy subjects. Methods: We elicited ACC activity in drug-free patients with MDD (n = 11) and healthy control subjects (n = 11) by rapidly presenting fearful faces, a paradigm known to activate rostral regions of the ACC. Spatial-filtering analyses were performed on magnetoencephalographic (MEG) recordings, which offer the temporal precision necessary to estimate ACC activity elicited by the rapid presentation of stimuli. Magnetoencephalographic recordings were obtained only once for both patients and control subjects. Patients were subsequently administered a single ketamine infusion followed by assessment of depressive symptoms 4 hours later. Results: Although healthy subjects had decreased neuromagnetic activity in the rostral ACC across repeated exposures, patients with MDD showed robust increases in pretreatment ACC activity. Notably, this increase was positively correlated with subsequent rapid antidepressant response to ketamine. Exploratory analyses showed that pretreatment amygdala activity was negatively correlated with change in depressive symptoms. Conclusions: Pretreatment rostral ACC activation may be a useful biomarker that identifies a subgroup of patients who will respond favorably to ketamine's antidepressant effects. C1 [Salvadore, Giacomo; Cornwell, Brian R.; Colon-Rosario, Veronica; Grillon, Christian; Zarate, Carlos A., Jr.; Manji, Husseini K.] NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Coppola, Richard] NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, 9000 Rockville Pike,Bldg 35,1C912, Bethesda, MD 20892 USA. EM manji@nih.gov FU National Institute of Mental Health-National Institutes of Health (NIMH-NIH); National Alliance for Reasearch on Schizophrenia and Depression Award FX This study was supported by the Intramural Research Program at the National Institute of Mental Health-National Institutes of Health (NIMH-NIH) and a National Alliance for Reasearch on Schizophrenia and Depression Award (CAZ). NR 42 TC 128 Z9 128 U1 2 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2009 VL 65 IS 4 BP 289 EP 295 DI 10.1016/j.biopsych.2008.08.014 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 405UO UT WOS:000263249900005 PM 18822408 ER PT J AU Lau, JYF Goldman, D Buzas, B Fromm, SJ Guyer, AE Hodgkinson, C Monk, CS Nelson, EE Shen, PH Pine, DS Ernst, M AF Lau, Jennifer Y. F. Goldman, David Buzas, Beata Fromm, Stephen J. Guyer, Amanda E. Hodgkinson, Colin Monk, Christopher S. Nelson, Eric E. Shen, Pei-Hong Pine, Daniel S. Ernst, Monique TI Amygdala Function and 5-HTT Gene Variants in Adolescent Anxiety and Major Depressive Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Adolescence; amygdala; anxiety; depression; emotional faces; serotonin transporter gene polymorphism ID SEROTONIN TRANSPORTER PROMOTER; OBSESSIVE-COMPULSIVE DISORDER; PREFRONTAL CORTEX ACTIVATION; EMOTIONAL FACIAL EXPRESSIONS; ENVIRONMENT INTERACTION; ATTENTIONAL BIAS; PANIC DISORDER; FEARFUL FACES; ANGRY FACES; CHILDREN AB Background: Associations between a functional polymorphism in the serotonin transporter gene and amygdala activation have been found in healthy, depressed, and anxious adults. This study explored these gene-brain associations in adolescents by examining predictive effects of serotonin transporter gene variants (Sand L(G) allele carriers vs. L(A) allele homozygotes) and their interaction with diagnosis (healthy vs. patients) on amygdala responses to emotional faces. Methods: Functional magnetic resonance data were collected from 33 healthy adolescents (mean age: 13.71, 55% female) and 31 medication-free adolescents with current anxiety or depressive disorders (or both; mean age: 13.58, 56% female) while viewing fearful, angry, happy, and neutral facial expressions under varying attention states. Results: A significant three-way genotype-by-diagnosis-by-face-emotion interaction characterized right amygdala activity while subjects monitored internal fear levels. This interaction was decomposed to map differential gene-brain associations in healthy and affected adolescents. First, consistent with healthy adult data, healthy adolescents with at least one copy of the S or L(G) allele showed stronger amygdala responses to fearful faces than healthy adolescents without these alleles. Second, patients with two copies of the L(A) allele exhibited greater amygdala responses to fearful faces relative to patients with S or L(G) alleles. Third, although weaker, genotype differences on amygdala responses in patients extended to happy faces. All effects were restricted to the fear-monitoring attention state. Conclusions: S/L(G) alleles in healthy adolescents, as in healthy adults, predict enhanced amygdala activation to fearful faces. Contrary findings of increased activation in patients with L(A)L(A) relative to the S or L(G) alleles require further exploration. C1 [Lau, Jennifer Y. F.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Lau, Jennifer Y. F.; Fromm, Stephen J.; Guyer, Amanda E.; Nelson, Eric E.; Pine, Daniel S.; Ernst, Monique] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Goldman, David; Hodgkinson, Colin; Shen, Pei-Hong] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Buzas, Beata] NIAAA, NIH, Rockville, MD 20852 USA. [Monk, Christopher S.] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. RP Lau, JYF (reprint author), Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. EM jennifer.lau@psy.ox.ac.uk RI Hodgkinson, Colin/F-9899-2010; Nelson, Eric/B-8980-2008; Monk, Christopher/J-1805-2014; Goldman, David/F-9772-2010 OI Nelson, Eric/0000-0002-3376-2453; Goldman, David/0000-0002-1724-5405 FU National Institute of Mental Health; National Institutes of Health FX We thank Jessica Jenness, Nina Shiffrin, Elizabeth Shroth, Veronica Temple, and Amber Williams for data processing assistance; Logina Akhtar and Gary Jenkins for assistance with genotyping; Dave luckenbaugh for advice on statistical procedures; Harvey Iwamoto for programming and computer support;and Ellen Leibenluft, Ken Towbin, and Alan Zametkin for medical oversight. This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 50 TC 72 Z9 72 U1 6 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2009 VL 65 IS 4 BP 349 EP 355 DI 10.1016/j.biopsych.2008.08.037 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 405UO UT WOS:000263249900013 PM 18950748 ER PT J AU Jacobson, O Weiss, ID Szajek, L Farber, JM Kiesewetter, DO AF Jacobson, Orit Weiss, Ido D. Szajek, Lawrence Farber, Joshua M. Kiesewetter, Dale O. TI Cu-64-AMD3100-A novel imaging agent for targeting chemokine receptor CXCR4 SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE AMD3100; CXCR4; PET; Copper-64 ID IN-VIVO BEHAVIOR; HUMAN-IMMUNODEFICIENCY-VIRUS; PROSTATE-CANCER METASTASIS; BIS-TETRAAZAMACROCYCLES; PROTECTING GROUPS; AROMATIC LINKER; BREAST-CANCER; TUMOR-GROWTH; CELLS; EXPRESSION AB CXCR4 is a chemokine receptor which has been shown to be exploited by various tumors for increased survival, invasion, and homing to target organs. We developed a one step radiosynthesis for labeling the CXCR4-specific antagonist AMD3100 with Cu-64 to produce Cu-64-AMD3100 with a specific activity of 11.28 Ci/mu mol (417 GBq/mu mol) at the end of radiosynthesis. Incorporation of Cu(II) ion into AMD3100 did not change its ability to inhibit cellular migration in response to the (only) CXCR4 ligand, SDF-1/CXCL12. Cu-64-AMD3100 binding affinity to CXCR4 was found to be 62.7 mu M. Biodistribution of Cu-64-AMD3100 showed accumulation in CXCR4-expressing organs and tissues, a renal clearance pathway, and an anomalous specific accumulation in the liver. We conclude that Cu-64-AMD3100 exhibits promise as a potential PET imaging agent for visualization of CXCR4-positive tumors and metastases and might be used to guide and monitor anti-CXCR4 tumor therapy. (c) Published by Elsevier Ltd. C1 [Jacobson, Orit; Kiesewetter, Dale O.] Natl Inst Biomed Imaging & Bioengn, Positron Emiss Tomog Radiochem Grp, Bethesda, MD 20892 USA. [Weiss, Ido D.; Farber, Joshua M.] NIAID, Lab Mol Immunol, Bethesda, MD 20892 USA. [Szajek, Lawrence] NIH, Positron Emiss Tomog Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Kiesewetter, DO (reprint author), Natl Inst Biomed Imaging & Bioengn, Positron Emiss Tomog Radiochem Grp, Bethesda, MD 20892 USA. EM dk7k@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institute of Allergy and Infectious Diseases (NIAID) FX This research was supported by Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the National Institute of Allergy and Infectious Diseases (NIAID). We would like to thank Dr. Amnon Peled from Hadassah-Hebrew University Medical Center, Jerusalem, Israel, fruitful discussions and Dr. Ying Ma for HPLC-MS analysis. NR 80 TC 50 Z9 54 U1 0 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD FEB 15 PY 2009 VL 17 IS 4 BP 1486 EP 1493 DI 10.1016/j.bmc.2009.01.014 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 409JP UT WOS:000263502300009 PM 19188071 ER PT J AU Kang, JH Garg, H Sigano, DM Francella, N Blumenthal, R Marquez, VE AF Kang, Ji-Hye Garg, Himanshu Sigano, Dina M. Francella, Nicholas Blumenthal, Robert Marquez, Victor E. TI Ceramides: Branched alkyl chains in the sphingolipid siblings of diacylglycerol improve biological potency SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Alkyl branched ceramides; D-Sphingosine; Apoptosis; SupT1 cells; Annexin V; DiOC6 ID PROTEIN-KINASE-C; CONFORMATIONALLY CONSTRAINED ANALOGS; CELL-DEATH; PK-C; INDUCED APOPTOSIS; BINDING-AFFINITY; CANCER-CELLS; DAG-LACTONES; METABOLISM; ALDEHYDES AB The synthesis of a small number of ceramide analogues containing a combination of linear and highly branched alkyl chains on either the D-sphingosine or the N-acyl core of the molecule is reported. Regardless of location, the presence of the branched chain improves potency relative to the positive control, C2 ceramide; however, the most potent compound (4) has the branched side chain as part of the D-sphingosine core. The induction of apoptosis by 4 in terms of Annexin V binding and DiOC(6) labeling was superior to that achieved with C2 ceramide. (c) 2009 Elsevier Ltd. All rights reserved. C1 [Garg, Himanshu; Francella, Nicholas; Blumenthal, Robert] NCI, Nanobiol Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Kang, Ji-Hye; Sigano, Dina M.; Marquez, Victor E.] NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Nanobiol Program, Ctr Canc Res, NIH, Bldg 469-152, Frederick, MD 21702 USA. EM blumen@helix.nih.gov; marquezv@mail.nih.gov RI Sigano, Dina/M-6144-2014 OI Sigano, Dina/0000-0001-7489-9555 FU NIH; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 39 TC 6 Z9 6 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD FEB 15 PY 2009 VL 17 IS 4 BP 1498 EP 1505 DI 10.1016/j.bmc.2009.01.005 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 409JP UT WOS:000263502300011 PM 19171486 ER PT J AU Han, XC Li, C Mosher, MD Rider, KC Zhou, PW Crawford, RL Fusco, W Paszczynski, A Natale, NR AF Han, Xiaochun Li, Chun Mosher, Michael D. Rider, Kevin C. Zhou, Peiwen Crawford, Ronald L. Fusco, William Paszczynski, Andrzej Natale, Nicholas R. TI Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Anthracene; Anti-tumor; G-quadruplex; Isoxazole; Pyrrole ID G-QUADRUPLEX DNA; DIFFERENTIAL CYTOTOXICITY DATA; HUMAN TELOMERIC DNA; DRUG DESIGN; C-MYC; MINOR-GROOVE; TARGET; DISTAMYCIN; BINDING; CANCER AB The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl(3) as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Mosher, Michael D.] Univ Nebraska, Dept Chem, Kearney, NE 68849 USA. [Han, Xiaochun; Li, Chun; Mosher, Michael D.; Rider, Kevin C.; Zhou, Peiwen; Natale, Nicholas R.] Univ Idaho, Dept Chem, Moscow, ID 83844 USA. [Crawford, Ronald L.; Fusco, William; Paszczynski, Andrzej] Univ Idaho, Environm Biotechnol Inst, Moscow, ID 83844 USA. [Zhou, Peiwen] AK Sci Inc, Mountain View, CA 94043 USA. RP Natale, NR (reprint author), Univ Montana, NIH COBRE Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, Skaggs Bldg 480, Missoula, MT 59812 USA. EM Nicholas.natale@umontana.edu FU National Institute of Neurological Disease and Stroke [NS38444, P20RR015583]; University of Idaho Research Council; National Cancer Institute FX N.R.N. thanks the National Institute of Neurological Disease and Stroke for Grant NS38444 and P20RR015583. We would like to thank the University of Idaho Research Council, and the National Cancer Institute for financial support. Dr. Dan Zaharevitz assisted us with the COMPARE calculation and interpretation. X. H., C. L. and K. C. R., acknowledge the Malcolm and Carol Renfrew Scholarship Endowment, University of Idaho. C. L. and K. C. R. also thank P20RR16454. NR 66 TC 15 Z9 15 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD FEB 15 PY 2009 VL 17 IS 4 BP 1671 EP 1680 DI 10.1016/j.bmc.2008.12.056 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 409JP UT WOS:000263502300031 PM 19167892 ER PT J AU Sikazwe, DMN Nkansah, NT Altundas, R Zhu, XY Roth, BL Setola, V Ablordeppey, SY AF Sikazwe, Donald M. N. Nkansah, Nancy T. Altundas, Ramazan Zhu, Xue Y. Roth, Bryan L. Setola, Vincent Ablordeppey, Seth Y. TI Synthesis and evaluation of ligands for D-2-like receptors: The role of common pharmacophoric groups SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Haloperidol analog; Antipsychotics; Butyrophenone; Dopamine receptor ligands; D-2-like receptor ligands; Diazepane; Bicyclic analogs ID PENILE ERECTION; HALOPERIDOL; ANALOGS; RATS; 2-(4-PYRIDIN-2-YLPIPERAZIN-1-YLMETHYL)-1H-BENZIMIDAZOLE; ACTIVATION; ABT-724; AGONIST; DESIGN; AGENT AB Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at D-2-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, that is, 40-fluorobutyrophenones and 3-methyl-7-azaindoles, to the potency and selectivity of synthesized agents at D-2-like receptors. Preliminary observation of binding affinities indicates that there is little predictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selectivity and potency at these receptors. Published by Elsevier Ltd. C1 [Sikazwe, Donald M. N.; Nkansah, Nancy T.; Altundas, Ramazan; Zhu, Xue Y.; Ablordeppey, Seth Y.] Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Div Basic Pharmaceut Sci, Tallahassee, FL 32307 USA. [Roth, Bryan L.; Setola, Vincent] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Roth, Bryan L.; Setola, Vincent] Univ N Carolina, Dept Med Chem, Chapel Hill, NC 27599 USA. [Roth, Bryan L.; Setola, Vincent] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Roth, Bryan L.; Setola, Vincent] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. RP Ablordeppey, SY (reprint author), Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Div Basic Pharmaceut Sci, Tallahassee, FL 32307 USA. EM dsikazwe@archerpharma.com; nkansahn@pharmacy.ucsf.edu; seth.ablordeppey@famu.edu RI Roth, Bryan/F-3928-2010 FU National Institute of General Medical Studies (NIGMS) [GM 08111]; RCMI [G12 RR 03020]; Florida AM University; Pharmaceutical Research Center NIH/NCRR [1 C06-RR12512-01] FX We gratefully acknowledge the financial support of the National Institute of General Medical Studies (NIGMS) for MBRS Grant No. GM 08111, NIMH Psychoactive Drug Screening Program, RCMI Grant No. G12 RR 03020 from NCRR, and a Title III Grant to Florida A&M University. The authors also acknowledge Dr Abdul Khan in the synthesis of compounds 8 and 9 and Dr. A. W. Schmidt at Pfizer Global Research for conducting the original binding studies for several of the reported compounds. This work was supported in part by the Pharmaceutical Research Center NIH/NCRR 1 C06-RR12512-01 Grant. NR 21 TC 8 Z9 8 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD FEB 15 PY 2009 VL 17 IS 4 BP 1716 EP 1723 DI 10.1016/j.bmc.2008.12.054 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 409JP UT WOS:000263502300036 PM 19155177 ER PT J AU Cannazza, G Jozwiak, K Parenti, C Braghiroli, D Carrozzo, MM Puia, G Losi, G Baraldi, M Lindner, W Wainer, IW AF Cannazza, Giuseppe Jozwiak, Krzysztof Parenti, Carlo Braghiroli, Daniela Carrozzo, Marina M. Puia, Giulia Losi, Gabriele Baraldi, Mario Lindner, Wolfgang Wainer, Irving W. TI A novel class of allosteric modulators of AMPA/Kainate receptors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE IDRA21; AMPA positive modulators; 2-Amino-5-chlorobenzensulfonamide ID AMPA RECEPTOR; 7-CHLORO-3-METHYL-3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE S,S-DIOXIDE; DESENSITIZATION; IDRA-21; CYCLOTHIAZIDE; DIAZOXIDE; CURRENTS; ACID; POTENTIATION; HIPPOCAMPUS AB The rapid hydrolysis in vivo of IDRA21 to 2-amino-5-chlorobenzensulfonamide has been demonstrated by microdialysis experiments. The IDRA21 metabolite possess in vitro a biological activity similar to that of IDRA21 itself. Taking 2-amino-5-chlorobenzensulfonamide as lead compound, a novel class of AMPAR positive allosteric modulators has been prepared. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Cannazza, Giuseppe; Parenti, Carlo; Braghiroli, Daniela; Carrozzo, Marina M.] Univ Modena, Dept Pharmaceut Sci, I-41100 Modena, Italy. [Jozwiak, Krzysztof] Med Univ Lublin, Dept Chem, Lab Drug Receptor Interact, PL-20950 Lublin, Poland. [Puia, Giulia; Losi, Gabriele; Baraldi, Mario] Univ Modena, Dept Biomed Sci, I-41100 Modena, Italy. [Lindner, Wolfgang] Univ Vienna, Dept Analyt Chem & Food Chem, A-1090 Vienna, Austria. [Wainer, Irving W.] NIA, Bioanalyt & Drug Discovery Unit, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Cannazza, G (reprint author), Univ Modena, Dept Pharmaceut Sci, Via Campi 183, I-41100 Modena, Italy. EM giuseppe.cannazza@unimo.it RI Puja, Giulia/C-3540-2015; Parenti, Carlo/D-3536-2015; Braghiroli, Daniela/D-3528-2015; CANNAZZA, GIUSEPPE/J-2699-2014 OI Losi, Gabriele/0000-0001-7796-9299; LOSI, GABRIELE/0000-0002-4931-6167; Puja, Giulia/0000-0001-8385-6020; Parenti, Carlo/0000-0003-3223-4111; Braghiroli, Daniela/0000-0002-0232-0193; CANNAZZA, GIUSEPPE/0000-0002-7347-7315 FU National Institute on Aging/NIH FX This work was support in part by funding from the Intramural Research Program of the National Institute on Aging/NIH. NR 28 TC 12 Z9 13 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 15 PY 2009 VL 19 IS 4 BP 1254 EP 1257 DI 10.1016/j.bmcl.2008.12.094 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 406KU UT WOS:000263295200049 PM 19162477 ER PT J AU Chill, L Trinh, L Azadi, P Ishihara, M Sonon, R Karnaukhova, E Ophir, Y Golding, B Shiloach, J AF Chill, Liat Trinh, Loc Azadi, Parastoo Ishihara, Mayumi Sonon, Roberto Karnaukhova, Elena Ophir, Yakir Golding, Basil Shiloach, Joseph TI Production, Purification, and Characterization of Human alpha 1 Proteinase Inhibitor From Aspergillus niger SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE Aspergillus niger; glycosylation; alpha 1-PI ID OXIDIZED ALPHA-1-PROTEINASE INHIBITOR; ACTIVE HUMAN ALPHA-1-ANTITRYPSIN; HIGH-LEVEL EXPRESSION; FUSION PROTEIN; FILAMENTOUS FUNGI; YEAST; ALPHA(1)-ANTITRYPSIN; GLYCOSYLATION; GLYCOPROTEINS; CONCENTRATE AB Human alpha one proteinase inhibitor (alpha 1-PI) was cloned and expressed in Aspergillus niger, filamentious fungus that can grow in defined media and can perform glycosylation. Submerged culture conditions were established using starch as carbon source, 30% dissolved oxygen concentration, pH 7.0 and 28 degrees C. Eight milligrams per liter of active alpha 1-PI were secreted to the growth media in about 40 h. Controlling the protein proteolysis was found to be an important factor in the production. The effects of various carbon sources, pH and temperature on the production and stability of the protein were tested and the product was purified and characterized. Two molecular weights variants of the recombinant alpha 1-PI were produced by the fungus; the difference is attributed to the glycosylated part of the molecule. The two glycoproteins were treated with PNGAse F and the released glycans were analyzed by HPAEC, MALDI/TOF-MS, NSI-MS(n) and GC-MS. The MALDI and NSI- full MS spectra of permethylated N-glycans revealed that the N-glycans of both variants contain a series of high-mannose type glycans with 5-20 hexose units. Monosaccharide analysis showed that these were composed of N-acetylglucosamine, mannose, and galactose. Linkage analysis revealed that the galactosyl component was in the furanoic conformation, which was attaching in a terminal non-reducing position. The Galactofuranose-containing high-mannnose type N-glycans are typical structures, which recently have been found as part of several glycoproteins produced by Aspergillus niger. C1 [Chill, Liat; Trinh, Loc; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. [Trinh, Loc; Azadi, Parastoo; Ishihara, Mayumi] Univ Georgia, Complex Carbohydrate Res Ctr, Analyt Serv, Athens, GA 30602 USA. [Karnaukhova, Elena; Ophir, Yakir; Golding, Basil] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Core Lab, NIH, Bldg 14A,Room 170,9000 Rockville Rike, Bethesda, MD 20892 USA. EM yossi@nih.gov FU National institute of Diabetes & Digestive & Kidney diseases; National Institutes of Health FX Funding was provided by the intramural program at the National institute of Diabetes & Digestive & Kidney diseases, National Institutes of Health. The authors thank Dr. John Cipollo, CBER, FDA, for reviewing the manuscript and for his valuable remarks and Suggestions, and for Mrs D Livilat for assisting with editing the manuscript. NR 43 TC 12 Z9 12 U1 2 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD FEB 15 PY 2009 VL 102 IS 3 BP 828 EP 844 DI 10.1002/bit.22099 PG 17 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 396NK UT WOS:000262598200019 PM 18828177 ER PT J AU Leitzmann, MF Koebnick, C Danforth, KN Brinton, LA Moore, SC Hollenbeck, AR Schatzkin, A Lacey, JV AF Leitzmann, Michael F. Koebnick, Corinna Danforth, Kim N. Brinton, Louise A. Moore, Steven C. Hollenbeck, Albert R. Schatzkin, Arthur Lacey, James V., Jr. TI Body Mass Index and Risk of Ovarian Cancer SO CANCER LA English DT Article DE ovarian cancer; obesity; multivariate relative risk; body mass index ID BREAST-CANCER; OBESITY; HEIGHT; HORMONES; COHORT; WOMEN AB BACKGROUND: Convincing epidemiologic evidence links excess body mass to increased risks of endometrial and postmenopausal breast cancers, but the relation between body mass index (BMI) and ovarian cancer risk remains inconclusive. Potential similarities regarding a hormonal mechanism in the etiology of female cancers highlight the importance of investigating associations according to menopausal hormone therapy (MHT) use. However, to the authors' knowledge, data addressing whether the relation between BMI and ovarian cancer differs by MHT use are very sparse. METHODS: The authors prospectively investigated the association between BMI and ovarian cancer among 94,525 US women who were followed between 1996 through 1997 to December 31, 2003. During 7 years of follow-up, 303 epithelial ovarian cancer cases were documented. RESULTS: Compared with normal weight women (BMI of 18.5-24.9 kg/m(2)), the multivariate relative risk (MVRR) of ovarian cancer for obese women (BMI of >= 30 kg/m(2)) in the cohort as a whole was 1.26 (95% confidence interval [95% CI], 0.94-1.68). Among women who never used MHT, the MVRR for obese versus normal weight women was 1.83 (95% CI, 1.18-2.84). In contrast, no relation between BMI and ovarian cancer was apparent among women who ever used MHT (MVRR=0.96; 95% CI, 0.65-1,43; P interaction = 0.02). Exploratory analyses also suggested a positive association between BMI and ovarian cancer among women without a family history of ovarian cancer (MVRR comparing obese vs normal weight women = 1.36; 95% CI, 1.00-1.86), but no relation with BMI was apparent among women with a positive family history of ovarian cancer (MVRR = 0.74; 95% CI, 0.34-1.62 [P interaction = .02]). CONCLUSIONS: Based on the results of the current study, the authors suspect that obesity is associated with enhanced ovarian cancer risk through a hormonal mechanism. Cancer 2009;115:812-22. Published 2009 by the American Cancer Society. C1 [Leitzmann, Michael F.; Koebnick, Corinna; Moore, Steven C.; Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Koebnick, Corinna] So Calif Permanente Med Grp, Dept Res & Evaluat, Oakland, CA USA. [Danforth, Kim N.; Brinton, Louise A.; Lacey, James V., Jr.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Dept Knowledge Management, Washington, DC USA. RP Leitzmann, MF (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Dept Hlth & Human Serv,NIH, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM michael.leitzmann@klinik.uni-regensburg.de RI Brinton, Louise/G-7486-2015; Koebnick, Corinna/P-4767-2016; Moore, Steven/D-8760-2016 OI Brinton, Louise/0000-0003-3853-8562; Koebnick, Corinna/0000-0001-8274-0309; Moore, Steven/0000-0002-8169-1661 FU Intramural NIH HHS [ZIA CP010196-05] NR 29 TC 59 Z9 61 U1 0 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 15 PY 2009 VL 115 IS 4 BP 812 EP 822 DI 10.1002/cncr.24086 PG 11 WC Oncology SC Oncology GA 405IQ UT WOS:000263216900017 PM 19127552 ER PT J AU Mishra, PJ Mishra, PJ Glod, JW Banerjee, D AF Mishra, Pravin J. Mishra, Prasun J. Glod, John W. Banerjee, Debabrata TI Mesenchymal Stem Cells: Flip Side of the Coin SO CANCER RESEARCH LA English DT Review ID TUMOR-ASSOCIATED MACROPHAGES; BREAST-CANCER; STROMAL CELLS; FIBROBLASTS; CARCINOMA; GROWTH; METASTASIS; ACTIVATION; TRANSITION; DELIVERY AB Tumor-associated fibroblasts or carcinoma-associated fibroblasts (CAF) play an important role in the growth of epithelial solid tumors. Although the cell type of origin of CAFs has not been conclusively established, it has been shown that they may be bone marrow derived. One side of the mesenchymal stem cell (MSC) coin is the well-accepted therapeutic potential of these cells for regenerative and immunomodulatory purposes. The ominous dark side is revealed by the recent work demonstrating that hMSCs may be a source of CATs. In this review, we discuss the role of stromal cells in the tumor microenvironment and suggest that by exploring the in vitro/in vivo interplay between different cell types within the tumor milieu, strategies for improved tumor therapy can be developed. [Cancer Res 2009:69(4):1255-8] C1 [Mishra, Pravin J.; Banerjee, Debabrata] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med, New Brunswick, NJ 08903 USA. [Glod, John W.; Banerjee, Debabrata] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Pharmacol, New Brunswick, NJ 08903 USA. [Glod, John W.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Pediat Oncol, New Brunswick, NJ 08903 USA. [Mishra, Prasun J.] NCI, Lab Canc Riol & Genet, NIH, Bethesda, MD USA. RP Banerjee, D (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med & Pharmacol, 195 Little Albany St, New Brunswick, NJ 08903 USA. EM banerjed@umdnj.edu NR 33 TC 105 Z9 114 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2009 VL 69 IS 4 BP 1255 EP 1258 DI 10.1158/0008-5472.CAN-08-3562 PG 4 WC Oncology SC Oncology GA 407YB UT WOS:000263399100002 PM 19208837 ER PT J AU Ogawa, M Kosaka, N Choyke, PL Kobayashi, H AF Ogawa, Mikako Kosaka, Nobuyuki Choyke, Peter L. Kobayashi, Hisataka TI In vivo Molecular Imaging of Cancer with a Quenching Near-Infrared Fluorescent Probe Using Conjugates of Monoclonal Antibodies and Indocyanine Green SO CANCER RESEARCH LA English DT Article ID FUTURE; AGENT; GENE AB Near-infrared (NIR) fluorophores have several advantages over visible fluorophores, including improved tissue penetration and lower autofluorescence; however, only indocyanine green (ICG) is clinically approved. Its use in molecular imaging probes is limited because it loses its fluorescence after protein binding. This property can be harnessed to create an activatable NIR probe. After cell binding and internalization, ICG dissociates from the targeting antibody, thus activating fluorescence. ICG was conjugated to the antibodies daclizumab (Dac), trastuzumab (Tra), or panitumumab (pan). The conjugates had almost no fluorescence in PBS but became fluorescent after SDS and 2-mercaptoethanol, with a quenching capacity of 10-fold for 1:1 conjugates and 40- to 50-fold for 1:5 conjugates. In vitro microscopy showed activation within the endolysosomes in target cells. In vivo imaging in mice showed that CD25-expressing tumors were specifically visualized with Dac-ICG. Furthermore, tumors overexpressing HER1 and HER2 were successfully characterized in vivo by using Pan-ICG(1:5) and Tra-ICG(1:5), respectively. Thus, we have developed an activatable NIR optical probe that "switches on" only in target cells. Because both the antibody and the fluorophore are Food and Drug Administration approved, the likelihood of clinical translation is improved. [Cancer lies 2009;69(4):1268-72] C1 [Ogawa, Mikako; Kosaka, Nobuyuki; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room 1B40, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX Grant support: Intramural Research program of the NIH, National Cancer Institute, Center for Cancer Research. NR 19 TC 150 Z9 155 U1 7 U2 40 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2009 VL 69 IS 4 BP 1268 EP 1272 DI 10.1158/0008-5472.CAN-08-3116 PG 5 WC Oncology SC Oncology GA 407YB UT WOS:000263399100007 PM 19176373 ER PT J AU Wright, ME Peters, U Gunter, MJ Moore, SC Lawson, KA Yeager, M Weinstein, SJ Snyder, K Virtamo, J Albanes, D AF Wright, Margaret E. Peters, Ulrike Gunter, Marc J. Moore, Steven C. Lawson, Karla A. Yeager, Meredith Weinstein, Stephanie J. Snyder, Kirk Virtamo, Jarmo Albanes, Demetrius TI Association of Variants in Two Vitamin E Transport Genes with Circulating Vitamin E Concentrations and Prostate Cancer Risk SO CANCER RESEARCH LA English DT Article ID TOCOPHEROL TRANSFER PROTEIN; ALPHA-TOCOPHEROL; BETA-CAROTENE; CHOLESTEROL-BIOSYNTHESIS; MENDELIAN RANDOMIZATION; PREVENTION TRIAL; PLASMA-LEVELS; E-DEFICIENCY; POLYMORPHISMS; CLONING AB Significant reductions in prostate cancer incidence and mortality were observed in men randomized to receive 50 mg supplemental vitamin E (alpha-tocopherol) per nay in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We hypothesized that variation in key vitamin E transport genes might directly affect prostate cancer risk or modify the effects of vitamin E supplementation. Associations between prostate cancer risk and 13 polymorphisms in two genes, TTPA and SEC14L2, were examined in 982 incident prostate cancer cases and 851 controls drawn from the ATBC Study. There was no association between the genetic variants and prostate cancer risk. Significant interactions were observed, however, between two variants in SEC14L2 (IVS11+931A>G and IVS11-896A>T) and the trial alpha-tocopherol supplement such that vitamin E supplementation reduced prostate cancer risk among men who were homozygous for either common allele [odds ratios (OR) and 95% confidence intervals (95% CI), 0.52 (0.30-0.90) and 0.64 (0.46-0.88), respectively] and nonsignificantly increased risk among those who carried one or two copies of either variant allele [ORs and 95% CIs, 1.27 (0.90-1.79) and 1.21 (0.96-1.52), respectively; both P for interaction < 0.05]. Genotype-phenotype analyses revealed significant but modest differences in baseline circulating concentrations of alpha-tocopherol and serum responses to the vitamin E supplementation for several polymorphisms. This study shows that genetic variation in TTPA and SEC14L2 is associated with serum alpha-tocopherol but does not have a direct effect on prostate cancer. Our results do, however, suggest that polymorphisms in SEC14L2 may modify the effect of vitamin supplementation regimens on prostate cancer risk. [Cancer Res 2009;69(4):1429-38] C1 [Wright, Margaret E.] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Gunter, Marc J.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Moore, Steven C.; Yeager, Meredith; Weinstein, Stephanie J.; Albanes, Demetrius] NCI, Div Cancer Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lawson, Karla A.] Dell Childrens Med Ctr Cent Texas, Trauma Serv Dept, Austin, TX USA. [Virtamo, Jarmo] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Snyder, Kirk] Informat Management Serv Inc, Rockville, MD USA. RP Wright, ME (reprint author), Univ Illinois, Dept Pathol, 840 S Wood St,CSN 130, Chicago, IL 60612 USA. EM mewright@uic.edu RI Albanes, Demetrius/B-9749-2015; Moore, Steven/D-8760-2016 OI Moore, Steven/0000-0002-8169-1661 FU National Cancer Institute, NIH FX Intramural Research Program of the National Cancer Institute, NIH.; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 36 TC 38 Z9 38 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 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2009 VL 69 IS 4 BP 1429 EP 1438 DI 10.1158/0008-5472.CAN-08-2343 PG 10 WC Oncology SC Oncology GA 407YB UT WOS:000263399100026 PM 19190344 ER PT J AU Stolzenberg-Solomon, RZ Hayes, RB Horst, RL Anderson, KE Hollis, BW Silverman, DT AF Stolzenberg-Solomon, Rachael Z. Hayes, Richard B. Horst, Ron L. Anderson, Kristin E. Hollis, Bruce W. Silverman, Debra T. TI Serum Vitamin D and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Screening Trial SO CANCER RESEARCH LA English DT Article ID CELLS IN-VITRO; 25-HYDROXYVITAMIN D-3-1-ALPHA-HYDROXYLASE; PLASMA 25-HYDROXYVITAMIN-D; UNITED-STATES; MALE SMOKERS; D ANALOGS; MORTALITY; INSULIN; PROLIFERATION; EXPRESSION AB Experimental evidence suggests that vitamin D has anticarcinogenic properties; however, a nested case-control study conducted in a population of male Finnish smokers found that higher 25-hydroxyvitamin D [25(OH)D], the best indicator of vitamin D status as determined by the sun and diet, was associated with a significant 3-fold increased risk for pancreatic cancer. We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Screening Trial cohort of men and women 55 to 74 years of age at baseline to test whether prediagnostic serum 25(OH)D concentrations were associated with pancreatic cancer risk. Between 1994 and 2006, 184 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Two controls (n = 368) who were alive at the time the case was diagnosed were selected for each case and matched by age, race, sex, and calendar date of blood draw (to control for seasonal variation). We calculated odds ratios (OR) and 95% confidence intervals (95% Cl) using conditional logistic regression, adjusting for smoking and hod-v mass index. Vitamin D concentrations were not associated with pancreatic cancer overall (highest versus lowest quintile, >82.3 versus <45.9 nmol/L: OR, 1.45; 95% Cl, 0.66-3.15; P trend = 0.49). However, positive associations were observed among subjects with low estimated annual residential solar UBV exposure, but not among those with moderate to high annual exposure (P interaction = 0.015). We did not confirm the previous strong positive association between 25(OH)D and pancreatic cancer; however, the increased risk among participants with low residential UVB exposure is similar. [Cancer Res 2009;69(4):1439-47] C1 [Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Hayes, Richard B.; Silverman, Debra T.] NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Horst, Ron L.; Hollis, Bruce W.] Iowa State Univ, Heartland Assays Inc, Ames, IA USA. [Anderson, Kristin E.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Stolzenberg-Solomon, RZ (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM rs221z@nih.gov FU NIH FX Intramural Research program of the NIH, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services. NR 49 TC 57 Z9 58 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2009 VL 69 IS 4 BP 1439 EP 1447 DI 10.1158/0008-5472.CAN-08-2694 PG 9 WC Oncology SC Oncology GA 407YB UT WOS:000263399100027 PM 19208842 ER PT J AU Kotliarov, Y Kotliarova, S Charong, N Li, AG Walling, J Aquilanti, E Ahn, S Steed, ME Su, Q Center, A Zenklusen, JC Fine, HA AF Kotliarov, Yuri Kotliarova, Svetlana Charong, Nurdina Li, Aiguo Walling, Jennifer Aquilanti, Elisa Ahn, Susie Steed, Mary Ellen Su, Qin Center, Angela Zenklusen, Jean C. Fine, Howard A. TI Correlation Analysis between Single-Nucleotide Polymorphism and Expression Arrays in Gliomas Identifies Potentially Relevant Target Genes SO CANCER RESEARCH LA English DT Article ID OLIGONUCLEOTIDE ARRAYS; MOLECULAR-GENETICS; TYROSINE KINASE; GLIOBLASTOMA; PATHOLOGY; PROFILES; RECEPTOR; REVEALS; TISSUE; PCR AB Primary brain tumors are a major cause of cancer mortality in the United States. Therapy for gliomas, the most common type of primary brain tumors, remains suboptimal. The development of improved therapeutics will require greater knowledge of the biology of gliomas at both the genomic and transcriptional levels. We have previously reported whole genome profiling of chromosome copy number alterations (CNA) in gliomas, and now present our findings on how those changes may affect transcription of genes that may be involved in tumor induction and progression. By calculating correlation values of mRNA expression versus DNA copy number average in a moving window around a given RNA probe set, biologically relevant information can be gained that is obscured by the analysis of a single data type. Correlation coefficients ranged from -0.6 to 0.7, highly significant when compared with previous studies. Most correlated genes are located on chromosomes 1, 7, 9, 10, 13, 14, 19, 20, and 22, chromosomes known to have genomic alterations in gliomas. Additionally, we were able to identify CNAs whose gene expression correlation suggests possible epigenetic regulation. This analysis revealed a number of interesting candidates such as CXCL12, PTER, and LRRN6C, among others. The results have been verified using real-time PCR and methylation sequencing assays. These data will further help differentiate genes involved in the induction and/or maintenance of the tumorigenic process from those that are mere passenger mutations, thereby enriching for a population of potentially new therapeutic molecular targets. [Cancer Res 2009;69(4):1596-603] C1 [Kotliarov, Yuri; Kotliarova, Svetlana; Charong, Nurdina; Li, Aiguo; Walling, Jennifer; Aquilanti, Elisa; Ahn, Susie; Steed, Mary Ellen; Su, Qin; Center, Angela; Zenklusen, Jean C.; Fine, Howard A.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), 8200 Old Georgetown Rd,Room 225, Bethesda, MD 20892 USA. EM hfine@mail.nih.gov RI Kotliarov, Yuri/B-6938-2017 FU NIH, National Cancer Institute, Center for Cancer Research FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 19 TC 24 Z9 24 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2009 VL 69 IS 4 BP 1596 EP 1603 DI 10.1158/0008-5472.CAN-08-2496 PG 8 WC Oncology SC Oncology GA 407YB UT WOS:000263399100045 PM 19190341 ER PT J AU Zheng, YL Hu, N Sun, Q Wang, CY Taylor, PR AF Zheng, Yun-Ling Hu, Nan Sun, Qing Wang, Chaoyu Taylor, Philip R. TI Telomere Attrition in Cancer Cells and Telomere Length in Tumor Stroma Cells Predict Chromosome Instability in Esophageal Squamous Cell Carcinoma: A Genome-Wide Analysis SO CANCER RESEARCH LA English DT Article ID INTRAEPITHELIAL NEOPLASIA; FAMILIAL AGGREGATION; BARRETTS-ESOPHAGUS; SHANXI-PROVINCE; BREAST-CANCER; ALLELIC LOSS; HIGH-RISK; IN-SITU; CHINA; HETEROZYGOSITY AB Previous studies showed that chromosomal instability was common in esophageal squamous cell carcinoma (ESCC); however, the mechanisms underlying this instability are unknown. Individuals with deficiencies in telomere maintenance are susceptible to enhanced telomere loss during cell proliferation; such deficiencies could result in telomere dysfunction and genomic instability. We investigated the association between genome-wide chromosomal changes in cancer cells and telomere length/attrition in cancer/stroma cells in 47 ESCC patients. Genome-wide detection of loss of heterozygosity was performed using the Affymetrix GeneChip single nucleotide polymorphism arrays. Telomere length was assessed separately for cancer cells, carcinoma-associated fibroblasts (CAF), infiltrative lymphocytes, and adjacent normal epithelial cells by quantitative fluorescent in situ hybridization using paraffin-embedded sections. Telomere length differed significantly among cell types, such that length in infiltrative lymphocytes > CAFs > cancer cells. Shortened telomeres were observed in cancer cells in 44 of 47 (94%) of the tumors examined. Telomere length in CAFs was significantly associated with chromosomal instability on 4q and 13q and lymphocyte telomere length was significantly associated with instability on chromosomal arms 15q. Although telomere length in cancer cells was not associated with chromosome arm instability, telomere attrition in cancer cells, defined as the telomere length in CAFs minus the telomere length in cancer cells, was significantly associated with chromosomal instability on 13q and 15q. This study provides evidence that telomere shortening is a common genetic alteration in ESCC and that chromosome arm instability is related to both telomere attrition in cancer cells and telomere length in tumor stroma cells. [Cancer Res 2009;69(4):1604-14] C1 [Zheng, Yun-Ling; Sun, Qing] Georgetown Univ, Lombardi Comprehens Canc Ctr, Canc Genet & Epidemiol Program, Washington, DC 20057 USA. [Hu, Nan; Wang, Chaoyu; Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Zheng, YL (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Canc Genet & Epidemiol Program, 3800 Reservoir Rd NW,Box 571465, Washington, DC 20057 USA. EM yz37@georgetown.edu FU Lombardi Comprehensive Cancer Center [2P30 CA051008-13]; National Cancer Institute. FX Lombardi Comprehensive Cancer Center Support grant 2P30 CA051008-13 and intramural research funds of the National Cancer Institute. NR 53 TC 16 Z9 16 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2009 VL 69 IS 4 BP 1604 EP 1614 DI 10.1158/0008-5472.CAN-08-3028 PG 11 WC Oncology SC Oncology GA 407YB UT WOS:000263399100046 PM 19190333 ER PT J AU Liu, BG Zhu, F Xia, XJ Park, E Hu, YL AF Liu, Bigang Zhu, Feng Xia, Xiaojun Park, Eumni Hu, Yinling TI A tale of terminal differentiation IKK alpha, the master keratinocyte regulator SO CELL CYCLE LA English DT Article DE IKK alpha; keratinocyte differentiation and proliferation; Ras; EGFR; tumorigenesis ID KAPPA-B-KINASE; GROWTH-FACTOR RECEPTOR; MICE LACKING; EPIGENETIC INACTIVATION; RAS ONCOGENE; SKIN-CANCER; 14-3-3-SIGMA; CARCINOMAS; EPIDERMIS; MOUSE AB Keratinocyte differentiation is the process of cellular maturation from a mitotic state to a terminally differentiated state during which skin builds up a tough yet soft skin barrier to protect the body. Its irreversibility also allows the shedding of excessive keratinocytes, thereby maintaining skin homeostasis and preventing skin diseases. Although the entire journey of keratinocyte differentiation is intricate and not well understood, it is known that Ras is able to block keratinocyte terminal differentiation and instead induce keratinocyte proliferation and transformation. It appears that uncontrolled proliferation actually interrupts differentiation. However, it has been unclear whether there are any innate surveillants that would be able to induce terminal differentiation by antagonizing excessive mitotic activities. Inhibitor of nuclear factor kappa B kinase-alpha (IKK alpha, previously known as Chuk) emerges as a master regulator in the coordinative control of keratinocyte differentiation and proliferation and as a major tumor suppressor in human and mouse skin squamous cell carcinomas. IKKa does so largely by integrating into the epidermal growth factor receptor (EGFR)/Ras/extracellular signal-regulated kinase (Erk)/EGFR ligand pathways during mitosis and differentiation. We discuss these findings herein to extend our understanding of how IKK alpha-mediated terminal differentiation serves as an innate surveillant in skin. C1 [Hu, Yinling] NCI, Canc & Inflammat Program, NIH, Ctr Canc Res, Frederick, MD 21701 USA. [Liu, Bigang; Zhu, Feng] Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX USA. [Xia, Xiaojun] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Park, Eumni] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Hu, YL (reprint author), NCI, Canc & Inflammat Program, NIH, Ctr Canc Res, Frederick, MD 21701 USA. EM huy2@mail.nih.gov FU National Cancer Institute [CA117314, CA102510] FX This work was supported by National Cancer Institute Grants (CA117314 and CA102510 to Hu). We thank the Fellows Editorial Broad in NIH for editing the view. NR 41 TC 9 Z9 10 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB 15 PY 2009 VL 8 IS 4 BP 527 EP 531 PG 5 WC Cell Biology SC Cell Biology GA 408KS UT WOS:000263434500006 PM 19197157 ER PT J AU Pagnan, G Di Paolo, D Carosio, R Pastorino, F Marimpietri, D Brignole, C Pezzolo, A Loi, M Galietta, LJV Piccardi, F Cilli, M Nico, B Ribatti, D Pistoia, V Ponzoni, M AF Pagnan, Gabriella Di Paolo, Daniela Carosio, Roberta Pastorino, Fabio Marimpietri, Danilo Brignole, Chiara Pezzolo, Annalisa Loi, Monica Galietta, Luis J. V. Piccardi, Federica Cilli, Michele Nico, Beatrice Ribatti, Domenico Pistoia, Vito Ponzoni, Mirco TI The Combined Therapeutic Effects of Bortezomib and Fenretinide on Neuroblastoma Cells Involve Endoplasmic Reticulum Stress Response SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; REFRACTORY SOLID TUMORS; PANCREATIC-CANCER CELLS; TRANS-RETINOIC ACID; PHASE-I TRIAL; PEDIATRIC-PATIENTS; MULTIPLE-MYELOMA; BREAST-CANCER; APOPTOSIS; COMBINATION AB Purpose: The proteasome inhibitor bortezomib inhibited cell growth and angiogenesis in neuroblastoma. Bortezomib has been shown to induce synergistic activity when combined with other antineoplastic agents. Here we have investigated the antitumor activity of bortezomib in combination with fenretinide, a synthetic retinoid, against neuroblastoma cells. Experimental Design: Different neuroblastoma cell lines were tested for sensitivity to bortezomib and fenretinide, given alone or in different dose-dependent and time-dependent combination schedules. Cell proliferation, cell viability, and apoptosis were evaluated by measuring 3 H-thymidine incorporation, trypan blue staining, DNA fragmentation, and western blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. An orthotopic neuroblastoma mouse model was used to examine in vivo sensitivity. Results: Each compound alone was able to induce a dose-dependent inhibition of cell proliferation, with a significant enhanced antiproliferative effect for the drugs used in combination. This inhibition was characterized by marked G(2)-M and G(1) cell cycle arrest with nearly complete depletion of S phase. Bortezomib and fenretinide in association triggered an increased apoptosis through activation of specific genes of the endoplasmic reticulum stress compared with either drug tested alone. Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone. Histologic evaluation and choriciallantoic membrane analysis of primary tumors showed that the combined therapeutic activity of bortezomib and fenretinide rested upon antitumor and antiangiogenic mechanisms. Conclusions: These findings provide the rationale for the development of a new therapeutic strategy for neuroblastoma based on this pharmacologic combination. C1 [Pagnan, Gabriella; Di Paolo, Daniela; Carosio, Roberta; Pastorino, Fabio; Marimpietri, Danilo; Brignole, Chiara; Pezzolo, Annalisa; Loi, Monica; Pistoia, Vito; Ponzoni, Mirco] G Gaslini Childrens Hosp, Lab Oncol, I-16147 Genoa, Italy. [Galietta, Luis J. V.] G Gaslini Childrens Hosp, Mol Genet Lab, I-16147 Genoa, Italy. [Piccardi, Federica; Cilli, Michele] Natl Canc Inst, Anim Res Facil, Genoa, Italy. [Nico, Beatrice; Ribatti, Domenico] Univ Bari, Dept Human Anat & Histol, Bari, Italy. RP Pagnan, G (reprint author), G Gaslini Childrens Hosp, Lab Oncol, Largo G Gaslini 5, I-16147 Genoa, Italy. EM gabriellapagnanc@ospedale-gaslini.ge.it; mircoponzoni@ospedale-gaslini.ge.it RI Di Paolo, Daniela/J-7681-2016; Ponzoni, Mirco/J-7713-2016; OI Di Paolo, Daniela/0000-0001-7264-6888; Ponzoni, Mirco/0000-0002-6164-4286; Galietta, Luis/0000-0001-8686-3461 FU Associazione Italiana Ricerca Cancro, Fondazione Italiana per la Lotta al Neuroblastoma; Ministry of Health FX Grant support: Associazione Italiana Ricerca Cancro, Fondazione Italiana per la Lotta al Neuroblastoma, and Ministry of Health, G. Pagnan and F. Pastorino are Fondazione Italiana per la Lotta al Neuroblastoma fellows. D. Di Paolo is a Fondazione Italiana Ricerca Cancro fellow. NR 44 TC 27 Z9 29 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2009 VL 15 IS 4 BP 1199 EP 1209 DI 10.1158/1078-0432.CCR-08-2477 PG 11 WC Oncology SC Oncology GA 410QI UT WOS:000263592600012 PM 19228726 ER PT J AU Azad, NS Aragon-Ching, JB Dahut, WL Gutierrez, M Figg, WD Jain, L Steinberg, SM Turner, ML Kohn, EC Kong, HH AF Azad, Nilofer S. Aragon-Ching, Jeanny B. Dahut, William L. Gutierrez, Martin Figg, William D. Jain, Lokesh Steinberg, Seth M. Turner, Maria L. Kohn, Elise C. Kong, Heidi H. TI Hand-Foot Skin Reaction Increases with Cumulative Sorafenib Dose and with Combination Anti-Vascular Endothelial Growth Factor Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; METASTATIC COLORECTAL-CANCER; INDEPENDENT PROSTATE-CANCER; REFRACTORY SOLID TUMORS; ANTITUMOR-ACTIVITY; TARGETED THERAPY; SAFETY; PHARMACOKINETICS; BEVACIZUMAB; MONOTHERAPY AB Purpose: Sorafenib, a vascular endothelial growth factor (VEGF) receptor-2 and RAF kinase inhibitor, commonly causes skin toxicity. We retrospectively analyzed dermatologic toxicity in patients receiving combined antiangiogenic therapy involving sorafenib and bevacizumab. Experimental Design: Castration-resistant prostate cancer and metastatic non-small cell lung cancer patients were accrued to phase II studies, receiving sorafenib 400 mg twice daily. A phase I study explored sorafenib 200 to 400 mg twice daily with bevacizumab 5 to 10 mg/kg every 2 weeks in patients with advanced solid tumors. The probability of development of maximum grade of dermatologic toxicity as a function of the cumulative dose of sorafenib was determined. Additional analyses compared extent of toxicity, pharmacokinetics, and patient risk factors. Results: Ninety-six patients were enrolled: 54 received sorafenib and 42 received bevacizumab/sorafenib. Hand-foot skin reaction (HFSR) was observed in 50 of 96 (52%) patients. Grade 2 to 3 HFSR developed in 16 of 54 (30%) sorafenib patients and 24 of 42 (57%) bevacizumab/sorafenib patients (P = 0.012) and was associated with cumulative sorafenib exposure (P = 0.0008). Twenty-four of 42 phase I patients randomized to start with bevacizumab had increased risk of grade 2 to 3 HFSR than those starting with sorafenib (P = 0.013) after adjusting for association between HFSR risk and hypertension (P = 0.01), which was the only toxicity associated with HFSR. There was no association between HFSR and baseline history of neuropathy, prior taxane/platinum treatment, or systemic sorafenib levels. Conclusions: Sorafenib-related HFSR is associated with increasing cumulative sorafenib dose. HFSR is increased in patients treated with bevacizumab/sorafenib combination anti-VEGF therapy, and this finding is not explained by pharmacokinetic interaction between the two agents. Our results suggest that the pathophysiology of HFSR may be related to VEGF inhibition. C1 [Azad, Nilofer S.; Aragon-Ching, Jeanny B.; Dahut, William L.; Gutierrez, Martin; Kohn, Elise C.] NIH, Med Oncol Branch, Ctr Canc Res, Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Figg, William D.; Jain, Lokesh] NIH, Mol Pharmacol Branch, Ctr Canc Res, Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NIH, Biostat & Data Management Sect, Ctr Canc Res, Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Turner, Maria L.; Kong, Heidi H.] NIH, Dermatol Branch, Ctr Canc Res, Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Kong, HH (reprint author), NCI, 10 Ctr Dr,Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov RI Figg Sr, William/M-2411-2016; OI Aragon-Ching, Jeanny/0000-0002-6714-141X; Kong, Heidi/0000-0003-4424-064X FU Intramural Research Program of the National Cancer Institute FX Intramural Research Program of the National Cancer Institute. NR 26 TC 81 Z9 87 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2009 VL 15 IS 4 BP 1411 EP 1416 DI 10.1158/1078-0432.CCR-08-1141 PG 6 WC Oncology SC Oncology GA 410QI UT WOS:000263592600035 PM 19228742 ER PT J AU Woo, S Gardner, ER Chen, XH Ockers, SB Baum, CE Sissung, TM Price, DK Frye, R Piekarz, RL Bates, SE Figg, WD AF Woo, Sukyung Gardner, Erin R. Chen, Xiaohong Ockers, Sandra B. Baum, Caitlin E. Sissung, Tristan M. Price, Douglas K. Frye, Robin Piekarz, Richard L. Bates, Susan E. Figg, William D. TI Population Pharmacokinetics of Romidepsin in Patients with Cutaneous T-Cell Lymphoma and Relapsed Peripheral T-Cell Lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; CHROMOBACTERIUM-VIOLACEUM NO-968; DEPSIPEPTIDE FR901228; PHASE-II; IN-VIVO; CANCER; FK228; POLYMORPHISMS; EXPRESSION; GENE AB Purpose: Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the pharmacokinetics of romidepsin in patients with T-cell lymphoma. Experimental Design: Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m(2) of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition. Results: A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 2677G>T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure. Conclusion: The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population. C1 [Woo, Sukyung; Chen, Xiaohong; Sissung, Tristan M.; Figg, William D.] NCI, Clin Pharmacol Program, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Gardner, Erin R.] NCI, Clin Pharmacol Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Ockers, Sandra B.; Baum, Caitlin E.; Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Frye, Robin; Piekarz, Richard L.; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Med Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU National Cancer Institute; NIH [N01-CO-12400]; Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400 (E.R. Gardner). 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 by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 32 TC 33 Z9 37 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2009 VL 15 IS 4 BP 1496 EP 1503 DI 10.1158/1078-0432.CCR-08-1215 PG 8 WC Oncology SC Oncology GA 410QI UT WOS:000263592600046 PM 19228751 ER PT J AU Jin, H Sood, R Xu, J Zhen, F English, MA Liu, PP Wen, ZL AF Jin, Hao Sood, Raman Xu, Jin Zhen, Fenghua English, Milton A. Liu, P. Paul Wen, Zilong TI Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI SO DEVELOPMENT LA English DT Article DE Zebrafish; Hematopoiesis; Ventral wall of dorsal aorta (VDA); Posterior blood island (PBI); Lineage differentiation; Ontogeny ID COMMON LYMPHOID PROGENITORS; CHICK-EMBRYO AORTA; STEM-CELLS; FETAL LIVER; YOLK-SAC; MOUSE; EXPRESSION; REGION; IKAROS; FATE AB One unique feature of vertebrate definitive hematopoiesis is the ontogenic switching of hematopoietic stem cells from one anatomical compartment or niche to another. In mice, hematopoietic stem cells are believed to originate in the aorta-gonadmesonephros ( AGM), subsequently migrate to the fetal liver (FL) and finally colonize the bone marrow ( BM). Yet, the differentiation potential of hematopoietic stem cells within early niches such as the AGM and FL remains incompletely defined. Here, we present in vivo analysis to delineate the differentiation potential of definitive hematopoietic stem/progenitor cells (HSPCs) in the zebrafish AGM and FL analogies, namely the ventral wall of dorsal aorta (VDA) and the posterior blood island (PBI), respectively. Cell fate mapping and analysis of zebrafish runx1(w84x) and vlad tepes ( vlt(m651)) mutants revealed that HSPCs in the PBI gave rise to both erythroid and myeloid lineages. However, we surprisingly found that HSPCs in the VDA were not quiescent but were uniquely adapted to generate myeloid but not erythroid lineage cells. We further showed that such distinct differentiation output of HSPCs was, at least in part, ascribed to the different micro-environments present in these two niches. Our results highlight the importance of niche in shaping the differentiation output of developing HSPCs. C1 [Sood, Raman; English, Milton A.; Liu, P. Paul] NHGRI, NIH, Bethesda, MD 20892 USA. [Jin, Hao; Xu, Jin; English, Milton A.; Wen, Zilong] Hong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China. RP Liu, PP (reprint author), NHGRI, NIH, Bldg 49,Room 3A26, Bethesda, MD 20892 USA. EM pliu@nhgri.nih.gov; zilong@ust.hk RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU National Human Genome Research Institute, NIH; Council of Hong Kong [662808] FX We thank Jagman Chahal and Kevin Bishop for technical assistance. This work was supported in part by the Intramural Research Program of National Human Genome Research Institute, NIH ( P. P. L.) and by grant from the Research Grants Council of Hong Kong to Z.L.W. ( 662808). Deposited in PMC for release after 12 months. NR 51 TC 42 Z9 43 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD FEB 15 PY 2009 VL 136 IS 4 BP 647 EP 654 DI 10.1242/dev.029637 PG 8 WC Developmental Biology SC Developmental Biology GA 397WI UT WOS:000262692500014 PM 19168679 ER PT J AU Cervantes, S Yamaguchi, TP Hebrok, M AF Cervantes, Sara Yamaguchi, Terry P. Hebrok, Matthias TI Wnt5a is essential for intestinal elongation in mice SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Wnt; Wnt5a; Endoderm; Midgut development; Small intestine elongation ID PLANAR-CELL-POLARITY; CONGENITAL SHORT-BOWEL; OF-THE-LITERATURE; CONVERGENT EXTENSION; EXPRESSION PATTERNS; XENOPUS-LAEVIS; DIFFERENTIATION; PATHWAY; MOVEMENTS; EMBRYOS AB Morphogenesis of the mammalian small intestine entails extensive elongation and folding of the primitive gut into a tightly coiled digestive tube. Surprisingly, little is known about the cellular and molecular mechanisms that mediate the morphological aspects of small intestine formation. Here, we demonstrate that Wnt5a, a member of the Wnt family of secreted proteins, is essential for the development and elongation of the small intestine from the midgut region. We found that the small intestine in mice lacking Wnt5a was dramatically shortened and duplicated, forming a bifurcated lumen instead of a single tube. In addition, cell proliferation was reduced and re-intercalation of post-mitotic cells into the elongating gut tube epithelium was disrupted. Thus, our study demonstrates that Wnt5a functions as a critical regulator of midgut formation and morphogenesis in mammals. (c) 2008 Elsevier Inc. All rights reserved. C1 [Cervantes, Sara; Hebrok, Matthias] Univ Calif San Francisco, Dept Med, Ctr Diabet, San Francisco, CA 94143 USA. [Yamaguchi, Terry P.] Natl Canc Inst Frederick, Canc & Dev Biol Lab, Canc Res Ctr, NIH Frederick, Ft Detrick, MD 21702 USA. RP Hebrok, M (reprint author), Univ Calif San Francisco, Dept Med, Ctr Diabet, San Francisco, CA 94143 USA. EM mhebrok@diabetes.ucsf.edu FU NIH [DK60533, CA112537]; UCSF Diabetes and Endocrinology Research Center [P30 DK63720]; National Cancer Institute; Center for Cancer Research; Spanish government; National Pancreas Foundation (NPF) FX We thank M. Kelley for the gift of the anti-Vangl2 antibody. We thank Dr. Patrick Heiser for initial observations and members of the Hebrok lab for helpful discussion. We also thank Drs. Sapna Puri, Grace Wei, David Cano and Limor Landsman for critical reading of the manuscript. We are indebted to Heather Heiser for assistance with animal genotyping, Cecilia Austin for help with tissue processing, and Jimmy Chen for assistance with graphics. Work in MH's lab is supported by an ADA grant and grants from the NIH (DK60533, CA112537). Confocal and other images were generated in the UCSF Diabetes and Endocrinology Research Center microscopy core (P30 DK63720). Research in TPY's lab was supported by the Intran'lUral Research Program of the NIH, National Cancer Institute, Center for Cancer Research. SC is supported by postdoctoral fellowships from the Ministerio de Educacion, Ciencia y Deportes from the Spanish government and the National Pancreas Foundation (NPF). NR 43 TC 67 Z9 73 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2009 VL 326 IS 2 BP 285 EP 294 DI 10.1016/j.ydbio.2008.11.020 PG 10 WC Developmental Biology SC Developmental Biology GA 406HI UT WOS:000263285200002 PM 19100728 ER PT J AU Maitra, M Schluterman, MK Nichols, HA Richardson, JA Lo, CW Srivastava, D Garg, V AF Maitra, Meenakshi Schluterman, Marie K. Nichols, Haley A. Richardson, James A. Lo, Cecilia W. Srivastava, Deepak Garg, Vidu TI Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Cardiac development; Congenital heart defects; Gata4; Gata6; Tbx5; Transcription factor ID CONGENITAL HEART-DISEASE; HOLT-ORAM-SYNDROME; HEAVY-CHAIN GENE; TRANSCRIPTION FACTOR; VENTRAL MORPHOGENESIS; TUBE FORMATION; EXPRESSION; DEFECTS; MUTATIONS; MURINE AB Congenital heart disease is the most common type of birth defect with an incidence of 1%. Previously, we described a point mutation in GATA4 that segregated with cardiac defects in a family with autosomal dominant disease. The mutation (G296S) exhibited biochemical deficits and disrupted a novel interaction between Gata4 and Tbx5. To determine if Gata4 and Tbx5 genetically interact in vivo, we generated mice heterozygous for both alleles. We found that nearly 100% of mice heterozygous for Gata4 and Tbx5 were embryonic or neonatal lethal and had complete atrioventricular (AV) septal defects with a single AV valve and myocardial thinning. Consistent with this phenotype, Gata4 and Tbx5 are co-expressed in the developing endocardial cushions and myocardium. In mutant embryos, cardiomyocyte proliferation deficits were identified compatible with the myocardial hypoplasia. Similar to Gata4, Gata6 and Tbx5 are co-expressed in the embryonic heart, and the transcription factors synergistically activate the atrial natiuretic factor promoter. We demonstrate a genetic interaction between Gata6 and Tbx5 with an incompletely penetrant phenotype of neonatal lethality and thin myocardium. Gene expression analyses were performed on both sets of compound heterozygotes and demonstrated downregulation of alpha-myosin heavy chain only in Gata4/Tbx5 heterozygotes. These findings highlight the unique genetic interactions of Gata4 and Gata6 with Tbx5 for normal cardiac morphogenesis in vivo. (c) 2008 Elsevier Inc. All rights reserved. C1 [Maitra, Meenakshi; Schluterman, Marie K.; Nichols, Haley A.; Srivastava, Deepak; Garg, Vidu] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Richardson, James A.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Richardson, James A.; Srivastava, Deepak; Garg, Vidu] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Garg, Vidu] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. [Lo, Cecilia W.] NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Garg, V (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pediat, 6000 Harry Hines Blvd,Rm NA8-124, Dallas, TX 75390 USA. EM vidu.garg@utsouthwestern.edu RI Garg, Vidu/E-3101-2011; Garg, Vidu/D-8240-2012 OI Garg, Vidu/0000-0002-3778-5927 FU NHLBI/NIH; March of Dimes Birth Defects Foundation; American Heart Association FX We thank members of the Molecular Pathology Core for histology assistance; B.G. Bruneau for providing the Tbx5 mutant mice; E. N. Olson for providing the Gata4 and Gata6 mutant mice; and B.G. Bruneau and E.N. Olson for critical review of the manuscript. This work was supported by grants from NHLBI/NIH, March of Dimes Birth Defects Foundation, and American Heart Association to D.S.; NHLBI/NIH, March of Dimes Birth Defects Foundation, and the American Heart Association-Texas Affiliate to V.G. NR 45 TC 77 Z9 81 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2009 VL 326 IS 2 BP 368 EP 377 DI 10.1016/j.ydbio.2008.11.004 PG 10 WC Developmental Biology SC Developmental Biology GA 406HI UT WOS:000263285200010 PM 19084512 ER PT J AU Chatterjee, S Ehrenshaft, M Bhattacharjee, S Deterding, LJ Bonini, MG Corbett, J Kadiiska, MB Tomer, KB Mason, RP AF Chatterjee, Saurabh Ehrenshaft, Marilyn Bhattacharjee, Suchandra Deterding, Leesa J. Bonini, Marcelo G. Corbett, Jean Kadiiska, Maria B. Tomer, Kenneth B. Mason, Ronald P. TI Immuno-spin trapping of a post-translational carboxypeptidase B1 radical formed by a dual role of xanthine oxidase and endothelial nitric oxide synthase in acute septic mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Oxidative stress; Immuno-spin trapping; Inflammation; Nitrone adduct ID HYDROGEN-PEROXIDE; NADPH OXIDASE; IN-VIVO; INFLAMMATORY RESPONSE; SUPEROXIDE-DISMUTASE; ENDOTOXIC-SHOCK; LUNG INJURY; PEROXYNITRITE; CELLS; SEPSIS AB Post-translational modification of proteins due to exposure to radicals and other reactive species are markers of metabolic and inflammatory oxidative stress Such as sepsis. This study uses the nitrone spin-trap DMPO and a combination of immuno-spin trapping and mass spectrometry to identify in vivo products of radical reactions in mice. We report the detection of dose-dependent production of DMPO-carboxypeptidase B1 (CPB1) adducts in the spleens of mice treated with lipopolysaccharide (LPS). Additionally, we report significant detection of DMPO-CPBI adducts in mice experiencing normal physiological conditions. Treatments with inhibitors and experiments with knock-out Mice indicate that xanthine oxidase and endothelial nitric oxide synthase are important sources of the reactive species that lead to CPBI adduct formation. We also report a significant loss of CPB1 activity following LPS challenge in conjunction with an increase in CPBI protein accumulation. This Suggests the presence of a possible mechanism for CPBI activity loss with compensatory protein production. Published by Elsevier Inc. C1 [Chatterjee, Saurabh; Ehrenshaft, Marilyn; Bhattacharjee, Suchandra; Bonini, Marcelo G.; Corbett, Jean; Kadiiska, Maria B.; Mason, Ronald P.] NIEHS, Pharmacol Lab, Free Rad Metabolites Grp, Res Triangle Pk, NC 27709 USA. [Deterding, Leesa J.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Chatterjee, S (reprint author), NIEHS, Pharmacol Lab, Free Rad Metabolites Grp, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM chatterjees2@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU National Institutes of Health; National Institute of Environmental Health Sciences FX This work has been supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. The authors sincerely acknowledge Dario C. Ramirez, T. Balkrishna Poduval and Jason Williams for their valuable input and suggestions. We sincerely thank Krisztian Stadler for valuable suggestions on immunostaining for confocal microscopy and Jeff Tucker for image analysis. We also sincerely thank Mary Mason and Ann Motten for helping in careful editing of this manuscript. NR 40 TC 21 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 15 PY 2009 VL 46 IS 4 BP 454 EP 461 DI 10.1016/j.freeradbiomed.2008.10.046 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 409LK UT WOS:000263507000002 PM 19049863 ER PT J AU Moore, SC Leitzmann, MF Albanes, D Weinstein, SJ Snyder, K Virtamo, J Ahn, J Mayne, ST Yu, H Peters, U Gunter, MJ AF Moore, Steven C. Leitzmann, Michael F. Albanes, Demetrius Weinstein, Stephanie J. Snyder, Kirk Virtamo, Jarmo Ahn, Jiyoung Mayne, Susan T. Yu, Herbert Peters, Ulrike Gunter, Marc J. TI Adipokine genes and prostate cancer risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE leptin; adipokines; cytokines prostate cancer; epidemiology ID GENOME-WIDE ASSOCIATION; LEPTIN GENE; MOLECULAR-INTERACTIONS; G-2548A POLYMORPHISM; -2548 G/A; OB GENE; OBESITY; REGION; PREVENTION; INSULIN AB Adiposity and adipocyte-derived cytokines have been implicated in prostate carcinogenesis. However. the relationship of adipokine gene variants with prostate cancer risk has not been thoroughly investigated. We therefore examined common variants of the IL6, LEP. LEPR, TNF and ADIPOQ genes in relation to prostate cancer in a case-control study nested within a large cohort of Finnish men. The study sample consisted of 1.053 cases of prostate cancer, diagnosed over an average 11 years of follow up, and 1,053 controls matched to the cases on age, intervention group and date of baseline blood draw. Logistic regression was used to model the relative odds of prostate cancer. We also examined genotypes in relation to serum insulin. IGF-1 and IGF-1:IGFBP-3 among 196 controls. Variant alleles at three loci (-14858A > G, - 13973A > C, -13736C > A) in a potential regulatory region of the LEP gene conferred a statistically significant 20% reduced risk of prostate cancer. For example. at the -14858A>G locus, heterozygotes and homozygotes for the A allele had an odds ratio (OR) of prostate cancer of 0.76 [95% confidence interval (CI) 0.62, 0.93] and 0.79 (95% Cl 0.60. 1.04), respectively. At 13288G > A, relative to the GG genotype, the AA genotype was associated with a suggestive increased risk of prostate cancer (OR = 1.29; 95% Cl 0.99,1.67; P(trend) = 0.05). Polymorphisms in the IL6, LEPR, TNF and ADIPOQ genes were not associated with prostate cancer. Allelic variants in the LEP gene are related to prostate cancer risk, supporting a role for leptin in prostate carcinogenesis. (c) 2008 Wiley-Liss. Inc. C1 [Moore, Steven C.; Leitzmann, Michael F.; Albanes, Demetrius; Weinstein, Stephanie J.; Ahn, Jiyoung; Gunter, Marc J.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Moore, Steven C.; Mayne, Susan T.; Yu, Herbert] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Leitzmann, Michael F.] Univ Hosp Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Snyder, Kirk] Informat Management Serv Inc, Silver Spring, MD USA. [Virtamo, Jarmo] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Peters, Ulrike] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Peters, Ulrike] Univ Washington, Sch Publ Hlth, Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98195 USA. [Gunter, Marc J.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Moore, SC (reprint author), 6120 Execut Blvd, Bethesda, MD 20892 USA. EM moorest@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Moore, Steven/D-8760-2016 OI Moore, Steven/0000-0002-8169-1661 FU National Cancer Institute [N01-CN-45165, N01-RC-45035, N01-RC-37004]; National Institutes of Health [TU2CA105666]; Department of Health and Human Services.; Intramural Research Program FX National Cancer Institute, National Institutes of Health: Grant number: TU2CA105666: Grain sponsor: Department of Health and Human Services. National Cancer Institute: Grant numbers: N01-CN-45165, N01-RC-45035. and N01-RC-37004: Grant sponsor: Intramural Research Program. NR 53 TC 36 Z9 37 U1 2 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2009 VL 124 IS 4 BP 869 EP 876 DI 10.1002/ijc.24043 PG 8 WC Oncology SC Oncology GA 396VD UT WOS:000262618400015 PM 19035456 ER PT J AU Chia, VM Li, Y Goldin, LR Graubard, BI Greene, MH Korde, L Rubertone, MV Erickson, RL McGlynn, KA AF Chia, Victoria M. Li, Yan Goldin, Lynn R. Graubard, Barry I. Greene, Mark H. Korde, Larissa Rubertone, Mark V. Erickson, Ralph L. McGlynn, Katherine A. TI Risk of cancer in first- and second-degree relatives of testicular germ cell tumor cases and controls SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE testicular cancer; family; aggregation ID FAMILY-HISTORY; POPULATION; BREAST; EPIDEMIOLOGY; BROTHERS; SWEDEN; TRENDS AB Risk factors for testicular germ cell tumors (TGCT) have not been well identified; however, data suggest that risks of cancer in family members or men with TGCT is elevated. Using family history data from 738 cases and 904 controls enrolled in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) Study from 2002 to 2005, the risk of cancer in first- and second-degree faimly members of these men was examined. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusting for reference age of case or control, race/ethnicity of case or control, sex of family member and lineage (maternal vs. paternal). An increased risk of all cancer among first-degree relatives of cases compared to controls was observed (RR = 1.17, 95% CI: 1.01-1.35). There were suggestions of differences in risk when stratifying all relatives by lineage. For maternal relatives, there was a statistically significant increased risk of all cancer (RR = 1.16, 95% CI: 1.04 1.30), digestive tract (RR 1.52, 95% CI: 1.15-2.00) and male genital organ cancer (RR 1.70, 95% CI: 1.15-2.51). there was also a suggestion of increased risks of hematopoetic cancers, cancers in the female genital organs and nonmelanoma skin cancer. For paternal relatives, there was a statistically significant association only with decreased risk of lung cancer (RR = 0.69, 95% CI: 0.51-0.0). Thus, this study suggests that there may be aggregation of cancer among families of men diagnosed with TGCT. C1 [Chia, Victoria M.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rubertone, Mark V.] USA, Ctr Hlth Promot & Prevent Med, Army Med Surveillance Act, Washington, DC 20310 USA. [Erickson, Ralph L.] Walter Reed Army Inst Res, GEIS, Div Prevent Med, Silver Spring, MD USA. RP Chia, VM (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, EPS Suite 550,6120 Execut Blvd, Bethesda, MD 20892 USA. EM chiav@mail.nih.gov FU Intramural NIH HHS [Z01 CP010126-12, NIH0013310441] NR 29 TC 10 Z9 10 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2009 VL 124 IS 4 BP 952 EP 957 DI 10.1002/ijc.23971 PG 6 WC Oncology SC Oncology GA 396VD UT WOS:000262618400026 PM 19035442 ER PT J AU Schuler, F Dolken, L Hirt, C Kiefer, T Berg, T Fusch, G Weitmann, K Hoffmann, W Fusch, C Janz, S Rabkin, CS Dolken, G AF Schueler, Frank Doelken, Lars Hirt, Carsten Kiefer, Thomas Berg, Tobias Fusch, Gerhard Weitmann, K. Hoffmann, W. Fusch, Christoph Janz, Siegfried Rabkin, Charles S. Doelken, Gottfried TI Prevalence and frequency of circulating t(14;18)-MBR translocation carrying cells in healthy individuals SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE t(14;18)-translocation; BCL2; quantitative real-time PCR; healthy individuals; follicular lymphoma ID CHAIN-REACTION DETECTION; FOLLICULAR LYMPHOMA; B-CELLS; INTERNATIONAL MULTICENTER; BCL-2-IGH TRANSLOCATION; PERIPHERAL-BLOOD; T(14-18); REARRANGEMENTS; ABNORMALITIES; HYPERPLASIA AB The t(14;18) translocation is a common genetic aberration that can be seen as an early step in pathogenesis of follicular lymphoma (FL). The significance of low level circulating t(14;18)-positive cells in healthy individuals its clonal lymphoma precursors or indicators of risk is still unclear. We determined the age dependent prevalence and frequency of BCL2/IgH rearrangements in 715 healthy, individuals ranging from newborns to octo- and nonagenarians. These results were compared with number of circulating 04;18)-positive cells in IN FL patients at initial presentation. The overall prevalence of BCL2/IgH junctions in this large sample was 46% (327/715). However, there was it striking dependence upon age. Specifically, among individuals up to 10 years old, none had detectable circulating t(14,18)-positive cells. In the age groups representing 10-50 years old, we found a steady elevation in the prevalence of BCL2/IgH junctions up to a prevalence of 66%. Further increases of the prevalence in individuals older than 50 years were not seen. The mean frequency of BCL2/IgH junctions in healthy individuals >= 40 Years (18-26 x 10(-6)) was significantly higher than ill younger subjects (7-9 x 10(-6)). Four percent (31/715) of individuals carried more than one t(I 4; 18)-positive cell per 25,1100 peripheral blood mononuclear cells (PBMNCs). In comparison, 108 stage III/IV FL patients hall it median number of Circulating t(14,18)-positive malignant FL cells of about 9200/1 million PBMNCs (range 7-1,000,000). These findings will further improve the understanding of the relevance of t(14;18)-positive,e cells in healthy individuals its a risk marker toward the development into lymphoma precursors. (C) 2008 Wiley-Liss, Inc. C1 [Doelken, Gottfried] Ernst Moritz Arndt Univ Greifswald, Klin & Poliklin Innere Med C, Hamatol & Onkol Transplantat Zentrum, Dept Hematol & Oncol, D-17475 Greifswald, Germany. [Fusch, Gerhard; Fusch, Christoph] Ernst Moritz Arndt Univ Greifswald, Dept Pediat, D-17475 Greifswald, Germany. [Weitmann, K.; Hoffmann, W.] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Janz, Siegfried] Univ Iowa, Dept Pathol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. [Rabkin, Charles S.] NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. RP Dolken, G (reprint author), Ernst Moritz Arndt Univ Greifswald, Klin & Poliklin Innere Med C, Hamatol & Onkol Transplantat Zentrum, Dept Hematol & Oncol, Sauerbruchstr, D-17475 Greifswald, Germany. EM doelken@uni-greifswald.de FU Alfried-Krupp-Graduiertenkolleg Tumorbiologie; Alfried Krupp Wisscoschaftskolleg, Greifswald; Federal Ministry of Education and Research [ZZ9603]; Ministry Of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania FX T. Berg Was Supported by a grant from the "Alfried-Krupp-Graduiertenkolleg Tumorbiologie" provided by the "Alfried Krupp Wisscoschaftskolleg, Greifswald". SHIP is part of the Community Medicine Research net (CMR) of the University of Greifswald. Germany, which is funded by the Federal Ministry of Education and Research (grant no, ZZ9603) and the Ministry Of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania (http://www.community-medicine.de). NR 29 TC 47 Z9 49 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2009 VL 124 IS 4 BP 958 EP 963 DI 10.1002/ijc.23958 PG 6 WC Oncology SC Oncology GA 396VD UT WOS:000262618400027 PM 19030176 ER PT J AU Wentzensen, N Schiffman, M Dunn, ST Zuna, RE Walker, J Allen, RA Zhang, R Sherman, ME Wacholder, S Jeronimo, J Gold, MA Wang, SS AF Wentzensen, Nicolas Schiffman, Mark Dunn, S. Terence Zuna, Rosemary E. Walker, Joan Allen, Richard A. Zhang, Roy Sherman, Mark E. Wacholder, Sholom Jeronimo, Jose Gold, Michael A. Wang, Sophia S. TI Grading the severity of cervical neoplasia based on combined histopathology, cytopathology, and HPV genotype distribution among 1,700 women referred to colposcopy in Oklahoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervical cancer; HPV; SUCCEED; epidemiology; molecular; CIN; biomarker ID HUMAN-PAPILLOMAVIRUS TYPE-16; ASCUS-LSIL TRIAGE; CANCER; RISK; EXPRESSION; SOFTWARE; CYTOLOGY; GRADE-2; BIOPSY; CIN3 AB Diagnosis and treatment of cervical cancer precursors rely on colposcopic biopsy, which is sometimes [tampered by incorrect biopsy placement an the unclear prognostic value of poorly reproducible diagnoses such as cervical intraepithelial neoplasia WIN) Grade 1 and 2. Searching for discrete disease categories that incorporate the value or cytology and that reflect the causal role of particular HPV types, we analyzed histology, cytology and HPV genotype distributions in the Study to Understand Cervical Cancer Endpoints and Early Determinants (SUCCEED). This cross-sectional study comprises similar to 1,700 women referred to colposcopy or treatment for the spectrum of cervical disease, including 439 women with 1, 1, and <1 bowel movement daily were 18.5, 18.8, 10.1 (P < 0.001) for dorsomedial: 15.3, 16.4, 10.2 (P < 0.03) for ventromedial; and 18.6, 18.3, 10.9 (P = 0.011) for ventrolateral quadrants. Relationships were not significant in the dorsolateral quadrant or in any quadrant among smokers. After adjustment for age, time to death, coffee drinking, tricep skinfold thickness, excessive daytime sleepiness, cognitive function, PD, and incidental LB, density ratios in nonsmokers with I or more bowel movement(s) daily were significantly higher compared to those with <1 daily. Constipation is associated with low SN neuron density independent of the presence of LB. (C) 2008 Movement Disorder Society C1 [Petrovitch, Helen; Abbott, Robert D.; Ross, G. Webster; Nelson, James; Masaki, Kamal H.; Tanner, Caroline M.; Launer, Lenore J.] Pacific Hlth Res Inst, Honolulu, HI USA. [Petrovitch, Helen; Abbott, Robert D.; Ross, G. Webster; Nelson, James; Masaki, Kamal H.; Tanner, Caroline M.; White, Lon R.] Kuakini Med Ctr, Honolulu Asia Aging Study, Honolulu, HI USA. [Petrovitch, Helen; Ross, G. Webster] Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. [Petrovitch, Helen; Ross, G. Webster; Masaki, Kamal H.; White, Lon R.] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. [Abbott, Robert D.] Univ Virginia, Sch Med, Div Biostat & Epidemiol, Charlottesville, VA 22908 USA. [Abbott, Robert D.] Shiga Univ Med Sci, Dept Hlth Sci, Otsu, Shiga 52021, Japan. [Ross, G. Webster] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Nelson, James] Univ Hawaii, John A Burns Sch Med, Dept Pathol, Honolulu, HI 96822 USA. [Tanner, Caroline M.] Parkinsons Inst, Sunnyvale, CA USA. [Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. RP Petrovitch, H (reprint author), 846 S Hotel St,Suite 307, Honolulu, HI 96813 USA. EM hpetrovitch@phrihawaii.org FU National Institutes of Health; National Institute of Neurological Disorders and Stroke [1 RO1 NS412265]; National Institute on Aging [1 U01 AG19349, 5 R01 AG017155]; Veterans Affair, Pacific Island Health Care System, Honolulu, Hawaii; Japan Society for the Promotion of Science; NIA FX This work was supported by the National Institutes of Health: National Institute of Neurological Disorders and Stroke Grant Number: 1 RO1 NS412265: National Institute on Aging, Grant Numbers: 1 U01 AG19349 and 5 R01 AG017155 and with resources from the Veterans Affair, Pacific Island Health Care System, Honolulu, Hawaii, the Japan Society for the Promotion of Science and the NIA Intramural Research Program. We thank the Honolulu-Asia Aging Study/Honolulu Heart Program cohort members for their important and long-term participation in the study and the Honolulu-Asia Aging Study staff who made the study possible. NR 38 TC 24 Z9 27 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB 15 PY 2009 VL 24 IS 3 BP 371 EP 376 DI 10.1002/mds.22360 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 412TN UT WOS:000263747200008 PM 19006191 ER PT J AU Yao, B Li, TQ van Gelderen, P Shmueli, K de Zwart, JA Duyn, JH AF Yao, Bing Li, Tie-Qiang van Gelderen, Peter Shmueli, Karin de Zwart, Jacco A. Duyn, Jeff H. TI Susceptibility contrast in high field MRI of human brain as a function of tissue iron content SO NEUROIMAGE LA English DT Article DE Phase; Ferritin; Relaxation; Susceptibility; Brain; Iron ID TRANSVERSE RELAXATION RATES; MAGNETIC-RESONANCE; ALZHEIMERS-DISEASE; FERRITIN; PHASE; STRENGTHS; IMAGES; T-1; AGE; R2 AB Magnetic susceptibility provides an important contrast mechanism for MRI. Increasingly, susceptibility-based contrast is being exploited to investigate brain tissue microstructure and to detect abnormal levels of brain iron as these have been implicated in a variety of neuro-degenerative diseases. However, it remains unclear to what extent magnetic susceptibility-related contrast at high field relates to actual brain iron concentrations. In this study, we performed susceptibility weighted imaging as a function of field strength on healthy brains in vivo and post-mortem brain tissues at 1.5 T, 3 T and 7 T. Iron histology was performed on the tissue samples for comparison. The calculated susceptibility-related parameters R(2)* and signal frequency shift in four iron-rich regions (putamen, globus pallidus, caudate, and thalamus) showed an almost linear dependence (r >= 0.90 for R(2)*; r >= 0.83 for phase, p<0.01) on field strength, suggesting that potential ferritin saturation effects are not relevant to susceptibility-weighted contrast for field strengths up to 7 T. The R(2)* dependence on the putative (literature-based) iron concentration was 0.048 Hz/T/ppm. The histological data from brain samples confirmed the linear dependence of R(2)* on field strength and showed a slope against iron concentration of 0.0099 Hz/T/ppm dry-weight, which is equivalent to 0.05 Hz/T/ppm wet-weight and closely matched the calculated value in vivo. These results confirm the validity of using susceptibility-weighted contrast as an indicator of iron content in iron-rich brain regions. The absence of saturation effects opens the way to exploit the benefits of MRI at high field strengths for the detection of iron distributions with high sensitivity and resolution. Published by Elsevier Inc. C1 [Yao, Bing; Li, Tie-Qiang; van Gelderen, Peter; Shmueli, Karin; de Zwart, Jacco A.; Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Yao, B (reprint author), NINDS, Adv MRI Sect, Lab Funct Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Room B1D728, Bethesda, MD 20892 USA. EM yaob@mail.nih.gov RI Duyn, Jozef/F-2483-2010; Shmueli, Karin/B-9432-2017; OI Li, Tieqiang/0000-0002-6636-8938; Li, Tie-Qiang/0000-0002-4866-5904 FU NIH; NINDS FX We thank Dr. Matsuda Rant, M. D. and Susan Fulton for their assistance with the experiments. This research was supported by the Intramural Research Program of the NIH, NINDS. NR 36 TC 166 Z9 170 U1 2 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2009 VL 44 IS 4 BP 1259 EP 1266 DI 10.1016/j.neuroimage.2008.10.029 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 414KG UT WOS:000263861800003 PM 19027861 ER PT J AU Schuyler, AD Jernigan, RL Qasba, PK Ramakrishnan, B Chirikjian, GS AF Schuyler, Adam D. Jernigan, Robert L. Qasba, Pradman K. Ramakrishnan, Boopathy Chirikjian, Gregory S. TI Iterative cluster-NMA: A tool for generating conformational transitions in proteins SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE protein mechanics; elastic network; normal mode analysis; cluster-NMA; rigid-body motions; beta 1,4-galactosyltransferase-T1; adenylate kinase ID NORMAL-MODE ANALYSIS; ELASTIC NETWORK MODELS; FREQUENCY NORMAL-MODES; MOLECULAR-DYNAMICS SIMULATIONS; ELECTRON-DENSITY MAPS; ADENYLATE KINASE; ALLOSTERIC TRANSITIONS; DISTANCE CONSTRAINTS; SEQUENCE VARIATIONS; ENERGY LANDSCAPES AB Computational models provide insight into the structure-function relationship in proteins. These approaches, especially those based on normal mode analysis, can identify the accessible motion space around a given equilibrium structure. The large magnitude, collective motions identified by these methods are often well aligned with the general direction of the expected conformational transitions. However, these motions cannot realistically be extrapolated beyond the local neighborhood of the starting conformation. In this article, the iterative cluster-NMA (icNMA) method is presented for traversing the energy landscape from a starting conformation to a desired goal conformation. This is accomplished by allowing the evolving geometry of the intermediate structures to define the local accessible motion space, and thus produce an appropriate displacement. Following the derivation of the icNMA method, a set of sample simulations. are performed to probe the robustness of the model. A detailed analysis of beta 1,4-galactosyltransferase-T1 is also given, to highlight many of the capabilities of icNMA. Remarkably, during the transition, a helix is seen to be extended by an additional turn, emphasizing a new unknown role for secondary structures to absorb slack during transitions. The transition pathway for adenylate kinase, which has been frequently studied in the literature, is also discussed. C1 [Chirikjian, Gregory S.] Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. [Schuyler, Adam D.] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Jernigan, Robert L.] Iowa State Univ, LH Baker Ctr Bioinformat & Biol Stat, Ames, IA 50011 USA. [Qasba, Pradman K.; Ramakrishnan, Boopathy] CCR Nanobiol Program, Struct Glycobiol Sect, Frederick, MD 21702 USA. [Ramakrishnan, Boopathy] NCI, Basic Sci Program, SAIC Frederick Inc, CCR, Frederick, MD 21702 USA. RP Chirikjian, GS (reprint author), Johns Hopkins Univ, Dept Mech Engn, 223 Latrobe Hall,3400 N Charles St, Baltimore, MD 21218 USA. EM gregc@jhu.edu RI Chirikjian, Gregory/A-3314-2010; Jernigan, Robert/A-5421-2012 FU Intramural NIH HHS [Z01 BC009304-13]; NIGMS NIH HHS [R01 GM075310, R01 GM072014, R01 GM073095, R01 GM075310-04, R01GM075310] NR 76 TC 25 Z9 25 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD FEB 15 PY 2009 VL 74 IS 3 BP 760 EP 776 DI 10.1002/prot.22200 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 396BH UT WOS:000262566700017 PM 18712827 ER PT J AU Do Carmo, GP Folk, JE Rice, KC Chartoff, E Carlezon, WA Negus, SS AF Do Carmo, Gail Pereira Folk, John E. Rice, Kenner C. Chartoff, Elena Carlezon, William A., Jr. Negus, S. Stevens TI The selective non-peptidic delta opioid agonist SNC80 does not facilitate intracranial self-stimulation in rats SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Delta opioid receptor agonists; SNC80; Amphetamine; U69,593; Intracranial self-stimulation ID DEPENDENT BEHAVIORAL STIMULATION; RHESUS-MONKEYS; NUCLEUS-ACCUMBENS; DOPAMINE RELEASE; RECEPTOR LIGANDS; PLACE-PREFERENCE; REWARD; DRUGS; AMPHETAMINE; BW373U86 AB Delta opioid receptor agonists are underdevelopment for a variety of clinical applications, and some findings in rats raise the possibility that agents with this mechanism have abuse liability. The present study assessed the effects of the non-peptidic delta opioid agonist SNC80 in an assay of intracranial self-stimulation (ICSS) in rats. ICSS was examined at multiple stimulation frequencies to permit generation of frequency-response rate curves and evaluation of curve shifts produced by experimental manipulations. Drug-induced leftward shifts in ICSS frequency-rate curves are often interpreted as evidence of abuse liability. However, SNC80 (1.0-10 mg/kg s.c.; 10-56 mg/kg i.p.) failed to alter ICSS frequency-rate curves at doses up to those that produced convulsions in the present study or other effects (e.g. antidepressant effects) in previous studies. For comparison, the monoamine releaser D-amphetamine (0.1-1.0 mg/kg, i.p.) and the kappa agonist U69,593 (0.1-0.56 mg/kg, i.p.) produced dose-dependent leftward and rightward shifts. respectively, in ICSS frequency-rate curves, confirming the sensitivity of the procedure to drug effects. ICSS frequency-rate curves were also shifted by two non-pharmacological manipulations (reductions in stimulus intensity and increases in response requirement). Thus, SNC80 failed to facilitate or attenuate ICSS-maintained responding under conditions in which other pharmacological and non-pharmacological manipulations were effective. These results suggest that non-peptidic delta opioid receptor agonists have negligible abuse-related effects in rats. (C) 2008 Elsevier B.V. All rights reserved. C1 [Negus, S. Stevens] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. [Do Carmo, Gail Pereira; Negus, S. Stevens] Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. [Folk, John E.; Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Folk, John E.; Rice, Kenner C.] NIAAA, NIH, DHHS, Bethesda, MD 20892 USA. [Chartoff, Elena; Carlezon, William A., Jr.] Harvard Univ, McLean Hosp, Sch Med, Behav Genet Lab, Belmont, MA 02478 USA. [Do Carmo, Gail Pereira] Marist Coll, Dept Psychol, Poughkeepsie, NY 12601 USA. RP Negus, SS (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 N 12th St,POB 980613, Richmond, VA 23298 USA. EM ssnegus@vcu.edu FU National Institute on Drug Abuse [R01-DA11460, R01-DA12736]; Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, NIH FX The authors would also like to thank Sam McWilliams, Katrina Schrode and David Potter for their excellent technical assistance. NR 53 TC 31 Z9 31 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 14 PY 2009 VL 604 IS 1-3 BP 58 EP 65 DI 10.1016/j.ejphar.2008.12.021 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 412XE UT WOS:000263756700008 PM 19133255 ER PT J AU Ohtani, M Daly, JW Oka, T AF Ohtani, Masahiro Daly, John W. Oka, Takami TI Co-existence of muscarinic and nicotinic receptors and their functional interaction in mouse Beta-TC6 cells SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Calcium; Carbamylcholine; Muscarinic receptor; Insulin secretion; Oxotremorine M; Nicotine ID STIMULATED INSULIN-SECRETION; EMBRYONAL CARCINOMA-CELLS; PANCREATIC B-CELLS; ACETYLCHOLINE-RECEPTORS; RINM5F CELLS; DEPENDENT MOBILIZATION; INTRACELLULAR CA2+; FREE CA-2+; IN-VITRO; RELEASE AB Mouse Beta-TC6 insulinoma cells possessing nicotinic receptor [Ohtani, M., Oka, T., Badyuk, M., Xiao, Y., Kellar, KJ., Daly, JW., 2006. Mouse beta-TC6 insulinoma cells: high expression of functional alpha 3 beta 4 nicotinic receptors mediating membrane potential, intracellular calcium, and insulin release. Mol. Pharmacol. 69, 899-907.] also expressed M(3) and M(4) muscarinic receptors. Carbamylcholine, a mixed muscarinc/nicotinic receptor agonist, or oxotremorine M, a selective muscarinic agonist, elicited an elevation of cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) and release of insulin. The maximal [Ca(2+)](i) response induced by carbamylcholine was larger than that of oxotremorine M or that of nicotine. suggesting that carbamylcholine enhanced the [Ca(2+)](i) response by stimulating two types of receptor. M(3) and M(4) muscarinic receptor antagonists inhibited the [Ca(2+)](i) responses to carbamylcholine and oxotremorine M, suggesting the involvement of these muscarinic receptors in the regulation of [Ca(2+)](i). In addition, pretreatment with carbamylcholine inhibited the [Ca(2+)](i) responses to oxotremorine M or nicotine, indicating that the effect of carbamylcholine on [Ca(2+)](i), was mediated by both muscarinic and nicotinic receptors. A phospholipase C (PLC) inhibitor U73122, a protein kinase C(PKC) inhibitor chelerythrine and a phospholipase A(2) (PLA(2)) inhibitor AACOCF(3) inhibited the [Ca(2+)](i) response to carbamylcholine or oxotremorine M, while these inhibitors did not block the effect of nicotine. Carbamylcholine induced a smaller extent of insulin secretion than oxotremorine M, suggesting that concomitant stimulation of muscarinic and nicotinic receptors by carbamylcholine resulted in the negative type of the receptor interaction. (C) 2008 Elsevier B.V. All rights reserved. C1 [Ohtani, Masahiro; Oka, Takami] Musashino Univ, Pharmaceut Sci Res Inst, Tokyo 2028585, Japan. [Ohtani, Masahiro; Oka, Takami] NIDDK, NIH, Bethesda, MD 20892 USA. [Daly, John W.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Oka, T (reprint author), Musashino Univ, Pharmaceut Sci Res Inst, 1-1-20 Shinmachi, Tokyo 2028585, Japan. EM toka@musashino-u.ac.jp FU Japanese Society for the Promotion of Sciences; National Institutes on Diabetes and Digestive and Kidney Diseases FX This work was supported in part by MEXT-HAITEKU and by a grant from the Japanese Society for the Promotion of Sciences (to Ohtani M). The research at the National Institutes of Health was supported by the intramural program of the National Institutes on Diabetes and Digestive and Kidney Diseases. We like to thank Ms. Yinghong Cui in the laboratory of Dr. Jurgen Wess at the National Institute of Diabetes and Digestive and Kidney Diseases (Bethesda, MD, USA) for carrying out the RT-PCR experiments. NR 34 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 14 PY 2009 VL 604 IS 1-3 BP 150 EP 157 DI 10.1016/j.ejphar.2008.12.018 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 412XE UT WOS:000263756700020 PM 19109944 ER PT J AU Ferrucci, L Perry, JRB Matteini, A Perola, M Tanaka, T Silander, K Rice, N Melzer, D Murray, A Cluett, C Fried, LR Albanes, D Corsi, AM Cherubini, A Guralnik, J Bandinelli, S Singleton, A Virtamo, J Walston, J Semba, RD Frayling, TM AF Ferrucci, Luigi Perry, John R. B. Matteini, Amy Perola, Markus Tanaka, Tosbiko Silander, Kaisa Rice, Neil Melzer, David Murray, Anna Cluett, Christie Fried, Linda R. Albanes, Demetrius Corsi, Anna-Maria Cherubini, Antonio Guralnik, Jack Bandinelli, Stefania Singleton, Andrew Virtamo, Jarmo Walston, Jeremy Semba, Richard D. Frayling, Timothy M. TI Common Variation in the beta-Carotene 15,15 '-Monooxygenase 1 Gene Affects Circulating Levels of Carotenoids: A Genome-wide Association Study SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID VITAMIN-E LEVELS; ALPHA-TOCOPHEROL; OLDER PERSONS; CARDIOVASCULAR-DISEASE; LIQUID-CHROMATOGRAPHY; PLASMA-CONCENTRATIONS; ELDERLY POPULATION; MEDITERRANEAN DIET; VEGETABLE INTAKE; FOLLOW-UP AB Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association Study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels anti known lipid variants associated with alpha-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study (n 2136). In meta-analyses including all three Studies, the G allele at rs6564851, near the beta-carotene 15,15'-monooxygenase 1 (BCMO1) gene, was associated with higher beta-carotene (p = 1.6 x 10(-24)) and alpha-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 x 10(-5)), and lutein (p = 7.3 x 10(-15)) levels, with effect sizes ranging from 0.10-0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOA5 gene, was associated with alpha-tocopherol (meta-analysis p = 7.8 x 10(-10)) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health. C1 [Ferrucci, Luigi; Tanaka, Tosbiko] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Perry, John R. B.; Rice, Neil; Melzer, David; Murray, Anna; Cluett, Christie; Frayling, Timothy M.] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England. [Matteini, Amy; Walston, Jeremy] Johns Hopkins Med Inst, Dept Med, Div Geriatr, Baltimore, MD 21224 USA. [Virtamo, Jarmo] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, FI-00271 Helsinki, Finland. [Perola, Markus; Silander, Kaisa] Inst Mol Med, Dept Mol Med, FIMM, FI-00271 Helsinki, Finland. [Tanaka, Tosbiko] MedStar Res Inst, Baltimore, MD 21225 USA. [Fried, Linda R.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Corsi, Anna-Maria] Tuscany Reg Hlth Agcy, I-50100 Florence, Italy. [Cherubini, Antonio] Univ Perugia, Sch Med, Dept Clin & Expt Med, Inst Gerontol & Geriatr, I-06122 Perugia, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, I-50125 Florence, Italy. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21224 USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. EM ferruccilu@grc.nia.nih.gov RI Singleton, Andrew/C-3010-2009; Albanes, Demetrius/B-9749-2015; OI Murray, Anna/0000-0002-2351-2522; Melzer, David/0000-0002-0170-3838 FU Italian Ministry of Health [ICS110.1\RS97.71]; National Institute on Aging [N01-AG-916413, N01-AG-821336]; US Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004]; National Cancer Institute, Department of Health and Human Service; National Institute on Aging, National Institutes of Health; National Institute on Aging, Pathogenesis of Physical Disability in Aging Women [R37 AG 19905, R01 AG027012]; Johns Hopkins Claude D. Pepper Older Americans Independence Center [P30 AG021334] FX The InCHIANTI study was supported as a "targeted project" (ICS110.1\RS97.71) by the Italian Ministry of Health and in part by the National Institute on Aging (contracts N01-AG-916413, N01-AG-821336). The ATBC study was Supported by the US Public Health Service contracts N01-CN-45165, N01-RC-45035, and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Service. This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. A portion of that support was through an R&D contract with the MedStar Research Institute. We would like to thank Dr. Arun Barua (Iowa State University) for precious help in interpreting our findings in the context of carotenoid metabolism in humans. We acknowledge the important contribution of Leena Peltonen Palotie of the Finnish Public Health Institute, who made genotyping the ATBC study possible. The WHAS was supported by a MERIT AWARD from the National Institute on Aging, Pathogenesis of Physical Disability in Aging Women (R37 AG 19905 and R01 AG027012) and the Johns Hopkins Claude D. Pepper Older Americans Independence Center (P30 AG021334). NR 56 TC 83 Z9 86 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 13 PY 2009 VL 84 IS 2 BP 123 EP 133 DI 10.1016/j.ajhg.2008.12.019 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 413NL UT WOS:000263799700004 PM 19185284 ER PT J AU Huang, L Li, Y Singleton, AB Hardy, JA Abecasis, G Rosenberg, NA Scheet, P AF Huang, Lucy Li, Yun Singleton, Andrew B. Hardy, John A. Abecasis, Goncalo Rosenberg, Noah A. Scheet, Paul TI Genotype-Imputation Accuracy across Worldwide Human Populations SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MISSING-DATA IMPUTATION; LINKAGE DISEQUILIBRIUM; HAPLOTYPE MAP; INFERENCE; DISEASE; LOCI; TRANSFERABILITY; VARIANTS; PATTERNS AB A Current approach to mapping complex-disease-susceptibility loci in genome-wide association (GWA) studies involves leveraging the information in a reference database of dense genotype data. By modeling the patterns of linkage disequilibrium in a reference panel, genotypes not directly measured In the study samples can be imputed and tested for disease association. This imputation strategy has been successful for GWA studies in populations well represented by existing reference panels. We used genotypes at 513,008 autosomal single-nucleotide polymorphism (SNP) loci in 443 unrelated individuals from 29 worldwide populations to evaluate the "portability" of the HapMap reference panels for imputation in studies of diverse populations. When a single HapMap panel was leveraged for imputation of randomly masked genotypes, European populations had the highest imputation accuracy, followed by populations from East Asia, Central and South Asia, the Americas, Oceania, the Middle East, and Africa. For each population, we identified "optimal" mixtures of reference panels that maximized imputation accuracy, and we found that in most populations, mixtures including individuals from at least two HapMap panels produced the highest imputation accuracy. From a separate survey of additional SNPs typed in the same samples, we evaluated imputation accuracy in the scenario in which all genotypes at a given SNP position were unobserved and were imputed on the basis of data from a commercial "SNP chip," again finding that most populations benefited from the use of combinations of two or more HapMap reference panels. Our results can serve as a guide for selecting appropriate reference panels for imputation-based GWA analysis in diverse populations. C1 [Huang, Lucy; Li, Yun; Abecasis, Goncalo; Rosenberg, Noah A.; Scheet, Paul] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Huang, Lucy; Rosenberg, Noah A.] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA. [Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hardy, John A.] UCL, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, John A.] UCL, Reta Lila Weston Inst Neurol Studies, Inst Neurol, London WC1N 3BG, England. [Rosenberg, Noah A.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Scheet, Paul] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Huang, L (reprint author), Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. EM hlucy@umich.edu RI Hardy, John/C-2451-2009; Abecasis, Goncalo/B-7840-2010; Singleton, Andrew/C-3010-2009; OI Abecasis, Goncalo/0000-0003-1509-1825 FU National Institutes of Health [R01 GM081441, R01 HL090564, U01 HL084729]; Burroughs Wellcome Fund; Alfred P. Sloan Foundation; National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01AG000949-02] FX This work was supported in part by grants from the National Institutes of Health (R01 GM081441, R01 HL090564, and U01 HL084729), the Burroughs Wellcome Fund, and the Alfred P. Sloan Foundation and by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (Z01AG000949-02). NR 32 TC 129 Z9 133 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 13 PY 2009 VL 84 IS 2 BP 235 EP 250 DI 10.1016/j.ajhg.2009.01.013 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 413NL UT WOS:000263799700013 PM 19215730 ER PT J AU Zang, Y Fung, WK Zheng, G AF Zang, Yong Fung, Wing K. Zheng, Gang TI Tail Strength to Combine Two p Values: Their Correlation Cannot Be Ignored SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID HARDY-WEINBERG DISEQUILIBRIUM; TREND TESTS; SAMPLE-SIZE; ASSOCIATION; POWER C1 [Zheng, Gang] NHLBI, Off Biostat Res, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Zang, Yong; Fung, Wing K.] Univ Hong Kong, Dept Stat & Actuarial Sci, Hong Kong, Hong Kong, Peoples R China. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, Div Prevent & Populat Sci, Bldg 10, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov RI Fung, Tony/D-3082-2009 NR 13 TC 2 Z9 2 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 13 PY 2009 VL 84 IS 2 BP 291 EP 295 DI 10.1016/j.ajhg.2009.01.014 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 413NL UT WOS:000263799700020 PM 19215733 ER PT J AU Murphy, E Eisner, DA AF Murphy, Elizabeth Eisner, David A. TI Regulation of Intracellular and Mitochondrial Sodium in Health and Disease SO CIRCULATION RESEARCH LA English DT Review DE sodium; ischemia/reperfusion; heart failure; calcium; mitochondria; ion transport ID NA+-H+ EXCHANGE; ISOLATED HEART-MITOCHONDRIA; RAT VENTRICULAR MYOCYTES; FAILING HUMAN HEART; NA/K PUMP FUNCTION; CARDIAC MYOCYTES; METABOLIC INHIBITION; NA+-CA2+ EXCHANGE; CALCIUM EXCHANGE; OXIDATIVE-PHOSPHORYLATION AB The transmembrane sodium gradient is essential for both excitability of the cardiac cell and the regulation of the cytoplasmic concentrations of Ca and protons. In addition, movements of Na across the mitochondrial membrane affect matrix protons and calcium. In the first part of the review, we discuss the most important pathways responsible for sarcolemmal and mitochondrial sodium movements. The bulk of the review considers the changes of intracellular Na concentration ([ Na(+)] (i)) that occur in disease, specifically, ischemia, reperfusion, and heart failure. We review evidence implicating the increase of intracellular sodium to either increased influx of sodium ( via either sodium channels or sodium/hydrogen exchange) or, alternatively, to decreased efflux on the Na/K pump. Although much has been learned about sodium regulation in the heart, there are still many unanswered questions, particularly concerning mitochondrial Na regulation. ( Circ Res. 2009; 104: 292-303.) C1 [Murphy, Elizabeth] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Eisner, David A.] Univ Manchester, Unit Cardiac Physiol, Core Technol Facil 3 18, Manchester, Lancs, England. RP Murphy, E (reprint author), NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov OI Eisner, David/0000-0002-7002-3748 FU British Heart Foundation; Intramural NIH HHS [Z99 HL999999] NR 128 TC 80 Z9 86 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD FEB 13 PY 2009 VL 104 IS 3 BP 292 EP 303 DI 10.1161/CIRCRESAHA.108.189050 PG 12 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 406QL UT WOS:000263309900006 PM 19213964 ER PT J AU Chiang, YJ Jordan, MS Horai, R Schwartzberg, PL Koretzky, GA Hodes, RJ AF Chiang, Y. Jeffrey Jordan, Martha S. Horai, Reiko Schwartzberg, Pamela L. Koretzky, Gary A. Hodes, Richard J. TI Cbl Enforces an SLP76-dependent Signaling Pathway for T Cell Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADAPTER PROTEIN SLP-76; C-CBL; NEGATIVE REGULATION; ANTIGEN RECEPTOR; TYROSINE PHOSPHORYLATION; THYMOCYTE DEVELOPMENT; POSITIVE SELECTION; ACTIVATION; TCR; MICE AB A signaling pathway involving ZAP-70, LAT, and SLP76 has been regarded as essential for receptor-driven T cell development and activation. Consistent with this model, mice deficient in SLP76 have a complete block at the double negative 3 stage of T cell development. Recently, however, it has been reported that inactivation of Cbl, a ubiquitin-protein isopeptide ligase, partially rescues T cell development in SLP76-deficient mice. To probe the influence of Cbl on domain-specific SLP76 functions, we reconstituted SLP76(-/-) Cbl(-/-) mice with Slp76 transgenes bearing mutations in each of three functional domains of SLP76 as follows: Y3F, in which the amino-terminal tyrosine residues of SLP76 were mutated, eliminating sites of SLP76 interaction with Vav, Nck, and Itk; Delta 20, in which 20 amino acids in the proline-rich region of SLP76 were deleted, removing a binding site for Gads; and RK, in which arginine 448 of SLP76 was replaced by lysine, abolishing function of the Src homology 2 domain. Although each of these transgenes has been shown to partially rescue T cell development in SLP76(-/-) mice, we report here that Cbl inactivation completely reverses the severe double negative 3 developmental block that occurs in SLP76-deficient mice expressing the Y3F transgene (Y3F mice) and partially rescues the defect in positive selection in T cell receptor transgenic Y3F mice, but in contrast fails to rescue thymic development of SLP76-deficient mice expressing the Delta 20 or RK transgene. Rescue in SLP76(-/-) Cbl(-/-) Y3F double-positive thymocytes is associated with enhanced tyrosine phosphorylation of signaling molecules, including Lck, Vav, PLC-gamma 1, and ERKs, but not Itk, in response to T cell receptor stimulation. Thus, our data demonstrate that Cbl suppresses activation of a bypass signaling pathway and thereby enforces SLP76 dependence of early T cell development. C1 [Chiang, Y. Jeffrey; Hodes, Richard J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Chiang, Y. Jeffrey; Hodes, Richard J.] NIA, NIH, Bethesda, MD 20892 USA. [Jordan, Martha S.; Koretzky, Gary A.] Univ Penn, Signal Transduct Program, Abramson Family Canc Res Inst, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Horai, Reiko; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Chiang, YJ (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,4B36, Bethesda, MD 20892 USA. EM chiangj@mail.nih.gov FU National Institutes of Health grant (NCI Intramural Research Program) FX This work was supported, in whole or in part, by a National Institutes of Health grant (NCI Intramural Research Program). NR 34 TC 5 Z9 5 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 13 PY 2009 VL 284 IS 7 BP 4429 EP 4438 DI 10.1074/jbc.M808679200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404ET UT WOS:000263134400043 PM 19074136 ER PT J AU Tsai, CM Jankowska-Stephens, E Mizanur, RM Cipollo, JF AF Tsai, Chao-Ming Jankowska-Stephens, Ewa Mizanur, Rahman M. Cipollo, John F. TI The Fine Structure of Neisseria meningitidis Lipooligosaccharide from the M986 Strain and Three of Its Variants SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INNER-CORE LIPOPOLYSACCHARIDE; OUTER-MEMBRANE PROTEINS; GROUP-B; IMMUNOTYPE EPITOPES; SECONDARY RESPONSE; GROUP-A; OLIGOSACCHARIDE; PHOSPHOETHANOLAMINE; IMMUNORESPONSES; IDENTIFICATION AB Neisseria meningitidis is a cause of fatal sepsis and epidemic meningitis. A major virulence factor is cell wall lipooligosaccharide (LOS). The M986 strain has been used extensively in immunological and vaccine research. Yet, the LOS repertoire of this strain is not known. Here we have investigated the LOS structures of M986 and three of its variants OP1, OP2-, and OP2+. This strain and its variants present a series of related LOS families that are increasingly truncated in their listed order. The major structural differences are seen in the lacto-N-neotetraose alpha-chain. The gamma-chain Hep II contains two phosphoethanolamine (PEA) substitutions at C3 and C6/7. These substitutions were seen in all strains except OP2+ where the canonical core Hep II is missing. The PEA disubstitution was present in nearly stoichiometric amounts with only minor amounts of monosubstitution observed, and no glycomers devoid of PEA were seen. This was also the case in LOS with a complete lacto-N-neotetraosyl alpha-chain even though previous reports suggested that the presence of an extended alpha-chain hinders C3 PEA substitution of Hep II. Approximately 50% of gamma-chain GlcNAc was present in its 3-OAc-substituted form. Because Hep II C3 PEA substitution and gamma-chain GlcNAc OAc addition have been reported to negatively interact, the co-existence of these two modifications in these strains is unique. The LOS structures of M986 and three of its variants have been determined, which better defines these strains as tools for immunological and vaccine research. C1 [Cipollo, John F.] NIH, Ctr Biol Evaluat & Res, US FDA, Bethesda, MD 20892 USA. RP Cipollo, JF (reprint author), NIH, Ctr Biol Evaluat & Res, US FDA, Bldg 29,Rm 126,8800 Rockville Pike, Bethesda, MD 20892 USA. EM john.cipollo@fda.hhs.gov FU Department of Energy [DE-FG09-93ER-20097] FX This work was supported by the Department of Energy-funded (Grant DE-FG09-93ER-20097) Center for Plant and Microbial Complex Carbohydrates. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 44 TC 14 Z9 14 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 13 PY 2009 VL 284 IS 7 BP 4616 EP 4625 DI 10.1074/jbc.M808209200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404ET UT WOS:000263134400061 PM 19095648 ER PT J AU Russell, RA Moore, MD Hu, WS Pathak, VK AF Russell, Rebecca A. Moore, Michael D. Hu, Wei-Shau Pathak, Vinay K. TI APOBEC3G induces a hypermutation gradient: purifying selection at multiple steps during HIV-1 replication results in levels of G-to-A mutations that are high in DNA, intermediate in cellular viral RNA, and low in virion RNA SO RETROVIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; FUSION INHIBITOR T-20; VIF PROTEIN; CYTIDINE DEAMINATION; IN-VIVO; NUCLEOPROTEIN COMPLEXES; INFECTIVITY FACTOR; ENZYME APOBEC3G; DEGRADATION; CELLS AB Background: Naturally occurring Vif variants that are unable to inhibit the host restriction factor APOBEC3G (A3G) have been isolated from infected individuals. A3G can potentially induce G-to-A hypermutation in these viruses, and hypermutation could contribute to genetic variation in HIV-1 populations through recombination between hypermutant and wild-type genomes. Thus, hypermutation could contribute to the generation of immune escape and drug resistant variants, but the genetic contribution of hypermutation to the viral evolutionary potential is poorly understood. In addition, the mechanisms by which these viruses persist in the host despite the presence of A3G remain unknown. Results: To address these questions, we generated a replication-competent HIV-1 Vif mutant in which the A3G-binding residues of Vif, Y(40)RHHY(44), were substituted with five alanines. As expected, the mutant was severely defective in an A3G-expressing T cell line and exhibited a significant delay in replication kinetics. Analysis of viral DNA showed the expected high level of G-to-A hypermutation; however, we found substantially reduced levels of G-to-A hypermutation in intracellular viral RNA ( cRNA), and the levels of G-to-A mutations in virion RNA (vRNA) were even further reduced. The frequencies of hypermutation in DNA, cRNA, and vRNA were 0.73%, 0.12%, and 0.05% of the nucleotides sequenced, indicating a gradient of hypermutation. Additionally, genomes containing start codon mutations and early termination codons within gag were isolated from the vRNA. Conclusion: These results suggest that sublethal levels of hypermutation coupled with purifying selection at multiple steps during the early phase of viral replication lead to the packaging of largely unmutated genomes, providing a mechanism by which mutant Vif variants can persist in infected individuals. The persistence of genomes containing mutated gag genes despite this selection pressure indicates that dual infection and complementation can result in the packaging of hypermutated genomes which, through recombination with wild-type genomes, could increase viral genetic variation and contribute to evolution. C1 [Russell, Rebecca A.; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. [Moore, Michael D.; Hu, Wei-Shau] NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Pathak, VK (reprint author), NCI, Viral Mutat Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. EM rebecca.russell@path.ox.ac.uk; kenny.moore@path.ox.ac.uk; whu@ncifcrf.gov; vpathak@ncifcrf.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX The authors would like to thank John Coffin and Frank Maldarelli for critical reading of the manuscript and valuable suggestions. We would also like to thank Wei Bu, Ryan Burdick, Yeshitila Friew, and Jessica Smith for critical reading of the manuscript. TZM-bl cells were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH from Dr. John C. Kappes and Dr. Xiaoyun Wu and Tranzyme Inc. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, 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 U. S. Government. NR 49 TC 41 Z9 41 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 13 PY 2009 VL 6 AR 16 DI 10.1186/1742-4690-6-16 PG 15 WC Virology SC Virology GA 425XU UT WOS:000264672100001 PM 19216784 ER PT J AU Feng, HQ Jenkins, LMM Durell, SR Hayashi, R Mazur, SJ Cherry, S Tropea, JE Miller, M Wlodawer, A Appella, E Bai, Y AF Feng, Hanqiao Jenkins, Lisa M. Miller Durell, Stewart R. Hayashi, Ryo Mazur, Sharlyn J. Cherry, Scott Tropea, Joseph E. Miller, Maria Wlodawer, Alexander Appella, Ettore Bai, Yawen TI Structural Basis for p300 Taz2-p53 TAD1 Binding and Modulation by Phosphorylation SO STRUCTURE LA English DT Article ID SUPPRESSOR TRANSACTIVATION DOMAIN; ACTIVATION DOMAINS; COMPUTER-PROGRAM; CHEMICAL-SHIFT; HEAT-CAPACITY; MDM2 BINDING; HUMAN P53; PROTEIN; NMR; ACETYLATION AB Coactivators CREB-binding protein and p300 play important roles in mediating the transcriptional activity of p53. Until now, however, no detailed structural information has been available on how any of the domains of p300 interact with p53. Here, we report the NMR structure of the complex of the Taz2 (C/H3) domain of p300 and the N-terminal transactivation domain of p53. In the complex, p53 forms a short alpha helix and interacts with the Taz2 domain through an extended surface. Mutational analyses demonstrate the importance of hydrophobic residues for complex stabilization. Additionally, they suggest that the increased affinity of Taz2 for p531-39 phosphorylated at Thr(18) is due in part to electrostatic interactions of the phosphate with neighboring arginine residues in Taz2. Thermodynamic experiments revealed the importance of hydrophobic interactions in the complex of Taz2 with p53 phosphorylated at Ser(15) and Thr(18). C1 [Jenkins, Lisa M. Miller; Durell, Stewart R.; Hayashi, Ryo; Mazur, Sharlyn J.; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Feng, Hanqiao; Bai, Yawen] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Cherry, Scott; Tropea, Joseph E.; Miller, Maria; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Appella, E (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM appellae@pop.nci.nih.gov RI Miller, Maria/I-1636-2013 OI Miller, Maria/0000-0003-0252-5348 FU NIH; 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. NR 53 TC 57 Z9 58 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD FEB 13 PY 2009 VL 17 IS 2 BP 202 EP 210 DI 10.1016/j.str.2008.12.009 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 407SO UT WOS:000263384800008 PM 19217391 ER PT J AU Gallagher, PG Nilson, DG Steiner, LA Maksimova, YD Lin, JY Bodine, DM AF Gallagher, Patrick G. Nilson, Douglas G. Steiner, Laurie A. Maksimova, Yelena D. Lin, Jolinta Y. Bodine, David M. TI An insulator with barrier-element activity promotes alpha-spectrin gene expression in erythroid cells SO BLOOD LA English DT Article ID BETA-GLOBIN LOCUS; ENHANCER-BLOCKING ACTIVITY; MEMBRANE SKELETAL PROTEINS; HIGH-LEVEL EXPRESSION; HEREDITARY SPHEROCYTOSIS; TRANSGENIC MICE; IN-VIVO; DROSOPHILA-MELANOGASTER; CHROMATIN INSULATORS; ACETYLATION REVEAL AB Understanding mechanisms controlling expression of the alpha-spectrin gene is important for understanding erythropoiesis, membrane biogenesis, and spectrin-linked hemolytic anemia. We showed previously that a minimal alpha-spectrin promoter directed low levels of expression only in early erythroid development, indicating elements outside the promoter are required for expression in adult erythrocytes. Addition of noncoding exon 1' and intron 1' conferred a 10-fold increase in activity in reporter gene assays. In this report, we used a transgenic mouse model to show that addition of exon 1' and intron 1' to the alpha-spectrin promoter conferred tissue-specific expression of a linked (A)gamma-globin gene in erythroid cells at all developmental stages. Expression was nearly position-independent, as 21 of 23 lines expressed the transgene, and gamma-globin protein was present in 100% of erythrocytes, indicating uniform expression. Additional in vivo studies revealed that exon 1' functions as an insulator with barrier-element activity. Chromatin immunoprecipitation assays demonstrated that this region was occupied by the upstream stimulatory factors 1/2 (USF1/USF2), similar to the well-characterized chicken HS4 insulator. These data identify the first barrier element described in an erythrocyte membrane protein gene and indicate that exon 1' and intron 1' are excellent candidate regions for mutations in patients with spectrin-linked hemolytic anemia. ( Blood. 2009; 113: 1547-1554) C1 [Gallagher, Patrick G.; Steiner, Laurie A.; Maksimova, Yelena D.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. [Nilson, Douglas G.; Lin, Jolinta Y.; Bodine, David M.] NHGRI, Hematopoiesis Sect, NIH, Bethesda, MD 20892 USA. RP Gallagher, PG (reprint author), Yale Univ, Sch Med, Dept Pediat, 333 Cedar St,POB 208064, New Haven, CT 06520 USA. EM patrick.gallagher@yale.edu FU National Heart, Lung, and Blood Institute, NIH [HL65448]; National Institute of Child Health and Human Development, NIH [HD000850]; National Human Genome Research Institute, NIH FX This work was supported in part by a grant from the National Heart, Lung, and Blood Institute, NIH (HL65448), the National Institute of Child Health and Human Development, NIH (HD000850), and intramural funds from the National Human Genome Research Institute, NIH. NR 75 TC 18 Z9 19 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 12 PY 2009 VL 113 IS 7 BP 1547 EP 1554 DI 10.1182/blood-2008-06-164954 PG 8 WC Hematology SC Hematology GA 406SY UT WOS:000263316400022 PM 19008453 ER PT J AU Briard, E Zoghbi, SS Simeon, FG Imaizumi, M Gourley, JP Shetty, HU Lu, SY Fujita, M Innis, RB Pike, VW AF Briard, Emmanuelle Zoghbi, Sami S. Simeon, Fabrice G. Imaizumi, Masao Gourley, Jonathan P. Shetty, H. Umesha Lu, Shuiyu Fujita, Masahiro Innis, Robert B. Pike, Victor W. TI Single-Step High-Yield Radiosynthesis and Evaluation of a Sensitive, F-18-Labeled Ligand for Imaging Brain Peripheral Benzodiazepine Receptors with PET SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; RAT CEREBRAL-CORTEX; PROTEIN 18 KDA; BINDING-SITES; IN-VIVO; NONHUMAN-PRIMATES; NEURONAL DAMAGE; RADIOLIGAND; CELLS; BIOSYNTHESIS AB Elevated levels of peripheral benzodiazepine receptors (PBR) are associated with activated microglia in their response to inflammation. Hence, PBR imaging in vivo is valuable for investigating brain inflammatory conditions. Sensitive, easily prepared, and readily available radioligands for imaging with positron emission tomography (PET) are desirable for this purpose. We describe a new F-18-labeled PBR radioligand, namely [F-18]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([F-18]9). [F-18]9 was produced easily through a single and highly efficient step, the reaction of [F-18]fluoride ion with the corresponding bromo precursor, 8. Ligand 9 exhibited high affinity for PBR in vitro. PET showed that [F-18]9 was avidly taken into monkey brain and gave a high ratio of PBR-specific to nonspecific binding. [F-18]9 was devoid of defluorination in rat and monkey and gave predominantly polar radiometabolite(s). In rat, a low level radiometabolite of intermediate lipophilicity was identified as [F-18]2-fluoro-N-(2-phenoxyphenyl)acetamide ([F-18]11). [F-18]9 is a promising radioligand for future imaging of PBR in living human brain. C1 [Briard, Emmanuelle; Zoghbi, Sami S.; Simeon, Fabrice G.; Imaizumi, Masao; Gourley, Jonathan P.; Shetty, H. Umesha; Lu, Shuiyu; Fujita, Masahiro; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov OI Lu, Shuiyu/0000-0003-0310-4318 FU National Institute of Mental Health [Z01-MH-002793] FX This study was supported by the Intramural Research Program of the National Institutes of Health, specifically the National Institute of Mental Health (project no. Z01-MH-002793). We thank Kimberley Jenko for assistance on experiments in rats. We also thank the NLH PET Department for fluorine-18 production and successful completion of the scanning experiments, and PMOD Technologies for providing the image analysis software. NR 59 TC 58 Z9 58 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 12 PY 2009 VL 52 IS 3 BP 688 EP 699 DI 10.1021/jm8011855 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 404HN UT WOS:000263142400012 PM 19119848 ER PT J AU Pan, PY Tian, JH Sheng, ZH AF Pan, Ping-Yue Tian, Jin-Hua Sheng, Zu-Hang TI Snapin Facilitates the Synchronization of Synaptic Vesicle Fusion SO NEURON LA English DT Article ID ORGANELLES COMPLEX-1 BLOC-1; SYNAPTOTAGMIN-I FUNCTIONS; NEUROTRANSMITTER RELEASE; MEMBRANE-FUSION; TRANSMITTER RELEASE; T-SNARE; SCHIZOPHRENIA SUSCEPTIBILITY; CA2+-TRIGGERED EXOCYTOSIS; ASYNCHRONOUS RELEASE; HIPPOCAMPAL-NEURONS AB Synaptic vesicle (SV) fusion is a fine-tuned process requiring a concert of fusion machineries. Using cortical neurons from snapin-deficient mice, we reveal a role for Snapin in facilitating synchronous release. In addition to reduced frequency of miniature excitatory postsynaptic currents (mini-EPSCs) and smaller release-ready vesicle pool (RRP) size, snapin deficiency results in EPSCs with multiple peaks and increased rise and decay times, reflecting "desynchronized" SV fusion. These defects impair both synaptic precision and efficacy during sustained neurotransmission. Transient expression of Snapin not only rescues the slowed kinetics of EPSCs, but also further accelerates the rate found in wild-type neurons. Furthermore, expression of Snapin-C66A, a dimerization-defective mutant with impaired interactions with SNAP-25 and Synaptotagmin, reduces the RRP size but exhibits less effect on synchronized fusion. Our studies provide mechanistic insights into a dual role of Snapin in enhancing the efficacy of SV priming and in fine-tuning synchronous SV fusion. C1 [Pan, Ping-Yue; Tian, Jin-Hua; Sheng, Zu-Hang] Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Pan, Ping-Yue] Shanghai Jiao Tong Univ, Dept Neurobiol, Sch Med, Shanghai 200025, Peoples R China. RP Sheng, ZH (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 3B203,35 Convent Dr, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU NINDS; NIH FX Snapin dimerization. Several groups discovered a direct interaction between Snapin and dysbindin We thank the following people for their help: J. Rettig and G. Chen for many insightful suggestions and comments throughout the study; D. Schoenberg, C. Gerwin, and C. Zyskind for critical reading of the manuscript; B. Lu, J. Diamond, and J. Kang for helpful discussions; and C. Gerwin for mouse maintenance and genotyping. P.-Y.P. is a doctoral student in the Joint Graduate Partnership Program in Neuroscience between NIH and Shanghai Jiao-Tong University, China. The work was supported by the Intramural Research Program of NINDS, NIH (Z.-H.S). NR 48 TC 53 Z9 56 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 12 PY 2009 VL 61 IS 3 BP 412 EP 424 DI 10.1016/j.neuron.2008.12.029 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 408BG UT WOS:000263407500011 PM 19217378 ER PT J AU Landgren, O Albitar, M Ma, WL Abbasi, F Hayes, RB Ghia, P Marti, GE Caporaso, NE AF Landgren, Ola Albitar, Maher Ma, Wanlong Abbasi, Fatima Hayes, Richard B. Ghia, Paolo Marti, Gerald E. Caporaso, Neil E. TI B-Cell Clones as Early Markers for Chronic Lymphocytic Leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HODGKINS-DISEASE; MUTATIONAL STATUS; NATURAL-HISTORY; IMMUNOGLOBULIN; BLOOD; MBL; CLL; CLASSIFICATION; EXPRESSION; RECEPTOR AB Background Otherwise healthy persons with a small number of B- cell clones circulating in the peripheral blood have been designated as having monoclonal B- cell lymphocytosis ( MBL). Hospital- based series indicate an excess risk of progression from MBL to chronic lymphocytic leukemia ( CLL). In this prospective cohort study, we tested the hypothesis that CLL is always preceded by MBL. Methods Among 77,469 healthy adults who were enrolled in the nationwide, population- based Prostate, Lung, Colorectal, and Ovarian ( PLCO) Cancer Screening Trial, we identified 45 subjects in whom CLL was subsequently diagnosed ( up to 6.4 years later) through the collection of a peripheral- blood sample. Using six- color flow cytometry ( with antibodies CD45, CD19, CD5, CD10, kappa, and lambda) and immunoglobulin heavy-chain gene rearrangement by reverse- transcriptase - polymerase- chain- reaction assay, we determined the association between MBL and subsequent CLL and characterized the immunoglobulin gene repertoire of the prediagnostic B- cell clones. Results On the basis of either flow- cytometric or molecular analysis, 44 of 45 patients with CLL ( 98%; 95% confidence interval [ CI], 88 to 100) had a prediagnostic B- cell clone; in 41 patients ( 91%; 95% CI, 79 to 98), the presence of the B- cell clone was confirmed by both methods. The presence of immunoglobulin heavy- chain variable ( IGHV) genes was determined in 35 of 45 prediagnostic clones ( 78%). Of these clones, 16 ( 46%) were IGHV3 subgroup genes ( including 6 [ 17%] IGHV3- 23 genes) and 9 ( 26%) were IGHV4 subgroup genes ( including 4 [ 11%] IGHV4- 34 genes). Furthermore, 27 of 35 of the IGHV sequences ( 77%) had mutations, with similar distributions after stratification either below or above the median time between the collection of the prediagnostic blood sample and the subsequent CLL diagnosis. Conclusions In peripheral blood obtained up to 77 months before a CLL diagnosis, prediagnostic B- cell clones were present in 44 of 45 patients with CLL. C1 [Landgren, Ola; Hayes, Richard B.; Caporaso, Neil E.] NCI, Canc Res Ctr, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Albitar, Maher; Ma, Wanlong] Nichols Inst, Quest Diagnost, San Juan Capistrano, CA USA. [Ghia, Paolo] Univ Vita Salute San raffaele, Unit & Lab Lymphoid Malignancies, Dept Oncol, Milan, Italy. [Ghia, Paolo] Ist Sci San Raffaele, Milan, Italy. RP Landgren, O (reprint author), NCI, Canc Res Ctr, Div Canc Epidemiol & Genet, NIH, Bldg 10,Rm 13N240,10 Center Dr, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Ghia, Paolo/K-7138-2016 OI Ghia, Paolo/0000-0003-3750-7342 FU Intramural Research Program of the National Cancer Institute; Italian Association for Cancer Research; CLL Global Research Foundation FX We thank Christine Berg and Philip Prorok of the Division of Cancer Prevention, National Cancer Institute; the Screening Center investigators and staff of the PLCO Cancer Screening Trial; Tom Riley and the staff of Information Management Services; Barbara O'Brien and the staff of Westat; Ruth Pfeiffer of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, for statistical help; Kostas Stamatopoulos of Thessaloniki, Greece, for his most helpful advice and suggestions; and the patients who made this study possible. NR 36 TC 155 Z9 161 U1 1 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 12 PY 2009 VL 360 IS 7 BP 659 EP 667 DI 10.1056/NEJMoa0806122 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 405YQ UT WOS:000263260500003 PM 19213679 ER PT J AU Tokunaga, M Seneca, N Shin, RM Maeda, J Obayashi, S Okauchi, T Nagai, Y Zhang, MR Nakao, R Ito, H Innis, RB Halldin, C Suzuki, K Higuchi, M Suhara, T AF Tokunaga, Masaki Seneca, Nicholas Shin, Ryong-Moon Maeda, Jun Obayashi, Shigeru Okauchi, Takashi Nagai, Yuji Zhang, Ming-Rong Nakao, Ryuji Ito, Hiroshi Innis, Robert B. Halldin, Christer Suzuki, Kazutoshi Higuchi, Makoto Suhara, Tetsuya TI Neuroimaging and Physiological Evidence for Involvement of Glutamatergic Transmission in Regulation of the Striatal Dopaminergic System SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine; glutamate; neurotransmission; PET; metabotropic glutamate receptor; methamphetamine; schizophrenia ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; IN-VIVO; ENDOGENOUS DOPAMINE; RECEPTOR AGONIST; PREFRONTAL CORTEX; SYNAPTIC TRANSMISSION; RADIOLIGAND-BINDING; MGLUR5 ANTAGONIST; NUCLEUS-ACCUMBENS AB Aberrant neurotransmissions via glutamate and dopamine receptors have been the focus of biomedical research on the molecular basis of psychiatric disorders, but the mode of their interaction is yet to be uncovered. In this study, we demonstrated the pharmacological reversal of methamphetamine-stimulated dopaminergic overflow by suppression of group I metabotropic glutamate (mGlu) receptor in living primates and rodents. In vivo positron emission tomography (PET) was conducted on cynomolgus monkeys and rats using a full agonistic tracer for dopamine D(2/3) receptor, [(11)C]MNPA [(R)-2-(11)CH(3)O-N-n-propylnorapomorphine], and fluctuation of kinetic data resulting from anesthesia was avoided by scanning awake subjects. Excessive release of dopamine induced by methamphetamine and abolishment of this alteration by treatment with an antagonist of group I mGlu receptors, 2-methyl-6-(phenylethynyl)pyridine (MPEP), were measured in both species as decreased binding potential because of increased dopamine and its recovery to baseline levels, respectively. Counteraction of MPEP to the methamphetamine-induced dopamine spillover was also supported neurochemically by microdialysis of unanesthetized rat striatum. Moreover, patch-clamp electrophysiological assays using acute brain slices prepared from rats indicated that direct targets of MPEP mechanistically involved in the effects of methamphetamine are present locally within the striatum. Because MPEP alone did not markedly alter the baseline dopaminergic neurotransmission according to our PET and electrophysiological data, the present findings collectively extend the insights on dopamine - glutamate cross talk from extrastriatal localization of responsible mGlu receptors to intrastriatal synergy and support therapeutic interventions in case of disordered striatal dopaminergic status using group I mGlu receptor antagonists assessable by in vivo imaging techniques. C1 [Tokunaga, Masaki; Shin, Ryong-Moon; Maeda, Jun; Obayashi, Shigeru; Okauchi, Takashi; Nagai, Yuji; Zhang, Ming-Rong; Nakao, Ryuji; Ito, Hiroshi; Suzuki, Kazutoshi; Higuchi, Makoto; Suhara, Tetsuya] Natl Inst Radiol Sci, Mol Imaging Ctr, Inage Ku, Chiba 2638555, Japan. [Seneca, Nicholas; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Halldin, Christer] Kalorinska Inst, Psychiat Sect, Dept Clin Neurosci, S-17176 Stockholm, Sweden. RP Higuchi, M (reprint author), Natl Inst Radiol Sci, Mol Imaging Ctr, Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan. EM mhiguchi@nirs.go.jp FU Ministry of Education, Culture, Sports, Science, and Technology, Japan [18790859, 18023040]; Intramural Research Program of the National Institutes of Health; National Institute of Mental Health FX This work was supported in part by grants-in-aid for the Molecular Imaging Program, Young Scientists (18790859; M. T.), and Scientific Research on Priority Areas Research on Pathomechanisms of Brain Disorders (18023040; M. H.) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; and by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health. We thank T. Minamihisamatsu and J. Kamei for technical assistance. NR 68 TC 19 Z9 19 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 11 PY 2009 VL 29 IS 6 BP 1887 EP 1896 DI 10.1523/JNEUROSCI.2559-08.2009 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 406NC UT WOS:000263301200030 PM 19211895 ER PT J AU Vivancos, V Chen, P Spassky, N Qian, D Dabdoub, A Kelley, M Studer, M Guthrie, S AF Vivancos, Valerie Chen, Ping Spassky, Nathalie Qian, Dong Dabdoub, Alain Kelley, Matthew Studer, Michele Guthrie, Sarah TI Wnt activity guides facial branchiomotor neuron migration, and involves the PCP pathway and JNK and ROCK kinases SO NEURAL DEVELOPMENT LA English DT Article ID PLANAR-CELL-POLARITY; CONVERGENT EXTENSION MOVEMENTS; SIGNALING PATHWAY; MOTOR-NEURONS; TUBE DEFECTS; NERVOUS-SYSTEM; BRAIN-STEM; HAIR-CELLS; MOUSE; ZEBRAFISH AB Background: Wnt proteins play roles in many biological processes, including axon guidance and cell migration. In the mammalian hindbrain, facial branchiomotor (FBM) neurons undergo a striking rostral to caudal migration, yet little is known of the underlying molecular mechanisms. In this study, we investigated a possible role of Wnts and the planar cell polarity (PCP) pathway in this process. Results: Here we demonstrate a novel role for Wnt proteins in guiding FBM neurons during their rostral to caudal migration in the hindbrain. We found that Wnt5a is expressed in a caudal(high) to rostral(low) gradient in the hindbrain. Wnt-coated beads chemoattracted FBM neurons to ectopic positions in an explant migration assay. The rostrocaudal FBM migration was moderately perturbed in Wnt5a mutant embryos and severely disrupted in Frizzled3 mutant mouse embryos, and was aberrant following inhibition of Wnt function by secreted Frizzled-related proteins. We also show the involvement of the Wnt/PCP pathway in mammalian FBM neuron migration. Thus, mutations in two PCP genes, Vangl2 and Scribble, caused severe defects in FBM migration. Inhibition of JNK and ROCK kinases strongly and specifically reduced the FBM migration, as well as blocked the chemoattractant effects of ectopic Wnt proteins. Conclusion: These results provide in vivo evidence that Wnts chemoattract mammalian FBM neurons and that Wnt5a is a candidate to mediate this process. Molecules of the PCP pathway and the JNK and ROCK kinases also play a role in the FBM migration and are likely mediators of Wnt signalling. C1 [Vivancos, Valerie; Guthrie, Sarah] Kings Coll London, MRC Ctr Dev Neurobiol, London SE1 1UL, England. [Chen, Ping; Qian, Dong] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA. [Spassky, Nathalie] Hop La Pitie Salpetriere, Unite Mixte Rech INSERM UPMC U711, F-75651 Paris, France. [Dabdoub, Alain] Univ Calif San Diego, Sch Med, Dept Surg, Div Otolaryngol, La Jolla, CA 92093 USA. [Kelley, Matthew] NIDCD, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Studer, Michele] TIGEM, I-80131 Naples, Italy. RP Guthrie, S (reprint author), Kings Coll London, MRC Ctr Dev Neurobiol, Guys Campus, London SE1 1UL, England. EM valerie.vivancos@kcl.ac.uk; ping.chen@emory.edu; spassky@ccr.jussieu.fr; dqian2@emory.edu; adabdoub@ucsd.edu; kelleymt@nidcd.nih.gov; studer@tigem.it; sarah.guthrie@kcl.ac.uk RI Guthrie, Sarah/C-5727-2009; Spassky, Nathalie/E-3932-2016; Studer, Michele/P-4580-2016 OI Studer, Michele/0000-0001-7105-2957 FU Wellcome Trust; Fondazione Telethon FX We are grateful to Dr Dawn Savery and Dr Andrew Copp for initial help with obtaining Vangl2 and Scribble mutant mice. We thank Dr Lorenza Ciani and Dr Patricia Salinas for providing reagents, Wnt7a mutant mice and helpful advice. Thanks also to Dr Britta Eickholt for help with inhibitor studies, and to Dr Uwe Drescher for valuable discussions on the manuscript. We thank the Wellcome Trust very much for funding the work described in this article. NR 66 TC 49 Z9 50 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1749-8104 J9 NEURAL DEV JI Neural Dev. PD FEB 11 PY 2009 VL 4 AR 7 DI 10.1186/1749-8104-4-7 PG 16 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 424XT UT WOS:000264602300001 PM 19210786 ER PT J AU Cheng, X Eisenbraun, M Xu, Q Zhou, HL Kulkarni, D Subbarao, K Kemble, G Jin, H AF Cheng, Xing Eisenbraun, Michael Xu, Qi Zhou, Helen Kulkarni, Deepali Subbarao, Kanta Kemble, George Jin, Hong TI H5N1 Vaccine-Specific B Cell Responses in Ferrets Primed with Live Attenuated Seasonal Influenza Vaccines SO PLOS ONE LA English DT Article AB Background: Live attenuated influenza H5N1 vaccines have been produced and evaluated in mice and ferrets that were never exposed to influenza A virus infection (Suguitan et al., Plos Medicine, e360: 1541, 2006). However, the preexisting influenza heterosubtypic immunity on live attenuated H5N1 vaccine induced immune response has not been evaluated. Methodology and Principal Findings: Primary and recall B cell responses to live attenuated H5N1 vaccine viruses were examined using a sensitive antigen-specific B cell ELISpot assay to investigate the effect of preexisting heterosubtypic influenza immunity on the development of H5N1-specific B cell immune responses in ferrets. Live attenuated H5N1 A/Hong Kong/213/03 and A/Vietnam/1203/04 vaccine viruses induced measurable H5-specific IgM and IgG secreting B cells after intranasal vaccination. However, H5-specific IgG secreting cells were detected significantly earlier and at a greater frequency after H5N1 inoculation in ferrets previously primed with trivalent live attenuated influenza (H1N1, H3N2 and B) vaccine. Priming studies further revealed that the more rapid B cell responses to H5 resulted from cross-reactive B cell immunity to the hemagglutinin H1 protein. Moreover, vaccination with the H1N1 vaccine virus was able to induce protective responses capable of limiting replication of the H5N1 vaccine virus to a level comparable with prior vaccination with the H5N1 vaccine virus without affecting H5N1 vaccine virus induced antibody response. Conclusion: The findings indicate that previous vaccination with seasonal influenza vaccine may accelerate onset of immunity by an H5N1 ca vaccine and the heterosubtypic immunity may be beneficial for pandemic preparedness. C1 [Cheng, Xing; Eisenbraun, Michael; Xu, Qi; Zhou, Helen; Kulkarni, Deepali; Kemble, George; Jin, Hong] MedImmune, Mountain View, CA USA. [Subbarao, Kanta] NIAID, NIH, Lab Infect Dis, Bethesda, MD USA. RP Cheng, X (reprint author), MedImmune, Mountain View, CA USA. EM jinh@medimmune.com FU Intramural Research Program of NIAID, NIH FX The funding was provided by MedImmune. This research was supported in part by the Intramural Research Program of NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 15 Z9 17 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 11 PY 2009 VL 4 IS 2 AR e4436 DI 10.1371/journal.pone.0004436 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437JP UT WOS:000265484100008 PM 19209231 ER PT J AU Hager, JH Ulanet, DB Hennighausen, L Hanahan, D AF Hager, Jeffrey H. Ulanet, Danielle B. Hennighausen, Lothar Hanahan, Douglas TI Genetic Ablation of Bcl-x Attenuates Invasiveness without Affecting Apoptosis or Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Cancer SO PLOS ONE LA English DT Article AB Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro-and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of human cancer and is implicated in human tumor progression. Previous gain-of-function studies in the RIP1-Tag2 model of pancreatic islet carcinogenesis, involving uniform or focal/temporal over-expression of Bcl-x(L), demonstrated accelerated tumor formation and growth. To specifically assess the role of endogenous Bcl-x in regulating apoptosis and tumor progression in this model, we engineered a pancreatic beta-cell-specific knockout of both alleles of Bcl-x using the Cre-LoxP system of homologous recombination. Surprisingly, there was no appreciable effect on tumor cell apoptosis rates or on tumor growth in the Bcl-x knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the Bcl-x-null tumors, suggestive of redundancy without compensatory transcriptional up-regulation. Interestingly, the incidence of invasive carcinomas was reduced, and tumor cells lacking Bcl-x were impaired in invasion in a two-chamber trans-well assay under conditions mimicking hypoxia. Thus, while the function of Bcl-x in suppressing apoptosis and thereby promoting tumor growth is evidently redundant, genetic ablation implicates Bcl-x in selectively facilitating invasion, consistent with a recent report documenting a pro-invasive capability of Bcl-x(L) upon exogenous over-expression. C1 [Hager, Jeffrey H.; Ulanet, Danielle B.; Hanahan, Douglas] Univ Calif San Francisco, Diabetes & Hellen Diller Family Comprehens Canc, Dept Biochem & Biophys, San Francisco, CA 94143 USA. [Hennighausen, Lothar] NIDDK, NIH, Lab Genet & Physiol, Bethesda, MD USA. RP Hager, JH (reprint author), Apoptos Inc, San Diego, CA USA. EM dh@biochem.ucsf.edu FU A.P. Giannini Foundation for Medical Research; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Cancer Institute [R01CA45234] FX This research was supported by the A.P. Giannini Foundation for Medical Research (D.B.U), The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (L.H.), and grants from the National Cancer Institute (D.H.; R01CA45234). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 8 Z9 8 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 11 PY 2009 VL 4 IS 2 AR e4455 DI 10.1371/journal.pone.0004455 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437JP UT WOS:000265484100013 PM 19209227 ER PT J AU Schell, J Rose, NF Fazo, N Marx, PA Hunter, M Ramsburg, E Montefiori, D Earl, P Moss, B Rose, JK AF Schell, John Rose, Nina F. Fazo, Nicole Marx, Preston A. Hunter, Meredith Ramsburg, Elizabeth Montefiori, David Earl, Patricia Moss, Bernard Rose, John K. TI Long-term vaccine protection from AIDS and clearance of viral DNA following SHIV89.6P challenge SO VACCINE LA English DT Article DE SHIV89.6P; Vaccine; VSV; MVA; Rhesus; Long-term ID SIMIAN IMMUNODEFICIENCY VIRUS; CD8(+) T-CELLS; NEUTRALIZING ANTIBODIES; CELLULAR-IMMUNITY; RHESUS MACAQUES; HIV VACCINE; REPLICATION; INFECTION; RESPONSES; TYPE-1 AB In an earlier Study, our group vaccinated rhesus macaques with vesicular stomatitis virus (VSV) vectors expressing Gag, Pol, and Env proteins from a hybrid simian/human immunodeficiency Virus (SHIV). This was followed by a single boost with modified vaccinia virus Ankara (MVA) vectors expressing the same proteins. Following challenge with SHIV89.6P, vaccinated animals cleared challenge virus RNA from the blood by day 150 and maintained normal CD4 T cell counts for 8 months. Here we report on the long-term (>5-year post-challenge) status of these animals and the immunological correlates of long-term protection. Using real-time PCR, we found that viral DNA in peripheral blood mononuclear cells (PBMCs) of the vaccinees declined continuously and fell to below detection (<5 copies/10(5) cells) by approximately 3 years post-challenge. SHIV DNA was also below the limit of detection in the lymph nodes of two of the four animals at 5 years post-challenge. We detected long-term persistence of multi-functional Gag-specific CD8(+) T cells in both PBMCs and lymph nodes of the two protected animals with the Mamu A*01(+) MHC 1 allele. All animals also maintained SHIV89.6P neutralizing antibody titers for 5 years. Our results show that this vaccine approach generates solid. long-term control of SHIV infection, and suggest that it is mediated by both cytotoxic T lymphocytes and neutralizing antibody. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Rose, John K.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Marx, Preston A.; Hunter, Meredith] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. [Ramsburg, Elizabeth; Montefiori, David] Duke Univ, Med Ctr, Durham, NC USA. [Earl, Patricia; Moss, Bernard] NIAID, Bethesda, MD 20892 USA. RP Rose, JK (reprint author), Yale Univ, Sch Med, Dept Pathol, 310 Cedar St, New Haven, CT 06510 USA. EM john.rose@yale.edu OI Schell, John/0000-0001-6707-7051 FU NIH [R37-AI40357, R01-A145510, R01-AI30034]; TNPRC; MAID, NIH FX This work was supported by NIH grants R37-AI40357, R01-A145510, R01-AI30034, and the TNPRC base grant and by the Intramural Research Program of the MAID, NIH. NR 30 TC 19 Z9 20 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 11 PY 2009 VL 27 IS 7 BP 979 EP 986 DI 10.1016/j.vaccine.2008.12.017 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 412GG UT WOS:000263712100004 PM 19135115 ER PT J AU Remondo, C Cereda, V Mostbock, S Sabzevari, H Franzusoff, A Schlom, J Tsang, KY AF Remondo, Cinzia Cereda, Vittore Mostboeck, Sven Sabzevari, Helen Franzusoff, Alex Schlom, Jeffrey Tsang, Kwong-Y. TI Human dendritic cell maturation and activation by a heat-killed recombinant yeast (Saccharomyces cerevisiae) vector encoding carcinoembryonic antigen SO VACCINE LA English DT Article DE Saccharomyces cerevisiae; Yeast-CEA; Human dendritic cell ID NECROSIS-FACTOR-ALPHA; TOLL-LIKE RECEPTORS; CYTOTOXIC T-CELLS; COSTIMULATORY MOLECULES; GENE-TRANSFER; ADENOVIRUS VECTORS; SIGNALING PATHWAY; MEDIATED-IMMUNITY; PRESENTING CELLS; AGONIST PEPTIDE AB Tumor-associated antigens are weakly immunogenic. Human carcinoembryonic antigen (CEA) is over-expressed on a wide range of human carcinomas and represents an attractive target for cancer immunotherapy. This study analyzes the ability of a Saccharomyces cerevisiae vector containing the transgene encoding CEA (yeast-CEA) to activate human dendritic cells (DCs) and stimulate CEA-specific T-cell responses. We demonstrate for the first time that treatment with yeast-CEA can activate human DCs, resulting in increases in surface expression of CD80, CD83, CD54, CD58, and MHC class II, and increased production by DCs of IL-12p70, TNF-alpha, IFN-gamma, IL-8, IL-2, IL-13, IL-10, and IL-1 beta. We also show that human DCs treated with yeast-CEA can activate CEA-specific T-cell lines and can act as antigen-presenting cells (APCs) to generate CEA-specific T-cell lines capable of lysing CEA(+) human tumor cells. Gene expression profiles of human DCs treated with yeast-CEA show increased expression of numerous genes involved in the production of chemokines and cytokines and their receptors, and genes related to antigen uptake, antigen presentation, and signal transduction. Published by Elsevier Ltd. C1 [Remondo, Cinzia; Cereda, Vittore; Mostboeck, Sven; Sabzevari, Helen; Schlom, Jeffrey; Tsang, Kwong-Y.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Franzusoff, Alex] GlobeImmune Inc, Louisville, CO USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov FU Intramural NIH HHS [Z01 BC010974-01]; NCI NIH HHS [Z01 BC010974-01] NR 48 TC 31 Z9 34 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 11 PY 2009 VL 27 IS 7 BP 987 EP 994 DI 10.1016/j.vaccine.2008.12.002 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 412GG UT WOS:000263712100005 PM 19110021 ER PT J AU Turner, GJ Chittiboyina, S Pohren, L Hines, KG Correia, JJ Mitchell, DC AF Turner, George J. Chittiboyina, Shirisha Pohren, Lauren Hines, Kirk G. Correia, John J. Mitchell, Drake C. TI The Bacteriorhodopsin Carboxyl-Terminus Contributes to Proton Recruitment and Protein Stability SO BIOCHEMISTRY LA English DT Article ID SOLID-STATE C-13; MEMBRANE-PROTEIN; PURPLE MEMBRANE; MONOMERIC BACTERIORHODOPSIN; HALOBACTERIUM-HALOBIUM; CYTOPLASMIC SURFACE; INTERHELICAL LOOPS; 2-STAGE MODEL; LOW PH; CHROMOPHORE AB We examined functional and structural roles for the bacteriorhodopsin (bR) carboxyl-terminus. The extramembranous and intracellular carboxyl-terminus was deleted by insertion of premature translation stop codons. Deletion of the carboxyl-terminus had no effect on purple membrane (PM) lattice dimensions, sheet size, or the electrogenic environment of the ground-state chromophore. Removal of the distal half of the carboxyl-terminus had no effect on light-activated proton pumping, however, truncation of the entire carboxyl-terminus accelerated the rates of M-state decay and proton uptake similar to 3.7-fold and severely distorted the kinetics of proton uptake. Differential scanning calorimetry (DSC) and SDS denaturation demonstrated that removal of the carboxyl-terminus decreased protein stability. The DSC melting temperature was lowered by 6 C and the calorimetric enthalpy reduced by 50% following removal of the carboxyl-terminus. Over the time range of milliseconds to hours at least 3 phases were required to describe the SDS denaturation kinetics for each bR construction. The fastest phases were indistinguishable for all bR's, and reflected PM solubilization. At pH 7.4, 20 degrees C, and in 0.3% SDS (w/v) the half-times of bR denaturation were 19.2 min for the wild-type, 12.0 min for the half-truncation and 3.6 min for the fulltruncation. Taken together the results of this study suggest that the bR ground state exhibits two "domains" of stability: (1) a core chromophore binding pocket domain that is insensitive to carboxyl-terminal interactions and (2) the surrounding helical bundle whose contributions to protein stability and proton pumping are influenced by long-range interactions with the extramembranous carboxyl-terminus. C1 [Turner, George J.; Chittiboyina, Shirisha; Pohren, Lauren] Seton Hall Univ, Dept Chem & Biochem, S Orange, NJ 07079 USA. [Hines, Kirk G.; Mitchell, Drake C.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20893 USA. [Correia, John J.] Univ Mississippi, Med Ctr, Dept Biochem, Jackson, MS 39216 USA. [Mitchell, Drake C.] Portland State Univ, Dept Phys, Portland, OR 97207 USA. RP Turner, GJ (reprint author), Seton Hall Univ, Dept Chem & Biochem, 400 S Orange Ave, S Orange, NJ 07079 USA. EM gturner@mac.edu FU Sigrid Juselius Foundation FX Support is acknowledged in the form of a Sigrid Juselius Foundation Research Fellowship to GTT. NR 62 TC 2 Z9 2 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 10 PY 2009 VL 48 IS 5 BP 1112 EP 1122 DI 10.1021/bi801799j PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 402YB UT WOS:000263047900033 PM 19140737 ER PT J AU Fischer, RS Gardel, M Ma, XF Adelstein, RS Waterman, CM AF Fischer, Robert S. Gardel, Margaret Ma, Xuefei Adelstein, Robert S. Waterman, Clare M. TI Local Cortical Tension by Myosin II Guides 3D Endothelial Cell Branching SO CURRENT BIOLOGY LA English DT Article ID EXTRACELLULAR-MATRIX; VASCULAR DEVELOPMENT; RHO-KINASE; ANGIOGENESIS; FIBROBLASTS; SUBSTRATE; MIGRATION; METALLOPROTEINASES; MECHANISMS; PLASTICITY AB A key feature of angiogenesis is directional control of endothelial cell (EC) morphogenesis and movement [1]. During angiogenic sprouting, endothelial "tip cells" directionally branch from existing vessels in response to biochemical cues such as VEGF or hypoxia and migrate and invade the surrounding extracellular matrix (ECM) in a process that requires ECM remodeling by matrix metalloproteases (MMPs) [2-4]. Tip EC branching is mediated by directional protrusion of subcellular pseudopodial branches [5, 6]. Here, we seek to understand how EC pseudopodial branching is locally regulated to directionally guide angiogenesis. We develop an in vitro 3D EC model system in which migrating ECs display branched pseudopodia morphodynamics similar to those in living zebrafish. Using this system, we find that ECM stiffness and ROCK-mediated myosin 11 activity inhibit EC pseudopodial branch initiation. Myosin 11 is dynamically localized to the EC cortex and is partially released under conditions that promote branching. Local depletion of cortical myosin 11 precedes branch initiation, and initiation can be induced by local inhibition of myosin 11 activity. Thus, local downregulation of myosin 11 cortical contraction allows pseudopodium initiation to mediate EC branching and hence guide directional migration and angiogenesis. C1 [Fischer, Robert S.; Waterman, Clare M.] NHLBI, Lab Cell & Tissue Morphodynam, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Gardel, Margaret] Univ Chicago, Dept Phys, Chicago, IL 60637 USA. [Ma, Xuefei; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Fischer, RS (reprint author), NHLBI, Lab Cell & Tissue Morphodynam, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM fischerr2@mail.nih.gov; watermancm@nhlbi.nih.gov RI Gardel, Margaret/D-1703-2012; OI Waterman, Clare/0000-0001-6142-6775; Adelstein, Robert/0000-0002-8683-2144 FU NIH/NHLBI FX We thank Roberta Nowak and Velia Fowler (Scripps Research Institute, La Jolla, CA, USA) for maintaining GFP-actin mice, Konstantin Stoletov and Richard Klemke (UCSD, San Diego, CA, USA) for fli1-gfp zebrafish embryos, and Gaudenz Danuser (Scripps) for technical advice and constructive discussion. We would also like to thank Mary Anne Conti for critical reading of the manuscript. This work was supported by the Intramural Research Program of the NIH/NHLBI. NR 24 TC 76 Z9 76 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 10 PY 2009 VL 19 IS 3 BP 260 EP 265 DI 10.1016/j.cub.2008.12.045 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 407CE UT WOS:000263340400032 PM 19185493 ER PT J AU Freedman, AN Slattery, ML Ballard-Barbash, R Willis, G Cann, BJ Pee, D Gail, MH Pfeiffer, RM AF Freedman, Andrew N. Slattery, Martha L. Ballard-Barbash, Rachel Willis, Gordon Cann, Bette J. Pee, David Gail, Mitchell H. Pfeiffer, Ruth M. TI Colorectal Cancer Risk Prediction Tool for White Men and Women Without Known Susceptibility SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROJECTING INDIVIDUALIZED PROBABILITIES; SOCIETY-TASK-FORCE; BODY-MASS INDEX; COLON-CANCER; PHYSICAL-ACTIVITY; BREAST-CANCER; RECTAL-CANCER; ADENOMA CHARACTERISTICS; FAMILY HISTORY; LUNG-CANCER AB Purpose Given the high incidence of colorectal cancer (CRC), and the availability of procedures that can detect disease and remove precancerous lesions, there is a need for a model that estimates the probability of developing CRC across various age intervals and risk factor profiles. Methods The development of separate CRC absolute risk models for men and women included estimating relative risks and attributable risk parameters from population-based case-control data separately for proximal, distal, and rectal cancer and combining these estimates with baseline age-specific cancer hazard rates based on Surveillance, Epidemiology, and End Results (SEER) incidence rates and competing mortality risks. Results For men, the model included a cancer-negative sigmoidoscopy/colonoscopy in the last 10 years, polyp history in the last 10 years, history of CRC in first-degree relatives, aspirin and nonsteroidal anti-inflammatory drug (NSAID) use, cigarette smoking, body mass index (BMI), current leisure-time vigorous activity, and vegetable consumption. For women, the model included sigmoidoscopy/colonoscopy, polyp history, history of CRC in first-degree relatives, aspirin and NSAID use, BMI, leisure-time vigorous activity, vegetable consumption, hormone-replacement therapy (HRT), and estrogen exposure on the basis of menopausal status. For men and women, relative risks differed slightly by tumor site. A validation study in independent data indicates that the models for men and women are well calibrated. Conclusion We developed absolute risk prediction models for CRC from population-based data, and a simple questionnaire suitable for self-administration. This model is potentially useful for counseling, for designing research intervention studies, and for other applications. C1 [Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Informat Management Syst, Rockville, MD USA. Univ Utah, Sch Med, Salt Lake City, UT USA. Kaiser Permanente Med Grp, Div Res, Oakland, CA USA. RP Freedman, AN (reprint author), NCI, Div Canc Control & Populat Sci, NIH, EPN 4005 MSC 7344,6130 Execut Blvd, Bethesda, MD 20892 USA. EM Andrew_Freedman@nih.gov RI Pfeiffer, Ruth /F-4748-2011 NR 42 TC 93 Z9 94 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2009 VL 27 IS 5 BP 686 EP 693 DI 10.1200/JCO.2008.17.4797 PG 8 WC Oncology SC Oncology GA 404GR UT WOS:000263139800007 PM 19114701 ER PT J AU Park, Y Freedman, AN Gail, MH Pee, D Hollenbeck, A Schatzkin, A Pfeiffer, RM AF Park, Yikyung Freedman, Andrew Nathan Gail, Mitchell H. Pee, David Hollenbeck, Albert Schatzkin, Arthur Pfeiffer, Ruth M. TI Validation of a Colorectal Cancer Risk Prediction Model Among White Patients Age 50 Years and Older SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HEALTH; WOMEN; DIET AB Purpose Validation of an absolute risk prediction model for colorectal cancer (CRC) by using a large, population-based cohort. Patients and Methods The National Institutes of Health (NIH)-American Association of Retired Persons (AARP) diet and health study, a prospective cohort study, was used to validate the model. Men and women age 50 to 71 years at baseline answered self-administered questionnaires that asked about demographic characteristics, diet, lifestyle, and medical histories. We compared expected numbers of CRC patient cases predicted by the model to the observed numbers of CRC patient cases identified in the NIH-AARP study overall and in subgroups defined by risk factor combinations. The discriminatory power was measured by the area under the receiver-operating characteristic curve (AUC). Results During an average of 6.9 years of follow-up, we identified 2,092 and 832 incident CRC patient cases in men and women, respectively. The overall expected/observed ratio was 0.99 (95% Cl, 0.95 to 1.04) in men and 1.05 (95% Cl, 0.98 to 1.11) in women. Agreement between the expected and the observed number of cases was good in most risk factor categories, except for in subgroups defined by CRC screening and polyp history. This discrepancy may be caused by differences in the question on screening and polyp history between two studies. The AUC was 0.61 (95% Cl, 0.60 to 0.62) for men and 0.61 (95% Cl, 0.59 to 0.62) for women, which was similar to other risk prediction models. Conclusion The absolute risk model for CRC was well calibrated in a large prospective cohort study. This prediction model, which estimates an individual's risk of CRC given age and risk factors, may be a useful tool for physicians, researchers, and policy makers. C1 [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20852 USA. Informat Management Syst, Rockville, MD USA. AARP, Washington, DC USA. RP Pfeiffer, RM (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20852 USA. EM pfeiffer@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Park, Yikyung/0000-0002-6281-489X NR 15 TC 56 Z9 57 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2009 VL 27 IS 5 BP 694 EP 698 DI 10.1200/JCO.2008.17.4813 PG 5 WC Oncology SC Oncology GA 404GR UT WOS:000263139800008 PM 19114700 ER PT J AU Kreisl, TN Kim, L Moore, K Duic, P Royce, C Stroud, I Garren, N Mackey, M Butman, JA Camphausen, K Park, J Albert, PS Fine, HA AF Kreisl, Teri N. Kim, Lyndon Moore, Kraig Duic, Paul Royce, Cheryl Stroud, Irene Garren, Nancy Mackey, Megan Butman, John A. Camphausen, Kevin Park, John Albert, Paul S. Fine, Howard A. TI Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HIGH-GRADE GLIOMAS; MALIGNANT GLIOMA; RESPONSE CRITERIA; PROGNOSTIC-FACTORS; FREE SURVIVAL; GROWTH; CHEMOTHERAPY; MULTIFORME; EXPRESSION; RECIST AB Purpose To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma. Patients and Methods Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) every 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks. Results Forty-eight heavily pretreated patients were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median progression-free survival (PFS) was 16 weeks (95% Cl, 12 to 26 weeks). The 6-month PFS was 29% (95% Cl, 18% to 48%). The 6-month overall survival was 57% (95% Cl, 44% to 75%). Median overall survival was 31 weeks (95% Cl, 21 to 54 weeks). Early magnetic resonance imaging response (first 96 hours and 4 weeks) was predictive of long-term PFS, with the Levin criteria being more predictive than Macdonald criteria. Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses. Eighteen patients (95%) experienced disease progression by the second cycle, and the median PFS was 30 days. Conclusion We conclude that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma. C1 [Fine, Howard A.] NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. NCI, Neurooncol Branch, Radiat Oncol Branch, Bethesda, MD 20892 USA. NCI, Biometr Branch, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NIH, Dept Radiol, Ctr Clin, 9030 Old Georgetown Rd,Bloch Bldg 82,Room 235,MSC, Bethesda, MD 20892 USA. EM hfine@mail.nih.gov RI Butman, John/A-2694-2008; leng, xianwei/F-9073-2011; Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 NR 21 TC 749 Z9 763 U1 3 U2 26 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2009 VL 27 IS 5 BP 740 EP 745 DI 10.1200/JCO.2008.16.3055 PG 6 WC Oncology SC Oncology GA 404GR UT WOS:000263139800015 PM 19114704 ER PT J AU Swartz, CD King, LC Nesnow, S Umbach, DM Kumar, S DeMarini, DM AF Swartz, Carol D. King, Leon C. Nesnow, Stephen Umbach, David M. Kumar, Subodh DeMarini, David M. TI Mutagenicity, stable DNA adducts, and abasic sites induced in Salmonella by phenanthro[3,4-b]- and phenanthro[4,3-b]thiophenes, sulfur analogs of benzo[c]phenanthrene SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Mutagenicity; Salmonella; Sulfur-PAH; DNA adducts ID REGION DIOL-EPOXIDES; MULTIPLE PATHWAYS; LIVER-MICROSOMES; HETEROCYCLES; METABOLISM; CHROMATOGRAPHY; BIOACTIVATION; DIHYDRODIOLS; CHRYSENE; DAMAGE AB Sulfur-containing polycyclic aromatic hydrocarbons (thia-PAHs or thiaarenes) are common constituents of air pollution and cigarette smoke, but only a few have been studied for health effects. We evaluated the mutagenicity in Salmonella TA98, TA100, and TA104 of two sulfur-containing derivatives of benzo[c]phenanthrene, phenanthro[3,4-b]thiophene (P[3,4-b]T), and phenanthro[4,3-b]thiophene (P[4,3-b]T) as well as their dihydrodiol and sulfone derivatives. In addition, we assessed levels of stable DNA adducts (by (32)P-postlabeling) as well as abasic sites (by an aldehydic-site assay) produced by six of these compounds in TA100. P[3,4-b]T and its 6,7- and 8,9-diols, P[3,4-b]T sulfone, P[4,3-b]T, and its 8,9-diol were mutagenic in TA100. P[3,4-b]T sulfone, the most potent mutagen, was approximately twice as potent as benzo[a]pyrene in both TA98 and TA100. Benzo-ring dihydrodiols were much more potent than K-region dihydrodiols, which had little or no mutagenic activity in any strain. P[3,4-b]T sulfone produced abasic sites and not stable DNA adducts; the other five compounds examined, B[c]P, B[c]P 3,4-diol, P[3,4-b]T, P[3,4-b]T 8,9-diol, and P[4,3-b]T 8,9-diol, produced only stable DNA adducts. P[3,4-b]T sulfone was the only compound that produced significant levels of frameshift mutagenicity and induced mutations primarily at GC sites. In contrast, B[c]P, its 3,4-diol, and the 8,9 diols of the phenanthrothiophenes induced mutations primarily at AT sites. P[3,4-b]T was not mutagenic in TA104, whereas P[3,4-b]T sulfone was. The two isomeric forms (P[3,4-b]T and P[4,3-b]T) are apparently activated differently, with the latter, but not the former, involving a diol pathway. This study is the first illustrating the potential importance of abasic sites in the mutagenicity of thia-PAHs. Published by Elsevier B,V. C1 [King, Leon C.; Nesnow, Stephen; DeMarini, David M.] US EPA, Div Environm Carcinogenesis, Res Triangle Pk, NC 27711 USA. [Swartz, Carol D.] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Kumar, Subodh] SUNY Coll Buffalo, Environm Toxicol & Chem Lab, Great Lakes Ctr, Buffalo, NY 14222 USA. RP DeMarini, DM (reprint author), US EPA, Div Environm Carcinogenesis, Res Triangle Pk, NC 27711 USA. EM demarini.david@epa.gov FU NHEERL-DESE Cooperative Training Agreement in Environmental Science Research [US EPA CT 82651301]; Phillip Morris USA; NIH; National Institute of Environmental Health Sciences; National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, FX We thank Peggy Matthews for preparation of medium and Linda Adams and Joycelyn Allison for help with the DNA adduct analyses. We thank Jeffrey Ross, Larry Claxton, and Daniel Shaughnessy for helpful comments on the manuscript. The authors declare that they have no conflicts of interest. C.D.S. was supported by a grant from the NHEERL-DESE Cooperative Training Agreement in Environmental Science Research, US EPA CT 82651301. S.K. acknowledges support from Phillip Morris USA. This work was also supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. NR 29 TC 12 Z9 12 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD FEB 10 PY 2009 VL 661 IS 1-2 BP 47 EP 56 DI 10.1016/j.mrfmmm.2008.11.001 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 410WO UT WOS:000263609200007 PM 19041882 ER PT J AU Ratner, L Harrington, W Feng, X Grant, C Jacobson, S Noy, A Sparano, J Lee, J Ambinder, R Campbell, N Lairmore, M AF Ratner, Lee Harrington, William Feng, Xuan Grant, Christian Jacobson, Steve Noy, Ariela Sparano, Joseph Lee, Jeannette Ambinder, Richard Campbell, Nancy Lairmore, Michael CA AIDS Malignancy Consortium TI Human T Cell Leukemia Virus Reactivation with Progression of Adult T-Cell Leukemia-Lymphoma SO PLOS ONE LA English DT Article AB Background: Human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma (ATLL) has a very poor prognosis, despite trials of a variety of different treatment regimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and this has suggested that secondary genetic or epigenetic changes are important in disease pathogenesis. Methods and Findings: We prospectively investigated combination chemotherapy followed by antiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and 2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide, doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH) given for two to six cycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine, lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than one month due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objective response with median duration of response of thirteen months, and two complete remissions. During chemotherapy induction, viral RNA expression increased (median 190-fold), and virus replication occurred, coincident with development of disease progression. Conclusions: EPOCH chemotherapy followed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma, but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternative therapies are sorely needed in this disease that simultaneously prevent virus expression, and are cytocidal for malignant cells. C1 [Ratner, Lee; Feng, Xuan; Campbell, Nancy] Washington Univ, Sch Med, Div Oncol, St Louis, MO 63130 USA. [Harrington, William] Univ Miami, Sch Med, Miami, FL USA. [Grant, Christian; Jacobson, Steve] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD USA. [Noy, Ariela] Mem Sloan Kettering Canc Ctr, Lymphoma Serv, New York, NY USA. [Sparano, Joseph] Albert Einstein Coll Med, Dept Oncol, Bronx, NY USA. [Lee, Jeannette] Univ Alabama, Sch Med, Div Hematol Oncol, Birmingham, AL USA. [Ambinder, Richard] Johns Hopkins Univ, Inst Med, Dept Oncol, Baltimore, MD 21218 USA. [Lairmore, Michael] Ohio State Univ, Coll Vet Med, Ctr Retrovirus Res, Columbus, OH 43210 USA. RP Ratner, L (reprint author), Washington Univ, Sch Med, Div Oncol, St Louis, MO 63130 USA. EM lratner@im.wustl.edu RI Ambinder, Richard/G-1607-2011; OI Noy, Ariela/0000-0002-3001-4898; Feng, Xueyang/0000-0003-4426-5732 FU Glaxo-Smith-Kline; PHS [U01CA070058, U01CA070054, U01CA071375, U01CA083038, U01CA070062, U01CA070019, CA10521] FX Combivir was provided by Glaxo-Smith-Kline. This study was supported by PHS grants U01CA070058, U01CA070054, U01CA071375, U01CA083038, U01CA070062, U01CA070019, and CA10521. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 18 Z9 18 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 10 PY 2009 VL 4 IS 2 AR e4420 DI 10.1371/journal.pone.0004420 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437JO UT WOS:000265484000009 PM 19204798 ER PT J AU Park, JE Li, LW Park, J Knecht, R Strebhardt, K Yuspa, SH Lee, KS AF Park, Jung-Eun Li, Luowei Park, Joobae Knecht, Rainald Strebhardt, Klaus Yuspa, Stuart H. Lee, Kyung S. TI Direct quantification of polo-like kinase 1 activity in cells and tissues using a highly sensitive and specific ELISA assay SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE p-T78 peptide; PBIP1; polo kinase; polo-box domain; PBIPtide ID EXPRESSION; POLO-LIKE-KINASE-1; PLK1; CARCINOMAS; MELANOMAS; DIVISION; CANCER; MARKER; PHASE AB Polo-like kinase 1 (Plk1) plays a pivotal role in the regulation of cellular proliferation. Plk1 is overexpressed in approximate to 80% of human tumors of diverse origins, and overexpression of Plk1 promotes neoplastic transformation of human cells. A growing body of evidence suggests that deregulation of Plk1 closely correlates with prognosis of various cancers in humans. Thus, accurate assessment of Plk1 deregulation would provide clear clinical advantages. However, because of the limited amount of cancer tissues available, quantification of the Plk1 activity has not been feasible. Here, we report the development of a rapid, highly sensitive, and specific ELISA-based Plk1 assay that can quantify the level of Plk1 activity with a small amount (2-20 mu g) of total cellular proteins. Unlike the conventional immunocomplex kinase assay, this assay directly utilizes total cellular lysates and does not require a Plk1 enrichment step such as immunoprecipitation or affinity purification. Using this assay, we demonstrated that Plk1 activity is elevated in tumors but not in the surrounding normal tissues and that the level of Plk1 activity significantly diminishes after an antiproliferative chemotherapy. The method described here may provide an innovative tool for assessing the predisposition for cancer development, monitoring early tumor response after therapy, and estimating the prognosis of patients with cancers from multiple organ sites. C1 [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Li, Luowei; Yuspa, Stuart H.] NCI, Labs Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Park, Joobae] Sungkyunkwan Univ, Sch Med, Dept Mol Cell Biol, Suwon 440746, South Korea. [Knecht, Rainald] Univ Med Ctr Hamburg Eppendorf, ENT, Head & Neck Dept, D-20246 Hamburg, Germany. [Strebhardt, Klaus] Univ Frankfurt, Sch Med, Dept Gynecol & Obstet, D-60590 Frankfurt, Germany. RP Lee, KS (reprint author), NCI, Lab Metab, NIH, 9000 Rockville Pike,Bldg 37,Room 3118, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov RI Strebhardt, Klaus/E-8765-2011 FU National Cancer Institut FX We thank Kenneth H. Kraemer, Michael Bustin, and Rachel H. Lee for critical reading of the manuscript; James L. Maller ( University of Colorado School of Medicine, Aurora, CO) for providing the anti- Plx antibody; and Ray L. Erikson ( Harvard University, Cambridge, MA) and Wei Dai ( New York University School of Medicine, New York, NY) for constructs. This work was supported in part by National Cancer Institute intramural grants ( to S. H. Y and K. S. L). NR 17 TC 15 Z9 15 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 10 PY 2009 VL 106 IS 6 BP 1725 EP 1730 DI 10.1073/pnas.0812135106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 405VO UT WOS:000263252500012 PM 19181852 ER PT J AU Le Pape, E Passeron, T Giubellino, A Valencia, JC Wolber, R Hearing, VJ AF Le Pape, Elodie Passeron, Thierry Giubellino, Alessio Valencia, Julio C. Wolber, Rainer Hearing, Vincent J. TI Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pigmentation; skin cancer ID CULTURED HUMAN MELANOCYTES; 1 RECEPTOR MC1R; NEURAL CREST; ULTRAVIOLET-RADIATION; GENETIC-DETERMINANTS; STIMULATING HORMONE; HUMAN PIGMENTATION; SKIN PIGMENTATION; INDUCED APOPTOSIS; MELANOMA-CELLS AB The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in mammals and is tightly linked to an increased risk of skin cancers, including melanoma, in humans. Physiologically activated by alpha-melanocyte stimulating hormone (alpha MSH), MC1R function can be antagonized by a secreted factor, agouti signal protein (ASP), which is responsible for the lighter phenotypes in mammals (including humans), and is also associated with increased risk of skin cancer. It is therefore of great interest to characterize the molecular effects elicited by those MC1R ligands. In this study, we determined the gene expression profiles of murine melan-a melanocytes treated with ASP or alpha MSH over a 4-day time course using genome-wide oligonucleotide microarrays. As expected, there were significant reductions in expression of numerous melanogenic proteins elicited by ASP, which correlates with its inhibition of pigmentation. ASP also unexpectedly modulated the expression of genes involved in various other cellular pathways, including glutathione synthesis and redox metabolism. Many genes up-regulated by ASP are involved in morphogenesis (especially in nervous system development), cell adhesion, and extracellular matrix-receptor interactions. Concomitantly, ASP enhanced the migratory potential and the invasiveness of melanocytic cells in vitro. These results demonstrate the role of ASP in the dedifferentiation of melanocytes, identify pigment-related genes targeted by ASP and by alpha MSH, and provide insights into the pleiotropic molecular effects of MC1R signaling that may function during development and may affect skin cancer risk. C1 [Le Pape, Elodie; Passeron, Thierry; Valencia, Julio C.; Hearing, Vincent J.] NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Giubellino, Alessio] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wolber, Rainer] Skin Res Ctr, Beiersdorf AG Res & Dev, D-20245 Hamburg, Germany. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM hearingv@nih.gov OI Giubellino, Alessio/0000-0002-5352-0662; Passeron, Thierry/0000-0002-0797-6570 FU National Cancer Institute at National Institutes of Health FX We thank Dr. Chandramouli Gadisetti for helpful advice regarding the statistical analyses of the microarrays and Drs. Heinz Arnheiter and Rainer Schmidt for very helpful discussions and suggestions. This work was supported in part by the Intramural Research Program of the National Cancer Institute at National Institutes of Health. The Ap-2a antibody (2B5-c), developed by Trevor Williams, was obtained from the Developmental Studies Hybridoma Bank, developed under the auspices of the National Institute of Child Health and Human Development, and maintained by the Department of Biological Sciences, University of Iowa, Iowa City. NR 72 TC 34 Z9 34 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 10 PY 2009 VL 106 IS 6 BP 1802 EP 1807 DI 10.1073/pnas.0806753106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 405VO UT WOS:000263252500025 PM 19174519 ER PT J AU Pluznick, JL Zou, DJ Zhang, XH Yan, QS Rodriguez-Gil, DJ Eisner, C Wells, E Greer, CA Wang, T Firestein, S Schnermann, J Caplan, MJ AF Pluznick, Jennifer L. Zou, Dong-Jing Zhang, Xiaohong Yan, Qingshang Rodriguez-Gil, Diego J. Eisner, Christoph Wells, Erika Greer, Charles A. Wang, Tong Firestein, Stuart Schnermann, Jurgen Caplan, Michael J. TI Functional expression of the olfactory signaling system in the kidney SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adenylate cyclase 3; glomerular filtration rate; G(olf); macula densa; renin ID SOLUBLE ADENYLYL-CYCLASE; TUBULOGLOMERULAR FEEDBACK; CYCLOOXYGENASE-2 EXPRESSION; ODORANT RECEPTORS; FILTRATION-RATE; MICE DEFICIENT; TUBULAR FLUID; MOUSE; RENIN; INHIBITION AB Olfactory-like chemosensory signaling occurs outside of the olfactory epithelium. We find that major components of olfaction, including olfactory receptors (ORs), olfactory-related adenylate cyclase (AC3) and the olfactory G protein ( Golf), are expressed in the kidney. AC3 and Golf colocalize in renal tubules and in macula densa ( MD) cells which modulate glomerular filtration rate (GFR). GFR is significantly reduced in AC3(-/-) mice, suggesting that AC3 participates in GFR regulation. Although tubuloglomerular feedback is normal in these animals, they exhibit significantly reduced plasma renin levels despite up-regulation of COX-2 expression and nNOS activity in the MD. Furthermore, at least one member of the renal repertoire of ORs is expressed in a MD cell line. Thus, key components of olfaction are expressed in the renal distal nephron and may play a sensory role in the MD to modulate both renin secretion and GFR. C1 [Rodriguez-Gil, Diego J.; Greer, Charles A.; Caplan, Michael J.] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT 06510 USA. [Pluznick, Jennifer L.; Yan, Qingshang; Wells, Erika; Wang, Tong; Caplan, Michael J.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. [Zou, Dong-Jing; Zhang, Xiaohong; Firestein, Stuart] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Eisner, Christoph; Schnermann, Jurgen] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Caplan, MJ (reprint author), Yale Univ, Sch Med, Dept Neurosurg, 333 Cedar St,SHM B-147, New Haven, CT 06510 USA. EM michael.caplan@yale.edu RI Marion-Poll, Frederic/D-8882-2011 OI Marion-Poll, Frederic/0000-0001-6824-0180 FU Polycystic Kidney Disease Foundation; National Institutes of HealthNational Institute of Diabetes and Digestive and Kidney Diseases [DK-17433]; National Institutes of Health [DK-17433, DK-57328] FX We thank SueAnn Mentone for preparation of histochemistry slides; David Geller and Junhui Zhang for measurement of blood pressure by telemetry and of plasma aldosterone; Laszlo Furu and Stephen Somlo for measurement of plasma creatinine; Michael Kashgarian for assistance with the histological analysis; the members of the M. J. C., S. F., and C. A. G. laboratories for helpful discussions; and Drs. Gerhard Giebisch and John Carlson for careful readings of the manuscript. This work was supported by a postdoctoral fellowship from the Polycystic Kidney Disease Foundation ( to J. L. P.), National Institutes of Health Grant DK-17433 ( Core E; to T. W.), intramural funds from National Institute of Diabetes and Digestive and Kidney Diseases ( to J. NS.), and National Institutes of Health Grants DK-57328 and DK-17433 ( to M. J. C.). NR 38 TC 89 Z9 93 U1 2 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 10 PY 2009 VL 106 IS 6 BP 2059 EP 2064 DI 10.1073/pnas.0812859106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 405VO UT WOS:000263252500070 PM 19174512 ER PT J AU Kino, T Takatori, H Manoli, I Wang, YH Tiulpakov, A Blackman, MR Su, YA Chrousos, GP DeCherney, AH Segars, JH AF Kino, Tomoshige Takatori, Hiroaki Manoli, Irini Wang, Yonghong Tiulpakov, Anatoly Blackman, Marc R. Su, Yan A. Chrousos, George P. DeCherney, Alan H. Segars, James H. TI Brx Mediates the Response of Lymphocytes to Osmotic Stress Through the Activation of NFAT5 SO SCIENCE SIGNALING LA English DT Article ID CELL-VOLUME REGULATION; CHRONIC-RENAL-FAILURE; ENHANCER-BINDING PROTEIN; RHO-FAMILY GTPASES; TRANSCRIPTIONAL ACTIVITY; GENE-EXPRESSION; GLUCOCORTICOID-RECEPTOR; SIGNAL-TRANSDUCTION; EPITHELIAL-CELLS; MAP KINASE AB Extracellular hyperosmolarity, or osmotic stress, generally caused by differences in salt and macromolecule concentrations across the plasma membrane, occurs in lymphoid organs and at inflammatory sites. The response of immune cells to osmotic stress is regulated by nuclear factor of activated T cells 5 (NFAT5), a transcription factor that induces the expression of hyperosmolarity-responsive genes and stimulates cytokine production. We report that the guanine nucleotide exchange factor (GEF) Brx [also known as protein kinase A-anchoring protein 13 (AKAP13)] is essential for the expression of nfat5 in response to osmotic stress, thus transmitting the extracellular hyperosmolarity signal and enabling differentiation of splenic B cells and production of immunoglobulin. This process required the activity of p38 mitogen-activated protein kinase (MAPK) and NFAT5 and involved a physical interaction between Brx and c-Jun N-terminal kinase (JNK)-interacting protein 4 (JIP4), a scaffold molecule specific to activation of the p38 MAPK cascade. Our results indicate that Brx integrates the responses of immune cells to osmotic stress and inflammation by elevating intracellular osmolarity and stimulating the production of cytokines. C1 [Kino, Tomoshige; Tiulpakov, Anatoly; Chrousos, George P.; DeCherney, Alan H.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Takatori, Hiroaki] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Manoli, Irini; Blackman, Marc R.] Natl Ctr Complementary & Alternat Med, Endocrine Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. [Manoli, Irini; Chrousos, George P.] Univ Athens, Dept Pediat 1, Athens 11527, Greece. [Wang, Yonghong] NCI, Adv Technol Ctr, NIH, Bethesda, MD 20892 USA. [Blackman, Marc R.] Washington DC VA Med Ctr, Washington, DC 20422 USA. [Su, Yan A.] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Catherine Birch McCormick Genom Ctr, Washington, DC 20037 USA. RP Kino, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941 FU Intramural NIH HHS [Z01 HD008737-07, Z01 HD000615-28] NR 90 TC 35 Z9 35 U1 0 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD FEB 10 PY 2009 VL 2 IS 57 AR ra5 DI 10.1126/scisignal.2000081 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 567UM UT WOS:000275472100002 PM 19211510 ER PT J AU Ingelsson, E Massaro, JM Sutherland, P Jacques, PF Levy, D D'Agostino, RB Vasan, RS Robins, SJ AF Ingelsson, Erik Massaro, Joseph M. Sutherland, Patrice Jacques, Paul F. Levy, Daniel D'Agostino, Ralph B. Vasan, Ramachandran S. Robins, Sander J. TI Contemporary Trends in Dyslipidemia in the Framingham Heart Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; METABOLIC SYNDROME; US ADULTS; OBESITY; PLASMA; LIPOLYSIS; CHYLOMICRONS; QUANTITATION; PREVALENCE; DISEASE AB Background: Recent cross-sectional population studies in the United States have shown an increase in obesity, a decrease in cholesterol values, but no changes in levels of high-density lipoprotein cholesterol (HDL-C) or triglycerides (TG). Methods: Plasma total cholesterol, HDL-C, and TG levels, measured by the same methods at the 3 most recently completed examinations of Framingham Offspring Study participants (1991-2001), were compared in 1666 participants without prevalent cardiovascular disease, lipid therapy, or hormone replacement therapy (56% were men; mean ages of participants at the first and last examinations, 53 and 60 years, respectively). Changes in age- and multivariate-adjusted mean lipid levels were related to changes in body mass index (BMI). Results: Over the 3 examinations, comparing the findings of the earliest examination with those of the most recent examination, the mean HDL-C level was significantly increased (multivariate-adjusted means, 44.4 and 46.6 mg/dL in men; 56.9 and 60.1 mg/dL in women; P value for trend, P < .001 in both sexes), whereas levels of TG were decreased (144.5 and 134.1 mg/dL in men; 122.3 and 112.3 mg/dL in women; P value for trend, P = .004 in men and <.001 in women). Over the same time interval, BMI (calculated as weight in kilograms divided by height in meters squared) increased (27.8 and 28.5 in men; 27.0 and 27.6 in women; P value for trend, P < .001 in men and P = .001 in women). There was an inverse relationship between changes in BMI and magnitude of dyslipidemia (ie, individuals with the least increase in BMI had the most favorable changes in levels of HDL-C and TG). Conclusion: During a 10-year period of recent examinations in the Framingham Heart Study there was a decrease in dyslipidemia with an increase in HDL-C levels and a decrease in levels of TG despite an overall increase in BMI. C1 [Ingelsson, Erik; Massaro, Joseph M.; Sutherland, Patrice; Levy, Daniel; D'Agostino, Ralph B.; Vasan, Ramachandran S.; Robins, Sander J.] Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02118 USA. [Levy, Daniel; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Levy, Daniel; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Massaro, Joseph M.; D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Jacques, Paul F.] Tufts Univ, Human Nutr Res Ctr, Dept Nutr Epidemiol, Boston, MA 02111 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Robins, SJ (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM sjrobins@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU Swedish Heart-Lung Foundation; National Institute of Health/National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-25195] FX This work was supported through the Swedish Heart-Lung Foundation (Dr Ingelsson) and National Institute of Health/National Heart, Lung, and Blood Institute (NHLBI) contract N01-HC-25195. NR 22 TC 25 Z9 31 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 9 PY 2009 VL 169 IS 3 BP 279 EP 286 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 405DK UT WOS:000263202600010 PM 19204219 ER PT J AU Kurzweil, VC Getman, M Green, ED Lane, RP AF Kurzweil, Vanessa C. Getman, Mike Green, Eric D. Lane, Robert P. CA NISC Comparative Sequencing TI Dynamic evolution of V1R putative pheromone receptors between Mus musculus and Mus spretus SO BMC GENOMICS LA English DT Article ID VOMERONASAL ORGAN; MULTIGENE FAMILY; MOLECULAR CLOCK; GENUS MUS; GENES; MAMMALS; RODENTS; HYBRIDIZATION; REPERTOIRES; DEFICIENT AB Background: The mammalian vomeronasal organ (VNO) expresses two G-protein coupled receptor gene families that mediate pheromone responses, the V1R and V2R receptor genes. In rodents, there are similar to 150 V1R genes comprising 12 subfamilies organized in gene clusters at multiple chromosomal locations. Previously, we showed that several of these subfamilies had been extensively modulated by gene duplications, deletions, and gene conversions around the time of the evolutionary split of the mouse and rat lineages, consistent with the hypothesis that V1R repertoires might be involved in reinforcing speciation events. Here, we generated genome sequence for one large cluster containing two V1R subfamilies in Mus spretus, a closely related and sympatric species to Mus musculus, and investigated evolutionary change in these repertoires along the two mouse lineages. Results: We describe a comparison of spretus and musculus with respect to genome organization and synteny, as well as V1R gene content and phylogeny, with reference to previous observations made between mouse and rat. Unlike the mouse-rat comparisons, synteny seems to be largely conserved between the two mouse species. Disruption of local synteny is generally associated with differences in repeat content, although these differences appear to arise more from deletion than new integrations. Even though unambiguous V1R orthology is evident, we observe dynamic modulation of the functional repertoires, with two of seven V1Rb and one of eleven V1Ra genes lost in spretus, two V1Ra genes becoming pseudogenes in musculus, two additional orthologous pairs apparently subject to strong adaptive selection, and another divergent orthologous pair that apparently was subjected to gene conversion. Conclusion: Therefore, eight of the 18 (similar to 44%) presumptive V1Ra/V1Rb genes in the musculus-spretus ancestor appear to have undergone functional modulation since these two species diverged. As compared to the rat-mouse split, where modulation is evident by independent expansions of these two V1R subfamilies, divergence between musculus and spretus has arisen more by mutations within coding sequences. These results support the hypothesis that adaptive changes in functional V1R repertoires contribute to the delineation of very closely related species. C1 [Kurzweil, Vanessa C.; Getman, Mike; Lane, Robert P.] Wesleyan Univ, Dept Mol Biol & Biochem, Middletown, CT 06457 USA. [Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Green, Eric D.; NISC Comparative Sequencing] NHGRI, NISC, NIH, Bethesda, MD 20892 USA. RP Lane, RP (reprint author), Wesleyan Univ, Dept Mol Biol & Biochem, Middletown, CT 06457 USA. EM vkurzweil@wesleyan.edu; mgetman@wesleyan.edu; egreen@nhgri.nih.gov; rlane@wesleyan.edu FU National Institutes of Health [R01-DC006267]; National Human Genome Research Institute FX This work was supported by National Institutes of Health Grant R01-DC006267. The work was also supported in part by the Intramural Program of the National Human Genome Research Institute, National Institutes of Health. We thank various members of the NIH Intramural Sequencing Center (NISC) for their role in generating the BAC sequences. In particular, we thank Robert Blakesley for his leadership in all aspects of the sequence generation and finishing process, including ensuring the accurate description of these activities in this manuscript, and Gerry Bouffard for his leadership in the bioinformatics components of the BAC-sequencing effort. NR 28 TC 6 Z9 7 U1 3 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 9 PY 2009 VL 10 AR 74 DI 10.1186/1471-2164-10-74 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 418CD UT WOS:000264123900001 PM 19203383 ER PT J AU Hao, JJ Liu, Y Kruhlak, M Debell, KE Rellahan, BL Shaw, S AF Hao, Jian-Jiang Liu, Yin Kruhlak, Michael Debell, Karen E. Rellahan, Barbara L. Shaw, Stephen TI Phospholipase C-mediated hydrolysis of PIP2 releases ERM proteins from lymphocyte membrane SO JOURNAL OF CELL BIOLOGY LA English DT Article ID T-CELL CHEMOTAXIS; F-ACTIN BINDING; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; EZRIN/RADIXIN/MOESIN PROTEINS; ACTIVATION MECHANISMS; SIGNALING PATHWAY; PLASMA-MEMBRANE; THREONINE 558; FERM DOMAIN; IN-VIVO AB Mechanisms controlling the disassembly of ezrin/radixin/moesin (ERM) proteins, which link the cytoskeleton to the plasma membrane, are incompletely understood. In lymphocytes, chemokine (e. g., SDF-1) stimulation inactivates ERM proteins, causing their release from the plasma membrane and dephosphorylation. SDF-1-mediated inactivation of ERM proteins is blocked by phospholipase C (PLC) inhibitors. Conversely, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) levels by activation of PLC, expression of active PLC mutants, or acute targeting of phosphoinositide 5-phosphatase to the plasma membrane promotes release and dephosphorylation of moesin and ezrin. Although expression of phosphomimetic moesin (T558D) or ezrin (T567D) mutants enhances membrane association, activation of PLC still relocalizes them to the cytosol. Similarly, in vitro binding of ERM proteins to the cytoplasmic tail of CD44 is also dependent on PIP2. These results demonstrate a new role of PLCs in rapid cytoskeletal remodeling and an additional key role of PIP2 in ERM protein biology, namely hydrolysis-mediated ERM inactivation. C1 [Hao, Jian-Jiang; Liu, Yin; Kruhlak, Michael; Shaw, Stephen] NIH, Natl Canc Inst, Expt Immunol Branch, Bethesda, MD 20892 USA. [Debell, Karen E.; Rellahan, Barbara L.] US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Shaw, S (reprint author), NIH, Natl Canc Inst, Expt Immunol Branch, Bldg 10, Bethesda, MD 20892 USA. EM shaws@mail.nih.gov FU National Cancer Institute Intramural Research Programs of the National Institutes of Health FX This research was supported by the National Cancer Institute Intramural Research Programs of the National Institutes of Health. NR 50 TC 66 Z9 67 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD FEB 9 PY 2009 VL 184 IS 3 BP 451 EP 462 PG 12 WC Cell Biology SC Cell Biology GA 409PK UT WOS:000263518100013 PM 19204146 ER PT J AU Parker Jellison Kohls Davis AF Parker Jellison Kohls Davis TI TULARAEMIA INFECTION FOUND IN STREAMS SO PUBLIC HEALTH REPORTS LA English DT Article C1 Publ Hlth Serv, Rocky Mt Lab, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1101 15TH ST NW, STE 910, WASHINGTON, DC 20005 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD FEB 9 PY 2009 VL 55 IS 6 BP 227 EP 227 PN 1 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V08PH UT WOS:000207340200001 ER PT J AU Al Sabbah, H Vereecken, CA Elgar, FJ Nansel, T Aasvee, K Abdeen, Z Ojala, K Ahluwalia, N Maes, L AF Al Sabbah, Haleama Vereecken, Carine A. Elgar, Frank J. Nansel, Tonja Aasvee, Katrin Abdeen, Ziad Ojala, Kristiina Ahluwalia, Namanjeet Maes, Lea TI Body weight dissatisfaction and communication with parents among adolescents in 24 countries: international cross-sectional survey SO BMC PUBLIC HEALTH LA English DT Article ID NON-OVERWEIGHT ADOLESCENTS; MENTAL-HEALTH; FAMILY MEALS; ADULT ATTACHMENT; LOSE WEIGHT; GIRLS; BOYS; BEHAVIORS; IMAGE; RISK AB Background: Parents have significant influence on behaviors and perceptions surrounding eating, body image and weight in adolescents. The aim of this study was to examine the prevalence of body weight dissatisfaction, difficulty in communication with the parents and the relationship between communication with parents and adolescents' dissatisfaction with their body weight (dieting or perceived need to diet). Methods: Survey data were collected from adolescents in 24 countries and regions in Europe, Canada, and the USA who participated in the cross-sectional 2001/2002 Health Behaviour of School-Aged Children (HBSC) study. The association between communication with parents and body weight dissatisfaction was examined using binary logistic regression analysis. Results: Body weight dissatisfaction was highly prevalent and more common among girls than boys, among overweight than non-overweight, and among older adolescents than younger adolescents. Difficulty in talking to father was more common than difficulty in talking to mother in all countries and it was greater among girls than among boys and increased with age. Difficulties in talking to father were associated with weight dissatisfaction among both boys and girls in most countries. Difficulties in talking to mother were rarely associated with body weight dissatisfaction among boys while among girls this association was found in most countries. Conclusion: The findings suggest that enhanced parent communication might contribute in most countries to less body dissatisfaction in girls and better communication with the father can help avoiding body weight dissatisfaction in boys. Professionals working with adolescents and their families should help adolescents to have a healthy weight and positive body image and promote effective parent - adolescent communication. C1 [Al Sabbah, Haleama; Vereecken, Carine A.; Maes, Lea] Univ Ghent, Fac Med, Dept Publ Hlth, B-9000 Ghent, Belgium. [Al Sabbah, Haleama; Abdeen, Ziad] Al Quds Univ, Nutr & Hlth Res Inst, Al Quds, Israel. [Elgar, Frank J.] Carleton Univ, Dept Psychol, Ottawa, ON K1S 5B6, Canada. [Nansel, Tonja] NICHHD, NIH, DHHS, Bethesda, MD 20892 USA. [Ahluwalia, Namanjeet] Fac Med Toulouse, INSERM, U558, F-31073 Toulouse, France. [Aasvee, Katrin] Natl Inst Hlth Dev, Dept Chron Dis, Tallinn, Estonia. [Ojala, Kristiina] Univ Jyvaskyla, Res Ctr Hlth Promot, Dept Hlth Sci, Jyvaskyla, Finland. RP Al Sabbah, H (reprint author), Univ Ghent, Fac Med, Dept Publ Hlth, B-9000 Ghent, Belgium. EM halimah.alsabbah@ugent.be; carine.vereecken@ugent.be; Frank_Elgar@carleton.ca; nanselt@mail.nih.gov; katrin.aasvee@tai.ee; zabdeen@planet.edu; kristiina.ojala@sport.jyu.fi; naman123@cict.fr; lea.maes@ugent.be RI Akkal, Maureen/P-6919-2014; OI Al Sabbah, Haleama/0000-0001-7357-5823; Nansel, Tonja/0000-0002-8298-7595 FU Research Foundation - Flanders (FWO-Flanders) FX The authors thank the Belgium Technical Cooperation (BTC) for sponsoring the first author doctorate study. Carine Vereecken is post-doctoral researcher funded by the Research Foundation - Flanders (FWO-Flanders). The international coordinator of 2001/2002 Health Behaviour of School-Aged Children (HBSC) survey was Candace Currie, University of Edinburgh, Scotland; the data bank manager was Oddrun Samdal, University of Bergen, Norway. A complete list of the participating researchers can be found on the HBSC-website: http://www.hbsc.org/. NR 46 TC 41 Z9 44 U1 2 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD FEB 6 PY 2009 VL 9 AR 52 DI 10.1186/1471-2458-9-52 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 420KT UT WOS:000264289400002 PM 19200369 ER PT J AU Creppe, C Malinouskaya, L Volvert, ML Gillard, M Close, P Malaise, O Laguesse, S Cornez, I Rahmouni, S Ormenese, S Belachew, S Malgrange, B Chapelle, JP Siebenlist, U Moonen, G Chariot, A Nguyen, L AF Creppe, Catherine Malinouskaya, Lina Volvert, Marie-Laure Gillard, Magali Close, Pierre Malaise, Olivier Laguesse, Sophie Cornez, Isabelle Rahmouni, Souad Ormenese, Sandra Belachew, Shibeshih Malgrange, Brigitte Chapelle, Jean-Paul Siebenlist, Ulrich Moonen, Gustave Chariot, Alain Nguyen, Laurent TI Elongator Controls the Migration and Differentiation of Cortical Neurons through Acetylation of alpha-Tubulin SO CELL LA English DT Article ID FAMILIAL DYSAUTONOMIA; IN-VIVO; CEREBRAL-CORTEX; CELL-MIGRATION; HISTONE ACETYLTRANSFERASE; ACTIN CYTOSKELETON; FILAMIN-A; PROTEIN; RNA; TRANSPORT AB The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons. C1 [Creppe, Catherine; Gillard, Magali; Close, Pierre; Cornez, Isabelle; Chapelle, Jean-Paul; Chariot, Alain] Univ Liege, CHU Sart Tilman, GIGA Signal Transduct, B-4000 Liege, Belgium. [Malinouskaya, Lina; Volvert, Marie-Laure; Malaise, Olivier; Laguesse, Sophie; Belachew, Shibeshih; Malgrange, Brigitte; Moonen, Gustave; Nguyen, Laurent] Univ Liege, CHU Sart Tilman, GIGA Neurosci, B-4000 Liege, Belgium. [Rahmouni, Souad] Univ Liege, CHU Sart Tilman, GIGA Infect Immun & Inflammat, B-4000 Liege, Belgium. [Ormenese, Sandra] Univ Liege, CHU Sart Tilman, GIGA Imaging & Flow Cytometry, B-4000 Liege, Belgium. [Belachew, Shibeshih; Moonen, Gustave] Univ Liege, CHU Sart Tilman, Dept Neurol, B-4000 Liege, Belgium. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Chariot, A (reprint author), Univ Liege, CHU Sart Tilman, GIGA Signal Transduct, B-4000 Liege, Belgium. EM alain.chariot@ulg.ac.be; lnguyen@ulg.ac.be NR 50 TC 250 Z9 256 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 6 PY 2009 VL 136 IS 3 BP 551 EP 564 DI 10.1016/j.cell.2008.11.043 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403ZN UT WOS:000263120600023 PM 19185337 ER PT J AU Paugh, BS Bryan, L Paugh, SW Wilczynska, KM Alvarez, SM Singh, SK Kapitonov, D Rokita, H Wright, S Griswold-Prenner, I Milstien, S Spiegel, S Kordula, T AF Paugh, Barbara S. Bryan, Lauren Paugh, Steven W. Wilczynska, Katarzyna M. Alvarez, Silvina M. Singh, Sandeep K. Kapitonov, Dmitri Rokita, Hanna Wright, Sarah Griswold-Prenner, Irene Milstien, Sheldon Spiegel, Sarah Kordula, Tomasz TI Interleukin-1 Regulates the Expression of Sphingosine Kinase 1 in Glioblastoma Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; ASTROCYTE-SPECIFIC EXPRESSION; TUMOR-HOST INTERACTIONS; EPIDERMAL-GROWTH-FACTOR; ACIDIC PROTEIN GENES; TRANSCRIPTION FACTOR; ALPHA(1)-ANTICHYMOTRYPSIN GENE; HUMAN LEUKEMIA; IN-VITRO; INVASIVENESS AB Chronic inflammation and inflammatory cytokines have recently been implicated in the development and progression of various types of cancer. In the brain, neuroinflammatory cytokines affect the growth and differentiation of both normal and malignant glial cells, with interleukin 1 (IL-1) shown to be secreted by the majority of glioblastoma cells. Recently, elevated levels of sphingosine kinase 1 (SphK1), but not SphK2, were correlated with a shorter survival prognosis for patients with glioblastoma multiforme. SphK1 is a lipid kinase that produces the pro-growth, anti-apoptotic sphingosine 1-phosphate, which can induce invasion of glioblastoma cells. Here, we show that the expression of IL-1 correlates with the expression of SphK1 in glioblastoma cells, and neutralizing anti-IL-1 antibodies inhibit both the growth and invasion of glioblastoma cells. Furthermore, IL-1 up-regulates SphK1 mRNA levels, protein expression, and activity in both primary human astrocytes and various glioblastoma cell lines; however, it does not affect SphK2 expression. The IL-1-induced SphK1 up-regulation can be blocked by the inhibition of JNK, the overexpression of the dominant-negative c-Jun(TAM67), and the down-regulation of c-Jun expression by small interference RNA. Activation of SphK1 expression by IL-1 occurs on the level of transcription and is mediated via a novel AP-1 element located within the first intron of the sphk1 gene. In summary, our results suggest that SphK1 expression is transcriptionally regulated by IL-1 in glioblastoma cells, and this pathway may be important in regulating survival and invasiveness of glioblastoma cells. C1 [Paugh, Barbara S.; Bryan, Lauren; Paugh, Steven W.; Wilczynska, Katarzyna M.; Alvarez, Silvina M.; Singh, Sandeep K.; Kapitonov, Dmitri; Spiegel, Sarah; Kordula, Tomasz] Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. [Paugh, Barbara S.; Bryan, Lauren; Paugh, Steven W.; Wilczynska, Katarzyna M.; Alvarez, Silvina M.; Singh, Sandeep K.; Kapitonov, Dmitri; Spiegel, Sarah; Kordula, Tomasz] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA. [Milstien, Sheldon] NIMH, Bethesda, MD 20892 USA. [Rokita, Hanna] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, PL-30387 Krakow, Poland. [Wright, Sarah; Griswold-Prenner, Irene] Elan Pharmaceut, San Francisco, CA 94080 USA. RP Kordula, T (reprint author), Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM tkordula@vcu.edu RI Paugh, Steven/A-7739-2008; Paugh, Barbara/B-3625-2009 OI Paugh, Steven/0000-0001-5697-9228; FU National Institutes of Health (NIH) [R21NS063283] FX This work was supported, in whole or in part, by National Institutes of Health (NIH) Grant R21NS063283 (to T. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 56 TC 41 Z9 44 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 6 PY 2009 VL 284 IS 6 BP 3408 EP 3417 DI 10.1074/jbc.M807170200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 400MO UT WOS:000262872500006 PM 19074142 ER PT J AU Sum, CS Tikhonova, IG Costanzi, S Gershengorn, MC AF Sum, Chi Shing Tikhonova, Irina G. Costanzi, Stefano Gershengorn, Marvin C. TI Two Arginine-Glutamate Ionic Locks Near the Extracellular Surface of FFAR1 Gate Receptor Activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; THYROTROPIN-RELEASING-HORMONE; A(2A) ADENOSINE RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; DRUG DISCOVERY; AGONIST RECOGNITION; LIGAND RECOGNITION; INSULIN-SECRETION; CRYSTAL-STRUCTURE; BINDING AB Activation of a number of class A G protein-coupled receptors (GPCRs) is thought to involve two molecular switches, a rotamer toggle switch within the transmembrane domain and an ionic lock at the cytoplasmic surface of the receptor; however, the mechanism by which agonist binding changes these molecular interactions is not understood. Importantly, 80% of GPCRs including free fatty acid receptor 1 (FFAR1) lack the complement of amino acid residues implicated in either or both of these two switches; the mechanism of activation of these GPCRs is therefore less clear. By homology modeling, we identified two Glu residues (Glu-145 and Glu-172) in the second extracellular loop of FFAR1 that form putative interactions individually with two transmembrane Arg residues (Arg-183(5.39) and Arg-258(7.35)) to create two ionic locks. Molecular dynamics simulations showed that binding of agonists to FFAR1 leads to breakage of these Glu-Arg interactions. In mutagenesis experiments, breakage of these two putative interactions by substituting Ala for Glu-145 and Glu-172 caused constitutive receptor activation. Our results therefore reveal a molecular switch for receptor activation present on the extracellular surface of FFAR1 that is broken by agonist binding. Similar ionic locks between the transmembrane domains and the extracellular loops may constitute a mechanism common to other class A GPCRs also. C1 [Sum, Chi Shing; Gershengorn, Marvin C.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Tikhonova, Irina G.; Costanzi, Stefano] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), 50 South Dr,Rm 4134, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov RI Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU Intramural Research Program; NIDDK; National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program, NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 44 TC 38 Z9 38 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 6 PY 2009 VL 284 IS 6 BP 3529 EP 3536 DI 10.1074/jbc.M806987200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 400MO UT WOS:000262872500020 PM 19068482 ER PT J AU Kliment, CR Englert, JM Gochuico, BR Yu, GY Kaminski, N Rosas, I Oury, TD AF Kliment, Corrine R. Englert, Judson M. Gochuico, Bernadette R. Yu, Guoying Kaminski, Naftali Rosas, Ivan Oury, Tim D. TI Oxidative Stress Alters Syndecan-1 Distribution in Lungs with Pulmonary Fibrosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXTRACELLULAR-SUPEROXIDE-DISMUTASE; HEPARAN-SULFATE PROTEOGLYCANS; IN-VITRO; SOLUBLE SYNDECAN-1; WOUND REPAIR; MOUSE LUNG; EC-SOD; INFLAMMATION; INJURY; NEUTROPHILS AB Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by severe, progressive fibrosis. Roles for inflammation and oxidative stress have recently been demonstrated, but despite advances in understanding the pathogenesis, there are still no effective therapies for IPF. This study investigates how extracellular superoxide dismutase (EC-SOD), a syndecan-binding antioxidant enzyme, inhibits inflammation and lung fibrosis. We hypothesize that EC-SOD protects the lung from oxidant damage by preventing syndecan fragmentation/shedding. Wild-type or EC-SOD-null mice were exposed to an intratracheal instillation of asbestos or bleomycin. Western blot was used to detect syndecans in the bronchoalveolar lavage fluid and lung. Human lung samples (normal and IPF) were also analyzed. Immunohistochemistry for syndecan-1 and EC-SOD was performed on human and mouse lungs. In vitro, alveolar epithelial cells were exposed to oxidative stress and EC-SOD. Cell supernatants were analyzed for shed syndecan-1 by Western blot. Syndecan-1 ectodomain was assessed in wound healing and neutrophil chemotaxis. Increases in human syndecan-1 are detected in lung homogenates and lavage fluid of IPF lungs. Syndecan-1 is also significantly elevated in the lavage fluid of EC-SOD-null mice after asbestos and bleomycin exposure. On IHC, syndecan-1 staining increases within fibrotic areas of human and mouse lungs. In vitro, EC-SOD inhibits oxidant-induced loss of syndecan-1 from A549 cells. Shed and exogenous syndecan-1 ectodomain induce neutrophil chemotaxis, inhibit alveolar epithelial wound healing, and promote fibrogenesis. Oxidative shedding of syndecan-1 is an underlying cause of neutrophil chemotaxis and aberrant wound healing that may contribute to pulmonary fibrosis. C1 [Kliment, Corrine R.; Englert, Judson M.; Oury, Tim D.] Univ Pittsburgh, Sch Med, Dept Cellular & Mol Pathol, Pittsburgh, PA 15213 USA. [Yu, Guoying; Kaminski, Naftali] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm, Pittsburgh, PA 15213 USA. [Gochuico, Bernadette R.] NHGRI, NIH, Bethesda, MD 20892 USA. [Rosas, Ivan] Brigham & Womens Hosp, Div Pulm, Boston, MA 02115 USA. RP Oury, TD (reprint author), Univ Pittsburgh, Dept Pathol, 200 Lothrop St,Biomed Sci Tower W904, Pittsburgh, PA 15261 USA. EM tdoury@pitt.edu FU National Institutes of Health [1F30ES016483-01]; Research Project Grant [R01HL063700-07]; Intramural Research Program of the NGRI and NHLBI FX This work was supported, in whole or in part, by the National Institutes of Health under a Ruth L. Kirschstein National Research Service Award (1F30ES016483-01, to C. R. K.), a Research Project Grant (R01HL063700-07, to T.D.O.), and by the Intramural Research Program of the NGRI and NHLBI. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 50 TC 76 Z9 82 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 6 PY 2009 VL 284 IS 6 BP 3537 EP 3545 DI 10.1074/jbc.M807001200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 400MO UT WOS:000262872500021 PM 19073610 ER PT J AU Scarselli, M Donaldson, JG AF Scarselli, Marco Donaldson, Julie G. TI Constitutive Internalization of G Protein-coupled Receptors and G Proteins via Clathrin-independent Endocytosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MUSCARINIC ACETYLCHOLINE-RECEPTORS; HETEROTRIMERIC G-PROTEINS; 3RD CYTOPLASMIC LOOP; BETA-ARRESTINS; BETA(2)-ADRENERGIC RECEPTOR; MEDIATED ENDOCYTOSIS; PLASMA-MEMBRANE; DOWN-REGULATION; LIVING CELLS; TRAFFICKING AB Although agonist-dependent endocytosis of G protein-coupled receptors (GPCRs) as a means to modulate receptor signaling has been widely studied, the constitutive endocytosis of GPCRs has received little attention. Here we show that two prototypical class I GPCRs, the beta 2 adrenergic and M3 muscarinic receptors, enter cells constitutively by clathrin-independent endocytosis and colocalize with markers of this endosomal pathway on recycling tubular endosomes, indicating that these receptors can subsequently recycle back to the plasma membrane (PM). This constitutive endocytosis of these receptors was not blocked by antagonists, indicating that receptor signaling was not required. Interestingly, the G proteins that these receptors couple to, G alpha(s) and G alpha(q), localized together with their receptors at the plasma membrane and on tubular recycling endosomes. Upon agonist stimulation, G alpha(s) and G alpha(q) remained associated with the PM and these endosomal membranes, whereas beta 2 and M3 receptors now entered cells via clathrin-dependent endocytosis. Deletion of the third intracellular loop (i3 loop), which is thought to play a role in agonist-dependent endocytosis of the M3 receptor, had no effect on the constitutive internalization of the receptor. Surprisingly, with agonist, the mutated M3 receptor still internalized and accumulated in cells but through clathrin-independent and not clathrin-dependent endocytosis. These findings demonstrate that GPCRs are versatile PM proteins that can utilize different mechanisms of internalization depending upon ligand activation. C1 [Scarselli, Marco; Donaldson, Julie G.] NHLBI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, NIH, Cell Biol Lab, Bldg 50,Rm 2503, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov OI Scarselli, Marco/0000-0001-5087-3182 FU Intramural Research Program of the NHLBI; National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of the NHLBI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 55 TC 43 Z9 44 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 6 PY 2009 VL 284 IS 6 BP 3577 EP 3585 DI 10.1074/jbc.M806819200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 400MO UT WOS:000262872500025 PM 19033440 ER PT J AU Kaneko, O Gong, L Zhang, JL Hansen, JK Hassan, R Lee, B Ho, M AF Kaneko, Osamu Gong, Lucy Zhang, Jingli Hansen, Johanna K. Hassan, Raffit Lee, Byungkook Ho, Mitchell TI A Binding Domain on Mesothelin for CA125/MUC16 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OVARIAN-CANCER ANTIGEN; MONOCLONAL-ANTIBODY; MOLECULAR-CLONING; EXTRACELLULAR SUPERSTRUCTURE; MALIGNANT MESOTHELIOMA; CELL-ADHESION; HIGH-AFFINITY; TUMOR-CELLS; CA-125 GENE; EXPRESSION AB Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296 359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors. C1 [Ho, Mitchell] NCI, Antibody Therapy Unit, Mol Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Ho, M (reprint author), NCI, Antibody Therapy Unit, Mol Biol Lab, Ctr Canc Res,NIH, 37 Convent Dr,Rm 5002C, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU National Institutes of Health Intramural Research Program of the NCI; Center for Cancer Research; Ovarian Cancer Research Fund Individual Investigator Award; Mesothelioma Applied Research Foundation FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NCI, Center for Cancer Research. This work was also supported in part by a Ovarian Cancer Research Fund Individual Investigator Award (M. H.) and an Mesothelioma Applied Research Foundation Grant in Honor of Craig Kozicki (M. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 32 TC 54 Z9 57 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 6 PY 2009 VL 284 IS 6 BP 3739 EP 3749 DI 10.1074/jbc.M806776200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 400MO UT WOS:000262872500042 PM 19075018 ER PT J AU Alcorlo, M Jimenez, M Ortega, A Hermoso, JM Salas, M Minton, AP Rivas, G AF Alcorlo, Martin Jimenez, Mercedes Ortega, Alvaro Hermoso, Jose M. Salas, Margarita Minton, Allen P. Rivas, German TI Analytical Ultracentrifugation Studies of Phage phi 29 Protein p6 Binding to DNA SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE macromolecular interactions; sedimentation equilibrium; sedimentation velocity; macromolecular crowding ID HISTONE-LIKE PROTEIN; TRACER SEDIMENTATION EQUILIBRIUM; BACILLUS-SUBTILIS; PHYSIOLOGICAL CONSEQUENCES; NUCLEOPROTEIN COMPLEX; REPLICATION-ORIGIN; IN-VIVO; TRANSCRIPTION; GENOME; INITIATION AB Protein p6 from Bacillus subtilis phage phi 29 binds double-stranded DNA, forming a large nucleoprotein complex all along the viral genome, and has been proposed to be an architectural protein with a global role in genome organization. Here, we have characterized quantitatively the DNA binding properties of protein p6 by means of sedimentation velocity and sedimentation equilibrium experiments permitting determination of the strength and stoichiometry of complex formation. The composition dependence of protein binding to DNA is quantitatively consistent with a model in which the protein undergoes a reversible monomer-dimer self-association, and the dimeric species binds noncooperatively to the DNA. We also have found that when the anisotropic bendability periodicity of the nucleotide sequence preferred by p. 6 is modified, nucleocomplex formation is impaired. In addition, suppression of complex formation at high ionic strength is reversed by the addition of high concentrations of an inert polymer, mimicking the crowded intracellular environment. The results obtained in this work illustrate how macromolecular crowding could act as a metabolic buffer that can significantly extend the range of intracellular conditions under which a specific reaction may occur. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Jimenez, Mercedes; Rivas, German] CSIC, Ctr Invest Biol, E-28040 Madrid, Spain. [Alcorlo, Martin; Hermoso, Jose M.; Salas, Margarita] CSIC UAM, Ctr Biol Mol Severo Ochoa, Madrid, Spain. [Ortega, Alvaro] Univ Montpellier, CNRS, Ctr Biochim Struct, F-34059 Montpellier, France. [Minton, Allen P.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD USA. RP Rivas, G (reprint author), CSIC, Ctr Invest Biol, Ramiro Maeztu 9, E-28040 Madrid, Spain. EM grivas@cib.csic.es RI Jimenez Sarmiento, Mercedes/K-2691-2014; Ortega, Alvaro/J-4266-2012; OI Jimenez Sarmiento, Mercedes/0000-0003-2006-1903; Ortega, Alvaro/0000-0001-8202-293X; Minton, Allen/0000-0001-8459-1247 NR 43 TC 3 Z9 3 U1 1 U2 8 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 6 PY 2009 VL 385 IS 5 BP 1616 EP 1629 DI 10.1016/j.jmb.2008.11.044 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 421UI UT WOS:000264383400023 PM 19084023 ER PT J AU Arumugam, TV Woodruff, TM Lathia, JD Selvaraj, PK Mattson, MP Taylor, SM AF Arumugam, T. V. Woodruff, T. M. Lathia, J. D. Selvaraj, P. K. Mattson, M. P. Taylor, S. M. TI NEUROPROTECTION IN STROKE BY COMPLEMENT INHIBITION AND IMMUNOGLOBULIN THERAPY SO NEUROSCIENCE LA English DT Review DE ischemic stroke; complement; IVIG; neuron; apoptosis; brain injury ID ISCHEMIA-REPERFUSION INJURY; C5A RECEPTOR ANTAGONIST; CENTRAL-NERVOUS-SYSTEM; AMYOTROPHIC-LATERAL-SCLEROSIS; MEMBRANE ATTACK COMPLEX; TRAUMATIC BRAIN-INJURY; INTRAVENOUS IMMUNE GLOBULIN; ANAPHYLATOXIN C3A RECEPTOR; FOCAL CEREBRAL-ISCHEMIA; NEURONAL CELL-DEATH AB Activation of the complement system occurs in a variety of neuroinflammatory diseases and neurodegenerative processes of the CNS. Studies in the last decade have demonstrated that essentially all of the activation components and receptors of the complement system are produced by astrocytes, microglia, and neurons. There is also rapidly growing evidence to indicate an active role of the complement system in cerebral ischemic injury. In addition to direct cell damage, regional cerebral ischemia and reperfusion (I/R) induces an inflammatory response involving complement activation and generation of active fragments, such as C3a and C5a anaphylatoxins, C3b, C4b, and iC3b. The use of specific inhibitors to block complement activation or their mediators such as C5a, can reduce local tissue injury after I/R. Consistent with therapeutic approaches that have been successful in models of autoimmune disorders, many of the same complement inhibition strategies are proving effective in animal models of cerebral I/R injury. One new form of therapy, which is less specific in its targeting of complement than monodrug administration, is the use of immunoglobulins. Intravenous immunoglobulin (IVIG) has the potential to inhibit multiple components of inflammation, including complement fragments, pro-inflammatory cytokine production and leukocyte cell adhesion. Thus, IVIG may directly protect neurons, reduce activation of intrinsic inflammatory cells (microglia) and inhibit transendothelial infiltration of leukocytes into the brain parenchyma following an ischemic stroke. The striking neuroprotective actions of IVIG in animal models of ischemic stroke suggest a potential therapeutic potential that merits consideration for clinical trials in stroke patients. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Arumugam, T. V.; Selvaraj, P. K.] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Sch Pharm, Amarillo, TX 79106 USA. [Woodruff, T. M.; Taylor, S. M.] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia. [Lathia, J. D.; Mattson, M. P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Arumugam, TV (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Sch Pharm, 1300 Coulter Dr, Amarillo, TX 79106 USA. EM thiruma.arumugam@ttuhsc.edu; s.taylor@uq.edu.au RI Arumugam, Thiruma/C-7969-2009; Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012; Woodruff, Trent/B-4861-2009 OI Woodruff, Trent/0000-0003-1382-911X FU National Institute on Aging; NIH, USA; NHMRC FX This work was supported by the Intramural Research Program of the National Institute on Aging, NIH, USA (Mark P. Mattson) and a NH&MRC grant to Stephen M. Taylor, The School of Biomedical Sciences, The University of Queensland, Australia. NR 169 TC 64 Z9 71 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD FEB 6 PY 2009 VL 158 IS 3 SI SI BP 1074 EP 1089 DI 10.1016/j.neuroscience.2008.07.015 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 409TW UT WOS:000263529700011 PM 18691639 ER PT J AU Lisco, A Margolis, L AF Lisco, Andrea Margolis, Leonid TI Integrating integrins into HIV pathogenesis SO BLOOD LA English DT Editorial Material AB In this issue of Blood, Ballana and colleagues show that integrins that mediate macrophage adhesion are important for HIV replication and inhibition of these integrins suppresses HIV replication at the transcriptional level. C1 [Lisco, Andrea; Margolis, Leonid] NIH, Bethesda, MD 20892 USA. RP Lisco, A (reprint author), NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 5 PY 2009 VL 113 IS 6 BP 1207 EP 1208 PG 2 WC Hematology SC Hematology GA 403ZA UT WOS:000263119300001 PM 19196869 ER PT J AU Chen, J Zhang, M Ju, W Waldmann, TA AF Chen, Jing Zhang, Meili Ju, Wei Waldmann, Thomas A. TI Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25 SO BLOOD LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; MONOCLONAL-ANTIBODY; THERAPEUTIC AGENT; INTERFERON-ALFA; LYMPHOMA; FR901228; APOPTOSIS; ZIDOVUDINE; EXPRESSION; RECEPTOR AB Adult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus I (HTLV-1) and is an aggressive malignancy of CD4, CD25-expressing leukemia, and lymphoma cells. There is no accepted curative therapy for ATL. Depsipeptide, a histone deacetylase inhibitor, has demonstrated major antitumor effects in leukemias and lymphomas. In this study, we investigated the therapeutic efficacy of depsipeptide alone and in combination with daclizumab (humanized anti-Tac) in a murine model of human ATL. The Met-1 ATL model was established by intraperitoneal injection of ex vivo leukemic cells into nonobese diabetic/severe combined immunodeficiency mice. Either depsipeptide, given at 0.5 mg/kg every other day for 2 weeks, or daclizumab, given at 100 mu g weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of soluble IL-2R-alpha (sIL-2R-alpha) and soluble beta(2)-microglobulin (beta(2)mu) (P < .001), and prolonged survival of the leukemia-bearing mice (P < .001) compared with the control group. Combination of depsipeptide with daclizumab enhanced the antitumor effect, as shown by both sIL-2R-alpha and beta(2)mu levels and survival of the leukemia-bearing mice, compared with those in the depsipeptide or daclizumab alone groups (P < .001). The significantly improved therapeutic efficacy by combining depsipeptide with daclizumab supports a clinical trial of this combination in the treatment of ATL. (Blood. 2009; 113: 1287-1293) C1 [Chen, Jing; Zhang, Meili; Ju, Wei; Waldmann, Thomas A.] NCI, Ctr Canc Res, Metab Branch, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NIH, Bldg 10,Room 4N115,10Ctr Dr, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU National Cancer Institute, National Institutes of Health (Bethesda, MD) FX This study was supported by the intramural research program of the National Cancer Institute, National Institutes of Health (Bethesda, MD). NR 42 TC 24 Z9 26 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 5 PY 2009 VL 113 IS 6 BP 1287 EP 1293 DI 10.1182/blood-2008-04-149658 PG 7 WC Hematology SC Hematology GA 403ZA UT WOS:000263119300013 PM 18948574 ER PT J AU Allard, JS Perez, E Zou, S de Cabo, R AF Allard, Joanne S. Perez, Evelyn Zou, Sige de Cabo, Rafael TI Dietary activators of Sirt1 SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Calorie restriction; Lifespan; Resveratrol; Sirtuins ID LIFE-SPAN EXTENSION; SMALL-MOLECULE ACTIVATORS; NF-KAPPA-B; CAENORHABDITIS-ELEGANS; CALORIE RESTRICTION; GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-MELANOGASTER; CELL-SURVIVAL; MITOCHONDRIAL-FUNCTION AB Calorie restriction (CR) is a non-genetic manipulation that reliably results in extended lifespan of several species ranging from yeast to dogs. The lifespan extension effect of CR has been strongly associated with an increased level and activation of the silent information regulator 2 (Sir2) histone deacetylase and its mammalian ortholog Sirt1. This association led to the search for potential Sirt1-activating, life-extending molecules. This review briefly outlines the experimental findings on resveratrol and other dietary activators of Sirt1. (C) 2008 Published by Elsevier Ireland Ltd. C1 [Allard, Joanne S.; Perez, Evelyn; Zou, Sige; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Lab Expt Gerontol, NIH, 6200 Seaforth St, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU National Institute on Aging Intramural Research Program FX This research was supported by the National Institute on Aging Intramural Research Program. NR 95 TC 42 Z9 43 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 5 PY 2009 VL 299 IS 1 BP 58 EP 63 DI 10.1016/j.mce.2008.10.018 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 410LX UT WOS:000263579900008 PM 19010386 ER PT J AU Minor, RK Chang, JW de Cabo, R AF Minor, Robin K. Chang, Joy W. de Cabo, Rafael TI Hungry for life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE NPY; Calorie restriction; Lifespan; Appetite; Hypothalamus; Aging ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; MESSENGER-RNA LEVELS; INHIBITS FOOD-INTAKE; GLUCAGON-LIKE PEPTIDE-1; DIETARY-INDUCED OBESITY; AGE-RELATED-CHANGES; BROWN-NORWAY RATS; GENE-EXPRESSION; BODY-WEIGHT; FEEDING-BEHAVIOR AB Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10-40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and severity of chronic diseases associated with aging such as cancer, and to extend the functional health span of important faculties like cognition. Less understood are the underlying mechanisms through which CR might act to induce such alterations. One theory postulates that CR's beneficial effects are intimately tied to the neuroendocrine response to low energy availability, of which the arcuate nucleus in the hypothalamus plays a pivotal role. Neuropeptide Y (NPY), a neurotransmitter in the front line of the arcuate response to low energy availability, is the primary hunger signal affected by CR and therefore may be a critical mechanism for lifespan extension. (C) 2008 Published by Elsevier Ireland Ltd. C1 [Minor, Robin K.; Chang, Joy W.; de Cabo, Rafael] NIA, Lab Expt Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Lab Expt Gerontol, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM decabora@mail.nih.gov RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural NIH HHS [Z01 AG000368-03] NR 221 TC 23 Z9 23 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 5 PY 2009 VL 299 IS 1 BP 79 EP 88 DI 10.1016/j.mce.2008.10.044 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 410LX UT WOS:000263579900011 PM 19041366 ER PT J AU Cardone, G Purdy, JG Cheng, NQ Craven, RC Steven, AC AF Cardone, Giovanni Purdy, John G. Cheng, Naiqian Craven, Rebecca C. Steven, Alasdair C. TI Visualization of a missing link in retrovirus capsid assembly SO NATURE LA English DT Article ID ROUS-SARCOMA-VIRUS; AMINO-TERMINAL DOMAIN; 3-DIMENSIONAL STRUCTURE; DIMERIZATION DOMAIN; CA PROTEIN; HIV-1 CORE; RESOLUTION; RECONSTRUCTIONS; ORGANIZATION; MODELS AB For a retrovirus such as HIV to be infectious, a properly formed capsid is needed; however, unusually among viruses, retrovirus capsids are highly variable in structure. According to the fullerene conjecture, they are composed of hexamers and pentamers of capsid protein (CA), with the shape of a capsid varying according to how the twelve pentamers are distributed and its size depending on the number of hexamers. Hexamers have been studied in planar and tubular arrays, but the predicted pentamers have not been observed. Here we report cryo- electron microscopic analyses of two in- vitro- assembled capsids of Rous sarcoma virus. Both are icosahedrally symmetric: one is composed of 12 pentamers, and the other of 12 pentamers and 20 hexamers. Fitting of atomic models of the two CA domains into the reconstructions shows three distinct inter- subunit interactions. These observations substantiate the fullerene conjecture, show how pentamers are accommodated at vertices, support the inference that nucleation is a crucial morphologic determinant, and imply that electrostatic interactions govern the differential assembly of pentamers and hexamers. C1 [Cardone, Giovanni; Cheng, Naiqian; Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Purdy, John G.; Craven, Rebecca C.] Penn State Univ, Coll Med, Dept Microbiol & Immunol, Hershey, PA 17033 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM rcc6@psu.edu; stevena@mail.nih.gov FU Intramural Research Program of NIAMS; IATAP Program; NIH [CA100322]; Pennsylvania Department of Health; Penn State Cancer Institute FX We thank J. Flanagan for advice on protein purification and analytic methods and access to equipment, R. Meyers for assistance in electron microscopy at the Penn State College of Medicine and B. Heymann for advice on data analysis. This work was supported by the Intramural Research Program of NIAMS and the IATAP Program (A.C.S.), and funding from NIH grant CA100322, the Pennsylvania Department of Health and the Penn State Cancer Institute (R.C.C.). NR 43 TC 67 Z9 67 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 5 PY 2009 VL 457 IS 7230 BP 694 EP U3 DI 10.1038/nature07724 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 403EA UT WOS:000263064700034 PM 19194444 ER PT J AU Hamdan, FF Gauthier, J Spiegelman, D Noreau, A Yang, Y Pellerin, S Dobrzeniecka, S Cote, M Perreault-Linck, E Carmant, L D'Anjou, G Fombonne, E Addington, AM Rapoport, JL Delisi, LE Krebs, MO Mouaffak, F Joober, R Mottron, L Drapeau, P Marineau, C Lafreniere, RG Lacaille, JC Rouleau, GA Michaud, JL AF Hamdan, Fadi F. Gauthier, Julie Spiegelman, Dan Noreau, Anne Yang, Yan Pellerin, Stephanie Dobrzeniecka, Sylvia Cote, Melanie Perreault-Linck, Elizabeth Carmant, Lionel D'Anjou, Guy Fombonne, Eric Addington, Anjene M. Rapoport, Judith L. Delisi, Lynn E. Krebs, Marie-Odile Mouaffak, Faycal Joober, Ridha Mottron, Laurent Drapeau, Pierre Marineau, Claude Lafreniere, Ronald G. Lacaille, Jean Claude Rouleau, Guy A. Michaud, Jacques L. CA Synapse Dis Grp TI Mutations in SYNGAP1 in Autosomal nonsyndromic Mental Retardation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SYNAPTIC PLASTICITY; NMDA RECEPTORS; PROTEIN; TRAFFICKING; COMPLEXES; GENETICS; DEFECT AB Although autosomal forms of nonsyndromic mental retardation account for the majority of cases of mental retardation, the genes that are involved remain largely unknown. We sequenced the autosomal gene SYNGAP1, which encodes a ras GTPAse-activating protein that is critical for cognition and synapse function, in 94 patients with nonsyndromic mental retardation. We identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three of these patients. In contrast, we observed no de novo or truncating mutations in SYNGAP1 in samples from 142 subjects with autism spectrum disorders, 143 subjects with schizophrenia, and 190 control subjects. These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation. C1 [Hamdan, Fadi F.; Pellerin, Stephanie; Carmant, Lionel; D'Anjou, Guy; Michaud, Jacques L.] CHU St Justine, Res Ctr, Montreal, PQ H3T 1C5, Canada. [Gauthier, Julie; Spiegelman, Dan; Noreau, Anne; Yang, Yan; Dobrzeniecka, Sylvia; Cote, Melanie; Marineau, Claude; Lafreniere, Ronald G.; Rouleau, Guy A.] Univ Montreal, Ctr Excellence Neurom, Ctr Hosp, Res Ctr, Montreal, PQ, Canada. [Gauthier, Julie; Spiegelman, Dan; Noreau, Anne; Yang, Yan; Dobrzeniecka, Sylvia; Cote, Melanie; Marineau, Claude; Lafreniere, Ronald G.; Rouleau, Guy A.] Univ Montreal, Ctr Excellence Neurom, Dept Med, Montreal, PQ, Canada. [Drapeau, Pierre] Univ Montreal, Ctr Excellence Neurom, Grp Rech Syst Nerveux Cent, Dept Pathol & Cell Biol, Montreal, PQ, Canada. [Lacaille, Jean Claude] Univ Montreal, Ctr Excellence Neurom, Dept Physiol, Montreal, PQ, Canada. [Perreault-Linck, Elizabeth; Mottron, Laurent] Univ Montreal, Ctr Excellence Neurom, Ctr Rech Fernand Seguin, Hop Riviere Prairies, Montreal, PQ, Canada. [Fombonne, Eric] Montreal Childrens Hosp, Dept Psychiat, Montreal, PQ H3H 1P3, Canada. [Joober, Ridha] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. [Addington, Anjene M.; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Delisi, Lynn E.] Nathan S Kline Inst Psychiat Res, Ctr Adv Brain Imaging, Orangeburg, NY 10962 USA. [Krebs, Marie-Odile; Mouaffak, Faycal] Univ Paris 05, INSERM, Unite 894, Paris, France. [Krebs, Marie-Odile; Mouaffak, Faycal] Hop St Anne, F-75674 Paris, France. RP Michaud, JL (reprint author), CHU St Justine, Res Ctr, 3175 Cote St Catherine, Montreal, PQ H3T 1C5, Canada. EM michaud@recherche-ste-justine.qc.ca FU Canadian Institute of Health Research; Fonds de la Recherche en Sant; Genome Canada; Genome Quebec; Universite de Montreal; Clinical Investigatorship Award; CIHR (Institute of Genetics); Fondation Pierre Deniker FX We thank the patients and their parents for participating in this study; the members of the Synapse to Disease Group, including Edouard Henrion and Ousmane Diallo of the bioinformatics division and Sandra Laurent, Frederic Kuku, Joannie Duguay, Laurie Destroismaisons, Karine Lachapelle, Philippe Jolivet, Pascale Thibodeau, and Annie Raymond of the genetic screening division; Annie Levert and Judith St.-Onge for performing DNA extraction and paternity testing, respectively; and Pierre Lepage, Sebastien Brunet, and Hao Fan Yam of McGill University and Genome Quebec Innovation Centre sequencing group and Louis Letourneau and Louis Dumond Joseph of the bioinformatics group. NR 24 TC 116 Z9 123 U1 4 U2 14 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 5 PY 2009 VL 360 IS 6 BP 599 EP 605 DI 10.1056/NEJMoa0805392 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 402QS UT WOS:000263028800006 PM 19196676 ER PT J AU Nelson, LM AF Nelson, Lawrence M. TI Primary Ovarian Insufficiency SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VITRO FERTILIZATION PREGNANCIES; HORMONE REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; NATURAL MENOPAUSE; VENOUS THROMBOEMBOLISM; OOCYTE DONATION; YOUNG-WOMEN; FAILURE; AGE AB A 30- year- old woman presents with a history of no menses since she stopped taking oral contraceptives 6 months ago in order to conceive. She had undergone puberty that was normal in both timing and development, with menarche at 12 years of age. At 18 years of age, she started taking oral contraceptives for irregular menses. She reports stress at work. Her weight is 59 kg, and her height 1.66 m; her body- mass index ( the weight in kilograms divided by the square of the height in meters) is 21.3. There is no galactorrhea, hirsutism, or acne. The pelvic examination is normal, a pregnancy test is negative, the prolactin level is normal, and the follicle- stimulating hormone ( FSH) level is in the menopausal range. How should she be evaluated and treated? C1 [Nelson, Lawrence M.] NICHHD, Integrat Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, NIH,CRC, Bethesda, MD 20892 USA. RP Nelson, LM (reprint author), NICHHD, Integrat Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, NIH,CRC, Rm 1-3330,10 Center Dr,MSC-1103, Bethesda, MD 20892 USA. EM lawrence_nelson@nih.gov FU Intramural NIH HHS [Z01 HD000633-17] NR 59 TC 299 Z9 315 U1 2 U2 24 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 5 PY 2009 VL 360 IS 6 BP 606 EP 614 DI 10.1056/NEJMcp0808697 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 402QS UT WOS:000263028800007 PM 19196677 ER PT J AU Zhou, A Rayabarapu, D Hanson, PR AF Zhou, Aihua Rayabarapu, Dinesh Hanson, Paul R. TI "Click, Click, Cyclize": A DOS Approach to Sultams Utilizing Vinyl Sulfonamide Linchpins SO ORGANIC LETTERS LA English DT Article ID DIVERSITY-ORIENTED SYNTHESIS; DIELS-ALDER REACTIONS; SKELETAL DIVERSITY; DRUG DISCOVERY; SOLID SUPPORT; INHIBITORS; SCAFFOLDS; STRATEGY; MICHAEL; MOLECULES AB A diversity-oriented synthesis (DOS) strategy termed "Click, Click, Cyclize" is reported. This approach relies on functional group (FG) pairing between a vinyl sulfonamide and an array of functional groups to synthesize skeletally diverse sultams. Several FG pairing pathways on central tertiary vinyl sulfonamide linchpins have been developed including intramolecular Heck, aza-Michael, ring-closing enyne metathesis, Pauson-Khand, and chemoselective oxidation/Baylis-Hillman reactions. C1 [Hanson, Paul R.] Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. Univ Kansas KU CMLD, NIH Ctr Chem Methodol & Lib Dev, Lawrence, KS 66047 USA. RP Hanson, PR (reprint author), Univ Kansas, Dept Chem, 1251 Wescoe Hall Dr, Lawrence, KS 66045 USA. EM phanson@ku.edu FU NIH [P50 GM069663]; NIGMS Pilot-Scale Libraries Program [NIH P41 GM076302] FX This investigation was generously supported by funds provided by the NIH Center for Chemical Methodologies and Library Development at the University of Kansas (P50 GM069663) and NIGMS Pilot-Scale Libraries Program (NIH P41 GM076302). The authors also thank Daiso Co., Ltd., Fine Chemical Department for donation of trityl-protected glycidol. NR 39 TC 53 Z9 53 U1 2 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD FEB 5 PY 2009 VL 11 IS 3 BP 531 EP 534 DI 10.1021/ol802467f PG 4 WC Chemistry, Organic SC Chemistry GA 401BQ UT WOS:000262913500009 PM 19115841 ER PT J AU Keck, GE Poudel, YB Welch, DS Kraft, MB Truong, AP Stephens, JC Kedei, N Lewin, NE Blumberg, PM AF Keck, Gary E. Poudel, Yam B. Welch, Dennie S. Kraft, Matthew B. Truong, Anh P. Stephens, Jeffrey C. Kedei, Noemi Lewin, Nancy E. Blumberg, Peter M. TI Substitution on the A-Ring Confers to Bryopyran Analogues the Unique Biological Activity Characteristic of Bryostatins and Distinct From That of the Phorbol Esters SO ORGANIC LETTERS LA English DT Article ID MYELOID-LEUKEMIA CELLS; PROTEIN-KINASE-C; PYRAN ANNULATION; ALZHEIMERS-DISEASE; PHASE-I; PACLITAXEL; LYMPHOMA; MEMORY; VIVO AB A close structural analogue of bryostatin 1, which differs from bryostatin 1 only by the absence of the C(30) carbomethoxy group (on the C(13) enoate of the B-ring), has been prepared by total synthesis. Biological assays reveal a crucial role for substitution in the bryostatin 1 A-ring in conferring those responses which are characteristic of bryostatin 1 and distinct from those observed with PMA. C1 [Keck, Gary E.; Poudel, Yam B.; Kraft, Matthew B.; Stephens, Jeffrey C.] Univ Utah, Dept Biochem, Salt Lake City, UT 84112 USA. [Kedei, Noemi; Lewin, Nancy E.; Blumberg, Peter M.] NCI, LCBG, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Keck, GE (reprint author), Univ Utah, Dept Biochem, 315 South 1400 East,RM 2020, Salt Lake City, UT 84112 USA. EM keck@chemistry.utah.edu RI Poudel, Yam/B-7160-2011 FU NIH [GM28961]; Intramural Research Program; CCR; NCI FX Financial support was provided by the NIH through grant GM28961 and through the Intramural Research Program, CCR, NCI, NIH. NR 28 TC 43 Z9 43 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD FEB 5 PY 2009 VL 11 IS 3 BP 593 EP 596 DI 10.1021/ol8027253 PG 4 WC Chemistry, Organic SC Chemistry GA 401BQ UT WOS:000262913500025 PM 19113896 ER PT J AU Hagan, JP O'Neill, BL Stewart, CL Kozlov, SV Croce, CM AF Hagan, John P. O'Neill, Brittany L. Stewart, Colin L. Kozlov, Serguei V. Croce, Carlo M. TI At Least Ten Genes Define the Imprinted Dlk1-Dio3 Cluster on Mouse Chromosome 12qF1 SO PLOS ONE LA English DT Article AB Background: Genomic imprinting is an exception to Mendelian genetics in that imprinted genes are expressed monoallelically, dependent on parental origin. In mammals, imprinted genes are critical in numerous developmental and physiological processes. Aberrant imprinted gene expression is implicated in several diseases including Prader-Willi/Angelman syndromes and cancer. Methodology/Principal Findings: To identify novel imprinted genes, transcription profiling was performed on two uniparentally derived cell lines, androgenetic and parthenogenetic primary mouse embryonic fibroblasts. A maternally expressed transcript termed Imprinted (R) under bar NA near (M) under bar eg3/ Gtl2 (Irm) was identified and its expression studied by Northern blotting and whole mounts in situ hybridization. The imprinted region that contains Irm has a parent of origin effect in three mammalian species, including the sheep callipyge locus. In mice and humans, both maternal and paternal uniparental disomies (UPD) cause embryonic growth and musculoskeletal abnormalities, indicating that both alleles likely express essential genes. To catalog all imprinted genes in this chromosomal region, twenty-five mouse mRNAs in a 1.96Mb span were investigated for allele specific expression. Conclusions/Significance: Ten imprinted genes were elucidated. The imprinting of three paternally expressed protein coding genes (Dlk1, Peg11, and Dio3) was confirmed. Seven noncoding RNAs (Meg3/Gtl2, Anti-Peg11, Meg8, Irm/"Rian", AK050713, AK053394, and Meg9/Mirg) are characterized by exclusive maternal expression. Intriguingly, the majority of these noncoding RNA genes contain microRNAs and/or snoRNAs within their introns, as do their human orthologs. Of the 52 identified microRNAs that map to this region, six are predicted to regulate negatively Dlk1, suggesting an additional mechanism for interactions between allelic gene products. Since several previous studies relied heavily on in silico analysis and RT-PCR, our findings from Northerns and cDNA cloning clarify the genomic organization of this region. Our results expand the number of maternally expressed noncoding RNAs whose loss may be responsible for the phenotypes associated with mouse pUPD12 and human pUPD14 syndromes. C1 [Hagan, John P.; O'Neill, Brittany L.; Croce, Carlo M.] Ohio State Univ, Med Ctr, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Stewart, Colin L.] NCI, NIH, Ctr Canc Res, Canc & Dev Biol Lab, Frederick, MD USA. [Kozlov, Serguei V.] NCI, NIH, SAIC Frederick Inc, Ctr Advanced Preclin Res Mouse Canc Genet Program, Frederick, MD USA. RP Hagan, JP (reprint author), Ohio State Univ, Med Ctr, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. EM microrna@gmail.com OI Hagan, John/0000-0003-0295-4898 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; and with Federal funds from the National Cancer 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 86 TC 69 Z9 78 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 5 PY 2009 VL 4 IS 2 AR e4352 DI 10.1371/journal.pone.0004352 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437JL UT WOS:000265483600004 PM 19194500 ER PT J AU Tondella, ML Carlone, GM Messonnier, N Quinn, CR Meade, BD Burns, DL Cherry, JD Guiso, N Hewlett, EL Edwards, KM Xing, D Giammanco, A von Konig, CHW Han, L Hueston, L Robbins, JB Powell, M Mink, CM Poolman, JT Hildreth, SW Lynn, F Morris, A AF Tondella, M. L. Carlone, G. M. Messonnier, N. Quinn, C. R. Meade, B. D. Burns, D. L. Cherry, J. D. Guiso, N. Hewlett, E. L. Edwards, K. M. Xing, D. Giammanco, A. von Koenig, C. H. Wirsing Han, L. Hueston, L. Robbins, J. B. Powell, M. Mink, C. M. Poolman, J. T. Hildreth, S. W. Lynn, F. Morris, A. TI International Bordetella pertussis assay standardization and harmonization meeting report. Centers for Disease Control and Prevention, Atlanta, Georgia, United States, 19-20 July 2007 SO VACCINE LA English DT Article DE Bordetella pertussis; Whooping cough; Standardization of serologic assays; ELISA; Pertussis vaccines ID ADENYLATE-CYCLASE TOXIN; LINKED IMMUNOSORBENT ASSAYS; TRACHEAL EPITHELIAL-CELLS; HOUSEHOLD EXPOSURE; FILAMENTOUS HEMAGGLUTININ; UNVACCINATED CHILDREN; LABORATORY DIAGNOSIS; MEDIATED-IMMUNITY; VACCINE EFFICACY; MURINE MODEL AB An international meeting on Bordetella pertussis assay standardization and harmonization was held at the Centers for Disease Control and Prevention (CDC), Atlanta, GA, 19-20 July 2007. The goal of the meeting was to harmonize the immunoassays used for pertussis diagnostics and vaccine evaluation, as agreed upon by academic and government researchers, regulatory authorities, vaccine manufacturers, and the World Health Organization (WHO). The primary objectives were (1) to provide epidemiologic, laboratory, and statistical background for support of global harmonization; (2) to overview the current status of global epidemiology, pathogenesis and immunology of pertussis; (3) to develop a consensus opinion on existing gaps in understanding standardization of pertussis assays used for serodiagnosis and vaccine evaluation; and (4) to search for a multicenter process for addressing these priority gaps. Presentations and discussions by content experts addressed these objectives. A prioritized list of action items to improve standardization and harmonization of pertussis assays was identified during a group discussion at the end of the meeting. The major items included: (I) to identify a group that will organize, prepare, maintain, and distribute proficiency panels and key reagents such as reference and control sera; (2) to encourage the development and identification of one or more reference laboratories that can serve as an anchor and resource for other laboratories; (3) to define a performance-based assay method that can serve as a reference point for evaluating laboratory differences; (4) to develop guidance on quality of other reagents, e.g., pertussis toxin and other antigens, and methods to demonstrate their Suitability; (5) to establish an international working group to harmonize the criteria to evaluate the results obtained on reference and proficiency panel sera; (6) to create an inventory to determine the amount of appropriate and well-characterized sera that are available globally to be used as bridging reagents for vaccine licensure: and (7) to seek specific guidance from regulatory authorities regarding the expectations and requirements for the licensure of new multicomponent pertussis vaccines. C1 [Tondella, M. L.; Carlone, G. M.; Messonnier, N.; Quinn, C. R.] Ctr Dis Control & Prevent, CDC, Atlanta, GA 30333 USA. [Burns, D. L.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Cherry, J. D.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Guiso, N.] Inst Pasteur, F-75724 Paris, France. [Hewlett, E. L.] Univ Virginia, Sch Med, Charlottesville, VA 22902 USA. [Edwards, K. M.] Vanderbilt Univ Sch Med, Nashville, TN 37232 USA. [Xing, D.] Natl Inst Biol Stand & Controls, Blanche Lane, Potters Bar EN6 3QG, Herts, England. [Giammanco, A.] Univ Palermo, Dept Hyg & Microbiol, I-90127 Palermo, Italy. [von Koenig, C. H. Wirsing] Stadt Krankenanstalten, Inst Hyg & Lab Med, D-47805 Krefeld, Germany. [Han, L.] Dept Publ Hlth, Bur Lab Sci, Boston, MA 02130 USA. [Hueston, L.] Univ Sydney, Westmead Hosp, Ctr Infect Dis & Microbiol, ICPMR, Westmead, NSW 2145, Australia. [Robbins, J. B.] NICHHD, NIH, Bethesda, MD 20892 USA. [Powell, M.] UK Med & Healthcare Prod Regulatory Agcy MHRA, London SW8 5NQ, England. [Mink, C. M.] Harbor UCLA Med Ctr, David Geffen Sch Med, Torrance, CA 90509 USA. [Poolman, J. T.] GlaxoSmithKline Biol, Bacterial Vaccine R&D, B-1330 Rixensart, Belgium. [Hildreth, S. W.] Sanofi Pasteur, Swiftwater, PA 18370 USA. [Lynn, F.] NIAID, NIH, Bethesda, MD 20892 USA. [Morris, A.] Dalhousie Univ, Canadian Ctr Vaccinol, IWK Hlth Ctr, Halifax, NS B3K 6R8, Canada. RP Tondella, ML (reprint author), Ctr Dis Control & Prevent, CDC, 1600 Clifton Rd NE,MS-D11, Atlanta, GA 30333 USA. EM mtondella@cdc.gov NR 93 TC 25 Z9 26 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 5 PY 2009 VL 27 IS 6 BP 803 EP 814 DI 10.1016/j.vaccine.2008.11.072 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 408FV UT WOS:000263421800001 PM 19071179 ER PT J AU Zhang, MY Wang, YP Mankowski, MK Ptak, RG Dimitrov, DS AF Zhang, Mei-Yun Wang, Yanping Mankowski, Marie K. Ptak, Roger G. Dimitrov, Dimiter S. TI Cross-reactive HIV-1-neutralizing activity of serum IgG from a rabbit immunized with gp41 fused to IgG1 Fc: Possible role of the prolonged half-life of the immunogen SO VACCINE LA English DT Article DE HIV/AIDS; Vaccines; Gp41 ID HUMAN MONOCLONAL-ANTIBODY; NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN; HIV-1; VIRUS; RECEPTOR; LIBRARY; CELLS AB The elicitation of broadly cross-reactive HIV-1 neutralizing antibodies in humans remains a major challenge in developing a viable AIDS vaccine. We hypothesized that prolonged exposure to candidate vaccine immunogens Could enhance the elicitation of such antibodies. In all attempt to develop HIV-1 vaccine immunogens with prolonged half-lives and increased stability, we constructed a fusion protein, gp41Fc, in was fused to a human IgG(1) Fc.Gp41Fc is stable in solution, retains its antigenic truncated HIV-1 gp41(89.6) genic structure and is highly immunogenic in rabbits. The serum titers reached 1: 102,400 for the gp41Fc and 1:5,120 for gp140(89.6). Rabbit IgG neutralized diverse HIV-1 isolates and HIV-2, and the neutralization activity was attributed to gp41-specific IgG. The concentration of the gp41Fc in the serum correlated with the neutralization activity of rabbit IgG which recognized mostly con formation-independent epitopes oil gp41 and predominantly bound to peptides derived from the gp41 immunodominant loop region. These results Suggest that the prolonged half-life of gp41Fc in the serum may enhance the generation of cross-reactive neutralizing antibodies. Further research is needed to confirm and extend these results which may have implications for the development of vaccine immunogens with enhanced capability to elicit cross-reactive HIV-1-neutralizing antibodies. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Zhang, Mei-Yun; Wang, Yanping; Dimitrov, Dimiter S.] NCI Frederick, Ctr Canc Res, Nanobiol Program, CCR,NIH, Frederick, MD 21702 USA. [Zhang, Mei-Yun; Wang, Yanping] NCI Frederick, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Mankowski, Marie K.; Ptak, Roger G.] So Res Inst, Frederick, MD 21701 USA. RP Zhang, MY (reprint author), NCI Frederick, Ctr Canc Res, Nanobiol Program, CCR,NIH, Bldg 469,Rm 131,POB B,Miller Dr, Frederick, MD 21702 USA. EM meiyunZhango@yahoo.com; dimitrov@nciferf.gov FU NIH; National Cancer Institute [N01-CO-12400]; Center for Cancer Research; Gates Foundation; Southern Research Institute FX We thank Dr. Shibo Jiang for providing mouse mAb NC-1 and Dr. Christopher Broder for mouse mAbs T3 and D61. We also thank Drs. Shibo Jiang and Xiaodong Xiao for helpful discussions, Vidita Choudhry for help with pseudovirus assay and John Owens for help with manuscript preparation. We thank one of the reviewers for Suggesting to explore gp140Fc fusion proteins as vaccine irnmunogens. This research was supported by the NIH Intramural AIDS Targeted Antiviral Program (IATAP), the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and the Gates Foundation to DSD, and by internal funds from Southern Research Institute. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 16 TC 21 Z9 24 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 5 PY 2009 VL 27 IS 6 BP 857 EP 863 DI 10.1016/j.vaccine.2008.11.083 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 408FV UT WOS:000263421800008 PM 19084043 ER PT J AU Chattopadhyay, R Iacob, R Sen, S Majumder, R Tomer, KB Lentz, BR AF Chattopadhyay, Rima Iacob, Roxana Sen, Shalmali Majumder, Rinku Tomer, Kenneth B. Lentz, Barry R. TI Functional and Structural Characterization of Factor Xa Dimer in Solution SO BIOPHYSICAL JOURNAL LA English DT Article ID BLOOD-COAGULATION FACTOR; FACTOR VA BINDING; PROTHROMBINASE COMPLEX; MEMBRANE-BINDING; PROCOAGULANT LIPIDS; CIRCULAR-DICHROISM; BOVINE PROTHROMBIN; CRYSTAL-STRUCTURE; GABA(B) RECEPTOR; PHOSPHATIDYLSERINE AB Previous studies showed that binding of water-soluble phosphatidylserine (C6PS) to bovine factor Xa (FXa) leads to Ca(2+)-dependent dimerization in solution. We report the effects of Ca(2+), C6PS, and dimerization on the activity and structure of human and bovine FXa. Both human and bovine dimers are 10(6)-to 10(7)-fold less active toward prothrombin than the monomer, with the decrease being attributed mainly to a substantial decrease in k(cat). Dimerization appears not to block the active site, since amidolytic activity toward a synthetic substrate is largely unaffected. Circular dichroism reveals a substantial change in tertiary or quaternary structure with a concomitant decrease in a-helix upon dimerization. Mass spectrometry identifies a lysine (K(270)) in the catalytic domain that appears to be buried at the dinner interface and is part of a synthetic peptide sequence reported to interfere with factor Va (FVa) binding. C6PS binding exposes K(351) (part of a reported FVa binding region), K(242) (adjacent to the catalytic triad), and K(420) (part of a substrate exosite). We interpret our results to mean that C6PS-induced dimerization produces substantial conformational changes or domain rearrangements such that structural data on PS-activated FXa is required to understand the structure of the FXa dinner or the FXa-FVa complex. C1 [Chattopadhyay, Rima; Sen, Shalmali; Majumder, Rinku; Lentz, Barry R.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27515 USA. [Chattopadhyay, Rima; Sen, Shalmali; Majumder, Rinku; Lentz, Barry R.] Univ N Carolina, Program Mol & Cellular Biophys, Chapel Hill, NC USA. [Iacob, Roxana; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Lentz, BR (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27515 USA. EM uncbrl@med.unc.edu RI Tomer, Kenneth/E-8018-2013; OI Lentz, Barry/0000-0001-9685-8690 FU National Institutes of Health., National Heart, Lung, and Blood Institute [HL 072827] FX This work was supported by a grant from the National Institutes of Health., National Heart, Lung, and Blood Institute (HL 072827 to BRL) and in part by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences. NR 58 TC 8 Z9 8 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB 4 PY 2009 VL 96 IS 3 BP 974 EP 986 DI 10.1016/j.bpj.2008.10.013 PG 13 WC Biophysics SC Biophysics GA 450CB UT WOS:000266377500019 PM 19186135 ER PT J AU Derrien, T Theze, J Vaysse, A Andre, C Ostrander, EA Galibert, F Hitte, C AF Derrien, Thomas Theze, Julien Vaysse, Amaury Andre, Catherine Ostrander, Elaine A. Galibert, Francis Hitte, Christophe TI Revisiting the missing protein-coding gene catalog of the domestic dog SO BMC GENOMICS LA English DT Article ID HUMAN GENOME; CHROMOSOME EVOLUTION; MAMMALIAN EVOLUTION; WEB SERVER; SEQUENCE; ANNOTATION; MOUSE; PSEUDOGENES; EXPRESSION; PREDICTION AB Background: Among mammals for which there is a high sequence coverage, the whole genome assembly of the dog is unique in that it predicts a low number of protein-coding genes, similar to 19,000, compared to the over 20,000 reported for other mammalian species. Of particular interest are the more than 400 of genes annotated in primates and rodent genomes, but missing in dog. Results: Using over 14,000 orthologous genes between human, chimpanzee, mouse rat and dog, we built multiple pairwise synteny maps to infer short orthologous intervals that were targeted for characterizing the canine missing genes. Based on gene prediction and a functionality test using the ratio of replacement to silent nucleotide substitution rates (d(N)/d(S)), we provide compelling structural and functional evidence for the identification of 232 new protein-coding genes in the canine genome and 69 gene losses, characterized as undetected gene or pseudogenes. Gene loss phyletic pattern analysis using ten species from chicken to human allowed us to characterize 28 canine-specific gene losses that have functional orthologs continuously from chicken or marsupials through human, and 10 genes that arose specifically in the evolutionary lineage leading to rodent and primates. Conclusion: This study demonstrates the central role of comparative genomics for refining gene catalogs and exploring the evolutionary history of gene repertoires, particularly as applied for the characterization of species-specific gene gains and losses. C1 [Derrien, Thomas; Theze, Julien; Vaysse, Amaury; Andre, Catherine; Galibert, Francis; Hitte, Christophe] Univ Rennes 1, Inst Genet & Dev, CNRS, UMR6061, F-35043 Rennes, France. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Derrien, Thomas] CRG, Bioinformat Program, Barcelona 08003, Spain. RP Hitte, C (reprint author), Univ Rennes 1, Inst Genet & Dev, CNRS, UMR6061, 2 Av Pr Leon Bernard, F-35043 Rennes, France. EM thomas.derrien@crg.es; theze.julien@gmail.com; amaury.vaysse@univ-rennes1.fr; catherine.andre@univ-rennes1.fr; eostrand@mail.nih.gov; francis.galibert@univrennes1.fr; hitte@univ-rennes1.fr OI Ostrander, Elaine/0000-0001-6075-9738 FU Centre National de la Recherche Scientifique; Conseil Regional de Bretagne; Intramural Program of the National Institutes of Health FX We are grateful to Roderic Guigo and to the reviewers for providing useful suggestions and helpful comments. We thank the OUEST-genopole bioinformatics plate-form for technical help and assistance. We acknowledge for support the Centre National de la Recherche Scientifique (JT, AV, CA, FG and CH) and the Conseil Regional de Bretagne for supporting TD with a fellowship and the Intramural Program of the National Institutes of Health (EAO). NR 60 TC 12 Z9 13 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 4 PY 2009 VL 10 AR 62 DI 10.1186/1471-2164-10-62 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 418BT UT WOS:000264122900002 PM 19193219 ER PT J AU Shah, YM Matsubara, T Ito, S Yim, SH Gonzalez, FJ AF Shah, Yatrik M. Matsubara, Tsutomu Ito, Shinji Yim, Sun-Hee Gonzalez, Frank J. TI Intestinal Hypoxia-inducible Transcription Factors Are Essential for Iron Absorption following Iron Deficiency SO CELL METABOLISM LA English DT Article ID METAL-ION TRANSPORTER; REGULATES HEPCIDIN EXPRESSION; DUODENAL CYTOCHROME-B; VHL TUMOR-SUPPRESSOR; DIETARY IRON; HEREDITARY HEMOCHROMATOSIS; ANTIMICROBIAL PEPTIDE; FERRIC REDUCTASE; MICE LACKING; HIF-ALPHA AB Iron deficiency and iron overload are among the most prevalent nutritional disorders worldwide. Duodenal cytochrome b (DcytB) and divalent metal transporter 1 (DMT1) are regulators of iron absorption. Their expression is increased during high systemic requirements for iron, but the molecular mechanisms that regulate DcytB and DMT1 expression are undefined. Hypoxia-inducible factor (HIF) signaling was induced in the intestine following acute iron deficiency in the duodenum, resulting in activation of DcytB and DMT1 expression and an increase in iron uptake. DcytB and DMT1 were demonstrated as direct HIF-2 alpha target genes. Genetic disruption of HIF signaling in the intestine abolished the adaptive induction of iron absorption following iron deficiency, resulting in low systemic iron and hematological defects. These results demonstrate that HIF signaling in the intestine is a critical regulator of systemic iron homeostasis. C1 [Shah, Yatrik M.; Matsubara, Tsutomu; Ito, Shinji; Yim, Sun-Hee; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU NCI Intramural Research Program; American Cancer Society [PF-06-014-01-CNE] FX We thank Volker H. Haase for providing the VhlF/F mice, and Richard Bruick and Oliver Hankinson for providing plasmids. We also appreciate technical assistance from John Buckley. This study was supported by the NCI Intramural Research Program, and Y.M.S was supported by a postdoctoral fellowship from the American Cancer Society PF-06-014-01-CNE. NR 65 TC 167 Z9 174 U1 2 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD FEB 4 PY 2009 VL 9 IS 2 BP 152 EP 164 DI 10.1016/j.cmet.2008.12.012 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 406BG UT WOS:000263269400007 PM 19147412 ER PT J AU Mazelova, J Astuto-Gribble, L Inoue, H Tam, BM Schonteich, E Prekeris, R Moritz, OL Randazzo, PA Deretic, D AF Mazelova, Jana Astuto-Gribble, Lisa Inoue, Hiroki Tam, Beatrice M. Schonteich, Eric Prekeris, Rytis Moritz, Orson L. Randazzo, Paul A. Deretic, Dusanka TI Ciliary targeting motif VxPx directs assembly of a trafficking module through Arf4 SO EMBO JOURNAL LA English DT Article DE Arfs; cilium; Rabs; rhodopsin; trafficking ID GTPASE-ACTIVATING PROTEIN; ADP-RIBOSYLATION FACTORS; POST-GOLGI TRAFFICKING; PRIMARY CILIUM; RAB11-INTERACTING PROTEINS; RETINAL PHOTORECEPTORS; RECYCLING ENDOSOMES; MOLECULAR CHARACTERIZATION; MEMBRANE TRAFFICKING; RETINITIS-PIGMENTOSA AB Dysfunctions of primary cilia and cilia-derived sensory organelles underlie a multitude of human disorders, including retinal degeneration, yet membrane targeting to the cilium remains poorly understood. Here, we show that the newly identified ciliary targeting VxPx motif present in rhodopsin binds the small GTPase Arf4 and regulates its association with the trans-Golgi network (TGN), which is the site of assembly and function of a ciliary targeting complex. This complex is comprised of two small GTPases, Arf4 and Rab11, the Rab11/Arf effector FIP3, and the Arf GTPase-activating protein ASAP1. ASAP1 mediates GTP hydrolysis on Arf4 and functions as an Arf4 effector that regulates budding of post-TGN carriers, along with FIP3 and Rab11. The Arf4 mutant I46D, impaired in ASAP1-mediated GTP hydrolysis, causes aberrant rhodopsin trafficking and cytoskeletal and morphological defects resulting in retinal degeneration in transgenic animals. As the VxPx motif is present in other ciliary membrane proteins, the Arf4-based targeting complex is most likely a part of conserved machinery involved in the selection and packaging of the cargo destined for delivery to the cilium. C1 [Deretic, Dusanka] Univ New Mexico, Sch Med, Dept Surg, Div Ophthalmol, Albuquerque, NM 87131 USA. [Inoue, Hiroki; Randazzo, Paul A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Tam, Beatrice M.; Moritz, Orson L.] Univ British Columbia, Dept Ophthalmol & Visual Sci, Vancouver, BC V5Z 1M9, Canada. [Schonteich, Eric; Prekeris, Rytis] Univ Colorado, Hlth Sci Ctr, Dept Cell & Dev Biol, Aurora, CO USA. [Deretic, Dusanka] Univ New Mexico, Dept Cell Biol & Physiol, Albuquerque, NM 87131 USA. RP Deretic, D (reprint author), Univ New Mexico, Sch Med, Dept Surg, Div Ophthalmol, Basic Med Sci Bldg,Room 377,915 Camino Salud, Albuquerque, NM 87131 USA. EM dderetic@salud.unm.edu FU NIH [EY-12421, DK-064380]; NCI, DHHS Intramural Program to PAR; CIHR; MSFHR; FFB-Canada; NCRR; NSF; NCI; UNM Cancer Center FX We thank Nancy Ransom, Andrew Williams and Cassandra Stiller-Moldovan for their help with the experiments. This study was supported by the NIH grant EY-12421 to DD, by the NCI, DHHS Intramural Program to PAR, by the NIH grant DK-064380 to RP, and by the grants from CIHR, MSFHR and FFB-Canada to OLM, who is a Michael Smith and a WK Stell Scholar. UNM Fluorescence Microscopy Facility is supported by NCRR, NSF, NCI and the UNM Cancer Center. NR 68 TC 123 Z9 123 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 4 PY 2009 VL 28 IS 3 BP 183 EP 192 DI 10.1038/emboj.2008.267 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403II UT WOS:000263075900006 PM 19153612 ER PT J AU de Gonzalez, A Berg, CD Visvanathan, K Robson, M AF Berrington de Gonzalez, Amy Berg, Christine D. Visvanathan, Kala Robson, Mark TI Estimated Risk of Radiation-Induced Breast Cancer From Mammographic Screening for Young BRCA Mutation Carriers SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID IONIZING-RADIATION; X-RAYS; MORTALITY; PROGRAM; WOMEN; MRI; UK AB BRCA mutation carriers are recommended to start mammographic screening for breast cancer as early as age 25-30 years. We used an excess relative risk model (based on a pooled analysis of three cohorts with 7600 subjects who received radiation exposure) to estimate the lifetime risk of radiation-induced breast cancer from five annual mammographic screenings in young (< 40 years) BRCA mutation carriers. We then estimated the reduction in breast cancer mortality required to outweigh the radiation risk. Breast cancer rates for mutation carriers were based on a pooled analysis of 22 pedigree studies with 8139 subjects. For BRCA1 mutation carriers, the estimated lifetime risk of radiation-induced breast cancer mortality per 10 000 women resulting from annual mammography was 26 (95% confidence interval [CI] = 14 to 49) for screening at age 25-29 years, 20 (95% CI = 11 to 39) for screening at age 30-34 years, and 13 (95% CI = 7 to 23) for screening at age 35-39 years. To outweigh these risks, screening would have to reduce breast cancer mortality by 51% (95% CI = 27% to 96%) at age 25-29 years, by 12% (95% CI = 6% to 23%) at age 30-34 years, and by 4% (95% CI = 2% to 7%) at age 35-39 years; estimates were similar for BRCA2 mutation carriers. If we assume that the mortality reduction from mammography is 15%-25% or less for young women, these results suggest that there would be no net benefit from annual mammographic screening of BRCA mutation carriers at age 25-29 years; the net benefit would be zero or small at age 30-34 years, but there should be some net benefit at age 35 or older. These results depend on a number of assumptions due to the absence of empiric data. The impact of varying these assumptions was therefore examined. C1 [Berrington de Gonzalez, Amy; Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Berg, Christine D.] NCI, Early Detect Res Grp, Canc Prevent Div, Rockville, MD USA. [Robson, Mark] Mem Sloan Kettering Canc Ctr, Clin Genet & Breast Canc Med Serv, New York, NY 10021 USA. RP de Gonzalez, A (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM aberring@jhsph.edu OI Robson, Mark/0000-0002-3109-1692 NR 29 TC 39 Z9 40 U1 0 U2 4 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-. Natl. Cancer Inst. PD FEB 4 PY 2009 VL 101 IS 3 BP 205 EP 209 DI 10.1093/jnci/djn440 PG 5 WC Oncology SC Oncology GA 404PI UT WOS:000263165100012 ER PT J AU Adermark, L Lovinger, DM AF Adermark, Louise Lovinger, David M. TI Frequency-Dependent Inversion of Net Striatal Output by Endocannabinoid-Dependent Plasticity at Different Synaptic Inputs SO JOURNAL OF NEUROSCIENCE LA English DT Article DE anandamide; basal ganglia; LTD; synaptic plasticity; GABA; glutamate ID LONG-TERM DEPRESSION; DORSAL STRIATUM; BASAL GANGLIA; SYNAPSES; INHIBITION; RELEASE; CANNABINOIDS; POTENTIATION; ACTIVATION; CHANNELS AB Understanding how striatal neurons integrate glutamatergic and GABAergic inputs is essential for understanding the control of movement and the formation of striatal-based memories. Here we show that GABAergic synapses on striatal medium spiny neurons (MSNs) are more sensitive than glutamatergic synapses on the same cells to endocannabinoid (eCB) signaling, and that protocols that induce short-lasting cannabinoid 1 receptor (CB1R)-dependent depression at glutamatergic synapses are sufficient to induce long-term depression (LTD) at GABAergic synapses. We also show that the frequency and duration of glutamatergic input are strong determinants of the net effect of eCB signaling, and key factors in determining if LTD has a net disinhibitory or inhibitory action in striatum. Plastic changes in net output from striatal MSNs are thus a complex function of disinhibitory and inhibitory LTD combined with other forms of synaptic plasticity such as long-term potentiation at excitatory synapses. C1 [Adermark, Louise; Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Adermark, Louise] Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Addict Biol Unit, S-40530 Gothenburg, Sweden. RP Lovinger, DM (reprint author), NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, 5625 Fishers Lane,TS-13, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov RI Adermark, Louise/D-2297-2014 OI Adermark, Louise/0000-0002-7165-9908 FU Intramural NIH HHS [Z01 AA000407-06] NR 27 TC 36 Z9 36 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 4 PY 2009 VL 29 IS 5 BP 1375 EP 1380 DI 10.1523/JNEUROSCI.3842-08.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 403GZ UT WOS:000263072400013 PM 19193884 ER PT J AU Kalbaugh, TL Zhang, J Diamond, JS AF Kalbaugh, Trisha L. Zhang, Jun Diamond, Jeffrey S. TI Coagonist Release Modulates NMDA Receptor Subtype Contributions at Synaptic Inputs to Retinal Ganglion Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article DE NMDA receptor; AMPA receptor; glycine; retinal ganglion cell; retinal bipolar cell; synaptic transmission; retina ID D-ASPARTATE RECEPTORS; SUBUNIT MESSENGER-RNAS; INNER PLEXIFORM LAYER; AMINO-ACID OXIDASE; RAT RETINA; D-SERINE; HIPPOCAMPAL-NEURONS; GLUTAMATE-RECEPTOR; VERTEBRATE RETINA; BIPOLAR CELLS AB NMDA receptors (NMDARs) are tetrameric protein complexes usually comprising two NR1 and two NR2 subunits. Different combinations of four potential NR2 subunits (NR2A-D) confer diversity in developmental expression, subsynaptic localization, and functional characteristics, including affinity for neurotransmitter. NR2B-containing NMDARs, for example, exhibit relatively high affinity both for glutamate and the coagonist glycine. Although multiple NMDAR subtypes can colocalize at individual synapses, particular subtypes often mediate inputs from distinct functional pathways. In retinal ganglion cells ( RGCs), NMDARs contribute to synaptic responses elicited by light stimulus onset ("ON") and offset ("OFF"), but roles for particular NMDAR subtypes, and potential segregation between the ON and OFF pathways, have not been explored. Moreover, elements in the retinal circuitry release two different NMDAR coagonists, glycine and D-serine, but the effects of endogenous coagonist release on the relative contribution of different NMDAR subtypes are unclear. Here, we show that coagonist release within the retina modulates the relative contribution of different NMDARs in the ON pathway of the rat retina. By pharmacologically stimulating functional pathways independently in acute slices and recording synaptic responses in RGCs, we show that ON inputs, but not OFF inputs, are mediated in part by NMDARs exhibiting NR2B-like pharmacology. Furthermore, suppressing release of NMDAR coagonist reduces NMDAR activation at ON synapses and increases the relative contribution of these putative NR2B-containing receptors. These results demonstrate direct evidence for evoked coagonist release onto NMDARs and indicate that modulating coagonist release may regulate the relative activation of different NMDAR subtypes in the ON pathway. C1 [Kalbaugh, Trisha L.; Zhang, Jun; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Diamond, JS (reprint author), NINDS, Synapt Physiol Sect, NIH, 35 Convent Dr,Bldg 35,Room 3C-1000, Bethesda, MD 20892 USA. EM diamondj@ninds.nih.gov RI Zhang, Jun/K-2424-2012; Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU Intramural NIH HHS [Z01 NS003039-01] NR 70 TC 47 Z9 47 U1 2 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 4 PY 2009 VL 29 IS 5 BP 1469 EP 1479 DI 10.1523/JNEUROSCI.4240-08.2009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 403GZ UT WOS:000263072400022 PM 19193893 ER PT J AU Cisneros, GA Perera, L Schaaper, RM Pedersen, LC London, RE Pedersen, LG Darden, TA AF Cisneros, G. Andres Perera, Lalith Schaaper, Roel M. Pedersen, Lars C. London, Robert E. Pedersen, Lee G. Darden, Thomas A. TI Reaction Mechanism of the epsilon Subunit of E-coli DNA Polymerase III: Insights into Active Site Metal Coordination and Catalytically Significant Residues SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID FAMILIAL CHILBLAIN LUPUS; TRANSFER-RNA SYNTHETASE; MINIMUM-ENERGY PATHS; HOT GENE-PRODUCT; CHEMICAL-REACTIONS; PROOFREADING EXONUCLEASE; ENZYME CATALYSIS; STRUCTURAL BASIS; THETA-SUBUNIT; COMPLEX AB The 28 kDa epsilon subunit of Escherichia coli DNA polymerase III is the exonucleotidic proofreader responsible for editing polymerase insertion errors. Here, we study the mechanism by which E carries out the exonuclease activity. We performed quantum mechanics/molecular mechanics calculations on the N-terminal domain containing the exonuclease activity. Both the free-E and a complex E bound to a 0 homologue (HOT) were studied. For the epsilon-HOT complex Mg2+ or Mn2+ were investigated as the essential divalent metal cofactors, while only Mg2+ was used for free-e. In all calculations a water molecule bound to the catalytic metal acts as the nucleophile for hydrolysis of the phosphate bond. Initially, a direct proton transfer to H162 is observed. Subsequently, the nucleophilic attack takes place followed by a second proton transfer to E14. Our results show that the reaction catalyzed with Mn2+ is faster than that with Mg2+, in agreement with experiment. In addition, the E-HOT complex shows a slightly lower energy barrier compared to free-E. In all cases the catalytic metal is observed to be pentacoordinated. Charge and frontier orbital analyses suggest that charge transfer may stabilize the pentacoordination. Energy decomposition analysis to study the contribution of each residue to catalysis suggests that there are several important residues. Among these, H98, D103, D129, and D146 have been implicated in catalysis by mutagenesis studies. Some of these residues were found to be structurally conserved on human TREX1, the exonuclease domains from E. coli DNA-Pol 1, and the DNA polymerase of bacteriophage RB69. C1 [Cisneros, G. Andres; Perera, Lalith; Pedersen, Lars C.; London, Robert E.; Pedersen, Lee G.; Darden, Thomas A.] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Schaaper, Roel M.] Natl Inst Environm Hlth Sci, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. RP Cisneros, GA (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. EM cisnero1@niehs.nih.gov; pereral2@niehs.nih.gov RI pedersen, lee/A-8567-2009; Cisneros, Gerardo/B-3128-2010; perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 FU NIH; NIEHS [Z01 ES09060111]; NIH [HL-06350]; NSF [FRG/DMR-0804549] FX This research was supported by the intramural research program of the NIH and NIEHS Z01 ES09060111. L.G.P. acknowledges support from NIH HL-06350 and NSF FRG/DMR-0804549. Computing-time from the NIEHS and UNC computing facilities are gratefully acknowledged. G.A.C. thanks Drs. J. M. Parks and H. Hu and Prof. W. Yang from Duke University and Prof. Y. Zhang from NYU. NR 76 TC 31 Z9 32 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 4 PY 2009 VL 131 IS 4 BP 1550 EP 1556 DI 10.1021/ja8082818 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 427PS UT WOS:000264791800052 PM 19119875 ER PT J AU Xi, LF Koutsky, LA Castle, PE Wheeler, CM Galloway, DA Mao, C Ho, J Kiviat, NB AF Xi, Long Fu Koutsky, Laura A. Castle, Philip E. Wheeler, Cosette M. Galloway, Denise A. Mao, Constance Ho, Jesse Kiviat, Nancy B. TI Human Papillomavirus Type 18 DNA Load and 2-Year Cumulative Diagnoses of Cervical Intraepithelial Neoplasia Grades 2-3 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CARCINOMA IN-SITU; POLYMERASE-CHAIN-REACTION; HIGH VIRAL LOADS; PHYSICAL STATE; PREDICT RISK; E6 PROMOTER; E2 PROTEINS; HPV DNA; LESIONS; WOMEN AB The clinical relevance of the amount of human papillomavirus type 18 (HPV18) DNA in cervical tissue (ie, HPV18 DNA load) is unknown. Study subjects were 303 women who were HPV18 positive at enrollment into the Atypical Squamous Cells of Undetermined Significance (ASC-US) and Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. HPV18 DNA load, expressed as copies of HPV18 per nanogram of cellular DNA, at enrollment was quantitatively measured. Subjects were followed up semiannually for a period of 2 years for detection of cervical intraepithelial neoplasia 2-3 (CIN2-3). A linear regression model was used to examine associations of CIN2-3 with HPV18 DNA load. All statistical tests were two-sided. CIN2-3 was confirmed in 92 of 303 (30.4%) HPV18-positive women. Among women without CIN2-3, HPV18 DNA load was positively associated with increasing severity of cervical cytology at enrollment (P(trend) < .001). However, among those with CIN2-3, HPV18 DNA load was not associated with severity of cervical cytology at enrollment (P(trend) = .33). The ratios of geometric means of HPV18 DNA load at enrollment among women with CIN2-3, relative to those without, were 6.06 (95% confidence interval [CI] = 0.31 to 117.92) for those with normal cytology at enrollment, 0.50 (95% CI = 0.10 to 2.44) for those with ASC-US, 0.11 (95% CI = 0.03 to 0.46) for those with LSIL, and 0.07 (95% CI = 0.01 to 0.80) for those with high-grade squamous intraepithelial lesion (HSIL). After adjusting for age and coinfection with other high-risk HPVs, a statistically significant association of lower HPV18 DNA load with CIN2-3 was observed among women with LSIL or HSIL at enrollment (P = .02). Within the 2-year period, HPV18 DNA load was unrelated to the timing of CIN2-3 diagnosis. Overall results were similar when the outcome was CIN3. HPV18 DNA load was higher for women with LSIL or HSIL at enrollment with no evidence of CIN2-3 during the 2-year follow-up period than it was for women with CIN2-3. Thus, testing for high levels of HPV18 DNA does not appear to be clinically useful. C1 [Xi, Long Fu; Ho, Jesse; Kiviat, Nancy B.] Univ Washington, Dept Pathol, Sch Med, Seattle, WA 98103 USA. [Mao, Constance] Univ Washington, Dept Obstet & Gynecol, Sch Med, Seattle, WA 98103 USA. [Xi, Long Fu; Koutsky, Laura A.] Univ Washington, Dept Epidemiol, Sch Publ Hlth & Community Med, Seattle, WA 98103 USA. [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Dept Microbiol, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Dept Mol Genet, Albuquerque, NM 87131 USA. [Galloway, Denise A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Xi, LF (reprint author), Univ Washington, Dept Pathol, Sch Med, 1914 N 34th St,Suite 300, Seattle, WA 98103 USA. EM longfu@u.washington.edu FU Public Health Service [CA 84396]; National Cancer Institute; National Institutes of Health Department of Health and Human Services [CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, CN-55105]; Digene Corporation (Gaithersburg, MD); Cytyc Corporation (Boxborough, MA); National Testing Laboratories (Fenton, MO); DenVu (Tucson, AZ); TriPath Imaging, Inc. (Burlington, NC); Roche Molecular Systems, Inc. (Alameda, CA); Roche Molecular Systems, Inc; Merck Research Laboratories FX The work was supported by a Public Health Service grant (CA 84396 to LFX). ALTS was supported by the National Cancer Institute, National Institutes of Health Department of Health and Human Services contracts CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105 and by the Intramural Research Program of the National Cancer Institute. In conducting ALTS, some of the equipment and supplies used in these studies were donated or provided at reduced cost by Digene Corporation (Gaithersburg, MD); Cytyc Corporation (Boxborough, MA); National Testing Laboratories ( Fenton, MO); DenVu (Tucson, AZ); TriPath Imaging, Inc. (Burlington, NC); and Roche Molecular Systems, Inc. (Alameda, CA). C. M. Wheeler received reagents from Roche Molecular Systems, Inc. and funds to conduct HPV vaccine trial from Merck and GlaxoSmith Kline. L. A. Koutsky received research funds from Merck Research Laboratories. NR 53 TC 17 Z9 19 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 4 PY 2009 VL 101 IS 3 BP 153 EP 161 DI 10.1093/jnci/djn461 PG 9 WC Oncology SC Oncology GA 404PI UT WOS:000263165100008 PM 19176451 ER PT J AU Alberg, AJ Chen, JP Ruczinski, I Jorgensen, TJ Alani, R Liegeois, NJ AF Alberg, Anthony J. Chen, Jiping Ruczinski, Ingo Jorgensen, Timothy J. Alani, Rhoda Liegeois, Nanette J. TI Response: Re: Nonmelanoma Skin Cancer and Risk for Subsequent Malignancy SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID VITAMIN-D; SOLAR; IRRADIANCE; SMOKING C1 [Alberg, Anthony J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Alberg, Anthony J.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. [Chen, Jiping] NCI, Canc Prevent Div, Rockville, MD USA. [Ruczinski, Ingo] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Jorgensen, Timothy J.] Georgetown Univ, Sch Med, Dept Radiat Med, Washington, DC USA. [Alani, Rhoda] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Alani, Rhoda; Liegeois, Nanette J.] Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21205 USA. RP Alberg, AJ (reprint author), Med Univ S Carolina, Hollings Canc Ctr, 86 Jonathan Lucas St,POB 250955, Charleston, SC 29425 USA. EM alberg@musc.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 4 PY 2009 VL 101 IS 3 BP 210 EP 211 DI 10.1093/jnci/djn466 PG 2 WC Oncology SC Oncology GA 404PI UT WOS:000263165100014 ER PT J AU Cookson, MR AF Cookson, Mark R. TI alpha-Synuclein and neuronal cell death SO MOLECULAR NEURODEGENERATION LA English DT Review ID FAMILIAL PARKINSONS-DISEASE; LEWY-BODY-DISEASE; CHAPERONE-MEDIATED AUTOPHAGY; TRANSGENIC MICE; CAENORHABDITIS-ELEGANS; DOPAMINERGIC-NEURONS; OXIDATIVE STRESS; SUBSTANTIA-NIGRA; YEAST MODEL; WILD-TYPE AB alpha-Synuclein is a small protein that has special relevance for understanding Parkinson disease and related disorders. Not only is alpha-synuclein found in Lewy bodies characteristic of Parkinson disease, but also mutations in the gene for alpha-synuclein can cause an inherited form of Parkinson disease and expression of normal alpha-synuclein can increase the risk of developing Parkinson disease in sporadic, or non-familial, cases. Both sporadic and familial Parkinson disease are characterized by substantial loss of several groups of neurons, including the dopaminergic cells of the substantia nigra that are the target of most current symptomatic therapies. Therefore, it is predicted that alpha-synuclein, especially in its mutant forms or under conditions where its expression levels are increased, is a toxic protein in the sense that it is associated with an increased rate of neuronal cell death. This review will discuss the experimental contexts in which alpha-synuclein has been demonstrated to be toxic. I will also outline what is known about the mechanisms by which alpha-synuclein triggers neuronal damage, and identify some of the current gaps in our knowledge about this subject. Finally, the therapeutic implications of toxicity of alpha-synuclein will be discussed. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20982 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, Bldg 35,Room 1A116,MSC 3707,35 Convent Dr, Bethesda, MD 20982 USA. EM cookson@mail.nih.gov FU NIH; National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 173 TC 157 Z9 161 U1 2 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD FEB 4 PY 2009 VL 4 AR 9 DI 10.1186/1750-1326-4-9 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 445PP UT WOS:000266064000003 PM 19193223 ER PT J AU Lin, J AF Lin, Jimmy TI Is searching full text more effective than searching abstracts? SO BMC BIOINFORMATICS LA English DT Article ID INFORMATION; ARTICLES; MODEL AB Background: With the growing availability of full-text articles online, scientists and other consumers of the life sciences literature now have the ability to go beyond searching bibliographic records (title, abstract, metadata) to directly access full-text content. Motivated by this emerging trend, I posed the following question: is searching full text more effective than searching abstracts? This question is answered by comparing text retrieval algorithms on MEDLINE (R) abstracts, full-text articles, and spans (paragraphs) within full-text articles using data from the TREC 2007 genomics track evaluation. Two retrieval models are examined: bm25 and the ranking algorithm implemented in the open-source Lucene search engine. Results: Experiments show that treating an entire article as an indexing unit does not consistently yield higher effectiveness compared to abstract-only search. However, retrieval based on spans, or paragraphs-sized segments of full-text articles, consistently outperforms abstract-only search. Results suggest that highest overall effectiveness may be achieved by combining evidence from spans and full articles. Conclusion: Users searching full text are more likely to find relevant articles than searching only abstracts. This finding affirms the value of full text collections for text retrieval and provides a starting point for future work in exploring algorithms that take advantage of rapidly-growing digital archives. Experimental results also highlight the need to develop distributed text retrieval algorithms, since full-text articles are significantly longer than abstracts and may require the computational resources of multiple machines in a cluster. The MapReduce programming model provides a convenient framework for organizing such computations. C1 [Lin, Jimmy] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Lin, Jimmy] Univ Maryland, iSch, College Pk, MD 20742 USA. RP Lin, J (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM jimmylin@umd.edu FU NIH; National Library of Medicine; NSF [IIS-0705832, IIS-0836560]; DARPA/IPTO [HR0011-06-2-0001] FX This work was supported by the Intramural Research Program of the NIH, National Library of Medicine; NSF under awards IIS-0705832 and IIS-0836560; DARPA/IPTO Contract No. HR0011-06-2-0001 under the GALE program. Any opinions, findings, conclusions, or recommendations expressed in this article are the author's and do not necessarily reflect those of the sponsors. I would like to thank Yahoo! for leading the development of Hadoop and Amazon for EC2/S3 support. This article benefited from the comments of two anonymous reviewers. Finally, I am grateful to Esther and Kiri for their kind support. NR 48 TC 15 Z9 15 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 3 PY 2009 VL 10 AR 46 DI 10.1186/1471-2105-10-46 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 427FS UT WOS:000264765800001 PM 19192280 ER PT J AU Abnet, CC Freedman, ND Kamangar, F Leitzmann, MF Hollenbeck, AR Schatzkin, A AF Abnet, C. C. Freedman, N. D. Kamangar, F. Leitzmann, M. F. Hollenbeck, A. R. Schatzkin, A. TI Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a meta-analysis SO BRITISH JOURNAL OF CANCER LA English DT Article DE aspirin; NSAIDs; oesophageal cancer; gastric cancer; cohort; meta-analysis ID SPHINCTER-RELAXING DRUGS; ASPIRIN USE; HELICOBACTER-PYLORI; BARRETTS-ESOPHAGUS; CANCER; POPULATION; ASSOCIATION; METAPLASIA; SITES; TRIAL AB Use of aspirin or other non-steroidal anti-inflammatory drugs ( NSAIDs) may reduce the risk of gastric or oesophageal adenocarcinomas. We examined the association between self-reported use of aspirin or non-aspirin NSAIDs in the earlier 12 months and gastric non-cardia (N = 182), gastric cardia ( N= 178), and oesophageal adenocarcinomas ( N =228) in a prospective cohort ( N= 311 115) followed for 7 years. Hazard ratios ( HRs) and 95% confidence intervals (CIs) come from Cox models adjusted for potential confounders. Use of any aspirin ( HR, 95% CI: 0.64, 0.47-0.86) or other NSAIDs ( 0.68, 0.51-0.92) was associated with a significantly lower risk of gastric non-cardia adenocarcinoma. Neither aspirin (0.86, 0.61-1.20) nor other NSAIDs ( 0.91, 0.67-1.22) had a significant association with gastric cardia cancer. We found no significant association between using aspirin ( 1.00, 0.73-1.37) or other NSAIDs ( 0.90, 69-1.17)and oesophageal adenocarcinoma. We also performed a meta-analysis of the association between the use of NSAIDs and risk of gastric and oesophageal adenocarcinoma. In this analysis, aspirin use was inversely associated with both gastric and oesophageal adenocarcinomas, with summary odds ratios ( 95% CI) for non-cardia, cardia, and oesophageal adenocarcinomas of 0.64 ( 0.52-0.80), 0.82 ( 0.65-1.04), and 0.64 ( 0.52-0.79), respectively. The corresponding numbers for other NSAIDs were 0.68 ( 0.57-0.81), 0.80 ( 0.67-0.95), and 0.65 ( 0.50-0.85), respectively. C1 [Abnet, C. C.; Freedman, N. D.; Kamangar, F.; Leitzmann, M. F.; Schatzkin, A.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Hollenbeck, A. R.] AARP, Washington, DC USA. RP Abnet, CC (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Execut Plaza S,Room 320,6120 Execut Blvd,MSC 7232, Rockville, MD 20852 USA. EM abnetc@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU NIH, National Cancer Institute. FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry; from Georgia by the Georgia Center for Cancer Statistics; from California by the California Department of Health Services, Cancer Surveillance Section; from Michigan by the Michigan Cancer Surveillance Program; from Florida by the Florida Cancer Data System under contract to the Department of Health ( DOH); from Louisiana by the Louisiana Tumor Registry; from Nevada by the Nevada Central Cancer registry; from New Jersey by the New Jersey State Cancer Registry; from North Carolina by the North Carolina Central Cancer Registry; from Pennsylvania by the Division of Health Statistics and Research, Pennsylvania Department of Health; and from Texas by the Texas Cancer Registry. The views expressed herein are solely those of the authors and do not necessarily reflect those of the cancer registries or contractors. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. CCA had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of data analysis. All authors have given full approval to the final paper. CCA, NDF, FK, MFL, and AS were involved in the study design, analysis, and interpretation of the data. CCA, NDF, FK, MFL, ARH, and AS were all involved in the critical revision of the paper. NR 46 TC 89 Z9 91 U1 4 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 3 PY 2009 VL 100 IS 3 BP 551 EP 557 DI 10.1038/sj.bjc.6604880 PG 7 WC Oncology SC Oncology GA 403HY UT WOS:000263074900018 PM 19156150 ER PT J AU Stewart, CA Trinchieri, G AF Stewart, C. Andrew Trinchieri, Giorgio TI Reinforcing Suppression Using Regulators: A New Link between STAT3, IL-23, and Tregs in Tumor Immunosuppression SO CANCER CELL LA English DT Editorial Material ID CELLS; DIFFERENTIATION C1 [Stewart, C. Andrew; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM trinchig@mail.nih.gov RI Stewart, Charles/G-2470-2012 NR 10 TC 13 Z9 14 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD FEB 3 PY 2009 VL 15 IS 2 BP 81 EP 83 DI 10.1016/j.ccr.2009.01.008 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 405VD UT WOS:000263251400002 PM 19185840 ER PT J AU Myerson, M Coady, S Taylor, H Rosamond, WD Goff, DC AF Myerson, Merle Coady, Sean Taylor, Herman Rosamond, Wayne D. Goff, David C., Jr. CA ARIC Investigators TI Declining Severity of Myocardial Infarction From 1987 to 2002 The Atherosclerosis Risk in Communities (ARIC) Study SO CIRCULATION LA English DT Article DE epidemiology; myocardial infarction; prevention ID CORONARY-HEART-DISEASE; UNITED-STATES COMMUNITIES; 4 US COMMUNITIES; TEMPORAL TRENDS; CARDIOVASCULAR-DISEASE; SECULAR TRENDS; ST-ELEVATION; MORTALITY; MINNESOTA; DEATH AB Background-Death rates for coronary heart disease have been declining in the United States, but the reasons for this decline are not clear. One factor that could contribute to this decline is a reduction in the severity of acute myocardial infarction (MI). We hypothesized that for those patients hospitalized in the Atherosclerosis Risk in Communities (ARIC) Study with acute incident MI, there was a decline in MI severity from 1987 to 2002. Methods and Results-The community surveillance component of the ARIC Study consisted of tracking residents 35 to 74 years of age with hospitalized MI or fatal coronary heart disease in 4 diverse communities. For incident, hospitalized MI, a probability sample of hospital discharges was validated and an MI classification was assigned according to an algorithm consisting of chest pain, ECG evidence, and cardiac biomarkers. Severity indicators were chosen from abstracted hospital charts validated as a definite or probable MI. With few exceptions, the MI severity indicators suggested a significant decline in the severity of MI during the period of 1987 to 2002. The percent of MI cases with major ECG abnormalities decreased as evidenced by a 1.9%/y ( P=0.002) decline in the proportion of those with initial ST-segment elevation, a 3.9%/y (P < 0.001) decline in those with subsequent Q-waves, and a 4.5%/y (P < 0.001) decline in those with any major Q wave. Maximum creatine kinase and creatine kinase-MB values declined (5.2% and 7.6%; P < 0.001, P < 0.001 per year, respectively), although in the later years, maximum troponin I values remained stable (1.1%/y decline; P=0.66). The percent with shock declined (5.7%/y; P < 0.001), although those with congestive heart failure remained stable. A combined severity score, the Predicting Risk of Death in Cardiac Disease Tool ( PREDICT) score, also declined (0.2%/y; P < 0.001). Results for blacks paralleled those of the entire group, as did results for women. Conclusions-Evidence from ARIC community surveillance suggests that the severity of acute MI has declined among community residents hospitalized for incident MI. This reduction in severity may have contributed, along with other factors, to the decline in death rates for coronary heart disease. (Circulation. 2009;119:503-514.) C1 [Goff, David C., Jr.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Rosamond, Wayne D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Taylor, Herman] Univ Mississippi, Med Ctr, Div Cardiol, Jackson, MS USA. [Myerson, Merle; Coady, Sean] NHLBI, NIH, Bethesda, MD 20892 USA. RP Myerson, M (reprint author), Columbia Univ, St Lukes Roosevelt Hosp, Div Cardiol, Cardiovasc Dis Prevent Program, 1111 Amsterdam Ave, New York, NY 10025 USA. EM myersonM@optonline.net FU National Heart, Lung, and Blood Institute [NO1-HC-55015, NO1-HC-55016, NO1-HC-55018, NO1-HC-55019, NO1-HC-55020, NO1-HC-55021, NO1-HC-55022]; Abbott Laboratories FX The ARIC Study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute contracts NO1-HC-55015, NO1-HC-55016, NO1-HC-55018, NO1-HC-55019, NO1-HC-55020, NO1-HC-55021, and NO1-HC-55022.; Dr Myerson was an employee of the National Heart, Lung, and Blood Institute during the initial preparation of this manuscript. Dr Myerson served on the speakers' bureau for GlaxoSmithKline and Daiichi Sankyo and received a research and educational grant from Abbott Laboratories. The other authors report no conflicts. NR 40 TC 59 Z9 61 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 3 PY 2009 VL 119 IS 4 BP 503 EP U40 DI 10.1161/CIRCULATIONAHA.107.693879 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 402RV UT WOS:000263031700004 PM 19153274 ER PT J AU Benjamin, EJ Chen, PS Bild, DE Mascette, AM Albert, CM Alonso, A Calkins, H Connolly, SJ Curtis, AB Darbar, D Ellinor, PT Go, AS Goldschlager, NF Heckbert, SR Jalife, J Kerr, CR Levy, D Lloyd-Jones, DM Massie, BM Nattel, S Olgin, JE Packer, DL Po, SS Tsang, TSM Van Wagoner, DR Waldo, AL Wyse, DG AF Benjamin, Emelia J. Chen, Peng-Sheng Bild, Diane E. Mascette, Alice M. Albert, Christine M. Alonso, Alvaro Calkins, Hugh Connolly, Stuart J. Curtis, Anne B. Darbar, Dawood Ellinor, Patrick T. Go, Alan S. Goldschlager, Nora F. Heckbert, Susan R. Jalife, Jose Kerr, Charles R. Levy, Daniel Lloyd-Jones, Donald M. Massie, Barry M. Nattel, Stanley Olgin, Jeffrey E. Packer, Douglas L. Po, Sunny S. Tsang, Teresa S. M. Van Wagoner, David R. Waldo, Albert L. Wyse, D. George TI Prevention of Atrial Fibrillation Report From a National Heart, Lung, and Blood Institute Workshop SO CIRCULATION LA English DT Article DE atrial fibrillation; atrium; epidemiology; prevention; risk factors; National Heart, Lung and Blood Institute ID OF-FUNCTION MUTATION; PULMONARY VEINS; RISK-FACTORS; RHYTHM-CONTROL; FAMILIAL AGGREGATION; CARDIAC-ARRHYTHMIAS; CHANNEL MUTATIONS; RANDOMIZED-TRIAL; SECULAR TRENDS; LIFETIME RISK AB The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations. (Circulation. 2009; 119: 606-618.) C1 [Benjamin, Emelia J.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Chen, Peng-Sheng] Indiana Univ, Krannert Inst Cardiol, Indianapolis, IN 46204 USA. [Bild, Diane E.; Mascette, Alice M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Albert, Christine M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Alonso, Alvaro] Univ Minnesota, Minneapolis, MN USA. [Calkins, Hugh] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Connolly, Stuart J.] McMaster Univ, Hamilton, ON, Canada. [Curtis, Anne B.] Univ S Florida, Tampa, FL USA. [Darbar, Dawood] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Ellinor, Patrick T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Go, Alan S.] Kaiser Permanente No Calif, Oakland, CA USA. [Go, Alan S.; Goldschlager, Nora F.; Massie, Barry M.; Olgin, Jeffrey E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Heckbert, Susan R.] Univ Washington, Seattle, WA 98195 USA. [Jalife, Jose] Univ Michigan, Ann Arbor, MI 48109 USA. [Kerr, Charles R.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Kerr, Charles R.] St Pauls Hosp, Vancouver, BC V6Z 1Y6, Canada. [Lloyd-Jones, Donald M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Packer, Douglas L.; Tsang, Teresa S. M.] Mayo Clin Rochester, Rochester, MN USA. [Nattel, Stanley] Univ Montreal, Montreal, PQ, Canada. [Nattel, Stanley] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Po, Sunny S.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Van Wagoner, David R.] Cleveland Clin, Cleveland, OH 44106 USA. [Waldo, Albert L.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Wyse, D. George] Univ Calgary, Libin Cardiovasc Inst Alberta, Calgary, AB, Canada. RP Benjamin, EJ (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@bu.edu RI Lloyd-Jones, Donald/C-5899-2009; Van Wagoner, David/C-6783-2008; Alonso, Alvaro/A-4917-2010; Darbar, Dawood/C-9079-2015; Jalife, Jose/L-4833-2015; OI Van Wagoner, David/0000-0001-8250-9828; Alonso, Alvaro/0000-0002-2225-8323; Darbar, Dawood/0000-0002-4103-5977; Jalife, Jose/0000-0003-0080-3500; Benjamin, Emelia/0000-0003-4076-2336 FU NHGRI NIH HHS [U01 HG004402, U01 HG004402-01]; NHLBI NIH HHS [R01 HL085690, K23 HL075266, K23 HL075266-01A1, K23 HL075266-04, N01 HC055015, N01 HC055016, N01 HC055018, N01 HC055019, N01 HC055020, N01 HC055021, N01 HC055022, P01 HL039707, P01 HL039707-18, P01 HL087226, P01 HL087226-01, R01 HL059367, R01 HL059367-02, R01 HL068986, R01 HL068986-01A1, R01 HL070074, R01 HL070074-01, R01 HL071140, R01 HL071140-01, R01 HL075431, R01 HL075431-01A1, R01 HL076784, R01 HL076784-01, R01 HL078932, R01 HL078932-01, R01 HL085690-01A2, R01 HL086694, R01 HL086694-01A1, R01 HL087641, R01 HL087641-01, R01 HL090620, R01 HL090620-01A1, R01 HL092577, R01 HL092577-01A1, R01 HL104156]; NIA NIH HHS [R01 AG028321, R01 AG028321-01]; NIDA NIH HHS [R21 DA027021] NR 92 TC 247 Z9 252 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 3 PY 2009 VL 119 IS 4 BP 606 EP 618 DI 10.1161/CIRCULATIONAHA.108.825380 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 402RV UT WOS:000263031700015 PM 19188521 ER PT J AU Huey, ED Goveia, EN Paviol, S Pardini, M Krueger, F Zamboni, G Tierney, MC Wassermann, EM Grafman, J AF Huey, E. D. Goveia, E. N. Paviol, S. Pardini, M. Krueger, F. Zamboni, G. Tierney, M. C. Wassermann, E. M. Grafman, J. TI Executive dysfunction in frontotemporal dementia and corticobasal syndrome SO NEUROLOGY LA English DT Article ID VOXEL-BASED MORPHOMETRY; LOBAR DEGENERATION; ALZHEIMERS-DISEASE; FUNCTION SYSTEM; CRITERIA; PROFILES; VALIDITY; CORTEX AB Objective: To determine the pattern of executive dysfunction in frontotemporal dementia (FTD) and corticobasal syndrome (CBS) and to determine the brain areas associated with executive dysfunction in these illnesses. Method: We administered the Delis-Kaplan Executive Function System (D-KEFS), a collection of standardized executive function tests, to 51 patients with behavioral-variant FTD and 50 patients with CBS. We also performed a discriminant analysis on the D-KEFS to determine which executive function tests best distinguished the clinical diagnoses of FTD and CBS. Finally, we used voxel-based morphometry (VBM) to determine regional gray matter volume loss associated with executive dysfunction. Results: Patients with FTD and patients with CBS showed executive dysfunction greater than memory dysfunction. Executive function was better preserved in the patients with CBS than the patients with FTD with the exception of tests that required motor, visuospatial ability, or both. In patients with CBS, dorsal frontal and parietal and temporal-parietal cortex was associated with executive function. In FTD, tests with a language component (Verbal Fluency) were associated with left perisylvian cortex, sorting with the left dorsolateral prefrontal cortex, and reasoning (the Twenty Questions task) with the left anterior frontal cortex. The Twenty Questions test best distinguished the clinical diagnoses of CBS and FTD. Conclusions: The neuroanatomic findings (especially in frontotemporal dementia [FTD]) agree with the previous literature on this topic. Patients with FTD and patients with corticobasal syndrome (CBS) show disparate performance on higher-order executive functions, especially the Twenty Questions test. It may be difficult to distinguish motor and visuospatial ability from executive function in patients with CBS using tests with significant motor and visuospatial demands such as Trail Making. Neurology (R) 2009;72:453-459 C1 [Huey, E. D.; Goveia, E. N.; Paviol, S.; Pardini, M.; Krueger, F.; Zamboni, G.; Tierney, M. C.; Wassermann, E. M.; Grafman, J.] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Wassermann, E. M.] NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. [Huey, E. D.] Feinstein Inst Med Res, Litwin Zucker Res Ctr Study Alzheimers Dis & Memo, Manhasset, NY USA. [Pardini, M.] Univ Genoa, Dept Neurosci Oftalmol & Genet, Genoa, Italy. [Zamboni, G.] Univ Modena & Reggio Emilia, Dept Neurosci, Modena, Italy. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 7D43,MSC 1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov RI Pardini, Matteo/F-8414-2010; Zamboni, Giovanna/F-3583-2017; OI Pardini, Matteo/0000-0002-4740-1982; Zamboni, Giovanna/0000-0002-6133-3373; Grafman, Jordan H./0000-0001-8645-4457 FU Intramural NIH HHS [Z01 NS002792-19] NR 33 TC 43 Z9 45 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 3 PY 2009 VL 72 IS 5 BP 453 EP 459 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 404YF UT WOS:000263188200011 PM 19188577 ER PT J AU Brown, JD Dutta, S Bharti, K Bonner, RF Munson, PJ Dawid, IB Akhtar, AL Onojafe, IF Alur, RP Gross, JM Hejtmancik, JF Jiao, X Chan, WY Brooks, BP AF Brown, Jacob D. Dutta, Sunit Bharti, Kapil Bonner, Robert F. Munson, Peter J. Dawid, Igor B. Akhtar, Amana L. Onojafe, Ighovie F. Alur, Ramakrishna P. Gross, Jeffrey M. Hejtmancik, J. Fielding Jiao, Xiaodong Chan, Wai-Yee Brooks, Brian P. TI Expression profiling during ocular development identifies 2 Nlz genes with a critical role in optic fissure closure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE coloboma; eye; pax2; zinc finger protein; zebrafish ID EYE; ZEBRAFISH; MUTATIONS; COLOBOMA; FAMILY; HEDGEHOG; PAX2; MALFORMATIONS; PROTEINS; MICROPHTHALMIA AB The gene networks underlying closure of the optic fissure during vertebrate eye development are poorly understood. Here, we profile global gene expression during optic fissure closure using laser capture microdissected (LCM) tissue from the margins of the fissure. From these data, we identify a unique role for the C(2)H(2) zinc finger proteins Nlz1 and Nlz2 in normal fissure closure. Gene knockdown of nlz1 and/or nlz2 in zebrafish leads to a failure of the optic fissure to close, a phenotype which closely resembles that seen in human uveal coloboma. We also identify misregulation of pax2 in the developing eye of morphant fish, suggesting that Nlz1 and Nlz2 act upstream of the Pax2 pathway in directing proper closure of the optic fissure. C1 [Dutta, Sunit; Dawid, Igor B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Brown, Jacob D.; Akhtar, Amana L.; Onojafe, Ighovie F.; Alur, Ramakrishna P.; Hejtmancik, J. Fielding; Jiao, Xiaodong; Brooks, Brian P.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Brown, Jacob D.; Chan, Wai-Yee] Georgetown Univ, Washington, DC 20007 USA. [Bonner, Robert F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Biophys, NIH, Bethesda, MD 20892 USA. [Chan, Wai-Yee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. [Bharti, Kapil] NINDS, Mammalian Dev Sect, NIH, Bethesda, MD 20892 USA. [Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Gross, Jeffrey M.] Univ Texas Austin, Austin, TX 78712 USA. RP Dawid, IB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM dawidi@mail.nih.gov; brooksb@nei.nih.gov; brooksb@nei.nih.gov RI Bonner, Robert/C-6783-2015 FU Intramural Research Program of the National Eye Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health FX The authors thank Abdel Elkalhoun of the National Human Genome Research Institute Microarray Core for his assistance with microarray processing and the National Eye Institute histology core. We thank A. Picker for the full-length pax2.1 plasmid (University of Technology, Dresden, Germany). This research was supported by the Intramural Research Program of the National Eye Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. J.D.B was partially supported by a stipend from the Georgetown University MD/PhD program. NR 41 TC 28 Z9 28 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2009 VL 106 IS 5 BP 1462 EP 1467 DI 10.1073/pnas.0812017106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 403HV UT WOS:000263074600033 PM 19171890 ER PT J AU Chen, S Whetstine, JR Ghosh, S Hanover, JA Gali, RR Grosu, P Shi, Y AF Chen, Shuzhen Whetstine, Johnathan R. Ghosh, Salil Hanover, John A. Gali, Reddy R. Grosu, Paul Shi, Yang TI The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; CtBP; transcription corepressor ID C-ELEGANS; INSULIN-RECEPTOR; STRESS-RESPONSE; ADENOVIRUS E1A; GENE; LONGEVITY; DAF-16; TRANSCRIPTION; SIGNALS; STORAGE AB CtBP (C-terminal binding protein) is an evolutionarily conserved NAD(H)-dependent transcriptional corepressor, whose activity has been shown to be regulated by the NAD/NADH ratio. Although recent studies have provided significant new insights into mechanisms by which CtBP regulates transcription, the biological function of CtBP remains incompletely understood. Here, we report that genetic inactivation of the Caenorhabditis elegans homolog, ctbp-1, results in life span extension, which is suppressed by reintroduction of the ctbp-1 genomic DNA encoding wild-type but not NAD(H)-binding defective CTBP-1 protein. We show that CTBP-1 possibly modulates aging through the insulin/IGF-1 signaling pathway, dependent on the forkhead transcription factor DAF-16, but independent of the NAD-dependent histone deacetylase SIR-2.1. Genome-wide microarray analysis identifies >200 potential CTBP-1 target genes. Importantly, RNAi inhibition of a putative triacylglycerol lipase genelips-7(C09E8.2) but not another lipase suppresses the life span extension phenotype. Consistently, metabolic analysis shows that the triacylglycerol level is reduced in the ctbp-1 deletion mutant, which is restored to the wild-type level by RNAi inhibition of lips-7. Taken together, our data suggest that CTBP-1 controls life span probably through the regulation of lipid metabolism. C1 [Chen, Shuzhen; Whetstine, Johnathan R.; Shi, Yang] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ghosh, Salil; Hanover, John A.] NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Gali, Reddy R.; Grosu, Paul] Harvard Univ, FAS Res Comp, Div Life Sci, Cambridge, MA 02138 USA. RP Shi, Y (reprint author), Harvard Univ, Sch Med, Dept Pathol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM yang_shi@hms.harvard.edu FU Ruth L. Kirschstein National Service Award [GM 70095]; Paul F. Glenn Labs for the Molecular Biology of Aging Pilot Project Grant Program; National Institutes of Health [GM 071004] FX We thank David Sinclair, Keith Blackwell, Marcia Haigis, and the Y.S. laboratory members for helpful discussion and comments on Ausubel (Harvard Medical School, Boston) for the P. aeruginosa PA14 strain and Christian Daly and Peter Boag for technical help. This work was supported by Ruth L. Kirschstein National Service Award GM 70095 (to J.R.W.), a grant from the Paul F. Glenn Labs for the Molecular Biology of Aging Pilot Project Grant Program (to Y.S.), and National Institutes of Health Grant GM 071004 (to Y.S.). NR 54 TC 31 Z9 33 U1 2 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2009 VL 106 IS 5 BP 1496 EP 1501 DI 10.1073/pnas.0802674106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 403HV UT WOS:000263074600039 PM 19164523 ER PT J AU Bubier, JA Sproule, TJ Foreman, O Spolski, R Shaffer, DJ Morse, HC Leonard, WJ Roopenian, DC AF Bubier, Jason A. Sproule, Thomas J. Foreman, Oded Spolski, Rosanne Shaffer, Daniel J. Morse, Herbert C., III Leonard, Warren J. Roopenian, Derry C. TI A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoimmune disease; autoantibodies; B cells; T cells ID HELPER T-CELLS; B-CELLS; MURINE LUPUS; IN-VIVO; AUTOIMMUNITY; DIFFERENTIATION; RESPONSES; DISEASE; INTERLEUKIN-21; GENERATION AB Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor gamma chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T-FH), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5(+) T-FH but instead was produced broadly by ICOS+ CD4(+) splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders. C1 [Bubier, Jason A.; Sproule, Thomas J.; Foreman, Oded; Shaffer, Daniel J.; Roopenian, Derry C.] Jackson Lab, Bar Harbor, ME 04609 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Roopenian, DC (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM dcr@jax.org OI Morse, Herbert/0000-0002-9331-3705; Bubier, Jason/0000-0001-5013-1234 FU Arthritis Foundation; Arthritis Foundation Innovative Research; National Institutes of Health [DK56597, R21 DK074463]; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute FX This work was supported in part by a postdoctoral fellowship from the Arthritis Foundation to J.A.B.; an Arthritis Foundation Innovative Research Grant and National Institutes of Health Grants DK56597 and R21 DK074463 to D. C. R.; and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute. NR 43 TC 151 Z9 159 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2009 VL 106 IS 5 BP 1518 EP 1523 DI 10.1073/pnas.0807309106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 403HV UT WOS:000263074600043 PM 19164519 ER PT J AU Reis, J Schambra, HM Cohen, LG Buch, ER Fritsch, B Zarahn, E Celnik, PA Krakauer, JW AF Reis, Janine Schambra, Heidi M. Cohen, Leonardo G. Buch, Ethan R. Fritsch, Brita Zarahn, Eric Celnik, Pablo A. Krakauer, John W. TI Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE long-term retention; motor cortex; motor learning; transcranial direct current stimulation (tDCS); transcranial magnetic stimulation (TMS) ID WARM-UP DECREMENT; CORTEX PLASTICITY; PERFORMANCE; MEMORY; EXCITABILITY; SLEEP; REPRESENTATION; FACILITATION; SPECIFICITY; ADAPTATION AB Motor skills can take weeks to months to acquire and can diminish over time in the absence of continued practice. Thus, strategies that enhance skill acquisition or retention are of great scientific and practical interest. Here we investigated the effect of noninvasive cortical stimulation on the extended time course of learning a novel and challenging motor skill task. A skill measure was chosen to reflect shifts in the task's speed-accuracy tradeoff function (SAF), which prevented us from falsely interpreting variations in position along an unchanged SAF as a change in skill. Subjects practiced over 5 consecutive days while receiving transcranial direct current stimulation (tDCS) over the primary motor cortex (M1). Using the skill measure, we assessed the impact of anodal (relative to sham) tDCS on both within-day (online) and between-day (offline) effects and on the rate of forgetting during a 3-month follow-up (long-term retention). There was greater total (online plus offline) skill acquisition with anodal tDCS compared to sham, which was mediated through a selective enhancement of offline effects. Anodal tDCS did not change the rate of forgetting relative to sham across the 3-month follow-up period, and consequently the skill measure remained greater with anodal tDCS at 3 months. This prolonged enhancement may hold promise for the rehabilitation of brain injury. Furthermore, these findings support the existence of a consolidation mechanism, susceptible to anodal tDCS, which contributes to offline effects but not to online effects or long-term retention. C1 [Reis, Janine; Schambra, Heidi M.; Cohen, Leonardo G.; Buch, Ethan R.; Fritsch, Brita] NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. [Reis, Janine; Schambra, Heidi M.; Cohen, Leonardo G.; Buch, Ethan R.; Fritsch, Brita] NINDS, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20892 USA. [Reis, Janine; Fritsch, Brita] Univ Freiburg, Dept Neurol, D-79106 Freiburg, Germany. [Zarahn, Eric; Krakauer, John W.] Columbia Univ Coll Phys & Surg, Dept Neurol, Motor Performance Lab, New York, NY 10032 USA. [Celnik, Pablo A.] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD 21287 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov; pcelnik@jhmi.edu RI Buch, Ethan/G-1981-2011; OI Fritsch, Brita/0000-0003-4884-9049 FU National Institutes of Health (NIH) [R01-052804, R01HD053793]; Alexander von Humboldt Foundation Germany; Graduate Partnerships Program Oxford-NIH PhD program; American Heart Association [0665347U]; Rehabilitation Medicine Scientist Training Program [5K12HD001097] FX We thank Dr. Steve Wise for helpful comments and Alana Bremers for help with analysis. This research was supported by the Intramural Research Program, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) (J.R., H. M. S., B. F., and L. G. C.), the Alexander von Humboldt Foundation Germany (J.R.), Graduate Partnerships Program Oxford-NIH PhD program (E. R. B.), the American Heart Association (0665347U, P. A. C.), National Institute of Child Health and Human Development (NICHD), NIH (R01HD053793, P. A. C.), the Rehabilitation Medicine Scientist Training Program (5K12HD001097, P. A. C.), and NINDS NIH R01-052804 (E.Z. and J.W.K.). NR 52 TC 477 Z9 484 U1 8 U2 81 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2009 VL 106 IS 5 BP 1590 EP 1595 DI 10.1073/pnas.0805413106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 403HV UT WOS:000263074600054 PM 19164589 ER PT J AU Bhirde, AA Patel, V Gavard, J Zhang, GF Sousa, AA Masedunskas, A Leapman, RD Weigert, R Gutkind, JS Rusling, JF AF Bhirde, Ashwin A. Patel, Vyomesh Gavard, Julie Zhang, Guofeng Sousa, Alioscka A. Masedunskas, Andrius Leapman, Richard D. Weigert, Roberto Gutkind, J. Silvio Rusling, James F. TI Targeted Killing of Cancer Cells in Vivo and in Vitro with EGF-Directed Carbon Nanotube-Based Drug Delivery SO ACS NANO LA English DT Article DE oral cancer; nanomedicine; intravital two-photon microscopy; carbon nanotubes; EGFR; EGF; quantum dots; cisplatin ID HEAD; NECK; TRANSPORTERS; CARCINOMA; CISPLATIN; MICE; DNA; FUNCTIONALIZATION; BIODISTRIBUTION; OPPORTUNITIES AB Carbon nanotube-based drug delivery holds great promise for cancer therapy. Herein we report the first targeted, in vivo killing of cancer cells using a drug-single wall carbon nanotube (SWNT) bioconjugate, and demonstrate efficacy superior to nontargeted bioconjugates. First line anticancer agent cisplatin and epidermal growth factor (EGF) were attached to SWNTs to specifically target squamous cancer, and the nontargeted control was SWNT-cisplatin without EGF. Initial in vitro imaging studies with head and neck squamous carcinoma cells (HNSCC) overexpressing EGF receptors (EGFR) using Qdot luminescence and confocal microscopy showed that SWNT-Qdot-EGF bioconjugates internalized rapidly into the cancer cells. Limited uptake occurred for control cells without EGF, and uptake was blocked by siRNA knockdown of EGFR in cancer cells, revealing the importance of EGF-EGFR binding. Three color, two-photon intravital video imaging in vivo showed that SWNT-Qdot-EGF injected into live mice was selectively taken up by HNSCC tumors, but SWNT-Qdot controls with no EGF were cleared from the tumor region in < 20 min. HNSCC cells treated with SWNT-cisplatin-EGF were also killed selectively, while control systems that did not feature EGF-EGFR binding did not influence cell proliferation. Most significantly, regression of tumor growth was rapid in mice treated with targeted SWNT-cisplatin-EGF relative to nontargeted SWNT-cisplatin. C1 [Patel, Vyomesh; Gavard, Julie; Masedunskas, Andrius; Weigert, Roberto; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Bhirde, Ashwin A.; Rusling, James F.] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. [Rusling, James F.] Univ Connecticut, Ctr Hlth, Dept Cell Biol, Farmington, CT 06032 USA. [Zhang, Guofeng; Sousa, Alioscka A.