FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Osuorji, I Dyson, G Yerasuri, D Philip, PA Shields, AF Choi, M AF Osuorji, Ikenna Dyson, Greg Yerasuri, Durga Philip, Philip Agop Shields, Anthony Frank Choi, Minsig TI Prognostic factors for metastatic colorectal cancer with and without bevacizumab therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Wayne State Univ, Karmanos Canc Inst, Providence Hosp, Detroit, MI USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Wayne State Univ, Karmanos Canc Inst, Natl Surg Adjuvant Breast & Bowel Project, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e14163 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009805067 ER PT J AU Phillips, CL Fouladi, M Perentesis, JP Leary, S McGovern, RM Reid, JM Ingle, AM Ahern, CH Ames, MM Houghton, P Doyle, LA Weigel, B Blaney, S AF Phillips, Christine L. Fouladi, Maryam Perentesis, John Peter Leary, Sarah McGovern, Renee M. Reid, Joel M. Ingle, Ashish M. Ahern, Charlotte H. Ames, Matthew M. Houghton, Peter Doyle, L. Austin Weigel, Brenda Blaney, Susan TI A phase I trial of MK 2206 in children with refractory solid tumors: A Children's Oncology Group study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. Seattle Childrens Hosp, Seattle, WA USA. Mayo Clin, Rochester, MN USA. Childrens Oncol Grp, Arcadia, CA USA. Baylor Coll Med, Houston, TX 77030 USA. Nationwide Childrens Hosp, Columbus, OH USA. NCI, Rockville, MD USA. Univ Minnesota, Minneapolis, MN USA. Texas Childrens Canc Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9581 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802234 ER PT J AU Pili, R Shen, L George, S Hammers, H Sandecki, A Collins, C Espinoza-Delgado, I Carducci, MA AF Pili, Roberto Shen, Li George, Saby Hammers, Hans Sandecki, Anita Collins, Connie Espinoza-Delgado, Igor Carducci, Michael Anthony TI Phase I/II study of high-dose interleukin 2, aldesleukin, in combination with the histone deacetylase inhibitor entinostat in patients with metastatic renal cell carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Johns Hopkins Univ, Baltimore, MD USA. Natl Canc Inst CTEP, Bethesda, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS4687 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802871 ER PT J AU Rahma, OE Hamilton, M Dakheel, O Steinberg, SM Bernstein, S Schlom, J Khleif, S AF Rahma, Osama E. Hamilton, Michael Dakheel, Omar Steinberg, Seth M. Bernstein, Sarah Schlom, Jeffrey Khleif, Samir TI Vaccine therapy with tumor-specific mutated ras peptides and IL-2, GM-CSF, or both in adult patients with solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. Walter Reed Mil Med Ctr, Bethesda, MD USA. Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 2577 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801628 ER PT J AU Rajan, A Riely, GJ Carter, CA Thomas, A Khozin, S Bergagnini, I Berman, AW Scepura, B Szabo, E Lee, MJ Trepel, JB Browne, SK Pancholi, MJ Cao, L Chen, HX Giaccone, G AF Rajan, Arun Riely, Gregory J. Carter, Corey Allan Thomas, Anish Khozin, Sean Bergagnini, Isabella Berman, Arlene W. Scepura, Barbara Szabo, Eva Lee, Min-Jung Trepel, Jane B. Browne, Sarah K. Pancholi, Minjal J. Cao, Liang Chen, Helen X. Giaccone, Giuseppe TI Phase II study of cixutumumab (IMC-A12) in thymic malignancies. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 7033 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800104 ER PT J AU Ramnath, N Daignault-Newton, S Dy, GK Muindi, J Adjei, A Kalemkerian, GP Cease, KB Stella, PJ Brenner, DE Johnson, CS Trump, DL AF Ramnath, Nithya Daignault-Newton, Stephanie Dy, Grace K. Muindi, Josephia Adjei, Araba Kalemkerian, Gregory Peter Cease, Kemp Bailey Stella, Philip J. Brenner, Dean E. Johnson, Candace S. Trump, Donald L. TI A phase I/II clinical trial of intravenous (IV) calcitriol with fixed doses of cisplatin and docetaxel in advanced non-small cell lung cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Ann Arbor Vet Adm Med Ctr, Ann Arbor, MI USA. Univ Michigan, Sch Med, Div Biostat, Ann Arbor, MI USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NSABP, Ann Arbor, MI USA. St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e18118 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804257 ER PT J AU Richardson, BS Anderson, WF Barnholtz-Sloan, J Tucker, MA Gerstenblith, MR AF Richardson, Blakely S. Anderson, William F. Barnholtz-Sloan, Jill Tucker, Margaret A. Gerstenblith, Meg R. TI Effect of gender on age-specific effects for ulcerated malignant melanomas. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Cleveland, OH USA. NCI, US Dept HHS, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Case Comprehens Canc Ctr, Cleveland, OH USA. NCI, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 1603 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801079 ER PT J AU Richter, S McWhirter, E Chen, EX Tran, B Hotte, SJ Stathis, A Hirte, HW Razak, ARA Laughlin, A Wang, LS Battista, K Stayner, LA Ivy, SP Moore, MJ Oza, AM Siu, LL Bedard, P AF Richter, Sue McWhirter, Elaine Chen, Eric Xueyu Ben Tran Hotte, Sebastien J. Stathis, Anastasios Hirte, Hal W. Razak, Albiruni R. A. Laughlin, Anne Wang, Lisa Battista, Kristina Stayner, Lee-Anne Ivy, S. Percy Moore, Malcolm J. Oza, Amit M. Siu, Lillian L. Bedard, Philippe TI A phase I study of R04929097, an oral gamma secretase inhibitor, in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. Oncol Inst Southern Switzerland, Bellinzona, Switzerland. Princess Margaret Hosp, Dept Biostat, Toronto, ON M4X 1K9, Canada. NCI, Bethesda, MD 20892 USA. Univ Toronto, Toronto, ON, Canada. Princess Margaret Hosp, Drug Dev Program, Div Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. Dept Med Oncol, Toronto, ON, Canada. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3082 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802417 ER PT J AU Rios-Perez, JA Beumer, JH Appleman, LJ Tawbi, HAH Chu, E Stoller, RG Belani, CP Jiang, YX Sobol, RW Shepherd, SP Giranda, VL Chen, AP Huggins-Puhalla, SL AF Rios-Perez, Jorge Arturo Beumer, Jan H. Appleman, Leonard Joseph Tawbi, Hussein Abdul-Hassan Chu, Edward Stoller, Ronald G. Belani, Chandra Prakash Jiang, Yixing Sobol, Robert W. Shepherd, Stacie Peacock Giranda, Vincent L. Chen, Alice P. Huggins-Puhalla, Shannon Leigh TI ABT-888 (veliparib) in combination with weekly carboplatin and paclitaxel in advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Canc, Pittsburgh, PA USA. Penn State Hershey Canc Inst, Hershey, PA USA. Abbott, Abbott Pk, IL USA. Abbott Labs, Abbott Pk, IL 60064 USA. NCI, Bethesda, MD 20892 USA. Univ Pittsburgh, Magee Womens Hosp, Inst Canc, Pittsburgh, PA 15213 USA. RI Sobol, Robert/E-4125-2013 OI Sobol, Robert/0000-0001-7385-3563 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS1138 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800773 ER PT J AU Robidoux, A Tang, G Rastogi, P Geyer, CE Azar, CA Atkins, JN Fehrenbacher, L Bear, HD Baez-Diaz, L Kuebler, JP Margolese, RG Farrar, WB Brufsky, A Shibata, HR Bandos, H Paik, S Costantino, JP Swain, SM Mamounas, EP Wolmark, N AF Robidoux, Andre Tang, Gong Rastogi, Priya Geyer, Charles E. Azar, Catherine A. Atkins, James Norman Fehrenbacher, Louis Bear, Harry Douglas Baez-Diaz, Luis Kuebler, J. Phillip Margolese, Richard G. Farrar, William Blair Brufsky, Adam Shibata, Henry R. Bandos, Hanna Paik, Soonmyung Costantino, Joseph P. Swain, Sandra M. Mamounas, Eleftherios P. Wolmark, Norman TI Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+operable breast cancer: NSABP protocol B-41 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol C1 Natl Surg Adjuvant Breast & Bowel Project, Montreal, PQ, Canada. Ctr Hosp Univ Montreal, Montreal, PQ, Canada. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Dallas, TX USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Natl Surg Adjuvant Breast & Bowel Project, Denver, CO USA. Kaiser Permanente, Denver, CO USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Natl Surg Adjuvant Breast & Bowel Project, Vallejo, CA USA. Kaiser Permanente Northern Calif, Vallejo, CA USA. Natl Surg Adjuvant Breast & Bowel Project, Richmond, VA USA. Virginia Commonwealth Univ, Masey Canc Ctr, Richmond, VA USA. Natl Surg Adjuvant Breast & Bowel Project, San Juan, PR USA. CCOP San Juan, San Juan, PR USA. Natl Surg Adjuvant Breast & Bowel Project, Columbus, OH USA. CCOP Columbus, Columbus, OH USA. McGill Univ, Jewish Gen Hosp, Segal Canc Ctr, Montreal, PQ H3T 1E2, Canada. Ohio State Univ, Arthur G James Canc Hosp, Richard J Solous Res Inst, Columbus, OH 43210 USA. Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. McGill Univ, Ctr Hlth, Montreal, PQ, Canada. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, NSABP Biostat Ctr, Pittsburgh, PA 15261 USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Washington, DC USA. MedStar Washington Hosp Ctr, Washington Canc Inst, Washington, DC USA. Natl Surg Adjuvant Breast & Bowel Project, Canton, OH USA. Aultman Hosp, Canton, OH USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA LBA506 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800436 ER PT J AU Ruane, T Stella, PJ Scott, JA Feinberg, BA Cooper, J AF Ruane, Thomas Stella, Philip J. Scott, Jeffrey A. Feinberg, Bruce A. Cooper, Joseph TI Physician participation and compliance with cancer clinical care pathways: A successful model of collaboration between payers and providers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Blue Cross Blue Shield Michigan, Detroit, MI USA. NSABP, Ann Arbor, MI USA. St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. Cardinal Hlth, Specialty Solut, Dublin, OH USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e16552 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802794 ER PT J AU Sarantopoulos, J Hoering, A Synold, TW Mahalingam, D Wang, D Lenz, HJ O'Rourke, P Sexton, R Van Veldhuizen, PJ Mita, MM Wong, L Mita, AC El-Khoueiry, AB Chung, VM Gandara, DR Tejwani, S Takebe, N Takimoto, CHM Ivy, SP Kurzrock, R AF Sarantopoulos, John Hoering, Antje Synold, Timothy W. Mahalingam, Devalingam Wang, Ding Lenz, Heinz-Josef O'Rourke, Pat Sexton, Rachel Van Veldhuizen, Peter J. Mita, Monica M. Wong, Lucas Mita, Alain C. El-Khoueiry, Anthony B. Chung, Vincent M. Gandara, David R. Tejwani, Sheela Takebe, Naoko Takimoto, Chris H. M. Ivy, S. Percy Kurzrock, Razelle TI Phase I pharmacokinetic study of dasatinib (BMS-354825) in patients with advanced malignancies and varying levels of liver dysfunction: S0711, a SWOG early therapeutics committee study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. SWOG Stat Ctr, Seattle, WA USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. Henry Ford Hlth Syst, Josephine Ford Canc Ctr, Detroit, MI USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Univ Kansas, Ctr Canc, Westwood, KS USA. Scott & White Mem Hosp & Clin, Temple, TX USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Invest Drug Branch, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3078 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802496 ER PT J AU Sarantopoulos, J Hoering, A Synold, TW Mahalingam, D Wang, D Lenz, HJ O'Rourke, P Sexton, R Van Veldhuizen, PJ Mita, MM Wong, L Mita, AC El-Khoueiry, AB Chung, VM Gandara, DR Tejwani, S Takebe, N Takimoto, CHM Ivy, SP Kurzrock, R AF Sarantopoulos, John Hoering, Antje Synold, Timothy W. Mahalingam, Devalingam Wang, Ding Lenz, Heinz-Josef O'Rourke, Pat Sexton, Rachel Van Veldhuizen, Peter J. Mita, Monica M. Wong, Lucas Mita, Alain C. El-Khoueiry, Anthony B. Chung, Vincent M. Gandara, David R. Tejwani, Sheela Takebe, Naoko Takimoto, Chris H. M. Ivy, S. Percy Kurzrock, Razelle TI Phase I pharmacokinetic study of dasatinib (BMS-354825) in patients with advanced malignancies and varying levels of liver dysfunction: S0711, a SWOG early therapeutics committee study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. SWOG Stat Ctr, Seattle, WA USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. Henry Ford Hlth Syst, Josephine Ford Canc Ctr, Detroit, MI USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Univ Kansas, Ctr Canc, Westwood, KS USA. Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. Scott & White Mem Hosp & Clin, Temple, TX USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Invest Drug Branch, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3078 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802476 ER PT J AU Siegel, RD Bryant, DM Stallings, H Kadlubek, P Borowski, L Castro, KM Clauser, SB AF Siegel, Robert D. Bryant, Donna M. Stallings, Holley Kadlubek, Pamela Borowski, Laurel Castro, Kathleen M. Clauser, Steven B. CA NCI Community Canc Ctr Program NCC TI Fertility preservation: Utilizing QOPI metrics in the quality improvement efforts of the NCI Community Cancer Centers Program (NCCCP). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Hartford Hosp, Helen & Harry Gray Canc Ctr, Hartford, CT 06115 USA. Canc Program Our Lady Lake & Mary Bird Perkins, Baton Rouge, LA USA. Norton Canc Inst, Louisville, KY USA. Amer Soc Clin Oncol, Alexandria, VA USA. NCI, Bethesda, MD 20892 USA. NCI, Outcomes Res Branch, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e16532 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804087 ER PT J AU Singer, EA Friend, JC Hawks, G Vocke, C Metwalli, AR Pinto, PA Bratslavsky, G Linehan, WM Srinivasan, R AF Singer, Eric A. Friend, Julia C. Hawks, Geri Vocke, Cathy Metwalli, Adam R. Pinto, Peter A. Bratslavsky, Gennady Linehan, W. Marston Srinivasan, Ramaprasad TI A phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer (RCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Chevy Chase, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS4680 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803071 ER PT J AU Singh, NK Bilusic, M Kim, JW Heery, CR Falk, MH Wood, BJ Pinto, PA Dahut, WL Kaushal, A Couvillon, A Rauckhorst, M Choyke, PL Turkbey, IB Trepel, JB Tsang, KY Schlom, J Gulley, JL Madan, RA AF Singh, Nishith K. Bilusic, Marijo Kim, Joseph W. Heery, Christopher Ryan Falk, Martin H. Wood, Bradford J. Pinto, Peter A. Dahut, William L. Kaushal, Aradhana Couvillon, Anna Rauckhorst, Myrna Choyke, Peter L. Turkbey, Ismail B. Trepel, Jane B. Tsang, Kwong Yok Schlom, Jeffrey Gulley, James L. Madan, Ravi A. TI Randomized phase II clinical trial to assess MUC1 specific immune response to L-BLP25 vaccine in addition to standard therapy in newly diagnosed high-risk prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Merck KGaA, Darmstadt, Germany. NCI, Dept Radiol & Imaging Sci, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, CCR, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD USA. Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA TPS4701 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803073 ER PT J AU Skapek, S Anderson, JR Barr, FG Bridge, JA Gastier-Foster, JM Parham, D Rudzinski, ER Triche, TJ Hawkins, DS AF Skapek, Stephen Anderson, James Robert Barr, Frederick G. Bridge, Julia Ann Gastier-Foster, Julie M. Parham, David Rudzinski, Erin R. Triche, Timothy J. Hawkins, Douglas S. CA Children's Oncology Grp TI Relationship of fusion protein status and outcome for children with intermediate-risk rhabdomyosarcoma: A Children's Oncology Group report. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE USA. NCI, Bethesda, MD 20892 USA. Univ Nebraska, Omaha, NE 68182 USA. Nationwide Childrens Hosp, Columbus, OH USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. GenomeDx Biosci Inc, Vancouver, BC, Canada. Univ Washington, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9535 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801161 ER PT J AU Smith, SM Cohen, KS Kline, JP Zavala, JD Conner, K Thomas, SP Lesho, P Doyle, LA Stadler, WM Karrison, T Kimball, AS AF Smith, Sonali M. Cohen, Kenneth Stuart Kline, Justin Paul Zavala, Jose D. Conner, Kathy Thomas, Sachdev P. Lesho, Patricia Doyle, Laurence A. Stadler, Walter Michael Karrison, Theodore Kimball, Amy Sarah TI Phase I trial of temsirolimus and lenalidomide in pts with rel/ref lymphomas. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Chicago, Chicago, IL 60637 USA. Illinois Canc Care, Peoria, IL USA. Univ Maryland, Baltimore, MD 21201 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 8075 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804048 ER PT J AU Soliman, HH Neuger, A Noyes, D Vahanian, NN Link, CJ Munn, D Streicher, H Sullivan, D Antonia, S AF Soliman, Hatem Hussein Neuger, Anthony Noyes, David Vahanian, Nicholas N. Link, Charles J. Munn, David Streicher, Howard Sullivan, Daniel Antonia, Scott TI A phase I study of 1-methyl-D-tryptophan in patients with advanced malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. NewLink Genet, Ames, IA USA. Med Coll Georgia, Augusta, GA 30912 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 4 U1 0 U2 1 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 MAY 20 PY 2012 VL 30 IS 15 SU S MA 2501 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801669 ER PT J AU Somlo, G Sparano, JA Cigler, T Fleming, GF Luu, TH Hurria, A Mortimer, JE Frankel, PH Chew, HK Nanda, R Ma, CX Chen, AP Garcia, A Vahdat, LT Gandara, DR Weitzel, JN AF Somlo, George Sparano, Joseph A. Cigler, Tessa Fleming, Gini F. Luu, Thehang H. Hurria, Arti Mortimer, Joanne E. Frankel, Paul Henry Chew, Helen K. Nanda, Rita Ma, Cynthia X. Chen, Alice P. Garcia, Agustin Vahdat, Linda T. Gandara, David R. Weitzel, Jeffrey N. TI ABT-888 (veliparib) in combination with carboplatin in patients with stage IV BRCA-associated breast cancer. A California Cancer Consortium Trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 City Hope Natl Med Ctr, Duarte, CA USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Weill Cornell Med Coll, New York, NY USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. City Hope Canc Ctr, Beckman Res Inst, Duarte, CA USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. Univ Chicago, Chicago, IL 60637 USA. Washington Univ, Sch Med, St Louis, MO USA. NCI, Bethesda, MD 20892 USA. USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. NR 0 TC 0 Z9 0 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 MAY 20 PY 2012 VL 30 IS 15 SU S MA 1010 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801006 ER PT J AU Spencer, SD Figg, WD Rosen, LS Gordon, MS Hurwitz, H Wong, MKK Goldman, JW Mendelson, DS Adams, BJ Alvarez, D Seon, BK Theuer, CP Leigh, BR AF Spencer, Shawn D. Figg, William Douglas Rosen, Lee S. Gordon, Michael S. Hurwitz, Herbert Wong, Michael K. K. Goldman, Jonathan Wade Mendelson, David S. Adams, Bonne J. Alvarez, Delia Seon, Ben K. Theuer, Charles P. Leigh, Bryan R. TI Dose-specific clearance of TRC105 (anti-CD105 antibody) in advanced solid tumor patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Natl Canc Inst Frederick, SAIC Frederick, Bethesda, MD USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Santa Monica, CA USA. Pinnacle Oncol Hematol, Scottsdale, AZ USA. Duke Univ, Med Ctr, Durham, NC USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. UCLA Hematol & Oncol, Santa Monica, CA USA. Tracon Pharmaceut Inc, San Diego, CA USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3042 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802248 ER PT J AU Speranza, G Kinders, RJ Khin, S Weil, MK Do, KT Horneffer, Y Juwara, L Allen, D Williams, PM Lih, CJ Rubinstein, L Doyle, LA Doroshow, JH Kummar, S AF Speranza, Giovanna Kinders, Robert J. Khin, Sonny Weil, Marcie K. Do, Khanh Tu Horneffer, Yvonne Juwara, Lamin Allen, Deborah Williams, P. Mickey Lih, Chih Jian Rubinstein, Larry Doyle, Laurence A. Doroshow, James H. Kummar, Shivaani TI Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal carcinoma (CRC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. SAIC Frederick, Frederick, MD USA. NCI, Rockville, MD USA. Div Canc Treatment & Diag, Bethesda, MD USA. NIH, Rockville, MD USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3529 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804809 ER PT J AU Speranza, G Kinders, RJ Khin, S Weil, MK Do, KT Horneffer, Y Juwara, L Allen, D Williams, PM Lih, CJ Rubinstein, L Doyle, LA Doroshow, JH Kummar, S AF Speranza, Giovanna Kinders, Robert J. Khin, Sonny Weil, Marcie K. Khanh Tu Do Horneffer, Yvonne Juwara, Lamin Allen, Deborah Williams, P. Mickey Lih, Chih Jian Rubinstein, Larry Doyle, Laurence A. Doroshow, James H. Kummar, Shivaani TI Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal carcinoma (CRC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Bethesda, MD 20892 USA. SAIC Frederick, Frederick, MD USA. NCI, Rockville, MD USA. NCI, Bethesda, MD, Canada. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Div Canc Treatment & Diag, Bethesda, MD USA. NIH, Rockville, MD USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 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 MAY 20 PY 2012 VL 30 IS 15 SU S MA 3529 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804757 ER PT J AU Suneja, G Shiels, MS Melville, SK Williams, MA Rengan, R Engels, EA AF Suneja, Gita Shiels, Meredith S. Melville, Sharon K. Williams, Melanie A. Rengan, Ramesh Engels, Eric A. TI Disparities in the treatment and outcomes of lung cancer among HIV-infected people in Texas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Texas Dept State Hlth Serv, Austin, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 6070 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802498 ER PT J AU Swain, SM Tang, G Geyer, CE Rastogi, P Atkins, JN Donnellan, PP Fehrenbacher, L Azar, CA Robidoux, A Polikoff, J Brufsky, A Biggs, DD Levine, EA Zapas, JL Provencher, L Perez, EA Paik, S Costantino, JP Mamounas, EP Wolmark, N AF Swain, Sandra M. Tang, Gong Geyer, Charles E. Rastogi, Priya Atkins, James Norman Donnellan, Paul P. Fehrenbacher, Louis Azar, Catherine A. Robidoux, Andre Polikoff, Jonathan Brufsky, Adam Biggs, David D. Levine, Edward A. Zapas, John L. Provencher, Louise Perez, Edith A. Paik, Soonmyung Costantino, Joseph P. Mamounas, Eleftherios P. Wolmark, Norman TI NSABP B-38: Definitive analysis of a randomized adjuvant trial comparing dose-dense (DD) AC followed by paclitaxel (P) plus gemcitabine (G) with DD AC followed by P and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol C1 Natl Surg Adjuvant Breast & Bowel Project, Washington, DC USA. MedStar Washington Hosp Ctr, Washington Canc Inst, Washington, DC USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Natl Surg Adjuvant Breast & Bowel Project, Dallas, TX USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. All Ireland Cooperat Oncol Res Grp, Galway, Ireland. Univ Hosp Galway, Galway, Ireland. Natl Surg Adjuvant Breast & Bowel Project, Vallejo, CA USA. Kaiser Permanente Northern Calif, Vallejo, CA USA. Natl Surg Adjuvant Breast & Bowel Project, Denver, CO USA. Kaiser Permanente, Denver, CO USA. Natl Surg Adjuvant Breast & Bowel Project, Montreal, PQ, Canada. Ctr Hosp Univ Montreal, Montreal, PQ, Canada. Natl Surg Breast & Bowel Project, San Diego, CA USA. Kaiser Permanente Southern Calif, San Diego, CA USA. Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. Natl Surg Adjuvant Breast & Bowel Project, Newark, DE USA. Christiana Care Hlth Syst, Helen F Graham Canc Ctr, Newark, DE USA. Natl Surg Adjuvant Breast & Bowel Project, Winston Salem, NC USA. Wake Forest Univ, Surg Oncol Serv, Winston Salem, NC 27109 USA. Natl Surg Adjuvant Breast & Bowel Project, Baltimore, MD USA. Medstar Franklin Sq Med Ctr, Baltimore, MD USA. Natl Surg Adjuvant Breast & Bowel Project, Quebec City, PQ, Canada. Hop St Sacrement, Ctr Hosp Affilie Univ Quebec, Quebec City, PQ, Canada. Natl Surg Adjuvant Breast & Bowel Project, Jacksonville, FL USA. Mayo Clin, Jacksonville, FL 32224 USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Canton, OH USA. Aultman Hosp, Canton, OH USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA LBA1000 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800719 ER PT J AU Tan, AR Buyse, ME Rastogi, P Jacobs, SA Robidoux, A Flynn, PJ Thirlwell, MP Fehrenbacher, L Stella, PJ Goel, R Julian, TB Provencher, L Bury, MJ Paik, S Geyer, CE Swain, SM Mamounas, EP Wolmark, N AF Tan, Antoinette R. Buyse, Marc E. Rastogi, Priya Jacobs, Samuel A. Robidoux, Andre Flynn, Patrick J. Thirlwell, Michael P. Fehrenbacher, Louis Stella, Philip J. Goel, Rakesh Julian, Thomas B. Provencher, Louise Bury, Martin Joseph Paik, Soonmyung Geyer, Charles E. Swain, Sandra M. Mamounas, Eleftherios P. Wolmark, Norman TI NSABP FB-6: Phase II trial of weekly paclitaxel (WP) and pazopanib following doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy for HER2-negative locally advanced breast cancer (LABC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Natl Surg Adjuvant Breast & Bowel Project, New Brunswick, NJ USA. Canc Inst New Jersey, New Brunswick, NJ USA. Int Inst Drug Dev, Louvain, Belgium. NSABP, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NSABP, Montreal, PQ, Canada. Ctr Hosp Univ Montreal, Montreal, PQ, Canada. NSABP, St Louis Pk, MN USA. Metro Minnesota Community Clin Oncol Project, St Louis Pk, MN USA. Montreal Gen Hosp, Montreal, PQ H3G 1A4, Canada. NSABP, Vallejo, CA USA. Kaiser Permanente Northern Calif, Vallejo, CA USA. NSABP, Ann Arbor, MI USA. St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. NSABP, Ottawa, ON, Canada. Ottawa Hosp Canc Ctr, Ottawa, ON, Canada. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NSABP, Quebec City, PQ, Canada. Ctr Hosp Affilie Univ Quebec, Hop St Sacrement, Quebec City, PQ 75390, Canada. NSABP, Grand Rapids, MI USA. Grand Rapids Clin Oncol Program, Grand Rapids, MI USA. NSABP, Dallas, TX USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. NSABP, Washington, DC USA. MedStar Washington Hosp Ctr, Washington Canc Inst, Washington, DC USA. NSABP, Canton, OH USA. Aultman Hosp, Canton, OH USA. NR 0 TC 1 Z9 1 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 MAY 20 PY 2012 VL 30 IS 15 SU S MA 1025 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800735 ER PT J AU Thomas, A Rajan, A Khozin, S Szabo, E Carter, CA Guha, U Manu, M Berman, AW Kunst, T Piekarz, R Schrump, DS Giaccone, G AF Thomas, Anish Rajan, Arun Khozin, Sean Szabo, Eva Carter, Corey Allan Guha, Udayan Manu, Michell Berman, Arlene W. Kunst, Tricia Piekarz, Richard Schrump, David S. Giaccone, Giuseppe TI A phase (Ph) I/II study of belinostat (Bel) in combination with cisplatin, doxorubicin, and cyclophosphamide (PAC) in the first-line treatment of advanced or recurrent thymic malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 [Thomas, Anish; Rajan, Arun; Khozin, Sean; Szabo, Eva; Carter, Corey Allan; Guha, Udayan; Manu, Michell; Berman, Arlene W.; Kunst, Tricia; Piekarz, Richard; Schrump, David S.; Giaccone, Giuseppe] NCI, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 7103 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800283 ER PT J AU Trucco, MM Wilky, BA Awad, O Shah, P Gul, N Xia, MH Huang, RL Loeb, DM AF Trucco, Matteo Maria Wilky, Breelyn A. Awad, Ola Shah, Preeti Gul, Naheed Xia, Menghang Huang, Ruili Loeb, David Mark TI Establishment of a chordoma xenograft and in vivo testing of compounds identified by high-throughput screening SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Johns Hopkins Univ, Baltimore, MD USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Suez Canal Univ, Ismailia, Egypt. NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 10025 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800394 ER PT J AU Turcotte, S Gros, A Wunderlich, JR Hogan, K Wang, QJ Fetsch, P Dudley, ME Rosenberg, SA AF Turcotte, Simon Gros, Alena Wunderlich, John R. Hogan, Katherine Wang, Qiong J. Fetsch, Patricia Dudley, Mark E. Rosenberg, Steven A. TI Study of tumor-infiltrating T-cell reactivity to metastatic gastrointestinal cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Cytopathol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e14179 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804726 ER PT J AU Twelves, C Schmoll, HJ O'Connell, M Cartwright, TH McKenna, E Sun, WJ Saif, WM Lee, LF Yothers, G Haller, DG AF Twelves, Christopher Schmoll, Hans-Joachim O'Connell, Michael Cartwright, Thomas H. McKenna, Edward Sun, Weijing Saif, Wasif M. Lee, Luen F. Yothers, Greg Haller, Daniel G. TI Effect of oxaliplatin-based adjuvant therapy on post-relapse survival (PRS) in patients with stage III colon cancer: A pooled analysis of individual patient data from four randomized controlled trials. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Leeds, Leeds, W Yorkshire, England. St James Univ Hosp, Leeds, W Yorkshire, England. Univ Clin Halle Saale, Halle, Germany. Natl Surg Adjuvant Breast & Bowel Project, Operat Off, Pittsburgh, PA USA. Ocala Oncol, Ocala, FL USA. Genentech Inc, San Francisco, CA 94080 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 3523 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803728 ER PT J AU Varadarajan, P Kotsakis, AP Martin, D Gutkind, JS Gibson, MK Argiris, A AF Varadarajan, Prakash Kotsakis, Athanasios Panayotis Martin, Daniel Gutkind, Jorge Silvio Gibson, Michael K. Argiris, Athanassios TI Phase II trial of everolimus in patients with previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Univ Crete, Iraklion, Greece. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Univ Pittsburgh, Pittsburgh, PA USA. RI Kotsakis, Athanasios/Q-4600-2016 NR 0 TC 0 Z9 0 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 MAY 20 PY 2012 VL 30 IS 15 SU S MA 5541 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009800039 ER PT J AU Wang, XS Zhao, FM Fisch, M Mendoza, TR O'Mara, AM Cella, D Cleeland, CS AF Wang, Xin Shelley Zhao, Fengmin Fisch, Michael Mendoza, Tito R. O'Mara, Ann M. Cella, David Cleeland, Charles S. TI Defining mild, moderate, and severe fatigue in cancer patients and survivors: E2Z02, a trial of the Eastern Cooperative Oncology Group. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 9099 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804274 ER PT J AU Wang, XS Zhao, FM Fisch, M Mendoza, TR O'Mara, AM Cella, D Cleeland, CS AF Wang, Xin Shelley Zhao, Fengmin Fisch, Michael Mendoza, Tito R. O'Mara, Ann M. Cella, David Cleeland, Charles S. TI Defining mild, moderate, and severe fatigue in cancer patients and survivors: E2Z02, a trial of the Eastern Cooperative Oncology Group. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 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 MAY 20 PY 2012 VL 30 IS 15 SU S MA 9099 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804071 ER PT J AU Wang-Gillam, A Wani, S Early, DS Edmundowicz, SA Mullady, D Murad, F Jonnalagadda, S Gao, F Hollander, T Langley, EJ Meyer, G Singh, S Kim, PS Lim, KH Linehan, D Azar, R AF Wang-Gillam, Andrea Wani, Sachin Early, Dayna S. Edmundowicz, Steven Alphonse Mullady, Daniel Murad, Faris Jonnalagadda, Sreenivasa Gao, Feng Hollander, Thomas Langley, Emma J. Meyer, Gary Singh, Sharat Kim, Phillip Sangwook Lim, Kian-Huat Linehan, David Azar, Riad TI A pilot study of evaluation of a phosphorylation signature from pancreatic cancer tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Washington Univ, Sch Med, St Louis, MO USA. Univ Colorado, Aurora, CO USA. Washington Univ, St Louis, MO USA. Siteman Canc Ctr, St Louis, MO USA. Prometheus Labs Inc, San Diego, CA USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e14584 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801340 ER PT J AU West, HJ Moon, J Hirsch, FR Mack, PC Wozniak, AJ Lau, D Fehrenbacher, L Bury, MJ Redman, MW Gandara, DR AF West, Howard Jack Moon, James Hirsch, Fred R. Mack, Philip C. Wozniak, Antoinette J. Lau, Derick Fehrenbacher, Louis Bury, Martin Joseph Redman, Mary Weber Gandara, David R. TI SWOG S0635 and S0636: Phase II trials in advanced-stage NSCLC of erlotinib (OSI-774) and bevacizumab in bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (adenoBAC), and in never-smokers with primary NSCLC adenocarcinoma (adenoCa). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Swedish Canc Inst, Seattle, WA USA. SW Oncol Grp, Ctr Stat, Seattle, WA USA. Univ Colorado, Ctr Canc, Aurora, CO USA. Univ Calif Davis, Sacramento, CA 95817 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Natl Surg Adjuvant Breast & Bowel Project, Vallejo, CA USA. Kaiser Permanente Northern Calif, Vallejo, CA USA. Grand Rapids Clin Oncol Program, Grand Rapids, MI USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 7517 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804209 ER PT J AU Widemann, BC Jayaprakash, N Howard, SC Daugherty, C Chauhan, N King, T Rush, J AF Widemann, Brigitte C. Jayaprakash, Nalini Howard, Scott C. Daugherty, Claire Chauhan, Nikhil King, Thomas Rush, Janet TI Clinical trial and compassionate use experience with glucarpidase for methotrexate toxicity SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. BTG Int Inc, W Conshohocken, PA USA. NR 0 TC 3 Z9 3 U1 0 U2 0 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 MAY 20 PY 2012 VL 30 IS 15 SU S MA 6530 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803294 ER PT J AU Wilkerson, J Amiri-Kordestani, L Madan, RA Adesunloye, B Zhuang, SH Wells, SA Fojo, AT Bates, SE Stein, WD AF Wilkerson, Julia Amiri-Kordestani, Laleh Madan, Ravi A. Adesunloye, Bamidele Zhuang, Sen Hong Wells, Samuel A. Fojo, Antonio Tito Bates, Susan Elaine Stein, Wilfred Donald TI A method for assessing tumor response to therapy and more precisely guiding treatment decisions so as to improve survival. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. Janssen Res & Dev, Raritan, NJ USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Jerusalem, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA e13122 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009802004 ER PT J AU Williams, GM Priest, JR Finkelstein, MJ Harris, A Doros, LA Kratz, C Schultz, KAP Hill, DA Dehner, LP Messinger, YH AF Williams, Gretchen M. Priest, John R. Finkelstein, Marsha J. Harris, Anne Doros, Leslie Ann Kratz, Christian Schultz, Kris Ann Pinekenstein Hill, D. Ashley Dehner, Louis P. Messinger, Yoav H. TI Effect of radiation on outcome of types II and III PPB: A report from the International Pleuropulmonary Blastoma Registry. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. Int Pleuropulm Blastoma Registry, Minneapolis, MN USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NCI, HGP, DCEG, NIH,DHHS, Rockville, MD USA. Washington Univ, Med Ctr, St Louis, MO USA. NR 0 TC 3 Z9 3 U1 0 U2 0 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 MAY 20 PY 2012 VL 30 IS 15 SU S MA 9521 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009801877 ER PT J AU Yang, SX Nguyen, D Rubinstein, L Sherman, ME Swain, SM Tomaszewski, JE Doroshow, JH AF Yang, Sherry X. Diana Nguyen Rubinstein, Larry Sherman, Mark E. Swain, Sandra M. Tomaszewski, Joseph E. Doroshow, James H. TI pAKT expression in paraffin-embedded xenograft tumors after fixation delays and human breast cancer by optimized immunohistochemistry. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Rockville, MD USA. Div Canc Epidemiol & Genet, Rockville, MD USA. MedStar Washington Hosp Ctr, Natl Surg Adjuvant Breast & Bowel Project, Washington, DC USA. MedStar Washington Hosp Ctr, Washington Canc Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 10603 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009804199 ER PT J AU Zhu, PX Degheidy, HA Marti, GE Li, SH Abbasi, F Wiestner, A Amstutz, PT Tang, CM AF Zhu, Peixuan Degheidy, Heba A. Marti, Gerald E. Li, Shuhong Abbasi, Fatima Wiestner, Adrian Amstutz, Platte T. Tang, Cha-Mei TI Quantitative detection of ZAP-70 expression in chronic lymphocytic leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 01-06, 2012 CL Chicago, IL SP Amer Soc Clin Oncol (ASCO) C1 Creatv MicroTech Inc, Potomac, MD USA. FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2012 VL 30 IS 15 SU S MA 6581 PG 1 WC Oncology SC Oncology GA 131QQ UT WOS:000318009803016 ER PT J AU Jeon, JP Hong, C Park, EJ Jeon, JH Cho, NH Kim, IG Choe, H Muallem, S Kim, HJ So, I AF Jeon, Jae-Pyo Hong, Chansik Park, Eun Jung Jeon, Ju-Hong Cho, Nam-Hyuk Kim, In-Gyu Choe, Han Muallem, Shmuel Kim, Hyun Jin So, Insuk TI Selective G alpha(i) Subunits as Novel Direct Activators of Transient Receptor Potential Canonical (TRPC) 4 and TRPC5 Channels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMOOTH-MUSCLE-CELLS; LIGHT-CHAIN KINASE; C-TERMINAL DOMAIN; BETA-GAMMA-SUBUNITS; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; CATIONIC CURRENT; CALCIUM-CHANNEL; HEK293 CELLS; I-TASSER; PROTEIN AB The ubiquitous transient receptor potential canonical (TRPC) channels function as non-selective, Ca2+-permeable channels and mediate numerous cellular functions. It is commonly assumed that TRPC channels are activated by stimulation of G alpha(q)-PLC-coupled receptors. However, whether the G alpha(q)-PLC pathway is the main regulator of TRPC4/5 channels and how other G alpha proteins may regulate these channels are poorly understood. We previously reported that TRPC4/TRPC5 can be activated by G alpha(i). In the current work, we found that G alpha(i) subunits, rather than G alpha(q), are the primary and direct activators of TRPC4 and TRPC5. We report a novel molecular mechanism in which TRPC4 is activated by several G alpha(i) subunits, most prominently by G alpha(i2), and TRPC5 is activated primarily by G alpha(i3). Activation of G alpha(i) by the muscarinic M2 receptors or expression of the constitutively active G alpha(i) mutants equally and fully activates the channels. Moreover, both TRPC4 and TRPC5 are activated by direct interaction of their conserved C-terminal SESTD (SEC14-like and spectrin-type domains) with the G alpha(i) subunits. Two amino acids (lysine 715 and arginine 716) of the TRPC4 C terminus were identified by structural modeling as mediating the interaction with G alpha(i2). These findings indicate an essential role of G alpha(i) proteins as novel activators for TRPC4/5 and reveal the molecular mechanism by which G-proteins activate the channels. C1 [Kim, Hyun Jin] Sungkyunkwan Univ, Sch Med, Dept Physiol, Suwon 440746, South Korea. [Jeon, Jae-Pyo; Hong, Chansik; Park, Eun Jung; Jeon, Ju-Hong; So, Insuk] Seoul Natl Univ, Coll Med, Dept Physiol, Seoul 110799, South Korea. [Cho, Nam-Hyuk] Seoul Natl Univ, Coll Med, Dept Microbiol & Immunol, Seoul 110799, South Korea. [Kim, In-Gyu] Seoul Natl Univ, Coll Med, Dept Biochem, Seoul 110799, South Korea. [Choe, Han] Univ Ulsan, Coll Med, Dept Physiol, Seoul 136748, South Korea. [Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Kim, HJ (reprint author), Sungkyunkwan Univ, Sch Med, Dept Physiol, Suwon 440746, South Korea. EM kimhyunjin@skku.edu; insuk@snu.ac.kr RI Jeon, Ju-Hong/D-5740-2012; Cho, Nam-Hyuk/D-6032-2012; Kim, In-Gyu/J-2747-2012; So, Insuk/J-2762-2012 FU National Research Foundation of Korea; Ministry of Education, Science and Technology (MEST) [2008-2005948, 2010-0019472] FX This work was supported by the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (MEST) (2008-2005948 and 2010-0019472). NR 43 TC 32 Z9 32 U1 0 U2 7 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 MAY 18 PY 2012 VL 287 IS 21 BP 17029 EP 17039 DI 10.1074/jbc.M111.326553 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 973PU UT WOS:000306373000004 PM 22457348 ER PT J AU Luo, RB Akpan, IO Hayashi, R Sramko, M Barr, V Shiba, Y Randazzo, PA AF Luo, Ruibai Akpan, Itoro O. Hayashi, Ryo Sramko, Marek Barr, Valarie Shiba, Yoko Randazzo, Paul A. TI GTP-binding Protein-like Domain of AGAP1 Is Protein Binding Site That Allosterically Regulates ArfGAP Protein Catalytic Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; CANINE KIDNEY-CELLS; RHO-GTPASES; ACTIVATING-PROTEIN; KINASE-ACTIVITY; PARKINSONS-DISEASE; ACTIN CYTOSKELETON; LEUCINE-RICH-REPEAT-KINASE-2 LRRK2; LYSOSOME TRAFFICKING; MYRISTOYLATED ARF1 AB AGAPs are a subtype of Arf GTPase-activating proteins (GAPs) with 11 members in humans. In addition to the Arf GAP domain, the proteins contain a G-protein-like domain (GLD) with homology to Ras superfamily proteins and a PH domain. AGAPs bind to clathrin adaptors, function in post Golgi membrane traffic, and have been implicated in glioblastoma. The regulation of AGAPs is largely unexplored. Other enzymes containing GTP binding domains are regulated by nucleotide binding. However, nucleotide binding to AGAPs has not been detected. Here, we found that neither nucleotides nor deleting the GLD of AGAP1 affected catalysis, which led us to hypothesize that the GLD is a protein binding site that regulates GAP activity. Two-hybrid screens identified RhoA, Rac1, and Cdc42 as potential binding partners. Coimmunoprecipitation confirmed that AGAP1 and AGAP2 can bind to RhoA. Binding was mediated by the C terminus of RhoA and was independent of nucleotide. RhoA and the C-terminal peptide from RhoA increased GAP activity specifically for the substrate Arf1. In contrast, a C-terminal peptide from Cdc42 neither bound nor activated AGAP1. Based on these results, we propose that AGAPs are allosterically regulated through protein binding to the GLD domain. C1 [Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, Natl Inst Hlth, Ctr Canc Res, Bethesda, MD 20892 USA. [Hayashi, Ryo] Saga Univ, Fac Sci & Engn, Dept Chem, Honjo, Saga 8408502, Japan. RP Randazzo, PA (reprint author), NCI, Lab Cellular & Mol Biol, Natl Inst Hlth, Ctr Canc Res, Bldg 37,Rm 2042, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov FU National Institutes of Health (Intramural Program of the NCI) [BC 007365] FX This work was supported, in whole or in part, by the National Institutes of Health Grant BC 007365 (Intramural Program of the NCI). NR 69 TC 4 Z9 4 U1 0 U2 5 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 MAY 18 PY 2012 VL 287 IS 21 BP 17176 EP 17185 DI 10.1074/jbc.M111.334458 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 973PU UT WOS:000306373000017 PM 22453919 ER PT J AU Rogers, MA Liu, J Kushnir, MM Bryleva, E Rockwood, AL Meikle, AW Shapiro, D Vaisman, BL Remaley, AT Chang, CCY Chang, TY AF Rogers, Maximillian A. Liu, Jay Kushnir, Mark M. Bryleva, Elena Rockwood, Alan L. Meikle, A. Wayne Shapiro, David Vaisman, Boris L. Remaley, Alan T. Chang, Catherine C. Y. Chang, Ta-Yuan TI Cellular Pregnenolone Esterification by Acyl-CoA:Cholesterol Acyltransferase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LECITHIN-CHOLESTEROL ACYLTRANSFERASE; FATTY-ACID-ESTERS; LIPOIDAL DERIVATIVES; IN-VITRO; COENZYME; BRAIN; MICE; ENZYMES; DEHYDROEPIANDROSTERONE; NEUROSTEROIDS AB Pregnenolone (PREG) can be converted to PREG esters (PE) by the plasma enzyme lecithin: cholesterol acyltransferase (LCAT), and by other enzyme(s) with unknown identity. Acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2) convert various sterols to steryl esters; their activities are activated by cholesterol. PREG is a sterol-like molecule, with 3-beta-hydroxy moiety at steroid ring A, but with much shorter side chain at steroid ring D. Here we show that without cholesterol, PREG is a poor ACAT substrate; with cholesterol, the V-max for PREG esterification increases by 100-fold. The binding affinity of ACAT1 for PREG is 30-50-fold stronger than that for cholesterol; however, PREG is only a substrate but not an activator, while cholesterol is both a substrate and an activator. These results indicate that the sterol substrate site in ACAT1 does not involve significant sterol-phospholipid interaction, while the sterol activator site does. Studies utilizing small molecule ACAT inhibitors show that ACAT plays a key role in PREG esterification in various cell types examined. Mice lacking ACAT1 or ACAT2 do not have decreased PREG ester contents in adrenals, nor do they have altered levels of the three major secreted adrenal steroids in serum. Mice lacking LCAT have decreased levels of PREG esters in the adrenals. These results suggest LCAT along with ACAT1/ACAT2 contribute to control pregnenolone ester content in different cell types and tissues. C1 [Rogers, Maximillian A.; Liu, Jay; Bryleva, Elena; Shapiro, David; Chang, Catherine C. Y.; Chang, Ta-Yuan] Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA. [Kushnir, Mark M.; Rockwood, Alan L.; Meikle, A. Wayne] ARUP Inst Clin & Expt Pathol, Salt Lake City, UT 84108 USA. [Kushnir, Mark M.; Rockwood, Alan L.; Meikle, A. Wayne] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT 84112 USA. [Vaisman, Boris L.; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Chang, CCY (reprint author), Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA. EM Catherine.Chang@Dartmouth.Edu; Ta.Yuan.Chang@Dartmouth.Edu OI Rogers, Maximillian/0000-0001-9277-3200; Chang, Ta-Yuan/0000-0002-3249-0468 FU National Institutes of Health (NIH) NRSA; ARUP Institute for Clinical and Experimental Pathology; NIH [R01AG37609, HL60306] FX This work was supported, in whole or in part, by a National Institutes of Health (NIH) NRSA T32 Postdoctoral Fellowship (to M. A. R.), an NIH Institutional Predoctoral Training Grant Fellowship (to J. L.), and NIH Grants R01AG37609 (to T. Y. C.), and HL60306 (to T. Y. C. and C. C. Y. C.). This work was also supported in part by the ARUP Institute for Clinical and Experimental Pathology. NR 27 TC 4 Z9 5 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 MAY 18 PY 2012 VL 287 IS 21 BP 17483 EP 17492 DI 10.1074/jbc.M111.331306 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 973PU UT WOS:000306373000048 PM 22474282 ER PT J AU O'Shea, PJ Kim, DW Logan, JG Davis, S Walker, RL Meltzer, PS Cheng, SY Williams, GR AF O'Shea, Patrick J. Kim, Dong Wook Logan, John G. Davis, Sean Walker, Robert L. Meltzer, Paul S. Cheng, Sheue-yann Williams, Graham R. TI Advanced Bone Formation in Mice with a Dominant-negative Mutation in the Thyroid Hormone Receptor beta Gene due to Activation of Wnt/beta-Catenin Protein Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-PLATE CHONDROCYTES; CYCLIN D1; REGULATES EXPRESSION; SKELETAL PHENOTYPES; COLON-CARCINOMA; FRACTURE RISK; HYPERTHYROIDISM; DIFFERENTIATION; HYPOTHYROIDISM; RESISTANCE AB Thyroid hormone (T-3) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance, but the signaling pathways mediating these effects are poorly understood. Thrb(PV/PV) mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant- negative mutant T-3 receptor (TR beta(PV)) that cannot bind T-3 and interferes with the actions of wild-type TR. Thrb(PV/PV) mice have accelerated skeletal development due to unknown mechanisms. Weperformed microarray studies in primary osteoblasts from wild-type mice and Thrb(PV/PV) mice. Activation of the canonical Wnt signaling in Thrb(PV/PV) mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during postnatal growth. By contrast, T-3 treatment inhibited Wnt signaling in osteoblastic cells, suggesting that T-3 inhibits the Wnt pathway by facilitating proteasomal degradation of beta-catenin and preventing its accumulation in the nucleus. Activation of the Wnt pathway in Thrb(PV/PV) mice, however, results from a gain of function for TR beta(PV) that stabilizes beta-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions betweenT(3) and Wnt signaling pathways in the regulation of skeletal development and bone formation. C1 [O'Shea, Patrick J.; Kim, Dong Wook; Cheng, Sheue-yann] NCI, Gene Regulat Sect, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Davis, Sean; Walker, Robert L.; Meltzer, Paul S.] NCI, Mol Genet Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. [O'Shea, Patrick J.; Logan, John G.; Williams, Graham R.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Mol Endocrinol Grp, London W12 0NN, England. RP Cheng, SY (reprint author), NCI, Gene Regulat Sect, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov; graham.williams@imperial.ac.uk FU Medical Research Council [G0501486] NR 59 TC 13 Z9 15 U1 0 U2 5 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 MAY 18 PY 2012 VL 287 IS 21 BP 17812 EP 17822 DI 10.1074/jbc.M111.311464 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 973PU UT WOS:000306373000079 PM 22442145 ER PT J AU Guo, N Lang, LX Li, WH Kiesewetter, DO Gao, HK Niu, G Xie, QG Chen, XY AF Guo, Ning Lang, Lixin Li, Weihua Kiesewetter, Dale O. Gao, Haokao Niu, Gang Xie, Qingguo Chen, Xiaoyuan TI Quantitative Analysis and Comparison Study of [F-18]AlF-NOTA-PRGD2, [18F]FPPRGD2 and [Ga-68]Ga-NOTA-PRGD2 Using a Reference Tissue Model SO PLOS ONE LA English DT Article ID INTEGRIN ALPHA(V)BETA(3) EXPRESSION; CYCLIC RGD PEPTIDES; GRAPHICAL ANALYSIS; CANCER-PATIENTS; DYNAMIC PET; TRACER; ANGIOGENESIS; TUMORS; MICE; STRATEGIES AB With favorable pharmacokinetics and binding affinity for alpha(v)beta(3) integrin, F-18-labeled dimeric cyclic RGD peptide ([F-18]FPPRGD2) has been intensively used as a PET imaging probe for lesion detection and therapy response monitoring. A recently introduced kit formulation method, which uses an F-18-fluoride-aluminum complex labeled RGD tracer ([F-18]AlF-NOTA-PRGD2), provides a strategy for simplifying the labeling procedure to facilitate clinical translation. Meanwhile, an easy-to-prepare Ga-68-labeled NOTA-PRGD2 has also been reported to have promising properties for imaging integrin alpha(v)beta(3). The purpose of this study is to quantitatively compare the pharmacokinetic parameters of [F-18]FPPRGD2, [F-18]AlF-NOTA-PRGD2, and [Ga-68]Ga-NOTA-PRGD2. U87MG tumor-bearing mice underwent 60-min dynamic PET scans following the injection of three tracers. Kinetic parameters were calculated using Logan graphical analysis with reference tissue. Parametric maps were generated using voxel-level modeling. All three compounds showed high binding potential (Bp(ND) = k(3)/k(4)) in tumor voxels. [F-18]AlF-NOTA-PRGD2 showed comparable Bp(ND) value (3.75 +/- 0.65) with those of [F-18]FPPRGD2 (3.39 +/- 0.84) and [Ga-68]Ga-NOTA-PRGD2 (3.09 +/- 0.21) (p > 0.05). Little difference was found in volume of distribution (V-T) among these three RGD tracers in tumor, liver and muscle. Parametric maps showed similar kinetic parameters for all three tracers. We also demonstrated that the impact of non-specific binding could be eliminated in the kinetic analysis. Consequently, kinetic parameter estimation showed more comparable results among groups than static image analysis. In conclusion, [F-18]AlF-NOTA-PRGD2 and [Ga-68]Ga-NOTA-PRGD2 have comparable pharmacokinetics and quantitative parameters compared to those of [F-18]FPPRGD2. Despite the apparent difference in tumor uptake (%ID/g determined from static images) and clearance pattern, the actual specific binding component extrapolated from kinetic modeling appears to be comparable for all three dimeric RGD tracers. C1 [Guo, Ning; Lang, Lixin; Li, Weihua; Kiesewetter, Dale O.; Gao, Haokao; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Guo, Ning; Xie, Qingguo] Huazhong Univ Sci & Technol, Dept Biomed Engn, Wuhan 430074, Hubei, Peoples R China. [Guo, Ning; Xie, Qingguo] Wuhan Natl Lab Optoelect, Wuhan, Hubei, Peoples R China. [Chen, Xiaoyuan] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen, Peoples R China. RP Guo, N (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering; National Institutes of Health; International Cooperative Program of the National Science Foundation of China (NSFC) [81028009]; NSFC [60972099, 61027006]; China Scholarship Council FX This work was supported in part by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, the National Institutes of Health, the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009), and NSFC Grants (60972099, 61027006). NG was partially sponsored by the China Scholarship Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 25 Z9 26 U1 1 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 18 PY 2012 VL 7 IS 5 AR e37506 DI 10.1371/journal.pone.0037506 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VG UT WOS:000305343500126 PM 22624041 ER PT J AU Krause, MA Diakite, SAS Lopera-Mesa, TM Amaratunga, C Arie, T Traore, K Doumbia, S Konate, D Keefer, JR Diakite, M Fairhurst, RM AF Krause, Michael A. Diakite, Seidina A. S. Lopera-Mesa, Tatiana M. Amaratunga, Chanaki Arie, Takayuki Traore, Karim Doumbia, Saibou Konate, Drissa Keefer, Jeffrey R. Diakite, Mahamadou Fairhurst, Rick M. TI alpha-Thalassemia Impairs the Cytoadherence of Plasmodium falciparum- Infected Erythrocytes SO PLOS ONE LA English DT Article ID RED-BLOOD-CELLS; HUMAN CEREBRAL MALARIA; ALPHA(+)-THALASSEMIA PROTECTS; PARASITIZED ERYTHROCYTES; SICKLE ERYTHROCYTES; AFRICAN CHILDREN; BETA-THALASSEMIA; HEMOGLOBIN-E; SURFACE; PHAGOCYTOSIS AB Background: alpha-thalassemia results from decreased production of alpha-globin chains that make up part of hemoglobin tetramers (Hb; alpha(2)beta(2)) and affects up to 50% of individuals in some regions of sub-Saharan Africa. Heterozygous (-alpha/alpha alpha) and homozygous (-alpha/-alpha) genotypes are associated with reduced risk of severe Plasmodium falciparum malaria, but the mechanism of this protection remains obscure. We hypothesized that alpha-thalassemia impairs the adherence of parasitized red blood cells (RBCs) to microvascular endothelial cells (MVECs) and monocytes - two interactions that are centrally involved in the pathogenesis of severe disease. Methods and Findings: We obtained P. falciparum isolates directly from Malian children with malaria and used them to infect alpha alpha/alpha alpha (normal), -alpha/alpha alpha and -alpha/-alpha RBCs. We also used laboratory-adapted P. falciparum clones to infect -/-alpha RBCs obtained from patients with HbH disease. Following a single cycle of parasite invasion and maturation to the trophozoite stage, we tested the ability of parasitized RBCs to bind MVECs and monocytes. Compared to parasitized alpha alpha/alpha alpha RBCs, we found that parasitized -alpha/alpha alpha, -alpha/-alpha and -/-alpha RBCs showed, respectively, 22%, 43% and 63% reductions in binding to MVECs and 13%, 33% and 63% reductions in binding to monocytes. alpha-thalassemia was associated with abnormal display of P. falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite's main cytoadherence ligand and virulence factor, on the surface of parasitized RBCs. Conclusions: Parasitized alpha-thalassemic RBCs show PfEMP1 display abnormalities that are reminiscent of those on the surface of parasitized sickle HbS and HbC RBCs. Our data suggest a model of malaria protection in which alpha-thalassemia ameliorates the pro-inflammatory effects of cytoadherence. Our findings also raise the possibility that other unstable hemoglobins such as HbE and unpaired alpha-globin chains (in the case of beta-thalassemia) protect against life-threatening malaria by a similar mechanism. C1 [Krause, Michael A.; Lopera-Mesa, Tatiana M.; Amaratunga, Chanaki; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Diakite, Seidina A. S.; Traore, Karim; Doumbia, Saibou; Konate, Drissa; Diakite, Mahamadou] Univ Bamako, Malaria Res & Training Ctr, Fac Med Pharm & Odontostomatol, Bamako, Mali. [Arie, Takayuki] Osaka Prefecture Univ, Dept Phys & Elect, Sch Engn, Osaka, Japan. [Keefer, Jeffrey R.] Johns Hopkins Sch Med, Div Pediat Hematol, Dept Pediat, Baltimore, MD USA. RP Krause, MA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rfairhurst@niaid.nih.gov FU Intramural Research Program of the NIAID; NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. The authors wish to acknowledge Jennifer M. Anderson, Steve Beaudry, Mory Doumbia, Seydou Doumbia, Robert W. Gwadz, Carole A. Long, Sam Moretz, Dick Sakai, Cheick Traore, and Thomas E. Wellems for their efforts in support of this work.; This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, 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 52 TC 19 Z9 21 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 18 PY 2012 VL 7 IS 5 AR e37214 DI 10.1371/journal.pone.0037214 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VG UT WOS:000305343500076 PM 22623996 ER PT J AU Xu, DS Yang, CZ Proescholdt, M Brundl, E Brawanski, A Fang, XP Lee, CS Weil, RJ Zhuang, ZP Lonser, RR AF Xu, David S. Yang, Chunzhang Proescholdt, Martin Bruendl, Elisabeth Brawanski, Alexander Fang, Xueping Lee, Cheng S. Weil, Robert J. Zhuang, Zhengping Lonser, Russell R. TI Neuronatin in a Subset of Glioblastoma Multiforme Tumor Progenitor Cells Is Associated with Increased Cell Proliferation and Shorter Patient Survival SO PLOS ONE LA English DT Article ID SECONDARY GLIOBLASTOMAS; GENE; EXPRESSION; CLONING; DIFFERENTIATION; IDENTIFICATION; MUTATIONS; GROWTH; BRAIN; MS AB Glioblastoma multiforme is the most common and malignant primary brain tumor. Recent evidence indicates that a subset of glioblastoma tumor cells have a stem cell like phenotype that underlies chemotherapy resistance and tumor recurrence. We utilized a new "multidimensional" capillary isoelectric focusing nano-reversed-phase liquid chromatography platform with tandem mass spectrometry to compare the proteomes of isolated glioblastoma tumor stem cell and differentiated tumor cell populations. This proteomic analysis yielded new candidate proteins that were differentially expressed. Specifically, two isoforms of the membrane proteolipid neuronatin (NNAT) were expressed exclusively within the tumor stem cells. We surveyed the expression of NNAT across 10 WHO grade II and III gliomas and 23 glioblastoma (grade IV) human tumor samples and found NNAT was expressed in a subset of primary glioblastoma tumors. Through additional in vitro studies utilizing the U87 glioma cell line, we found that expression of NNAT is associated with significant increases in cellular proliferation. Paralleling the in vitro results, when NNAT levels were evaluated in tumor specimens from a consecutive cohort of 59 glioblastoma patients, the presence of increased levels of NNAT were found to be a an independent risk factor (P = 0.006) for decreased patient survival through Kaplan-Meier and multivariate analysis. These findings indicate that NNAT may have utility as a prognostic biomarker, as well as a cell-surface target for chemotherapeutic agents. C1 [Xu, David S.; Yang, Chunzhang; Zhuang, Zhengping; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Weil, Robert J.] Cleveland Clin Fdn, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44195 USA. [Proescholdt, Martin; Bruendl, Elisabeth; Brawanski, Alexander] Univ Regensburg, Med Ctr, Dept Neurosurg, Regensburg, Germany. [Fang, Xueping; Lee, Cheng S.] Calibrant Biosyst, Gaithersburg, MD USA. RP Xu, DS (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov; Lonserr@ninds.nih.gov OI Xu, David/0000-0001-8987-4545 FU National Institutes of Neurological Disorders and Stroke, National Institutes of Health FX All work was funded through the intramural research program at the National Institutes of Neurological Disorders and Stroke as a part of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 13 Z9 13 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 18 PY 2012 VL 7 IS 5 AR e37811 DI 10.1371/journal.pone.0037811 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VG UT WOS:000305343500153 PM 22624064 ER PT J AU Sambuughin, N Swietnicki, W Techtmann, S Matrosova, V Wallace, T Goldfarb, L Maynard, E AF Sambuughin, Nyamkhishig Swietnicki, Wieslaw Techtmann, Stephen Matrosova, Vera Wallace, Tarina Goldfarb, Lev Maynard, Ernest TI KBTBD13 interacts with Cullin 3 to form a functional ubiquitin ligase SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Nemaline Myopathy; Muscle; BTB and Kelch domain containing 13 protein; Cullin 3; Ubiquitin ligase ID SEDIMENTATION-VELOCITY; NEMALINE MYOPATHY; DOMAIN PROTEINS; DEGRADATION; SUBSTRATE; FAMILY; ULTRACENTRIFUGATION; ADAPTERS AB Autosomal dominant mutations in BTB and Kelch domain containing 13 protein (KBTBD13) are associated with a new type of Nemaline Myopathy (NEM). NEM is a genetically heterogeneous group of muscle disorders. Mutations causing phenotypically distinct NEM variants have previously been identified in components of muscle thin filament. KBTBD13 is a muscle specific protein composed of an N terminal BTB domain and a C terminal Ketch-repeat domain. The function of this newly identified protein in muscle remained unknown. In this study, we show that KBTBD13 interacts with Cullin 3 (Cul3) and the BTB domain mediates this interaction. Using ubiquitination assays, we determined that KBTBD13 participates in the formation of a Cul3 based RING ubiquitin ligase (Cul3-RL) capable of ubiquitin conjugation. Confocal microscopy of transiently expressed KBTBD13 revealed its co-localization with ubiquitin. Taken together, our results demonstrate that KBTBD13 is a putative substrate adaptor for Cul3-RL that functions as a muscle specific ubiquitin ligase, and thereby implicate the ubiquitin proteasome pathway in the pathogenesis of KBTBD13-associated NEM. Published by Elsevier Inc. C1 [Sambuughin, Nyamkhishig; Swietnicki, Wieslaw; Matrosova, Vera; Wallace, Tarina] Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. [Techtmann, Stephen; Maynard, Ernest] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. [Goldfarb, Lev] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Sambuughin, N (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM nyamkhishig.sambuughin@usuhs.edu; wieslaw_swietnicki@hotmail.com; stephen.techtmann@usuhs.edu; vera.matrosova@usuhs.edu; tarina.wallace@usuh-s.edu; goldfarbl@ninds.nih.gov; ernest.maynard@usuhs.edu FU Intramural NIH HHS [Z01 NS002973-10] NR 24 TC 11 Z9 12 U1 0 U2 0 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 MAY 18 PY 2012 VL 421 IS 4 BP 743 EP 749 DI 10.1016/j.bbrc.2012.04.074 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 957NB UT WOS:000305168600019 PM 22542517 ER PT J AU Wardill, TJ List, O Li, XF Dongre, S McCulloch, M Ting, CY O'Kane, CJ Tang, SM Lee, CH Hardie, RC Juusola, M AF Wardill, Trevor J. List, Olivier Li, Xiaofeng Dongre, Sidhartha McCulloch, Marie Ting, Chun-Yuan O'Kane, Cahir J. Tang, Shiming Lee, Chi-Hon Hardie, Roger C. Juusola, Mikko TI Multiple Spectral Inputs Improve Motion Discrimination in the Drosophila Visual System SO SCIENCE LA English DT Article ID PHOTORECEPTOR CELLS; WILD-TYPE; COLOR; MELANOGASTER; RHODOPSIN; PATHWAYS; CHANNEL; STIMULATION; DISSECTION; BEHAVIOR AB Color and motion information are thought to be channeled through separate neural pathways, but it remains unclear whether and how these pathways interact to improve motion perception. In insects, such as Drosophila, it has long been believed that motion information is fed exclusively by one spectral class of photoreceptor, so-called R1 to R6 cells; whereas R7 and R8 photoreceptors, which exist in multiple spectral classes, subserve color vision. Here, we report that R7 and R8 also contribute to the motion pathway. By using electrophysiological, optical, and behavioral assays, we found that R7/R8 information converge with and shape the motion pathway output, explaining flies' broadly tuned optomotor behavior by its composite responses. Our results demonstrate that inputs from photoreceptors of different spectral sensitivities improve motion discrimination, increasing robustness of perception. C1 [Wardill, Trevor J.; List, Olivier; Li, Xiaofeng; Dongre, Sidhartha; McCulloch, Marie; Juusola, Mikko] Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England. [Li, Xiaofeng; Tang, Shiming; Juusola, Mikko] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. [Ting, Chun-Yuan; Lee, Chi-Hon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [O'Kane, Cahir J.] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Hardie, Roger C.] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB3 2EG, England. RP Juusola, M (reprint author), Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England. EM m.juusola@sheffield.ac.uk RI Lee, Chi-Hon/G-9190-2012; List, Olivier/F-3049-2011; Ting, chun-yuan/F-6448-2013; OI List, Olivier/0000-0002-8302-8089; Wardill, Trevor/0000-0002-2049-113X; O'Kane, Cahir/0000-0002-3488-2078; Juusola, Mikko/0000-0002-4428-5330; Dongre, Sidhartha/0000-0003-2575-4362 FU Gatsby Charitable Foundation [GAT2839]; State Key Laboratory of Cognitive Neuroscience and Learning; Biotechnology and Biological Sciences Research Council [BB/H013849/1, BB/F012071/1, BB/G006865/1, BB/D007585/1]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD008776-06]; NSFC [30810103906] FX We thank G. de Polavieja and people of the Juusola lab for discussions and I. Meinertzhagen and P. Gonzalez Bellido for assistance with electron microscopy. The work was supported by the Gatsby Charitable Foundation (GAT2839: M.J.), the open research fund of the State Key Laboratory of Cognitive Neuroscience and Learning (M.J. and S.T.), the Biotechnology and Biological Sciences Research Council grants (BB/H013849/1 and BB/F012071/1: M.J.) and (BB/G006865/1 and BB/D007585/1: R.C.H.), and the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD008776-06: C.H.L.), the NSFC project (30810103906: S.T. and M.J.). The authors declare no competing financial interests. Supplementary materials accompany the paper on Science Online. Author contributions: Project initiation: M.J.; genetics: T.J.W., O.L., C.H.L., R.C.H., C.J.O'K., X.L.; electrophysiology: X.L., M.J., R.C.H., T.J.W.; behavior: S.D., M.M.C., T.J.W., M.J., S.T.; imaging: O.L., T.J.W., S.D., M.J.; electronmicroscopy: T.J.W.; immunohistochemistry: C.Y.T.; wrote the paper: M.J., with contributions from all authors. NR 42 TC 39 Z9 39 U1 1 U2 44 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 18 PY 2012 VL 336 IS 6083 BP 925 EP 931 DI 10.1126/science.1215317 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 943SN UT WOS:000304145600068 PM 22605779 ER PT J AU Hunt, D Wilson, JE Weih, KA Ishido, S Harton, JA Roche, PA Drake, JR AF Hunt, Danielle Wilson, Justin E. Weih, Karis A. Ishido, Satoshi Harton, Jonathan A. Roche, Paul A. Drake, James R. TI Francisella tularensis Elicits IL-10 via a PGE2-Inducible Factor, to Drive Macrophage MARCH1 Expression and Class II Down-Regulation SO PLOS ONE LA English DT Article ID MHC CLASS-II; KILLED SALMONELLA-TYPHI; DENDRITIC CELLS; PROSTAGLANDIN E-2; UBIQUITINATION; RELEASE AB Francisella tularensis is a bacterial pathogen that uses host-derived PGE(2) to subvert the host's adaptive immune responses in multiple ways. Francisella-induced PGE(2) acts directly on CD4 T cells to blunt production of IFN-gamma. Francisella-induced PGE(2) can also elicit production of a > 10 kDa soluble host factor termed FTMempty setSN (F. tularensis macrophage supernatant), which acts on IFN-gamma pre-activated Mempty set to down-regulate MHC class II expression via a ubiquitin-dependent mechanism, blocking antigen presentation to CD4 T cells. Here, we report that FTMempty setSN-induced down-regulation of Mempty set class II is the result of the induction of MARCH1, and that Mempty set expressing MARCH1 "resistant" class II molecules are resistant to FTMempty setSN-induced class II down-regulation. Since PGE(2) can induce IL-10 production and IL-10 is the only reported cytokine able to induce MARCH1 expression in monocytes and dendritic cells, these findings suggested that IL-10 is the active factor in FTMempty setSN. However, use of IL-10 knockout Mempty set established that IL-10 is not the active factor in FTMempty setSN, but rather that Francisella-elicited PGE(2) drives production of a > 10 kDa host factor distinct from IL-10. This factor then drives Mempty set IL-10 production to induce MARCH1 expression and the resultant class II down-regulation. Since many human pathogens such as Salmonella typhi, Mycobacterium tuberculosis and Legionella pneumophila also induce production of host PGE(2), these results suggest that a yet-to-be-identified PGE(2)-inducible host factor capable of inducing IL-10 is central to the immune evasion mechanisms of multiple important human pathogens. C1 [Hunt, Danielle; Harton, Jonathan A.; Drake, James R.] Albany Med Coll, Ctr Immunol & Microbial Dis, Albany, NY 12208 USA. [Wilson, Justin E.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Weih, Karis A.; Roche, Paul A.] RIKEN Yokohama Inst, RIKEN Res Ctr Allergy & Immunol, Lab Infect Immun, Yokohama, Kanagawa, Japan. [Ishido, Satoshi] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Hunt, D (reprint author), Albany Med Coll, Ctr Immunol & Microbial Dis, Albany, NY 12208 USA. EM drakej@mail.amc.edu RI Harton, Jonathan/F-2848-2010 OI Harton, Jonathan/0000-0002-0350-1877 FU National Institutes of Health [PO1 AI-056321]; Intramural Research Program of the National Institutes of Health; T32 training grant [AI-49822] FX This study was supported in part by National Institutes of Health grant PO1 AI-056321 to the Center for Immunology and Microbial Disease and by the Intramural Research Program of the National Institutes of Health. J.E.W. was supported by a T32 training grant (AI-49822) to the Center for Immunology and Microbial Disease. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 14 Z9 14 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 17 PY 2012 VL 7 IS 5 AR e37330 DI 10.1371/journal.pone.0037330 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UQ UT WOS:000305341200061 PM 22615981 ER PT J AU Moreau, M Le Tortorec, A Deleage, C Brown, C Denis, H Satie, AP Bourry, O Deureuddre-Bosquet, N Roques, P Le Grand, R Dejucq-Rainsford, N AF Moreau, Marina Le Tortorec, Anna Deleage, Claire Brown, Charles Denis, Helene Satie, Anne-Pascale Bourry, Olivier Deureuddre-Bosquet, Nathalie Roques, Pierre Le Grand, Roger Dejucq-Rainsford, Nathalie TI Impact of Short-Term HAART Initiated during the Chronic Stage or Shortly Post-Exposure on SIV Infection of Male Genital Organs SO PLOS ONE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; SEMEN-PRODUCING ORGANS; IN-VIVO; RHESUS MACAQUES; HIV-INFECTION; SEXUAL TRANSMISSION; REPRODUCTIVE-TRACT; T-LYMPHOCYTES; SEMINAL CELLS AB Background: The male genital tract is suspected to constitute a viral sanctuary as persistent HIV shedding is found in the semen of a subset of HIV-infected men receiving effective antiretroviral therapy (HAART). The origin of this persistent shedding is currently unknown. Phylogenetic studies indicated that HIV in semen from untreated men arises from local sources and/or passive diffusion from the blood. We previously demonstrated in human and macaque low levels and localized infection of several semen-producing organs by HIV/SIV. Using a macaque model, this study investigates the impact of short term HAART (2-4 weeks) initiated either during the asymptomatic chronic stage or 4 h post-intravenous inoculation of SIVmac251 on the infection of male genital organs. Methodology/Principal Findings: Short term HAART during the chronic stage decreased blood viral load. No major impact of HAART was observed on SIV DNA levels in male genital organs using a sensitive nested PCR assay. Using in situ hybridization, SIV RNA+ cells were detected in all male genital tract organs from untreated and treated animals with undetectable blood viral load following HAART. Infected CD68+ myeloid cells and CD3+ T lymphocytes were detected pre-and post-HAART. In contrast, short term HAART initiated 4 h post-SIV exposure led to a drastic decrease of the male genital tissues infection, although it failed to prevent systemic infection. In both cases, HAART tended to decrease the number of CD3+ T cells in the male organs. Conclusions: Our results indicate that the established infection of male genital organs is not greatly impacted by short term HAART, whereas the same treatment during pre-acute phase of the infection efficiently impairs viral dissemination to the male genital tract. Further investigations are now needed to determine whether infection of male genital organs is responsible for long term persistent HIV shedding in semen despite HAART. C1 [Moreau, Marina; Le Tortorec, Anna; Deleage, Claire; Denis, Helene; Satie, Anne-Pascale; Dejucq-Rainsford, Nathalie] Univ Rennes 1, INSERM, IRSET U1085, Inst Federatif Rech 140, Rennes, France. [Bourry, Olivier; Deureuddre-Bosquet, Nathalie; Roques, Pierre; Le Grand, Roger] CEA, DSV, Inst Emerging Dis & Innovat Therapies, Div Immunovirol, Fontenay Aux Roses, France. [Brown, Charles] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Bourry, Olivier; Deureuddre-Bosquet, Nathalie; Roques, Pierre; Le Grand, Roger] Univ Paris 11, UMR E1, Orsay, France. RP Moreau, M (reprint author), Univ Rennes 1, INSERM, IRSET U1085, Inst Federatif Rech 140, Rennes, France. EM nathalie.dejucq-rainsford@inserm.fr RI Roques, Pierre/M-2212-2013; DEJUCQ-RAINSFORD, Nathalie/I-2571-2015; Le Tortorec, Anna/J-5291-2015 OI Roques, Pierre/0000-0003-1825-1054; FU ANRS; Sidaction; Inserm; Region Bretagne FX This work was funded by ANRS, Sidaction, Inserm and Region Bretagne. Marina Moreau is the recipient of stipends from Region Bretagne and Sidaction. Claire Deleage and Helene Denis are supported by ANRS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 5 Z9 5 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 17 PY 2012 VL 7 IS 5 AR e37348 DI 10.1371/journal.pone.0037348 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UQ UT WOS:000305341200066 PM 22615988 ER PT J AU Mendoza, D Johnson, SA Peterson, BA Natarajan, V Salgado, M Dewar, RL Burbelo, PD Doria-Rose, NA Graf, EH Greenwald, JH Hodge, JN Thompson, WL Cogliano, NA Chairez, CL Rehm, CA Jones, S Hallahan, CW Kovacs, JA Sereti, I Sued, O Peel, SA O'Connell, RJ O'Doherty, U Chun, TW Connors, M Migueles, SA AF Mendoza, Daniel Johnson, Sarah A. Peterson, Bennett A. Natarajan, Ven Salgado, Maria Dewar, Robin L. Burbelo, Peter D. Doria-Rose, Nicole A. Graf, Erin H. Greenwald, Jamieson H. Hodge, Jessica N. Thompson, William L. Cogliano, Nancy A. Chairez, Cheryl L. Rehm, Catherine A. Jones, Sara Hallahan, Claire W. Kovacs, Joseph A. Sereti, Irini Sued, Omar Peel, Sheila A. O'Connell, Robert J. O'Doherty, Una Chun, Tae-Wook Connors, Mark Migueles, Stephen A. TI Comprehensive analysis of unique cases with extraordinary control over HIV replication SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; LONG-TERM NONPROGRESSORS; LOW-LEVEL VIREMIA; ELITE SUPPRESSORS; VIRAL REPLICATION; IMMUNE CONTROL; HIV-1-INFECTED PATIENTS; EX-VIVO AB True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without anti-retroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8(+) T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLAallele and CD8(+) T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies. (Blood. 2012; 119(20): 4645-4655) C1 [Migueles, Stephen A.] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Natarajan, Ven; Dewar, Robin L.; Jones, Sara] Sci Applicat Int Corp Frederick Inc, Frederick, MD USA. [Salgado, Maria] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Salgado, Maria] Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Inst Recerca SIDA, IrsiCaixa, Badalona, Spain. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Lab Sensory Biol, NIH, Bethesda, MD USA. [Graf, Erin H.; O'Doherty, Una] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hallahan, Claire W.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Sued, Omar] Fdn Huesped, Buenos Aires, DF, Argentina. [Peel, Sheila A.; O'Connell, Robert J.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Migueles, SA (reprint author), NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 11B-07, Bethesda, MD 20892 USA. EM smigueles@niaid.nih.gov RI Salgado, Maria /G-3462-2016; OI Mendoza, Daniel/0000-0002-6362-0771; Sued, Omar/0000-0001-5818-770X FU Intramural Research Program of NIAID; Intramural Research Program of National Institute of Dental and Craniofacial Research (NIDCR); NIAID [HHSN261200800001E] FX This work was supported in part by the Intramural Research Programs of NIAID and National Institute of Dental and Craniofacial Research (NIDCR) and (NIAID contract HHSN261200800001E; V.N., R.L.D., and S.J.). NR 53 TC 25 Z9 26 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 MAY 17 PY 2012 VL 119 IS 20 BP 4645 EP 4655 DI 10.1182/blood-2011-10-381996 PG 11 WC Hematology SC Hematology GA 959CM UT WOS:000305288400013 PM 22490332 ER PT J AU Wu, HX Wacker, D Mileni, M Katritch, V Han, GW Vardy, E Liu, W Thompson, AA Huang, XP Carroll, FI Mascarella, SW Westkaemper, RB Mosier, PD Roth, BL Cherezov, V Stevens, RC AF Wu, Huixian Wacker, Daniel Mileni, Mauro Katritch, Vsevolod Han, Gye Won Vardy, Eyal Liu, Wei Thompson, Aaron A. Huang, Xi-Ping Carroll, F. Ivy Mascarella, S. Wayne Westkaemper, Richard B. Mosier, Philip D. Roth, Bryan L. Cherezov, Vadim Stevens, Raymond C. TI Structure of the human kappa-opioid receptor in complex with JDTic SO NATURE LA English DT Article ID PROTEIN-COUPLED RECEPTORS; A(2A) ADENOSINE RECEPTOR; CRYSTAL-STRUCTURE; TRANSMEMBRANE DOMAIN; ANTAGONIST ACTIVITY; LIPIDIC MESOPHASES; MEMBRANE-PROTEINS; OPIATE RECEPTOR; LIGAND DOCKING; SALVINORIN-A AB Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and-in the case of kappa-opioid receptor (kappa-OR)-dysphoria and psychotomimesis. Here we report the crystal structure of the human kappa-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 angstrom resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human kappa-OR. Modelling of other important kappa-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for kappa-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human kappa-OR. C1 [Wu, Huixian; Wacker, Daniel; Mileni, Mauro; Katritch, Vsevolod; Han, Gye Won; Liu, Wei; Thompson, Aaron A.; Cherezov, Vadim; Stevens, Raymond C.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Vardy, Eyal; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Vardy, Eyal; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Carroll, F. Ivy; Mascarella, S. Wayne] Res Triangle Inst, Ctr Organ & Med Chem, Res Triangle Pk, NC 27709 USA. [Westkaemper, Richard B.; Mosier, Philip D.] Virginia Commonwealth Univ, Dept Med Chem, Richmond, VA 23298 USA. RP Stevens, RC (reprint author), Scripps Res Inst, Dept Mol Biol, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM stevens@scripps.edu RI Cherezov, Vadim/L-9812-2013; Wu, Huixian/N-6353-2014; Roth, Bryan/F-3928-2010; Katritch, Vsevolod/Q-8357-2016; OI Cherezov, Vadim/0000-0002-5265-3914; Wu, Huixian/0000-0003-1357-9747; Mascarella, Wayne/0000-0003-0092-8178 FU PSI:Biology [U54 GM094618]; NIH [P50 GM073197, R01 DA017624, R01 DA027170, R01 DA009045]; NIMH; Michael Hooker Distinguished Chair of Pharmacology; Boehringer Ingelheim Fonds; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104] FX This work was supported by PSI:Biology grant U54 GM094618 (V. K., V. C., R. C. S.) for biological studies and structure production, NIH Roadmap grant P50 GM073197 (V. C., R. C. S.) for technology development and R01 DA017624 (B. L. R., E. V., R. B. M., P. D. M.), R01 DA027170 (B. L. R.), the NIMH Psychoactive Drug Screening Program Contract (B. L. R., X.-P. H.), the Michael Hooker Distinguished Chair of Pharmacology (B. L. R.), and the NIH grant R01 DA009045 (F. I. C.). D. W. is supported by a Boehringer Ingelheim Fonds PhD Fellowship. The JDTic X-ray structure was determined by C. George at the Laboratory for the Structure of Matter, Naval Research Laboratory. We thank J. Velasquez for help on molecular biology; T. Trinh, K. Allin and M. Chu for help on baculovirus expression; V. Setola for help with functional activity assays; J. Evans for help acquiring compounds; the National Institute of Drug Abuse Drug Supply Program for supplying JDTic and other opioid ligands used in these studies; K. Kadyshevskaya for assistance with figure preparation; E. Abola for assistance with manuscript preparation; A. Walker for assistance with manuscript preparation; J. Smith, R. Fischetti and N. Sanishvili for assistance in the development and use of the minibeam and beamtime at GM/CA-CAT beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104. NR 50 TC 413 Z9 421 U1 8 U2 107 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 17 PY 2012 VL 485 IS 7398 BP 327 EP U69 DI 10.1038/nature10939 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 943CW UT WOS:000304099100033 PM 22437504 ER PT J AU Thompson, AA Liu, W Chun, E Katritch, V Wu, HX Vardy, E Huang, XP Trapella, C Guerrini, R Calo, G Roth, BL Cherezov, V Stevens, RC AF Thompson, Aaron A. Liu, Wei Chun, Eugene Katritch, Vsevolod Wu, Huixian Vardy, Eyal Huang, Xi-Ping Trapella, Claudio Guerrini, Remo Calo, Girolamo Roth, Bryan L. Cherezov, Vadim Stevens, Raymond C. TI Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic SO NATURE LA English DT Article ID SITE-DIRECTED MUTAGENESIS; PROTEIN-COUPLED RECEPTORS; ORL1 RECEPTOR; ORPHANIN-FQ; CRYSTALLIZING MEMBRANE; LIPIDIC MESOPHASES; BINDING; ANTAGONIST; AGONIST; IDENTIFICATION AB Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, delta, kappa and mu (delta-OR, kappa-OR and mu-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR(1). Although it shares high sequence similarity with classical opioid GPCR subtypes (similar to 60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands(2,3). Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors k (ref. 5) and m (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands. C1 [Thompson, Aaron A.; Liu, Wei; Chun, Eugene; Katritch, Vsevolod; Wu, Huixian; Cherezov, Vadim; Stevens, Raymond C.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Vardy, Eyal; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Vardy, Eyal; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Trapella, Claudio; Guerrini, Remo] Univ Ferrara, Dept Pharmaceut Sci, I-44121 Ferrara, Italy. [Trapella, Claudio; Guerrini, Remo] Univ Ferrara, LTTA, I-44121 Ferrara, Italy. [Calo, Girolamo] Univ Ferrara, Pharmacol Sect, Dept Expt & Clin Med, I-44121 Ferrara, Italy. [Calo, Girolamo] Univ Ferrara, Natl Inst Neurosci, I-44121 Ferrara, Italy. RP Stevens, RC (reprint author), Scripps Res Inst, Dept Mol Biol, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM stevens@scripps.edu RI Cherezov, Vadim/L-9812-2013; Trapella, Claudio/I-2128-2012; Wu, Huixian/N-6353-2014; Roth, Bryan/F-3928-2010; Katritch, Vsevolod/Q-8357-2016; OI Cherezov, Vadim/0000-0002-5265-3914; Trapella, Claudio/0000-0002-6666-143X; Wu, Huixian/0000-0003-1357-9747; Guerrini, Remo/0000-0002-7619-0918; Katritch, Vsevolod/0000-0003-3883-4505 FU PSI:Biology [U54 GM094618]; NIH [P50 GM073197, R01 DA017204, R01 DA27170]; NIMH; Michael Hooker Chair of Pharmacology; University of Ferrara (FAR); Italian Ministry of University (FIRB); National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104] FX This work was supported by PSI:Biology grant U54 GM094618 for biological studies and structure production, NIH Roadmap grant P50 GM073197 for technology development and R01 DA017204, R01 DA27170, and the NIMH Psychoactive Drug Screening Program(X.-P. H., E. V. and B. L. R.) and the Michael Hooker Chair of Pharmacology (B. L. R.), University of Ferrara (FAR grant to G. C.), Italian Ministry of University (FIRB Futuro in Ricerca 2010 grant to C. T.). We thank J. Francis for suggesting the idea to pursue the NOP receptor; J. Velasquez for help on molecular biology; T. Trinh, K. Allin and M. Chu for help on baculovirus expression; A. Walker and E. Abola for assistance with manuscript preparation; J. Smith, R. Fischetti and N. Sanishvili for assistance in development and use of the minibeam and beamtime at GM/CA-CAT beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104. NR 41 TC 250 Z9 255 U1 7 U2 81 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 17 PY 2012 VL 485 IS 7398 BP 395 EP U150 DI 10.1038/nature11085 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 943CW UT WOS:000304099100048 PM 22596163 ER PT J AU Freedman, ND Park, Y Abnet, CC Hollenbeck, AR Sinha, R AF Freedman, Neal D. Park, Yikyung Abnet, Christian C. Hollenbeck, Albert R. Sinha, Rashmi TI Association of Coffee Drinking with Total and Cause-Specific Mortality SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; MYOCARDIAL-INFARCTION; TEA CONSUMPTION; CARDIOVASCULAR-DISEASE; NATIONAL-INSTITUTES; PROSPECTIVE COHORT; FOLLOW-UP; RISK AB BACKGROUND Coffee is one of the most widely consumed beverages, but the association between coffee consumption and the risk of death remains unclear. METHODS We examined the association of coffee drinking with subsequent total and cause-specific mortality among 229,119 men and 173,141 women in the National Institutes of Health-AARP Diet and Health Study who were 50 to 71 years of age at baseline. Participants with cancer, heart disease, and stroke were excluded. Coffee consumption was assessed once at baseline. RESULTS During 5,148,760 person-years of follow-up between 1995 and 2008, a total of 33,731 men and 18,784 women died. In age-adjusted models, the risk of death was increased among coffee drinkers. However, coffee drinkers were also more likely to smoke, and, after adjustment for tobacco-smoking status and other potential confounders, there was a significant inverse association between coffee consumption and mortality. Adjusted hazard ratios for death among men who drank coffee as compared with those who did not were as follows: 0.99 (95% confidence interval [CI], 0.95 to 1.04) for drinking less than 1 cup per day, 0.94 (95% CI, 0.90 to 0.99) for 1 cup, 0.90 (95% CI, 0.86 to 0.93) for 2 or 3 cups, 0.88 (95% CI, 0.84 to 0.93) for 4 or 5 cups, and 0.90 (95% CI, 0.85 to 0.96) for 6 or more cups of coffee per day (P<0.001 for trend); the respective hazard ratios among women were 1.01 (95% CI, 0.96 to 1.07), 0.95 (95% CI, 0.90 to 1.01), 0.87 (95% CI, 0.83 to 0.92), 0.84 (95% CI, 0.79 to 0.90), and 0.85 (95% CI, 0.78 to 0.93) (P<0.001 for trend). Inverse associations were observed for deaths due to heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, but not for deaths due to cancer. Results were similar in subgroups, including persons who had never smoked and persons who reported very good to excellent health at baseline. CONCLUSIONS In this large prospective study, coffee consumption was inversely associated with total and cause-specific mortality. Whether this was a causal or associational finding cannot be determined from our data. C1 [Freedman, Neal D.; Park, Yikyung; Abnet, Christian C.; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Freedman, ND (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 320,MSC 7232, Rockville, MD 20852 USA. EM freedmanne@mail.nih.gov RI Abnet, Christian/C-4111-2015; Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015; OI Abnet, Christian/0000-0002-3008-7843; Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 39 TC 163 Z9 167 U1 5 U2 50 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 MAY 17 PY 2012 VL 366 IS 20 BP 1891 EP 1904 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 942WU UT WOS:000304083000008 PM 22591295 ER PT J AU Tatem, AJ Adamo, S Bharti, N Burgert, CR Castro, M Dorelien, A Fink, G Linard, C John, M Montana, L Montgomery, MR Nelson, A Noor, AM Pindolia, D Yetman, G Balk, D AF Tatem, Andrew J. Adamo, Susana Bharti, Nita Burgert, Clara R. Castro, Marcia Dorelien, Audrey Fink, Gunter Linard, Catherine John, Mendelsohn Montana, Livia Montgomery, Mark R. Nelson, Andrew Noor, Abdisalan M. Pindolia, Deepa Yetman, Greg Balk, Deborah TI Mapping populations at risk: improving spatial demographic data for infectious disease modeling and metric derivation SO POPULATION HEALTH METRICS LA English DT Review DE Population; Epidemiology; Demography; Disease mapping ID TRANSMITTED HELMINTH INFECTIONS; PLASMODIUM-FALCIPARUM; LARGE-SCALE; SCHISTOSOMA-MANSONI; GLOBAL EPIDEMIOLOGY; CONTROL PROGRAM; MALARIA; TRANSMISSION; INFLUENZA; AFRICA AB The use of Global Positioning Systems (GPS) and Geographical Information Systems (GIS) in disease surveys and reporting is becoming increasingly routine, enabling a better understanding of spatial epidemiology and the improvement of surveillance and control strategies. In turn, the greater availability of spatially referenced epidemiological data is driving the rapid expansion of disease mapping and spatial modeling methods, which are becoming increasingly detailed and sophisticated, with rigorous handling of uncertainties. This expansion has, however, not been matched by advancements in the development of spatial datasets of human population distribution that accompany disease maps or spatial models. Where risks are heterogeneous across population groups or space or dependent on transmission between individuals, spatial data on human population distributions and demographic structures are required to estimate infectious disease risks, burdens, and dynamics. The disease impact in terms of morbidity, mortality, and speed of spread varies substantially with demographic profiles, so that identifying the most exposed or affected populations becomes a key aspect of planning and targeting interventions. Subnational breakdowns of population counts by age and sex are routinely collected during national censuses and maintained in finer detail within microcensus data. Moreover, demographic and health surveys continue to collect representative and contemporary samples from clusters of communities in low-income countries where census data may be less detailed and not collected regularly. Together, these freely available datasets form a rich resource for quantifying and understanding the spatial variations in the sizes and distributions of those most at risk of disease in low income regions, yet at present, they remain unconnected data scattered across national statistical offices and websites. In this paper we discuss the deficiencies of existing spatial population datasets and their limitations on epidemiological analyses. We review sources of detailed, contemporary, freely available and relevant spatial demographic data focusing on low income regions where such data are often sparse and highlight the value of incorporating these through a set of examples of their application in disease studies. Moreover, the importance of acknowledging, measuring, and accounting for uncertainty in spatial demographic datasets is outlined. Finally, a strategy for building an open-access database of spatial demographic data that is tailored to epidemiological applications is put forward. C1 [Tatem, Andrew J.; Pindolia, Deepa] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.; Pindolia, Deepa] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Adamo, Susana; Yetman, Greg] Columbia Univ, CIESIN, New York, NY USA. [Dorelien, Audrey] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Princeton, NJ 08544 USA. [Burgert, Clara R.] ICF Int, Int Hlth & Dev Div, Demog & Hlth Surveys, Washington, DC USA. [Castro, Marcia; Fink, Gunter; Montana, Livia] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Dorelien, Audrey] Princeton Univ, Off Populat Res, Princeton, NJ 08544 USA. [Linard, Catherine] Univ Libre Brussels, Brussels, Belgium. [Linard, Catherine] Fonds Natl Rech Sci FRS FNRS, Brussels, Belgium. [John, Mendelsohn] Res & Informat Serv Namibia, Windhoek, Namibia. [Montgomery, Mark R.] Populat Council, New York, NY 10021 USA. [Nelson, Andrew] Int Rice Res Inst, Los Banos, Philippines. [Noor, Abdisalan M.; Pindolia, Deepa] KEMRI Univ Oxford Wellcome Trust Res Programme, Malaria Publ Hlth & Epidemiol Grp, Ctr Geog Med, Nairobi, Kenya. [Balk, Deborah] CUNY, Baruch Coll, Sch Publ Affairs, New York, NY 10021 USA. [Montgomery, Mark R.] SUNY Stony Brook, Dept Econ, Stony Brook, NY USA. RP Tatem, AJ (reprint author), Univ Florida, Dept Geog, Gainesville, FL 32611 USA. EM andy.tatem@gmail.com RI Nelson, Andrew/G-3649-2012 OI Nelson, Andrew/0000-0002-7249-3778 FU Wellcome Trust [092654] NR 68 TC 23 Z9 23 U1 4 U2 42 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-7954 J9 POPUL HEALTH METR JI Popul. Health Metr. PD MAY 16 PY 2012 VL 10 AR 8 DI 10.1186/1478-7954-10-8 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 032YG UT WOS:000310756100001 PM 22591595 ER PT J AU Balasingham, SV Zegeye, ED Homberset, H Rossi, ML Laerdahl, JK Bohr, VA Tonjum, T AF Balasingham, Seetha V. Zegeye, Ephrem Debebe Homberset, Havard Rossi, Marie L. Laerdahl, Jon K. Bohr, Vilhelm A. Tonjum, Tone TI Enzymatic Activities and DNA Substrate Specificity of Mycobacterium tuberculosis DNA Helicase XPB SO PLOS ONE LA English DT Article ID NUCLEOTIDE-EXCISION-REPAIR; STRAND BREAK REPAIR; COMPLETE GENOME SEQUENCE; ESCHERICHIA-COLI; COCKAYNE-SYNDROME; XERODERMA-PIGMENTOSUM; RNA HELICASES; PROTEIN; TFIIH; PREDICTION AB XPB, also known as ERCC3 and RAD25, is a 3'-->5' DNA repair helicase belonging to the superfamily 2 of helicases. XPB is an essential core subunit of the eukaryotic basal transcription factor complex TFIIH. It has two well-established functions: in the context of damaged DNA, XPB facilitates nucleotide excision repair by unwinding double stranded DNA (dsDNA) surrounding a DNA lesion; while in the context of actively transcribing genes, XPB facilitates initiation of RNA polymerase II transcription at gene promoters. Human and other eukaryotic XPB homologs are relatively well characterized compared to conserved homologs found in mycobacteria and archaea. However, more insight into the function of bacterial helicases is central to understanding the mechanism of DNA metabolism and pathogenesis in general. Here, we characterized Mycobacterium tuberculosis XPB (Mtb XPB), a 3'-->5' DNA helicase with DNA-dependent ATPase activity. Mtb XPB efficiently catalyzed DNA unwinding in the presence of significant excess of enzyme. The unwinding activity was fueled by ATP or dATP in the presence of Mg2+/Mn2+. Consistent with the 3'-->5' polarity of this bacterial XPB helicase, the enzyme required a DNA substrate with a 3' overhang of 15 nucleotides or more. Although Mtb XPB efficiently unwound DNA model substrates with a 3' DNA tail, it was not active on substrates containing a 3' RNA tail. We also found that Mtb XPB efficiently catalyzed ATP-independent annealing of complementary DNA strands. These observations significantly enhance our understanding of the biological roles of Mtb XPB. C1 [Balasingham, Seetha V.; Zegeye, Ephrem Debebe; Homberset, Havard; Laerdahl, Jon K.; Tonjum, Tone] Univ Oslo, CMBN, Oslo, Norway. [Balasingham, Seetha V.; Zegeye, Ephrem Debebe; Homberset, Havard; Laerdahl, Jon K.; Tonjum, Tone] Univ Oslo, Dept Microbiol, Oslo, Norway. [Balasingham, Seetha V.; Laerdahl, Jon K.; Tonjum, Tone] Oslo Univ Hosp, Rikshosp, Dept Microbiol, Oslo, Norway. [Rossi, Marie L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Laerdahl, Jon K.] Univ Oslo, Dept Informat, Bioinformat Core Facil, N-0316 Oslo, Norway. RP Balasingham, SV (reprint author), Univ Oslo, CMBN, Oslo, Norway. EM tone.tonjum@medisin.uio.no OI Laerdahl, Jon Kristen/0000-0002-0826-9464; Tonjum, Tone/0000-0002-1709-6921 FU EU 6th Framework project TBadapt; Research Council of Norway Centre of Excellence funding; Norwegian State Educational Loan Fund; Intramural Program of the National Institute on Aging, NIH FX This work was supported by the EU 6th Framework project TBadapt, the Research Council of Norway Centre of Excellence funding, and the Norwegian State Educational Loan Fund. Support from the Intramural Program of the National Institute on Aging, NIH is acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 7 Z9 7 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 16 PY 2012 VL 7 IS 5 SI 1 AR e36960 DI 10.1371/journal.pone.0036960 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UR UT WOS:000305341300048 PM 22615856 ER PT J AU Maiga, M Siddiqui, S Diallo, S Diarra, B Traore, B Shea, YR Zelazny, AM Dembele, BPP Goita, D Kassambara, H Hammond, AS Polis, MA Tounkara, A AF Maiga, Mamoudou Siddiqui, Sophia Diallo, Souleymane Diarra, Bassirou Traore, Brehima Shea, Yvonne R. Zelazny, Adrian M. Dembele, Bindongo P. P. Goita, Drissa Kassambara, Hamadoun Hammond, Abdulrahman S. Polis, Michael A. Tounkara, Anatole TI Failure to Recognize Nontuberculous Mycobacteria Leads to Misdiagnosis of Chronic Pulmonary Tuberculosis SO PLOS ONE LA English DT Article ID CLINICAL-SIGNIFICANCE; SP-NOV.; RESPIRATORY SPECIMENS; INFECTIONS; IDENTIFICATION; EPIDEMIOLOGY; FORTUITUM; RELEVANCE; DIAGNOSIS; DISEASE AB Background: Nontuberculous mycobacterial (NTM) infections cause morbidity worldwide. They are difficult to diagnose in resource-limited regions, and most patients receive empiric treatment for tuberculosis (TB). Our objective here is to evaluate the potential impact of NTM diseases among patients treated presumptively for tuberculosis in Mali. Methods: We re-evaluated sputum specimens among patients newly diagnosed with TB (naive) and those previously treated for TB disease (chronic cases). Sputum microscopy, culture and Mycobacterium tuberculosis drug susceptibility testing were performed. Identification of strains was performed using molecular probes or sequencing of secA1 and/or 16S rRNA genes. Results: Of 142 patients enrolled, 61 (43%) were clinically classified as chronic cases and 17 (12%) were infected with NTM. Eleven of the 142 (8%) patients had NTM disease alone (8 M. avium, 2 M. simiae and 1 M. palustre). All these 11 were from the chronic TB group, comprising 11/61 (18%) of that group and all were identified as candidates for second line treatment. The remaining 6/17 (35.30%) NTM infected patients had coinfection with M. tuberculosis and all 6 were from the TB treatment naive group. These 6 were candidates for the standard first line treatment regimen of TB. M. avium was identified in 11 of the 142 (8%) patients, only 3/11 (27.27%) of whom were HIV positive. Conclusions: NTM infections should be considered a cause of morbidity in TB endemic environments especially when managing chronic TB cases to limit morbidity and provide appropriate treatment. C1 [Maiga, Mamoudou; Diallo, Souleymane; Diarra, Bassirou; Traore, Brehima; Dembele, Bindongo P. P.; Goita, Drissa; Kassambara, Hamadoun; Hammond, Abdulrahman S.; Tounkara, Anatole] Univ Bamako Res Collaborat HIV TB, Project SEREFO NIAID, Bamako, Mali. [Siddiqui, Sophia; Polis, Michael A.] NIAID, CCRB, Div Clin Res, Bethesda, MD 20892 USA. [Shea, Yvonne R.; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Maiga, M (reprint author), Univ Bamako Res Collaborat HIV TB, Project SEREFO NIAID, Bamako, Mali. EM ssiddiqui@niaid.nih.gov OI Traore, Brehima/0000-0001-9075-9157; Polis, Michael/0000-0002-9151-2268 FU National Institutes of Health, Bethesda, Maryland, USA FX National Institutes of Health, Bethesda, Maryland, USA funded this work conducted at the Mali International Centers for Excellence in Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 30 Z9 32 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 16 PY 2012 VL 7 IS 5 SI 1 AR e36902 DI 10.1371/journal.pone.0036902 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UR UT WOS:000305341300040 PM 22615839 ER PT J AU Reder, NP Tayo, BO Salako, B Ogunniyi, A Adeyemo, A Rotimi, C Cooper, RS AF Reder, Nicholas P. Tayo, Bamidele O. Salako, Babatunde Ogunniyi, Adesola Adeyemo, Adebowale Rotimi, Charles Cooper, Richard S. TI Adrenergic Alpha-1 Pathway Is Associated with Hypertension among Nigerians in a Pathway-focused Analysis SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; CONVERTING ENZYME-INHIBITORS; BLOOD-PRESSURE REGULATION; SUSCEPTIBILITY GENES; AFRICAN; RISK; POPULATIONS; DISEASES; THERAPY; LINKAGE AB Background: The pathway-focused association approach offers a hypothesis driven alternative to the agnostic genome-wide association study. Here we apply the pathway-focused approach to an association study of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in 1614 Nigerians with genome-wide data. Methods and Results: Testing of 28 pathways with biological relevance to hypertension, selected a priori, containing a total of 101 unique genes and 4,349 unique single-nucleotide polymorphisms (SNPs) showed an association for the adrenergic alpha 1 (ADRA1) receptor pathway with hypertension (p < 0.0009) and diastolic blood pressure (p < 0.0007). Within the ADRA1 pathway, the genes PNMT (hypertension P-gene < 0.004, DBP P-gene < 0.004, and SBP P-gene < 0.009, and ADRA1B (hypertension P-gene < 0.005, DBP P-gene < 0.02, and SBP P-gene < 0.02) displayed the strongest associations. Neither ADRA1B nor PNMT could be the sole mediator of the observed pathway association as the ADRA1 pathway remained significant after removing ADRA1B, and other pathways involving PNMT did not reach pathway significance. Conclusions: We conclude that multiple variants in several genes in the ADRA1 pathway led to associations with hypertension and DBP. SNPs in ADRA1B and PNMT have not previously been linked to hypertension in a genome-wide association study, but both genes have shown associations with hypertension through linkage or model organism studies. The identification of moderately significant (10(-2)> p > 10(-5)) SNPs offers a novel method for detecting the "missing heritability" of hypertension. These findings warrant further studies in similar and other populations to assess the generalizability of our results, and illustrate the potential of the pathway-focused approach to investigate genetic variation in hypertension. C1 [Reder, Nicholas P.; Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. [Salako, Babatunde; Ogunniyi, Adesola] Univ Ibadan, Dept Med, Ibadan, Nigeria. [Adeyemo, Adebowale; Rotimi, Charles] NHGRI, NIH, Intramural Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. RP Reder, NP (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. EM nireder@lumc.edu OI Reder, Nicholas/0000-0001-6563-8644; Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health [R01HL053353]; Intramural Research Program of the National Human Genome Research Institute FX This work was supported by the National Institutes of Health grant numbers R01HL053353 and in part by the Intramural Research Program of the National Human Genome Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 6 Z9 6 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 16 PY 2012 VL 7 IS 5 SI 1 AR e37145 DI 10.1371/journal.pone.0037145 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UR UT WOS:000305341300078 PM 22615923 ER PT J AU Yutin, N Puigbo, P Koonin, EV Wolf, YI AF Yutin, Natalya Puigbo, Pere Koonin, Eugene V. Wolf, Yuri I. TI Phylogenomics of Prokaryotic Ribosomal Proteins SO PLOS ONE LA English DT Article ID HORIZONTAL GENE-TRANSFER; ANGSTROM RESOLUTION; ARCHAEAL GENOMES; EVOLUTION; SUBUNIT; LIFE; BACTERIAL; DOMAIN; TREES; EUKARYOTES AB Archaeal and bacterial ribosomes contain more than 50 proteins, including 34 that are universally conserved in the three domains of cellular life (bacteria, archaea, and eukaryotes). Despite the high sequence conservation, annotation of ribosomal (r-) protein genes is often difficult because of their short lengths and biased sequence composition. We developed an automated computational pipeline for identification of r-protein genes and applied it to 995 completely sequenced bacterial and 87 archaeal genomes available in the RefSeq database. The pipeline employs curated seed alignments of r-proteins to run position-specific scoring matrix (PSSM)-based BLAST searches against six-frame genome translations, mitigating possible gene annotation errors. As a result of this analysis, we performed a census of prokaryotic r-protein complements, enumerated missing and paralogous r-proteins, and analyzed the distributions of ribosomal protein genes among chromosomal partitions. Phyletic patterns of bacterial and archaeal r-protein genes were mapped to phylogenetic trees reconstructed from concatenated alignments of r-proteins to reveal the history of likely multiple independent gains and losses. These alignments, available for download, can be used as search profiles to improve genome annotation of r-proteins and for further comparative genomics studies. C1 [Yutin, Natalya; Puigbo, Pere; Koonin, Eugene V.; Wolf, Yuri I.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Yutin, N (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM wolf@ncbi.nlm.nih.gov FU Department of Health and Human Services intramural program (National Institutes of Health, National Library of Medicine) FX The authors are supported by the Department of Health and Human Services intramural program (National Institutes of Health, National Library of Medicine). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 75 Z9 76 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 16 PY 2012 VL 7 IS 5 SI 1 AR e36972 DI 10.1371/journal.pone.0036972 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UR UT WOS:000305341300050 PM 22615861 ER PT J AU Ohzeki, J Bergmann, JH Kouprina, N Noskov, VN Nakano, M Kimura, H Earnshaw, WC Larionov, V Masumoto, H AF Ohzeki, Jun-ichirou Bergmann, Jan H. Kouprina, Natalay Noskov, Vladimir N. Nakano, Megumi Kimura, Hiroshi Earnshaw, William C. Larionov, Vladimir Masumoto, Hiroshi TI Breaking the HAC Barrier: Histone H3K9 acetyl/methyl balance regulates CENP-A assembly SO EMBO JOURNAL LA English DT Article DE CENP-A; centromeres; chromosomes; epigenetic regulation; heterochromatin ID FISSION YEAST SCM3; CENTROMERIC CHROMATIN; CELL-CYCLE; KINETOCHORE; HETEROCHROMATIN; CONSTRUCTION; COMPLEX; DNA; CHROMOSOMES; NUCLEOSOMES AB The kinetochore is responsible for accurate chromosome segregation. However, the mechanism by which kinetochores assemble and are maintained remains unclear. Here we report that de novo CENP-A assembly and kinetochore formation on human centromeric alphoid DNA arrays is regulated by a histone H3K9 acetyl/methyl balance. Tethering of histone acetyltransferases (HATs) to alphoid DNA arrays breaks a cell type-specific barrier for de novo stable CENP-A assembly and induces assembly of other kinetochore proteins at the ectopic alphoid site. Similar results are obtained following tethering of CENP-A deposition factors hMis18 alpha or HJURP. HAT tethering bypasses the need for hMis18 alpha, but HJURP is still required for de novo kinetochore assembly. In contrast, H3K9 methylation following tethering of H3K9 tri-methylase (Suv39h1) to the array prevents de novo CENP-A assembly and kinetochore formation. CENP-A arrays assembled de novo by this mechanism can form human artificial chromosomes (HACs) that are propagated indefinitely in human cells. The EMBO Journal (2012) 31, 2391-2402. doi: 10.1038/emboj.2012.82; Published online 3 April 2012 C1 [Ohzeki, Jun-ichirou; Nakano, Megumi; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Human Genome Res, Lab Cell Engn, Kisarazu, Chiba 2920818, Japan. [Ohzeki, Jun-ichirou; Kouprina, Natalay; Noskov, Vladimir N.; Larionov, Vladimir] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Bergmann, Jan H.; Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH8 9YL, Midlothian, Scotland. [Kimura, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka, Japan. RP Masumoto, H (reprint author), Kazusa DNA Res Inst, Dept Human Genome Res, Lab Cell Engn, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 2920818, Japan. EM masumoto@kazusa.or.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan; NIH, National Cancer Institute, Center for Cancer Research, USA; Kazusa DNA Research Institute Foundation; Wellcome Trust [073915]; Wellcome Trust Centre for Cell Biology [092076] FX We would like to thank N Nozaki, K Yoda, M Yanagida, I Cheeseman and T Yen for antibodies, T Jenuwein for giving us MEFs derived from wild type or from Suv39h1Suv39h2 double null (Suv39h dn) embryos, T Ebersole for fruitful discussions and K Sumi for technical assistance. This work was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA, and the Kazusa DNA Research Institute Foundation. WCE. is a Principal Research Fellow of the Wellcome Trust [grant number 073915], and the Wellcome Trust Centre for Cell Biology is supported by grant number 092076. NR 48 TC 56 Z9 56 U1 0 U2 11 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 MAY 16 PY 2012 VL 31 IS 10 BP 2391 EP 2402 DI 10.1038/emboj.2012.82 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 945AN UT WOS:000304245300017 PM 22473132 ER PT J AU Kothmann, WW Trexler, EB Whitaker, CM Li, W Massey, SC O'Brien, J AF Kothmann, W. Wade Trexler, E. Brady Whitaker, Christopher M. Li, Wei Massey, Stephen C. O'Brien, John TI Nonsynaptic NMDA Receptors Mediate Activity-Dependent Plasticity of Gap Junctional Coupling in the AII Amacrine Cell Network SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CA2+/CALMODULIN-DEPENDENT KINASE-II; INNER PLEXIFORM LAYER; ACID TRANSPORTER 5; MAMMALIAN RETINA; RABBIT RETINA; RAT RETINA; ELECTRICAL SYNAPSES; GLUTAMATE TRANSPORTER; MIXED SYNAPSES; ROD PATHWAYS AB Many neurons are coupled by electrical synapses into networks that have emergent properties. In the retina, coupling in these networks is dynamically regulated by changes in background illumination, optimizing signal integration for the visual environment. However, the mechanisms that control this plasticity are poorly understood. We have investigated these mechanisms in the rabbit AII amacrine cell, a multifunctional retinal neuron that forms an electrically coupled network via connexin 36 (Cx36) gap junctions. We find that presynaptic activity of glutamatergic ON bipolar cells drives increased phosphorylation of Cx36, indicative of increased coupling in the AII network. The phosphorylation is dependent on activation of nonsynaptic NMDA receptors that colocalize with Cx36 on AII amacrine cells, and is mediated by CaMKII. This activity-dependent increase in Cx36 phosphorylation works in opposition to dopamine-driven reduction of phosphorylation, establishing a local dynamic regulatory mechanism, and accounting for the nonlinear control of AII coupling by background illumination. C1 [Kothmann, W. Wade; Whitaker, Christopher M.; Massey, Stephen C.; O'Brien, John] Univ Texas Med Sch, Richard S Ruiz Dept Ophthalmol & Visual Sci, Houston, TX 77030 USA. [Kothmann, W. Wade; Massey, Stephen C.; O'Brien, John] Univ Texas Grad Sch Biomed Sci Houston, Houston, TX 77030 USA. [Trexler, E. Brady] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY 10029 USA. [Trexler, E. Brady] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Li, Wei] NEI, Unit Retinal Neurophysiol, Bethesda, MD 20892 USA. RP Kothmann, WW (reprint author), NINDS, Synapt Physiol Sect, 35 Convent Dr, Bethesda, MD 20892 USA. EM Wade.Kothmann@gmail.com OI O'Brien, John/0000-0002-0270-3442 FU NRSA [NS63534]; NIH [EY12857, EY16392, EY06515, EY10608]; Research to Prevent Blindness FX This research was supported by an NRSA fellowship to W.W.K. (NS63534), NIH awards to J.O. (EY12857), E.B.T. (EY16392), and S.C.M. (EY06515), an NIH core grant (EY10608), and a Research to Prevent Blindness grant to the Department of Ophthalmology and Visual Science. We are grateful to R. Heidelberger, S. Mills, and J. Diamond for insightful discussions on this work, and H. Wassle for a prescient suggestion. NR 68 TC 28 Z9 28 U1 1 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 MAY 16 PY 2012 VL 32 IS 20 BP 6747 EP 6759 DI 10.1523/JNEUROSCI.5087-11.2012 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 947HH UT WOS:000304419700002 PM 22593045 ER PT J AU Clark, AM Bouret, S Young, AM Richmond, BJ AF Clark, Andrew M. Bouret, Sebastien Young, Adrienne M. Richmond, Barry J. TI Intersection of Reward and Memory in Monkey Rhinal Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIAL TEMPORAL-LOBE; ORBITOFRONTAL CORTEX; RECOGNITION MEMORY; PERIRHINAL CORTEX; ENTORHINAL CORTEX; RHESUS-MONKEYS; REINFORCER MAGNITUDE; HIPPOCAMPAL-LESIONS; OBJECT RECOGNITION; PRIMATE STRIATUM AB In humans and other animals, the vigor with which a reward is pursued depends on its desirability, that is, on the reward's predicted value. Predicted value is generally context-dependent, varying according to the value of rewards obtained in the recent and distant past. Signals related to reward prediction and valuation are believed to be encoded in a circuit centered around midbrain dopamine neurons and their targets in the prefrontal cortex and basal ganglia. Notably absent from this hypothesized reward pathway are dopaminergic targets in the medial temporal lobe. Here we show that a key part of the medial temporal lobe memory system previously reported to be important for sensory mnemonic and perceptual processing, the rhinal cortex (Rh), is required for using memories of previous reward values to predict the value of forthcoming rewards. We tested monkeys with bilateral Rh lesions on a task in which reward size varied across blocks of uncued trials. In this experiment, the only cues for predicting current reward value are the sizes of rewards delivered in previous blocks. Unexpectedly, monkeys with Rh ablations, but not intact controls, were insensitive to differences in predicted reward, responding as if they expected all rewards to be of equal magnitude. Thus, it appears that Rh is critical for using memory of previous rewards to predict the value of forthcoming rewards. These results are in agreement with accumulating evidence that Rh is critical for establishing the relationships between temporally interleaved events, which is a key element of episodic memory. C1 [Clark, Andrew M.; Bouret, Sebastien; Young, Adrienne M.; Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, 49 S Convent Dr, Bethesda, MD 20892 USA. EM bjr@ln.nimh.nih.gov RI Bouret, Sebastien/J-9383-2013 OI Bouret, Sebastien/0000-0003-2279-6161 FU National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. We thank Dr. R. Saunders for making and assisting in reconstructing the rhinal lesions as well as for comments during development of this manuscript, Drs. M. Eldridge, L. Optican, and M. Mishkin for their comments during development of this manuscript, M. Malloy for assistance in lesion reconstructions, and R. Reoli for assistance in obtaining MRimages. The opinions expressed in this article are the authors' own and do not reflect the view of the U. S. National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 55 TC 11 Z9 11 U1 4 U2 10 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 MAY 16 PY 2012 VL 32 IS 20 BP 6869 EP 6877 DI 10.1523/JNEUROSCI.0887-12.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 947HH UT WOS:000304419700013 PM 22593056 ER PT J AU Wei, SM Eisenberg, DP Kohn, PD Kippenhan, JS Kolachana, BS Weinberger, DR Berman, KF AF Wei, Shau-Ming Eisenberg, Daniel P. Kohn, Philip D. Kippenhan, Jonathan S. Kolachana, Bhaskar S. Weinberger, Daniel R. Berman, Karen F. TI Brain-Derived Neurotrophic Factor Val(66)Met Polymorphism Affects Resting Regional Cerebral Blood Flow and Functional Connectivity Differentially in Women Versus Men SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BDNF VAL66MET POLYMORPHISM; DEPENDENT SYNAPTIC PLASTICITY; FACTOR MESSENGER-RNA; PREFRONTAL CORTEX; DENTATE GYRUS; NEURONAL DEVELOPMENT; HIPPOCAMPAL ACTIVITY; MAJOR DEPRESSION; MEMORY FORMATION; FACTOR GENE AB The human Val(66)Met single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene impacts BDNF signaling at the cellular level. At the neural-systems level, it is associated with differences in prefrontal cortex (PFC) and hippocampal function during performance of cognitive and affective tasks. Because the impact of this variant on basal prefrontal and hippocampal activity is not known but may be relevant to understanding the function of this gene in health and disease, we studied 94 healthy individuals withH(2) (15)0 PET to assess regional cerebral blood flow (rCBF) during rest and tested for between-genotype differences. Because BDNF and gonadal steroid hormones conjointly influence neuronal growth, survival, and plasticity in hippocampus and PFC, we also tested for sex X genotype interactions. Finally, in light of the known impact of BDNF on plasticity and dendritic arborization, we complimented direct rCBF comparisons with connectivity analyses to determine how activity in hippocampal and prefrontal regions showing between-genotype group differences covaries with rCBF in other nodes throughout the brain in a genotype-or sex-dependent manner. Compared with Val homozygotes, Met carriers had higher rCBF in prefrontal (BA25 extending into BA10) and hippocampal/parahippocampal regions. Moreover, there were significant sex X genotype interactions in regions (including frontal, parahippocampal, and lateral temporal cortex) in which Val homozygotes showed higher rCBF in females than males, but Met carriers showed the opposite relationship. Functional connectivity analysis demonstrated that correlations of BA25, hippocampus, and parahippocampus with frontal and temporal networks were positive for Val homozygotes and negative for Met carriers. In addition, sex X genotype analysis of functional connectivity revealed that genotype affected directionality of the inter-regional correlations differentially in men versus women. Our data indicate that BDNF allelic variation and sex interactively affect basal prefrontal and hippocampal function. C1 [Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Intramural Res Programs,NIH, Bethesda, MD 20892 USA. [Wei, Shau-Ming; Eisenberg, Daniel P.; Kohn, Philip D.; Kippenhan, Jonathan S.; Kolachana, Bhaskar S.; Weinberger, Daniel R.; Berman, Karen F.] NIMH, Clin Brain Disorders Branch, Cognit & Psychosis Program, Intramural Res Programs,NIH, Bethesda, MD 20892 USA. [Wei, Shau-Ming] Brown Univ, Providence, RI 02912 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP Berman, KF (reprint author), NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Intramural Res Programs,NIH, 10 Ctr Dr,Bldg 10,Room 3C209, Bethesda, MD 20892 USA. EM bermank@mail.nih.gov RI Eisenberg, Daniel/C-7432-2014; Eisenberg, Daniel/S-4342-2016 FU Intramural Research Program; National Institute of Mental Health; National Institutes of Health FX This research was supported by the Intramural Research Program, National Institute of Mental Health, National Institutes of Health. NR 69 TC 13 Z9 13 U1 0 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 MAY 16 PY 2012 VL 32 IS 20 BP 7074 EP 7081 DI 10.1523/JNEUROSCI.5375-11.2012 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 947HH UT WOS:000304419700032 PM 22593075 ER PT J AU Elia, N Fabrikant, G Kozlov, MM Lippincott-Schwartz, J AF Elia, Natalie Fabrikant, Gur Kozlov, Michael M. Lippincott-Schwartz, Jennifer TI Computational Model of Cytokinetic Abscission Driven by ESCRT-III Polymerization and Remodeling SO BIOPHYSICAL JOURNAL LA English DT Article ID MEMBRANE FISSION; CELL-DIVISION; MACHINERY; COMPLEX; VPS4; CONSTRICTION; HYDROLYSIS; MECHANISMS; FILAMENTS; PROTEINS AB The endosomal sorting complex required for transport (ESCRT)-III complex, capable of polymerization and remodeling, participates in abscission of the intercellular membrane bridge connecting two daughter cells at the end of cytokinesis. Here, we integrate quantitative imaging of ESCRT-III during cytokinetic abscission with biophysical properties of ESCRT-III complexes to formulate and test a computational model for ESCRT-mediated cytokinetic abscission. We propose that cytokinetic abscission is driven by an ESCRT-III fission complex, which arises from ESCRT-III polymerization at the edge of the cytokinetic midbody structure, located at the center of the intercellular bridge. Formation of the fission complex is completed by remodeling and breakage of the ESCRT-III polymer assisted by VPS4. Subsequent spontaneous constriction of the fission complex generates bending deformation of the intercellular bridge membrane. The related membrane elastic force propels the fission complex along the intercellular bridge away from the midbody until it reaches an equilibrium position, determining the scission site. Membrane attachment to the dome-like end-cap of the fission complex drives membrane fission, completing the abscission process. We substantiate the model by theoretical analysis of the membrane elastic energy and by experimental verification of the major model assumptions. C1 [Elia, Natalie; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Cell Biol & Metab Program, NIH, Bethesda, MD USA. [Elia, Natalie] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel. [Elia, Natalie] Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, IL-84105 Beer Sheva, Israel. [Fabrikant, Gur; Kozlov, Michael M.] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Cell Biol & Metab Program, NIH, Bethesda, MD USA. EM michk@post.tau.ac.il; lippincj@mail.nih.gov FU National Institutes of Health; Eunice Shriver National Institute of Child Health and Development; Intramural AIDS Targeted Antiviral Program; Israel Science Foundation; Marie Curie Network "Virus Entry" FX J.L.-S. was supported by the Intramural program of the National Institutes of Health, the Intramural Program of Eunice Shriver National Institute of Child Health and Development, and Intramural AIDS Targeted Antiviral Program. M.M.K. was supported by the Israel Science Foundation and the Marie Curie Network "Virus Entry". NR 31 TC 28 Z9 28 U1 1 U2 7 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 MAY 16 PY 2012 VL 102 IS 10 BP 2309 EP 2320 DI 10.1016/j.bpj.2012.04.007 PG 12 WC Biophysics SC Biophysics GA 942ZV UT WOS:000304091100010 PM 22677384 ER PT J AU Wan, W Wille, H Stohr, J Baxa, U Prusiner, SB Stubbs, G AF Wan, William Wille, Holger Stoehr, Jan Baxa, Ulrich Prusiner, Stanley B. Stubbs, Gerald TI Degradation of Fungal Prion HET-s(218-289) Induces Formation of a Generic Amyloid Fold SO BIOPHYSICAL JOURNAL LA English DT Article ID HET-S PRION; X-RAY-DIFFRACTION; SOLID-STATE NMR; FIBER DIFFRACTION; ISOMORPHOUS REPLACEMENT; PODOSPORA-ANSERINA; CORE STRUCTURE; PROTEIN; FIBRILS; CONFORMATION AB The prion-forming domain of the fungal prion protein HET-s, HET-s(218-289), is known from solid-state NMR studies to have a beta-solenoidal structure; the beta-solenoid has the cross-beta structure characteristic of all amyloids, but is inherently more complex than the generic stacked beta-sheets found in studies of small synthetic peptides. At low pH HET-s(218-289) has also been reported to form an alternative structure, which has not been characterized. We have confirmed by x-ray fiber diffraction that HET-s(218-289) adopts a beta-solenoidal structure at neutral pH, and shown that at low pH, it forms either a beta-solenoid or a stacked beta-sheet structure, depending on the integrity of the protein and the conditions of fibrillization. The low pH stacked-sheet structure is usually formed only by proteolyzed HET-s(218-289), but intact HET-s(218-289) can form stacked sheets when seeded with proteolyzed stacked-sheet HET-s(218-289). The polymorphism of HET-s parallels the structural differences between the infectious brain-derived and the much less infectious recombinant mammalian prion protein PrP. Taken together, these observations suggest that the functional or pathological forms of amyloid proteins are more complex than the simple generic stacked-sheet amyloids commonly formed by short peptides. C1 [Wan, William; Stubbs, Gerald] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37203 USA. [Wan, William; Stubbs, Gerald] Vanderbilt Univ, Struct Biol Ctr, Nashville, TN USA. [Wille, Holger; Stoehr, Jan; Prusiner, Stanley B.] Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA. [Wille, Holger; Stoehr, Jan; Prusiner, Stanley B.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Baxa, Ulrich] Natl Inst Arthrit Musculoskeletal & Skin Dis, Struct Biol Lab, NIH, Bethesda, MD USA. RP Stubbs, G (reprint author), Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37203 USA. EM gerald.stubbs@vanderbilt.edu RI Wille, Holger/C-2280-2008; Stohr, Jan/A-9638-2009; ID, BioCAT/D-2459-2012 OI Wille, Holger/0000-0001-5102-8706; Stohr, Jan/0000-0003-2610-7458; FU U.S. National Institutes of Health (NIH) [AG002132, T32-GM008320-21]; Department of Energy, Office of Biological and Environmental Research; NIH National Center for Research Resources; U.S. Department of Energy; NIH [RR-007707, RR-008630] FX This work was supported by U.S. National Institutes of Health (NIH) grants AG002132 and T32-GM008320-21. The Stanford Synchrotron Radiation Laboratory is a national user facility operated by Stanford University on behalf of the U.S. Department of Energy, Office of Basic Energy Sciences. The Stanford Synchrotron Radiation Lightsource (SSRL) Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the NIH National Center for Research Resources. Use of the Advanced Photon Source was supported by the U.S. Department of Energy. BioCAT and BioCARS are NIH-supported Research Centers RR-007707 and RR-008630. NR 37 TC 13 Z9 13 U1 0 U2 6 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 MAY 16 PY 2012 VL 102 IS 10 BP 2339 EP 2344 DI 10.1016/j.bpj.2012.04.011 PG 6 WC Biophysics SC Biophysics GA 942ZV UT WOS:000304091100013 PM 22677387 ER PT J AU Ix, JH Biggs, ML Mukamal, KJ Kizer, JR Zieman, SJ Siscovick, DS Mozzaffarian, D Jensen, MK Nelson, L Ruderman, N Djousse, L AF Ix, Joachim H. Biggs, Mary L. Mukamal, Kenneth J. Kizer, Jorge R. Zieman, Susan J. Siscovick, David S. Mozzaffarian, Dariush Jensen, Majken K. Nelson, Lauren Ruderman, Neil Djousse, Luc TI Association of Fetuin-A With Incident Diabetes Mellitus in Community-Living Older Adults SO CIRCULATION LA English DT Article DE cardiovascular diseases; diabetes mellitus; alpha-2-HS-Glycoprotein; geriatrics; obesity; risk factors ID RECEPTOR TYROSINE KINASE; CARDIOVASCULAR HEALTH; INSULIN-RESISTANCE; MYOCARDIAL-INFARCTION; METABOLIC SYNDROME; CYSTATIN-C; RISK; SERUM; INHIBITOR; DISEASE AB Background-The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD). Methods and Results-Among 3710 community-living individuals >= 65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60% were female; 15% were black; and 16% had CVD. Mean fetuin-A concentrations were 0.47 +/- 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19% higher risk of diabetes mellitus (hazard ratio, 1.19; 95% confidence interval, 1.06-1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95% confidence interval, 1.00-1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01). Conclusions-Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those >75 years of age. C1 [Ix, Joachim H.] Univ Calif San Diego, San Diego VA Healthcare Syst, Dept Med, Div Nephrol & Hypertens,Nephrol Sect, San Diego, CA 92161 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92161 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92161 USA. [Biggs, Mary L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98195 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Kizer, Jorge R.] Cornell Univ, Dept Med, Weill Med Coll, New York, NY USA. [Kizer, Jorge R.] Cornell Univ, Dept Publ Hlth, Weill Med Coll, New York, NY USA. [Zieman, Susan J.] NIA, NIH, Bethesda, MD 20892 USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Mozzaffarian, Dariush] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Jensen, Majken K.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Nelson, Lauren; Ruderman, Neil] Boston Univ, Dept Med, Div Endocrinol, Boston, MA USA. [Djousse, Luc] Brigham & Womens Hosp, Boston Vet Affairs Healthcare Syst, Div Aging, Boston, MA 02115 USA. RP Ix, JH (reprint author), Univ Calif San Diego, San Diego VA Healthcare Syst, Dept Med, Div Nephrol & Hypertens,Nephrol Sect, 3350 La Jolla Village Dr,Mail Code 111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute (NHLBI) [R01 HL094555]; NHLBI [N01HC-85079, N01HC-85086, N01HC-35129, N01HC-15103, N01HC-55222, N01HC-75150, N01HC-54133, N01-HC85239, U01 HL080295]; National Institute of Neurological Disorders and Stroke FX This work was supported by National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL094555 ( to Drs Ix, Mukamal, Djousse, Kizer, and Zieman). The Cardiovascular Health Study was supported by contracts N01HC-85079 through N01HC-85086, N01HC-35129, N01HC-15103, N01HC-55222, N01HC-75150, N01HC-54133, and N01-HC85239 and grant U01 HL080295 from the NHLBI, with additional contributions from the National Institute of Neurological Disorders and Stroke. This material is the result of work supported with resources of the VA San Diego Healthcare System. Dr Biggs had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 44 TC 36 Z9 37 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 15 PY 2012 VL 125 IS 19 BP 2316 EP 2322 DI 10.1161/CIRCULATIONAHA.111.072751 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981YQ UT WOS:000307009202011 PM 22511752 ER PT J AU Koh, K Quon, M AF Koh, Kwang Quon, Michael TI Significant differential metabolic effects of rosuvastatin and pravastatin in hypercholesterolemic patients SO CIRCULATION LA English DT Meeting Abstract CT World Congress of Cardiology Scientific Sessions CY APR 18-21, 2012 CL Dubai, U ARAB EMIRATES C1 [Koh, Kwang] Gachon Univ, Gil Med Ctr, Inchon, South Korea. [Quon, Michael] NIH, Diabet Unit, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 15 PY 2012 VL 125 IS 19 MA O315 BP E734 EP E734 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981YQ UT WOS:000307009200290 ER PT J AU Haigis, MC Deng, CX Finley, LWS Kim, HS Gius, D AF Haigis, Marcia C. Deng, Chu-Xia Finley, Lydia W. S. Kim, Hyun-Seok Gius, David TI SIRT3 Is a Mitochondrial Tumor Suppressor: A Scientific Tale That Connects Aberrant Cellular ROS, the Warburg Effect, and Carcinogenesis SO CANCER RESEARCH LA English DT Review ID DNA-DAMAGE RESPONSE; CANCER-CELLS; STRESS; INSTABILITY; METABOLISM; SIRTUINS; BIOLOGY AB Tumors exhibit metabolic reprogramming characterized by increased cellular reactive oxygen species (ROS) and the preferential use of glucose, which is known as the Warburg effect. However, the mechanisms by which these processes are linked remain largely elusive. Murine tumors lacking Sirt3 exhibit abnormally high levels of ROS that directly induce genomic instability and increase hypoxia-inducible factor 1 alpha(HIF-1 alpha) protein levels. The subsequent transcription of HIF alpha-dependent target genes results in cellular metabolic reprogramming and increased cellular glucose consumption. In addition, agents that scavenge ROS or reverse the Warburg effect prevent the transformation and malignant phenotype observed in cells lacking Sirt3. Thus, mice lacking Sirt3 provide a model that mechanistically connects aberrant ROS, the Warburg effect, and carcinogenesis. Cancer Res; 72(10); 2468-72. (C) 2012 AACR. C1 [Haigis, Marcia C.; Finley, Lydia W. S.] Harvard Univ, Sch Med, Dept Pathol, Paul F Glenn Labs Aging, Boston, MA 02115 USA. [Deng, Chu-Xia] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Kim, Hyun-Seok; Gius, David] Ewha Womans Univ, Coll Nat Sci, Dept Life Sci, Seoul 127750, South Korea. RP Gius, D (reprint author), Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, D4105 MCN, Nashville, TN 37232 USA. EM David.Gius@vanderbilt.edu RI deng, chuxia/N-6713-2016 FU National Institutes of Health [NCI-1B01CA152601-01, 1B01CA152799-01A1, DOD-BC093803, NIH-AG032375]; Paul F. Glenn Foundation FX National Institutes of Health (NCI-1B01CA152601-01, 1B01CA152799-01A1, and DOD-BC093803 to D. Gius, and NIH-AG032375 to M.C. Haigis); Paul F. Glenn Foundation (M.C. Haigis). NR 21 TC 51 Z9 53 U1 0 U2 21 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 MAY 15 PY 2012 VL 72 IS 10 BP 2468 EP 2472 DI 10.1158/0008-5472.CAN-11-3633 PG 5 WC Oncology SC Oncology GA 986MX UT WOS:000307346800002 PM 22589271 ER PT J AU Swartz, MA Iida, N Roberts, EW Sangaletti, S Wong, MH Yull, FE Coussens, LM DeClerck, YA AF Swartz, Melody A. Iida, Noriho Roberts, Edward W. Sangaletti, Sabina Wong, Melissa H. Yull, Fiona E. Coussens, Lisa M. DeClerck, Yves A. TI Tumor Microenvironment Complexity: Emerging Roles in Cancer Therapy SO CANCER RESEARCH LA English DT Editorial Material ID BREAST-CANCER; LYMPHATIC VESSELS; METASTASIS; INFLAMMATION; STROMA; CELLS; MACROPHAGES; INFECTION; CARCINOMA; INVASION AB The tumor microenvironment (TME) consists of cells, soluble factors, signaling molecules, extracellular matrix, and mechanical cues that can promote neoplastic transformation, support tumor growth and invasion, protect the tumor from host immunity, foster therapeutic resistance, and provide niches for dormant metastases to thrive. An American Association for Cancer Research (AACR) special conference held on November 3-6, 2011, addressed five emerging concepts in our understanding of the TME: its dynamic evolution, how it is educated by tumor cells, pathways of communication between stromal and tumor cells, immunomodulatory roles of the lymphatic system, and contribution of the intestinal microbiota. These discussions raised critical questions on how to include the analysis of the TME in personalized cancer diagnosis and treatment. Cancer Res; 72(10); 2473-80. (C) 2012 AACR. C1 [Swartz, Melody A.] Ecole Polytech Fed Lausanne, Inst Bioengn, Lausanne, Switzerland. [Swartz, Melody A.] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res, Lausanne, Switzerland. [Iida, Noriho] NCI, NIH, Bethesda, MD 20892 USA. [Roberts, Edward W.] Univ Cambridge, Cambridge, England. [Sangaletti, Sabina] Fdn IRCCS Inst Nazl Tumori, Milan, Italy. [Wong, Melissa H.; Coussens, Lisa M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Yull, Fiona E.] Vanderbilt Univ, Nashville, TN USA. [DeClerck, Yves A.] Univ So Calif, Los Angeles, CA USA. RP DeClerck, YA (reprint author), Childrens Hosp Los Angeles, 4650 Sunset Blvd,MS 54, Los Angeles, CA 90027 USA. EM declerck@usc.edu RI Swartz, Melody/F-9563-2011; Sangaletti, Sabina/C-4495-2017 OI Sangaletti, Sabina/0000-0001-7047-287X FU NCI NIH HHS [R01 CA155331, R01 CA130980, R01 CA140943, R13 CA165812] NR 38 TC 142 Z9 150 U1 1 U2 41 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 MAY 15 PY 2012 VL 72 IS 10 BP 2473 EP 2480 DI 10.1158/0008-5472.CAN-12-0122 PG 8 WC Oncology SC Oncology GA 986MX UT WOS:000307346800003 PM 22414581 ER PT J AU Coulouarn, C Corlu, A Glaise, D Guenon, I Thorgeirsson, SS Clement, B AF Coulouarn, Cedric Corlu, Anne Glaise, Denise Guenon, Isabelle Thorgeirsson, Snorri S. Clement, Bruno TI Hepatocyte-Stellate Cell Cross-Talk in the Liver Engenders a Permissive Inflammatory Microenvironment That Drives Progression in Hepatocellular Carcinoma SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION SIGNATURES; HEPATITIS-B VIRUS; EXTRACELLULAR-MATRIX; MESENCHYMAL TRANSITION; NEXT-GENERATION; IN-VIVO; CANCER; GROWTH; SUPPRESSES; ACTIVATION AB Many solid malignant tumors arise on a background of inflamed and/or fibrotic tissues, features that are found in more than 80% hepatocellular carcinomas (HCC). Activated hepatic stellate cells (HSC) play a critical role in fibrogenesis associated with HCC onset and progression, yet their functional impact on hepatocyte fate remains largely unexplored. Here, we used a coculture model to investigate the cross-talk between hepatocytes (human hepatoma cells) and activated human HSCs. Unsupervised genome-wide expression profiling showed that hepatocyte-HSC cross-talk is bidirectional and results in the deregulation of functionally relevant gene networks. Notably, coculturing increased the expression of proinflammatory cytokines and modified the phenotype of hepatocytes toward motile cells. Hepatocyte-HSC cross-talk also generated a permissive proangiogenic microenvironment, particularly by inducing VEGFA and matrix metalloproteinase (MMP) 9 expression in HSCs. An integrative genomic analysis revealed that the expression of genes associated with hepatocyte-HSC cross-talk correlated with HCC progression in mice and was predictive of a poor prognosis and metastasis propensity in human HCCs. Interestingly, the effects of cross-talk on migration and angiogenesis were reversed by the histone deacetylase inhibitor trichostatin A. Our findings, therefore, indicate that the cross-talk between hepatoma cells and activated HSCs is an important feature of HCC progression, which may be targeted by epigenetic modulation. Cancer Res; 72(10); 2533-42. (C) 2012 AACR. C1 [Coulouarn, Cedric; Corlu, Anne; Glaise, Denise; Guenon, Isabelle; Clement, Bruno] Pontchaillou Univ Hosp, INSERM, UMR991, F-35033 Rennes, France. [Coulouarn, Cedric; Corlu, Anne; Glaise, Denise; Guenon, Isabelle; Clement, Bruno] Univ Rennes 1, Rennes, France. [Thorgeirsson, Snorri S.] NCI, Lab Expt Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Coulouarn, C (reprint author), Pontchaillou Univ Hosp, INSERM, UMR991, 2 Rue Henri Le Guilloux, F-35033 Rennes, France. EM cedric.coulouarn@univ-rennes1.fr RI Clement, Bruno/E-5546-2016; Coulouarn, Cedric/E-5472-2011 FU INSERM; CNRS; University of Rennes 1; Institut National du Cancer Agence Nationale pour la Recherche; Association pour la Recherche sur le Cancer, France FX This research was supported by INSERM, CNRS, University of Rennes 1, Institut National du Cancer Agence Nationale pour la Recherche and Association pour la Recherche sur le Cancer, France. NR 45 TC 67 Z9 73 U1 0 U2 15 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 MAY 15 PY 2012 VL 72 IS 10 BP 2533 EP 2542 DI 10.1158/0008-5472.CAN-11-3317 PG 10 WC Oncology SC Oncology GA 986MX UT WOS:000307346800009 PM 22419664 ER PT J AU Shiee, N Bazin, PL Zackowski, KM Farrell, SK Harrison, DM Newsome, SD Ratchford, JN Caffo, BS Calabresi, PA Pham, DL Reich, DS AF Shiee, Navid Bazin, Pierre-Louis Zackowski, Kathleen M. Farrell, Sheena K. Harrison, Daniel M. Newsome, Scott D. Ratchford, John N. Caffo, Brian S. Calabresi, Peter A. Pham, Dzung L. Reich, Daniel S. TI Revisiting Brain Atrophy and Its Relationship to Disability in Multiple Sclerosis SO PLOS ONE LA English DT Article ID RELAPSING-REMITTING MS; WHITE-MATTER; CORTICAL ATROPHY; LESION LOAD; VOLUME CHANGES; SPINAL-CORD; GRAY; DYSFUNCTION; SEGMENTATION; ALGORITHM AB Background: Brain atrophy is a well-accepted imaging biomarker of multiple sclerosis (MS) that partially correlates with both physical disability and cognitive impairment. Methodology/Principal Findings: Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, putamen, thalamus, ventricles, and brainstem using a validated and completely automated segmentation method. We correlated these volumes with the Expanded Disability Status Scale (EDSS), MS Severity Scale (MSSS), MS Functional Composite (MSFC), and quantitative measures of ankle strength and toe sensation. Normalized volumes of both cortical and subcortical GM structures were abnormally low in the MS group, whereas no abnormality was found in the volume of the cerebral WM. High physical disability was associated with low cerebral WM, thalamus, and brainstem volumes (partial correlation coefficients similar to 0.3-0.4) but not with low cortical GM volume. Thalamus volumes were inversely correlated with lesion load (r = 20.36, p<0.005). Conclusion: The GM is atrophic in MS. Although lower WM volume is associated with greater disability, as might be expected, WM volume was on average in the normal range. This paradoxical result might be explained by the presence of coexisting pathological processes, such as tissue damage and repair, that cause both atrophy and hypertrophy and that underlie the observed disability. C1 [Shiee, Navid; Pham, Dzung L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Reich, Daniel S.] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Bazin, Pierre-Louis] Max Planck Inst Human Cognit & Brain Sci, Dept Neurophys, Leipzig, Germany. [Shiee, Navid; Pham, Dzung L.; Reich, Daniel S.] Johns Hopkins Univ, Neuroradiol Div, Dept Radiol, Baltimore, MD USA. [Shiee, Navid; Pham, Dzung L.; Reich, Daniel S.] Johns Hopkins Univ, Neuroradiol Div, Dept Radiol Sci, Baltimore, MD USA. [Zackowski, Kathleen M.] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD USA. [Zackowski, Kathleen M.; Farrell, Sheena K.; Harrison, Daniel M.; Newsome, Scott D.; Ratchford, John N.; Calabresi, Peter A.; Reich, Daniel S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Caffo, Brian S.; Reich, Daniel S.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Pham, Dzung L.] Henry M Jackson Fdn Adv Mil Med, Ctr Neurosci & Regenerat Med, Bethesda, MD USA. RP Shiee, N (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. EM daniel.reich@nih.gov RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Bazin, Pierre-Louis/0000-0002-0141-5510 FU National Institute of Neurological Disorders and Stroke [R01NS054255, R01NS070906, K99NS064098]; National Institute of Drug Abuse [K25DA025356]; Eunice Kennedy Shriver National Institute for Child Health and Development [5K01HD049476]; National Center for Research Resources [P41RR015241]; National Multiple Sclerosis Society [TR3760A3]; EMD Serono; MS Center of Brigham and Women's Hospital, Boston, MA; Bayer Schering Pharma; National MS Society; Biogen-IDEC; Nancy Davis Foundation for MS; Novartis; University of California-Los Angeles; Merck Pharmacueticals; Pfizer Pharmaceuticals; Teva; Vertex; Bayer; Genentech; Abbott Labs FX This project was partially supported by grants R01NS054255, R01NS070906, and K99NS064098 from, and the Intramural Research Program of, the National Institute of Neurological Disorders and Stroke; grant K25DA025356 from the National Institute of Drug Abuse; grant 5K01HD049476 from the Eunice Kennedy Shriver National Institute for Child Health and Development; grant P41RR015241 from the National Center for Research Resources; grant TR3760A3 from the National Multiple Sclerosis Society; and an unrestricted grant from EMD Serono for MRI data acquisition. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; An unrestricted grant from EMD Serono for MRI data acquisition was received for this study. Daniel S. Harrison received fellowship funding from the Partners MS Center of Brigham and Women's Hospital, Boston, MA and research funding from Bayer Schering Pharma. Scott D. Newsome received fellowship funding from the National MS Society (Sylvia Lawry Physician Fellowship) and has received consultant fees from Biogen-IDEC. John N. Ratchford received research support from the Nancy Davis Foundation for MS and support for clinical trials from Novartis, Biogen-Idec, and the University of California-Los Angeles. Brian S. Caffo received funding from Merck Pharmacueticals and Pfizer Pharmaceuticals. Peter A. Calabresi received grants from Biogen-IDEC, Teva, Vertex, Bayer, Genentech, Abbott Labs, and EMD Serono. He received consulting fees from Novartis, Biogen-IDEC, and Teva. There are no patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 48 TC 49 Z9 52 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 15 PY 2012 VL 7 IS 5 AR e37049 DI 10.1371/journal.pone.0037049 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TM UT WOS:000305336300065 PM 22615886 ER PT J AU Takagi, M Ishii, T Barnes, AM Weis, M Amano, N Tanaka, M Fukuzawa, R Nishimura, G Eyre, DR Marini, JC Hasegawa, T AF Takagi, Masaki Ishii, Tomohiro Barnes, Aileen M. Weis, MaryAnn Amano, Naoko Tanaka, Mamoru Fukuzawa, Ryuji Nishimura, Gen Eyre, David R. Marini, Joan C. Hasegawa, Tomonobu TI A Novel Mutation in LEPRE1 That Eliminates Only the KDEL ER- Retrieval Sequence Causes Non-Lethal Osteogenesis Imperfecta SO PLOS ONE LA English DT Article ID PROLYL 3-HYDROXYLATION COMPLEX; ENDOPLASMIC-RETICULUM; CYCLOPHILIN-B; I COLLAGEN; LETHAL; IDENTIFICATION; CRTAP; DEFICIENCY; RECURRENCE; COL1A1 AB Prolyl 3-hydroxylase 1 (P3H1), encoded by the LEPRE1 gene, forms a molecular complex with cartilage-associated protein (CRTAP) and cyclophilin B (encoded by PPIB) in the endoplasmic reticulum (ER). This complex is responsible for one step in collagen post-translational modification, the prolyl 3-hydroxylation of specific proline residues, specifically alpha 1(I) Pro986. P3H1 provides the enzymatic activity of the complex and has a Lys-Asp-Glu-Leu (KDEL) ER-retrieval sequence at the carboxyl terminus. Loss of function mutations in LEPRE1 lead to the Pro986 residue remaining unmodified and lead to slow folding and excessive helical post-translational modification of type I collagen, which is seen in both dominant and recessive osteogenesis imperfecta (OI). Here, we present the case of siblings with non-lethal OI due to novel compound heterozygous mutations in LEPRE1 (c.484delG and c.2155dupC). The results of RNA analysis and real-time PCR suggest that mRNA with c.2155dupC escapes from nonsense-mediated RNA decay. Without the KDEL ER- retrieval sequence, the product of the c.2155dupC variant cannot be retained in the ER. This is the first report of a mutation in LEPRE1 that eliminates only the KDEL ER-retrieval sequence, whereas other functional domains remain intact. Our study shows, for the first time, that the KDEL ER- retrieval sequence is essential for P3H1 functionality and that a defect in KDEL is sufficient for disease onset. C1 [Takagi, Masaki; Ishii, Tomohiro; Amano, Naoko; Hasegawa, Tomonobu] Keio Univ, Sch Med, Dept Pediat, Tokyo, Japan. [Takagi, Masaki] Tokyo Metropolitan Childrens Med Ctr, Dept Endocrinol & Metab, Tokyo, Japan. [Barnes, Aileen M.; Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD USA. [Weis, MaryAnn; Eyre, David R.] Univ Washington, Orthopaed Res Labs, Seattle, WA 98195 USA. [Tanaka, Mamoru] Keio Univ, Sch Med, Dept Obstet & Gynecol, Tokyo 160, Japan. [Fukuzawa, Ryuji] Tokyo Metropolitan Childrens Med Ctr, Dept Pathol & Lab Med, Tokyo, Japan. [Nishimura, Gen] Tokyo Metropolitan Childrens Med Ctr, Dept Radiol, Tokyo, Japan. RP Takagi, M (reprint author), Keio Univ, Sch Med, Dept Pediat, Tokyo, Japan. EM thaseg@a6.keio.jp RI Hasegawa, Tomonobu/L-3331-2013; OI Ishii, Tomohiro/0000-0001-7360-2465 FU Ministry of Health, Labour and Welfare of Japan [H22-Nanji-Ippan-194]; Japan Society for the Promotion of Science [22790999] FX This work was supported by Research on Intractable Diseases of Health and Labour Sciences Research Grants (Diagnosis and treatment of osteogenesis imperfect; H22-Nanji-Ippan-194) from the Ministry of Health, Labour and Welfare of Japan, and by a grant from the Japan Society for the Promotion of Science (Grant-in-Aid for Young Scientists (B) (22790999)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 13 Z9 13 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 15 PY 2012 VL 7 IS 5 AR e36809 DI 10.1371/journal.pone.0036809 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TM UT WOS:000305336300038 PM 22615817 ER PT J AU Miller, TC Jaques, JT Szkudlinski, MW MacKenzie, DS AF Miller, T. C. Jaques, J. T. Szkudlinski, M. W. MacKenzie, D. S. TI Thyrotropic activity of recombinant human glycoprotein hormone analogs and pituitary mammalian gonadotropins in goldfish (Carassius auratus): Insights into the evolution of thyrotropin receptor specificity SO GENERAL AND COMPARATIVE ENDOCRINOLOGY LA English DT Article DE Thyrotropin; Teleost; Gonadotropin; Thyroid hormone; Carassius auratus ID THYROID-STIMULATING HORMONE; PLASMA THYROXINE; LINKED OLIGOSACCHARIDES; FUNDULUS-HETEROCLITUS; SALMO-GAIRDNERI; RAINBOW-TROUT; ALPHA-SUBUNIT; TSH; BOVINE; BIOASSAY AB Thyrotropin (TSH) is a pituitary glycoprotein hormone heterodimer that binds to its G-protein coupled receptor (TSH-R) at the thyroid to promote the synthesis and secretion of thyroid hormone. Very little is known about TSH-TSH-R interactions in teleost fish. Mammalian gonadotropins have been reported to have an intrinsic ability to activate teleost fish TSH-Rs, suggesting the TSH-R in teleost fish is more promiscuous than in other vertebrates. In this study we utilized the goldfish T-4-release response and recombinant human TSH analogs as in vivo tools to evaluate the structural constraints on hormone-receptor interactions. We found that four positively charged lysines substituted for neutral or negatively charged amino acids within positions 11-20 of the glycoprotein hormone subunit alpha (GSU alpha) significantly increased biological activity of hTSH in fish, as it does in mammals. We further found that bovine follicle stimulating hormone but not luteinizing hormone, whose GSU alpha subunits also contain four lysine or arginine amino acid residues in the N-terminal portion of GSU alpha, was thyrotropic in goldfish, suggesting gonadotropin p subunit contributes to the heterothyrotropic activity. Though recombinant human FSH did not produce a dose-dependent increase in 14, thyrotropic activity could be acquired with the addition of positively charged amino acids at the N-terminal portion of its GSU alpha confirming the importance of the charge on those amino acids for activation of the goldfish TSH-R. These studies demonstrate that mammalian glycoprotein hormone analogs can be utilized to evaluate the conservation of receptor binding and activation mechanisms between fish and mammals. Published by Elsevier Inc. C1 [Miller, T. C.; MacKenzie, D. S.] Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. [Jaques, J. T.] Texas Vet Med Diagnost Labs, Coll Stn Lab, Endocrine Diagnost Lab, College Stn, TX 77841 USA. [Szkudlinski, M. W.] Trophogen Inc, Rockville, MD 20850 USA. RP Miller, TC (reprint author), NICHD, NIH, Lab Gene Regulat & Dev, Bldg 18T,Room 106,18 Lib Dr, Bethesda, MD 20892 USA. EM millertc@mail.nih.gov; j-jaques@tvmdl.tamu.edu; mszkudlinski@trophogen.com; duncan@bio.tamu.edu FU Department of Biology at Texas AM University FX We wish to acknowledge Dr. Bruce D. Weintraub, Dr. Valerie Fremont, and Dr. Meng Zhang for their contributions to the development, production, purification, and characterization of TR-1401 and TR-9401 analogs. We also acknowledge the National Hormone and Pituitary Program (NIADDDK, USDA) for providing purified mammalian pituitary hormones. We would like to thank Richard Jones, Rhonda Patterson, and Malcolm Delovio for their assistance with fish care, experimental design, and hormone measurement. Finally, we thank Dr. Delbert Gatlin, Brian Ray, and staff at the Texas A&M Aquaculture Research and Teaching Facility for space and assistance with goldfish maintenance. Funding for this project was provided in part by the Department of Biology at Texas A&M University. NR 32 TC 3 Z9 3 U1 0 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0016-6480 J9 GEN COMP ENDOCR JI Gen. Comp. Endocrinol. PD MAY 15 PY 2012 VL 177 IS 1 BP 70 EP 75 DI 10.1016/j.ygcen.2012.02.012 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 948OC UT WOS:000304511500009 PM 22387984 ER PT J AU Chuang, ML Gona, P Salton, CJ Yeon, SB Kissinger, KV Blease, SJ Levy, D O'Donnell, CJ Manning, WJ AF Chuang, Michael L. Gona, Philimon Salton, Carol J. Yeon, Susan B. Kissinger, Kraig V. Blease, Susan J. Levy, Daniel O'Donnell, Christopher J. Manning, Warren J. TI Usefulness of the Left Ventricular Myocardial Contraction Fraction in Healthy Men and Women to Predict Cardiovascular Morbidity and Mortality SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PRESERVED EJECTION FRACTION; CORONARY-HEART-DISEASE; HYPERTENSION; GEOMETRY; FAILURE; MASS; PREVALENCE; MECHANICS; COHORT; RISK AB We sought to determine whether depressed myocardial contraction fraction (MCF; ratio of left ventricular [LV] stroke volume to myocardial volume) predicts cardiovascular disease (CVD) events in initially healthy adults. A subset (n = 318, 60 9 years old, 158 men) of the Framingham Heart Study Offspring cohort free of clinical CVD underwent volumetric cardiovascular magnetic resonance imaging in 1998 through 1999. LV ejection fraction (EF), mass, and MCF were determined. "Hard" CVD events consisted of cardiovascular death, myocardial infarction, stroke, or new heart failure. A Cox proportional hazards model adjusting for Framingham Coronary Risk Score was used to estimate hazard ratios for incident hard CVD events for gender-specific quartiles of MCF, LV mass, and LVEF. The lowest quartile of LV mass and highest quartiles of MCF and EF served as referents. Kaplan-Meier survival plots and log-rank test were used to compare event-free survival. MCF was greater in women (0.58 +/- 0.13) than in men (0.52 +/- 0.11, p <0.01). Nearly all participants (99%) had EF >= 0.55. During an up to 9-year follow-up (median 5.2), 31 participants (10%) developed an incident hard CVD event. Lowest-quartile MCF was 7 times more likely to develop a hard CVD (hazard ratio 7.11, p = 0.010) compared to the remaining quartiles, and increased hazards persisted even after adjustment for LV mass (hazard ratio 6.09, p = 0.020). The highest-quartile LV mass/height 2.7 had a nearly fivefold risk (hazard ratio 4.68, p = 0.016). Event-free survival was shorter in lowest-quartile MCF (p = 0.0006) but not in lowest-quartile LVEF. In conclusion, in a cohort of adults initially without clinical CVD, lowest-quartile MCF conferred an increased hazard for hard CVD events after adjustment for traditional CVD risk factors and LV mass. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:1454-1458) C1 [Chuang, Michael L.; Salton, Carol J.; Yeon, Susan B.; Kissinger, Kraig V.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Chuang, Michael L.; Gona, Philimon; Blease, Susan J.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Gona, Philimon] Boston Univ, Dept Math & Stat, Stat Consulting Unit, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Manning, Warren J.] Harvard Univ, Sch Med, Boston, MA USA. RP Manning, WJ (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. EM wmanning@bidmc.harvard.edu FU National Institutes of Health, Bethesda, Maryland [ROI AG17509, N01-HC-38038] FX This work was supported in part by Grant ROI AG17509 and Subcontract N01-HC-38038 from the National Institutes of Health, Bethesda, Maryland. NR 17 TC 5 Z9 5 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2012 VL 109 IS 10 BP 1454 EP 1458 DI 10.1016/j.amjcard.2012.01.357 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 948KO UT WOS:000304502300011 PM 22381161 ER PT J AU Simons-Morton, BG Zhang, ZW Jackson, JC Albert, PS AF Simons-Morton, Bruce G. Zhang, Zhiwei Jackson, John C. Albert, Paul S. TI Do Elevated Gravitational-Force Events While Driving Predict Crashes and Near Crashes? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE accident prevention; adolescent behavior; area under the curve; motor vehicle crashes; prediction; receiver operating characteristic; risk-taking; safety ID DRIVERS; MODELS; RISK AB The purpose of this research was to determine the extent to which elevated gravitational-force event rates predict crashes and near crashes. Accelerometers, global positioning systems, cameras, and other technology were installed in vehicles driven by 42 newly licensed Virginia teenage drivers for a period of 18 months between 2006 and 2009. Elevated gravitational force and crash and near-crash events were identified, and rates per miles driven were calculated. (One mile = 1.6 km.) The correlation between crashes and near crashes and elevated gravitational-force event rates was 0.60. Analyses were done by using generalized estimating equations with logistic regression. Higher elevated gravitational-force event rates in the past month substantially increased the risk of a crash in the subsequent month (odds ratio = 1.07, 95% confidence interval: 1.02, 1.12). Although the difference in this relation did not vary significantly by time, it was highest in the first 6 months compared with the second and third 6-month periods. With a receiver operating characteristic curve, the risk models showed relatively high predictive accuracy with an area under the curve of 0.76. The authors conclude that elevated gravitational-force event rates can be used to assess risk and to show high predictive accuracy of a near-future crash. C1 [Simons-Morton, Bruce G.; Zhang, Zhiwei; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Jackson, John C.] US Mil Acad, Dept Math Sci, West Point, NY 10996 USA. RP Simons-Morton, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B13M, Bethesda, MD 20892 USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU National Institutes of Health [N01-HD-5-3405] FX This research was supported by the Intramural Research Program of the National Institutes of Health (contract N01-HD-5-3405). NR 13 TC 14 Z9 14 U1 0 U2 7 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 MAY 15 PY 2012 VL 175 IS 10 BP 1075 EP 1079 DI 10.1093/aje/kwr440 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 944KC UT WOS:000304199000013 PM 22271924 ER PT J AU Bates, SE AF Bates, Susan E. TI Progress in Pediatric Cancer SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 Natl Canc Inst, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), Natl Canc Inst, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 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 MAY 15 PY 2012 VL 18 IS 10 BP 2734 EP 2734 DI 10.1158/1078-0432.CCR-12-1014 PG 1 WC Oncology SC Oncology GA 945CG UT WOS:000304249800003 PM 22589481 ER PT J AU Thiele, CJ Cohn, SL AF Thiele, Carol J. Cohn, Susan L. TI Genetically InFormed Therapies-A "GIFT" for Children with Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ACTIVATING MUTATIONS; ANTITUMOR-ACTIVITY; ALK KINASE; T-CELLS; NEUROBLASTOMA; ANTIBODY; GENE; DNA; RETINOBLASTOMA; IDENTIFICATION AB The national investment that was made in oncology research with the passage of the National Cancer Act in 1971 is now coming to fruition. Nowhere is this more apparent than in the exciting prospects for genetically informed precision medicine as applied to the treatment of children with cancer. The wealth of information gleaned from intensive genetic analyses and NexGen sequencing studies has identified a number of viable targets in leukemias and solid tumors. Our rapidly evolving understanding of the enzymatic controls that regulate chromatin dynamics during normal differentiation of stem cells and their mutation or dysregulation in tumor cells is leading to a new library of therapeutically tractable tumor targets. The recent identification of germline variants associated with toxicity and/or response to therapy has further enhanced our ability to deliver individualized treatments for pediatric cancer patients. Our challenge today is to determine how best to use genomic data and integrate it into evolving clinical protocols to provide more efficacious therapies and a better quality of life for children with cancer. Clin Cancer Res; 18(10); 2735-9. (C)2012 AACR. C1 [Thiele, Carol J.] Natl Canc Inst, CRC, Pediat Oncol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Cohn, Susan L.] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. RP Thiele, CJ (reprint author), Natl Canc Inst, CRC, Pediat Oncol Branch, Natl Inst Hlth, 1W-3940,10 Ctr Dr,MSC-1105, Bethesda, MD 20892 USA. EM ct47a@nih.gov; scohn@peds.bsd.uchicago.edu OI Cohn, Susan/0000-0001-5749-7650 FU Intramural NIH HHS [Z99 CA999999] NR 42 TC 4 Z9 4 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 MAY 15 PY 2012 VL 18 IS 10 BP 2735 EP 2739 DI 10.1158/1078-0432.CCR-11-1940 PG 5 WC Oncology SC Oncology GA 945CG UT WOS:000304249800004 PM 22589482 ER PT J AU Lawlor, ER Thiele, CJ AF Lawlor, Elizabeth R. Thiele, Carol J. TI Epigenetic Changes in Pediatric Solid Tumors: Promising New Targets SO CLINICAL CANCER RESEARCH LA English DT Article ID EMBRYONIC STEM-CELLS; MIXED LINEAGE LEUKEMIA; CPG ISLAND SHORES; EWINGS-SARCOMA; DNA METHYLATION; PHASE-I; ONCOGENIC TRANSFORMATION; TRANSCRIPTION FACTOR; DEVELOPMENTAL GENES; NEUROBLASTOMA-CELLS AB Cancer is being reinterpreted in the light of recent discoveries related to the histone code and the dynamic nature of epigenetic regulation and control of gene programs during development, as well as insights gained from whole cancer genome sequencing. Somatic mutations in or deregulated expression of genes that encode chromatin-modifying enzymes are being identified with high frequency. Nowhere is this more relevant than in pediatric embryonal solid tumors. A picture is emerging that shows that classic genetic alterations associated with these tumors ultimately converge on the epigenome to dysregulate developmental programs. In this review, we relate how alterations in components of the transcriptional machinery and chromatin modifier genes contribute to the initiation and progression of pediatric solid tumors. We also discuss how dramatic progress in our understanding of the fundamental mechanisms that contribute to epigenetic deregulation in cancer is providing novel avenues for targeted cancer therapy. Clin Cancer Res; 18(10); 2768-79. (C)2012 AACR. C1 [Lawlor, Elizabeth R.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Lawlor, Elizabeth R.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Thiele, Carol J.] Natl Canc Inst, Pediatr Oncol Branch, Natl Inst Hlth, Bethesda, MD USA. RP Lawlor, ER (reprint author), 1150 W Med Ctr Dr,MSRBIII 1200, Ann Arbor, MI 48109 USA. EM elawlor@umich.edu FU Entertainment Industry Foundation [AACR-SU2C-IRB-1309]; Department of Pediatrics, University of Michigan; National Institutes of Health [R01-CA134604]; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX E.R. Lawlor was supported by a Stand Up To Cancer Innovative Research Grant, a program of the Entertainment Industry Foundation (AACR-SU2C-IRB-1309); the Russell G. Adderley Endowment, Department of Pediatrics, University of Michigan; and the National Institutes of Health (R01-CA134604). C.J. Thiele was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 105 TC 30 Z9 32 U1 0 U2 6 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 MAY 15 PY 2012 VL 18 IS 10 BP 2768 EP 2779 DI 10.1158/1078-0432.CCR-11-1921 PG 12 WC Oncology SC Oncology GA 945CG UT WOS:000304249800007 PM 22589485 ER PT J AU Lee, DW Barrett, DM Mackall, C Orentas, R Grupp, SA AF Lee, Daniel W. Barrett, David M. Mackall, Crystal Orentas, Rimas Grupp, Stephan A. TI The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CD8(+) T-CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; IN-VIVO PERSISTENCE; ADOPTIVE IMMUNOTHERAPY; METASTATIC MELANOMA; ANTITUMOR-ACTIVITY; RETROVIRAL TRANSDUCTION; CELLULAR IMMUNOTHERAPY; CD28 COSTIMULATION; ENHANCED SURVIVAL AB Improved outcomes for children with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, gene therapy, and cell-processing technologies have paved the way for clinical applications of chimeric antigen receptor-based therapies. This is a new form of targeted immunotherapy that merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity, potential for expansion, and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B-cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. In pediatric oncology, CD19 and GD2 are compelling antigens that have already been identified for targeting pre-B acute lymphoblastic leukemia and neuroblastoma, respectively, with this approach, but it is likely that other antigens expressed in a variety of childhood cancers will also soon be targeted using this therapy. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of childhood cancer. Clin Cancer Res; 18(10); 2780-90. (C)2012 AACR. C1 [Lee, Daniel W.; Mackall, Crystal; Orentas, Rimas] Natl Canc Inst, Pediat Oncol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Barrett, David M.; Grupp, Stephan A.] Childrens Hosp Philadelphia, Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA. [Barrett, David M.; Grupp, Stephan A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Mackall, C (reprint author), Natl Canc Inst, Pediat Oncol Branch, Natl Inst Hlth, Bldg 10-CRC 1W-3750,10 Ctr Dr,MSC 1104, Bethesda, MD 20892 USA. EM cm35c@nih.gov FU NCI NIH HHS [P30 CA016520] NR 86 TC 48 Z9 53 U1 3 U2 21 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 MAY 15 PY 2012 VL 18 IS 10 BP 2780 EP 2790 DI 10.1158/1078-0432.CCR-11-1920 PG 11 WC Oncology SC Oncology GA 945CG UT WOS:000304249800008 PM 22589486 ER PT J AU Burnichon, N Cascon, A Schiavi, F Morales, NP Comino-Mendez, I Abermil, N Inglada-Perez, L de Cubas, AA Amar, L Barontini, M de Quiros, SB Bertherat, J Bignon, YJ Blok, MJ Bobisse, S Borrego, S Castellano, M Chanson, P Chiara, MD Corssmit, EPM Giacche, M de Krijger, RR Ercolino, T Girerd, X Gomez-Garcia, EB Gomez-Grana, A Guilhem, I Hes, FJ Honrado, E Korpershoek, E Lenders, JWM Leton, R Mensenkamp, AR Merlo, A Mori, L Murat, A Pierre, P Plouin, PF Prodanov, T Quesada-Chameco, M Qin, N Rapizzi, E Raymond, V Reisch, N Roncador, G Ruiz-Ferrer, M Schillo, F Stegmann, APA Suarez, C Taschin, E Timmers, HJLM Tops, CMJ Urioste, M Beuschlein, F Pacak, K Mannelli, M Dahia, PLM Opocher, G Eisenhofer, G Gimenez-Roqueplo, AP Robledo, M AF Burnichon, Nelly Cascon, Alberto Schiavi, Francesca Morales, Nicole Paes Comino-Mendez, Inaki Abermil, Nassera Inglada-Perez, Lucia de Cubas, Aguirre A. Amar, Laurence Barontini, Marta de Quiros, Sandra Bernaldo Bertherat, Jerome Bignon, Yves-Jean Blok, Marinus J. Bobisse, Sara Borrego, Salud Castellano, Maurizio Chanson, Philippe Chiara, Maria-Dolores Corssmit, Eleonora P. M. Giacche, Mara de Krijger, Ronald R. Ercolino, Tonino Girerd, Xavier Gomez-Garcia, Encarna B. Gomez-Grana, Alvaro Guilhem, Isabelle Hes, Frederik J. Honrado, Emiliano Korpershoek, Esther Lenders, Jacques W. M. Leton, Rocio Mensenkamp, Arjen R. Merlo, Anna Mori, Luigi Murat, Arnaud Pierre, Peggy Plouin, Pierre-Francois Prodanov, Tamara Quesada-Chameco, Miguel Qin, Nan Rapizzi, Elena Raymond, Victoria Reisch, Nicole Roncador, Giovanna Ruiz-Ferrer, Macarena Schillo, Frank Stegmann, Alexander P. A. Suarez, Carlos Taschin, Elisa Timmers, Henri J. L. M. Tops, Carli M. J. Urioste, Miguel Beuschlein, Felix Pacak, Karel Mannelli, Massimo Dahia, Patricia L. M. Opocher, Giuseppe Eisenhofer, Graeme Gimenez-Roqueplo, Anne-Paule Robledo, Mercedes TI MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; GERM-LINE MUTATIONS; SUCCINATE-DEHYDROGENASE; FAMILIAL PHEOCHROMOCYTOMA; LINDAU DISEASE; SDHB; SUSCEPTIBILITY; CANCER; DNA AB Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients. Clin Cancer Res; 18(10); 2828-37. (C)2012 AACR. C1 [Robledo, Mercedes] CNIO, Ctr Nacl Invest Oncol, Human Canc Genet Programme, Hereditary Endocrine Canc Grp, Madrid 28029, Spain. [Burnichon, Nelly; Abermil, Nassera; Gimenez-Roqueplo, Anne-Paule] Assistance Publ Hop Paris, Hop Europeen Georges Pompidou, Serv Genet, Paris, France. [Burnichon, Nelly; Abermil, Nassera; Amar, Laurence; Bertherat, Jerome; Plouin, Pierre-Francois; Gimenez-Roqueplo, Anne-Paule] Univ Paris 05, Sorbonne Paris Cite, Fac Med, Paris, France. [Burnichon, Nelly; Abermil, Nassera; Amar, Laurence; Plouin, Pierre-Francois; Gimenez-Roqueplo, Anne-Paule] INSERM, UMR970, Paris Cardiovasc Res Ctr, Paris, France. [Amar, Laurence; Plouin, Pierre-Francois] Assistance Publ Hop Paris, Hop Europeen Georges Pompidou, Serv Med vasc & Hypertens arterielle, Paris, France. [Bertherat, Jerome] Inst Cochin, INSERM, U1016, CNRS,UMR 8104, Paris, France. [Chanson, Philippe] Assistance Publ Hop Paris, Opital Bictr Endocrinol, Paris, France. [Girerd, Xavier] Assistance Publ Hop Paris, Grp Hosp Pitie Salpetriere, Unite Prevent Cardiovasc, Pole Endocrinol, Paris, France. [Cascon, Alberto; Comino-Mendez, Inaki; Inglada-Perez, Lucia; de Cubas, Aguirre A.; Gomez-Grana, Alvaro; Leton, Rocio; Robledo, Mercedes] Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Madrid, Spain. [Roncador, Giovanna] Spanish Natl Canc Res Ctr CNIO, Monoclonal Antibodies Unit, Madrid, Spain. [Urioste, Miguel] Spanish Natl Canc Res Ctr CNIO, Human Genet Canc Grp, Madrid, Spain. [Schiavi, Francesca; Bobisse, Sara] Univ Padua, Veneto Inst Oncol, Familial Canc Clin & Oncoendocrinol, IRCCS, Padua, Italy. [Opocher, Giuseppe] Univ Padua, Dept Med & Surg Sci, Padua, Italy. [Morales, Nicole Paes; Dahia, Patricia L. M.] Univ Texas Hlth Sci Ctr, Dept Med, San Antonio, TX USA. [Dahia, Patricia L. M.] Univ Texas Hlth Sci Ctr, Canc Therapy & Res Ctr, San Antonio, TX USA. [Barontini, Marta] Hosp Ninos Dr Ricardo Gutierrez, Ctr Endocrinol Invest CEDIE, Buenos Aires, DF, Argentina. [de Quiros, Sandra Bernaldo; Merlo, Anna] Hosp Univ Cent Asturias, Inst Univ Oncol Principado Asturias, Othorhinolaryngol Serv, Oviedo, Spain. [Bignon, Yves-Jean] Ctr Jean Perrin, Oncogenet Dept, Clermont Ferrand, France. [Blok, Marinus J.; Gomez-Garcia, Encarna B.; Stegmann, Alexander P. A.] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Borrego, Salud] Univ Seville, Hosp Univ Virgen Rocio, CSIC, Inst Biomed Sevilla,Unidad Gestion Clin Genet Rep, Seville, Spain. [Castellano, Maurizio; Giacche, Mara] Univ Brescia, Med Clin, Endocrine & Metab Dis Unit, Brescia, Italy. [Castellano, Maurizio; Giacche, Mara] Univ Brescia, Spedali Civili Brescia, Mol Med Lab, Brescia, Italy. [Corssmit, Eleonora P. M.] Leiden Univ, Med Ctr, Dept Endocrinol, Leiden, Netherlands. [Hes, Frederik J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [de Krijger, Ronald R.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Pathol, Rotterdam, Netherlands. [Rapizzi, Elena; Mannelli, Massimo] Univ Florence, Dept Clin Physiopathol, I-50121 Florence, Italy. [Mannelli, Massimo] Ist Toscano Tumori, Florence, Italy. [Guilhem, Isabelle] Ctr Hosp Rennes, Endocrinol Unit, Rennes, France. [Honrado, Emiliano] Hosp Leon, Anat Pathol Serv, Leon, Spain. [Lenders, Jacques W. M.; Mensenkamp, Arjen R.; Timmers, Henri J. L. M.] Radboud Univ Nijmegen Med Ctr, Nijmegen, Netherlands. [Murat, Arnaud] Hop Laennec, Endocrinol Unit, Nantes, France. [Pierre, Peggy] Ctr Hosp Regional Univ Bretonneau, Endocrinol Unit, Tours, France. [Pacak, Karel] Natl Inst Child Hlth & Human Dev, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. [Prodanov, Tamara] Natl Inst Child Hlth & Human Dev, Program Reprod & Adult crinol, NIH, Bethesda, MD USA. [Quesada-Chameco, Miguel] Hosp Clin Univ San Cecilio, Endocrinol Serv, Granada, Spain. [Qin, Nan; Eisenhofer, Graeme] Univ Hosp Dresden, Inst Clin Chem & Lab Med, Dresden, Germany. [Qin, Nan; Eisenhofer, Graeme] Univ Hosp Dresden, Dept Med, Dresden, Germany. [Raymond, Victoria] Univ Michigan, Div Mol Med & Genet, Ann Arbor, MI 48109 USA. [Reisch, Nicole; Beuschlein, Felix] Klin LMU, Med Klin Campus Innenstadt, Endocrine Res Unit, Munich, Germany. [Schillo, Frank] Univ Besancon, Ctr Hosp, Endocrinol Unit, F-25030 Besancon, France. RP Robledo, M (reprint author), CNIO, Ctr Nacl Invest Oncol, Human Canc Genet Programme, Hereditary Endocrine Canc Grp, Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM mrobledo@cnio.es RI elisa, taschin/K-3847-2016; IBIS, REPRODUCCION/P-3399-2015; Castellano, Maurizio/C-1096-2011; Chanson, Philippe/F-8511-2013; Opocher, Giuseppe/F-3950-2014; Cascon, Alberto/G-3160-2014; IBIS, GENETICA/P-3384-2015; Borrego, Salud/M-6314-2015; Mensenkamp, A.R./L-4520-2015; Robledo, Mercedes/O-2230-2013; Roncador, Giovanna /L-1764-2014; inglada-perez, lucia/H-5378-2015; Lenders, J.W.M./L-4487-2015; Ruiz-Ferrer, Macarena/M-6168-2015 OI schiavi, francesca/0000-0001-8529-4455; elisa, taschin/0000-0001-9426-4071; Mannelli, Massimo/0000-0002-8001-9857; Beuschlein, Felix/0000-0001-7826-3984; Castellano, Maurizio/0000-0002-4569-2659; Opocher, Giuseppe/0000-0002-9845-9623; Cascon, Alberto/0000-0003-2119-891X; Robledo, Mercedes/0000-0001-6256-5902; INGLADA, LUCIA/0000-0001-9523-2717; Roncador, Giovanna /0000-0002-9807-2875; FU European Union (ENS@T-CANCER) [HEALTH-F2-2010-259735]; European Science Foundation (ESF-ENS@T); Fondo de Investigaciones Sanitarias [PI11/01359, PS09/00942, PI10/01290, PI08/0531, P108/0883]; Mutua Madrilena [AP2775/2008]; Consejeria de Innovacion Ciencia y Empresa de la Junta de Andalucia [CTS-2590]; Red Tematica de Investigacion Cooperativa en Cancer [RD06/0020/0034]; Programme Hospitalier de Recherche Clinique grant COMETE 3 [AOM 06 179]; INSERM; Ministere Delegue a la Recherche et des Nouvelles Technologies; Institut National du Cancer; Agence Nationale de la Recherche (ANR) [08 GENOPATH 029 MitOxy]; national program "Cartes d'Identite des Tumeurs"; "Ligue Nationale contre le Cancer"; NIH, NICHD; Voelcker Fund; Fondazione Comunita Bresciana; Fondazione Guido Berlucchi FX The ENS@T consortium received funding from the European Union Seventh Framework Programme (ENS@T-CANCER; HEALTH-F2-2010-259735). The ENS@T registry is supported by a grant of the European Science Foundation (ESF-ENS@T).; This work was supported in part by the Fondo de Investigaciones Sanitarias (projects PI11/01359, PS09/00942, PI10/01290, PI08/0531 and P108/0883), Mutua Madrilena (AP2775/2008), Consejeria de Innovacion Ciencia y Empresa de la Junta de Andalucia (CTS-2590), Red Tematica de Investigacion Cooperativa en Cancer (RD06/0020/0034).; The French COMETE network is supported in part by the Programme Hospitalier de Recherche Clinique grant COMETE 3(AOM 06 179), by grants from INSERM and Ministere Delegue a la Recherche et des Nouvelles Technologies and by the Institut National du Cancer.; This work was also funded by grants from the Agence Nationale de la Recherche (ANR 08 GENOPATH 029 MitOxy) and by the national program "Cartes d'Identite des Tumeurs" funded and developed by the "Ligue Nationale contre le Cancer" (http://cit.ligue-cancer.net).; This research was supported, in part, by the Intramural Research Program of the NIH, NICHD.; This work received funding support from the Voelcker Fund to P. L. M. Dahia.; This work was also supported in part by grants from the Fondazione Comunita Bresciana and the Fondazione Guido Berlucchi. NR 34 TC 89 Z9 92 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY 15 PY 2012 VL 18 IS 10 BP 2828 EP 2837 DI 10.1158/1078-0432.CCR-12-0160 PG 10 WC Oncology SC Oncology GA 945CG UT WOS:000304249800013 PM 22452945 ER PT J AU LoRusso, PM Venkatakrishnan, K Ramanathan, RK Sarantopoulos, J Mulkerin, D Shibata, SI Hamilton, A Dowlati, A Mani, S Rudek, MA Takimoto, CH Neuwirth, R Esseltine, DL Ivy, P AF LoRusso, Patricia M. Venkatakrishnan, Karthik Ramanathan, Ramesh K. Sarantopoulos, John Mulkerin, Daniel Shibata, Stephen I. Hamilton, Anne Dowlati, Afshin Mani, Sridhar Rudek, Michelle A. Takimoto, Chris H. Neuwirth, Rachel Esseltine, Dixie-Lee Ivy, Percy TI Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase I NCI Organ Dysfunction Working Group Study NCI-6432 SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; ADVANCED SOLID TUMORS; RELAPSED MULTIPLE-MYELOMA; ADULT CANCER-PATIENTS; CELL LUNG-CANCER; MULTICENTER; LYMPHOMA; TRIAL; METABOLISM; PS-341 AB Purpose: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Experimental Design: Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m(2) standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m(2), respectively, up to a 1.3 mg/m(2) maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results: Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC(0-tlast)) or C-max compared with patients with normal function. Mean dose-normalized AUC(0-tlast) was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions: Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m(2). Clin Cancer Res; 18(10); 2954-63. (C)2012 AACR. C1 [LoRusso, Patricia M.] Karmanos Canc Inst, Detroit, MI 48201 USA. [Venkatakrishnan, Karthik] Millennium Pharmaceut Inc, Clin Pharmacol, Cambridge, MA USA. [Neuwirth, Rachel] Millennium Pharmaceut Inc, Biostatist, Cambridge, MA USA. [Esseltine, Dixie-Lee] Millennium Pharmaceut Inc, Clin Res, Cambridge, MA USA. [Ramanathan, Ramesh K.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Sarantopoulos, John; Takimoto, Chris H.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Inst Drug Dev, San Antonio, TX 78229 USA. [Mulkerin, Daniel] Univ Wisconsin, Paul P Carbone Comprehens Canc Ctr, Madison, WI USA. [Shibata, Stephen I.] City Hope Comprehens Canc Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA USA. [Hamilton, Anne] Univ Sydney, Royal Prince Alfred Hosp, Sydney Canc Ctr, Sydney, NSW 2006, Australia. [Dowlati, Afshin] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Mani, Sridhar] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. [Rudek, Michelle A.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Ivy, Percy] Natl Canc Inst, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Invest Drug Branch, Bethesda, MD USA. RP LoRusso, PM (reprint author), Barbara Ann Karmanos Canc Inst, Detroit, MI 48201 USA. EM lorussop@karmanos.org; karthik.venkatakrishnan@mpi.com FU Millennium Pharmaceuticals, Inc.; NIH [U01-CA062487, U01-CA099168, U01-CA70095, U01-CA069853, U01-CA062505, U01-C 062491]; Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, TX: Cancer Center [P30CA054174]; Johns Hopkins University Cancer Center [P30 CA006973]; Janssen Global Services FX The authors thank the patients and their caregivers for their participation in this study; Michael Bargfrede for his contributions to coordination of bortezomib bioanalyses and bioanalytical data management; the writing assistance of Steve Hill and Sunethra Wimalasundera of FireKite, which is funded by Millennium Pharmaceuticals, Inc., during the development of this publication; and Janssen Global Services.; The study was supported by NIH grants nos: U01-CA062487 (Karmanos Cancer Institute, Detroit, MI); U01-CA099168 (University of Pittsburgh, Pittsburgh, PA); U01-CA70095 (Johns Hopkins University, Baltimore, MD); U01-CA069853 (Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, TX); U01-CA062505 (City of Hope, Duarte, CA); and U01-C 062491 (University of Wisconsin Paul P Carbone Comprehensive Cancer Center, Madison, WI). The study was also supported by the Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, TX: Cancer Center Support Grant P30CA054174; Johns Hopkins University Cancer Center Core Grant Support P30 CA006973. NR 37 TC 23 Z9 23 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 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY 15 PY 2012 VL 18 IS 10 BP 2954 EP 2963 DI 10.1158/1078-0432.CCR-11-2873 PG 10 WC Oncology SC Oncology GA 945CG UT WOS:000304249800025 PM 22394984 ER PT J AU Afonso, PV Janka-Junttila, M Lee, YJ McCann, CP Oliver, CM Aamer, KA Losert, W Cicerone, MT Parent, CA AF Afonso, Philippe V. Janka-Junttila, Mirkka Lee, Young Jong McCann, Colin P. Oliver, Charlotte M. Aamer, Khaled A. Losert, Wolfgang Cicerone, Marcus T. Parent, Carole A. TI LTB4 Is a Signal-Relay Molecule during Neutrophil Chemotaxis SO DEVELOPMENTAL CELL LA English DT Article ID INFL AMMATORY ARTHRITIS; LEUKOTRIENE B-4; POLYMORPHONUCLEAR LEUKOCYTES; ADENYLYL-CYCLASE; MIGRATION; RECEPTORS; 5-LIPOXYGENASE; ACTIVATION; FMLP; ADHESION AB Neutrophil recruitment to inflammation sites purportedly depends on sequential waves of chemoattractants. Current models propose that leukotriene B-4 (LTB4), a secondary chemoattractant secreted by neutrophils in response to primary chemoattractants such as formyl peptides, is important in initiating the inflammation process. In this study we demonstrate that LTB4 plays a central role in neutrophil activation and migration to formyl peptides. We show that LTB4 production dramatically amplifies formyl peptide-mediated neutrophil polarization and chemotaxis by regulating specific signaling pathways acting upstream of actin polymerization and Myoll phosphorylation. Importantly, by analyzing the migration of neutrophils isolated from wildtype mice and mice lacking the formyl peptide receptor 1, we demonstrate that LTB4 acts as a signal to relay information from cell to cell over long distances. Together, our findings imply that LTB4 is a signal-relay molecule that exquisitely regulates neutrophil chemotaxis to formyl peptides, which are produced at the core of inflammation sites. C1 [Afonso, Philippe V.; Janka-Junttila, Mirkka; McCann, Colin P.; Oliver, Charlotte M.; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Young Jong; Aamer, Khaled A.; Cicerone, Marcus T.] NIST, Div Polymers, Gaithersburg, MD 20899 USA. [McCann, Colin P.; Losert, Wolfgang] Univ Maryland, Dept Phys, Inst Res Elect & Appl Phys, College Pk, MD 20742 USA. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov RI Lee, Young Jong/B-7129-2008; Afonso, Philippe/D-2234-2014 OI Lee, Young Jong/0000-0001-7754-3001; Afonso, Philippe/0000-0002-4828-3797 FU Center for Cancer Research, NCI, National Institutes of Health Center for Cancer Research FX We thank Amy Melpolder and the NIH Blood Bank for providing human blood from healthy volunteers. We are grateful to Dr. Philip Murphy for providing fpr1-/- mice and, in particular, to Dr. Jiliang Gao for his help with the mice. We wish to thank Drs. Ronald Germain and Tim Lammermann for providing the blt1-/- mice. We also thank the C.A.P. laboratory members for excellent discussions and suggestions and for valuable input on the manuscript. W.L. participated in this work while on sabbatical at the LCMB, CCR. This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health. Official contribution of the National Institute of Standards and Technology; not subject to copyright in the United States. Certain commercial equipment, instruments, or materials are identified in this paper in order to specify the experimental procedure adequately. Such identification is not intended to imply recommendation or endorsement by the National Institute of Standards and Technology, nor is it intended to imply that the materials or equipment identified are necessarily the best available for the purpose. NR 67 TC 67 Z9 67 U1 2 U2 12 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 MAY 15 PY 2012 VL 22 IS 5 BP 1079 EP 1091 DI 10.1016/j.devcel.2012.02.003 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 945QS UT WOS:000304291700019 PM 22542839 ER PT J AU Ullah, Z DePamphilis, M AF Ullah, Zakir DePamphilis, Melvin TI Checkpoint kinase-1: One actor playing two roles in "maintaining genomic integrity" SO CELL CYCLE LA English DT News Item ID GIANT-CELLS; CHK1; DIFFERENTIATION; P53 C1 [Ullah, Zakir] Lahore Univ Management Sci, Sch Sci & Engn, Dept Biol, Lahore, Pakistan. [DePamphilis, Melvin] NICHHD, NIH, Bethesda, MD 20892 USA. RP Ullah, Z (reprint author), Lahore Univ Management Sci, Sch Sci & Engn, Dept Biol, Lahore, Pakistan. EM zakirullah@lums.edu.pk; depamphm@mail.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 15 PY 2012 VL 11 IS 10 BP 1873 EP 1874 DI 10.4161/cc.20509 PG 2 WC Cell Biology SC Cell Biology GA 942JJ UT WOS:000304039900007 PM 22580458 ER PT J AU Goloudina, AR Mazur, SJ Appella, E Garrido, C Demidov, ON AF Goloudina, Anastasia R. Mazur, Sharlyn J. Appella, Ettore Garrido, Carmen Demidov, Oleg N. TI Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-x(L) ratio SO CELL CYCLE LA English DT Article DE Wip1; p53-negative; Bax; Bcl-x(L); cisplatin; NF kappa B; phosphatase; Runx2 ID NF-KAPPA-B; DNA-DAMAGE RESPONSE; DRUG DEVELOPMENT; GENE-EXPRESSION; CELL-DEATH; P53; PHOSPHATASE; CHK1; BAX; PHOSPHORYLATION AB Wip1 is a stress-response phosphatase that negatively regulates several tumor suppressors, including p53. In a sizeable fraction of tumors, overexpression or amplification of Wip1 compromises p53 functions; inhibition of Wip1 activity is an attractive strategy for improving treatment of these tumors. However, over half of human tumors contain mutations in the p53 gene or have lost both alleles. Recently, we observed that in cancer cells lacking wild-type p53, reduction of Wip1 expression was ineffective, whereas, surprisingly, overexpression of Wip1 increased anticancer drug sensitivity. The increased sensitivity resulted from activation of the intrinsic pathway of apoptosis through increased levels of the pro-apoptotic protein Bax and decreased levels of the anti-apoptotic protein Bcl-x(L). We showed that interaction of Wip1 and the transcription factor RUNX2, specifically through dephosphorylation of RUNX2 phospho-S432, resulted in increased expression of Bax. Interestingly, overexpression of Wip1 increased drug sensitivity only in the p53-negative tumor cells while protecting the wild-type, p53-containing normal cells from drug-induced collateral injury. Here, we provide evidence that Wip1 overexpression decreases expression of Bcl-x(L) through negative regulation of NF kappa B activity. Thus, Wip1 overexpression increases the sensitivity of p53-negative cancer cells to anticancer drugs by separately affecting Bax and Bcl-x(L) protein levels. C1 [Goloudina, Anastasia R.; Garrido, Carmen; Demidov, Oleg N.] Univ Burgundy, INSERM, Unite Mixte Rech 866, Dijon, France. [Mazur, Sharlyn J.; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Garrido, Carmen; Demidov, Oleg N.] Univ Burgundy, Fac Med & Pharm, Dijon, France. [Garrido, Carmen] Ctr Hosp Univ Dijon, Dijon, France. RP Demidov, ON (reprint author), Univ Burgundy, INSERM, Unite Mixte Rech 866, Dijon, France. EM Oleg.Demidov@u-bourgogne.fr OI Demidov, Oleg/0000-0003-4323-7174 FU Ligue Contre le Cancer Interregionale du Grand Est; Conseil Regional de Bourgogne; C. Garrido group, "La Ligue Contre le Cancer"; National Cancer Institute, National Institutes of Health FX This work was supported by the "Ligue Contre le Cancer Interregionale du Grand Est," the "Conseil Regional de Bourgogne," C. Garrido group has the label "La Ligue Contre le Cancer." This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 44 TC 19 Z9 21 U1 0 U2 12 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 15 PY 2012 VL 11 IS 10 BP 1883 EP 1887 DI 10.4161/cc.19901 PG 5 WC Cell Biology SC Cell Biology GA 942JJ UT WOS:000304039900012 PM 22544321 ER PT J AU Zhou, H Thompson, WW Viboud, CG Ringholz, CM Cheng, PY Steiner, C Abedi, GR Anderson, LJ Brammer, L Shay, DK AF Zhou, Hong Thompson, William W. Viboud, Cecile G. Ringholz, Corinne M. Cheng, Po-Yung Steiner, Claudia Abedi, Glen R. Anderson, Larry J. Brammer, Lynnette Shay, David K. TI Hospitalizations Associated With Influenza and Respiratory Syncytial Virus in the United States, 1993-2008 SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID YOUNG-CHILDREN; POPULATION; EPIDEMICS; MORTALITY; BURDEN; IMPACT; SURVEILLANCE; INFECTION; INFANTS; DISEASE AB Background. Age-specific comparisons of influenza and respiratory syncytial virus (RSV) hospitalization rates can inform prevention efforts, including vaccine development plans. Previous US studies have not estimated jointly the burden of these viruses using similar data sources and over many seasons. Methods. We estimated influenza and RSV hospitalizations in 5 age categories (<1, 1-4, 5-49, 50-64, and >= 65 years) with data for 13 states from 1993-1994 through 2007-2008. For each state and age group, we estimated the contribution of influenza and RSV to hospitalizations for respiratory and circulatory disease by using negative binomial regression models that incorporated weekly influenza and RSV surveillance data as covariates. Results. Mean rates of influenza and RSV hospitalizations were 63.5 (95% confidence interval [CI], 37.5-237) and 55.3 (95% CI, 44.4-107) per 100 000 person-years, respectively. The highest hospitalization rates for influenza were among persons aged >= 65 years (309/100 000; 95% CI, 186-1100) and those aged,1 year (151/100 000; 95% CI, 151-660). For RSV, children aged,1 year had the highest hospitalization rate (2350/100 000; 95% CI, 2220-2520) followed by those aged 1-4 years (178/100 000; 95% CI, 155-230). Age-standardized annual rates per 100 000 person-years varied substantially for influenza (33-100) but less for RSV (42-77). Conclusions. Overall US hospitalization rates for influenza and RSV are similar; however, their age-specific burdens differ dramatically. Our estimates are consistent with those from previous studies focusing either on influenza or RSV. Our approach provides robust national comparisons of hospitalizations associated with these 2 viral respiratory pathogens by age group and over time. C1 [Zhou, Hong; Cheng, Po-Yung; Brammer, Lynnette; Shay, David K.] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA 30333 USA. [Abedi, Glen R.; Anderson, Larry J.] Ctr Dis Control & Prevent, Div Viral Dis, Atlanta, GA 30333 USA. [Thompson, William W.] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Anderson, Larry J.] Emory Univ, Div Pediat Infect Dis, Atlanta, GA 30322 USA. [Viboud, Cecile G.; Ringholz, Corinne M.] Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD USA. [Steiner, Claudia] Agcy Healthcare Res & Qual, Rockville, MD USA. [Ringholz, Corinne M.] Analyt Serv Inc, Arlington, VA USA. RP Shay, DK (reprint author), Ctr Dis Control & Prevent, Influenza Div, 1600 Clifton Rd NE,MS A-20, Atlanta, GA 30333 USA. EM dshay@cdc.gov OI Shay, David/0000-0001-9619-4820 FU Centers for Disease Control and Prevention; National Institutes of Health; Agency for Healthcare Research and Quality; Medimmune; Novartis Vaccines; Trellis Bioscience FX This work was supported by internal funds from the Centers for Disease Control and Prevention, the National Institutes of Health, and the Agency for Healthcare Research and Quality.; Dr. Anderson has received consulting fees from Medimmune and Novartis Vaccines, grants from Trellis Bioscience, and travel expenses from Medimmune. All other authors have no conflicts to report. NR 31 TC 167 Z9 169 U1 2 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2012 VL 54 IS 10 BP 1427 EP 1436 DI 10.1093/cid/cis211 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 942MW UT WOS:000304049300013 PM 22495079 ER PT J AU Sassi, M Ripamonti, C Mueller, NJ Yazaki, H Kutty, G Ma, L Huber, C Gogineni, E Oka, S Goto, N Fehr, T Gianella, S Konrad, R Sing, A Kovacs, JA AF Sassi, Monica Ripamonti, Chiara Mueller, Nicolas J. Yazaki, Hirohisa Kutty, Geetha Ma, Liang Huber, Charles Gogineni, Emile Oka, Shinichi Goto, Norihiko Fehr, Thomas Gianella, Sara Konrad, Regina Sing, Andreas Kovacs, Joseph A. TI Outbreaks of Pneumocystis Pneumonia in 2 Renal Transplant Centers Linked to a Single Strain of Pneumocystis: Implications for Transmission and Virulence SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID JIROVECII PNEUMONIA; INTERHUMAN TRANSMISSION; MOLECULAR EVIDENCE; RECIPIENTS; CARINII; INFECTION; CLUSTER; FREQUENCY; DIAGNOSIS; HOMINIS AB Background. There have been numerous reports of clustered outbreaks of Pneumocystis pneumonia (PCP) at renal transplant centers over the past 2 decades. It has been unclear whether these outbreaks were linked epidemiologically to 1 or several unique strains, which could have implications for transmission patterns or strain virulence. Methods. Restriction fragment length polymorphism (RFLP) analysis was used to compare Pneumocystis isolates from 3 outbreaks of PCP in renal transplant patients in Germany, Switzerland, and Japan, as well as nontransplant isolates from both human immunodeficiency virus (HIV)-infected and uninfected patients. Results. Based on RFLP analysis, a single Pneumocystis strain caused pneumonia in transplant patients in Switzerland (7 patients) and Germany (14 patients). This strain was different from the strain that caused an outbreak in transplant patients in Japan, as well as strains causing sporadic cases of PCP in nontransplant patients with or without HIV infection. Conclusions. Two geographically distinct clusters of PCP in Europe were due to a single strain of Pneumocystis. This suggests either enhanced virulence of this strain in transplant patients or a common, but unidentified, source of transmission. Outbreaks of PCP can be better understood by enhanced knowledge of transmission patterns and strain variation. C1 [Kovacs, Joseph A.] Natl Inst Hlth Clin Ctr, Natl Inst Hlth, Dept Crit Care Med, Bethesda, MD 20892 USA. [Huber, Charles] Natl Inst Hlth Clin Ctr, Dept Lab Med, Bethesda, MD USA. [Mueller, Nicolas J.; Gianella, Sara] Univ Zurich Hosp, Div Infect Dis, Zurich, Switzerland. [Mueller, Nicolas J.; Gianella, Sara] Univ Zurich Hosp, Hosp Epidemiol, Zurich, Switzerland. [Yazaki, Hirohisa; Oka, Shinichi] Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo, Japan. [Oka, Shinichi] Kumamoto Univ, Ctr AIDS Res, Div 9, Kumamoto 860, Japan. [Goto, Norihiko] Nagoya Daini Red Cross Hosp, Dept Transplant & Endocrine Surg, Nagoya, Aichi, Japan. [Fehr, Thomas] Univ Zurich Hosp, Div Nephrol, Zurich, Switzerland. [Konrad, Regina; Sing, Andreas] Bavarian Hlth & Food Safety Author Bavarian LGL, Oberschleissheim, Germany. RP Kovacs, JA (reprint author), Natl Inst Hlth Clin Ctr, Natl Inst Hlth, Dept Crit Care Med, Bldg 10,Room 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@mail.nih.gov RI Kumamoto University, CAIDS/G-8446-2013; Infektiologie, USZ/A-6921-2011; Mueller, Nicolas/B-6864-2013 OI Mueller, Nicolas/0000-0002-1059-3191 FU National Institutes of Health Clinical Center FX This research was supported in part by the Intramural Research Program of the National Institutes of Health Clinical Center. NR 24 TC 28 Z9 30 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2012 VL 54 IS 10 BP 1437 EP 1444 DI 10.1093/cid/cis217 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 942MW UT WOS:000304049300014 PM 22431811 ER PT J AU Yeetong, P Tongkobpetch, S Kingwatanakul, P Deekajorndech, T Bernardini, IM Suphapeetiporn, K Gahl, WA Shotelersuk, V AF Yeetong, Patra Tongkobpetch, Siraprapa Kingwatanakul, Pornchai Deekajorndech, Tawatchai Bernardini, Isa M. Suphapeetiporn, Kanya Gahl, William A. Shotelersuk, Vorasuk TI Two novel CTNS mutations in cystinosis patients in Thailand SO GENE LA English DT Article DE Cystinosis; CTNS; Novel mutations; Thai ID NEPHROPATHIC CYSTINOSIS; GENE AB Cystinosis is an autosomal recessive disorder characterized by defective transport of cystine across the lysosomal membrane and resulting in renal, ophthalmic, and other organ abnormalities. Mutations in the CTNS gene cause a deficiency of the transport protein, cystinosin. We performed mutation analysis of CTNS in six cystinosis patients from four families in Thailand. Using PCR sequencing of the entire coding regions, we identified all eight mutant alleles, including two mutations, p.G309D and p.Q284X, that have not been previously reported. This study expands the mutational and population spectrum of nephropathic cystinosis. (C) 2012 Elsevier B.V. All rights reserved. C1 [Suphapeetiporn, Kanya] King Chulalongkorn Mem Hosp, Div Med Genet & Metab, Dept Pediat, Excellence Ctr Med Genet, Bangkok 10330, Thailand. [Yeetong, Patra; Tongkobpetch, Siraprapa; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk] Chulalongkorn Univ, Fac Med, Dept Pediat, Ctr Excellence Med Genet, Bangkok 10330, Thailand. [Kingwatanakul, Pornchai; Deekajorndech, Tawatchai] Chulalongkorn Univ, Pediat Nephrol Div, Dept Pediat, Fac Med, Bangkok 10330, Thailand. [Yeetong, Patra] Chulalongkorn Univ, Fac Grad Sch, Interdept Program Biomed Sci, Bangkok 10330, Thailand. [Bernardini, Isa M.; Gahl, William A.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. RP Suphapeetiporn, K (reprint author), King Chulalongkorn Mem Hosp, Div Med Genet & Metab, Dept Pediat, Excellence Ctr Med Genet, Sor Kor Bldg,11th Floor, Bangkok 10330, Thailand. EM kanya.su@chula.ac.th FU Royal Golden jubilee Ph.D. Program [PHD/0022/2550]; 90th Anniversary of Chulalongkorn University Fund; National Science and Technology Development Agency; Thailand Research Fund; National Research University, Office of the Higher Education Commission [HR1163A] FX This study was supported by the Royal Golden jubilee Ph.D. Program to PY (Grant no. PHD/0022/2550), the 90th Anniversary of Chulalongkorn University Fund, the National Science and Technology Development Agency, the Thailand Research Fund, and the National Research University Project, Office of the Higher Education Commission (HR1163A). NR 9 TC 3 Z9 5 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 15 PY 2012 VL 499 IS 2 BP 323 EP 325 DI 10.1016/j.gene.2012.03.047 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 942EW UT WOS:000304026400014 PM 22450360 ER PT J AU Gopich, IV Szabo, A AF Gopich, Irina V. Szabo, Attila TI Theory of the energy transfer efficiency and fluorescence lifetime distribution in single-molecule FRET SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE connectivity of kinetic schemes; diffusion; recoloring; quenching ID STRUCTURAL HETEROGENEITIES; PHOTON DISTRIBUTION; DYNAMICS; SPECTROSCOPY; SYSTEMS AB In single-molecule FRET experiments with pulsed lasers, not only the colors of the photons but also the fluorescence lifetimes can be monitored. Although these quantities appear to be random, they are modulated by conformational dynamics. In order to extract information about such dynamics, we develop the theory of the joint distribution of FRET efficiencies and fluorescence lifetimes determined from bins (or bursts) of photons. Our starting point is a rigorous formal expression for the distribution of the numbers of donor and acceptor photons and donor lifetimes in a bin that treats the influence of conformational dynamics on all timescales. This formula leads to an analytic result for a two-state system interconverting on a timescale slower than the interphoton time and to an efficient simulation algorithm for multistate dynamics. The shape of the joint distribution contains more information about conformational dynamics than the FRET efficiency histogram alone. In favorable cases, the connectivity of the underlying conformational states can be determined directly by simple inspection of the projection of the joint distribution on the efficiency-lifetime plane. C1 [Gopich, Irina V.; Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gopich, IV (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM irinag@niddk.nih.gov; attilas@nih.gov RI Szabo, Attila/H-3867-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX The authors would like to thank H. S. Chung, W. A. Eaton, K. Truex, and the referees for helpful comments, and D. Doty, National Institutes of Health Library Writing Center, for helpful assistance with the manuscript. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 28 TC 36 Z9 39 U1 3 U2 56 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 MAY 15 PY 2012 VL 109 IS 20 BP 7747 EP 7752 DI 10.1073/pnas.1205120109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 946QW UT WOS:000304369800043 PM 22550169 ER PT J AU Kapetanovic, S Aaron, L Montepiedra, G Burchett, SK Kovacs, A AF Kapetanovic, Suad Aaron, Lisa Montepiedra, Grace Burchett, Sandra K. Kovacs, Andrea TI T-cell activation and neurodevelopmental outcomes in perinatally HIV-infected children SO AIDS LA English DT Article DE HIV-associated central nervous system disease; immune activation; neurodevelopmental outcomes; pediatric neuro-AIDS; perinatally HIV-infected children ID ACTIVE ANTIRETROVIRAL THERAPY; 3-COLOR FLOW-CYTOMETRY; LYMPHOCYTES; ENCEPHALOPATHY; PREDICTORS; EXPRESSION; DISEASE; YOUTH; DEMENTIA; MARKERS AB Objective: To evaluate baseline T-cell activation and neurodevelopmental outcomes over time in a cohort of perinatally HIV-infected (PHIV-infected) children with severe disease. Design: Pediatric AIDS Clinical Trials Group protocol 366 (PACTG 366) was a partially randomized, open-label, multicenter 96-week antiretroviral treatment-algorithm study. Neurodevelopmental status, measured by age-dependent evaluations (Bayley scales of infant development-II; Wechsler preschool and primary scale of intelligence-revised; Wechsler intelligence scale for children-III), was a secondary outcome. Methods: Linear mixed models were used to assess the baseline and follow-up neurodevelopmental outcomes in relation to immune activation, measured by CD38 and human leukocyte antigen (HLA) DR expression on peripheral CD4(+) and CD8(+) T cells at study baseline. Models were adjusted for age, sex, race/ethnicity, baseline viral load, baseline CD4%, cytomegalovirus (CMV) infection status at entry, study treatment arms, central nervous system penetrance score of antiretroviral regimen at entry, and viral load response 16 weeks postentry. Results: Among 126 PACTG 366 enrollees who were at least 1 year old and had both immune activation and age-appropriate neurodevelopmental assessments at baseline, 80 (63%) were black non-Hispanic, 71 (56%) males, 122 (97%) were on antiretrovirals, and 45 (36%) were in Centers for Disease Control and Prevention (CDC) disease category C at entry. CD4(+)CD38(+)HLADR(+)%, CD4(+)CD38(-)HLADR(+)%, and CD8(+)CD38(+)HLADR(+)% were positively associated with full-scale Intelligence Quotient scores (FSIQ) (slope = 0.18, 0.70, and 0.15, respectively; P = 0.02, 0.03, and 0.04, respectively). CD4(+)CD38(+)HLADR(-)% was negatively associated with FSIQ (slope = -0.16, P = 0.01). Conclusion: Contrary to HIV-infected adults, in PHIV-infected children higher CD4(+)CD38(+)HLADR(+)% may be associated with a neuroprotective effect and higher percentage of CD4(+)CD38(+) but HLADR(-) T cells may be deleterious. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Kapetanovic, Suad] NIMH, NIH, Bethesda, MD 20892 USA. [Aaron, Lisa; Montepiedra, Grace] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Burchett, Sandra K.] Harvard Univ, Childrens Hosp Boston, Sch Med, Boston, MA USA. [Kovacs, Andrea] Univ So Calif, Keck Sch Med, Maternal Child & Adolescent Ctr Infect Dis & Viro, Los Angeles, CA 90033 USA. RP Kapetanovic, S (reprint author), NIMH Off Clin Director, Bldg 10-CRC,Room 6-5340,10 Ctr Dr, Bethesda, MD 20892 USA. EM suad.kapetanovic@nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health under National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG); IMPAACT Group [1 U01 AI068616]; NICHD [N01-DK-9-001/HHSN267200800001C] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632). This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). NR 34 TC 7 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 15 PY 2012 VL 26 IS 8 BP 959 EP 969 DI 10.1097/QAD.0b013e328352cee7 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 937JY UT WOS:000303656000007 PM 22382148 ER PT J AU Irungu, E Chersich, MF Sanon, C Chege, R Gaillard, P Temmerman, M Read, JS Luchters, S AF Irungu, Eunice Chersich, Matthew F. Sanon, Clarisse Chege, Rosemary Gaillard, Philippe Temmerman, Marleen Read, Jennifer S. Luchters, Stanley CA Kesho Bora Study Grp TI Changes in sexual behaviour among HIV-infected women in west and east Africa in the first 24 months after delivery SO AIDS LA English DT Article DE condom use; HIV prevention; postpartum period; safe sex; sexual behaviour; sub-Saharan Africa ID TO-CHILD TRANSMISSION; SUB-SAHARAN AFRICA; SEROSTATUS DISCLOSURE; SOUTH-AFRICA; ANTIRETROVIRAL TREATMENT; PROSPECTIVE COHORT; POSTNATAL CARE; RISK BEHAVIOR; COITAL ACT; KENYA AB Objective: Describe changes in sexual behaviour and determinants of unsafe sex among HIV-infected women in the 24 months after delivery. Design: Cohort analysis nested within a prevention of mother-to-child transmission trial in Burkina Faso (n = 339) and Kenya (n = 432). Methods: Women were followed during pregnancy and until 12-24 months after delivery. At each visit, structured questionnaires were administered about sexual activity and condom use, and risk-reduction counselling and condoms were provided. Results: At study entry, a median 2 months after HIV testing (interquartile range = 1-4), 411/770 (53.4%) of women reported partner disclosure, increasing to 284/392 (71.9%) at the final visit. Although most partners were supportive following disclosure, between 5 and 10% of disclosed women experienced hostile or unsupportive partner responses during follow-up visits. At each visit, about a third of sexually active women reported unsafe sex (unprotected sex with HIV-uninfected or unknown status partner). In multi-variable logistic regression, unsafe sex was 1.70-fold more likely in Kenyan than in Burkinabe women [95% confidence interval (95% CI) = 1.14-2.54], and in those with less advanced HIV disease or aged 16-24 years. Compared with women who disclosed their status to partners and others, unsafe sex was over six-fold higher in nondisclosers (95% CI = 3.31-12.11), the effect size reducing with increasing disclosure. Conclusion: HIV-infected women who recently delivered have a high potential for further HIV transmission, especially as HIV discordance is common in Africa. Longitudinal care for women, including positive-prevention interventions, is needed within new services providing antiretroviral prophylaxis during breastfeeding - this repeated interface with services could focus on reducing unsafe sex. Much remains unknown about how to facilitate beneficial disclosure. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Chersich, Matthew F.; Temmerman, Marleen; Luchters, Stanley] Univ Ghent, Int Ctr Reprod Hlth, Dept Obstet & Gynaecol, B-9000 Ghent, Belgium. [Irungu, Eunice; Chege, Rosemary; Luchters, Stanley] Int Ctr Reprod Hlth, Mombasa, Kenya. [Chersich, Matthew F.] Univ Witwatersrand, Fac Hlth Sci, Sch Publ Hlth, Ctr Hlth Policy, Johannesburg, South Africa. [Sanon, Clarisse] Ctr Muraz, Bobo Dioulasso, Burkina Faso. [Gaillard, Philippe] WHO, Dept Reprod Hlth & Res, CH-1211 Geneva, Switzerland. [Read, Jennifer S.] CRMC NICHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. [Read, Jennifer S.] NVPO OASH OS DHHS, Washington, DC USA. [Luchters, Stanley] Burnet Inst, Ctr Int Hlth, Melbourne, Vic, Australia. RP Luchters, S (reprint author), Univ Ghent, Int Ctr Reprod Hlth, Dept Obstet & Gynaecol, De Pintelaan 185 P3, B-9000 Ghent, Belgium. EM stanley.luchters@ugent.be RI Van de Perre, Philippe/B-9692-2008; OI Van de Perre, Philippe/0000-0002-3912-0427; Bork, Kirsten/0000-0002-5909-7332; Njagi, Ephantus/0000-0002-1484-0241 FU l'Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS); UNDP/UNFPA/World Bank/WHO (WHO/HRP); ANRS; WHO/HRP; European and Developing Countries Clinical Trials Partnership (EDCTP); Thrasher Research Fund; Belgian Directorate General for International Cooperation; Centers for Disease Control and Prevention (CDC); Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NIH); Department for International Development (DFID); EDCTP; UNICEF FX The Bobo Dioulasso site was funded by l'Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS) and UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP).; The Mombasa site was funded by ANRS, WHO/HRP, European and Developing Countries Clinical Trials Partnership (EDCTP), Thrasher Research Fund, Belgian Directorate General for International Cooperation,; The Nairobi site was funded by the Centers for Disease Control and Prevention (CDC) and Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NIH) through a cooperative agreement.; The South African sites were funded by the Department for International Development (DFID), EDCTP, UNICEF and WHO/HRP. NR 59 TC 9 Z9 9 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 15 PY 2012 VL 26 IS 8 BP 997 EP 1007 DI 10.1097/QAD.0b013e3283524ca1 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 937JY UT WOS:000303656000011 PM 22343965 ER PT J AU Goedert, JJ AF Goedert, James J. TI HIV-associated lung cancer: ambiguities and challenges SO AIDS LA English DT Editorial Material DE HIV; lung cancer; risk ID HUMAN-IMMUNODEFICIENCY-VIRUS; UNITED-STATES; ANTIRETROVIRAL THERAPY; SMOKING-CESSATION; INFECTED PATIENTS; RISK; AIDS; PEOPLE; COHORT; POPULATION C1 [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Goedert, JJ (reprint author), NCI, Suite 7068,6120 Execut Blvd, Rockville, MD USA. EM goedertj@mail.nih.gov FU Intramural NIH HHS [Z01 CP010150-08] NR 31 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 15 PY 2012 VL 26 IS 8 BP 1031 EP 1033 DI 10.1097/QAD.0b013e3283522d94 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 937JY UT WOS:000303656000015 PM 22552477 ER PT J AU Zhu, XM Zhu, H Zhang, LL Huang, SX Cao, JJ Ma, G Feng, GY He, L Yang, YZ Guo, XZ AF Zhu, Xuming Zhu, Huang Zhang, Lingling Huang, Sixia Cao, Jingjing Ma, Gang Feng, Guoying He, Lin Yang, Yingzi Guo, Xizhi TI Wls-mediated Wnts differentially regulate distal limb patterning and tissue morphogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Wntless; Wnt; Limb; Patterning; Tissue morphogenesis; Tendon/ligament ID APICAL ECTODERMAL RIDGE; VERTEBRATE LIMB; BETA-CATENIN; FEEDBACK LOOP; SIGNALS; BUD; SECRETION; WNTLESS; MOUSE; PATHWAY AB Wnt proteins are diffusible morphogens that play multiple roles during vertebrate limb development. However, the complexity of Wnt signaling cascades and their overlapping expression prevent us from dissecting their function in limb patterning and tissue morphogenesis. Depletion of the Wntless (Wls) gene, which is required for the secretion of various Wnts, makes it possible to genetically dissect the overall effect of Wnts in limb development. In this study, the Wls gene was conditionally depleted in limb mesenchyme and ectoderm. The loss of mesenchymal Wls prevented the differentiation of distal mesenchyme and arrested limb outgrowth, most likely by affecting Wnt5a function. Meanwhile, the deletion of ectodermal Wls resulted in agenesis of distal limb tissue and premature regression of the distal mesenchyme. These observations suggested that Wnts from the two germ layers differentially regulate the pool of undifferentiated distal limb mesenchyme cells. Cellular behavior analysis revealed that ectodermal Wnts sustain mesenchymal cell proliferation and survival in a manner distinct from Fgf. Ectodermal Wnts were also shown for the first time to be essential for distal tendon/ligament induction, myoblast migration and dermis formation in the limb. These findings provide a comprehensive view of the role of Wnts in limb patterning and tissue morphogenesis. (C) 2012 Elsevier Inc. All rights reserved. C1 [Zhu, Xuming; He, Lin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Beijing 100864, Peoples R China. [Zhu, Xuming; He, Lin] Chinese Acad Sci, Grad Sch, Beijing 100864, Peoples R China. [Zhu, Xuming; Zhu, Huang; Zhang, Lingling; Huang, Sixia; Cao, Jingjing; Ma, Gang; Feng, Guoying; He, Lin; Guo, Xizhi] Shanghai Jiao Tong Univ, Key Lab Genet Dev & Neuropsychiat Disorders, Bio X Inst, Shanghai 200240, Peoples R China. [Yang, Yingzi] NHGRI, Dev Genet Sect, NIH, Bethesda, MD 20892 USA. RP Guo, XZ (reprint author), 800 Dongchuan Rd,Biomed Bldg 1-205, Shanghai 200240, Peoples R China. EM xzguo2005@sjtu.edu.cn FU National Major Fundamental Research 973 program of China [2007CB947301, 2012CB966903]; National Natural Science Foundation of China [31171396, 31100624]; Pujiang Talent [08PJ1407200] FX We thank Dr. Mark Lewandoski of the NIH/NCI for providing us with the Msx2-Cre mice. This work was supported by the National Major Fundamental Research 973 program of China under grant (2007CB947301 and 2012CB966903) and by grants from the National Natural Science Foundation of China (31171396 and 31100624) and Pujiang Talent (08PJ1407200). NR 45 TC 25 Z9 25 U1 2 U2 10 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 MAY 15 PY 2012 VL 365 IS 2 BP 328 EP 338 DI 10.1016/j.ydbio.2012.02.019 PG 11 WC Developmental Biology SC Developmental Biology GA 939DR UT WOS:000303788100002 PM 22377357 ER PT J AU Neilson, KM Klein, SL Mhaske, P Mood, K Daar, IO Moody, SA AF Neilson, Karen M. Klein, Steven L. Mhaske, Pallavi Mood, Kathy Daar, Ira O. Moody, Sally A. TI Specific domains of FoxD4/5 activate and repress neural transcription factor genes to control the progression of immature neural ectoderm to differentiating neural plate SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Neural induction; sox2; sox3; sox11; soxD; zic2; zic1; zic3; irx1; irx2; irx3; Transcription; foxD4; foxD4L1 ID SECONDARY STRUCTURE PREDICTION; COMPACTED CHROMATIN; XENOPUS DEVELOPMENT; INDUCTION; EXPRESSION; FAMILY; GEMININ; SOX11; FATE; FOX AB FoxD4/5, a forkhead transcription factor, plays a critical role in establishing and maintaining the embryonic neural ectoderm. It both up-regulates genes that maintain a proliferative, immature neural ectoderm and down-regulates genes that promote the transition to a differentiating neural plate. We constructed deletion and mutant versions of FoxD4/5 to determine which domains are functionally responsible for these opposite activities, which regulate the critical developmental transition of neural precursors to neural progenitors to differentiating neural plate cells. Our results show that up-regulation of genes that maintain immature neural precursors (gem, zic2) requires the Acidic blob (AB) region in the N-terminal portion of the protein, indicating that the AB is the transactivating domain. Additionally, down-regulation of those genes that promote the transition to neural progenitors (sox) and those that lead to neural differentiation (zic, irx) involves: 1) an interaction with the Groucho co-repressor at the Eh-1 motif in the C-terminus; and 2) sequence downstream of this motif. Finally, the ability of FoxD4/5 to induce the ectopic expression of neural precursor genes in the ventral ectoderm also involves both the AB region and the Eh-1 motif; FoxD4/5 accomplishes ectopic neural induction by both activating neural precursor genes and repressing BMP signaling and epidermal genes. This study identifies the specific, conserved domains of the FoxD4/5 protein that allow this single transcription factor to regulate a network of genes that controls the transition of a proliferative neural ectodermal population to a committed neural plate population poised to begin differentiation. (C) 2012 Elsevier Inc. All rights reserved. C1 [Neilson, Karen M.; Klein, Steven L.; Mhaske, Pallavi; Moody, Sally A.] George Washington Univ, Sch Med & Hlth Sci, Dept Anat & Regenerat Biol, Washington, DC 20037 USA. [Mood, Kathy; Daar, Ira O.] NCI, Lab Cell & Dev Signaling, NIH, Frederick Natl Lab, Frederick, MD 21701 USA. RP Moody, SA (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Anat & Regenerat Biol, 2300 I St NW, Washington, DC 20037 USA. EM samoody@gwu.edu OI Daar, Ira/0000-0003-2657-526X; Moody, Sally/0000-0003-4192-1087 FU NSF [10S-0817902]; George Washington University Medical Center; NIH [S10 RR025565, P30 HD040677]; National Cancer Institute; National Science Foundation FX This work was supported in part by NSF grant 10S-0817902, funds from the George Washington University Medical Center, and the Intramural Research Program of the NIH, National Cancer Institute. Confocal microscopy was performed at the GWU Center for Microscopy and Image Analysis with support from NIH grants S10 RR025565 and P30 HD040677 (IDDRC at CNMC). We thank Dr. Anastas Popratil-off (GWUMC) for confocal microscopy, Dr. John Orban (Univ. Maryland) for advice on protein structure analyses and Ms. Rebecca He for immunostaining. Dr. Klein's efforts were supported by the National Science Foundation while working at the Foundation. Any opinion, finding, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. NR 62 TC 9 Z9 9 U1 0 U2 3 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 MAY 15 PY 2012 VL 365 IS 2 BP 363 EP 375 DI 10.1016/j.ydbio.2012.03.004 PG 13 WC Developmental Biology SC Developmental Biology GA 939DR UT WOS:000303788100005 PM 22425621 ER PT J AU Joseph-Strauss, D Gorjanacz, M Santarella-Mellwig, R Voronina, E Audhya, A Cohen-Fix, O AF Joseph-Strauss, Daphna Gorjanacz, Matyas Santarella-Mellwig, Rachel Voronina, Ekaterina Audhya, Anjon Cohen-Fix, Orna TI Sm protein down-regulation leads to defects in nuclear pore complex disassembly and distribution in C-elegans embryoss SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Nuclear pore complex; Nuclear envelope breakdown; Sm proteins; Early embryonic divisions ID CAENORHABDITIS-ELEGANS; CELL-CYCLE; ENDOPLASMIC-RETICULUM; ENVELOPE BREAKDOWN; DROSOPHILA-MELANOGASTER; MEMBRANE-PROTEINS; NUCLEOPORINS; DYNAMICS; MITOSIS; GENES AB Nuclear pore complexes (NPCs) are large macromolecular structures embedded in the nuclear envelope (NE), where they facilitate exchange of molecules between the cytoplasm and the nucleoplasm. In most cell types, NPCs are evenly distributed around the NE. However, the mechanisms dictating NPC distribution are largely unknown. Here, we used the model organism Caenorhabditis elegans to identify genes that affect NPC distribution during early embryonic divisions. We found that down-regulation of the Sm proteins, which are core components of the spliceosome, but not down-regulation of other splicing factors, led to clustering of NPCs. Down-regulation of Sm proteins also led to incomplete disassembly of NPCs during mitosis, but had no effect on lamina disassembly, suggesting that the defect in NPC disassembly was not due to a general defect in nuclear envelope breakdown. We further found that these mitotic NPC remnants persisted on an ER membrane that juxtaposes the mitotic spindle. At the end of mitosis, the remnant NPCs moved toward the chromatin and the reforming NE, where they ultimately clustered by forming membrane stacks perforated by NPCs. Our results suggest a novel, splicing-independent, role for Sm proteins in NPC disassembly, and point to a possible link between NPC disassembly in mitosis and NPC distribution in the subsequent interphase. Published by Elsevier Inc. C1 [Joseph-Strauss, Daphna; Cohen-Fix, Orna] Natl Inst Diabet Digest & Kidney Dis, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. [Gorjanacz, Matyas; Santarella-Mellwig, Rachel] European Mol Biol Lab, D-69117 Heidelberg, Germany. [Voronina, Ekaterina] Johns Hopkins Sch Med, Ctr Cell Dynam, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Audhya, Anjon] Univ Wisconsin, Madison Med Sch, Dept Biomol Chem, Madison, WI 53706 USA. RP Cohen-Fix, O (reprint author), 8 Ctr Dr,Bldg 8,Room 319, Bethesda, MD 20892 USA. EM ornacf@helix.nih.gov FU NIDDK; NIH [GM088151, 5F32GM080923] FX We thank Kevin O'Connell, lain Mattaj and Geraldine Seydoux for advice and comments on the manuscript. We thank Andy Golden and members of the Golden lab for reagents and invaluable assistance. D. J. S. and O. C. F. are supported by an intramural NIDDK grant. A. A. is supported by an NIH grant GM088151. E. V. was supported by an NIH fellowship 5F32GM080923. NR 53 TC 4 Z9 4 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAY 15 PY 2012 VL 365 IS 2 BP 445 EP 457 DI 10.1016/j.ydbio.2012.02.036 PG 13 WC Developmental Biology SC Developmental Biology GA 939DR UT WOS:000303788100012 PM 22426005 ER PT J AU Casey, KA Fraser, KA Schenkel, JM Moran, A Abt, MC Beura, LK Lucas, PJ Artis, D Wherry, EJ Hogquist, K Vezys, V Masopust, D AF Casey, Kerry A. Fraser, Kathryn A. Schenkel, Jason M. Moran, Amy Abt, Michael C. Beura, Lalit K. Lucas, Philip J. Artis, David Wherry, E. John Hogquist, Kristin Vezys, Vaiva Masopust, David TI Antigen-Independent Differentiation and Maintenance of Effector-like Resident Memory T Cells in Tissues SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTRAEPITHELIAL LYMPHOCYTES; PROMOTES DIFFERENTIATION; INTESTINAL EPITHELIUM; NONLYMPHOID TISSUE; VIRAL-INFECTION; FACTOR-BETA; IN-VIVO; RECEPTOR; SUBSETS; EXPRESSION AB Differentiation and maintenance of recirculating effector memory CD8 T cells (T-EM) depends on prolonged cognate Ag stimulation. Whether similar pathways of differentiation exist for recently identified tissue-resident effector memory T cells (T-RM), which contribute to rapid local protection upon pathogen re-exposure, is unknown. Memory CD8 alpha beta(+) T cells within small intestine epithelium are well-characterized examples of T-RM, and they maintain a long-lived effector-like phenotype that is highly suggestive of persistent Ag stimulation. This study sought to define the sources and requirements for prolonged Ag stimulation in programming this differentiation state, including local stimulation via cognate or cross-reactive Ags derived from pathogens, microbial flora, or dietary proteins. Contrary to expectations, we found that prolonged cognate Ag stimulation was dispensable for intestinal T-RM ontogeny. In fact, chronic antigenic stimulation skewed differentiation away from the canonical intestinal T cell phenotype. Resident memory signatures, CD69 and CD103, were expressed in many nonlymphoid tissues including intestine, stomach, kidney, reproductive tract, pancreas, brain, heart, and salivary gland and could be driven by cytokines. Moreover, TGF-beta-driven CD103 expression was required for T-RM maintenance within intestinal epithelium in vivo. Thus, induction and maintenance of long-lived effector-like intestinal T-RM differed from classic models of T-EM ontogeny and were programmed through a novel location-dependent pathway that was required for the persistence of local immunological memory. The Journal of Immunology, 2012, 188: 4866-4875. C1 [Casey, Kerry A.; Fraser, Kathryn A.; Schenkel, Jason M.; Beura, Lalit K.; Vezys, Vaiva; Masopust, David] Univ Minnesota, Ctr Immunol, Dept Microbiol, Minneapolis, MN 55455 USA. [Abt, Michael C.; Artis, David; Wherry, E. John] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Abt, Michael C.; Artis, David; Wherry, E. John] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA. [Abt, Michael C.