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20982 USA. RP Patel, V (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM vpatel@dir.nidcr.nih.gov; gutkind@dir.nidcr.nih.gov; james.rusling@uconn.edu RI Gutkind, J. Silvio/A-1053-2009; Gavard, Julie/I-5487-2012; OI Gavard, Julie/0000-0002-7985-9007; Masedunskas, Andrius/0000-0002-4533-5467 FU National Institute of Dental and Craniofacial Research; National Institute of Biomedical Imaging and Bioengineering, NIH; NIEHS/NIH [ES013557] FX This research was supported by the intramural programs of the National Institute of Dental and Craniofacial Research and the National Institute of Biomedical Imaging and Bioengineering, NIH, and in part by PHS grant ES013557 from NIEHS/NIH. NR 54 TC 437 Z9 447 U1 28 U2 163 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD FEB PY 2009 VL 3 IS 2 BP 307 EP 316 DI 10.1021/nn800551s PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 412AR UT WOS:000263696100010 PM 19236065 ER PT J AU Soyka, M Gorelick, DA AF Soyka, Michael Gorelick, David A. TI Why should addiction medicine be an attractive field for young physicians? SO ADDICTION LA English DT Article DE Addiction medicine; addiction psychiatry; profession; specialty; stigma; training; treatment ID ILLICIT DRUGS; DSM-V; COST; CHALLENGES; DEPENDENCE; PSYCHIATRY; SUBSTANCE; OUTCOMES; ALCOHOL; TOBACCO AB The clinical practice and science of addiction are increasingly active fields, which are attracting professionals from diverse disciplines such as psychology and neurobiology. Our scientific knowledge of the pathophysiology of addiction is rapidly growing, along with the variety of effective treatments available to clinicians. Yet, we believe that the medical specialties of addiction medicine/psychiatry are not attracting the interest and enthusiasm of young physicians. What can be done? We offer the opinions of two experience addiction psychiatrists. In the US, there has been a decline in the number of psychiatrists seeking training or board certification in addiction psychiatry; about one-third of graduates with such training are not practicing in an addiction psychiatry setting. There is widespread neglect of addiction medicine/psychiatry among the medical profession, academia and national health authorities. This neglect is unfortunate, given the enormous societal costs of addiction (3-5% of the gross domestic product in some developed countries), the substantial unmet need for addiction treatment, and the highly favourable benefit to cost yield (at least 7:1) from treatment. We believe that addiction medicine/psychiatry can be made more attractive for young physicians. Helpful steps include widening acceptance as a medical specialty or subspecialty, reducing the social stigma against people with substance use disorders, expanding insurance coverage and increasing the low rates of reimbursement for physicians. These steps would be easier to take with broader societal (and political) recognition of substance use disorders as a major cause of premature death, morbidity and economic burden. C1 [Gorelick, David A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Soyka, Michael] Univ Munich, Hosp Psychiat, D-8000 Munich, Germany. [Soyka, Michael] Private Hosp Meiringen, Meiringen, Switzerland. RP Gorelick, DA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov FU Intramural Research Program; US National Institutes of Health; National Institute on Drug Abuse FX Dr Gorelick is supported by the Intramural Research Program, US National Institutes of Health, National Institute on Drug Abuse. NR 26 TC 9 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD FEB PY 2009 VL 104 IS 2 BP 169 EP 172 DI 10.1111/j.1360-0443.2008.02330.x PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 394MK UT WOS:000262450600002 PM 18778386 ER PT J AU Gorelick, DA Soyka, M AF Gorelick, David A. Soyka, Michael TI FURTHER REFLECTIONS ON 'WHY SHOULD ADDICTION MEDICINE BE AN ATTRACTIVE FIELD FOR YOUNG PHYSICIANS?' SO ADDICTION LA English DT Editorial Material C1 [Gorelick, David A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [Soyka, Michael] Univ Munich, Hosp Psychiat, D-8000 Munich, Germany. [Soyka, Michael] Private Hosp Meiringen, Meiringen, Switzerland. RP Gorelick, DA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. EM dgorelic@intra.nida.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD FEB PY 2009 VL 104 IS 2 BP 177 EP 178 DI 10.1111/j.1360-0443.2008.02424.x PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 394MK UT WOS:000262450600006 ER PT J AU Maggio, M Lauretani, F Bandinelli, S Luci, M Basaria, S Ablondi, F Volpi, R Guralnik, JM Valenti, G Ferrucci, L Ceda, GP AF Maggio, M. Lauretani, F. Bandinelli, S. Luci, M. Basaria, S. Ablondi, F. Volpi, R. Guralnik, J. M. Valenti, G. Ferrucci, L. Ceda, G. P. TI GONADAL STATUS AND SUBSYSTEMS OF WALKING IN OLDER MEN SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract C1 [Maggio, M.; Luci, M.; Ablondi, F.; Volpi, R.; Valenti, G.; Ceda, G. P.] Univ Parma, Sect Geriatr, Dept Internal & Biomed Sci, I-43100 Parma, Italy. [Lauretani, F.] Univ Parma, Azienda Osped, Geriatr Rehabil Dept, I-43100 Parma, Italy. [Bandinelli, S.] ASF, Geriatr Rehabil Unit, Florence, Italy. [Basaria, S.] Boston Univ, Sch Med, Boston Med Ctr, Div Endocrinol & Metab, Boston, MA 02118 USA. [Guralnik, J. M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, L.] NIA, Longitud Studies Sect, Clin Res Branch, IRP,NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD FEB PY 2009 VL 21 IS 1 BP 88 EP 88 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 417GK UT WOS:000264064300037 ER PT J AU Maggio, M Valenti, G Schwartz, RS Ferrucci, L Lauretani, F Ceresini, G Luci, M Bandinelli, S Ceda, GP AF Maggio, M. Valenti, G. Schwartz, R. S. Ferrucci, L. Lauretani, F. Ceresini, G. Luci, M. Bandinelli, S. Ceda, G. P. TI DHEAS AND COGNITIVE FUNCTION IN THE ELDERLY SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract C1 [Maggio, M.; Valenti, G.; Ceresini, G.; Luci, M.; Ceda, G. P.] Univ Parma, Sect Geriatr, Dept Internal & Biomed Sci, I-43100 Parma, Italy. [Schwartz, R. S.] Univ Colorado, Div Geriatr Med, Denver, CO 80202 USA. [Ferrucci, L.] NIA, Longitud Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Lauretani, F.] Univ Parma, Geriatr Rehabil Dept, Azienda Osped, I-43100 Parma, Italy. [Bandinelli, S.] AUSL 10, Geriatr Unit, Florence, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD FEB PY 2009 VL 21 IS 1 BP 89 EP 89 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 417GK UT WOS:000264064300038 ER PT J AU Rossi, L Galvani, M Cavalieri, M Sioulis, F Volpato, S Ferrucci, L Guralnik, J Fellin, R Zuliani, G AF Rossi, L. Galvani, M. Cavalieri, M. Sioulis, F. Volpato, S. Ferrucci, L. Guralnik, J. Fellin, R. Zuliani, G. TI RELATIONSHIP BETWEEN PLASMA LIPIDS AND DEMENTIA IN THE ELDERLY: DATA FROM THE InCHIANTI STUDY SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract C1 [Rossi, L.; Galvani, M.; Cavalieri, M.; Sioulis, F.; Fellin, R.; Zuliani, G.] Univ Ferrara, Sect Internal Med Gerontol & Geriatr, Dept Clin & Expt Med, I-44100 Ferrara, Italy. [Ferrucci, L.; Guralnik, J.] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD USA. RI Cavalieri, Margherita/G-8053-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD FEB PY 2009 VL 21 IS 1 BP 93 EP 93 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 417GK UT WOS:000264064300057 ER PT J AU Sioulis, F Cavalieri, M Guerra, G Rossi, L Fellin, R Guranlnik, JM Volpato, S AF Sioulis, F. Cavalieri, M. Guerra, G. Rossi, L. Fellin, R. Guranlnik, J. M. Volpato, S. TI PREDICTIVE VALUE OF PERFORMANCE-BASED FUNCTIONAL ASSESSMENT IN OLDER HOSPITALIZED PATIENTS SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract C1 [Sioulis, F.; Cavalieri, M.; Guerra, G.; Rossi, L.; Fellin, R.; Volpato, S.] Univ Ferrara, Sez Med Interna Gerontol & Geriatr, I-44100 Ferrara, Italy. [Guranlnik, J. M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. RI Cavalieri, Margherita/G-8053-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD FEB PY 2009 VL 21 IS 1 BP 94 EP 94 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 417GK UT WOS:000264064300061 ER PT J AU Nakamura, AJ Redon, CE Bonner, WM Sedelnikova, OA AF Nakamura, Asako J. Redon, Christophe E. Bonner, William M. Sedelnikova, Olga A. TI Telomere-dependent and telomere-independent origins of endogenous DNA damage in tumor cells SO AGING-US LA English DT Article DE DNA damage; double-strand breaks; gamma-H2AX; metaphase; telomeres; tumors ID DOUBLE-STRAND BREAKS; GENOMIC INSTABILITY; CANCER; GAMMA-H2AX; KINETICS; LESIONS; REPAIR; H2AX AB Human tumors and cultured cells contain elevated levels of endogenous DNA damage resulting from telomere dysfunction, replication and transcription errors, reactive oxygen species, and genome instability. However, the contribution of telomere-associated versus telomere-independent endogenous DNA lesions to this damage has never been examined. In this study, we characterized the relative amounts of these two types of DNA damage in five tumor cell lines by noting whether gamma-H2AX foci, generally considered to mark DNA double-strand breaks (DSBs), were on chromosome arms or at chromosome ends. We found that while the numbers of non-telomeric DSBs were remarkably similar in these cultures, considerable variation was detected in the level of telomeric damage. The distinct heterogeneity in the numbers of gamma-H2AX foci in these tumor cell lines was found to be due to foci associated with uncapped telomeres, and the amount of total telomeric damage also appeared to inversely correlate with the telomerase activity present in these cells. These results indicate that damaged telomeres are the major factor accounting for the variability in the amount of DNA DSB damage in tumor cells. This characterization of DNA damage in tumor cells helps clarify the contribution of non-telomeric DSBs and damaged telomeres to major genomic alterations. C1 [Nakamura, Asako J.; Redon, Christophe E.; Bonner, William M.; Sedelnikova, Olga A.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sedelnikova, OA (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bldg 37 Rm 5050,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sedelnio@mail.nih.gov FU National Cancer Institute; Center for Cancer Research, NIH FX We thank Jennifer Dickey, NCI, for critical reading of the manuscript. This work was funded by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. NR 28 TC 41 Z9 43 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 FEB PY 2009 VL 1 IS 2 BP 212 EP U24 PG 8 WC Cell Biology SC Cell Biology GA 579UL UT WOS:000276400900006 PM 20157510 ER PT J AU Aggarwal, M Brosh, RM AF Aggarwal, Monika Brosh, Robert M., Jr. TI WRN helicase defective in the premature aging disorder Werner syndrome genetically Interacts with topoisomerase 3 and restores the top3 slow growth phenotype of sgs1 top3 SO AGING-US LA English DT Article DE Werner syndrome; helicase; topoisomerase; RecQ; Bloom's syndrome; Sgs1; genomic instability ID SGS1 DNA HELICASE; HOLLIDAY JUNCTION DISSOLVASOME; SYNDROME PROTEIN FUNCTION; BLOOM-SYNDROME PROTEIN; HOMOLOGOUS RECOMBINATION; RECQ HELICASES; SACCHAROMYCES-CEREVISIAE; FISSION YEAST; III-ALPHA; DOMAIN AB Werner syndrome (WS) is a premature aging disorder characterized by genomic instability. The WRN gene defective in WS encodes a protein with both helicase and exonuclease activities that interacts with proteins implicated in DNA metabolism. To understand its genetic functions, we examined the ability of human WRN to rescue phenotypes associated with sgs1, the sole RecQ helicase in Saccharomyces cerevisiae. WRN failed to rescue sgs1 sensitivity to the DNA damaging agent methylmethane sulfonate or replication inhibitor hydroxyurea, suggesting divergent functions of human and yeast RecQ helicases. However, physiological expression of WRN in sgs1 top3 restored top3 slow growth phenotype, whereas no effect on growth was observed with wild-type or sgs1 strains. Slow growth of WRN-transformed sgs1 top3 correlated with an elevated population of large-budded cells with undivided nuclei, indicating restoration of cell cycle delay in late S/G2 characteristic of top3. WRN helicase but not exonuclease activity was genetically required for restoration of top3 growth phenotype, demonstrating separation of function of WRN catalytic activities. A naturally occurring missense polymorphism in WRN that interferes with helicase activity abolished its ability to restore top3 slow growth phenotype. Proposed roles of WRN in genetic pathways important for the suppression of genomic instability are discussed. C1 [Aggarwal, Monika; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Rm 06B125, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU NIH FX This work was supported in full by the Intramural Research program of the NIH, National Institute on Aging. We thank Dr. Rodney Rothstein Columbia University) for the yeast strains and Dr. Brad Johnson University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania) for the SGS1 expression plasmid. We thank Dr. Jian Lu Laboratory of Molecular Gerontology, NIA-NIH) for helpful comments on the manuscript. NR 47 TC 9 Z9 9 U1 0 U2 1 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 FEB PY 2009 VL 1 IS 2 BP 219 EP 233 PG 15 WC Cell Biology SC Cell Biology GA 579UL UT WOS:000276400900007 PM 20157511 ER PT J AU Choi, SH Bosetti, F AF Choi, Sang-Ho Bosetti, Francesca TI Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid SO AGING-US LA English DT Article DE cyclooxygenase; microglia; neuroinflammation; oxidative stress; neurotoxicity ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ALZHEIMERS-DISEASE BRAIN; CSF PROSTAGLANDIN E-2; NITRIC-OXIDE SYNTHASE; IN-VIVO; NEURONAL DEGENERATION; HIPPOCAMPAL-NEURONS; LIPID-PEROXIDATION; PROTEIN OXIDATION; CONTROLLED-TRIAL AB Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletion on the inflammatory response and neurodegeneration induced by beta-amyloid. beta-amyloid (A beta(1-42)) was centrally injected in the lateral ventricle of COX-1-deficient (COX-1(-/-)) and their respective wild-type (WT) mice. In COX-1(-/-) mice, A beta(1-42)-induced inflammatory response and neuronal damage were attenuated compared to WT mice, as shown by Fluoro-Jade B and nitrotyrosine staining. These results indicate that inhibition of COX-1 activity may be valid therapeutic strategy to reduce brain inflammatory response and neurodegeneration. C1 [Choi, Sang-Ho; Bosetti, Francesca] NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bosetti, F (reprint author), NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, 9 Mem Dr Bldg 9 Rm 1S126, Bethesda, MD 20892 USA. EM frances@mail.nih.gov FU National Institute on Aging; National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. We thank Dr. Robert Langenbach for providing COX-1-/- and WT mice. We also thank Drs. Saba Aid, Sara Palumbo, and Christopher D. Toscano for experimental suggestions and critical comments. NR 76 TC 45 Z9 46 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 FEB PY 2009 VL 1 IS 2 BP 234 EP 244 PG 11 WC Cell Biology SC Cell Biology GA 579UL UT WOS:000276400900008 PM 20157512 ER PT J AU Dmitrieva, NI Chen, HT Nussenzweig, A Burg, MB AF Dmitrieva, Natalia I. Chen, Hua Tang Nussenzweig, Andre Burg, Maurice B. TI Knockout of Ku86 accelerates cellular senescence induced by high NaCl SO AGING-US LA English DT Article DE Salt; DNA damage; osmotic stress; senescence; aging; dehydration; Ku86 mice ID V(D)J RECOMBINATION; DNA BREAKS; IN-VIVO; CELLS; EXPRESSION; DELETION; MICE; CULTURE; PROTEIN; KIDNEY AB NaCl induces DNA breaks, thus leading to cellular senescence. Here we showed that Ku86 deficiency accelerated the high NaCl-induced cellular senescence. We find that 1) high NaCl induces rapid cellular senescence in Ku86 deficient (xrs5) cells, 2) Ku86 deficiency shortens lifespan of C. elegans in high NaCl, and 3) cellular senescence is greatly accelerated in renal inner medullas of Ku86(-/-) mice. Further, although water balance is known to be compromised in old mice, this occurs at much earlier age in Ku86(-/-) mice. When subjected to mild water restriction, 3 month old Ku86(-/-), but not Ku86(+/+), mice rapidly become dehydrated as evidenced by decrease in body weight, increased production of antidiuretic hormone, increased urine osmolality and decreased urine volume. The deficiency in water balance does not occur in Ku86(+/+) mice until they are much older (14 months). We conclude that Ku86 deficiency accelerates high NaCl-induced cellular senescence, particularly in the renal medulla where NaCl normally is high. C1 [Dmitrieva, Natalia I.; Burg, Maurice B.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. [Chen, Hua Tang; Nussenzweig, Andre] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Dmitrieva, NI (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 FU NIH; NHLBI; NCI FX We thank Joseph Handler for suggestions on experimental design and Chris Combs and Daniela Malide of the National Heart, Lung, and Blood Institute (NHLBI) Light Microscopy Core Facility for help with microscopy. This research was supported by the Intramural Research Program of the NIH, NHLBI and NCI. NR 30 TC 3 Z9 4 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 FEB PY 2009 VL 1 IS 2 BP 245 EP 253 PG 9 WC Cell Biology SC Cell Biology GA 579UL UT WOS:000276400900009 PM 19946467 ER PT J AU Ducci, F Enoch, MA Yuan, Q Shen, PH White, KV Hodgkinson, C Albaugh, B Virkkunen, M Goldman, D AF Ducci, Francesca Enoch, Mary-Anne Yuan, Qiaoping Shen, Pei-Hong White, Kenneth V. Hodgkinson, Colin Albaugh, Bernard Virkkunen, Matti Goldman, David TI HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power-an intermediate phenotype for alcoholism and co-morbid behaviors SO ALCOHOL LA English DT Article DE Antisocial Personality Disorder; Serotonin; HTR3; Alcoholism; EEG ID 5-HT3 RECEPTOR ANTAGONIST; DOPAMINE RELEASE; USE DISORDERS; PERSONALITY-DISORDER; SEROTONIN-3 RECEPTOR; NUCLEUS-ACCUMBENS; SUBUNIT; NEURONS; GENE; MEN AB Alcohol use disorders (AUD) with co-morbid antisocial personality disorder (ASPD) have been associated with serotonin (5-HT) dysfunction. 5-HT3 receptors are potentiated by ethanol and appear to modulate reward. 5-HT3 receptor antagonists may be useful in the treatment of early-onset alcoholics with co-morbid ASPD. Low-voltage alpha electroencephalogram (EEG) power, a highly heritable trait, has been associated with both AUD and ASPD. A recent whole genome linkage scan in one of our samples, Plains American Indians (PI), has shown a suggestive linkage peak for alpha power at the 5-HT3R locus. We tested whether genetic variation within the HTR3A and HTR3B genes influences vulnerability to AUD with comorbid ASPD (AUD + ASPD) and moderates alpha power. Our study included three samples: 284 criminal alcoholic Finnish Caucasians and 234 controls; two independent community-ascertained samples with resting EEG recordings: a predominantly Caucasian sample of 191 individuals (Bethesda) and 306 PI. In the Finns, an intronic HTR3B SNP rs3782025 was associated with AUD + ASPD (P = .004). In the Bethesda sample, the same allele predicted lower alpha power (P = 7.37e(-5)). Associations between alpha power and two other HTR3B SNPs were also observed among PI (P = .03). One haplotype in the haplotype block at the 3' region of the gene that included rs3782025 was associated with AUD + ASPD in the Finns (P = .02) and with reduced alpha power in the Bethesda population (P = .00009). Another haplotype in this block was associated with alpha power among PI (P = .03). No associations were found for HTR3A. Genetic variation within HTR3B may influence vulnerability to develop AUD with comorbid ASPI). 5-HT3R might contribute to the imbalance between excitation and inhibition that characterize the brain of alcoholics. (C) 2009 Elsevier Inc. All rights reserved. C1 [Ducci, Francesca] P080 Inst Psychiat, SGDP Ctr, Div Psychol, London SE5 8AF, England. [Enoch, Mary-Anne; Yuan, Qiaoping; Shen, Pei-Hong; White, Kenneth V.; Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, Nihon Univ, Bethesda, MD USA. [Albaugh, Bernard] Ctr Human Behav Studies Inc, Weatherford, TX USA. [Virkkunen, Matti] Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. RP Ducci, F (reprint author), P080 Inst Psychiat, SGDP Ctr, Div Psychol, 16 De Crespigny Pk, London SE5 8AF, England. EM Francesca.Ducci@iop.kcl.uk RI Hodgkinson, Colin/F-9899-2010; Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z99 AA999999, Z01 AA000306-02] NR 54 TC 25 Z9 26 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 J9 ALCOHOL JI Alcohol PD FEB PY 2009 VL 43 IS 1 BP 73 EP 84 DI 10.1016/j.alcohol.2008.09.005 PG 12 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 410KY UT WOS:000263577100009 PM 19185213 ER PT J AU Purohit, V Gao, B Song, BJ AF Purohit, Vishnudutt Gao, Bin Song, Byoung-Joon TI Molecular Mechanisms of Alcoholic Fatty Liver SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE Alcohol; Fatty Liver; NADH; NAD(+); Oxidative Stress; Cytokines; Adipokines; Oxidation of Fatty Acids; Signaling Pathways ID ACTIVATED RECEPTOR-ALPHA; TUMOR-NECROSIS-FACTOR; CHRONIC ETHANOL-CONSUMPTION; CYTOCHROME-P450 2E1 INDUCTION; INDUCED INSULIN-RESISTANCE; ELEMENT-BINDING PROTEIN-1; DIETARY SATURATED FAT; HEPATIC CB1 RECEPTORS; N-TERMINAL KINASE; PPAR-ALPHA AB Alcoholic fatty liver is a potentially pathologic condition which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. Alcohol exposure may induce fatty liver by increasing NADH/NAD(+) ratio, increasing sterol regulatory element-binding protein-1 (SREBP-1) activity, decreasing peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity, and increasing complement C3 hepatic levels. Alcohol may increase SREBP-1 activity by decreasing the activities of AMP-activated protein kinase and sirtuin-1. Tumor necrosis factor-alpha (TNF-alpha) produced in response to alcohol exposure may cause fatty liver by up-regulating SREBP-1 activity, whereas betaine and pioglitazone may attenuate fatty liver by down-regulating SREBP-1 activity. PPAR-alpha agonists have potentials to attenuate alcoholic fatty liver. Adiponectin and interleukin-6 may attenuate alcoholic fatty liver by up-regulating PPAR-alpha and insulin signaling pathways while down-regulating SREBP-1 activity and suppressing TNF-alpha production. Recent studies show that paracrine activation of hepatic cannabinoid receptor 1 by hepatic stellate cell-derived endocannabinoids also contributes to the development of alcoholic fatty liver. Furthermore, oxidative modifications and inactivation of the enzymes involved in the mitochondrial and/or peroxisomal beta-oxidation of fatty acids could contribute to fat accumulation in the liver. C1 [Purohit, Vishnudutt] NIAAA, Div Metab & Hlth Effects, NIH, Bethesda, MD 20892 USA. [Gao, Bin] NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Purohit, V (reprint author), NIAAA, Div Metab & Hlth Effects, NIH, 5635 Fishers Lane,Room 2035,MSC 9304, Bethesda, MD 20892 USA. EM vpurohit@mail.nih.gov; bjs@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the Intramural and Extramural Programs of National Institute on Alcohol Abuse and Alcoholism. We are grateful to the anonymous reviewers' expert comments and constructive criticisms to improve our manuscript. We are also thankful to Dr. James P. Hardwick, Northeastern Ohio University Medical College, for his critical reading and helpful comments. NR 199 TC 122 Z9 136 U1 1 U2 11 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2009 VL 33 IS 2 BP 191 EP 205 DI 10.1111/j.1530-0277.2008.00827.x PG 15 WC Substance Abuse SC Substance Abuse GA 397KS UT WOS:000262662200001 PM 19032584 ER PT J AU Flegal, KM Shepherd, JA Looker, AC Graubard, BI Borrud, LG Ogden, CL Harris, TB Everhart, JE Schenker, N AF Flegal, Katherine M. Shepherd, John A. Looker, Anne C. Graubard, Barry I. Borrud, Lori G. Ogden, Cynthia L. Harris, Tamara B. Everhart, James E. Schenker, Nathaniel TI Comparisons of percentage body fat, body mass index, waist circumference, and waist-stature ratio in adults SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID X-RAY ABSORPTIOMETRY; ALL-CAUSE MORTALITY; MIDDLE-AGED MEN; WHITE WOMEN; 4-COMPARTMENT MODELS; POSTMENOPAUSAL WOMEN; DEFINE OVERWEIGHT; ASIAN POPULATIONS; AFRICAN-AMERICAN; ETHNIC-GROUPS AB Background: Body mass index (BMI), waist circumference (WC), and the waist-stature ratio (WSR) are considered to be possible proxies for adiposity. Objective: The objective was to investigate the relations between BMI, WC, WSR, and percentage body fat (measured by dual-energy X-ray absorptiometry) in adults in a large nationally representative US population sample from the National Health and Nutrition Examination Survey (NHANES). Design: BMI, WC, and WSR were compared with percentage body fat in a sample of 12,901 adults. Results: WC, WSR, and BMI were significantly more correlated with each other than with percentage body fat (P < 0.0001 for all sex-age groups). Percentage body fat tended to be significantly more correlated with WC than with BMI in men but significantly more correlated with BMI than with WC in women (P, 0.0001 except in the oldest age group). WSR tended to be slightly more correlated with percentage body fat than was WC. Percentile values of BMI, WC, and WSR are shown that correspond to percentiles of percentage body fat increments of 5 percentage points. More than 90% of the sample could be categorized to within one category of percentage body fat by each measure. Conclusions: BMI, WC, and WSR perform similarly as indicators of body fatness and are more closely related to each other than with percentage body fat. These variables may be an inaccurate measure of percentage body fat for an individual, but they correspond fairly well overall with percentage body fat within sex-age groups and distinguish categories of percentage body fat. Am J Clin Nutr 2009; 89: 500-8 C1 [Flegal, Katherine M.; Looker, Anne C.; Borrud, Lori G.; Ogden, Cynthia L.; Schenker, Nathaniel] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Shepherd, John A.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Graubard, Barry I.] NCI, NIH, Bethesda, MD 20892 USA. [Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Everhart, James E.] NIDDK, NIH, Bethesda, MD USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 4201, Hyattsville, MD 20782 USA. EM kmf2@cdc.gov RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 56 TC 224 Z9 235 U1 2 U2 53 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB 1 PY 2009 VL 89 IS 2 BP 500 EP 508 DI 10.3945/ajcn.2008.26847 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 396RL UT WOS:000262608700006 PM 19116329 ER PT J AU Yang, G Shu, XO Li, HL Chow, WH Cai, H Zhang, XL Gao, YT Zheng, W AF Yang, Gong Shu, Xiao-Ou Li, Honglan Chow, Wong-Ho Cai, Hui Zhang, Xianglan Gao, Yu-Tang Zheng, Wei TI Prospective cohort study of soy food intake and colorectal cancer risk in women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID ESTROGEN-RECEPTOR-BETA; HEALTHY POSTMENOPAUSAL WOMEN; RANDOMIZED CONTROLLED-TRIAL; LARGE-BOWEL CANCER; COLON-CANCER; OXIDATIVE STRESS; PLUS PROGESTIN; BREAST-CANCER; ER-BETA; DIETARY PHYTOESTROGENS AB Background: Soy and some of its constituents, such as isoflavones, have been shown to have cancer-inhibitory activities in experimental studies. Data from epidemiologic studies linking usual soy food intake with colorectal cancer are limited and inconsistent. Objective: The objective was to investigate whether soy food intake is associated with colorectal cancer risk. Design: We prospectively examined 68,412 women aged 40-70 y and free of cancer and diabetes at enrollment. Usual soy food intake was assessed at baseline (1997-2000) and reassessed during the first follow-up (2000-2002) through in-person interviews with a validated food-frequency questionnaire. We excluded the first year of observation to minimize lifestyle changes related to preclinical disease. Results: During a mean follow- up of 6.4 y, 321 incident colorectal cancer cases were identified. After adjustment for potential confounding factors, total soy food intake was inversely associated with colorectal cancer risk. Each 5-g/d increment in intake of soy foods as assessed by dry weight [equivalent to approximate to 1 oz (28.35 g) tofu/d] was associated with an 8% reduction in risk (95% CI: 3%, 14%). Women in the highest tertile of intake had a multivariate relative risk of 0.67 (95% CI: 0.49, 0.90) compared with those in the lowest tertile (P for trend = 0.008). This inverse association was primarily confined to postmenopausal women. Similar results were also found for intakes of soy protein and isoflavones. Conclusion: This prospective study suggests that consumption of soy foods may reduce the risk of colorectal cancer in postmenopausal women. Am J Clin Nutr 2009; 89: 577-83. C1 [Yang, Gong; Shu, Xiao-Ou; Cai, Hui; Zhang, Xianglan; Zheng, Wei] Vanderbilt Univ, Med Ctr, Dept Med, Sch Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Yang, Gong; Shu, Xiao-Ou; Cai, Hui; Zhang, Xianglan; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37203 USA. [Li, Honglan; Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Yang, G (reprint author), Vanderbilt Univ, Med Ctr, Dept Med, Sch Med,Vanderbilt Epidemiol Ctr, 6th Floor,Suite 600,2525 W End Ave, Nashville, TN 37203 USA. EM gong.yang@vanderbilt.edu FU USPHS [R01CA70867, R01CA 122364]; NIH [3 N02 CP1101066] FX Supported by USPHS grant R01CA70867, the NIH intramural program (N02 CP1101066), and USPHS grant R01CA 122364. NR 64 TC 37 Z9 39 U1 3 U2 7 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB 1 PY 2009 VL 89 IS 2 BP 577 EP 583 DI 10.3945/ajcn.2008.26742 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 396RL UT WOS:000262608700016 PM 19073792 ER PT J AU Stolzenberg-Solomon, RZ Sheffler-Collins, S Weinstein, S Garabrant, DH Mannisto, S Taylor, P Virtamo, J Albanes, D AF Stolzenberg-Solomon, Rachael Z. Sheffler-Collins, Seth Weinstein, Stephanie Garabrant, David H. Mannisto, Satu Taylor, Philip Virtamo, Jarmo Albanes, Demetrius TI Vitamin E intake, alpha-tocopherol status, and pancreatic cancer in a cohort of male smokers SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID SYRIAN GOLDEN-HAMSTERS; LIPID-PEROXIDATION; DIETARY-FAT; FOLLOW-UP; CARDIOVASCULAR-DISEASE; BETA-CAROTENE; RISK; VALIDITY; CARCINOGENESIS; TRIAL AB Background: Evidence indicates that vitamin E has anticarcinogenic properties for gastrointestinal cancers; however, few studies have examined this with respect to exocrine pancreatic cancer. Objective: The objective was to examine whether vitamin E intake and serum alpha-tocopherol concentrations were prospectively associated with exocrine pancreatic cancer. Design: We conducted a cohort analysis of prediagnostic vitamin E intake (4 tocopherols, 4 tocotrienols), serum alpha-tocopherol concentrations, and pancreatic cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male Finnish smokers aged 50-69 y at baseline. During follow-up from 1985 to 2004 (maximum: 19.4 y; median: 16 y), 318 incident cases were diagnosed among cohort participants with complete serum samples (n = 29,092); 306 cases had complete dietary data (n = 27,111). Cox proportional hazards models adjusted for age, smoking history, history of diabetes mellitus, and/or serum cholesterol were used to calculate hazard ratios (HRs) and 95% CIs. Results: Higher alpha-tocopherol concentrations were associated with lower pancreatic cancer risk (highest compared with lowest quintile, HR: 0.52; 95% CI: 0.34, 0.80; P for trend = 0.03; continuous HR: 0.91; 95% CI: 0.84, 0.99). Polyunsaturated fat, a putative prooxidant nutrient, modified the association such that the inverse alpha-tocopherol association was most pronounced in subjects with a high polyunsaturated fat intake (ie, >9.9 g/d; highest compared with lowest quintile, HR: 0.38; 95% CI: 0.20, 0.70; P for trend = 0.03; continuous HR: 0.86; 95% CI: 0.75, 0.97; P for interaction = 0.05 and 0.02, respectively). No associations were observed for dietary tocopherols and tocotrienols. Conclusion: Our results support the hypothesis that higher alpha-tocopherol concentrations may play a protective role in pancreatic carcinogenesis in male smokers. Am J Clin Nutr 2009; 89: 584-91. C1 [Stolzenberg-Solomon, Rachael Z.; Sheffler-Collins, Seth; Weinstein, Stephanie; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth Human Serv, Rockville, MD USA. [Sheffler-Collins, Seth; Garabrant, David H.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Garabrant, David H.] Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Garabrant, David H.] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48109 USA. [Mannisto, Satu; Virtamo, Jarmo] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Taylor, Philip] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth Human Serv, Rockville, MD USA. RP Stolzenberg-Solomon, RZ (reprint author), 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM rs221z@nih.gov RI Albanes, Demetrius/B-9749-2015 FU National Institutes of Health; Division of Cancer Epidemiology and Genetics; National Cancer Institute [N01-CN-45165, N01-RC-45035, N01-RC-37004]; Department of Health and Human Services FX Supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, and the US Public Health Service contracts N01-CN-45165, N01-RC-45035, and N01-RC-37004 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 45 TC 19 Z9 19 U1 0 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB 1 PY 2009 VL 89 IS 2 BP 584 EP 591 DI 10.3945/ajcn.2008.26423 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 396RL UT WOS:000262608700017 PM 19116326 ER PT J AU Picciano, MF McGuire, MK AF Picciano, Mary Frances McGuire, Michelle K. TI Use of dietary supplements by pregnant and lactating women in North America SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Experimental Biology 2008 Annual Meeting CY APR 05-09, 2008 CL San Diego, CA SP Amer Soc Pharmacol & Expt Therapeut, Amer Soc Investigat Pathol, Amer Soc Nutr, Amer Soc Biochem & Mol Biol, Amer Assoc Immunologists, Amer Assoc Anatomists, Amer Physiol Soc ID PERICONCEPTIONAL MULTIVITAMIN USE; NEURAL-TUBE DEFECTS; UNITED-STATES; NATIONAL-HEALTH; RISK; VITAMIN; ASSOCIATION; PREVENTION; NUTRITION; BIRTH AB Nutrient requirements increase during periods of growth and development such as pregnancy and lactation. In response, many clinicians recommend dietary supplements during these important periods of the life cycle. Although there exist some recommendations concerning the need for a limited number of nutrients in supplemental form (eg, iron, folic acid, and iodine), there is a relative paucity of data concerning the use of dietary supplements during pregnancy and lactation. Limited data suggest, however, that usage is dependent on demographic, sociologic, and economic factors. Thus, it is possible that the nation's most at-risk populations may be those who are least likely to comply with these recommendations. As researchers continue to study what is meant by "optimal nutrition" during pregnancy and lactation, it is likely that additional recommendations concerning dietary supplements will emerge. For example, it is possible that increased consumption of some of the long-chain polyunsaturated fatty acids during pregnancy or lactation may impart a benefit to infant health. Understanding better the population dynamics related to supplement use during these periods will be critical in implementation of campaigns designed to encourage appropriate use - and discourage inappropriate use - of dietary supplements during these important phases of human reproduction. The purpose of this article is to briefly review what is known about the use of dietary supplements in North America and, more specifically, in pregnant and lactating women. In addition, information concerning barriers to supplement use is discussed as are current recommendations for dietary supplement consumption during these periods of the life cycle. Am J Clin Nutr 2009; 89(suppl): 663S-7S. C1 [Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [McGuire, Michelle K.] Washington State Univ, Dept Nutr & Exercise Metab, Pullman, WA 99164 USA. RP Picciano, MF (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,3B01, Bethesda, MD 20892 USA. EM piccianomf@od.nih.gov OI McGuire, Michelle/0000-0001-8214-2229 NR 42 TC 31 Z9 33 U1 3 U2 10 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB 1 PY 2009 VL 89 IS 2 BP 663S EP 667S DI 10.3945/ajcn.2008.26811B PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 396RL UT WOS:000262608700031 PM 19073789 ER PT J AU Kontos, MC Roberts, BD Tatum, JL Roberts, CS Jesse, RL Ornato, JP AF Kontos, Michael C. Roberts, Brett D. Tatum, James L. Roberts, Charlotte S. Jesse, Robert L. Ornato, Joseph P. TI Mortality Based on the presenting electrocardiogram in patients with myocardial infarction in the troponin era SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID CORONARY-ARTERY DISEASE; BUNDLE-BRANCH BLOCK; INITIAL ELECTROCARDIOGRAM; PROGNOSTIC VALUE; CHEST PAIN; PREDICTIVE INSTRUMENT; ADMISSION; MULTICENTER; EMERGENCY; STRATEGY AB Background: Studies reporting short-term mortality in patients with myocardial infarction (MI) based on the initial electrocardiogram (ECG) are often limited by requiring an ischemic ECG for inclusion. Because few patients with normal or nonspecific findings were included, outcomes in these patients are less clear, especially in the troponin era. Methods: Consecutive patients diagnosed as having MI using troponin I (TnI) over a 6-year period were included and classified into 8 mutually exclusive groups based on the initial ECG using standard criteria. Patients were included in only 1 group. The MI size was estimated using multiples of peak creatine kinase-MB (CK-MB), and 30-day mortality rate was assessed. Results: Among 1641 patients with MI, patients with ST elevation represented only 22% of all MIs. Patients with ST elevation had the largest MI size, with 2 of 3 having a peak CK-MB greater than 10 times normal. In contrast, most of the patients representing all the other ECG groups had a peak CK-MB less than 5 times normal, with approximately I of 3 having no CK-MB elevation and were diagnosed by Till elevation alone. Patients could be separated into a high-risk group (ST elevation, ischemia, other, or left bundle-branch block), in which mortality rate exceeded 9% (mean, 14%), and a lower-risk group (prior MI, left ventricular hypertrophy, nonspecific changes, and normal), in which the 30-day mortality rate averaged 6% (P < .001; range, 5.23%-7.1%). Conclusions: Specific ECG findings other than ischemia portend poor outcomes in patients with MI. Once MI is diagnosed, patients are no longer low risk. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kontos, Michael C.] Virginia Commonwealth Univ, Med Coll Virginia, Dept Internal Med, Div Cardiol, Richmond, VA 23298 USA. [Kontos, Michael C.; Ornato, Joseph P.] Virginia Commonwealth Univ, Dept Emergency Med, Richmond, VA 23298 USA. [Kontos, Michael C.] Virginia Commonwealth Univ, Dept Radiol, Richmond, VA 23298 USA. [Tatum, James L.] NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. RP Kontos, MC (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Internal Med, Div Cardiol, POB 980051,1200 E Marshall St, Richmond, VA 23298 USA. EM mkontos@mcvh-vcu.edu NR 23 TC 5 Z9 5 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 0735-6757 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD FEB PY 2009 VL 27 IS 2 BP 146 EP 152 DI 10.1016/j.ajem.2008.02.002 PG 7 WC Emergency Medicine SC Emergency Medicine GA 416DN UT WOS:000263985600003 PM 19371520 ER PT J AU Bunt, JC AF Bunt, Joy C. TI The Emergence of "Adult" Diseases During Childhood: Impact of a Diabetic Pregnancy SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Editorial Material ID BLOOD-PRESSURE; EXPOSURE C1 NIDDK, Obes & Diabet Clin Res Sect, NIH, Dept Hlth & Human Serv, Phoenix, AZ USA. RP Bunt, JC (reprint author), NIDDK, Obes & Diabet Clin Res Sect, NIH, Dept Hlth & Human Serv, Phoenix, AZ USA. EM jbunt@mail.nih.gov NR 7 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 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD FEB PY 2009 VL 22 IS 2 BP 131 EP 131 DI 10.1038/ajh.2008.345 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 395PZ UT WOS:000262537300004 PM 19158673 ER PT J AU Menon, V Kopple, JD Wang, XL Beck, GJ Collins, AJ Kusek, JW Greene, T Levey, AS Sarnak, MJ AF Menon, Vandana Kopple, Joel D. Wang, Xuelei Beck, Gerald J. Collins, Allan J. Kusek, John W. Greene, Tom Levey, Andrew S. Sarnak, Mark J. TI Effect of a Very Low-Protein Diet on Outcomes: Long-term Follow-up of the Modification of Diet in Renal Disease (MDRD) Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; low-protein diet; outcomes ID INDOXYL SULFATE; KIDNEY-DISEASE; BLOOD-PRESSURE; MAINTENANCE DIALYSIS; NUTRITIONAL-STATUS; BODY-COMPOSITION; UREMIC PATIENTS; ORAL SORBENT; AMINO-ACIDS; KETO ACID AB Background: The long-term effect of a very low-protein diet on the progression of kidney disease is unknown. We examined the effect of a very low-protein diet on the development of kidney failure and death during long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Study Design: Long-term follow-up of study B of the MDRD Study (1989-1993). Setting & Participants: The MDRD Study examined the effects of dietary protein restriction and blood pressure control on progression of kidney disease. This analysis includes 255 trial participants with predominantly stage 4 nondiabetic chronic kidney disease. Intervention: A low-protein diet (0.58 g/kg/d) versus a very low-protein diet (0.28 g/kg/d) supplemented with a mixture of essential keto acids and amino acids (0.28 g/kg/d). Outcomes: Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality until December 31, 2000. Results: Kidney failure developed in 227 (89%) participants, 79 (30.9%) died, and 244 (95.7%) reached the composite outcome of either kidney failure or death. Median duration of follow-up until kidney failure, death, or administrative censoring was 3.2 years, and median time to death was 10.6 years. In the low-protein group, 117 (90.7%) participants developed kidney failure, 30 (23.3%) died, and 124 (96.1%) reached the composite outcome. In the very low-protein group, 110 (87.3%) participants developed kidney failure, 49 (38.9%) died, and 120 (95.2%) reached the composite outcome. After adjustment for a priori-specified covariates, hazard ratios were 0.83 (95% confidence interval, 0.62 to 1.12) for kidney failure, 1.92 (95% confidence interval, 1.15 to 3.20) for death, and 0.89 (95% confidence interval, 0.67 to 1.18) for the composite outcome in the very low-protein diet group compared with the low-protein diet group. Limitations: Lack of dietary protein measurements during follow-up. Conclusion: In long-term follow-up of the MDRD Study, assignment to a very low-protein diet did not delay progression to kidney failure, but appeared to increase the risk of death. C1 [Menon, Vandana; Levey, Andrew S.; Sarnak, Mark J.] Tufts Med Ctr, Dept Med, Div Nephrol, Boston, MA USA. [Kopple, Joel D.] Univ Calif Los Angeles, David Geffen Sch Med, Harbor UCLA Med Ctr, Div Nephrol,Los Angeles Biomed Res Inst,Sch Publ, Los Angeles, CA 90095 USA. [Wang, Xuelei; Beck, Gerald J.] Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. [Collins, Allan J.] Hennepin Cty Med Ctr, Div Nephrol, Minneapolis, MN 55415 USA. [Kusek, John W.] NIH, Bethesda, MD 20892 USA. [Greene, Tom] Univ Utah, Div Clin Epidemiol, Salt Lake City, UT USA. RP Sarnak, MJ (reprint author), 800 Washington St 391, Boston, MA 02111 USA. EM msarnak@tuftsmedicalcenter.org FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD) [K23 DK067303, K23 DK02904, K24 DK078204, UO1 DK35073] FX This study was supported by grants K23 DK067303, K23 DK02904, K24 DK078204, and UO1 DK35073 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The NIDDKD had no role in the design, conduct, and analysis of this study or in the decision to submit the manuscript for publication. Drs Sarnak, Menon, Greene, and Wang had full access to the data. NR 49 TC 64 Z9 71 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2009 VL 53 IS 2 BP 208 EP 217 DI 10.1053/j.ajkd.2008.08.009 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 404GX UT WOS:000263140600006 PM 18950911 ER PT J AU Flessner, MF Wyatt, SB Akylbekova, EL Coady, S Fulop, T Lee, F Taylor, HA Crook, E AF Flessner, Michael F. Wyatt, Sharon B. Akylbekova, Elmeg L. Coady, Sean Fulop, Tibor Lee, Frederick Taylor, Herman A. Crook, Errol TI Prevalence and Awareness of CKD Among African Americans: The Jackson Heart Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Renal insufficiency; proteinuria; African American; chronic disease; epidemiology; population ID CHRONIC KIDNEY-DISEASE; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; CARDIOVASCULAR-DISEASE; DIABETIC-NEPHROPATHY; ALBUMINURIA; POPULATION; COMMUNITY; RISK; EPIDEMIOLOGY AB Background: Chronic kidney disease (CKD) leads to end-stage renal disease and is a growing epidemic throughout the world. In the United States, African Americans have an incidence of end-stage renal disease 4 times that of whites. Study Design: Cross-sectional to examine the prevalence and awareness of CKD in African Americans. Setting & Participants: Observational cohort in the Jackson Heart Study (JHS). Predictor: CKD was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m(2), the presence of albuminuria, or dialysis therapy. Outcomes & Measurements: Data from the JHS were analyzed. Medical history, including disease awareness and drug therapy, anthropometric measurements, and serum and urine samples, were obtained from JHS participants at the baseline visit. Associations between CKD prevalence and awareness and selected demographic, socioeconomic, health care access, and disease status parameters were assessed by using logistic regression models. Results: The prevalence of CKD in the JHS was 20%; CKD awareness was only 15.8%. Older participants had a greater prevalence, but also were more aware of CKD. Hypertension, diabetes, cardiovascular disease, hypercholesterolemia, hypertriglyceridemia, increasing age and waist circumference, and being single or less physically active were associated with CKD. Only advancing CKD stage was associated with awareness. Limitations: Cross-sectional assessment, single urine measurement. Conclusions: The JHS has a high prevalence and low awareness of CKD, especially in those with less severe disease status. This emphasizes the need for earlier diagnosis and increased education of health care providers and the general population. C1 [Flessner, Michael F.] Univ Mississippi, Med Ctr, Div Nephrol, Sch Med, Jackson, MS 39216 USA. [Wyatt, Sharon B.] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Akylbekova, Elmeg L.] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. [Coady, Sean] NHLBI, Bethesda, MD 20892 USA. [Crook, Errol] Univ S Alabama, Mobile, AL 36688 USA. RP Flessner, MF (reprint author), Univ Mississippi, Med Ctr, Div Nephrol, Sch Med, 2500 N State St, Jackson, MS 39216 USA. EM mflessner@medicine.unismed.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health FX This study was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 32 TC 30 Z9 30 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2009 VL 53 IS 2 BP 238 EP 247 DI 10.1053/j.ajkd.2008.08.035 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 404GX UT WOS:000263140600009 PM 19166799 ER PT J AU Dennis, TR Raptoulis, GN Stalker, HJ Boles, D Meck, JM Krasnewich, DM Schiffmann, R Zori, RT AF Dennis, Thomas R. Raptoulis, Gina N. Stalker, Heather J. Boles, Debra Meck, Jeanne M. Krasnewich, Donna M. Schiffmann, Raphael Zori, Roberto T. TI Molecular Cytogenetic Characterization of Two Small Supernumerary Marker Chromosomes Derived from Chromosome 19 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID PRENATAL-DIAGNOSIS; MICRODISSECTION; FISH; IDENTIFICATION; TRISOMY C1 [Dennis, Thomas R.] Shodair Childrens Hosp, Dept Genet, Helena, MT 59601 USA. [Raptoulis, Gina N.] Nova SE Univ, Coll Osteopath Med, Ft Lauderdale, FL 33314 USA. [Stalker, Heather J.; Zori, Roberto T.] Univ Florida, Dept Pediat, Div Genet, Gainesville, FL USA. [Boles, Debra] Cytogenet Lab, Caril Labs, Charlotte, NC USA. [Meck, Jeanne M.] Cytogenet Lab, Quest Diagnost Nichols Inst, Chantilly, VA USA. [Krasnewich, Donna M.] NHGRI, Med Genet Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Schiffmann, Raphael] Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, Natl Inst Hlth, Bethesda, MD USA. RP Dennis, TR (reprint author), Shodair Childrens Hosp, Dept Genet, 2755 Colonial Dr, Helena, MT 59601 USA. EM tdennis@shodair.org FU Intramural NIH HHS NR 15 TC 3 Z9 3 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB PY 2009 VL 149A IS 2 BP 262 EP 265 DI 10.1002/ajmg.a.32512 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 408KH UT WOS:000263433400022 PM 19133694 ER PT J AU Gucev, Z Biesecker, LG AF Gucev, Zoran Biesecker, Leslie G. TI Response to "CLOVE(S) Syndrome: Expanding the Acronym" SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID CONGENITAL LIPOMATOUS OVERGROWTH; VASCULAR MALFORMATIONS C1 [Gucev, Zoran] Univ Skopje, Skopje 1000, Macedonia. [Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Gucev, Z (reprint author), Univ Skopje, Vodnjanska BB, Skopje 1000, Macedonia. EM gucevz@gmail.com NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB PY 2009 VL 149A IS 2 BP 295 EP 295 DI 10.1002/ajmg.a.32636 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 408KH UT WOS:000263433400031 ER PT J AU Roberson, R Cameroni, I Toso, L Abebe, D Bissel, S Spong, CY AF Roberson, Robin Cameroni, Irene Toso, Laura Abebe, Daniel Bissel, Stephanie Spong, Catherine Y. TI Alterations in phosphorylated cyclic adenosine monophosphate response element of binding protein activity: a pathway for fetal alcohol syndrome-related neurotoxicity SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the Society-of-Maternal-Fetal-Medicine CY FEB 05-10, 2007 CL San Francisco, CA SP Soc Maternal Fetal Med DE apoptosis; fetal alcohol syndrome; hippocampus; mouse; phosphorylated cyclic adenosine monophosphate response element of binding protein ID HIPPOCAMPAL CA1 REGION; CREB PHOSPHORYLATION; EXPRESSION; EXPOSURE; NEURONS; LESIONS; MEMORY; PLACE; CAMP; RAT AB OBJECTIVE: Fetal alcohol syndrome (FAS) is the leading cause of a spectrum of preventable nongenetic learning and behavioral disorders. In adult (FAS) mice, we measured phosphorylated cyclic adenosine monophosphate response element of binding protein (pCREB) staining in hippocampal subregions to evaluate a possible mechanism underlying FAS learning deficits. STUDY DESIGN: Pregnant C57BL6/J mice were treated on gestational day 8 with alcohol or control (saline). After learning assessment, the offspring were perfused for immunohistochemistry and brain sections probed using SER 133 pCREB antibody. Relative staining density was assessed using National Institutes of Health Image software. Statistical analysis included analysis of variance with P < .05 considered significant. RESULTS: In all hippocampal subregions, pCREB staining was greater in the control animals than in the alcohol-treated group (P <= .0001). CONCLUSION: In utero alcohol exposure decreased pCREB activity in hippocampal subregions of adult mice. The dentate gyrus had the most robust cumulative decrease in pCREB staining, suggesting FAS adult learning deficits may correlate to enhanced dentate gyrus neurodegeneration. C1 [Roberson, Robin; Toso, Laura; Abebe, Daniel; Bissel, Stephanie; Spong, Catherine Y.] NICHHD, Unit Perinatal & Dev Neurobiol, NIH, Bethesda, MD 20895 USA. [Cameroni, Irene] Univ Milano Bicocca, Dept Obstet & Gynecol, Milan, Italy. RP Roberson, R (reprint author), NICHHD, Unit Perinatal & Dev Neurobiol, NIH, 9000 Rockville Pike, Bethesda, MD 20895 USA. EM robersor@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 40 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2009 VL 200 IS 2 AR 193.e1 DI 10.1016/j.ajog.2008.08.054 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 401YF UT WOS:000262979100029 PM 19110231 ER PT J AU Babbin, BA Koch, S Bachar, M Conti, MA Parkos, CA Adelstein, RS Nusrat, A Ivanov, AI AF Babbin, Brian A. Koch, Stefan Bachar, Moshe Conti, Mary-Anne Parkos, Charles A. Adelstein, Robert S. Nusrat, Asma Ivanov, Andrei I. TI Non-Muscle Myosin IIA Differentially Regulates Intestinal Epithelial Cell Restitution and Matrix Invasion SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID 3-DIMENSIONAL COLLAGEN MATRICES; TAXOL-INDUCED APOPTOSIS; MAP-KINASE PATHWAYS; ADHESION DYNAMICS; TUMOR PROGRESSION; MIGRATING CELLS; PLASMA-MEMBRANE; FOCAL ADHESIONS; CANCER INVASION; RHO-KINASE AB Epithelial cell motility is critical for self-rejuvenation of normal intestinal mucosa, wound repair, and cancer metastasis. This process is regulated by the reorganization of the F-actin cytoskeleton, which is driven by a myosin 11 motor. However, the role of myosin 11 in regulating epithelial cell migration remains poorly understood. This study addressed the role of non-muscle myosin (NM) IIA in two different modes of epithelial cell migration: two-dimensional (2-D) migration that occurs during wound closure and three-dimensional (3-D) migration through a Matrigel matrix that occurs during cancer metastasis. Phamacological inhibition or siRNA-mediated knockdown of NM IIA in SK-CO15 human colonic epithelial cells resulted in decreased 2-D migration and increased 3-D invasion. The attenuated 2-D migration was associated with increased cell adhesiveness to collagen and laminin and enhanced expression of beta 1-integrin and paxillin. On the 2-D surface, NM IIA-deficient SKCO15 cells failed to assemble focal adhesions and F-actin stress fibers. In contrast, the enhanced invasion of NM IIA-depleted cells was dependent on Raf-ERK1/2 signaling pathway activation, enhanced calpain activity, and increased calpain-2 expression. Our findings suggest that NM IIA promotes 2-D epithelial cell migration but antagonizes 3-D invasion. These observations indicate multiple functions for NM IIA, which, along with the regulation of the F-actin cytoskeleton and cell-matrix adhesions, involve previously unrecognized control of intracellular signaling and protein expression. (Am J Pathol 2009, 174:436-448; DOI: 10.2353/ajpath.2009.080171) C1 [Ivanov, Andrei I.] Univ Rochester, Dept Med, Div Gastroenterol & Hepatol, Rochester, NY 14642 USA. [Babbin, Brian A.; Koch, Stefan; Bachar, Moshe; Parkos, Charles A.; Nusrat, Asma; Ivanov, Andrei I.] Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA. [Conti, Mary-Anne; Adelstein, Robert S.] Natl Heart Lung Blood Inst, Mol Cardiol Lab, NIH, Bethesda, MD USA. RP Ivanov, AI (reprint author), Univ Rochester, Dept Med, Div Gastroenterol & Hepatol, Rochester, NY 14642 USA. EM Andrei_Ivanov@urmc.rochester.edu RI Nusrat, Asma/B-3887-2009; Parkos, Charles/B-3896-2009; OI Adelstein, Robert/0000-0002-8683-2144 FU Crohn's and Colitis Foundation of America; NIH career development award [K08 DK074706-01]; National Institutes of Health [DK 61379, DK 72564, DK 55679, DK 59888, DK 064399] FX Supported by a Career Development Award from Crohn's and Colitis Foundation of America (to A.I.I.), a NIH career development award (K08 DK074706-01 to B.A.B) and by National Institutes of Health grants DK 61379 and DK 72564 (to C.A.P.). DK 55679, and DK 59888 (to A.N.) and a digestive diseases minicenter grant DK 064399 (epithelial tissue culture and morphology cores). NR 81 TC 30 Z9 30 U1 0 U2 7 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 2009 VL 174 IS 2 BP 436 EP 448 DI 10.2353/ajpath.2009.080171 PG 13 WC Pathology SC Pathology GA 397TK UT WOS:000262684800009 PM 19147824 ER PT J AU Li, QL Schurgers, LJ Smith, ACM Tsokos, M Uitto, J Cowen, EW AF Li, Qiaoli Schurgers, Leon J. Smith, Ann C. M. Tsokos, Maria Uitto, Jouni Cowen, Edward W. TI Co-Existent Pseudoxanthoma Elasticum and Vitamin K-Dependent Coagulation Factor Deficiency Compound Heterozygosity for Mutations in the GGCX Gene SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MATRIX-GLA-PROTEIN; GAMMA-GLUTAMYL-CARBOXYLASE; CLOTTING FACTORS; CALCIFICATION; RESISTANCE; LIVER AB Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes, and cardiovascular system. The classic forms of PXE, are due to mutations in the ABCC6 gene that encodes the ABCC6 protein, a putative transmembrane transporter expressed primarily in the liver and the kidneys. PXE-like clinical findings have been encountered in association with vitamin K-dependent coagulation factor deficiency, an autosomal recessive disorder that is due to mutations in either the GGCX or VKORC1 genes. In this study, we investigated a family with two siblings with characteristic features of PXE and vitamin K-dependent coagulation factor deficiency. Mutation analysis identified two GGCX mutations in the affected individuals (p. R83W and p.Q374X); however, no mutations in either ABCC6 or VKORC1 could be found. GGCX encodes a gamma-glutamyl carboxylase necessary for activation of both coagulation factors in the liver and matrix gla protein, which, in fully carboxylated form, is able to prevent ectopic mineralization. Analysis of skin by specific antibodies demonstrated that matrix gla protein was found predominantly in undercarboxylated form and was associated with the mineralized areas in the patients' lesional skin. These observations pathomechanistically suggest that, in our patients, reduced carboxylase activity results in a reduction of matrix gla protein carboxylation, thus allowing peripheral mineralization to occur. Our findings also confirm GGCX as the second gene locus causing PXE. (Am J Pathol 2009, 174:534-540; DOI: 10.2353/ajpath.2009.080865) C1 [Li, Qiaoli; Uitto, Jouni] Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Inst Mol Med, Philadelphia, PA 19107 USA. [Schurgers, Leon J.] Univ Maastricht, Cardiovasc Res Inst & Vitak, Maastricht, Netherlands. [Smith, Ann C. M.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Tsokos, Maria] NCI, Pediat Tumor Biol & Ultrastruct Pathol Sect, 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 Uitto, J (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, 233 S 10th St,Suite 450 BLSB, Philadelphia, PA 19107 USA. EM jouni.uitto@jefferson.edu RI SMITH, ANN C.M./C-1122-2008; Li, Qiaoli/F-8383-2013 FU National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR28450, R01AR52627]; Intramural Program of the National Institutes of Health; Center for Cancer Research; National Cancer Institute and Medical Genetics Branch; National Human Genome Research Institute FX Supported by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR28450 and R01AR52627 to J.U.) and by the Intramural Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute and Medical Genetics Branch, and National Human Genome Research Institute. NR 24 TC 26 Z9 27 U1 0 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 2009 VL 174 IS 2 BP 534 EP 540 DI 10.2353/ajpath.2009.080865 PG 7 WC Pathology SC Pathology GA 397TK UT WOS:000262684800017 PM 19116367 ER PT J AU Braiterman, L Nyasae, L Guo, Y Bustos, R Lutsenko, S Hubbard, A AF Braiterman, Lelita Nyasae, Lydia Guo, Yan Bustos, Rodrigo Lutsenko, Svetlana Hubbard, Ann TI Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE Wilson protein; WIF-B cells; mutagenesis; in vivo; trans-Golgi network ID PLASMA-MEMBRANE PROTEINS; WILSONS-DISEASE PROTEIN; POLARIZED HEPATIC CELLS; METAL-BINDING SITES; MENKES PROTEIN; INTRACELLULAR-LOCALIZATION; TRANSPORTING ATPASES; IN-VITRO; TRAFFICKING; RAT AB Braiterman L, Nyasae L, Guo Y, Bustos R, Lutsenko S, Hubbard A. Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B. Am J Physiol Gastrointest Liver Physiol 296: G433-G444, 2009. First published November 25, 2008; doi:10.1152/ajpgi.90489.2008.-ATP7B is a copper-transporting P-type ATPase present predominantly in liver. In basal copper, hepatic ATP7B is in a post-trans-Golgi network (TGN) compartment where it loads cytoplasmic Cu(I) onto newly synthesized ceruloplasmin. When copper levels rise, the protein redistributes via unique vesicles to the apical periphery where it exports intracellular Cu(I) into bile. We want to understand the mechanisms regulating the copper-sensitive trafficking of ATP7B. Earlier, our laboratory reported the presence of apical targeting/TGN retention information within residues 1-63 of human ATP7B; deletion of these residues resulted in a mutant protein that was not efficiently retained in the post-TGN in low copper and constitutively trafficked to the basolateral membrane of polarized, hepatic WIF-B cells with and without copper (13). In this study, we used mutagenesis and adenovirus infection of WIF-B cells followed by confocal immunofluorescence microscopy analysis to identify the precise retention/targeting sequences in the context of full-length ATP7B. We also analyzed the expression of selected mutants in livers of copper-deficient and -loaded mice. Our combined results clearly demonstrate that nine amino acids, F(37)AFDNVGYE(45), comprise an essential apical targeting determinant for ATP7B in elevated copper and participate in the TGN retention of the protein under low-copper conditions. The signal is novel, does not require phosphorylation, and is highly conserved in similar to 24 species of ATP7B. Furthermore, N41S, which is part of the signal we identified, is the first and only Wilson disease-causing missense mutation in residues 1-63 of ATP7B. Expression of N41S-ATP7B in WIF-B cells severely disabled the targeting and retention of the protein. We present a working model of how this physiologically relevant signal might work. C1 [Braiterman, Lelita; Nyasae, Lydia; Hubbard, Ann] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. [Guo, Yan] NIDDK, NIH, Bethesda, MD USA. [Bustos, Rodrigo] Harvard Univ, Childrens Hosp, Sch Med, GI Cell Biol Lab, Boston, MA 02115 USA. [Lutsenko, Svetlana] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. RP Hubbard, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Cell Biol, 725 N Wolfe St, Baltimore, MD 21205 USA. EM alh@jhmi.edu FU NIH [DK072084, DK063096, DK064388] FX This work was supported by NIH (DK072084, DK063096 and DK064388). NR 46 TC 35 Z9 36 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD FEB PY 2009 VL 296 IS 2 BP G433 EP G444 DI 10.1152/ajpgi.90489.2008 PG 12 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 399EC UT WOS:000262782200034 PM 19033537 ER PT J AU Blood, AB Tiso, M Verma, ST Lo, J Joshi, MS Azarov, I Longo, LD Gladwin, MT Kim-Shapiro, DB Power, GG AF Blood, Arlin B. Tiso, Mauro Verma, Shilpa T. Lo, Jennifer Joshi, Mahesh S. Azarov, Ivan Longo, Lawrence D. Gladwin, Mark T. Kim-Shapiro, Daniel B. Power, Gordon G. TI Increased nitrite reductase activity of fetal versus adult ovine hemoglobin SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE kinetics; nitric oxide; vascular control; fetus ID HIGH-ALTITUDE HYPOXIA; CEREBRAL-BLOOD-FLOW; PLASMA NITRITE; LIGAND-BINDING; NITRATE LEVELS; PREGNANT EWES; OXIDE; OXYGEN; SHEEP; NO AB Blood AB, Tiso M, Verma ST, Lo J, Joshi MS, Azarov I, Longo LD, Gladwin MT, Kim-Shapiro DB, Power GG. Increased nitrite reductase activity of fetal versus adult ovine hemoglobin. Am J Physiol Heart Circ Physiol 296: H237-H246, 2009. First published November 21, 2008; doi: 10.1152/ajpheart.00601.2008.-Growing evidence indicates that nitrite, NO(2)(-), serves as a circulating reservoir of nitric oxide (NO) bioactivity that is activated during physiological and pathological hypoxia. One of the intravascular mechanisms for nitrite conversion to NO is a chemical nitrite reductase activity of deoxyhemoglobin. The rate of NO production from this reaction is increased when hemoglobin is in the R conformation. Because the mammalian fetus exists in a low-oxygen environment compared with the adult and is exposed to episodes of severe ischemia during the normal birthing process, and because fetal hemoglobin assumes the R conformation more readily than adult hemoglobin, we hypothesized that nitrite reduction to NO may be enhanced in the fetal circulation. We found that the reaction was faster for fetal than maternal hemoglobin or blood and that the reactions were fastest at 50-80% oxygen saturation, consistent with an R-state catalysis that is predominant for fetal hemoglobin. Nitrite concentrations were similar in blood taken from chronically instrumented normoxic ewes and their fetuses but were elevated in response to chronic hypoxia. The findings suggest an augmented nitrite reductase activity of fetal hemoglobin and that the production of nitrite may participate in the regulation of vascular NO homeostasis in the fetus. C1 [Blood, Arlin B.; Lo, Jennifer] Loma Linda Univ, Sch Med, Dept Pediat, Div Neonatol, Loma Linda, CA 92350 USA. [Blood, Arlin B.; Longo, Lawrence D.; Power, Gordon G.] Loma Linda Univ, Sch Med, Ctr Perinatal Biol, Loma Linda, CA USA. [Verma, Shilpa T.] Loma Linda Univ, Sch Med, Dept Anesthesiol, Loma Linda, CA USA. [Tiso, Mauro; Gladwin, Mark T.] NHLBI, Pulm & Vasc Med Branch, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Gladwin, Mark T.] NHLBI, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Joshi, Mahesh S.; Azarov, Ivan; Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. RP Blood, AB (reprint author), Loma Linda Univ, Sch Med, Dept Pediat, Div Neonatol, Loma Linda, CA 92350 USA. EM ablood@llu.edu OI Azarov, Ivan/0000-0002-9886-3298 FU NIH [HL-058091, HL-078706, HD-03807] FX This work was partially supported by NIH Grants HL-058091 and HL-078706 ( to D. B. Kim-Shapiro) and HD-03807 (to L. D. Longo). NR 59 TC 21 Z9 21 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD FEB PY 2009 VL 296 IS 2 BP H237 EP H246 DI 10.1152/ajpheart.00601.2008 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 399DK UT WOS:000262780400001 PM 19028797 ER PT J AU Kim, SM Theilig, F Qin, Y Cai, T Mizel, D Faulhaber-Walter, R Hirai, H Bachmann, S Briggs, JP Notkins, AL Schnermann, J AF Kim, Soo Mi Theilig, Franziska Qin, Yan Cai, Tao Mizel, Diane Faulhaber-Walter, Robert Hirai, Hiroki Bachmann, Sebastian Briggs, Josephine P. Notkins, Abner L. Schnermann, Jurgen TI Dense-core vesicle proteins IA-2 and IA-2 beta affect renin synthesis and secretion through the beta-adrenergic pathway SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE knockout mice; renin mRNA; propranolol; blood pressure; heart rate; salt intake ID INSULIN-SECRETION; TYROSINE-PHOSPHATASE; TARGETED DISRUPTION; MICE; EXPRESSION; AUTOANTIGEN; CYCLOOXYGENASE-2; IDENTIFICATION AB Kim SM, Theilig F, Qin Y, Cai T, Mizel D, Faulhaber-Walter R, Hirai H, Bachmann S, Briggs JP, Notkins AL, Schnermann J. Dense-core vesicle proteins IA-2 and IA-2 beta affect renin synthesis and secretion through the beta-adrenergic pathway. Am J Physiol Renal Physiol 296: F382-F389, 2009. First published November 19, 2008; doi:10.1152/ajprenal.90543.2008.-IA-2 and IA-2 beta, major autoantigens in type 1 diabetes, are transmembrane proteins in dense-core vesicles, and their expression influences the secretion of hormones and neurotransmitters. The present experiments were performed to examine whether IA-2 and IA-2 beta modulate the release of renin from dense- core vesicles of juxtaglomerular granular cells in the kidney. Plasma renin concentration (PRC; ng angiotensin I.ml(-1).h(-1)) was significantly reduced in mice with null mutations in IA-2, IA-2 beta, or both IA-2 and IA-2 beta compared with wild-type mice (876 +/- 113, 962 +/- 130, and 596 +/- 82 vs. 1,367 +/- 93; P < 0.01, P < 0.02, and P < 0.001). Renin mRNA levels were reduced to 26.4 +/- 5.1, 39 +/- 5.4, and 35.3 +/- 5.5% of wild-type in IA-2-/-, IA-2 beta-/-, and IA-2/IA-2 beta-/- mice. Plasma aldosterone levels were not significantly different among genotypes. The regulation of PRC by furosemide and salt intake, and of aldosterone by salt intake, was maintained in all genotypes. IA-2 and IA-2 beta expression did not colocalize with renin but showed overlapping immunoreactivity with tyrosine hydroxylase. While propranolol reduced PRC in wild-type mice, it had no effect on PRC in IA-2/ IA-2 beta-/- mice. Renal tyrosine hydroxylase mRNA and immunoreactivity were reduced in IA-2/IA-2 beta-/- mice as was the urinary excretion of catecholamines. We conclude that IA-2 and IA-2 beta are required to maintain normal levels of renin expression and renin release, most likely by permitting normal rates of catecholamine release from sympathetic nerve terminals. C1 [Kim, Soo Mi; Qin, Yan; Mizel, Diane; Faulhaber-Walter, Robert; Schnermann, Jurgen] NIDDKD, NIH, Bethesda, MD 20892 USA. [Theilig, Franziska; Bachmann, Sebastian; Notkins, Abner L.] Charite Univ Med Berlin, Inst Anat, D-13353 Berlin, Germany. [Cai, Tao; Hirai, Hiroki] NICHHD, Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Briggs, Josephine P.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDKD, NIH, Bldg 10,Rm 4D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Dental and Craniofacial Research (NIDCR); Deutsche Forschungsgemeinschaft through Forschergruppe 667 FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and National Institute of Dental and Craniofacial Research (NIDCR), and by the Deutsche Forschungsgemeinschaft through Forschergruppe 667. NR 21 TC 13 Z9 13 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2009 VL 296 IS 2 BP F382 EP F389 DI 10.1152/ajprenal.90543.2008 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 399EH UT WOS:000262782700019 PM 19019914 ER PT J AU Kono, K Kamijo, Y Hora, K Takahashi, K Higuchi, M Kiyosawa, K Shigematsu, H Gonzalez, FJ Aoyama, T AF Kono, Keiichi Kamijo, Yuji Hora, Kazuhiko Takahashi, Kyoko Higuchi, Makoto Kiyosawa, Kendo Shigematsu, Hidekazu Gonzalez, Frank J. Aoyama, Toshifumi TI PPAR alpha attenuates the proinflammatory response in activated mesangial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE inflammatory response; lipopolysaccharide; nuclear factor-kappa B; phenotypic changes; peroxisome proliferator-activated receptor alpha ID RECEPTOR-ALPHA; DIABETIC-NEPHROPATHY; IGA NEPHROPATHY; MICE LACKING; RAT; EXPRESSION; GLOMERULONEPHRITIS; INDUCTION; MOUSE; INFLAMMATION AB Kono K, Kamijo Y, Hora K, Takahashi K, Higuchi M, Kiyosawa K, Shigematsu H, Gonzalez FJ, Aoyama T. PPAR alpha attenuates the proinflammatory response in activated mesangial cells. Am J Physiol Renal Physiol 296: F328-F336, 2009. First published November 26, 2008; doi:10.1152/ajprenal.00484.2007.-The activated mesangial cell is an important therapeutic target for the control of glomerulonephritis. The peroxisome proliferator-activated receptor alpha (PPAR alpha) has attracted considerable attention for its anti-inflammatory effects; however, its roles in the mesangial cells remain unknown. To determine the anti-inflammatory function of PPAR alpha in mesangial cells, wild-type and Ppara-null cultured mesangial cells were exposed to lipopolysaccharide (LPS). LPS treatment caused enhanced proinflammatory responses in the Ppara-null cells compared with wildtype cells, as revealed by the induction of interleukin-6, enhanced cell proliferation, and the activation of the nuclear factor (NF)-kappa B signaling pathway. In wild-type cells resistant to inflammation, constitutive expression of PPAR alpha was undetectable. However, LPS treatment induced the significant appearance and substantial activation of PPAR alpha, which would attenuate the proinflammatory responses through its antagonizing effects on the NF-kappa B signaling pathway. The induction of PPAR alpha was coincident with the appearance of alpha-smooth muscle actin, which might be associated with the phenotypic changes of mesangial cells. Moreover, another examination using LPS-injected wild-type mice demonstrated the appearance of PPAR alpha-positive cells in glomeruli, suggesting in vivo correlation with PPAR alpha induction. These results suggest that PPAR alpha plays crucial roles in the attenuation of inflammatory response in activated mesangial cells. PPAR alpha might be a novel therapeutic target against glomerular diseases. C1 [Kono, Keiichi; Kamijo, Yuji; Takahashi, Kyoko; Aoyama, Toshifumi] Shinshu Univ, Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. [Kono, Keiichi; Kamijo, Yuji; Hora, Kazuhiko; Takahashi, Kyoko; Higuchi, Makoto; Kiyosawa, Kendo] Shinshu Univ, Sch Med, Dept Internal Med, Matsumoto, Nagano 3908621, Japan. [Shigematsu, Hidekazu] Shinshu Univ, Sch Med, Dept Pathol, Matsumoto, Nagano 3908621, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Kamijo, Y (reprint author), Shinshu Univ, Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. EM yujibeat@shinshu-u.ac.jp NR 45 TC 24 Z9 25 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2009 VL 296 IS 2 BP F328 EP F336 DI 10.1152/ajprenal.00484.2007 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 399EH UT WOS:000262782700013 PM 19036849 ER PT J AU Leitzmann, MF Koebnick, C Freedman, ND Park, Y Ballard-Barbash, R Hollenbeck, A Schatzkin, A Abnet, CC AF Leitzmann, Michael F. Koebnick, Corinna Freedman, Neal D. Park, Yikyung Ballard-Barbash, Rachel Hollenbeck, Albert Schatzkin, Arthur Abnet, Christian C. TI Physical Activity and Esophageal and Gastric Carcinoma in a Large Prospective Study SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID C-REACTIVE PROTEIN; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PLASMA LEPTIN CONCENTRATIONS; BODY-MASS INDEX; CELLS IN-VITRO; HELICOBACTER-PYLORI; HEART-DISEASE; UNITED-STATES; RISK-FACTORS; CANCER-RISK AB Background: Few studies have investigated the relationship of physical activity to esophageal and gastric carcinoma according to histology and anatomic site. Methods: This study prospectively investigated the association between physical activity and esophageal and gastric carcinoma in a cohort of 487,732 U.S. men and women, followed from 1995-1996 to December 31, 2003. All analyses were performed in 2007-2008. Results: During 8 years of follow-up study, 523 cases of esophageal carcinoma (149 squamous Cell and 374 adenocarcinoma) and 642 cases of gastric carcinoma (313 cardia and 329 noncardia) were documented. Physical activity was associated with reduced risk of esophageal and gastric adenocarcinomas but Was Unrelated to esophageal squamous cell carcinoma. The inverse association with physical activity was strongest for gastric noncardia adenocarcinoma (multivariate relative risk [RR] For highest versus lowest physical activity level=0.62, 95% CI=0.44, 0.87). Relationships were weaker but evident for gastric cardia adenocarcinoma (RR=0.81; 95% CI=0.58, 1.19) and esophageal adenocarcinoma (RR=0.75; 95% CI=0.53, 1.06). No significant relationship with physical activity was observed for esophageal squamous cell carcinoma (RR=1.05; 95% CI=0.64, 1.74). Exclusion of cases diagnosed during the first 2 follow-up years did not change those estimates, indicating that the findings are not due to decreased activity levels among participants With Undiagnosed cancer at entry. tract Conclusions: Physical activity may play a role in the prevention of upper gastrointestinal adenocarcinomas. No association was seen between physical activity and esophageal squamous cell carcinoma. C1 [Leitzmann, Michael F.] Univ Hosp Regenburg, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Leitzmann, Michael F.; Koebnick, Corinna; Freedman, Neal D.; Park, Yikyung; Schatzkin, Arthur; Abnet, Christian C.] NCI, NIH, Dept Hlth & Human Serv, Nutr Epidemiol Branch,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Freedman, Neal D.] NCI, NIH, Dept Hlth & Human Serv, Canc Prevent Fellowship Program,Div Canc Prevent, Bethesda, MD 20892 USA. [Ballard-Barbash, Rachel] NCI, NIH, Dept Hlth & Human Serv, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Koebnick, Corinna] Res & Evaluat Kaiser Permanente So Calif, Pasadena, CA USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Leitzmann, MF (reprint author), Univ Hosp Regenburg, Inst Epidemiol & Prevent Med, Franz Josef Str Allee 11, D-93053 Regensburg, Germany. EM michael.leitzmann@klinik.uni-regensburg.de RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Koebnick, Corinna/P-4767-2016; OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Koebnick, Corinna/0000-0001-8274-0309; Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS [Z01 CP010196-01] NR 59 TC 29 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 2009 VL 36 IS 2 BP 112 EP 119 DI 10.1016/j.amepre.2008.09.033 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 397RK UT WOS:000262679600004 PM 19062237 ER PT J AU Huang, TTK AF Huang, Terry T-K TI Solution-Oriented Research: Converging Efforts of Promoting Environmental Sustainability and Obesity Prevention SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material C1 [Huang, Terry T-K] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Huang, TTK (reprint author), NICHD, Obes Res Strateg Core, NIH, 6100 Execut Blvd,4B11, Bethesda, MD 20892 USA. EM huangter@mail.nih.gov NR 11 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 2009 VL 36 IS 2 BP S60 EP S62 DI 10.1016/j.amepre.2008.11.002 PG 3 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 397RP UT WOS:000262680100011 PM 19147062 ER PT J AU Frye, MA Helleman, G McElroy, SL Altshuler, LL Black, DO Keck, PE Nolen, WA Kupka, R Leverich, GS Grunze, H Mintz, J Post, RM Suppes, T AF Frye, Mark A. Helleman, Gerhard McElroy, Susan L. Altshuler, Lori L. Black, David O. Keck, Paul E., Jr. Nolen, Willem A. Kupka, Ralph Leverich, Gabriele S. Grunze, Heinz Mintz, Jim Post, Robert M. Suppes, Trisha TI Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID I DISORDER; MOOD-STABILIZERS; STEP-BD; SWITCH; STATES; RISK; VENLAFAXINE; SYMPTOMS; ILLNESS; COMBINATION C1 Mayo Clin, Dept Psychiat & Psychol, Coll Med, Rochester, MN 55901 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Groningen, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands. Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. Univ Med Ctr, Utrecht, Netherlands. Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Texas San Antonio, Dept Psychiat, San Antonio, TX USA. Bipolar Collaborat Network, Bethesda, MD USA. Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. RP Frye, MA (reprint author), Mayo Clin, Dept Psychiat, Mayo Mood Clin, 200 1st St SW, Rochester, MN 55901 USA. EM mfrye@mayo.edu RI Nolen, Willem/E-9006-2014; OI Grunze, Heinz/0000-0003-4712-8979 FU Stanley Medical Research Institute FX Supported by the Stanley Medical Research Institute. Drug and matching placebo for the antidepressant clinical trial was supplied by GlaxoSmithKline (bupropion), Pfizer US Pharmaceuticals (sertraline), and Wyeth Pharmaceuticals (venlafaxine). NR 48 TC 96 Z9 102 U1 0 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2009 VL 166 IS 2 BP 164 EP 172 DI 10.1176/appi.ajp.2008.08030322 PG 9 WC Psychiatry SC Psychiatry GA 402RT UT WOS:000263031500009 PM 19015231 ER PT J AU Rasetti, R Mattay, VS Wiedholz, LM Kolachana, BS Hariri, AR Callicott, JH Meyer-Lindenberg, A Weinberger, DR AF Rasetti, Roberta Mattay, Venkata S. Wiedholz, Lisa M. Kolachana, Bhaskar S. Hariri, Ahmad R. Callicott, Joseph H. Meyer-Lindenberg, Andreas Weinberger, Daniel R. TI Evidence That Altered Amygdala Activity in Schizophrenia Is Related to Clinical State and Not Genetic Risk SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Society-for-Neuroscience CY OCT 14-18, 2006 CL Atlanta, GA SP Soc Neurosci ID METHYLTRANSFERASE VAL(158)MET GENOTYPE; MONOZYGOTIC TWINS DISCORDANT; SEROTONIN TRANSPORTER; PREFRONTAL CORTEX; NEURAL MECHANISMS; RECOGNITION; ACTIVATION; EMOTION; BRAIN; ENDOPHENOTYPES AB Objective: Although amygdala dysfunction is reported in schizophrenia, it is unknown whether this deficit represents a heritable phenotype that is related to risk for schizophrenia or whether it is related to disease state. The purpose of the present study was to examine amygdala response to threatening faces among healthy siblings of schizophrenia patients in whom a subtler heritable deficit might be observed. Method: Participants were 34 schizophrenia patients, 29 unaffected siblings, and 20 healthy comparison subjects. Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted during an implicit facial information processing task. The N-back working memory task, which has been shown to elicit prefrontal cortex abnormalities in unaffected siblings of schizophrenia patients, was employed as a positive experimental control. Results: Schizophrenia patients demonstrated a deficit in amygdala reactivity to negative face stimuli and an alteration, correlated with neuroleptic drug dosage, in the functional coupling between the amygdala and subgenual cingulate. In contrast, unaffected siblings showed a pattern that was not statistically different from that of healthy comparison subjects. During the N-back working memory task, both schizophrenia patients and their unaffected siblings demonstrated a pattern of inefficient prefrontal cortex engagement, which is consistent with earlier evidence that this pattern is related to genetic risk for schizophrenia. Conclusions: These data suggest that the pathophysiological mechanism underlying the inability of individuals with schizophrenia to normally engage the amygdala in processing fearful and angry facial representations is more likely a phenomenon related to the disease state, specifically to treatment. C1 [Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, IRP,NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. Cent Inst Mental Hlth, D-6800 Mannheim, Germany. RP Weinberger, DR (reprint author), NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, IRP,NIH, Rm 4S-235,10 Ctr Dr, Bethesda, MD 20892 USA. EM daniel.weinberger@mail.nih.gov RI Hariri, Ahmad/D-5761-2011; Callicott, Joseph/C-9102-2009; Meyer-Lindenberg, Andreas/H-1076-2011 OI Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Intramural NIH HHS [Z01 MH002716-13] NR 39 TC 68 Z9 70 U1 0 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2009 VL 166 IS 2 BP 216 EP 225 DI 10.1176/appi.ajp.2008.08020261 PG 10 WC Psychiatry SC Psychiatry GA 402RT UT WOS:000263031500015 PM 19074979 ER PT J AU Moro, PL Shah, J Li, O Gilman, RH Harris, N Moro, MH AF Moro, Pedro L. Shah, Jyotsna Li, Olga Gilman, Robert H. Harris, Nick Moro, Manuel H. TI Short Report: Serologic Evidence of Human Ehrlichiosis in Peru SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID HUMAN INFECTION; SPOTTED-FEVER; CANIS; VENEZUELA; CHAFFEENSIS AB A serosurvey for human ehrlichiosis caused by Ehrlichia chaffeensis and Anaplasma phagocytophilum was performed in different regions of Peru by using indirect immunofluorescence assays (IFAs). Regions included an urban community in a shantytown in Lima (Pampas) and three rural communities located on the northern coast of Peru (Cura Mori), in the southern Peruvian Andes (Cochapata), and in the Peruvian jungle region (Santo Tomas). An overall E. chaffeensis seroprevalence of 13% (21 of 160) was found by IFA. Seroprevalences in females and males was 15% (16 of 106) and 9% (5 of 53), respectively. Seroprevalences in Cura Mori, Cochapata, Pampas, and Santo Tomas were 25% (10 of 40), 23% (9 of 40), 3% (1 of 40), and 3% (1 of 40), respectively. Seroprevalences in Cura Mori and Cochapata were significantly higher than in Santo Tomas or Pampas (P < 0.01). No sera were reactive to A. phagocytophilum. These findings suggest that human infection with E. chaffeensis occurs in Peru. Further studies are needed to characterize Ehrlichia species in Peru, their vectors and their clinical significance. C1 [Moro, Pedro L.] Ctr Dis Control & Prevent, Immunizat Safety Off, Off Chief Sci Officer, Atlanta, GA 30333 USA. [Harris, Nick] IGeneX Inc, Palo Alto, CA 94303 USA. [Li, Olga] Univ Nacl Mayor San Marcos, Fac Med Vet, Laba Patol Clin, Lima 14, Peru. [Gilman, Robert H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Moro, Manuel H.] NIH, Div Comparat Med, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Moro, MH (reprint author), NIH, Div Comparat Med, Natl Ctr Res Resources, 6701 Democracy Blvd, Bethesda, MD 20892 USA. EM pmoro@cdc.gov; jyotsna@aol.com; Olgalie@hotmail.com; rgilman@jhsph.edu; nharris@aol.com; manuel.moro@nih.gov NR 13 TC 7 Z9 10 U1 1 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD FEB PY 2009 VL 80 IS 2 BP 242 EP 244 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 406RG UT WOS:000263312000017 PM 19190221 ER PT J AU Coleman, CN Hrdina, C Bader, JL Norwood, A Hayhurst, R Forsha, J Yeskey, K Knebel, A AF Coleman, C. Norman Hrdina, Chad Bader, Judith L. Norwood, Ann Hayhurst, Robert Forsha, Joseph Yeskey, Kevin Knebel, Ann TI Medical Response to a Radiologic/Nuclear Event: Integrated Plan From the Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID SOLID CANCER INCIDENCE; RADIATION-EXPOSURE; MANAGEMENT; CASUALTIES; ACCIDENT; INJURY; CARE AB The end of the Cold War led to a reduced concern for a major nuclear event. However, the current threats from terrorism make a radiologic (dispersal or use of radioactive material) or nuclear (improvised nuclear device) event a possibility. The specter and enormousness of the catastrophe resulting from a state-sponsored nuclear attack and a sense of nihilism about the effectiveness of a response were such that there had been limited civilian medical response planning. Although the consequences of a radiologic dispersal device are substantial, and the detonation of a modest-sized (10 kiloton) improvised nuclear device is catastrophic, it is both possible and imperative that a medical response be planned. To meet this need, the Office of the Assistant Secretary for Preparedness and Response in the Department of Health and Human Services, in collaboration within government and with nongovernment partners, has developed a scientifically based comprehensive planning framework and Web-based "just-in-time" medical response information called Radiation Event Medical Management (available at http://www.remm.nlm.gov). The response plan includes (1) underpinnings from basic radiation biology, (2) tailored medical responses, (3) delivery of medical countermeasures for postevent mitigation and treatment, (4) referral to expert centers for acute treatment, and (5) long-term follow-up. Although continuing to evolve and increase in scope and capacity, current response planning is sufficiently mature that planners and responders should be aware of the basic premises, tools, and resources available. An effective response will require coordination, communication, and cooperation at an unprecedented level. The logic behind and components of this response are presented to allow for active collaboration among emergency planners and responders and federal, state, local, and tribal governments. [Ann Emerg Med. 2009; 53:213-222.] C1 [Coleman, C. Norman; Hrdina, Chad; Bader, Judith L.; Norwood, Ann; Hayhurst, Robert; Forsha, Joseph; Yeskey, Kevin; Knebel, Ann] Off Assistant Secretary Preparedness & Response, Dept Hlth & Human Serv, Washington, DC 20201 USA. [Coleman, C. Norman; Bader, Judith L.] NCI, NIH, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), Off Assistant Secretary Preparedness & Response, Dept Hlth & Human Serv, HHH Bldg,Suite 638G,200 Independence Ave SW, Washington, DC 20201 USA. EM ccoleman@mail.nih.gov NR 40 TC 39 Z9 39 U1 0 U2 10 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 FEB PY 2009 VL 53 IS 2 BP 213 EP 222 DI 10.1016/j.annemergmed.2007.12.021 PG 10 WC Emergency Medicine SC Emergency Medicine GA 405LI UT WOS:000263225900010 PM 18387707 ER PT J AU Stolzenberg-Solomon, RZ AF Stolzenberg-Solomon, Rachael Z. TI Vitamin D and Pancreatic Cancer SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Vitamin D Intake; 25-Hydroxy-Vitamin D Status; Pancreatic Cancer ID INSULIN-RECEPTOR GENE; PROSTATE-CANCER; UNITED-STATES; MALE SMOKERS; D ANALOGS; 25-HYDROXYVITAMIN D-3-1-ALPHA-HYDROXYLASE; 1,25-DIHYDROXYVITAMIN D-3; COLORECTAL-CANCER; EXOGENOUS INSULIN; SUBSEQUENT RISK AB Sun exposure has been associated with lower death rates for pancreatic cancer in ecological studies. Skin exposure to solar ultraviolet B radiation induces cutaneous production of precursors to 25-hydroxy (OH) vitamin D (D) and is considered the primary contributor to vitamin D status in most Populations. Pancreatic islet and duct cells express 25-(OH) D(3)-1 alpha-hydroxylase that generates the biologically active 1,25, dihydroxy(OH), D form. Thus, 25(OH)D concentrations could affect pancreatic function and possibly pancreatic cancer etiology. Serum 25-(OH)D is the major circulating vitamin D metabolite and is considered the best indicator of vitamin D status as determined by the sun and diet. Although recent prospective epidemiologic studies of higher predicted vitamin D status score and vitamin D intake and pancreatic cancer risk suggest protective associations, a nested case,control study showed a significant 3-fold increased risk for pancreatic cancer with higher vitamin D status. Limitations of these Studies include the former do not measure vitamin D status on pancreatic cancer cases and the later was conducted in a male smoker population. More research is needed, particularly examination of pre-diagnostic vitamin D status and risk of pancreatic cancer, prior to conclusions for vitamin D's potential role in the etiology of this highly fatal cancer. C1 [Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth Human Serv, Rockville, MD USA. RP Stolzenberg-Solomon, RZ (reprint author), 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM rs221z@nih.gov FU Intramural Research Program of the National Institutes of Health; Division of Cancer Epidemiology and Genetics; National Cancer Institute; Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services. NR 66 TC 16 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2009 VL 19 IS 2 BP 89 EP 95 DI 10.1016/j.annepidem.2008.03.010 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 407UC UT WOS:000263388800004 PM 18504144 ER PT J AU Fischbeck, KH Bryan, WW AF Fischbeck, Kenneth H. Bryan, Wilson W. TI Anti-androgen Treatment for Spinal and Bulbar Muscular Atrophy SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID TRANSGENIC MOUSE MODEL; ANDROGEN RECEPTOR C1 [Fischbeck, Kenneth H.; Bryan, Wilson W.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Fischbeck, KH (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA NS003037-03] NR 6 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2009 VL 65 IS 2 BP 119 EP 120 DI 10.1002/ana.21633 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 415KM UT WOS:000263932700003 PM 19259961 ER PT J AU Burstein, AH Boudreau, EA Theodore, WH AF Burstein, Aaron H. Boudreau, Eilis A. Theodore, William H. TI Increase in Tiagabine Serum Concentration with Coadministration of Gemfibrozil SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE gemfibrozil; interaction; pharmacokinetics; tiagabine ID DRUG AB OBJECTIVE: To report a case of possible acute tiagabine toxicity secondary to administration of gemfibrozil. CASE SUMMARY: A 39-year-old male was taking tiagabine 16 mg orally 3 times per day and carbamazepine 500 mg orally twice per day for complex partial seizures secondary to mesial temporal sclerosis. He was found to have type IV hypertriglyceridemia and was prescribed gemfibrozil. Because he reported severe confusion and altered consciousness shortly after a single 600-mg dose of gemfibrozil, he was admitted for controlled challenge with that drug. A single 300-mg dose of gemfibrozil resulted in lightheadedness and led to a 59% and 75% increase in total tiagabine serum concentrations at 2 and 5 hours, respectively, without significant change in baseline carbamazapine concentrations. DISCUSSION: This is the first report of an interaction between the widely used antihyperlipidemic drug gemfibrozil and tiagabine. Since tiagabine, which was originally developed as an antiepileptic medication, is now being used widely for a variety of other indications such as anxiety and depression, there is an increased risk for clinically significant interactions with gemfibrozil. CONCLUSIONS: Increased total and unbound tiagabine concentrations following a single 300-mg dose of gemfibrozil and reproduction of clinical symptoms with gemfibrozil rechallenge suggests the toxicity our patient experienced was due to a pharmacokinetic drug interaction. Use of the Horn Drug Interaction Probability Scale showed a probable interaction between gemfibrozil and tiagabine. C1 [Theodore, William H.] Natl Inst Neurol Disorders & Stroke, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Boudreau, Eilis A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Boudreau, Eilis A.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. [Burstein, Aaron H.] NIH, Clin Ctr Pharm Dept, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Epilepsy Sect, NIH, 10 Ctr Dr,Bldg 10,Rm 5N250,MSC 1408, Bethesda, MD 20892 USA. EM Theodorw@ninds.nih.gov FU National Institutes of Neurologic Disorders and Stroke; National Institutes of Health; Division of Intramural Research FX Funding for this study was supplied by the National Institutes of Neurologic Disorders and Stroke, National Institutes of Health, Division of Intramural Research. NR 10 TC 4 Z9 4 U1 1 U2 1 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD FEB PY 2009 VL 43 IS 2 BP 379 EP 382 DI 10.1345/aph.1L080 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 407UD UT WOS:000263388900028 PM 19193595 ER PT J AU Wilkinson, NW Yothers, G Lopa, SH Costantino, J Petrelli, N Wolmark, N AF Wilkinson, N. W. Yothers, G. Lopa, S. H. Costantino, J. Petrelli, N. Wolmark, N. TI Long Term Survival Results of Surgery Alone verses Surgery plus 5-Fluorouracil and Leucovorin for Stage II and Stage III Colon Cancer: Pooled Analysis of NSABP adjuvant trials C-01 through C-05 SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 [Wilkinson, N. W.] Univ Iowa, Iowa City, IA USA. [Yothers, G.; Lopa, S. H.; Costantino, J.; Wolmark, N.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Petrelli, N.] Helen F Graham Canc Ctr Newark, Newark, DE USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2009 VL 16 SU 1 BP 5 EP 5 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA V16GF UT WOS:000207857400012 ER PT J AU Ripley, RT Davis, JL Klapper, JA Kammula, U Royal, RE Yang, JC Sherry, RM Hughes, MS Libutti, SK White, DE Steinberg, SM Dudley, ME Rosenberg, SA Avital, I AF Ripley, R. T. Davis, J. L. Klapper, J. A. Kammula, U. Royal, R. E. Yang, J. C. Sherry, R. M. Hughes, M. S. Libutti, S. K. White, D. E. Steinberg, S. M. Dudley, M. E. Rosenberg, S. A. Avital, I. TI Liver Resection for Metastatic Melanoma with Post-Operative Tumor-Infiltrating Lymphocyte Therapy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 [Ripley, R. T.; Davis, J. L.; Klapper, J. A.; Kammula, U.; Royal, R. E.; Yang, J. C.; Sherry, R. M.; Hughes, M. S.; Libutti, S. K.; White, D. E.; Dudley, M. E.; Rosenberg, S. A.; Avital, I.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, S. M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2009 VL 16 SU 1 BP 11 EP 11 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA V16GF UT WOS:000207857400032 ER PT J AU Miao, N Pingpank, JF Alexander, HR Royal, R Steinberg, SM Quezado, MM Beresnev, T Quezado, ZMN AF Miao, Ning Pingpank, James F. Alexander, H. Richard Royal, Richard Steinberg, Seth M. Quezado, Martha M. Beresnev, Tatiana Quezado, Zenaide M. N. TI Cytoreductive Surgery and Continuous Hyperthermic Peritoneal Perfusion in Patients with Mesothelioma and Peritoneal Carcinomatosis: Hemodynamic, Metabolic, and Anesthetic Considerations SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID INTRAPERITONEAL INTRAOPERATIVE CHEMOTHERAPY; PSEUDOMYXOMA PERITONEI; COLISEUM TECHNIQUE; MANAGEMENT; MALIGNANCIES; MORTALITY; CANCER; ADENOCARCINOMA; DISSEMINATION; MORBIDITY AB Cytoreductive surgery and continuous hyperthermic peritoneal perfusion (CHPP) involve the conduct of a complex surgical procedure and delivery of high-dose hyperthermic chemotherapy to the peritoneum. This therapeutic modality has been shown to benefit patients with peritoneal carcinomatosis resulting from gastrointestinal and ovarian tumors and mesothelioma. However, it is unknown whether the primary disease (mesothelioma versus peritoneal carcinomatosis) affects hemodynamic and metabolic perturbations during the course of CHPP with cisplatin. We examined the perioperative course of patients undergoing CHPP with cisplatin and evaluated the effect of primary diagnosis (mesothelioma versus peritoneal carcinomatosis) on hemodynamic and metabolic parameters in response to peritoneal perfusion. Sixty-nine mesothelioma and 100 peritoneal carcinomatosis patients underwent 169 consecutive cytoreduction and CHPP procedures with general anesthesia. During CHPP, patients from both groups developed significant increases in central venous pressure, and heart rate, decreases in mean arterial pressure (all P < 0.0001), metabolic acidosis with significant decreases in pH and bicarbonate (P < 0.0001), deterioration of gas exchange with significant increases in PaCO(2) and oxygen alveolar-arterial gradient (P < 0.0001), and significant increases in activated partial thromboplastin time (aPTT) and prothrombin time (PT) and decreases in hematocrit and platelet counts (all P < 0.0001). However, patients with mesothelioma had lesser increases in temperature (P < 0.01) and heart rate (P < 0.0001) and lesser decreases in hematocrit (P = 0.0013) during CHPP and greater decreases in sodium bicarbonate (P = 0.0082) after completion of CHPP compared with patients with peritoneal carcinomatosis. We conclude that the transient hemodynamic and metabolic perturbations associated with cytoreductive surgery and CHPP with cisplatin can vary according to the primary diagnosis (mesothelioma versus peritoneal carcinomatosis) warranting this therapy. C1 [Miao, Ning; Quezado, Zenaide M. N.] NIH, Dept Anesthesia & Surg Serv, Ctr Clin, Bethesda, MD 20892 USA. [Pingpank, James F.; Alexander, H. Richard; Royal, Richard; Beresnev, Tatiana] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Quezado, Martha M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Miao, N (reprint author), NIH, Dept Anesthesia & Surg Serv, Ctr Clin, 10 Ctr Dr,MSC 1512,Bldg 10,Room 2C624, Bethesda, MD 20892 USA. EM zquezado@nih.gov RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU National Institutes of Health; National Cancer Institute; NIH Clinical Center FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and NIH Clinical Center. The authors would like to thank Mr. Jesse White for assistance with manuscript preparation and Margaret Smith, CRNA, for data collection. NR 32 TC 17 Z9 19 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2009 VL 16 IS 2 BP 334 EP 344 DI 10.1245/s10434-008-0253-z PG 11 WC Oncology; Surgery SC Oncology; Surgery GA 401TM UT WOS:000262965300016 PM 19050961 ER PT J AU Yee, LJ Im, K Wahed, AS Bugawan, T Li, J Rhodes, SL Erlich, H Rosen, HR Liang, TJ Yang, HY AF Yee, Leland J. Im, KyungAh Wahed, Abdus S. Bugawan, Teodorica Li, Jia Rhodes, Shannon L. Erlich, Henry Rosen, Hugo R. Liang, T. Jake Yang, Huiying CA Virahep-C Study TI Polymorphism in the Human Major Histocompatibility Complex and Early Viral Decline during Treatment of Chronic Hepatitis C SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SUSTAINED VIROLOGICAL RESPONSE; T-CELL REACTIVITY; VIRUS-INFECTION; RIBAVIRIN TREATMENT; ANTIVIRAL THERAPY; JAPANESE PATIENTS; AMERICAN PATIENTS; AFRICAN-AMERICAN; PLUS RIBAVIRIN; PEGINTERFERON AB The dynamics of the viral decline immediately after the start of therapy for chronic hepatitis C virus (HCV) infection may have prognostic potential for ultimate sustained virologic response. Considerable interindividual variability in the decline has been reported, including differences by race. The human major histocompatability complex (MHC) genes encode the human leukocyte antigens, which are important in the immune response to viral infections. We examined whether carriage of specific human MHC alleles are associated with the rate of the early viral decline. Longitudinal viral level data ( baseline and days 1, 2, 7, 14, and 28 of treatment), medium resolution MHC genotyping, and random coefficients models were used to examine associations between MHC class I and class II allele carriage and the dynamics of the viral decline in 180 African-Americans (AAs) and 194 Caucasian Americans (CAs) with genotype-1 HCV infection over the first 28 days of treatment with peginterferon alpha 2a plus ribavirin. Baseline viral levels were similar by race, irrespective of allele carriage. However, the rate of change in the viral decline was associated with both allele and race. Among the four subgroups defined by race and specific allele, the fastest rates of decline were observed ( in terms of estimated mean viral declines log(10) IU/ml during the first four weeks) in CA noncarriers for A*03 (2.75; P = 0.018), in CA carriers for Cw*03 (2.99; P = 0.046), and in CA noncarriers for DQA1*04 (2.66; P = 0.018) or DQB1*0402 (2.65; P = 0.018). MHC alleles are associated with the viral decline during the first 28 days of peginterferon therapy. C1 [Yee, Leland J.; Im, KyungAh] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Yee, Leland J.] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA USA. [Im, KyungAh; Wahed, Abdus S.] Univ Pittsburgh, Dept Biostat, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Bugawan, Teodorica; Li, Jia; Erlich, Henry] Roche Mol Syst Inc, Alameda, CA USA. [Rhodes, Shannon L.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Rosen, Hugo R.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Liang, T. Jake] NIDDK, Liver Dis Branch, Bethesda, MD USA. RP Yee, LJ (reprint author), Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, A511 Crabtree Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. EM YeeL@edc.pitt.edu OI Wahed, Abdus/0000-0001-6911-7221 FU NIDDK; National Center on Minority Health and Health Disparities; Cooperative Research and Development Agreement with Roche Laboratories, Inc. [U01 DK60329, U01 DK60340, U01 DK60324, U01 DK60344, U01 DK60327, U01 DK60335, U01 DK60352, U01 DK60342, U01 DK60345, U01 DK60309, U01 DK60346, U01 DK60349, U01 DK60341]; National Center for Research Resources; National Institutes of Health; National Cancer Institute; Center for Cancer Research; General Clinical Research Centers program [M01 RR00645, M02 RR000079, M01 RR16500, M01 RR000042, M01 RR00046]; National Institutes of Health Clinical Research Career Development Award Grant [1KL2 RR024154-02]; Beth Israel Deaconess Medical Center, Boston, MA; New York-Presbyterian Medical Center, New York, NY; University of California, San Francisco, CA; Rush University, Chicago, IL; University of Maryland, Baltimore, MD; University of Miami, Miami; University of Michigan, Ann Arbor, MI; University of North Carolina, Chapel Hill, NC; St. Louis University, St. Louis, MO; Cedars-Sinai Medical Center, Los Angeles, CA; University of Colorado Health Sciences Center, Denver; Veteran's Administration, Portland, OR; Indiana University, BloomingtonN; National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute, Bethesda, Maryland. FX This clinical study was a cooperative agreement funded by the NIDDK and cofunded by the National Center on Minority Health and Health Disparities, with a Cooperative Research and Development Agreement with Roche Laboratories, Inc., under grants U01 DK60329, U01 DK60340, U01 DK60324, U01 DK60344, U01 DK60327, U01 DK60335, U01 DK60352, U01 DK60342, U01 DK60345, U01 DK60309, U01 DK60346, U01 DK60349, and U01 DK60341. Other support was provided by the National Center for Research Resources, the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, the Center for Cancer Research, and General Clinical Research Centers program grants M01 RR00645 ( New York Presbyterian), M02 RR000079 ( University of California, San Francisco), M01 RR16500 ( University of Maryland), M01 RR000042 ( University of Michigan), and M01 RR00046 ( University of North Carolina). Additional support for L. J. Y. was provided by a National Institutes of Health Clinical Research Career Development Award Grant ( 1KL2 RR024154-02). The members of Virahep-C included Nezam Afdhal and Tiffany Geahigan from the Beth Israel Deaconess Medical Center, Boston, MA; Robert S. Brown, Jr., Lorna Dove, and Shana Stovel from the New York-Presbyterian Medical Center, New York, NY; Norah Terrault, Stephanie Straley, Eliana Agudelo, and Melissa Hinds from the University of California, San Francisco, CA; Thelma E. Wiley and Monique Williams from Rush University, Chicago, IL; Charles D. Howell and Karen Callison from the University of Maryland, Baltimore, MD; Lennox J. Jeffers, Shvawn McPherson Baker, Maria DeMedina, and Carol Hermitt from the University of Miami, Miami; Hari S. Conjeevaram, Robert J. Fontana, and Donna Harsh from the University of Michigan, Ann Arbor, MI; Michael W. Fried, Scott R. Smith, Dickens Theodore, Steven Zacks, Roshan Shrestha, Karen Dougherty, Paris Davis, and Shirley Brown from the University of North Carolina, Chapel Hill, NC; John E. Tavis, Adrian Di Bisceglie, Ermei Yao, Maureen Donlin, Nathan Cannon, and Ping Wang from St. Louis University, St. Louis, MO; Huiying Yang, George Tang, and Dai Wang from Cedars-Sinai Medical Center, Los Angeles, CA; Hugo R. Rosen, James R. Burton, and Jared Klarquist from the University of Colorado Health Sciences Center, Denver; Scott Weston from the Veteran's Administration, Portland, OR; Milton W. Taylor, Corneliu Sanda, Joel Schaley, and Mary Ferris from Indiana University, BloomingtonN; Steven H. Belle, Richard A. Bilonick, Geoffrey Block, Jennifer Cline, Marika Haritos, KyungAh Im, Stephanie Kelley, Sherry Kelsey, Laurie Koozer, Sharon Lawlor, Stephen B. Thomas, Abdus Wahed, Yuling Wei, and Leland J. Yee from the Data Coordinating Center, Graduate School of Public Health at the University of Pittsburgh, Pittsburgh; Patricia Robuck, James Everhart, Jay H. Hoofnagle, Edward Doo, T. Jake Liang, and Leonard B. Seeff from the National Institute of Diabetes and Digestive and Kidney Diseases; and David E. Kleiner from the National Cancer Institute, Bethesda, Maryland. NR 31 TC 9 Z9 9 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2009 VL 53 IS 2 BP 615 EP 621 DI 10.1128/AAC.00947-08 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 397EY UT WOS:000262646500034 PM 18852273 ER PT J AU Ricciardi, R Metter, EJ Cavanaugh, EW Ghambaryan, A Talbot, LA AF Ricciardi, Richard Metter, E. Jeffery Cavanaugh, Erica W. Ghambaryan, Anna Talbot, Laura A. TI Predicting cardiovascular risk using measures of regional and total body fat SO APPLIED NURSING RESEARCH LA English DT Article ID CORONARY-HEART-DISEASE; BIOELECTRICAL-IMPEDANCE ANALYSIS; TO-HIP RATIO; WAIST CIRCUMFERENCE; MASS INDEX; METABOLIC SYNDROME; POSTMENOPAUSAL WOMEN; ABDOMINAL OBESITY; ADIPOSE-TISSUE; VISCERAL FAT AB Excessive body fat is associated with increased risk for coronary heart disease (CHD). Various anthropometric methods are currently used to quantify regional and total body fat. The objectives of this study were to provide more insight into differences in cutoff points between methods for measuring total body fat and those for measuring regional body fat, independently and in combination, and to determine how well anthropometric and bioelectrical impedance methods of estimating body composition predict cardiovascular risk in a sample of unfit National Guard soldiers. Unfit healthy men (n = 123) and women (n = 32) between 21 and 55 years old from the Army National Guard were assessed for total and regional body fat. After having their degree of total and regional body fat assessed, the participants were categorized by level of body fat and 10-year CHD risk. Comparisons and predictions were made between degree of total as well as regional body fat and 10-year CHD risk estimated from Framingham Heart Study equations. A significant positive relationship was observed between waist circumference and 10-year CHD risk in men. When controlling for age, waist circumference was predictive of 10-year CHD risk, contributing to 6.4% of the variance, whereas waist-to-hip ratio did not contribute to the model significantly. The results of this study show that waist circumference is the best measure for identifying unfit male individuals at risk for CHD. (c) 2009 Elsevier Inc. All rights reserved. C1 [Ricciardi, Richard] Walter Reed Army Med Ctr, Walter Reed Stn, Washington, DC 20012 USA. [Metter, E. Jeffery] Harbor Hosp, NIA, Intramural Res Program, NIH, Baltimore, MD 21225 USA. [Cavanaugh, Erica W.] Henry M Jackson Fdn, Rockville, MD 20852 USA. [Ghambaryan, Anna] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Talbot, Laura A.] Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Bethesda, MD 20814 USA. RP Ricciardi, R (reprint author), Walter Reed Army Med Ctr, Walter Reed Stn, Washington, DC 20012 USA. EM richard.ricciardi@us.army.mil; metterj@grc.nia.nih.gov; ewitham@usuhs.mil; aghambaryan@usuhs.mil; ltalbot@usuhs.mil FU Uniformed Services University of the Health Sciences; National Institutes of Health-National Institute on Aging FX This research was sponsored by the TriService Nursing Research Program of the Uniformed Services University of the Health Sciences and in part by the Intramural Research Program of the National Institutes of Health-National Institute on Aging; however, the information or content and conclusions do not necessarily represent the official positions or policies of the Triservice Nursing Research Program, the Uniformed Services University of the Health Sciences, the Department of Defense, the National Institutes of Health, and the U.S. Government. Neither should any official endorsement by these entities be inferred. NR 32 TC 6 Z9 7 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 0897-1897 J9 APPL NURS RES JI Appl. Nurs. Res. PD FEB PY 2009 VL 22 IS 1 BP 2 EP 9 DI 10.1016/j.apnr.2007.01.011 PG 8 WC Nursing SC Nursing GA 409BG UT WOS:000263480600002 PM 19171289 ER PT J AU Insel, TR AF Insel, Thomas R. TI Translating Scientific Opportunity Into Public Health Impact A Strategic Plan for Research on Mental Illness SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID COMORBIDITY SURVEY REPLICATION; SUPPORTED EMPLOYMENT; UNITED-STATES; DISORDERS; SCHIZOPHRENIA; PARTICIPANTS; PREVALENCE; PSYCHIATRY; IDEATION; BEHAVIOR AB Context: Research has transformed many areas of medicine, with profound effects on morbidity and mortality. Exciting advances in neuroscience and genomics have transformed research but have not yet been translated to public health impact in psychiatry. Current treatments are necessary but not sufficient for most patients. Objectives: To improve outcomes we will need to (1) identify the neural circuitry of mental disorders, (2) detect the earliest manifestations of risk or illness even before cognition or behavior appear abnormal, (3) personalize care based on individual responses, and (4) implement broader use of effective psychosocial interventions. Results: To address these objectives, NIMH, working with its many stakeholders, developed a strategic plan for research. The plan calls for research that will (1) define the pathophysiology of disorders from genes to behavior, (2) map the trajectory of illness to determine when, where, and how to intervene to preempt disability, (3) develop new interventions based on a personalized approach to the diverse needs and circumstances of people with mental illnesses, and (4) strengthen the public health impact of NIMH-supported research by focusing on dissemination science and disparities in care. Conclusions: The NIMH is shifting its funding priorities to close the gap between basic biological knowledge and effective mental health care, paving the way for prevention, recovery, and cure. C1 NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov NR 44 TC 224 Z9 226 U1 6 U2 29 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X EI 1538-3636 J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2009 VL 66 IS 2 BP 128 EP 133 PG 6 WC Psychiatry SC Psychiatry GA 402CQ UT WOS:000262992200002 PM 19188534 ER PT J AU Masdeu, JC Pascual, B Bressi, F Casale, M Prieto, E Arbizu, J Fernandez-Seara, MA AF Masdeu, Joseph C. Pascual, Belen Bressi, Federica Casale, Manuele Prieto, Elena Arbizu, Javier Fernandez-Seara, Maria A. TI Ventricular Wall Granulations and Draining of Cerebrospinal Fluid in Chronic Giant Hydrocephalus SO ARCHIVES OF NEUROLOGY LA English DT Article; Proceedings Paper CT 60th Annual Meeting of the American-Academy-of-Neurology CY APR 12-19, 2008 CL Chicago, IL SP Amer Acad Neurol ID BRAIN; FLOW; ADULTS AB Background: In rare cases, adults with normal or almost normal cognition may have giant brain ventricles surrounded by a sliver of brain. Because the usual flow of cerebrospinal fluid (CSF) is interrupted in these individuals, they may develop alternative CSF pathways to preserve brain function. Objective: To describe novel morphologic autopsy findings in a patient with chronic giant hydrocephalus that suggest the existence of alternative CSF draining pathways. Design: Case report. Setting: Autopsy study. Patient: A 48-year-old man with chronic compensated hydrocephalus associated with a Dandy-Walker malformation. Main Outcome Measure: Autopsy findings. Results: We observed microscopic structures on the ventricular wall that may facilitate CSF resorption. Their histologic appearance, reminiscent of pacchionian granulations, showed the opposite relation in regard to CSF/blood compartments: whereas the core of a pacchionian granulation contains CSF and the granulation is bathed in blood of the venous sinus, the core of the ventricular granulation in our patient contained venules, with the granulation bathed in ventricular CSF. Conclusions: These previously unreported (to our knowledge) ventricular wall granulations may facilitate draining of CSF into the venous system when CSF outflow from the ventricular system is occluded. The presence of these ventricular structures illustrates biologic adaptation to anomalous conditions and successful compensation. C1 [Masdeu, Joseph C.] Univ Navarra, Sch Med, Dept Neurol & Neurosurg, E-31080 Pamplona, Spain. [Prieto, Elena; Arbizu, Javier] Univ Navarra, Sch Med, Dept Nucl Med, E-31080 Pamplona, Spain. [Masdeu, Joseph C.; Pascual, Belen; Fernandez-Seara, Maria A.] Univ Navarra, Sch Med, Univ Navarra Clin, Neuroimaging Lab,Ctr Appl Med Res, E-31080 Pamplona, Spain. [Masdeu, Joseph C.; Fernandez-Seara, Maria A.] CIBER, Pamplona, Spain. [Bressi, Federica] Campus Biomed Univ, Dept Neurol, Rome, Italy. [Casale, Manuele] Campus Biomed Univ, Dept Otorhinolaryngol, Rome, Italy. RP Masdeu, JC (reprint author), NIMH, Sect Integrat Neuroimaging, Intramural Res Program, Clin Brain Disorders Branch,NIH, 9000 Rockville Pike,Bldg 10,Room 4C101, Bethesda, MD 20892 USA. EM masdeu@nih.gov RI Fernandez-Seara, Maria/K-1246-2014; Prieto, Elena/N-2142-2014 OI Fernandez-Seara, Maria/0000-0001-8536-6295; Prieto, Elena/0000-0002-3609-1210 NR 15 TC 3 Z9 3 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD FEB PY 2009 VL 66 IS 2 BP 262 EP 267 DI 10.1001/archneurol.2008.547 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 405DP UT WOS:000263203200018 PM 19204166 ER PT J AU Forooghian, F Yeh, S Faia, LJ Nussenblatt, RB AF Forooghian, Farzin Yeh, Steven Faia, Lisa J. Nussenblatt, Robert B. TI Uveitic Foveal Atrophy Clinical Features and Associations SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; INTRAOCULAR INFLAMMATORY DISEASE; KOYANAGI-HARADA SYNDROME; MACULAR EDEMA; RETINAL-DETACHMENT; POSTERIOR UVEITIS; BEHCET-DISEASE; CHOROIDAL NEOVASCULARIZATION; BIRDSHOT CHORIORETINOPATHY; AQUEOUS-HUMOR AB Objective: To characterize foveal atrophy in a heterogeneous group of patients with uveitis using clinical findings and high-definition (HD) optical coherence tomography (OCT). Design: Cross-sectional, retrospective case series. Results: The HD-OCT scans of 140 patients seen in a tertiary referral center were reviewed and 23 patients (33 eyes) with foveal atrophy were identified. All of the patients with foveal atrophy were diagnosed with intermediate uveitis, posterior uveitis, or panuveitis. The status of the photoreceptor layer as visualized with HD-OCT was associated with significant differences in mean visual acuity (P < .001). Clinical findings associated with foveal atrophy included atrophy of the retinal pigment epithelium and choroid (30 eyes [91%]), macular ischemia (13 eyes [39%]), cystoid macular edema (5 eyes [15%]), choroidal neovascularization (4 eyes [12%]), retinal detachment involving the macula (2 eyes [6%]), and serum antiretinal antibodies (2 eyes [6%]). Conclusions: Foveal atrophy can be a complication of intraocular inflammation in a variety of uveitic syndromes. The cause of foveal atrophy is multifactorial and may include dysfunction and atrophy of the retinal pigment epithelium and choroid, cystoid macular edema, macular ischemia secondary to occlusive retinal vasculitis, choroidal neovascularization, retinal detachment, and possibly antibody-mediated damage directed against photoreceptors. Careful observation of the photoreceptor layer using HD-OCT may help to identify patients who are at risk for visual loss secondary to foveal atrophy. C1 [Yeh, Steven; Faia, Lisa J.; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Forooghian, Farzin] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU National Eye Institute Intramural Research Program FX This work was supported by the National Eye Institute Intramural Research Program. NR 35 TC 15 Z9 16 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 2009 VL 127 IS 2 BP 179 EP 186 PG 8 WC Ophthalmology SC Ophthalmology GA 405DR UT WOS:000263203400008 PM 19204236 ER PT J AU Barisoni, L Schnaper, HW Kopp, JB AF Barisoni, Laura Schnaper, H. William Kopp, Jeffrey B. TI Advances in the Biology and Genetics of the Podocytopathies Implications for Diagnosis and Therapy SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Review ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GLOMERULAR TIP LESION; CONGENITAL NEPHROTIC SYNDROME; IDIOPATHIC COLLAPSING GLOMERULOPATHY; DIFFUSE MESANGIAL SCLEROSIS; HIV-ASSOCIATED NEPHROPATHY; PUROMYCIN AMINONUCLEOSIDE; DIABETIC-NEPHROPATHY; PODOCYTE APOPTOSIS; SLIT DIAPHRAGM AB Context.-Etiologic factors and pathways leading to altered podocyte phenotype are clearly numerous and involve the activity of different cellular function. Objective.-To focus on recent discoveries in podocyte biology and genetics and their relevance to these human glomerular diseases, named podocytopathies. Data Sources.-Genetic mutations in genes encoding for proteins in the nucleus, slit diaphragm, podocyte cytoplasm, and cell membrane are responsible for podocyte phenotype and functional abnormalities. Podocyte injury may also derive from secondary stimuli, such as mechanical stress, infections, or use of certain medications. Podocytes can respond to injury in a limited number of ways, which include (1) effacement, (2) apoptosis, (3) arrest of development, and (4) dedifferentiation. Each of these pathways results in a specific glomerular morphology: minimal change nephropathy, focal segmental glomerulosclerosis, diffuse mesangial sclerosis, and collapsing glomerulopathy. Conclusions.-Based on current knowledge of podocyte biology, we organized etiologic factors and morphologic features in a taxonomy of podocytopathies, which provides a novel approach to the classification of these diseases. Current and experimental therapeutic approaches are also discussed. C1 [Barisoni, Laura] NYU, Sch Med, Dept Pathol & Med, Div Nephrol, New York, NY 10017 USA. [Schnaper, H. William] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Div Kidney Dis, Chicago, IL 60611 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, US Dept HHS, Bethesda, MD USA. RP Barisoni, L (reprint author), NYU, Sch Med, Dept Pathol, New York, NY 10017 USA. EM barisol01@med.nyu.edu OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS [Z01 DK043308-12]; NCRR NIH HHS [UL1 RR025741] NR 109 TC 54 Z9 66 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD FEB PY 2009 VL 133 IS 2 BP 201 EP 216 PG 16 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 404LK UT WOS:000263153200008 PM 19195964 ER PT J AU Wendler, D AF Wendler, David TI Minimal Risk in Pediatric Research as a Function of Age SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID CHILDREN; CONSENT; PARTICIPATION; ADOLESCENTS; STANDARD AB The minimal risk standard allows institutional review boards (IRBs) to approve pediatric research when the risks do not exceed the risks children face in daily life or during routine examinations. The fact that the risks children face in daily life vary with age raises the question of whether IRBs should implement this standard by adopting 1, 2, 3, or even more risk standards. The level of research risks to which it is appropriate to expose children depends on their maturity level. While younger children should be exposed to only very low research risks, it can be appropriate to expose older children to somewhat higher risks. This analysis supports 2 thresholds for minimal risk in pediatric research: one for research with younger children and a distinct standard for older children who can understand and who agree to participate. C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 21 TC 11 Z9 11 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD FEB PY 2009 VL 163 IS 2 BP 115 EP 118 PG 4 WC Pediatrics SC Pediatrics GA 402CM UT WOS:000262991800003 PM 19188642 ER PT J AU Kuntsche, E Simons-Morton, B Fotiou, A ter Bogt, T Kokkevi, A AF Kuntsche, Emmanuel Simons-Morton, Bruce Fotiou, Anastasios ter Bogt, Tom Kokkevi, Anna CA Hlth Behav Sch-Aged Children Study TI Decrease in Adolescent Cannabis Use From 2002 to 2006 and Links to Evenings Out With Friends in 31 European and North American Countries and Regions SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID SCHOOL; MARIJUANA; ALCOHOL AB Objective: To compare adolescent cannabis use between 2002 and 2006 and to investigate links to the frequency of evenings spent out with friends. Design: The Health Behavior in School-Aged Children study, an international study carried out in collaboration with the World Health Organization/Europe. Setting: A total of 31 mostly European and North American countries and regions. Participants: A total of 93 297 students aged 15 years. Outcome Measure: Cannabis use in the last 12 months in relation to the mean frequency of evenings out with friends per week. Results: A decrease in the prevalence of cannabis use was found in most of the 31 participating countries and regions. The most marked decreases were found in England, Portugal, Switzerland, Slovenia, and Canada. Increases occurred only in Estonia, Lithuania, Malta, and among Russian girls. The more frequently adolescents reported going out with their friends in the evenings, the more likely they were to report using cannabis. This link was consistent for boys and girls and across survey years. Across countries, changes in the mean frequency of evenings spent out were strongly linked to changes in cannabis use. Conclusions: The findings are consistent with the hypothesis that by going out less frequently in the evenings with friends, adolescents had fewer opportunities to obtain and use cannabis. Future research is needed to learn more about the nature of evenings out with friends and related factors that might explain changes in adolescent cannabis use over time. C1 [Kuntsche, Emmanuel] Swiss Inst Prevent Alcohol & Drug Problems, Res Dept, CH-1001 Lausanne, Switzerland. [Simons-Morton, Bruce] NICHHD, Prevent Res Branch, NIH, Bethesda, MD 20892 USA. [Fotiou, Anastasios; Kokkevi, Anna] Univ Mental Hlth Res Inst, Athens, Greece. [ter Bogt, Tom] Univ Utrecht, Netherlands Inst Mental Heath & Addict, Utrecht, Netherlands. [Kokkevi, Anna] Univ Athens, Sch Med, Dept Psychiat, GR-11527 Athens, Greece. RP Kuntsche, E (reprint author), Swiss Inst Prevent Alcohol & Drug Problems, Res Dept, POB 870, CH-1001 Lausanne, Switzerland. EM ekuntsche@sfa-ispa.ch RI Gaspar de Matos, Margarida/H-3824-2012; OI Simons-Morton, Bruce/0000-0003-1099-6617; Gaspar de Matos, Margarida/0000-0003-2114-2350; Fotiou, Anastasios/0000-0001-7905-3241 FU Swiss Federal Office of Public Health [04.001776/2.24.02.-64] FX This study was supported by the Swiss Institute for the Prevention of Alcohol and Drug Problems and grant 04.001776/2.24.02.-64 from the Swiss Federal Office of Public Health (Dr Kuntsche). NR 20 TC 21 Z9 21 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD FEB PY 2009 VL 163 IS 2 BP 119 EP 125 PG 7 WC Pediatrics SC Pediatrics GA 402CM UT WOS:000262991800004 PM 19188643 ER PT J AU Hayashi, K Hooper, LC Detrick, B Hooks, JJ AF Hayashi, Kozaburo Hooper, Laura C. Detrick, Barbara Hooks, John J. TI HSV immune complex (HSV-IgG: IC) and HSV-DNA elicit the production of angiogenic factor VEGF and MMP-9 SO ARCHIVES OF VIROLOGY LA English DT Article ID TOLL-LIKE-RECEPTOR; HERPETIC STROMAL KERATITIS; SIMPLEX VIRUS; CELLS; KINASE; NEOVASCULARIZATION; EXPRESSION; MATURATION; INFECTION; CYTOKINES AB Angiogenesis and inflammatory mediators are critical pathogenic factors in herpetic stromal keratitis (HSK). Since disease progresses without infectious virus, HSV-DNA and HSV-IgG complexes (HSV-IC) may contribute to HSK by triggering these factors. Production of VEGF and MMP-9 was studied in vitro using corneal epithelial cells (HCE), fibroblasts (HCRF) and macrophages (THP-1). VEGF was elevated in HCRF and THP-1 following treatment with HSV-DNA and HSV-IC. MMP-9 was elevated in THP-1 but not in corneal cells. When anti-HSV-IgG(Fab')(2) complexes stimulated THP-1, MMP-9 was reduced to control levels. Pretreatment of THP-1 with anti-TLR-2 and -3 inhibited MMP-9 production. Thus, HSV-IC may stimulate THP-1 through the Fc receptor and TLRs. Proinflammatory cytokines (IL-1b, IL-6, and TNF-alpha) increased VEGF and MMP-9 in corneal cells and macrophages. These studies indicate that the continued presence of HSV-DNA and HSV-IC contribute to angiogenesis and inflammation in HSK. Thus, cytokines and TLRs may be potential targets for intervention. C1 [Hayashi, Kozaburo; Hooper, Laura C.; Hooks, John J.] NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Detrick, Barbara] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. RP Hayashi, K (reprint author), NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM hayashik@nei.nih.gov FU NIH National Eye Institute FX We thank Dr. Chandraskharam Naginini for providing us HCRFs. This research was supported (in part) by the Intramural Research program of NIH National Eye Institute. NR 30 TC 22 Z9 25 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD FEB PY 2009 VL 154 IS 2 BP 219 EP 226 DI 10.1007/s00705-008-0303-7 PG 8 WC Virology SC Virology GA 407GR UT WOS:000263352100005 PM 19115032 ER PT J AU Clauw, DJ Witter, J AF Clauw, Daniel J. Witter, James TI Pain and Rheumatology: Thinking Outside the Joint SO ARTHRITIS AND RHEUMATISM LA English DT Editorial Material ID DISEASE-ACTIVITY; KNEE PAIN; FIBROMYALGIA; OSTEOARTHRITIS; LUPUS; COMT; DISCORDANCE; PERCEPTION; MODULATION; DISORDERS C1 [Clauw, Daniel J.] Univ Michigan, Ann Arbor, MI 48106 USA. [Witter, James] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Clauw, DJ (reprint author), Univ Michigan, 24 Frank Lloyd Wright Dr,POB 385, Ann Arbor, MI 48106 USA. EM dclauw@umich.edu NR 30 TC 32 Z9 36 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD FEB PY 2009 VL 60 IS 2 BP 321 EP 324 DI 10.1002/art.24326 PG 4 WC Rheumatology SC Rheumatology GA 406DY UT WOS:000263276400003 PM 19180503 ER PT J AU Lee, HS Korman, BD Le, JM Kastner, DL Remmers, EF Gregersen, PK Bae, SC AF Lee, Hye-Soon Korman, Benjamin D. Le, Julie M. Kastner, Daniel L. Remmers, Elaine F. Gregersen, Peter K. Bae, Sang-Cheol TI Genetic Risk Factors for Rheumatoid Arthritis Differ in Caucasian and Korean Populations SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISM; ASIAN POPULATIONS; ASSOCIATION; SUSCEPTIBILITY; PTPN22; PADI4; METAANALYSIS; HAPLOTYPE; DISEASES; ALLELE AB Objective. Recent studies have identified a number of novel rheumatoid arthritis (RA) susceptibility loci in Caucasian populations. The aim of this study was to determine whether the genetic variants at 4q27, 6q23, CCL21, TRAF1/C5, and CD40 identified in Caucasians are also associated with RA in a Korean case-control collection. We also comprehensively evaluated the genetic variation within PTPN22, a well-established autoimmune disease-associated gene. Methods. We designed an experiment to thoroughly evaluate the PTPN22 linkage disequilibrium region, using tag single-nucleotide polymorphisms (SNPs) and disease-associated SNPs at 5 RA-associated loci recently identified in Caucasians, in 1,128 Korean patients with RA and 1,022 ethnically matched control subjects. We also resequenced the PTPN22 gene to seek novel coding variants that might be contributing to disease in this population. Results. None of the susceptibility loci identified in Caucasian patients with RA contributed significantly to disease in Koreans. Although tag SNPs covering the PTPN22 linkage disequilibrium block were polymorphic, they did not reveal any disease association, and resequencing did not identify any new common coding region variants in this population. The 6q23 and 4q27 SNPs assayed were nonpolymorphic in this population, and the TRAF1/C5, CD40, and CCL21 SNPs did not show any evidence for association with RA in this population of Korean patients. Conclusion. The genetic risk factors for RA are different in Caucasian and Korean patients. Although patients of different ethnic groups share the HLA region as a major genetic risk locus, most other genes shown to be significantly associated with disease in Caucasians appear not to play a role in Korean patients with RA. C1 [Korman, Benjamin D.; Le, Julie M.; Kastner, Daniel L.; Remmers, Elaine F.] NIAMSD, Bethesda, MD 20892 USA. [Lee, Hye-Soon; Bae, Sang-Cheol] Hanyang Univ, Coll Med, Seoul 133791, South Korea. [Lee, Hye-Soon; Bae, Sang-Cheol] Hosp Rheumat Dis, Seoul, South Korea. [Lee, Hye-Soon; Gregersen, Peter K.] Feinstein Inst Med Res, Manhasset, NY USA. RP Remmers, EF (reprint author), NIH, 9 Mem Dr,9-1 W108,MSC 0908, Bethesda, MD 20892 USA. EM remmerse@mail.nih.gov FU Korea Health 21 RD Project [01-PJ3-PG6-01GN11-0002]; NIH [R01-AR-44422 and N01-AI-95386] FX Supported in part by the Korea Health 21 R&D Project (grant 01-PJ3-PG6-01GN11-0002) and by the NIH (Intramural Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases). Mr. Korman's work was supported by the NIH Clinical Research Training Program. Dr. Gregersen's work was supported by grants from the NIH (R01-AR-44422 and N01-AI-95386). NR 27 TC 70 Z9 72 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD FEB PY 2009 VL 60 IS 2 BP 364 EP 371 DI 10.1002/art.24245 PG 8 WC Rheumatology SC Rheumatology GA 406DY UT WOS:000263276400008 PM 19180477 ER PT J AU Fedorova, I Hussein, N Baumann, MH Di Martino, C Salem, N AF Fedorova, Irina Hussein, Nahed Baumann, Michael H. Di Martino, Carmine Salem, Norman, Jr. TI An n-3 Fatty Acid Deficiency Impairs Rat Spatial Learning in the Barnes Maze SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE docosahexaenoic acid; DHA; n-3 fatty acid deficiency; Barnes maze; reversal teaming ID NUCLEUS-ACCUMBENS; SEROTONINERGIC NEUROTRANSMISSION; FRONTAL-CORTEX; DOCOSAPENTAENOIC ACID; DOPAMINERGIC-NEURONS; DIETARY DEFICIENCY; TASK-PERFORMANCE; BRAIN-FUNCTION; MOUSE MODEL; BEHAVIOR AB In this study, the authors demonstrate that rats with n-3 fatty acid deficiency display spatial learning deficits in the Barnes circular maze. Dams were deprived of n-3 fatty acids during pregnancy and lactation, and their offspring were weaned to the same deficient diet. There was a 58% loss of brain docosahexaenoic acid (DHA) in the n-3 fatty acid-deficient rats in comparison to n-3 fatty acid-adequate rats. At 8 weeks of age, deficient rats demonstrated moderate impairment in Barnes maze performance compared with the n-3 fatty acid-adequate rats during the initial training. In the reversal learning task, the n-3 fatty acid-deficient rats showed a profound deficit in performance: They required more time to find a new position of the escape tunnel, which was accompanied by a higher number of errors and perseverations. The n-3 fatty acid-deficient rats had reduced tissue levels of dopamine in the ventral striatum and enhanced levels of the metabolite 3,4-dihydroxyphenylacetic acid in frontal cortex and hypothalamus. In summary, this study demonstrates that rats with low brain DHA have a deficit in spatial reversal learning that could be related to changes in dopamine transmission in critical brain circuits. C1 [Fedorova, Irina; Hussein, Nahed; Di Martino, Carmine; Salem, Norman, Jr.] NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. [Baumann, Michael H.] NIDA, Clin Psychopharmacol Sect, Rockville, MD 90034 USA. RP Fedorova, I (reprint author), Martek Biosci Corp, 6480 Dobbin Rd, Columbia, MD 21045 USA. EM ifedorova@martek.com FU National Institutes of Health; NIAAA; NIDA FX This research was supported by the Intramural Research Programs of the National Institutes of Health, NIAAA, and NIDA. NR 64 TC 43 Z9 46 U1 1 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD FEB PY 2009 VL 123 IS 1 BP 196 EP 205 DI 10.1037/a0013801 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 399JO UT WOS:000262796400020 PM 19170444 ER PT J AU Lissek, S Rabin, SJ McDowell, DJ Dvir, S Bradford, DE Geraci, M Pine, DS Grillon, C AF Lissek, Shmuel Rabin, Stephanie J. McDowell, Dana J. Dvir, Sharone Bradford, Daniel E. Geraci, Marilla Pine, Daniel S. Grillon, Christian TI Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Panic disorder; Classical fear conditioning; Safety learning; Stimulus generalization; Fear potentiated startle; Psychophysiology ID POSTTRAUMATIC-STRESS-DISORDER; STIMULUS-GENERALIZATION; POTENTIATED STARTLE; HIPPOCAMPAL-LESIONS; THEORY PERSPECTIVE; ANXIETY DISORDERS; HUMANS; RATS; ETIOLOGY; DEFICITS AB Classical fear-conditioning is central to many etiologic accounts of panic disorder (PD), but few lab-based conditioning studies in PD have been conducted. One conditioning perspective proposes associative-learning deficits characterized by deficient safety learning among PD patients. The current study of PD assesses acquisition and retention of discriminative aversive conditioning using a fear-potentiated startle paradigm. This paradigm was chosen for its specific capacity to independently assess safety- and danger learning in the service of characterizing putative anomalies in each type of learning among those with PD. Though no group difference in fear-potentiated startle was found at retention, acquisition results demonstrate impaired discriminative learning among PD patients as indexed by measures of conditioned startle-potentiation to learned safety and danger Cues. Importantly, this discrimination deficit was driven by enhanced startle-potentiation to the learned safety cue rather than aberrant reactivity to the danger cue. Consistent with this finding, PD patients relative to healthy individuals reported higher expectancies of dangerous outcomes in the presence of the safety cue, but equal danger expectancies during exposure to the danger cue. Such results link PD to impaired discrimination learning, reflecting elevated fear responding to learned safety Cues. Published by Elsevier Ltd. C1 [Lissek, Shmuel; Rabin, Stephanie J.; McDowell, Dana J.; Dvir, Sharone; Bradford, Daniel E.; Geraci, Marilla; Pine, Daniel S.; Grillon, Christian] NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH,DHHS, Bethesda, MD 20892 USA. RP Lissek, S (reprint author), NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH,DHHS, 15K N Dr,Rm 200, Bethesda, MD 20892 USA. EM lisseks@mail.nih.gov OI Rabin, Stephanie/0000-0002-8282-0867 FU Intramural NIH HHS [Z01 MH002798-06] NR 36 TC 111 Z9 111 U1 3 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD FEB PY 2009 VL 47 IS 2 BP 111 EP 118 DI 10.1016/j.brat.2008.10.017 PG 8 WC Psychology, Clinical SC Psychology GA 413FG UT WOS:000263777700003 PM 19027893 ER PT J AU Hurley, JH Im, YJ Lee, HH Ren, XF Wollert, T Yang, D AF Hurley, James H. Im, Young Jun Lee, Hyung Ho Ren, Xuefeng Wollert, Thomas Yang, Dong TI Piecing together the ESCRTs SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Conference on ESCRTs - From Cell Biology to Pathogensis CY AUG 26-28, 2008 CL Robinson Coll, Cambridge, ENGLAND HO Robinson Coll DE ALG-2 (apoptosis-linked gene 2)-interacting protein X (Alix); endosomal sorting complex required for transport (ESCRT); membrane; small-angle X-ray scattering (SAXS); ubiquitin ID C-TERMINAL DOMAIN; STRUCTURAL BASIS; UBIQUITIN RECOGNITION; TRAFFICKING COMPLEX; EAP45-GLUE DOMAIN; CRYSTAL-STRUCTURE; GLUE DOMAIN; PROTEIN; VPS4; PATHWAY AB High-resolution structural analysis has characterized nearly all of the individual domains of ESCRT (endosomal sorting complex required for transport) subunits, all of the core structures of the soluble complexes and many of the interactions involving domains. Recent emphasis in structural studies has shifted towards efforts to integrate these structures into a larger-scale model. molecular simulations, hydrodynamic analysis, small-angle X-ray scattering and cryo-EM (electron microscopy) techniques have all been brought to bear on the ESCRT system over the last year. C1 [Hurley, James H.; Im, Young Jun; Lee, Hyung Ho; Ren, Xuefeng; Wollert, Thomas; Yang, Dong] NIDDK, Mol Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov OI Wollert, Thomas/0000-0001-9732-4789 FU Intramural NIH HHS NR 50 TC 8 Z9 8 U1 0 U2 1 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD FEB PY 2009 VL 37 BP 161 EP 166 DI 10.1042/BST0370161 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 402MI UT WOS:000263017400032 PM 19143623 ER PT J AU Martin-Soelch, C AF Martin-Soelch, Chantal TI Is depression associated with dysfunction of the central reward system? SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT 2nd Neuroscience Ireland Conference CY AUG 28-29, 2009 CL Natl Univ Ireland, Galway, IRELAND SP Galway Co HO Natl Univ Ireland DE anhedonia; depression; dopamine; mood; reward; striatum ID INDUCED DOPAMINE RELEASE; EVENT-RELATED FMRI; POSITRON-EMISSION-TOMOGRAPHY; MAJOR DEPRESSION; ORBITOFRONTAL CORTEX; MONETARY REWARD; MOOD-DISORDERS; HUMAN BRAIN; GREATER AVAILABILITY; TRANSPORTER BINDING AB The neural substrates of MDD (major depressive disorder) are complex and not yet fully understood. in the present review, I provide a short overview of the findings supporting the hypothesis of a dysfunctional dopamine system in the pathophysiology of depression. Because the mesocorticolimbic dopamine system is involved in reward processing, it has been hypothesized that a reduced function of this system could underlie the anhedonia and amotivation associated with depression. This hypothesis is supported by several observations providing indirect evidence for reduced central dopaminergic transmission in depression. However, some of the differences observed between controls and depressed patients in dopamine function seem to be specific to a subsample of patients, and influenced by the methods chosen. Studies that investigated the neural bases of some MDD behavioural symptoms showed that anhedonia, loss of motivation and the diminished ability to concentrate or make decisions could be associated with a blunted reaction to positive reinforcers and rewards on one side, and with a bias towards negative feedback on the other side. only a few studies have investigated the neural basis of anhedonia and the responses to rewards in MDD subjects, mostly evidencing a blunted response to reward signals that was associated with reduced brain activation in regions associated with the brain reward system. in conclusion, there is evidence for a dysfunction of the dopamine system in depression and for blunted response to reward signals. However, the exact nature of this dysfunction is not yet clear and needs to be investigated in further studies. C1 [Martin-Soelch, Chantal] Univ Zurich Hosp, Dept Psychiat, CH-8091 Zurich, Switzerland. [Martin-Soelch, Chantal] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Martin-Soelch, C (reprint author), Univ Zurich Hosp, Dept Psychiat, Culmannstr 8, CH-8091 Zurich, Switzerland. EM chantal.martinsoelch@usz.ch NR 72 TC 47 Z9 47 U1 5 U2 12 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD FEB PY 2009 VL 37 BP 313 EP 317 DI 10.1042/BST0370313 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 402MI UT WOS:000263017400063 PM 19143654 ER PT J AU Gerlitz, G Hock, R Ueda, T Bustin, M AF Gerlitz, Gabi Hock, Robert Ueda, Tetsuya Bustin, Michael TI The dynamics of HMG protein-chromatin interactions in living cells SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT Annual Meeting of the Canadian-Society-of-Biochemistry-Molecular-and-Cellular-Biology on Epigenetics and Chromatin Dynamics CY MAR 06-09, 2008 CL Banff, CANADA SP Canadian Soc Biochem Mole & Cellular Biol DE chromatin; HMG proteins; protein-DNA interactions ID MOBILITY-GROUP PROTEINS; 4-WAY JUNCTION DNA; GROUP CHROMOSOMAL-PROTEINS; NUCLEOSOMAL BINDING-PROTEIN; IN-VIVO MODIFICATIONS; GROUP A1 PROTEINS; HISTONE H1; POSTTRANSLATIONAL MODIFICATIONS; LINKER HISTONES; GENE-EXPRESSION AB The dynamic interaction between nuclear proteins and chromatin leads to the functional plasticity necessary to mount adequate responses to regulatory signals. Here, we review the factors regulating the chromatin interactions of the high mobility group proteins (HMGs), in abundant and ubiquitous superfamily of chromatin-binding proteins ill living cells. HMGs are highly mobile and interact with the chromatin fiber in a highly dynamic fashion, as part of a protein network. The major factors that affect the binding of HMGs to chromatin are operative at the level of the single nucleosome. These factors include structural features of the HMGs, competition with other chromatin-binding proteins for nucleosome binding sites, complex formation with protein partners, and post-translational modifications in the protein or in the chromatin-binding sites. The versatile modulation of the interaction between HMG proteins and chromatin plays a role in processes that establish the cellular phenotype. C1 [Gerlitz, Gabi; Ueda, Tetsuya; Bustin, Michael] NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. [Hock, Robert] Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, NIH, 37 Convent Dr,Bldg 37, Bethesda, MD 20892 USA. EM Bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Intramural NIH HHS [ZIA BC004496-32] NR 101 TC 49 Z9 51 U1 0 U2 7 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2009 VL 87 IS 1 BP 127 EP 137 DI 10.1139/O08-110 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 439CM UT WOS:000265605100013 PM 19234529 ER PT J AU Dalal, Y AF Dalal, Yamini TI Epigenetic specification of centromeres SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT Annual Meeting of the Canadian-Society-of-Biochemistry-Molecular-and-Cellular-Biology on Epigenetics and Chromatin Dynamics CY MAR 06-09, 2008 CL Banff, CANADA SP Canadian Soc Biochem Mole & Cellular Biol DE centromeres; epigenetics; chromatin; CenH3 nucleosome; pericentric heterochromatin; assembly ID HISTONE H3 VARIANT; CENP-A CHROMATIN; FISSION YEAST; SACCHAROMYCES-CEREVISIAE; PROTEIN-A; STRUCTURAL DETERMINANTS; COLORECTAL-CANCER; NUCLEOSOME CORE; IN-VITRO; KINETOCHORE AB Centromeres are the discrete sites of spindle microtubule attachment on chromosomes during mitosis and meiosis in all eukaryotes. These highly specialized chromatin structures typically occupy the same site for thousands of generations, yet the mechanism by which centromeres are established, maintained, and function remain a mystery. In metazoans, centromeric DNA sequence has proven not to be the key determinant of centromeric identity; therefore, centromeres are thought to be epigenetically specified by their specialized chromatin structure. In all eukaryotes, the centromere-specific histone H3 variant CenH3 replaces canonical H3 within nucleosomes at centric chromatin. This specialized nucleosome is the building block upon which all other centromere-associated proteins depend. This review highlights exciting new findings that have resulted in a paradigm shift in our understanding of CenH3 assembly into centromeric chromatin, CenH3 nucleosomal structure, CenH3 chromatin folding, the contribution of these factors to centromeric identity, and finally, the intimate role cell-cycle-regulated transcription and pericentric heterochromatin play in the maintenance and integrity of centromeres. C1 NCI, Chromatin Struct & Epigenet Mech Unit, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Dalal, Y (reprint author), NCI, Chromatin Struct & Epigenet Mech Unit, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov OI Dalal, Yamini/0000-0002-7655-6182 FU Intramural NIH HHS [ZIA BC011207-01, ZIA BC011207-02, ZIA BC011207-03, ZIA BC011207-04, ZIA BC011207-05, ZIA BC011207-06, ZIA BC011209-01, ZIA BC011209-02, ZIA BC011209-03, ZIA BC011209-04, ZIA BC011209-05, ZIA BC011209-06] NR 65 TC 14 Z9 15 U1 0 U2 3 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2009 VL 87 IS 1 BP 273 EP 282 DI 10.1139/O08-135 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 439CM UT WOS:000265605100025 PM 19234541 ER PT J AU Gong, F Fahy, D Liu, H Wang, W Smerdon, MJ AF Gong, F. Fahy, D. Liu, H. Wang, W. Smerdon, M. J. TI Role of the mammalian SWI/SNF chromatin remodeling complex in the cellular response to UV damage SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Meeting Abstract C1 Univ Miami, Miller Sch Med, Dept Biochem & Mol Biol, Miami, FL 33136 USA. Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2009 VL 87 IS 1 BP 383 EP 383 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 439CM UT WOS:000265605100093 ER PT J AU Richard, JP Leikina, E Chernomordik, LV AF Richard, Jean-Philippe Leikina, Eugenia Chernomordik, Leonid V. TI Cytoskeleton reorganization in influenza hemagglutinin-initiated syncytium formation SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Cytoskeleton; Membrane fusion; Syncytium; Influenza hemagglutinin ID CELL-CELL FUSION; PROTEIN-KINASE-C; MEMBRANE-FUSION; MYOBLAST FUSION; ACTIN-POLYMERIZATION; MYOSIN-II; MACROPHAGE FUSION; VIRUS; MICROTUBULE; MOVEMENT AB Little is known about the mechanisms of cell-cell fusion in development and diseases and, especially, about fusion stages downstream of an opening of nascent fusion pore(s). Earlier works on different cell-cell fusion reactions have indicated that cytoskeleton plays important role in syncytium formation. However, due to complexity of these reactions and multifaceted contributions of cytoskeleton in cell physiology, it has remained unclear whether cytoskeleton directly drives fusion pore expansion or affects preceding fusion stages. Here we explore cellular reorganization associated with fusion pore expansion in syncytium formation using relatively simple experimental system. Fusion between murine embryonic fibroblasts NIH3T3-based cells is initiated on demand by well-characterized fusogen influenza virus hemagglutinin. We uncouple early fusion stages dependent on protein fusogens from subsequent fusion pore expansion stage and establish that the transition from local fusion to syncytium requires metabolic activity of living cells. Effective syncytium formation for cells with disorganized actin and microtubule cytoskeleton argues against hypothesis that cytoskeleton drives fusion expansion. (c) Published by Elsevier B.V. C1 [Richard, Jean-Philippe; Leikina, Eugenia; Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chernomordik, LV (reprint author), Bldg 10,Room 10D04,10 Ctr Dr, Bethesda, MD 20892 USA. EM chernoml@mail.nih.gov FU Intramural Research Program of the NIH, NICHD FX We thank A. Bershadsky, A. Chen, L Joubert-Mang, M. Kozlov, B. Lebleu, K. Melikov, B. Podbilewicz, E. Zaitseva, and J. Zimmerberg for very helpful discussions. This research was supported by the Intramural Research Program of the NIH, NICHD. NR 62 TC 9 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD FEB PY 2009 VL 1788 IS 2 BP 450 EP 457 DI 10.1016/j.bbamem.2008.09.014 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 413LN UT WOS:000263794700016 PM 18976631 ER PT J AU Igarashi, M Gao, F Kim, HW Ma, KZ Bell, JM Rapoport, SI AF Igarashi, Miki Gao, Fei Kim, Hyung-Wook Ma, Kaizong Bell, Jane M. Rapoport, Stanley I. TI Dietary n-6 PUFA deprivation for 15 weeks reduces arachidonic acid concentrations while increasing n-3 PUFA concentrations in organs of post-weaning male rats SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE Linoleic acid; Arachidonic acid; Dietary deficiency; PUFA ID POLYUNSATURATED FATTY-ACIDS; ALPHA-LINOLENIC ACID; LONG-TERM POTENTIATION; AIN-93 PURIFIED DIETS; DOCOSAHEXAENOIC ACID; BRAIN PHOSPHOLIPIDS; AGED RATS; PLATELET CYCLOOXYGENASE; GENE-TRANSCRIPTION; LIVER CONVERSION AB Few studies have examined effects of feeding animals a diet deficient in n-6 polyunsaturated fatty acids (PUFAs) but with an adequate amount of n-3 PUFAs. To do this, we fed post-weaning male rats a control n-6 and n-3 PUFA adequate diet and an n-6 deficient diet for 15 weeks, and measured stable lipid and fatty acid concentrations in different organs. The deficient diet contained nutritionally essential linoleic acid (LA, 18:2n-6) as 2.3% of total fatty acids (10% of the recommended minimum LA requirement for rodents) but no arachidonic acid (AA, 20:4n-6), and an adequate amount (4.8% of total fatty acids) of alpha-linolenic acid (18:3n-3). The deficient compared with adequate diet did not significantly affect body weight, but decreased testis weight by 10%. AA concentration was decreased significantly in serum (-86%), brain (-27%), liver (-68%), heart (-39%), testis (-25%), and epididymal adipose tissue (-77%). Eicosapentaenoic (20:5n-3) and docosahexaenoic acid (22:6n-3) concentrations were increased in all but adipose tissue, and the total monounsaturated fatty acid concentration was increased in all organs. The concentration of 20:3n-9, a marker of LA deficiency, was increased by the deficient diet, and serum concentrations of triacylglycerol, total cholesterol and total phospholipid were reduced. In summary, 15 weeks of dietary n-6 PUFA deficiency with n-3 PUFA adequacy significantly reduced n-6 PUFA concentrations in different organs of male rats, while increasing n-3 PUFA and monounsaturated fatty acid concentrations. This rat model could be used to study metabolic, functional and behavioral effects of dietary n-6 PUFA deficiency. Published by Elsevier B.V. C1 [Igarashi, Miki; Gao, Fei; Kim, Hyung-Wook; Ma, Kaizong; Bell, Jane M.; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Igarashi, M (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM mikii@mail.nih.gov RI Igarashi, Miki/B-1085-2017 FU National Institute on Aging, NIH FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH. The authors thank the NIH Fellows Editorial Board and Ms. Kathy Benjamin for editorial assistance. NR 67 TC 38 Z9 38 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD FEB PY 2009 VL 1791 IS 2 BP 132 EP 139 DI 10.1016/j.bbalip.2008.11.002 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 410ZE UT WOS:000263616000007 PM 19073280 ER PT J AU Li, LY Soetandyo, N Wang, QY Ye, YH AF Li, Lianyun Soetandyo, Nia Wang, Qiuyan Ye, Yihong TI The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE A20; TRAF2; NF kappa B; Ubiquitin; Lysosomal degradation ID NF-KAPPA-B; RECEPTOR-ASSOCIATED FACTOR-2; NECROSIS-FACTOR RECEPTOR; CELL-DEATH; TNF RECEPTOR-1; INHIBITS TNF; ACTIVATION; COMPLEX; JNK; UBIQUITINATION AB The zinc finger-containing protein A20 is a negative regulator of TNF-induced JNK (c-jun-N-terminal kinase) and NF kappa B (nuclear factor kappa B) signaling. A20 is an unusual enzyme that contains both ubiquitinating and deubiquitinating activities. Although A20 is mostly localized in the cytosol, our recent studies reveal that a fraction of A20 can associate with a lysosome-interacting compartment in a manner that requires its carboxy terminal zinc fingers, but independent of its ubiquitin modifying activities. Whether the lysosome-associated A20 has a function in cellular signaling is unclear. Here, we demonstrate that A20 is capable of targeting an associated signaling molecule such as TRAF2 to the lysosomes for degradation. This process is dependent on the membrane tethering zinc finger domains of A20, but does not require A20 ubiquitin modifying activity. Our findings suggest a novel mode of A20 action that involves lysosomal targeting of signal molecules bound to A20. Published by Elsevier B.V C1 [Li, Lianyun; Soetandyo, Nia; Wang, Qiuyan; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bldg 5,Room 433,5 Ctr Dr, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank Michael Krause, Zheng-Gang Liu, Jonathan Ashwell, and Harris Bernstein for critical reading of the manuscript, Zheng-Gang Liu for TRAF2+ MEF cells, Averil Ma for A20+ MEF cells, Jennifer Macdonald for constructing the plasmids expressing the TRAF2 variants. This Research is supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 40 TC 45 Z9 49 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD FEB PY 2009 VL 1793 IS 2 BP 346 EP 353 DI 10.1016/j.bbamcr.2008.09.013 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 407ZK UT WOS:000263402600013 PM 18952128 ER PT J AU Nomoto, M Miyata, M Yin, S Kurata, Y Shimada, M Yoshinari, K Gonzalez, FJ Suzuki, K Shibasaki, S Kurosawa, T Yamazoe, Y AF Nomoto, Masahiro Miyata, Masaaki Yin, Shanai Kurata, Yasushi Shimada, Miki Yoshinari, Kouichi Gonzalez, Frank J. Suzuki, Kokichi Shibasaki, Shigeki Kurosawa, Tohru Yamazoe, Yasushi TI Bile Acid-Induced Elevated Oxidative Stress in the Absence of Farnesoid X Receptor SO BIOLOGICAL & PHARMACEUTICAL BULLETIN LA English DT Article DE farnesoid X receptor; bile acid; nuclear factor (erythroid-2 like) factor 2; oxidative stress; 8-hydroxy-2 '-deoxyguanosine ID VITAMIN-E; LIPID-PEROXIDATION; HEME OXYGENASE; RAT-LIVER; BINDING PROTEIN; DEFICIENT MICE; NULL MICE; TOXICITY; METALLOTHIONEIN; HEPATOTOXICITY AB The major function of farnesoid X receptor (FXR) is to maintain bile acid and lipid homeostasis. Fxr-null mice, in which the levels of hepatic bile acid and lipid have been elevated, develop spontaneous liver tumors. We evaluated differences in hepatic bile acid and triglyceride concentrations, and in generation of oxidative stress between wild-type mice and Fxr-null mice. The hepatic levels of 8-hydroxy-2'-deoxyguanosine (8OHdG), thiobarbituric acid-reactive substance (TBARS) and hydroperoxides, oxidative stress-related genes, and nuclear factor (erythroid-2 like) factor 2 (Nrf2) protein in Fxr-null mice were significantly higher than those in wild-type mice. An increase in the hepatic bile acid concentration in Fxr-null mice fed a cholic acid (CA) diet resulted in an increase in the hepatic levels of hydroperoxides, TBARS and 8OHdG, whereas a decrease in the hepatic concentration in mice fed a diet containing ME3738 (22 beta-methoxyolean-12-ene-3 beta,24(4 beta)-diol) resulted in a decrease in these oxidative stress marker levels. A good correlation was observed between the hepatic bile acid concentrations and the hepatic oxidative stress marker levels, although there was no significant correlation between the hepatic triglyceride concentrations and oxidative stress. The results show that oxidative stress is spontaneously enhanced in Fxr-null mice, which may be attributable to a continuously high level of hepatic bile acids. C1 [Nomoto, Masahiro; Miyata, Masaaki; Shimada, Miki; Yoshinari, Kouichi; Yamazoe, Yasushi] Tohoku Univ, Grad Sch Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Aoba Ku, Sendai, Miyagi 9808578, Japan. [Nomoto, Masahiro; Yin, Shanai; Kurata, Yasushi; Suzuki, Kokichi; Shibasaki, Shigeki; Kurosawa, Tohru] Meiji Seika Kaisha Ltd, Pharmaceut Res Ctr, Appl Pharmacol Res Labs, Kohoku Ku, Yokohama, Kanagawa 2228567, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Yamazoe, Yasushi] Tohoku Univ, CRESCENDO, 21st Century Ctr Excellence Program, Sendai, Miyagi 9808578, Japan. RP Miyata, M (reprint author), Tohoku Univ, Grad Sch Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Aoba Ku, 6-3 Aoba, Sendai, Miyagi 9808578, Japan. EM miyata@mail.pharm.tohoku.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labor and Welfare of Japan FX We would like to express our sincere thanks to Dr. Yoko Shoji, Dr. Shoji Nishiyama, Ms. Mariko Takagi and Dr. Kiyoshi Nagata for skillful technical advice and support. This study was supported by a Grant-inAid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan. NR 53 TC 17 Z9 17 U1 0 U2 3 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0918-6158 J9 BIOL PHARM BULL JI Biol. Pharm. Bull. PD FEB PY 2009 VL 32 IS 2 BP 172 EP 178 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 399ZW UT WOS:000262838800003 PM 19182371 ER PT J AU Antoniadis, EA Winslow, JT Davis, M Amaral, DG AF Antoniadis, Elena A. Winslow, James T. Davis, Michael Amaral, David G. TI The Nonhuman Primate Amygdala Is Necessary for the Acquisition but not the Retention of Fear-Potentiated Startle SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Amygdaloid complex; emotional learning; fear; fear-conditioning; memory ID BASOLATERAL AMYGDALA; ORBITOFRONTAL CORTEX; TEMPORAL GRADIENT; CONDITIONAL FEAR; CENTRAL NUCLEUS; ANXIOUS TEMPERAMENT; RETROGRADE-AMNESIA; MONKEYS MACACA; RHESUS-MONKEYS; BED NUCLEUS AB Background: In a previous study, we found that rhesus monkeys prepared with bilateral lesions of the amygdala failed to acquire fear-potentiated startle to a visual cue. However, a second group of monkeys, which received the lesion after training, successfully demonstrated fear-potentiated startle learned prior to the lesion. Methods: In the current experiment, the eight monkeys used in the second part of the original study, four of which had bilateral amygdala lesions and the four control animals, were trained using an auditory cue and tested in the fear-potentiated startle paradigm. This test was performed to determine whether they could acquire fear-potentiated startle to a new cue. Results: Monkeys with essentially complete damage to the amygdala (based on histological analysis) that had retained and expressed fear-potentiated startle to a visual cue learned before the lesion failed to acquire fear-potentiated startle to an auditory cue when training occurred after the lesion. Conclusions: The results suggest that while the nonhuman primate amygdala is essential for the initial acquisition of fear conditioning, it does not appear to be necessary for the memory and expression of conditioned fear. These findings are discussed in relation to a network of connections between the amygdala and the orbitofrontal cortex that may subserve different component processes of fear conditioning. C1 [Amaral, David G.] Univ Calif Davis, MIND Inst, Sacramento, CA 95817 USA. [Antoniadis, Elena A.; Amaral, David G.] Univ Calif Davis, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. [Antoniadis, Elena A.; Amaral, David G.] Univ Calif Davis, Calif Natl Primate Res Ctr, Sacramento, CA 95817 USA. [Winslow, James T.] NIMH, Bethesda, MD 20892 USA. [Davis, Michael] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Davis, Michael] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Davis, Michael] Emory Univ, Ctr Behav Neurosci, Atlanta, GA 30322 USA. RP Amaral, DG (reprint author), Univ Calif Davis, MIND Inst, 2825 50th St, Sacramento, CA 95817 USA. EM dgamaral@ucdavis.edu FU National Institutes of Health (NIH) [R37 MH057502, MH 41479, R37 MH47840, 2P50 MH58922]; McDonnell Foundation; Natural Sciences and Engineering Research Council of Canada; Intramural Program of the National Institute of Mental Health; California National Primate Research Center (NIH) [RR00169] FX Supplementary material cited in this article is available online. NR 54 TC 34 Z9 35 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2009 VL 65 IS 3 BP 241 EP 248 DI 10.1016/j.biopsych.2008.07.007 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 395QK UT WOS:000262538400009 PM 18823878 ER PT J AU Hasler, G van der Veen, JW Geraci, M Shen, J Pine, D Drevets, WC AF Hasler, Gregor van der Veen, Jan Willem Geraci, Marilla Shen, Jun Pine, Daniel Drevets, Wayne C. TI Prefrontal Cortical Gamma-Aminobutyric Acid Levels in Panic Disorder Determined by Proton Magnetic Resonance Spectroscopy SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anxiety disorders; depression; gamma-aminobutyric acid; glutamate; MRS ID GABA LEVELS; ANTERIOR CINGULATE; MAJOR DEPRESSION; MENSTRUAL-CYCLE; HUMAN BRAIN; GLUTAMATE; REGION; WOMEN AB Background: Panic disorder (PD) is hypothesized to be associated with altered function of the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Previous proton magnetic resonance spectroscopy (MRS) studies found lower GABA concentrations in the occipital cortex of subjects with PD relative to healthy control subjects. The current study is the first MRS study to compare GABA concentrations between unmedicated PD subjects and control subjects in the prefrontal cortex (PFC). Methods: Unmedicated subjects with PD (n = 17) and age- and sex-matched healthy control subjects (n = 17) were scanned on a 3 Tesla scanner using a transmit-receive head coil that provided a sufficiently homogenous radiofrequency field to obtain spectroscopic measurements in the dorsomedial/dorsal anterolateral and ventromedial areas of the PFC. Results: The prefrontal cortical GABA concentrations did not differ significantly between PD subjects and control subjects. There also was no statistically significant difference in glutamate/glutamine (Glx), choline, or N-acetyl aspartate concentrations. Conclusions: The previously reported finding of reduced GABA concentrations in the occipital cortex of PD subjects does not appear to extend to the PFC. C1 [Hasler, Gregor] Univ Zurich Hosp, Dept Psychiat, CH-8091 Zurich, Switzerland. [Geraci, Marilla; Drevets, Wayne C.] NIMH, Mood & Anxiety Disorders Program, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Pine, Daniel] NIMH, Mood & Anxiety Disorders Program, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. RP Hasler, G (reprint author), Univ Zurich Hosp, Dept Psychiat, Culmannstr 8, CH-8091 Zurich, Switzerland. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 FU Intramural Research Program of the National Institutes of Mental Health FX Supplemental material cited in this article is available online. NR 20 TC 29 Z9 29 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2009 VL 65 IS 3 BP 273 EP 275 DI 10.1016/j.biopsych.2008.06.023 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 395QK UT WOS:000262538400014 PM 18692172 ER PT J AU Van Diest, I Bradley, MM Guerra, P Van den Bergh, O Lang, PJ AF Van Diest, Ilse Bradley, Margaret M. Guerra, Pedro Van den Bergh, Omer Lang, Peter J. TI Fear-conditioned respiration and its association to cardiac reactivity SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Fear conditioning; Respiration; Heart rate; Hyperventilation ID HEART-RATE; PANIC DISORDER; AUTONOMIC RESPONSE; EMOTIONAL IMAGERY/; HYPERVENTILATION; HUMANS; PATTERNS; BLOOD; BLOCKADE; BEHAVIOR AB This study aimed to investigate ventilatory correlates of conditioned fear responses. Respiratory, end-tidal carbon dioxide pressure (PetCO(2)) and heart rate changes were studied in a differential fear-conditioning paradigm. Forty-two participants viewed pictures of faces. One picture (CS+) was followed by a human scream (US) during the acquisition phase, but not in a subsequent extinction phase. Conditioning of PetCO(2) (decrease), respiratory cycle time (decrease) and inspiratory duty time (increase) was established and subsequently extinguished. When participants were clustered according to their conditioned PetCO(2) responses during acquisition, only a group showing a conditioned decrease in PetCO(2) showed also a differential cardiac acceleration, a decrease in expiratory duration and an increase in inspiratory duty time in response to the CS+. These results suggest that preparation for defensive action is characterized by a tendency towards hyperventilation and cardiac acceleration. (C) 2008 Elsevier B.V. All rights reserved. C1 [Van Diest, Ilse; Van den Bergh, Omer] Univ Louvain, Dept Psychol, B-3000 Louvain, Belgium. [Bradley, Margaret M.; Lang, Peter J.] Univ Florida, NIMH, CSEA, Gainesville, FL USA. [Guerra, Pedro] Univ Granada, E-18071 Granada, Spain. RP Van Diest, I (reprint author), Univ Louvain, Dept Psychol, Tiensestr 102, B-3000 Louvain, Belgium. EM llse.VanDiest@psy.kuleuven.be FU National Institute of Dental Research [DE 13956]; National Institute of Mental Health [P50 MH 72850]; Fund of Scientific Research - Flanders FX This research was supported in part by grants from the National Institute of Dental Research (DE 13956) to Margaret M. Bradley and the National Institute of Mental Health (P50 MH 72850) to Peter J. Lang. The research was conducted while Ilse Van Diest was at the NIMH Center for the Study of Emotion and Attention at the University of Florida, funded as a post-doctoral research associate by the Fund of Scientific Research - Flanders. NR 43 TC 16 Z9 17 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD FEB PY 2009 VL 80 IS 2 BP 212 EP 217 DI 10.1016/j.biopsycho.2008.09.006 PG 6 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 416ZO UT WOS:000264044300008 PM 18955105 ER PT J AU O'Donnell, P Pedersen, T Confer, D Pulsipher, M Rizzo, JD Stroneek, D Leitman, S Anderlini, P AF O'Donnell, P. Pedersen, T. Confer, D. Pulsipher, M. Rizzo, J. D. Stroneek, D. Leitman, S. Anderlini, P. TI PRACTICE PATTERNS FOR EVALUATION, CONSENT AND CARE OF RELATED DONORS AND RECIPIENTS AT HEMATOPOIETIC STEM CELL TRANSPLANT CENTERS IN THE UNITED STATES: IS CONFLICT-OF-INTEREST AN UNRECOGNIZED ISSUE? SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [O'Donnell, P.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Pedersen, T.; Confer, D.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Pulsipher, M.] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Rizzo, J. D.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Leitman, S.] NIH, Bethesda, MD 20892 USA. [Anderlini, P.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 16 BP 8 EP 9 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800017 ER PT J AU Ramanathan, M Lundqvist, A Yokoyama, H Smith, A Childs, R AF Ramanathan, M. Lundqvist, A. Yokoyama, H. Smith, A. Childs, R. TI NATURAL KILLER (NK) CELLS ARE RESISTANT TO THE APOPTOTIC EFFECTS OF CORTICOSTEROIDS COMPARED TO T CELLS: IMPLICATIONS FOR ADOPTIVE NK CELL THERAPY FOLLOWING ALLOGENEIC HCT SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Ramanathan, M.; Lundqvist, A.; Yokoyama, H.; Smith, A.; Childs, R.] 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 19 BP 9 EP 10 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800020 ER PT J AU Le Blanc, K Remberger, M Barrett, J AF Le Blanc, K. Remberger, M. Barrett, J. TI LYMPHOCYTE RECOVERY IS A MAJOR DETERMINANT OF TRANSPLANT OUTCOME AFTER MYELOABLATIVE TRANSPLANTATION IN PATIENTS WITH MYELOID MALIGNANCIES RECEIVING MATCHED UNRELATED STEM CELL ALLOGRAFTS SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Le Blanc, K.; Remberger, M.] Karolinska Inst, Stockholm, Sweden. [Le Blanc, K.] Karolinska Univ Hosp Huddinge, Stockholm, Sweden. [Barrett, J.] 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 27 BP 12 EP 13 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800028 ER PT J AU Sokolic, R Podsakoff, G Muul, L Engel, B Jagadeesh, J Garabedian, E Kesserwan, C Carbonaro, D Choi, YC Shaw, K Hershfield, M Wayne, A Kohn, D Candotti, F AF Sokolic, R. Podsakoff, G. Muul, L. Engel, B. Jagadeesh, J. Garabedian, E. Kesserwan, C. Carbonaro, D. Choi, Y. C. Shaw, K. Hershfield, M. Wayne, A. Kohn, D. Candotti, F. TI IMMUNE RECONSTITUTION AFTER GENE THERAPY (GTX) FOR ADENOSINE DEAMINASE DEFICIENT SEVERE COMBINED IMMUNE DEFICIENCY (ADA-SCID) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Sokolic, R.; Muul, L.; Jagadeesh, J.; Garabedian, E.; Kesserwan, C.; Wayne, A.; Candotti, F.] NIH, Bethesda, MD 20892 USA. [Podsakoff, G.; Engel, B.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Carbonaro, D.; Choi, Y. C.; Shaw, K.; Kohn, D.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Hershfield, M.] Duke Univ, Med Ctr, Durham, NC USA. RI Sokolic, Robert/I-6072-2012 NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 65 BP 27 EP 27 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800066 ER PT J AU Bevans, M Mitchell, S Wehrleu, L Prachenko, O Soeken, K Koklanaris, E Cook, L Odom, J Prince, P Le, Q Castro, K Cusack, G Savani, B Fowler, D Childs, R Barrett, AJ AF Bevans, M. Mitchell, S. Wehrleu, L. Prachenko, O. Soeken, K. Koklanaris, E. Cook, L. Odom, J. Prince, P. Le, Q. Castro, K. Cusack, G. Savani, B. Fowler, D. Childs, R. Barrett, A. J. TI PSYCHOSOCIAL ADJUSTMENT IN LONG TERM SURVIVORS OF ALLOGENEIC HSCT: A COMPARISON OF PATIENTS TREATED WITH MYELOABLATIVE (MC) AND REDUCED INTENSITY CONDITIONING (RIC) REGIMENS SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Bevans, M.; Mitchell, S.; Wehrleu, L.; Prachenko, O.; Koklanaris, E.; Cook, L.; Odom, J.; Prince, P.; Le, Q.; Castro, K.; Cusack, G.; Fowler, D.; Childs, R.; Barrett, A. J.] NIH, Bethesda, MD 20892 USA. [Savani, B.] Vanderbilt Univ, Nashville, TN 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 78 BP 32 EP 32 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800079 ER PT J AU Sundin, M Barrett, J Ringden, O Uzunel, M Lonnies, H Dackland, AL Christensson, B Le Blanc, K AF Sundin, M. Barrett, J. Ringden, O. Uzunel, M. Lonnies, H. Dackland, A. -L Christensson, B. Le Blanc, K. TI HLA MISMATCHED MSC SUPPRESS T LYMPHOCYTE ALLORESPONSES IN VITRO AND DO NOT INDUCE IMMUNOLOGICAL MEMORY IN RECIPIENTS OF MSC INFUSION SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Sundin, M.; Ringden, O.; Uzunel, M.; Lonnies, H.; Dackland, A. -L; Christensson, B.; Le Blanc, K.] Karolinska Inst, Stockholm, Sweden. [Barrett, J.] NIH, Bethesda, MD 20892 USA. [Le Blanc, K.] Karolinska Univ Hosp Huddinge, Stockholm, Sweden. 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 121 BP 47 EP 47 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800122 ER PT J AU Mitchell, SA Hakim, FT Baird, K Wayne, AS Mooney, KH Rehman, NK Dickinson, J Palit, P Beck, SL Kline, LN Cole, ML Dudley, WN Gress, RE Pavletic, SZ AF Mitchell, S. A. Hakim, F. T. Baird, K. Wayne, A. S. Mooney, K. H. Rehman, N. K. Dickinson, J. Palit, P. Beck, S. L. Kline, Leidy N. Cole, M. L. Dudley, W. N. Gress, R. E. Pavletic, S. Z. TI PLASMA CYTOKINE LEVELS DISTINGUISH CHRONIC GRAFT VERSUS HOST DISEASE (CGVHD) SYMPTOM PROFILE GROUPS SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Hakim, F. T.; Baird, K.; Wayne, A. S.; Rehman, N. K.; Gress, R. E.; Pavletic, S. Z.] NCI, NIH, Bethesda, MD 20892 USA. [Mitchell, S. A.; Mooney, K. H.; Beck, S. L.; Dudley, W. N.] Univ Utah, Coll Nursing, Salt Lake City, UT 84112 USA. [Dickinson, J.] Washington Univ, Sch Med, St Louis, MO USA. [Kline, Leidy N.] United BioSource, Bethesda, MD USA. [Cole, M. L.] Lawrence Technol Univ, Southfield, MI 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 SU 2 MA 330 BP 118 EP 119 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800331 ER PT J AU Williams, KM Gladwin, MT Chien, JW Louie, A Baird, K Shelhamer, JH Blacklock-Schuver, BAJ Avila, D Mitchell, S Krumlauf, M Gress, RE Pavletic, SZ AF Williams, K. M. Gladwin, M. T. Chien, J. W. Louie, A. Baird, K. Shelhamer, J. H. Blacklock-Schuver, B. A. J. Avila, D. Mitchell, S. Krumlauf, M. Gress, R. E. Pavletic, S. Z. TI AMENDING NIH CONSENSUS CRITERIA FOR THE CLINICAL DIAGNOSIS OF BRONCHIOLITIS OBLITERANS AFTER HSCT SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Williams, K. M.; Baird, K.; Blacklock-Schuver, B. A. J.; Avila, D.; Krumlauf, M.; Gress, R. E.; Pavletic, S. Z.] NCI, NIH, Bethesda, MD 20892 USA. [Gladwin, M. T.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Chien, J. W.] Univ Washington, Seattle, WA 98195 USA. [Shelhamer, J. H.] CC NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 349 BP 125 EP 125 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800350 ER PT J AU Yong, ASM Keyvanfar, K Hensel, N Eniafe, R Savani, BN Berg, M Lundqvist, A Adams, S Sloand, EM Goldman, JM Childs, R Barrett, AJ AF Yong, A. S. M. Keyvanfar, K. Hensel, N. Eniafe, R. Savani, B. N. Berg, M. Lundqvist, A. Adams, S. Sloand, E. M. Goldman, J. M. Childs, R. Barrett, A. J. TI BORTEZOMIB TREATMENT OF PRIMITIVE QUIESCENT CD34+CELL S IN CHRONIC MYELOID LEUKEMIA ENHANCES TARGETING BY IN VITRO EXPANDED ALLOGENEIC NATURAL KILLER CELL S SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Yong, A. S. M.; Keyvanfar, K.; Hensel, N.; Eniafe, R.; Berg, M.; Lundqvist, A.; Adams, S.; Sloand, E. M.; Childs, R.; Barrett, A. J.] NHLBI, NIH, Bethesda, MD 20892 USA. [Savani, B. N.] Vanderbilt Univ, Nashville, TN USA. [Savani, B. N.] VAMC Transplant Program, Nashville, TN USA. [Goldman, J. M.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 353 BP 126 EP 127 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800354 ER PT J AU Qin, H Capitini, CM Wayne, AS Fry, TJ AF Qin, H. Capitini, C. M. Wayne, A. S. Fry, T. J. TI POST-TRANSPLANT IMMUNOTHERAPY FOR PEDIATRIC ALL SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Qin, H.; Capitini, C. M.; Wayne, A. S.; Fry, T. J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 359 BP 129 EP 129 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800360 ER PT J AU Williams, KM Lucas, PJ Bare, CV Wang, J Mella, HA Gress, RE AF Williams, K. M. Lucas, P. J. Bare, C., V Wang, J. Mella, H. A. Gress, R. E. TI THYMIC EPITHELIAL CELLS AND DENDRITIC CELLS MEDIATE THYMIC RENEWAL THROUGH CCL25 PRODUCTION SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem Meeting on Biology of Blood and Marrow Transplantation CY FEB 11-15, 2009 CL Tampa, FL SP Amer Soc Blood & Marrow Transplantat C1 [Williams, K. M.; Lucas, P. J.; Bare, C., V; Wang, J.; Mella, H. A.; Gress, R. E.] NCI, 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 MA 372 BP 133 EP 133 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MC UT WOS:000263016800373 ER PT J AU Pollack, SM Steinberg, SM Odom, J Dean, RM Fowler, DH Bishop, MR AF Pollack, Seth M. Steinberg, Seth M. Odom, Jeanne Dean, Robert M. Fowler, Daniel H. Bishop, Michael R. TI Assessment of the Hematopoietic Cell Transplantation Comorbidity Index in Non-Hodgkin Lymphoma Patients Receiving Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Comorbidity index; Non-Hodgkin lymphoma; Reduced intensity conditioning; Allogeneic ID BONE-MARROW-TRANSPLANTATION; AUTOLOGOUS TRANSPLANTATION; PERFORMANCE STATUS; EUROPEAN GROUP; BLOOD; CHEMOTHERAPY; MALIGNANCIES; MORTALITY; TOXICITY; SURVIVAL AB The hematopoietic cell transplantation comorbidity index (HCT-CI), a weighted index of 17 pretransplantation comorbidities, has been validated in nonmyeloablative and myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) studies, but it has not been specifically tested in patients with non-Hodgkin lymphoma (NHL) receiving reduced-intensity conditioning (RIC). We performed a retrospective analysis to assess the impact of the HCT-CI on outcomes of NHL patients treated with HSCT relative to treatmentrelated mortality (TRM), disease-related mortality (DRM), with a specific emphasis on overall survival (OS). Individual pretransplantation and disease-related factors also were analyzed with HCT-CI relative to their impact on CS. All patients were uniformly treated with an identical pretransplantation induction regimen and an identical RIC regimen (cyclophosphamide [Cy]/fludarabine [Flu]), and received T cell-replete allografts from HILA-matched siblings. The analysis included 63 NHL patients with a median HCT-CI score of 2 (range, 0 to 11). The HCT-CI (0 to 2 comorbidities vs 3+ comorbidities) demonstrated a potential association with TRM, but not with DRM, at 100 days (4.5% vs 26.3%) and at 1 year (13.6% vs 36.8%) posttransplantation. The factor most strongly associated with OS was response to pretransplantation chemotherapy (P =.0001), based on a composite measure. In a Cox model, pretransplantation chemotherapy response remained the most important factor (P <.0001) relative to OS, and there was a trend (P =.056) toward HCT-CI adding predictive value for OS. Although HCT-CI may be useful for predicting TRM, our data further underscore the importance of response to chemotherapy before transplantation as a predictor of overall transplantation outcome in NHL patients being considered for RIC allogeneic HSCT. C1 [Pollack, Seth M.; Odom, Jeanne; Dean, Robert M.; Fowler, Daniel H.; Bishop, Michael R.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Dean, Robert M.] Cleveland Clin Fdn, Taussig Canc Inst, Cleveland, OH 44195 USA. [Pollack, Seth M.] George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. RP Bishop, MR (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, 10 Ctr Dr,CRC Room 4-3152, Bethesda, MD 20892 USA. EM mbishop@mail.nih.gov FU Center for Cancer Research; National Cancer Institute; Intramural Research Program FX Financial disclosure: This work was supported by the Center for Cancer Research, National Cancer Institute, Intramural Research Program. NR 26 TC 26 Z9 26 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2009 VL 15 IS 2 BP 223 EP 230 DI 10.1016/j.bbmt.2008.11.023 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 402MA UT WOS:000263016600008 PM 19167682 ER PT J AU Yu, X Wang, QM Yang, JC Buch, I Tsai, CJ Ma, BY Cheng, SZD Nussinov, R Zheng, J AF Yu, Xiang Wang, Qiuming Yang, Jui-Chen Buch, Idit Tsai, Chung-Jung Ma, Buyong Cheng, Stephen Z. D. Nussinov, Ruth Zheng, Jie TI Mutational Analysis and Allosteric Effects in the HIV-1 Capsid Protein Carboxyl-Terminal Dimerization Domain SO BIOMACROMOLECULES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MOLECULAR-DYNAMICS; BUILDING-BLOCKS; ALZHEIMER A-BETA(17-42); NANOSTRUCTURE DESIGN; VIRION MORPHOGENESIS; CYCLOPHILIN-A; ASSOCIATION; SIMULATIONS; INHIBITOR AB The carboxyl-terminal domain (CTD, residues 146-231) of the HIV-1 capsid (CA) protein plays an important role in the CA-CA dimerization and viral assembly of the human immunodeficiency virus type 1. Disrupting the native conformation of the CA is essential for blocking viral capsid formation and viral replication. Thus, it is important to identify the exact nature of the structural changes and driving forces of the CTD dimerization that take place in mutant forms. Here, we compare the structural stability, conformational dynamics, and association force of the CTD dimers for both wild-type and mutated sequences using all-atom explicit-solvent molecular dynamics (MD). The simulations show that Q155N and E159D at the major homology region (MHR) and W184A and M185A at the helix 2 region are energetically less favorable than the wild-type, imposing profound negative effects on intermolecular CA-CA dimerization. Detailed structural analysis shows that three mutants Q155N, E159D, and W184A) display much more flexible local structures and weaker CA-CA association than the wildtype, primarily due to the loss of interactions (hydrogen bonds, side chain hydrophobic contacts, and pi-stacking) with their neighboring residues. Most interestingly, the MHR that is far from the interacting dimeric interface is more sensitive to the mutations than the helix 2 region that is located at the CA-CA dimeric interface, indicating that structural changes in the distinct motif of the CA could similarly allosterically prevent the CA capsid formation. In addition, the structural and free energy comparison of the five residues shorter CA (151-231) dimer with the CA (146-231) dimer further indicates that hydrophobic interactions, side chain packing, and hydrogen bonds are the major, dominant driving forces in stabilizing the CA interface. C1 [Tsai, Chung-Jung; Ma, Buyong; Nussinov, Ruth] NCI, Nanobiol Program, Ctr Canc Res, SAIC Frederick Inc,Basic Res Program, Frederick, MD 21702 USA. [Yu, Xiang; Wang, Qiuming; Yang, Jui-Chen] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. [Cheng, Stephen Z. D.] Univ Akron, Dept Polymer Sci, Akron, OH 44325 USA. [Buch, Idit; Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Nanobiol Program, Ctr Canc Res, SAIC Frederick Inc,Basic Res Program, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov; zhengj@uakron.edu RI Ma, Buyong/F-9491-2011; Yu, Xiang/A-9765-2012; Zheng, Jie/B-5057-2013; Wang, Qiuming/E-6254-2014 OI Ma, Buyong/0000-0002-7383-719X; Yu, Xiang/0000-0002-0486-1110; Zheng, Jie/0000-0003-1547-3612; FU American Chemical Society Petroleum Research Fund [48188-G5]; Faculty Research Summer Fellowship; University of Akron; National Cancer Institute, National Institutes of Health [N01-CO-12400]; National Cancer Institute; Center for Cancer Research FX This work is supported by American Chemical Society Petroleum Research Fund (48188-G5), Faculty Research Summer Fellowship, and Firestone Research Program at the University of Akron. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, 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 U.S. Government. NR 47 TC 13 Z9 13 U1 4 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD FEB PY 2009 VL 10 IS 2 BP 390 EP 399 DI 10.1021/bm801151r PG 10 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 405LM UT WOS:000263226300025 PM 19199580 ER PT J AU Krsko, P McCann, TE Thach, TT Laabs, TL Geller, HM Libera, MR AF Krsko, Peter McCann, Thomas E. Thach, Thu-Trang Laabs, Tracy L. Geller, Herbert M. Libera, Matthew R. TI Length-scale mediated adhesion and directed growth of neural cells by surface-patterned poly(ethylene glycol) hydrogels SO BIOMATERIALS LA English DT Article DE Cell adhesion; Hydrogel; Micropatterning; Nerve regeneration; Astrocyte; Polyethylene oxide ID CENTRAL-NERVOUS-SYSTEM; MICROPATTERNED LAMININ SURFACES; NEURITE OUTGROWTH; SPINAL-CORD; AXONAL OUTGROWTH; SCHWANN-CELLS; REGENERATION; GUIDANCE; NEURONS; CULTURE AB We engineered surfaces that permit the adhesion and directed growth of neuronal cell processes but that prevent the adhesion of astrocytes. This effect was achieved based on the spatial distribution of submicron-sized cell-repulsive poly(ethylene glycol) [PEG] hydrogels patterned on an otherwise cell-adhesive substrate. Patterns were identified that promoted cellular responses ranging from complete non-attachment, selective attachment, and directed growth at both cellular and subcellular length scales. At the highest patterning density where the individual hydrogels almost overlapped, there was no cellular adhesion. As the spacing between individual hydrogels was increased, patterns were identified where neurites could grow on the adhesive surface between hydrogels while astrocytes were unable to adhere. Patterns such as lines or arrays were identified that could direct the growth of these subcellular neuronal processes. At higher hydrogel spacings, both neurons and astrocytes adhered and grew in a manner approaching that of unpatterned control surfaces. Patterned lines could once again direct growth at cellular length scales. Significantly, we have demonstrated that the patterning of sub-micron/nano scale cell-repulsive features at microscale lengths on an otherwise cell-adhesive surface can differently control the adhesion and growth of cells and cell processes based on the difference in their characteristic sizes. This concept could potentially be applied to an implantable nerve-guidance device that would selectively enable regrowing axons to bridge a spinal-cord injury without interference from the glial scar. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Krsko, Peter; Libera, Matthew R.] Stevens Inst Technol, Dept Chem Engn & Mat Sci, Hoboken, NJ 07030 USA. [McCann, Thomas E.; Thach, Thu-Trang; Laabs, Tracy L.; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Libera, MR (reprint author), Stevens Inst Technol, Dept Chem Engn & Mat Sci, 1 Castle Point Terrace, Hoboken, NJ 07030 USA. EM mlibera@stevens.edu OI Geller, Herbert/0000-0002-7048-6144 FU Army Research Office (ARO) [DAAD19-03-1-0271, W911NF-071-0543] FX This research project has been supported in part by the Army Research Office (ARO grants #DAAD19-03-1-0271 and W911NF-071-0543). NR 62 TC 42 Z9 44 U1 2 U2 33 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD FEB PY 2009 VL 30 IS 5 BP 721 EP 729 DI 10.1016/j.biomaterials.2008.10.011 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 395VW UT WOS:000262552600003 PM 19026443 ER PT J AU Durkalski, VL Berger, VW AF Durkalski, Valerie L. Berger, Vance W. TI Re-Formulating Non-inferiority Trials as Superiority Trials: The Case of Binary Outcomes SO BIOMETRICAL JOURNAL LA English DT Article DE Active Control Trial; Information-Preserving Composite Endpoint; Non-inferiority Trials; Ordered Categorical Data ID ORDERED CATEGORICAL-DATA; NONINFERIORITY TRIALS; THERAPEUTIC EQUIVALENCE; ISSUES; CHOICE; TESTS; METHODOLOGY; DESIGN; MARGIN; TABLES AB Non-inferiority trials are conducted for a variety of reasons including to show that a new treatment has a negligible reduction in efficacy or safety when compared to the current standard treatment, or a more complex setting of showing that a new treatment has a negligible reduction in efficacy when compared to the current standard yet is superior in terms of other treatment characteristics. The latter reason for conducting a non-inferiority trial presents the challenge of deciding on a balance between a suitable reduction in efficacy, known as the non-inferiority margin, in return for a gain in other important treatment characteristics/findings. It would be ideal to alleviate the dilemma on the choice of margin in this setting by reverting to a traditional superiority trial design where a single p-value for superiority of both the most important endpoint (efficacy) and the most important finding (treatment characteristic) is provided. We discuss how this can be done using the information-preserving composite endpoint (IPCE) approach and consider binary outcome cases in which the combination of efficacy and treatment characteristics, but not one itself, paints a clear picture that the novel treatment is superior to the active control. C1 [Durkalski, Valerie L.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. [Berger, Vance W.] NCI, Biometry Res Grp, DCP, Bethesda, MD 20892 USA. RP Durkalski, VL (reprint author), Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, 135 Cannon St,Ste 303,MSC 815, Charleston, SC 29425 USA. EM durkalsv@musc.edu NR 32 TC 3 Z9 4 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0323-3847 J9 BIOMETRICAL J JI Biom. J. PD FEB PY 2009 VL 51 IS 1 BP 185 EP 192 DI 10.1002/bimj.200810499 PG 8 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 417NE UT WOS:000264082000015 PM 19197960 ER PT J AU Mitchell, A Pangilinan, F VanderMeer, J Molloy, AM Troendle, J Conley, M Kirke, PN Scott, JM Brody, LC Mills, JL AF Mitchell, Adam Pangilinan, Faith VanderMeer, Julie Molloy, Anne M. Troendle, James Conley, Mary Kirke, Peadar N. Scott, John M. Brody, Lawrence C. Mills, James L. TI Uncoupling Protein 2 Polymorphisms as Risk Factors for NTDs SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE neural tube defects; spina bifida; UCP2; obesity ID NEURAL-TUBE DEFECTS; MIDDLE-AGED HUMANS; COMMON POLYMORPHISM; INSULIN-SECRETION; MUTATIONAL ANALYSIS; MULTIPLE-SCLEROSIS; CANDIDATE GENE; OBESITY RISK; UCP2 GENE; PROMOTER AB BACKGROUND: Both environmental and genetic factors are involved in the etiology of NTDs. Inadequate folate intake and obesity are important environmental risk factors. Several folate-related genetic variants have been identified as risk factors; however, little is known about how genetic variants relate to the increased risk seen in obese women. Uncoupling Protein 2 (UCP2) is an attractive candidate to screen for NTD risk because of its possible role in obesity as well as energy metabolism, type-2 diabetes, and the regulation of reactive oxygen species. Interestingly, a previous study found that a common UCP2 compound homozygous genotype was associated with a threefold increase in NTD risk. METHODS: We evaluated three polymorphisms, -866G>A, A55V, and the 3'UTR 45 by insertion/deletion, as risk factors for NTDs in Irish NTD cases (n = 169), their mothers (n = 163), their fathers (n = 167), and normal control subjects (n = 332). RESULTS: Allele and genotype frequencies were not significantly different when comparing NTD mothers, NTD fathers, or affected children to controls. Additionally, the previously reported risk genotype (combined homozygosity of 55VV and 3'UTR 45 by deletion/deletion) was not present at a higher frequency in any NTD group when compared to controls. CONCLUSIONS: In our Irish study population, UCP2 polymorphisms did not influence NTD risk. Moreover, the prevalence of this allele in other populations was similar to the Irish prevalence but far lower than reported in the previous NTD study, suggesting that this previous finding of an association with NTDs might have been due to an unrepresentative study sample. Birth Defects Research (Part A) 85:156-160, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Mitchell, Adam; Pangilinan, Faith; VanderMeer, Julie; Brody, Lawrence C.] NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD 20892 USA. [Molloy, Anne M.] Univ Dublin Trinity Coll, Dept Clin Med, Dublin 2, Ireland. [Troendle, James; Conley, Mary; Mills, James L.] NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Kirke, Peadar N.] Hlth Res Board, Child Hlth Epidemiol Unit, Dublin, Ireland. [Scott, John M.] Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. RP Brody, LC (reprint author), NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bldg 50,Room 5306,50 S Dr,MSC 8004, Bethesda, MD 20892 USA. EM lbrody@helix.nih.gov OI Molloy, Anne/0000-0002-1688-9049 FU National Human Genome Research Institute; Health Research Board, Ireland; National Institute of Child Health and Human Development FX Grant sponsor: National Human Genome Research Institute.; Grant sponsor: Health Research Board, Ireland.; Grant sponsor: National Institute of Child Health and Human Development.; Grant sponsor: Health Research Board, Ireland. NR 31 TC 7 Z9 7 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD FEB PY 2009 VL 85 IS 2 BP 156 EP 160 DI 10.1002/bdra.20520 PG 5 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 414WK UT WOS:000263895700008 PM 19137581 ER PT J AU Mbwana, J Berl, MM Ritzl, EK Rosenberger, L Mayo, J Weinstein, S Conry, JA Pearl, PL Shamim, S Moore, EN Sato, S Vezina, LG Theodore, WH Gaillard, WD AF Mbwana, J. Berl, M. M. Ritzl, E. K. Rosenberger, L. Mayo, J. Weinstein, S. Conry, J. A. Pearl, P. L. Shamim, S. Moore, E. N. Sato, S. Vezina, L. G. Theodore, W. H. Gaillard, W. D. TI Limitations to plasticity of language network reorganization in localization related epilepsy SO BRAIN LA English DT Article DE fMRI; language; epilepsy ID TEMPORAL-LOBE EPILEPSY; RIGHT-HEMISPHERIC ORGANIZATION; FUNCTIONAL MRI; SENTENCE COMPREHENSION; BRAIN ACTIVATION; WADA TEST; CORTICAL STIMULATION; ATYPICAL LANGUAGE; SEX-DIFFERENCES; FOCAL EPILEPSY AB Neural networks for processing language often are reorganized in patients with epilepsy. However, the extent and location of within and between hemisphere re-organization are not established. We studied 45 patients, all with a left hemisphere seizure focus (mean age 22.8, seizure onset 13.3), and 19 normal controls (mean age 24.8) with an fMRI word definition language paradigm to assess the location of language processing regions. Individual patient SPM maps were compared to the normal group in a voxel-wise comparison; a voxel was considered to be significant if its z-value exceeded 2. Subsequently, we used principal component analysis with hierarchical clustering of variance patterns from individual difference maps to identify four patient sub-groups. One did not differ from normal controls; one had increased left temporal activation on the margin of regions activated in controls; two others had recruitment in right inferior frontal gyrus, middle frontal gyrus and temporal cortex. Right hemisphere activation in these two groups occurred in homologues of left hemisphere regions that sustained task activation. Our study used novel data driven methods to find evidence for constraints on inter-hemispheric reorganization of language in recruitment of right homologues, and, in a subpopulation of patients, evidence for intra-hemispheric reorganization of language limited to the margins of typical left temporal regional activation. These methods may be applied to investigate both normal and pathological variance in other developmental disorders and cognitive domains. C1 [Mbwana, J.; Berl, M. M.; Rosenberger, L.; Mayo, J.; Weinstein, S.; Conry, J. A.; Pearl, P. L.; Moore, E. N.; Vezina, L. G.; Gaillard, W. D.] George Washington Univ, Dept Neurosci, Childrens Natl Med Ctr, Sch Med, Washington, DC 20010 USA. [Mbwana, J.; Ritzl, E. K.; Rosenberger, L.; Mayo, J.; Shamim, S.; Moore, E. N.; Sato, S.; Theodore, W. H.; Gaillard, W. D.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Ritzl, E. K.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Vezina, L. G.] George Washington Univ, Dept Radiol, Childrens Natl Med Ctr, Sch Med, Washington, DC 20010 USA. [Gaillard, W. D.] Georgetown Univ, Dept Neurol, Sch Med, Baltimore, MD USA. RP Gaillard, WD (reprint author), George Washington Univ, Dept Neurosci, Childrens Natl Med Ctr, Sch Med, 111 Michigan Ave NW, Washington, DC 20010 USA. EM wgaillar@cnmc.org FU NICHD NIH HHS [HD007446]; NINDS NIH HHS [R01 NS44280] NR 84 TC 46 Z9 47 U1 7 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2009 VL 132 BP 347 EP 356 DI 10.1093/brain/awn329 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 408BI UT WOS:000263407700008 PM 19059978 ER PT J AU Tang, Y Chen, JC Young, NS AF Tang, Yong Chen, Jichun Young, Neal S. TI Expansion of haematopoietic stem cells from normal donors and bone marrow failure patients by recombinant hoxb4 SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE recombinant homobox b4; haematopoietic stem and progenitor cells; CD34; bone marrow failure; mouse models ID EX-VIVO EXPANSION; ACQUIRED APLASTIC-ANEMIA; IN-VITRO; MYELODYSPLASTIC SYNDROME; MICE; PATHOPHYSIOLOGY; OVEREXPRESSION; EXPRESSION; INFUSION AB In this study six versions of recombinant human hoxb4 proteins were produced and their effectiveness evaluated in expanding human haematopoietic stem and progenitor cells in vitro and in vivo. An N-terminal-tat and C-terminal histidine-tagged version of hoxb4 (T-hoxb4-H) showed the highest activity in expanding colony forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) when used at 50 nmol/l concentration in cell culture. Human cord blood CD34(+) cells cultured with 50 nmol/l T-hoxb4-H showed a significant increase in severe-combined immunodeficient mouse-repopulating cells (SRCs). In a mouse model of immune-mediated bone marrow (BM) failure, T-hoxb4-H showed an additive effect with cyclosporine in alleviating pancytopenia. In addition, T-hoxb4-H expanded CFC and LTC-IC on BM samples from patients with refractory severe aplastic anaemia and myelodysplastic syndromes: after culturing with 50 nmol/l T-hoxb4-H for 4 d, BM cells from 10 of the 11 patients showed increases in CFC and LTC-IC, and the increase in LTC-IC was statistically significant in samples from four patients. Recombinant human hoxb4 could be a promising therapeutic agent for BM failure. C1 [Tang, Yong; Chen, Jichun; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 Clin Res Ctr,Room 3E 5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM youngn@nhlbi.nih.gov FU National Heart, Lung and Blood Institute FX We thank Cynthia Dunbar and Andre LaRochelle from Haematology Brach, NHLBI for helpful discussions; Jan Melenhorst from Haematology Branch, NHLBI for providing human cord blood cells; and William DeGraff from Radiation Biology Branch, NCI for providing assistance in feeder layer cell irradiation. This research was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute. NR 29 TC 13 Z9 18 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD FEB PY 2009 VL 144 IS 4 BP 603 EP 612 DI 10.1111/j.1365-2141.2008.07509.x PG 10 WC Hematology SC Hematology GA 397AZ UT WOS:000262635500016 PM 19120358 ER PT J AU Lee, S Tsang, A Von Korff, M de Graaf, R Benjet, C Haro, JM Angermeyer, M Demyttenaere, K de Girolamo, G Gasquet, I Merikangas, K Posada-Villa, J Takeshima, T Kessler, RC AF Lee, Sing Tsang, Adley Von Korff, Michael de Graaf, Ron Benjet, Corina Haro, Josep Maria Angermeyer, Matthias Demyttenaere, Koen de Girolamo, Giovanni Gasquet, Isabelle Merikangas, Kathleen Posada-Villa, Jose Takeshima, Tadashi Kessler, Ronald C. TI Association of headache with childhood adversity and mental disorder: cross-national study SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID WORLD-HEALTH-ORGANIZATION; DIAGNOSTIC INTERVIEW CIDI; COMORBIDITY SURVEY; MIGRAINE; DEPRESSION; ABUSE; HISTORY; WOMEN; VALIDITY; VERSION AB Background Community studies about the association of headache with both childhood family adversities and depression/anxiety disorders are limited. Aims To assess the independent and joint associations of childhood family adversities and early-onset depression and anxiety disorders with risks of adult-onset headache. Method Data were pooled from cross-sectional community surveys conducted in ten Latin and North American, European and Asian countries (n-18303) by using standardised instruments. Headache and a range of childhood family adversities were assessed by self-report. Results The number of childhood family adversities was associated with adult-onset headache after adjusting for gender, age, country and early-onset depression/anxiety disorder status (for one adversity, hazard ratio (HR)=1.22-1.6; for two adversities, HR=11.19-1.67; for three or more adversities, HR=1.37-1.95). Early and Current onset of depression/anxiety disorders were independently associated (HR=1.42-1.89) with adult onset headache after controlling for number of childhood family adversities. Conclusions The findings call for a broad developmental perspective concerning risk factors for development of headache. C1 Chinese Univ Hong Kong, Dept Psychiat, Hong Kong Mood Disorders Ctr, Hong Kong, Hong Kong, Peoples R China. [Von Korff, Michael] Grp Hlth Cooperat, Ctr Hlth Studies, Washington, DC USA. [de Graaf, Ron] Netherlands Inst Mental Hlth & Addict, Utrecht, Netherlands. [Haro, Josep Maria] St Joan Deu SSM, Barcelona, Spain. [Demyttenaere, Koen] Univ Hosp Gasthuisberg, Dept Neusci & Psychiat, Gasthuisberg, Belgium. [de Girolamo, Giovanni] Reg Hlth Care Agcy, Bologna, Italy. [Gasquet, Isabelle] AP HP, Direct Port Med, Paris, France. [Merikangas, Kathleen] NIMH, Bethesda, MD 20892 USA. [Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. RP Lee, S (reprint author), Prince Wales Hosp, Shatin, Hong Kong, Peoples R China. EM singlee@cuhk.edu.hk RI Benjet, Corina/D-7363-2012; Lee, Sing/O-2136-2015; Haro, Josep Maria/D-1423-2011; OI Haro, Josep Maria/0000-0002-3984-277X; Benjet, Corina/0000-0002-4569-6094 FU US National institute of Mental Health [R01-MH070884]; John D. and Catherine T. MacArthur Foundation; Pfizer Foundation; US Public Health Service [R13-MH066849, R01-MH069864, R01-DA016558]; Fogarty International Center [FIRCA R01-TW006481]; Pan American Health Organization; Eli Lilly Co; Ortho McNeil Pharmaceutical Inc,; GlaxoSmithKline; Bristol-Myers Squibb; European Commission [QLG5-1999-01042, SANCO 2004123]; Piedmont Region (Italy); Fondo de Investigacion Santana, instituto de Salud Carlos III, Spain [FIS 00/0028]; Minsterio de Ciencia y Tecnologia, Spain [SAP 2000-158-CE]; Department de Salut, Generalitat de Catalunya, Spain [CIBER CB06/02/0046, RETICS RD06/0011 REM-TAP]; Japan Ministry of Health, labour and Welfare [H13-SHOGAI023, H14-TOKUBETSU 026, H16 KOKORO-013]; National institute of Psychiatry Ramon de la Euente [INPREMDIFS 4280]; National Council on Science and technology [CONACyT-G30544-11]; National institute of Mental Health [U01-MH60220]; National Institute of Drug Abuse; Substance Abuse and Mental Health Services Administration; Robert Wood Johnson Foundation [044708]; John W Alden Trust FX The surveys discussed in this article were carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative, We thank the WMH staff for assistance, with Instrumentation, fieldwork, and data analysis. These activities were supported by the US National institute of Mental Health (R01-MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13-MH066849, R01-MH069864 and R01-DA016558), the Fogarty International Center (FIRCA R01-TW006481), the Pan American Health Organization, Eli Lilly & Co, Ortho McNeil Pharmaceutical Inc, GlaxoSmithKline, and Bristol-Myers Squibb. A complete list of WMH publications can be found at www.hcp.med.harvarded.edu/wmn/. The Colombian National Study of Mental Health is supported by the Ministry of Social Protection. The ESEMeD project 15 funded by the European Commission (Contracts QLG5-1999-01042; SANCO 2004123); the Piedmont Region (Italy), Fondo de Investigacion Santana, instituto de Salud Carlos III, Spain (FIS 00/0028), Minsterio de Ciencia y Tecnologia, Spain (SAP 2000-158-CE); Department de Salut, Generalitat de Catalunya, Spain (CIBER CB06/02/0046, RETICS RD06/0011 REM-TAP), other local agencies, and by an unrestricted educational grant from GlaxoSmithKline. The World Mental Health Japan Survey is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI023, H14-TOKUBETSU 026, H16 KOKORO-013) from the Japan Ministry of Health, labour and Welfare. The Mexican National Comorbidity Survey is supported by the National institute of Psychiatry Ramon de la Euente (INPREMDIFS 4280) and by the National Council on Science and technology (CONACyT-G30544-11), with supplemental support from the Pan American Health Organization. The US National Comorbidity Survey Replication is. supported by the National institute of Mental Health (U01-MH60220) with supplemental support from the National Institute of Drug Abuse, the Substance Abuse and Mental Health Services Administration, the Robert Wood Johnson Foundation (Grant 044708), and the John W Alden Trust. NR 24 TC 17 Z9 17 U1 0 U2 1 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD FEB PY 2009 VL 194 IS 2 BP 111 EP 116 DI 10.1192/bjp.bp.108.052159 PG 6 WC Psychiatry SC Psychiatry GA 407BJ UT WOS:000263338300003 PM 19182169 ER PT J AU Jehan, I Harris, H Salat, S Zeb, A Mobeen, N Pasha, O McClure, EM Moore, J Wright, LL Goldenberg, RL AF Jehan, Imtiaz Harris, Hillary Salat, Sohail Zeb, Amna Mobeen, Naushaba Pasha, Omrana McClure, Elizabeth M. Moore, Janet Wright, Linda L. Goldenberg, Robert L. TI Neonatal mortality, risk factors and causes: a prospective population-based cohort study in urban Pakistan SO BULLETIN OF THE WORLD HEALTH ORGANIZATION LA English DT Article ID DEVELOPING-COUNTRIES; SURVIVAL; NEWBORN; QUALITY; DEATHS; HEALTH; TIME AB Objective To evaluate the prevalence, sex distribution and causes of neonatal mortality, as well as its risk factors, in an urban Pakistani population with access to obstetric and neonatal care. Methods Study area women were enrolled at 20-26 weeks' gestation in a prospective population-based cohort study that was conducted from 2003 to 2005. Physical examinations, antenatal laboratory tests and anthropometric measures were performed, and gestational age was determined by ultrasound to confirm eligibility. Demographic and health data were also collected on pretested study forms by trained female research staff. The women and neonates were seen again within 48 hours postpartum and at day 28 after the birth, All neonatal deaths were reviewed using the Pattinson et al, system to assign obstetric and final causes of death; the circumstances of the death were determined by asking the mother or family and by reviewing hospital records. Frequencies and rates were calculated, and 95% confidence intervals were determined for mortality rates. Relative risks were calculated to evaluate the associations between potential risk factors and neonatal death. Logistic regression models were used to compute adjusted odds ratios. Findings Birth outcomes were ascertained for 1280 (94%) of the 1369 women enrolled. The 28-day neonatal mortality rate was 47.3 per 1000 live births, Preterm birth, Caesarean section and intrapartum complications were associated with neonatal death. Some 45% of the deaths occurred within 48 hours and 73% within the first week. The primary obstetric causes of death were preterm labour (34%) and intrapartum asphyxia (21%). Final causes were classified as immaturity-related (26%), birth asphyxia or hypoxia (26%) and infection (23%). Neither delivery in a health facility nor by health professionals was associated with fewer neonatal deaths. The Caesarean section rate was 19%. Almost all (88%) neonates who died received treatment and 75% died in the hospital. Conclusion In an urban population with good access to professional care, we found a high neonatal mortality rate, often due to preventable conditions. These results suggest that, to decrease neonatal mortality, improved health service quality is crucial. C1 [Harris, Hillary; McClure, Elizabeth M.; Moore, Janet] Res Triangle Inst, Durham, NC 27709 USA. [Jehan, Imtiaz; Salat, Sohail; Zeb, Amna; Mobeen, Naushaba; Pasha, Omrana] Aga Khan Univ, Karachi, Pakistan. [Wright, Linda L.] Natl Inst Child Hlth & Human Dev, Rockville, MD USA. [Goldenberg, Robert L.] Drexel Univ, Philadelphia, PA 19104 USA. RP McClure, EM (reprint author), Res Triangle Inst, 3040 Cornwallis Rd, Durham, NC 27709 USA. EM mcclure@rti.org FU NICHD NIH HHS [U01 HD040636, U01HD040607, U01 HD040607]; PHS HHS [U0104063606] NR 25 TC 53 Z9 55 U1 0 U2 5 PU WORLD HEALTH ORGANIZATION PI GENEVA 27 PA MARKETING AND DISSEMINATION, CH-1211 GENEVA 27, SWITZERLAND SN 0042-9686 J9 B WORLD HEALTH ORGAN JI Bull. World Health Organ. PD FEB PY 2009 VL 87 IS 2 BP 130 EP 138 DI 10.2471/BLT.08.050963 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 405CD UT WOS:000263198800014 PM 19274365 ER PT J AU Massad, LS Seaberg, EC Watts, DH Minkoff, H Levine, AM Henry, D Colie, C Darragh, TM Hessol, NA AF Massad, L. Stewart Seaberg, Eric C. Watts, D. Heather Minkoff, Howard Levine, Alexandra M. Henry, Donna Colie, Christine Darragh, Teresa M. Hessol, Nancy A. TI Long-Term Incidence of Cervical Cancer in Women With Human Immunodeficiency Virus SO CANCER LA English DT Article DE cervical cancer; human immunodeficiency virus; women; cancer prevention ID SQUAMOUS INTRAEPITHELIAL LESIONS; HIV-INFECTED WOMEN; HUMAN-PAPILLOMAVIRUS; INTERAGENCY HIV; UNITED-STATES; RISK; PREVALENCE; ABNORMALITIES; AFRICA; HPV AB BACKGROUND: The objective of this study was to estimate the incidence of invasive cervical cancer (ICC) in women with human immunodeficiency virus (HIV) and compare it with the incidence in HIV-uninfected women. METHODS: In a cohort study of HIV-infected and uninfected women who had Papanicolaou tests obtained every 6 months, pathology reports were retrieved for women who had biopsy results or a self-report of ICC. Histology was reviewed when reports confirmed ICC. Incidence rates were calculated and compared with those in HIV-negative women. RESULTS: After a median follow-up of 10.3 years, 3 ICCs were confirmed in HIV-seropositive women, and none were confirmed in HIV-seronegative women. The ICC incidence rate was not found to be associated significantly with HIV status (HIV-negative women [O of 100,000 person-years] vs HIV-positive women [21.4 of 100,000 person-years]; P = .59). A calculated incidence rate ratio standardized to expected results from the Surveillance Epidemiology and End Results database that was restricted to HIV-infected Women's Interagency HIV Study participants was 1.32 (95% confidence interval, 0.27-3.85; P = 0.80). CONCLUSIONS: Among women with HIV in a prospective study that incorporated cervical cancer prevention measures, the incidence of ICC was not significantly higher than that in a comparison group of HIV-negative women. Cancer 2009;115:524-30. Published 2009 by the American Cancer Society.* C1 [Massad, L. Stewart] Washington Univ, Sch Med, Div Gynecol Oncol, St Louis, MO 63110 USA. [Seaberg, Eric C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Watts, D. Heather] Eunice Kennedy Shriver NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Minkoff, Howard] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Levine, Alexandra M.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Levine, Alexandra M.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Henry, Donna] Montefiore Med Ctr, Dept Obstet & Gynecol, New York, NY USA. [Colie, Christine] Georgetown Univ, Dept Obstet & Gynecol, Washington, DC USA. [Darragh, Teresa M.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA. [Hessol, Nancy A.] Univ Calif San Francisco, Dept Clin Pharm & Med, San Francisco, CA 94143 USA. RP Massad, LS (reprint author), Washington Univ, Sch Med, Div Gynecol Oncol, POB 8064, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu FU National Institute of Allergy and Infectious Diseases [UO1-Al-35,004, UO1-Al-31,834, UO1-Al-34,994, UO1-Al-34,989, UO1-Al-34,993, UO1-Al-42,590]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [UO1-HD-32,632]; National Cancer Institute; National Institute on Drug Abuse; National Institute On Deafness and Other Communication Disorders; National Center for Research Resources [MO1-RR-00,071, MO1-RR-00,079, MO1-RR-00,083] FX The Women's Interagency Human Immunodeficiency Virus Study is funded by the National Institute of Allergy and Infectious Diseases (UO1-Al-35,004, UO1-Al-31,834, UO1-Al-34,994, UO1-Al-34,989, UO1-Al-34,993, and UO1-Al-42,590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32,632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute On Deafness and Other Communication Disorders. Funding also is provided by the National Center for Research Resources (MO1-RR-00,071, MO1-RR-00,079, MO1-RR-00,083). NR 33 TC 26 Z9 29 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2009 VL 115 IS 3 BP 524 EP 530 DI 10.1002/cncr.24067 PG 7 WC Oncology SC Oncology GA 402GY UT WOS:000263003400010 PM 19127538 ER PT J AU McGregor, LM Spunt, SL Santana, VM Stewart, CF Ward, DA Watkins, A Laningham, FH Ivy, P Furman, WL Fouladi, M AF McGregor, Lisa M. Spunt, Sheri L. Santana, Victor M. Stewart, Clinton F. Ward, Deborah A. Watkins, Amy Laningham, Fred H. Ivy, Percy Furman, Wayne L. Fouladi, Maryam TI Phase 1 Study of an Oxaliplatin and Etoposide Regimen in Pediatric Patients With Recurrent Solid Tumors SO CANCER LA English DT Article DE clinical trial; phase 1; oxaliplatin; etoposide; child; adolescent ID CHILDHOOD BRAIN-TUMORS; FRANCAISE-DONCOLOGIE-PEDIATRIQUE; CHILDRENS CANCER GROUP; SOFT-TISSUE SARCOMA; HIGH-DOSE CISPLATIN; GERM-CELL TUMORS; FRENCH-SOCIETY; OVARIAN-CANCER; HEARING-LOSS; II TRIAL AB BACKGROUND: The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors. METHODS: Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21-day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 75 mg/m(2), 2) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 100 mg/m(2), and 3) oxaliplatin at a dose of 145 mg/m(2) and etoposide at a dose of 100 mg/m(2). Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single-agent MTD. RESULTS: The 16 patients received a total of 63 courses. At dose level 1, dose-limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose-limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose-limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization. CONCLUSIONS: The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m(2) given on Day 1 and etoposide at a dose of 100 mg/m(2)/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well-tolerated and demonstrated antitumor activity. Cancer 2009;115:655-64. (c) 2008 American Cancer Society. C1 [McGregor, Lisa M.; Spunt, Sheri L.; Santana, Victor M.; Furman, Wayne L.; Fouladi, Maryam] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [McGregor, Lisa M.; Spunt, Sheri L.; Santana, Victor M.; Furman, Wayne L.; Fouladi, Maryam] Univ Tennessee, Ctr Hlth Sci, Coll Med, Dept Pediat, Memphis, TN 38163 USA. [Stewart, Clinton F.; Ward, Deborah A.