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Lucas, Philip J.] NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Masopust, D (reprint author), Univ Minnesota, Ctr Immunol, Dept Microbiol, 2-182 Med Biosci Bldg,2641 Campus Delivery,2101 6, Minneapolis, MN 55455 USA. EM masopust@umn.edu RI Casey, Kerry/B-5274-2011; vezys, vaiva/N-3144-2013; OI Vezys, Vaiva/0000-0002-2520-809X; Hogquist, Kristin/0000-0001-9963-5687 FU National Institutes of Health [R01 AI084913, AI084622, AI007313-23] FX This work was supported by National Institutes of Health Grants R01 AI084913 (to D.M.), AI084622 (to K.A.F.), and AI007313-23 (to J.M.S.). NR 53 TC 129 Z9 131 U1 0 U2 15 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2012 VL 188 IS 10 BP 4866 EP 4875 DI 10.4049/jimmunol.1200402 PG 10 WC Immunology SC Immunology GA 937BP UT WOS:000303634300019 PM 22504644 ER PT J AU Gowdy, KM Cardona, DM Nugent, JL Giamberardino, C Thomas, JM Mukherjee, S Martinu, T Foster, WM Plevy, SE Pastva, AM Wright, JR Palmer, SM AF Gowdy, Kymberly M. Cardona, Diana M. Nugent, Julia L. Giamberardino, Charles Thomas, Joseph M. Mukherjee, Sambudho Martinu, Tereza Foster, W. Michael Plevy, Scott E. Pastva, Amy M. Wright, Jo Rae Palmer, Scott M. TI Novel Role for Surfactant Protein A in Gastrointestinal Graft-versus-Host Disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IDIOPATHIC PNEUMONIA SYNDROME; BONE-MARROW-TRANSPLANTATION; INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; LUNG INFLAMMATION; MICE; MACROPHAGES; INFECTION; LIPOPOLYSACCHARIDE; MANIFESTATIONS AB Graft-versus-host disease (GVHD) is a severe and frequent complication of allogeneic bone marrow transplantation (BMT) that involves the gastrointestinal (GI) tract and lungs. The pathobiology of GVHD is complex and involves immune cell recognition of host Ags as foreign. We hypothesize a central role for the collectin surfactant protein A (SP-A) in regulating the development of GVHD after allogeneic BMT. C57BL/6 (H2b; WT) and SP-A-deficient mice on a C57BL/6 background (H2b; SP-A(-/-)) mice underwent allogeneic or syngeneic BMT with cells from either C3HeB/FeJ (H2k; SP-A-deficient recipient mice that have undergone an allogeneic BMT [SP-A(-/-)alloBMT] or SP-A-sufficient recipient mice that have undergone an allogeneic BMT) or C57BL/6 (H2b; SP-A-deficient recipient mice that have undergone a syngeneic BMT or SP-A-sufficient recipient mice that have undergone a syngeneic BMT) mice. Five weeks post-BMT, mice were necropsied, and lung and GI tissue were analyzed. SP-A(-/-)alloBMT or SP-A-sufficient recipient mice that have undergone an allogeneic BMT had no significant differences in lung pathology; however, SP-A(-/-)alloBMT mice developed marked features of GI GVHD, including decreased body weight, increased tissue inflammation, and lymphocytic infiltration. SP-A(-/-)alloBMT mice also had increased colon expression of IL-1 beta, IL-6, TNF-alpha, and IFN-gamma and as well as increased Th17 cells and diminished regulatory T cells. Our results demonstrate the first evidence, to our knowledge, of a critical role for SP-A in modulating GI GVHD. In these studies, we demonstrate that mice deficient in SP-A that have undergone an allogeneic BMT have a greater incidence of GI GVHD that is associated with increased Th17 cells and decreased regulatory T cells. The results of these studies demonstrate that SP-A protects against the development of GI GVHD and establishes a role for SP-A in regulating the immune response in the GI tract. The Journal of Immunology, 2012, 188: 4897-4905. C1 [Gowdy, Kymberly M.; Martinu, Tereza; Foster, W. Michael; Palmer, Scott M.] Duke Univ, Med Ctr, Dept Med, Div Pulm & Crit Care Med, Durham, NC 27710 USA. [Cardona, Diana M.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Nugent, Julia L.; Giamberardino, Charles; Thomas, Joseph M.; Mukherjee, Sambudho; Pastva, Amy M.; Wright, Jo Rae] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Plevy, Scott E.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. RP Gowdy, KM (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Bldg 101,Mail Drop D2-01, Res Triangle Pk, NC 27709 USA. EM kymberly.gowdy@nih.gov FU National Institutes of Health [1P50-HL084917-01, 1F32HL090265-01, RR024 127-03, 1K24 HL91140-01A2, HL-68072-07, 1P50-HL-084917-03, AI-81672, K08AI068822, DK54452-09] FX This work was supported by National Institutes of Health Grants 1P50-HL084917-01 (Project 3 to S.M.P. and training core to K.M.G. and T.M.). 1F32HL090265-01 (to T.M.), RR024 127-03 (to T.M.), 1K24 HL91140-01A2 (to S.M.P.), HL-68072-07 and 1P50-HL-084917-03 (to J.R.W.), AI-81672 (to W.M.F.), K08AI068822 (to A.M.P.), and DK54452-09 (to S.E.P.). NR 50 TC 4 Z9 4 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2012 VL 188 IS 10 BP 4897 EP 4905 DI 10.4049/jimmunol.1103558 PG 9 WC Immunology SC Immunology GA 937BP UT WOS:000303634300022 PM 22508928 ER PT J AU Mok, SWF Proia, RL Brinkmann, V Mabbott, NA AF Mok, Simon W. F. Proia, Richard L. Brinkmann, Volker Mabbott, Neil A. TI B Cell-Specific S1PR1 Deficiency Blocks Prion Dissemination between Secondary Lymphoid Organs SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FOLLICULAR DENDRITIC CELLS; CREUTZFELDT-JAKOB-DISEASE; REDUCES SCRAPIE SUSCEPTIBILITY; CHRONIC WASTING DISEASE; BLOOD-TRANSFUSION; MARGINAL-ZONE; ALLOGRAFT SURVIVAL; KNOCKOUT MICE; NEUROINVASION; PROTEIN AB Many prion diseases are peripherally acquired (e.g., orally or via lesions to skin or mucous membranes). After peripheral exposure, prions replicate first upon follicular dendritic cells (FDC) in the draining lymphoid tissue before infecting the brain. However, after replication upon FDC within the draining lymphoid tissue, prions are subsequently propagated to most nondraining secondary lymphoid organs (SLO), including the spleen, by a previously underdetermined mechanism. The germinal centers in which FDC are situated produce a population of B cells that can recirculate between SLO. Therefore, we reasoned that B cells were ideal candidates by which prion dissemination between SLO may occur. Sphingosine 1-phosphate receptor (S1PR)1 stimulation controls the egress of T and B cells from SLO. S1PR1 signaling blockade sequesters lymphocytes within SLO, resulting in lymphopenia in the blood and lymph. We show that, in mice treated with the S1PR modulator FTY720 or with S1PR1 deficiency restricted to B cells, the dissemination of prions from the draining lymph node to nondraining SLO is blocked. These data suggest that B cells interacting with and acquiring surface proteins from FDC and recirculating between SLO via the blood and lymph mediate the initial propagation of prions from the draining lymphoid tissue to peripheral tissues. The Journal of Immunology, 2012, 188: 5032-5040. C1 [Mok, Simon W. F.; Mabbott, Neil A.] Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland. [Mok, Simon W. F.; Mabbott, Neil A.] Univ Edinburgh, Royal Dick Sch Vet Sci, Easter Bush EH25 9RG, Midlothian, Scotland. [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. [Brinkmann, Volker] Novartis Inst BioMed Res Autoimmun Transplantat &, CH-4056 Basel, Switzerland. RP Mabbott, NA (reprint author), Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland. EM neil.mabbott@roslin.ed.ac.uk OI Mabbott, Neil/0000-0001-7395-1796 FU Medical Research Council [G0700640]; Biotechnology and Biological Sciences Research Council; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Medical Research Council (Grant G0700640), Institute Strategic Programme Grant funding from the Biotechnology and Biological Sciences Research Council (to N.A.M.), and the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (to R.L.P.). NR 72 TC 11 Z9 11 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2012 VL 188 IS 10 BP 5032 EP 5040 DI 10.4049/jimmunol.1200349 PG 9 WC Immunology SC Immunology GA 937BP UT WOS:000303634300036 PM 22504650 ER PT J AU Qiu, LQ Stumpo, DJ Blackshear, PJ AF Qiu, Lian-Qun Stumpo, Deborah J. Blackshear, Perry J. TI Myeloid-Specific Tristetraprolin Deficiency in Mice Results in Extreme Lipopolysaccharide Sensitivity in an Otherwise Minimal Phenotype SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; AU-RICH ELEMENTS; MESSENGER-RNA; FACTOR-ALPHA; ENDOTOXIC-SHOCK; TNF-ALPHA; PROTEIN; DESTABILIZATION; DEADENYLATION; SEQUENCE AB Tristetraprolin (TTP) is a mRNA-destabilizing protein that binds to AU-rich elements in labile transcripts, such as the mRNA encoding TNF, and promotes their deadenylation and degradation. TTP-deficient (knockout [KO]) mice exhibit an early-onset, severe inflammatory phenotype, with cachexia, erosive arthritis, left-sided cardiac valvulitis, myeloid hyperplasia, and autoimmunity, which can be prevented by injections of anti-TNF Abs, or interbreeding with TNF receptor-deficient mice. To determine whether the excess TNF that causes the TTP KO phenotype is produced by myeloid cells, we performed myeloid-specific disruption of Zfp36, the gene encoding TTP. We documented the lack of TTP expression in LPS-stimulated bone marrow-derived macrophages from the mice, whereas fibroblasts expressed TTP mRNA and protein normally in response to serum. The mice exhibited a minimal phenotype, characterized by slight slowing of weight gain late in the first year of life, compared with the early-onset, severe weight loss and inflammation seen in the TTP KO mice. Instead, the myeloid-specific TTP KO mice were highly and abnormally susceptible to a low-dose LPS challenge, with rapid development of typical endotoxemia signs and extensive organ damage, and elevations of serum TNF levels to 110-fold greater than control. We conclude that myeloid-specific TTP deficiency does not phenocopy complete TTP deficiency in C57BL/6 mice under normal laboratory conditions, implying contributions from other cell types to the complete phenotype. However, myeloid cell TTP plays a critical role in protecting mice against LPS-induced septic shock, primarily through its posttranscriptional regulation of TNF mRNA stability. The Journal of Immunology, 2012, 188: 5150-5159. C1 [Qiu, Lian-Qun; Stumpo, Deborah J.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Black009@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 32 TC 37 Z9 37 U1 0 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2012 VL 188 IS 10 BP 5150 EP 5159 DI 10.4049/jimmunol.1103700 PG 10 WC Immunology SC Immunology GA 937BP UT WOS:000303634300048 PM 22491258 ER PT J AU de Souza, MS Ratto-Kim, S Chuenarom, W Schuetz, A Chantakulkij, S Nuntapinit, B Valencia-Micolta, A Thelian, D Nitayaphan, S Pitisuttithum, P Paris, RM Kaewkungwal, J Michael, NL Rerks-Ngarm, S Mathieson, B Marovich, M Currier, JR Kim, JH AF de Souza, Mark S. Ratto-Kim, Silvia Chuenarom, Weerawan Schuetz, Alexandra Chantakulkij, Somsak Nuntapinit, Bessara Valencia-Micolta, Anais Thelian, Doris Nitayaphan, Sorachai Pitisuttithum, Punnee Paris, Robert M. Kaewkungwal, Jaranit Michael, Nelson L. Rerks-Ngarm, Supachai Mathieson, Bonnie Marovich, Mary Currier, Jeffrey R. Kim, Jerome H. CA Minist Publ Hlth Thai AIDS Vaccine TI The Thai Phase III Trial (RV144) Vaccine Regimen Induces T Cell Responses That Preferentially Target Epitopes within the V2 Region of HIV-1 Envelope SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BOOST VACCINE; VIRAL LOAD; INTEGRIN ALPHA(4)BETA(7); SIMIAN IMMUNODEFICIENCY; IMMUNODOMINANT REGIONS; FUNCTIONAL SIGNATURES; LYMPHOCYTE RESPONSES; PROTECTIVE VACCINE; EFFECTOR FUNCTIONS AB The Thai HIV phase HI prime/boost vaccine trial (RV144) using ALVAC-HIV (vCP1521) and AIDS VAX B/E was, to our knowledge, the first to demonstrate acquisition efficacy. Vaccine-induced, cell-mediated immune responses were assessed. T cell epitope mapping studies using IFN-gamma ELISPOT was performed on PBMCs from HIV-1 uninfected vaccine (n = 61) and placebo (n = 10) recipients using HIV-1 Env peptides. Positive responses were measured in 25 (41%) vaccinees and were predominantly CD4(+) T cell-mediated. Responses were targeted within the HIV Env region, with 15 of 25 (60%) of vaccinees recognizing peptides derived from the V2 region of HIV-1 Env, which includes the alpha(4)beta(7) integrin binding site. Intracellular cytokine staining confirmed that Env responses predominated (19 of 30; 63% of vaccine recipients) and were mediated by polyfunctional effector memory CD4(+) T cells, with the majority of responders producing both IL-2 and IFN-gamma (12 of 19; 63%). HIV Env Ab titers were higher in subjects with IL-2 compared with those without IL-2 secreting HIV Env-specific effector memory T cells. Proliferation assays revealed that HIV Ag-specific T cells were CD4(+), with the majority (80%) expressing CD107a. HIV-specific T cell lines obtained from vaccine recipients confirmed V2 specificity, polyfunctionality, and functional cytolytic capacity. Although the RV144 T cell responses were modest in frequency compared with humoral immune responses, the CD4(+) T cell response was directed to HIV-1 Env and more particularly the V2 region. The Journal of Immunology, 2012, 188: 5166-5176. C1 [de Souza, Mark S.; Chuenarom, Weerawan; Schuetz, Alexandra; Chantakulkij, Somsak; Nuntapinit, Bessara] Armed Forces Res Inst Med Sci, US Mil HIV Res Program, US Army Med Component, Bangkok 10400, Thailand. [de Souza, Mark S.; Ratto-Kim, Silvia; Schuetz, Alexandra; Valencia-Micolta, Anais; Thelian, Doris; Paris, Robert M.; Michael, Nelson L.; Marovich, Mary; Currier, Jeffrey R.; Kim, Jerome H.] Walter Reed Army Med Ctr, US Mil HIV Res Program, Div Retrovirol, Rockville, MD 20850 USA. [Pitisuttithum, Punnee] Mahidol Univ, Fac Trop Med, Vaccine Trials Ctr, Bangkok 10400, Thailand. [Kaewkungwal, Jaranit] Mahidol Univ, Fac Trop Med, Ctr Excellence Biomed & Publ Hlth Informat, Bangkok 10400, Thailand. [Rerks-Ngarm, Supachai] Minist Publ Hlth, Dept Dis Control, Nonthaburi 11000, Thailand. [Mathieson, Bonnie] NIH, Off AIDS Res, Bethesda, MD 20892 USA. RP de Souza, MS (reprint author), Armed Forces Res Inst Med Sci, US Mil HIV Res Program, US Army Med Component, 315-6 Rajvithi Rd, Bangkok 10400, Thailand. EM desouzams@afrims.org FU U.S. Army Medical Research and Materiel Command [Y1-AI-2642-12]; National Institute of Allergy and Infectious Diseases [Y1-AI-2642-12]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; U.S. Department of Defense [W81XWH-07-2-0067] FX This work was supported in part by Interagency Agreement Y1-AI-2642-12 between the U.S. Army Medical Research and Materiel Command and the National Institute of Allergy and Infectious Diseases. In addition, this work was supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense. Portions of this work were presented at the AIDS Vaccine Meeting 2009, October 19-22, 2009, Paris, France (Abstract OA07-04LB); the 2010 Keystone Symposium "HIV Vaccines/Viral Immunity", March 21-26, 2010, Banff, Alberta, Canada (Abstract X5 159); the 4th Vaccine and ISV Annual Global Congress, October 3-5, 2010, Vienna, Austria (Abstract O2.1); and the Europrise: Rational Design of HIV Vaccines and Microbicides Network Annual Conference, November 15-18, 2010, Lisbon, Portugal. NR 58 TC 81 Z9 81 U1 2 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2012 VL 188 IS 10 BP 5166 EP 5176 DI 10.4049/jimmunol.1102756 PG 11 WC Immunology SC Immunology GA 937BP UT WOS:000303634300050 PM 22529301 ER PT J AU Irfanoglu, MO Walker, L Sarlls, J Marenco, S Pierpaoli, C AF Irfanoglu, M. Okan Walker, Lindsay Sarlls, Joelle Marenco, Stefano Pierpaoli, Carlo TI Effects of image distortions originating from susceptibility variations and concomitant fields on diffusion MRI tractography results SO NEUROIMAGE LA English DT Article DE Echo planar imaging; Diffusion tensor imaging; Fiber tractography; Image distortions; Susceptibility ID PERSISTENT ANGULAR STRUCTURE; WEIGHTED MRI; GEOMETRIC DISTORTION; SPIN-ECHO; TENSOR; ORIENTATION; BRAIN; DTI; DECONVOLUTION; RESOLUTION AB In this work we investigate the effects of echo planar imaging (EPI) distortions on diffusion tensor imaging (DTI) based fiber tractography results. We propose a simple experimental framework that would enable assessing the effects of EPI distortions on the accuracy and reproducibility of fiber tractography from a pilot study on a few subjects. We compare trajectories computed from two diffusion datasets collected on each subject that are identical except for the orientation of phase encode direction, either right-left (RL) or anterior-posterior (AP). We define metrics to assess potential discrepancies between RL and AP trajectories in association, commissural, and projection pathways. Results from measurements on a 3 Tesla clinical scanner indicated that the effects of EPI distortions on computed fiber trajectories are statistically significant and large in magnitude, potentially leading to erroneous inferences about brain connectivity. The correction of EPI distortion using an image-based registration approach showed a significant improvement in tract consistency and accuracy. Although obtained in the context of a DTI experiment, our findings are generally applicable to all EPI-based diffusion MRI tractography investigations, including high angular resolution (HARDI) methods. On the basis of our findings, we recommend adding an EPI distortion correction step to the diffusion MRI processing pipeline if the output is to be used for fiber tractography. (c) 2012 Elsevier Inc. All rights reserved. C1 [Irfanoglu, M. Okan; Walker, Lindsay; Pierpaoli, Carlo] NICHD, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Irfanoglu, M. Okan; Walker, Lindsay] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Sarlls, Joelle] NINDS, NIH, Bethesda, MD USA. [Marenco, Stefano] NIMH, Sect Clin Studies, NIH, Bethesda, MD 20892 USA. RP Irfanoglu, MO (reprint author), NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. EM irfanoglumo@mail.nih.gov RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH); Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). Support for this work included funding from Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM). The authors would also like to thank Liz Salak for editing this manuscript and the Henry M. Jackson Foundation (HJF) for their administrative support. NR 50 TC 48 Z9 48 U1 1 U2 11 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 MAY 15 PY 2012 VL 61 IS 1 BP 275 EP 288 DI 10.1016/j.neuroimage.2012.02.054 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 941HP UT WOS:000303954600028 PM 22401760 ER PT J AU Bertagnolio, S Penazzato, M Jordan, MR Persaud, D Mofenson, LM Bennett, DE AF Bertagnolio, Silvia Penazzato, Martina Jordan, Michael R. Persaud, Deborah Mofenson, Lynne M. Bennett, Diane E. CA Pediat HIV ResNet Working Grp TI World Health Organization Generic Protocol to Assess Drug-Resistant HIV Among Children < 18 Months of Age and Newly Diagnosed With HIV in Resource-Limited Countries SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; EARLY INFANT DIAGNOSIS; REDUCES NEVIRAPINE RESISTANCE; SINGLE-DOSE NEVIRAPINE; DRIED BLOOD SPOTS; INFECTED INFANTS; ANTIRETROVIRAL TREATMENT; VERTICAL TRANSMISSION; IMMUNIZATION CLINICS; SUBTYPE-C AB Increased use of nonnucleoside reverse transcriptase inhibitors (NNRTIs) in pregnant and breastfeeding women will result in fewer children infected with human immunodeficiency virus (HIV). However, among children infected despite prevention of mother-to-child transmission (PMTCT), a substantial proportion will acquire NNRTI-resistant HIV, potentially compromising response to NNRTI-based antiretroviral therapy (ART). In countries scaling up PMTCT and pediatric ART programs, it is crucial to assess the proportion of young children with drug-resistant HIV to improve health outcomes and support national and global decision making on optimal selection of pediatric first-line ART. This article summarizes a new World Health Organization surveillance protocol to assess resistance using remnant dried blood spot specimens from a representative sample of children aged < 18 months being tested for early infant diagnosis. C1 [Bertagnolio, Silvia; Jordan, Michael R.] World Hlth Org, HIV Dept, CH-1211 Geneva 27, Switzerland. [Penazzato, Martina] Univ Padua, Dept Pediat, I-35100 Padua, Italy. [Jordan, Michael R.] Tufts Univ, Sch Med, Dept Geog Med & Infect Dis, Boston, MA 02111 USA. [Persaud, Deborah] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD USA. [Mofenson, Lynne M.] Natl Inst Hlth, Pediat Adolescent & Maternal AIDS Branch, Rockville, MD USA. [Bennett, Diane E.] US Ctr Dis Control & Prevent, Global AIDS Program, Atlanta, GA USA. RP Bertagnolio, S (reprint author), World Hlth Org, HIV Dept, 20 Ave Appia, CH-1211 Geneva 27, Switzerland. EM bertagnolios@who.int OI Mofenson, Lynne/0000-0002-2818-9808 FU Bill & Melinda Gates Foundation [38180]; National Institutes of Health (NIH) [K23 AI074423-05]; European Community [223131] FX This work was supported by The Bill & Melinda Gates Foundation (grant 38180) and the National Institutes of Health (NIH K23 AI074423-05 to M. R. J.). The research leading to these results has received part funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under the project Collaborative HIV and Anti-HIV Drug Resistance Network"-grant agreement no 223131. NR 43 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2012 VL 54 SU 4 BP S254 EP S260 DI 10.1093/cid/cis003 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 933EA UT WOS:000303341300003 PM 22544184 ER PT J AU Dreher, JC Koch, P Kohn, P Apud, J Weinberger, DR Berman, KF AF Dreher, Jean-Claude Koch, Paul Kohn, Philip Apud, Jose Weinberger, Daniel R. Berman, Karen Faith TI Common and Differential Pathophysiological Features Accompany Comparable Cognitive Impairments in Medication-Free Patients with Schizophrenia and in Healthy Aging Subjects SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Aging; dorsolateral prefrontal cortex; neuroimaging; schizophrenia; working memory ID DORSOLATERAL PREFRONTAL CORTEX; WORKING-MEMORY PERFORMANCE; DEFAULT-MODE NETWORK; FUNCTIONAL CONNECTIVITY; AGE-DIFFERENCES; BRAIN ACTIVITY; DYSFUNCTION; ACTIVATION; DISEASE; SYSTEMS AB Background: Dysfunction of the dorsolateral prefrontal cortex (DLPFC) and parahippocampal region along with poor working memory are common neurophysiological and behavioral features associated with schizophrenia and normal aging. It is, however, unknown whether the associated patterns of neural activation differ between these two groups when their cognitive performance is closely matched in a pairwise manner. The authors sought to pinpoint common and differential pathophysiological features that accompany comparable working memory impairments in schizophrenia and healthy aging. Methods: Fifty-three subjects were scanned with oxygen-15 water positron emission tomography regional cerebral blood flow measurements during working memory. Seventeen medication-free patients with schizophrenia were individually matched for working memory performance with 17 healthy aging subjects. Brain activation of the two index groups were compared with each other and with 19 young healthy individuals. Results: Patients with schizophrenia showed right DLPFC hypoactivation, both when compared with age-matched control subjects and after direct comparison with working memory performance-matched elderly subjects. Moreover, both groups with working memory deficits shared an inability to suppress parahippocampal and anterior medial prefrontal cortex activation. Conclusions: These results provide new insights into the mechanisms by which impaired working memory performance can arise by showing that both common (parahippocampal/anterior medial PFC) and differential (DLPFC) pathophysiological features accompany similar cognitive impairments. The aging data also demonstrate that poor performance is not necessarily accompanied by the DLPFC hypofunction that was seen in schizophrenia. Finally, these results more closely link the DLPFC functional abnormalities in schizophrenia to the pathophysiology of the disorder rather than to poor performance per se. C1 [Dreher, Jean-Claude] CNRS, UMR 5229, Reward & Decis Making Team, Ctr Neurosci Cognit,Reward & Decis Making Grp, F-69675 Bron, France. [Dreher, Jean-Claude] Univ Lyon 1, F-69365 Lyon, France. [Dreher, Jean-Claude; Koch, Paul; Kohn, Philip; Berman, Karen Faith] NIMH, Sect Integrat Neuroimaging, NIH, Intramural Res Program, Bethesda, MD 20892 USA. [Dreher, Jean-Claude; Koch, Paul; Apud, Jose; Weinberger, Daniel R.; Berman, Karen Faith] NIMH, Clin Brain Disorders Branch, NIH, Intramural Res Program, Bethesda, MD 20892 USA. RP Dreher, JC (reprint author), CNRS, UMR 5229, Reward & Decis Making Team, Ctr Neurosci Cognit,Reward & Decis Making Grp, 67 Bd Pinel, F-69675 Bron, France. EM dreher@isc.cnrs.fr FU National Institute of Mental Health FX This work was supported by the National Institute of Mental Health Intramural Research Program. All authors report no biomedical financial disclosures or potential conflicts of interest. NR 46 TC 11 Z9 12 U1 2 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 MAY 15 PY 2012 VL 71 IS 10 BP 890 EP 897 DI 10.1016/j.biopsych.2012.01.002 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 929ZQ UT WOS:000303104900008 PM 22341369 ER PT J AU Saha, A Sarkar, C Singh, SP Zhang, ZJ Munasinghe, J Peng, SY Chandra, G Kong, EY Mukherjee, AB AF Saha, Arjun Sarkar, Chinmoy Singh, Satya P. Zhang, Zhongjian Munasinghe, Jeeva Peng, Shiyong Chandra, Goutam Kong, Eryan Mukherjee, Anil B. TI The blood-brain barrier is disrupted in a mouse model of infantile neuronal ceroid lipofuscinosis: amelioration by resveratrol SO HUMAN MOLECULAR GENETICS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; MATRIX METALLOPROTEINASES; PATHOLOGICAL CONDITIONS; OXIDATIVE STRESS; KNOCKOUT MICE; T-CELLS; INCL; ACTIVATION; APOPTOSIS; DISEASE AB Disruption of the blood-brain barrier (BBB) is a serious complication frequently encountered in neurodegenerative disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It remains unclear whether BBB is disrupted in INCL and if so, what might be the molecular mechanism(s) of this complication. We previously reported that the Ppt1-knockout (Ppt1-KO) mice that mimic INCL manifest high levels of oxidative stress and neuroinflammation. Recently, it has been reported that CD4 T-helper 17 (T(H)17) lymphocytes may mediate BBB disruption and neuroinflammation, although the precise molecular mechanism(s) remain unclear. We sought to determine: (i) whether the BBB is disrupted in Ppt1-KO mice, (ii) if so, do T(H)17-lymphocytes underlie this complication, and (iii) how might T(H)17 lymphocytes breach the BBB. Here, we report that the BBB is disrupted in Ppt1-KO mice and that T(H)17 lymphocytes producing IL-17A mediate disruption of the BBB by stimulating production of matrix metalloproteinases (MMPs), which degrade the tight junction proteins essential for maintaining BBB integrity. Importantly, dietary supplementation of resveratrol (RSV), a naturally occurring antioxidant/anti-inflammatory polyphenol, markedly reduced the levels of T(H)17 cells, IL-17A and MMPs, and elevated the levels of tight junction proteins, which improved the BBB integrity in Ppt1-KO mice. Intriguingly, we found that RSV suppressed the differentiation of CD4 T lymphocytes to IL-17A-positive T(H)17 cells. Our findings uncover a mechanism by which T(H)17 lymphocytes mediate BBB disruption and suggest that small molecules such as RSV that suppress T(H)17 differentiation are therapeutic targets for neurodegenerative disorders such as INCL. C1 [Saha, Arjun; Sarkar, Chinmoy; Zhang, Zhongjian; Peng, Shiyong; Chandra, Goutam; Kong, Eryan; Mukherjee, Anil B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Endocrinol & Genet, Sect Dev Genet, Bethesda, MD 20892 USA. [Singh, Satya P.] NIAID, Lab Mol Immunol, Bethesda, MD 20892 USA. [Munasinghe, Jeeva] NINDS, Vivo NMR Ctr HNQ2 3, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov RI Peng, Shiyong/D-6391-2014 OI Peng, Shiyong/0000-0003-0697-3674 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD]; National Institute of Allergy and Infectious Diseases (NIAID), NIH FX This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD], and by Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), NIH. NR 37 TC 27 Z9 28 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2012 VL 21 IS 10 BP 2233 EP 2244 DI 10.1093/hmg/dds038 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 933BH UT WOS:000303333700009 PM 22331300 ER PT J AU Keenan, BT Shulman, JM Chibnik, LB Raj, T Tran, D Sabuncu, MR Allen, AN Corneveaux, JJ Hardy, JA Huentelman, MJ Lemere, CA Myers, AJ Nicholson-Weller, A Reiman, EM Evans, DA Bennett, DA De Jager, PL AF Keenan, Brendan T. Shulman, Joshua M. Chibnik, Lori B. Raj, Towfique Tran, Dong Sabuncu, Mert R. Allen, April N. Corneveaux, Jason J. Hardy, John A. Huentelman, Matthew J. Lemere, Cynthia A. Myers, Amanda J. Nicholson-Weller, Anne Reiman, Eric M. Evans, Denis A. Bennett, David A. De Jager, Philip L. CA Alzheimers Dis Neuroimaging TI A coding variant in CR1 interacts with APOE-?4 to influence cognitive decline SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ALZHEIMER-DISEASE PATHOLOGY; MANNAN-BINDING LECTIN; OLDER PERSONS; COMPLEMENT RECEPTOR-TYPE-1; CEREBRAL INFARCTIONS; IDENTIFIES VARIANTS; AMYLOID DEPOSITION; COMMON VARIANTS; MOUSE MODELS AB Complement receptor 1 (CR1) is an Alzheimers disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D 1, r(2) 0.084) on this trait. Further, we demonstrate that the coding variants effect is largely dependent on an interaction with APOE-?4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variants effect and suggest that CR1 may be an important intermediate in the clearance of A42 particles by C1q. C1 [Keenan, Brendan T.; Shulman, Joshua M.; Chibnik, Lori B.; Raj, Towfique; Tran, Dong; De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [Keenan, Brendan T.; Shulman, Joshua M.; Chibnik, Lori B.; Raj, Towfique; Tran, Dong; De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Shulman, Joshua M.; Chibnik, Lori B.; Raj, Towfique; Lemere, Cynthia A.; Nicholson-Weller, Anne; De Jager, Philip L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sabuncu, Mert R.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sabuncu, Mert R.] MIT, CSAIL, Cambridge, MA 02139 USA. [Sabuncu, Mert R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Allen, April N.; Corneveaux, Jason J.; Huentelman, Matthew J.; Reiman, Eric M.] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ 85004 USA. [Allen, April N.; Corneveaux, Jason J.; Huentelman, Matthew J.; Reiman, Eric M.] Arizona Alzheimers Consortium, Phoenix, AZ 85004 USA. [Hardy, John A.] NIA, Neurogenet Lab, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Hardy, John A.] Inst Neurol, Dept Mol Neurosci, Reta Lila Weston Labs, London WC1N 3BG, England. [Lemere, Cynthia A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Myers, Amanda J.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Myers, Amanda J.] Johnnie B Byrd Sr Alzheimers Ctr & Res Inst, Tampa, FL 33136 USA. [Nicholson-Weller, Anne] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Reiman, Eric M.] Univ Arizona, Banner Alzheimers Inst, Phoenix, AZ 85006 USA. [Reiman, Eric M.] Univ Arizona, Dept Psychiat, Phoenix, AZ 85006 USA. [Evans, Denis A.] Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA. [Evans, Denis A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Evans, Denis A.; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. RP De Jager, PL (reprint author), Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, 77 Ave Louis Pasteur,NRB168, Boston, MA 02115 USA. EM pdejager@rics.bwh.harvard.edu RI Hardy, John/C-2451-2009; Myers, Amanda/B-1796-2010 OI Myers, Amanda/0000-0002-3100-9396 FU National Institutes of Health (NIH) [R01 AG30146, R01 AG179917, R01 AG15819, K08 AG034290, P30 AG10161, R01 AG11101, R01NS059873, P50 AG16573, R01 AG034504, K01AG024079, U01 AG024904, P30 AG010129, K01 AG030514]; Illinois Department of Public Health; Burroughs Wellcome Fund; Beth Israel Deaconess Medical Center-Harvard/MIT Health Sciences and Technology; Pfizer, Inc.; Merck Co.; Arizona Alzheimer's Disease Center [P30 AG19610, RO1 AG023193]; Mayo Clinic Alzheimer's Disease Center [P50 AG16574]; Kronos Life Sciences Laboratories, the National Alzheimer's Coordinating Center [U01 AG016976]; NIH Neuroscience Blueprint [U24NS051872]; ENDGAME Consortium [UO1HL084744]; state of Arizona; National Institute of Biomedical Imaging and Bioengineering; Northern California Institute for Research and Education; Dana Foundation FX This work is supported by the National Institutes of Health (NIH) (R01 AG30146, R01 AG179917, R01 AG15819, K08 AG034290, P30 AG10161 and R01 AG11101) and the Illinois Department of Public Health. J.M.S. was additionally supported by the Burroughs Wellcome Fund and the Clinical Investigator Training Program (Beth Israel Deaconess Medical Center-Harvard/MIT Health Sciences and Technology in collaboration with Pfizer, Inc. and Merck & Co.). M.J.H., J.J.C. and E. M. R. are supported by grants from the NIH (R01NS059873), Arizona Alzheimer's Disease Center P30 AG19610, RO1 AG023193, Mayo Clinic Alzheimer's Disease Center P50 AG16574 and Intramural Research Program, Kronos Life Sciences Laboratories, the National Alzheimer's Coordinating Center (U01 AG016976), the NIH Neuroscience Blueprint (U24NS051872), the ENDGAME Consortium (UO1HL084744), NIH grants to Carl Cotman (University of California, Irvine, P50 AG16573) and K01AG024079, and the state of Arizona. A.J.M. is supported by the NIH grant R01 AG034504 and the Johnnie B. Byrd Institute. J.A.H. would like to thank the Verum Foundation. Data collection and sharing for ADNI was funded by the NIH Grant U01 AG024904. ADNI is funded by the NIH, the National Institute of Biomedical Imaging and Bioengineering, through generous contributions from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer, Inc., F. Hoffman-La Roche, Schering-Plough, Synarc, Inc. and non-profit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions are facilitated by the Foundation for the NIH (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 37 Z9 37 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2012 VL 21 IS 10 BP 2377 EP 2388 DI 10.1093/hmg/dds054 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 933BH UT WOS:000303333700020 PM 22343410 ER PT J AU Imamichi, H Lane, HC AF Imamichi, Hiromi Lane, H. Clifford TI Regulatory T Cells in HIV-1 Infection: The Good, the Bad, and the Ugly SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID TRANSCRIPTION FACTOR FOXP3; VIRUS TYPE-1 INFECTION; IMMUNE ACTIVATION; EXPRESSING FOXP3; TGF-BETA; INTERLEUKIN-2; PATHOGENESIS; PROGRESSION; INDUCTION; TOLERANCE C1 [Imamichi, Hiromi; Lane, H. Clifford] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Lane, HC (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM clane@niaid.nih.gov NR 30 TC 15 Z9 15 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 IS 10 BP 1479 EP + DI 10.1093/infdis/jis238 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZO UT WOS:000303329200001 PM 22457283 ER PT J AU Otto, M AF Otto, Michael TI How Staphylococcus aureus Breaches Our Skin to Cause Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID ALPHA-HEMOLYSIN; VIRULENCE DETERMINANTS; PEPTIDES; MODEL C1 NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bldg 33 1W10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural NIH HHS; NIAID NIH HHS [ZIA AI000904-08] NR 18 TC 3 Z9 3 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 IS 10 BP 1483 EP 1485 DI 10.1093/infdis/jis248 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZO UT WOS:000303329200002 PM 22457276 ER PT J AU Cuevas, LE Browning, R Bossuyt, P Casenghi, M Cotton, MF Cruz, AT Dodd, LE Drobniewski, F Gale, M Graham, SM Grzemska, M Heinrich, N Hesseling, AC Huebner, R Jean-Philippe, P Kabra, SK Kampmann, B Lewinsohn, D Li, MJ Lienhardt, C Mandalakas, AM Marais, BJ Menzies, HJ Montepiedra, G Mwansambo, C Oberhelman, R Palumbo, P Russek-Cohen, E Shapiro, DE Smith, B Soto-Castellares, G Starke, JR Swaminathan, S Wingfield, C Worrell, C AF Cuevas, Luis E. Browning, Renee Bossuyt, Patrick Casenghi, Martina Cotton, Mark F. Cruz, Andrea T. Dodd, Lori E. Drobniewski, Francis Gale, Marianne Graham, Stephen M. Grzemska, Malgosia Heinrich, Norbert Hesseling, Anneke C. Huebner, Robin Jean-Philippe, Patrick Kabra, Sushil Kumar Kampmann, Beate Lewinsohn, Deborah Li, Meijuan Lienhardt, Christian Mandalakas, Anna M. Marais, Ben J. Menzies, Heather J. Montepiedra, Grace Mwansambo, Charles Oberhelman, Richard Palumbo, Paul Russek-Cohen, Estelle Shapiro, David E. Smith, Betsy Soto-Castellares, Giselle Starke, Jeffrey R. Swaminathan, Soumya Wingfield, Claire Worrell, Carol TI Evaluation of Tuberculosis Diagnostics in Children: 2. Methodological Issues for Conducting and Reporting Research Evaluations of Tuberculosis Diagnostics for Intrathoracic Tuberculosis in Children. Consensus From an Expert Panel(a) SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID DRUG-SUSCEPTIBILITY ASSAY; POLYMERASE-CHAIN-REACTION; MYCOBACTERIUM-TUBERCULOSIS; MICROSCOPIC-OBSERVATION; PULMONARY TUBERCULOSIS; ACCURACY; SPUTUM; TESTS AB Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children. In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children. C1 [Cuevas, Luis E.] Univ Liverpool, Liverpool Sch Trop Med, Child & Reprod Hlth Grp, Liverpool L3 5QA, Merseyside, England. [Browning, Renee; Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn, HIV AIDS Sci & Operat Support HJF DAIDS, Bethesda, MD 20892 USA. [Bossuyt, Patrick] Univ Amsterdam, NL-1012 WX Amsterdam, Netherlands. [Casenghi, Martina] Med Sans Frontieres, Geneva, Switzerland. [Cotton, Mark F.] Univ Stellenbosch, Tygerberg Childrens Hosp, Childrens Infect Dis Clin Res Unit, Cape Town, South Africa. [Cruz, Andrea T.; Starke, Jeffrey R.] Baylor Sch Med, Houston, TX USA. [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Drobniewski, Francis] Barts & London Queen Marys Sch Med & Dent, Hlth Protect Agcy, Natl Mycobacterium Reference Lab, London, England. [Drobniewski, Francis] Barts & London Queen Marys Sch Med & Dent, Clin TB & HIV Grp, London, England. [Gale, Marianne] Med Sans Frontieres, Sydney, NSW, Australia. [Graham, Stephen M.] Univ Melbourne, Dept Paediat, Ctr Int Child Hlth, Melbourne, Vic 3010, Australia. [Graham, Stephen M.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Murdoch, WA, Australia. [Grzemska, Malgosia; Lienhardt, Christian] WHO, STOP TB Dept, CH-1211 Geneva, Switzerland. [Heinrich, Norbert] Univ Munich, Med Ctr, Div Infect Dis & Trop Med, D-80539 Munich, Germany. [Hesseling, Anneke C.] Univ Stellenbosch, Desmond Tutu TB Ctr, Cape Town, South Africa. [Huebner, Robin] NIAID, Epidemiol Branch, Div Aids, NIH, Bethesda, MD 20892 USA. [Kabra, Sushil Kumar] All India Inst Med Sci, New Delhi, India. [Kampmann, Beate] Univ London Imperial Coll Sci Technol & Med, Dept Paediat, London SW7 2AZ, England. [Kampmann, Beate] MRC, Banjul, Gambia. [Lewinsohn, Deborah] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97201 USA. [Li, Meijuan] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Mandalakas, Anna M.] Texas Childrens Hosp, Baylor Coll Med, Ctr Global Hlth, Sect Retrovirol & Global Hlth, Houston, TX 77030 USA. [Marais, Ben J.] Univ Sydney, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [Menzies, Heather J.] Ctr Dis Control & Prevent, Int Res & Programs Branch, Div TB Eliminat, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA USA. [Montepiedra, Grace; Shapiro, David E.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Mwansambo, Charles] Minist Hlth, Lilongwe, Malawi. [Oberhelman, Richard] Tulane Sch Publ Hlth & Trop Med, Dept Trop Med, New Orleans, LA USA. [Oberhelman, Richard] Tulane Sch Publ Hlth & Trop Med, Dept Pediat, New Orleans, LA USA. [Palumbo, Paul] Dartmouth Med Sch, Lebanon, NH USA. [Russek-Cohen, Estelle] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Smith, Betsy] NIAID, Maternal Adolescent Pediat Res Branch, Div Aids, NIH, Bethesda, MD 20892 USA. [Soto-Castellares, Giselle] USN, Dept Emerging Infect Dis, Med Res Unit 6, Bellavista, Callao, Peru. [Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Wingfield, Claire] Treatment Act Grp, New York, NY USA. [Worrell, Carol] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. RP Cuevas, LE (reprint author), Univ Liverpool, Liverpool Sch Trop Med, Child & Reprod Hlth Grp, Pembroke Pl, Liverpool L3 5QA, Merseyside, England. EM lcuevas@liv.ac.uk RI Bossuyt, Patrick/B-4557-2016; Heinrich, Norbert/B-3750-2014; OI Bossuyt, Patrick/0000-0003-4427-0128; Cuevas, Luis E./0000-0002-6581-0587 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health; National Institute of Child Health and Human Development; Centers for Disease Control and Prevention; Office of Global AIDS Coordinator; US Department of Department of Health and Human Services [HHSN272200800014C]; International Maternal Pediatric Adolescent AIDS Clinical Trials Group Statistical and Data Management Center [UM01 AI068616]; Thrasher Research Fund [02824-6] FX This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institute of Child Health and Human Development, Centers for Disease Control and Prevention, and Office of Global AIDS Coordinator. Funding from these institutions was not associated with a research grant but supported directly the scientific workshop from which this work was generated. The project was also supported in part with US federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and US Department of Department of Health and Human Services (contract HHSN272200800014C). D. S. and G. M. were supported by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group Statistical and Data Management Center grant (grant No UM01 AI068616). L. E. C. was supported by a Thrasher Research Fund grant (contract 02824-6). NR 26 TC 37 Z9 37 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S209 EP S215 DI 10.1093/infdis/jir879 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700008 PM 22476719 ER PT J AU Graham, SM Ahmed, T Amanullah, F Browning, R Cardenas, V Casenghi, M Cuevas, LE Gale, M Gie, RP Grzemska, M Handelsman, E Hatherill, M Hesseling, AC Jean-Philippe, P Kampmann, B Kabra, SK Lienhardt, C Lighter-Fisher, J Madhi, S Makhene, M Marais, BJ McNeeley, DF Menzies, H Mitchell, C Modi, S Mofenson, L Musoke, P Nachman, S Powell, C Rigaud, M Rouzier, V Starke, JR Swaminathan, S Wingfield, C AF Graham, Stephen M. Ahmed, Tahmeed Amanullah, Farhana Browning, Renee Cardenas, Vicky Casenghi, Martina Cuevas, Luis E. Gale, Marianne Gie, Robert P. Grzemska, Malgosia Handelsman, Ed Hatherill, Mark Hesseling, Anneke C. Jean-Philippe, Patrick Kampmann, Beate Kabra, Sushil Kumar Lienhardt, Christian Lighter-Fisher, Jennifer Madhi, Shabir Makhene, Mamodikoe Marais, Ben J. McNeeley, David F. Menzies, Heather Mitchell, Charles Modi, Surbhi Mofenson, Lynne Musoke, Philippa Nachman, Sharon Powell, Clydette Rigaud, Mona Rouzier, Vanessa Starke, Jeffrey R. Swaminathan, Soumya Wingfield, Claire TI Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTED ADULTS; XPERT MTB/RIF TEST; CHILDHOOD TUBERCULOSIS; PULMONARY TUBERCULOSIS; SOUTH-AFRICA; PEDIATRIC TUBERCULOSIS; RESISTANT TUBERCULOSIS; ACCURACY AB There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis. C1 [Graham, Stephen M.] Univ Melbourne, Royal Childrens Hosp, Ctr Int Child Hlth, Dept Paediat & Murdoch Childrens,Res Inst, Parkville, Vic 3052, Australia. [Graham, Stephen M.] Int Union TB & Lung Dis, Paris, France. [Ahmed, Tahmeed] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Amanullah, Farhana] Indus Hosp, Karachi, Pakistan. [Browning, Renee; Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn, Maternal Adolescent Pediat Res Branch, Div Aids,NIH, Bethesda, MD 20892 USA. [Cardenas, Vicky] Aeras, Rockville, MD USA. [Casenghi, Martina] Med Sans Frontieres, Geneva, Switzerland. [Cuevas, Luis E.] Univ Liverpool, Sch Trop Med, Liverpool L69 3BX, Merseyside, England. [Gale, Marianne] Med Sans Frontieres, Sydney, NSW, Australia. [Gie, Robert P.] Univ Stellenbosch, Dept Paediat & Child Hlth, Cape Town, South Africa. [Grzemska, Malgosia; Lienhardt, Christian] WHO, Stop TB Partnership, CH-1211 Geneva, Switzerland. [Handelsman, Ed] NIAID, Maternal Adolescent Pediat Res Branch, Div Aids, NIH, Bethesda, MD 20892 USA. [Hatherill, Mark] Univ Cape Town, Sch Child & Adolescent Hlth, S African TB Vaccine Initiat, ZA-7925 Cape Town, South Africa. [Hesseling, Anneke C.] Univ Stellenbosch, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Cape Town, South Africa. [Kampmann, Beate] Univ London Imperial Coll Sci Technol & Med, Dept Paediat, London, England. [Kampmann, Beate] MRC Labs, Banjul, Gambia. [Kabra, Sushil Kumar] All India Inst Med Sci, New Delhi, India. [Lighter-Fisher, Jennifer; Rigaud, Mona] NYU, Sch Med, New York, NY USA. [Madhi, Shabir] Natl Inst Communicable Dis, Natl Hlth Lab Serv, Johannesburg, South Africa. [Makhene, Mamodikoe] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Marais, Ben J.] Univ Sydney, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [McNeeley, David F.] Med Serv Corp Int, Arlington, VA USA. [Menzies, Heather] Ctr Dis Control & Prevent, Int Res & Programs Branch, Div TB Eliminat, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA USA. [Mitchell, Charles] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Modi, Surbhi] Ctr Dis Control & Prevent, Maternal & Child Hlth Branch, Div Global HIV AIDS, Atlanta, GA USA. [Mofenson, Lynne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. [Musoke, Philippa] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [Nachman, Sharon] SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. [Powell, Clydette] US Agcy Int Dev, Div Infect Dis, Off Hlth Infect Dis & Nutr, Bur Global Hlth, Washington, DC 20523 USA. [Rouzier, Vanessa] GHESKIO Ctr, Port Au Prince, Haiti. [Starke, Jeffrey R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Swaminathan, Soumya] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Wingfield, Claire] Treatment Act Grp, New York, NY USA. RP Graham, SM (reprint author), Univ Melbourne, Royal Childrens Hosp, Ctr Int Child Hlth, Dept Paediat, Flemington Rd, Parkville, Vic 3052, Australia. EM steve.graham@rch.org.au; jeanphilippep@niaid.nih.gov OI Mofenson, Lynne/0000-0002-2818-9808; Lighter, Jennifer/0000-0002-9313-2103; Cuevas, Luis E./0000-0002-6581-0587; Kampmann, Beate/0000-0002-6546-4709 FU NIAID/NIH; Eunice Kennedy Shriver NICHD; CDC; OGAC; NIAID/NIH, US DHHS [HHSN272200800014C] FX This work was supported by NIAID/NIH, Eunice Kennedy Shriver NICHD, CDC, and OGAC. This project has also been supported in part with federal funds from the NIAID/NIH, US DHHS, under contract no. HHSN272200800014C. NR 32 TC 124 Z9 124 U1 0 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S199 EP S208 DI 10.1093/infdis/jis008 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700007 PM 22448023 ER PT J AU Kim, PS Makhene, M Sizemore, C Hafner, R AF Kim, Peter S. Makhene, Mamodikoe Sizemore, Christine Hafner, Richard TI Viewpoint: Challenges and Opportunities in Tuberculosis Research SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TRANSLATION C1 [Kim, Peter S.] NIAID, TB Clin Res Team, Therapeut Res Program, Div Aids,NIH, Bethesda, MD 20892 USA. [Makhene, Mamodikoe; Sizemore, Christine] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Kim, PS (reprint author), NIAID, TB Clin Res Team, Therapeut Res Program, Div Aids,NIH, 6700B Rockledge Dr,Room 4256, Bethesda, MD 20892 USA. EM kimp2@niaid.nih.gov NR 18 TC 7 Z9 9 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S347 EP S352 DI 10.1093/infdis/jis190 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700023 PM 22448021 ER PT J AU Lienhardt, C Raviglione, M Spigelman, M Hafner, R Jaramillo, E Hoelscher, M Zumla, A Gheuens, J AF Lienhardt, Christian Raviglione, Mario Spigelman, Mel Hafner, Richard Jaramillo, Ernesto Hoelscher, Michael Zumla, Alimuddin Gheuens, Jan TI New Drugs for the Treatment of Tuberculosis: Needs, Challenges, Promise, and Prospects for the Future SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MULTIDRUG-RESISTANT TUBERCULOSIS; PULMONARY TUBERCULOSIS; ANTIRETROVIRAL THERAPY; CLINICAL-TRIALS; PHASE-II; MOXIFLOXACIN; CHEMOTHERAPY; OPPORTUNITIES; ETHAMBUTOL; INFECTION AB For the first time in 40 years, a portfolio of promising new compounds for the treatment of tuberculosis is on the horizon. The introduction of new drugs in combination treatment for all forms of tuberculosis raises several issues related to patients' access to novel treatments, programmatic feasibility, cost effectiveness, and implications for monitoring and surveillance, particularly with regard to the development of drug resistance. Particular attention should be given to the identification of optimal drug combination(s) for the treatment of all forms of tuberculosis, particularly in high-risk and vulnerable groups, such as human immunodeficiency virus-coinfected persons and children, and to the rational use of new drugs. Addressing these issues adequately requires the establishment of clear guidelines to assist countries in the development of policies for the proper use of tuberculosis drugs in a way that guarantees access to best treatments for all those in need and avoids inappropriate use of new drugs. After a description of these various challenges, we present activities that will be carried out by the World Health Organization in collaboration with key stakeholders for the development of policy guidelines for optimal treatment of tuberculosis. C1 [Lienhardt, Christian] WHO, Stop TB Partnership, CH-1211 Geneva 27, Switzerland. [Lienhardt, Christian; Raviglione, Mario; Jaramillo, Ernesto] WHO, Stop TB Dept, CH-1211 Geneva 27, Switzerland. [Spigelman, Mel] Global Alliance TB Drug Dev, New York, NY USA. [Hafner, Richard] NIAID, Div Aids, Bethesda, MD 20892 USA. [Hoelscher, Michael] Univ Munich, Dept Infect Dis & Trop Med, D-80539 Munich, Germany. [Zumla, Alimuddin] UCL, Sch Med, Div Infect & Immun, London WC1E 6BT, England. [Gheuens, Jan] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Lienhardt, C (reprint author), WHO, Stop TB Partnership, 20 Ave Appia, CH-1211 Geneva 27, Switzerland. EM lienhardtc@who.int; a.zumla@ucl.ac.uk RI Hoelscher, Michael/D-3436-2012; OI Zumla, Alimuddin/0000-0002-5111-5735 NR 43 TC 77 Z9 80 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S241 EP S249 DI 10.1093/infdis/jis034 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700011 PM 22448022 ER PT J AU McNerney, R Maeurer, M Abubakar, I Marais, B Mchugh, TD Ford, N Weyer, K Lawn, S Grobusch, MP Memish, Z Squire, SB Pantaleo, G Chakaya, J Casenghi, M Migliori, GB Mwaba, P Zijenah, L Hoelscher, M Cox, H Swaminathan, S Kim, PS Schito, M Harari, A Bates, M Schwank, S O'Grady, J Pletschette, M Ditui, L Atun, R Zumla, A AF McNerney, Ruth Maeurer, Markus Abubakar, Ibrahim Marais, Ben Mchugh, Timothy D. Ford, Nathan Weyer, Karin Lawn, Steve Grobusch, Martin P. Memish, Ziad Squire, S. Bertel Pantaleo, Giuseppe Chakaya, Jeremiah Casenghi, Martina Migliori, Giovanni-Batista Mwaba, Peter Zijenah, Lynn Hoelscher, Michael Cox, Helen Swaminathan, Soumya Kim, Peter S. Schito, Marco Harari, Alexandre Bates, Matthew Schwank, Samana O'Grady, Justin Pletschette, Michel Ditui, Lucica Atun, Rifat Zumla, Alimuddin TI Tuberculosis Diagnostics and Biomarkers: Needs, Challenges, Recent Advances, and Opportunities SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID XPERT MTB/RIF ASSAY; GAMMA RELEASE ASSAYS; T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; EXTRAPULMONARY TUBERCULOSIS; INTRATHORACIC TUBERCULOSIS; RESISTANT TUBERCULOSIS; ACTIVE TUBERCULOSIS; RIFAMPIN RESISTANCE AB Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics. C1 [Zumla, Alimuddin] Royal Free Hosp, Ctr Clin Microbiol, Div Infect & Immun, Univ Coll London Med Sch, London NW3 2PF, England. [McNerney, Ruth] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Pathogen Mol Biol, London, England. [Maeurer, Markus] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Maeurer, Markus] Karolinska Inst, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Maeurer, Markus] Karolinska Inst, Dept Lab Med, Stockholm, Sweden. [Abubakar, Ibrahim] Hlth Protect Agcy, TB Sect, Hlth Protect Serv, London, England. [Abubakar, Ibrahim] Univ E Anglia, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England. [Marais, Ben] Univ Sydney, Sydney Emerging Infect Dis & Biosecur Inst, Sydney, NSW 2006, Australia. [Marais, Ben] Univ Sydney, Sydney Med Sch, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [Ford, Nathan; Casenghi, Martina; Cox, Helen] Med Sans Frontieres, S Africa Unit, Cape Town, South Africa. [Weyer, Karin] WHO, TB Diagnost & Lab Strengthening, Stop TB Dept, CH-1211 Geneva, Switzerland. [Lawn, Steve] Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7700 Rondebosch, South Africa. [Grobusch, Martin P.] Univ Amsterdam, Acad Med Ctr, Div Internal Med, Dept Infect Dis, NL-1105 AZ Amsterdam, Netherlands. [Memish, Ziad] Alfaisal Univ, Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Squire, S. Bertel] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Pantaleo, Giuseppe; Harari, Alexandre; Bates, Matthew] Univ Lausanne, CHU Vaudois, Swiss Vaccine Res Inst, CH-1015 Lausanne, Switzerland. [Pantaleo, Giuseppe; Harari, Alexandre; Bates, Matthew] Univ Lausanne, CHU Vaudois, Div Immunol & Allergy, CH-1015 Lausanne, Switzerland. [Chakaya, Jeremiah] Kenya Govt Med Res Ctr, Ctr Resp Dis Res, Nairobi, Kenya. [Chakaya, Jeremiah] Minist Hlth, Natl TB Programme, Nairobi, Kenya. [Migliori, Giovanni-Batista] Fdn S Maugeri, Care & Res Inst, WHO Collaborating Ctr TB & Lung Dis, Tradate, Italy. [Mwaba, Peter] Minist Hlth, Lusaka, Zambia. [Mwaba, Peter; Schwank, Samana; O'Grady, Justin; Zumla, Alimuddin] UNZA UCLMS Project, Lusaka, Zambia. [Zijenah, Lynn] Univ Zimbabwe, Coll Hlth Sci, Dept Immunol, Harare, Zimbabwe. [Hoelscher, Michael] Univ Munich, Dept Infect Dis & Trop Med, D-80539 Munich, Germany. [Cox, Helen] Monash Univ, Melbourne, Vic 3004, Australia. [Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Kim, Peter S.] NIAID, TB Team, Div Acquired Immunodeficiency Syndrome, NIH, Bethesda, MD 20892 USA. [Schito, Marco] NIAID, Vaccine Clin Res Branch, Div Acquired Immunodeficiency Syndrome, NIH, Bethesda, MD 20892 USA. [Schito, Marco] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Harari, Alexandre; Bates, Matthew] Univ Lausanne, CHU Vaudois, Swiss Vaccine Res Inst, CH-1015 Lausanne, Switzerland. [Pletschette, Michel] European Commiss Brussels, Unit Evaluat, Brussels, Belgium. [Pletschette, Michel] European Commiss Brussels, Audit Directorate Publ Hlth, Brussels, Belgium. [Ditui, Lucica] WHO, STOP TB Partnership, CH-1211 Geneva, Switzerland. [Atun, Rifat] Global Fund, Geneva, Switzerland. [Atun, Rifat] Univ London Imperial Coll Sci Technol & Med, London, England. RP Zumla, A (reprint author), Royal Free Hosp, Ctr Clin Microbiol, Div Infect & Immun, Univ Coll London Med Sch, Royal Free Campus,2nd Floor,Rowland Hill St, London NW3 2PF, England. EM Markus.Maeurer@ki.se; kimp2@niaid.nih.gov; schitom@niaid.nih.gov; r.atun@imperial.ac.uk; a.zumla@ucl.ac.uk RI Hoelscher, Michael/D-3436-2012; O'Grady, Justin/I-2982-2012; Pantaleo, Giuseppe/K-6163-2016; OI O'Grady, Justin/0000-0001-5412-7152; Abubakar, Ibrahim/0000-0002-0370-1430; Migliori, Giovanni Battista/0000-0002-2597-574X; MCNERNEY, Ruth/0000-0002-1957-443X; Cox, Helen/0000-0002-6538-7192; McHugh, Timothy D/0000-0003-4658-8594; Harari, Alexandre/0000-0002-1055-2090; Zumla, Alimuddin/0000-0002-5111-5735 FU EuropeAID, Belgium; European and Developing Countries Clinical Trials Partnership (EDCTP), Netherlands; UK Medical Research Council (MRC); UBS Optimus Foundation, Switzerland; University College London Hospitals Comprehensive Biomedical Research Centre (UCLH-CBRC); UCL Hospitals National Health Service (NHS) Foundation Trust FX This work was supported by EuropeAID, Belgium; European and Developing Countries Clinical Trials Partnership (EDCTP), Netherlands; UK Medical Research Council (MRC); and UBS Optimus Foundation, Switzerland. A. Z. is supported by the University College London Hospitals Comprehensive Biomedical Research Centre (UCLH-CBRC) and the UCL Hospitals National Health Service (NHS) Foundation Trust. NR 94 TC 74 Z9 76 U1 2 U2 46 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S147 EP S158 DI 10.1093/infdis/jir860 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700002 PM 22496353 ER PT J AU Nahid, P Kim, PS Evans, CA Alland, D Barer, M Diefenbach, J Ellner, J Hafner, R Hamilton, CD Iademarco, MF Ireton, G Kimerling, ME Lienhardt, C MacKenzie, WR Murray, M Perkins, MD Posey, JE Roberts, T Sizemore, C Stevens, WS Via, L Williams, SD Yew, WW Swindells, S AF Nahid, Payam Kim, Peter S. Evans, Carlton A. Alland, David Barer, Michael Diefenbach, Jane Ellner, Jerrold Hafner, Richard Hamilton, Carol Dukes Iademarco, Michael F. Ireton, Gregory Kimerling, Michael E. Lienhardt, Christian MacKenzie, William R. Murray, Megan Perkins, Mark D. Posey, Jamie E. Roberts, Teri Sizemore, Christine Stevens, Wendy S. Via, Laura Williams, Sharon D. Yew, Wing W. Swindells, Susan TI Clinical Research and Development of Tuberculosis Diagnostics: Moving From Silos to Synergy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MEDIATED ISOTHERMAL AMPLIFICATION; MULTIDRUG-RESISTANT TUBERCULOSIS; DRUG-SUSCEPTIBILITY ASSAY; SPUTUM SMEAR MICROSCOPY; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; MOLECULAR-DETECTION; MASS-SPECTROMETRY; META-REGRESSION; LIQUID CULTURE AB The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations. C1 [Nahid, Payam] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA 94110 USA. [Nahid, Payam] Univ Calif San Francisco, Curry Int TB Ctr, San Francisco, CA 94110 USA. [Kim, Peter S.; Hafner, Richard; Williams, Sharon D.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Evans, Carlton A.] Univ Peruana Cayetano Heredia, IFHAD, Lima, Peru. [Evans, Carlton A.] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis & Immun, London SW7 2AZ, England. [Alland, David] Univ Med & Dent New Jersey, Dept Med, Ctr Emerging & Reemerging Pathogens, Newark, NJ 07103 USA. [Barer, Michael] Univ Leicester, Dept Infect Immun & Inflammat, Leicester LE1 7RH, Leics, England. [Diefenbach, Jane] PharmaStat LLC, Newark, CA USA. [Ellner, Jerrold] Boston Univ Sch Med & Med Ctr, Dept Med, Infect Dis Sect, Boston, MA USA. [Hamilton, Carol Dukes] Family Hlth Int, Durham, NC USA. [Ireton, Gregory] Bill & Melinda Gates Fdn, Infect Dis Res Inst, Seattle, WA USA. [Kimerling, Michael E.] Bill & Melinda Gates Fdn, Global Hlth Program, Seattle, WA USA. [Lienhardt, Christian] WHO, Stop TB Partnership, CH-1211 Geneva, Switzerland. [Iademarco, Michael F.; MacKenzie, William R.; Posey, Jamie E.] Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA USA. [Murray, Megan] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Perkins, Mark D.] Fdn Innovat New Diagnost, Geneva, Switzerland. [Roberts, Teri] Med San Frontieres, Campaign Access Essential Med, Geneva, Switzerland. [Sizemore, Christine] NIAID, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. [Stevens, Wendy S.] Univ Witwatersrand, Johannesburg, South Africa. [Stevens, Wendy S.] Natl Hlth Lab Serv, Johannesburg, South Africa. [Via, Laura] NIAID, Lab Clin Infect Dis, TB Res Sect, Bethesda, MD 20892 USA. [Yew, Wing W.] Hong Kong TB Chest & Heart Dis Assoc, Hong Kong, Hong Kong, Peoples R China. [Swindells, Susan] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. RP Nahid, P (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Dept Pulm & Crit Care Med, 1001 Potrero Ave,5K1, San Francisco, CA 94110 USA. EM pnahid@ucsf.edu; kimp2@niaid.nih.gov; rhafner@niaid.nih.gov RI Mac Kenzie, William /F-1528-2013; OI Mac Kenzie, William /0000-0001-7723-0339; Evans, Carlton/0000-0002-6873-5447; Via, Laura/0000-0001-6074-9521 FU CDC; NIAID; Office of the Global AIDS Coordinator; National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute of the NIH [K23HL092629]; Wellcome Trust; Bill and Melinda Gates Foundation [28766.01]; FIND; Innovation For Health and Development FX We thank the meeting organizing committee (Ms Bonnie Plikaytis [CDC], and Drs Gail Jacobs [NIAID], Mamodikoe Makhene [NIAID], and Christine Sizemore [NIAID]), and the sponsors (CDC, NIAID, Office of the Global AIDS Coordinator, and the National Institute of Child Health and Human Development) for organizing and supporting this workshop.; This work was supported by the National Heart, Lung, and Blood Institute of the NIH (K23HL092629 to P. N.) and the Wellcome Trust, FIND, and Innovation For Health and Development (to C.A. E.).; M. P. has no commercial associations or other conflicts of interest relevant to the work presented. He was supported by a grant from the Bill and Melinda Gates Foundation (grant number 28766.01). A. D. reports that he and his laboratory receive licensing income for the use of molecular beacons in the GeneXpert MTB/RIF assay. His personal income has been voluntarily and irrevocably capped at $5,000 per year and income to his laboratory has been voluntarily capped at $50,000 per year. All other authors: no reported conflicts. NR 61 TC 14 Z9 15 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S159 EP S168 DI 10.1093/infdis/jis194 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700003 PM 22476718 ER PT J AU Palamountain, KM Baker, J Cowan, EP Essajee, S Mazzola, LT Metzler, M Schito, M Stevens, WS Young, GJ Domingo, GJ AF Palamountain, Kara M. Baker, Jeff Cowan, Elliot P. Essajee, Shaffiq Mazzola, Laura T. Metzler, Mutsumi Schito, Marco Stevens, Wendy S. Young, Gloria J. Domingo, Gonzalo J. TI Perspectives on Introduction and Implementation of New Point-of-Care Diagnostic Tests SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RESOURCE-LIMITED SETTINGS; RANDOMIZED CONTROLLED-TRIAL; ANTIRETROVIRAL THERAPY; CONSTRAINED SETTINGS; RIFAMPIN RESISTANCE; LABORATORY SYSTEMS; INFORMATION-SYSTEM; QUALITY-ASSURANCE; POOR SETTINGS; HIV-1 STRAINS AB In recent years, there has been significant investment from both the private and public sectors in the development of diagnostic technologies to meet the need for human immunodeficiency virus (HIV) and tuberculosis testing in low-resource settings. Future investments should ensure that the most appropriate technologies are adopted in settings where they will have a sustainable impact. Achieving these aims requires the involvement of many stakeholders, as their needs, operational constraints, and priorities are often distinct. Here, we discuss these considerations from different perspectives representing those of various stakeholders involved in the development, introduction, and implementation of diagnostic tests. We also discuss some opportunities to address these considerations. C1 [Metzler, Mutsumi; Domingo, Gonzalo J.] PATH, Seattle, WA 98109 USA. [Palamountain, Kara M.] Northwestern Univ, Kellogg Sch Management, Evanston, IL USA. [Baker, Jeff] Alere, Infect Dis Strateg Business Unit, Waltham, MA USA. [Cowan, Elliot P.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Essajee, Shaffiq] WHO, HIV Dept, CH-1211 Geneva, Switzerland. [Mazzola, Laura T.] Wave 80 Biosci, San Francisco, CA USA. [Schito, Marco] NIH, Henry M Jackson Fdn, Div Aids, Bethesda, MD 20892 USA. [Stevens, Wendy S.] Univ Witwatersrand, Dept Mol Med & Haematol, Johannesburg, South Africa. [Stevens, Wendy S.] Natl Hlth Lab Serv, Johannesburg, South Africa. [Young, Gloria J.] Becton Dickinson Biosci, San Jose, CA USA. RP Domingo, GJ (reprint author), PATH, POB 900922, Seattle, WA 98109 USA. EM schitom@niaid.nih.gov; gdomingo@path.org FU National Institute of Allergy and Infectious Diseases; US National Institutes of Health (NIH); US Department of Health and Human Services [HHSN272200800014C]; National Institute of Biomedical Imaging and Bioengineering, NIH [1U54EB007949-01] FX This work was supported by the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH), and the US Department of Health and Human Services (contract HHSN272200800014C). Preparation of the manuscript was funded in part by the National Institute of Biomedical Imaging and Bioengineering, NIH (grant 1U54EB007949-01). NR 60 TC 24 Z9 25 U1 0 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S181 EP S190 DI 10.1093/infdis/jis203 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700005 PM 22402038 ER PT J AU Phillips, PPJ Gillespie, SH Boeree, M Heinrich, N Aarnoutse, R McHugh, T Pletschette, M Lienhardt, C Hafner, R Mgone, C Zumla, A Nunn, AJ Hoelscher, M AF Phillips, Patrick P. J. Gillespie, Stephen H. Boeree, Martin Heinrich, Norbert Aarnoutse, Rob McHugh, Tim Pletschette, Michel Lienhardt, Christian Hafner, Richard Mgone, Charles Zumla, Alimuddin Nunn, Andrew J. Hoelscher, Michael TI Innovative Trial Designs Are Practical Solutions for Improving the Treatment of Tuberculosis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; CLINICAL-TRIALS; MESSENGER-RNA; PULMONARY TUBERCULOSIS; PHASE-II; MOXIFLOXACIN; SURROGATE; METHODOLOGY; BIOMARKER; CANCER AB A growing number of new drugs for the treatment of tuberculosis are in clinical development. Confirmatory phase 3 trials are expensive and time-consuming and the question of whether one particular drug combination can be used to treat tuberculosis is less important from a public health perspective than the question of which are the shortest, simplest, most effective, and safest regimens. While preclinical and phase 1 studies provide some guidance in the selection of combinations for clinical evaluation, a large number of combinations will require phase 2 testing to ensure that only the best regimens advance to phase 3. The multi-arm multi-stage trial design is an example of a treatment selection-adaptive design where multiple experimental arms are each simultaneously compared with a common control and interim analyses allow for poor performing arms to be dropped early. Such designs, if designed and implemented correctly, require fewer patients, can be completed in a shorter time frame, and answer more relevant questions without any loss in statistical validity or scientific integrity. There are, however, practical issues that must be considered in applying this in tuberculosis treatment trials. More innovative trials designs should be considered to speed drug and regimen development for the treatment of tuberculosis. C1 [Heinrich, Norbert; Pletschette, Michel; Hoelscher, Michael] Univ Munich LMU, Div Infect Dis & Trop Med, Med Ctr, Munich, Germany. [Phillips, Patrick P. J.; Nunn, Andrew J.] MRC, Clin Trials Unit, London, England. [Gillespie, Stephen H.] Univ St Andrews, Sch Med N Haugh, St Andrews, Fife, Scotland. [Boeree, Martin; Aarnoutse, Rob] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [McHugh, Tim; Zumla, Alimuddin] UCL, Sch Med, London WC1E 6BT, England. [Lienhardt, Christian] WHO, Stop TB Partnership, CH-1211 Geneva, Switzerland. [Lienhardt, Christian] WHO, Stop TB Dept, CH-1211 Geneva, Switzerland. [Hafner, Richard] NIAID, Div Aids, Bethesda, MD 20892 USA. [Mgone, Charles] European & Dev Countries Clin Trials Partnership, The Hague, Netherlands. [Hoelscher, Michael] Univ Munich LMU, German Ctr Infect Res, Munich, Germany. RP Hoelscher, M (reprint author), Univ Munich, LMU, Dept Infect Dis & Trop Med, Leopoldstr 5, D-80802 Munich, Germany. EM a.zumla@ucl.ac.uk; hoelscher@lrz.uni-muenchen.de RI Heinrich, Norbert/B-3750-2014; Hoelscher, Michael/D-3436-2012; Aarnoutse, R.E./L-4168-2015 OI Zumla, Alimuddin/0000-0002-5111-5735; Phillips, Patrick/0000-0002-6336-7024; FU EDCTP [IP 2007 32011 013] FX Part of this work has been funded by the EDCTP to the Pan African Consortium for the Evaluation of Antituberculosis Antibiotics (EDCTP grant number IP 2007 32011 013). NR 23 TC 33 Z9 33 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S250 EP S257 DI 10.1093/infdis/jis041 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700012 PM 22448027 ER PT J AU Schito, M Peter, TF Cavanaugh, S Piatek, AS Young, GJ Alexander, H Coggin, W Domingo, GJ Ellenberger, D Ermantraut, E Jani, IV Katamba, A Palamountain, KM Essajee, S Dowdy, DW AF Schito, Marco Peter, Trevor F. Cavanaugh, Sean Piatek, Amy S. Young, Gloria J. Alexander, Heather Coggin, William Domingo, Gonzalo J. Ellenberger, Dennis Ermantraut, Eugen Jani, Ilesh V. Katamba, Achilles Palamountain, Kara M. Essajee, Shaffiq Dowdy, David W. TI Opportunities and Challenges for Cost-Efficient Implementation of New Point-of-Care Diagnostics for HIV and Tuberculosis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RESOURCE-LIMITED SETTINGS; ANTIRETROVIRAL THERAPY; INFECTED ADULTS; SCALING-UP; HEALTH; TESTS; PREVENTION; TRANSMISSION; TECHNOLOGIES; METAANALYSIS AB Stakeholders agree that supporting high-quality diagnostics is essential if we are to continue to make strides in the fight against human immunodeficiency virus (HIV) and tuberculosis. Despite the need to strengthen existing laboratory infrastructure, which includes expanding and developing new laboratories, there are clear diagnostic needs where conventional laboratory support is insufficient. Regarding HIV, rapid point-of-care (POC) testing for initial HIV diagnosis has been successful, but several needs remain. For tuberculosis, several new diagnostic tests have recently been endorsed by the World Health Organization, but a POC test remains elusive. Human immunodeficiency virus and tuberculosis are coendemic in many high prevalence locations, making parallel diagnosis of these conditions an important consideration. Despite its clear advantages, POC testing has important limitations, and laboratory-based testing will continue to be an important component of future diagnostic networks. Ideally, a strategic deployment plan should be used to define where and how POC technologies can be most efficiently and cost effectively integrated into diagnostic algorithms and existing test networks prior to widespread scale-up. In this fashion, the global community can best harness the tremendous capacity of novel diagnostics in fighting these 2 scourges. C1 [Schito, Marco] NIAID, Henry M Jackson Fdn Adv Mil Med, Vaccine Clin Res Branch, Div Aids,NIH, Bethesda, MD 20892 USA. [Peter, Trevor F.] Clinton Hlth Access Initiat, Boston, MA USA. [Cavanaugh, Sean] Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA USA. [Piatek, Amy S.] US Agcy Int Dev, Washington, DC 20523 USA. [Young, Gloria J.] Becton Dickinson Biosci, San Jose, CA USA. [Alexander, Heather; Ellenberger, Dennis] Ctr Dis Control & Prevent, Div Global HIV AIDS, Atlanta, GA USA. [Coggin, William] US Dept State, Off US Global AIDS, Washington, DC 20520 USA. [Domingo, Gonzalo J.] PATH, Seattle, WA USA. [Ermantraut, Eugen] Alere Technol GmbH, Jena, Germany. [Jani, Ilesh V.] Inst Nacl Saude, Maputo, Mozambique. [Katamba, Achilles] Makerere Univ, Kampala, Uganda. [Palamountain, Kara M.] Northwestern Univ, Kellogg Sch Management, Evanston, IL USA. [Essajee, Shaffiq] WHO, HIV Dept, CH-1211 Geneva, Switzerland. [Dowdy, David W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Schito, M (reprint author), NIAID, Henry M Jackson Fdn Adv Mil Med, Vaccine Clin Res Branch, Div Aids,NIH, 6700-B Rockledge Dr,Rm 5255, Bethesda, MD 20892 USA. EM schitom@niaid.nih.gov FU Office of the US Global AIDS Coordinator, US Department of State; US Centers for Disease Control and Prevention; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX This project has been funded in part with federal funds from the Office of the US Global AIDS Coordinator, US Department of State, US Centers for Disease Control and Prevention, and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (contract HHSN272200800014C). NR 67 TC 34 Z9 34 U1 0 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S169 EP S180 DI 10.1093/infdis/jis044 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700004 PM 22457286 ER PT J AU Zumla, A Atun, R Maeurer, M Kim, PS Jean-Philippe, P Hafner, R Schito, M AF Zumla, Alimuddin Atun, Rifat Maeurer, Markus Kim, Peter S. Jean-Philippe, Patrick Hafner, Richard Schito, Marco TI Eliminating Tuberculosis and Tuberculosis-HIV Co-Disease in the 21st Century: Key Perspectives, Controversies, Unresolved Issues, and Needs SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID INFECTION C1 [Zumla, Alimuddin] Royal Free Hosp, Univ Coll London, Div Infect & Immun, Ctr Clin Microbiol,Dept Infect, London NW3 2QG, England. [Atun, Rifat] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Maeurer, Markus] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Maeurer, Markus] Karolinska Inst, Dept Lab Med, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Kim, Peter S.; Hafner, Richard] NIAID, TB Clin Res Branch, Natl Inst Hlth Bethesda, Bethesda, MD USA. NIAID, Henry M Jackson Fdn Adv Mil Med, Div Aids, Natl Inst Hlth Bethesda, Bethesda, MD USA. RP Zumla, A (reprint author), Royal Free Hosp, Univ Coll London, Div Infect & Immun, Ctr Clin Microbiol,Dept Infect, Rowland Hill St, London NW3 2QG, England. EM a.zumla@ucl.ac.uk; r.atun@imperial.ac.uk; Markus.Maeurer@ki.se; kimp2@niaid.nih.gov; jeanphilippep@niaid.nih.gov; rhafner@niaid.nih.gov; schitom@niaid.nih.gov OI Zumla, Alimuddin/0000-0002-5111-5735 FU NIAID NIH HHS [HHSN272200800014C] NR 12 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S141 EP S146 DI 10.1093/infdis/jir880 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700001 PM 22448019 ER PT J AU Zumla, A Abubakar, I Raviglione, M Hoelscher, M Ditiu, L Mchugh, TD Squire, SB Cox, H Ford, N McNerney, R Marais, B Grobusch, M Lawn, SD Migliori, GB Mwaba, P O'Grady, J Pletschette, M Ramsay, A Chakaya, J Schito, M Swaminathan, S Memish, Z Maeurer, M Atun, R AF Zumla, Alimuddin Abubakar, Ibrahim Raviglione, Mario Hoelscher, Michael Ditiu, Lucica Mchugh, Timothy D. Squire, S. Bertel Cox, Helen Ford, Nathan McNerney, Ruth Marais, Ben Grobusch, Martin Lawn, Stephen D. Migliori, Giovanni-Battista Mwaba, Peter O'Grady, Justin Pletschette, Michel Ramsay, Andrew Chakaya, Jeremiah Schito, Marco Swaminathan, Soumya Memish, Ziad Maeurer, Markus Atun, Rifat TI Drug-Resistant Tuberculosis-Current Dilemmas, Unanswered Questions, Challenges, and Priority Needs SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; TREATMENT OUTCOMES; SOUTH-AFRICA; CHILDHOOD TUBERCULOSIS; CHILDREN; DIAGNOSIS; TB; MANAGEMENT; CLARITHROMYCIN; IMPLEMENTATION AB Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and > 12 years of MDR tuberculosis-specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discussed. C1 [Zumla, Alimuddin] Royal Free Hosp, Univ Coll London, Sch Med, Ctr Clin Microbiol,Div Infect & Immun, London NW3 2PF, England. [Abubakar, Ibrahim] Hlth Protect Agcy, Hlth Protect Serv, London, England. [Raviglione, Mario] WHO, STOP TB Dept, CH-1211 Geneva, Switzerland. [Hoelscher, Michael] Univ Munich, Dept Infect Dis & Trop Med, Munich, Germany. [Ditiu, Lucica] WHO, STOP TB Partnership, CH-1211 Geneva, Switzerland. [Squire, S. Bertel] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Cox, Helen] Med Sans Frontieres, Cape Town, South Africa. [Ford, Nathan] Med Sans Frontieres, Geneva, Switzerland. [Ford, Nathan] Univ Cape Town, Ctr Infect Dis Epidemiol & Res, ZA-7700 Rondebosch, South Africa. [McNerney, Ruth] London Sch Hyg & Trop Med, Dept Pathogen Mol Biol, Fac Infect & Trop Dis, London, England. [Marais, Ben] Univ Sydney, Sydney Med Sch, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [Marais, Ben] Univ Sydney, Sydney Emerging Infect Dis & Biosecur Inst, Sydney, NSW 2006, Australia. [Grobusch, Martin] Univ Amsterdam, Acad Med Ctr, Div Internal Med, Dept Infect Dis, NL-1012 WX Amsterdam, Netherlands. [Lawn, Stephen D.] Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Lawn, Stephen D.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England. [Migliori, Giovanni-Battista] Fdn S Maugeri Care & Res Inst, WHO Collaborating Ctr TB & Lung Dis, Tradate, Italy. [Mwaba, Peter] Minist Hlth, Lusaka, Zambia. [Mwaba, Peter] Univ Zambia, Lusaka, Zambia. [Mwaba, Peter] Univ Coll London, Med R&D Project, Lusaka, Zambia. [Pletschette, Michel] Commiss European Communities, Unit Evaluat, B-1049 Brussels, Belgium. [Pletschette, Michel] Commiss European Communities, Audit Directorate Publ Hlth, B-1049 Brussels, Belgium. [Ramsay, Andrew] WHO, UNICEF, UNDP, World Bank,WHO Special Programme Res & Training T, CH-1211 Geneva, Switzerland. [Chakaya, Jeremiah] Kenya Govt Med Res Ctr, Ctr Resp Dis Res, Nairobi, Kenya. [Chakaya, Jeremiah] Minist Hlth, Natl TB Programme, Nairobi, Kenya. [Schito, Marco] NIAID, Vaccine Clin Res Branch, Div Acquired Immunodeficiency Syndrome, NIH, Bethesda, MD USA. [Schito, Marco] Henry M Jackson Fdn Adv Mil Med Bethesda, Bethesda, MD USA. [Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Memish, Ziad] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Memish, Ziad] Alfaisal Univ, Minist Hlth, Riyadh, Saudi Arabia. [Maeurer, Markus] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Maeurer, Markus] Karolinska Inst, Dept Lab Med, Ctr Allogene Stem Cell Transplantat CAST, Stockholm, Sweden. [Atun, Rifat] Global Fund Fight AIDS TB & Malaria, Geneva, Switzerland. [Atun, Rifat] Univ London Imperial Coll Sci Technol & Med, London, England. RP Zumla, A (reprint author), Royal Free Hosp, Univ Coll London, Sch Med, Ctr Clin Microbiol,Div Infect & Immun, 2nd Floor,Rowland Hill St, London NW3 2PF, England. EM a.zumla@ucl.ac.uk; schitom@niaid.nih.gov; Markus.Maeurer@ki.se; r.atun@imperial.ac.uk RI O'Grady, Justin/I-2982-2012; Hoelscher, Michael/D-3436-2012; OI McHugh, Timothy D/0000-0003-4658-8594; Zumla, Alimuddin/0000-0002-5111-5735; O'Grady, Justin/0000-0001-5412-7152; Migliori, Giovanni Battista/0000-0002-2597-574X; Abubakar, Ibrahim/0000-0002-0370-1430; MCNERNEY, Ruth/0000-0002-1957-443X; Cox, Helen/0000-0002-6538-7192 FU European Commission (EuropeAid), Belgium; European and Developing Countries Clinical Trials Partnership (EDCTP), Netherlands; Union Bank of Switzerland (UBS) Optimus Foundation, Switzerland; University College London Hospitals (UCLH) National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre (CBRC); UCLH National Health Service (NHS) Foundation Trust FX This work was supported by the European Commission (EuropeAid), Belgium; European and Developing Countries Clinical Trials Partnership (EDCTP), Netherlands; and Union Bank of Switzerland (UBS) Optimus Foundation, Switzerland. A. Z is supported by the University College London Hospitals (UCLH) National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre (CBRC) and the UCLH National Health Service (NHS) Foundation Trust. NR 72 TC 71 Z9 71 U1 0 U2 40 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2012 VL 205 SU 2 BP S228 EP S240 DI 10.1093/infdis/jir858 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 932ZT UT WOS:000303329700010 PM 22476720 ER PT J AU Awasthi, S Simons, SS AF Awasthi, Smita Simons, S. Stoney, Jr. TI Separate regions of glucocorticoid receptor, coactivator TIF2, and comodulator STAMP modify different parameters of glucocorticoid-mediated gene induction SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Glucocorticoid receptors; Dose-response curve; Maximal induced activity; Partial agonist activity; TIF2; STAMP ID PARTIAL AGONIST ACTIVITY; ESTROGEN-RECEPTOR; ANTAGONIST COMPLEXES; LIGAND-BINDING; DNA-BINDING; TRANSCRIPTION; TRANSACTIVATION; ACTIVATION; EXPRESSION; IDENTIFICATION AB Increased specificity in steroid-regulated gene expression is a long-sought goal of endocrinologists. Considerable progress has resulted from the discovery of coactivators, corepressors, and comodulators that adjust the total activity (A(max)) of gene induction. Two less frequently quantitated, but equally potent, means of improving specificity are the concentration of agonist steroid required for half-maximal activity (EC50) and the residual or partial agonist activity displayed by most antisteroids (PAA). It is usually assumed that the modulatory activity of transcriptional cofactors coordinately regulates A(max), E-50, and PAA. Here we examine the hypothesis that these three parameters can be independently modified by separate protein domains. The test system involves three differently sized fragments of each of three factors (glucocorticoid receptor [GR], coactivator TIF2, and comodulator STAMP), which are shown to form a ternary complex and similarly affect the induction properties of transfected and endogenous genes. Twenty-five different fragment combinations of the ternary complex are examined for their ability to modulate the Amax, EC50, and PAA of a transiently transfected synthetic reporter gene. Different combinations selectively alter one, two, or all three parameters. These results clearly demonstrate that Amax, EC50, and PAA can be independently regulated under some conditions by different pathways or molecular interactions. This new mechanistic insight suggests that selected activities of individual transcription factors are attractive targets for small molecules, which would have obvious clinical applications for increasing the specificity of steroids during endocrine therapies. Published by Elsevier Ireland Ltd. C1 [Awasthi, Smita; Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, LERB, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, LERB, NIH, Bldg 10,Room 8N-307B, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov FU NIH, NIDDK FX We thank Yun-Bo Shi (NICHD, NIH) and members of the Steroid Hormones Section for constructive criticism. This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 47 TC 12 Z9 12 U1 0 U2 1 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 MAY 15 PY 2012 VL 355 IS 1 BP 121 EP 134 DI 10.1016/j.mce.2012.02.001 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 930KN UT WOS:000303138400013 PM 22342989 ER PT J AU Koss, WA Einat, H Schloesser, RJ Manji, HK Rubinow, DR AF Koss, Wendy A. Einat, Haim Schloesser, Robert J. Manji, Husseini K. Rubinow, David R. TI Estrogen effects on the forced swim test differ in two outbred rat strains SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Estrogen; Forced swim test; Depression; Strain differences; Estrogen receptors ID SEROTONIN REUPTAKE INHIBITORS; RECEPTOR MESSENGER-RNA; ANIMAL-MODEL; FEMALE RATS; POSTPARTUM DEPRESSION; IMMUNOREACTIVE CELLS; OVARIECTOMIZED RATS; PREFRONTAL CORTEX; GONADAL-STEROIDS; MENSTRUAL-CYCLE AB Changes in reproductive hormones, such as estrogen, play a role in mood regulation. The present study examined strain differences (Long-Evans vs. Wistar-Hannover) in the behavioral and biochemical effects of estrogen manipulation. Adult ovariectomized female rats were treated with estradiol, vehicle, or withdrawn from estradiol. The two strains demonstrated differential behavioral responses to short-term estradiol administration in the forced swim test; estradiol induced an antidepressant-like effect in Long-Evans rats but not in Wistar rats. Conversely, withdrawal from estradiol resulted in a depressive-like state in the Wistar rats but not in the Long-Evans rats. Western blot analyses found no differences in estrogen receptors alpha and beta within the hippocampus or the frontal cortex, two brain areas strongly implicated in affective disorders. These data demonstrate the importance of strain as a variable when interpreting behavioral effects of estrogen. Published by Elsevier Inc. C1 [Koss, Wendy A.; Einat, Haim; Schloesser, Robert J.; Manji, Husseini K.; Rubinow, David R.] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Koss, WA (reprint author), Univ Illinois, Dept Psychol, 731 Psychol Bldg,MC 716,603 E Daniel St, Champaign, IL 61821 USA. EM wkoss2@illinois.edu; heinat@d.umn.edu; schloesr@mail.nih.gov; Hmanji@prdus.jnj.com; david_rubinow@med.unc.edu FU NIMH NIH HHS [Z01 MH002766-09] NR 57 TC 12 Z9 12 U1 1 U2 4 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 MAY 15 PY 2012 VL 106 IS 2 BP 81 EP 86 DI 10.1016/j.physbeh2012.01.004 PG 6 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 930YW UT WOS:000303181900001 PM 22266677 ER PT J AU Li, F Patterson, AD Krausz, KW Dick, B Frey, FJ Gonzalez, FJ Idle, JR AF Li, Fei Patterson, Andrew D. Krausz, Kristopher W. Dick, Bernhard Frey, Felix J. Gonzalez, Frank J. Idle, Jeffrey R. TI Metabolomics reveals the metabolic map of procainamide in humans and mice SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Procainamide; Systemic lupus erythematosus; Metabolomics; N-Oxidation; Ultra-performance liquid chromatography; Time-of-flight mass spectrometry ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ANTI-NUCLEAR ANTIBODIES; N-ACETYLPROCAINAMIDE; ACETYLATOR PHENOTYPE; HUMAN CYP2D6; MOUSE; PHARMACOKINETICS; HYDROXYLAMINE; RAT; POLYMORPHISM AB Procainamide, a type I antiarrhythmic agent, is used to treat a variety of atrial and ventricular dysrhythmias. It was reported that long-term therapy with procainamide may cause lupus erythematosus in 25-30% of patients. Interestingly, procainamide does not induce lupus erythematosus in mouse models. To explore the differences in this side-effect of procainamide between humans and mouse models, metabolomic analysis using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) was conducted on urine samples from procainamide-treated humans, CYP2D6-humanized mice, and wild-type mice. Thirteen urinary procainamide metabolites, including nine novel metabolites, derived from P450-dependent, FMO-dependent oxidations and acylation reactions, were identified and structurally elucidated. In vivo metabolism of procainamide in CYP2D6-humanized mice as well as in vitro incubations with microsomes and recombinant P450s suggested that human CYP2D6 plays a major role in procainamide metabolism. Significant differences in N-acylation and N-oxidation of the drug between humans and mice largely account for the interspecies differences in procainamide metabolism. Significant levels of the novel N-oxide metabolites produced by FMO1 and FMO3 in humans might be associated with the development of procainamide-induced systemic lupus erythematosus. Observations based on this metabolomic study offer clues to understanding procainamide-induced lupus in humans and the effect of P450s and FMOs on procainamide N-oxidation. (C) 2012 Elsevier Inc. All rights reserved. C1 [Idle, Jeffrey R.] Univ Bern, Dept Clin Res, Hepatol Res Grp, CH-3010 Bern, Switzerland. [Li, Fei; Patterson, Andrew D.; Krausz, Kristopher W.; Gonzalez, Frank J.; Idle, Jeffrey R.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Dick, Bernhard; Frey, Felix J.] Inselspital Bern, Dept Hypertens & Nephrol, CH-3010 Bern, Switzerland. RP Idle, JR (reprint author), Univ Bern, Dept Clin Res, Hepatol Res Grp, Murtenstr 35, CH-3010 Bern, Switzerland. EM lif3@mail.nih.gov; adp117@psu.edu; krauszk@intra.nci.nih.gov; bernhard.dick@insel.ch; felix.frey@insel.ch; fjgonz@helix.nih.gov; jeff.idle@ikp.unibe.ch RI Patterson, Andrew/G-3852-2012; Li, Fei/F-6849-2013; OI Patterson, Andrew/0000-0003-2073-0070; Idle, Jeff/0000-0002-6143-1520 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; Swiss National Science Foundation [31003A-102153] FX This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. FJF acknowledges Swiss National Science Foundation support for grant no. 31003A-102153. NR 39 TC 12 Z9 12 U1 1 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 15 PY 2012 VL 83 IS 10 BP 1435 EP 1444 DI 10.1016/j.bcp.2012.02.013 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 920UY UT WOS:000302435000012 PM 22387617 ER PT J AU Garces, A McClure, EM Chomba, E Patel, A Pasha, O Tshefu, A Esamai, F Goudar, S Lokangaka, A Hambidge, KM Wright, LL Koso-Thomas, M Bose, C Carlo, WA Liechty, EA Hibberd, PL Bucher, S Whitworth, R Goldenberg, RL AF Garces, Ana McClure, Elizabeth M. Chomba, Elwyn Patel, Archana Pasha, Omrana Tshefu, Antoinette Esamai, Fabian Goudar, Shivaprasad Lokangaka, Adrien Hambidge, K. Michael Wright, Linda L. Koso-Thomas, Marion Bose, Carl Carlo, Waldemar A. Liechty, Edward A. Hibberd, Patricia L. Bucher, Sherri Whitworth, Ryan Goldenberg, Robert L. TI Home birth attendants in low income countries: who are they and what do they do? SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Home births; Traditional birth attendants; Perinatal mortality ID NEWBORN-CARE; BANGLADESH; PREGNANCY; GUATEMALA; COMMUNITY; MORTALITY; DEATHS AB Background: Nearly half the world's babies are born at home. We sought to evaluate the training, knowledge, skills, and access to medical equipment and testing for home birth attendants across 7 international sites. Methods: Face-to-face interviews were done by trained interviewers to assess level of training, knowledge and practices regarding care during the antenatal, intrapartum and postpartum periods. The survey was administered to a sample of birth attendants conducting home or out-of-facility deliveries in 7 sites in 6 countries (India, Pakistan, Guatemala, Democratic Republic of the Congo, Kenya and Zambia). Results: A total of 1226 home birth attendants were surveyed. Less than half the birth attendants were literate. Eighty percent had one month or less of formal training. Most home birth attendants did not have basic equipment (e. g., blood pressure apparatus, stethoscope, infant bag and mask manual resuscitator). Reporting of births and maternal and neonatal deaths to government agencies was low. Indian auxilliary nurse midwives, who perform some home but mainly clinic births, were far better trained and differed in many characteristics from the birth attendants who only performed deliveries at home. Conclusions: Home birth attendants in low-income countries were often illiterate, could not read numbers and had little formal training. Most had few of the skills or access to tests, medications and equipment that are necessary to reduce maternal, fetal or neonatal mortality. C1 [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY 10027 USA. [Garces, Ana] IMSALUD, Guatemala City, Guatemala. [McClure, Elizabeth M.; Whitworth, Ryan] Res Triangle Inst, Durham, NC USA. [Chomba, Elwyn] Univ Teaching Hosp, Dept Pediat, Lusaka, Zambia. [Patel, Archana] Indira Ghandi Coll Med, Nagpur, Maharashtra, India. [Pasha, Omrana] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Tshefu, Antoinette; Lokangaka, Adrien] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Esamai, Fabian] Moi Univ, Dept Pediat, Eldoret, Kenya. [Goudar, Shivaprasad] Jawaharlal Nehru Med Coll, Dept Med Educ, Belgaum, India. [Hambidge, K. Michael] Univ Denver, Sch Publ Hlth, Dept Pediat Nutr, Denver, CO USA. [Wright, Linda L.; Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Res Mothers & Children, Bethesda, MD USA. [Bose, Carl] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Liechty, Edward A.; Bucher, Sherri] Indiana Univ, Dept Pediat, Indianapolis, IN 46204 USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Goldenberg, RL (reprint author), Columbia Univ, Dept Obstet & Gynecol, New York, NY 10027 USA. OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU Bill & Melinda Gates Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The study was funded by the Bill & Melinda Gates Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The investigators were solely responsible for the design and implementation of the study, without influence by the funding agencies (uoi HD040636). NR 18 TC 17 Z9 17 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD MAY 14 PY 2012 VL 12 AR 34 DI 10.1186/1471-2393-12-34 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 038ZJ UT WOS:000311212300001 PM 22583622 ER PT J AU Li, Z Sheng, M AF Li, Zheng Sheng, Morgan TI Caspases in synaptic plasticity SO MOLECULAR BRAIN LA English DT Review ID LONG-TERM POTENTIATION; RAT DENTATE GYRUS; CELL-DEATH; HIPPOCAMPAL SYNAPSES; DENDRITIC SPINES; CYTOCHROME-C; INTERLEUKIN-1-BETA; ACTIVATION; DEPRESSION; APOPTOSIS AB Caspases are a family of cysteine proteases that play key roles in programmed cell death (apoptosis). Mounting evidence in recent years shows that caspases also have important non-apoptotic functions in multiple cellular processes, such as synaptic plasticity, dendritic development, learning and memory. In this article, we review the studies on the non-apoptotic functions of caspases in neurons, with a focus on their roles in synaptic plasticity, learning and memory and neurodegeneration. C1 [Li, Zheng] NIMH, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. [Sheng, Morgan] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA. RP Li, Z (reprint author), NIMH, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. EM lizheng2@mail.nih.gov RI Li, Zheng/I-8016-2014 OI Li, Zheng/0000-0002-2978-2531 NR 48 TC 27 Z9 27 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-6606 J9 MOL BRAIN JI Mol. Brain PD MAY 14 PY 2012 VL 5 AR 15 DI 10.1186/1756-6606-5-15 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 008DI UT WOS:000308937100001 PM 22583788 ER PT J AU Nabi, G Temchura, V Grossmann, C Kuate, S Tenbusch, M Uberla, K AF Nabi, Ghulam Temchura, Vladimir Grossmann, Claudius Kuate, Seraphin Tenbusch, Matthias Ueberla, Klaus TI T cell independent secondary antibody responses to the envelope protein of simian immunodeficiency virus SO RETROVIROLOGY LA English DT Article DE SIV; HIV; Adenoviral vectors; T-independent antibody response; VLP ID MEMORY B-CELLS; VESICULAR STOMATITIS-VIRUS; HIV TYPE-1 INFECTION; LIVED PLASMA-CELLS; DYNAMICS IN-VIVO; LONG-TERM; DISEASE PROGRESSION; LENTIVIRAL VECTORS; HUMORAL IMMUNITY; LYMPHOID ORGANS AB Background: During human (HIV) and simian (SIV) immunodeficiency virus infection, loss of CD4+ T cells and progression to AIDS are associated with a decline in antibody titers to the viral Gag protein, while antibodies to the Env protein remain high, suggesting a T cell independent antibody response to Env. Results: To explore differential regulation of Gag and Env antibody responses, immunocompetent BALB/c and T cell deficient nude mice were immunized with virus like particles (VLP) of simian immunodeficiency virus or adenoviral vectors expressing SIV Gag and Env. High levels of antibodies against Gag and Env could only be induced in immunocompetent mice, but not in the immunodeficient mice. Thus, neither cells expressing Env after adenoviral gene transfer nor VLPs induce a T cell independent primary anti-Env antibody response. However, secondary B cell responses to Env, but not to Gag, were observed in immunodeficient mice after transfer of primed B cells and boosting with VLPs or adenoviral vectors expressing Gag and Env. This T cell independent secondary antibody response to Env was reduced after stimulation with VLPs modified to contain monomeric membrane bound gp130 surface subunit of Env and undetectable after injection of soluble gp130. Conclusions: Membrane-bound trimeric Env seems to be responsible for the maintenance of high levels of anti-Env antibodies during progression to AIDS. This T cell independent secondary antibody response may prevent T cell-dependent affinity maturation and thus contribute to viral immune escape by favoring persistence of non-protective antibodies. C1 [Nabi, Ghulam; Temchura, Vladimir; Grossmann, Claudius; Kuate, Seraphin; Tenbusch, Matthias; Ueberla, Klaus] Ruhr Univ Bochum, Dept Mol & Med Virol, D-44780 Bochum, Germany. [Kuate, Seraphin] NCI, VB, CCR, NIH, Bethesda, MD 20892 USA. RP Uberla, K (reprint author), Ruhr Univ Bochum, Dept Mol & Med Virol, D-44780 Bochum, Germany. EM klaus.ueberla@ruhr-uni-bochum.de FU DFG [TRR-60]; Higher Education Commission of Pakistan, Islamabad FX Dr. Ghulam Nabi was funded and supported by Higher Education Commission of Pakistan, Islamabad. This work was funded by a transregional collaborative research grant (TRR-60) from the DFG. NR 45 TC 3 Z9 4 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD MAY 14 PY 2012 VL 9 AR 42 DI 10.1186/1742-4690-9-42 PG 11 WC Virology SC Virology GA 985XS UT WOS:000307304400001 PM 22583867 ER PT J AU Chadwick, W Martin, B Chapter, MC Park, SS Wang, LY Daimon, CM Brenneman, R Maudsley, S AF Chadwick, Wayne Martin, Bronwen Chapter, Megan C. Park, Sung-Soo Wang, Liyun Daimon, Caitlin M. Brenneman, Randall Maudsley, Stuart TI GIT2 Acts as a Potential Keystone Protein in Functional Hypothalamic Networks Associated with Age-Related Phenotypic Changes in Rats SO PLOS ONE LA English DT Article ID GTPASE-ACTIVATING PROTEINS; LIFE-SPAN; ALZHEIMERS-DISEASE; C-ELEGANS; CAENORHABDITIS-ELEGANS; CALORIC RESTRICTION; GENE-EXPRESSION; NERVOUS-SYSTEM; MICE; BRAIN AB The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. Using novel combinatorial bioinformatics analyses, we were able to gain a better understanding of the proteomic and phenotypic changes that occur during the aging process and have potentially identified the G protein-coupled receptor/cytoskeletal-associated protein GIT2 as a vital integrator and modulator of the normal aging process. C1 [Chadwick, Wayne; Chapter, Megan C.; Park, Sung-Soo; Wang, Liyun; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Neurosci Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Martin, Bronwen; Daimon, Caitlin M.] NIA, Metab Unit, Clin Invest Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Brenneman, Randall] Univ Miami, Miller Sch Med, Dodson Interdisciplinary Immunotherapy Inst, Miami, FL 33136 USA. RP Chadwick, W (reprint author), NIA, Receptor Pharmacol Unit, Neurosci Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. EM maudsleyst@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX This work was supported entirely by the Intramural Research Program of the National Institute on Aging, 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 74 TC 10 Z9 13 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 14 PY 2012 VL 7 IS 5 AR e36975 DI 10.1371/journal.pone.0036975 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UF UT WOS:000305339400048 PM 22606319 ER PT J AU Loh, KC Leong, WI Carlson, ME Oskouian, B Kumar, A Fyrst, H Zhang, M Proia, RL Hoffman, EP Saba, JD AF Loh, Kenneth C. Leong, Weng-In Carlson, Morgan E. Oskouian, Babak Kumar, Ashok Fyrst, Henrik Zhang, Meng Proia, Richard L. Hoffman, Eric P. Saba, Julie D. TI Sphingosine-1-Phosphate Enhances Satellite Cell Activation in Dystrophic Muscles through a S1PR2/STAT3 Signaling Pathway SO PLOS ONE LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; SPHINGOSINE 1-PHOSPHATE LYASE; ISCHEMIA-REPERFUSION INJURY; PROTEIN-COUPLED RECEPTOR; DEFICIENT MDX MICE; SKELETAL-MUSCLE; STEM-CELL; S1P LYASE; MYOGENIC DIFFERENTIATION; LYMPHOCYTE SEQUESTRATION AB Sphingosine-1-phosphate (S1P) activates a widely expressed family of G protein-coupled receptors, serves as a muscle trophic factor and activates muscle stem cells called satellite cells (SCs) through unknown mechanisms. Here we show that muscle injury induces dynamic changes in S1P signaling and metabolism in vivo. These changes include early and profound induction of the gene encoding the S1P biosynthetic enzyme SphK1, followed by induction of the catabolic enzyme sphingosine phosphate lyase (SPL) 3 days later. These changes correlate with a transient increase in circulating S1P levels after muscle injury. We show a specific requirement for SphK1 to support efficient muscle regeneration and SC proliferation and differentiation. Mdx mice, which serve as a model for muscular dystrophy (MD), were found to be S1P-deficient and exhibited muscle SPL upregulation, suggesting that S1P catabolism is enhanced in dystrophic muscle. Pharmacological SPL inhibition increased muscle S1P levels, improved mdx muscle regeneration and enhanced SC proliferation via S1P receptor 2 (S1PR2)-dependent inhibition of Rac1, thereby activating Signal Transducer and Activator of Transcription 3 (STAT3), a central player in inflammatory signaling. STAT3 activation resulted in p21 and p27 downregulation in a S1PR2-dependent fashion in myoblasts. Our findings suggest that S1P promotes SC progression through the cell cycle by repression of cell cycle inhibitors via S1PR2/STAT3-dependent signaling and that SPL inhibition may provide a therapeutic strategy for MD. C1 [Loh, Kenneth C.; Leong, Weng-In; Carlson, Morgan E.; Oskouian, Babak; Kumar, Ashok; Fyrst, Henrik; Zhang, Meng; Saba, Julie D.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Hoffman, Eric P.] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. RP Loh, KC (reprint author), Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. EM jsaba@chori.org FU National Institutes of Health [GM66954, CA77528, 5T32CA009041, NIH 5R24HD050846-06, CIRM TG2-01164]; Muscular Dystrophy Association USA; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by National Institutes of Health Grants GM66954 and CA77528 (JDS), 5T32CA009041 (WIL), NIH 5R24HD050846-06 (EPH) and CIRM TG2-01164 (KCL), and grants from the Muscular Dystrophy Association USA (EPH and JDS). This research was supported in part by the Intramural Research Programs of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (RLP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 28 Z9 28 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 14 PY 2012 VL 7 IS 5 AR e37218 DI 10.1371/journal.pone.0037218 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UF UT WOS:000305339400076 PM 22606352 ER PT J AU Martin, B Chadwick, W Yi, T Park, SS Lu, DY Ni, B Gadkaree, S Farhang, K Becker, KG Maudsley, S AF Martin, Bronwen Chadwick, Wayne Yi, Tie Park, Sung-Soo Lu, Daoyuan Ni, Bin Gadkaree, Shekhar Farhang, Kathleen Becker, Kevin G. Maudsley, Stuart TI VENNTURE-A Novel Venn Diagram Investigational Tool for Multiple Pharmacological Dataset Analysis SO PLOS ONE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; EXCHANGER REGULATORY FACTOR; GROWTH-FACTOR RECEPTOR; TERNARY COMPLEX MODEL; BETA(2)-ADRENERGIC RECEPTOR; ADRENERGIC-RECEPTOR; SIGNAL-TRANSDUCTION; ERK1/2 ACTIVATION; MASS-SPECTROMETRY; SELECTIVITY AB As pharmacological data sets become increasingly large and complex, new visual analysis and filtering programs are needed to aid their appreciation. One of the most commonly used methods for visualizing biological data is the Venn diagram. Currently used Venn analysis software often presents multiple problems to biological scientists, in that only a limited number of simultaneous data sets can be analyzed. An improved appreciation of the connectivity between multiple, highly-complex datasets is crucial for the next generation of data analysis of genomic and proteomic data streams. We describe the development of VENNTURE, a program that facilitates visualization of up to six datasets in a user-friendly manner. This program includes versatile output features, where grouped data points can be easily exported into a spreadsheet. To demonstrate its unique experimental utility we applied VENNTURE to a highly complex parallel paradigm, i.e. comparison of multiple G protein-coupled receptor drug dose phosphoproteomic data, in multiple cellular physiological contexts. VENNTURE was able to reliably and simply dissect six complex data sets into easily identifiable groups for straightforward analysis and data output. Applied to complex pharmacological datasets, VENNTURE's improved features and ease of analysis are much improved over currently available Venn diagram programs. VENNTURE enabled the delineation of highly complex patterns of dose-dependent G protein-coupled receptor activity and its dependence on physiological cellular contexts. This study highlights the potential for such a program in fields such as pharmacology, genomics, and bioinformatics. C1 [Martin, Bronwen; Yi, Tie] NIA, Metab Unit, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Chadwick, Wayne; Park, Sung-Soo; Lu, Daoyuan; Ni, Bin; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Gadkaree, Shekhar; Farhang, Kathleen] NIA, Diabet Sect, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Becker, Kevin G.] NIA, Gene Express & Genom Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Martin, B (reprint author), NIA, Metab Unit, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. EM maudsleyst@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU National Institute on Aging, National Institutes of Health FX This work was supported entirely by the Intramural Program of the National Institute on Aging, 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 50 TC 30 Z9 30 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 14 PY 2012 VL 7 IS 5 AR e36911 DI 10.1371/journal.pone.0036911 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UF UT WOS:000305339400041 PM 22606307 ER PT J AU Mitra, K Rikhy, R Lilly, M Lippincott-Schwartz, J AF Mitra, Kasturi Rikhy, Richa Lilly, Mary Lippincott-Schwartz, Jennifer TI DRP1-dependent mitochondrial fission initiates follicle cell differentiation during Drosophila oogenesis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID WARTS-HIPPO PATHWAY; EMBRYONIC-DEVELOPMENT; GERM-LINE; PROLIFERATION; FUSION; POLARIZATION; DEGRADATION; AUTOPHAGY; NETWORK; PARKIN AB Exit from the cell cycle is essential for cells to initiate a terminal differentiation program during development, but what controls this transition is incompletely understood. In this paper, we demonstrate a regulatory link between mitochondrial fission activity and cell cycle exit in follicle cell layer development during Drosophila melanogaster oogenesis. Posterior-localized clonal cells in the follicle cell layer of developing ovarioles with down-regulated expression of the major mitochondrial fission protein DRP1 had mitochondrial elements extensively fused instead of being dispersed. These cells did not exit the cell cycle. Instead, they excessively proliferated, failed to activate Notch for differentiation, and exhibited downstream developmental defects. Reintroduction of mitochondrial fission activity or inhibition of the mitochondrial fusion protein Marf-1 in posterior-localized DRP1-null clones reversed the block in Notch-dependent differentiation. When DRP1-driven mitochondrial fission activity was unopposed by fusion activity in Marf-1-depleted clones, premature cell differentiation of follicle cells occurred in mitotic stages. Thus, DRP1-dependent mitochondrial fission activity is a novel regulator of the onset of follicle cell differentiation during Drosophila oogenesis. C1 [Mitra, Kasturi; Rikhy, Richa; Lilly, Mary; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov RI Rikhy, Richa/J-4481-2012; OI Lilly, Mary/0000-0003-1564-619X; Rikhy, Richa/0000-0002-4262-0238 NR 29 TC 25 Z9 25 U1 0 U2 12 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 MAY 14 PY 2012 VL 197 IS 4 BP 487 EP 497 DI 10.1083/jcb.201110058 PG 11 WC Cell Biology SC Cell Biology GA 941SV UT WOS:000303986300005 PM 22584906 ER PT J AU Lu, YJ Zhang, F Sayeed, S Thompson, CM Szu, S Anderson, PW Malley, R AF Lu, Ying-Jie Zhang, Fan Sayeed, Sabina Thompson, Claudette M. Szu, Shousun Anderson, Porter W. Malley, Richard TI A bivalent vaccine to protect against Streptococcus pneumoniae and Salmonella typhi SO VACCINE LA English DT Article DE Streptococcus pneumoniae; Salmonella typhi; Vaccine; Vi polysaccharide ID PNEUMOCOCCAL CONJUGATE VACCINES; CELL-WALL POLYSACCHARIDE; INTRANASAL IMMUNIZATION; MURINE MODEL; VI; COLONIZATION; FEVER; CHILDREN; PHOSPHOCHOLINE; IMMUNOGENICITY AB Pneumococcal and Salmonella typhi infections are two major diseases for children in developing countries. For typhoid fever, licensed Vi polysaccharide vaccines are ineffective in children <2-year old. While investigational Vi conjugate vaccines have been shown effective in clinical trials, they are currently only available to restricted areas. Pneumococcal capsular polysaccharide conjugate vaccines are highly effective in children, but suffer from some limitations including cost and limited serotype coverage. We have previously shown that a fusion conjugate vaccine, consisting of pneumococcal fusion protein PsaA and pneumolysoid (PdT) conjugated to a polysaccharide, results in enhanced antibody and CD4+ Th17 cell responses as well as protection against pneumococcal colonization and disease in mice. Here we applied this approach to develop a bivalent vaccine against pneumococcus and S. typhi. Two species-conserved pneumococcal antigens (SP1572 or SP2070) were fused to the nonhemolytic pneumolysoid PdT. SP1572-PdT was then conjugated to Vi polysaccharide and SP2070-PdT was conjugated to the pneumococcal cell wall polysaccharide (CWPS; also conserved). Mice immunized with this bivalent conjugate were protected against pneumococcal colonization and sepsis challenges, and made anti-Vi antibody concentrations higher by 40-fold compared to mice that received equimolar mixtures of the antigens. An enhanced killing of Vi-bearing Salmonellae in vitro was demonstrated from plasma of mice that received the fusion conjugate but not the mixture of antigens. Our results support further evaluation of this bivalent immunogen for the prevention of pneumococcal colonization and disease, and of typhoid fever. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Lu, Ying-Jie; Zhang, Fan; Sayeed, Sabina; Anderson, Porter W.; Malley, Richard] Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Lu, Ying-Jie; Zhang, Fan; Sayeed, Sabina; Thompson, Claudette M.; Anderson, Porter W.; Malley, Richard] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Szu, Shousun] NIH, Sect Bacterial Dis Pathogenesis & Immun, Bethesda, MD USA. RP Lu, YJ (reprint author), Childrens Hosp, Div Infect Dis, 300 Longwood Ave, Boston, MA 02115 USA. EM yingjie.lu@childrens.harvard.edu FU Bill & Melinda Gates Foundation; Children's Hospital; Children's Hospital Boston; NIH [R01 AI067737] FX We thank Drs. Christine Hale and Gordon Dougan for providing S. typhimurium strains C5 and C5.507. We thank Drs. Rachel Schneerson and John Robbins for helpful discussion and suggestions. This work was supported by The Bill & Melinda Gates Foundation through the Grand Challenge Explorations program and Children's Hospital Technology Development grant. R.M. gratefully acknowledges support from the Translational Research Program at Children's Hospital Boston and NIH grant R01 AI067737. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 8 Z9 9 U1 0 U2 4 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 MAY 14 PY 2012 VL 30 IS 23 BP 3405 EP 3412 DI 10.1016/j.vaccine.2012.03.039 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 937WW UT WOS:000303695500009 PM 22465750 ER PT J AU Kumar, A Li, L Chaturvedi, A Brzostowski, J Chittigori, J Pierce, S Samuelson, LA Sandman, D Kumar, J AF Kumar, Abhishek Li, Lian Chaturvedi, Akanksha Brzostowski, Joseph Chittigori, Joshna Pierce, Susan Samuelson, Lynne A. Sandman, Daniel Kumar, Jayant TI Two-photon fluorescence properties of curcumin as a biocompatible marker for confocal imaging SO APPLIED PHYSICS LETTERS LA English DT Article ID CROSS-SECTIONS; MICROSCOPY; CELLS; DOTS AB Two-photon (TP) fluorescence properties of an antioxidant and anti-tumor molecule, curcumin, were investigated. The two-photon absorption (TPA) action cross-section was measured in organic solvents and found to be 6 GM in tetrahydrofuran and 2 GM in dimethyl sulfoxide. The measured TPA cross-section is comparable to that of rhodamine 6G. One-photon and TP confocal microscopy has demonstrated that curcumin is internalized in cells and can be used for imaging applications. Our investigation indicates that curcumin is a viable biocompatible TP fluorescent marker. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4717753] C1 [Kumar, Abhishek; Chittigori, Joshna; Sandman, Daniel; Kumar, Jayant] Univ Massachusetts Lowell, Ctr Adv Mat, Lowell, MA 01854 USA. [Kumar, Abhishek; Kumar, Jayant] Univ Massachusetts Lowell, Dept Phys, Lowell, MA 01854 USA. [Li, Lian; Samuelson, Lynne A.] USA, Natick Soldier Res Dev & Engn Ctr, Natick, MA 01760 USA. [Chaturvedi, Akanksha; Brzostowski, Joseph; Pierce, Susan] NIAID, LIG, NIH, Rockville, MD 20852 USA. [Chittigori, Joshna; Sandman, Daniel] Univ Massachusetts Lowell, Dept Chem, Lowell, MA 01854 USA. RP Kumar, A (reprint author), Univ Massachusetts Lowell, Ctr Adv Mat, Lowell, MA 01854 USA. EM Jayant_Kumar@uml.edu NR 14 TC 13 Z9 13 U1 2 U2 16 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD MAY 14 PY 2012 VL 100 IS 20 AR 203701 DI 10.1063/1.4717753 PG 4 WC Physics, Applied SC Physics GA 945HZ UT WOS:000304265000097 ER PT J AU Polettini, A Cone, EJ Gorelick, DA Huestis, MA AF Polettini, Aldo Cone, Edward J. Gorelick, David A. Huestis, Marilyn A. TI Incorporation of methamphetamine and amphetamine in human hair following controlled oral methamphetamine administration SO ANALYTICA CHIMICA ACTA LA English DT Article DE Methamphetamine; LC-MS-MS; Hair; Controlled administration; Melanin ID N-ACETYLAMPHETAMINE; COCAINE CONTAMINATION; ETHYL GLUCURONIDE; MASS-SPECTROMETRY; BINDING-SITE; MELANIN; DRUGS; ABUSE; METABOLITES; SELEGILINE AB Background: Although hair testing is well established for the assessment of past drug exposure, uncertainties persist about mechanisms of drug incorporation into hair and interpretation of results. The aim of this study was to administer methamphetamine (MAMP) under controlled conditions as a model drug to investigate drug incorporation into human hair. Material and methods: Seven volunteers with a history of stimulant use received 4 x 10 mg (low) doses of sustained release S-(+)-MAMP HCI within 1 week, with weekly head hair samples collected by shaving. 3 weeks later, 4 of them received 4 x 20 mg (high) doses. After extensive isopropanol/phosphate buffer washing of the hair, MAMP and its metabolite amphetamine (AMP) concentrations were determined in all weekly hair samples by LC-MS-MS in selected reaction monitoring mode with the undeca- and deca-deuterated drugs, respectively, as internal standards (LLOQ 0.005 ng mg(-1)). Results: MAMP T-max occurred from 1 to 2 weeks after both doses, with C-max ranging from 0.6 to 3.5 ng mg(-1) after the low and 1.2 to 5.3 ng mg(-1) after the high MAMP doses. AMP C-max in hair was 0.1-0.3 ng mg(-1) and 0.2-0.5 ng mg(-1), respectively, for low and high doses. Highly dose-related concentrations within subjects, but large variability between subjects were observed. MAMP concentrations were above the 0.2 ng mg(-1) cut-off for at least 2 weeks following administration of both low and high closes. The overall AMP/MAMP ratio ranged from 0.07 to 0.37 with a mean value of 0.15 +/- 0.07, and a median of 0.13. The percentage of MAMP and AMP removed with the washing procedure decreased with time after administration. A strong correlation was found between area under the curve of MAMP (r(2) = 0.90, p = 0.00) and AMP (r(2) = 0.94. p = 0.00) concentrations calculated for the 3-week period following administration and the total melanin concentration in hair. Significant correlations were observed also between C-max and melanin. Conclusions: This study demonstrated that despite large inter-individual differences, the incorporation of MAMP and AMP into hair is dose-related with much of the observed scatter of MAMP and AMP concentrations explained by melanin concentration in hair. (c) 2012 Elsevier B.V. All rights reserved. C1 [Polettini, Aldo] Univ Verona, Dept Publ Hlth & Community Med, I-37134 Verona, Italy. [Cone, Edward J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Gorelick, David A.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. RP Polettini, A (reprint author), Univ Verona, Dept Publ Hlth & Community Med, Ple Scuro 10, I-37134 Verona, Italy. EM aldo.polettini@univr.it FU Intramural NIH HHS [Z01 DA000412-11, Z01 DA000412-10] NR 50 TC 20 Z9 21 U1 0 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0003-2670 J9 ANAL CHIM ACTA JI Anal. Chim. Acta PD MAY 13 PY 2012 VL 726 BP 35 EP 43 DI 10.1016/j.aca.2012.01.042 PG 9 WC Chemistry, Analytical SC Chemistry GA 937XY UT WOS:000303698700005 PM 22541011 ER PT J AU Coovadia, H Maldonado, B Fowler, MG Zwerski, S Mofenson, L AF Coovadia, Hoosen Maldonado, Bonnie Fowler, Mary Glenn Zwerski, Sheryl Mofenson, Lynne TI Nevirapine prophylaxis during breastfeeding Reply SO LANCET LA English DT Letter C1 [Coovadia, Hoosen] Overport, Maternal Adolescent & Child Hlth MatCH, ZA-4091 Durban, South Africa. [Maldonado, Bonnie] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Fowler, Mary Glenn] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Zwerski, Sheryl] NIAID, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Mofenson, Lynne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Rockville, MD USA. RP Coovadia, H (reprint author), Overport, Maternal Adolescent & Child Hlth MatCH, ZA-4091 Durban, South Africa. EM hcoovadia@match.org.za NR 4 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 0140-6736 J9 LANCET JI Lancet PD MAY 12 PY 2012 VL 379 IS 9828 BP 1788 EP 1788 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 941BR UT WOS:000303937700025 ER PT J AU Portugal, S Doumtabe, D Traore, B Miller, LH Troye-Blomberg, M Doumbo, OK Dolo, A Pierce, SK Crompton, PD AF Portugal, Silvia Doumtabe, Didier Traore, Boubacar Miller, Louis H. Troye-Blomberg, Marita Doumbo, Ogobara K. Dolo, Amagana Pierce, Susan K. Crompton, Peter D. TI B cell analysis of ethnic groups in Mali with differential susceptibility to malaria SO MALARIA JOURNAL LA English DT Article ID PLASMODIUM-FALCIPARUM; MEMORY B; INTERETHNIC DIFFERENCES; SYMPATRIC TRIBES; INDIVIDUALS; PROTEIN AB Background: Several studies indicate that people of the Fulani ethnic group are less susceptible to malaria compared to those of other ethnic groups living sympatrically in Africa, including the Dogon ethnic group. Although the mechanisms of this protection remain unclear, the Fulani are known to have higher levels of Plasmodium falciparum-specific antibodies of all Ig classes as compared to the Dogon. However, the proportions of B cell subsets in the Fulani and Dogon that may account for differences in the levels of Ig have not been characterized. Methods: In this cross-sectional study, venous blood was collected from asymptomatic Fulani (n = 25) and Dogon (n = 25) adults in Mali during the malaria season, and from P. falciparum-naive adults in the U. S. (n = 8). At the time of the blood collection, P. falciparum infection was detected by blood-smear in 16% of the Fulani and 36% of the Dogon volunteers. Thawed lymphocytes were analysed by flow cytometry to quantify B cell subsets, including immature and naive B cells; plasma cells; and classical, activated, and atypical memory B cells (MBCs). Results: The overall distribution of B cell subsets was similar between Fulani and Dogon adults, although the percentage of activated MBCs was higher in the Fulani group (Fulani: 11.07% [95% CI: 9.317 - 12.82]; Dogon: 8.31% [95% CI: 6.378 - 10.23]; P = 0.016). The percentage of atypical MBCs was similar between Fulani and Dogon adults (Fulani: 28.3% [95% CI: 22.73 - 34.88]; Dogon: 29.3% [95% CI: 25.06 - 33.55], but higher than U. S. adults (U. S.: 3.0% [95% CI: -0.21 - 6.164]; P < 0.001). Plasmodium falciparum infection was associated with a higher percentage of plasma cells among Fulani (Fulani infected: 3.3% [95% CI: 1.788 - 4.744]; Fulani uninfected: 1.71% [95% CI: 1.33 - 2.08]; P = 0.011), but not Dogon adults. Conclusion: These data show that the malaria-resistant Fulani have a higher percentage of activated MBCs compared to the Dogon, and that P. falciparum infection is associated with a higher percentage of plasma cells in the Fulani compared to the Dogon, findings that may account for the higher levels of P. falciparum antibodies in the Fulani. C1 [Portugal, Silvia; Pierce, Susan K.; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Doumtabe, Didier; Traore, Boubacar; Doumbo, Ogobara K.; Dolo, Amagana] Univ Bamako, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali. [Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Troye-Blomberg, Marita] Stockholm Univ, Wenner Gren Inst, Dept Immunol, S-10691 Stockholm, Sweden. RP Crompton, PD (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM pcrompton@niaid.nih.gov RI Troye-Blomberg, Marita/B-9210-2016; Crompton, Peter/N-1130-2016 OI Troye-Blomberg, Marita/0000-0002-2804-0325; FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; BioMalPar consortium project; European Molecular Biology Organization long-term fellowship FX We sincerely thank the residents of Manteourou, Mali for their participation in this study. We also thank Dr. Richard Sakai and the staff of the Mali Service Center in Bamako for logistical support. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health and by BioMalPar consortium project. SP is supported by a European Molecular Biology Organization long-term fellowship. NR 17 TC 17 Z9 17 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD MAY 11 PY 2012 VL 11 AR 162 DI 10.1186/1475-2875-11-162 PG 7 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 046FV UT WOS:000311751800001 PM 22577737 ER PT J AU Katsounas, A Trippler, M Kottilil, S Lempicki, RA Gerken, G Schlaak, JF AF Katsounas, Antonios Trippler, Martin Kottilil, Shyam Lempicki, Richard A. Gerken, Guido Schlaak, Joerg F. TI Cytokine/chemokine patterns connect host and viral characteristics with clinics during chronic hepatitis C SO EUROPEAN JOURNAL OF MEDICAL RESEARCH LA English DT Article DE HCV; Cytokines; Chemokines; Microarrays ID INFECTION; CHEMOKINES; ACTIVATION; THERAPY; VIRUS AB Background: In chronic hepatitis C virus (HCV) infection, liver tissue pathology and HCV genotype are important determinants of clinical and/or treatment-related outcome. Although consistent epidemiological and/or molecular-biological clues derived from different studies on single virus-host interactions are meanwhile published, the in vivo transcriptional responses and cellular pathways affected in >1 key aspects of the disease or treatment process are far from being understood. Methods: Microarray analysis was performed in peripheral whole blood (PB) samples from 36 therapy-naive HCV-infected patients with known liver histology. Linear regression analysis identified gene expression profiles significantly correlating (P < 0.015) with >= 1 out of 7 variables: sustained viral response (SVR), viral non-response (NR), end of treatment viral response (ETR), viral breakthrough (VB), HCV genotype (Gt. 1 vs. Gt. 2/3), stage of hepatic fibrosis [St. 0/1 vs. St. 2/3/4] and grade of hepatic inflammation (Gr. 0/1 vs. Gr. 2/3/4). Correlation values across all seven contrasts were considered for hierarchical clustering (HCL). Results: A total of 1,697 genes showed >= 1 significant correlation results and genes involved in cell differentiation (183), immune response (53), and apoptosis (170) were leading fractions. HCL grouped the genes into six major clusters. Functional annotation analysis using DAVID (http://david.abcc.ncifcrf.gov) revealed that expression profiles that best linked these variables were highly enriched in cytokine/chemokine activity (Fisher-exact P < 0.0001) and specific biological module-centric algorithms finally led our focus on four out of fifty-three immune response genes: SMAD family member 3 (SMAD3), interleukin 1 receptor accessory protein (IL1RAP), tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), and chemokine 'C-C motif' receptor 5 (CCR5). Of those, TNFRSF1A and CCR5 showed significant correlation with two out of seven variables based on microarray and/or quantitative real-time polymerase chain reaction (qRT-PCR) data. Conclusion: We identified molecular targets of the innate and adaptive immune system and validated their transcriptional specificity in vivo suggesting significant involvement in two unique outcomes during HCV treatment. C1 [Katsounas, Antonios; Trippler, Martin; Gerken, Guido; Schlaak, Joerg F.] Univ Hosp Essen, Dept Gastroenterol & Hepatol, D-45122 Essen, Germany. [Katsounas, Antonios; Lempicki, Richard A.] SAIC Frederick Inc, NCI Frederick, Lab Immunopathogenesis & Bioinformat, Frederick, MD 21702 USA. [Kottilil, Shyam] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. RP Katsounas, A (reprint author), Univ Hosp Essen, Dept Gastroenterol & Hepatol, Hufelandstr 55, D-45122 Essen, Germany. EM antonios.katsounas@uk-essen.de RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Schlaak, Joerg/0000-0002-9499-1014; Gerken, Guido/0000-0001-6734-5001 FU Association for the Promotion of Scientific Research and Science of the Department for Gastroenterology and Hepatology at the University Hospital Essen (Essen, Germany); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was funded in part with funds from the Association for the Promotion of Scientific Research and Science of the Department for Gastroenterology and Hepatology at the University Hospital Essen (Essen, Germany) and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 16 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 0949-2321 J9 EUR J MED RES JI Eur. J. Med. Res. PD MAY 11 PY 2012 VL 17 AR 9 DI 10.1186/2047-783X-17-9 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 040FX UT WOS:000311308700001 PM 22577869 ER PT J AU Yedidi, RS Liu, ZG Wang, Y Brunzelle, JS Kovari, IA Woster, PM Kovari, LC Gupta, D AF Yedidi, Ravikiran S. Liu, Zhigang Wang, Yong Brunzelle, Joseph S. Kovari, Iulia A. Woster, Patrick M. Kovari, Ladislau C. Gupta, Deepak TI Crystal structures of multidrug-resistant HIV-1 protease in complex with two potent anti-malarial compounds SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE HIV-1 protease; Plasmepsin-II; Aspartyl protease; Multidrug-resistance; Mechanism-based inhibitors; Crystallography; Docking ID ASPARTIC PROTEASES; VIRAL INFECTIVITY; REFINEMENT; INHIBITORS; MECHANISMS; VARIANTS; PROGRAM; BARRIER AB Two potent inhibitors (compounds 1 and 2) of malarial aspartyl protease, plasmepsin-II, were evaluated against wild type (NL4-3) and multidrug-resistant clinical isolate 769 (MDR) variants of human immunodeficiency virus type-1 (HIV-1) aspartyl protease. Enzyme inhibition assays showed that both 1 and 2 have better potency against NL4-3 than against MDR protease. Crystal structures of MDR protease in complex with 1 and 2 were solved and analyzed. Crystallographic analysis revealed that the MDR protease exhibits a typical wide-open conformation of the flaps (Gly48 to Gly52) causing an overall expansion in the active site cavity, which, in turn caused unstable binding of the inhibitors. Due to the expansion of the active site cavity, both compounds showed loss of direct contacts with the MDR protease compared to the docking models of NL4-3. Multiple water molecules showed a rich network of hydrogen bonds contributing to the stability of the ligand binding in the distorted binding pockets of the MDR protease in both crystal structures. Docking analysis of 1 and 2 showed a decrease in the binding affinity for both compounds against MDR supporting our structure-function studies. Thus, compounds 1 and 2 show promising inhibitory activity against HIV-1 protease variants and hence are good candidates for further development to enhance their potency against NL4-3 as well as MDR HIV-1 protease variants. (C) 2012 Elsevier Inc. All rights reserved. C1 [Brunzelle, Joseph S.] Northwestern Univ, Feinberg Sch Med, Dept Mol Pharmacol & Biol Chem, Life Sci Collaborat Access Team, Chicago, IL 60611 USA. [Woster, Patrick M.] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. [Gupta, Deepak] LECOM, Sch Pharm, Bradenton, FL 34211 USA. [Yedidi, Ravikiran S.; Liu, Zhigang; Wang, Yong; Kovari, Iulia A.; Kovari, Ladislau C.] Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI 48201 USA. RP Yedidi, RS (reprint author), NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, 10 Ctr Dr,Room 5A24, Bethesda, MD 20892 USA. EM yedidirs@mail.nih.gov RI Liu, Zhigang/A-2003-2014; OI Yedidi, Ravikiran/0000-0003-2755-1307; Woster, Patrick/0000-0002-9471-1916 FU National Institutes of Health [AI65294]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor [085P1000817] FX We thank the National Institutes of Health for funding to LCK (Grant # AI65294). We thank the APS-LS-CAT for X-ray diffraction data collection. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (Grant 085P1000817). NR 32 TC 6 Z9 6 U1 0 U2 8 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 MAY 11 PY 2012 VL 421 IS 3 BP 413 EP 417 DI 10.1016/j.bbrc.2012.03.096 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 970SG UT WOS:000306152000002 PM 22469467 ER PT J AU Gough, SM Chung, YJ Aplan, PD AF Gough, Sheryl M. Chung, Yang Jo Aplan, Peter D. TI Depletion of Cytotoxic T-Cells Does Not Protect NUP98-HOXD13 Mice from Myelodysplastic Syndrome but Reveals a Modest Tumor Immunosurveillance Effect SO PLOS ONE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; TRANSGENIC MICE; BETHESDA PROPOSALS; ANTIGEN RECEPTOR; MOUSE MODEL; EXPRESSION; APOPTOSIS; CANCER; PAK5 AB Myelodysplastic syndrome (MDS) and aplastic anemia (AA) patients both present with symptoms of bone marrow failure. In many AA patients, these features are thought to result from an oligoclonal expansion of cytotoxic T-cells that destroy haematopoietic stem or progenitor cells. This notion is supported by the observation that AA patients respond to immunosuppressive therapy. A fraction of MDS patients also respond well to immunosuppressive therapy suggesting a similar role for cytotoxic T-cells in the etiology of MDS, however the role of cytotoxic T-cells in MDS remains unclear. Mice that express a NUP98-HOXD13 (NHD13) transgene develop a MDS that closely mimics the human condition in terms of dysplasia, ineffective hematopoiesis, and transformation to acute myeloid leukemia (AML). We followed a cohort of NHD13 mice lacking the Rag1 protein (NHD13/Rag1KO) to determine if the absence of lymphocytes might 1) delay the onset and/or diminish the severity of the MDS, or 2) effect malignant transformation and survival of the NHD13 mice. No difference was seen in the onset or severity of MDS between the NHD13 and NHD13/Rag1KO mice. However, NHD13/Rag1KO mice had decreased survival and showed a trend toward increased incidence of transformation to AML compared to the NHD13 mice, suggesting protection from AML transformation by a modest immuno-surveillance effect. In the absence of functional Tcrb signaling in the NHD13/Rag1KO T-cell tumors, Pak7 was identified as a potential Tcrb surrogate survival signal. C1 [Gough, Sheryl M.; Chung, Yang Jo; Aplan, Peter D.] NCI, Leukemia Biol Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Gough, SM (reprint author), NCI, Leukemia Biol Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. EM aplanp@mail.nih.gov RI Aplan, Peter/K-9064-2016 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of 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 53 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 11 PY 2012 VL 7 IS 5 AR e36876 DI 10.1371/journal.pone.0036876 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TW UT WOS:000305338200054 PM 22606303 ER PT J AU Ryan, BM McClary, AC Valeri, N Robinson, D Paone, A Bowman, ED Robles, AI Croce, C Harris, CC AF Ryan, Brid M. McClary, Andrew C. Valeri, Nicola Robinson, Dillon Paone, Alessio Bowman, Elise D. Robles, Ana I. Croce, Carlo Harris, Curtis C. TI rs4919510 in hsa-mir-608 Is Associated with Outcome but Not Risk of Colorectal Cancer SO PLOS ONE LA English DT Article ID TUMOR-SUPPRESSOR GENES; EXPRESSION; TARGETS; POLYMORPHISMS; DISPARITIES; PROGNOSIS; SITES AB Background: Colorectal cancer is the third most incident cancer and cause of cancer-related death in the United States. MicroRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis and prognosis of colorectal cancer, although few studies have examined the relationship between germline mutation in the microRNAs with risk and prognosis. We therefore investigated the association between a SNP in hsa-mir-608, which lies within the 10q24 locus, and colorectal cancer. Methods and Results: A cohort consisting of 245 cases and 446 controls was genotyped for rs4919510. The frequency of the GG genotype was significantly higher in African Americans (15%) compared to Caucasians (3%) controls. There was no significant association between rs4919510 and colorectal cancer risk (African American: ORGG (vs.) (CC) 0.89 [95% CI, 0.41-1.80]) (Caucasian: ORGG vs. CC 1.76, ([95% CI, 0.48-6.39]). However, we did observe an association with survival. The GG genotype was associated with an increased risk of death in Caucasians (HRGG vs. CC 3.54 ([95% CI, 1.38-9.12]) and with a reduced risk of death in African Americans (HRGG vs. CC 0.36 ([95% CI 0.12-1.07). Conclusions: These results suggest that rs4910510 may be associated with colorectal cancer survival in a manner that is dependent on race. C1 [Ryan, Brid M.; McClary, Andrew C.; Robinson, Dillon; Bowman, Elise D.; Robles, Ana I.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [McClary, Andrew C.] NCI, Howard Hughes Med Inst, Bethesda, MD 20892 USA. [Valeri, Nicola; Paone, Alessio; Croce, Carlo] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RP Ryan, BM (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov OI valeri, nicola/0000-0002-5426-5683; Paone, Alessio/0000-0001-9406-3982 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute Center of Excellence for the Integration of Chromosome Biology and Genetics FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and in part by the National Cancer Institute Center of Excellence for the Integration of Chromosome Biology and Genetics. No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 27 Z9 29 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 11 PY 2012 VL 7 IS 5 AR e36306 DI 10.1371/journal.pone.0036306 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TW UT WOS:000305338200022 PM 22606253 ER PT J AU Reiter, DA Fathallah, FA Farouki, RT Walton, JH AF Reiter, David A. Fathallah, Fadi A. Farouki, Rida T. Walton, Jeffery H. TI Noninvasive high resolution mechanical strain maps of the spine intervertebral disc using nonrigid registration of magnetic resonance images SO JOURNAL OF BIOMECHANICS LA English DT Article DE Intervertebral disc; Deformation; Strain; MRI; Nonrigid registration ID BREAST MR-IMAGES; ARTICULAR-CARTILAGE; DEFORMATION; COMPRESSION; DEGENERATION; BONE AB High resolution strain measurements are of particular interest in load bearing tissues such as the intervertebral disc (IVD), permitting characterization of biomechanical conditions which could lead to injury and degenerative outcomes. Magnetic resonance (MR) imaging produces excellent image contrast in cartilaginous tissues, allowing for image-based strain determination. Nonrigid registration (NRR) of MR images has previously demonstrated sub-voxel registration accuracy although its accuracy and precision in determining strain has not been evaluated. Accuracy and precision of NRR-derived strain measurements were evaluated using computer generated deformations applied to both computer generated images and MR images. Two different measures of registration similarity the cost function which drives the registration algorithm were compared: Mutual Information (MI) and Least Squares (LS). Strain error was evaluated with respect to signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and strain heterogeneity. Additionally, the creep strain response from an in vitro loaded porcine IVD is shown and comparisons between similarity measures are presented. MI showed a decrease in strain precision with increasing CNR and decreasing SNR while LS was insensitive to both. Both similarity measures showed a decrease in strain precision with increasing strain heterogeneity. When computer generated heterogeneous strains were applied to MR images of the IVD, LS showed substantially lower strain error in comparison to MI. Results suggest that LS-driven NRR provides a more accurate image-based method for mapping large and heterogeneous strain fields and this method can be applied to studies of the IVD and, potentially, other soft tissues which present sufficient image texture. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Reiter, David A.; Farouki, Rida T.] Univ Calif Davis, Dept Mech & Aerosp Engn, Davis, CA 95616 USA. [Fathallah, Fadi A.] Univ Calif Davis, Dept Biol & Agr Engn, Davis, CA 95616 USA. [Walton, Jeffery H.] Univ Calif Davis, Nucl Magnet Resonance Facil, Davis, CA 95616 USA. RP Reiter, DA (reprint author), NIA, Clin Res Branch, NIH, 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. EM reiterda@mail.nih.gov NR 19 TC 4 Z9 4 U1 2 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD MAY 11 PY 2012 VL 45 IS 8 BP 1534 EP 1539 DI 10.1016/j.jbiomech.2012.03.005 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 944PK UT WOS:000304216100030 PM 22503578 ER PT J AU Kato, M Han, TNW Xie, SH Shi, K Du, XL Wu, LC Mirzaei, H Goldsmith, EJ Longgood, J Pei, JM Grishin, NV Frantz, DE Schneider, JW Chen, S Li, L Sawaya, MR Eisenberg, D Tycko, R McKnight, SL AF Kato, Masato Han, Tina W. Xie, Shanhai Shi, Kevin Du, Xinlin Wu, Leeju C. Mirzaei, Hamid Goldsmith, Elizabeth J. Longgood, Jamie Pei, Jimin Grishin, Nick V. Frantz, Douglas E. Schneider, Jay W. Chen, She Li, Lin Sawaya, Michael R. Eisenberg, David Tycko, Robert McKnight, Steven L. TI Cell-free Formation of RNA Granules: Low Complexity Sequence Domains Form Dynamic Fibers within Hydrogels SO CELL LA English DT Article ID GERMLINE P GRANULES; STRESS GRANULES; SACCHAROMYCES-CEREVISIAE; AMYLOID FIBRILS; MESSENGER-RNA; CAENORHABDITIS-ELEGANS; PROTEIN AGGREGATION; SCRAPIE PRION; C. ELEGANS; DROSOPHILA AB Eukaryotic cells contain assemblies of RNAs and proteins termed RNA granules. Many proteins within these bodies contain KH or RRM RNA-binding domains as well as low complexity (LC) sequences of unknown function. We discovered that exposure of cell or tissue lysates to a biotinylated isoxazole (b-isox) chemical precipitated hundreds of RNA-binding proteins with significant overlap to the constituents of RNA granules. The LC sequences within these proteins are both necessary and sufficient for b-isox-mediated aggregation, and these domains can undergo a concentration-dependent phase transition to a hydrogel-like state in the absence of the chemical. X-ray diffraction and EM studies revealed the hydrogels to be composed of uniformly polymerized amyloid-like fibers. Unlike pathogenic fibers, the LC sequence-based polymers described here are dynamic and accommodate heterotypic polymerization. These observations offer a framework for understanding the function of LC sequences as well as an organizing principle for cellular structures that are not membrane bound. C1 [Kato, Masato; Han, Tina W.; Xie, Shanhai; Shi, Kevin; Du, Xinlin; Wu, Leeju C.; Mirzaei, Hamid; Goldsmith, Elizabeth J.; Longgood, Jamie; Pei, Jimin; Grishin, Nick V.; McKnight, Steven L.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Schneider, Jay W.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Pei, Jimin; Grishin, Nick V.] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Frantz, Douglas E.] Univ Texas San Antonio, Dept Chem, San Antonio, TX 78249 USA. [Chen, She; Li, Lin] Natl Inst Biol Sci, Beijing 102206, Peoples R China. [Sawaya, Michael R.; Eisenberg, David] Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP McKnight, SL (reprint author), Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. EM steven.mcknight@utsouthwestern.edu OI Sawaya, Michael/0000-0003-0874-9043 NR 51 TC 403 Z9 405 U1 12 U2 131 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 11 PY 2012 VL 149 IS 4 BP 753 EP 767 DI 10.1016/j.cell.2012.04.017 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 941AR UT WOS:000303934700010 PM 22579281 ER PT J AU Niere, M Mashimo, M Agledal, L Dolle, C Kasamatsu, A Kato, J Moss, J Ziegler, M AF Niere, Marc Mashimo, Masato Agledal, Line Dolle, Christian Kasamatsu, Atsushi Kato, Jiro Moss, Joel Ziegler, Mathias TI ADP-ribosylhydrolase 3 (ARH3), Not Poly(ADP-ribose) Glycohydrolase (PARG) Isoforms, Is Responsible for Degradation of Mitochondrial Matrix-associated Poly(ADP-ribose) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID APOPTOSIS-INDUCING FACTOR; DNA-DAMAGE; CELL-DEATH; MAMMALIAN-CELLS; PROTEIN; IDENTIFICATION; LOCALIZATION; POLYMERASE; RIBOSYLATION; RIBOSE AB Important cellular processes are regulated by poly(ADP-ribosyl)ation. This protein modification is catalyzed mainly by nuclear poly(ADP-ribose) polymerase (PARP) 1 in response to DNA damage. Cytosolic PARP isoforms have been described, whereas the presence of poly(ADP-ribose) (PAR) metabolism in mitochondria is controversial. PAR is degraded by poly(ADPribose) glycohydrolase (PARG). Recently, ADP-ribosylhydrolase 3 (ARH3) was also shown to catalyze PAR-degradation in vitro. PARG is encoded by a single, essential gene. One nuclear and three cytosolic isoforms result from alternative splicing. The presence and origin of a mitochondrial PARG is still unresolved. We establish here the genetic background of a human mitochondrial PARG isoform and investigate the molecular basis for mitochondrial poly(ADP-ribose) degradation. In common with a cytosolic 60-kDa human PARG isoform, the mitochondrial protein did not catalyze PAR degradation because of the absence of exon 5-encoded residues. In mice, we identified a transcript encoding an inactive cytosolic 52-kDa PARG lacking the mitochondrial targeting sequence and a substantial portion of exon 5. Thus, mammalian PARG genes encode isoforms that do not catalyze PAR degradation. On the other hand, embryonic fibroblasts from ARH3(-/-) mice lack most of the mitochondrial PAR degrading activity detected in wild-type cells, demonstrating a potential involvement of ARH3 in PAR metabolism. C1 [Niere, Marc; Agledal, Line; Dolle, Christian; Ziegler, Mathias] Univ Bergen, Dept Mol Biol, N-5020 Bergen, Norway. [Mashimo, Masato; Kasamatsu, Atsushi; Kato, Jiro; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Ziegler, M (reprint author), Univ Bergen, Dept Mol Biol, Postbox 7803, N-5020 Bergen, Norway. EM mathias.ziegler@mbi.uib.no OI Ziegler, Mathias/0000-0001-6961-2396 FU National Heart, Lung, and Blood Institute, National Institutes of Health; Norwegian Cancer Society FX This study was supported, in whole or in part, by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health. This work was also supported by the Norwegian Cancer Society. NR 43 TC 42 Z9 46 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 MAY 11 PY 2012 VL 287 IS 20 BP 16088 EP 16102 DI 10.1074/jbc.M112.349183 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 942GB UT WOS:000304030900002 PM 22433848 ER PT J AU Ben-Aissa, K Patino-Lopez, G Belkina, NV Maniti, O Rosales, T Hao, JJ Kruhlak, MJ Knutson, JR Picart, C Shaw, S AF Ben-Aissa, Khadija Patino-Lopez, Genaro Belkina, Natalya V. Maniti, Ofelia Rosales, Tilman Hao, Jian-Jiang Kruhlak, Michael J. Knutson, Jay R. Picart, Catherine Shaw, Stephen TI Activation of Moesin, a Protein That Links Actin Cytoskeleton to the Plasma Membrane, Occurs by Phosphatidylinositol 4,5-bisphosphate (PIP2) Binding Sequentially to Two Sites and Releasing an Autoinhibitory Linker SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLECKSTRIN HOMOLOGY DOMAINS; ERM PROTEINS; FERM DOMAIN; STRUCTURAL BASIS; IN-VIVO; EZRIN; PHOSPHORYLATION; EZRIN/RADIXIN/MOESIN; PHOSPHOINOSITIDES; RECOGNITION AB Many cellular processes depend on ERM (ezrin, moesin, and radixin) proteins mediating regulated linkage between plasma membrane and actin cytoskeleton. Although conformational activation of the ERM protein is mediated by the membrane PIP2, the known properties of the two described PIP2-binding sites do not explain activation. To elucidate the structural basis of possible mechanisms, we generated informative moesin mutations and tested three attributes: membrane localization of the expressed moesin, moesin binding to PIP2, and PIP2-induced release of moesin autoinhibition. The results demonstrate for the first time that the POCKET containing inositol 1,4,5-trisphosphate on crystal structure (the "POCKET" Lys-63, Lys-278 residues) mediates all three functions. Furthermore the second described PIP2-binding site (the "PATCH," Lys253/Lys-254, Lys-262/Lys-263) is also essential for all three functions. In native autoinhibited ERM proteins, the POCKET is a cavity masked by an acidic linker, which we designate the "FLAP." Analysis of three mutant moesin constructs predicted to influence FLAP function demonstrated that the FLAP is a functional autoinhibitory region. Moreover, analysis of the cooperativity and stoichiometry demonstrate that the PATCH and POCKET do not bind PIP2 simultaneously. Based on our data and supporting published data, we propose a model of progressive activation of autoinhibited moesin by a single PIP2 molecule in the membrane. Initial transient binding of PIP2 to the PATCH initiates release of the FLAP, which enables transition of the same PIP2 molecule into the newly exposed POCKET where it binds stably and completes the conformational activation. C1 [Shaw, Stephen] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Rosales, Tilman; Knutson, Jay R.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Maniti, Ofelia; Picart, Catherine] Grenoble Inst Technol, F-38016 Grenoble, France. [Maniti, Ofelia; Picart, Catherine] LMGP, CNRS, UMR 5628, F-38016 Grenoble, France. RP Shaw, S (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Shaws@mail.nih.gov OI PICART, Catherine/0000-0002-4854-6366; PICART, Catherine/0000-0003-0130-1000; Patino-Lopez, Genaro/0000-0002-8716-722X FU National Institutes of Health of the NCI; National Institutes of Health of NHLBI; National Institutes of Health of Agence Nationale de la Recherche [ANR-08-PCVI-026]; European Research Council [GA259370] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Programs of the NCI and NHLBI and Agence Nationale de la Recherche (ANR-08-PCVI-026) and by the European Research Council (GA259370). NR 35 TC 22 Z9 22 U1 0 U2 13 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 MAY 11 PY 2012 VL 287 IS 20 BP 16311 EP 16323 DI 10.1074/jbc.M111.304881 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 942GB UT WOS:000304030900023 PM 22433855 ER PT J AU Kessl, JJ Jena, N Koh, Y Taskent-Sezgin, H Slaughter, A Feng, L de Silva, S Wu, L Le Grice, SFJ Engelman, A Fuchs, JR Kvaratskhelia, M AF Kessl, Jacques J. Jena, Nivedita Koh, Yasuhiro Taskent-Sezgin, Humeyra Slaughter, Alison Feng, Lei de Silva, Suresh Wu, Li Le Grice, Stuart F. J. Engelman, Alan Fuchs, James R. Kvaratskhelia, Mamuka TI Multimode, Cooperative Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-VITRO; CATALYTIC DOMAIN; STRUCTURAL BASIS; COACTIVATOR P75; DNA INTEGRATION; BINDING DOMAIN; LEDGF/P75; PROTEIN; IDENTIFICATION AB The multifunctional HIV-1 enzyme integrase interacts with viral DNA and its key cellular cofactor LEDGF to effectively integrate the reverse transcript into a host cell chromosome. These interactions are crucial for HIV-1 replication and present attractive targets for antiviral therapy. Recently, 2-(quinolin-3-yl) acetic acid derivatives were reported to selectively inhibit the integrase-LEDGF interaction in vitro and impair HIV-1 replication in infected cells. Here, we show that this class of compounds impairs both integrase-LEDGF binding and LEDGF-independent integrase catalytic activities with similar IC50 values, defining them as bona fide allosteric inhibitors of integrase function. Furthermore, we show that 2-(quinolin-3-yl) acetic acid derivatives block the formation of the stable synaptic complex between integrase and viral DNA by allosterically stabilizing an inactive multimeric form of integrase. In addition, these compounds inhibit LEDGF binding to the stable synaptic complex. This multimode mechanism of action concordantly results in cooperative inhibition of the concerted integration of viral DNA ends in vitro and HIV-1 replication in cell culture. Our findings, coupled with the fact that high cooperativity of antiviral inhibitors correlates with their increased instantaneous inhibitory potential, an important clinical parameter, argue strongly that improved 2-(quinolin-3-yl) acetic acid derivatives could exhibit desirable clinical properties. C1 [Kessl, Jacques J.; Slaughter, Alison; Feng, Lei; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Kessl, Jacques J.; Slaughter, Alison; Feng, Lei; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Jena, Nivedita; Fuchs, James R.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Koh, Yasuhiro; Engelman, Alan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Koh, Yasuhiro; Engelman, Alan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [de Silva, Suresh; Wu, Li] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Taskent-Sezgin, Humeyra; Le Grice, Stuart F. J.] Ohio State Univ, Dept Vet Biosci, Ctr Retrovirus Res, Columbus, OH 43210 USA. RP Kvaratskhelia, M (reprint author), Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, 500 W 12Th Ave, Columbus, OH 43210 USA. EM kvaratskhelia.1@osu.edu RI Jena, Nivedita/F-4945-2012; Fuchs, James/B-4625-2012; Wu, Li/E-4330-2011; Kessl, Jacques/J-6073-2015 OI Wu, Li/0000-0002-5468-2487; FU National Institutes of Health [AI081581, AI062520, CA100730, AI097044, AI039394]; NCI, National Institutes of Health, Department of Health and Human Services FX This work was supported by National Institutes of Health Grants AI081581, AI062520, and CA100730 (to M. K.), AI097044 (to J. J. K. and J. R. F.), AI039394 (to A. E.); the Intramural Research Program of the NCI, National Institutes of Health, Department of Health and Human Services (to H. T. S. and S. F. J. L. G.). NR 40 TC 76 Z9 77 U1 0 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 MAY 11 PY 2012 VL 287 IS 20 BP 16801 EP 16811 DI 10.1074/jbc.M112.354373 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 942GB UT WOS:000304030900067 PM 22437836 ER PT J AU Utreras, E Keller, J Terse, A Prochazkova, M Iadarola, MJ Kulkarni, AB AF Utreras, Elias Keller, Jason Terse, Anita Prochazkova, Michaela Iadarola, Michael J. Kulkarni, Ashok B. TI Transforming Growth Factor-beta 1 Regulates Cdk5 Activity in Primary Sensory Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DEPENDENT KINASE-5 ACTIVITY; B104 NEUROBLASTOMA-CELLS; FACTOR-BETA FAMILY; PERIPHERAL INFLAMMATION; TARGETED DISRUPTION; GROWTH; MICE; PAIN; EXPRESSION; ALZHEIMERS AB In addition to many important roles for Cdk5 in brain development and synaptic function, we reported previously that Cdk5 regulates inflammatory pain signaling, partly through phosphorylation of transient receptor potential vanilloid 1 (TRPV1), an important Na+/Ca2+ channel expressed in primary nociceptive afferent nerves. Because TGF-beta regulates inflammatory processes and its receptor is expressed in TRPV1-positive afferents, we studied the cross-talk between these two pathways in sensory neurons during experimental peripheral inflammation. We demonstrate that TGF-beta 1 increases transcription and protein levels of the Cdk5 co-activator p35 through ERK1/2, resulting in an increase in Cdk5 activity in rat B104 neuroblastoma cells. Additionally, TGF-beta 1 enhances the capsaicin-induced Ca2+ influx in cultured primary neurons from dorsal root ganglia (DRG). Importantly, Cdk5 activity was reduced in the trigeminal ganglia and DRG of 14-day-old TGF-beta 1 knock-out mice, resulting in reduced Cdk5-dependent phosphorylation of TRPV1. The decreased Cdk5 activity is associated with attenuated thermal hyperalgesia in TGF-beta 1 receptor conditional knock-out mice, where TGF-beta signaling is significantly reduced in trigeminal ganglia and DRG. Collectively, our results indicate that active cross-talk between the TGF-beta and Cdk5 pathways contributes to inflammatory pain signaling. C1 [Utreras, Elias; Terse, Anita; Prochazkova, Michaela; Kulkarni, Ashok B.] NIDCR, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Keller, Jason; Iadarola, Michael J.] NIDCR, Neurobiol & Pain Therapeut Sect, NIH, Bethesda, MD 20892 USA. RP Kulkarni, AB (reprint author), NIDCR, LCDB, NIH, 30 Convent Dr,Rm 130,MSC 4395, Bethesda, MD 20892 USA. EM ak40m@nih.gov RI utreras, elias/I-1038-2013 OI utreras, elias/0000-0002-1004-0466 FU National Institutes of Health Division of Intramural Research, NIDCR FX This work was supported, in whole or in part, by the National Institutes of Health Division of Intramural Research, NIDCR. NR 50 TC 19 Z9 20 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 MAY 11 PY 2012 VL 287 IS 20 BP 16917 EP 16929 DI 10.1074/jbc.M111.329979 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 942GB UT WOS:000304030900077 PM 22451679 ER PT J AU Weisz, A Witten, JJ Zeng, Y Mazzola, EP Ito, Y AF Weisz, Adrian Witten, Jacob J. Zeng, Yun Mazzola, Eugene P. Ito, Yoichiro TI Preparation of two novel monobrominated 2-(2 ',4 '-dihydroxybenzoyl)-3,4,5,6-tetrachlorobenzoic acids and their separation from crude synthetic mixtures using vortex counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Vortex counter-current chromatography; VCCC; pH-zone-refining CCC; Chemoselective ortho-bromination; 2-(2 '.4 '-Dihydroxy-3 '-bromobenzoyl)-3,4,5,6-tetrachlorobenzoic acid; 2-(2 '.4 '-Dihydroxy-5 '-bromobenzoyl)-3.4,5,6-tetrachlorobenzoic acid ID COLOR ADDITIVES D; PERFORMANCE LIQUID-CHROMATOGRAPHY; RED NOS. 27; SOLID-PHASE MICROEXTRACTION; PHLOXINE-B; PARTITION CHROMATOGRAPHY; MASS SPECTROMETRY; ORTHO-BROMINATION; QUANTIFICATION; COMPONENTS AB The present work describes the preparation of two compounds considered to be likely precursors of an impurity present in samples of the color additives D&C Red No. 27 (Color Index 45410:1) and D&C Red No. 28 (Color Index 45410, phloxine B) submitted to the U.S. Food and Drug Administration for batch certification. The two compounds, 2-(2',4'-dihydroxy-3'-bromobenzoyl)-3,4,5,6-tetrachlorobenzoic acid (3BrHBBA) and its 5'-brominated positional isomer (5BrHBBA), both not reported previously, were separated from synthetic mixtures by vortex counter-current chromatography (VCCC). 3BrHBBA was prepared by chemoselective ortho-bromination of the dihydroxybenzoyl moiety. Two portions of the obtained synthetic mixture, 200 mg and 210 mg, respectively, were separated by VCCC using two two-phase solvent systems that consisted of hexane-ethyl acetate-methanol-aqueous 0.2% trifluoroacetic acid (TFA) in the volume ratios of 8:2:5:5 and 7:3:5:5, respectively. These separations produced 35 mg and 78 mg of 3BrHBBA, respectively, each product of over 98% purity by HPLC at 254 urn. 5BrHBBA was prepared by monobromination of the dihydroxybenzoyl moiety in the presence of glacial acetic acid. To separate the obtained synthetic mixture. VCCC was performed in the pH-zone-refining mode with a solvent system consisting of hexane-ethyl acetate-methanol-water (6:4:5:5, v/v) and with TFA used as the retainer acid and aqueous ammonia as the eluent base. Separation of a 1-g mixture under these conditions resulted in 142 mg of 5BrHBBA of similar to 99% purity by HPLC at 254 nm. The isolated compounds were characterized by high-resolution mass spectrometry and proton nuclear magnetic resonance spectroscopy. Published by Elsevier B.V. C1 [Weisz, Adrian] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Witten, Jacob J.; Zeng, Yun; Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Witten, Jacob J.] Amherst Coll, Amherst, MA 01002 USA. [Zeng, Yun] N Sichuan Med Coll, Inst Mat Med, Nanchong 637007, Sichuan Provinc, Peoples R China. [Zeng, Yun] N Sichuan Med Coll, Dept Pharmacol, Nanchong 637007, Sichuan Provinc, Peoples R China. [Mazzola, Eugene P.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Weisz, A (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, HFS 106,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM adrian.weisz@fda.hhs.gov OI Witten, Jacob/0000-0003-0037-5999 FU Intramural NIH HHS [ZIA HL001060-03] NR 41 TC 6 Z9 6 U1 0 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAY 11 PY 2012 VL 1237 BP 106 EP 114 DI 10.1016/j.chroma.2012.03.040 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 932CW UT WOS:000303269000012 PM 22475185 ER PT J AU Bergerson, RJ Collier, LS Sarver, AL Been, RA Lugthart, S Diers, MD Zuber, J Rappaport, AR Nixon, MJ Silverstein, KAT Fan, DH Lamblin, AFJ Wolff, L Kersey, JH Delwel, R Lowe, SW O'Sullivan, MG Kogan, SC Adams, DJ Largaespada, DA AF Bergerson, Rachel J. Collier, Lara S. Sarver, Aaron L. Been, Raha A. Lugthart, Sanne Diers, Miechaleen D. Zuber, Johannes Rappaport, Amy R. Nixon, Molly J. Silverstein, Kevin A. T. Fan, Danhua Lamblin, Anne-Francoise J. Wolff, Linda Kersey, John H. Delwel, Ruud Lowe, Scott W. O'Sullivan, M. Gerard Kogan, Scott C. Adams, David J. Largaespada, David A. TI An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; FUSION GENE; MICE; CANCER; EXPRESSION; LOCUS; MLL; AML; OVEREXPRESSION; TRANSLOCATIONS AB Patients with a t(9;11) translocation (MLL-AF9) develop acute myeloid leukemia (AML), and while in mice the expression of this fusion oncogene also results in the development of myeloid leukemia, it is with long latency. To identify mutations that cooperate with Mll-AF9, we infected neonatal wild-type (WT) or Mll-AF9 mice with a murine leukemia virus (MuLV). MuLV-infected Mll-AF9 mice succumbed to disease significantly faster than controls presenting predominantly with myeloid leukemia while infected WT animals developed predominantly lymphoid leukemia. We identified 88 candidate cancer genes near common sites of proviral insertion. Analysis of transcript levels revealed significantly elevated expression of Mn1, and a trend toward increased expression of Bcl11a and Fosb in Mll-AF9 murine leukemia samples with proviral insertions proximal to these genes. Accordingly, FOSB and BCL11A were also overexpressed in human AML harboring MLL gene translocations. FOSB was revealed to be essential for growth in mouse and human myeloid leukemia cells using shRNA lentiviral vectors in vitro. Importantly, MN1 cooperated with Mll-AF9 in leukemogenesis in an in vivo BM viral transduction and transplantation assay. Together, our data identified genes that define transcription factor networks and important genetic pathways acting during progression of leukemia induced by MLL fusion oncogenes. (Blood. 2012; 119(19): 4512-4523) C1 [Bergerson, Rachel J.; Been, Raha A.; Diers, Miechaleen D.; Nixon, Molly J.; Kersey, John H.; Largaespada, David A.] Univ Minnesota Twin Cities, Dept Genet Cell Biol & Dev, Mason Canc Ctr, Minneapolis, MN 55455 USA. [Bergerson, Rachel J.; Been, Raha A.; Diers, Miechaleen D.; Nixon, Molly J.; Kersey, John H.; Largaespada, David A.] Univ Minnesota Twin Cities, Dept Pediat, Mason Canc Ctr, Minneapolis, MN 55455 USA. [Collier, Lara S.] Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, Madison, WI 53706 USA. [Lugthart, Sanne; Delwel, Ruud] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands. [Rappaport, Amy R.; Lowe, Scott W.] Watson Sch Biol Sci, Cold Spring Harbor, NY USA. [Wolff, Linda] NIH, Lab Cellular Oncol, Ctr Canc Res, Bethesda, MD 20892 USA. [Lowe, Scott W.] Cold Spring Harbor Lab, Howard Hughes Med Inst, Cold Spring Harbor, NY 11724 USA. [Kogan, Scott C.] Univ Calif San Francisco, Dept Lab Med, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Adams, David J.] Wellcome Trust Sanger Inst, Hinxton, England. RP Largaespada, DA (reprint author), Univ Minnesota Twin Cities, Dept Genet Cell Biol & Dev, Mason Canc Ctr, 6-160 Jackson Hall,321 Church St, Minneapolis, MN 55455 USA. EM larga002@umn.edu RI Largaespada, David/C-9832-2014 FU National Cancer Institute [U01 CA84221, F32 CA106192, K01 CA122183]; Leukemia & Lymphoma Society of America [LLS 7019-04]; University of Minnesota Cancer Biology training grant [CA009138]; Cancer Research UK; TheWellcome Trust; American Cancer Society [PF-05-153-01] FX This work was supported by National Cancer Institute grant U01 CA84221 (D. A. L.), the Leukemia & Lymphoma Society of America LLS 7019-04 (D. A. L.), the University of Minnesota Cancer Biology training grant CA009138, and grants from Cancer Research UK and TheWellcome Trust (D.J.A.). S. C. K. is a scholar of the Leukemia & Lymphoma Society. L. S. C. is supported by fellowships from the National Cancer Institute (F32 CA106192 and K01 CA122183) and a postdoctoral fellowship from the American Cancer Society PF-05-153-01. NR 41 TC 8 Z9 8 U1 0 U2 8 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 MAY 10 PY 2012 VL 119 IS 19 BP 4512 EP 4523 DI 10.1182/blood-2010-04-281428 PG 12 WC Hematology SC Hematology GA 959CC UT WOS:000305286900026 PM 22427200 ER PT J AU Tosh, DK Phan, K Gao, ZG Gakh, AA Xu, F Deflorian, F Abagyan, R Stevens, RC Jacobson, KA Katritch, V AF Tosh, Dilip K. Phan, Khai Gao, Zhan-Guo Gakh, Andrei A. Xu, Fei Deflorian, Francesca Abagyan, Ruben Stevens, Raymond C. Jacobson, Kenneth A. Katritch, Vsevolod TI Optimization of Adenosine 5 '-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; STRUCTURE-BASED DISCOVERY; HISTAMINE H-1 RECEPTOR; X-RAY-STRUCTURE; CRYSTAL-STRUCTURE; DRUG DISCOVERY; A(2A) RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; BETA(2) ADRENOCEPTOR; SUBTYPE-SELECTIVITY AB Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse ago fists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5' derivatives, we evaluated the performance of an agonist-bound A(2A) adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A(1)AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs. C1 [Xu, Fei; Stevens, Raymond C.; Katritch, Vsevolod] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Tosh, Dilip K.; Phan, Khai; Gao, Zhan-Guo; Gakh, Andrei A.; Deflorian, Francesca; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Abagyan, Ruben] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. RP Katritch, V (reprint author), Scripps Res Inst, Dept Mol Biol, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM kajacobs@helix.nih.gov; katritch@scripps.edu RI Jacobson, Kenneth/A-1530-2009; Katritch, Vsevolod/Q-8357-2016; OI Jacobson, Kenneth/0000-0001-8104-1493; Katritch, Vsevolod/0000-0003-3883-4505 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases; NIH [U54 GM094618] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases, and the NIH PSI:Biology grant (U54 GM094618) to R.C.S., RA., and V.K. NR 65 TC 34 Z9 34 U1 0 U2 10 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 MAY 10 PY 2012 VL 55 IS 9 BP 4297 EP 4308 DI 10.1021/jm300095s PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 939CY UT WOS:000303785900019 PM 22486652 ER PT J AU LaLonde, JM Kwon, YD Jones, DM Sun, AW Courter, JR Soeta, T Kobayashi, T Princiotto, AM Wu, XL Schon, A Freire, E Kwong, PD Mascola, JR Sodroski, J Madani, N Smith, AB AF LaLonde, Judith M. Kwon, Young Do Jones, David M. Sun, Alexander W. Courter, Joel R. Soeta, Takahiro Kobayashi, Toyoharu Princiotto, Amy M. Wu, Xueling Schoen, Arne Freire, Ernesto Kwong, Peter D. Mascola, John R. Sodroski, Joseph Madani, Navid Smith, Amos B., III TI Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROTEIN-PROTEIN INTERACTIONS; MULTIPLE SEQUENCE ALIGNMENT; GP120 ENVELOPE GLYCOPROTEIN; NEUTRALIZING ANTIBODIES; DRUG DISCOVERY; STRUCTURE VALIDATION; CD4-BOUND STATE; ATOM CONTACTS; BINDING-SITE AB Cellular infection by HIV-1 is initiated with a binding event between the viral envelope glycoprotein gp120 and the cellular receptor protein CD4. The CD4-gp120 interface is dominated by two hotspots: a hydrophobic gp120 cavity capped by Phe43(CD4) and an electrostatic interaction between residues Arg59(CD4) and Asp368(gp120). The CD4 mimetic small-molecule NBD-556 (1) binds within the gp120 cavity; however, 1 and related congeners demonstrate limited viral neutralization breadth. Herein, we report the design, synthesis, characterization, and X-ray structures of gp120 in complex with small molecules that simultaneously engage both binding hotspots. The compounds specifically inhibit viral infection of 42 tier 2 clades B and C viruses and are shown to be antagonists of entry into CD4-negative cells. Dual hotspot design thus provides both a means to enhance neutralization potency of HIV-1 entry inhibitors and a novel structural paradigm for inhibiting the CD4-gp120 protein-protein interaction. C1 [LaLonde, Judith M.] Bryn Mawr Coll, Dept Chem, Rosemont, PA 19010 USA. [Kwon, Young Do; Wu, Xueling; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Jones, David M.; Sun, Alexander W.; Courter, Joel R.; Soeta, Takahiro; Kobayashi, Toyoharu; Smith, Amos B., III] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Princiotto, Amy M.; Sodroski, Joseph; Madani, Navid] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Schoen, Arne; Freire, Ernesto] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Sodroski, Joseph] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Sodroski, Joseph] Ragon Inst MGH MIT & Harvard, Boston, MA 02115 USA. RP LaLonde, JM (reprint author), Bryn Mawr Coll, Dept Chem, Rosemont, PA 19010 USA. EM jlalonde@brynmawr.edu; smithab@sas.upenn.edu RI Kwon, Young Do/A-6957-2010; SOETA, Takahiro/E-7060-2015 OI SOETA, Takahiro/0000-0001-9883-4772 FU NIH [GM 56550]; NIH Intramural IATAP; NIAID; Pittsburgh Supercomputing Center [MCB090108] FX We thank Irwin Chaiken and Wayne Hendrickson and all the members of the PO1 Consortium "Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry". We also thank Jonathan Stuckey for assistance with figures, and members of the Structural Biology Section, Vaccine Research Center, NIAID for comments on the manuscript. Funding was provided by NIH Grant GM 56550 to J.M.L., E.F., A.B.S., by NIH Intramural IATAP and NIAID programs to Y.D.K., P.D.K., J.R.M., and J.S. J.M.L. thanks the Pittsburgh Supercomputing Center for an allocation for computing resources, Grant MCB090108. NR 94 TC 51 Z9 51 U1 0 U2 24 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 MAY 10 PY 2012 VL 55 IS 9 BP 4382 EP 4396 DI 10.1021/jm300265j PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 939CY UT WOS:000303785900026 PM 22497421 ER PT J AU Nguyen, TX Morrell, A Conda-Sheridan, M Marchand, C Agama, K Bermingam, A Stephen, AG Chergui, A Naumova, A Fisher, R O'Keefe, BR Pommier, Y Cushman, M AF Trung Xuan Nguyen Morrell, Andrew Conda-Sheridan, Martin Marchand, Christophe Agama, Keli Bermingam, Alun Stephen, Andrew G. Chergui, Adel Naumova, Alena Fisher, Robert O'Keefe, Barry R. Pommier, Yves Cushman, Mark TI Synthesis and Biological Evaluation of the First Dual Tyrosyl-DNA Phosphodiesterase I (Tdp1)-Topoisomerase I (Top1) Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MAMMALIAN TOPOISOMERASE-I; SPINOCEREBELLAR ATAXIA; COVALENT COMPLEXES; CLEAVAGE COMPLEXES; CRYSTAL-STRUCTURE; HUMAN-CELLS; TDP1; REPAIR; DAMAGE; CAMPTOTHECIN AB Substances with dual tyrosyl-DNA phosphodiesterase I-topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1-Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC50 = 1.52 +/- 0.05 mu M), and it was also equipotent to camptothecin as a Top 1 inhibitor. Significant insights into enzyme-drug interactions were gained via structure-activity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1-Tdp1 inhibitors. C1 [Trung Xuan Nguyen; Morrell, Andrew; Conda-Sheridan, Martin; Cushman, Mark] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Trung Xuan Nguyen; Morrell, Andrew; Conda-Sheridan, Martin; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Marchand, Christophe; Agama, Keli; Chergui, Adel; Naumova, Alena; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Bermingam, Alun; O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Stephen, Andrew G.; Fisher, Robert] NCI, Prot Chem Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Cushman, M (reprint author), Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@purdue.edu FU National Institutes of Health (NIH) [UO1 CA89566]; Purdue Research Foundation; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was made possible by the National Institutes of Health (NIH) through support with Research Grant UO1 CA89566, and by a Purdue Research Foundation Grant. This research was also supported in part 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 no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 47 TC 35 Z9 37 U1 1 U2 27 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 MAY 10 PY 2012 VL 55 IS 9 BP 4457 EP 4478 DI 10.1021/jm300335n PG 22 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 939CY UT WOS:000303785900032 PM 22536944 ER PT J AU Kwok, M Korde, N Landgren, O AF Kwok, Mary Korde, Neha Landgren, Ola TI Bortezomib to Treat the TEMPI Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Kwok, Mary; Korde, Neha; Landgren, Ola] NCI, Bethesda, MD 20892 USA. RP Kwok, M (reprint author), NCI, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov FU Intramural NIH HHS NR 1 TC 9 Z9 9 U1 0 U2 3 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 MAY 10 PY 2012 VL 366 IS 19 BP 1843 EP 1845 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 939NB UT WOS:000303817000024 PM 22571216 ER PT J AU Karuri, SW Simon, R AF Karuri, Stella Wanjugu Simon, Richard TI A two-stage Bayesian design for co-development of new drugs and companion diagnostics SO STATISTICS IN MEDICINE LA English DT Article DE clinical trials design; predictive biomarkers; Bayesian inference; prior distribution; type I error probabilities ID PHASE-III TRIAL; RANDOMIZED CLINICAL-TRIALS; CANCER; CHEMOTHERAPY; GEMCITABINE; EFFICIENCY; CISPLATIN; ONCOLOGY; SUBSET; PLUS AB Most new drug development in oncology is based on targeting specific molecules. Genomic profiles and deregulated drug targets vary from patient to patient making new treatments likely to benefit only a subset of patients traditionally grouped in the same clinical trials. Predictive biomarkers are being developed to identify patients who are most likely to benefit from a particular treatment; however, their biological basis is not always conclusive. The inclusion of marker-negative patients in a trial is therefore sometimes necessary for a more informative evaluation of the therapy. In this paper, we present a two-stage Bayesian design that includes both marker-positive and marker-negative patients in a clinical trial. We formulate a family of prior distributions that represent the degree of a priori confidence in the predictive biomarker. To avoid exposing patients to a treatment to which they may not be expected to benefit, we perform an interim analysis that may stop accrual of marker-negative patients or accrual of all patients. We demonstrate with simulations that the design and priors used control type I errors, give adequate power, and enable the early futility analysis of test-negative patients to be based on prior specification on the strength of evidence in the biomarker. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Karuri, Stella Wanjugu; Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov NR 21 TC 12 Z9 12 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 10 PY 2012 VL 31 IS 10 BP 901 EP 914 DI 10.1002/sim.4462 PG 14 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 923JU UT WOS:000302616400001 PM 22238151 ER PT J AU Huang, QF Deng, XF Best, SM Bloom, ME Li, Y Qiu, JM AF Huang, Qinfeng Deng, Xuefeng Best, Sonja M. Bloom, Marshall E. Li, Yi Qiu, Jianming TI Internal polyadenylation of parvoviral precursor mRNA limits progeny virus production SO VIROLOGY LA English DT Article DE Parvovirus; Polyadenylation; Virus production ID ALEUTIAN-MINK-DISEASE; MINUTE VIRUS; TRANSCRIPTION PROFILE; UNIQUE FEATURES; HUMAN BOCAVIRUS; CANINE PARVOVIRUS; INFECTIOUS CLONE; CELL-CULTURE; REPLICATION; PROTEIN AB Aleutian Mink Disease Virus (AMDV) is the only virus in the genus Amdovirus of family Parvoviridae. In adult mink, AMDV causes a persistent infection associated with severe dysfunction of the immune system. Cleavage of AMDV capsid proteins has been previously shown to play a role in regulating progeny virus production (Fang Cheng et al., J. Virol. 84:2687-2696,2010). The present study shows that AMDV has evolved a second strategy to limit expression of capsid proteins by preventing processing of the full-length capsid protein-encoding mRNA transcripts. Characterization of the cis-elements of the proximal polyadenylation site [(pA)p] in the infectious clone of AMDV revealed that polyadenylation at the (pA)p site is controlled by an upstream element (USE) of 200 nts in length, the AAUAAA signal, and a downstream element (DSE) of 40 nts. A decrease in polyadenylation at the (pA)p site, either by mutating the AAUAAA signal or the DSE, which does not affect the encoding of amino acids in the infectious clone, increased the expression of capsid protein VP1/VP2 and thereby increased progeny virus production approximately 2-3-fold. This increase was accompanied by enhanced replication of the AMDV genome. Thus, this study reveals correlations among internal polyadenylation, capsid production, viral DNA replication and progeny virus production of AMDV, indicating that internal polyadenylation is a limiting step for parvovirus replication and progeny virus production. (C) 2012 Elsevier Inc. All rights reserved. C1 [Huang, Qinfeng; Deng, Xuefeng; Qiu, Jianming] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66160 USA. [Deng, Xuefeng; Li, Yi] Cent China Normal Univ, Sch Life Sci, Wuhan, Peoples R China. [Best, Sonja M.; Bloom, Marshall E.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Qiu, JM (reprint author), Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Mail Stop 3029,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM jqiu@kumc.edu RI perumal, murugiah/D-1565-2012; DENG, XUEFENG/E-1936-2016 FU PHS [R01 AI070723, R21 AI085236]; National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by PHS grant R01 AI070723 and R21 AI085236, and was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Allergy and Infectious Diseases (NIAID). We thank members in the Qiu lab for valuable discussions, and are indebted to Fang Cheng for excellent technical support. NR 48 TC 9 Z9 11 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 10 PY 2012 VL 426 IS 2 BP 167 EP 177 DI 10.1016/j.virol.2012.01.031 PG 11 WC Virology SC Virology GA 909KH UT WOS:000301562900010 PM 22361476 ER PT J AU Lee, JK Sayers, BC Chun, KS Lao, HC Shipley-Phillips, JK Bonner, JC Langenbach, R AF Lee, Jong Kwon Sayers, Brian C. Chun, Kyung-Soo Lao, Huei-Chen Shipley-Phillips, Jeanette K. Bonner, James C. Langenbach, Robert TI Multi-walled carbon nanotubes induce COX-2 and iNOS expression via MAP Kinase-dependent and -independent mechanisms in mouse RAW264.7 macrophages SO PARTICLE AND FIBRE TOXICOLOGY LA English DT Article DE Carbon nanotubes; Nanoparticles; Lung inflammation; Macrophages; Prostaglandins; Nitric oxide ID NITRIC-OXIDE SYNTHASE; CYCLOOXYGENASE-2-DEFICIENT MICE; PULMONARY TOXICITY; UP-REGULATION; LUNG INJURY; RESPONSES; FIBROSIS; ASBESTOS; NANOPARTICLES; CELLS AB Background: Carbon nanotubes (CNTs) are engineered graphene cylinders with numerous applications in engineering, electronics and medicine. However, CNTs cause inflammation and fibrosis in the rodent lung, suggesting a potential human health risk. We hypothesized that multi-walled CNTs (MWCNTs) induce two key inflammatory enzymes in macrophages, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), through activation of extracellular signal-regulated kinases (ERK1,2). Methods: RAW264.7 macrophages were exposed to MWCNTs or carbon black nanoparticles (CBNPs) over a range of doses and time course. Uptake and subcellular localization of MWCNTs was visualized by transmission electron microscopy (TEM). Protein levels of COX-2, iNOS, and ERK1,2 (total ERK and phosphorylated ERK) were measured by Western blot analysis. Prostaglandin-E-2 (PGE(2)) and nitric oxide (NO) levels in cell supernatants were measured by ELISA and Greiss assay, respectively. Results: MWCNTs, but not CBNPs, induced COX-2 and iNOS in a time-and dose-dependent manner. COX-2 and iNOS induction by MWCNTs correlated with increased PGE2 and NO production, respectively. MWCNTs caused ERK1,2 activation and inhibition of ERK1,2 (U0126) blocked MWCNT induction of COX-2 and PGE2 production, but did not reduce the induction of iNOS. Inhibition of iNOS (L-NAME) did not affect ERK1,2 activation, nor did L-NAME significantly decrease COX-2 induction by MWCNT. Nickel nanoparticles (NiNPs), which are present in MWCNTs as a residual catalyst, also induced COX-2 via ERK-1,2. However, a comparison of COX-2 induction by MWCNTs containing 4.5 and 1.8% Ni did not show a significant difference in ability to induce COX-2, indicating that characteristics of MWCNTs in addition to Ni content contribute to COX-2 induction. Conclusion: This study identifies COX-2 and subsequent PGE2 production, along with iNOS induction and NO production, as inflammatory mediators involved in the macrophage response to MWCNTs. Furthermore, our work demonstrates that COX-2 induction by MWCNTs in RAW264.7 macrophages is ERK1,2-dependent, while iNOS induction by MWCNTs is ERK1,2-independent. Our data also suggest contributory physicochemical factors other than residual Ni catalyst play a role in COX-2 induction to MWCNT. C1 [Sayers, Brian C.; Bonner, James C.; Langenbach, Robert] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. [Lee, Jong Kwon; Chun, Kyung-Soo; Lao, Huei-Chen; Langenbach, Robert] NIEHS, Lab Toxicol & Pharmacol, Durham, NC 27709 USA. [Lee, Jong Kwon] Korea Food & Drug Adm, Toxicol Res Div, Natl Inst Food & Drug Safety Evaluat, Osong 363951, South Korea. [Chun, Kyung-Soo] Keimyung Univ, Coll Pharm, Dae Gu 704701, South Korea. [Shipley-Phillips, Jeanette K.] N Carolina State Univ, Dept Populat Hlth & Pathobiol, Lab Adv Elect & Light Opt Methods, Coll Vet Med, Raleigh, NC 27695 USA. RP Bonner, JC (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. EM james_bonner@ncsu.edu; langenb1@niehs.nih.gov FU Korea Food and Drug Administration; NIH [RC2-ES018772-01]; NIEHS [T32-ES007046-31] FX This work was conducted in the Intramural Research Division (JKL, KSC, HCL, RL) of the NIH at the National Institute of Environmental Health Sciences. JKL was supported in part by the Korea Food and Drug Administration. JCB was funded by NIH Grant RC2-ES018772-01 and BCS was supported by NIEHS training grant T32-ES007046-31. NR 50 TC 31 Z9 31 U1 0 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-8977 J9 PART FIBRE TOXICOL JI Part. Fibre Toxicol. PD MAY 9 PY 2012 VL 9 AR 14 DI 10.1186/1743-8977-9-14 PG 11 WC Toxicology SC Toxicology GA 033DI UT WOS:000310773600001 PM 22571318 ER PT J AU Boura, E Rozycki, B Chung, HS Herrick, DZ Canagarajah, B Cafiso, DS Eaton, WA Hummer, G Hurley, JH AF Boura, Evzen Rozycki, Bartosz Chung, Hoi Sung Herrick, Dawn Z. Canagarajah, Bertram Cafiso, David S. Eaton, William A. Hummer, Gerhard Hurley, James H. TI Solution Structure of the ESCRT-I and -II Supercomplex: Implications for Membrane Budding and Scission SO STRUCTURE LA English DT Article ID MULTIVESICULAR BODY BIOGENESIS; ENDOSOME-ASSOCIATED COMPLEX; SINGLE-MOLECULE FRET; SORTING COMPLEX; UBIQUITINATED PROTEINS; TRAFFICKING COMPLEX; GLUE DOMAIN; MACHINERY; TRANSPORT; DYNAMICS AB The ESCRT-I and ESCRT-II supercomplex induces membrane buds that invaginate into the lumen of endosomes, a process central to the lysosomal degradation of ubiquitinated membrane proteins. The solution conformation. of the membrane-budding ESCRT-I-II supercomplex from yeast was refined against small-angle X-ray scattering (SAXS), single-molecule Forster resonance energy transfer (smFRET), and double electron-electron resonance (DEER) spectra. These refinements yielded an ensemble of 18 ESCRT-I-II supercomplex structures that range from compact to highly extended. The crescent shapes of the ESCRT-I-II supercomplex structures provide the basis for a detailed mechanistic model, in which ESCRT-I-II stabilizes membrane buds and coordinates cargo sorting by lining the pore of the nascent bud necks. The hybrid refinement used here is general and should be applicable to other dynamic multiprotein assmeblies. C1 [Rozycki, Bartosz; Chung, Hoi Sung; Eaton, William A.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Boura, Evzen; Canagarajah, Bertram; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Herrick, Dawn Z.; Cafiso, David S.] Univ Virginia, Dept Chem, Biophys Program, Charlottesville, VA 22904 USA. [Herrick, Dawn Z.; Cafiso, David S.] Univ Virginia, Ctr Membrane Biol, Charlottesville, VA 22904 USA. RP Hummer, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov; hurley@helix.nih.gov RI Rozycki, Bartosz/B-7005-2009; Chung, Hoi Sung/C-2624-2009; Boura, Evzen/I-2626-2012; Hummer, Gerhard/A-2546-2013; Boura, Evzen/G-5275-2014 OI Rozycki, Bartosz/0000-0001-5938-7308; Hummer, Gerhard/0000-0001-7768-746X; FU Department of Energy, Office of Biological and Environmental Research; National Institutes of Health (NIH), National Center for Research Resources; European Community; Intramural AIDS Research Fellowship; NIH, National Institute of Diabetes and Digestive and Kidney Diseases; Office of the Director, NIH; NIH [GM072694] FX We thank E. Tyler for generating Figure 8 and Movie Si. SAXS data were collected at the Stanford Synchrotron Radiation Laboratory, a national user facility operated by Stanford University on behalf of the U.S. Department of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the National Institutes of Health (NIH), National Center for Research Resources, Biomedical Technology Program. B.R. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme. E.B. was supported by an Intramural AIDS Research Fellowship. This work was supported by the Intramural Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (G.H., J.H.H., and W.A.E.), the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH (J.H.H.), and an NIH grant (GM072694 to D.S.C.). NR 56 TC 32 Z9 32 U1 1 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAY 9 PY 2012 VL 20 IS 5 BP 874 EP 886 DI 10.1016/j.str.2012.03.008 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 944OT UT WOS:000304214400013 PM 22579254 ER PT J AU Mu, RL Dussupt, V Jiang, JS Sette, P Rudd, V Chuenchor, W Bello, NF Bouamr, F Xiao, TS AF Mu, Ruiling Dussupt, Vincent Jiang, Jiansheng Sette, Paola Rudd, Victoria Chuenchor, Watchalee Bello, Nana F. Bouamr, Fadila Xiao, Tsan Sam TI Two Distinct Binding Modes Define the Interaction of Brox with the C-Terminal Tails of CHMP5 and CHMP4B SO STRUCTURE LA English DT Article ID ESCRT-III RECOGNITION; STRUCTURAL BASIS; SACCHAROMYCES-CEREVISIAE; BETA-HAIRPIN; HELICAL STRUCTURES; PROTEIN STRUCTURES; PLASMA-MEMBRANE; DOMAIN; VPS4; PATHWAY AB Interactions of the CHMP protein carboxyl terminal tails with effector proteins play important roles in retroviral budding, cytokinesis, and multivesicular body biogenesis. Here we demonstrate that hydrophobic residues at the CHMP4B C-terminal amphipathic a helix bind a concave surface of Brox, a mammalian paralog of Alix. Unexpectedly, CHMP5 was also found to bind Brox and specifically recruit endogenous Brox to detergent-resistant membrane fractions through its C-terminal 20 residues. Instead of an a helix, the CHMP5 C-terminal tail adopts a tandem beta-hairpin structure that binds Brox at the same site as CHMP4B. Additional Brox:CHMP5 interface is furnished by a unique CHMP5 hydrophobic pocket engaging the Brox residue Y348 that is not conserved among the Bro1 domains. Our studies thus unveil a beta-hairpin conformation of the CHMP5 protein C-terminal tail, and provide insights into the overlapping but distinct binding profiles of ESCRT-III and the Bro1 domain proteins. C1 [Dussupt, Vincent; Sette, Paola; Rudd, Victoria; Bello, Nana F.; Bouamr, Fadila] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Mu, Ruiling; Jiang, Jiansheng; Chuenchor, Watchalee; Xiao, Tsan Sam] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Bouamr, F (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM bouamrf@mail.nih.gov; xiaot@niaid.nih.gov RI MU, RUILING/H-3655-2012; Xiao, Tsan/A-8590-2010; Xiao, Tsan/I-7616-2013 OI Xiao, Tsan/0000-0001-9688-475X FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; Office of AIDS Research (OAR, NIH) FX The authors would like to thank the X29A beam line scientists at the Brookhaven National Laboratory for their assistance with X-ray diffraction data collection. We thank Masatoshi Maki for reagents and Alicia Buckler-White and her team at LMM for DNA sequencing and the Biological Imaging team at the Research Technologies Branch, NIAID for assistance with confocal microscopy. We are grateful to Tengchuan Jin for help with the FP assay, Grzegorz Piszczek at the Biochemistry and Biophysics Center of NHLBI for assistance with CD spectroscopy, and D. Eric Anderson at the Mass Spectrometry facility of NIDDK for technical support. F. B. and T.S.X. are supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. This project was also supported by funds from the Office of AIDS Research (OAR, NIH) to FB and TSX. NR 69 TC 6 Z9 6 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAY 9 PY 2012 VL 20 IS 5 BP 887 EP 898 DI 10.1016/j.str.2012.03.001 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 944OT UT WOS:000304214400014 PM 22484091 ER PT J AU Yang, M Bozdagi, O Scattoni, ML Wohr, M Roullet, FI Katz, AM Abrams, DN Kalikhman, D Simon, H Woldeyohannes, L Zhang, JY Harris, MJ Saxena, R Silverman, JL Buxbaum, JD Crawley, JN AF Yang, Mu Bozdagi, Ozlem Scattoni, Maria Luisa Woehr, Markus Roullet, Florence I. Katz, Adam M. Abrams, Danielle N. Kalikhman, David Simon, Harrison Woldeyohannes, Leuk Zhang, James Y. Harris, Mark J. Saxena, Roheeni Silverman, Jill L. Buxbaum, Joseph D. Crawley, Jacqueline N. TI Reduced Excitatory Neurotransmission and Mild Autism-Relevant Phenotypes in Adolescent Shank3 Null Mutant Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article ID 22Q13.3 DELETION SYNDROME; BTBR-T+TF/J MICE; TF/J MOUSE MODEL; SPECTRUM DISORDERS; ULTRASONIC VOCALIZATIONS; POSTSYNAPTIC DENSITY; KNOCKOUT MICE; BEHAVIORAL PHENOTYPES; OBJECT RECOGNITION; UNUSUAL REPERTOIRE AB Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan-McDermid 22q13 deletion syndrome. The precise location of the mutation within the Shank3 gene is key to its phenotypic outcomes. Here, we report the physiological and behavioral consequences of null and heterozygous mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and heterozygous mice showed reduced glutamatergic transmission and long-term potentiation in the hippocampus with more severe deficits detected in the homozygous mice. Three independent cohorts were evaluated for magnitude and replicability of behavioral endophenotypes relevant to autism and Phelan-McDermid syndrome. Mild social impairments were detected, primarily in juveniles during reciprocal interactions, while all genotypes displayed normal adult sociability on the three-chambered task. Impaired novel object recognition and rotarod performance were consistent across cohorts of null mutants. Repetitive self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of water maze learning were detected only in some cohorts, emphasizing the importance of replication analyses. These results demonstrate the exquisite specificity of deletions in discrete domains within the Shank3 gene in determining severity of symptoms. C1 [Yang, Mu] NIMH, Lab Behav Neurosci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Bozdagi, Ozlem; Buxbaum, Joseph D.] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA. [Bozdagi, Ozlem; Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Psychiat, Lab Mol Neuropsychiat, New York, NY 10029 USA. RP Yang, M (reprint author), NIMH, Lab Behav Neurosci, Intramural Res Program, NIH, Bldg 35,Room 1C-903-909,Mail Code 3730, Bethesda, MD 20892 USA. EM yangmu@mail.nih.gov OI Buxbaum, Joseph/0000-0001-8898-8313 FU Simons Foundation; National Institute of Mental Health FX This work was supported by The Simons Foundation and the National Institute of Mental Health Intramural Research Program. NR 77 TC 113 Z9 114 U1 1 U2 13 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 MAY 9 PY 2012 VL 32 IS 19 BP 6525 EP 6541 DI 10.1523/JNEUROSCI.6107-11.2012 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 940DL UT WOS:000303870100013 PM 22573675 ER PT J AU Stanika, RI Villanueva, I Kazanina, G Andrews, SB Pivovarova, NB AF Stanika, Ruslan I. Villanueva, Idalis Kazanina, Galina Andrews, S. Brian Pivovarova, Natalia B. TI Comparative Impact of Voltage-Gated Calcium Channels and NMDA Receptors on Mitochondria-Mediated Neuronal Injury SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HIPPOCAMPAL-NEURONS; GLUTAMATE EXCITOTOXICITY; ALZHEIMERS-DISEASE; CELL-DEATH; VULNERABILITY; NEUROTOXICITY; DYSFUNCTION; EXPRESSION; INDICATORS; DEPOLARIZATION AB Glutamate excitotoxicity, a major component of many neurodegenerative disorders, is characterized by excessive calcium influx selectively through NMDARs. However, there is a substantial uncertainty concerning why other known routes of significant calcium entry, in particular, VGCCs, are not similarly toxic. Here, we report that in the majority of neurons in rat hippocampal and cortical cultures, maximal L-type VGCC activation induces much lower calcium loading than toxic NMDAR activation. Consequently, few depolarization-activated neurons exhibit calcium deregulation and cell death. Activation of alternative routes of calcium entry induced neuronal death in proportion to the degree of calcium loading. In a small subset of neurons, depolarization evoked stronger calcium elevations, approaching those induced by toxic NMDA. These neurons were characterized by elevated expression of VGCCs and enhanced voltage-gated calcium currents, mitochondrial dysfunction and cell death. Preventing VGCC-dependent mitochondrial calcium loading resulted in stronger cytoplasmic calcium elevations, whereas inhibiting mitochondrial calcium clearance accelerated mitochondrial depolarization. Both observations further implicate mitochondrial dysfunction in VGCC-mediated cell death. Results indicate that neuronal vulnerability tracks the extent of calcium loading but does not appear to depend explicitly on the route of calcium entry. C1 [Stanika, Ruslan I.; Villanueva, Idalis; Kazanina, Galina; Andrews, S. Brian; Pivovarova, Natalia B.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Pivovarova, NB (reprint author), NINDS, Neurobiol Lab, NIH, 49-3A52,49 Convent Dr, Bethesda, MD 20892 USA. EM PivovarN@ninds.nih.gov FU NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. We are grateful to Christine A. Winters and Dr. Paul E. Gallant for excellent technical assistance. NR 44 TC 24 Z9 24 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 MAY 9 PY 2012 VL 32 IS 19 BP 6642 EP 6650 DI 10.1523/JNEUROSCI.6008-11.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 940DL UT WOS:000303870100024 PM 22573686 ER PT J AU Wood, ET Ronen, I Techawiboonwong, A Jones, CK Barker, PB Calabresi, P Harrison, D Reich, DS AF Wood, Emily T. Ronen, Itamar Techawiboonwong, Aranee Jones, Craig K. Barker, Peter B. Calabresi, Peter Harrison, Daniel Reich, Daniel S. TI Investigating Axonal Damage in Multiple Sclerosis by Diffusion Tensor Spectroscopy SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; APPEARING WHITE-MATTER; N-ACETYLASPARTATE; CORPUS-CALLOSUM; SPINAL-CORD; HUMAN BRAIN; IN-VIVO; LESIONS; DISABILITY; INJURY AB Sensitive and specific in vivo measures of axonal damage, an important determinant of clinical status in multiple sclerosis (MS), might greatly benefit prognostication and therapy assessment. Diffusion tensor spectroscopy (DTS) combines features of diffusion tensor imaging and magnetic resonance spectroscopy, allowing measurement of the diffusion properties of intracellular, cell-type-specific metabolites. As such, it may be sensitive to disruption of tissue microstructure within neurons. In this cross-sectional pilot study, diffusion of the neuronal metabolite N-acetylaspartate (NAA) was measured in the human normal-appearing corpus callosum on a 7 tesla MRI scanner, comparing 15 MS patients and 14 healthy controls. We found that NAA parallel diffusivity is lower in MS (p = 0.030) and inversely correlated with both water parallel diffusivity (p = 0.020) and clinical severity (p = 0.015). Interpreted in the context of previous experiments, our findings provide preliminary evidence that DTS can distinguish axonopathy from other processes such as inflammation, edema, demyelination, and gliosis. By detecting reduced diffusion of NAA parallel to axons in white matter, DTS may thus be capable of distinguishing axonal disruption in MS in the setting of increased parallel diffusion of water, which is commonly observed in MS but pathologically nonspecific. C1 [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, NIH, NeuroImmunol Branch, Bethesda, MD 20892 USA. [Wood, Emily T.] Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21205 USA. [Ronen, Itamar] Leiden Univ, CJ Gorter Ctr High Field MRI, Dept Radiol, Med Ctr, NL-2333 ZA Leiden, Netherlands. [Techawiboonwong, Aranee] Mahidol Univ, Dept Elect Engn, Salaya 73170, Nakhon Pathom, Thailand. [Jones, Craig K.; Barker, Peter B.] Kennedy Krieger Inst, FM Kirby Res Ctr Funct Brain Imaging, Baltimore, MD 21205 USA. [Jones, Craig K.; Barker, Peter B.; Reich, Daniel S.] Johns Hopkins Univ, Dept Radiol, Sch Med, Baltimore, MD 21287 USA. [Calabresi, Peter; Harrison, Daniel; Reich, Daniel S.] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21287 USA. [Reich, Daniel S.] Johns Hopkins Univ, Dept Biostat, Sch Publ Hlth, Baltimore, MD 21205 USA. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Unit, NIH, NeuroImmunol Branch, Bldg 10,Room 5C103,10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. EM daniel.reich@nih.gov RI Reich, Daniel/E-5701-2010; Ronen, Itamar/E-8518-2016; OI Reich, Daniel/0000-0002-2628-4334; Ronen, Itamar/0000-0002-6872-4895; Wood, Emily/0000-0003-0395-4849 FU National Institute of Neurological Disorders and Stroke; NIH [P41RR015241]; Bayer Schering Pharma; Johns Hopkins Institute for Clinical and Translational Research FX This study was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, as well as by grants from NIH (P41RR015241), Bayer Schering Pharma (to P.C. and D.H.), and the Johns Hopkins Institute for Clinical and Translational Research to support data collection. We thank Terri Brawner, Kathie Kahl, and Ivana Kusevic for their attention to detail and exceptional subject care; and Peter van Zijl, Joe Gillen, and Richard Edden for technical support. NR 44 TC 26 Z9 26 U1 1 U2 11 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 MAY 9 PY 2012 VL 32 IS 19 BP 6665 EP 6669 DI 10.1523/JNEUROSCI.0044-12.2012 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 940DL UT WOS:000303870100026 PM 22573688 ER PT J AU Volkow, ND Tomasi, D Wang, GJ Telang, F Fowler, JS Logan, J Benveniste, H Kim, R Thanos, PK Ferre, S AF Volkow, Nora D. Tomasi, Dardo Wang, Gene-Jack Telang, Frank Fowler, Joanna S. Logan, Jean Benveniste, Helene Kim, Ron Thanos, Panayotis K. Ferre, Sergi TI Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ADENOSINE A(2A) RECEPTORS; POSITRON-EMISSION-TOMOGRAPHY; PROTEIN-COUPLED RECEPTORS; HOMEOSTATIC REGULATION; NUCLEUS-ACCUMBENS; EXTRACELLULAR DOPAMINE; ORAL METHYLPHENIDATE; CAFFEINE; WAKEFULNESS; INCREASES AB Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [C-11]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([C-11] raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [C-11] raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans. C1 [Volkow, Nora D.; Ferre, Sergi] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Volkow, Nora D.; Telang, Frank; Kim, Ron; Thanos, Panayotis K.] NIAAA, Bethesda, MD 20892 USA. [Tomasi, Dardo; Wang, Gene-Jack; Fowler, Joanna S.; Logan, Jean] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Benveniste, Helene] SUNY Stony Brook, Dept Anesthesiol, Stony Brook, NY 11794 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI Ferre, Sergi/K-6115-2014; Tomasi, Dardo/J-2127-2015 OI Ferre, Sergi/0000-0002-1747-1779; FU National Institutes of Health (National Institute on Alcohol Abuse and Alcoholism); Department of Energy [DE-AC01-76CH00016] FX Research was supported by the National Institutes of Health Intramural Research Program (National Institute on Alcohol Abuse and Alcoholism) and by the Department of Energy (Grant DE-AC01-76CH00016). We thank David Schlyer, David Alexoff, Paul Vaska, Colleen Shea, Youwen Xu, Pauline Carter, Christopher Wong, Millard Jayne, and Karen Apelskog for their contributions; and Ruben Baler for editorial assistance. NR 59 TC 36 Z9 39 U1 1 U2 21 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 MAY 9 PY 2012 VL 32 IS 19 BP 6711 EP 6717 DI 10.1523/JNEUROSCI.0045-12.2012 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 940DL UT WOS:000303870100031 PM 22573693 ER PT J AU Cheng, SS Rhee, EP Larson, MG Lewis, GD McCabe, EL Shen, DX Palma, MJ Roberts, LD Dejam, A Souza, AL Deik, AA Magnusson, M Fox, CS O'Donnell, CJ Vasan, RS Melander, O Clish, CB Gerszten, RE Wang, TJ AF Cheng, Susan Rhee, Eugene P. Larson, Martin G. Lewis, Gregory D. McCabe, Elizabeth L. Shen, Dongxiao Palma, Melinda J. Roberts, Lee D. Dejam, Andre Souza, Amanda L. Deik, Amy A. Magnusson, Martin Fox, Caroline S. O'Donnell, Christopher J. Vasan, Ramachandran S. Melander, Olle Clish, Clary B. Gerszten, Robert E. Wang, Thomas J. TI Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans SO CIRCULATION LA English DT Article DE epidemiology; metabolic syndrome; metabolomics; risk factors ID CORONARY-HEART-DISEASE; GLUCOSE-TOLERANCE TEST; AMINO-ACID; INSULIN-RESISTANCE; GLUTAMINE SUPPLEMENTATION; BLOOD-PRESSURE; SENSITIVITY; HOMEOSTASIS; EXPRESSION; SECRETION AB Background-Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. Methods and Results-To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmo Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; P<0.001), glutamate (0.05 to 0.14; P<0.001), and the glutamine-toglutamate ratio (-0.05 to -0.20; P<0.001) in the discovery sample (FHS); similar associations were observed in the replication sample (MDC). High glutamine-to-glutamate ratio was associated with lower risk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (P=0.05). Conclusions-Biochemical profiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice. (Circulation. 2012;125:2222-2231.) C1 [Cheng, Susan; Lewis, Gregory D.; McCabe, Elizabeth L.; Shen, Dongxiao; Palma, Melinda J.; Roberts, Lee D.; Dejam, Andre; O'Donnell, Christopher J.; Gerszten, Robert E.; Wang, Thomas J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Rhee, Eugene P.; Lewis, Gregory D.; Gerszten, Robert E.; Wang, Thomas J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Rhee, Eugene P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Renal, Boston, MA 02114 USA. [Cheng, Susan; Larson, Martin G.; McCabe, Elizabeth L.; Fox, Caroline S.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Wang, Thomas J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cheng, Susan; Larson, Martin G.; McCabe, Elizabeth L.; Fox, Caroline S.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Wang, Thomas J.] Boston Univ, Sch Med, Framingham, MA USA. [Cheng, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol, Boston, MA 02115 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Rhee, Eugene P.; Lewis, Gregory D.; Souza, Amanda L.; Deik, Amy A.; Clish, Clary B.; Gerszten, Robert E.] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. [Magnusson, Martin; Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. RP Wang, TJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM rgerszten@partners.org; tjwang@partners.org OI Larson, Martin/0000-0002-9631-1254; Magnusson, Martin/0000-0003-1710-5936; Ramachandran, Vasan/0000-0001-7357-5970; Roberts, Lee/0000-0002-1455-5248 FU National Institutes of Health [N01-HC-25195, R01-DK-HL081572]; Donald W. Reynolds Foundation; Leducq Foundation; Ellison Foundation; American Heart Association grant [10CRP2660009]; American Heart Association Established Investigator Award FX This work was supported by National Institutes of Health contracts N01-HC-25195 and R01-DK-HL081572, the Donald W. Reynolds Foundation, and the Leducq Foundation. Dr Cheng is supported by the Ellison Foundation. Dr Dejam is supported by American Heart Association grant 10CRP2660009. Dr Gerszten is supported by an American Heart Association Established Investigator Award. NR 46 TC 131 Z9 135 U1 8 U2 53 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 8 PY 2012 VL 125 IS 18 BP 2222 EP U132 DI 10.1161/CIRCULATIONAHA.111.067827 PG 24 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981JI UT WOS:000306962600015 PM 22496159 ER PT J AU Nakhleh, N Francis, R Giese, RA Tian, X Li, Y Zariwala, MA Yagi, H Khalifa, O Kureshi, S Chatterjee, B Sabol, SL Swisher, M Connelly, PS Daniels, MP Srinivasan, A Kuehl, K Kravitz, N Burns, K Sami, I Omran, H Barmada, M Olivier, K Chawla, KK Leigh, M Jonas, R Knowles, M Leatherbury, L Lo, CW AF Nakhleh, Nader Francis, Richard Giese, Rachel A. Tian, Xin Li, You Zariwala, Maimoona A. Yagi, Hisato Khalifa, Omar Kureshi, Safina Chatterjee, Bishwanath Sabol, Steven L. Swisher, Matthew Connelly, Patricia S. Daniels, Mathew P. Srinivasan, Ashok Kuehl, Karen Kravitz, Nadav Burns, Kimberlie Sami, Iman Omran, Heymut Barmada, Michael Olivier, Kenneth Chawla, Kunal K. Leigh, Margaret Jonas, Richard Knowles, Michael Leatherbury, Linda Lo, Cecilia W. TI High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy SO CIRCULATION LA English DT Article DE genomic studies; heart defects; congenital; heterotaxy; nitric oxide; primary ciliary dyskinesia ID NASAL NITRIC-OXIDE; DYSKINESIA; DEFECTS; MUTATIONS; CHILDREN; COMPLEX; ULTRASTRUCTURE; LATERALITY; GENETICS; ADULTS AB Background-Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. Methods and Results-We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged >6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. Conclusions-Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD. (Circulation. 2012;125:2232-2242.) C1 [Francis, Richard; Li, You; Yagi, Hisato; Khalifa, Omar; Chatterjee, Bishwanath; Srinivasan, Ashok; Lo, Cecilia W.] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 15201 USA. [Nakhleh, Nader; Francis, Richard; Giese, Rachel A.; Kureshi, Safina; Chatterjee, Bishwanath; Sabol, Steven L.; Swisher, Matthew; Kravitz, Nadav; Leatherbury, Linda; Lo, Cecilia W.] NHLBI, Dev Biol Lab, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Connelly, Patricia S.; Daniels, Mathew P.] NHLBI, Electron Microscopy Core, Bethesda, MD 20892 USA. [Barmada, Michael] Univ Pittsburgh, Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15260 USA. [Zariwala, Maimoona A.; Burns, Kimberlie] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Chawla, Kunal K.; Leigh, Margaret] Univ N Carolina, Dept Med, Div Pediat Pulmonol, Chapel Hill, NC USA. [Kuehl, Karen; Leatherbury, Linda] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. [Nakhleh, Nader; Kureshi, Safina; Sami, Iman] Childrens Natl Med Ctr, Dept Cardiac Surg, Div Pulm & Sleep Med, Washington, DC 20010 USA. [Omran, Heymut] Univ Klinikum Munster, Klin & Poliklin Kinder & Jugendmed, Munster, Germany. [Olivier, Kenneth] NIAID, NIH, Res Scholars Program, Bethesda, MD 20892 USA. [Giese, Rachel A.; Swisher, Matthew] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Lo, CW (reprint author), Univ Pittsburgh, Sch Med, Dept Dev Biol, 530 45th St, Pittsburgh, PA 15201 USA. EM cel36@pitt.edu RI Francis, Richard/P-2524-2015; OI Barmada, M Michael/0000-0002-3604-6460 FU National Institutes of Health [ZO1-HL005701, HL071798, U54-HL09645806]; DFG [Om 6/4]; Pennsylvania Department of Health FX Supported by National Institutes of Health grants ZO1-HL005701 (to C.W.L.), HL071798 (to M.W.), U54-HL09645806 (to M.W.), DFG Om 6/4 (to H.O.), and Pennsylvania Department of Health (to C.W.L.). NR 37 TC 49 Z9 49 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 8 PY 2012 VL 125 IS 18 BP 2232 EP U164 DI 10.1161/CIRCULATIONAHA.111.079780 PG 31 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981JI UT WOS:000306962600016 PM 22499950 ER PT J AU Shi, YB AF Shi, Yun-Bo TI The 2011 Ming K Jeang Award for Excellence in Cell & Bioscience SO CELL AND BIOSCIENCE LA English DT Editorial Material AB Two research groups led by Dr T.C. Wu of Johns Hopkins Medical Institutions and Dr P. Liu of National Human Genome Research Institute, National Institutes of Health, respectively, have won the 2011 Ming K Jeang Award for Excellence in Cell & Bioscience. C1 NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD MAY 8 PY 2012 VL 2 AR 16 DI 10.1186/2045-3701-2-16 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 988SX UT WOS:000307512100001 PM 22569111 ER PT J AU Cai, YM Zhou, Q Yu, CX Wang, XM Hu, SN Yu, J Yu, XM AF Cai, Yimei Zhou, Qing Yu, Caixia Wang, Xumin Hu, Songnian Yu, Jun Yu, Xiaomin TI Transposable-Element Associated Small RNAs in Bombyx mori Genome SO PLOS ONE LA English DT Article ID ENDOGENOUS SIRNAS; INTERFERING RNAS; MOBILE ELEMENTS; HUMAN MICRORNAS; SOMATIC-CELLS; MOUSE OOCYTES; DROSOPHILA; SILKWORM; EVOLUTION; DEFENSE AB Small RNAs are a group of regulatory RNA molecules that control gene expression at transcriptional or post-transcriptional levels among eukaryotes. The silkworm, Bombyx mori L., genome harbors abundant repetitive sequences derived from families of retrotransposons and transposons, which together constitute almost half of the genome space and provide ample resource for biogenesis of the three major small RNA families. We systematically discovered transposable-element (TE)-associated small RNAs in B. mori genome based on a deep RNA-sequencing strategy and the effort yielded 182, 788 and 4,990 TE-associated small RNAs in the miRNA, siRNA and piRNA species, respectively. Our analysis suggested that the three small RNA species preferentially associate with different TEs to create sequence and functional diversity, and we also show evidence that a Bombyx non-LTR retrotransposon, bm1645, alone contributes to the generation of TE-associated small RNAs in a very significant way. The fact that bm1645-associated small RNAs partially overlap with each other implies a possibility that this element may be modulated by different mechanisms to generate different products with diverse functions. Taken together, these discoveries expand the small RNA pool in B. mori genome and lead to new knowledge on the diversity and functional significance of TE-associated small RNAs. C1 [Cai, Yimei; Zhou, Qing; Yu, Caixia; Wang, Xumin; Hu, Songnian; Yu, Jun; Yu, Xiaomin] Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, Beijing, Peoples R China. [Yu, Xiaomin] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Cai, YM (reprint author), Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, Beijing, Peoples R China. EM junyu@big.ac.cn; yuxm@big.ac.cn RI Yu, Xiaomin/I-6407-2016; OI Hu, Songnian/0000-0003-3966-3111 FU National Natural Science Foundation of China [31000578]; Chinese Academy of Sciences FX This work was supported by the Knowledge Innovation Program of the Chinese Academy of Sciences and the National Natural Science Foundation of China (31000578). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 10 Z9 12 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 8 PY 2012 VL 7 IS 5 AR e36599 DI 10.1371/journal.pone.0036599 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TF UT WOS:000305335500019 ER PT J AU Goula, AV Pearson, CE Della Maria, J Trottier, Y Tomkinson, AE Wilson, DM Merienne, K AF Goula, Agathi-Vasiliki Pearson, Christopher E. Della Maria, Julie Trottier, Yvon Tomkinson, Alan E. Wilson, David M., III Merienne, Karine TI The Nucleotide Sequence, DNA Damage Location, and Protein Stoichiometry Influence the Base Excision Repair Outcome at CAG/CTG Repeats SO BIOCHEMISTRY LA English DT Article ID MYOTONIC-DYSTROPHY TYPE-1; SPINOCEREBELLAR ATAXIA TYPE-1; CENTRAL-NERVOUS-SYSTEM; KNOCK-IN MICE; CAG REPEAT; LIGASE-I; CTG REPEAT; POLYMERASE-BETA; TRINUCLEOTIDE REPEATS; TRANSGENIC MICE AB Expansion of CAG/CTG repeats is the underlying cause of >14 genetic disorders, including Huntington's disease (HD) and myotonic dystrophy. The mutational process is ongoing, with increases in repeat size enhancing the toxicity of the expansion in specific tissues. In many repeat diseases, the repeats exhibit high instability in the striatum, whereas instability is minimal in the cerebellum. We provide molecular insights into how base excision repair (BER) protein stoichiometry may contribute to the tissue-selective instability of CAG/CTG repeats by using specific repair assays. Oligonucleotide substrates with an abasic site were mixed with either reconstituted BER protein stoichiometries mimicking the levels present in HD mouse striatum or cerebellum, or with protein extracts prepared from HD mouse striatum or cerebellum. In both cases, the repair efficiency at CAG/CTG repeats and at control DNA sequences was markedly reduced under the striatal conditions, likely because of the lower level of APEI, FEN1, and LIG1. Damage located toward the 5' end of the repeat tract was poorly repaired, with the accumulation of incompletely processed intermediates as compared to an AP lesion in the center or at the 3' end of the repeats or within control sequences. Moreover, repair of lesions at the 5' end of CAG or CTG repeats involved multinucleotide synthesis, particularly at the cerebellar stoichiometry, suggesting that long-patch BE R processes lesions at sequences susceptible to hairpin formation. Our results show that the BER stoichiometry, nucleotide sequence, and DNA damage position modulate repair outcome and suggest that a suboptimal long-patch BER activity promotes CAG/CTG repeat instability. C1 [Goula, Agathi-Vasiliki; Trottier, Yvon; Merienne, Karine] UMR 7104 CNRS INSERM UdS, Dept Neurogenet & Translat Med, Inst Genet & Mol & Cellular Biol IGBMC, Illkirch Graffenstaden, France. [Pearson, Christopher E.] Hosp Sick Children, Toronto, ON M5G 1L7, Canada. [Pearson, Christopher E.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Della Maria, Julie; Tomkinson, Alan E.] Univ Maryland, Dept Radiat Oncol, Sch Med, Baltimore, MD 21201 USA. [Della Maria, Julie; Tomkinson, Alan E.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Sch Med, Baltimore, MD 21201 USA. [Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Merienne, K (reprint author), UMR 7104 CNRS INSERM UdS, Dept Neurogenet & Translat Med, Inst Genet & Mol & Cellular Biol IGBMC, Illkirch Graffenstaden, France. EM merienne@igbmc.fr RI Trottier, Yvon/H-8852-2016 FU Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de le Recherche Medicale (INSERM); University of Strasbourg; French Agence Nationale de la Recherche [ANR-2011-JSV6-003-01]; National Institutes of Health (NIH), National Institute on Aging; Muscular Dystrophy Association Canada; Canadian Institutes of Health Research [MOP-94966]; Paul Wellstone Muscular Dystrophy Cooperative Research Center; NIH [U54NS48843, GM57479, ES012512]; French Ministry of Research; Fondation de la Recherche Medicale (FRM) FX This research was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Sante et de le Recherche Medicale (INSERM), and the University of Strasbourg (K.M.), by a grant from the French Agence Nationale de la Recherche (ANR-2011-JSV6-003-01 to K.M.), by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging (D.M.W.), by the Muscular Dystrophy Association Canada (C.E.P.), the Canadian Institutes of Health Research (MOP-94966 to C.E.P.), and the Paul Wellstone Muscular Dystrophy Cooperative Research Center (C.E.P.), and by grants from the NIH (U54NS48843 to C.E.P. and GM57479 and ES012512 to A.E.T.). A.-V.G. was supported by the French Ministry of Research and the Fondation de la Recherche Medicale (FRM). NR 65 TC 20 Z9 20 U1 4 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 8 PY 2012 VL 51 IS 18 BP 3919 EP 3932 DI 10.1021/bi300410d PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 936ZG UT WOS:000303628200023 PM 22497302 ER PT J AU Prado, CMM Bekaii-Saab, T Doyle, LA Shrestha, S Ghosh, S Baracos, VE Sawyer, MB AF Prado, C. M. M. Bekaii-Saab, T. Doyle, L. A. Shrestha, S. Ghosh, S. Baracos, V. E. Sawyer, M. B. TI Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE cholangiocarcinoma; skeletal muscle; cachexia; interleukin 6 ID CANCER CACHEXIA; CHEMOTHERAPY TOXICITY; CLINICAL-IMPLICATIONS; BODY-COMPOSITION; ACID-METABOLISM; ASSOCIATION; SURVIVAL; INTERLEUKIN-6; HYPERTROPHY; DETERMINANT AB BACKGROUND: Cancer cachexia is characterised by skeletal muscle wasting; however, potential for muscle anabolism in patients with advanced cancer is unproven. METHODS: Quantitative analysis of computed tomography images for loss/gain of muscle in cholangiocarcinoma patients receiving selumetinib (AZD6244; ARRY-142886) in a Phase II study, compared with a separate standard therapy group. Selumetinib is an inhibitor of mitogen-activated protein/extracellular signal-regulated kinase and of interleukin-6 secretion, a putative mediator of muscle wasting. RESULTS: Overall, 84.2% of patients gained muscle after initiating selumetinib; mean overall gain of total lumbar muscle cross-sectional area was 13.6 cm(2)/100 days (similar to 2.3 kg on a whole-body basis). Cholangiocarcinoma patients who began standard treatment were markedly catabolic, with overall muscle loss of -7.3 cm(2)/100 days (similar to 1.2 kg) and by contrast only 16.7% of these patients gained muscle. CONCLUSION: Our findings suggest that selumetinib promotes muscle gain in patients with cholangiocarcinoma. Specific mechanisms and relevance for cachexia therapy remain to be investigated. British Journal of Cancer (2012) 106, 1583-1586. doi:10.1038/bjc.2012.144 www.bjcancer.com Published online 17 April 2012 (C) 2012 Cancer Research UK C1 [Prado, C. M. M.; Shrestha, S.; Ghosh, S.; Baracos, V. E.; Sawyer, M. B.] Univ Alberta, Cross Canc Inst, Dept Oncol, Edmonton, AB T6G 1Z2, Canada. [Bekaii-Saab, T.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Columbus, OH 43210 USA. [Bekaii-Saab, T.] Ohio State Univ, Ctr Comprehens Canc, Dept Pharmacol, Columbus, OH 43210 USA. [Doyle, L. A.