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Watkins, Amy] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. [Laningham, Fred H.] St Jude Childrens Res Hosp, Dept Radiol Sci, Memphis, TN 38105 USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP McGregor, LM (reprint author), St Jude Childrens Res Hosp, Dept Oncol, 262 Danny Thomas Pl,Mailstop 260, Memphis, TN 38105 USA. EM lisa.mcgregor@stjude.org FU NCI NIH HHS [CA21765, P30 CA021765, P30 CA021765-31] NR 63 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 1 PY 2009 VL 115 IS 3 BP 655 EP 664 DI 10.1002/cncr.24054 PG 10 WC Oncology SC Oncology GA 402GY UT WOS:000263003400024 PM 19117350 ER PT J AU Ghiotto, F Fais, F Tenca, C Tomati, V Morabito, F Casciaro, S Mumot, A Zoppoli, G Ciccone, E Parodi, S Bruno, S AF Ghiotto, Fabio Fais, Franco Tenca, Claudya Tomati, Valeria Morabito, Fortunato Casciaro, Salvatore Mumot, Anna Zoppoli, Gabriele Ciccone, Ermanno Parodi, Silvio Bruno, Silvia TI Apoptosis of B-cell chronic lymphocytic leukemia cells induced by a novel BH3 peptidomimetic SO CANCER BIOLOGY & THERAPY LA English DT Article DE B-cell chronic lymphocytic leukemia; apoptosis; Bim-BH3; multiparameter flow cytometry; targeted therapy ID ACUTE LYMPHOBLASTIC-LEUKEMIA; IN-VITRO; BH3-ONLY PROTEINS; ANTIGEN RECEPTORS; MIMETIC ABT-737; CD38 EXPRESSION; BCL-2 PROTEINS; MCL-1; DEATH; BIM AB B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in human adults of the Western world and no definitive cure is yet available. The disease is characterized by accumulation of clonal malignant B lymphocytes resistant to apoptosis. Strategies to hit the anti-apoptotic drift of the Bcl-2 family in B-CLL cells are being explored. A novel peptidomimetic based on the BH3 domain of the pro-apoptotic protein Bim and recently shown to exert significant apoptotic activity on acute myeloid leukemia cells, both in vitro and in vivo, was assayed on ex-vivo derived leukemic cells from untreated B-CLL patients (n = 7). We found that this peptide, named 072RB, induced apoptosis of B-CLL samples at a concentration that does not affect viability of peripheral and bone marrow derived lymphocytes from healthy donors. Apoptosis was demonstrated by activation of Bak and Bax, externalization of plasma membranes phosphadydilserines, appearance of hypodiploid events in DNA flow cytometry histograms and was accompanied by dissipation of the mitochondrial transmembrane potential. Before the onset of marked apoptotic signs a progressive decline of the relevant anti-apoptotic proteins Bcl-XL and Mcl-1 could be observed. The negative control peptide 072RBL94A was ineffective for B-CLL cells, supporting the sequence specificity of 072RB activity. No relationship was found between responsiveness to 072RB and Mcl-1/Bcl-X(L) basal levels or decrease magnitude, possibly because of the limited sample size of the study. Altogether, we demonstrate that 072RB induces significant apoptosis of B-CLL cells subsequent to Bcl-XL and Mcl-1 downregulation. C1 [Ghiotto, Fabio; Fais, Franco; Tenca, Claudya; Ciccone, Ermanno; Bruno, Silvia] Univ Genoa, Dept Expt Med, Human Anat Sect, I-16132 Genoa, Italy. [Tomati, Valeria; Mumot, Anna; Zoppoli, Gabriele; Parodi, Silvio] Univ Genoa, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. [Mumot, Anna; Parodi, Silvio] Natl Canc Inst, Expt Oncol Lab, Genoa, Italy. [Tomati, Valeria] Adv Biotechnol Ctr, Genoa, Italy. [Morabito, Fortunato] Azienda Osped Cosenza, Dipartimento Med Interna, Unita Operat Ematol, Cosenza, Italy. [Casciaro, Salvatore; Zoppoli, Gabriele] Univ Genoa, Dipartimento Med Interna & Specialita Med, I-16132 Genoa, Italy. RP Bruno, S (reprint author), Univ Genoa, Dept Expt Med, Human Anat Sect, Via Toni 14, I-16132 Genoa, Italy. EM silvia.bruno@unige.it RI Zoppoli, Gabriele/A-9540-2010; Morabito, Fortunato/I-7819-2012; OI Ghiotto, Fabio/0000-0002-2301-8698; FAIS, FRANCO/0000-0002-6643-7083 FU MIUR PRIN; Associazione "Davide Ciavattini" Onlus; Compagnia di San Paolo [4824 SD/CV-2007.2880, 4998 IT/CV, 2007.0087]; National project Compagnia di San Paolo [2489 IT/CV]; Fondazione Maria Piaggio Casarsa FX This work was supported by grants from MIUR PRIN 2006; Associazione "Davide Ciavattini" Onlus; Progetto Ateneo 2008; Compagnia di San Paolo 4824 SD/CV-2007.2880 and 4998 IT/CV, 2007.0087; MIUR PRIN 2007 with U. Bertazzoni et al.; National project Compagnia di San Paolo 2489 IT/CV, 2006.1997, Genoa Operative Unit (O.U.); Regione Liguria, Cap. 5296 F. S. R. Nr. Prov. 23, Prot. Gen. 616, 2007; Istituto Superiore di Oncologia, O. U. of the "Istituto Oncologico Veneto" project; "Regione Campania" 2007 project with G. Vecchio et al.; CA. RI. GE. 2008 Genoa University project with F. Patrone et al. C. T. is supported by Fondazione Maria Piaggio Casarsa. NR 58 TC 0 Z9 0 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD FEB PY 2009 VL 8 IS 3 BP 259 EP 267 PG 9 WC Oncology SC Oncology GA 400FS UT WOS:000262854000011 ER PT J AU Villanueva, CM Silverman, DT Murta-Nascimento, C Malats, N Garcia-Closas, M Castro, F Tardon, A Garcia-Closas, R Serra, C Carrato, A Rothman, N Real, FX Dosemeci, M Kogevinas, M AF Villanueva, Cristina M. Silverman, Debra T. Murta-Nascimento, Cristiane Malats, Nuria Garcia-Closas, Montserrat Castro, Francesc Tardon, Adonina Garcia-Closas, Reina Serra, Consol Carrato, Alfredo Rothman, Nathaniel Real, Francisco X. Dosemeci, Mustafa Kogevinas, Manolis TI Coffee consumption, genetic susceptibility and bladder cancer risk SO CANCER CAUSES & CONTROL LA English DT Article DE Bladder cancer; Coffee; Genetic susceptibility; Epidemiology ID TOTAL FLUID CONSUMPTION; CAFFEINE; FOODS; NAT2; TEA AB We evaluated the bladder cancer risk associated with coffee consumption in a case-control study in Spain and examined the gene-environment interactions for genetic variants of caffeine-metabolizing enzymes. The analyses included 1,136 incident cases with urothelial carcinoma of the urinary bladder and 1,138 controls. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for area, age, gender, amount of cigarette smoking, and years since quitting among former smokers. The OR (95% CI) for ever consumed coffee was 1.25 (0.95-1.64). For consumers of 1, 2, 3, and 4 or more cups/day relative to never drinkers, OR were, respectively, 1.24 (0.92-1.66), 1.11 (95% CI 0.82-1.51), 1.57 (1.13-2.19), and 1.27 (0.88-1.81). Coffee consumption was higher in smokers compared to never smokers. The OR for drinking at least 4 cups/day was 1.13 (0.61-2.09) in current smokers, 1.57 (0.86-2.90) in former smokers, and 1.23 (0.55-2.76) in never smokers. Gene-coffee interactions evaluated in NAT2, CYP1A2, and CYP2E1-02 and CYP1A1 were not identified after adjusting for multiple testing. We observed a modest increased bladder cancer risk among coffee drinkers that may, in part, be explained by residual confounding by smoking. The findings from the gene-coffee interactions need replication in further studies. C1 [Villanueva, Cristina M.; Murta-Nascimento, Cristiane; Malats, Nuria; Castro, Francesc; Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona 08003, Spain. [Villanueva, Cristina M.; Castro, Francesc; Kogevinas, Manolis] CIBERESP, Barcelona, Spain. [Silverman, Debra T.; Garcia-Closas, Montserrat; Rothman, Nathaniel; Dosemeci, Mustafa] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Garcia-Closas, Montserrat] Hosp Univ Canarias, Santa Cruz de Tenerife, Spain. [Serra, Consol] Univ Pompeu Fabra, Unit Res Occupat Hlth, Dept Expt & Hlth Sci, Barcelona, Spain. [Serra, Consol] Consorci Hosp Parc Tauli, Sabadell, Spain. [Carrato, Alfredo] Hosp Gen Elche, Elche, Spain. [Real, Francisco X.] Hosp del Mar, IMIM, Municipal Inst Med Res, Cellular & Mol Biol Res Unit, Barcelona, Spain. [Kogevinas, Manolis] Univ Crete, Dept Social Med, Sch Med, Iraklion, Greece. RP Villanueva, CM (reprint author), Ctr Res Environm Epidemiol CREAL, PRBB Bldg,Doctor Aiguader 88, Barcelona 08003, Spain. EM cvillanueva@creal.cat RI Murta-Nascimento, Cristiane/G-3738-2012; Serra, C/E-6879-2014; Benavides, Fernando/A-5137-2008; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Villanueva, Cristina/N-1942-2014; Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015; OI Serra, C/0000-0001-8337-8356; Benavides, Fernando/0000-0003-0747-2660; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Villanueva, Cristina/0000-0002-0783-1259; Real, Francisco X/0000-0001-9501-498X; Castro-Giner, Francesc/0000-0001-6111-0754 FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics [N02-CP-11015]; FIS/Spain [00/0745, G03/174, G03/160, C03/09, C03/90]; Instituto de Salud Carlos III, Spanish Health Ministry [CP06/00341] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics contract no. N02-CP-11015 and the FIS/Spain grants 00/0745 and G03/174,G03/160, C03/09, and C03/90. Cristina M. Villanueva has a contract with the Instituto de Salud Carlos III, Spanish Health Ministry, CP06/00341. NR 21 TC 18 Z9 19 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2009 VL 20 IS 1 BP 121 EP 127 DI 10.1007/s10552-008-9226-6 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 395DU UT WOS:000262504100014 PM 18798002 ER PT J AU Krishnamurthi, SS Brell, JM Hoppel, CL Egorin, MJ Weaver, KC Li, X Ingalls, ST Zuhowski, EG Schluchter, MD Dowlati, A Cooney, MM Gibbons, J Overmoyer, BA Ivy, SP Remick, SC AF Krishnamurthi, Smitha S. Brell, Joanna M. Hoppel, Charles L. Egorin, Merrill J. Weaver, Karen C. Li, Xiaolin Ingalls, Stephen T. Zuhowski, Eleanor G. Schluchter, Mark D. Dowlati, Afshin Cooney, Matthew M. Gibbons, Joseph Overmoyer, Beth A. Ivy, S. Percy Remick, Scot C. TI Phase I clinical and pharmacokinetic study of oxaliplatin, irinotecan and capecitabine SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Irinotecan; Oxaliplatin; Capecitabine; Phase I study; Chemotherapy ID METASTATIC COLORECTAL-CANCER; PERFORMANCE LIQUID-CHROMATOGRAPHY; CAMPTOTHECIN ANALOG CPT-11; ACTIVE METABOLITE SN-38; CONTINUOUS-INFUSION; RANDOMIZED-TRIAL; FLUOROURACIL FAILURE; 1ST-LINE TREATMENT; FOLINIC ACID; 5-FLUOROURACIL AB To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the combination of weekly oxaliplatin x 4, weekly irinotecan x 4 and capecitabine Monday through Friday for 4 weeks of every 6 week cycle in patients with solid tumors; to determine the pharmacokinetic profile of these agents in this combination; to observe patients for clinical anti-tumor response. Twenty-two patients with metastatic solid tumors received oxaliplatin 60 mg/m(2) weekly x 4, irinotecan beginning at a dose of 40 mg/m(2) weekly x 4, and capecitabine Monday through Friday for 4 weeks of every 6 week cycle, initially at 1,000 mg twice daily (bid). The MTD was oxaliplatin 60 mg/m(2) weekly x 4, irinotecan 50 mg/m(2) weekly x 4 and capecitabine 450 mg bid Monday through Friday for 4 weeks of every 6 week cycle. One of six patients at this dose level developed DLT of nausea, vomiting, and diarrhea. Among patients treated with a constant capecitabine dose of 450 mg bid, there was a higher mean AUC of 5-FU in women than in men (mean +/- A SD: 892 +/- A 287 nM h vs. 537 +/- A 182 nM h; Mann-Whitney two-tailed, P = 0.02). There was one complete response in a patient with gastric cancer. The novel schedule of weekly oxaliplatin, weekly irinotecan, and capecitabine Monday through Friday, all administered for 4 weeks of every 6 week cycle, evaluated in this phase I trial is well-tolerated and demonstrated activity in a patient with gastric cancer. C1 [Krishnamurthi, Smitha S.; Brell, Joanna M.; Hoppel, Charles L.; Dowlati, Afshin; Cooney, Matthew M.; Gibbons, Joseph; Overmoyer, Beth A.; Remick, Scot C.] Univ Hosp Cleveland, Case Med Ctr, Dept Med, Cleveland, OH 44106 USA. [Krishnamurthi, Smitha S.; Brell, Joanna M.; Hoppel, Charles L.; Weaver, Karen C.; Li, Xiaolin; Ingalls, Stephen T.; Dowlati, Afshin; Cooney, Matthew M.; Gibbons, Joseph; Overmoyer, Beth A.; Remick, Scot C.] Case Comprehens Canc Ctr, Dev Therapeut Program, Cleveland, OH USA. [Hoppel, Charles L.; Li, Xiaolin; Ingalls, Stephen T.] Univ Hosp Cleveland, Case Med Ctr, Dept Pharmacol, Cleveland, OH 44106 USA. [Egorin, Merrill J.; Zuhowski, Eleanor G.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Schluchter, Mark D.] Case Comprehens Canc Ctr, Div Biostat, Cleveland, OH USA. [Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Krishnamurthi, SS (reprint author), Univ Hosp Cleveland, Case Med Ctr, Dept Med, 11100 Euclid Ave,Lakeside 1243, Cleveland, OH 44106 USA. EM ssk7@case.edu FU NCI NIH HHS [K12 CA076917, K12 CA76917, P30 CA043703, P30 CA047904, P30 CA43703, P30CA47904, U01 CA062502, U01 CA099168, U01 CA62502, U01-CA099168-01]; NCRR NIH HHS [M01-RR-00080, M01 RR000080, UL1 RR024989] NR 44 TC 4 Z9 4 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 2009 VL 63 IS 3 BP 441 EP 450 DI 10.1007/s00280-008-0754-2 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 387MB UT WOS:000261955200008 PM 18414865 ER PT J AU Yu, CL Li, Y Freedman, DM Fears, TR Kwok, R Chodick, G Alexander, B Kimlin, MG Kricker, A Armstrong, BK Linet, MS AF Yu, Chu-Ling Li, Yan Freedman, D. Michal Fears, Thomas R. Kwok, Richard Chodick, Gabriel Alexander, Bruce Kimlin, Michael G. Kricker, Anne Armstrong, Bruce K. Linet, Martha S. TI Assessment of Lifetime Cumulative Sun Exposure Using a Self-Administered Questionnaire: Reliability of Two Approaches SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NON-HODGKIN-LYMPHOMA; TIME SPENT OUTDOORS; ULTRAVIOLET-RADIATION; VITAMIN-D; RADIOLOGIC TECHNOLOGISTS; MULTIPLE-SCLEROSIS; PROSTATE-CANCER; UNITED-STATES; SKIN-CANCER; RISK AB Few studies have evaluated the reliability of lifetime sun exposure estimated from inquiring about the number of hours people spent outdoors in a given period on a typical weekday or weekend day (the time-based approach). Some investigations have suggested that women have a particularly difficult task in estimating time outdoors in adulthood due to their family and occupational roles. We hypothesized that people might gain additional memory cues and estimate lifetime hours spent outdoors more reliably if asked about time spent outdoors according to specific activities (an activity-based approach). Using self-administered, mailed questionnaires, test-retest responses to time-based and to activity-based approaches were evaluated in 124 volunteer radiologic technologist participants from the United States: 64 females and 60 males 48 to 80 years of age. Intraclass correlation coefficients (ICC) were used to evaluate the test-retest reliability of average number of hours spent outdoors in the summer estimated for each approach. We tested the differences between the two ICCs, corresponding to each approach, using a t test with the variance of the difference estimated by the jackknife method. During childhood and adolescence, the two approaches gave similar ICCs for average numbers of hours spent outdoors in the summer. By contrast, compared with the time-based approach, the activity-based approach showed significantly higher ICCs during adult ages (0.69 versus 0.43, P = 0.003) and over the lifetime (0.69 versus 0.52, P = 0.05); the higher ICCs for the activity-based questionnaire were primarily derived from the results for females. Research is needed to further improve the activity-based questionnaire approach for long-term sun exposure assessment. (Cancer Epidemiol Biomarkers Prev 2009;18(2):464-71) C1 [Yu, Chu-Ling] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20892 USA. [Kwok, Richard] RTI Int, Stat & Epidemiol Div, Res Triangle Pk, NC USA. [Chodick, Gabriel] Maccabi Healthcare Serv, Tel Aviv, Israel. [Alexander, Bruce] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Kimlin, Michael G.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Kricker, Anne; Armstrong, Bruce K.] Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. RP Yu, CL (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Room 7053, Rockville, MD 20892 USA. EM yuchu@mail.nih.gov RI Armstrong, Bruce/K-9464-2015; Kwok, Richard/B-6907-2017; OI Armstrong, Bruce/0000-0001-8940-7525; Kwok, Richard/0000-0002-6794-8360; Kimlin, Michael/0000-0002-9536-8646 FU Intramural Research Program of the NIH; National Cancer Institute. FX Grant support: Intramural Research Program of the NIH and the National Cancer Institute. NR 31 TC 10 Z9 10 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2009 VL 18 IS 2 BP 464 EP 471 DI 10.1158/1055-9965.EPI-08-0894 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 410AS UT WOS:000263547800013 PM 19190171 ER PT J AU Hashibe, M Brennan, P Chuang, SC Boccia, S Castellsague, X Chen, C Curado, MP Dal Maso, L Daudt, AW Fabianova, E Fernandez, L Wunsch-Filho, V Franceschi, S Hayes, RB Herrero, R Kelsey, K Koifman, S La Vecchia, C Lazarus, P Levi, F Lence, JJ Mates, D Matos, E Menezes, A McClean, MD Muscat, J Eluf-Neto, J Olshan, AF Purdue, M Rudnai, P Schwartz, SM Smith, E Sturgis, EM Szeszenia-Dabrowska, N Talamini, R Wei, QY Winn, DM Shangina, O Pilarska, A Zhang, ZF Ferro, G Berthiller, J Boffetta, P AF Hashibe, Mia Brennan, Paul Chuang, Shu-Chun Boccia, Stefania Castellsague, Xavier Chen, Chu Curado, Maria Paula Dal Maso, Luigino Daudt, Alexander W. Fabianova, Eleonora Fernandez, Leticia Wuensch-Filho, Victor Franceschi, Silvia Hayes, Richard B. Herrero, Rolando Kelsey, Karl Koifman, Sergio La Vecchia, Carlo Lazarus, Philip Levi, Fabio Lence, Juan J. Mates, Dana Matos, Elena Menezes, Ana McClean, Michael D. Muscat, Joshua Eluf-Neto, Jose Olshan, Andrew F. Purdue, Mark Rudnai, Peter Schwartz, Stephen M. Smith, Elaine Sturgis, Erich M. Szeszenia-Dabrowska, Neonilia Talamini, Renato Wei, Qingyi Winn, Deborah M. Shangina, Oxana Pilarska, Agnieszka Zhang, Zuo-Feng Ferro, Gilles Berthiller, Julien Boffetta, Paolo TI Interaction between Tobacco and Alcohol Use and the Risk of Head and Neck Cancer: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID UPPER AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMA; ORAL-CANCER; HUMAN-PAPILLOMAVIRUS; PHARYNGEAL CANCER; SMOKING; POLYMORPHISMS; DRINKING; ASSOCIATION; ESOPHAGUS AB Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (psi) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (psi = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases < 45 years, 73% for cases > 60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541-50) C1 [Hashibe, Mia] IARC, Environm & Canc Grp, Genet & Epidemiol Cluster, F-69008 Lyon, France. [Boccia, Stefania] Univ Cattolica Sacro Cuore, Inst Hyg, Rome, Italy. [Castellsague, Xavier] Inst Catala Oncol, Barcelona, Spain. [Chen, Chu; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Curado, Maria Paula] Hosp Araujo Jorge, Goiania, Go, Brazil. [Dal Maso, Luigino; Talamini, Renato] Aviano Canc Ctr, I-33081 Aviano, Italy. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Fabianova, Eleonora] Specialized State Hlth Inst, Banska Bystrica, Slovakia. [Fernandez, Leticia; Lence, Juan J.] Natl Inst Oncol & Radiobiol, Havana, Cuba. [Wuensch-Filho, Victor; Eluf-Neto, Jose] Univ Sao Paulo, Sao Paulo, Brazil. [Hayes, Richard B.; Purdue, Mark; Winn, Deborah M.] NCI, Bethesda, MD 20892 USA. [Herrero, Rolando] Inst Invest Epidemiol, San Jose, Costa Rica. [Kelsey, Karl] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [McClean, Michael D.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Kelsey, Karl] Brown Univ, Providence, RI 02912 USA. [Koifman, Sergio] Fundacao Oswaldo Cruz, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. [La Vecchia, Carlo] Ist Ric Farmacol Mario Negri, Milan, Italy. [La Vecchia, Carlo] Univ Milan, Milan, Italy. [Lazarus, Philip; Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Levi, Fabio] Univ Lausanne, Inst Social & Prevent Med, Lausanne, Switzerland. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Matos, Elena] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Smith, Elaine] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Sturgis, Erich M.; Wei, Qingyi] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Lodz, Poland. [Shangina, Oxana] Russian Acad Med Sci, Canc Res Ctr, Moscow, Russia. [Pilarska, Agnieszka] Med Acad Warsaw, Maxillofacial Surg Clin 2, Warsaw, Poland. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. RP Hashibe, M (reprint author), IARC, Environm & Canc Grp, Genet & Epidemiol Cluster, 150 Cours Albert Thomas, F-69008 Lyon, France. EM hashibe@iarc.fr RI Wunsch Filho, Victor/C-4475-2012; Inca, Inct/K-2204-2013; Epidemiologicas, Centro de pesquisas /D-4561-2013; Chuang, Shu-Chun/N-3358-2013; Eluf-Neto, Jose/B-2522-2009; Menezes, Ana/G-7266-2012; Szeszenia-Dabrowska, Neonila/F-7190-2010; McClean, Michael/J-2934-2015; Castellsague Pique, Xavier/N-5795-2014; Curado, Maria Paula/M-6200-2013; OI mates, dana/0000-0002-6219-9807; dal maso, luigino/0000-0001-6163-200X; La Vecchia, Carlo/0000-0003-1441-897X; Hayes, Richard/0000-0002-0918-661X; Eluf-Neto, Jose/0000-0001-7504-2115; Castellsague Pique, Xavier/0000-0002-0802-3595; Curado, Maria Paula/0000-0001-8172-2483; McClean, Michael/0000-0002-3902-8823 FU Aviano and Italy Multicenter studies: Italian Association for Research on Cancer, Italian League Against Cancer, and Italian Ministry of Research; Milan study: Italian Association for Research on Cancer; Swiss study: Swiss League against Cancer; Swiss Research against Cancer/Oncosuisse [KFS-700, OCS1633]; Central Europe study: World Cancer Research Fund; European Commission's NCO-COPERNICUS Program [IC15-CT98-0332]; New York study: NTH [POICA068384, K07CAI04231.]; Seattle study: NTH [ROICA048896, ROI DE012609]; Boston Study: NTH [R01CA078609]; Iowa study: NTH [R01DE11979, R01DE13110]; North Carolina Study: NTH [R01CA61188, 1130ES010126]; Tampa study: NTH [POICA068384, K07CA104231]; Los Angeles study: NTH [P50CA90388, R01DAII386, RMCA7M4, T32CA09142, UOICA96134, R21ES011667]; Houston study: NTH [R01ES11740, R01CA100264]; National Cancer Institute and National hisfitute of Dental and Cranicifacial Research intramural programs; IARC Multicenter study: Fondo cle Investigaciones Sanitarias of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013]; [R01CA100679] FX 15. IARC Multicenter study: Fondo cle Investigaciones Sanitarias of the Spanish Government (FIS 97/0024, FIS 97/0662, and BAE 01/5013), International Union Against Cancer, and Yamagiwa-Yoshida Memorial International Cancer Study Grant. NR 32 TC 271 Z9 273 U1 3 U2 29 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2009 VL 18 IS 2 BP 541 EP 550 DI 10.1158/1055-9965.EPI-08-0347 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 410AS UT WOS:000263547800022 PM 19190158 ER PT J AU Parks, CG Miller, DB McCanlies, EC Cawthon, RM Andrew, ME DeRoo, LA Sandler, DP AF Parks, Christine G. Miller, Diane B. McCanlies, Erin C. Cawthon, Richard M. Andrew, Michael E. DeRoo, Lisa A. Sandler, Dale P. TI Telomere Length, Current Perceived Stress, and Urinary Stress Hormones in Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CIGARETTE-SMOKING; CORTISOL; RISK; DISEASE; CANCER; BLOOD; AGE; INITIATION; MORTALITY; RESPONSES AB Telomeres are repetitive DNA sequences that cap and protect the ends of chromosomes; critically short telomeres may lead to cellular senescence or carcinogenic transformation. Previous findings suggest a link between psychosocial stress, shorter telomeres, and chronic disease risk. This cross-sectional study examined relative telomere length in relation to perceived stress and urinary stress hormones in a sample of participants (n = 647) in the National Institute of Environmental Health Sciences Sister Study, a cohort of women ages 35 to 74 years who have a sister with breast cancer. Average leukocyte telomere length was determined by quantitative PCR. Current stress was assessed using the Perceived Stress Scale and creatinine-adjusted neuroendocrine hormones in first morning urines. Linear regression models estimated differences in telomere length base pairs (bp) associated with stress measures adjusted for age, race, smoking, and obesity. Women with higher perceived stress had somewhat shorter telomeres [adjusted difference of -129bp for being at or above moderate stress levels; 95% confidence interval (CI), -292 to 33], but telomere length did not decrease monotonically with higher stress levels. Shorter telomeres were independently associated with increasing age (-27bp/year), obesity, and current smoking. Significant stress-related differences in telomere length were seen in women ages 55 years and older (-289bp; 95% Cl, -519 to -59), those with recent major losses (-420bp; 95% Cl, -814 to -27), and those with above-average urinary catecholamines (e.g., epinephrine: -484bp; 95% Cl, -709 to -259). Although current perceived stress was only modestly associated with shorter telomeres in this broad sample of women, our findings suggest the effect of stress on telomere length may vary depending on neuroendocrine responsiveness, external stressors, and age. (Cancer Epidemiol Biomarkers Prev 2009;18(2):551-60) C1 [Parks, Christine G.; DeRoo, Lisa A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27599 USA. [McCanlies, Erin C.; Andrew, Michael E.] NIOSH, Biostat & Epidemiol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV USA. [Miller, Diane B.] NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV USA. [Cawthon, Richard M.] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. RP Parks, CG (reprint author), NIEHS, Epidemiol Branch, NIH, A3-05,POB 12233, Res Triangle Pk, NC 27599 USA. EM Parks1@mail.nih.gov OI Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU NIH; National Institute for Environmental Health Sciences [Z01 ES04400509]; Department of Defense Breast Cancer Research Concept Award [BC045286] FX Grant support: NIH, National Institute for Environmental Health Sciences (Z01 ES04400509), and by Department of Defense Breast Cancer Research Concept Award (BC045286). NR 39 TC 84 Z9 84 U1 0 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2009 VL 18 IS 2 BP 551 EP 560 DI 10.1158/1055-9965.EPI-08-0614 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 410AS UT WOS:000263547800023 PM 19190150 ER PT J AU Yang, HP Garcia-Closas, M Lacey, JV Brinton, LA Lissowska, J Peplonska, B Chanock, S Gaudet, MM AF Yang, Hannah P. Garcia-Closas, Montserrat Lacey, James V., Jr. Brinton, Louise A. Lissowska, Jolanta Peplonska, Beta Chanock, Stephen Gaudet, Mia M. TI Genetic Variation in the Androgen Receptor Gene and Endometrial Cancer Risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID N-TERMINAL DOMAIN; STEROID-HORMONES; REPEAT; WOMEN; TRACT AB Genetic variation in the androgen receptor (AR) gene may be associated with endometrial cancer risk based on the role of AR in regulating androgen levels. However, endometrial cancer studies reported inconsistent associations for a CAG repeat polymorphism in exon 1. Only one of these studies measured haplotype-tagging single nucleotide polymorphisms (htSNP) in AR and found statistically nonsignificant, decreased associations with endometrial cancer risk. In a population-based case-control study of 497 cases and 1,024 controls, we examined the CAG repeat polymorphism and six htSNPs (rs962458, rs6152, rs1204038, rs2361634, rsl337080, and rsl337082), which cover an estimated 80% of the known common variation in AR among Caucasian populations. CAG repeat length was not significantly associated with endometrial cancer [odds ratio per unit increase in the average number of repeats, 1.02 (95% confidence interval, 0.97-1.08); P(trend) = 0.29]. Minor alleles in three correlated htSNPs (rs6152, rs1204038, and rsl337082; r(2) >0.6) were associated with increased risk for endometrial cancer. The strongest association was observed for rs6152, with the odds ratios (95% confidence interval) being 1.13 (0.89-1.44) for heterozygous and 2.40 (1.28-4.51) for homozygous minor genotypes (P(trend) = 0.02) compared with homozygous major allele genotype. However, these associations were not statistically significant after permutation adjustment for multiple comparisons (P(trend) > 0-09) Haplotype analyses did not reveal any additional associations with endometrial cancer. Results from our study, taken together with previously published studies, provide little evidence of a consistent association between common genetic variation in AR and endometrial cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(2):585-9) C1 [Yang, Hannah P.; Garcia-Closas, Montserrat; Lacey, James V., Jr.; Brinton, Louise A.; Lissowska, Jolanta; Chanock, Stephen; Gaudet, Mia M.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Chanock, Stephen] NCI, Core Genotype Facil, Adv Technol Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Yang, Hannah P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Peplonska, Beta] Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. RP Yang, HP (reprint author), Natl Canc Inst, 6120 Execut Blvd,EPS 503A, Rockville, MD 20852 USA. EM yanghan@mail.nih.gov RI Peplonska, Beata/F-6004-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS [Z99 CA999999] NR 21 TC 10 Z9 10 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 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2009 VL 18 IS 2 BP 585 EP 589 DI 10.1158/1055-9965.EPI-08-0677 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 410AS UT WOS:000263547800028 PM 19190146 ER PT J AU Smith, AW Alfano, CM Reeve, BB Irwin, ML Bernstein, L Baumgartner, K Bowen, D McTiernan, A Ballard-Barbash, R AF Smith, Ashley Wilder Alfano, Catherine M. Reeve, Bryce B. Irwin, Melinda L. Bernstein, Leslie Baumgartner, Kathy Bowen, Deborah McTiernan, Anne Ballard-Barbash, Rachel TI Race/Ethnicity, Physical Activity, and Quality of Life in Breast Cancer Survivors SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PUBLIC-HEALTH; HISPANIC PATIENTS; EXERCISE; REHABILITATION; INTERVENTION; ASSOCIATIONS; GUIDELINES; DIAGNOSIS; OUTCOMES; MODELS AB Purpose: To examine associations between recreational physical activity and quality of life (QOL) in a multiethnic cohort of breast cancer survivors, specifically testing whether associations are consistent across racial/ethnic groups after accounting for relevant medical and demographic factors that might explain disparities in QOL outcomes. Methods: Data were collected from a population-based cohort of non-Hispanic White (n = 448), Black (n = 197), and Hispanic (n = 84) breast cancer survivors (stage 0-IIIa) in the Health, Eating, Activity, and Lifestyle Study. Physical activity was assessed similar to 2.5 years after breast cancer diagnosis, with QOL assessed on average 6 to 12 months later. We used structural equation modeling to examine relationships between meeting recommended levels of physical activity and QOL, stratifying by race/ethnicity and adjusting for other demographic, comorbidity, and treatment effects. Results: Structural equation modeling indicated that meeting recommended levels of physical activity had significant positive associations with QOL for Black and non-Hispanic White women (P < 0.05). Fewer Black women reported meeting recommended physical activity levels (P < 0.001), but meeting recommendations was associated with better QOL. Post hoc tests showed that meeting physical activity recommendations was specifically associated with better vitality, social functioning, emotional roles, and global QOL (P < 0.05 for all). Conclusions: These results suggest that meeting recommended levels of physical activity is associated with better QOL in non-Hispanic White and Black breast cancer survivors. Findings may help support future interventions among breast cancer survivors and promote supportive care that includes physical activity, although more research is needed to determine these relationships among Hispanic and other ethnic minority women. (Cancer Epidemiol Biomarkers Prev 2009;18(2):656-63) C1 [Smith, Ashley Wilder] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Alfano, Catherine M.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Alfano, Catherine M.] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. [Irwin, Melinda L.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Bernstein, Leslie] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Bernstein, Leslie] Univ So Calif, Keck Sch Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Baumgartner, Kathy] Univ Louisville, Dept Epidemiol & Clin Informat Sci, Louisville, KY 40292 USA. [Bowen, Deborah; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Smith, AW (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344,Execut Plaza N,Room 409, Bethesda, MD 20892 USA. EM smithas@mail.nih.gov FU National Cancer Institute [N01-CN-75036-20, N01-CN-05228, N01-PC-67010] FX Grant support: National Cancer Institute grants N01-CN-75036-20, N01-CN-05228, and N01-PC-67010. NR 46 TC 33 Z9 34 U1 3 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2009 VL 18 IS 2 BP 656 EP 663 DI 10.1158/1055-9965.EPI-08-0352 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 410AS UT WOS:000263547800039 PM 19190157 ER PT J AU Johnson, KA AF Johnson, Karen A. TI The Standard of Perfection: Thoughts about the Laying Hen Model of Ovarian Cancer SO CANCER PREVENTION RESEARCH LA English DT Editorial Material ID GENE-EXPRESSION PATTERNS; ORAL-CONTRACEPTIVES; CHICKEN; CHEMOPREVENTION; CARCINOGENESIS; PROGESTERONE; CARCINOMA; SEQUENCE; GROWTH; TUMORS C1 NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Johnson, KA (reprint author), NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, EPN 2124,6130 Execut Blvd, Bethesda, MD 20892 USA. EM johnsonn@mail.nih.gov NR 26 TC 16 Z9 17 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2009 VL 2 IS 2 BP 97 EP 99 DI 10.1158/1940-6207.CAPR-08-0244 PG 3 WC Oncology SC Oncology GA 420MR UT WOS:000264294400001 PM 19174576 ER PT J AU Schatzkin, A Abnet, CC Cross, AJ Gunter, M Pfeiffer, R Gail, M Lim, U Davey-Smith, G AF Schatzkin, Arthur Abnet, Christian C. Cross, Amanda J. Gunter, Marc Pfeiffer, Ruth Gail, Mitchell Lim, Unhee Davey-Smith, George TI Mendelian Randomization: How It Can-and Cannot-Help Confirm Causal Relations between Nutrition and Cancer SO CANCER PREVENTION RESEARCH LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; INCIDENT COLORECTAL-CANCER; BREAST-CANCER; METHYLENETETRAHYDROFOLATE REDUCTASE; UNITED-STATES; LUNG-CANCER; PROSPECTIVE COHORT; COMMON MUTATION; POOLED ANALYSIS; FOLATE STATUS AB Observational epidemiologic studies of nutrition and cancer have faced formidable methodologic obstacles, including dietary measurement error and confounding. We consider whether Mendelian randomization can help surmount these obstacles. The Mendelian randomization strategy, building on both the accuracy of genotyping and the random assortment of alleles at meiosis, involves searching for an association between a nutritional exposure-mimicking gene variant (a type of "instrumental variable") and cancer outcome. Necessary assumptions are that the gene is independent of cancer, given the exposure, and also independent of potential confounders. An allelic variant can serve as a proxy for diet and other nutritional factors through its effects on either metabolic processes or consumption behavior. Such a genetic proxy is measured with little error and usually is not confounded by nongenetic characteristics. Examples of potentially informative genes include LCT (lactase), ALDH2 (aldehyde dehydrogenase), and HFE (hemochromatosis), proxies, respectively, for dairy product intake, alcoholic beverage drinking, and serum iron levels. We show that use of these and other genes in Mendelian randomization studies of nutrition and cancer may be more complicated than previously recognized and discuss factors that can invalidate the instrumental variable assumptions or cloud the interpretation of these studies. Sample size requirements for Mendelian randomization studies of nutrition and cancer are shown to be potentially daunting; strong genetic proxies for exposure are necessary to make such studies feasible. We conclude that Mendelian randomization is not universally applicable, but, under the right conditions, can complement evidence for causal associations from conventional epidemiologic studies. C1 [Schatzkin, Arthur; Abnet, Christian C.; Cross, Amanda J.; Pfeiffer, Ruth; Gail, Mitchell; Lim, Unhee] NCI, NIH, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Gunter, Marc] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Davey-Smith, George] Univ Bristol, Bristol, Avon, England. RP Schatzkin, A (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 3040, Rockville, MD 20852 USA. EM schatzka@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS [Z99 CA999999]; Medical Research Council [G0600705] NR 83 TC 31 Z9 31 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 FEB PY 2009 VL 2 IS 2 BP 104 EP 113 DI 10.1158/1940-6207.CAPR-08-0070 PG 10 WC Oncology SC Oncology GA 420MR UT WOS:000264294400003 PM 19174578 ER PT J AU Hakim, AA Barry, CP Barnes, HJ Anderson, KE Petitte, J Whitaker, R Lancaster, JM Wenham, RM Carver, DK Turbov, J Berchuck, A Kopelovich, L Rodriguez, GC AF Hakim, Amy A. Barry, Catherine P. Barnes, H. John Anderson, Kenneth E. Petitte, James Whitaker, Regina Lancaster, Jonathan M. Wenham, Robert M. Carver, Donna K. Turbov, Jane Berchuck, Andrew Kopelovich, Levy Rodriguez, Gustavo C. TI Ovarian Adenocarcinomas in the Laying Hen and Women Share Similar Alterations in p53, ras, and HER-2/neu SO CANCER PREVENTION RESEARCH LA English DT Article ID PROGNOSTIC-SIGNIFICANCE; CANCER CHEMOPREVENTION; EPITHELIAL NEOPLASMS; XENOGRAFT MODEL; MOUSE MODELS; ANIMAL-MODEL; AVIAN MODEL; GUINEA-PIGS; K-RAS; EXPRESSION AB We examined alterations in the p53 tumor suppressor gene and the ras and HER-2/neu oncogenes in chicken ovarian cancers to determine if these tumors have genetic alterations similar to those in human ovarian adenocarcinomas. Mutations in the p53 tumor suppressor gene and the H-ras and K-ras oncogenes were assessed by direct sequencing in 172 ovarian cancers obtained from 4-year-old birds enrolled at age 2 in two separate 2-year chemoprevention trials. Birds in trial B had approximately twice as many lifetime ovulations as those in trial A. Immunohistochemical staining for the HER-2/neu oncogene was done on a subset of avian ovarian and oviductal adenocarcinomas. Alterations in p53 were detected in 48% of chicken ovarian cancers. Incidence of p53 alterations varied according to the number of lifetime ovulations, ranging from 14% in trial A to 96% in trial B ( P < 0.01). No mutations were seen in H-ras, and only 2 of 172 (1.2%) tumors had K-ras mutations. Significant HER-2/neu staining was noted in 10 of 19 ovarian adenocarcinomas but in only 1 of 17 oviductal adenocarcinomas. Similar to human ovarian cancers, p53 alterations are common in chicken ovarian adenocarcinomas and correlate with the number of lifetime ovulations. Ras mutations are rare, similar to high-grade human ovarian cancers. HER-2/neu overexpression is common and may represent a marker to exclude an oviductal origin in cancers involving both the ovary and oviduct. C1 [Hakim, Amy A.; Turbov, Jane; Rodriguez, Gustavo C.] City Hope Natl Med Ctr, Dept Gynecol Oncol, Duarte, CA USA. [Barry, Catherine P.] Abbott Mol, Dept Assay Res & Dev, Des Plaines, IL USA. [Barnes, H. John] N Carolina State Univ, Coll Vet Med, Raleigh, NC USA. [Anderson, Kenneth E.; Petitte, James; Carver, Donna K.] N Carolina State Univ, Dept Poultry Sci, Raleigh, NC 27695 USA. [Whitaker, Regina; Berchuck, Andrew] Duke Univ, Med Ctr, Div Gynecol Oncol, Durham, NC USA. [Lancaster, Jonathan M.; Wenham, Robert M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Kopelovich, Levy] NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Rodriguez, GC (reprint author), Northwestern Univ, Div Gynecol Oncol, Evanston NW Healthcare, Suite 1507,Walgreen Bldg,2650 Ridge Ave, Evanston, IL 60201 USA. EM grodriguez@enh.org FU NCI NIH HHS [N01 CN005114] NR 47 TC 41 Z9 42 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2009 VL 2 IS 2 BP 114 EP 121 DI 10.1158/1940-6207.CAPR-08-0065 PG 8 WC Oncology SC Oncology GA 420MR UT WOS:000264294400004 PM 19174584 ER PT J AU Gray, NE Liu, XX Choi, R Blackman, MR Arnold, JT AF Gray, Nora E. Liu, Xunxian Choi, Renee Blackman, Marc R. Arnold, Julia T. TI Endocrine-Immune-Paracrine Interactions in Prostate Cells as Targeted by Phytomedicines SO CANCER PREVENTION RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; CANCER CELLS; STROMAL CELLS; DIETARY ISOFLAVONES; REACTIVE STROMA; DHEA; ANDROGEN; CARCINOGENESIS; EXPRESSION AB Dehydroepiandrosterone ( DHEA) is used as a dietary supplement and can be metabolized to androgens and/or estrogens in the prostate. We investigated the hypothesis that DHEA metabolism may be increased in a reactive prostate stroma environment in the presence of proinflammatory cytokines such as transforming growth factor beta 1 (TGF beta 1), and further, whether red clover extract, which contains a variety of compounds including isoflavones, can reverse this effect. LAPC-4 prostate cancer cells were grown in coculture with prostate stromal cells (6S) and treated with DHEA +/- TGF1 or interleukin-6. Prostate-specific antigen (PSA) expression and testosterone secretion in LAPC-4/6S cocultures were compared with those in monocultured epithelial and stromal cells by real-time PCR and/or ELISA. Combined administration of TGF beta 1 + DHEA to cocultures increased PSA protein secretion two to four times, and PSA gene expression up to 50-fold. DHEA + TGF beta 1 also increased coculture production of testosterone over DHEA treatment alone. Red clover isoflavone treatment led to a dose-dependent decrease in PSA protein and gene expression and testosterone metabolism induced by TGF beta 1 + DHEA in prostate LAPC-4/6S cocultures. In this coculture model of endocrine-immune-paracrine interactionsin the prostate, TGF beta 1 greatly increased stromal-mediated DHEA effects on testosterone production and epithelial cell PSA production, whereas red clover isoflavones reversed these effects. C1 [Gray, Nora E.; Liu, Xunxian; Choi, Renee; Blackman, Marc R.; Arnold, Julia T.] NIH, Endocrine Sect, Clin Invest Lab, Div Intramural Res,Natl Ctr Complementary & Alter, Bethesda, MD 20892 USA. RP Arnold, JT (reprint author), NIH, Endocrine Sect, Clin Invest Lab, Div Intramural Res,Natl Ctr Complementary & Alter, Bldg 10,Room 2B47,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jarnold@mail.nih.gov FU Intramural NIH HHS [Z01 AT000006-06] NR 38 TC 8 Z9 8 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2009 VL 2 IS 2 BP 134 EP 142 DI 10.1158/1940-6207.CAPR-08-0062 PG 9 WC Oncology SC Oncology GA 420MR UT WOS:000264294400007 PM 19141600 ER PT J AU Lubet, RA Boring, D Steele, VE Ruppert, JM Juliana, MM Grubbs, CJ AF Lubet, Ronald A. Boring, Daniel Steele, Vernon E. Ruppert, J. Michael Juliana, M. Margaret Grubbs, Clinton J. TI Lack of Efficacy of the Statins Atorvastatin and Lovastatin in Rodent Mammary Carcinogenesis SO CANCER PREVENTION RESEARCH LA English DT Article ID HUMAN BREAST-CANCER; TRANSGENIC MICE; CARCINOMA MODEL; PREVENTION; TUMORS; RISK; INHIBITOR; MUTATIONS; TARGRETIN; CHEMOPREVENTION AB The statins are highly effective in lowering cholesterol by inhibiting 3-hydroxy-3-methylglutaryl CoA reductase. Recently, there has been conflicting epidemiologic data indicating that statins decrease the incidence of certain types of cancer, including breast cancer. Atorvastatin and lovastatin, statins with different lipophicilities, were administered in diet either as single agents or in combination with suboptimal doses of tamoxifen or the retinoid X receptor agonist bexarotene were evaluated for prevention of estrogen receptor-positive mammary cancers induced in the rat with methylnitrosourea. Atorvastatin (125 or 500 mg/kg diet) alone did not significantly alter cancer incidence or multiplicity. Suboptimal doses of tamoxifen (0.4 mg/kg diet) or bexarotene (80 mg/kg diet) reduced cancer multiplicity from 3.8 (control) to 2.9 and 0.9, respectively. Combining atorvastatin (500 mg/kg diet) with either of these effective agents minimally altered their efficacy. Although this dose of atorvastatin did not decrease serum triglyceride levels in control rats, it significantly decreased triglyceride levels that had been increased in bexarotene-treated rats. Experiments done with a second statin, lovastatin (100 and 400 mg/kg diet), yielded similar results: (a) limited activity when administered alone, (b) no obvious synergy with bexarotene, and (c) an ability to decrease bexarotene-induced increases in serum triglycerides. Thus, the statins had minimal activity in this model of mammary cancer in which approximately half of the cancers are mutated in the Ha Ras oncogene. Similarly, atorvastatin failed to alter the development of estrogen receptor-negative mammary carcinomas in a new animal model using bitransgenic mice (MMTV-Neu(+/-)/p53KO(+/-)), whereasbexarotene (250 mg/kg diet) was effective. C1 [Lubet, Ronald A.; Boring, Daniel; Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20852 USA. [Ruppert, J. Michael; Juliana, M. Margaret; Grubbs, Clinton J.] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. [Ruppert, J. Michael; Juliana, M. Margaret; Grubbs, Clinton J.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Ruppert, J. Michael; Juliana, M. Margaret; Grubbs, Clinton J.] Univ Alabama, Dept Genet, Birmingham, AL USA. RP Lubet, RA (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Execut Plaza N,Suite 2110,6130 Execut Blvd, Bethesda, MD 20852 USA. EM lubetr@nih.gov FU NCI NIH HHS [R01 CA127405]; PHS HHS [HHSN261200433001C] NR 33 TC 21 Z9 21 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD FEB PY 2009 VL 2 IS 2 BP 161 EP 167 DI 10.1158/1940-6207.CAPR-08-0134 PG 7 WC Oncology SC Oncology GA 420MR UT WOS:000264294400010 PM 19196723 ER PT J AU Jin, CY Yang, YA Anver, MR Morris, N Wang, XC Zhang, YE AF Jin, Chaoyang Yang, Yu-an Anver, Miriam R. Morris, Nicole Wang, Xiangchun Zhang, Ying E. TI Smad Ubiquitination Regulatory Factor 2 Promotes Metastasis of Breast Cancer Cells by Enhancing Migration and Invasiveness SO CANCER RESEARCH LA English DT Article ID LIGASE SMURF2; DEGRADATION; PROGRESSION; EXPRESSION; PLASTICITY; CARCINOMA; MOTILITY; POLARITY; LINES; RHOA AB Controlled protein degradation mediated by ubiquitin/proteasome system (UPS) plays a crucial role in modulating a broad range of cellular responses. Dysregulation of the UPS often accompanies tumorigenesis and progression. Here, we report that Smad ubiquitination regulatory factor 2 (Smurf2), a HECT-domain containing E3 ubiquitin ligase, is up-regulated in certain breast cancer tissues and cells. We show that reduction of Smurf2 expression with specific short interfering RNA in metastatic breast cancer cells induces cell rounding and reorganization of the actin cytoskeleton, which are associated with a less motile and invasive phenotype. Overexpression of Smurf2 promotes metastasis in a nude mouse model and increases migration and invasion of breast cancer cells. Moreover, expression of Smurf2CG, an E3 ligase-defective mutant of Smurf2, suppresses the above metastatic behaviors. These results establish an important role for Smurf2 in breast cancer progression and indicate that Smurf2 is a novel regulator of breast cancer cell migration and invasion. [Cancer Res 2009;69(3):735-40] C1 [Zhang, Ying E.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Anver, Miriam R.] NCI, Pathol Histotechnol Lab, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Morris, Nicole] NCI, Anim Sci Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. RP Zhang, YE (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37,RM 2056B, Bethesda, MD 20892 USA. EM yingz@helix.nih.gov RI Zhang, Ying/G-3657-2015 OI Zhang, Ying/0000-0003-2753-7601 FU Center for Cancer Research; National Cancer Institute [N01-CO-12400] FX We thank Dr. F. Miller for providing MCF10Cala cells, and Drs. B. Tang and L. Wakefield for advice in culturing these cells. NR 20 TC 32 Z9 36 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 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2009 VL 69 IS 3 BP 735 EP 740 DI 10.1158/0008-5472.CAN-08-1463 PG 6 WC Oncology SC Oncology GA 402YJ UT WOS:000263048700004 PM 19155312 ER PT J AU Killian, JK Bilke, S Davis, S Walker, RL Killian, MS Jaeger, EB Chen, YD Hipp, J Pittaluga, S Raffeld, M Cornelison, R Smith, WI Bibikova, M Fan, JB Emmert-Buck, MR Jaffe, ES Meltzer, PS AF Killian, J. Keith Bilke, Sven Davis, Sean Walker, Robert L. Killian, M. Scott Jaeger, Erich B. Chen, Yidong Hipp, Jason Pittaluga, Stefania Raffeld, Mark Cornelison, Robert Smith, William I., Jr. Bibikova, Marina Fan, Jian-Bing Emmert-Buck, Michael R. Jaffe, Elaine S. Meltzer, Paul S. TI Large-Scale Profiling of Archival Lymph Nodes Reveals Pervasive Remodeling of the Follicular Lymphoma Methylome SO CANCER RESEARCH LA English DT Article ID UNIVERSAL BEAD ARRAYS; B-CELL LYMPHOMA; DNA METHYLATION; GENE-EXPRESSION; CANCER AB Emerging technologies allow broad profiling of the cancer genome for differential DNA methylation relative to benign cells. Herein, bisulfite-modified DNA from lymph nodes with either reactive hyperplasia or follicular lymphoma (FL) were analyzed using a commercial C/UpG genotyping assay. Two hundred fifty-nine differentially methylated targets (DMT) distributed among 183 unique genes were identified in FL. Comparison of matched formalin-fixed, paraffin-embedded and frozen surgical pathology replicates showed the complete preservation of the cancer methylome among differently archived tissue specimens. Analysis of the DMT profile is consistent with a pervasive epigenomic remodeling process in FL that affects predominantly nonlymphoid genes. [Cancer Res 2009;69(3):758-64] C1 [Killian, J. Keith; Bilke, Sven; Davis, Sean; Walker, Robert L.; Chen, Yidong; Cornelison, Robert; Meltzer, Paul S.] NIH, Genet Branch, NCI, Bethesda, MD 20892 USA. [Killian, J. Keith; Hipp, Jason; Pittaluga, Stefania; Raffeld, Mark; Emmert-Buck, Michael R.; Jaffe, Elaine S.] NIH, Pathol Lab, NCI, Bethesda, MD 20892 USA. [Smith, William I., Jr.] Suburban Hosp, Dept Pathol, Bethesda, MD USA. [Jaeger, Erich B.; Bibikova, Marina; Fan, Jian-Bing] Illumina Inc, San Diego, CA USA. [Killian, M. Scott] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Meltzer, PS (reprint author), Room 6138,37 Convent Dr,MSC 4265, Bethesda, MD 20892 USA. EM pmeltzer@mail.nih.gov OI Davis, Sean/0000-0002-8991-6458 FU NIH; National Cancer Institute; Center for Cancer Research FX We thank Marhin Pineda, Theresa Davies-Hill. and Dr. Lynn Sorbara for technical assistance; Julie Stewart for help with figures; and Art Glatfelter, Shannon Harmon, Shyam Kalavar CT. Rachel Dove HT, Marie Mueller CTR, and Dr. Gene Passamani for facilitating pathology archive research. NR 17 TC 32 Z9 33 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2009 VL 69 IS 3 BP 758 EP 764 DI 10.1158/0008-5472.CAN-08-2984 PG 7 WC Oncology SC Oncology GA 402YJ UT WOS:000263048700008 PM 19155300 ER PT J AU Kuznetsov, SG Haines, DC Martin, BK Sharan, SK AF Kuznetsov, Sergey G. Haines, Diana C. Martin, Betty K. Sharan, Shyam K. TI Loss of Rad51c Leads to Embryonic Lethality and Modulation of Trp53-Dependent Tumorigenesis in Mice SO CANCER RESEARCH LA English DT Article ID SEBACEOUS GLAND CARCINOMAS; HIGH-LEVEL AMPLIFICATION; MUIR-TORRE-SYNDROME; BREAST-CANCER; TUMOR-SUPPRESSOR; MAMMARY-TUMORS; OVARIAN-CANCER; GENE; REPAIR; P53 AB RecA/Rad51 protein family members (Rad51, Rad51b, Rad51c, Rad51d, Xrcc2, and Xrcc3) are essential for DNA repair by homologous recombination, and their role in cancers has been anticipated. Here we provide the first direct evidence for a tumor suppressor function for a member of the Rad51 family. We show that Rad51c deficiency leads to early embryonic lethality, which can be delayed on a Trp53-null background. To uncover the role of Rad51c in tumorigenesis, we have exploited the fact that Rad51c and Trp53 are both closely located on the mouse chromosome 11. We have generated double heterozygous (DH) mice carrying mutant alleles of both genes either on different (DH-trans) or on the same chromosome (DH-cis), the latter allowing for a deletion of wild-type alleles of both genes by loss of heterozygosity. DH-trans mice, in contrast to DH-cis, developed tumors with latency and spectrum similar to Trp53 heterozygous mice. Strikingly, Rad51c mutation in DH-cis mice promoted the development of tumors of specialized sebaceous glands and suppressed tumors characteristic of Trp53 mutation. In addition, DH-cis females developed tumors significantly earlier than any other group. [Cancer Res 2009;69(3):863-72] C1 [Kuznetsov, Sergey G.; Martin, Betty K.; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Haines, Diana C.] NCI, Pathol Histotechnol Lab, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560,Room 32-31C,1050 Boyles St, Frederick, MD 21702 USA. EM sharans@mail.nih.gov OI Kuznetsov, Sergey/0000-0002-5662-9700 FU Center for Cancer Research; National Cancer Institute; NIH FX Grant support: Center for Cancer Research, National Cancer Institute, NIH.; The costs of publication of this article were defrayed in part. by the payment of page charges. This article must therefore be hereby marked advertisement in accordance kith IS U.S.C. Section 1734 solely to indicate this fact.; We thank J. Acharya, K. Biswas, S. Chang, I. Daar, S. Philip, K. Reilly, E. Sterneck, and L. Tessarollo for helpful discussions and critical review of the manuscript; E. Southon, S. Reid, D. Butcher, and S. Burkett for technical assistance: J. Wada for illustrations; and M. Lewandoski for providing the beta-actin-Cre mouse strain. NR 54 TC 38 Z9 38 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2009 VL 69 IS 3 BP 863 EP 872 DI 10.1158/0008-5472.CAN-08-3057 PG 10 WC Oncology SC Oncology GA 402YJ UT WOS:000263048700020 PM 19155299 ER PT J AU Lam, TK Cross, AJ Consonni, D Randi, G Bagnardi, V Bertazzi, PA Caporaso, NE Sinha, R Subar, AF Landi, MT AF Lam, Tram Kim Cross, Amanda J. Consonni, Dario Randi, Giorgia Bagnardi, Vincenzo Bertazzi, Pier Alberto Caporaso, Neil E. Sinha, Rashmi Subar, Amy F. Landi, Maria Teresa TI Intakes of Red Meat, Processed Meat, and Meat Mutagens Increase Lung Cancer Risk SO CANCER RESEARCH LA English DT Article ID N-NITROSO COMPOUNDS; EPIDEMIOLOGIC EVIDENCE; METABOLIC-ACTIVATION; HETEROCYCLIC AMINES; BLADDER-CANCER; UNITED-STATES; DNA-ADDUCTS; DIETARY-FAT; WELL-DONE; URUGUAY AB Red and processed meat intake may increase lung cancer risk. However, the epidemiologic evidence is inconsistent and few studies have evaluated the role of meat mutagens formed during high cooking temperatures. We investigated the association of red meat, processed meat, and meat mutagen intake with lung cancer risk in Environment And Genetics in Lung cancer Etiology, a population-based case-control study. Primary lung cancer cases (n = 2,101) were recruited from 13 hospitals within the Lombardy region of Italy examining similar to 80% of the cases from the area Noncancer population controls (n = 2,120), matched to cases on gender, residence, and age, were randomly selected from the same catchment area Diet was assessed in 1,903 cases and 2,073 controls and used in conjunction with a meat mutagen database to estimate intake of heterocyclic amines (HCA) and benzo(a)pyrene (BaP). Multivariable odds ratios (OR) and 95% confidence intervals (95% CI) for sex-specific tertiles of intake were calculated using unconditional logistic regression. Red and processed meat were positively associated with lung cancer risk (highest-versus-lowest tertile: OR, 1.8; 95% CI, 1.5-2.2; P trend < 0.001 and OR, 1.7; 95% CI, 1.4-2.1; P trend < 0.001, respectively); the risks were strongest among never smokers (OR, 2.4; 95% CI, 1.4-4.0; P trend = 0.001 and OR, 2.5; 95% CI, 1.5-4.2; P trend = 0.001, respectively). HCAs and BaP were significantly associated with increased risk of lung cancer. When separated by histology, significant positive associations for both meat groups were restricted to adenocarcinoma and squamous cell carcinoma but not small cell carcinoma of the lung. In summary, red meat, processed meat, and meat mutagens were independently associated with increased risk of lung cancer. [Cancer Res 2009;69(3):932-9] C1 [Lam, Tram Kim; Caporaso, Neil E.; Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cross, Amanda J.; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lam, Tram Kim] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol,Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human, Bethesda, MD 20892 USA. [Randi, Giorgia] Univ Milan, Ist Stat Med & Biometria GA Maccacaro, I-20122 Milan, Italy. [Bagnardi, Vincenzo] Univ Milan, Dept Occupat Hlth, Milan, Italy. [Subar, Amy F.] NCI, Risk Factor Monitoring & Method Branch, Div Canc Control & Populat Sci, NIH,Dept Hlth & Human Serv, Rockville, MD USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7114, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Sinha, Rashmi/G-7446-2015; bertazzi, pietro alberto/D-5039-2017 OI Sinha, Rashmi/0000-0002-2466-7462; bertazzi, pietro alberto/0000-0003-3475-2449 FU Intramural Research Program of NIH; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX Intramural Research Program of NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 50 TC 47 Z9 47 U1 2 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2009 VL 69 IS 3 BP 932 EP 939 DI 10.1158/0008-5472.CAN-08-3162 PG 8 WC Oncology SC Oncology GA 402YJ UT WOS:000263048700028 PM 19141639 ER PT J AU Rao, VA Klein, SR Agama, KK Toyoda, E Adachi, N Pommier, Y Shacter, EB AF Rao, V. Ashutosh Klein, Sarah R. Agama, Keli K. Toyoda, Eriko Adachi, Noritaka Pommier, Yves Shacter, Emily B. TI The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase II alpha in Breast Cancer Cells SO CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE 3-AP; POTENT ANTITUMOR-ACTIVITY; RIBONUCLEOTIDE REDUCTASE; ISONICOTINOYL HYDRAZONE; CYCLE ARREST; TUMOR-GROWTH; DEXRAZOXANE; DOXORUBICIN; GAMMA-H2AX AB Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) is being developed as an iron chelator with selective anticancer activity. We investigated the mechanism whereby Dp44mT kills breast cancer cells, both as a single agent and in combination with doxorubicin. Dp44mT alone induced selective cell killing in the breast cancer cell line MDA-MB-231 when compared with healthy mammary epithelial cells (MCF-12A). It induces G(1) cell cycle arrest and reduces cancer cell clonogenic growth at nanomolar concentrations. Dp44mT, but not the iron chelator desferal, induces DNA double-strand breaks quantified as S139 phosphorylated historic foci (gamma-H2AX) and Comet tails induced in MDA-MB-231 cells. Doxorubicin-induced cytotoxicity and DNA damage were both enhanced significantly in the presence of low concentrations of Dp44mT. The chelator caused selective poisoning of DNA topoisomerase II alpha (top2 alpha) as measured by an in vitro DNA cleavage assay and cellular topoisomerase-DNA complex formation. Heterozygous Nalm-6 top2 alpha knockout cells (top2 alpha(+/-)) were partially resistant to Dp44mT-induced cytotoxicity compared with isogenic top2 alpha(+/+) or top2 beta(-/-) cells. Specificity for top2 alpha was confirmed using top2 alpha and top2 beta small interfering RNA knockdown in HeLa cells. The results show that Dp44mT is cytotoxic to breast cancer cells, at least in part, due to selective inhibition of top2 alpha. Thus, Dp44mT may serve as a mechanistically unique treatment for cancer due to its dual ability to chelate iron and inhibit top2 alpha activity. [Cancer Res 2009;69(3):948-57] C1 [Rao, V. Ashutosh] NCI, Food & Drug Adm, Interagency Oncol Task Force Program, Bethesda, MD 20892 USA. [Agama, Keli K.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, US Dept HHS, Bethesda, MD 20892 USA. [Toyoda, Eriko; Adachi, Noritaka] Yokohama City Univ, Yokohama, Kanagawa 232, Japan. RP Rao, VA (reprint author), 29 Lincoln Dr,Bldg 29A,Room 2A-11,HFD-122, Bethesda, MD 20892 USA. EM ashutosh.rao@fda.hhs.gov; emily.shacter@fda.hhs.gov FU Intramural Research Program; Center for Cancer Research; National Cancer Institute; NIH FX Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. NR 50 TC 77 Z9 77 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2009 VL 69 IS 3 BP 948 EP 957 DI 10.1158/0008-5472.CAN-08-1437 PG 10 WC Oncology SC Oncology GA 402YJ UT WOS:000263048700030 PM 19176392 ER PT J AU Schild-Hay, LJ Leil, TA Divi, RL Olivero, OA Weston, A Poirier, MC AF Schild-Hay, Laura J. Leil, Tarek A. Divi, Rao L. Olivero, Ofelia A. Weston, Ainsley Poirier, Miriam C. TI Tamoxifen Induces Expression of Immune Response-Related Genes in Cultured Normal Human Mammary Epithelial Cells SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; DNA-ADDUCTS; MASS-SPECTROMETRY; HUMAN ENDOMETRIUM; INTERFERON; TOREMIFENE; PATTERNS; ESTROGEN; RISK; CARCINOGENICITY AB Use of tamoxifen is associated with a 50% reduction in breast cancer incidence and an increase in endometrial cancer incidence. Here, we documented tamoxifen-induced gene expression changes in cultured normal human mammary epithelial cells (strains 5, 16, and 40), established from tissue taken at reduction mammoplasty from three individuals. Cells exposed to 0, 10, or 50 mu mol/L of tamoxifen for 48 hours were evaluated for (E)-alpha-(deoxyguanosine-N(2)-yl)-tamoxifen (dG-N(2)-TAM) adduct formation using TAM-DNA (DNA modified with dG-N2-TAM) chemiluminescence immunoassay, gene expression changes using National Cancer Institute DNA-oligonucleotide microarray, and real-time PCR. At 48 hours, cells exposed to 10 and 50 mu mol/L of tamoxifen were 85.6% and 48.4% viable, respectively, and there were no measurable dG-N(2)-TAM adducts. For microarrays, cells were exposed to 10 mu mol/L of tamoxifen and genes with expression changes of >3-fold were as follows: 13 genes up-regulated and 1 down-regulated for strain 16; 17 genes up-regulated for strain 5, and 11 genes up-regulated for strain 40. Interferon-inducible genes (IFITM1, IFIT1, MXI, and GIP3), and a potassium ion channel (KCNJ1) were up-regulated in all three strains. No significant expression changes were found for genes related to estrogen or xenobiotic metabolism. Real-time PCR revealed the upregulation of IFNA1 and confirmed the tamoxifen-induced upregulation of the five other genes identified by microarray, with the exception of GIP3 and MX1, which were not upregulated in strain 40. Induction of IFN-related genes in the three normal human mammary epithelial cell strains suggests that, in addition to hormonal effects, tamoxifen exposure may enhance immune response in normal breast tissue. [Cancer Res 2009;69(3):1150-5] C1 [Schild-Hay, Laura J.; Leil, Tarek A.; Divi, Rao L.; Olivero, Ofelia A.; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, CCR, LCBG,NIH, Bethesda, MD 20892 USA. [Weston, Ainsley] NIOSH, Div Resp Dis Studies, Morgantown, WV 26505 USA. [Leil, Tarek A.] Bristol Myers Squibb Co, Discovery Med & Clin Pharmacol, Pennington, NJ USA. [Schild-Hay, Laura J.] PPD, Richmond, VA USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, CCR, LCBG,NIH, Bldg 37 Room 4032,MSC-4255,37 Convent Dr, Bethesda, MD 20892 USA. EM poirierm@exchange.nih.gov FU NIH; NCI; Center for Cancer Research; National Institute for Occupational Safety and Health FX Grant support: Intramural program of the NIH, NCI, Center for Cancer Research and used cell strains developed at the National Institute for Occupational Safety and Health. NR 42 TC 11 Z9 13 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2009 VL 69 IS 3 BP 1150 EP 1155 DI 10.1158/0008-5472.CAN-08-2806 PG 6 WC Oncology SC Oncology GA 402YJ UT WOS:000263048700053 PM 19155303 ER PT J AU Purdue, MP Lan, Q Wang, SS Kricker, A Menashe, I Zheng, TZ Hartge, P Grulich, AE Zhang, Y Morton, LM Vajdic, CM Holford, TR Severson, RK Leaderer, BP Cerhan, JR Yeager, M Cozen, W Jacobs, K Davis, S Rothman, N Chanock, SJ Chatterjee, N Armstrong, BK AF Purdue, Mark P. Lan, Qing Wang, Sophia S. Kricker, Anne Menashe, Idan Zheng, Tong-Zhang Hartge, Patricia Grulich, Andrew E. Zhang, Yawei Morton, Lindsay M. Vajdic, Claire M. Holford, Theodore R. Severson, Richard K. Leaderer, Brian P. Cerhan, James R. Yeager, Meredith Cozen, Wendy Jacobs, Kevin Davis, Scott Rothman, Nathaniel Chanock, Stephen J. Chatterjee, Nilanjan Armstrong, Bruce K. TI A pooled investigation of Toll-like receptor gene variants and risk of non-Hodgkin lymphoma SO CARCINOGENESIS LA English DT Article ID B-CELL LYMPHOMA; SINGLE-NUCLEOTIDE POLYMORPHISMS; C VIRUS-INFECTION; BORRELIA-BURGDORFERI; HELICOBACTER-PYLORI; LINKAGE DISEQUILIBRIUM; EPIDEMIOLOGIC RESEARCH; PROSTATE-CANCER; ASSOCIATION; IMMUNE AB Toll-like receptors (TLRs) may influence the development of non-Hodgkin lymphoma (NHL) given their important roles in recognizing microbial pathogens and stimulating multiple immune pathways. We conducted an investigation of TLR gene variants in a pooled analysis including three population-based case-control studies of NHL (1946 cases and 1808 controls). Thirty-six tag single-nucleotide polymorphisms (SNPs) in TLR2, TLR4 and the TLR10-TLR1-TLR6 gene cluster were genotyped. Two TLR10-TLR1-TLR6 variants in moderate linkage disequilibrium were significantly associated with NHL: rs10008492 [odds ratio for CT genotype (OR(CT)) 1.12, 95% confidence interval (CI) 0.97-1.30; OR(TT) 1.40, 95% CI 1.15-1.71; P(trend) = 0.001] and rs4833103 (OR(AC) 0.75, 95% CI 0.64-0.88; OR(AA) 0.74, 95% CI 0.62-0.90; P(trend) = 0.002; P(dominant) = 0.0002). Associations with these SNPs were consistent across all the three studies and did not appreciably differ by histologic subtype. We found little evidence of association between TLR2 variation and all NHL, although the rare variant rs3804100 was significantly associated with marginal zone lymphoma (MZL), both overall (OR(CT/CC) 1.89, 95% CI 1.27-2.81; P(dominant) = 0.002) and in two of the three studies. No associations with TLR4 variants were observed. This pooled analysis provides strong evidence that variation in the TLR10-TLR1-TLR6 region is associated with NHL risk and suggests that TLR2 variants may influence susceptibility to MZL. C1 [Purdue, Mark P.; Lan, Qing; Wang, Sophia S.; Menashe, Idan; Hartge, Patricia; Morton, Lindsay M.; Rothman, Nathaniel; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20892 USA. [Kricker, Anne; Armstrong, Bruce K.] Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Zheng, Tong-Zhang; Zhang, Yawei; Holford, Theodore R.; Leaderer, Brian P.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Grulich, Andrew E.] Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2010, Australia. [Vajdic, Claire M.] Univ New S Wales, Prince Wales Clin Sch, Univ New S Wales Canc Res Ctr, Sydney, NSW 2052, Australia. [Severson, Richard K.] Wayne State Univ, Dept Family Med, Detroit, MI 48201 USA. [Severson, Richard K.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN 55905 USA. [Yeager, Meredith; Jacobs, Kevin; Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,Dept Hlth & Human Serv, Gaithersburg, MD 20877 USA. [Cozen, Wendy] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Davis, Scott] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Davis, Scott] Univ Washington, Seattle, WA 98109 USA. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20892 USA. EM purduem@mail.nih.gov RI Morton, Lindsay/B-5234-2015; Armstrong, Bruce/K-9464-2015; Purdue, Mark/C-9228-2016; OI Morton, Lindsay/0000-0001-9767-2310; Armstrong, Bruce/0000-0001-8940-7525; Purdue, Mark/0000-0003-1177-3108; Vajdic, Claire/0000-0002-3612-8298; Cerhan, James/0000-0002-7482-178X FU Intramural Research Program of the National Institutes of Health (National Cancer Institute); Public Health Service [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC71105]; National Cancer Institute National Institutes of Health grant [CA62006]; National Health and Medical Research Council of Australia [990920]; Cancer Council New South Wales (NSW); University of Sydney Medical Foundation; NSW Health Department FX Intramural Research Program of the National Institutes of Health (National Cancer Institute) to all genotyping and statistical analysis for this work and NCI-SEER study; Public Health Service (N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC71105) to NCI-SEER study; National Cancer Institute National Institutes of Health grant (CA62006) to Connecticut study; National Health and Medical Research Council of Australia (990920 to B. K. A), Cancer Council New South Wales (NSW), University of Sydney Medical Foundation to NSW study; NSW Health Department to NSW Central Cancer Registry. NR 51 TC 49 Z9 52 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2009 VL 30 IS 2 BP 275 EP 281 DI 10.1093/carcin/bgn262 PG 7 WC Oncology SC Oncology GA 404OK UT WOS:000263162500011 PM 19029192 ER PT J AU Huang, J Chen, KQ Huang, JQ Gong, WH Dunlop, NM Howard, OMZ Bian, XW Gao, YQ Wang, JM AF Huang, Jian Chen, Keqiang Huang, Jiaqiang Gong, Wanghua Dunlop, Nancy M. Howard, O. M. Zack Bian, Xiuwu Gao, Yuqi Wang, Ji Ming TI Regulation of the leucocyte chemoattractant receptor FPR in glioblastoma cells by cell differentiation SO CARCINOGENESIS LA English DT Article ID NF-KAPPA-B; WILD-TYPE P53; FORMYL-PEPTIDE RECEPTORS; TUMOR-SUPPRESSOR P53; FORMYLPEPTIDE RECEPTOR; 5-AZA-2'-DEOXYCYTIDINE DECITABINE; TRANSCRIPTIONAL ACTIVITY; ANTINEOPLASTIC ACTION; PROMOTER METHYLATION; DNA METHYLATION AB The G protein-coupled formylpeptide receptor (FPR), known to mediate phagocytic leucocyte chemotaxis in reponse to bacterial- and host-derived agonists, was expressed by tumor cells in specimens of surgically removed more highly malignant human gliomas. In human glioblastoma cell lines, FPR activation increased cell motility, tumorigenicity and production of angiogenic factors. In studies of the mechanistic basis for the selective expression of FPR in more highly malignant gliomas, we found that the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza), while promoting the differentiation of human glioblastoma cells, downregulated FPR expression. Aza also reduced the global methylation levels in glioblastoma cells and activated the pathway of p53 tumor suppressor. Methylation-specific polymerase chain reaction revealed that Aza treatment of tumor cells reduced the methylation of p53 promoter, which was accompanied by increased expression of p53 gene and protein. In addition, overexpression of p53 in glioblastoma cells mimicked the effect of Aza treatment as shown by increased cell differentiation but reduction in FPR expression, the capacity of tumor sphere formation in soft agar and tumorigenesis in nude mice. Furthermore, Aza treatment or overexpression of the wild-type p53 in glioblastoma cells increased the binding of p53 to FPR promoter region shown by chromatin immunoprecipitation. These results indicate that increased methylation of p53 gene retains human glioblastoma cells at a more poorly differentiated phase associated with the aberrant expression of FPR as a tumor-promoting cell surface receptor. C1 [Huang, Jian; Chen, Keqiang; Dunlop, Nancy M.; Howard, O. M. Zack; Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Huang, Jian; Bian, Xiuwu; Gao, Yuqi] Third Mil Med Univ, Dept Pathophysiol, Chongqing 400038, Peoples R China. [Huang, Jiaqiang] SuperArray Biosci Corp, Frederick, MD 21704 USA. [Gong, Wanghua] NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. RP Wang, JM (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Bldg 560,Room 31-76, Frederick, MD 21702 USA. EM wangji@mail.ncifcrf.gov RI Bian, Xiuwu/F-1569-2011; Howard, O M Zack/B-6117-2012; Bian, Xiu-wu/D-4736-2017 OI Howard, O M Zack/0000-0002-0505-7052; Bian, Xiu-wu/0000-0003-4383-0197 FU National Cancer Institute; National Institutes of Health [NO1-CO-12400] FX Federal funds from the National Cancer Institute, National Institutes of Health (Contract No. NO1-CO-12400); Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 51 TC 13 Z9 13 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2009 VL 30 IS 2 BP 348 EP 355 DI 10.1093/carcin/bgn266 PG 8 WC Oncology SC Oncology GA 404OK UT WOS:000263162500021 PM 19037090 ER PT J AU Koontongkaew, S Amornphimoltham, P Yapong, B AF Koontongkaew, Sittichai Amornphimoltham, Panomwat Yapong, Bunjird TI Tumor-stroma interactions influence cytokine expression and matrix metalloproteinase activities in paired primary and metastatic head and neck cancer cells SO CELL BIOLOGY INTERNATIONAL LA English DT Article DE Cell invasion; Collagen; Cytokine; Fibroblast; Head and neck cancer; MMPs; Stromal-epithelial interaction ID NECROSIS-FACTOR-ALPHA; IN-VITRO; CARCINOMA; INVASIVENESS; ACTIVATION; INVASION; INTERLEUKIN-6; FIBROBLASTS; PHENOTYPE; MELANOMA AB This study evaluates the effects of gingival fibroblasts, type I collagen and autocrine/paracrine elements on cytokine expression in paired primary and metastatic human squamous cell carcinoma (HNSCC) cell lines. Additionally, the effects of IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, TGF-beta and HGF on MMPs and cell invasion were investigated. RT-PCR results indicated the presence of mRNAs for IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, and TGF-beta in primary and metastatic HNSCC cell lines but high expression of cytokines was not a prerequisite for metastatic cancer cells. HGF mRNA was not detected in the cancer cell lines. Co-culturing of HNSCC cells with fibroblasts caused increases in cytokine expression. Type I collagen and conditioned media derived from HNSCC cells or fibroblasts enhanced cytokine expression in the cancer cells. Cytokines also enhanced MMP-2 and MMP-9 enzymatic activities as well as HNSCC cell invasion. Our findings suggest that the interactions between cancer cells, the extracellular matrix and fibroblasts, as mediated by cytokines, play important roles in the progression of HNSCC. (C) 2008 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved. C1 [Koontongkaew, Sittichai] Thammasat Univ, Fac Dent, Tani 12121, Thailand. [Amornphimoltham, Panomwat] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20882 USA. [Yapong, Bunjird] Prince Songkla Univ, Dept Oral Biol & Occlus, Fac Dent, Hat Yai 90112, Songkhla, Thailand. RP Koontongkaew, S (reprint author), Thammasat Univ, Fac Dent, Tani 12121, Thailand. EM koontongkaew@yahoo.com; pamornph@mail.nih.gov; bunjerd.y@psu.ac.th FU Thailand Research Foundation FX This work was supported by grant RDG from Thailand Research Foundation. We thank Montira Leelakriangsak for her skillful technical assistance. NR 31 TC 21 Z9 21 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-6995 EI 1095-8355 J9 CELL BIOL INT JI Cell Biol. Int. PD FEB PY 2009 VL 33 IS 2 BP 165 EP 173 DI 10.1016/j.cellbi.2008.10.009 PG 9 WC Cell Biology SC Cell Biology GA 401YO UT WOS:000262980300005 PM 18996211 ER PT J AU Liu, TT Shi, J Epstein, DH Bao, YP Lu, L AF Liu, Ting-Ting Shi, Jie Epstein, David H. Bao, Yan-Ping Lu, Lin TI A Meta-Analysis of Chinese Herbal Medicine in Treatment of Managed Withdrawal from Heroin SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE Chinese herbal medicine; Heroin; Detoxification; Meta-analysis ID RANDOMIZED CONTROLLED-TRIAL; ACUTE OPIOID WITHDRAWAL; DETOXIFICATION; ADDICTION; IBOGAINE AB Chinese herbal medicine has shown promise for heroin detoxification. This review extends a prior meta-analysis of Chinese herbal medicine for heroin detoxification, with particular attention to the time course of symptoms. Both English and Chinese databases were searched for randomized trials comparing Chinese herbal medicine to either alpha 2-adrenergic agonists or opioid agonists for heroin detoxification. The methodological quality of each study was assessed with Jadad's scale (1-2 = low; 3-5 = high). Meta-analysis was performed with fixed- or random-effect models in RevMan software; outcome measures assessed were withdrawal-symptoms score, anxiety, and adverse effects of treatment. Twenty-one studies (2,949 participants) were included. For withdrawal-symptoms score relieving during the 10-day observation, Chinese herbal medicine was superior to alpha 2-adrenergic agonists in relieving opioid-withdrawal symptoms during 4-10 days (except D8) and no difference was found within the first 3 days. Compared with opioid agonists, Chinese herbal medicine was inferior during the first 3 days, but the difference became non-significant during days 4-9. Chinese herbal medicine has better effect on anxiety relieving at late stage of intervention than alpha 2-adrenergic agonists, and no difference with opioid agonists. The incidence of some adverse effects (fatigue, dizziness) was significantly lower for Chinese herbal medicine than for alpha 2-adrenergic agonists (sufficient data for comparison with opioid agonists were not available). Findings were robust to file-drawer effects. Our meta-analysis suggests that Chinese herbal medicine is an effective and safety treatment for heroin detoxification. And more work is needed to determine the specific effects of specific forms of Chinese herbal medicine. C1 [Liu, Ting-Ting; Shi, Jie; Bao, Yan-Ping; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100083, Peoples R China. [Epstein, David H.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Shi, J (reprint author), Peking Univ, Natl Inst Drug Dependence, 38 Xue Yuan Rd, Beijing 100083, Peoples R China. EM shijie@bjmu.edu.cn; linlu@bjmu.edu.cn FU National Basic Research Program of China [2003CB515400]; National High Technology Research and Development Program of China [2006AA02Z4D1]; China-Canada Joint Health Research Program [30611120528] FX This work was supported in part by the National Basic Research Program of China (973 Program, 2003CB515400), the National High Technology Research and Development Program of China (863 Program, 2006AA02Z4D1), and the China-Canada Joint Health Research Program (No: 30611120528) NR 42 TC 8 Z9 8 U1 2 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD FEB PY 2009 VL 29 IS 1 BP 17 EP 25 DI 10.1007/s10571-008-9290-1 PG 9 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 403XA UT WOS:000263114100003 PM 18584321 ER PT J AU Zahn, R Moll, J Paiva, M Garrido, G Krueger, F Huey, ED Grafman, J AF Zahn, Roland Moll, Jorge Paiva, Mirella Garrido, Griselda Krueger, Frank Huey, Edward D. Grafman, Jordan TI The Neural Basis of Human Social Values: Evidence from Functional MRI SO CEREBRAL CORTEX LA English DT Article ID PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; SELF; FMRI; BRAIN; ACTIVATION; DEPRESSION; COGNITION; BEHAVIOR; DAMAGE AB Social values are composed of social concepts (e.g., "generosity") and context-dependent moral sentiments (e.g., "pride"). The neural basis of this intricate cognitive architecture has not been investigated thus far. Here, we used functional magnetic resonance imaging while subjects imagined their own actions toward another person (self-agency) which either conformed or were counter to a social value and were associated with pride or guilt, respectively. Imagined actions of another person toward the subjects (other-agency) in accordance with or counter to a value were associated with gratitude or indignation/anger. As hypothesized, superior anterior temporal lobe (aTL) activity increased with conceptual detail in all conditions. During self-agency, activity in the anterior ventromedial prefrontal cortex correlated with pride and guilt, whereas activity in the subgenual cingulate solely correlated with guilt. In contrast, indignation/anger activated lateral orbitofrontal-insular cortices. Pride and gratitude additionally evoked mesolimbic and basal forebrain activations. Our results demonstrate that social values emerge from coactivation of stable abstract social conceptual representations in the superior aTL and context-dependent moral sentiments encoded in fronto-mesolimbic regions. This neural architecture may provide the basis of our ability to communicate about the meaning of social values across cultural contexts without limiting our flexibility to adapt their emotional interpretation. C1 [Zahn, Roland; Moll, Jorge; Paiva, Mirella; Krueger, Frank; Huey, Edward D.; Grafman, Jordan] NINDS, NIH, Cognit Neurosci Sect, Bethesda, MD 20892 USA. [Zahn, Roland] Univ Manchester, Sch Psychol Sci, Neurosci & Aphasia Res Unit, Manchester M13 9PL, Lancs, England. [Moll, Jorge] LABS DOr Hosp Network, Cognit & Behav Neurosci Unit, BR-22280080 Rio De Janeiro, Brazil. [Garrido, Griselda] Inst Israelita Ensino & Pesquisa Albert Einstein, BR-05651901 Sao Paulo, Brazil. RP Grafman, J (reprint author), NINDS, NIH, Cognit Neurosci Sect, 10 Ctr Dr,Room 7D43, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov RI Zahn, Roland/C-4665-2008; Moll, Jorge/B-2654-2013; Neurociencia, Inct/I-1011-2013; OI Zahn, Roland/0000-0002-8447-1453; Grafman, Jordan H./0000-0001-8645-4457 FU National Institute of Neurological Disorders and Stroke; Federal Ministry of Education and Research [BMBF-LPD 9901/8-122]; Brazilian Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [03/11794-6]; LABS-D'Or Hospital Network, Rio de Janeiro, Brazil FX National Institute of Neurological Disorders and Stroke intramural funding to J.G.; German Academy of Natural Scientists Leopoldina Fellowship funded by the Federal Ministry of Education and Research (BMBF-LPD 9901/8-122) to R. Z; Brazilian Fundacao de Amparo a Pesquisa do Estado de Sao Paulo grant (03/11794-6) supported G. G; LABS-D'Or Hospital Network, Rio de Janeiro, Brazil, supported J. M. NR 49 TC 124 Z9 128 U1 6 U2 40 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD FEB PY 2009 VL 19 IS 2 BP 276 EP 283 DI 10.1093/cercor/bhn080 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 395IW UT WOS:000262518800003 PM 18502730 ER PT J AU Tao, XC Dai, CY Cao, XJ Cai, LS Pike, VW AF Tao Xiaochun Dai Chunya Cao Xiongjie Cai Lisheng Pike, Victor W. TI Palladium-catalyzed Substitution of Ketone or Aldehyde Bearing Aryl Triflates by Amines or Amides SO CHINESE JOURNAL OF CHEMISTRY LA English DT Article DE aryl triflate; substitution; amine; amide; palladium; phosphine ligand ID HYDROGENSULFIT BUCHERER-REAKTION; NUCLEOPHILIC AROMATIC-SUBSTITUTION; VISCOSITY-SENSITIVE FLUOROPHORE; NUCLEAR MAGNETIC RESONANCE; AMINATION; HALIDES; LIGANDS; COPPER; DERIVATIVES; INHIBITORS AB Various aryl triflates, bearing ketone or aldehyde groups, were evaluated for palladium-mediated introduction of an amino group at the triflate position in the presence of various phosphine ligands. BINAP was best for secondary amines, MOP-type ligand for primary or small secondary amines and Xantphos for primary or cyclic secondary amides. No ligand was found effective for acyclic secondary amides. C1 [Tao Xiaochun; Dai Chunya; Cao Xiongjie] E China Univ Sci & Technol, Lab Organometall Chem, Shanghai 200237, Peoples R China. [Cai Lisheng; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Tao, XC (reprint author), E China Univ Sci & Technol, Lab Organometall Chem, Shanghai 200237, Peoples R China. EM xctao@ecust.edu.cn NR 50 TC 1 Z9 1 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1001-604X J9 CHINESE J CHEM JI Chin. J. Chem. PD FEB PY 2009 VL 27 IS 2 BP 403 EP 407 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 434NL UT WOS:000265281300031 ER PT J AU Nazarian, S Bluemke, DA Halperin, HR AF Nazarian, Saman Bluemke, David A. Halperin, Henry R. TI Applications of Cardiac Magnetic Resonance in Electrophysiology SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE ablation; cardiomyopathy; electrophysiology; magnetic resonance imaging ID RIGHT-VENTRICULAR DYSPLASIA; IMPLANTABLE-CARDIOVERTER-DEFIBRILLATORS; DELAYED CONTRAST ENHANCEMENT; ACUTE MYOCARDIAL-INFARCTION; CONGENITAL HEART-DISEASE; CORONARY-ARTERY-DISEASE; HYPERTROPHIC CARDIOMYOPATHY; SUDDEN-DEATH; DILATED CARDIOMYOPATHY; ATRIAL-FIBRILLATION C1 [Nazarian, Saman; Halperin, Henry R.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol Cardiac Arrhythmia, Baltimore, MD 21205 USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Nazarian, S (reprint author), Johns Hopkins Univ Hosp, Carnegie 592C,600 N Wolfe St, Baltimore, MD 21287 USA. EM snazarian@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA CL090019-02, ZIA EB000072-02] NR 100 TC 9 Z9 9 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD FEB PY 2009 VL 2 IS 1 BP 63 EP 71 DI 10.1161/CIRCEP.108.811562 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 446NC UT WOS:000266127300011 PM 19808444 ER PT J AU Magnani, JW Williamson, MA Ellinor, PT Monahan, KM Benjamin, EJ AF Magnani, Jared W. Williamson, Mary Ann Ellinor, Patrick T. Monahan, Kevin M. Benjamin, Emelia J. TI P Wave Indices Current Status and Future Directions in Epidemiology, Clinical, and Research Applications SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE P-wave indices; epidemiology; PR interval; electrocardiography; atrial fibrillation ID PAROXYSMAL ATRIAL-FIBRILLATION; RADIOFREQUENCY CATHETER ABLATION; GENERAL-HOSPITAL POPULATION; SIGNAL-AVERAGED ECG; YOUNG HEALTHY-MEN; INTERATRIAL BLOCK; SINUS RHYTHM; HYPERTENSIVE PATIENTS; CARDIAC-SURGERY; OBESE SUBJECTS C1 [Magnani, Jared W.; Monahan, Kevin M.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Framingham, MA 01702 USA. [Williamson, Mary Ann] Boston Univ, Sch Med, Div Med, Framingham, MA 01702 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Div Prevent Med, Framingham, MA 01702 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Framingham, MA 01702 USA. [Benjamin, Emelia J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Benjamin, Emelia J.] Natl Heart Lung & Blood Inst Framingham Study, Framingham, MA USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med & Publ Hlth, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM emelia@bu.edu OI Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [R01 HL092577-01A1, HL076784, L30 HL097675, L30 HL097675-01, N01 HC025195, N01-HC-25195, N01HC25195, R01 HL076784, R01 HL076784-01, R01 HL076784-02, R01 HL076784-03, R01 HL076784-04, R01 HL076784-05, R01 HL092577, R01 HL104156]; NIA NIH HHS [AG028321, R01 AG028321, R01 AG028321-01, R01 AG028321-02, R01 AG028321-03]; NINDS NIH HHS [6R01-NS 17950, R01 NS017950, R01 NS017950-23, R01 NS017950-24, R01 NS017950-25, R01 NS017950-26, R01 NS017950-27, R01 NS017950-28] NR 68 TC 47 Z9 48 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD FEB PY 2009 VL 2 IS 1 BP 72 EP 79 DI 10.1161/CIRCEP.108.806828 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 446NC UT WOS:000266127300012 PM 19808445 ER PT J AU Tayo, BO Luke, A Zhu, XF Adeyemo, A Cooper, RS AF Tayo, Bamidele O. Luke, Amy Zhu, Xiaofeng Adeyemo, Adebowale Cooper, Richard S. TI Association of Regions on Chromosomes 6 and 7 With Blood Pressure in Nigerian Families SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE blood pressure; genes; mapping; association ID GENOME-WIDE ASSOCIATION; GENE-ENVIRONMENT INTERACTIONS; BODY-MASS INDEX; ESSENTIAL-HYPERTENSION; QUANTITATIVE TRAITS; PEDIGREE ANALYSIS; COMMON VARIANT; FTO GENE; LOCI; LINKAGE AB Background-Elevated blood pressure (BP) shares a level of heritability similar to many other traits related to cardiovascular risk; however, specific susceptibility loci have been difficult to localize. We conducted a multistage study of BP as a continuous trait in a low-risk West African population in which it was anticipated that environmental exposures would be reduced in complexity and intensity. In our earlier genome-wide linkage study for BP in this population, strong linkage evidence was noted on chromosomes 6 and 7. Methods and Results-We subsequently genotyped a total of 3431 tag single-nucleotide polymorphisms (SNPs) in 3 regions (viz, 152.68 to 165.99 Mb on chromosome 6, 0.29 to 20.67 Mb, and 104.09 to 123.06 Mb on chromosome 7) in 713 individuals from 199 families. We conducted a family-based association analysis using individual SNPs and associated haplotypes. After correction for multiple comparisons, 6 intronic and 1 intergenic SNPs achieved nominal statistical significance (P < 0.05) for the association with BP. The associated intronic SNPs include 2 in the PARK2 gene on chromosome 6; 2 in the KCND2 gene, and 1 each in the C7orf58 and HDAC9 genes on chromosome 7. The intergenic SNP is located between the RPA3 and GLCCI1 genes on chromosome 7. The haplotypes on which these SNPs resided were more strongly associated with BP than their respective single SNPs. The frequency of the "at-risk" haplotypes ranged from 14% to 48%. Conclusions-These data provide preliminary evidence that regions on chromosomes 6 and 7 may influence susceptibility to elevations in BP. (Circ Cardiovasc Genet. 2009;2:38-45.) C1 [Tayo, Bamidele O.; Luke, Amy; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Epidemiol & Prevent Med, Maywood, IL USA. [Zhu, Xiaofeng] Case Western Reserve Univ, Dept Biostat & Epidemiol, Cleveland, OH 44106 USA. [Adeyemo, Adebowale] NHGRI, NIH, Intramural Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Tayo, BO (reprint author), Loyola Med Sch, Dept Epidemiol & Prevent Med, 2160 S 1st Ave, Maywood, IL 60153 USA. EM btayo@lumc.edu OI Adeyemo, Adebowale/0000-0002-3105-3231 FU National Heart, Lung, and Blood Institute [HL045508, HL053353, HL074166]; National Human Genome Research Institute [HG003054]; Intramural Research Program of the National Human Genome Research Institute FX This work was supported by the National Heart, Lung, and Blood Institute (NIH grants HL045508, HL053353, and HL074166), by the National Human Genome Research Institute (NIH grant HG003054), and in part by the Intramural Research Program of the National Human Genome Research Institute. NR 51 TC 9 Z9 9 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2009 VL 2 IS 1 BP 38 EP 45 DI 10.1161/CIRCGENETICS.108.817064 PG 8 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 574AF UT WOS:000275960100007 PM 20031566 ER PT J AU Psaty, BM O'Donnell, CJ Gudnason, V Lunetta, KL Folsom, AR Rotter, JI Uitterlinden, AG Harris, TB Witteman, JCM Boerwinkle, E AF Psaty, Bruce M. O'Donnell, Christopher J. Gudnason, Vilmundur Lunetta, Kathryn L. Folsom, Aaron R. Rotter, Jerome I. Uitterlinden, Andre G. Harris, Tamara B. Witteman, Jacqueline C. M. Boerwinkle, Eric CA CHARGE Consortium TI Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE epidemiology; meta-analysis; genetics; genomics ID OBJECTIVES; TRAITS AB Background-The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods-The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci. Conclusions-The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events. (Circ Cardiovasc Genet. 2009;2:73-80.) C1 [Psaty, Bruce M.] Univ Wash, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Wash, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Wash, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Univ Iceland, Iceland Heart Assoc, Reykjavik, Iceland. Univ Iceland, Dept Cardiovasc Genet, Reykjavik, Iceland. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD USA. [Boerwinkle, Eric] Univ Texas Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Houston, Div Epidemiol, Houston, TX USA. RP Psaty, BM (reprint author), Univ Wash, Cardiovasc Hlth Res Unit, Dept Med, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA. EM psaty@u.washington.edu RI Gudnason, Vilmundur/K-6885-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Lunetta, Kathryn/0000-0002-9268-810X FU NIH [N01-AG-12100]; NIA Intramural Re-search Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, U01 HL080295, R01 HL087652]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; NIH Roadmap for Medical Research. Cardiovascular Health Study [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133]; National Institute of Neurological Disorders and Stroke; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; National Institute of Neurological Disorders and Stroke [NS17950]; National Institute of Aging [AG08122, AG16495]; Netherlands Organization of Scientific Research NWO [nr.175.010.2005.011]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam FX Age, Gene/Environment Susceptibility-Reykjavik Study has been funded by NIH contract N01-AG-12100, the NIA Intramural Re-search Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).; The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, and R01HL087641; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study: The research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. Framingham Heart Study: From the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278), and by grants from the National Institute of Neurological Disorders and Stroke (NS17950; PAW) and the National Institute of Aging, (AG08122, AG16495; PAW). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. Rotterdam Study: The GWA database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (nr.175.010.2005.011). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. NR 25 TC 245 Z9 246 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2009 VL 2 IS 1 BP 73 EP U128 DI 10.1161/CIRCGENETICS.108.829747 PG 11 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 574AF UT WOS:000275960100011 PM 20031568 ER PT J AU Alderson, RF Kreitman, RJ Chen, TL Yeung, P Herbst, R Fox, JA Pastan, I AF Alderson, Ralph F. Kreitman, Robert J. Chen, Tianling Yeung, Peter Herbst, Ronald Fox, Judy A. Pastan, Ira TI CAT-8015: A Second-Generation Pseudomonas Exotoxin A-Based Immunotherapy Targeting CD22-Expressing Hematologic Malignancies SO CLINICAL CANCER RESEARCH LA English DT Article ID NON-HODGKINS-LYMPHOMA; HUMANIZED ANTI-CD22 ANTIBODY; B-CELL LYMPHOMA; RECOMBINANT IMMUNOTOXIN; MONOCLONAL-ANTIBODIES; CYTOTOXIC ACTIVITY; TRIAL; EPRATUZUMAB; CANCER; CD22 AB Purpose: To compare the in vitro and in vivo efficacy of CAT-8015, a second-generation recombinant immunotoxin composed of disulfide-linked affinity matured V(H) and V(L) chains of the mouse anti-CD22 monoclonal antibody RFB4 fused to PE38, to the parental compound CAT-3888. Experimental Design: The biological activity of CAT-8015 was examined in vitro using B-cell tumor lines and in vivo in a JD38-based s.c. tumor model in NCr athymic mice. Pharmacokinetics and interspecies scaling of CAT-8015 were evaluated in mice, rats, and cynomolgus monkeys. The potential toxicity of CAT-8015 was assessed in monkeys in a toxicologic study and compared with CAT-3888. Results:The IC(50) values of CAT-8015 in vitro using the EHEB, MEC1, Daudi, CA46, and JD38 cell lines ranged from 0.3 to 8.6 ng/mL. Pharmacokinetic studies with CAT-8015 were conducted in mouse, rat, and cynomolgus monkey. The t(1/2) was calculated to be 0.42, 0.61, and 0.79 hours and the Vss was 1.37, 5.57, and 140.3 mL in mouse, rat, and monkey, respectively. In vivo, when JD38 tumor-bearing animals were treated with CAT-8015 at doses >= 75 mu g/kg at 48-hour intervals for a total of three doses, a rapid reduction in tumor volume and in some cases complete remission in tumor growth was observed. The comparative toxicologic study showed comparable clinical and anatomic pathology changes for CAT-8015 and CAT-3888. Conclusions: CAT-8015 is a CD22-targeting immunotoxin that, in preclinical studies, has greatly improved efficacy compared with CAT-3888. C1 [Herbst, Ronald] MedImmune Inc, Gaithersburg, MD 20878 USA. [Alderson, Ralph F.] Cambridge Antibody Technol Inc, Palo Alto, CA USA. [Chen, Tianling; Yeung, Peter; Fox, Judy A.] Genencor Int Inc, Palo Alto, CA USA. [Kreitman, Robert J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Herbst, R (reprint author), MedImmune Inc, 1 MedImmuneWay, Gaithersburg, MD 20878 USA. EM herbstR@MedImmune.com FU Intramural NIH HHS [Z01 BC008753-25] NR 23 TC 39 Z9 39 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2009 VL 15 IS 3 BP 832 EP 839 DI 10.1158/1078-0432.CCR-08-1456 PG 8 WC Oncology SC Oncology GA 405HK UT WOS:000263213600012 PM 19188153 ER PT J AU Miyashita, K Kawakami, K Nakada, M Mai, W Shakoori, A Fujisawa, H Hayashi, Y Hamada, JI Minamoto, T AF Miyashita, Katsuyoshi Kawakami, Kazuyuki Nakada, Mitsutoshi Mai, Wei Shakoori, Abbas Fujisawa, Hironori Hayashi, Yutaka Hamada, Jun-ichiro Minamoto, Toshinari TI Potential Therapeutic Effect of Glycogen Synthase Kinase 3 beta Inhibition against Human Glioblastoma SO CLINICAL CANCER RESEARCH LA English DT Article ID FACTOR-KAPPA-B; CANCER-CELLS; COLORECTAL-CANCER; MALIGNANT GLIOMAS; COLON-CANCER; KINASE-3-BETA; APOPTOSIS; EXPRESSION; SURVIVAL; P53 AB Purpose: Glioblastoma represents the malignant brain tumor that is most refractory to treatment and in which the identification of molecular target(s) is urgently required. We investigated the expression, activity, and putative pathologic role of glycogen synthase kinase 3 beta (GSK3 beta), an emerging therapeutic target for neurodegenerative diseases, in human glioblastoma. Experimental Design: The active fraction of GSK3 beta that is phosphorylated at the tyrosine 216 residue (pGSK3 beta(Y216)) was identified in glioblastoma cell lines. GSK3 beta activity for phosphorylating its substrate was detected in these cells by nonradioisotopic in vitro kinase assay. Results: Higher expression levels of GSK3 beta and pGSK3 beta(Y216) were frequently detected in glioblastomas compared with nonneoplastic brain tissues. Inhibition of GSK3 beta activity by escalating doses of a small-molecule inhibitor (AR-A014418) or inhibition of its expression by RNA interference induced the apoptosis and attenuated the survival and proliferation of glioblastoma cells in vitro. Inhibition of GSK3 beta was associated with increased expression of p53 and p21 in glioblastoma cells with wild-type p53 and with decreased Rb phosphorylation and expression of cyclin-dependent kinase 6 in all glioblastoma cell lines. Administration of AR-A014418 at a low dose significantly sensitized glioblastoma cells to temozolomide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, chemotherapeutic agents used in the clinical setting, as well as to ionizing radiation. Conclusion: These results indicate that GSK3 beta exerts a pathologic role by promoting the survival and proliferation of glioblastoma cells and by protecting them from apoptosis via the inactivation of p53- and/or Rb-mediated pathways. Consequently, we propose that GSK3 beta provides a potential therapeutic target in glioblastoma. C1 [Minamoto, Toshinari] Kanazawa Univ, Canc Res Inst, Div Translat & Clin Oncol, Mol & Cellular Targeting Translat Oncol Ctr, Kanazawa, Ishikawa 9200934, Japan. [Miyashita, Katsuyoshi; Nakada, Mitsutoshi; Fujisawa, Hironori; Hayashi, Yutaka; Hamada, Jun-ichiro] Kanazawa Univ, Dept Neurosurg, Grad Sch Med Sci, Kanazawa, Ishikawa 9200934, Japan. [Shakoori, Abbas] NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Fujisawa, Hironori] Fukui Prefectural Hosp, Dept Neurosurg, Fukui, Japan. RP Minamoto, T (reprint author), Kanazawa Univ, Canc Res Inst, Div Translat & Clin Oncol, Mol & Cellular Targeting Translat Oncol Ctr, 13-1 Takara Machi, Kanazawa, Ishikawa 9200934, Japan. EM minamoto@staff.kanazawa-u.ac.jp FU Japanese Ministry of Education, Science, Sports, Technology and Culture; Ministry of Health, Labour and welfare; Japan Society for the Promotion of Science FX Grants-in-Aids for Scientific Research from the Japanese Ministry of Education, Science, Sports, Technology and Culture (T. Minamoto, K. Kawakami, and W. Mai); from the Ministry of Health, Labour and welfare (T Minamoto); and from the Japan Society for the Promotion of Science (T Minamoto). NR 50 TC 43 Z9 43 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2009 VL 15 IS 3 BP 887 EP 897 DI 10.1158/1078-0432.CCR-08-0760 PG 11 WC Oncology SC Oncology GA 405HK UT WOS:000263213600018 PM 19188159 ER PT J AU Tabe, Y Sebasigari, D Jin, L Rudelius, M Davies-Hill, T Miyake, K Miida, T Pittaluga, S Raffeld, M AF Tabe, Yoko Sebasigari, Denise Jin, Linhua Rudelius, Martina Davies-Hill, Theresa Miyake, Kazunori Miida, Takashi Pittaluga, Stefania Raffeld, Mark TI MDM2 Antagonist Nutlin-3 Displays Antiproliferative and Proapoptotic Activity in Mantle Cell Lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMAS; P53 ACTIVATION; DNA-DAMAGE; IN-VITRO; P53-DEPENDENT APOPTOSIS; AGGRESSIVE VARIANTS; CDK INHIBITORS; POOR-PROGNOSIS AB Purpose: Mantle cell lymphoma (MCL) has one of the poorest prognoses of the non-Hodgkin's lymphomas, and novel therapeutic approaches are needed. We wished to determine whether Nutlin-3, a novel small-molecule murine double minute 2 (MDM2) antagonist that efficiently activates TP53, might be effective in inducing cell death in MCL. Experimental Design: MCL cell lines with known TP53 status were treated with Nutlin-3, and biological and biochemical consequences were studied. Synergies with the prototypic genotoxic agent doxorubicin and the novel proteasome inhibitor bortezomib were assessed. Results: Nutlin-3 resulted in a reduction in cell proliferation/viability (IC(50) < 10 mu mol/L), an increase in the apoptotic fraction, and cell cycle arrest in wild-type (wt) TP53 Z-138 and Granta 519 cells. These effects were accompanied by TP53 accumulation and induction of TP53-dependent proteins p21, MDM2, Puma, and Noxa, Cell cycle arrest was characterized by suppression of S phase and an increase in the G(0)-G(1) and G(2)-M fractions and accompanied by suppression of total and phosphorylated retinoblastoma protein and a decrease in G(2)-M-associated proteins cyclin B and CDC2. The combination of Nutlin-3 with doxorubicin or bortezomib was synergistic in wt-TP53 MCL cells. Nutlin-3 also induced cell cycle arrest and reduced cell viability in the mutant TP53 MINO cells but at a significantly higher IC(50) (22,5 mu mol/L). These effects were associated with induction of theTP53 homologue p73, slight increases ill p21 and Noxa, and caspase activation. Nutlin-3 and bortezomib synergistically inhibited cell growth of MINO. Conclusion: These findings suggest that the MDM2 antagonist Nutlin-3 may be an effective agent in the treatment of MCL with or without wt-TP53. C1 [Tabe, Yoko; Sebasigari, Denise; Rudelius, Martina; Davies-Hill, Theresa; Pittaluga, Stefania; Raffeld, Mark] NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Tabe, Yoko; Jin, Linhua; Miyake, Kazunori; Miida, Takashi] Juntendo Univ, Sch Med, Dept Clin Pathol, Bunkyo Ku, Tokyo 113, Japan. RP Raffeld, M (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mraff@box.m.nih.gov RI Miida, Takashi/A-5589-2012 OI Miida, Takashi/0000-0002-4294-8030 NR 61 TC 55 Z9 57 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2009 VL 15 IS 3 BP 933 EP 942 DI 10.1158/1078-0432.CCR-08-0399 PG 10 WC Oncology SC Oncology GA 405HK UT WOS:000263213600023 PM 19188164 ER PT J AU Abdoler, E Wendler, D AF Abdoler, Emily Wendler, David TI Ethical Responsibility of Phase 0 Trials Reply SO CLINICAL CANCER RESEARCH LA English DT Letter ID DRUG DEVELOPMENT C1 [Abdoler, Emily; Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Abdoler, E (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 3 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 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2009 VL 15 IS 3 BP 1121 EP 1122 DI 10.1158/1078-0432.CCR-08-2394 PG 2 WC Oncology SC Oncology GA 405HK UT WOS:000263213600048 ER PT J AU Guan, HJ Wang, PH Hui, RT Edin, ML Zeldin, DC Wang, DW AF Guan, Hongjing Wang, Peihua Hui, Rutai Edin, Matthew L. Zeldin, Darryl C. Wang, Dao Wen TI Adeno-Associated Virus-Mediated Human C-Reactive Protein Gene Delivery Causes Endothelial Dysfunction and Hypertension in Rats SO CLINICAL CHEMISTRY LA English DT Article ID NITRIC-OXIDE SYNTHASE; BLOOD-PRESSURE; RECEPTOR; MICE; INFLAMMATION; DISEASE; ATHEROSCLEROSIS; PROGRESSION; INHIBITION; ANTAGONISM AB BACKGROUND: Prospective studies have shown that C-reactive protein (CRP) is a predictor of hypertension. Because of confounding variables, a causal linkage between CRP and hypertension has not been clearly shown. We investigated whether high circulating concentrations of human CRP can induce hypertension in rats. METHODS: We administered a single intravenous injection of adeno-associated virus-green fluorescent protein (AAV-GFP) or AAV-hCRP and measured blood pressure. Using ELISA, we measured serum hCRP, serum endothelium I (ET-1), and urine cGMP, and we measured serum nitric oxide (NO) using the Griess method. We recorded heart rate, maximum pressure arterial elastance, mean aortic pressure, cardiac output: and maximum rate of rise in left ventricular pressure (dP/dt max). RESULTS: A single injection of AAV-hCRP resulted in efficient and sustained hCRP expression and led to increased blood pressure 2 months after gene transfer that persisted for another 2 months. This effect was associated with decreased NO production, as demonstrated by decreased serum NO concentration and urinary cGMP excretion, and impairment of endothelial-dependent vascular relaxation. CRP transduction also increased expression of angiotensin type I receptor, ET-1, and endothelin type A receptor, decreased expression of angiotensin type 2 receptor and endothelial NO synthase in thoracic aortas, and increased arterial stiffness. Ex vivo studies indicated a similar detrimental effect of CRP that was reversed by the NO donor. CONCLUSION: A-AV vector-mediated CRP expression resulted in hypertension mediated through reduced NO production and subsequent alteration in ET-1 and renin-angiotensin system activation. Impaired arterial elasticity may also contribute to CRP-induced hypertension. These results support a causal role for CRP in the pathogenesis of hypertension. (C) 2008 American Association for Clinical Chemistry C1 [Guan, Hongjing; Wang, Peihua; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Internal Med, Tongji Hosp, Wuhan 430030, Peoples R China. [Guan, Hongjing; Wang, Peihua; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Inst Hypertens, Tongji Hosp, Wuhan 430030, Peoples R China. [Hui, Rutai] Peking Union Med Coll, Fuwai Hosp, Beijing, Peoples R China. [Hui, Rutai] Chinese Acad Med Sci, Beijing 100037, Peoples R China. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Guan, Hongjing] Wuhan Univ, Renmin Hosp, Dept Cardiol, Wuhan 430072, Peoples R China. RP Wang, PH (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Internal Med, Tongji Hosp, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn OI Edin, Matthew/0000-0002-7042-500X FU National Nature Science Foundation Committee of China [30430320, 30540087]; National "973" projects [2007CB512004]; International Collaboration project [2005DFA30880]; the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This work was supported by grants from National Nature Science Foundation Committee of China (30430320 and 30540087), National "973" projects (2007CB512004), and International Collaboration project (2005DFA30880), and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 28 TC 36 Z9 38 U1 0 U2 6 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2009 VL 55 IS 2 BP 274 EP 284 DI 10.1373/clinchem.2008.115857 PG 11 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 401ED UT WOS:000262921300011 PM 19056836 ER PT J AU Laiyemo, AO Murphy, G Sansbury, LB Wang, ZQ Albert, PS Marcus, PM Schoen, RE Cross, AJ Schatzkin, A Lanza, E AF Laiyemo, Adeyinka O. Murphy, Gwen Sansbury, Leah B. Wang, Zhuoqiao Albert, Paul S. Marcus, Pamela M. Schoen, Robert E. Cross, Amanda J. Schatzkin, Arthur Lanza, Elaine TI Hyperplastic Polyps and the Risk of Adenoma Recurrence in the Polyp Prevention Trial SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID COLORECTAL ADENOMAS; RECTOSIGMOID POLYPS; SERRATED ADENOMAS; NATIONAL-SURVEY; PROXIMAL COLON; FOLLOW-UP; COLONOSCOPY; POLYPECTOMY; NEOPLASIA; CANCER AB Background and Aims: Recent studies have suggested that some hyperplastic polyps may be associated with an increased risk of colorectal cancer. Prospective information on the risk of adenoma. recurrence associated with hyperplastic polyps is limited. We sought to investigate whether the coexistence of hyperplastic polyps with adenomas increases the risk of adenoma recurrence. Methods: We used unconditional logistic regression models to examine the association between baseline hyperplastic polyps and subsequent adenoma recurrence during a 3-year follow-up evaluation, among 1637 participants in the Polyp Prevention Trial. Results: A total of 437 participants (26.7%) had hyperplastic polyps coexisting with adenomas at baseline. Of these, 132 (30.2%) had at least one hyperplastic polyp in the proximal colon, whereas 305 (69.8%) had only distal hyperplastic polyps. When compared with subjects without any hyperplastic polyps at baseline, there was no statistically significant association between the presence of baseline hyperplastic polyps and recurrence of any adenoma (odds ratio [OR], 1.19; 95% confidence interval [0], 0.94-1.51) or advanced adenoma (OR, 1.25; 95% CI, 0.78-2.03). Also, there was no association between hyperplastic polyp location and adenoma recurrence (OR, 1.01; 95% CI, 0.69-1.48) for any proximal hyperplastic polyp (OR, 1.26; 95% CI, 0.96-1.65) and for distal hyperplastic polyps. Conclusions: The coexistence of hyperplastic polyps with adenomas, irrespective of location, does not confer an increased risk of adenoma recurrence beyond that of adenomas alone within 3 years of follow-up evaluation. Prospective long-term studies on adenoma recurrence risk associated with hyperplastic polyps in screening populations are needed. C1 [Laiyemo, Adeyinka O.] NCI, Canc Prevent Fellowship Program, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Laiyemo, Adeyinka O.; Murphy, Gwen] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Bethesda, MD 20892 USA. [Murphy, Gwen] NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. [Cross, Amanda J.; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sansbury, Leah B.] NCI, Modifiable Risk Factors Branch, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Albert, Paul S.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Lanza, Elaine] NCI, Lab Canc Prevent, Ctr Canc Res, Bethesda, MD 20892 USA. [Wang, Zhuoqiao] Informat Management Serv Inc, Rockville, MD USA. [Schoen, Robert E.] Univ Pittsburgh, Pittsburgh, PA USA. RP Laiyemo, AO (reprint author), NCI, Canc Prevent Fellowship Program, Biometry Res Grp, Canc Prevent Div, 6130 Execut Blvd,Suite 3121, Bethesda, MD 20892 USA. EM lalyemoa@mall.nih.gov RI Murphy, Gwen/G-7443-2015 FU Intramural Research Program of the Center for Cancer Research; Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Division of Cancer Prevention FX The study was funded by the Intramural Research Program of the Center for Cancer Research and Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; and the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The funding agency had a role In the design and reporting of the study, In the decision to submit the manuscript for publication, and approved the final version of the manuscript. NR 31 TC 20 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD FEB PY 2009 VL 7 IS 2 BP 192 EP 197 DI 10.1016/j.cgh.2008.08.031 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 410QE UT WOS:000263592100014 PM 18849014 ER PT J AU Martinez-Gamboa, L Mei, H Loddenkemper, C Ballmer, B Hansen, A Lipsky, PE Emmerich, F Radbruch, A Salama, A Dorner, T AF Martinez-Gamboa, Lorena Mei, Henrik Loddenkemper, Christoph Ballmer, Boris Hansen, Arne Lipsky, Peter E. Emmerich, Florian Radbruch, Andreas Salama, Abdulgabar Doerner, Thomas TI Role of the spleen in peripheral memory B-cell homeostasis in patients with autoimmune thrombocytopenia purpura SO CLINICAL IMMUNOLOGY LA English DT Article DE Autoimmune thrombocytopenia; B cells; Splenectomy; Immunological memory ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; COMMON VARIABLE IMMUNODEFICIENCY; HIV-1 INFECTION; PLATELET DESTRUCTION; SJOGRENS-SYNDROME; FAS LIGAND; DISEASE; RITUXIMAB; SUBSETS; ADULTS AB The effect of splenectomy on circulating memory B cells in autoimmune thrombocytopenia purpura (AITP) patients has not yet been addressed. We therefore analyzed the distribution and phenotypic characteristics of B-cell. subsets in non-splenectomized and splenectomized AITP patients and controls, as well as CD95 expression after B cell. activation. Decreased frequencies of memory B cells in splenectomized individuals were observed, with a rapid decline of CD27+IgD+ and a slower decrease of CD27+IgD- and CD27-/IgD- cells. Similar results were noted following splenectomy in healthy donors (HD). CD95+ B cells were substantially increased in all subsets in patients with active AITP, indicating their enhanced activation status. After splenectomy, the percentage of CD95+ B cells were further increased in the CD27+IgD- post-switch memory population in AITP, but not in HD. CD95+CD27+ memory B cells largely reside in the region in the human spleen analogous to the murine marginal zone. Thus, the spleen plays a fundamental role in controlling peripheral memory B cell homeostasis in both AITP and HD and regulates activated CD95+ B cells in patients with AITP. (C) 2008 Elsevier Inc. All rights reserved. C1 [Martinez-Gamboa, Lorena; Mei, Henrik; Ballmer, Boris; Emmerich, Florian; Salama, Abdulgabar; Doerner, Thomas] Charite Univ Med Berlin, Inst Transfus Med & Immune Hematol, Charite Ctr Tumor Med 14, Berlin, Germany. [Loddenkemper, Christoph] Charite Univ Med Berlin, Inst Pathol, Charite Ctr 5, Berlin, Germany. [Hansen, Arne] Charite Univ Med Berlin, Charite Ctr Internal Med 12, Berlin, Germany. [Lipsky, Peter E.] NIAMS, NIH, Bethesda, MD USA. [Radbruch, Andreas; Doerner, Thomas] German Ctr Rheumat Res DRFZ, Berlin, Germany. RP Dorner, T (reprint author), Charite Univ Med Berlin, Inst Transfus Med & Immune Hematol, Charite Ctr Tumor Med 14, Berlin, Germany. EM thomas.doerner@charite.de FU DFG [Do491/7-1, Do491/5-5]; [SFB650/TP16]; [SFB421/B13]; [Z3] FX This work was supported by SFB650/TP16, SFB421/B13 and Z3 as well as DFG projects Do491/7-1 and Do491/5-5. NR 41 TC 34 Z9 35 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD FEB PY 2009 VL 130 IS 2 BP 199 EP 212 DI 10.1016/j.clim.2008.09.009 PG 14 WC Immunology SC Immunology GA 400QG UT WOS:000262882800009 PM 18977183 ER PT J AU Mekmullica, J Brouwers, P Charurat, M Paul, M Shearer, W Mendez, H Diaz, C Read, JS Mondal, P Smith, R McIntosh, K AF Mekmullica, Jutarat Brouwers, Pim Charurat, Manhattan Paul, Mary Shearer, William Mendez, Hermann Diaz, Clemente Read, Jennifer S. Mondal, Prosanta Smith, Renee McIntosh, Kenneth TI Early Immunological Predictors of Neurodevelopmental Outcomes in HIV-Infected Children SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DISEASE PROGRESSION; INFANTS BORN; T-CELLS; CEREBROSPINAL-FLUID; LYMPHOCYTE SUBSETS; TYPE-1 INFECTION; CLINICAL-TRIALS; FLOW-CYTOMETRY; ENCEPHALOPATHY AB Background. A previous analysis of children infected with human immunodeficiency virus (HIV) in the Women and Infants Transmission Study showed a strong correlation between low activated CD8(+) T lymphocytes in the first 2 months of life and good immunological prognosis. We sought to extend these observations to neurodevelopmental prognosis. Methods. Ninety-eight HIV-infected children born before 1994 with flow cytometric data from the first 2 months of life and adequate neurodevelopmental testing through age 30 months were studied. Children were divided into those with low (<= 5% CD8(+) HLA-DR(+) cells or <= 25% CD8(+) CD38(+) cells) or high (>5% CD8(+) HLA-DR(+) cells or >25% CD8(+) CD38(+) cells) immune activation at 1 and/or 2 months of age. Analysis was performed using survival analysis, Cox's proportional hazard regression, and longitudinal regression models. Results. Absence of immune activation, measured as <= 5% CD8(+)HLA-DR(+) cells, was strongly associated with better performance on the psychomotor developmental index of the Bayley scales of infant development through the third year of life. This association persisted after adjustment for CD4 cell count, viral load, and progression to acquired immunodeficiency syndrome (P = .005). An association with the mental development index was also present (P = .048). Significant association between neurodevelopmental outcomes and <= 25% CD8(+)CD(38+) cells was not seen. Conclusions. In this prospective cohort study of HIV-infected children, there was a significant favorable association of low immune activation in peripheral T cells at age 1 or 2 months, measured by a low percentage of CD8(+)HLA-DR(+) cells, with subsequent psychomotor and mental development. This association was independent of other indices of severity and progression of HIV infection. C1 [Mekmullica, Jutarat; McIntosh, Kenneth] Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Brouwers, Pim; Paul, Mary; Shearer, William] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Brouwers, Pim] NIMH, Ctr Mental Hlth Res AIDS, NIH, Rockville, MD 20857 USA. [Charurat, Manhattan; Mondal, Prosanta] Univ Maryland, Inst Human Virol, Div Epidemiol & Prevent, Baltimore, MD 21201 USA. [Read, Jennifer S.] NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. [Mendez, Hermann] SUNY Downstate, Dept Pediat, Brooklyn, NY USA. [Diaz, Clemente] Univ Puerto Rico, Dept Pediat, San Juan, PR 00936 USA. [Smith, Renee] Univ Illinois, Dept Pediat, Chicago, IL USA. [Mekmullica, Jutarat] Bhumibol Adulyadej Hosp, Dept Pediat, Bangkok, Thailand. RP McIntosh, K (reprint author), Childrens Hosp, Div Infect Dis, 300 Longwood Ave, Boston, MA 02115 USA. EM Kenneth.mcintosh@childrens.harvard.edu FU National Institutes of Health [NIH]; General Clinical Research Center [GCRC] [RR02174]; Baylor College of Medicine [RR00188]; Columbia University [RR00645]; [U01 AI 34858]; [9U01 DA 15054]; [U01 DA 15053]; [HD-3-6117]; [U01 AI 34841]; [U01 HD 41983]; [N01 AI 085339]; [U01 AI 50274-01] FX Funding for the Women and Infants Transmission Study includes grants U01 AI 34858 (to University of Puerto Rico), 9U01 DA 15054 (to Boston/Worcester site), U01 DA 15053 (to Columbia Presbyterian Hospital), HD-3-6117 (to State University of New York at Downstate), U01 AI 34841 (to University of Illinois at Chicago), U01 HD 41983 (to Baylor College of Medicine), N01 AI 085339 (to Clinical Trials and Surveys Corporation), and U01 AI 50274-01 (to study coordinator Delmyra Turpin). Additional support was provided by local clinical research centers: Children's Hospital Boston (National Institutes of Health [NIH] General Clinical Research Center [GCRC] RR02174), Baylor College of Medicine (NIH GCRC RR00188), and Columbia University (NIH GCRC RR00645). NR 39 TC 18 Z9 21 U1 1 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 1 PY 2009 VL 48 IS 3 BP 338 EP 346 DI 10.1086/595885 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 392GM UT WOS:000262291200011 PM 19115969 ER PT J AU Hurst, FP Neff, RT Falta, EM Jindal, RM Lentine, KL Swanson, JS Agodoa, LY Abbott, KC AF Hurst, Frank P. Neff, Robert T. Falta, Edward M. Jindal, Rahul M. Lentine, Krista L. Swanson, John S. Agodoa, Lawrence Y. Abbott, Kevin C. TI Incidence, Predictors, and Associated Outcomes of Prostatism after Kidney Transplantation SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE URINARY RETENTION; RENAL-TRANSPLANTATION; UNITED-STATES; UROLOGICAL COMPLICATIONS; CLINICAL PROGRESSION; NATURAL-HISTORY; HYPERPLASIA; DISEASE; RISK; FINASTERIDE AB Background and objectives: Renal transplantation is increasingly performed in elderly patients, and the incidence of benign prostatic hyperplasia (BPH) increases with age. Anuric males on dialysis may have occult BPH and not develop obstructive symptoms until urine flow is restored after transplantation. If left untreated, BPH poses a risk for numerous complications, including acute urinary retention (AUR), recurrent urinary tract infections (UTI), and renal failure. The authors hypothesized that incident BPH after renal transplantation would adversely affect allograft survival. Design, setting, participants, & measurements: Medicare claims for BPH, AUR, UTI, and prostate resection procedures (transurethral resection of the prostate; TURP) were assessed in a retrospective cohort of 23,622 adult male Medicare primary renal transplant recipients in the United States Renal Data System database who received transplants from 1 January 2000 to 31 July 2005 and followed through 31 December 2005. Results: The 3-yr incidence of BPH post-transplant was 9.7%. The incidences of AUR, UTI, and TURP after BPH diagnosis (up to 3 yr posttransplant) were 10.3%, 6.5%, and 7.3% respectively, and each was significantly associated with BPH. Cox regression analysis showed that recipient age per year, later year of transplant, and dialysis vintage were associated with incident BPH. Using Cox nonproportional hazards regression, BPH was significantly associated with renal allograft loss (including death). Conclusions: BPH is common in males after renal transplant and is independently associated with AUR, UTI, and graft loss. It is unknown whether treatment of BPH, either medical or surgical, attenuates these risks. C1 [Hurst, Frank P.] Walter Reed Army Med Ctr, Dept Nephrol, Serv Nephrol, Washington, DC 20307 USA. [Falta, Edward M.; Jindal, Rahul M.] Walter Reed Army Med Ctr, Organ Transplantat Serv, Washington, DC 20307 USA. [Hurst, Frank P.; Neff, Robert T.; Falta, Edward M.; Abbott, Kevin C.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Lentine, Krista L.] St Louis Univ, Sch Med, Div Nephrol, Ctr Outcomes Res, St Louis, MO USA. [Swanson, John S.] Christiana Care Hlth Network, Organ Transplantat Serv, Newark, DE USA. [Agodoa, Lawrence Y.] NIDDK, NIH, Bethesda, MD USA. RP Hurst, FP (reprint author), Walter Reed Army Med Ctr, Dept Nephrol, Serv Nephrol, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM frank.hurst@us.army.mil OI Abbott, Kevin/0000-0003-2111-7112 NR 25 TC 14 Z9 17 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD FEB PY 2009 VL 4 IS 2 BP 329 EP 336 DI 10.2215/CJN.04370808 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 407NY UT WOS:000263372800013 PM 19176793 ER PT J AU Bergsagel, PL Keats, JJ Chesi, M Kuehl, WM AF Bergsagel, P. Leif Keats, J. Jonathan Chesi, Marta Kuehl, W. Michael TI Targeting NF-kappa B Signaling in Multiple Myeloma SO CLINICAL LYMPHOMA & MYELOMA LA English DT Meeting Abstract ID CELL-GROWTH; INHIBITOR; PATHWAY C1 [Bergsagel, P. Leif; Keats, J. Jonathan; Chesi, Marta] Mayo Clin, Scottsdale, AZ USA. [Kuehl, W. Michael] NCI, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1557-9190 J9 CLIN LYMPHOMA MYELOM JI Clin. Lymphoma Myeloma PD FEB PY 2009 VL 9 BP S14 EP S16 PG 3 WC Oncology SC Oncology GA 472EE UT WOS:000268111400012 ER PT J AU Kuehl, WM Demchenko, Y Glebov, O Zingone, A Staudt, L Brents, L Weiss, B Barlogie, B Shaughnessy, J Bergsagel, PL AF Kuehl, W. M. Demchenko, Y. Glebov, O. Zingone, A. Staudt, L. Brents, L. Weiss, B. Barlogie, B. Shaughnessy, J. Bergsagel, P. L. TI Molecular Pathogenesis of MGUS and Multiple Myeloma SO CLINICAL LYMPHOMA & MYELOMA LA English DT Meeting Abstract C1 [Kuehl, W. M.; Demchenko, Y.; Glebov, O.; Zingone, A.; Staudt, L.; Brents, L.] NCI, Bethesda, MD 20892 USA. [Weiss, B.] Walter Reed Army Med Ctr, Washington, DC USA. [Barlogie, B.; Shaughnessy, J.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1557-9190 J9 CLIN LYMPHOMA MYELOM JI Clin. Lymphoma Myeloma PD FEB PY 2009 VL 9 BP S149 EP S149 PG 1 WC Oncology SC Oncology GA 473LB UT WOS:000268206500343 ER PT J AU Kuehl, WM Demchenko, Y Glebov, O Zingone, A Staudt, L Brents, L Weiss, B Barlogie, B Shaughnessy, J Bergsagel, L AF Kuehl, W. M. Demchenko, Y. Glebov, O. Zingone, A. Staudt, L. Brents, L. Weiss, B. Barlogie, B. Shaughnessy, J. Bergsagel, L. TI Molecular Pathogenesis of MGUS and Multiple Myeloma SO CLINICAL LYMPHOMA & MYELOMA LA English DT Meeting Abstract C1 [Kuehl, W. M.; Demchenko, Y.; Glebov, O.; Zingone, A.; Staudt, L.; Brents, L.] NCI, Bethesda, MD 20892 USA. [Weiss, B.] Walter Reed Army Med Ctr, Silver Spring, MD USA. [Barlogie, B.; Shaughnessy, J.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1557-9190 J9 CLIN LYMPHOMA MYELOM JI Clin. Lymphoma Myeloma PD FEB PY 2009 VL 9 BP S11 EP S11 PG 1 WC Oncology SC Oncology GA 472EE UT WOS:000268111400008 ER PT J AU Roccaro, AM Jia, X Ngo, HT Melhem, MR Sacco, A Chen, C Leleu, X Runnels, J Azab, F Azab, AK Quang, P Varticovski, L Novina, CD Rollins, BJ Anderson, KC Ghobrial, IM AF Roccaro, A. M. Jia, X. Ngo, H. T. Melhem, M. R. Sacco, A. Chen, C. Leleu, X. Runnels, J. Azab, F. Azab, A. K. Quang, P. Varticovski, L. Novina, C. D. Rollins, B. J. Anderson, K. C. Ghobrial, I. M. TI MicroRNA Expression in the Biology, Prognosis, and Therapy of Waldenstrom Macroglobulinemia SO CLINICAL LYMPHOMA & MYELOMA LA English DT Meeting Abstract C1 [Roccaro, A. M.; Jia, X.; Ngo, H. T.; Melhem, M. R.; Sacco, A.; Chen, C.; Leleu, X.; Runnels, J.; Azab, F.; Azab, A. K.; Quang, P.; Novina, C. D.; Rollins, B. J.; Anderson, K. C.; Ghobrial, I. M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Varticovski, L.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1557-9190 J9 CLIN LYMPHOMA MYELOM JI Clin. Lymphoma Myeloma PD FEB PY 2009 VL 9 BP S126 EP S126 PG 1 WC Oncology SC Oncology GA 473LB UT WOS:000268206500285 ER PT J AU Turesson, I Velez, R Kristinsson, SY Landgren, O AF Turesson, I. Velez, R. Kristinsson, S. Y. Landgren, O. TI Improved Survival in Younger Patients with Multiple Myeloma: A Population-Based Study from Malmo, Sweden SO CLINICAL LYMPHOMA & MYELOMA LA English DT Meeting Abstract C1 [Turesson, I.] Malmo Univ Hosp, Dept Med, Malmo, Sweden. [Velez, R.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Kristinsson, S. Y.] Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden. [Landgren, O.] NCI, NIH, Bethesda, MD 20892 USA. RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1557-9190 J9 CLIN LYMPHOMA MYELOM JI Clin. Lymphoma Myeloma PD FEB PY 2009 VL 9 BP S17 EP S17 PG 1 WC Oncology SC Oncology GA 473LB UT WOS:000268206500035 ER PT J AU Turesson, I Velez, R Kristinsson, S Landgren, O AF Turesson, I. Velez, R. Kristinsson, S. Landgren, O. TI Incidence of Myeloma Over 56 Years (1950-2006): A Population-Based Study from Malmo, Sweden SO CLINICAL LYMPHOMA & MYELOMA LA English DT Meeting Abstract C1 [Turesson, I.] Malmo Univ Hosp, Dept Med, Malmo, Sweden. [Velez, R.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Kristinsson, S.] Karolinska Univ Hosp Solna, Div Hematol, Dept Med, Stockholm, Sweden. [Landgren, O.] NCI, NIH, Bethesda, MD 20892 USA. RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1557-9190 J9 CLIN LYMPHOMA MYELOM JI Clin. Lymphoma Myeloma PD FEB PY 2009 VL 9 BP S14 EP S14 PG 1 WC Oncology SC Oncology GA 473LB UT WOS:000268206500029 ER PT J AU McArdle, JJ Mari, Z Pursley, RH Schulz, GM Braun, AR AF McArdle, J. J. Mari, Z. Pursley, R. H. Schulz, G. M. Braun, A. R. TI Electrophysiological evidence of functional integration between the language and motor systems in the brain: A study of the speech Bereitschaftspotential SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Bereitschaftspotential; Lexical access; ERP; Language; Motor; Speech ID POTENTIALS PRECEDING SPEECH; MOVEMENT; HANDEDNESS; EVOLUTION AB Objective: We investigated whether the Bereitschaftspotential (BP), an event related potential believed to reflect motor planning, would be modulated by language-related parameters prior to speech. We anticipated that articulatory complexity would produce effects on the BP distribution similar to those demonstrated for complex limb movements. We also hypothesized that lexical semantic operations would independently impact the BP. Methods: Eighteen participants performed 3 speech tasks designed to differentiate lexical semantic and articulatory contributions to the BP. EEG epochs were time-locked to the earliest source of speech movement per trial. Lip movements were assessed using EMG recordings. Doppler imaging was used to determine the onset of tongue movement during speech, providing a means of identification and elimination of potential artifact. Results: Compared to simple repetition, complex articulations produced an anterior shift in the maximum midline BP. Tasks requiring lexical search and selection augmented these effects and independently elicited a left lateralized asymmetry in the frontal distribution. Conclusions: The findings indicate that the BP is significantly modulated by linguistic processing, suggesting that the premotor system might play a role in lexical access. Significance: These novel findings support the notion that the motor systems may play a significant role in the formulation of language. Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology. C1 [McArdle, J. J.; Braun, A. R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD 20892 USA. [Mari, Z.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Pursley, R. H.] NIH, Ctr Informat Technol, Signal Proc & Instrumentat Sect, Bethesda, MD 20892 USA. [Schulz, G. M.] George Washington Univ, Columbian Coll Arts & Sci, Monroe Hall Govt, Washington, DC 20052 USA. RP McArdle, JJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bldg 10,Room 5C310, Bethesda, MD 20892 USA. EM mcardle@nidcd.nih.gov OI Schulz, Geralyn/0000-0003-3831-8105 FU NIDCD FX The authors thank Dr. Ou Bai for his critical and insightful review of this manuscript. This work was supported by the Intramural Program of NIDCD. NR 33 TC 15 Z9 15 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD FEB PY 2009 VL 120 IS 2 BP 275 EP 284 DI 10.1016/j.clinph.2008.10.159 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 416XZ UT WOS:000264040100008 PM 19109058 ER PT J AU Balis, FM Fox, E Widemann, BC Adamson, PC AF Balis, F. M. Fox, E. Widemann, B. C. Adamson, P. C. TI Clinical Drug Development for Childhood Cancers SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID RHABDOMYOSARCOMA; ONCOLOGY; TRIALS C1 [Balis, F. M.; Fox, E.; Widemann, B. C.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Adamson, P. C.] Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. RP Balis, FM (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM balisf@nih.gov NR 4 TC 8 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2009 VL 85 IS 2 BP 127 EP 129 DI 10.1038/clpt.2008.237 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 399RI UT WOS:000262816600007 PM 19151636 ER PT J AU Collins, JM AF Collins, J. M. TI Phase 0 Clinical Studies in Oncology SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID DRUG DEVELOPMENT; BREAST-CANCER; TRIALS AB In the design of first-in-human (FIH) studies in oncology, some changes are incremental; others are major shifts in goals and approaches. The contemporary emphasis on molecularly targeted agents has accelerated the trend toward biomarker studies, but these investigations remain as secondary findings in phase I behind the classic end points of toxicity and occasional tumor shrinkage. In contrast, evaluation of target modulation is the primary goal of phase 0 and is intended to inform decision making regarding further development of the relevant compound. C1 NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Rockville, MD USA. RP Collins, JM (reprint author), NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Rockville, MD USA. EM collinsje@mail.nih.gov NR 12 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2009 VL 85 IS 2 BP 204 EP 207 DI 10.1038/clpt.2008.246 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 399RI UT WOS:000262816600023 PM 19109589 ER PT J AU Gren, L Broski, K Childs, J Cordes, J Engelhard, D Gahagan, B Gamito, E Gardner, V Geisser, M Higgins, D Jenkins, V Lamerato, L Lappe, K Lowery, H McGuire, C Miedzinski, M Ogden, S Tenorio, S Watt, G Wohlers, B Marcus, P AF Gren, Lisa Broski, Karen Childs, Jeffery Cordes, Jill Engelhard, Deborah Gahagan, Betsy Gamito, Eduard Gardner, Vivien Geisser, Mindy Higgins, Darlene Jenkins, Victoria Lamerato, Lois Lappe, Karen Lowery, Heidi McGuire, Colleen Miedzinski, Mollie Ogden, Sheryl Tenorio, Sally Watt, Gavin Wohlers, Bonita Marcus, Pamela TI Recruitment methods employed in the prostate, lung, colorectal, and ovarian cancer screening trial SO CLINICAL TRIALS LA English DT Article ID MAILING STRATEGIES; CLINICAL-TRIAL; HEAVY SMOKERS; PREVENTION; INTERVENTION; PARTICIPANTS; EXPERIENCE; CARET AB Background The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is a US National Cancer Institute (NCI)-funded randomized controlled trial designed to evaluate whether certain screening tests reduce mortality from prostate, lung, colorectal, and ovarian cancer. To obtain adequate statistical power, it was necessary to enroll over 150,000 healthy volunteers. Recruitment began in 1993 and ended in 2001. Purpose Our goal is to evaluate the success of recruitment methods employed by the 10 PLCO screening centers. We also provide estimates of recruitment yield and cost for our most successful strategy, direct mail. Methods Each screening center selected its own methods of recruitment. Methods changed throughout the recruitment period as needed. For this manuscript, representatives from each screening center provided information on methods utilized and their success. Results In the United States between 1993 and 2001, ten screening centers enrolled 154,934 study participants. Based on participant self-report, an estimated 95% of individuals were recruited by direct mail. Overall, enrollment yield for direct mail was 1.0%. Individual center enrollment yield ranged from 0.7% to 3.8%. Cost per enrolled participant was $9.64-35.38 for direct mail, excluding personnel costs. Limitations Numeric data on recruitment processes were not kept consistently at individual screening centers. Numeric data in this manuscript are based on the experiences of 5 of the 10 centers. Conclusions Direct mail, using rosters of names and addresses from profit and not-for-profit (including government) organizations, was the most successful and most often used recruitment method. Other recruitment strategies, such as community outreach and use of mass media, can be an important adjunct to direct mail in recruiting minority populations. Clinical Trials 2009;6: 52-59. http://ctj.sagepub.com C1 [Gren, Lisa; Childs, Jeffery] Univ Utah, Salt Lake City, UT 84112 USA. [Cordes, Jill; Engelhard, Deborah; Geisser, Mindy; Watt, Gavin] Univ Minnesota, Minneapolis, MN 55455 USA. [Gahagan, Betsy] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Gamito, Eduard; Ogden, Sheryl; Tenorio, Sally] Univ Colorado, Boulder, CO 80309 USA. [Gardner, Vivien; Lowery, Heidi] Washington Univ, St Louis, MO 63130 USA. [Higgins, Darlene] Univ Alabama, Tuscaloosa, AL 35487 USA. [Lappe, Karen] Marshfield Clin Res Fdn, Marshfield, WI USA. [McGuire, Colleen] Georgetown Univ, Washington, DC 20057 USA. [Marcus, Pamela] Natl Canc Inst, Bethesda, MD 20892 USA. RP Gren, L (reprint author), Univ Utah, Salt Lake City, UT 84112 USA. EM lisa.gren@hsc.utah.edu OI Broski, Karen/0000-0003-1503-8768 FU NCI NIH HHS [N01 CN25524] NR 21 TC 19 Z9 19 U1 2 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2009 VL 6 IS 1 BP 52 EP 59 DI 10.1177/1740774508100974 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 419XH UT WOS:000264252500007 PM 19254935 ER PT J AU Pon, JJ Nahm, M Wakim, P Cushing, C Poole, L Tai, B Pieper, CF AF Pon, Jeng-Jong Nahm, Meredith Wakim, Paul Cushing, Carol Poole, Lori Tai, Betty Pieper, Carl F. TI A centralized informatics infrastructure for the National Institute on Drug Abuse Clinical Trials Network SO CLINICAL TRIALS LA English DT Article ID DATA COORDINATING CENTER; DATA-MANAGEMENT; EXPERIENCE AB Background Clinical trial networks (CTNs) were created to provide a sustaining infrastructure for the conduct of multisite clinical trials. As such, they must withstand changes in membership. Centralization of infrastructure including knowledge management, portfolio management, information management, process automation, work policies, and procedures in clinical research networks facilitates consistency and ultimately research. Purpose In 2005, the National Institute on Drug Abuse (NIDA) CTN transitioned from a distributed data management model to a centralized informatics infrastructure to support the network's trial activities and administration. We describe the centralized informatics infrastructure and discuss our challenges to inform others considering such an endeavor. Methods During the migration of a clinical trial network from a decentralized to a centralized data center model, descriptive data were captured and are presented here to assess the impact of centralization. Results We present the framework for the informatics infrastructure and evaluative metrics. The network has decreased the time from last patient-last visit to database lock from an average of 7.6 months to 2.8 months. The average database error rate decreased from 0.8% to 0.2%, with a corresponding decrease in the interquartile range from 0.04%-1.0% before centralization to 0.01-0.27% after centralization. Centralization has provided the CTN with integrated trial status reporting and the first standards-based public data share. A preliminary cost-benefit analysis showed a 50% reduction in data management cost per study participant over the life of a trial. Limitations A single clinical trial network comprising addiction researchers and community treatment programs was assessed. The findings may not be applicable to other research settings. Conclusions The identified informatics components provide the information and infrastructure needed for our clinical trial network. Post centralization data management operations are more efficient and less costly, with higher data quality. Clinical Trials 2009; 6: 67-75. http://ctj.sagepub.com C1 [Nahm, Meredith] Duke Translat Med Inst, Durham, NC 27705 USA. [Pon, Jeng-Jong] Vet Hlth Adm, Washington, DC USA. [Wakim, Paul; Cushing, Carol; Tai, Betty] Natl Inst Drug Abuse, Ctr Clin Trials Network, Bethesda, MD USA. [Poole, Lori] Duke Clin Res Inst, Durham, NC USA. [Pieper, Carl F.] Duke Univ, Med Ctr, Biostat & Bioinformat Dept, Durham, NC USA. RP Nahm, M (reprint author), Duke Translat Med Inst, 5162 Hock Plaza,2424 Erwin Rd, Durham, NC 27705 USA. EM meredith.nahm@duke.edu FU NIDA [HHSN271200522071C] FX This work was partially supported by NIDA Contract No. HHSN271200522071C. The authors wish to acknowledge those, who have contributed to the NIDA CTN, especially the principal investigators and staff at the regional research training centers and community treatment centers. Their dedication to addiction treatment, participative leadership, and open engagement has created a productive and improvement-oriented research endeavor. The authors also appreciate the comments from reviewers and the editorial assistance of Amanda McMillan, both of which contributed to the improvement of this article. NR 25 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2009 VL 6 IS 1 BP 67 EP 75 DI 10.1177/1740774508100983 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 419XH UT WOS:000264252500009 ER PT J AU Sun, DL Chen, ZJ Ma, N Zhang, XC Fu, XM Zhang, DR AF Sun, De-Lin Chen, Zu-Ji Ma, Ning Zhang, Xiao-Chu Fu, Xian-Ming Zhang, Da-Ren TI Decision-Making and Prepotent Response Inhibition Functions in Excessive Internet Users SO CNS SPECTRUMS LA English DT Article ID PREFRONTAL CORTEX; BEHAVIORAL ADDICTIONS; FUTURE CONSEQUENCES; TOURETTE-SYNDROME; SUBSTANCE; SELF; DYSFUNCTION; ACTIVATION; CINGULATE; EMOTION AB Introduction: Excessive Internet use (EIU), also described as Internet addiction or pathological Internet use, has already become a serious social problem around the world. Some researchers consider EIU as a kind of behavioral addiction. However, there are few experimental studies on the cognitive functions of excessive Internet users (ElUers) and limited data are available to compare EIU with other addictive behaviors, such as drug abuse and pathological gambling. Methods: In this study, we examined ElUers' functions of decision-making and prepotent response inhibition. Two groups of participants, ElUers and controls, were compared on these two functions by using a Gambling Task and a Go/no-go Task, respectively. Results: Compared with controls, ElUers selected significantly less net. decks in the Gambling Task (P=.007). Furthermore, the ElUers made progress in selecting strategy, but more slowly than did the control group (ElUers, chunk 3 > chunk 1, P<.001; controls, chunk 2 > chunk 1, P<.001). Interestingly, ElUers' accuracy during the no-go condition was significantly higher than that of controls (P=.018). Conclusion: These results showed some similarities and dissimilarities between ElU and other addictive behaviors such as drug abuse and pathological gambling. The findings from the Gambling Task indicated that ElUers have deficits in decision-making function, which are characterized by a strategy learning lag rather than an inability to learn from task contingencies. ElUers' better performance in the Go/no-go Task suggested some dissociation between mechanisms of decision-making and those of prepotent response inhibition. However, ElUers could hardly suppress their excessive online behaviors in real life. Their ability of inhibition,still needs to be further studied with more specific assessments. C1 [Sun, De-Lin; Zhang, Xiao-Chu; Zhang, Da-Ren] Univ Sci & Technol China, Div Bio X Interdisciplinary Sci, Hefei Natl Lab Phys Sci Microscale, Hefei 230027, Anhui, Peoples R China. [Sun, De-Lin; Chen, Zu-Ji; Ma, Ning; Zhang, Xiao-Chu; Zhang, Da-Ren] Univ Sci & Technol China, Cognit Neuropsychol Lab, Sch Life Sci, Hefei 230027, Anhui, Peoples R China. [Zhang, Xiao-Chu] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD USA. [Fu, Xian-Ming] Anhui Provincial Inst Stereotact Neurosurg, Hefei, Peoples R China. RP Zhang, DR (reprint author), Univ Sci & Technol China, Div Bio X Interdisciplinary Sci, Hefei Natl Lab Phys Sci Microscale, Hefei 230027, Anhui, Peoples R China. EM drzhang@ustc.edu.cn RI Zhang, Xiaochu/O-9592-2014; Sun, Delin/A-4154-2010 OI Zhang, Xiaochu/0000-0002-7541-0130; Sun, Delin/0000-0003-3283-423X NR 40 TC 45 Z9 53 U1 4 U2 21 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD FEB PY 2009 VL 14 IS 2 BP 75 EP 81 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 414XA UT WOS:000263897300007 PM 19238122 ER PT J AU Neammanee, P Reodecha, M AF Neammanee, Patcharaporn Reodecha, Manop TI A memetic algorithm-based heuristic for a scheduling problem in printed circuit board assembly SO COMPUTERS & INDUSTRIAL ENGINEERING LA English DT Article DE Memetic algorithm; Genetic algorithm; PCB scheduling; Sequence-dependent setup times ID DEPENDENT SETUP TIMES; GENETIC ALGORITHM; GROUP-TECHNOLOGY; SINGLE-MACHINE; ASSIGNMENT AB This research develops a memetic algorithm to solve Printed Circuit Board (PCB) scheduling with sequence-dependent setup times on a single machine with constrained feeder capacity. The objective of the scheduling problem is to minimize the total weighted tardiness. A memetic algorithm-based heuristics is developed by integrating a genetic algorithm, Minimum Slack Time (MST) scheduling rule, "Keep Tool Needed Soonest" (KTNS) policy, and a local search procedure. Application of the MA results in two outcome plans: a scheduling plan and a feeder setup plan. Numerical experiments show that compared to a number of commonly used dispatching rules, the memetic algorithm provides better solutions in term of minimum total weighted tardiness. Even the computation is the highest, it still practical. Calibration of MA parameter values is also explored in this study. Crown copyright (C) 2008 Published by Elsevier Ltd. All rights reserved. C1 [Neammanee, Patcharaporn] NIDA, Sch Appl Stat, Bangkok 10240, Thailand. [Reodecha, Manop] Chulalongkorn Univ, Fac Engn, Dept Ind Engn, Bangkok 10400, Thailand. RP Neammanee, P (reprint author), NIDA, Sch Appl Stat, Serithai Rd, Bangkok 10240, Thailand. EM patchara@as.nida.ac.th FU The Thailand Research Fund (TRF); Commission on Higher Education [MRG4580040] FX This work was supported by The Thailand Research Fund (TRF) and Commission on Higher Education (MRG4580040). NR 23 TC 8 Z9 10 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0360-8352 J9 COMPUT IND ENG JI Comput. Ind. Eng. PD FEB PY 2009 VL 56 IS 1 BP 294 EP 305 DI 10.1016/j.cie.2008.06.010 PG 12 WC Computer Science, Interdisciplinary Applications; Engineering, Industrial SC Computer Science; Engineering GA 396NS UT WOS:000262599000037 ER PT J AU Ding, XY Bishop, RJ Herzlich, AA Patel, M Chan, CC AF Ding, Xiaoyuan Bishop, Rachel. J. Herzlich, Alexandra A. Patel, Mrinali Chan, Chi-Chao TI Limbal Stem Cell Deficiency Arising From Systemic Chemotherapy With Hydroxycarbamide SO CORNEA LA English DT Article DE limbal stem cell; ocular surface disease; chemotherapy drugs; hydroxycarbamide ID OCULAR SURFACE AB Purpose: The purpose of this study was to report a case of limbal stem cell deficiency (LSCD) after systemic chemotherapy with hydroxycarbamide. Methods: Clinical manifestations and pathology are detailed. Results: We describe the case of a woman with sickle cell disease, who developed bilateral LSCD after treatment with hydroxycarbamide. Histologic examination confirmed the diagnosis of LSCD, revealing goblet cells, inflammatory cells, deposits of new collagen components. and neovascularization in the peripheral cornea. Matrix metalloproteinase-3, fibronectin. and collagen III were also detected in the lesions. Conclusions: The systemic use of the antineoplastic drug, hydroxycarbamide, may cause severe LSCD. We recommend that a medication history, including that of cytotoxic drugs, be considered in evaluating LSCD. C1 [Ding, Xiaoyuan; Herzlich, Alexandra A.; Patel, Mrinali; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Ding, Xiaoyuan] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Bishop, Rachel. J.] NEI, Clin Branch, NIH, Bethesda, MD 20892 USA. [Patel, Mrinali] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, Bldg 10,Room 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU NEI Intramural Research Program FX Supported by NEI Intramural Research Program. NR 7 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD FEB PY 2009 VL 28 IS 2 BP 221 EP 223 PG 3 WC Ophthalmology SC Ophthalmology GA 400BX UT WOS:000262844100021 PM 19158571 ER PT J AU Sala, SD Grafman, J AF Sala, Sergio Della Grafman, Jordan TI Cortex new open access policy SO CORTEX LA English DT Editorial Material C1 [Sala, Sergio Della] Univ Edinburgh, Edinburgh EH8 9JZ, Midlothian, Scotland. [Grafman, Jordan] NINDS, Cognit Neurosci Sect, Bethesda, MD 20892 USA. RP Sala, SD (reprint author), Univ Edinburgh, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. EM sergio@ed.ac.uk OI Grafman, Jordan H./0000-0001-8645-4457 NR 3 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD FEB PY 2009 VL 45 IS 2 BP 135 EP 136 DI 10.1016/j.cortex.2008.11.008 PG 2 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 405EU UT WOS:000263206400001 ER PT J AU Ackerman, HC Beaudry, SD Fairhurst, RM AF Ackerman, Hans C. Beaudry, Steven D. Fairhurst, Rick M. TI Antioxidant therapy: Reducing malaria severity? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE oxidative stress; cytoadherence; Plasmodium falciparum; endothelium; artesunate; N-acetylcysteine; lactate; glucose-6-phosphate dehydrogenase deficiency ID PLASMODIUM-FALCIPARUM MALARIA; BLOOD-CELL DEFORMABILITY; INFECTED ERYTHROCYTES; OXIDATIVE STRESS; CEREBRAL MALARIA; N-ACETYLCYSTEINE; ARTESUNATE; CHILDREN C1 [Ackerman, Hans C.; Beaudry, Steven D.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, Rockville, MD USA. [Ackerman, Hans C.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Ackerman, HC (reprint author), NIAID, Lab Malaria & Vector Res, Rockville, MD USA. FU Intramural NIH HHS [ZIA AI001000-03, Z99 AI999999] NR 15 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2009 VL 37 IS 2 BP 758 EP 760 DI 10.1097/CCM.0b013e318194d5de PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 402LI UT WOS:000263014800059 PM 19325374 ER PT J AU Haas, DM Renbarger, JL Denne, S Ahmed, MS Easterling, T Feibus, K Meslin, EM Koren, G Zajicek, A Snodgrass, WR Flockhart, DA AF Haas, David M. Renbarger, Jamie L. Denne, Scott Ahmed, Mahmoud S. Easterling, Thomas Feibus, Karen Meslin, Eric M. Koren, Gideon Zajicek, Anne Snodgrass, Wayne R. Flockhart, David A. TI Pharmacotherapy and Pregnancy HIGHLIGHTS FROM THE FIRST INTERNATIONAL CONFERENCE FOR INDIVIDUALIZED PHARMACOTHERAPY IN PREGNANCY SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Editorial Material ID WOMEN; DEPRESSION C1 [Haas, David M.; Renbarger, Jamie L.; Denne, Scott; Meslin, Eric M.; Flockhart, David A.] Indiana Univ, Sch Med, PREGMED, Ctr Pharmacogenet & Therapeut Res Maternal & Chil, Indianapolis, IN 46204 USA. [Ahmed, Mahmoud S.; Snodgrass, Wayne R.] Univ Texas Med Branch Galveston, Galveston, TX USA. [Easterling, Thomas] Univ Washington, Sch Med, Seattle, WA USA. [Feibus, Karen] US FDA, Washington, DC 20204 USA. [Meslin, Eric M.] Indiana Univ, Ctr Bioeth, Indianapolis, IN 46204 USA. [Koren, Gideon] SickKids Hosp, Toronto, ON, Canada. [Zajicek, Anne] NICHHD, Washington, DC USA. RP Haas, DM (reprint author), Indiana Univ, Sch Med, PREGMED, Ctr Pharmacogenet & Therapeut Res Maternal & Chil, Indianapolis, IN 46204 USA. EM dahaas@iupui.edu FU NICHD NIH HHS [U10 HD063094] NR 17 TC 3 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2009 VL 2 IS 1 BP 11 EP 14 DI 10.1111/j.1752-8062.2009.00079.x PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 532RW UT WOS:000272768200009 PM 20443863 ER PT J AU Becker, RE Unni, LK Greig, NH AF Becker, Robert E. Unni, Latha K. Greig, Nigel H. TI Resurrecting Clinical Pharmacology As a Context for Alzheimer Disease Drug Development SO CURRENT ALZHEIMER RESEARCH LA English DT Article ID DOUBLE-BLIND; ACETYLCHOLINESTERASE; METRIFONATE; RECOVERY; INACTIVATION; INHIBITOR; INVIVO; CELLS; RAT AB Commercial priorities have been identified as negative factors in drug development. We trace the problem to inattention to sound clinical pharmacology practices. When properly applied, clinical pharmacology and associated drug development sciences can, hand in hand, facilitate success in commercial drug development. C1 [Becker, Robert E.; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Unni, Latha K.] Sigma Aldrich Corp, St Louis, MO 63103 USA. RP Becker, RE (reprint author), POB 442, S Freeport, ME USA. EM rebecker2008@comcast.net FU Intramural NIH HHS [Z01 AG000311-08, ] NR 21 TC 8 Z9 9 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD FEB PY 2009 VL 6 IS 1 BP 79 EP 81 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 406HT UT WOS:000263286300011 PM 19199879 ER PT J AU Onda, M AF Onda, Masanori TI Reducing the Immunogenicity of Protein Therapeutics SO CURRENT DRUG TARGETS LA English DT Review DE Toxin; antibody; B cell epitope; ELISA; conformational epitope ID AMINO-ACID SUBSTITUTIONS; ALANINE-SCANNING MUTAGENESIS; ANTIBODY-BINDING REGIONS; EGG-WHITE LYSOZYME; RED-CELL APLASIA; RECOMBINANT STAPHYLOKINASE VARIANTS; ERYTHROPOIESIS STIMULATING PROTEIN; MULTIPLE-SCLEROSIS PATIENTS; BOTULINUM NEUROTOXIN-A; CRYSTAL-STRUCTURE AB Protein therapeutics, such as antibodies, enzymes and toxins, are very promising reagents for the treatment of human disease. However, many therapeutic proteins are known to elicit immune responses when administered to humans. Certain antibodies work by neutralization; others reduce drug efficacy. It is clear that helper T cells are an important factor in the development of class-switched and affinity-maturated anti-therapeutic protein antibodies. Elimination of the T cell epitope seems reasonable, but it is probably impossible to remove all T cell epitopes from protein drugs because T cell epitopes are closely related to the major histocompatibility complex (MHC) molecules, which are known to be highly polymorphic. Accordingly, a possible practical approach for reducing immunogenicity involves the removal of B cell epitopes. In this case, reducing the affinity between the antigen and the B cell receptor may reduce B cell activation, even though the T cell will still be activated. Also a B cell epitope is not restricted by MHC class II molecules. This review seeks to address the identification and the characterization of B cell epitopes, and reports on the development of strategies for reducing immune response with modified B cell epitopes. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Onda, M (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Room 5110, Bethesda, MD 20892 USA. EM ondam@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 135 TC 20 Z9 21 U1 0 U2 20 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-4501 J9 CURR DRUG TARGETS JI Curr. Drug Targets PD FEB PY 2009 VL 10 IS 2 BP 131 EP 139 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 406JN UT WOS:000263290900008 PM 19199909 ER PT J AU Arbab, AS Janic, B Haller, J Pawelczyk, E Liu, W Frank, JA AF Arbab, Ali S. Janic, Branislava Haller, Jodi Pawelczyk, Edyta Liu, Wei Frank, Joseph A. TI In Vivo Cellular Imaging for Translational Medical Research SO CURRENT MEDICAL IMAGING REVIEWS LA English DT Review DE Cellular magnetic resonance (CMRI); Stem cells; cell tracking; SPION; Magnetic cell labeling ID SUPERPARAMAGNETIC IRON-OXIDE; MESENCHYMAL STEM-CELLS; SODIUM-IODIDE SYMPORTER; MAGNETIC-RESONANCE TRACKING; GREEN FLUORESCENT PROTEIN; SPINAL-CORD-INJURY; MR CONTRAST AGENTS; BIOLUMINESCENCE OPTICAL TOMOGRAPHY; HUMAN SODIUM/IODIDE SYMPORTER; POSITRON-EMISSION-TOMOGRAPHY AB Personalized treatment using stem, modified or genetically engineered, cells is becoming a reality in the field of medicine, in which allogenic or autologous cells can be used for treatment and possibly for early diagnosis of diseases. Hematopoietic, stromal and organ specific stem cells are under evaluation for cell-based therapies for cardiac, neurological, autoimmune and other disorders. Cytotoxic or genetically altered T-cells are under clinical trial for the treatment of hematopoietic or other malignant diseases. Before using stem cells in clinical trials, translational research in experimental animal models are essential, with a critical emphasis on developing noninvasive methods for tracking the temporal and spatial homing of these cells to target tissues. Moreover, it is necessary to determine the transplanted cells, engraftment efficiency and functional capability. Various in vivo imaging modalities are in use to track the movement and incorporation of administered cells. Tagging cells with reporter genes, fluorescent dyes or different contrast agents transforms them into cellular probes or imaging agents. Recent reports have shown that magnetically labeled cells can be used as cellular magnetic resonance imaging (MRI) probes, demonstrating the cell trafficking to target tissues. In this review, we will discuss the methods to transform cells into probes for in vivo imaging, along with their advantages and disadvantages as well as the future clinical applicability of cellular imaging method and corresponding imaging modality. C1 [Arbab, Ali S.; Janic, Branislava] Henry Ford Hosp, Dept Radiol, Cellular & Mol Imaging Lab, Detroit, MI 48202 USA. [Haller, Jodi; Pawelczyk, Edyta; Liu, Wei] NIH, Ctr Clin, Frank Lab Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Frank, Joseph A.] NIBIB, NIH, Bethesda, MD USA. RP Arbab, AS (reprint author), Henry Ford Hosp, Dept Radiol, Cellular & Mol Imaging Lab, 1 Ford Pl,2F, Detroit, MI 48202 USA. EM saali@rad.hfh.edu FU National Institutes of Health [NS058589, CA129801, CA122031] FX This work was performed in part from support by the intramural research program in the Clinical Center at the National Institutes of Health and the following extramural supports; NS058589, CA129801, CA122031. NR 246 TC 51 Z9 55 U1 0 U2 16 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1573-4056 J9 CURR MED IMAGING REV JI Curr. Med. Imaging Rev. PD FEB PY 2009 VL 5 IS 1 BP 19 EP 38 PG 20 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 415VN UT WOS:000263964400005 PM 19768136 ER PT J AU Kim, HS Lee, MS AF Kim, Hun Sik Lee, Myung-Shik TI Role of Innate Immunity in Triggering and Tuning of Autoimmune Diabetes SO CURRENT MOLECULAR MEDICINE LA English DT Review DE Innate immunity; beta-cell death; macrophages; dendritic cells; NK cells; NK T cells; gamma delta T cells; TLRs ID TOLL-LIKE-RECEPTORS; REGULATORY T-CELLS; NATURAL-KILLER-CELLS; ANTIGEN-PRESENTING CELLS; TUMOR-NECROSIS-FACTOR; PANCREATIC BETA-CELLS; TOLEROGENIC DENDRITIC CELLS; PRONE BB RAT; NOD MICE; APOPTOTIC CELLS AB Type 1 diabetes (T1D) is an organ-specific autoimmune disease resulting from the specific destruction of insulin-producing pancreatic beta-cells, culminating in a state of hypoinsulinemia and hyperglycemia. Pathogenesis of T1D comprises complex series of events from the initial sensitization of antigen-presenting cells (APCs) to beta-cell antigens to almost total insulin deficiency due to islet destruction. Although it is established that the interaction of environmental factors with genetic traits plays a pivotal role in the pathogenesis of T1D, in most cases, the exact trigger of anti-islet autoimmunity and how genetic and environmental factors regulate its progression, ultimately leading to the development of T1D remain elusive. In this review, based on the recent advances in understanding the role of innate immunity in development of autoimmune diseases, we focus on the possibility that aberrant regulation of the innate immune system frequently observed in animal models and patients with T1D, induces T1D by triggering anti-islet autoimmunity in the context of the autoimmune-prone environment; this information might provide an insight into possibilities for therapeutic intervention modulating innate immunity to mitigate or prevent T1D. C1 [Kim, Hun Sik; Lee, Myung-Shik] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med, Seoul, South Korea. [Kim, Hun Sik] NIAID, Immunogenet Lab, Rockville, MD 20852 USA. RP Lee, MS (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med, Seoul, South Korea. EM mslee0923@skku.edu RI Lee, Myung Shik/C-9606-2011 FU Nano/Bio Science Program [2004-00716]; 21C Frontier Functional Proteomics Project [FPR08B1-210]; JDRF [5-2007-361]; KOSEF [M10861020003] FX This work was supported by the Nano/Bio Science Program Grant (2004-00716), and 21C Frontier Functional Proteomics Project (FPR08B1-210). M.-S. L. is an awardee of the JDRF Grant (5-2007-361) and SRC Grants/M10861020003 from KOSEF. NR 207 TC 23 Z9 25 U1 1 U2 11 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD FEB PY 2009 VL 9 IS 1 BP 30 EP 44 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 415VL UT WOS:000263964200005 PM 19199940 ER PT J AU Jacobs, A Blumenthal, R AF Jacobs, Amy Blumenthal, Robert TI Understanding the Design Principles of Living Systems at the Nanoscale SO CURRENT NANOSCIENCE LA English DT Article DE Nanobiology; nanotechnology; cancer drug delivery; mechanical biology; single-molecule imaging; in vivo proteomics ID OPTICAL RECONSTRUCTION MICROSCOPY; QUANTUM DOTS AB This is a summary of the Third Annual Cancer Nanobiology Think Tank hosted by the Nanobiology Program at the Center for Cancer Research at the National Cancer Institute-Frederick, National Institutes of Health. The Third Annual Nanobiology Think Tank was held in May of 2008 and was entitled "Understanding the Design Principles of Living Systems at the Nanoscale." C1 [Jacobs, Amy; Blumenthal, Robert] NCI, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Ctr Canc Res Nanobiol Program, NIH, POB B, Frederick, MD 21702 USA. EM blumenthalr@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX The research in the Nanobiology Program is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research NR 13 TC 1 Z9 1 U1 2 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1573-4137 J9 CURR NANOSCI JI Curr. Nanosci. PD FEB PY 2009 VL 5 IS 1 BP 45 EP 50 PG 6 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics; Materials Science GA 415UO UT WOS:000263961400006 ER PT J AU Gordon, S Trinchieri, G AF Gordon, Siamon Trinchieri, Giorgio TI Innate resistance and inflammation SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material C1 [Gordon, Siamon] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Trinchieri, Giorgio] NCI, NIH, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Gordon, S (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. EM siamon.gordon@path.ox.ac.uk; trinchig@mail.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2009 VL 21 IS 1 BP 1 EP 2 DI 10.1016/j.coi.2009.02.001 PG 2 WC Immunology SC Immunology GA 443EA UT WOS:000265891800001 PM 19223161 ER PT J AU Ford, JW McVicar, DW AF Ford, Jill W. McVicar, Daniel W. TI TREM and TREM-like receptors in inflammation and disease SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID MYELOID CELLS; SEPTIC SHOCK; CUTTING EDGE; EXPRESSION PATTERNS; IMMUNE-RESPONSES; BONE HOMEOSTASIS; I INTERFERON; SIGLEC-H; MACROPHAGES; ACTIVATION AB Since the discovery of triggering receptor expressed on myeloid cells (TREM)-1 in 2000, evidence documenting the profound ability of the TREM and TREM-like receptors to regulate inflammation has rapidly accumulated. Monocytes, macrophages, myeloid dendritic cells, plasmacytoid dendritic cells, neutrophils, microglia, osteoclasts, and platelets all express at least one member of the TREM family, underscoring the importance of these proteins in the regulation of innate resistance. Recent work on the TREM family includes: characterization of a new receptor expressed on plasmacytoid dendritic cells; definition of a key role for TREM in inflammatory bowel disease and multiple sclerosis; an expanded list of diseases associated with the release of soluble forms of TREM proteins; and identification of the first well characterized TREM ligand: B7-H3, a ligand for TREM-like Transcript (TLT)-2. Moreover, analysis of TREM signaling has now identified key regulatory components and defined pathways that may be responsible for the complex functional interactions between the TREM and toll-like receptors. In addition, there is expanding evidence of a role for TREM in the regulation of integrin function via Plexin-A1. Together these new findings define the TREM and TREM-like receptors as pluripotent modifiers of disease through the integration of inflammatory signals with those associated with leukocyte adhesion. C1 [Ford, Jill W.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. RP McVicar, DW (reprint author), NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. EM mcvicard@mail.nih.gov RI McVicar, Daniel/G-1970-2015 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX This research was supported partly by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 59 TC 183 Z9 193 U1 3 U2 17 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2009 VL 21 IS 1 BP 38 EP 46 DI 10.1016/j.coi.2009.01.009 PG 9 WC Immunology SC Immunology GA 443EA UT WOS:000265891800007 PM 19230638 ER PT J AU Voth, DE Heinzen, RA AF Voth, Daniel E. Heinzen, Robert A. TI Coxiella type IV secretion and cellular microbiology SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID ENTEROPATHOGENIC ESCHERICHIA-COLI; PNEUMOPHILA DOT/ICM SYSTEM; LEGIONELLA-PNEUMOPHILA; Q-FEVER; CHLAMYDIAL PROTEASE; ANKYRIN REPEAT; BURNETII; PROTEINS; VIRULENCE; CELLS AB Coxiella burnetii is a widespread zoonotic bacterial pathogen that causes human Q fever. In vivo, Coxiella displays a tropism for mononuclear phagocytes where it participates in biogenesis of a lysosome-like replication compartment to conduct its obligate intracellular lifestyle. Coxiella actively regulates multiple events during infection, presumably via proteins with effector functions that are delivered to the host cytosol by a Dot/Icm type IV secretion system. Because the organism is currently refractory to genetic manipulation, Coxiella Dot/Icm substrates have been identified using bioinformatics and Legionella pneumophila as a surrogate type IV delivery system. Functional characterization of the biological activity of these effector proteins will dramatically aid our ability to model Coxiella-host cell interactions. C1 [Voth, Daniel E.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000931-05] NR 50 TC 46 Z9 48 U1 1 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2009 VL 12 IS 1 BP 74 EP 80 DI 10.1016/j.mib.2008.11.005 PG 7 WC Microbiology SC Microbiology GA 420WE UT WOS:000264319100012 PM 19144560 ER PT J AU Mohebtash, M Gulley, JL Madan, RA Ferrara, T Arlen, PM AF Mohebtash, Mahsa Gulley, James L. Madan, Ravi A. Ferrara, Theresa Arlen, Philip M. TI Cancer vaccines: Current directions and perspectives in prostate cancer SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Review DE Cancer vaccine; immune response; prostrate cancer; tumor-associated antigen ID REGULATORY T-CELLS; COLONY-STIMULATING FACTOR; IMMUNE-RESPONSES; DOSE CYCLOPHOSPHAMIDE; COMBINATION THERAPY; CTLA-4 BLOCKADE; LYMPH-NODES; IMMUNOTHERAPY; ANTIGEN; RADIOTHERAPY AB Numerous research groups are investigating the use of cancer vaccines as a potential therapeutic modality for various tumor types. The efficacy of cancer vaccines has improved because of advances in the characterization of tumor-associated antigens, the development of improved vaccine delivery systems, and the combination of vaccines with cytokines and other immunostimulants to enhance immune responses. Although cancer vaccines are under investigation for the treatment of various different tumor types, several characteristics of prostate cancer make it an ideal target for immunotherapy. The relative indolence of prostrate cancer allows sufficient time to generate immune responses, which usually take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal tissue. This review focuses on promising new strategies for combining vaccines with other therapeutic approaches, as well as novel perspectives in the treatment of prostate cancer. C1 [Mohebtash, Mahsa; Gulley, James L.; Madan, Ravi A.; Ferrara, Theresa; Arlen, Philip M.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Arlen, PM (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM arlenp@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010666-03] NR 55 TC 3 Z9 3 U1 0 U2 0 PU THOMSON REUTERS (SCIENTIFIC) LTD PI LONDON PA 77 HATTON GARDEN, LONDON, EC1N 8JS, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD FEB PY 2009 VL 11 IS 1 BP 31 EP 36 PG 6 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 412JP UT WOS:000263721400004 PM 19169957 ER PT J AU Ferrara, TA Hodge, JW Gulley, JL AF Ferrara, Theresa A. Hodge, James W. Gulley, James L. TI Combining radiation and immunotherapy for synergistic antitumor therapy SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Review DE Cancer; immunopotentiation; radiotherapy; therapeutic vaccine ID CYTOTOXIC T-LYMPHOCYTES; APOPTOSIS IN-VIVO; TUMOR-CELLS; PROSTATE-CANCER; IMMUNOLOGICAL RESPONSE; RADIOTHERAPY; VACCINE; ANTIGEN; COMBINATION; PHENOTYPE AB The combination of radiation therapy and immunotherapy holds enticing promise as a strategy for cancer treatment. Preclinical studies have shown that radiation may act synergistically with immunotherapy to enhance or broaden antitumor immune responses, in part, because of radiation-induced phenotypic alterations of tumor cells that render them more susceptible to immune-mediated killing. Clinical trials utilizing the combination of therapeutic vaccines with radiation have supported many of these findings, and other clinical trials are both ongoing and planned. This review examines the evidence that radiation induces immunological death, the mechanisms by which radiation therapy can induce or augment antitumor immune responses, and translational studies demonstrating that immunotherapy can be effectively combined with radiation therapy. Finally, recent and current clinical trials combining radiation therapy with immunotherapy are reviewed. C1 [Ferrara, Theresa A.; Hodge, James W.; Gulley, James L.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010945-01] NR 32 TC 25 Z9 26 U1 0 U2 4 PU THOMSON REUTERS (SCIENTIFIC) LTD PI LONDON PA 77 HATTON GARDEN, LONDON, EC1N 8JS, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD FEB PY 2009 VL 11 IS 1 BP 37 EP 42 PG 6 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 412JP UT WOS:000263721400005 PM 19169958 ER PT J AU Clayberger, C AF Clayberger, Carol TI Cytolytic molecules in rejection SO CURRENT OPINION IN ORGAN TRANSPLANTATION LA English DT Review DE Fas ligand; granulysin; granzymes; perforin ID RENAL-ALLOGRAFT REJECTION; REGULATORY T-CELLS; GENE-EXPRESSION MEASUREMENTS; MESSENGER-RNA EXPRESSION; NATURAL-KILLER-CELLS; GRANZYME-B; NONINVASIVE DIAGNOSIS; NK CELLS; TRANSPLANTATION TOLERANCE; MEDIATED CYTOTOXICITY AB Purpose of review Acute and chronic rejection are major problems in clinical transplantation. Rejection is largely mediated by natural killer (NK) and T cells that use cytolytic molecules, including perforin, granzymes, granulysin, and Fas ligand, to eliminate the allograft. The purpose of this review is to inform the reader of recent advances in our understanding of the roles of cytolytic molecules in rejection and their potential as biomarkers of rejection. Recent findings Although it is well accepted that T cells are the major effector cells in acute rejection, there is an increasing recognition that cells of the innate immune system, and in particular NK cells, also play a major role in allograft rejection. Summary Both NK cells and cytotoxic T cells contribute to acute rejection. The major molecules involved include perforin, granzymes, granulysin, and Fas ligand. Molecular profiles that include these and other molecules may allow better management of organ allograft recipients. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clayberger, C (reprint author), NCI, Mol Cell Biol Lab, NIH, Bldg 37,Room 2016,37 Convent Dr, Bethesda, MD 20892 USA. EM claybergerc@mail.nih.gov FU National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, and Center for Cancer Research. NR 51 TC 18 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1087-2418 J9 CURR OPIN ORGAN TRAN JI Curr. Opin. Organ Transpl. PD FEB PY 2009 VL 14 IS 1 BP 30 EP 33 DI 10.1097/MOT.0b013e32831c8462 PG 4 WC Transplantation SC Transplantation GA 420TU UT WOS:000264312900006 PM 19337143 ER PT J AU Moore, RA Taubner, LM Priola, SA AF Moore, Roger A. Taubner, Lara M. Priola, Suzette A. TI Prion protein misfolding and disease SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID IN-VITRO CONVERSION; NMR STRUCTURE; AMYLOID FIBRILS; TRANSGENIC MICE; SECONDARY STRUCTURE; SEEDED CONVERSION; CRYSTAL-STRUCTURE; ATOMIC MODELS; HAMSTER PRP; SCRAPIE AB Transmissible spongiform encephalopathies (TSEs or prion diseases) are a rare group of invariably fatal neurodegenerative disorders that affect humans and other mammals. TSEs are protein misfolding diseases that involve the accumulation of an abnormally aggregated form of the normal host prion protein (PrP). They are unique among protein misfolding disorders in that they are transmissible and have different strains of infectious agents that are associated with unique phenotypes in vivo. A wealth of biological and biophysical evidence now suggests that the molecular basis for prion diseases may be encoded by protein conformation. The purpose of this review is to provide an overview of the existing structural information for PrP within the context of what is known about the biology of prion disease. C1 [Moore, Roger A.; Taubner, Lara M.; Priola, Suzette A.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Moore, RA (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM rmoore@niaid.nih.gov; spriola@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 74 TC 41 Z9 41 U1 1 U2 24 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD FEB PY 2009 VL 19 IS 1 BP 14 EP 22 DI 10.1016/j.sbi.2008.12.007 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 420IH UT WOS:000264282000004 PM 19157856 ER PT J AU Lu, G Dolgner, SJ Hall, TMT AF Lu, Gang Dolgner, Stephen J. Hall, Traci M. Tanaka TI Understanding and engineering RNA sequence specificity of PUF proteins SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID PUMILIO-HOMOLOGY DOMAIN; MESSENGER-RNA; BINDING-SPECIFICITY; FAMILY; YEAST; LOCALIZATION; TRANSLATION AB PUF proteins are RNA-binding proteins named for founding members PUMILIO and fem-3 binding factor (FBF). Together these proteins represent the range of known RNA recognition properties. PUMILIO is a prototypical PUF protein whose RNA sequence specificity is simple, elegant, and predictable. FBF displays differences in RNA recognition that represent divergence from the prototype. Here we review recent studies that examine the engineering of sequence specificity of PUF proteins and its applications as well as studies that increase our understanding of the natural diversity of RNA recognition by this family of proteins. C1 [Lu, Gang; Dolgner, Stephen J.; Hall, Traci M. Tanaka] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Lu, G (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM lug@niehs.nih.gov; dolgn001@mc.duke.edu; hall4@niehs.nih.gov FU National Institute of Environmental Health Sciences FX We are grateftil to our colleagLICS for critical reading ofthis manLiScript and 11 Cacioppo of the NJ EHS Arts and Photography grOLIP for graphics design. 'Fhis work was supported by the Intramural escarch Program of the National InStitLlteS of Health, National Institute of Environmental Health Sciences. NR 21 TC 44 Z9 44 U1 2 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD FEB PY 2009 VL 19 IS 1 BP 110 EP 115 DI 10.1016/j.sbi.2008.12.009 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 420IH UT WOS:000264282000017 PM 19186050 ER PT J AU Humeniuk, R Mishra, PJ Bertino, JR Banerjee, D AF Humeniuk, Rita Mishra, Prasun J. Bertino, Joseph R. Banerjee, Debabrata TI Molecular Targets for Epigenetic Therapy of Cancer SO CURRENT PHARMACEUTICAL BIOTECHNOLOGY LA English DT Review DE Drug resistance; epigenetic therapy; chromatin modifications; DNA methylation; combination chemotherapy ID HISTONE DEACETYLASE INHIBITORS; ABERRANT DNA METHYLATION; HEMATOLOGICAL MALIGNANCIES; LYMPHOID MALIGNANCIES; DRUG-RESISTANCE; GENE-EXPRESSION; PHASE-I; PROMOTER; HYPERMETHYLATION; INACTIVATION AB Recent advances in cancer research showed that changes of the cell "epigenome" contribute significantly to the development and progression of cancer. Similar to genetic alterations, epigenetic modifications can be transmitted to the next generation and used to turn off and/or on certain genes or pathways that may confer survival benefit to a malignant cell. However, epigenetic changes are readily reversible raising the possibility of "epigenetic therapy". A potential problem in this therapeutic approach is the lack of specificity, as epigenetic modifications are used by both normal and cancer cells to regulate expression of various genes. Ongoing studies to identify genes that are differentially expressed in cancer cells vs. normal cells are providing valuable information about molecular targets for epigenetic therapy. The present article will focus on summarizing some of these studies and will discus the differences between conventional chemotherapy and epigenetic therapy utilizing epigenetic drugs like DNA methyltransferase inhibitors or histone deacetylase inhibitors. Current perspectives on the future of epigenetic therapy are also discussed. C1 [Banerjee, Debabrata] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med & Pharmacol, New Brunswick, NJ 08903 USA. [Mishra, Prasun J.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Humeniuk, Rita] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Banerjee, D (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med & Pharmacol, 195 Little Albany St,Room 3035, New Brunswick, NJ 08903 USA. EM banerjed@umdnj.edu NR 39 TC 11 Z9 15 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2010 J9 CURR PHARM BIOTECHNO JI Curr. Pharm. Biotechnol. PD FEB PY 2009 VL 10 IS 2 BP 161 EP 165 PG 5 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 415WX UT WOS:000263968300004 PM 19199948 ER PT J AU Wang, DF AF Wang, Difei TI Computational Studies on the Histone Deacetylases and the Design of Selective Histone Deacetylase Inhibitors SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review ID SMALL-MOLECULE INHIBITOR; 2 CATALYTIC DOMAINS; CRYSTAL-STRUCTURE; ZINC-BINDING; STRUCTURAL BASIS; HDAC INHIBITORS; BIOLOGICAL EVALUATION; PROTEIN DEACETYLASE; SUBSTRATE-BINDING; HYDROXAMIC ACIDS AB The catalytic activity of the histone deacetylase ( HDAC) enzymes is directly relevant to the pathogenesis of cancer as well as several other diseases. HDAC inhibitors have been shown to have the potential to treat several types of cancers. The role of computational study of the HDAC enzymes is reviewed, with particular emphasis on the important role of molecular modeling to the development of HDAC inhibitors with improved efficacy and selectivity. The use of two computational approaches - one structure-based, and the second ligand-based - toward inhibitors against the different HDAC sub-classes, are summarized. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, DF (reprint author), NCI, Cell Biol Lab, NIH, Bldg 12B,B105, Bethesda, MD 20892 USA. EM wangdi@mail.nih.gov RI Wang, Difei/E-7066-2010 FU Intramural NIH HHS [Z99 CA999999] NR 91 TC 24 Z9 24 U1 0 U2 8 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD FEB PY 2009 VL 9 IS 3 BP 241 EP 256 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 441VJ UT WOS:000265798300004 PM 19355989 ER PT J AU Suzuki, K Yamaguchi, Y Villacorte, M Mihara, K Akiyama, M Shimizu, H Taketo, MM Nakagata, N Tsukiyama, T Yamaguchi, TP Birchmeier, W Kato, S Yamada, G AF Suzuki, Kentaro Yamaguchi, Yuji Villacorte, Mylah Mihara, Kenichiro Akiyama, Masashi Shimizu, Hiroshi Taketo, Makoto M. Nakagata, Naomi Tsukiyama, Tadasuke Yamaguchi, Terry P. Birchmeier, Walter Kato, Shigeaki Yamada, Gen TI Embryonic hair follicle fate change by augmented beta-catenin through Shh and Bmp signaling SO DEVELOPMENT LA English DT Article DE Skin; Hair follicle (HF); Wnt; beta-catenin; Bmp; Shh; Cell fate ID SONIC-HEDGEHOG; SHAFT DIFFERENTIATION; SKIN DEVELOPMENT; MORPHOGENESIS; MOUSE; MICE; GENE; INDUCTION; CELLS; MODELS AB beta-catenin signaling is one of the key factors regulating the fate of hair follicles (HFs). To elucidate the regulatory mechanism of embryonic HF fate determination during epidermal development/differentiation, we analyzed conditional mutant mice with keratinocytes expressing constitutively active beta-catenin (K5-Cre Catnb((ex3)fl/+)). The mutant mice developed scaly skin with a thickened epidermis and showed impaired epidermal stratification. The hair shaft keratins were broadly expressed in the epidermis but there was no expression of the terminal differentiation markers K1 and loricrin. Hair placode markers (Bmp2 and Shh) and follicular dermal condensate markers ( noggin, patched 1 and Pdgfra) were expressed throughout the epidermis and the upper dermis, respectively. These results indicate that the embryonic epidermal keratinocytes have switched extensively to the HF fate. A series of genetic studies demonstrated that the epidermal switching to HF fate was suppressed by introducing the conditional mutation K5-Cre Catnb((ex3)fl/+) Shh(fl/-) ( with additional mutation of Shh signaling) or K5-Cre Catnb((ex3)fl/+) BmprIA(fl/fl) ( with additional mutation of Bmp signaling). These results demonstrate that Wnt/beta-catenin signaling relayed through Shh and Bmp signals is the principal regulatory mechanism underlying the HF cell fate change. Assessment of Bmp2 promoter activities suggested a putative regulation by beta-catenin signaling relayed by Shh signaling towards Bmp2. We also found that Shh protein expression was increased and expanded in the epidermis of K5-Cre Catnb((ex3)fl/+) BmprIAfl/fl mice. These results indicate the presence of growth factor signal cross-talk involving beta- catenin signaling, which regulates the HF fate. C1 [Suzuki, Kentaro; Villacorte, Mylah; Mihara, Kenichiro; Nakagata, Naomi; Yamada, Gen] Kumamoto Univ, CARD, Kumamoto 8600811, Japan. [Suzuki, Kentaro; Villacorte, Mylah; Yamada, Gen] Kumamoto Univ, Global COE Cell Fate Regulat Res & Educ Unit, Kumamoto 8600811, Japan. [Yamaguchi, Yuji] Nagoya City Univ, Grad Sch Med Sci, Dept Geriatr & Environm Dermatol, Nagoya, Aichi 4678601, Japan. [Akiyama, Masashi; Shimizu, Hiroshi] Hokkaido Univ, Grad Sch Med, Dept Dermatol, Sapporo, Hokkaido 0608638, Japan. [Taketo, Makoto M.] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto 6068501, Japan. [Tsukiyama, Tadasuke] Hokkaido Univ, Dept Mol Biochem, Sapporo, Hokkaido 0608638, Japan. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. [Birchmeier, Walter] Max Delbruck Ctr Mol Med, Dept Canc Biol, D-13125 Berlin, Germany. [Kato, Shigeaki] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan. RP Yamada, G (reprint author), Kumamoto Univ, CARD, Kumamoto 8600811, Japan. EM gensan@gpo.kumamoto-u.ac.jp RI Tsukiyama, Tadasuke/D-7589-2012 NR 44 TC 26 Z9 27 U1 0 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 J9 DEVELOPMENT JI Development PD FEB 1 PY 2009 VL 136 IS 3 BP 367 EP 372 DI 10.1242/dev.021295 PG 6 WC Developmental Biology SC Developmental Biology GA 393XJ UT WOS:000262409500003 PM 19141668 ER PT J AU Pei, WH Feldman, B AF Pei, Wuhong Feldman, Benjamin TI Identification of common and unique modifiers of zebrafish midline bifurcation and cyclopia SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Zebrafish; Cyclopia; Midline bifurcation; Squint; Nodal; Wnt5b; Wnt11; Hsp90 ID NO TAIL; WILD-TYPE; EMBRYOS; GASTRULATION; EXPRESSION; HSP90; AXIS; GENE; EMBRYOGENESIS; SILBERBLICK AB Loss of the zebrafish Nodal-related protein Squint causes a spectrum of phenotypes including cyclopia and midline bifucations (MB). Here we examine MBs and their relation to cyclopia in maternal-zygotic squint (MZsqt) mutants. There is a concordance of NIB with cyclopia in MZsqt embryos. Heat treatment and depletion of Hsp90a are "common" risk factors, each of which increases the incidence of both phenotypes. Midline identity is specified on both sides of MBs, and deep-layer cells are initially lacking within bifurcations, whereas enveloping layer cells are intact. Bifurcations do not appear until the completion of gastrulation and are preceded by gaps in the expression of wnt5b, an essential regulator of dorsal convergence. The incidence of early MBs and wnt5b expression defects in heated MZsqt embryos is high, but there is also substantial recovery. Wnt5b depletion increases the incidence of MB, but not cyclopia, and as such Wnt5b is a "unique" risk factor for RIB. Reciprocally, depletion of Wnt11 or Hsp90b increases cyclopia only. In summary, we find that NIB arises after gastrulation in regions that fail to express wnt56, and we show that two complex dysmorphologies - NIB and cyclopia - can be promoted by either common or unique risk factors. Published by Elsevier Inc. C1 [Pei, Wuhong; Feldman, Benjamin] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Feldman, B (reprint author), NHGRI, Med Genet Branch, NIH, 9000 Rockville Pike,Bldg 35,Room 1B 205, Bethesda, MD 20892 USA. EM bfeldman@mail.nih.gov OI Feldman, Benjamin/0000-0003-4838-8641 FU Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health FX We thank Bo Xiong and Anming Meng for the LEF-luc and control DNA constructs; Jamie Brown and Sung-Kook Hong for technical advice; Erich Roessler for critical reading of the manuscript and inspiring discussions; Maximilian Muenke for permission to cite unpublished data. This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 50 TC 7 Z9 7 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD FEB 1 PY 2009 VL 326 IS 1 BP 201 EP 211 DI 10.1016/j.ydbio.2008.11.008 PG 11 WC Developmental Biology SC Developmental Biology GA 404HC UT WOS:000263141100018 PM 19046963 ER PT J AU Nguyen, MT Zhu, JJ Nakamura, E Bao, XZ Macken, S AF Nguyen, Minh-Thanh Zhu, Jianjian Nakamura, Eiichiro Bao, Xiaozhong Macken, Susan TI Tamoxifen-Dependent, Inducible Hoxb6CreER(T) Recombinase Function in Lateral Plate and Limb Mesoderm, CNS Isthmic Organizer, Posterior Trunk Neural Crest, Hindgut, and Tailbud SO DEVELOPMENTAL DYNAMICS LA English DT Article DE tamoxifen-dependent Cre; Hoxb6 transgenic promoter; limb; lateral plate; neural crest; CNS isthmic organizer; tailbud; gut endoderm ID GENE-EXPRESSION; SONIC-HEDGEHOG; MOUSE; MICE; EMBRYOS; FORM; BUD AB The ability to generate conditional mutant alleles in mice using Cre-lox technology has facilitated analysis of genes playing critical roles in multiple developmental processes at different times. We used a transgenic Hoxb6 promoter to drive tamoxifen-dependent Cre recombinase expression in several developing systems that serve as major models for elucidating inductive interactions and mechanisms of morphogenesis, including lateral plate mesoderm and descendant limb buds, neural crest progenitors of the neural tube, tailbud, and CNS isthmic organizer. The Hoxb6CreER(T) line gives very rapid and complete recombination over a short time window after a single tamoxifen dose, allowing precise time requirements for gene function to be assessed accurately. Embryonic cells cultured from the Hoxb6CreER(T) line also display rapid recombination ex vivo after tamoxifen exposure. Hence, the Hoxb6CreER(T) line provides a valuable tool for analyzing gene function, as well as lineage tracing studies using genetic cell marking, in several developing systems. Developmental Dynamics 238:467-474, 2009. Published 2009 Wiley-Liss, Inc.dagger C1 [Macken, Susan] NCI, Ctr Canc Res, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Macken, S (reprint author), NCI, Ctr Canc Res, Pathol Lab, NIH, Bldg 10,Room 2A33, Bethesda, MD 20892 USA. EM smack@helix.nih.gov FU Center for Cancer Research; National Cancer Institute; NIH FX We thank Daniel Metzger and Pierre Chambon for providing the CreERT coding construct, Maus Schughart for the Hoxb6 promoter construct, and Lionel Feigenbaum (Director, LASP, SAIC/NCI-FCRDC) for pronuclear injections to generate transgenic lines. This research was supported by the Center for Cancer Research, National Cancer Institute, NIH. NR 31 TC 17 Z9 17 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD FEB PY 2009 VL 238 IS 2 BP 467 EP 474 DI 10.1002/dvdy.21846 PG 8 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 405MO UT WOS:000263229100023 PM 19161221 ER PT J AU Martin, B Golden, E Carlson, OD Pistell, P Zhou, J Kim, W Frank, BP Thomas, S Chadwick, WA Greig, NH Bate, GP Sathasivam, K Bernier, M Maudsley, S Mattson, MP Egan, JM AF Martin, Bronwen Golden, Erin Carlson, Olga D. Pistell, Paul Zhou, Jie Kim, Wook Frank, Brittany P. Thomas, Sam Chadwick, Wayne A. Greig, Nigel H. Bate, Gillian P. Sathasivam, Kirupa Bernier, Michel Maudsley, Stnart Mattson, Mark P. Egan, Josephine M. TI Exendin-4 Improves Glycemic Control, Ameliorates Brain and Pancreatic Pathologies, and Extends Survival in a Mouse Model of Huntington's Disease SO DIABETES LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; ANIMAL-MODEL; INSULIN-RESISTANCE; DIABETES-MELLITUS; CAG REPEAT; RECEPTOR; INHIBITION; MICE; RATS; NEUROPROTECTION AB OBJECTIVE-The aim of this study was to find an effective treatment for the genetic form of diabetes that is present in some Huntington's disease patients and in Huntington's disease mouse models. Huntington's disease is a neurodegenerative disorder caused by a polyglutamine expansion within the huntingtin protein. Huntington's disease patients exhibit neuronal dysfunction/degeneration, chorea, and progressive weight loss. Additionally, they suffer from abnormalities in energy metabolism affecting both the brain and periphery. Similarly to Huntington's disease patients, mice expressing the mutated human huntingtin protein also exhibit neurodegenerative changes, motor dysfunction, perturbed energy metabolism, and elevated blood glucose levels. RESEARCH DESIGN AND METHODS-Huntington's disease mice were treated with an FDA-approved antidiabetic glucagon-like peptide 1 receptor agonist, exendin-4 (Ex-4), to test whether euglycemia could be achieved, whether pancreatic dysfunction could be alleviated, and whether the mice showed any neurological benefit. Blood glucose and insulin levels and various appetite hormone concentrations were measured during the study. Additionally, motor performance and life span were quantified and mutant huntingtin (mhtt) aggregates were measured in both the pancreas and brain. RESULTS-Ex-4 treatment ameliorated abnormalities in peripheral glucose regulation and suppressed cellular pathology in both brain and pancreas in a mouse model of Huntington's disease. The treatment also improved motor function and extended the survival time of the Huntington's disease mice. These clinical improvements were correlated with reduced accumulation of mhtt protein aggregates in both islet and brain cells. CONCLUSIONS-Targeting both peripheral and neuronal deficits, Ex-4 is an attractive agent for therapeutic intervention in Huntington's disease patients suffering from diabetes. Diabetes 58:318-328, 2009 C1 [Martin, Bronwen; Golden, Erin; Chadwick, Wayne A.; Greig, Nigel H.; Maudsley, Stnart; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Carlson, Olga D.; Zhou, Jie; Kim, Wook; Thomas, Sam; Bernier, Michel; Egan, Josephine M.] NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Pistell, Paul] NIA, Lab Expt Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. [Frank, Brittany P.] NIA, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Bate, Gillian P.; Sathasivam, Kirupa] Kings Coll London, Sch Med, Guys Hosp, London WC2R 2LS, England. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov; eganj@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; Bates, Gillian/E-1146-2012; OI Bates, Gillian/0000-0002-4041-6305; Bernier, Michel/0000-0002-5948-368X FU Huntington's Disease Society of America; National Institute on Aging FX We thank the National Institute on Aging animal facility staff and Marveia Daniel for the expert animal care, Alfred May for microscopy assistance, and Dr. David Borchelt for advice during the study. NR 50 TC 92 Z9 93 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2009 VL 58 IS 2 BP 318 EP 328 DI 10.2337/db08-0799 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401GI UT WOS:000262927500006 PM 18984744 ER PT J AU Bergouignan, A Trudel, G Simon, C Chopard, A Schoeller, DA Momken, I Votruba, SB Desage, M Burdge, GC Gauquelin-Koch, G Normand, S Blanc, S AF Bergouignan, Audrey Trudel, Guy Simon, Chantal Chopard, Angele Schoeller, Dale A. Momken, Iman Votruba, Susanne B. Desage, Michel Burdge, Graham C. Gauquelin-Koch, Guillemette Normand, Sylvie Blanc, Stephane TI Physical Inactivity Differentially Alters Dietary Oleate and Palmitate Trafficking SO DIABETES LA English DT Article ID FREE FATTY-ACIDS; ACTIVATED PROTEIN-KINASE; BED REST; SKELETAL-MUSCLE; TRIACYLGLYCEROL SYNTHESIS; SIMULATED MICROGRAVITY; ENERGY-EXPENDITURE; INSULIN-RESISTANCE; RAT-LIVER; EXERCISE AB OBJECTIVE-Obesity and diabetes are characterized by the incapacity to use fat as fuel. We hypothesized that this reduced fat oxidation is secondary to a sedentary lifestyle. RESEARCH DESIGN AND METHODS-We investigated the effect of a 2-month bed rest on the dietary oleate and palmitate trafficking in lean women (control group, n = 8) and the effect of concomitant resistance/aerobic exercise training as a counter-measure (exercise group, n = 8). Trafficking of stable isotope-labeled dietary fats was combined with muscle gene expression and magnetic resonance imaging-derived muscle fat content. analyses. RESULTS-In the control group, bed rest increased the cumulative [1-(13)C]oleate and [d(31)]palmitate appearance in triglycerides (37%, P = 0.009, and 34%, P = 0.016, respectively) and nonesterified fatty acids (NEFAs) (37%, P = 0.038, and 38%, P = 0.002) and decreased muscle lipoprotein lipase (P = 0.043) and fatty acid translocase CD36 (P = 0.043) mRNA expressions. Plasma NEFA-to-triglyceride ratios for [1-(13)C]oleate and [d(31)]palmitate remained unchanged, suggesting that the same proportion of tracers enters the peripheral tissues after bed rest. Bed rest did not affect [1-(13)C]oleate oxidation but decreased [d(31)]palmitate oxidation by -8.2 +/- 4.9% (P < 0.0001). Despite a decreased spontaneous energy intake and a reduction of 1.9 +/- 0.3 kg (P = 0.001) in fat mass, exercise training did not mitigate these alterations but partially maintained fat-free mass, insulin sensitivity, and total lipid oxidation in fasting and fed states. In both groups, muscle fat content increased by 2.7% after bed rest and negatively correlated with the reduction in [d(31)]palmitate oxidation (r(2) = 0.48, P = 0.003). CONCLUSIONS-While saturated and monounsaturated fats have similar plasma trafficking and clearance, physical inactivity affects the partitioning of saturated fats toward storage, likely leading to an accumulation of palmitate in muscle fat. Diabetes 58:367-376, 2009 C1 [Bergouignan, Audrey; Momken, Iman; Blanc, Stephane] Louis Pasteur Univ, Dept Ecol Physiol & Ethol, Hubert Curten Pluridisciplinary Inst, CNRS,UMR 7178, Strasbourg, France. [Trudel, Guy] Univ Ottawa, Dept Med, Bone & Joint Res Lab, Ottawa, ON, Canada. [Simon, Chantal] Louis Pasteur Univ, Dept Nutr, Hautepierre Hosp, Strasbourg, France. [Chopard, Angele] Nice Sophia Antipolis Univ, Physiol Adapt Lab, Nice, France. [Chopard, Angele] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada. [Schoeller, Dale A.] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. [Votruba, Susanne B.] NIDDKD, Obes & Diabet Res Sect, NIH, Phoenix, AZ USA. [Desage, Michel; Normand, Sylvie] Human Nutr Res Ctr Rhone Alpes CNRHL, Laennec Med Fac, Lyon, France. [Burdge, Graham C.] Univ Southampton, Inst Human Nutr, Southampton, Hants, England. [Gauquelin-Koch, Guillemette] French Space Agcy CNES, Paris, France. RP Blanc, S (reprint author), Louis Pasteur Univ, Dept Ecol Physiol & Ethol, Hubert Curten Pluridisciplinary Inst, CNRS,UMR 7178, Strasbourg, France. EM stephane.blanc@c-strassbourg.fr RI Simon, Chantal/B-2895-2011; Burdge, Graham/A-2370-2014; Bergouignan, Audrey/A-2750-2016 OI Simon, Chantal/0000-0002-7820-3233; Burdge, Graham/0000-0002-7665-2967; Bergouignan, Audrey/0000-0002-1266-5144 FU Centre National d'Etudes Spatiales; Centre National de la Recherche Francaise, l'Universite Louis Pasteur; Canadian Institutes of Health Research; British Heart Foundation FX The authors are indebted to the administrative and medical staff of the Institute of Space Medicine for the outstanding organization of the bed rest supported by CNES, ESA, NASA, and CSA. We particularly thank Eliane Mioskowski for performing hormones and metabolites assays, Caroline Childs for her precious advice on the development of the solid phase extraction method, Martin Lecompte for Magnetic Resonance imaging, Hakim Louati and Liz Coletta for MR muscle fat measures, and Georges Favre for his help in data analysis. The most credit, however, must be given to the participants of the study. NR 54 TC 39 Z9 40 U1 0 U2 15 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2009 VL 58 IS 2 BP 367 EP 376 DI 10.2337/db08-0263 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401GI UT WOS:000262927500012 PM 19017764 ER PT J AU de Victoria, EOM Xu, XY Koska, J Francisco, AM Scalise, M Ferrante, AW Krakoff, J AF de Victoria, Emilio Ortega Martinez Xu, Xiaoyuan Koska, Juraj Francisco, Ann Marie Scalise, Michael Ferrante, Anthony W., Jr. Krakoff, Jonathan TI Macrophage Content in Subcutaneous Adipose Tissue Associations With Adiposity, Age, Inflammatory Markers, and Whole-Body Insulin Action in Healthy Pima Indians SO DIABETES LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; MONOCYTE CHEMOATTRACTANT PROTEIN-1; NECROSIS-FACTOR-ALPHA; ENDOTHELIAL DYSFUNCTION; INCREASED EXPRESSION; SKELETAL-MUSCLE; GENE-EXPRESSION; OBESE SUBJECTS; PPAR-GAMMA; LIVER FAT AB OBJECTIVE-In severely obese individuals and patients with diabetes, accumulation and activation of macrophages in adipose tissue has been implicated in the development of obesity-associated complications, including insulin resistance. We sought, to determine whether in a healthy population, adiposity, sex, age, or insulin action is associated with adipose tissue macrophage content (ATMc) and/or markers of macrophage activation. RESEARCH DESIGN AND METHODS-Subcutaneous ATMc from young adult Pima Indians with a wide range of adiposity (13-46% body fat, by whole-body dual-energy X-ray absorptiometry) and insulin action (glucose disposal rate 1.6-9 mg/kg estimated metabolic body size/min, by glucose clamp) were measured. We also measured expression in adipose tissue of factors implicated in macrophage recruitment and activation to determine any association with ATMc and insulin action. RESULTS-ATMc, as assessed by immunohistochemistry (Mphi) and by macrophage-specific gene expression (CD68, CD11b, and CSF1R), were correlated with percent body fat, age, and female sex. Gene expression of CD68, CD11b, mid CSF1R but not Mphi was correlated negatively with glucose disposal rate but not after adjustment for percent body fat, age, and sex. However, adipose tissue expression of plasminogen activator inhibitor type-1 (PAI-1) and CD11 antigen-like family member C (CD11c), markers produced by macrophages, were negatively correlated with adjusted glucose disposal rate (r = -0.28, P = 0.05 and r = -0.31, P = 0.03). CONCLUSIONS-ATMc is correlated with age and adiposity but not with insulin action independent of adiposity in healthy human subjects. However, PAI-1 and CD11c expression are independent predictors of insulin action, indicating a possible role for adipose tissue macrophage activation. Diabetes 58:385-393, 2009 C1 [de Victoria, Emilio Ortega Martinez; Koska, Juraj; Krakoff, Jonathan] NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ USA. [Xu, Xiaoyuan; Francisco, Ann Marie; Scalise, Michael; Ferrante, Anthony W., Jr.] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY USA. RP de Victoria, EOM (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ USA. EM eortega1@clinic.ub.es NR 63 TC 38 Z9 40 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2009 VL 58 IS 2 BP 385 EP 393 DI 10.2337/db08-0536 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401GI UT WOS:000262927500014 ER PT J AU Berthier, CC Zhang, H Schin, M Henger, A Nelson, RG Yee, B Boucherot, A Neusser, MA Cohen, CD Carter-Su, C Argetsinger, LS Rastaldi, MP Brosius, FC Kretzler, M AF Berthier, Celine C. Zhang, Hongyru Schin, MaryLee Henger, Anna Nelson, Robert G. Yee, Berne Boucherot, Anissa Neusser, Matthias A. Cohen, Clemens D. Carter-Su, Christin Argetsinger, Lawrence S. Rastaldi, Maria P. Brosius, Frank C. Kretzler, Matthias TI Enhanced Expression of Janus Kinase-Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy SO DIABETES LA English DT Article ID JAK/STAT PATHWAY; OXIDATIVE STRESS; MESANGIAL CELLS; HIGH GLUCOSE; KIDNEY; DISEASE; MOUSE; SUSCEPTIBILITY; COMPLICATIONS; PROGRESSION AB OBJECTIVE-Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy, whereas tubulointerstitial injury and fibrosis are critical for progression of diabetic nephropathy to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from diabetic nephropathy patients to identity pathways that may be activated in humans but note in murine models of diabetic nephropathy that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis, and kidney failure. RESEARCH DESIGN AND METHODS-Kidney biopsies were obtained from 74 patients (control subjects, early and progressive type 2 diabetic nephropathy). Glomerular and tubulointerstitial mRNAs were microarrayed, followed by bioinformatics analyses. Gene expression changes were confirmed by real-time RT-PCR and immunohistological staining. Samples from db/db C57BLKS and streptozotocin-induced DBA/2J mice, commonly studied murine models of diabetic nephropathy, were analyzed. RESULTS-In human glomeruli and tubulointerstitial samples, the Janus kinase (Jak)-signal transducer and activator of transcription (Stat) pathway was highly and significantly regulated. Jak-1, -2, and -3 as well as Stat-1 and -3 were expressed at higher levels in patients with diabetic nephropathy than in control subjects. The estimated glomerular filtration rate significantly correlated with tubulointerstitial Jak-1, -2, and -3 and Stat-1 expression (R(2) = 0.30-0.44). Immunohistochemistry found strong Jak-2 staining in glomerular and tubulointerstitial compartments in diabetic nephropathy compared with control subjects. In contrast, there was little or no increase in expression of Jak/Stat genes in the db/db C57BLKS or diabetic DBA/2J mice. CONCLUSIONS-These data suggest a direct relationship between tubulointerstitial Jak/Stat expression and progression of kidney failure in patients with type 2 diabetic nephropathy and distinguish progressive human diabetic nephropathy from nonprogressive murine diabetic nephropathy. Diabetes 58:469-477, 2009 C1 [Berthier, Celine C.; Zhang, Hongyru; Schin, MaryLee; Henger, Anna; Boucherot, Anissa; Neusser, Matthias A.; Brosius, Frank C.; Kretzler, Matthias] Univ Michigan, Dept Internal Med Nephrol, Ann Arbor, MI 48109 USA. [Nelson, Robert G.] NIDDKD, Dept Epidemiol, Phoenix, AZ USA. [Nelson, Robert G.] NIDDKD, Clin Res Branch, Phoenix, AZ USA. [Yee, Berne] SW Kidney Inst, Phoenix, AZ USA. [Cohen, Clemens D.] Univ Zurich Hosp, Clin Nephrol, CH-8091 Zurich, Switzerland. [Neusser, Matthias A.; Cohen, Clemens D.] Univ Zurich Hosp, Dept Physiol, CH-8091 Zurich, Switzerland. [Carter-Su, Christin; Argetsinger, Lawrence S.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Rastaldi, Maria P.] Fondaz Amico Ric Malattie Renali, Renal Res Lab, Milan, Italy. [Rastaldi, Maria P.] Fondaz IRCCS Policlin, Milan, Italy. RP Brosius, FC (reprint author), Univ Michigan, Dept Internal Med Nephrol, Ann Arbor, MI 48109 USA. EM fbrosius@umich.edu RI Nelson, Robert/B-1470-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK60994, U01 DK076139, R21 DK079441]; National Institutes of Health [DK20572] FX We are indebted to Drs. Almut Nitsche and Bodo Brunner (sanoft-aventis Deutschland, Frankfurt, Germany) for DNA chip hybridizations and delivery of the dataset of hybridization results. NR 37 TC 104 Z9 108 U1 0 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2009 VL 58 IS 2 BP 469 EP 477 DI 10.2337/db08-1328 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401GI UT WOS:000262927500024 PM 19017763 ER PT J AU Rong, R Hanson, RL Ortiz, D Wiedrich, C Kobes, S Knowler, WC Bogardus, C Baier, LJ AF Rong, Rong Hanson, Robert L. Ortiz, Daniel Wiedrich, Christopher Kobes, Sayuko Knowler, William C. Bogardus, Clifton Baier, Leslie J. TI Association Analysis of Variation in/Near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B With Type 2 Diabetes and Related Quantitative Traits in Pima Indians SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; OBESITY-RELATED TRAITS; FAT MASS; JAPANESE POPULATION; GENETIC-VARIANTS; ADULT OBESITY; RISK LOCI; POLYMORPHISMS; REPLICATION; CHILDHOOD AB OBJECTIVE-In recent genome-wide association studies, variants in CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, CDKN2B, LOC387761, and FTO were associated with risk for type 2 diabetes in Caucasians. We investigated the association of these single nucleotide polymorphisms (SNPs) and some additional tag SNPs with type 2 diabetes and related quantitative traits in Pima Indians. RESEARCH DESIGN AND METHODS-Forty-seven SNPs were genotyped in 3,501 Pima Indians informative for type 2 diabetes and BMI, among whom 370 had measures of quantitative traits. RESULTS-FTO provided the strongest evidence for replication, where SNPs were associated with type 2 diabetes (odds ratio = 1.20 per copy of the risk allele, P = 0.03) and BMI (P = 0.002). None of tire other previously reported SNPs were associated with type 2 diabetes; however, associations were found between CDKAL1 and HHEX variants and acute insulin response (AIR), where the Caucasian risk alleles for type 2 diabetes were associated with reduced insulin secretion in normoglycemic Pima, Indians. Multiallelic analyses of carrying risk alleles for multiple genes showed correlations between number of risk alleles and type 2 diabetes and impaired insulin secretion in normoglycemic subjects (P = 0.006 and 0.0001 for type 2 diabetes and AIR, respectively), supporting the hypothesis that many of these genes influence diabetes risk by affecting insulin secretion. CONCLUSIONS-Variation in FTO impacts BMI, but the implicated common variants in the other genes did not confer a significant risk for type 2 diabetes in Pima Indians. However, confidence intervals for their estimated effects were consistent with the small effects reported in Caucasians, and the multiallelic "genetic risk profile" identified in Caucasians is associated with diminished early insulin secretion in Pima Indians. Diabetes 58: 478-488, 2009 C1 [Rong, Rong; Hanson, Robert L.; Ortiz, Daniel; Wiedrich, Christopher; Kobes, Sayuko; Knowler, William C.; Bogardus, Clifton; Baier, Leslie J.] NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Baier, LJ (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM lbaier@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU American Diabetes Association; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX R.R. has received a mentor grant from the American Diabetes Association. This study was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.; No potential conflicts of interest relevant to this article were reported.; We gratefully acknowledge the volunteers from the Gila River Indian Community, whose cooperation made these studies possible. NR 40 TC 79 Z9 84 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2009 VL 58 IS 2 BP 478 EP 488 DI 10.2337/db08-0877 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401GI UT WOS:000262927500025 PM 19008344 ER PT J AU Cukierman-Yaffe, T Gerstein, HC Williamson, JD Lazar, RM Lovato, L Miller, ME Coker, LH Murray, A Sullivan, MD Marcovina, SM Launer, LJ AF Cukierman-Yaffe, Tali Gerstein, Hertzel C. Williamson, Jeff D. Lazar, Ronald M. Lovato, Laura Miller, Michael E. Coker, Laura H. Murray, Anne Sullivan, Mark D. Marcovina, Santica M. Launer, Lenore J. CA Action Control Cardiovasc Risk Dia TI Relationship Between Baseline Glycemic Control and Cognitive Function in Individuals With Type 2 Diabetes and Other Cardiovascular Risk Factors The Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial SO DIABETES CARE LA English DT Article ID ALZHEIMERS-DISEASE; DEMENTIA; MELLITUS; GLUCOSE; ADULTS; HEALTH; ASSOCIATION; DECLINE; COHORT AB OBJECTIVE - Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory ill Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS - The relationship of AIC and fasting plasma glucose (FPG) levels to performance on four cognitive tests was assessed, adjusting lot age and Other determinants of cognitive status. The tests were the Digit Symbol Substitution Test (DSST), Mini Mental Status Examination (MMSE), Rey Auditory Verbal Learning Test, and Stroop Test. RESULTS - A Statistically significant age-adjusted association was observed between the A1C level and the score on all four Cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI -1.22 to -2.28; P < 0.0001), a 0.20-point lower MMSE score (-0.11 to -0.28 P < 0.0001), a 0.11-point lower memory score (-0.02 to -0.1.9, P = 0.0142),and a worse score (i.e., 0.75 s more) on the Stroop Test(1.31-0.19, P = 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated With test performance. CONCLUSIONS- Higher A1C levels are associated With lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial. C1 [Cukierman-Yaffe, Tali] Tel Aviv Univ, Sackler Sch Med, Chaim Sheba Med Ctr, Inst Endocrinol,Gertner Inst Epidemiol & Hlth Pol, IL-69978 Tel Aviv, Israel. [Cukierman-Yaffe, Tali; Gerstein, Hertzel C.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Cukierman-Yaffe, Tali; Gerstein, Hertzel C.] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. [Cukierman-Yaffe, Tali; Gerstein, Hertzel C.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Williamson, Jeff D.] Wake Forest Univ, Dept Internal Med, Roena B Kulynych Ctr Memory, Winston Salem, NC 27109 USA. [Lazar, Ronald M.] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Lazar, Ronald M.] Columbia Univ Coll Phys & Surg, Dept Neurol Surg, New York, NY 10032 USA. [Lovato, Laura; Miller, Michael E.] Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Coker, Laura H.] Wake Forest Univ, Dept Social Sci & Hlth Policy, Roena B Kulynych Ctr Memory, Winston Salem, NC 27109 USA. [Murray, Anne] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Murray, Anne] Chron Dis Res Grp, Minneapolis, MN USA. [Marcovina, Santica M.] Univ Washington, NW Lipid Metab & Diabet Res Labs, Seattle, WA 98195 USA. [Launer, Lenore J.] NIA, Intramural Res Programme, NIH, Bethesda, MD 20892 USA. RP Cukierman-Yaffe, T (reprint author), Tel Aviv Univ, Sackler Sch Med, Chaim Sheba Med Ctr, Inst Endocrinol,Gertner Inst Epidemiol & Hlth Pol, IL-69978 Tel Aviv, Israel. EM cukierm@mcmastcr.ca FU National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute, Bethesda; National Institute on Aging (NIA); Centers for Disease Control and Prevention; NIA/NHLBI; [NIHNHLBI-HC-99-16] FX Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, Bethesda, MD; the National Institute on Aging (NIA); and the Centers for Disease Control and Prevention. This study was also supported by Grant NIHNHLBI-HC-99-16 from the NIA/NHLBI, by the National Institutes of Health-funded General Clinical Research Centers, and by the Intramural Research Program at the NIA. NR 24 TC 164 Z9 179 U1 1 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2009 VL 32 IS 2 BP 221 EP 226 DI 10.2337/dc08-1153 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402MV UT WOS:000263018700003 PM 19171735 ER PT J AU Cowie, CC Rust, KF Ford, ES Eberhardt, MS Byrd-Holt, DD Li, CY Williams, DE Gregg, EW Bainbridge, KE Saydah, SH Geiss, LS AF Cowie, Catherine C. Rust, Keith F. Ford, Earl. S. Eberhardt, Mark S. Byrd-Holt, Danita D. Li, Chaoyang Williams, Desmond E. Gregg, Edward W. Bainbridge, Kathleen E. Saydah, Sharon H. Geiss, Linda S. TI Full Accounting of Diabetes and Pre-Diabetes in the US Population in 1988-1994 and 2005-2006 SO DIABETES CARE LA English DT Article ID IMPAIRED FASTING GLUCOSE; NUTRITION EXAMINATION SURVEY; DISEASE RISK-FACTORS; NATIONAL-HEALTH; PREVALENCE; ADULTS; TOLERANCE; MELLITUS; INTERVENTION; ASSOCIATION AB OBJECTIVE - We examined the prevalences of diagnosed diabetes, and undiagnosed diabetes and pre-diabetes using fasting and 2-h oral glucose tolerance test values, in the U.S. during 2005-2006. We then compared the prevalences of these conditions with those in 1988-1994. RESEARCH DESIGN AND METHODS - In 2005-2006, the National Health and Nutrition Examination Survey included a probability sample of 7,267 people aged :12 years, Participants were classified according to glycemic Status by interview for diagnosed diabetes and by fasting and 2-h glucoses measured in subsamples. RESULTS - In 2005-2006, the crude prevalence of total diabetes in people aged >= 20 years was 12.9%, of which similar to 40% was undiagnosed. in people aged >= 20 years, the crude prevalence of impaired fasting glucose was 25.7% and of impaired glucose tolerance was 13.8%, with almost 30% having either. Over 40% of individuals had diabetes or pre-diabetes. Almost one-third of the elderly had diabetes, and three-quarters had diabetes or pre-diabetes. Compared with non-Hispanic whites, age- and sex-standardized prevalence of diagnosed diabetes was approximately twice as high in non-Hispanic blacks (P < 0.0001.) and Mexican Americans (P = 0.0001), whereas undiagnosed diabetes was not higher. Crude prevalence of diagnosed diabetes in people aged >= 20 years rose from 5.1% in 1988-1994 to 7.7% in 2005-2006 (P = 0.0001); this was significant after accounting for differences in age and sex, particularly in non-Hispanic blacks. Prevalences of undiagnosed diabetes and pre-diabetes were generally stable, although the proportion of total diabetes that was undiagnosed decreased in Mexican Americans. CONCLUSIONS - Over 40% of people aged >= 20 years have hyperglycemic conditions, and prevalence is higher in minorities. Diagnosed diabetes has increased over time, but other conditions have been relatively stable. C1 [Cowie, Catherine C.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Rust, Keith F.] WESTAT Corp, Rockville, MD 20850 USA. [Ford, Earl. S.; Li, Chaoyang] Ctr Dis Control & Prevent, Div Adult & Community Hlth, Atlanta, GA USA. [Eberhardt, Mark S.; Saydah, Sharon H.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Byrd-Holt, Danita D.; Bainbridge, Kathleen E.] Social & Sci Syst Inc, Silver Spring, MD USA. [Williams, Desmond E.; Gregg, Edward W.; Geiss, Linda S.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. RP Cowie, CC (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. EM cowiec@mail.nih.gov NR 25 TC 653 Z9 664 U1 3 U2 23 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2009 VL 32 IS 2 BP 287 EP 294 DI 10.2337/dc08-1296 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402MV UT WOS:000263018700015 PM 19017771 ER PT J AU Rich, SS Nierras, C Akolkar, B AF Rich, S. S. Nierras, C. Akolkar, B. TI Setting the stage SO DIABETES OBESITY & METABOLISM LA English DT Article C1 [Rich, S. S.] Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Nierras, C.] Juvenile Diabet Res Fdn, New York, NY USA. [Akolkar, B.] NIDDK, Bethesda, MD USA. RP Rich, SS (reprint author), Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, 6111 W Complex,POB 800717, Charlottesville, VA 22908 USA. EM ssr4n@virginia.edu FU NIDDK NIH HHS [U01 DK062418, U01 DK062418-06] NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1462-8902 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD FEB PY 2009 VL 11 BP 1 EP 1 DI 10.1111/j.1463-1326.2008.00996.x PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 394YR UT WOS:000262489600001 PM 19143808 ER PT J AU Rich, SS Akolkar, B Concannon, P Erlich, H Hilner, J Julier, C Morahan, G Nerup, J Nierras, C Pociot, F Todd, JA AF Rich, S. S. Akolkar, B. Concannon, P. Erlich, H. Hilner, J. Julier, C. Morahan, G. Nerup, J. Nierras, C. Pociot, F. Todd, J. A. TI Results of the MHC Fine Mapping Workshop SO DIABETES OBESITY & METABOLISM LA English DT Article DE association; HLA; MHC; microsatellite; SNP; type 1 diabetes C1 [Rich, S. S.] Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Akolkar, B.] NIDDK, Bethesda, MD USA. [Erlich, H.] Roche Mol Syst, Pleasanton, CA USA. [Hilner, J.] Wake Forest Univ, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Julier, C.] INSERM, Ctr Natl Genotypage, U730, Evry, France. [Morahan, G.] Western Australian Inst Med Res, Perth, WA, Australia. [Nerup, J.; Pociot, F.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Nierras, C.] Juvenile Diabet Res Fdn, New York, NY USA. [Todd, J. A.] Univ Cambridge, Cambridge, England. RP Rich, SS (reprint author), Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, 6111 W Complex,POB 800717, Charlottesville, VA 22908 USA. EM ssr4n@virginia.edu RI Todd, John/A-3542-2010; OI Concannon, Patrick/0000-0002-5801-1859; Pociot, Flemming/0000-0003-3274-5448 FU NIDDK NIH HHS [U01 DK062418, U01 DK062418-06]; Wellcome Trust [061858] NR 0 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1462-8902 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD FEB PY 2009 VL 11 BP 108 EP 109 DI 10.1111/j.1463-1326.2008.01011.x PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 394YR UT WOS:000262489600016 PM 19143823 ER PT J AU Wasko, BM Holland, CL Resnick, MA Lewis, LK AF Wasko, Brian M. Holland, Cory L. Resnick, Michael A. Lewis, L. Kevin TI Inhibition of DNA double-strand break repair by the Ku heterodimer in mrx mutants of Saccharomyces cerevisiae SO DNA REPAIR LA English DT Article DE Telomerase; Exonuclease; DNA repair; End-joining; Homologous recombination ID YEAST TELOMERASE RNA; HOMOLOGOUS RECOMBINATION; CHECKPOINT ACTIVATION; GENOME STABILITY; MRE11 COMPLEX; PROTEIN; MAINTENANCE; INTERACTS; COMPONENT; DAMAGE AB Yeast rad50 and mre11 nuclease mutants are hypersensitive to physical and chemical agents that induce DNA double-strand breaks (DSBs). This sensitivity was suppressed by elevating intracellular levels of TLC1, the RNA subunit of telomerase. Suppression required proteins linked to homologous recombination, including Rad51. Rad52, Rad59 and Exo1. but not genes of the nonhomologous end-joining (NHEJ) repair pathway. Deletion mutagenesis experiments demonstrated that the 5'-end of TLC1 RNA was essential and a segment containing a binding site for the Yku70/Yku80 complex was sufficient for suppression. A mutant TLC1 RNA unable to associate with Yku80 protein did not increase resistance. These and other genetic studies indicated that association of the Ku heterodimer with broken DNA ends inhibits recombination in mrx mutants. but not in repair-proficient cells or in other DNA repair single mutants. In support of this model, DNA damage resistance of mrx cells was enhanced when YKU70 was co-inactivated. Defective recombinational repair of DSBs in mrx cells thus arises from at least two separate processes: loss of Mrx nuclease-associated DNA end-processing and inhibition of the Exo1-mediated secondary recombination pathway by Ku. (C) 2008 Elsevier B.V. All rights reserved. C1 [Wasko, Brian M.; Holland, Cory L.; Lewis, L. Kevin] Texas State Univ, Dept Chem & Biochem, San Marcos, TX 78666 USA. [Resnick, Michael A.] Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Lewis, LK (reprint author), Texas State Univ, Dept Chem & Biochem, 601 Univ Dr, San Marcos, TX 78666 USA. EM LL18@txstate.edu FU Research Corporation [CC5767]; National Institutes of Health [1R15AG02852001A1] FX The authors wish to thank Dan Gottschling and Nancy Kleckner for gifts of plasmids and Shanna Calero for expert technical assistance. KL was supported in part by Research Corporation grant CC5767 and National Institutes of Health Grant 1R15AG02852001A1. NR 52 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD FEB 1 PY 2009 VL 8 IS 2 BP 162 EP 169 DI 10.1016/j.dnarep.2008.09.010 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 405GU UT WOS:000263211900004 PM 18992851 ER PT J AU Kirkali, G de Souza-Pinto, NC Jaruga, P Bohr, VA Dizdaroglu, M AF Kirkali, Gueldal de Souza-Pinto, Nadja C. Jaruga, Pawel Bohr, Vilhelm A. Dizdaroglu, Miral TI Accumulation of (5 ' S)-8,5 '-cyclo-2 '-deoxyadenosine in organs of Cockayne syndrome complementation group B gene knockout mice SO DNA REPAIR LA English DT Article DE Cockayne syndrome; 8,5 '-Cyclopurine-2 '-deoxynucleosides; Helix-distorting lesion; Hydroxyl radical; Intramolecular cyclization; Mass spectrometry; Nucleotide excision repair; Oxidatively induced DNA damage ID OXIDATIVE DNA-DAMAGE; BASE EXCISION-REPAIR; COLI FPG PROTEIN; HUMAN-CELLS; XERODERMA-PIGMENTOSUM; CELLULAR REPAIR; IONIZING-RADIATION; PURINE LESIONS; BREAST-CANCER; ACTIVE GENES AB Cockayne syndrome (CS) is a human genetic disorder characterized by sensitivity to UV radiation, neurodegeneration, premature aging among other phenotypes. CS complementation group B (CS-B) gene (csb) encodes the CSB protein (CSB) that is involved in base excision repair of a number of oxidatively induced lesions in genomic DNA in vivo. We hypothesized that CSB may also play a role in cellular repair of the DNA helix-distorting tandem lesion (5'S)-8,5'-cyclo-2'-deoxyadenosine (S-cdA). Among many DNA lesions. S-cdA is unique in that it represents a concomitant damage to both the sugar and base moieties of the same nucleoside. Because of the presence of the C8-C5' covalent bond, S-cdA is repaired by nucleotide excision repair unlike most of other oxidatively induced lesions in DNA, which are subject to base excision repair. To test our hypothesis, we isolated genomic DNA from brain, kidney and liver of wild type and csb knockout (csb(-/-)) mice. Animals were not exposed to any exogenous oxidative stress before the experiment. DNA samples were analysed by liquid chromatography/mass spectrometry with isotope-dilution. Statistically greater background levels of S-cdA were observed in all three organs of csb(-/-) mice than in those of wild type mice. These results suggest the in vivo accumulation of S-cdA in genomic DNA due to lack of its repair in csb(-/-) mice. Thus, this study provides, for the first time, the evidence that CSB plays a role in the repair of the DNA helix-distorting tandem lesion S-cdA. Accumulation of unrepaired S-cdA in vivo may contribute to the pathology associated with CS. Published by Elsevier B.V. C1 [Kirkali, Gueldal; Jaruga, Pawel; Dizdaroglu, Miral] Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. [Kirkali, Gueldal] Dokuz Eylul Univ, Dept Biochem, Fac Medicin, Izmir, Turkey. [de Souza-Pinto, Nadja C.] Univ Sao Paulo, Dept Bioquim, Inst Quim, BR-05508 Sao Paulo, Brazil. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Dizdaroglu, M (reprint author), Natl Inst Stand & Technol, Chem Sci & Technol Lab, 100 Bur Dr,MS8311, Gaithersburg, MD 20899 USA. EM miral@nist.gov RI Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; Jaruga, Pawel/M-4378-2015 OI Souza-Pinto, Nadja/0000-0003-4206-964X; FU Intramural NIH HHS [Z01 AG000727-15] NR 53 TC 45 Z9 45 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD FEB 1 PY 2009 VL 8 IS 2 BP 274 EP 278 DI 10.1016/j.dnarep.2008.09.009 PG 5 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 405GU UT WOS:000263211900015 PM 18992371 ER PT J AU Sharova, LV Sharov, AA Nedorezov, T Piao, Y Shaik, N Ko, MSH AF Sharova, Lioudmila V. Sharov, Alexei A. Nedorezov, Timur Piao, Yulan Shaik, Nabeebi Ko, Minoru S. H. TI Database for mRNA Half-Life of 19 977 Genes Obtained by DNA Microarray Analysis of Pluripotent and Differentiating Mouse Embryonic Stem Cells SO DNA RESEARCH LA English DT Article DE mRNA decay; mRNA degradation; microarray; transcript; exon junction; AU-rich elements (ARE); embryonic stem cells; leukemia inhibitory factor (LIF); retinoic acid (RA); cell differentiation; mouse strain ID NONSENSE-MEDIATED DECAY; GENOME-WIDE ANALYSIS; AU-RICH ELEMENTS; DEVELOPMENTAL EXPRESSION; SACCHAROMYCES-CEREVISIAE; DEGRADATION; STABILITY; PROTEIN; YEAST; TRANSCRIPTION AB Degradation of mRNA is one of the key processes that control the steady-state level of gene expression. However, the rate of mRNA decay for the majority of genes is not known. We successfully obtained the rate of mRNA decay for 19 977 non-redundant genes by microarray analysis of RNA samples obtained from mouse embryonic stem (ES) cells. Median estimated half-life was 7.1 h and only <100 genes, including Prdm1, Myc, Gadd45 g, Foxa2, HesS and Trib1, showed half-life less than 1 h. In general, mRNA species with short half-life were enriched among genes with regulatory functions (transcription factors), whereas mRNA species with long half-life were enriched among genes related to metabolism and structure (extracellular matrix, cytoskeleton). The stability of mRNAs correlated more significantly with the structural features of genes than the function of genes: mRNA stability showed the most significant positive correlation with the number of exon junctions per open reading frame length, and negative correlation with the presence of PUF-binding motifs and AU-rich elements in T-untranslated region (UTR) and CpG dinucleotides in the 5'-UTR. The mRNA decay rates presented in this report are the largest data set for mammals and the first for ES cells. C1 [Sharova, Lioudmila V.; Sharov, Alexei A.; Nedorezov, Timur; Piao, Yulan; Shaik, Nabeebi; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM KoM@grc.nia.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural Research Program of the National Institute on Aging, NIH [Z01 AG000656] FX The work was supported by the Intramural Research Program of the National Institute on Aging, NIH (Z01 AG000656). NR 54 TC 188 Z9 191 U1 1 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1340-2838 J9 DNA RES JI DNA Res. PD FEB PY 2009 VL 16 IS 1 BP 45 EP 58 DI 10.1093/dnares/dsn030 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 416JM UT WOS:000264002100004 PM 19001483 ER PT J AU Aiba, K Nedorezov, T Piao, Y Nishiyama, A Matoba, R Sharova, LV Sharov, AA Yamanaka, S Niwa, H Ko, MSH AF Aiba, Kazuhiro Nedorezov, Timur Piao, Yulan Nishiyama, Akira Matoba, Ryo Sharova, Lioudmila V. Sharov, Alexei A. Yamanaka, Shinya Niwa, Hitoshi Ko, Minoru S. H. TI Defining Developmental Potency and Cell Lineage Trajectories by Expression Profiling of Differentiating Mouse Embryonic Stem Cells SO DNA RESEARCH LA English DT Article DE embryonic stem; embryonic germ; induced pluripotent stem; mouse embryo fibroblast; embryonal carcinoma; retinoic acids; neural stem/progenitor; trophoblast stem; principal component analysis; leukemia inhibitory factor; epigenetic landscape; Waddington; developmental potency; cell lineage trajectory; gene expression profiling; DNA microarray analysis ID PRIMORDIAL GERM-CELLS; NUCLEAR TRANSPLANTATION; MICROARRAY DATA; RETINOIC ACID; ES CELLS; CULTURE; PROLIFERATION; GENERATION; ENDODERM; GENES AB Biologists rely on morphology, function and specific markers to define the differentiation status of cells. Transcript profiling has expanded the repertoire of these markers by providing the snapshot of cellular status that reflects the activity of all genes. However, such data have been used only to assess relative similarities and differences of these cells. Here we show that principal component analysis of global gene expression profiles map cells in multidimensional transcript profile space and the positions of differentiating cells progress in a stepwise manner along trajectories starting from undifferentiated embryonic stem (ES) cells located in the apex. We present three 'cell lineage trajectories', which represent the differentiation of ES cells into the first three lineages in mammalian development: primitive endoderm, trophoblast and primitive ectoderm/neural ectoderm. The positions of the cells along these trajectories seem to reflect the developmental potency of cells and can be used as a scale for the potential of cells. indeed, we show that embryonic germ cells and induced pluripotent cells are mapped near the origin of the trajectories, whereas mouse embryo fibroblast and fibroblast cell lines are mapped near the far end of the trajectories. We suggest that this method can be used as the non-operational semi-quantitative definition of cell differentiation status and developmental potency. Furthermore, the global expression profiles of cell lineages provide a framework for the future study of in vitro and in vivo cell differentiation. C1 [Aiba, Kazuhiro; Nedorezov, Timur; Piao, Yulan; Nishiyama, Akira; Matoba, Ryo; Sharova, Lioudmila V.; Sharov, Alexei A.; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. [Yamanaka, Shinya] Kyoto Univ, Inst Frontier Med Sci, Dept Stem Cell Biol, Kyoto 3320012, Japan. [Niwa, Hitoshi] RIKEN, Ctr Dev Biol, Lab Pluripotent Cell Studies, Kobe, Hyogo 6500047, Japan. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM kom@mail.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural Research Program of National institutes of Health, National Institute on Aging [Z01 AG000662] FX This work was entirely supported by the Intramural Research Program of National institutes of Health, National Institute on Aging (Z01 AG000662). NR 35 TC 29 Z9 31 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1340-2838 J9 DNA RES JI DNA Res. PD FEB PY 2009 VL 16 IS 1 BP 73 EP 80 DI 10.1093/dnares/dsn035 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 416JM UT WOS:000264002100006 PM 19112179 ER PT J AU Ghanayem, BI Bai, R Burka, LT AF Ghanayem, Burhan I. Bai, Re Burka, Leo T. TI Effect of Dose Volume on the Toxicokinetics of Acrylamide and Its Metabolites and 2-Deoxy-D-glucose SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID URINARY METABOLITES; CYTOCHROME-P450 2E1; MALE-MICE; GLYCIDAMIDE; GENOTOXICITY; CYP2E1-NULL; DNA AB Acrylamide (AA) is a known mutagen and animal carcinogen. Comparison of recent studies revealed significant quantitative differences in AA-induced germ cell mutagenicity. It was hypothesized that despite the administration of AA at similar doses, the discrepancy in the observed effects was most likely due to varying AA concentrations in the administered dosing solution. To test this hypothesis, AA was administered i.p. to mice at 50 mg/kg in a dose volume of 5 or 50 ml/kg, blood was collected at various time points, and AA and its metabolites were quantitated. Changes in dose volume resulted in significant differences in the toxicokinetics of AA and its metabolites and suggested that increased C(max) of AA led to increased metabolism. This theory, in conjunction with the fact that higher levels of AA-derived radioactivity were detected in the testes, may explain the greater toxicity of a 50 mg/kg dose when administered in 5 versus 50 ml/kg. The impact of dose volume on the toxicokinetics of 2-deoxy-D-glucose (DG), a nonreactive, nonmetabolizable substance, was also investigated. The areas under the curve for DG were not different for the two dose volumes; however, C(max) for the more concentrated dose was significantly higher. In conclusion, current studies show that the toxicokinetics of an administered xenobiotic and its metabolites is influenced by the concentration of the parent chemical in the dosing solution. Therefore, it is important to consider the concentration of an administered xenobiotic in the dosing solution because it may affect its toxicokinetics and metabolism and subsequently affect the biological effects of the administered chemical. C1 [Ghanayem, Burhan I.; Bai, Re; Burka, Leo T.] Natl Inst Environm Hlth Sci, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Ghanayem, BI (reprint author), Natl Inst Environm Hlth Sci, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM Ghanayem@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences. NR 19 TC 1 Z9 1 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2009 VL 37 IS 2 BP 259 EP 263 DI 10.1124/dmd.108.024265 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 396WV UT WOS:000262623000003 PM 19022940 ER PT J AU Miyata, M Matsuda, Y Nomoto, M Takamatsu, Y Sato, N Hamatsu, M Dawson, PA Gonzalez, FJ Yamazoe, Y AF Miyata, Masaaki Matsuda, Yoshiki Nomoto, Masahiro Takamatsu, Yuki Sato, Nozomi Hamatsu, Mayumi Dawson, Paul A. Gonzalez, Frank J. Yamazoe, Yasushi TI Cholesterol Feeding Prevents Hepatic Accumulation of Bile Acids in Cholic Acid-Fed Farnesoid X Receptor (FXR)-Null Mice: FXR-Independent Suppression of Intestinal Bile Acid Absorption SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID INDUCED LIVER TOXICITY; NEGATIVE FEEDBACK-REGULATION; ORGANIC SOLUTE TRANSPORTER; ALPHA-OST-BETA; HYDROXYSTEROID SULFOTRANSFERASE; INDUCED CHOLESTASIS; NUCLEAR RECEPTORS; POOL SIZE; HOMEOSTASIS; PROTECTION AB Cholic acid (CA) feeding of farnesoid X receptor (Fxr)-null mice results in markedly elevated hepatic bile acid levels and liver injury. In contrast, Fxr-null mice fed cholesterol plus CA (CA+Chol) do not exhibit liver injury, and hepatic bile acid levels and bile acid pool size are reduced 51 and 40%, respectively, compared with CA-treated Fxr-null mice. These decreases were not observed in wild-type mice. Despite a reduced bile acid pool size, hepatic Cyp7a1 mRNA expression was increased in Fxr-null mice fed the CA+Chol diet, and biliary bile acid output was not changed. Analysis of other potential protective mechanisms revealed significant decreases in portal blood bile acid concentrations and a reduced ileal bile acid absorption capacity, as estimated using an in situ loop method. Fecal bile acid excretion was also increased in Fxr-null mice fed the CA+Chol versus CA diet. The decreased ileal bile acid absorption correlated with decreased ileal apical sodium-dependent bile salt transporter (ASBT) protein expression in brush-border membranes. These results suggest a critical role for ileal bile acid absorption in regulation of hepatic bile acid levels in Fxr-null mice fed CA+Chol. Furthermore, experiments with Fxr-null mice suggest that cholesterol feeding can down-regulate ASBT expression through a pathway independent of FXR. C1 [Miyata, Masaaki; Matsuda, Yoshiki; Nomoto, Masahiro; Takamatsu, Yuki; Sato, Nozomi; Hamatsu, Mayumi; Yamazoe, Yasushi] Tohoku Univ, Grad Sch Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Aoba Ku, Sendai, Miyagi 9808578, Japan. [Dawson, Paul A.] Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Yamazoe, Yasushi] Tohoku Univ, 21st Century Ctr Excellence Program, CRESCENDO, Sendai, Miyagi 980, Japan. RP Miyata, M (reprint author), Tohoku Univ, Grad Sch Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Aoba Ku, 6-3 Aoba, Sendai, Miyagi 9808578, Japan. EM miyata@mail.pharm.tohoku.ac.jp FU Ministry of Education, Science and Culture, Japan [17390039, 17590114]; Ministry of Health, Labor and Welfare, Japan [H17-toxico-ippan-001]; National Institutes of Health [DK-47987] FX This study was supported by the Ministry of Education, Science and Culture, Japan [Grants 17390039, 17590114]; the Ministry of Health, Labor and Welfare, Japan [Grant H17-toxico-ippan-001]; and the National Institutes of Health [Grant DK-47987]. NR 44 TC 11 Z9 11 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2009 VL 37 IS 2 BP 338 EP 344 DI 10.1124/dmd.108.022590 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 396WV UT WOS:000262623000015 PM 18988759 ER PT J AU Shukla, S Robey, RW Bates, SE Ambudkar, SV AF Shukla, Suneet Robey, Robert W. Bates, Susan E. Ambudkar, Suresh V. TI Sunitinib (Sutent, SU11248), a Small-Molecule Receptor Tyrosine Kinase Inhibitor, Blocks Function of the ATP-Binding Cassette (ABC) Transporters P-Glycoprotein (ABCB1) and ABCG2 SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; CANCER RESISTANCE PROTEIN; HIGH-AFFINITY INTERACTION; HEMATOPOIETIC STEM-CELLS; MEDIATED DRUG EFFLUX; IMATINIB MESYLATE; MULTIDRUG TRANSPORTER; DIFFERENTIAL IMMUNOREACTIVITY; ANTITUMOR-ACTIVITY; MRP1 ABCC1 AB Sunitinib malate (Sutent, SU11248) is a small-molecule receptor tyrosine kinase inhibitor that inhibits cellular signaling of multiple targets such as the platelet-derived growth factor receptors and the vascular endothelial growth factor receptors and is used in the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Because tyrosine kinase inhibitors are known to increase the p.o. bioavailability and brain penetration of chemotherapy drugs in animal models, we sought to examine the effect of sunitinib on the ATP-binding cassette (ABC) drug transporters P-glycoprotein (P-gp, ABCB1), the multidrug resistance-associated protein 1 (ABCC1), and ABCG2, which are known to transport a wide variety of anticancer drugs. In this study, we show that sunitinib inhibits P-gp- and ABCG2-mediated efflux of fluorescent substrates in cells overexpressing these transporters. In 4-day cytotoxicity assays, at a nontoxic concentration (2 mu M) sunitinib was able to partially reverse drug resistance mediated by P-gp and completely reverse resistance mediated by ABCG2. We further show a direct interaction of sunitinib with the substrate binding pocket of these transporters as it inhibited binding of the photoaffinity substrate [(125)I] iodoarylazidoprazosin to P-gp (IC(50) = 14.2 mu M) and ABCG2 (IC(50) = 1.33 mu M). Sunitinib stimulated the ATP hydrolysis by both transporters in a concentration-dependent manner. Conformation-sensitive antibody binding assays with the P-gp- and ABCG2-specific antibodies, UIC2 and 5D3, respectively, also confirmed the interaction of sunitinib with these transporters. Taken together, this is the first report showing that sunitinib inhibits transport mediated by ABC drug transporters, which may affect the bioavailability of drugs coadministered with sunitinib. C1 [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Robey, Robert W.; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI shukla, suneet/B-4626-2012 FU 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. NR 45 TC 122 Z9 130 U1 2 U2 11 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2009 VL 37 IS 2 BP 359 EP 365 DI 10.1124/dmd.108.024612 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 396WV UT WOS:000262623000018 PM 18971320 ER PT J AU Hoehle, SI Knudsen, GA Sanders, JM Sipes, IG AF Hoehle, Simone I. Knudsen, Gabriel A. Sanders, J. Michael Sipes, I. Glenn TI Absorption, Distribution, Metabolism, and Excretion of 2,2-Bis(bromomethyl)-1,3-propanediol in Male Fischer-344 Rats SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID TETRABROMOBISPHENOL-A; FLAME-RETARDANT; F344/N RATS; DISPOSITION; CARCINOGENICITY; GLUCURONIDATION; IDENTIFICATION; ACETAMINOPHEN; MICE AB 2,2-Bis(bromomethyl)-1,3-propanediol (BMP) is a brominated flame retardant, previously shown to be a multisite carcinogen in experimental animals. Studies were performed to characterize the dispositional and metabolic fate of BMP after oral or intravenous administration to male Fischer-344 rats. After a single oral administration of [(14)C] BMP (10 or 100 mg/kg) >80% of the low dose and 48% of the high dose were excreted by 12 h in the urine predominantly as a glucuronide metabolite. After repeated daily oral doses for 5 or 10 days, route and rate of elimination were similar to those obtained after single administrations of BMP. In all studies, the radioactivity recovered in feces was low (<15%). The total amount of radioactivity remaining in tissues at 72 h after a single oral administration of BMP (100 mg/kg) was less than 1% of the dose, and repeated daily dosing did not lead to retention in tissues. After intravenous administration, the radiolabel found in blood decreased rapidly. Excretion profiles were similar to those after oral administration. Parent BMP and BMP glucuronide were present in blood plasma after oral or intravenous dosing. After an intravenous dose of BMP (15 mg/kg) the hepatic BMP glucuronide was primarily exported into the bile (>50% within 6 h), but it underwent enterohepatic recycling with subsequent elimination in the urine. These data indicate that the extensive extraction and rapid glucuronidation by the liver limits exposure of internal tissues to BMP by greatly reducing its systemic bioavailability after oral exposure. C1 [Hoehle, Simone I.; Knudsen, Gabriel A.; Sipes, I. Glenn] Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. [Sanders, J. Michael] Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, Natl Toxicol Program, Res Triangle Pk, NC USA. RP Sipes, IG (reprint author), Univ Arizona, Coll Med, Dept Pharmacol, POB 245050, Tucson, AZ 85724 USA. EM sipes@email.arizona.edu RI Knudsen, Gabriel/G-3706-2013 OI Knudsen, Gabriel/0000-0002-7208-6451 FU National Toxicology Program/National Institute of Environmental Health Science (NIEHS) [N01-ES-45529]; National Institutes of Health; NIEHS; Southwest Environmental Health Science Center [P30-ES06694] FX This work was supported by the National Toxicology Program/National Institute of Environmental Health Science (NIEHS) (Contract N01-ES-45529) and in part by the Intramural Research Program of the National Institutes of Health and NIEHS. We also acknowledge support provided by the Analytical Core of the NIEHS-funded Southwest Environmental Health Science Center [Grant P30-ES06694]. NR 22 TC 5 Z9 5 U1 1 U2 10 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2009 VL 37 IS 2 BP 408 EP 416 DI 10.1124/dmd.108.023937 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 396WV UT WOS:000262623000024 PM 19029203 ER PT J AU Hayashi, T Stahl, SM AF Hayashi, T. Stahl, S. M. TI THE SIGMA-1 (sigma(1)) RECEPTOR AND ITS ROLE IN THE TREATMENT OF MOOD DISORDERS SO DRUGS OF THE FUTURE LA English DT Review ID FORCED SWIMMING TEST; NEUROACTIVE STEROIDS; ANTIDEPRESSANT-LIKE; IN-VITRO; NEUROPSYCHIATRIC DISORDERS; DELUSIONAL DEPRESSION; NEGATIVE SYMPTOMS; MAJOR DEPRESSION; LIGAND-BINDING; POTENTIAL ROLE AB Sigma (sigma) receptors have long been implicated in a variety of neuronal and brain functions, although their precise biochemical and physiological role, and potential involvement in neurological and psychiatric disorders, remains elusive. However, nearly 30 years after their characterization, evidence arising from various research fields has begun to unveil the biological function and clinical implications of sigma receptors. These receptors ore intracellular molecules consisting of at least two subtypes - sigma(1) ond sigma(2). The sigma(1) receptor, an integral membrane protein with two transmembrane domains, mainly localizes at the endoplasmic reticulum (ER). A recent study identified the sigma(1) receptor as possessing innate biological activity as a molecular chaperone, activity that can be activated/inactivated by synthetic compounds that bind to sigma(1) receptors. The sigma(1) receptor regulates Ca2+ signaling, ion channel activity, trophic factor signaling, cell Survival, myelination and synaptogenesis. Certain clinically used antidepressants and steroids bind to the sigma(1) receptor, and selective sigma(1) agonists have demonstrated relatively rapid antidepressant-like actions in preclinical studies; such agents have been introduced into clinical trials. The recent discoveries regarding the hitherto enigmatic sigma receptor have fueled expectation that this receptor class may provide novel opportunities for pharmacological interventions. In this review, we present current data supporting the notion that this novel ligand-operated molecular chaperone may provide a new intracellular target for future therapeutic agents. C1 [Hayashi, T.] Natl Inst Drug Abuse, Cellular Pathobiol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Stahl, S. M.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Hayashi, T (reprint author), Natl Inst Drug Abuse, Cellular Pathobiol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. EM thayashi@mail.nih.gov; smstahl@neiglobal.com FU Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services FX Part of this work was supported by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. NR 92 TC 26 Z9 28 U1 2 U2 5 PU PROUS SCIENCE, SA-THOMSON REUTERS PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD FEB PY 2009 VL 34 IS 2 BP 137 EP 146 DI 10.1358/dof.2009.34.2.1336115 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 561MS UT WOS:000274982300007 ER PT J AU Jones, JL Zalewski, C Brewer, C Lucker, J Drayna, D AF Jones, Jennifer L. Zalewski, Christopher Brewer, Carmen Lucker, Jay Drayna, Dennis TI Widespread Auditory Deficits in Tune Deafness SO EAR AND HEARING LA English DT Article ID PITCH PERCEPTION; CONGENITAL AMUSIA; BRAIN SPECIALIZATION; TONE-DEAFNESS; MUSIC; CORTEX; NOISE; DISCRIMINATION; ORGANIZATION; FREQUENCY AB Objective: The goal of this study was to investigate auditory function in individuals with deficits in musical pitch perception. We hypothesized that such individuals have deficits in nonspeech areas of auditory processing. Design: We screened 865 randomly selected individuals to identify those who scored poorly on the Distorted Tunes test (DTT), a measure of musical pitch recognition ability. Those who scored poorly were given a comprehensive audiologic examination, and those with hearing loss or other confounding audiologic factors were excluded from further testing. Thirty-five individuals with tune deafness constituted the experimental group. Thirty-four individuals with normal hearing and normal OTT scores, matched for age, gender, handedness, and education, and without overt or reported psychiatric disorders made up the normal control group. Individual and group performance for pure-tone frequency discrimination at 1000 Hz was determined by measuring the difference limen for frequency (DLF). Auditory processing abilities were assessed using tests of pitch pattern recognition, duration pattern recognition, and auditory gap detection. In addition, we evaluated both attention and short- and long-term memory as variables that might influence performance on our experimental measures. Differences between groups were evaluated statistically using Wilcoxon nonparametric tests and t-tests as appropriate. Results: The DLF at 1000 Hz in the group with tune deafness was significantly larger than that of the normal control group. However, approximately one-third of participants with tune deafness had DLFs within the range of performance observed in the control group. Many individuals with tune deafness also displayed a high degree of variability in their intertrial frequency discrimination performance that could not be explained by deficits in memory or attention. Pitch and duration pattern discrimination and auditory gap-detection ability were significantly poorer in the group with tune deafness than the normal control group. Approximately one-third of our participants with tune deafness displayed evidence of attention deficit with hyperactivity disorder on the Test of Variables of Attention. Test of Variables of Attention scores were significantly correlated with gap-detection scores, but not significantly correlated with any of the other experimental measures, including the OTT, DLF, and auditory pattern discrimination tests. Short- and long-term memory was not significantly related to any of the experimental measures. Conclusions: Individuals with tune deafness identified by the OTT have poor performance on many tests of auditory function. These include pure-tone frequency discrimination, pitch and duration pattern discrimination, and temporal resolution. Overall, reduction in performance does not seem to derive from deficits in memory or attention. However, because of the prevalence of attention deficit with hyperactivity disorder in those with tune deafness, this variable should be considered as a potentially confounding factor in future studies of tune deafness and its characteristics, Pure-tone frequency discrimination varied widely in individuals with tune deafness, and the high degree of intertrial variability suggests that frequency discrimination may be unstable in tune-deaf individuals. C1 [Jones, Jennifer L.; Zalewski, Christopher; Brewer, Carmen; Drayna, Dennis] Natl Inst Deafness & Other Commun, NIH, Bethesda, MD USA. [Jones, Jennifer L.; Lucker, Jay] Howard Univ, Dept Commun Sci & Disorders, Washington, DC 20059 USA. RP Drayna, D (reprint author), 5 Res Court, Rockville, MD 20854 USA. EM drayna@nidcd.nih.gov FU National Institutes of Health/NIDCD Intramural Research [Z01-000046-06, Z01-DC-000064-06] FX This work was supported by National Institutes of Health/NIDCD Intramural Research Grant Z01-000046-06 (to D. D.) and Z01-DC-000064-06 (to C. B. and C. Z.). NR 39 TC 21 Z9 21 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD FEB PY 2009 VL 30 IS 1 BP 63 EP 72 PG 10 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 392OM UT WOS:000262312000008 PM 19125028 ER PT J AU Donaldson, JG McPherson, PS AF Donaldson, Julie G. McPherson, Peter S. TI Membrane trafficking heats up in Pavia Golgi Meeting on Membrane Trafficking in Global Cellular Responses SO EMBO REPORTS LA English DT Editorial Material DE Arf; clathrin; endoplasmic reticulum; Golgi; membrane curvature C1 [Donaldson, Julie G.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [McPherson, Peter S.] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Room 2503, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov; peter.mcpherson@mcgill.ca FU Intramural NIH HHS NR 5 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD FEB PY 2009 VL 10 IS 2 BP 132 EP 136 DI 10.1038/embor.2008.248 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403ZE UT WOS:000263119700009 PM 19165142 ER PT J AU Meade-White, KD Barbian, KD Race, B Favara, C Gardner, D Taubner, L Porcella, S Race, R AF Meade-White, Kimberly D. Barbian, Kent D. Race, Brent Favara, Cynthia Gardner, Don Taubner, Lara Porcella, Stephen Race, Richard TI Characteristics of 263K Scrapie Agent in Multiple Hamster Species SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CHRONIC WASTING DISEASE; TRANSMISSIBLE MINK ENCEPHALOPATHY; DISTINCT PRION PROTEINS; STRAIN VARIATION; TRANSGENIC MICE; NATURAL SCRAPIE; MOUSE SCRAPIE; PRP; GENE; SHEEP AB Transmissible spongiform encephalopathy (TSE) diseases are known to cross species barriers, but the pathologic and biochemical changes that occur during transmission are not well understood. To better understand these changes, we infected 6 hamster species with 263K hamster scrapie strain and, after each of 3 successive passages in the new species, analyzed abnormal proteinase K (PK)resistant prion protein (PrPres) glycoform ratios, PrPres PK sensitivity, incubation periods, and lesion profiles. Unique 263K molecular and biochemical profiles evolved in each of the infected hamster species. Characteristics of 263K in the new hamster species seemed to correlate best with host factors rather than agent strain. Furthermore, 2 polymorphic regions of the prion protein amino acid sequence correlated with profile differences in these TSE-infected hamster species. C1 [Meade-White, Kimberly D.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Meade-White, KD (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM kmcade-white@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX This work Was supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. NR 38 TC 14 Z9 14 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2009 VL 15 IS 2 BP 207 EP 215 DI 10.3201/eid1502.081173 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 405NE UT WOS:000263230700009 PM 19193264 ER PT J AU Japee, S Crocker, L Carver, F Pessoa, L Ungerleider, LG AF Japee, Shruti Crocker, Laura Carver, Frederick Pessoa, Luiz Ungerleider, Leslie G. TI Individual Differences in Valence Modulation of Face-Selective M170 Response SO EMOTION LA English DT Article DE MEG; face-selective M170; sensitivity to fearful faces; valence effect; trait anxiety ID EVENT-RELATED POTENTIALS; REGIONAL BRAIN ACTIVITY; VENTRAL VISUAL PATHWAY; FACIAL EXPRESSIONS; TIME-COURSE; EMOTIONAL FACES; FEARFUL FACES; AMYGDALA ACTIVATION; DECISION-MAKING; TEMPORAL CORTEX AB Magnetoencephalography was used to examine the effect of individual differences on the temporal dynamics of emotional face processing by grouping subjects based on their ability to detect masked valence-laden stimuli. Receiver operating characteristic curves and a nonparametric sensitivity measure were used to categorize subjects into those that could and could not reliably detect briefly presented fearful faces that were backward-masked by neutral faces. Results showed that, in a cluster of face-responsive sensors, the strength of the M 170 response was modulated by valence only when subjects could reliably detect the masked fearful faces. Source localization of the M170 peak using synthetic aperture magnetometry identified sources in face processing areas such as right middle occipital gyros and left fusiform gyrus that showed the valence effect for those target durations at which subjects were sensitive to the fearful stimulus. Subjects who were better able to detect fearful faces also showed higher trait anxiety levels. These results suggest that individual differences between subjects, such as trait anxiety levels and sensitivity to fearful stimuli, may be an important factor to consider when studying emotion processing. C1 [Japee, Shruti] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Carver, Frederick] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Pessoa, Luiz] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. RP Japee, S (reprint author), NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr,Room 4C104, Bethesda, MD 20892 USA. EM japees@mail.nih.gov FU Intramural NIH HHS [Z01 MH002035-27]; NIMH NIH HHS [1 R01 MH071589-01, R01 MH071589, R01 MH071589-05] NR 85 TC 21 Z9 21 U1 5 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 J9 EMOTION JI Emotion PD FEB PY 2009 VL 9 IS 1 BP 59 EP 69 DI 10.1037/a0014487 PG 11 WC Psychology, Experimental SC Psychology GA 401WC UT WOS:000262972200006 PM 19186917 ER PT J AU Rath, MF Bailey, MJ Kim, JS Ho, AK Gaildrat, P Coon, SL Moller, M Klein, DC AF Rath, Martin F. Bailey, Michael J. Kim, Jong-So Ho, Anthony K. Gaildrat, Pascaline Coon, Steven L. Moller, Morten Klein, David C. TI Developmental and Diurnal Dynamics of Pax4 Expression in the Mammalian Pineal Gland: Nocturnal Down-Regulation Is Mediated by Adrenergic-Cyclic Adenosine 3 ',5 '-Monophosphate Signaling SO ENDOCRINOLOGY LA English DT Article ID SEROTONIN N-ACETYLTRANSFERASE; HYDROXYINDOLE-O-METHYLTRANSFERASE; MESSENGER-RIBONUCLEIC-ACID; RAT PINEAL; TRANSCRIPTIONAL REPRESSOR; ADENOSINE 3',5'-MONOPHOSPHATE; CIRCADIAN EXPRESSION; MELATONIN PRODUCTION; INSULINOMA CELLS; BETA AB Pax4 is a homeobox gene that is known to be involved in embryonic development of the endocrine pancreas. In this tissue, Pax4 counters the effects of the related protein, Pax6. Pax6 is essential for development of the pineal gland. In this study we report that Pax4 is strongly expressed in the pineal gland and retina of the rat. Pineal Pax4 transcripts are low in the fetus and increase postnatally; Pax6 exhibits an inverse pattern of expression, being more strongly expressed in the fetus. In the adult the abundance of Pax4 mRNA exhibits a diurnal rhythm in the pineal gland with maximal levels occurring late during the light period. Sympathetic denervation of the pineal gland by superior cervical ganglionectomy prevents the nocturnal decrease in pineal Pax4 mRNA. At night the pineal gland is adrenergically stimulated by release of norepinephrine from the sympathetic innervation; here, we found that treatment with adrenergic agonists suppresses pineal Pax4 expression in vivo and in vitro. This suppression appears to be mediated by cAMP, a second messenger of norepinephrine in the pineal gland, based on the observation that treatment with a cAMP mimic reduces pineal Pax4 mRNA levels. These findings suggest that the nocturnal decrease in pineal Pax4 mRNA is controlled by the sympathetic neural pathway that controls pineal function acting via an adrenergic-cAMP mechanism. The daily changes in Pax4 expression may influence gene expression in the pineal gland. (Endocrinology 150: 803-811, 2009) C1 [Rath, Martin F.] Univ Copenhagen, Panum Inst, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark. [Rath, Martin F.; Bailey, Michael J.; Kim, Jong-So; Gaildrat, Pascaline; Coon, Steven L.; Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Bailey, Michael J.] Texas A&M Univ, Dept Poultry Sci, College Stn, TX 77843 USA. [Ho, Anthony K.] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2H7, Canada. RP Rath, MF (reprint author), Univ Copenhagen, Panum Inst, Dept Neurosci & Pharmacol, 24-3 Blegdamsvej 3, DK-2200 Copenhagen, Denmark. EM mrath@sund.ku.dk OI Rath, Martin/0000-0002-4047-6324 FU Lundbeck Foundation; Danish Medical Research Council [271-07-0412, 271-06-0754]; Novo Nordisk Foundation; Carlsberg Foundation; Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health FX This study was supported by the Lundbeck Foundation, Danish Medical Research Council (Grants 271-07-0412 and 271-06-0754), Novo Nordisk Foundation, Carlsberg Foundation, and Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 54 TC 26 Z9 28 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2009 VL 150 IS 2 BP 803 EP 811 DI 10.1210/en.2008-0882 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 400EQ UT WOS:000262851200028 PM 18818287 ER PT J AU Nacci, C Tarquinio, M De Benedictis, L Mauro, A Zigrino, A Carratu, MR Quon, MJ Montagnani, M AF Nacci, Carmela Tarquinio, Mariela De Benedictis, Leonarda Mauro, Annamaria Zigrino, Addolorata Carratu, Maria Rosaria Quon, Michael J. Montagnani, Monica TI Endothelial Dysfunction in Mice with Streptozotocin-induced Type 1 Diabetes Is Opposed by Compensatory Overexpression of Cyclooxygenase-2 in the Vasculature SO ENDOCRINOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SPONTANEOUSLY HYPERTENSIVE-RATS; ACTIVATED PROTEIN-KINASE; PROSTAGLANDIN-H SYNTHASE; LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE; HIGH GLUCOSE; INSULIN-RESISTANCE; GENE-EXPRESSION AB Cardiovascular complications of diabetes result from endothelial dysfunction secondary to persistent hyperglycemia. We investigated potential compensatory mechanisms in the vasculature that oppose endothelial dysfunction in diabetes. BALB/c mice were treated with streptozotocin (STZ) to induce type 1 diabetes (T1D). In mesenteric vascular beds (MVBs), isolated ex vivo from mice treated with STZ for 1 wk, dose-dependent vasorelaxation to acetylcholine (ACh) or sodium nitroprusside was comparable with that in age-matched control mice (CTRL). By contrast, MVBs from mice treated with STZ for 8 wk had severely impaired vasodilator responses to ACh consistent with endothelial dysfunction. Pretreatment of MVBs from CTRL mice with nitric oxide synthase inhibitor nearly abolished vasodilation to ACh. In MVB from 1-wk STZ-treated mice, vasodilation to ACh was only partially impaired by L-N(omega)-arginine methyl ester. Thus, vasculature of mice with T1D may have compensatory nitric oxide-independent mechanisms to augment vasodilation to ACh and oppose endothelial dysfunction. Indeed, pretreatment of MVBs isolated from 1-wk STZ-treated mice with NS-398[selective cyclooxygenase (COX)-2 inhibitor] unmasked endothelial dysfunction not evident in CTRL mice pretreated without or with NS-398. Expression of COX-2 in MVBs, aortic endothelial cells, and aortic vascular smooth muscle cells from STZ-treated mice was significantly increased (vs. CTRL). Moreover, concentrations of the COX-2-dependent vasodilator 6-keto-prostaglandin F-1 alpha was elevated in conditioned media from aorta of STZ-treated mice. We conclude that endothelial dysfunction in a mouse model of T1D is opposed by compensatory up-regulation of COX-2 expression and activity in the vasculature that may be relevant to developing novel therapeutic strategies for diabetes and its cardiovascular complications. (Endocrinology 150: 849-861, 2009) C1 [Nacci, Carmela; Tarquinio, Mariela; De Benedictis, Leonarda; Mauro, Annamaria; Zigrino, Addolorata; Carratu, Maria Rosaria; Montagnani, Monica] Univ Bari, Dept Pharmacol & Human Physiol, Sch Med, I-70124 Bari, Italy. [Quon, Michael J.] Natl Ctr Complementary & Alternat Med, Diabet Unit, NIH, Bethesda, MD 20892 USA. RP Montagnani, M (reprint author), Univ Bari, Dept Pharmacol & Human Physiol, Sch Med, Piazza Giulio Cesare 1, I-70124 Bari, Italy. EM monica@farmacol.uniba.it OI NACCI, CARMELA/0000-0002-0451-5680; Quon, Michael/0000-0002-9601-9915; Carrato, Maria/0000-0002-9709-6533; montagnani, monica/0000-0002-5697-8185; Quon , Michael /0000-0002-5289-3707 FU Italian Ministry for University and Research; Juvenile Diabetes Research Foundation [CDA 2-2006-32]; Intramural Research Program; National Center for Complementary and Alternative Medicine; National Institutes of Health FX This work was supported by in part by research grant awards from the Italian Ministry for University and Research and the Juvenile Diabetes Research Foundation (CDA 2-2006-32; to M. M.) and the Intramural Research Program, National Center for Complementary and Alternative Medicine, National Institutes of Health (to M.J.Q.). NR 89 TC 34 Z9 34 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2009 VL 150 IS 2 BP 849 EP 861 DI 10.1210/en.2008-1069 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 400EQ UT WOS:000262851200033 PM 18845644 ER PT J AU Ogasawara, K Nogami, H Tsuda, MC Gustafsson, JA Korach, KS Ogawa, S Harigaya, T Hisano, S AF Ogasawara, Kiyomoto Nogami, Haruo Tsuda, Mumeko C. Gustafsson, Jan-Ake Korach, Kenneth S. Ogawa, Sonoko Harigaya, Toshio Hisano, Setsuji TI Hormonal Regulation of Prolactin Cell Development in the Fetal Pituitary Gland of the Mouse SO ENDOCRINOLOGY LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; GROWTH-HORMONE; GENE-EXPRESSION; POSTNATAL-DEVELOPMENT; EMBRYONIC-DEVELOPMENT; ELECTRON-MICROSCOPY; RAT PITUITARY; PARS-DISTALIS; MICE; LACTOTROPHS AB The developmental process of prolactin (PRL) cells in the fetal pituitary gland was studied in mice. Although PRL cells were hardly detectable in the pituitary gland of intact fetuses, a treatment with 17 beta-estradiol (E(2)) in vitro induced a number of PRL cells that varied drastically in number depending on the stage of gestation with a peak at embryonic d 15. This effect was specific to E(2), with epidermal growth factor, insulin, and forskolin failing to induce PRL cells. Although both estrogen receptor (ER)alpha and ER beta were expressed in the fetal pituitary gland, the results from ER knockout models showed that only ER alpha mediates E(2) action on PRL cells. A few PRL cells were observed in ER alpha-deficient mice as well as in their control littermates, suggesting that estrogen is not required for the phenotype determination of PRL cells. Unexpectedly, the effect of E(2) on the induction of PRL cells in vitro was diminished after embryonic d 15. Present results suggest that the exposure of fetal PRL cells to glucocorticoids (GCs) results in a reduction of sensitivity to E(2). The mechanism underlying the down-regulation of estrogen sensitivity by GCs was found not to be down-regulation of ER levels, induction of annexin 1, a GC-inducible inhibitor of PRL secretion, or a decrease in the number of PRL precursors by apoptosis. The effect of GCs appeared within 2 h and did not require a de novo protein synthesis. GCs are considered to be involved in the mechanisms of silencing pituitary PRL in gestation possibly through a novel mechanism. (Endocrinology 150: 1061-1068, 2009) C1 [Ogasawara, Kiyomoto; Nogami, Haruo; Hisano, Setsuji] Univ Tsukuba, Inst Basic Med Sci, Neuroendocrinol Lab, Tsukuba, Ibaraki 3058575, Japan. [Tsuda, Mumeko C.; Ogawa, Sonoko] Univ Tsukuba, Lab Behav Neuroendocrinol, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058575, Japan. [Gustafsson, Jan-Ake] Karolinska Inst, Dept Biosci & Nutr, S-14186 Huddinge, Sweden. [Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Harigaya, Toshio] Meiji Univ, Fac Agr, Funct Anat Lab, Kanagawa 21471, Japan. RP Nogami, H (reprint author), Univ Tsukuba, Inst Basic Med Sci, Neuroendocrinol Lab, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058575, Japan. EM hnogami@md.tsukuba.ac.jp OI Korach, Kenneth/0000-0002-7765-418X FU Twenty-First Century Center of Excellence Program FX This work was supported by Twenty-First Century Center of Excellence Program (to H. N.). NR 37 TC 7 Z9 8 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2009 VL 150 IS 2 BP 1061 EP 1068 DI 10.1210/en.2008-1151 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 400EQ UT WOS:000262851200054 PM 18927214 ER PT J AU Shen, M Chapman, RS Vermeulen, R Tian, LW Zheng, TZ Chen, BE Engels, EA He, XZ Blair, A Lan, Q AF Shen, Min Chapman, Robert S. Vermeulen, Roel Tian, Linwei Zheng, Tongzhang Chen, Bingshu E. Engels, Eric A. He, Xingzhou Blair, Aaron Lan, Qing TI Coal Use, Stove Improvement, and Adult Pneumonia Mortality in Xuanwei, China: A Retrospective Cohort Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE coal; cohort study; indoor air pollution; pneumonia ID INDOOR AIR-POLLUTION; ACUTE RESPIRATORY-INFECTIONS; SOLID-FUEL; HOSPITAL ADMISSIONS; LUNG-CANCER; RISK; CHILDREN; COMBUSTION AB BACKGROUND: In Xuanwei County, China, unvented indoor coal burning is strongly associated with increased risk of lung cancer and chronic obstructive pulmonary disease. However, the impact of coal burning and stove improvement on risk of pneumonia is not clear. METHODS: We conducted a retrospective cohort study among all farmers born 1917 through 1951 and living in Xuanwei as of I January 1976. The analysis included a total of 42,422 cohort members. Follow-up identified all deaths in the cohort from 1976 through 1996. Ages at entry into and at exit from follow-up ranged from 24 to 59 years and from 25 to 80 years, respectively. The record search detected 225 deaths from pneumonia, and 32,332 (76%) were alive as of 31 December 1996. We constructed multivariable Cox models (time variable = age) to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Use of coal, especially smokeless coal, was positively associated with pneumonia mortality. Annual tonnage and lifetime duration of smoky and smokeless coal use were positively associated with pneumonia mortality. Stove improvement was associated with a 50% reduction in pneumonia deaths (smoky coal users: HR, 0.521; 95% Cl, 0.340-0.798; smokeless coal users: HR, 0.449; 95% Cl, 0.215-0.937). CONCLUSIONS: Our analysis is the first to suggest that indoor air pollution from unvented coal burning is an important risk factor for pneumonia death in adults and that improving ventilation by installing a chimney is an effective measure to decrease it. C1 [Shen, Min; Engels, Eric A.; Blair, Aaron; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Chapman, Robert S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok, Thailand. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Tian, Linwei] Chinese Univ Hong Kong, Sch Publ Hlth, Stanley Ho Ctr Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China. [Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Chen, Bingshu E.] Concordia Univ, Dept Math & Stat, Montreal, PQ, Canada. [He, Xingzhou] Chinese Ctr Dis Control & Prevent, Inst Environm Hlth & Engn, Beijing, Peoples R China. RP Shen, M (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, MSC 7240,6120 Execut Blvd,EPS 8122, Bethesda, MD 20892 USA. EM shenmi@mail.nih.gov RI Tian, Linwei/A-9736-2009; Vermeulen, Roel/F-8037-2011; OI Tian, Linwei/0000-0002-4739-1534; Vermeulen, Roel/0000-0003-4082-8163; Chen, Bingshu/0000-0001-6139-0696 FU Intramural NIH HHS [, NIH0011547510]; PHS HHS [NIH0011547510] NR 26 TC 27 Z9 29 U1 1 U2 12 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 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2009 VL 117 IS 2 BP 261 EP 266 DI 10.1289/ehp.11521 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 401VO UT WOS:000262970700036 PM 19270797 ER PT J AU Patlolla, AK Barnes, C Yedjou, C Velma, VR Tchounwou, PB AF Patlolla, Anita K. Barnes, Constance Yedjou, Clement Velma, V. R. Tchounwou, Paul B. TI Oxidative Stress, DNA Damage, and Antioxidant Enzyme Activity Induced by Hexavalent Chromium in Sprague-Dawley Rats SO ENVIRONMENTAL TOXICOLOGY LA English DT Article DE chromium; malondialdehyde; antioxidant enzymes; superoxide dismutase; catalase; Sprague-Dawley rats; liver; kidneys ID LIPID-PEROXIDATION; POTASSIUM DICHROMATE; CARCINOGENICITY; TOXICITY; MECHANISMS; CR(VI); MICE; NEPHROTOXICITY; BIOMARKERS; INDUCTION AB Chromium is a widespread industrial compound. The soluble hexavalent chromium Cr (VI) is an environmental contaminant widely recognized as carcinogen, mutagen, and teratogen toward humans and animals. The fate of chromium in the environment is dependent on its oxidation state. The reduction of Cr (VI) to Cr (III) results in the formation of reactive intermediates leading to oxidative tissue damage and cellular injury. In the present investigation, Potassium dichromate was given intraperitoneally to Sprague-Dawley rats for 5 days with the doses of 2.5, 5.0, 7.5, and 10 mg/kg body weight per day. Oxidative stress including the level of reactive oxygen species (ROS), the extent of lipid peroxidation and the activity of antioxidant enzymes in both liver and kidney was determined. DNA damage in peripheral blood lymphocytes was determined by single-cell gel electrophoresis (comet assay). The results indicated that administration of Cr (VI) had caused a significant increase of ROS level in both liver and kidney after 5 days of exposure, accompanied with a dose-dependent increase in superoxide dismutase and catalase activities. The malondialdehyde content in liver and kidney was elevated as compared with the control animals. Dose- and time-dependent effects were observed on DNA damage after 24, 48, 72, and 96 h posttreatment. The results obtained from the present study showed that Cr (VI) could induce dose- and time-dependent effects on DNA damage, both liver and kidney show defense against chromium-induced oxidative stress by enhancing their antioxidant enzyme activity. However, liver was found to exhibit more antioxidant defense than the kidney. (C) 2008 Wiley Periodicals, Inc. Environ Toxicol 24: 66-73, 2009. C1 [Patlolla, Anita K.; Barnes, Constance; Yedjou, Clement; Velma, V. R.; Tchounwou, Paul B.] Jackson State Univ, Coll Sci Engn & Technol, Ctr Environm Hlth, NIH,Mol Toxicol Res Lab,CSET, Jackson, MS 39217 USA. RP Tchounwou, PB (reprint author), Jackson State Univ, Coll Sci Engn & Technol, Ctr Environm Hlth, NIH,Mol Toxicol Res Lab,CSET, Jackson, MS 39217 USA. EM paul.b.tchounwou@jsunis.edu FU The National Institutes of Health - RCMI [1G12RR13459] FX The National Institutes of Health - RCMI. 1G12RR13459. NR 48 TC 42 Z9 49 U1 0 U2 15 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1520-4081 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD FEB PY 2009 VL 24 IS 1 BP 66 EP 73 DI 10.1002/tox.20395 PG 8 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA 409VD UT WOS:000263533000008 PM 18508361 ER PT J AU Liew, CJ Lim, YM Bonwetsch, R Shamim, S Sato, S Reeves-Tyer, P Herscovitch, P Dustin, I Bagic, A Giovacchini, G Theodore, WH AF Liew, Clarissa J. Lim, Young-Min Bonwetsch, Robert Shamim, Sadat Sato, Susumu Reeves-Tyer, Patricia Herscovitch, Peter Dustin, Irene Bagic, Anto Giovacchini, Giampiero Theodore, William H. TI (18)F-FCWAY and (18)F-FDG PET in MRI-negative temporal lobe epilepsy SO EPILEPSIA LA English DT Article DE Epilepsy; Positron emission tomography; Serotonin receptors; Temporal lobe; Glucose metabolism ID POSITRON-EMISSION-TOMOGRAPHY; 5-HT1A RECEPTOR-BINDING; DENTATE GYRUS; GLUCOSE-METABOLISM; CELL-PROLIFERATION; QUANTITATIVE MRI; HYPOMETABOLISM; DEPRESSION; VOLUME; HIPPOCAMPUS AB Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) shows widespread hypometabolism even in temporal lobe epilepsy (TLE) patients with mesial temporal foci. (18)F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexane carboxamide ((18)F-FCWAY) PET may show more specific 5-HT(1A)-receptor binding reduction in seizure initiation than in propagation regions. (18)FCWAY PET might be valuable for detecting epileptic foci, and distinguishing mesial from lateral temporal foci in MRI-negative patients with TLE. We performed (18)F-FCWAY-PET and (18)F-FDG-PET in 12 MRI-negative TLE patients who had had either surgery or subdural electrode recording, and 15 healthy volunteers. After partial volume correction for brain atrophy, free fraction-corrected volume of distribution (V/f1) measurement and asymmetry indices (AIs) were computed. We compared (18)F-FCWAY-PET and (18)F-FDG-PET results with scalp video electroencephalography (EEG), invasive EEG, and surgical outcome. Mean (18)F-FCWAY V/f1, compared with normal controls, was decreased significantly in fusiform gyrus, hippocampus, and parahippocampus ipsilateral to epileptic foci, and AIs were significantly greater in hippocampus, parahippocampus, fusiform gyrus, amygdala, and inferior temporal regions. Eleven patients had clearly lateralized epileptogenic zones. Nine had congruent, and two nonlateralized, (18)F-FCWAY PET. One patient with bitemporal seizure onset had nonlateralized (18)F-FCWAY-PET. (18)F-FDG-PET showed congruent hypometabolism in 7 of 11 EEG-lateralized patients, bilateral hypometabolic regions in one, contralateral hypometabolism in one, as well as lateralized hypometabolism in the patient with bitemporal subdural seizure onset. Patients with mesial temporal foci tended to have lower superior and midtemporal (18)F-FCWAY V/f1 binding AI than those with lateral or diffuse foci. (18)F-FCWAY-PET can detect reduced binding in patients with normal MRI, and may be more accurate than (18)F-FDG-PET. C1 [Liew, Clarissa J.; Lim, Young-Min; Bonwetsch, Robert; Shamim, Sadat; Reeves-Tyer, Patricia; Dustin, Irene; Bagic, Anto; Theodore, William H.] NIH, Clin Epilepsy Sect, Bethesda, MD 20892 USA. [Sato, Susumu] Natl Inst Hlth, EEG Sect, Bethesda, MD USA. [Herscovitch, Peter; Giovacchini, Giampiero] NINDS, PET Dept, Ctr Clin, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), NIH, Clin Epilepsy Sect, Bldg 10,Room 5N-250, Bethesda, MD 20892 USA. EM theodorw@ninds.nih.gov RI shengkun, yu/B-8440-2012 FU NIH NINDS Division of Intramural Research FX We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. NR 34 TC 38 Z9 40 U1 1 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD FEB PY 2009 VL 50 IS 2 BP 234 EP 239 DI 10.1111/j.1528-1167.2008.01789.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 399DY UT WOS:000262781800008 PM 18801033 ER PT J AU Latella, G Vetuschi, A Sferra, R Zanninelli, G D'Angelo, A Catitti, V Caprilli, R Flanders, KC Gaudio, E AF Latella, G. Vetuschi, A. Sferra, R. Zanninelli, G. D'Angelo, A. Catitti, V. Caprilli, R. Flanders, K. C. Gaudio, E. TI Smad3 loss confers resistance to the development of trinitrobenzene sulfonic acid-induced colorectal fibrosis SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE ECM; fibrosis; Smad proteins; TGF-beta; TNBS-induced colitis ID INFLAMMATORY-BOWEL-DISEASE; GROWTH-FACTOR-BETA; TGF-BETA; CROHNS-DISEASE; INTESTINAL MYOFIBROBLASTS; TARGETED DISRUPTION; DIFFERENTIAL EXPRESSION; RENAL FIBROSIS; LIVER FIBROSIS; STELLATE CELLS AB Transforming growth factor-beta (TGF-beta)/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of extracellular matrix (ECM) protein accumulation. The aim of this study was to evaluate the potential role of Smad3 in the pathogenesis of colonic fibrosis induced by trinitrobenzene sulfonic acid (TNBS) in Smad3 null mice. Chronic colitis-associated fibrosis was induced in 15 Smad3 null and 13 wild-type mice by intra-rectal administration of TNBS. Each mouse received an incremental dose of TNBS (0.5-1.0 mg per week) over a 6-week period. The colon was excised for macroscopic examination and histological, morphometric and immunohistochemical analyses. For immunohistochemistry, alpha-smooth muscle actin (alpha-SMA), collagen types I-III, TGF-beta 1, connective tissue growth factor (CTGF), Smad3, Smad7, and CD3 antibodies were used. At macroscopic examination, the colon of Smad3 wild-type mice appeared significantly harder, thicker and shorter than that of the Smad3 null mice. Of the wild-type mice, 50% presented colonic adhesions and strictures. Histological and morphometric evaluation revealed a significantly higher degree of colonic fibrosis and accumulation of collagen in the Smad3 wild-type compared to null mice, whereas the degree of colonic inflammation did not differ between the two groups of mice. Immunohistochemical evaluation showed a marked increase in CTGF, collagen I-III, TGF-beta and Smad3 staining in the colon of Smad3 wild-type compared to null mice, whereas Smad7 was increased only in null mice. These results indicate that Smad3 loss confers resistance to the development of TNBS-induced colonic fibrosis. The reduced fibrotic response appears to be due to a reduction in fibrogenic mesenchymal cell activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of intestinal fibrosis, especially in inflammatory bowel disease. Eur J Clin Invest 2009; 39 (2): 145-156. C1 [Latella, G.; Zanninelli, G.; D'Angelo, A.; Catitti, V.] Univ Aquila, GI Unit, Dept Internal Med, I-67100 Laquila, Italy. [Vetuschi, A.; Sferra, R.] Univ Aquila, Dept Expt Med, I-67100 Laquila, Italy. [Caprilli, R.] Univ Roma La Sapienza, GI Unit, Dept Clin Sci, Rome, Italy. [Flanders, K. C.] NCI, NIH, Bethesda, MD 20892 USA. [Gaudio, E.] Univ Roma La Sapienza, Dept Human Anat, Rome, Italy. RP Latella, G (reprint author), Univ Aquila, Div Gastroenterol Epatol & Nutr, Dipartimento Med Interna & Sanita Pubbl, Piazza Salvatore Tommasi,1 Coppito, I-67100 Laquila, Italy. EM giolatel@tin.it NR 52 TC 30 Z9 37 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD FEB PY 2009 VL 39 IS 2 BP 145 EP 156 DI 10.1111/j.1365-2362.2008.02076.x PG 12 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 397CE UT WOS:000262638800008 PM 19200168 ER PT J AU Fan, H Kotsikorou, E Hoffman, AF Ravert, HT Holt, D Hurst, DP Lupica, CR Reggio, PH Dannals, RF Horti, AG AF Fan, Hong Kotsikorou, Evangelia Hoffman, Alexander F. Ravert, Hayden T. Holt, Daniel Hurst, Dow P. Lupica, Carl R. Reggio, Patricia H. Dannals, Robert F. Horti, Andrew G. TI Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CBI): Development of ligands with optimized lipophilicity and binding affinity SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Cannabinoid receptor; Carbon-11; JHU75528; Rimonabant; Positron emission tomography; Molecular modeling; Receptor docking ID NUCLEUS-ACCUMBENS; PREFRONTAL CORTEX; F-18 SR144385; RAT-BRAIN; ANTAGONISTS; RADIOLIGANDS; LOCALIZATION; AGONIST; PHARMACOLOGY; RADIOTRACER AB Cyano analogs of Rimonabant with high binding affinity for the cerebral cannabinoid receptor (CB1) and with optimized lipophilicity have been synthesized as potential positron emission tomography (PET) ligands. The best ligands of the series are optimal targets for the future radiolabeling with PET isotopes and in vivo evaluation as radioligands with enhanced properties for PET imaging of CB1 receptors in human subjects. Extracellular electrophysiological recordings in rodent brain slices demonstrated that JHU75528, 4, the lead compound of the new series, has functional CB antagonist properties that are consistent with its structural relationship to Rimonabant. Molecular modeling analysis revealed an important role of the binding of the cyano group with the CB1 binding pocket. (C) 2008 Elsevier Masson SAS. All rights reserved. C1 [Fan, Hong; Ravert, Hayden T.; Holt, Daniel; Dannals, Robert F.; Horti, Andrew G.] Johns Hopkins Univ Hosp, Sch Med, Dept Radiol, Div Nucl Med,PET Ctr, Baltimore, MD 21287 USA. [Kotsikorou, Evangelia; Hurst, Dow P.; Reggio, Patricia H.] Univ N Carolina, Dept Chem & Biochem, Ctr Drug Discovery, Greensboro, NC 27402 USA. [Hoffman, Alexander F.; Lupica, Carl R.] NIDA, Intramural Res Program, Cellular Neurobiol Branch, Electrophysiol Res Unit, Baltimore, MD 21224 USA. RP Horti, AG (reprint author), Johns Hopkins Univ Hosp, Sch Med, Dept Radiol, Div Nucl Med,PET Ctr, 600 N Wolfe St,Nelson B1-122, Baltimore, MD 21287 USA. EM ahorti1@jhmi.edu RI Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU NIDA NIH HHS [DA-03934, DA-021358, K05 DA021358, R01 DA003934]; NIMH NIH HHS [MH-079017, R21 MH079017, R21 MH079017-01A1, R33 MH079017] NR 56 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD FEB PY 2009 VL 44 IS 2 BP 593 EP 608 DI 10.1016/j.ejmech.2008.03.040 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 422DQ UT WOS:000264407800016 PM 18511157 ER PT J AU Semba, R Fink, JC Sun, K Bandinelli, S Guralnik, JM Ferrucci, L AF Semba, Richard D. Fink, Jeffrey C. Sun, Kai Bandinelli, Stefania Guralnik, Jack M. Ferrucci, Luigi TI Carboxymethyl-lysine, an advanced glycation end product, and decline of renal function in older community-dwelling adults SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE advanced glycation end products; aging; carboxymethyl-lysine; chronic kidney disease; renal function ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; PROXIMAL TUBULAR CELLS; DIETARY GLYCOTOXINS; DIABETIC-NEPHROPATHY; SERUM CREATININE; FAILURE PATIENTS; RISK-FACTOR; PYRIDOXAMINE; INFLAMMATION AB Advanced glycation end products (AGEs) are bioactive molecules found in greater concentrations in foods that have been processed at high temperatures. AGEs have been associated with impaired renal function in diabetes and in uremia. The relationship between AGEs and renal function in community-dwelling adults has not been well characterized. The objective was to determine whether plasma AGEs are independently associated with chronic kidney disease (CKD) and predictive of renal function in older adults. The relationship between plasma carboxymethyl-lysine (CML), an AGE, and CKD (a parts per thousand yen stage 3 of National Kidney Foundation classification; estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m(2)) and eGFR at 3- and 6-years follow-up was examined in a population-based study of aging, the InCHIANTI study, in Tuscany, Italy. Of 1,008 adults, aged a parts per thousand yen65 years, 153 (15.2%) had CKD at enrollment. Mean (standard deviation [S.D.]) plasma CML was 365 (110) ng/ml. Plasma CML was associated with CKD (odds ratio [O.R.] expressed per 1 S.D., 1.53, 95% confidence interval [C.I.] 1.27-1.84, P < 0.0001) in a multivariate logistic regression model, adjusting for potential confounders. Plasma CML was associated with eGFR (beta = -2.77, standard error [S.E.] = 0.51, P < 0.0001) at baseline, 3-year (beta = -2.54, S.E. = 0.61, P < 0.0001) and 6-year follow-up visits (beta = -1.21, S.E. = 0.70, P = 0.08) in multivariate linear regression models, adjusting for potential confounders. The associations between plasma CML and prevalent CKD, eGFR, and eGFR at 3- and 6-year follow-up were significant and nearly unchanged after exclusion of adults with diabetes. Plasma CML is independently associated with CKD and is an independent predictor of decline in renal function in older community-dwelling adults. C1 [Semba, Richard D.; Sun, Kai] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Fink, Jeffrey C.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Bethesda, MD 20892 USA. RP Semba, R (reprint author), Johns Hopkins Univ, Sch Med, 550N Broadway,Suite 700, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu OI Fink, Jeffrey/0000-0002-5622-5052 FU National Institute on Aging [R01 AG027012, R01 AG029148]; Intramural Research Program, National Institute on Aging, NIH FX This work was supported by National Institute on Aging Grants R01 AG027012, R01 AG029148 and the Intramural Research Program, National Institute on Aging, NIH. NR 31 TC 23 Z9 23 U1 0 U2 4 PU DR DIETRICH STEINKOPFF VERLAG PI HEIDELBERG PA TIERGARTENSTRASSE 17, 69121 HEIDELBERG, GERMANY SN 1436-6207 J9 EUR J NUTR JI Eur. J. Nutr. PD FEB PY 2009 VL 48 IS 1 BP 38 EP 44 DI 10.1007/s00394-008-0757-0 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 399FF UT WOS:000262785100006 PM 19031098 ER PT J AU Richardson, SP Bliem, B Voller, B Dang, N Hallett, M AF Richardson, Sarah Pirio Bliem, Barbara Voller, Bernhard Dang, Nguyet Hallett, Mark TI Long-latency afferent inhibition during phasic finger movement in focal hand dystonia SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Dystonia; Transcranial magnetic stimulation; Afferent inhibition; Surround inhibition ID SENSORIMOTOR INTEGRATION; WRITERS CRAMP; MOTOR CORTEX; MEDIAN NERVE; STIMULATION; PLASTICITY; MODULATION; DISEASE; HUMANS; SYSTEM AB In the motor system, one specific movement is generated, and, simultaneously, other possible movements are suppressed; a process called surround inhibition. Focal hand dystonia (FHD) is a movement disorder characterized by a loss of surround inhibition. In order to explain the deficit in surround inhibition induced by volitional movement in FHD patients, we examined the inhibitory circuit activated by afferent stimulation at "long latency". We studied 14 patients (age 48.9 +/- A 13.2 years, 3 females, 11 males) with idiopathic task-related FHD. To measure long-latency afferent inhibition (LAI), transcranial magnetic stimulation (TMS) was applied to the affected hemisphere for FHD patients and to the dominant hemisphere for 17 healthy volunteers. Motor evoked potentials (MEPs) were recorded over abductor digiti minimi (ADM) and first dorsal interosseous (FDI) during rest and during voluntary phasic flexion of the second digit. Subjects were given electrical stimulation to either their fifth digit (homotopic to ADM, heterotopic to FDI) or their second digit (heterotopic to FDI, homotopic to ADM) at twice sensory perceptual threshold 180 ms prior to TMS application. Additionally, F-waves were recorded from ADM. At rest, we found a significant decrease in ADM MEP amplitudes with both homotopic and heterotopic stimulation compared to the corresponding non-stimulated trials. There was a trend toward less LAI in FHD patients. During movement, LAI was significantly decreased in both patients and controls. There was no significant group effect. The results for LAI in FDI were similar to those from ADM. F-wave area in ADM was greater during movement for both homo- and heterotopic stimulation. We found no difference in F-wave area between patients and healthy volunteers. Our results indicate that LAI is unlikely to be an underlying mechanism that contributes to the generation of normal surround inhibition in healthy volunteers or in the disruption of surround inhibition in FHD. C1 [Richardson, Sarah Pirio] Hlth Sci Ctr, Dept Neurol, Albuquerque, NM 87131 USA. [Bliem, Barbara] Ruhr Univ Bochum, Int Grad Sch Neurosci, Bochum, Germany. [Voller, Bernhard] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Richardson, Sarah Pirio; Bliem, Barbara; Voller, Bernhard; Dang, Nguyet; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Richardson, SP (reprint author), Hlth Sci Ctr, Dept Neurol, MSC 5620,1 Univ New Mexico, Albuquerque, NM 87131 USA. EM spiriorichardson@salud.unm.edu OI Voller, Bernhard/0000-0001-5809-874X FU Intramural Research Program of the NIH; NINDS; International Graduate School of Neuroscience; Ruhr University, Bochum; German Exchange Service FX This research was supported by the Intramural Research Program of the NIH, NINDS, by the International Graduate School of Neuroscience, Ruhr University, Bochum (B. B.) and a travel grant of German Exchange Service (B. B.). NR 20 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD FEB PY 2009 VL 193 IS 2 BP 173 EP 179 DI 10.1007/s00221-008-1605-4 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 404DT UT WOS:000263131600002 ER PT J AU Szegedi, A Payer, E Czifra, G Toth, BI Schmidt, E Kovacs, L Blumberg, PM Biro, T AF Szegedi, Andrea Payer, Edit Czifra, Gabriella Toth, Balazs I. Schmidt, Emese Kovacs, Laszlo Blumberg, Peter M. Biro, Tamas TI Protein kinase C isoenzymes differentially regulate the differentiation-dependent expression of adhesion molecules in human epidermal keratinocytes SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE adhesion molecules; differentiation; isoenzymes; protein kinase C ID RADIATION-INDUCED APOPTOSIS; DESMOSOMAL CADHERINS; HACAT KERATINOCYTES; PEMPHIGUS-VULGARIS; SIGNAL-TRANSDUCTION; CARCINOMA-CELLS; CALCIUM; PROLIFERATION; INVOLVEMENT; MEMBRANE AB Epidermal expression of adhesion molecules such as desmogleins (Dsg) and cadherins is strongly affected by the differentiation status of keratinocytes. We have previously shown that certain protein kinase C (PKC) isoforms differentially alter the growth and differentiation of human epidermal HaCaT keratinocytes. In this paper, using recombinant overexpression and RNA interference, we define the specific roles of the different PKC isoenzymes in modulation of expression of adhesion molecules in HaCaT keratinocytes. The level of Dsg1, a marker of differentiating keratinocytes, was antagonistically regulated by two Ca-independent 'novel' nPKC isoforms; i.e. it increased by the differentiation-promoting nPKC delta and decreased by the growth-promoting nPKC epsilon. The expression of Dsg3 (highly expressed in proliferating epidermal layers) was conversely regulated by these isoenzymes, and was also inhibited by the differentiation inducer Ca-dependent 'conventional' cPKC alpha. Finally, the expression of P-cadherin (a marker of proliferating keratinocytes) was regulated by all of the examined PKCs, also in an antagonistic manner (inhibited by cPKC alpha/nPKC delta and stimulated by cPKC beta/nPKC epsilon). Collectively, the presented results strongly argue for the marked, differential, and in some instances antagonistic roles of individual Ca-dependent and Ca-independent PKC isoforms in the regulation of expression of adhesion molecules of desmosomes and adherent junctions in human epidermal keratinocytes. C1 [Biro, Tamas] Univ Debrecen, Dept Physiol, Med & Hlth Sci Ctr, Res Ctr Mol Med, H-4032 Debrecen, Hungary. [Szegedi, Andrea; Payer, Edit; Schmidt, Emese] Univ Debrecen, Dept Dermatol, H-4032 Debrecen, Hungary. [Toth, Balazs I.; Kovacs, Laszlo; Biro, Tamas] Univ Debrecen, Hungarian Acad Sci, Cell Physiol Res Grp, H-4032 Debrecen, Hungary. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Biro, T (reprint author), Univ Debrecen, Dept Physiol, Med & Hlth Sci Ctr, Res Ctr Mol Med, Nagyerdei Krt 98, H-4032 Debrecen, Hungary. EM biro@phys.dote.hu RI Toth, Balazs/K-1214-2013 FU Hungarian research grants: OTKA [T49231, K63153, K60262]; Hungarian Academy of Sciences FX The technical assistance of Ms Ibolya Varga is gratefully appreciated. This work was supported by the following Hungarian research grants: OTKA T49231, K63153 and K60262. Tamas Biro is the recipient of the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. NR 52 TC 13 Z9 13 U1 2 U2 4 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 FEB PY 2009 VL 18 IS 2 BP 122 EP 129 DI 10.1111/j.1600-0625.2008.00771.x PG 8 WC Dermatology SC Dermatology GA 394TD UT WOS:000262469800004 PM 18637128 ER PT J AU Gulyani, S Earley, CJ Camandola, S Maudsley, S Ferre, S Mughal, MR Martin, B Cheng, AW Gleichmann, M Jones, BC Allen, RP Mattson, MR AF Gulyani, Seema Earley, Christopher J. Camandola, Simonetta Maudsley, Stuart Ferre, Sergi Mughal, Mohamed R. Martin, Bronwen Cheng, Aiwu Gleichmann, Marc Jones, Byron C. Allen, Richard P. Mattson, Mark R. TI Diminished iron concentrations increase adenosine A(2A) receptor levels in mouse striatum and cultured human neuroblastoma cells SO EXPERIMENTAL NEUROLOGY LA English DT Article DE CGS-21680; Desferrioxamine; Dietary iron deficiency; Adenosine receptors; Restless legs syndrome; SH-SY5Y ID RESTLESS LEGS SYNDROME; CENTRAL-NERVOUS-SYSTEM; TRANSFERRIN RECEPTOR; DOPAMINE TRANSPORTER; PARKINSONS-DISEASE; DOWN-REGULATION; BASAL GANGLIA; RAT STRIATUM; BRAIN IRON; IN-VIVO AB Brain iron insufficiency has been implicated in several neurological disorders. The dopamine system is consistently altered ill Studies of iron deficiency in rodent models. Changes in striatal dopamine D-2 receptors are directly proportional to the degree of iron deficiency. In light of the unknown mechanism for the iron deficiency-dopamine connection and because of the known interplay between adenosinergic and dopaminergic systems in the striatum we examined the effects of iron deficiency on the adenosine system. We first attempted to assess whether there is a functional change in the levels of adenosine receptors in response to this low iron. Mice made iron-deficient by diet had an increase in the density of striatal adenosine A(2A) (A(2A)R) but not A, receptor (A(1)R) compared to mice on a normal diet. Between two inbred murine Strains, which had 2-fold differences in their striatal iron concentrations under normal dietary conditions, the strain with the lower striatal iron had the highest striatal A(2A)R density. Treatment of SH-SY5Y (human neuroblastoma) cells with an iron chelator resulted in increased density of A(2A)R. In these cells, A(2A)R agonist-induced cyclic AMP production was enhanced in response to iron chelation, also demonstrating a functional upregulation of AMR. A significant correlation (r(2)=0.79) was found between a primary marker of cellular iron status (transferrin receptor (TfR)) and A(2A)R protein density. In conclusion, the A(2A)R is increased across different iron-insufficient conditions. The relation between A(2A)R and cellular iron status may be an important pathway by which adenosine may alter the function of the dopaminergic system. (c) 2008 Elsevier Inc. All rights reserved. C1 [Earley, Christopher J.] Johns Hopkins Univ, Med Ctr, Sch Med, Dept Neurol,JHAAC, Baltimore, MD 21224 USA. [Gulyani, Seema; Camandola, Simonetta; Maudsley, Stuart; Mughal, Mohamed R.; Martin, Bronwen; Cheng, Aiwu; Gleichmann, Marc; Mattson, Mark R.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Ferre, Sergi] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. [Jones, Byron C.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. RP Earley, CJ (reprint author), Johns Hopkins Univ, Med Ctr, Sch Med, Dept Neurol,JHAAC, Room 1B-82,5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM cearley@jhmi.edu RI Ferre, Sergi/K-6115-2014 OI Ferre, Sergi/0000-0002-1747-1779 FU NIH [PO1-AG21190] FX This research was supported by the Intramural Research Programs of the National Institute on Aging and the National Institute on Drug Abuse and by NIH grant PO1-AG21190. NR 49 TC 8 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD FEB PY 2009 VL 215 IS 2 BP 236 EP 242 DI 10.1016/j.expneurol.2008.10.007 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 400TG UT WOS:000262890900005 PM 19013457 ER PT J AU Lazar, J Gharat, L Khairathkar-Joshi, N Blumberg, PM Szallasi, A AF Lazar, Jozsef Gharat, Laxmikant Khairathkar-Joshi, Neelima Blumberg, Peter M. Szallasi, Arpad TI Screening TRPV1 antagonists for the treatment of pain: lessons learned over a decade SO EXPERT OPINION ON DRUG DISCOVERY LA English DT Review DE pain; TRPV1 ID PROTEIN-KINASE-C; VANILLOID RECEPTOR TRPV1; AFFINITY COMPETITIVE ANTAGONIST; EXTERNAL PROTONATION SITES; BLOCKS CHANNEL ACTIVATION; CAPSAICIN RECEPTOR; IODO-RESINIFERATOXIN; SENSORY NEURONS; IN-VITRO; NEUROPATHIC PAIN AB Background: The capsaicin receptor TRPV1, a polymodal nociceptor whose expression is up-regulated in a number of painful inflammatory disorders, represents a promising therapeutic target for pain relief. Potent small molecule TRPV1 antagonists are now undergoing clinical trials in patients with inflammatory or neuropathic pain. This review focuses on the multiplicity of factors regulating this channel and on their contributions to the emerging complexity of responses to TRPV1 and partial antagonists. For example, it is now clear that antagonists of capsaicin response can also antagonize, have no effect, or stimulate response to heat or protons. The complexity of TRPV1 regulation affords the potential to optimize agents for a specific therapeutic indication. An encouraging advance is the dissection of therapeutic efficacy of antagonists from induction of hyperthermia, a side effect that initially had raised concerns about the suitability of systemically administered TRPV1 antagonists for therapy. Objectives and methods: To discuss the challenges facing the development of clinically useful TRPV1 antagonists based on our experience and a comprehensive review of the literature. Results/conclusions: TRPV1 is a polymodal receptor. Some antagonists block all modalities of TRPV1 stimulation whereas others are more selective in their pharmacological profile. A number of antagonists can, conversely, potentiate certain modes of TRPV1 activation (e.g., protons and heat). The selectivity of TRPV1 antagonists is species-dependent, posing a problem for extrapolation from animal models to patients. At present, this rich pharmacology of TRPV1 antagonists complicates drug development but for the future it promises great opportunities for drug design. C1 [Szallasi, Arpad] Monmouth Med Ctr, Dept Pathol, Long Branch, NJ 07740 USA. [Lazar, Jozsef; Blumberg, Peter M.] NCI, NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Gharat, Laxmikant] Glenmark Res Ctr, Dept Discovery Chem, Navi Mumbai 400709, India. RP Szallasi, A (reprint author), Monmouth Med Ctr, Dept Pathol, 300 2nd Ave, Long Branch, NJ 07740 USA. EM ASZALLASI@SBHCS.COM FU NIH FX Research by J Lazar and PM Blumberg was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute. L Gharat and N Khairathkar-joshi are employees of Glenmark Pharmaceuticals Ltd that did research in the area of TR.PVI antagonists. A Szallasi is member of the Scientific Advisory Board to Glenmark Pharmaceuticals. NR 134 TC 30 Z9 30 U1 2 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1746-0441 J9 EXPERT OPIN DRUG DIS JI Expert. Opin. Drug Discov. PD FEB PY 2009 VL 4 IS 2 BP 159 EP 180 DI 10.1517/17460440802681300 PG 22 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 411QA UT WOS:000263663200004 PM 23480514 ER PT J AU Bianco, C Salomon, DS AF Bianco, Caterina Salomon, David S. TI Human Cripto-1 as a target for a cancer vaccine: WO2008040759 SO EXPERT OPINION ON THERAPEUTIC PATENTS LA English DT Review DE cancer vaccines; Cripto-1; breast cancer; colon cancer ID TUMOR-GROWTH; INHIBITION; IMMUNOTHERAPY; EMBRYOGENESIS; CARCINOMA; PEPTIDES; PATHWAYS; BLOCKADE; CELLS AB Human Cripto-1 is a cell membrane protein that has been shown to be overexpressed in different types of human tumors. Because Cripto-1 is expressed at low levels in normal tissues, it represents a promising candidate for therapeutic intervention in cancer. The present patent describes a novel approach to target Cripto-1 in cancer using a vaccine. Immunization with Cripto-1 modified by addition of a foreign peptide to overcome T-cell tolerance for self-proteins has the potential to generate an antibody-based immune response that ultimately will block Cripto-1 activity in cancer cells. Although targeting Cripto-1 with a vaccine in cancer patients is promising, several experimental and clinical studies need to be done to validate this approach. C1 [Bianco, Caterina; Salomon, David S.] NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. RP Bianco, C (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. NR 20 TC 5 Z9 6 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3776 J9 EXPERT OPIN THER PAT JI Expert Opin. Ther. Patents PD FEB PY 2009 VL 19 IS 2 BP 141 EP 144 DI 10.1517/13543770802646956 PG 4 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 411QC UT WOS:000263663400004 PM 19441915 ER PT J AU Lau, CY Stansbury, JP Gust, DA Kafaar, Z AF Lau, Chuen-Yen Stansbury, James P. Gust, Deborah A. Kafaar, Zuhayr TI Social and behavioral science in HIV vaccine trials: a gap assessment of the literature SO EXPERT REVIEW OF VACCINES LA English DT Review DE clinical trial; HIV; social science; sociobehavioral; vaccine ID QUALITY-OF-LIFE; ETHICAL-LEGAL FRAMEWORK; SEXUAL RISK BEHAVIOR; INJECTION-DRUG USERS; SUB-SAHARAN AFRICA; AIDS VACCINE; CLINICAL-TRIALS; EFFICACY TRIALS; SOUTH-AFRICA; US COMMUNITIES AB Social and behavioral science research is integral to the conduct of HIV vaccine trials, especially because the vaccine targets an infection laden with sensitive human issues. Although social and behavioral sciences have played a larger role in HIV vaccine clinical trials than other vaccine clinical trials to date, this role should be expanded. Fortunately, related publications, conference coverage and research proposals are on the rise; community engagement is receiving more attention during the earlier stages of product development; and collaboration between HIV vaccine scientists and social and behavioral scientists is being fostered. Greater attention to social and behavioral science issues could not only facilitate accrual, but also improve research efficiency and relevance. in this review, gaps in the literature on social and behavioral science issues in HIV vaccine clinical research, including barriers and facilitators to trial participation, enhancing feasibility of trial success, health systems, policy and monitoring social and behavioral issues, are identified and directions are suggested for filling those gaps. Development of a safe, efficacious and acceptable HIV vaccine will be nurtured by addressing the gaps through interdisciplinary collaborations. C1 [Lau, Chuen-Yen] NIAID, Vaccine Clin Res Branch, Vaccine Res Program, NIH, Bethesda, MD 20817 USA. [Stansbury, James P.] EnCompass LLC, Potomac, MD USA. [Gust, Deborah A.] Ctr Dis Control & Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA USA. [Kafaar, Zuhayr] Univ Stellenbosch, Dept Psychol, Cape Town, South Africa. RP Lau, CY (reprint author), NIAID, Vaccine Clin Res Branch, Vaccine Res Program, NIH, 6700 B Rockledge,Room 5126, Bethesda, MD 20817 USA. EM lauc@niaid.nih.gov RI Stansbury, James/A-7858-2009 NR 111 TC 4 Z9 4 U1 0 U2 4 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD FEB PY 2009 VL 8 IS 2 BP 179 EP 190 DI 10.1586/14760584.8.2.179 PG 12 WC Immunology SC Immunology GA 410MS UT WOS:000263582200012 PM 19196198 ER PT J AU Abramowitz, J Birnbaumer, L AF Abramowitz, Joel Birnbaumer, Lutz TI Physiology and pathophysiology of canonical transient receptor potential channels SO FASEB JOURNAL LA English DT Review DE calcium; cardiovascular system; epithelium; lung; neuron ID SMOOTH-MUSCLE-CELLS; CAPACITATIVE CA2+ ENTRY; PROTEIN-KINASE-C; CA2+-PERMEABLE CATION CHANNEL; ARTERY ENDOTHELIAL-CELLS; METABOTROPIC GLUTAMATE RECEPTORS; INTESTINAL EPITHELIAL-CELLS; GLOMERULAR MESANGIAL CELLS; OPERATED CALCIUM-ENTRY; NECROSIS-FACTOR-ALPHA AB The existence of a mammalian family of TRPC ion channels, direct homologues of TRP, the visual transduction channel of flies, was discovered during 1995-1996 as a consequence of research into the mechanism by which the stimulation of the receptor-Gq-phospholipase C beta signaling pathway leads to sustained increases in intracellular calcium. Mammalian TRPs, TRPCs, turned out to be nonselective, calcium-permeable cation channels, which cause both a collapse of the cell's membrane potential and entry of calcium. The family comprises 7 members and is widely expressed. Many cells and tissues express between 3 and 4 of the 7 TRPCs. Despite their recent discovery, a wealth of information has accumulated, showing that TRPCs have widespread roles in almost all cells studied, including cells from excitable and nonexcitable tissues, such as the nervous and cardiovascular systems, the kidney and the liver, and cells from endothelia, epithelia, and the bone marrow compartment. Disruption of TRPC function is at the root of some familial diseases. More often, TRPCs are contributing risk factors in complex diseases. The present article reviews what has been uncovered about physiological roles of mammalian TRPC channels since the time of their discovery. This analysis reveals TRPCs as major and unsuspected gates of Ca(2+) entry that contribute, depending on context, to activation of transcription factors, apoptosis, vascular contractility, platelet activation, and cardiac hypertrophy, as well as to normal and abnormal cell proliferation. TRPCs emerge as targets for a thus far nonexistent field of pharmacological intervention that may ameliorate complex diseases. - Abramowitz, J., Birnbaumer, L. Physiology and pathophysiology of canonical transient receptor potential channels. FASEB J. 23, 297 - 328 ( 2009) C1 [Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Transmembrane Signaling Grp, Neurobiol Lab, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Abramowitz, J (reprint author), NIEHS, Transmembrane Signaling Grp, Neurobiol Lab, NIH,Dept Hlth & Human Serv, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM abramow1@niehs.nih.gov; birnbau1@niehs.nih.gov RI Abramowitz, Joel/A-2620-2015 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101684] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project Z01 ES101684). NR 321 TC 174 Z9 184 U1 2 U2 25 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2009 VL 23 IS 2 BP 297 EP 328 DI 10.1096/fj.08-119495 PG 32 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 400TZ UT WOS:000262892900004 PM 18940894 ER PT J AU Luo, S Levine, RL AF Luo, Shen Levine, Rodney L. TI Methionine in proteins defends against oxidative stress SO FASEB JOURNAL LA English DT Article DE norleucine; elongation factor Tu; hypochlorous acid ID SULFOXIDE-REDUCTASE-A; PERFORMANCE LIQUID-CHROMATOGRAPHY; WERNER SYNDROME PROTEIN; ESCHERICHIA-COLI-CELLS; SACCHAROMYCES-CEREVISIAE; GLUTAMINE-SYNTHETASE; ANTIOXIDANT DEFENSE; CELLULAR-REGULATION; OXIDIZED PROTEINS; CRYSTAL-STRUCTURE AB A variety of reactive oxygen species react readily with methionine residues in proteins to form methionine sulfoxide, thus scavenging the reactive species. Most cells contain methionine sulfoxide reductases, which catalyze a thioredoxin-dependent reduction of methionine sulfoxide back to methionine. Thus, methionine residues may act as catalytic antioxidants, protecting both the protein where they are located and other macromolecules. To test this hypothesis directly, we replaced 40% of the methionine residues in Escherichia coli with norleucine, the carbon-containing analog, in which the sulfur of methionine is substituted by a methylene group (-CH2-). The intracellular free methionine and S-adenosylmethionine pools were not altered, nor was the specific activity of the key enzyme, glutamine synthetase. When unstressed, both control and norleucine-substituted cells survived equally well at stationary phase for at least 32 h. However, oxidative stress was more damaging to the norleucine-substituted cells. They died more rapidly than control cells when challenged by hypochlorite, hydrogen peroxide, or ionizing radiation. One of the most abundant proteins in the cell, elongation factor Tu, was found to be more oxidatively modified in norleucine-substituted cells, consistent with loss of the antioxidant defense provided by methionine residues. The results of these studies support the hypothesis that methionine in protein acts as an endogenous antioxidant in cells. - Luo, S., Levine, R. L. Methionine in proteins defends against oxidative stress. FASEB J. 23, 464-472 (2009) C1 [Luo, Shen; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Rm 2351, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health FX The authors thank Elena K. Gaidamakova and Alexander Vasilenko for performing the irradiation of the E. coli. This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 61 TC 148 Z9 154 U1 2 U2 27 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2009 VL 23 IS 2 BP 464 EP 472 DI 10.1096/fj.08-118414 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 400TZ UT WOS:000262892900018 PM 18845767 ER PT J AU Sun, W Hu, W Xu, RJ Jin, JF Szulc, ZM Zhang, GF Galadari, SH Obeid, LM Mao, CG AF Sun, Wei Hu, Wei Xu, Ruijuan Jin, Junfei Szulc, Zdzislaw M. Zhang, Guofeng Galadari, Sehamuddin H. Obeid, Lina M. Mao, Cungui TI Alkaline ceramidase 2 regulates beta 1 integrin maturation and cell adhesion SO FASEB JOURNAL LA English DT Article DE retinoic acid; protein kinase C; Golgi; sphingolipid ID INTEGRIN RECEPTORS; ALPHA-5-BETA-1 INTEGRIN; MOLECULAR-CLONING; CARCINOMA-CELLS; SPHINGOID BASES; DOWN-REGULATION; RETINOIC ACID; GLYCOSYLATION; APOPTOSIS; EXPRESSION AB The polypeptide core of the integrin beta 1 subunit (beta 1) is glycosylated sequentially in the endoplasmic reticulum and the Golgi complex to form beta 1 precursor and mature beta 1, respectively. The beta 1 precursor to mature beta 1 conversion, termed beta 1 maturation, regulates the cell surface levels and function of beta 1-containing integrins, beta 1 integrins. Here we demonstrate that the human alkaline ceramidase 2 (ACER2), a Golgi enzyme, regulates beta 1 maturation by controlling the generation of sphingosine. ACER2 overexpression inhibited beta 1 maturation, thus leading to a decrease in the levels of mature beta-1 in T-REx HeLa cells, whereas RNA interference-mediated knockdown of ACER2 enhanced beta 1 maturation in MCF-7 cells. ACER2 overexpression decreased the cell surface levels of beta 1 integrins, thus inhibiting cell adhesion to fibronectin or collagen, whereas ACER2 knockdown has the opposite effects. Treatment with all-trans retinoic acid (ATRA) increased both the expression of ACER2 and the generation of sphingosine in HeLa cells and inhibited beta 1 maturation. ACER2 knockdown attenuated the inhibitory effects of ATRA on both beta 1 maturation and cell adhesion. In contrast, treatment with phorbol myristate acetate (PMA), a protein kinase C activator, decreased the expression of ACER2 and sphingosine in T-REx HeLa cells, thus enhancing beta 1 maturation. ACER2 overexpression inhibited the stimulatory effects of PMA on both beta 1 maturation and cell adhesion. These results suggest that the ACER2/sphingosine pathway plays an important role in regulating beta 1 maturation and cell adhesion mediated by beta 1 integrins. Sun, W., Hu, W., Xu, R., Jin, J., Szulc, Z. M., Zhang, G., Galadari, S. H., Obeid, L. M, Mao, C. Alkaline ceramidase 2 regulates beta 1 integrin maturation and cell adhesion. FASEB J. 23, 656-666 (2009) C1 [Sun, Wei; Xu, Ruijuan; Obeid, Lina M.; Mao, Cungui] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Hu, Wei; Jin, Junfei; Szulc, Zdzislaw M.; Obeid, Lina M.; Mao, Cungui] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Zhang, Guofeng] NIH, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. [Galadari, Sehamuddin H.] United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Biochem, Al Ain, U Arab Emirates. [Obeid, Lina M.] Ralph H Johnson Vet Adm Hosp, Charleston, SC USA. RP Mao, CG (reprint author), Div Gen Internal Med, 114 Doughty St,Rm 605 STB,POB 250779, Charleston, SC 29425 USA. EM maoc@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [R01CA104834]; Veterans Affairs Merit award FX This work is supported by the National Institutes of Health grant R01CA104834 (to C.M.) and a Veterans Affairs Merit award (to L.M.O.). NR 40 TC 21 Z9 24 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2009 VL 23 IS 2 BP 656 EP 666 DI 10.1096/fj.08-115634 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 400TZ UT WOS:000262892900036 PM 18945876 ER PT J AU Manipalviratn, S DeCherney, A Segars, J AF Manipalviratn, Somjate DeCherney, Alan Segars, James TI Imprinting disorders and assisted reproductive technology SO FERTILITY AND STERILITY LA English DT Article DE Imprinting disorders; epigenetic; Beckwith-Wiedemann syndrome; Angelman syndrome; retinoblastoma; assisted reproductive technology; IVF; ICSI ID BECKWITH-WIEDEMANN-SYNDROME; IN-VITRO FERTILIZATION; INTRACYTOPLASMIC SPERM INJECTION; ABERRANT DNA METHYLATION; ANGELMAN-SYNDROME; EPIGENETIC INHERITANCE; MOUSE EMBRYOS; GERM-CELLS; CHILDREN BORN; HUMAN OOCYTES AB Objective: To review currently available literature on the association between imprinting disorders (Beckwith-Wiedemann syndrome [BWS], Angelman syndrome [AS] and retinoblastoma) and assisted reproductive technology (ART) in humans. Design: Publications related to imprinting/epigenetic disorders including BWS, AS, and retinoblastoma. with ART, as well as articles publishing outcome of ART, including IVF and ICSI from July 1978 to February 2008, were identified using PubMed, Medline, and EMBASE. Result(s): Considerable evidence in animal studies has demonstrated alteration in gene imprinting of embryos cultured in vitro. Publications from Europe, the United States, and Australia have suggested an association between ART and BWS. Importantly, more than 90% of children with BWS that were born after ART had imprinting defects, compared with 40%-50% of children with BWS and conceived without ART. Moreover, there have been other reports suggesting an association between AS and ART. The majority of children with AS born after ART had an imprinting defect as the underlying etiology, specifically loss of methylation of the maternal allele. There was a single report suggesting an increased incidence of retinoblastoma in children conceived with ART. Conclusion(s): Because the absolute incidence of imprinting disorders is small (< 1:12,000 births), routine screening for imprinting disorders in children conceived by ART is not recommended. Additional large cohort studies of children born after ART are needed to determine whether there is a genuine association between ART and imprinting disorders. (Fertil Steril (R) 2009;91:305-15. (C)2009 by American Society for Reproductive Medicine.) C1 [Manipalviratn, Somjate; DeCherney, Alan; Segars, James] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. RP Segars, J (reprint author), NICHD, NIH, Reprod Biol & Med Branch, Bldg 10,CRC,1 E,Rm 1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU National Institute of Child Health and Human Development; National Institutes of Health, Bethesda, Maryland FX Supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 81 TC 162 Z9 176 U1 3 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2009 VL 91 IS 2 BP 305 EP 315 DI 10.1016/j.fertnstert.2009.01.002 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 408OW UT WOS:000263445300001 PM 19201275 ER PT J AU Lamar, CA DeCherney, AH AF Lamar, Charisee A. DeCherney, Alan H. TI Fertility preservation: state of the science and future research directions SO FERTILITY AND STERILITY LA English DT Editorial Material DE Fertility preservation; cryopreservation; cancer treatment; research recommendations; oocyte; sperm ID MALE CANCER SURVIVORS; FEMALE AB Objective: To identify issues related to fertility preservation, discuss the state of the science, and make specific recommendations to guide future research supported by the U.S. National Institutes of Health in the field of fertility preservation. Design: A 1-day meeting of an expert advisory panel convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development on January 23, 2007, at the National Institutes of Health in Bethesda, Maryland. The panelists represented the disciplines of reproductive endocrinology and infertility, urology, neurobiology, physiology, radiation oncology, pediatrics, genetics, behavioral science, surgery, and occupational health. Conclusion(s): The panel members recognized the emerging focus on fertility preservation to help women and men have biological children. Among those who might benefit from research in this area are those at risk for impaired fertility or infertility, including not only cancer survivors but also others with genetic predispositions to infertility, environmental occupational exposure to hazardous substances or conditions, or reproductive diseases such as endometriosis. The panelists highlighted the need for education and awareness among health-care providers to help people understand options for preserving fertility, the need for technologic advances, the lack of data on long-term consequences of fertility preservation, and emerging ethical and social questions. This report describes the process for developing a multidisciplinary, collaborative approach for research in this area, summarizes the discussions of the panelists, and outlines the recommendations for future research. (Fertil Steril (R) 2009;91:316-9. (C)2009 by American Society for Reproductive Medicine.) C1 [Lamar, Charisee A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Sci Branch, Populat Res Ctr, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Lamar, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Sci Branch, Populat Res Ctr, Dept Hlth & Human Serv,NIH, 6100 Execut Blvd,Room 8B01, Bethesda, MD 20892 USA. EM lamarc@mail.nih.gov NR 12 TC 29 Z9 30 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2009 VL 91 IS 2 BP 316 EP 319 DI 10.1016/j.fertnstert.2008.08.133 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 408OW UT WOS:000263445300002 PM 18976748 ER PT J AU Norian, JM Zeitlian, G Adel, G Freeman, RG Santoro, NF Pal, L AF Norian, John M. Zeitlian, Gohar Adel, Goli Freeman, Ruth G. Santoro, Nanette F. Pal, Lubna TI Low serum osteoprotegerin levels in premenopausal infertile women with low bone density: an association of relevance? SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 15-19, 2006 CL Philadelphia, PA SP Amer Soc Bone & Mineral Res DE Osteoprotegerin; premenopause; BMD; infertility; RANKL ID POPULATION-BASED COHORT; TERM FRACTURE RISK; POSTMENOPAUSAL WOMEN; MINERAL DENSITY; INHIBITORY FACTOR; HORMONE-LEVELS; OSTEOPOROSIS; OVARIAN; MASS; PREDICTION AB Objective: To evaluate if the levels of the central regulators of osteoclast activity, osteoprotegerin (OPG) and receptor activator for nuclear factor KB-ligand (RANk-L), correlate with bone mineral density (BMD) parameters in premenopausal infertile women. Design: Cross-sectional study. Setting: Academic infertility practice. Patient(s): 82 Infertile, but otherwise healthy, premenopausal women < 42 years age presenting for routine care. Intervention(S): BMD assessment; serum samples (cycle days 1 to 3), questionnaire addressing demographics. medical, social, family, and personal histories. Main Outcome Measure(s): BMD categorized as "Low" (Z <= -1.0) or "Normal" (Z > -1.0); Biomarkers of bone metabolism (BAP, TRAP, NTX, OPG, RANK-L) and ovarian reserve (FSH, estradiol). Result(S): The prevalence of low BMD was 23% (19/82). Significantly lower levels of OPG were observed in association with low BMD compared with normal BNM (1.37 +/- 0.57 versus 2.0 +/- 1.05 pMoI/L). Multivariable logistic regression analyses revealed low OPG levels as independent predictors of low BMD after adjusting for parameters known to influence bone density. Conclusion(s): We demonstrate an independent relationship between low circulating levels of OPG and low BMD in premenopausal healthy, albeit infertile, women. (Fertil Steril(R) 2009;91:542-8. (C)2009 by American Society for Reproductive Medicine.) C1 [Pal, Lubna] Yale Univ, Sch Med, Dept Obstet & Gynecol & Reprod Sci, Div Reprod Endocrinol & Infertil, New Haven, CT 06520 USA. [Norian, John M.] NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. [Zeitlian, Gohar; Adel, Goli; Freeman, Ruth G.; Santoro, Nanette F.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Zeitlian, Gohar; Adel, Goli; Santoro, Nanette F.] Albert Einstein Coll Med, Div Reprod Endocrinol & Infertil, Bronx, NY 10467 USA. [Zeitlian, Gohar; Adel, Goli; Santoro, Nanette F.] Montefiore Med Ctr, Bronx, NY 10467 USA. RP Pal, L (reprint author), Yale Univ, Sch Med, Dept Obstet & Gynecol & Reprod Sci, Div Reprod Endocrinol & Infertil, 333 Cedar St,POB 208063, New Haven, CT 06520 USA. EM lubnapal@hotmail.com FU NCRR NIH HHS [5K12 RR17672, KL2 RR025749] NR 32 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2009 VL 91 IS 2 BP 542 EP 548 DI 10.1016/j.fertnstert.2007.11.089 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 408OW UT WOS:000263445300032 PM 18490014 ER PT J AU Guo, L Li, QZ Xia, QS Dial, S Chan, PC Fu, P AF Guo, Lei Li, Quanzhen Xia, Qingsu Dial, Stacey Chan, Po-Chuen Fu, Peter TI Analysis of gene expression changes of drug metabolizing enzymes in the livers of F344 rats following oral treatment with kava extract SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Drug metabolizing enzyme; Drug metabolizing gene; Gene expression; Kava extract; Microarray; TaqMan assay ID ST-JOHNS-WORT; DIETARY-SUPPLEMENTS; PIPER-METHYSTICUM; PYRROLIZIDINE ALKALOIDS; GINKGO-BILOBA; IN-VIVO; CYTOCHROME-P450; KAVALACTONES; TOXICITY; PHARMACOKINETICS AB The association of kava product use with liver-related risks has prompted regulatory action in many countries. We studied the changes in gene expression of drug metabolizing enzymes in the livers of Fischer 344 male rats administered kava extract by gavage for 14 weeks. Analysis of 22,226 genes revealed that there were 14, 41, 110, 386, and 916 genes significantly changed in the 0.125, 0.25, 0.5, 1.0, and 2.0 g/kg treatment groups, respectively. There were 16 drug metabolizing genes altered in all three high-dose treatment groups, among which seven genes belong to cytochrome P450 isozymes. While gene expression of Cyp1a1, 1a2, 26, 3a1, and 3a3 increased: Cyp 2c23 and 2c40 decreased, all in a dose-dependent manner. Real-time PCR analyses of several genes verified these results. Our results indicate that kava extract can significantly modulate drug metabolizing enzymes, particularly the CYP isozymes, which could cause herb-drug interactions and may potentially lead to hepatotoxicity. Published by Elsevier Ltd. C1 [Guo, Lei; Dial, Stacey] US FDA, Natl Ctr Toxicol Res, Div Syst Toxicol, Jefferson, AR 72079 USA. [Li, Quanzhen] Univ Texas SW Med Ctr Dallas, Microarray Core Facil, Dallas, TX 75390 USA. [Xia, Qingsu; Fu, Peter] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Chan, Po-Chuen] NIEHS, Res Triangle Pk, NC 27709 USA. RP Guo, L (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM lei.guo@fda.hhs.gov; peter.fu@fda.hhs.gov RI Guo, Lei/E-9232-2011 NR 52 TC 33 Z9 33 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD FEB PY 2009 VL 47 IS 2 BP 433 EP 442 DI 10.1016/j.fct.2008.11.037 PG 10 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 408IX UT WOS:000263429800026 PM 19100306 ER EF