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Sawyer, MB (reprint author), Univ Alberta, Cross Canc Inst, Dept Oncol, 11560 Univ Ave, Edmonton, AB T6G 1Z2, Canada. EM Michael.Sawyer@albertahealthservices.ca RI Bekaii-Saab, Tanios/E-2733-2011; OI Baracos, Vickie/0000-0002-9609-1001 FU Roche from Alberta Health Services; Alberta Heritage Foundation; [NO1-CM62207] FX We thank Linda Harris for her bibliographic expertise. This study was supported by Grant Support NO1-CM62207, Roche Fellowship in Translational Research from Alberta Health Services (CMMP), Alberta Heritage Foundation for Medical Research Fellowship (CMMP). NR 32 TC 34 Z9 34 U1 0 U2 4 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 MAY 8 PY 2012 VL 106 IS 10 BP 1583 EP 1586 DI 10.1038/bjc.2012.144 PG 4 WC Oncology SC Oncology GA 939PB UT WOS:000303823400002 PM 22510747 ER PT J AU Beale, H Ostrander, EA AF Beale, Holly Ostrander, Elaine A. TI Sizing up dogs SO CURRENT BIOLOGY LA English DT Editorial Material C1 [Beale, Holly; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Beale, H (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM Eostrand@mail.nih.gov NR 4 TC 3 Z9 3 U1 1 U2 3 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 MAY 8 PY 2012 VL 22 IS 9 BP R315 EP R316 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 941MP UT WOS:000303967600013 PM 22575471 ER PT J AU Zhao, Y Biertumpfel, C Gregory, MT Hua, YJ Hanaoka, F Yang, W AF Zhao, Ye Biertuempfel, Christian Gregory, Mark T. Hua, Yue-Jin Hanaoka, Fumio Yang, Wei TI Structural basis of human DNA polymerase eta-mediated chemoresistance to cisplatin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemotherapy; inhibitor; translesion DNA synthesis; yeast polymerase eta ID INTRASTRAND CROSS-LINK; THYMINE DIMER BYPASS; TRANSLESION SYNTHESIS; XERODERMA-PIGMENTOSUM; CRYSTAL-STRUCTURE; 2-POLYMERASE MECHANISMS; DODECAMER DUPLEX; OXALIPLATIN; ADDUCTS; LESIONS AB Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase eta (hPol eta). Here, we report crystal structures of hPol eta complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol eta is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol eta differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-crosslinked guanines, hPol eta undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol eta is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol eta is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance. C1 [Zhao, Ye; Biertuempfel, Christian; Gregory, Mark T.; Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Ye; Hua, Yue-Jin] Zhejiang Univ, Inst Nucl Agr Sci, Hangzhou 310029, Zhejiang, Peoples R China. [Biertuempfel, Christian] Max Planck Inst Biochem, Dept Struct Cell Biol, D-82152 Martinsried, Germany. [Gregory, Mark T.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Hanaoka, Fumio] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. [Hanaoka, Fumio] Gakushuin Univ, Fac Sci, Tokyo 1718588, Japan. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM weiy@mail.nih.gov RI Yang, Wei/D-4926-2011; Zhao, Ye/I-2936-2014 OI Yang, Wei/0000-0002-3591-2195; Zhao, Ye/0000-0002-5455-2586 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Natural Science Foundation of China [30830006]; Ministry of Education, Culture, Sports, Science, and Technology of Japan [22131008, 22249005] FX We thank Drs. R. Craigie, D. Leahy, and M. Gellert for critical reading of the manuscript. This work was supported by the Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Y.Z., C.B., M.T.G., and W.Y.), National Natural Science Foundation of China Grant 30830006 (to Y.-J.H.), and Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan Grants 22131008 and 22249005 (to F.H.). NR 45 TC 54 Z9 54 U1 2 U2 17 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 MAY 8 PY 2012 VL 109 IS 19 BP 7269 EP 7274 DI 10.1073/pnas.1202681109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 942ZQ UT WOS:000304090600036 PM 22529383 ER PT J AU Wu, L Parekh, VV Gabriel, CL Bracy, DP Marks-Shulman, PA Tamboli, RA Kim, S Mendez-Fernandez, YV Besra, GS Lomenick, JP Williams, B Wasserman, DH Van Kaer, L AF Wu, Lan Parekh, Vrajesh V. Gabriel, Curtis L. Bracy, Deanna P. Marks-Shulman, Pamela A. Tamboli, Robyn A. Kim, Sungjune Mendez-Fernandez, Yanice V. Besra, Gurdyal S. Lomenick, Jefferson P. Williams, Brandon Wasserman, David H. Van Kaer, Luc TI Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cluster of differentiation 1d; glycolipid-reactive T cells; alpha-galactosylceramide; obesity-induced inflammation ID INNATE IMMUNE-SYSTEM; NKT CELLS; ADIPOSE-TISSUE; FATTY-ACIDS; INKT CELLS; NONALCOHOLIC STEATOHEPATITIS; GLUCOSE-INTOLERANCE; GLYCOLIPID ANTIGENS; DANGER SIGNALS; DEFICIENT MICE AB Obesity triggers a low-grade systemic inflammation, which plays an important role in the development of obesity-associated metabolic diseases. In searching for links between lipid accumulation and chronic inflammation, we examined invariant natural killer T (iNKT) cells, a subset of T lymphocytes that react with lipids and regulate inflammatory responses. We show that iNKT cells respond to dietary lipid excess and become activated before or at the time of tissue recruitment of inflammatory leukocytes, and that these cells progressively increase proinflammatory cytokine production in obese mice. Such iNKT cells skew other leukocytes toward proinflammatory cytokine production and induce an imbalanced proinflammatory cytokine environment in multiple tissues. Further, iNKT cell deficiency ameliorates tissue inflammation and provides protection against obesity-induced insulin resistance and hepatic steatosis. Conversely, chronic iNKT cell stimulation using a canonical iNKT cell agonist exacerbates tissue inflammation and obesity-associated metabolic disease. These findings place iNKT cells into the complex network linking lipid excess to inflammation in obesity and suggest new therapeutic avenues for obesity-associated metabolic disorders. C1 [Wu, Lan; Parekh, Vrajesh V.; Gabriel, Curtis L.; Kim, Sungjune; Mendez-Fernandez, Yanice V.; Van Kaer, Luc] Vanderbilt Univ, Dept Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA. [Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. [Marks-Shulman, Pamela A.; Tamboli, Robyn A.; Williams, Brandon] Vanderbilt Univ, Dept Surg, Sch Med, Nashville, TN 37232 USA. [Lomenick, Jefferson P.] Vanderbilt Univ, Dept Pediat, Sch Med, Div Endocrinol, Nashville, TN 37232 USA. [Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Vanderbilt Natl Inst Hlth, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37232 USA. [Besra, Gurdyal S.] Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England. RP Wu, L (reprint author), Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA. EM lan.wu@vanderbilt.edu; luc.van.kaer@vanderbilt.edu RI Van Kaer, Luc/H-1033-2015; OI Van Kaer, Luc/0000-0001-5275-2309; Besra, Gurdyal/0000-0002-5605-0395 FU NIH [U24 DK59637, DK081536, AI070305, HL089667, DK50277]; American Diabetes Association; Diabetes Research and Training Center at Vanderbilt University; personal research chair from James Bardrick; Royal Society; Medical Research Council; Wellcome Trust; National Multiple Sclerosis Society; Cancer Research Institute FX We thank the Kirin Brewery Co. for providing KRN7000; the National Institutes of Health (NIH) tetramer facility for CD1d monomers; Dr. M. Taniguchi for J alpha 18-deficient mice; the Vanderbilt Mouse Metabolic Phenotyping Center (supported by NIH Grant U24 DK59637) for support with the metabolic studies; and Drs. Sebastian Joyce, Jacek Hawiger, and Alvin C. Powers for helpful discussions. This work was supported by a Junior Faculty Award from the American Diabetes Association (to L. W.); a Pilot and Feasibility Grant from the Diabetes Research and Training Center at Vanderbilt University (to L. W.); NIH Grants DK081536 (to L. W. and L. V. K.), AI070305 (to L. V. K.), HL089667 (to L. V. K.), and DK50277 (to D. H. W.); a personal research chair from James Bardrick (to G. S. B.); a Royal Society Wolfson Research Merit Award (to G. S. B.); the Medical Research Council (G. S. B.); the Wellcome Trust (G. S. B.); a postdoctoral fellowship from the National Multiple Sclerosis Society (to V. V. P.); an individual predoctoral fellowship from NIH (to C. L. G.); and a postdoctoral fellowship from the Irvington Institute Fellowship Program of the Cancer Research Institute (to Y.V.M.-F.). NR 66 TC 61 Z9 62 U1 0 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 MAY 8 PY 2012 VL 109 IS 19 BP E1143 EP E1152 DI 10.1073/pnas.1200498109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 942ZQ UT WOS:000304090600004 PM 22493234 ER PT J AU Lu, JH Sun, PD AF Lu, Jinghua Sun, Peter D. TI The Structure of the TLR5-Flagellin Complex: A New Mode of Pathogen Detection, Conserved Receptor Dimerization for Signaling (vol 5, pg er3, 2012) SO SCIENCE SIGNALING LA English DT Correction ID TOLL-LIKE RECEPTORS; TLR4-MD-2 COMPLEX; CRYSTAL-STRUCTURE; RECOGNITION; FLAGELLIN C1 [Lu, Jinghua; Sun, Peter D.] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM psun@nih.gov RI lu, jinghua/G-5872-2012 NR 12 TC 1 Z9 1 U1 2 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 MAY 8 PY 2012 VL 5 IS 223 AR er3 DI 10.1126/scisignal.5223er3 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 939LG UT WOS:000303811600002 ER PT J AU Maroun, M Kavushansky, A Holmes, A Wellman, C Motanis, H AF Maroun, Mouna Kavushansky, Alexandra Holmes, Andrew Wellman, Cara Motanis, Helen TI Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex SO PLOS ONE LA English DT Article ID MEDIAL PREFRONTAL CORTEX; CONDITIONED TASTE-AVERSION; LONG-TERM POTENTIATION; FEAR EXTINCTION; PROTEIN-SYNTHESIS; GABA(A) AGONIST; STRESS; AMYGDALA; CONSOLIDATION; RECONSOLIDATION AB Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion. C1 [Maroun, Mouna; Kavushansky, Alexandra; Motanis, Helen] Univ Haifa, Fac Nat Sci, Dept Neurobiol, IL-31999 Haifa, Israel. [Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Wellman, Cara] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. [Wellman, Cara] Indiana Univ, Ctr Integrat Study Anim Behav, Bloomington, IN USA. RP Maroun, M (reprint author), Univ Haifa, Fac Nat Sci, Dept Neurobiol, IL-31999 Haifa, Israel. EM mouna.maroun@gmail.com FU United States-Israel Binational Science Foundation; Ministry of Health FX Supported by the United States-Israel Binational Science Foundation (to AH, CLW and MM) and the Ministry of Health grant (to MM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 29 Z9 30 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 7 PY 2012 VL 7 IS 5 AR e35853 DI 10.1371/journal.pone.0035853 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959TC UT WOS:000305335000015 PM 22586453 ER PT J AU Palendira, U Low, C Bell, AI Ma, CS Abbott, RJM Phan, TG Riminton, DS Choo, S Smart, JM Lougaris, V Giliani, S Buckley, RH Grimbacher, B Alvaro, F Klion, AD Nichols, KE Adelstein, S Rickinson, AB Tangye, SG AF Palendira, Umaimainthan Low, Carol Bell, Andrew I. Ma, Cindy S. Abbott, Rachel J. M. Phan, Tri Giang Riminton, D. Sean Choo, Sharon Smart, Joanne M. Lougaris, Vassilios Giliani, Silvia Buckley, Rebecca H. Grimbacher, Bodo Alvaro, Frank Klion, Amy D. Nichols, Kim E. Adelstein, Stephen Rickinson, Alan B. Tangye, Stuart G. TI Expansion of somatically reverted memory CD8(+) T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; WISKOTT-ALDRICH-SYNDROME; IN-VIVO REVERSION; ADHESION DEFICIENCY TYPE-1; INHERITED MUTATION; MISSENSE MUTATIONS; ENCODING GENE; SAP; MOSAICISM; SLAM AB Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8(+) T cell subset, displayed a CD45RA(-)CCR7(-) effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8(+)SAP(+) T cells, but not SAP(-) cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection. C1 [Palendira, Umaimainthan; Low, Carol; Ma, Cindy S.; Phan, Tri Giang; Tangye, Stuart G.] St Vincents Hosp, Garvan Inst Med Res, Immunol Res Program, Darlinghurst, NSW 2010, Australia. [Palendira, Umaimainthan; Ma, Cindy S.; Phan, Tri Giang; Tangye, Stuart G.] Univ New S Wales, St Vincents Clin Sch, Darlinghurst, NSW 2010, Australia. [Bell, Andrew I.; Abbott, Rachel J. M.; Rickinson, Alan B.] Univ Birmingham, Sch Canc Sci, Birmingham B15 2TT, W Midlands, England. [Bell, Andrew I.; Abbott, Rachel J. M.; Rickinson, Alan B.] Univ Birmingham, MRC, Ctr Immune Regulat, Birmingham B15 2TT, W Midlands, England. [Riminton, D. Sean] Concord Hosp, Dept Immunol, Sydney, NSW 2139, Australia. [Choo, Sharon; Smart, Joanne M.] Royal Childrens Hosp Melbourne, Dept Allergy & Immunol, Parkville, Vic 3052, Australia. [Lougaris, Vassilios; Giliani, Silvia] Univ Brescia, Pediat Clin, I-25121 Brescia, Italy. [Lougaris, Vassilios; Giliani, Silvia] Univ Brescia, Angelo Nocivelli Inst Mol Med, I-25121 Brescia, Italy. [Buckley, Rebecca H.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Buckley, Rebecca H.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Grimbacher, Bodo] UCL, Royal Free Hosp, Dept Immunol, London WC1E 6BT, England. [Alvaro, Frank] John Hunter Hosp, New Lambton, NSW 2305, Australia. [Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Nichols, Kim E.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Adelstein, Stephen] Royal Prince Alfred Hosp, Dept Clin Immunol, Sydney, NSW 2050, Australia. RP Palendira, U (reprint author), St Vincents Hosp, Garvan Inst Med Res, Immunol Res Program, Darlinghurst, NSW 2010, Australia. EM m.palendira@garvan.org.au; s.tangye@garvan.org.au RI Phan, Tri/G-3937-2012; Tangye, Stuart/H-4023-2014; Adelstein, Stephen/I-7936-2016; OI Abbott, Rachel/0000-0003-1902-1429; Bell, Andrew/0000-0001-9520-4417; Phan, Tri/0000-0002-4909-2984; Adelstein, Stephen/0000-0001-7221-6298; Klion, Amy/0000-0002-4986-5326 FU XLP Research Trust; Cancer Council New South Wales; Association for International Cancer Research; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health; Medical Research Council UK; Cancer Research UK; National Health and Medical Research Council of Australia FX This project was funded by grants from the XLP Research Trust, Cancer Council New South Wales, and the Association for International Cancer Research (to S. G. Tangye), the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (to A. D. Klion), and the Medical Research Council UK and Cancer Research UK (to A. B. Rickinson). S. G. Tangye is the recipient of a Senior Research Fellowship from the National Health and Medical Research Council of Australia. NR 47 TC 22 Z9 24 U1 1 U2 6 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 MAY 7 PY 2012 VL 209 IS 5 BP 911 EP 922 DI 10.1084/jem.20112391 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 937UK UT WOS:000303684300005 PM 22493517 ER PT J AU Miller, JC Slim, AC Volz, EM AF Miller, Joel C. Slim, Anja C. Volz, Erik M. TI Edge-based compartmental modelling for infectious disease spread SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE infectious disease; network; edge-based compartmental model ID RANDOM GRAPHS; TRANSMISSION DYNAMICS; CONTACT NETWORK; EPIDEMIC MODEL; SIR DYNAMICS; OUTBREAKS AB The primary tool for predicting infectious disease spread and intervention effectiveness is the mass action susceptible-infected-recovered model of Kermack & McKendrick. Its usefulness derives largely from its conceptual and mathematical simplicity; however, it incorrectly assumes that all individuals have the same contact rate and partnerships are fleeting. In this study, we introduce edge-based compartmental modelling, a technique eliminating these assumptions. We derive simple ordinary differential equation models capturing social heterogeneity (heterogeneous contact rates) while explicitly considering the impact of partnership duration. We introduce a graphical interpretation allowing for easy derivation and communication of the model and focus on applying the technique under different assumptions about how contact rates are distributed and how long partnerships last. C1 [Miller, Joel C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Miller, Joel C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Volz, Erik M.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. RP Miller, JC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. EM joel.c.miller.research@gmail.com RI Miller, Joel/C-4229-2015; OI Miller, Joel/0000-0003-4426-0405; Volz, Erik/0000-0001-6268-8937 FU RAPIDD of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health from the National Institute Of General Medical Sciences [U54GM088558]; NIH [K01 AI091440] FX J.C.M. was supported by the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health and the Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health under award number U54GM088558 from the National Institute Of General Medical Sciences. Much of this work was a result of ideas catalysed by the China Canada Colloquium on Modelling Infectious Diseases held in Xi'an, China in September 2009. E.M.V. was supported by NIH K01 AI091440. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. We thank S. Bansal, M. Lipsitch, R. Meza, B. Pourbohloul, P. Trapman and J. Wallinga for useful conversations. NR 52 TC 54 Z9 54 U1 1 U2 26 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD MAY 7 PY 2012 VL 9 IS 70 BP 890 EP 906 DI 10.1098/rsif.2011.0403 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 916WQ UT WOS:000302134300009 PM 21976638 ER PT J AU Koelle, K Rasmussen, DA AF Koelle, Katia Rasmussen, David A. TI Rates of coalescence for common epidemiological models at equilibrium SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE phylodynamics; viral evolution; disease dynamics; epidemiological models; coalescent theory ID INFECTIOUS PERIODS; DYNAMICS; DISEASE; VIRUS AB Coalescent theory provides a mathematical framework for quantitatively interpreting gene genealogies. With the increased availability of molecular sequence data, disease ecologists now regularly apply this body of theory to viral phylogenies, most commonly in attempts to reconstruct demographic histories of infected individuals and to estimate parameters such as the basic reproduction number. However, with few exceptions, the mathematical expressions at the core of coalescent theory have not been explicitly linked to the structure of epidemiological models, which are commonly used to mathematically describe the transmission dynamics of a pathogen. Here, we aim to make progress towards establishing this link by presenting a general approach for deriving a model's rate of coalescence under the assumption that the disease dynamics are at their endemic equilibrium. We apply this approach to four common families of epidemiological models: standard susceptible-infected-susceptible/susceptible-infected-recovered/susceptible-infected-recovered-susceptible models, models with individual heterogeneity in infectivity, models with an exposed but not yet infectious class and models with variable distributions of the infectious period. These results improve our understanding of how epidemiological processes shape viral genealogies, as well as how these processes affect levels of viral diversity and rates of genetic drift. Finally, we discuss how a subset of these coalescent rate expressions can be used for phylodynamic inference in non-equilibrium settings. For the ones that are limited to equilibrium conditions, we also discuss why this is the case. These results, therefore, point towards necessary future work while providing intuition on how epidemiological characteristics of the infection process impact gene genealogies. C1 [Koelle, Katia; Rasmussen, David A.] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Koelle, K (reprint author), Duke Univ, Dept Biol, Box 90338, Durham, NC 27708 USA. EM katia.koelle@duke.edu FU RAPIDD of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Centre, National Institutes of Health; NSF; [NSF-EF-08-27416] FX We thank Chris Castorena and Allen Rodrigo for helpful comments and useful discussions. This work was supported by grant NSF-EF-08-27416 to K.K., by the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Centre, National Institutes of Health and by an NSF graduate research fellowship to D.A.R. NR 26 TC 21 Z9 21 U1 3 U2 12 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD MAY 7 PY 2012 VL 9 IS 70 BP 997 EP 1007 DI 10.1098/rsif.2011.0495 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 916WQ UT WOS:000302134300018 PM 21920961 ER PT J AU Khatau, SB Kusuma, S Hanjaya-Putra, D Mali, P Cheng, LZ Lee, JSH Gerecht, S Wirtz, D AF Khatau, Shyam B. Kusuma, Sravanti Hanjaya-Putra, Donny Mali, Prashant Cheng, Linzhao Lee, Jerry S. H. Gerecht, Sharon Wirtz, Denis TI The Differential Formation of the LINC-Mediated Perinuclear Actin Cap in Pluripotent and Somatic Cells SO PLOS ONE LA English DT Article ID EMBRYONIC STEM-CELLS; REGULATES NUCLEAR SHAPE; ENVELOPE; PROTEIN; MIGRATION; SUN; LOCALIZATION; KASH; REQUIREMENTS; CYTOSKELETON AB The actin filament cytoskeleton mediates cell motility and adhesion in somatic cells. However, whether the function and organization of the actin network are fundamentally different in pluripotent stem cells is unknown. Here we show that while conventional actin stress fibers at the basal surface of cells are present before and after onset of differentiation of mouse (mESCs) and human embryonic stem cells (hESCs), actin stress fibers of the actin cap, which wrap around the nucleus, are completely absent from undifferentiated mESCs and hESCs and their formation strongly correlates with differentiation. Similarly, the perinuclear actin cap is absent from human induced pluripotent stem cells (hiPSCs), while it is organized in the parental lung fibroblasts from which these hiPSCs are derived and in a wide range of human somatic cells, including lung, embryonic, and foreskin fibroblasts and endothelial cells. During differentiation, the formation of the actin cap follows the expression and proper localization of nuclear lamin A/C and associated linkers of nucleus and cytoskeleton (LINC) complexes at the nuclear envelope, which physically couple the actin cap to the apical surface of the nucleus. The differentiation of hESCs is accompanied by the progressive formation of a perinuclear actin cap while induced pluripotency is accompanied by the specific elimination of the actin cap, and that, through lamin A/C and LINC complexes, this actin cap is involved in progressively shaping the nucleus of hESCs undergoing differentiation. While, the localization of lamin A/C at the nuclear envelope is required for perinuclear actin cap formation, it is not sufficient to control nuclear shape. C1 [Khatau, Shyam B.; Kusuma, Sravanti; Hanjaya-Putra, Donny; Lee, Jerry S. H.; Gerecht, Sharon; Wirtz, Denis] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Khatau, Shyam B.; Kusuma, Sravanti; Hanjaya-Putra, Donny; Gerecht, Sharon; Wirtz, Denis] Johns Hopkins Univ, Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD USA. [Khatau, Shyam B.; Kusuma, Sravanti; Hanjaya-Putra, Donny; Gerecht, Sharon; Wirtz, Denis] Johns Hopkins Univ, Inst NanoBioTechnol, Baltimore, MD USA. [Kusuma, Sravanti; Mali, Prashant] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Cheng, Linzhao] Johns Hopkins Sch Med, Inst Cell Engn, Baltimore, MD USA. [Cheng, Linzhao] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Lee, Jerry S. H.] NCI, Ctr Strateg Sci Initiat, Off Director, NIH, Bethesda, MD 20892 USA. RP Khatau, SB (reprint author), Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. EM wirtz@jhu.edu RI Lee, Jerry/A-3189-2008; Lee, Jerry/K-4553-2014; OI Lee, Jerry/0000-0003-1515-0952; Hanjaya-Putra, Donny/0000-0002-3039-9206 FU National Institutes of Health [R01GM075305, U54CA143868, RC2HL101582]; March of Dimes Basil O'Conner Scholar Award; National Science Foundation graduate training program in the Johns Hopkins Institute for NanoBioTechnology FX This work was supported by National Institutes of Health grants R01GM075305 and U54CA143868 (to DW), RC2HL101582 (to LC), and March of Dimes Basil O'Conner Scholar Award (to SG). SBK was partially supported by a National Science Foundation graduate training program in the Johns Hopkins Institute for NanoBioTechnology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 27 Z9 27 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 4 PY 2012 VL 7 IS 5 AR e36689 DI 10.1371/journal.pone.0036689 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959WV UT WOS:000305349800112 PM 22574215 ER PT J AU Wei, JH Xue, Y Wu, L Ma, J Yi, XL Zhang, JR Lu, B Li, CY Shi, DS Shi, ST Feng, XH Cai, T AF Wei, Jianhua Xue, Yang Wu, Lian Ma, Jie Yi, Xiuli Zhang, Junrui Lu, Bin Li, Chunying Shi, Dashuang Shi, Songtao Feng, Xinghua Cai, Tao TI Analysis of Large Phenotypic Variability of EEC and SHFM4 Syndromes Caused by K193E Mutation of the TP63 Gene SO PLOS ONE LA English DT Article ID SPLIT-HAND/SPLIT-FOOT; DNA-BINDING DOMAIN; P63 GENE; CLEFT-LIP; HAND/FOOT MALFORMATION; ECTODERMAL DYSPLASIA; CHINESE FAMILY; HAND; INHERITANCE; PALATE AB EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) is an autosomal dominant developmental disorder resulting mainly from pathogenic mutations of the DNA-binding domain (DBD) of the TP63 gene. In this study, we showed that K193E mutation in nine affected individuals of a four-generation kindred with a large degree of phenotypic variability causes four different syndromes or TP63-related disorders: EEC, Ectrodactyly-ectodermal dysplasia (EE), isolated ectodermal dysplasia, and isolated Split Hand/Foot Malformation type 4 (SHFM4). Genotype-phenotype and DBD structural modeling analysis showed that the K193-located loop L2-A is associated with R280 through hydrogen bonding interactions, while R280 mutations also often cause large phenotypic variability of EEC and SHFM4. Thus, we speculate that K193 and several other DBD mutation-associated syndromes may share similar pathogenic mechanisms, particularly in the case of the same mutation with different phenotypes. Our study and others also suggest that the phenotypic variability of EEC is attributed, at least partially, to genetic and/or epigenetic modifiers. C1 [Wei, Jianhua; Ma, Jie; Zhang, Junrui; Lu, Bin; Feng, Xinghua; Cai, Tao] Fourth Mil Med Univ, Sch Stomatol, Dept Oral & Maxillofacial Surg, Xian 710032, Shaanxi Provinc, Peoples R China. [Xue, Yang; Li, Chunying] Fourth Mil Med Univ, Sch Stomatol, Dept Oral Biol, Xian 710032, Shaanxi Provinc, Peoples R China. [Wu, Lian] Fourth Mil Med Univ, Sch Stomatol, Dept Paediat Dent, Xian 710032, Shaanxi Provinc, Peoples R China. [Yi, Xiuli] Fourth Mil Med Univ, Xijing Hosp, Dept Dermatol, Xian 710032, Shaanxi Provinc, Peoples R China. [Shi, Dashuang] George Washington Univ, Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC USA. [Shi, Dashuang] George Washington Univ, Childrens Natl Med Ctr, Dept Integrat Syst Biol, Washington, DC USA. [Shi, Songtao] Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90089 USA. [Cai, Tao] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Natl Inst Hlth, Bethesda, MD USA. RP Wei, JH (reprint author), Fourth Mil Med Univ, Sch Stomatol, Dept Oral & Maxillofacial Surg, Xian 710032, Shaanxi Provinc, Peoples R China. EM fengxh@fmmu.edu.cn; tcai@dir.nidcr.nih.gov FU Fourth Military Medical University (FMMU), China FX This research was partially supported by the Genetic Disease Research Fund (2011) at the Fourth Military Medical University (FMMU), China. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 4 Z9 4 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 4 PY 2012 VL 7 IS 5 AR e35337 DI 10.1371/journal.pone.0035337 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959WV UT WOS:000305349800013 PM 22574117 ER PT J AU Kawahara, A Endo, S Dawid, IB AF Kawahara, Atsuo Endo, Sumie Dawid, Igor B. TI Vap (Vascular Associated Protein): A novel factor involved in erythropoiesis and angiogenesis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Zebrafish; Vascular development; Knockdown; Erythropoiesis ID ZEBRAFISH EMBRYOS; VEGF; MIGRATION; RECEPTORS; LINEAGES; GENE AB Both endothelial and erythroid cells are generated in the intermediate cell mass (ICM) during zebrafish embryogenesis, but the nature of the genes that contribute to the processes of erythrocyte maturation and blood vessel network formation is not fully understood. From our in situ-based screening, we have identified a novel factor, yap (Vascular Associated Protein) that is predominantly expressed in the ICM, and subsequently enriched in endothelial cells. yap expression in the ICM was drastically suppressed in the cloche mutant that has defects in both vasculogenesis and hematopoiesis, whereas yap expression was not affected in the vlad tepes/gata1 mutant. Knockdown of yap using anti-sense morpholinos (VAP-MO) not only resulted in decreased numbers of erythrocytes but also in the strong suppression of hemoglobin production. Further, we found that yap knockdown caused the disorganization of the intersegmental vessels (ISVs), which show irregular branching. We propose that yap plays an important role in the maturation of endothelial and erythroid cells in zebrafish. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kawahara, Atsuo] Riken Quantitat Biol Ctr, Lab Cardiovasc Mol Dynam, Suita, Osaka 5650874, Japan. [Kawahara, Atsuo; Endo, Sumie] Kyoto Univ, Fac Med, HMRO, Sakyo Ku, Kyoto 6068501, Japan. [Dawid, Igor B.] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Kawahara, A (reprint author), Riken Quantitat Biol Ctr, Lab Cardiovasc Mol Dynam, Furuedai 6-2-3, Suita, Osaka 5650874, Japan. EM a.kawahara@riken.jp FU Funding Program for Next Generation World-Leading Researchers (NEXT Program); Japan Society for the Promotion of Science; Takeda Science Foundation; Sumitomo Foundation; NICHD, NIH FX The authors thank Y. Kaziro for suggestions and encouragement for the project; B.M. Weinstein, P.P. Liu, L.I. Zon and R.Y. Tsien for transgenic fish, mutant fish and reagents. The work described in this report was supported by the Funding Program for Next Generation World-Leading Researchers (NEXT Program), by the Japan Society for the Promotion of Science, by the Takeda Science Foundation, by the Sumitomo Foundation (A.K.) and by the Intramural Program, NICHD, NIH (I.B.D). NR 23 TC 3 Z9 3 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 MAY 4 PY 2012 VL 421 IS 2 BP 367 EP 374 DI 10.1016/j.bbrc.2012.04.019 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 944QZ UT WOS:000304220200036 PM 22510405 ER PT J AU Hu, G Wade, PA AF Hu, Guang Wade, Paul A. TI NuRD and Pluripotency: A Complex Balancing Act SO CELL STEM CELL LA English DT Review ID EMBRYONIC STEM-CELLS; LSD1; DIFFERENTIATION; MAINTENANCE; METHYLATION; EXPRESSION; REPRESSION; COMPONENT; PROGRAMS; GENOME AB Embryonic stem cells (ESCs) are defined by two essential features-pluripotency and self-renewal whose balance requires the concerted action of signal transduction pathways, transcription factor networks, and epigenetic regulators. Recent findings have implicated the NuRD chromatin remodeling complex in the sophisticated choreography of ESC regulatory pathways. C1 [Hu, Guang; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Wade, PA (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM hug4@niehs.nih.gov; wadep2@niehs.nih.gov RI Hu, Guang/E-7474-2016 OI Hu, Guang/0000-0003-0437-4723 FU National Institute of Environmental Health Sciences; NIH [ES102745, ES101965] FX The authors express gratitude to Dr. Raja Jothi for many useful discussions during the course of preparation of this manuscript. This manuscript was substantially improved by critical comments derived from the peer review process at Cell Stem Cell. Work in the authors' laboratories is supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (ES102745 to G.H. and ES101965 to PAW.). NR 32 TC 41 Z9 42 U1 1 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD MAY 4 PY 2012 VL 10 IS 5 BP 497 EP 503 DI 10.1016/j.stem.2012.04.011 PG 7 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 944WN UT WOS:000304234600008 PM 22560073 ER PT J AU Akiyama, K Chen, C Wang, DD Xu, XT Qu, CY Yamaza, T Cai, T Chen, WJ Sun, LY Shi, ST AF Akiyama, Kentaro Chen, Chider Wang, DanDan Xu, Xingtian Qu, Cunye Yamaza, Takayoshi Cai, Tao Chen, WanJun Sun, Lingyun Shi, Songtao TI Mesenchymal-Stem-Cell-Induced Immunoregulation Involves FAS-Ligand-/FAS-Mediated T Cell Apoptosis SO CELL STEM CELL LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; VERSUS-HOST-DISEASE; GROWTH-FACTOR-BETA; STROMAL CELLS; NITRIC-OXIDE; IFN-GAMMA; TISSUE; RESPONSES; MICE; IMMUNOSUPPRESSION AB Systemic infusion of bone marrow mesenchymal stem cells (BMMSCs) yields therapeutic benefit for a variety of autoimmune diseases, but the underlying mechanisms are poorly understood. Here we show that in mice systemic infusion of BMMSCs induced transient T cell apoptosis via the FAS ligand (FASL)dependent FAS pathway and could ameliorate disease phenotypes in fibrillin-1 mutated systemic sclerosis (SS) and dextran-sulfate-sodium-induced experimental colitis. FASL(-/-) BMMSCs did not induce T cell apoptosis in recipients, and could not ameliorate SS and colitis. Mechanistic analysis revealed that FAS-regulated monocyte chemotactic protein 1 (MCP-1) secretion by BMMSCs recruited T cells for FASL-mediated apoptosis. The apoptotic T cells subsequently triggered macrophages to produce high levels of TGF beta, which in turn led to the upregulation of Ca4(+)CD25(+)Foxp3(+) regulatory T cells and, ultimately, immune tolerance. These data therefore demonstrate a previously unrecognized mechanism underlying BMMSC-based immunotherapy involving coupling via FAS/FASL to induce T cell apoptosis. C1 [Wang, DanDan; Sun, Lingyun] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Rheumatol & Immunol, Nanjing 210008, Jiangsu, Peoples R China. [Akiyama, Kentaro; Chen, Chider; Xu, Xingtian; Qu, Cunye; Yamaza, Takayoshi; Shi, Songtao] Univ So Calif, Ostrow Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. [Akiyama, Kentaro] Okayama Univ, Grad Sch, Dept Oral Rehabil & Regenerat Med, Kita Ku, Okayama 7008525, Japan. [Cai, Tao; Chen, WanJun] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Sun, LY (reprint author), Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Rheumatol & Immunol, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China. EM lingyunsun2011@yahoo.com.cn; songtaos@usc.edu RI XU, XINGTIAN/E-4518-2014; Chen, Chider/L-9880-2016 OI Chen, Chider/0000-0003-2899-1208 FU National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services [RO1DE017449, RO1 DE019932, RO1 DE019413]; California Institute for Regenerative Medicine [RN1-00572]; NIDCR; NIH; China Major International [81120108021]; ClinicalTrials.gov [NCT00962923] FX Basic research parts of this work were supported by grants from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services (RO1DE017449, RO1 DE019932, and RO1 DE019413 to S.S.), a grant from the California Institute for Regenerative Medicine (RN1-00572 for S.S.), and the Intramural Research Program of NIDCR, NIH (for W.J.C. and T.C.). Clinical studies were supported by a grant from the China Major International (Regional) Joint Research Project (81120108021). ClinicalTrials.gov Identifier: NCT00962923. NR 35 TC 175 Z9 196 U1 6 U2 46 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD MAY 4 PY 2012 VL 10 IS 5 BP 544 EP 555 DI 10.1016/j.stem.2012.03.007 PG 12 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 944WN UT WOS:000304234600013 PM 22542159 ER PT J AU Jong, A Wu, CH Gonzales-Gomez, I Kwon-Chung, KJ Chang, YC Tseng, HK Cho, WL Huang, SH AF Jong, Ambrose Wu, Chun-Hua Gonzales-Gomez, Ignacio Kwon-Chung, Kyung J. Chang, Yun C. Tseng, Hsiang-Kuang Cho, Wen-Long Huang, Sheng-He TI Hyaluronic Acid Receptor CD44 Deficiency Is Associated with Decreased Cryptococcus neoformans Brain Infection SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MICROVASCULAR ENDOTHELIAL-CELLS; CENTRAL-NERVOUS-SYSTEM; BINDING-SITE; LIPID RAFTS; SIMVASTATIN; INVOLVEMENT; MICE; PATHOGENESIS; RECRUITMENT; ACTIVATION AB Cryptococcus neoformans is a pathogenic yeast that can invade the brain and cause meningoencephalitis. Our previous in vitro studies suggested that the interaction between C. neoformans hyaluronic acid and human brain endothelial CD44 could be the initial step of brain invasion. In this report, we used a CD44 knock-out (KO or CD44(-/-)) mouse model to explore the importance of CD44 in C. neoformans brain invasion. Our results showed that C. neoformans-infected CD44 KO mice survived longer than the infected wild-type mice. Consistent with our in vitro results, the brain and cerebrospinal fluid fungal burden was reduced in CD44-deficient mice. Histopathological studies showed smaller and fewer cystic lesions in the brains of CD44 KO mice. Interestingly, the cystic lesions contained C. neoformans cells embedded within their polysaccharide capsule and were surrounded by host glial cells. We also found that a secondary hyaluronic acid receptor, RHAMM (receptor of hyaluronan-mediated motility), was present in the CD44 KO mice. Importantly, our studies demonstrated an in vivo blocking effect of simvastatin. These results suggest that the CD44 and RHAMM receptors function on membrane lipid rafts during invasion and that simvastatin may have a potential therapeutic role in C. neoformans infections of the brain. C1 [Jong, Ambrose; Wu, Chun-Hua] Childrens Hosp Los Angeles, Div Hematol Oncol, Saban Res Inst, Los Angeles, CA 90027 USA. [Huang, Sheng-He] Childrens Hosp Los Angeles, Div Infect Dis, Saban Res Inst, Los Angeles, CA 90027 USA. [Gonzales-Gomez, Ignacio] Univ S Florida, All Childrens Hosp, Dept Pathol & Lab Med, St Petersburg, FL 33701 USA. [Kwon-Chung, Kyung J.; Chang, Yun C.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Tseng, Hsiang-Kuang; Cho, Wen-Long] Mackay Mem Hosp, Dept Internal Med, New Taipei 252, Taiwan. [Tseng, Hsiang-Kuang; Cho, Wen-Long] MacKay Med Coll, New Taipei 252, Taiwan. RP Jong, A (reprint author), Childrens Hosp Los Angeles, Div Hematol Oncol, Saban Res Inst, Mailstop 57,4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM ajong@chla.usc.edu FU National Institutes of Health [R01-NS047599, R56-AI40635]; National Institutes of Health NIAID FX This work was supported, in whole or in part, by National Institutes of Health Grants R01-NS047599 (to A. J.) and R56-AI40635 (to S. H. H.).; Supported by the National Institutes of Health NIAID intramural research program. NR 30 TC 26 Z9 29 U1 0 U2 8 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 MAY 4 PY 2012 VL 287 IS 19 BP 15298 EP 15306 DI 10.1074/jbc.M112.353375 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 941YS UT WOS:000304006300013 PM 22418440 ER PT J AU Aghazadeh, Y Rone, MB Blonder, J Ye, XY Veenstra, TD Hales, DB Culty, M Papadopoulos, V AF Aghazadeh, Yasaman Rone, Malena B. Blonder, Josip Ye, Xiaoying Veenstra, Timothy D. Hales, D. Buck Culty, Martine Papadopoulos, Vassilios TI Hormone-induced 14-3-3 gamma Adaptor Protein Regulates Steroidogenic Acute Regulatory Protein Activity and Steroid Biosynthesis in MA-10 Leydig Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALPHA-ASSOCIATED PROTEIN; RAT-LIVER CYTOSOL; BENZODIAZEPINE RECEPTOR; MITOCHONDRIAL PROTEIN; CHOLESTEROL-BINDING; ADRENAL-CORTEX; TUMOR-CELLS; STIMULATE STEROIDOGENESIS; FUNCTIONAL SPECIFICITY; MOLTEN GLOBULE AB Cholesterol is the sole precursor of steroid hormones in the body. The import of cholesterol to the inner mitochondrial membrane, the rate-limiting step in steroid biosynthesis, relies on the formation of a protein complex that assembles at the outer mitochondrial membrane called the transduceosome. The transduceosome contains several mitochondrial and cytosolic components, including the steroidogenic acute regulatory protein (STAR). Human chorionic gonadotropin (hCG) induces de novo synthesis of STAR, a process shown to parallel maximal steroid production. In the hCG-dependent steroidogenic MA-10 mouse Leydig cell line, the 14-3-3 gamma protein was identified in native mitochondrial complexes by mass spectrometry and immunoblotting, and its levels increased in response to hCG treatment. The 14-3-3 proteins bind and regulate the activity of many proteins, acting via target protein activation, modification and localization. In MA-10 cells, cAMPinduces 14-3-3 gamma expression parallel to STAR expression. Silencing of 14-3-3 gamma expression potentiates hormone-induced steroidogenesis. Binding motifs of 14-3-3 gamma were identified in components of the transduceosome, including STAR. Immunoprecipitation studies demonstrate a hormone-dependent interaction between 14-3-3 gamma and STAR that coincides with reduced 14-3-3 gamma homodimerization. The binding site of 14-3-3 gamma on STAR was identified to be Ser-194 in the STAR-related sterol binding lipid transfer (START) domain, the site phosphorylated in response to hCG. Taken together, these results demonstrate that 14-3-3 gamma negatively regulates steroidogenesis by binding to Ser-194 of STAR, thus keeping STAR in an unfolded state, unable to induce maximal steroidogenesis. Over time 14-3-3 gamma homodimerizes and dissociates from STAR, allowing this protein to induce maximal mitochondrial steroid formation. C1 [Aghazadeh, Yasaman; Rone, Malena B.; Culty, Martine; Papadopoulos, Vassilios] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H3G 1A4, Canada. [Aghazadeh, Yasaman; Rone, Malena B.; Culty, Martine; Papadopoulos, Vassilios] McGill Univ, Dept Med, Montreal, PQ H3G 1A4, Canada. [Culty, Martine; Papadopoulos, Vassilios] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1A4, Canada. [Papadopoulos, Vassilios] McGill Univ, Dept Biochem, Montreal, PQ H3G 1A4, Canada. [Blonder, Josip; Ye, Xiaoying; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc,NIH, Frederick, MD 21702 USA. [Hales, D. Buck] So Illinois Univ, Sch Med, Dept Physiol, Carbondale, IL 62901 USA. RP Papadopoulos, V (reprint author), McGill Univ, Ctr Hlth, Res Inst, 1650 Cedar Ave,C10-148, Montreal, PQ H3G 1A4, Canada. EM vassilios.papadopoulos@mcgill.ca FU Canadian Institutes of Health Research [MOP102647]; Canada Research Chair in Biochemical Pharmacology; Le Fonds de la Recherche du Quebec-Sante; Research Institute of McGill University Health Centre FX This work was supported by Canadian Institutes of Health Research Grant MOP102647 and a Canada Research Chair in Biochemical Pharmacology (to V. P.). The Research Institute of McGill University Health Centre was supported by a Center grant from Le Fonds de la Recherche du Quebec-Sante.; Supported in part by a predoctoral fellowship from the Research Institute of McGill University Health Centre.; Supported in part by a postdoctoral fellowship from the Research Institute of McGill University Health Centre. NR 68 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2012 VL 287 IS 19 BP 15380 EP 15394 DI 10.1074/jbc.M112.339580 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 941YS UT WOS:000304006300020 PM 22427666 ER PT J AU Kang, JH Chang, YC Maurizi, MR AF Kang, Jeong Han Chang, Young-Chae Maurizi, Michael R. TI 4-O-Carboxymethyl Ascochlorin Causes ER Stress and Induced Autophagy in Human Hepatocellular Carcinoma Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED-PROTEIN RESPONSE; SIGNALING PATHWAY; GENE-EXPRESSION; LON PROTEASE; IN-VIVO; ACTIVATION; APOPTOSIS; CHOP; AS-6 AB The synthetic derivative of ascochlorin, 4-O-carboxymethyl ascochlorin (AS-6) is an agonist of the nuclear hormone receptor PPAR gamma and has been shown to induce differentiation in mouse pre-adipocytes and to ameliorate type II diabetes in a murine model. AS-6 was cytotoxic when added at micromolar concentrations to cultures of three different human cancer cell lines. We used gel electrophoresis and mass spectrometry to identify proteins with altered expression in human hepatocarcinoma cells (HepG2) cells after 12 h in the presence of AS-6 and found 58 proteins that were differentially expressed. Many of the proteins showing increased expression in cells treated with AS-6 are involved in protein quality control, including glucose-regulated protein 78 (GRP78/BiP), a regulator of ER stress responses, and the transcriptional regulator CHOP, which mediates ER stress-induced apoptosis. Cells treated with AS-6 undergo an autophagic response accompanied by increased expression of beclin1, ATG5, and LC3-II and autophagosome formation marked by the appearance of large vesicles containing LC3-II. Grp78 induction was inhibited when the PPAR gamma antagonist, GW9662, was added together with AS-6, and autophagy and cell death were partially blocked. 3-methyl-adenine (3-MA), an inhibitor of phosphatidyl inositol 3-kinase (PI3-kinase) prevented induction of ATG5 and activation of LC3-II and blocked autophagosome formation. 3-MA also blocked induction of GRP78 and CHOP, suggesting that PI3-kinase, which is known to mediate ER stress-induced autophagy, also plays a role in initiating apoptosis in response to ER stress. Together these data establish that the cytotoxicity of AS-6 operates by a mechanism dependent on ER stress-induced autophagy and apoptosis. C1 [Kang, Jeong Han; Maurizi, Michael R.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Chang, Young-Chae] Catholic Univ Daegu, Sch Med, Dept Pathol, Res Inst Biomed Engn, Namgu 705718, Daegu, South Korea. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 2128,37 Convent Dr, Bethesda, MD 20892 USA. EM mmaurizi@helix.nih.gov FU Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD. NR 42 TC 15 Z9 16 U1 0 U2 11 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 MAY 4 PY 2012 VL 287 IS 19 BP 15661 EP 15671 DI 10.1074/jbc.M112.358473 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 941YS UT WOS:000304006300045 PM 22433868 ER PT J AU Jordan, CT Cao, L Roberson, EDO Pierson, KC Yang, CF Joyce, CE Ryan, C Duan, SH Helms, CA Liu, Y Chen, YQ McBride, AA Hwu, WL Wu, JY Chen, YT Menter, A Goldbach-Mansky, R Lowes, MA Bowcock, AM AF Jordan, Catherine T. Cao, Li Roberson, Elisha D. O. Pierson, Katherine C. Yang, Chi-Fan Joyce, Cailin E. Ryan, Caitriona Duan, Shenghui Helms, Cynthia A. Liu, Yin Chen, Yongqing McBride, Alison A. Hwu, Wuh-Liang Wu, Jer-Yuarn Chen, Yuan-Tsong Menter, Alan Goldbach-Mansky, Raphaela Lowes, Michelle A. Bowcock, Anne M. TI PSORS2 Is Due to Mutations in CARD14 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID NF-KAPPA-B; PSORIASIS SUSCEPTIBILITY LOCI; GENOME-WIDE ASSOCIATION; GENERALIZED PUSTULAR PSORIASIS; EPIDERMAL-KERATINOCYTES; FAMILIAL PSORIASIS; GENE; IDENTIFICATION; ARTHRITIS; 17Q AB Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis. C1 [Jordan, Catherine T.; Cao, Li; Roberson, Elisha D. O.; Joyce, Cailin E.; Duan, Shenghui; Helms, Cynthia A.; Bowcock, Anne M.] Washington Univ, Sch Med, Dept Genet, Div Human Genet, St Louis, MO 63110 USA. [Pierson, Katherine C.; Lowes, Michelle A.] Rockefeller Univ, Invest Dermatol Lab, New York, NY 10065 USA. [Yang, Chi-Fan; Wu, Jer-Yuarn; Chen, Yuan-Tsong] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Ryan, Caitriona; Menter, Alan] Baylor Univ, Med Ctr, Psoriasis Res Inst, Dallas, TX 75246 USA. [Liu, Yin; Chen, Yongqing; Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [McBride, Alison A.] NIAID, NIH, Bethesda, MD 20892 USA. [Hwu, Wuh-Liang] Natl Taiwan Univ Hosp, Dept Pediat & Med Genet, Taipei 100, Taiwan. [Hwu, Wuh-Liang] Natl Taiwan Univ, Coll Med, Taipei 100, Taiwan. RP Bowcock, AM (reprint author), Washington Univ, Sch Med, Dept Genet, Div Human Genet, St Louis, MO 63110 USA. EM bowcock@genetics.wustl.edu RI Roberson, Elisha/J-1747-2012; OI Roberson, Elisha/0000-0001-5921-2399; HWU, WUH-LIANG/0000-0001-6690-4879; Ryan, Caitriona/0000-0003-1915-546X; Bowcock, Anne/0000-0001-8691-9090; Lowes, Michelle A/0000-0003-4256-478X; McBride, Alison/0000-0001-5607-5157 FU National Institutes of Health [AR050266, 5RC1AR058681, T32AR007279, T32HL083822, T32GM07200, AR060222, T32HG000045]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Allergy and Infectious Diseases; Academia Sinica; National Science Council (National Clinical Core, National Genotyping Core) of Taiwan; National Psoriasis Foundation FX This research was supported by the following grants from the National Institutes of Health: AR050266 and 5RC1AR058681 (A.M.B.), T32AR007279 (E.D.O.R.), T32HL083822 and T32GM07200 (C.T.J), AR060222 (M.A.L and K.C.P), and T32HG000045 (C.E.J). R.G.M., Y.L., and Y.C. are supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. A.A.M. was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases. Additional funding came from the Academia Sinica and National Science Council (National Clinical Core, National Genotyping Core) of Taiwan. The authors thank the many individuals with psoriasis and the controls who participated in this study. Mike Lovett provided helpful comments on the manuscript. The authors are indebted to the National Psoriasis Foundation for continuing support during the course of this study. NR 50 TC 116 Z9 122 U1 0 U2 13 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 MAY 4 PY 2012 VL 90 IS 5 BP 784 EP 795 DI 10.1016/j.ajhg.2012.03.012 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 940QG UT WOS:000303907500003 PM 22521418 ER PT J AU Jordan, CT Cao, L Roberson, EDO Duan, SH Helms, CA Nair, RP Duffin, KC Stuart, PE Goldgar, D Hayashi, G Olfson, EH Feng, BJ Pullinger, CR Kane, JP Wise, CA Goldbach-Mansky, R Lowes, MA Peddle, L Chandran, V Liao, W Rahman, P Krueger, GG Gladman, D Elder, JT Menter, A Bowcock, AM AF Jordan, Catherine T. Cao, Li Roberson, Elisha D. O. Duan, Shenghui Helms, Cynthia A. Nair, Rajan P. Duffin, Kristina Callis Stuart, Philip E. Goldgar, David Hayashi, Genki Olfson, Emily H. Feng, Bing-Jian Pullinger, Clive R. Kane, John P. Wise, Carol A. Goldbach-Mansky, Raphaela Lowes, Michelle A. Peddle, Lynette Chandran, Vinod Liao, Wilson Rahman, Proton Krueger, Gerald G. Gladman, Dafna Elder, James T. Menter, Alan Bowcock, Anne M. TI Rare and Common Variants in CARD14, Encoding an Epidermal Regulator of NF-kappaB, in Psoriasis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; INFLAMMATORY DISEASES; MACULAR DEGENERATION; CROHNS-DISEASE; HLA-C; GENE; RISK; IDENTIFICATION; PATHOGENESIS AB Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5x higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-alpha) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD 14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 x 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw(star)0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. C1 [Jordan, Catherine T.; Cao, Li; Roberson, Elisha D. O.; Duan, Shenghui; Helms, Cynthia A.; Olfson, Emily H.; Bowcock, Anne M.] Washington Univ, Sch Med, Dept Genet, Div Human Genet, St Louis, MO 63110 USA. [Nair, Rajan P.; Stuart, Philip E.; Elder, James T.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. [Duffin, Kristina Callis; Goldgar, David; Feng, Bing-Jian; Krueger, Gerald G.] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT 84132 USA. [Hayashi, Genki; Liao, Wilson] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94115 USA. [Kane, John P.] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Med, San Francisco, CA 94143 USA. [Pullinger, Clive R.] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Kane, John P.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. [Wise, Carol A.] Texas Scottish Rite Hosp Children, Sarah M & Charles E Seay Ctr Musculoskeletal Res, Dallas, TX 75219 USA. [Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Lowes, Michelle A.] Rockefeller Univ, Invest Dermatol Lab, New York, NY 10065 USA. [Peddle, Lynette; Rahman, Proton] Mem Univ Newfoundland, Dept Med, Div Rheumatol, St John, NF A1C 5S7, Canada. [Chandran, Vinod; Gladman, Dafna] Univ Toronto, Toronto, ON M5T 2S8, Canada. [Chandran, Vinod; Gladman, Dafna] Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. [Menter, Alan] Baylor Univ, Med Ctr, Psoriasis Res Inst, Dallas, TX 75246 USA. RP Bowcock, AM (reprint author), Washington Univ, Sch Med, Dept Genet, Div Human Genet, St Louis, MO 63110 USA. EM bowcock@genetics.wustl.edu RI Roberson, Elisha/J-1747-2012; OI Roberson, Elisha/0000-0001-5921-2399; Wise, Carol/0000-0002-6790-2194; Bowcock, Anne/0000-0001-8691-9090 FU National Institutes of Health (NIH) [AR050266, 5RC1AR058681, T32AR007279, T32HL083822, T32 GM07200, AR060222, T32HG000045, K08AR057763, R01 AR042742, R01 AR050511, AR054966]; Babcock Memorial Trust; Ann Arbor Veterans Affairs Hospital; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Arthritis Society of Canada; Atlantic Innovation Fund; Canadian Institute of Health Research; Arthritis Society; Dana Foundation; Academia Sinica; National Science Council (National Clinical Core, National Genotyping Core) of Taiwan; National Psoriasis Foundation FX This work was supported by grants from the National Institutes of Health (NIH): AR050266 and 5RC1AR058681 (A.M.B.), T32AR007279 (E.D.O.R.), T32HL083822 and T32 GM07200 (C.T.J), AR060222 (M.A.L), T32HG000045 (C.E.J), and K08AR057763 (W.L.). J.T.E., R.N., and P.S. were supported by NIH grants R01 AR042742, R01 AR050511, and AR054966 and by the Babcock Memorial Trust. J.T.E. is supported by the Ann Arbor Veterans Affairs Hospital. R.G.M. is supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Additional funding came from the Arthritis Society of Canada, the Atlantic Innovation Fund, the Canadian Institute of Health Research, the Arthritis Society, the Dana Foundation, and the Academia Sinica and National Science Council (National Clinical Core, National Genotyping Core) of Taiwan. The authors thank the many individuals with psoriasis and the controls who participated in this study. We thank Linus Schwantes-An, Weimin Duan, and Nancy Saccone for advice on statistical analyses. We also thank Mayte Suarez-Farinas for biostatistical assistance, Haoyan Chen, Olivia Lai, Fawnda Pellet, and M.J. Malloy for assembling the control population, Pui-Yan Kwok for sample procurement, Trilokraj Tejasvi for clinical evaluation of study subjects, Nikki Plass for patient scheduling and study logistics, Damaris Garcia for the management of samples, and Debbie Stone and Dawn Chapelle for patient care. Mike Lovett provided helpful comments on the manuscript. The authors are indebted to the National Psoriasis Foundation for continuing support during the course of this study. NR 40 TC 103 Z9 107 U1 3 U2 12 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 MAY 4 PY 2012 VL 90 IS 5 BP 796 EP 808 DI 10.1016/j.ajhg.2012.03.013 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 940QG UT WOS:000303907500004 PM 22521419 ER PT J AU Bhattacharjee, S Rajaraman, P Jacobs, KB Wheeler, WA Melin, BS Hartge, P Yeager, M Chung, CC Chanock, SJ Chatterjee, N AF Bhattacharjee, Samsiddhi Rajaraman, Preetha Jacobs, Kevin B. Wheeler, William A. Melin, Beatrice S. Hartge, Patricia Yeager, Meredith Chung, Charles C. Chanock, Stephen J. Chatterjee, Nilanjan CA GliomaScan Consortium TI A Subset-Based Approach Improves Power and Interpretation for the Combined Analysis of Genetic Association Studies of Heterogeneous Traits SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; TELOMERASE REVERSE-TRANSCRIPTASE; SUSCEPTIBILITY LOCI; BREAST-CANCER; COLORECTAL-CANCER; PROSTATE-CANCER; SHARED CONTROLS; COMMON VARIANT; RISK; GLIOMA AB Pooling genome-wide association studies (GWASs) increases power but also poses methodological challenges because studies are often heterogeneous. For example, combining GWASs of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical approaches for meta-analysis or pooled analysis, however, might not be suitable for such analysis because individual variants are likely to be associated with only a subset of the traits or might demonstrate effects in different directions. We propose a method that exhaustively explores subsets of studies for the presence of true association signals that are in either the same direction or possibly opposite directions. An efficient approximation is used for rapid evaluation of p values. We present two illustrative applications, one for a meta-analysis of separate case-control studies of six distinct cancers and another for pooled analysis of a case-control study of glioma, a class of brain tumors that contains heterogeneous subtypes. Both the applications and additional simulation studies demonstrate that the proposed methods offer improved power and more interpretable results when compared to traditional methods for the analysis of heterogeneous traits. The proposed framework has applications beyond genetic association studies. C1 [Bhattacharjee, Samsiddhi; Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Rajaraman, Preetha] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Jacobs, Kevin B.; Yeager, Meredith] NCI, Core Genotyping Facil, NIH, Dept Hlth & Human Serv, Gaithersburg, MD 20877 USA. [Wheeler, William A.] Informat Management Serv Inc, Rockville, MD 20852 USA. [Melin, Beatrice S.] Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden. [Hartge, Patricia] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Chung, Charles C.; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Chatterjee, N (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd, Rockville, MD 20852 USA. EM chattern@mail.nih.gov RI Ruder, Avima/I-4155-2012; Albanes, Demetrius/B-9749-2015; Beane Freeman, Laura/C-4468-2015 OI Ruder, Avima/0000-0003-0419-6664; Beane Freeman, Laura/0000-0003-1294-4124 FU National Cancer Institute, National Institutes of Health, USA FX This work was supported by the intramural program of the National Cancer Institute, National Institutes of Health, USA. The authors would like to thank the GliomaScan Consortium investigators (Demetrius Albanes, Ulrika Andersson, Laura Beane-Freeman, Christine D. Berg, Julie E. Buring, Mary Ann Butler, Tania Carreon, Helle Collatz Christensen, Maria Feychting, Susan M. Gapstur, J. Michael Gaziano, Graham G. Giles, Goran Hallmans, Susan E. Hankinson, Roger Henriksson, Jane Hoppin, Ann W. Hsing, Peter D. Inskip, Christoffer Johansen, Laurence N. Kolonel, Roberta McKean-Cowdin, Dominique Michaud, Ulrike Peters, Mark P. Purdue, Avima M. Ruder, Howard D. Sesso, Gianluca Seven, Victoria L. Stevens, Kala Visvanathan, Zhaoming Wang, Emily White, Walter C. Willett, and Anne Zeleniuch-Jacquotte) for providing data for the glioma example. The simulation experiments utilized the high-performance computational capabilities of the StatPro Linux cluster at the National Cancer Institute and the Biowulf Linux cluster at the National Institutes of Health, USA. We would also like to thank Alan Genz and Fabio Iwamoto for helpful discussions and two anonymous reviewers for comments and suggestions that helped improve the manuscript. NR 56 TC 44 Z9 45 U1 1 U2 9 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 MAY 4 PY 2012 VL 90 IS 5 BP 821 EP 835 DI 10.1016/j.ajhg.2012.03.015 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 940QG UT WOS:000303907500006 PM 22560090 ER PT J AU Kitazume, E Koikawa, S Hui, L Sannohe, S Yang, YJ Maki, Y Ito, Y AF Kitazume, Eiichi Koikawa, Saki Hui, Lu Sannohe, Syou Yang, Yanjun Maki, Yonosuke Ito, Yoichiro TI Sequential determination of anionic-type detergents by complexation with methylene blue using dual high speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Dual countercurrent chromatography; Anionic-type detergents; Methylene blue complex; River water; Sequential analysis AB A new dual high-speed counter-current chromatographic system using organic extraction phase and aqueous mobile phase containing methylene blue was applied to the analysis of anionic-type detergents. After selecting appropriate conditions such as flow rate leach mobile phase and sample volume, the new system was successfully applied to the analysis of anionic detergent in river water. As all the analytical procedures can be made in a closed system, the method has no health hazard. The present method is safe, precise, and highly sensitive, and can be applied for sequential determination of multiple samples in a short analysis time. (C) 2012 Elsevier B.V. All rights reserved. C1 [Kitazume, Eiichi; Koikawa, Saki; Hui, Lu; Sannohe, Syou; Yang, Yanjun; Maki, Yonosuke] Iwate Univ, Fac Humanities & Social Sci, Ueda, Iwate 0208550, Japan. [Ito, Yoichiro] NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kitazume, E (reprint author), Iwate Univ, Fac Humanities & Social Sci, 3-18-37 Morioka, Ueda, Iwate 0208550, Japan. EM kitazume@iwate-u.ac.jp FU Ministry of Education, Science, Sports and Culture; Japan Science and Technology Agency; [21510003] FX This research was partially supported by the Ministry of Education, Science, Sports and Culture, Grant-in-Aid for 21510003 and Japan Science and Technology Agency. NR 4 TC 5 Z9 5 U1 1 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAY 4 PY 2012 VL 1236 BP 148 EP 151 DI 10.1016/j.chroma.2012.03.016 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 930WF UT WOS:000303174700017 PM 22443889 ER PT J AU Ascierto, PA Kirkwood, JM Grob, JJ Simeone, E Grimaldi, AM Maio, M Palmieri, G Testori, A Marincola, FM Mozzillo, N AF Ascierto, Paolo A. Kirkwood, John M. Grob, Jean-Jacques Simeone, Ester Grimaldi, Antonio M. Maio, Michele Palmieri, Giuseppe Testori, Alessandro Marincola, Francesco M. Mozzillo, Nicola TI The role of BRAF V600 mutation in melanoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material DE BRAF; Vemurafenib; Melanoma ID B-RAF; WILD-TYPE; METASTATIC MELANOMA; TUMOR PROGRESSION; HUMAN CANCER; C-RAF; HETERODIMERIZATION; PATHWAY; INHIBITOR; KINASES AB BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naive patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors. C1 [Ascierto, Paolo A.; Simeone, Ester; Grimaldi, Antonio M.; Mozzillo, Nicola] Ist Nazl Tumori Fdn G Pascale, Dept Melanoma, Naples, Italy. [Ascierto, Paolo A.] Ist Nazl Studio & Cura Tumori Fdn G Pascale, Unit Med Oncol & Innovat Therapy, I-80131 Naples, Italy. [Kirkwood, John M.] Univ Pittsburgh, Pittsburgh Canc Inst, Dept Med, Div Hematol Oncol, Pittsburgh, PA USA. [Grob, Jean-Jacques] Hop La Timone, F-13885 Marseille 05, France. [Grob, Jean-Jacques] Aix Marseille Univ, F-13885 Marseille 05, France. [Maio, Michele] Univ Hosp Siena, Dept Oncol, Ist Toscano Tumori, Siena, Italy. [Palmieri, Giuseppe] CNR, Natl Res Council, Unit Canc Genet, Inst Biomol Chem, Sassari, Italy. [Testori, Alessandro] Ist Europeo Oncol, Melanoma & Muscle Cutaneous Sarcomas Div, Milan, Italy. [Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, CHI, Bethesda, MD 20892 USA. RP Ascierto, PA (reprint author), Ist Nazl Tumori Fdn G Pascale, Dept Melanoma, Naples, Italy. EM paolo.ascierto@gmail.com OI coral, sandra/0000-0002-1308-3082; Palmieri, Giuseppe/0000-0002-4350-2276 FU NCI NIH HHS [P50 CA121973] NR 46 TC 96 Z9 101 U1 3 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAY 3 PY 2012 VL 10 AR 85 DI 10.1186/1479-5876-10-85 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 975DY UT WOS:000306488300001 PM 22554099 ER PT J AU Cuddapah, S Roh, TY Cui, KR Jose, CC Fuller, MT Zhao, KJ Chen, X AF Cuddapah, Suresh Roh, Tae-Young Cui, Kairong Jose, Cynthia C. Fuller, Margaret T. Zhao, Keji Chen, Xin TI A Novel Human Polycomb Binding Site Acts As a Functional Polycomb Response Element in Drosophila SO PLOS ONE LA English DT Article ID HISTONE METHYLTRANSFERASE ACTIVITY; EMBRYONIC STEM-CELLS; GROUP PROTEIN COMPLEX; DEVELOPMENTAL REGULATORS; SILENCING MECHANISMS; CHROMATIN DOMAINS; CELLULAR MEMORY; TARGET GENES; BAF COMPLEX; DNA-BINDING AB Polycomb group (PcG) proteins are key chromatin regulators implicated in multiple processes including embryonic development, tissue homeostasis, genomic imprinting, X-chromosome inactivation, and germ cell differentiation. The PcG proteins recognize target genomic loci through cis DNA sequences known as Polycomb Response Elements (PREs), which are well characterized in Drosophila. However, mammalian PREs have been elusive until two groups reported putative mammalian PREs recently. Consistent with the existence of mammalian PREs, here we report the identification and characterization of a potential PRE from human T cells. The putative human PRE has enriched binding of PcG proteins, and such binding is dependent on a key PcG component SUZ12. We demonstrate that the putative human PRE carries both genetic and molecular features of Drosophila PRE in transgenic flies, implying that not only the trans PcG proteins but also certain features of the cis PREs are conserved between mammals and Drosophila. C1 [Cuddapah, Suresh; Jose, Cynthia C.] NYU, Dept Environm Med, Sch Med, New York, NY 10016 USA. [Roh, Tae-Young; Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Chen, Xin] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Fuller, Margaret T.] Stanford Univ, Dept Dev Biol & Genet, Sch Med, Stanford, CA 94305 USA. RP Cuddapah, S (reprint author), NYU, Dept Environm Med, Sch Med, 550 1St Ave, New York, NY 10016 USA. EM Suresh.Cuddapah@nyumc.org; xchen32@jhu.edu OI Fuller, Margaret T/0000-0002-3804-4987 FU Leukemia and Lymphoma Society [LLS-3598-06]; National Institutes of Health (NIH) [K99/R00 HD055052, 1R01HD065816, 1R01GM61986]; National Heart, Lung and Blood Institute (NHLBI), NIH FX This work was supported by Leukemia and Lymphoma Society Special Fellowship (grant LLS-3598-06), National Institutes of Health (NIH) grants K99/R00 HD055052 Pathway to Independence Award and 1R01HD065816 to XC, NIH grant 1R01GM61986 to MTF, and National Heart, Lung and Blood Institute (NHLBI), NIH intramural grants to KZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 13 Z9 14 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 3 PY 2012 VL 7 IS 5 AR e36365 DI 10.1371/journal.pone.0036365 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VF UT WOS:000305343400023 PM 22570707 ER PT J AU Kohn, KW Zeeberg, BR Reinhold, WC Sunshine, M Luna, A Pommier, Y AF Kohn, Kurt W. Zeeberg, Barry R. Reinhold, William C. Sunshine, Margot Luna, Augustin Pommier, Yves TI Gene Expression Profiles of the NCI-60 Human Tumor Cell Lines Define Molecular Interaction Networks Governing Cell Migration Processes SO PLOS ONE LA English DT Article ID RECEPTOR TYROSINE KINASES; R-RAS; MESENCHYMAL TRANSITION; INTERACTION MAPS; OVARIAN-CANCER; E-CADHERIN; KAPPA-B; ACTIVATION; AXL; PATHWAY AB Although there is extensive information on gene expression and molecular interactions in various cell types, integrating those data in a functionally coherent manner remains challenging. This study explores the premise that genes whose expression at the mRNA level is correlated over diverse cell lines are likely to function together in a network of molecular interactions. We previously derived expression-correlated gene clusters from the database of the NCI-60 human tumor cell lines and associated each cluster with function categories of the Gene Ontology (GO) database. From a cluster rich in genes associated with GO categories related to cell migration, we extracted 15 genes that were highly cross-correlated; prominent among them were RRAS, AXL, ADAM9, FN14, and integrin-beta1. We then used those 15 genes as bait to identify other correlated genes in the NCI-60 database. A survey of current literature disclosed, not only that many of the expression-correlated genes engaged in molecular interactions related to migration, invasion, and metastasis, but that highly cross-correlated subsets of those genes engaged in specific cell migration processes. We assembled this information in molecular interaction maps (MIMs) that depict networks governing 3 cell migration processes: degradation of extracellular matrix, production of transient focal complexes at the leading edge of the cell, and retraction of the rear part of the cell. Also depicted are interactions controlling the release and effects of calcium ions, which may regulate migration in a spaciotemporal manner in the cell. The MIMs and associated text comprise a detailed and integrated summary of what is currently known or surmised about the role of the expression cross-correlated genes in molecular networks governing those processes. C1 [Kohn, Kurt W.; Zeeberg, Barry R.; Reinhold, William C.; Sunshine, Margot; Luna, Augustin; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kohn, KW (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kohnk@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 91 TC 12 Z9 12 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 3 PY 2012 VL 7 IS 5 AR e35716 DI 10.1371/journal.pone.0035716 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959VF UT WOS:000305343400007 PM 22570691 ER PT J AU Kerkar, SP Restifo, NP AF Kerkar, Sid P. Restifo, Nicholas P. TI The power and pitfalls of IL-12 SO BLOOD LA English DT Editorial Material ID T-CELLS; EXPRESSION; THERAPY; SAFETY; TUMORS C1 [Kerkar, Sid P.; Restifo, Nicholas P.] NHLBI, NCI, Bethesda, MD 20892 USA. RP Kerkar, SP (reprint author), NHLBI, NCI, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 NR 10 TC 4 Z9 6 U1 0 U2 2 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 MAY 3 PY 2012 VL 119 IS 18 BP 4096 EP 4097 DI 10.1182/blood-2012-03-415018 PG 4 WC Hematology SC Hematology GA 959BL UT WOS:000305284600002 PM 22555659 ER PT J AU Xie, ZH Ghosh, CC Patel, R Iwaki, S Gaskins, D Nelson, C Jones, N Greipp, PR Parikh, SM Druey, KM AF Xie, Zhihui Ghosh, Chandra C. Patel, Roshni Iwaki, Shoko Gaskins, Donna Nelson, Celeste Jones, Nina Greipp, Philip R. Parikh, Samir M. Druey, Kirk M. TI Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome) SO BLOOD LA English DT Article ID GROWTH-FACTOR; PERMEABILITY FACTOR; TUMOR ANGIOGENESIS; CELL PERMEABILITY; BARRIER FUNCTIONS; SKELETAL-MUSCLE; VE-CADHERIN; ANGIOPOIETIN-2; EDEMA; BETA AB The systemic capillary leak syndrome (SCLS) is a rare disorder characterized by transient episodes of hypotensive shock and anasarca thought to arise from reversible microvascular barrier dysfunction. Although the high prevalence of a monoclonal gammopathy of unknown significance in SCLS suggests a pathogenic contribution of endogenous immunoglobulins, the mechanisms of vascular hyperpermeability remain obscure. Herein, we report clinical and molecular findings on 23 patients, the largest SCLS case series to date. Application of episodic SCLS sera, but neither the purified immunoglobulin fraction nor sera obtained from patients during remission, to human microvascular endothelial cells caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. Intravenous immunoglobulin, one promising therapy for SCLS, mitigated the permeability effects of episodic sera. Consistent with the presence of endogenous, nonimmunoglobulin, circulating permeability factor(s) constrained to SCLS episodes, we found that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Ab-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Comparable experiments with anti-VEGF Ab (bevacizumab) yielded less interpretable results, probably because of endothelial toxicity of VEGF withdrawal. Our results support a model of SCLS pathogenesis in which nonimmunoglobulin humoral factors such as VEGF and Ang2 contribute to transient endothelial contraction, suggesting a molecular mechanism for this highly lethal disorder. (Blood. 2012;119(18): 4321-4332) C1 [Xie, Zhihui; Patel, Roshni; Iwaki, Shoko; Gaskins, Donna; Nelson, Celeste; Jones, Nina; Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD USA. [Ghosh, Chandra C.; Parikh, Samir M.] Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA. [Ghosh, Chandra C.; Parikh, Samir M.] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Greipp, Philip R.] Mayo Clin, Coll Med, Div Hematol, Rochester, MN USA. [Ghosh, Chandra C.; Parikh, Samir M.] Harvard Univ, Sch Med, Boston, MA USA. RP Druey, KM (reprint author), 10 Ctr Dr,Rm 11N242, Bethesda, MD 20982 USA. EM sparikh1@bidmc.harvard.edu; kdruey@niaid.nih.gov FU National Institutes of Health (NIH) [R01HL093234, R01HL093234-01S1, K08DK06916]; National Institute of Allergy and Infectious Diseases [AI001083 LAD] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases grant AI001083 LAD (K.M.D.) and by NIH grants R01HL093234, R01HL093234-01S1, and K08DK06916 (S.M.P.). NR 59 TC 33 Z9 34 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 MAY 3 PY 2012 VL 119 IS 18 BP 4321 EP 4332 DI 10.1182/blood-2011-08-375816 PG 12 WC Hematology SC Hematology GA 959BL UT WOS:000305284600030 PM 22411873 ER PT J AU Intarasunanont, P Navasumrit, P Waraprasit, S Chaisatra, K Suk, WA Mahidol, C Ruchirawat, M AF Intarasunanont, Ponpat Navasumrit, Panida Waraprasit, Somchamai Chaisatra, Krittinee Suk, William A. Mahidol, Chulabhorn Ruchirawat, Mathuros TI Effects of arsenic exposure on DNA methylation in cord blood samples from newborn babies and in a human lymphoblast cell line SO ENVIRONMENTAL HEALTH LA English DT Article DE Arsenic; Exposure in utero; Global DNA methylation; p53 promoter methylation; Lymphoblast cell line; Cord blood lymphocyte ID CPG ISLAND HYPERMETHYLATION; ABERRANT GENE-EXPRESSION; DRINKING-WATER; MALIGNANT-TRANSFORMATION; PROSTATE-CANCER; LUNG-CANCER; IN-UTERO; CD1 MICE; TUMOR; HYPOMETHYLATION AB Background: Accumulating evidence indicates that in utero exposure to arsenic is associated with congenital defects and long-term disease consequences including cancers. Recent studies suggest that arsenic carcinogenesis results from epigenetic changes, particularly in DNA methylation. This study aimed to investigate DNA methylation changes as a result of arsenic exposure in utero and in vitro. Methods: For the exposure in utero study, a total of seventy-one newborns (fifty-five arsenic-exposed and sixteen unexposed newborns) were recruited. Arsenic concentrations in the drinking water were measured, and exposure in newborns was assessed by measurement of arsenic concentrations in cord blood, nails and hair by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). In the in vitro study, human lymphoblasts were treated with arsenite at 0-100 mu M for two, four and eight hours (short-term) and at 0, 0.5 and 1.0 mu M for eight-weeks period (long-term). DNA methylation was analyzed in cord blood lymphocytes and lymphoblasts treated with arsenite in vitro. Global DNA methylation was determined as LINE-1 methylation using combined bisulfite restriction analysis (COBRA) and total 5-methyldeoxycytidine (5MedC) content which was determined by HPLC-MS/MS. Methylation of p53 was determined at the promoter region using methylation-specific restriction endonuclease digestion with MspI and HpaII. Results: Results showed that arsenic-exposed newborns had significantly higher levels of arsenic in cord blood, fingernails, toenails and hair than those of the unexposed subjects and a slight increase in promoter methylation of p53 in cord blood lymphocytes which significantly correlated with arsenic accumulation in nails (p < 0.05) was observed, while LINE-1 methylation was unchanged. Short-term in vitro arsenite treatment in lymphoblastoid cells clearly demonstrated a significant global hypomethylation, determined as reduction in LINE-1 methylation and total 5-MedC content, and p53 hypermethylation (p < 0.05). However, a slight LINE-1 hypomethylation and transient p53 promoter hypermethylation were observed following long-term in vitro treatment. Conclusions: This study provides an important finding that in utero arsenic exposure affects DNA methylation, particularly at the p53 promoter region, which may be linked to the mechanism of arsenic carcinogenesis and the observed increased incidence of cancer later in life. C1 [Intarasunanont, Ponpat; Navasumrit, Panida; Waraprasit, Somchamai; Chaisatra, Krittinee; Ruchirawat, Mathuros] Chulabhorn Res Inst, Lab Environm Toxicol, Bangkok 10210, Thailand. [Intarasunanont, Ponpat; Navasumrit, Panida; Ruchirawat, Mathuros] Asian Inst Technol, Interuniv Post Grad Program Environm Toxicol Tech, Chulabhorn Res Inst, Bangkok 10501, Thailand. [Intarasunanont, Ponpat; Navasumrit, Panida; Ruchirawat, Mathuros] Mahidol Univ, Ctr Excellence Environm Hlth & Toxicol, CHE, Minist Educ, Bangkok 10700, Thailand. [Suk, William A.] NIEHS, Ctr Risk & Integrated Sci, Res Triangle Pk, NC 27709 USA. [Mahidol, Chulabhorn] Chulabhorn Res Inst, Lab Chem Carcinogenesis, Bangkok 10210, Thailand. [Ruchirawat, Mathuros] Mahidol Univ, Dept Pharmacol, Fac Sci, Bangkok 10400, Thailand. RP Ruchirawat, M (reprint author), Chulabhorn Res Inst, Lab Environm Toxicol, Bangkok 10210, Thailand. EM mathuros@cri.or.th FU Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education FX This work was supported by the grant from the Chulabhorn Research Institute, Bangkok 10210, Thailand and in part by the grant from Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education. Cooperation and assistance from the Director and the medical team of the Ron Pibul Hospital and Rajvithi Hospital, Thailand in subject recruitment and sample collection are gratefully acknowledged. NR 66 TC 38 Z9 44 U1 2 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD MAY 2 PY 2012 VL 11 AR 31 DI 10.1186/1476-069X-11-31 PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 044PV UT WOS:000311634600001 PM 22551203 ER PT J AU Ascierto, PA Grimaldi, AM Curti, B Faries, MB Ferrone, S Flaherty, K Fox, BA Gajewski, TF Gershenwald, JE Gogas, H Grossmann, K Hauschild, A Hodi, FS Kefford, R Kirkwood, JM Leachmann, S Maio, M Marais, R Palmieri, G Morton, DL Ribas, A Stroncek, DF Stewart, R Wang, E Mozzillo, N Marincola, FM AF Ascierto, Paolo A. Grimaldi, Antonio M. Curti, Brendan Faries, Mark B. Ferrone, Soldano Flaherty, Keith Fox, Bernard A. Gajewski, Thomas F. Gershenwald, Jeffrey E. Gogas, Helen Grossmann, Kenneth Hauschild, Axel Hodi, F. Stephen Kefford, Richard Kirkwood, John M. Leachmann, Sancy Maio, Michele Marais, Richard Palmieri, Giuseppe Morton, Donald L. Ribas, Antoni Stroncek, David F. Stewart, Rodney Wang, Ena Mozzillo, Nicola Marincola, Franco M. TI FUTURE PERSPECTIVES IN MELANOMA RESEARCH. Meeting report from the "Melanoma Research: a bridge from Naples to the World. Napoli, December 5th-6th 2011" SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; ZEBRAFISH NEURAL CREST; HIGH-RISK MELANOMA; STAGE-IV MELANOMA; METASTATIC MELANOMA; PROGNOSTIC-SIGNIFICANCE; CUTANEOUS MELANOMA; INTERFERON-ALPHA; ADJUVANT THERAPY; FOXD3 AB After more than 30 years, landmark progress has been made in the treatment of cancer, and melanoma in particular, with the success of new molecules such as ipilimumab, vemurafenib and active specific immunization. After the first congress in December 2010, the second edition of "Melanoma Research: a bridge from Naples to the World" meeting, organized by Paolo A. Ascierto (INT, Naples, Italy), Francesco M. Marincola (NIH, Bethesda, USA), and Nicola Mozzillo (INT, Naples, Italy) took place in Naples, on 5-6 December 2011. We have identified four new topics of discussion: Innovative Approaches in Prevention, Diagnosis and Surgical Treatment, New Pathways and Targets in Melanoma: An Update about Immunotherapy, and Combination Strategies. This international congress gathered more than 30 international faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive atmosphere which stimulated discussion of new approaches and strategies in the field of melanoma. C1 [Ascierto, Paolo A.; Grimaldi, Antonio M.; Mozzillo, Nicola] Fdn Pascale, Ist Nazl Tumori, Dept Melanoma Sarcoma & Head & Neck Dis, Naples, Italy. [Curti, Brendan] Providence Canc Ctr, Earle A Chiles Res Inst, Portland, OR USA. [Faries, Mark B.; Morton, Donald L.] St Johns Hlth Ctr, John Wayne Canc Inst, Dept Melanoma Res, Santa Monica, CA USA. [Ferrone, Soldano] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Flaherty, Keith] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Fox, Bernard A.] Providence Portland Med Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Lab Mol & Tumor Immunol, Portland, OR USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Gajewski, Thomas F.] Univ Chicago, Chicago, IL 60637 USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Gogas, Helen] Univ Athens, Athens Med Sch, Dept Med 1, Athens, Greece. [Grossmann, Kenneth; Leachmann, Sancy; Stewart, Rodney] Univ Utah, Melanoma & Cutaneous Oncol Program, Huntsman Canc Inst, Salt Lake City, UT USA. [Hauschild, Axel] Univ Kiel, Dept Dermatol, D-2300 Kiel, Germany. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kefford, Richard] Westmead Millennium Inst, Westmead Inst Canc Res, Sydney, NSW, Australia. [Kefford, Richard] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA USA. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Dept Dermatol, Div Hematol Oncol, Pittsburgh, PA 15261 USA. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Dept Translat Sci, Div Hematol Oncol, Pittsburgh, PA USA. [Kirkwood, John M.] Pittsburgh Canc Inst, Melanoma Program, Pittsburgh, PA 15213 USA. [Maio, Michele] Univ Hosp Siena, Ist Toscano Tumori, Dept Oncol, Siena, Italy. [Marais, Richard] Paterson Inst Canc Res, Mol Oncol Grp, Manchester M20 4BX, Lancs, England. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Unit Canc Genet, Sassari, Italy. [Ribas, Antoni] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA USA. [Stroncek, David F.] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Franco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Franco M.] NIH, CHI, Bethesda, MD 20892 USA. [Ascierto, Paolo A.; Grimaldi, Antonio M.] Fdn G Pascale, Ist Nazl Studio & Cura Tumori, Unit Med Oncol & Innovat Therapy, I-80131 Naples, Italy. RP Ascierto, PA (reprint author), Fdn Pascale, Ist Nazl Tumori, Dept Melanoma Sarcoma & Head & Neck Dis, Naples, Italy. EM paolo.ascierto@gmail.com OI Marais, Richard/0000-0001-7484-4183 FU Fondazione Melanoma Onlus; Society of ImmunoTherapy of Cancer (SITC); Collage Congressi of Napoli; BC Prometheus Pharmaceuticals; BMS; Boehringer Ingelheim; Celgene; Eisai; GSK; IGEA; MSD; Novartis; Roche-Genentech FX The meeting was supported by Fondazione Melanoma Onlus and the Society of ImmunoTherapy of Cancer (SITC). A special thanks to Collage Congressi of Napoli for their support and cooperation in organizing the meeting and to Michael Hoetzel for providing us the group picture from the meeting.; PAA participated to Advisory Board from Bristol Myers Squibb, MSD, Roche-Genentech, GSK, Celgene, Amgen, Medimmune, and Novartis and received honoraria from Brystol Myers Squibb, MSD and Roche-Genentech. AMG has no competing interest. BC Prometheus Pharmaceuticals: grant support and speakers bureau. MBF has no competing interests. SF has no competing interests. KF Consultant: Roche/Genentech, GlaxoSmithKline. BAF has no competing interests. TG consultant for GSK-Bio, Incyte, BMS, Roche-Genentech, and Eisai. JEG has no competing interest. HG has an Advisor role in MSD compensated. KG has participated on Advisory Board for BMS, and has received honoraria from BMS. AH consultancies, paid presentations or financial trial support from: BMS, Boehringer Ingelheim, Celgene, Eisai, GSK, IGEA, MSD, Novartis, Roche-Genentech. SH has served as a nonpaid consultant to BMS and Genentech, and received clinical trial support from BMS and Genentech. RK Institutional reimbursement for Advisory Boards and conference travel from GSK and Roche. JMK is a consultant to GSKbio, and has participated in advisory boards for Novartis, Merck, and GSK. SL serves on an Advisory Board for Myriad Genetics Laboratories. MM Advisory Boards from BMS, Roche and GSK. RM receives research support from Novartis, and has consulted for Roche. He is eligible to income from drugs that are commercialized by the Institute of Cancer Research through the "Rewards to Inventors Scheme". DLM has no competing interest. GP has no competing interest. AR participated to Advisory Board from Amgen, Bristol Myers Squibb, Celgene, Roche-Genentech, GSK, Merck, Millennium, Novartis and Prometheus and received honoraria from these companies. DFS is a co-inventor on a patent related to the growth of TIL in gas permeable flasks. RS has no competing interest. EW has no competing interest. NM has no competing interest. FMM has no competing interest. NR 40 TC 6 Z9 7 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAY 2 PY 2012 VL 10 AR 83 DI 10.1186/1479-5876-10-83 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 968IR UT WOS:000305972700001 PM 22551296 ER PT J AU Nishiyama, A Dey, A Tamura, T Ko, M Ozato, K AF Nishiyama, Akira Dey, Anup Tamura, Tomohiko Ko, Minoru Ozato, Keiko TI Activation of JNK Triggers Release of Brd4 from Mitotic Chromosomes and Mediates Protection from Drug-Induced Mitotic Stress SO PLOS ONE LA English DT Article ID N-TERMINAL KINASE; BROMODOMAIN PROTEIN BRD4; CELL-DEATH; TRANSCRIPTION FACTOR; HISTONE H3; S-PHASE; P-TEFB; MITOSIS; PHOSPHORYLATION; PROGRESSION AB Some anti-cancer drugs, including those that alter microtubule dynamics target mitotic cells and induce apoptosis in some cell types. However, such drugs elicit protective responses in other cell types allowing cells to escape from drug-induced mitotic inhibition. Cells with a faulty protective mechanism undergo defective mitosis, leading to genome instability. Brd4 is a double bromodomain protein that remains on chromosomes during mitosis. However, Brd4 is released from mitotic chromosomes when cells are exposed to anti-mitotic drugs including nocodazole. Neither the mechanisms, nor the biological significance of drug-induced Brd4 release has been fully understood. We found that deletion of the internal C-terminal region abolished nocodazole induced Brd4 release from mouse P19 cells. Furthermore, cells expressing truncated Brd4, unable to dissociate from chromosomes were blocked from mitotic progression and failed to complete cell division. We also found that pharmacological and peptide inhibitors of the c-jun-N-terminal kinases (JNK) pathway, but not inhibitors of other MAP kinases, prevented release of Brd4 from chromosomes. The JNK inhibitor that blocked Brd4 release also blocked mitotic progression. Further supporting the role of JNK in Brd4 release, JNK2-/- embryonic fibroblasts were defective in Brd4 release and sustained greater inhibition of cell growth after nocodazole treatment. In sum, activation of JNK pathway triggers release of Brd4 from chromosomes upon nocodazole treatment, which mediates a protective response designed to minimize drug-induced mitotic stress. C1 [Nishiyama, Akira; Dey, Anup; Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Nishiyama, Akira; Tamura, Tomohiko] Yokohama City Univ, Dept Immunol, Grad Sch Med, Kanazawa Ku, Yokohama, Kanagawa 232, Japan. [Nishiyama, Akira; Ko, Minoru] NIA, Sect Dev Genom & Aging, NIH, Baltimore, MD 21224 USA. RP Nishiyama, A (reprint author), NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Program of National Institute of Child Health and Human Development, 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 59 TC 2 Z9 3 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 2 PY 2012 VL 7 IS 5 AR e34719 DI 10.1371/journal.pone.0034719 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959US UT WOS:000305341500006 PM 22567088 ER PT J AU Kandpal, RP Rajasimha, HK Brooks, MJ Nellissery, J Wan, J Qian, J Kern, TS Swaroop, A AF Kandpal, Raj P. Rajasimha, Harsha K. Brooks, Matthew J. Nellissery, Jacob Wan, Jun Qian, Jiang Kern, Timothy S. Swaroop, Anand TI Transcriptome analysis using next generation sequencing reveals molecular signatures of diabetic retinopathy and efficacy of candidate drugs SO MOLECULAR VISION LA English DT Article ID DEVELOPING MOUSE RETINA; GENE-EXPRESSION; ALPHA-CRYSTALLIN; RNA-SEQ; DISEASE; INFLAMMATION; ACTIVATION; MICROARRAY; GLYCATION; ANTIOXIDANTS AB Purpose: To define gene expression changes associated with diabetic retinopathy in a mouse model using next generation sequencing, and to utilize transcriptome signatures to assess molecular pathways by which pharmacological agents inhibit diabetic retinopathy. Methods: We applied a high throughput RNA sequencing (RNA-seq) strategy using Illumina GAIIx to characterize the entire retinal transcriptome from nondiabetic and from streptozotocin-treated mice 32 weeks after induction of diabetes. Some of the diabetic mice were treated with inhibitors of receptor for advanced glycation endproducts (RAGE) and p38 mitogen activated protein (MAP) kinase, which have previously been shown to inhibit diabetic retinopathy in rodent models. The transcripts and alternatively spliced variants were determined in all experimental groups. Results: Next generation sequencing-based RNA-seq profiles provided comprehensive signatures of transcripts that are altered in early stages of diabetic retinopathy. These transcripts encoded proteins involved in distinct yet physiologically relevant disease-associated pathways such as inflammation, microvasculature formation, apoptosis, glucose metabolism, Wnt signaling, xenobiotic metabolism, and photoreceptor biology. Significant upregulation of crystallin transcripts was observed in diabetic animals, and the diabetes-induced upregulation of these transcripts was inhibited in diabetic animals treated with inhibitors of either RAGE or p38 MAP kinase. These two therapies also showed dissimilar regulation of some subsets of transcripts that included alternatively spliced versions of arrestin, neutral sphingomyelinase activation associated factor (Nsmaf), SH3-domain GRB2-like interacting protein 1 (Sgip1), and axin. Conclusions: Diabetes alters many transcripts in the retina, and two therapies that inhibit the vascular pathology similarly inhibit a portion of these changes, pointing to possible molecular mechanisms for their beneficial effects. These therapies also changed the abundance of various alternatively spliced versions of signaling transcripts, suggesting a possible role of alternative splicing in disease etiology. Our studies clearly demonstrate RNA-seq as a comprehensive strategy for identifying disease-specific transcripts, and for determining comparative profiles of molecular changes mediated by candidate drugs. C1 [Kandpal, Raj P.] Western Univ Hlth Sci, Dept Basic Med Sci, Pomona, CA 91766 USA. [Kandpal, Raj P.] Western Univ Hlth Sci, Western Diabet Inst, Pomona, CA 91766 USA. [Kandpal, Raj P.; Rajasimha, Harsha K.; Brooks, Matthew J.; Nellissery, Jacob; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Wan, Jun; Qian, Jiang] Johns Hopkins Sch Med, Dept Ophthalmol, Baltimore, MD USA. [Kern, Timothy S.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. [Kern, Timothy S.] Stokes Vet Adm Hosp, Cleveland, OH USA. [Kern, Timothy S.] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA. [Kern, Timothy S.] Case Western Reserve Univ, Sch Med, Dept Ophthalmol, Cleveland, OH 44106 USA. RP Kandpal, RP (reprint author), Western Univ Hlth Sci, Dept Basic Med Sci, 309 E 2nd St, Pomona, CA 91766 USA. EM rkandpal@westernu.edu RI Wan, Jun/H-7132-2013; Wan, Jun/A-2177-2014; OI Wan, Jun/0000-0001-9286-6562; Wan, Jun/0000-0001-9286-6562; Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute IPA; OneSight Foundation; NEI; Medical Research Service of the Department of Veteran Affairs; [NIH-EY00300] FX This work was supported by National Eye Institute IPA and OneSight Foundation (R. P. K.), NEI intramural program (A. S.), and NIH-EY00300 and the Medical Research Service of the Department of Veteran Affairs (T. S. K.). The drugs were donated by Galactica Pharmaceutical Inc., and Pfizer Research Laboratories. NR 61 TC 18 Z9 19 U1 0 U2 9 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAY 2 PY 2012 VL 18 IS 119-20 BP 1123 EP 1146 PG 24 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 947NA UT WOS:000304435500001 PM 22605924 ER PT J AU Gurnev, PA Queralt-Martin, M Aguilella, VM Rostovtseva, TK Bezrukov, SM AF Gurnev, Philip A. Queralt-Martin, Maria Aguilella, Vicente M. Rostovtseva, Tatiana K. Bezrukov, Sergey M. TI Probing Tubulin-Blocked State of VDAC by Varying Membrane Surface Charge SO BIOPHYSICAL JOURNAL LA English DT Article ID DEPENDENT ANION CHANNEL; OUTER MITOCHONDRIAL-MEMBRANE; ALPHA-BETA-TUBULIN; ION CHANNEL; VOLTAGE; CONDUCTANCE; PROTEIN; RESPIRATION; INHIBITION; RESOLUTION AB Reversible blockage of the voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane by dimeric tubulin is being recognized as a potent regulator of mitochondrial respiration. The tubulin-blocked state of VDAC is impermeant for ATP but only partially closed for small ions. This residual conductance allows studying the nature of the tubulin-blocked state in single-channel reconstitution experiments. Here we probe this state by changing lipid bilayer charge from positive to neutral to negative. We find that voltage sensitivity of the tubulin-VDAC blockage practically does not depend on the lipid charge and salt concentration with the effective gating charge staying within the range of 10-14 elementary charges. At physiologically relevant low salt concentrations, the conductance of the tubulin-blocked state is decreased by positive and increased by negative charge of the lipids, whereas the conductance of the open channel is much less sensitive to this parameter. Such a behavior supports the model in which tubulin's negatively charged tail enters the VDAC pore, inverting its anionic selectivity to cationic and increasing proximity of ion pathways to the nearest lipid charges as compared with the open state of the channel. C1 [Gurnev, Philip A.; Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Queralt-Martin, Maria; Aguilella, Vicente M.] Univ Jaume 1, Dept Fis, Castellon de La Plana, Spain. RP Rostovtseva, TK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM rostovtt@mail.nih.gov RI Aguilella, Vicente/B-7592-2008; Queralt-Martin, Maria/I-8214-2015 OI Aguilella, Vicente/0000-0002-2420-2649; Queralt-Martin, Maria/0000-0002-0644-6746 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Spanish Ministry of Science and Innovation [FIS2010-19810]; Fundacio Caixa Castello-Bancaixa [P1-1A2009-13]; European Molecular Biology Organization [ASTF 274.00-2010] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and by the Spanish Ministry of Science and Innovation (grant No. FIS2010-19810) and Fundacio Caixa Castello-Bancaixa (grant No. P1-1A2009-13). M. Q. M. acknowledges support from the European Molecular Biology Organization (grant No. ASTF 274.00-2010). NR 41 TC 10 Z9 10 U1 1 U2 6 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 MAY 2 PY 2012 VL 102 IS 9 BP 2070 EP 2076 DI 10.1016/j.bpj.2012.03.058 PG 7 WC Biophysics SC Biophysics GA 935US UT WOS:000303547700008 PM 22824270 ER PT J AU Price, NL Gomes, AP Ling, AJY Duarte, FV Martin-Montalvo, A North, BJ Agarwal, B Ye, L Ramadori, G Teodoro, JS Hubbard, BP Varela, AT Davis, JG Varamini, B Hafner, A Moaddel, R Rolo, AP Coppari, R Palmeira, CM de Cabo, R Baur, JA Sinclair, DA AF Price, Nathan L. Gomes, Ana P. Ling, Alvin J. Y. Duarte, Filipe V. Martin-Montalvo, Alejandro North, Brian J. Agarwal, Beamon Ye, Lan Ramadori, Giorgio Teodoro, Joao S. Hubbard, Basil P. Varela, Ana T. Davis, James G. Varamini, Behzad Hafner, Angela Moaddel, Ruin Rolo, Anabela P. Coppari, Roberto Palmeira, Carlos M. de Cabo, Rafael Baur, Joseph A. Sinclair, David A. TI SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function SO CELL METABOLISM LA English DT Article ID HIGH-FAT DIET; PROTEIN-KINASE ACTIVATION; SMALL-MOLECULE ACTIVATORS; CALORIE RESTRICTION; SKELETAL-MUSCLE; ENDOTHELIAL-CELLS; GENE-EXPRESSION; LIFE-SPAN; INSULIN SENSITIVITY; ENERGY-EXPENDITURE AB Resveratrol induces mitochondrial biogenesis and protects against metabolic decline, but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of germline SIRT1 knockouts, we have developed an inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD(+) levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. A mouse overexpressing SIRT1 mimicked these effects. A high dose of resveratrol activated AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Importantly, at both doses of resveratrol no improvements in mitochondrial function were observed in animals lacking SIRT1. Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo. C1 [Price, Nathan L.; Gomes, Ana P.; Ling, Alvin J. Y.; North, Brian J.; Hubbard, Basil P.; Hafner, Angela; Sinclair, David A.] Harvard Univ, Sch Med, Glenn Labs Biol Mech Aging, Boston, MA 02115 USA. [Gomes, Ana P.; Duarte, Filipe V.; Teodoro, Joao S.; Varela, Ana T.; Rolo, Anabela P.; Palmeira, Carlos M.] Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal. [Martin-Montalvo, Alejandro; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Moaddel, Ruin] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Agarwal, Beamon; Ye, Lan; Davis, James G.; Varamini, Behzad; Baur, Joseph A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ramadori, Giorgio; Coppari, Roberto] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hypothalam Res, Dallas, TX 75390 USA. [Rolo, Anabela P.] Univ Aveiro, Dept Biol, P-3810193 Aveiro, Portugal. [Coppari, Roberto] Univ Politecn Marche, Dipartimento Med Sperimentale & Clin, I-60020 Ancona, Italy. [Palmeira, Carlos M.] Univ Coimbra, Fac Sci & Technol, Dept Life Sci, P-3004517 Coimbra, Portugal. [Sinclair, David A.] Univ New S Wales, Lowy Canc Res Ctr, Dept Pharmacol, Sydney, NSW 2052, Australia. RP Sinclair, DA (reprint author), Harvard Univ, Sch Med, Glenn Labs Biol Mech Aging, Boston, MA 02115 USA. EM david_sinclair@hms.harvard.edu RI Rolo, Anabela/D-6062-2011; Valente Duarte, Flipe/M-7714-2013; Coppari, Roberto/B-4799-2014; Palmeira, Carlos/L-3390-2014; Teodoro, Joao/F-5432-2011; Varela, Ana /L-4306-2014; de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI Sinclair, David/0000-0002-9936-436X; , rafael/0000-0003-2830-5693; Rolo, Anabela/0000-0003-3535-9630; Valente Duarte, Flipe/0000-0003-0287-0328; Palmeira, Carlos/0000-0002-2639-7697; Teodoro, Joao/0000-0002-1244-275X; Varela, Ana /0000-0003-3599-1660; de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Varamini, Behzad/0000-0001-8076-6628; Baur, Joseph/0000-0001-8262-6549 FU National Center for Research Resources; National Institutes of Health (NIH) [R01AG028730, DK080836]; NIH/NIA; Glenn Foundation for Medical Research; Ellison Medical Foundation; NSERC; Portuguese Foundation for Science and Technology [SFRH/BD/44674/2008]; American Heart Association FX This project was supported by the National Center for Research Resources and the new funding component of the National Institutes of Health (NIH) through grant number R01AG028730. D.A.S. was supported by grants from the NIH/NIA. The Sinclair lab is grateful to the Glenn Foundation for Medical Research and the Ellison Medical Foundation for funding support. B.J.N. was supported by an NIH/NIA training grant. B.P.H. was supported by an NSERC PGS-D. A.P.G. is the recipient of an individual fellowship from the Portuguese Foundation for Science and Technology (SFRH/BD/44674/2008). J.A.B. was supported by a Pathway to Independence Award from NIA/NIH and a New Scholar Award from the Ellison Medical Foundation. R.d.C. was supported by grants from the American Heart Association (Scientist Development Grant) and the National Institutes of Health (DK080836). We would like to thank Chen Yan, Maria Elena Correa, Andrew Le, Mitesh Sanghvi, and Anuradha Ramamoorthy for their assistance on this project; Pere Puigserver and Zachary Gerhart-Hines for providing PGC1 alpha and SIRT1 adenoviral vectors; Mengwei Zang and Jason Dyck for providing the LKB1 adenoviral vector; and Eric Brown for kindly providing ERT2 mice. D.A.S. is a consultant to Cohbar and Ovascience, and consultant and inventor on patents licensed to Signs, a GlaxoSmithKline company developing drugs based on sirtuin modulation. NR 103 TC 407 Z9 418 U1 16 U2 127 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAY 2 PY 2012 VL 15 IS 5 BP 675 EP 690 DI 10.1016/j.cmet.2012.04.003 PG 16 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 937WL UT WOS:000303694100016 PM 22560220 ER PT J AU Califf, RM Zarin, DA Kramer, JM Sherman, RE Aberle, LH Tasneem, A AF Califf, Robert M. Zarin, Deborah A. Kramer, Judith M. Sherman, Rachel E. Aberle, Laura H. Tasneem, Asba TI Characteristics of Clinical Trials Registered in ClinicalTrials.gov, 2007-2010 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; MEDICAL-JOURNAL-EDITORS; INTERNATIONAL-COMMITTEE; RESEARCH ENTERPRISE; PRACTICE GUIDELINES; REGISTRATION; STATEMENT; RECOMMENDATIONS; GLOBALIZATION; QUALITY AB Context Recent reports highlight gaps between guidelines-based treatment recommendations and evidence from clinical trials that supports those recommendations. Strengthened reporting requirements for studies registered with ClinicalTrials.gov enable a comprehensive evaluation of the national trials portfolio. Objective To examine fundamental characteristics of interventional clinical trials registered in the ClinicalTrials.gov database. Methods A data set comprising 96 346 clinical studies from ClinicalTrials.gov was downloaded on September 27, 2010, and entered into a relational database to analyze aggregate data. Interventional trials were identified and analyses were focused on 3 clinical specialties-cardiovascular, mental health, and oncology-that together encompass the largest number of disability-adjusted life-years lost in the United States. Main Outcome Measures Characteristics of registered clinical trials as reported data elements in the trial registry; how those characteristics have changed over time; differences in characteristics as a function of clinical specialty; and factors associated with use of randomization, blinding, and data monitoring committees (DMCs). Results The number of registered interventional clinical trials increased from 28 881(October 2004-September 2007) to 40 970 (October 2007-September 2010), and the number of missing data elements has generally declined. Most interventional trials registered between 2007 and 2010 were small, with 62% enrolling 100 or fewer participants. Many clinical trials were single-center (66%; 24 788/37 520) and funded by organizations other than industry or the National Institutes of Health (NIH) (47%; 17 592/37 520). Heterogeneity in the reported methods by clinical specialty; sponsor type; and the reported use of DMCs, randomization, and blinding was evident. For example, reported use of DMCs was less common in industry-sponsored vs NIH-sponsored trials (adjusted odds ratio [OR], 0.11; 95% CI, 0.09-0.14), earlier-phase vs phase 3 trials (adjusted OR, 0.83; 95% CI, 0.76-0.91), and mental health trials vs those in the other 2 specialties. In similar comparisons, randomization and blinding were less frequently reported in earlier-phase, oncology, and device trials. Conclusion Clinical trials registered in ClinicalTrials.gov are dominated by small trials and contain significant heterogeneity in methodological approaches, including reported use of randomization, blinding, and DMCs. JAMA. 2012;307(17):1838-1847 www.jama.com C1 [Califf, Robert M.; Kramer, Judith M.] Duke Translat Med Inst, Durham, NC 27710 USA. [Zarin, Deborah A.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Sherman, Rachel E.] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Kramer, Judith M.; Aberle, Laura H.; Tasneem, Asba] Duke Clin Res Inst, Durham, NC USA. RP Califf, RM (reprint author), Duke Translat Med Inst, 200 Trent Dr,1117 Davison Bldg, Durham, NC 27710 USA. EM robert.califf@duke.edu FU Amylin; Johnson & Johnson (Scios); Merck; Novartis Pharma; Schering Plough; Bristol-Myers Squibb Foundation; Aterovax; Bayer; Roche; Lilly; Kowa Research Institute; Nile; Parkview; Orexigen Therapeutics; Pozen; Servier International; WebMD; AstraZeneca; Bayer-OrthoMcNeil; BMS; Boerhinger Ingelheim; Daiichi Sankyo; GlaxoSmithKline; Li Ka Shing Knowledge Institute; Medtronic; Novartis; sanofi-aventis; XOMA; University of Florida; Duke Clinical Research Institute; CTTI; Pfizer; US Food and Drug Administration [U19FD003800] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Califf reports receiving research grants that partially support his salary from Amylin, Johnson & Johnson (Scios), Merck, Novartis Pharma, Schering Plough, Bristol-Myers Squibb Foundation, Aterovax, Bayer, Roche, and Lilly; all grants are paid to Duke University. Dr Califf also consults for TheHeart.org, Johnson & Johnson (Scios), Kowa Research Institute, Nile, Parkview, Orexigen Therapeutics, Pozen, Servier International, WebMD, Bristol-Myers Squibb Foundation, AstraZeneca, Bayer-OrthoMcNeil, BMS, Boerhinger Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Li Ka Shing Knowledge Institute, Medtronic, Merck, Novartis, sanofi-aventis, XOMA, and University of Florida; all income from these consultancies is donated to nonprofit organizations, with the majority going to the clinical research fellowship fund of the Duke Clinical Research Institute. Dr Califf holds equity in Nitrox LLC. Dr Kramer is the executive director of the Clinical Trials Transformation Institute (CTTI), a public-private partnership. A portion of Dr Kramer's salary is supported by pooled funds from CTTI members (https://www.ctticlinicaltrials.org/about/membership). Dr Kramer reports receiving a research grant from Pfizer that supports a small percentage of her salary; this grant is paid to Duke University. Dr Kramer also served on an advisory board for the "Pharmacovigilance Center of Excellence" at GlaxoSmithKline, for which she received an honorarium. Financial disclosure information for Drs Califf and Kramer is also publicly available at https://www.dcri.org/about-us/conflict-of-interest. No other disclosures were reported.; Financial support for this project was provided by grant U19FD003800 from the US Food and Drug Administration awarded to Duke University for the Clinical Trials Transformation Initiative. NR 33 TC 141 Z9 142 U1 2 U2 24 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 2 PY 2012 VL 307 IS 17 BP 1838 EP 1847 DI 10.1001/jama.2012.3424 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 933TV UT WOS:000303386800023 PM 22550198 ER PT J AU Gore, AV Monzo, K Cha, YR Pan, WJ Weinstein, BM AF Gore, Aniket V. Monzo, Kathryn Cha, Young R. Pan, Weijun Weinstein, Brant M. TI Vascular Development in the Zebrafish SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID ENDOTHELIAL-GROWTH-FACTOR; INHIBITS SPROUTING ANGIOGENESIS; ARTERIAL-VENOUS DIFFERENTIATION; BLOOD-VESSEL FORMATION; LUMEN FORMATION; TUBE FORMATION; IN-VIVO; LYMPHATIC VASCULATURE; CELL MIGRATION; VE-CADHERIN AB The zebrafish has emerged as an excellent vertebrate model system for studying blood and lymphatic vascular development. The small size, external and rapid development, and optical transparency of zebrafish embryos are some of the advantages the zebrafish model system offers. Multiple well-established techniques have been developed for imaging and functionally manipulating vascular tissues in zebrafish embryos, expanding on and amplifying these basic advantages and accelerating use of this model system for studying vascular development. In the past decade, studies performed using zebrafish as a model system have provided many novel insights into vascular development. In this article we discuss the amenability of this model system for studying blood vessel development and review contributions made by this system to our understanding of vascular development. C1 [Gore, Aniket V.; Monzo, Kathryn; Cha, Young R.; Pan, Weijun; Weinstein, Brant M.] NICHD, Program Genom Differentiat, Mol Genet Lab, Sect Vertebrate Organogenesis,NIH, Bethesda, MD 20892 USA. RP Gore, AV (reprint author), NICHD, Program Genom Differentiat, Mol Genet Lab, Sect Vertebrate Organogenesis,NIH, Bethesda, MD 20892 USA. EM flyingfish2@nih.gov FU NICHD, NIH; Leducq Foundation FX We thank members of the Weinstein lab for comments, advice, and suggestions. This work was supported by the intramural program of the NICHD, NIH, and by the Leducq Foundation. NR 128 TC 49 Z9 49 U1 1 U2 21 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD MAY PY 2012 VL 2 IS 5 AR a006684 DI 10.1101/cshperspect.a006684 PG 21 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080XO UT WOS:000314277700007 PM 22553495 ER PT J AU Kawel, N Nacif, M Arai, AE Gomes, AS Hundley, WG Johnson, WC Prince, MR Stacey, RB Lima, JAC Bluemke, DA AF Kawel, Nadine Nacif, Marcelo Arai, Andrew E. Gomes, Antoinette S. Hundley, W. Gregory Johnson, W. Craig Prince, Martin R. Stacey, R. Brandon Lima, Joao A. C. Bluemke, David A. TI Trabeculated (Noncompacted) and Compact Myocardium in Adults The Multi-Ethnic Study of Atherosclerosis SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE cardiomyopathy; cardiovascular MRI; noncompaction; trabeculation ID VENTRICULAR NON-COMPACTION; DIAGNOSIS; VOLUME; MASS AB Background-A high degree of noncompacted (trabeculated) myocardium in relationship to compact myocardium (trabeculated to compact myocardium [T/M] ratio >2.3) has been associated with a diagnosis of left ventricular noncompaction (LVNC). The purpose of this study was to determine the normal range of the T/M ratio in a large population-based study and to examine the relationship to demographic and clinical parameters. Methods and Results-The thickness of trabeculation and the compact myocardium were measured in 8 left ventricular regions on long axis cardiac MR steady-state free precession cine images in 1000 participants (551 women; 68.1 +/- 8.9 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Of 323 participants without cardiac disease or hypertension and with all regions evaluable, 140 (43%) had a T/M ratio >2.3 in at least 1 region; in 20 of 323 (6%), T/M >2.3 was present in >2 regions. A multivariable linear regression model revealed no association of age, sex, ethnicity, height, and weight with maximum T/M ratio in participants without cardiac disease or hypertension (P > 0.05). In the entire cohort (n = 1000), left ventricular ejection fraction (beta = -0.02/%; P = 0.015), left ventricular end-diastolic volume (beta = 0.01/mL; P < 0.0001), and left ventricular end-systolic volume (beta = 0.01/mL; P < 0.001) were associated with maximum T/M ratio in adjusted models, whereas there was no association with hypertension or myocardial infarction (P > 0.05). At the apical level, T/M ratios were significantly lower when obtained on short-compared with long-axis images (P = 0.017). Conclusions-A ratio of T/M of >2.3 is common in a large population-based cohort. These results suggest re-evaluation of the current cardiac MR criteria for left ventricular noncompaction may be necessary. (Circ Cardiovasc Imaging. 2012;5:357-366.) C1 [Kawel, Nadine; Nacif, Marcelo; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Gomes, Antoinette S.] Univ Calif Los Angeles, Sch Med, Dept Radiol, Los Angeles, CA 90024 USA. [Hundley, W. Gregory; Stacey, R. Brandon] Wake Forest Univ, Dept Internal Med Cardiol, Winston Salem, NC 27109 USA. [Johnson, W. Craig] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Prince, Martin R.] Cornell Univ, New York, NY 10021 USA. [Prince, Martin R.] Columbia Univ, New York, NY USA. [Lima, Joao A. C.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. RP Bluemke, DA (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, 10 Ctr Dr,Room 10-1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI Prince, Martin/S-6850-2016; OI Bluemke, David/0000-0002-8323-8086; Prince, Martin/0000-0002-9883-0584 FU National Institutes of Health; National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169]; US Government Cooperative Research and Development Award; Siemens; Bayer FX This research was supported by the intramural research program of the National Institutes of Health and contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute.; Dr Arai has a US Government Cooperative Research and Development Award with Siemens. Dr Prince has patent agreements with General Electric, Siemens, Philips, Toshiba, and Hitachi and received payment for speakers' bureau appointments from Bayer. NR 12 TC 39 Z9 40 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAY PY 2012 VL 5 IS 3 BP 357 EP 366 DI 10.1161/CIRCIMAGING.111.971713 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 071FG UT WOS:000313572500014 PM 22499849 ER PT J AU Buxton, DB AF Buxton, Denis B. TI Molecular Imaging of Aortic Aneurysms SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE aneurysm; aorta; imaging ID MATRIX METALLOPROTEINASES; INTRALUMINAL THROMBUS; GROWTH-RATE; INFLAMMATION; WALL; MANAGEMENT; DISEASE; AGENT; AAA C1 NHLBI, Div Cardiovasc Sci, Bethesda, MD 20817 USA. RP Buxton, DB (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr, Bethesda, MD 20817 USA. EM db225a@nih.gov OI Buxton, Denis/0000-0003-3077-6435 FU Intramural NIH HHS [Z99 HL999999] NR 46 TC 5 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAY PY 2012 VL 5 IS 3 BP 392 EP 399 DI 10.1161/CIRCIMAGING.112.973727 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 071FG UT WOS:000313572500018 PM 22592009 ER PT J AU David, SP Hamidovic, A Chen, GK Bergen, AW Wessel, J Kasberger, JL Brown, WM Petruzella, S Thacker, EL Kim, Y Nalls, MA Tranah, GJ Sung, YJ Ambrosone, CB Arnett, D Bandera, EV Becker, DM Becker, L Berndt, SI Bernstein, L Blot, WJ Broeckel, U Buxbaum, SG Caporaso, N Casey, G Chanock, SJ Deming, SL Diver, WR Eaton, CB Evans, DS Evans, MK Fornage, M Franceschini, N Harris, TB Henderson, BE Hernandez, DG Hitsman, B Hu, JJ Hunt, SC Ingles, SA John, EM Kittles, R Kolb, S Kolonel, LN Le Marchand, L Liu, Y Lohman, KK McKnight, B Millikan, RC Murphy, A Neslund-Dudas, C Nyante, S Press, M Psaty, BM Rao, DC Redline, S Rodriguez-Gil, JL Rybicki, BA Signorello, LB Singleton, AB Smoller, J Snively, B Spring, B Stanford, JL Strom, SS Swan, GE Taylor, KD Thun, MJ Wilson, AF Witte, JS Yamamura, Y Yanek, LR Yu, K Zheng, W Ziegler, RG Zonderman, AB Jorgenson, E Haiman, CA Furberg, H AF David, S. P. Hamidovic, A. Chen, G. K. Bergen, A. W. Wessel, J. Kasberger, J. L. Brown, W. M. Petruzella, S. Thacker, E. L. Kim, Y. Nalls, M. A. Tranah, G. J. Sung, Y. J. Ambrosone, C. B. Arnett, D. Bandera, E. V. Becker, D. M. Becker, L. Berndt, S. I. Bernstein, L. Blot, W. J. Broeckel, U. Buxbaum, S. G. Caporaso, N. Casey, G. Chanock, S. J. Deming, S. L. Diver, W. R. Eaton, C. B. Evans, D. S. Evans, M. K. Fornage, M. Franceschini, N. Harris, T. B. Henderson, B. E. Hernandez, D. G. Hitsman, B. Hu, J. J. Hunt, S. C. Ingles, S. A. John, E. M. Kittles, R. Kolb, S. Kolonel, L. N. Le Marchand, L. Liu, Y. Lohman, K. K. McKnight, B. Millikan, R. C. Murphy, A. Neslund-Dudas, C. Nyante, S. Press, M. Psaty, B. M. Rao, D. C. Redline, S. Rodriguez-Gil, J. L. Rybicki, B. A. Signorello, L. B. Singleton, A. B. Smoller, J. Snively, B. Spring, B. Stanford, J. L. Strom, S. S. Swan, G. E. Taylor, K. D. Thun, M. J. Wilson, A. F. Witte, J. S. Yamamura, Y. Yanek, L. R. Yu, K. Zheng, W. Ziegler, R. G. Zonderman, A. B. Jorgenson, E. Haiman, C. A. Furberg, H. TI Genome-wide meta-analyses of smoking behaviors in African Americans SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE African American; genome-wide association; health disparities; nicotine; smoking; tobacco ID HAPLOTYPE-PHASE INFERENCE; NICOTINE DEPENDENCE; LUNG-CANCER; GENOTYPE IMPUTATION; BRONCHOPULMONARY DYSPLASIA; SUSCEPTIBILITY LOCUS; EUROPEAN-AMERICANS; RACIAL-DIFFERENCES; CIGARETTE-SMOKING; TWIN REGISTRY AB The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32 389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (beta = 0.040, s.e. = 0.007, P = 1.84 x 10(-)8). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans. Translational Psychiatry (2012) 2, e119; doi:10.1038/tp.2012.41; published online 22 May 2012 C1 [David, S. P.] Stanford Univ, Sch Med, Div Gen Med Disciplines, Ctr Educ & Res Family & Community Med, Stanford, CA 93405 USA. [David, S. P.; Bergen, A. W.; Wessel, J.; Swan, G. E.] SRI Int, Policy Div, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [David, S. P.; Eaton, C. B.] Brown Alpert Med Sch, Ctr Primary Care & Prevent, Dept Family Med, Pawtucket, RI USA. [Hamidovic, A.; Hitsman, B.; Spring, B.] Northwestern Univ, Dept Preventat Med, Chicago, IL 60611 USA. [Chen, G. K.; Casey, G.; Henderson, B. E.; Ingles, S. A.; Press, M.; Haiman, C. A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Wessel, J.] Indiana Univ Sch Med, Div Epidemiol & Environm Hlth, Dept Publ Hlth, Indianapolis, IN USA. [Wessel, J.] Indiana Univ Sch Med, Div Cardiol, Dept Med, Indianapolis, IN USA. [Kasberger, J. L.; Jorgenson, E.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Dept Neurol, San Francisco, CA 94143 USA. [Brown, W. M.; Lohman, K. K.; Snively, B.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Petruzella, S.; Furberg, H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Thacker, E. L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kim, Y.; Wilson, A. F.] NHGRI, Genometr Sect, NIH, Baltimore, MD USA. [Nalls, M. A.; Hernandez, D. G.; Singleton, A. B.] NIA, Neurogenet Lab, NIH, Baltimore, MD 21224 USA. [Tranah, G. J.; Evans, D. S.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Sung, Y. J.; Rao, D. C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Ambrosone, C. B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Arnett, D.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Bandera, E. V.] Canc Inst New Jersey, New Brunswick, NJ USA. [Becker, D. M.; Becker, L.; Yanek, L. R.] Johns Hopkins Univ, Sch Med, Dept Med, Johns Hopkins GeneSTAR Res Program, Baltimore, MD 21205 USA. [Berndt, S. I.; Caporaso, N.; Chanock, S. J.; Yu, K.; Ziegler, R. G.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bernstein, L.] City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, Duarte, CA 91010 USA. [Blot, W. J.; Signorello, L. B.] Int Epidemiol Inst, Rockville, MD USA. [Blot, W. J.; Deming, S. L.; Zheng, W.] Vanderbilt Univ, Dept Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Blot, W. J.; Deming, S. L.; Zheng, W.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Broeckel, U.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Buxbaum, S. G.] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. [Diver, W. R.; Thun, M. J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Evans, M. K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Fornage, M.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Brown Fdn Inst Mol Med, Div Epidemiol, Houston, TX USA. [Franceschini, N.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hu, J. J.; Rodriguez-Gil, J. L.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Hunt, S. C.] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [John, E. M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, E. M.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA USA. [Kittles, R.] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Dept Med, Chicago, IL USA. [Kolb, S.; Stanford, J. L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kolonel, L. N.; Le Marchand, L.] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Liu, Y.] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [McKnight, B.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Millikan, R. C.; Nyante, S.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Murphy, A.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Neslund-Dudas, C.; Rybicki, B. A.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Psaty, B. M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, B. M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, B. M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, B. M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Redline, S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Redline, S.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Smoller, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Ctr Human Genet Res, Boston, MA USA. [Strom, S. S.; Yamamura, Y.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Taylor, K. D.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Witte, J. S.] Univ Calif San Francisco, Inst Human Genet, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Witte, J. S.] Univ Calif San Francisco, Inst Human Genet, Dept Urol, San Francisco, CA 94143 USA. [Zonderman, A. B.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. RP David, SP (reprint author), Stanford Univ, Sch Med, Div Gen Med Disciplines, Ctr Educ & Res Family & Community Med, 1215 Welch Rd, Stanford, CA 93405 USA. EM spdavid@stanford.edu; ejorgenson@gallo.ucsf.edu; haiman@usc.edu RI Bandera, Elisa/M-4169-2014; Singleton, Andrew/C-3010-2009; Buxbaum, Sarah/E-1970-2013; OI Bandera, Elisa/0000-0002-8789-2755; Thacker, Evan/0000-0002-3813-0885; David, Sean/0000-0002-4922-2603; Buxbaum, Sarah/0000-0002-4886-3564; Bergen, Andrew/0000-0002-1237-7644; Wessel, Jennifer/0000-0002-7031-0085; Zonderman, Alan B/0000-0002-6523-4778 FU NCATS NIH HHS [UL1 TR000124, UL1 TR000150]; NCI NIH HHS [P30 CA015704, P50 CA058223, R01 CA092447]; NCRR NIH HHS [UL1 RR025741]; NHLBI NIH HHS [R01 HL105756]; NIDA NIH HHS [R21 DA027331, U01 DA020830]; NIEHS NIH HHS [P30 ES010126]; NIMHD NIH HHS [P20 MD006899]; WHI NIH HHS [N01 WH032108, N01 WH022110, N01 WH032105, N01 WH032109, N01 WH032111, N01 WH32115] NR 60 TC 35 Z9 36 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD MAY PY 2012 VL 2 AR e119 DI 10.1038/tp.2012.41 PG 8 WC Psychiatry SC Psychiatry GA 062CC UT WOS:000312895700012 PM 22832964 ER PT J AU Lowenthal, J Lipnick, S Rao, M Hull, SC AF Lowenthal, Justin Lipnick, Scott Rao, Mahendra Hull, Sara Chandros TI Specimen Collection for Induced Pluripotent Stem Cell Research: Harmonizing the Approach to Informed Consent SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Clinical translation; Ethics; iPS; Induced pluripotent stem cells ID HUMAN SOMATIC-CELLS; HUMAN CORD BLOOD; IPS CELLS; ALTERNATIVE SOURCES; BIOLOGICAL SAMPLES; ISSCR GUIDELINES; DEFINED FACTORS; GENE CORRECTION; COPY NUMBER; LINES AB Induced pluripotent stem cells (iPSCs) have elicited excitement in both the scientific and ethics communities for their potential to advance basic and translational research. They have been hailed as an alternative to derivation from embryos that provides a virtually unlimited source of pluripotent stem cells for research and therapeutic applications. However, research with iPSCs is ethically complex, uniquely encompassing the concerns associated with genomics, immortalized cell lines, transplantation, human reproduction, and biobanking. Prospective donation of tissue specimens for iPSC research thus requires an approach to informed consent that is constructed for this context. Even in the nascent stages of this field, approaches to informed consent have been variable in ways that threaten the simultaneous goals of protecting donors and safeguarding future research and translation, and investigators are seeking guidance. We address this need by providing concrete recommendations for informed consent that balance the perspectives of a variety of stakeholders. Our work combines analysis of consent form language collected from investigators worldwide with a conceptual balancing of normative ethical concerns, policy precedents, and scientific realities. Our framework asks people to consent prospectively to a broad umbrella of foreseeable research, including future therapeutic applications, with recontact possible in limited circumstances. We argue that the long-term goals of regenerative medicine, interest in sharing iPSC lines, and uncertain landscape of future research all would be served by a framework of ongoing communication with donors. Our approach balances the goals of iPSC and regenerative medicine researchers with the interests of individual research participants. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:409-421 C1 [Lowenthal, Justin; Hull, Sara Chandros] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Lipnick, Scott; Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Rao, Mahendra] NIAMSD, Lab Stem Cell Biol, NIH, Bethesda, MD 20892 USA. [Hull, Sara Chandros] NHGRI, NIH, Bethesda, MD 20892 USA. RP Hull, SC (reprint author), 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM shull@nih.gov RI Lowenthal, Justin/H-3728-2013; OI Lowenthal, Justin/0000-0001-5909-0520 FU NIH FX We gratefully acknowledge the investigators and administrators who generously shared their consent forms, templates, and guidance documents with us. We thank Samantha Finstad, Hans Hermans, and Mine Kimura for providing us with thorough English translations of the Dutch and Japanese consent forms. We are also grateful to Miriam Rosenbaum for her assistance at the inception of this project, and to the many people who provided helpful feedback on earlier drafts of the manuscript and consent template, including Benjamin Berkman, Barbara Karp, and members of the NIH Office of General Counsel, the NIH Hunian Subjects Research Advisory Committee, the NIH Clinical Center's Department of Bioethics, and the NIH hESC Administrative Review Committee. This research was supported by the Intramural Research Program of the NIH. NR 136 TC 23 Z9 23 U1 0 U2 26 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD MAY PY 2012 VL 1 IS 5 BP 409 EP 421 DI 10.5966/sctm.2012-0029 PG 13 WC Cell & Tissue Engineering SC Cell Biology GA 057OA UT WOS:000312571700007 PM 23197820 ER PT J AU Hastie, ML Headlam, MJ Patel, NB Bukreyev, AA Buchholz, UJ Dave, KA Norris, EL Wright, CL Spann, KM Collins, PL Gorman, JJ AF Hastie, Marcus L. Headlam, Madeleine J. Patel, Nirav B. Bukreyev, Alexander A. Buchholz, Ursula J. Dave, Keyur A. Norris, Emma L. Wright, Cassandra L. Spann, Kirsten M. Collins, Peter L. Gorman, Jeffrey J. TI The Human Respiratory Syncytial Virus Nonstructural Protein 1 Regulates Type I and Type II Interferon Pathways SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID TUMOR-NECROSIS-FACTOR; MANGANESE-SUPEROXIDE-DISMUTASE; NF-KAPPA-B; EPITHELIAL-CELLS; GENE-EXPRESSION; A549 CELLS; SIGNAL-TRANSDUCTION; VACCINE DEVELOPMENT; RSV INFECTION; NS2 PROTEIN AB Respiratory syncytial viruses encode a nonstructural protein (NS1) that interferes with type I and III interferon and other antiviral responses. Proteomic studies were conducted on human A549 type II alveolar epithelial cells and type I interferon-deficient Vero cells (African green monkey kidney cells) infected with wild-type and NS1-deficient clones of human respiratory syncytial virus to identify other potential pathway and molecular targets of NS1 interference. These analyses included two-dimensional differential gel electrophoresis and quantitative Western blotting. Surprisingly, NS1 was found to suppress the induction of manganese superoxide dismutase (SOD2) expression in A549 cells and to a much lesser degree Vero cells in response to infection. Because SOD2 is not directly inducible by type I interferons, it served as a marker to probe the impact of NS1 on signaling of other cytokines known to induce SOD2 expression and/or indirect effects of type I interferon signaling. Deductive analysis of results obtained from cell infection and cytokine stimulation studies indicated that interferon-gamma signaling was a potential target of NS1, possibly as a result of modulation of STAT1 levels. However, this was not sufficient to explain the magnitude of the impact of NS1 on SOD2 induction in A549 cells. Vero cell infection experiments indicated that NS1 targeted a component of the type I interferon response that does not directly induce SOD2 expression but is required to induce another initiator of SOD2 expression. STAT2 was ruled out as a target of NS1 interference using quantitative Western blot analysis of infected A549 cells, but data were obtained to indicate that STAT1 was one of a number of potential targets of NS1. A label-free mass spectrometry-based quantitative approach is proposed as a means of more definitive identification of NS1 targets. Molecular & Cellular Proteomics 11: 10.1074/mcp.M111.015909, 108-127, 2012. C1 [Hastie, Marcus L.; Headlam, Madeleine J.; Patel, Nirav B.; Dave, Keyur A.; Norris, Emma L.; Wright, Cassandra L.; Gorman, Jeffrey J.] QIMR, Prot Discovery Ctr, Herston, Qld 4029, Australia. [Bukreyev, Alexander A.; Buchholz, Ursula J.; Collins, Peter L.] NIAID, Resp Virus Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Spann, Kirsten M.] Univ Queensland, Clin Med Virol Ctr, Herston, Qld 4029, Australia. [Spann, Kirsten M.] Royal Childrens Hosp, Sir Albert Sakzewski Virus Res Ctr, Herston, Qld 4029, Australia. RP Gorman, JJ (reprint author), QIMR, Prot Discovery Ctr, PO Royal Brisbane Hosp, Herston, Qld 4029, Australia. EM jeff.gorman@qimr.edu.au RI Spann, Kirsten/B-4524-2013; Dave, Keyur /L-2862-2016; Hastie, Marcus/L-4366-2016; OI Spann, Kirsten/0000-0003-0567-8382; Dave, Keyur /0000-0002-6476-8399; Hastie, Marcus/0000-0002-8386-5549; Headlam, Madeleine/0000-0001-6812-2459 FU National Health and Medical Research Council Australia; Brisbane Royal Children's Hospital Research Foundation; NIAID, National Institutes of Health Intramural Program; Australian Government National Collaborative Infrastructure Scheme provided via Bioplatforms Australia; Queensland State Government FX This work was supported by project grant funding from National Health and Medical Research Council Australia and the Brisbane Royal Children's Hospital Research Foundation. Preparation of infected cell lysates described in this work was funded by the NIAID, National Institutes of Health Intramural Program. Access to proteomic infrastructure funding was made possible through funds from the Australian Government National Collaborative Infrastructure Scheme provided via Bioplatforms Australia and the Queensland State Government. 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 84 TC 26 Z9 26 U1 2 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD MAY PY 2012 VL 11 IS 5 BP 108 EP 127 DI 10.1074/mcp.M111.015909 PG 20 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 974BS UT WOS:000306405400010 PM 22322095 ER PT J AU Pizzarelli, F Dattolo, P Tripepi, G Michelassi, S Rossi, C Bandinelli, S Mieth, M Mass, R Ferrucci, L Zoccali, C AF Pizzarelli, Francesco Dattolo, Pietro Tripepi, Giovanni Michelassi, Stefano Rossi, Cristina Bandinelli, Stefania Mieth, Maren Mass, Renke Ferrucci, Luigi Zoccali, Carmine TI EFFECT MODIFICATION BY ARGININE OF ADMA-RELATED LONG-TERM CLINICAL OUTCOMES IN AN ELDERLY GENERAL POPULATION SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Meeting Abstract CT 49th Congress of the European-Renal-Association/European-Dialysis-and-Transplant-Association (ERA-EDTA) CY MAY 24-27, 2012 CL Paris, FRANCE SP European Renal Assoc (ERA), European Dialysis & Transplant Assoc (EDTA) C1 [Pizzarelli, Francesco; Dattolo, Pietro; Michelassi, Stefano] SM Annunziata Hosp, Florence, Italy. [Tripepi, Giovanni; Zoccali, Carmine] Osped Riuniti Bergamo, Cnr Ibim, Reggio Di Calabria, Italy. [Tripepi, Giovanni; Zoccali, Carmine] Osped Riuniti Bergamo, Nephrol Transplant Unit, Reggio Di Calabria, Italy. [Rossi, Cristina; Bandinelli, Stefania] Geriatr Unit, Florence, Italy. [Rossi, Cristina; Bandinelli, Stefania] Inchianti Study, Florence, Italy. [Mieth, Maren; Mass, Renke] Univ Erlangen Nurnberg, Nurnberg, Bavaria, Germany. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 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 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD MAY PY 2012 VL 27 SU 2 BP 390 EP 391 PG 2 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 042TU UT WOS:000311494701290 ER PT J AU Gennuso, KP Thraen-Borowski, KM Matthews, CE Colbert, LH AF Gennuso, Keith P. Thraen-Borowski, Keith M. Matthews, Charles E. Colbert, Lisa H. TI Sedentary Behavior And Biomarkers Of Cardio-metabolic Risk By Level Of Physical Activity In Older Adults SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Gennuso, Keith P.; Thraen-Borowski, Keith M.; Colbert, Lisa H.] Univ Wisconsin, Madison, WI USA. [Matthews, Charles E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 213 EP 213 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363301227 ER PT J AU Lyden, K Kozey-Keadle, S Libertine, A Matthews, C Freedson, P AF Lyden, Kate Kozey-Keadle, Sarah Libertine, Amanda Matthews, Charles Freedson, Patty TI Associations Between Physical Activity And Sedentary Behavior In Active And Inactive Groups SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Lyden, Kate; Kozey-Keadle, Sarah; Libertine, Amanda; Freedson, Patty] Univ Massachusetts, Amherst, MA 01003 USA. [Matthews, Charles] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 215 EP 215 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363301232 ER PT J AU Barros, MP Lorenco-Lima, L Ganini, D Vardaris, CV Bechara, EJH Curi, R Souza, TP AF Barros, Marcelo P. Lorenco-Lima, Leandro Ganini, Douglas Vardaris, Cristina V. Bechara, Etelvino J. H. Curi, Rui Souza-Junior, Tacito P. TI Uric Acid Is A Key Antioxidant Against Iron-mediated Oxidative Stress In Resistance/power Exercise SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Barros, Marcelo P.; Lorenco-Lima, Leandro; Vardaris, Cristina V.] Univ Cruzeiro, Sao Paulo, SP, Brazil. [Ganini, Douglas] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Bechara, Etelvino J. H.] UNIFESP, Diadema, SP, Brazil. [Curi, Rui] Univ Sao Paulo, Sao Paulo, Brazil. [Souza-Junior, Tacito P.] Univ Fed Parana, BR-80060000 Curitiba, Parana, Brazil. RI Barros, Marcelo/K-1410-2013; Bechara, Etelvino/M-6251-2013 OI Barros, Marcelo/0000-0003-3565-8331; Bechara, Etelvino/0000-0001-9526-2529 NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 318 EP 318 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363302182 ER PT J AU So, RN Tsujimoto, T Eto, M Matsuo, T Sasai, H Tanaka, K AF So, Rina Tsujimoto, Takehiko Eto, Miki Matsuo, Tomoaki Sasai, Hiroyuki Tanaka, Kiyoji TI Influence Of Measurement Location Of Visceral Adiposity On Hdl Cholesterol In Obese Japanese Men SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [So, Rina; Tsujimoto, Takehiko; Eto, Miki; Matsuo, Tomoaki; Tanaka, Kiyoji] Univ Tsukuba, Tsukuba, Ibaraki, Japan. [Sasai, Hiroyuki] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 501 EP 501 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363303013 ER PT J AU Chin, LMK Keyser, RE Woolstenhulme, J Kennedy, M Drinkard, B Connors, G Nathan, SD Chan, L AF Chin, Lisa M. K. Keyser, Randall E. Woolstenhulme, Joshua Kennedy, Michelle Drinkard, Bart Connors, Gerilynn Nathan, Steven D. Chan, Leighton TI Severity of Exercise Intolerance and Functional Aerobic Impairment in Patients with Pulmonary Hypertension SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Chin, Lisa M. K.; Woolstenhulme, Joshua; Kennedy, Michelle; Drinkard, Bart; Chan, Leighton] NIH, Bethesda, MD 20892 USA. [Keyser, Randall E.] George Mason Univ, Fairfax, VA 22030 USA. [Connors, Gerilynn; Nathan, Steven D.] Inova Fairfax Hosp, Falls Church, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 600 EP 600 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363303355 ER PT J AU Woolstenhulme, JG Keyser, RE Drinkard, BE Chin, LS Kennedy, M Nathan, SD Connors, G Chan, L AF Woolstenhulme, Joshua G. Keyser, Randall E. Drinkard, Bart E. Chin, Lisa Kennedy, Michelle Nathan, Steven D. Connors, Gerilynn Chan, Leighton TI Effects of a 10-week Aerobic Exercise Program on Cardiorespiratory Function in Patients with Interstitial Lung Disease SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Woolstenhulme, Joshua G.; Drinkard, Bart E.; Chin, Lisa; Kennedy, Michelle; Chan, Leighton] NIH, Bethesda, MD 20892 USA. [Keyser, Randall E.] George Mason Univ, Fairfax, VA 22030 USA. [Nathan, Steven D.; Connors, Gerilynn] Inova Fairfax Hosp, Falls Church, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 601 EP 601 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363303357 ER PT J AU Perron, RM Brychta, RJ Chen, KY Prado, CMM Siervo, M Musse, L Hall, KD AF Perron, Rachel M. Brychta, Robert J. Chen, Kong Y. Prado, Carla M. M. Siervo, Mario Musse, Laura Hall, Kevin D. TI Energy Expenditure During and After Standard Exercise While on a Carbohydrate or Fat Restriction Diet SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Perron, Rachel M.; Brychta, Robert J.; Chen, Kong Y.; Prado, Carla M. M.; Siervo, Mario; Musse, Laura; Hall, Kevin D.] NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 607 EP 607 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363303379 ER PT J AU Matthews, CE Keadle, S Sampson, J Lyden, K Libertine, A Bowles, HR Freedson, PS Fowke, JH AF Matthews, Charles E. Keadle, Sarah Sampson, Joshua Lyden, Kate Libertine, Amanda Bowles, Heather R. Freedson, Patty S. Fowke, Jay H. TI Validation of a Previous Day Recall Measuring Time Spent in Physically Active and Sedentary Behaviors SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Matthews, Charles E.; Sampson, Joshua; Bowles, Heather R.] NCI, Bethesda, MD 20892 USA. [Keadle, Sarah; Lyden, Kate; Libertine, Amanda; Freedson, Patty S.] Univ Massachusetts, Amherst, MA 01003 USA. [Fowke, Jay H.] Vanderbilt Univ, Nashville, TN USA. NR 0 TC 1 Z9 1 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 642 EP 642 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363303498 ER PT J AU Glancy, B Hsu, LY Dao, L Bakalar, M French, S Chess, DJ Taylor, JL Daniels, MP Esfahani, S Balaban, RS AF Glancy, Brian Hsu, Li-Yueh Dao, Lam Bakalar, Matthew French, Stephanie Chess, David J. Taylor, Joni L. Daniels, Mathew P. Esfahani, Shervin Balaban, Robert S. TI Selective Embedding of Capillaries within Murine Slow Twitch Skeletal Muscle Fibers Visualized Using In Vivo Microscopy SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Glancy, Brian; Hsu, Li-Yueh; Dao, Lam; Bakalar, Matthew; French, Stephanie; Chess, David J.; Taylor, Joni L.; Daniels, Mathew P.; Esfahani, Shervin; Balaban, Robert S.] NIH, Bethesda, MD 20892 USA. RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 682 EP 682 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363303636 ER PT J AU Steiner, J Davis, JM McClellan, J Green, J Murphy, EA AF Steiner, Jennifer Davis, J. Mark McClellan, Jamie Green, Jeffrey Murphy, E. Angela TI High Fat Diet Enhances Tumorigenesis And Pro-tumoral Factors in the C3(1)SV40Tag Breast Cancer Mouse Model SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Steiner, Jennifer; Davis, J. Mark; McClellan, Jamie; Murphy, E. Angela] Univ S Carolina, Columbia, SD USA. [Green, Jeffrey] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 699 EP 699 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363303699 ER PT J AU Steiner, J Davis, JM McClellan, J Green, J Murphy, EA AF Steiner, Jennifer Davis, J. Mark McClellan, Jamie Green, Jeffrey Murphy, E. Angela TI High Fat Diet Enhances Tumorigenesis And Pro-tumoral Factors in the C3(1)SV40Tag Breast Cancer Mouse Model SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Murphy, E. Angela] Univ S Carolina, Sch Med, Columbia, SC USA. [Green, Jeffrey] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2012 VL 44 SU 2 BP 758 EP 758 PG 1 WC Sport Sciences SC Sport Sciences GA 027OT UT WOS:000310363304104 ER PT J AU Kadoya, R Chattoraj, DK AF Kadoya, Ryosuke Chattoraj, Dhruba K. TI Insensitivity of Chromosome I and the Cell Cycle to Blockage of Replication and Segregation of Vibrio cholerae Chromosome II SO MBIO LA English DT Article ID ESCHERICHIA-COLI CHROMOSOME; BACTERIAL-DNA REPLICATION; PLASMID PARTITION; ORIGIN; INITIATION; FORK; INACTIVATION; CHECKPOINT; STABILITY; HOMOLOG AB Vibrio cholerae has two chromosomes (chrI and chrII) whose replication and segregation are under different genetic controls. The region covering the replication origin of chrI resembles that of the Escherichia coli chromosome, and both origins are under control of the highly conserved initiator, DnaA. The origin region of chrII resembles that of plasmids that have iterated initiator-binding sites (iterons) and is under control of the chrII-specific initiator, RctB. Both chrI and chrII encode chromosome-specific orthologs of plasmid partitioning proteins, ParA and ParB. Here, we have interfered with chrII replication, segregation, or both, using extra copies of sites that titrate RctB or ParB. Under these conditions, replication and segregation of chrI remain unaffected for at least 1 cell cycle. In this respect, chrI behaves similarly to the E. coli chromosome when plasmid maintenance is disturbed in the same cell. Apparently, no checkpoint exists to block cell division before the crippled chromosome is lost by a failure to replicate or to segregate. Whether blocking chrI replication can affect chrII replication remains to be tested. IMPORTANCE Chromosome replication, chromosome segregation, and cell division are the three main events of the cell cycle. They occur in an orderly fashion once per cell cycle. How the sequence of events is controlled is only beginning to be answered in bacteria. The finding of bacteria that possess more than one chromosome raises the important question: how are different chromosomes coordinated in their replication and segregation? It appears that in the evolution of the two-chromosome genome of V. cholerae, either the secondary chromosome adapted to the main chromosome to ensure its maintenance or it is maintained independently, as are bacterial plasmids. An understanding of chromosome coordination is expected to bear on the evolutionary process of chromosome acquisition and on the efficacy of possible strategies for selective elimination of a pathogen by targeting a specific chromosome. C1 [Kadoya, Ryosuke; Chattoraj, Dhruba K.] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chattoraj, DK (reprint author), NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM chattoraj@nih.gov FU Intramural Research Program, Center for Cancer Research of the National Cancer Institute FX This work was supported by the Intramural Research Program, Center for Cancer Research of the National Cancer Institute. NR 54 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAY-JUN PY 2012 VL 3 IS 3 AR e00067-12 DI 10.1128/mBio.00067-12 PG 9 WC Microbiology SC Microbiology GA 003DE UT WOS:000308587600004 ER PT J AU Ngamskulrungroj, P Chang, Y Sionov, E Kwon-Chung, KJ AF Ngamskulrungroj, Popchai Chang, Yun Sionov, Edward Kwon-Chung, Kyung J. TI The Primary Target Organ of Cryptococcus gattii Is Different from That of Cryptococcus neoformans in a Murine Model SO MBIO LA English DT Article ID VANCOUVER-ISLAND; BRITISH-COLUMBIA; INFECTION; OUTBREAK; GENOTYPE; BRAIN; EPIDEMIOLOGY; PATHOGENESIS; PREVALENCE; VIRULENCE AB Cryptococcosis is caused by the opportunistic pathogen Cryptococcus neoformans or by the primary pathogen Cryptococcus gattii. Epidemiological studies suggest that patients infected with C. gattii mainly present with pulmonary disease, while those infected with C. neoformans commonly manifest meningoencephalitis. We compared the pathogenesis of the two species using the C. neoformans H99 and C. gattii R265 strains in a murine inhalation model. C. neoformans grew faster in the brain and caused death by meningoencephalitis, while C. gattii grew faster in the lungs and caused death without producing fulminating meningoencephalitis. Despite the consistent failure to recover R265 cells from blood, a fraction of the R265 population was detected in the extrapulmonary organs, including the brain. Upon intravenous (i.v.) inoculation of 10(4) cells via the tail vein, however, C. gattii produced severe meningoencephalitis, demonstrating that C. gattii cells can efficiently cross the blood-brain barrier. Interestingly, i.v. inoculation with five cells caused brain infection in only 10% of C. gattii-infected mice, compared to 60% of mice infected with C. neoformans. In mice that had been initially inoculated via the pulmonary route and subsequently challenged intravenously, a protective effect was observed only in mice infected with C. gattii. C. neoformans cells grew 10 to 100 times faster than C. gattii cells in blood or serum collected from naive mice. The paucity of meningoencephalitis upon inhalation of C. gattii, therefore, may be partly due to an unknown factor(s) in the host's blood coupled with immune protection that reduces dissemination to the brain and fosters lung infection. IMPORTANCE While Cryptococcus neoformans is the most common cause of fatal meningoencephalitis, especially in HIV patients, Cryptococcus gattii causes disease mainly in non-HIV patients. Clinical studies revealed that most patients infected with C. gattii VGII strains have lung infections with minimal brain involvement. Despite extensive clinicopathological studies on cryptococcosis in animal models, only a few have included C. gattii. We compared the pathogenesis of the two species in mice using an inhalation model. Similar to infection in humans, even though C. gattii can cross the blood-brain barrier, it failed to cause fatal meningoencephalitis but caused fatal lung infection. We show that growth of C. gattii in mouse blood is significantly slower than that of C. neoformans and that a secondary protective phenomenon, though weak, manifests itself only in C. gattii infection. Our study provides a model for understanding the clinicopathological differences between these two closely genetically related pathogens. C1 [Ngamskulrungroj, Popchai; Chang, Yun; Sionov, Edward; Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Ngamskulrungroj, Popchai] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Microbiol, Bangkok 10700, Thailand. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov FU intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by funds from the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.; We thank Daniel Barber and Katrin Mayer Barber and Ashok Varma for their suggestions and critical readings of the manuscript. NR 36 TC 27 Z9 27 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAY-JUN PY 2012 VL 3 IS 3 AR e00103-12 DI 10.1128/mBio.00103-12 PG 9 WC Microbiology SC Microbiology GA 003DE UT WOS:000308587600010 ER PT J AU O'Donnell, CD Vogel, L Wright, A Das, SR Wrammert, J Li, GM McCausland, M Zheng, NY Yewdell, JW Ahmed, R Wilson, PC Subbarao, K AF O'Donnell, Christopher D. Vogel, Leatrice Wright, Amber Das, Suman R. Wrammert, Jens Li, Gui-Mei McCausland, Megan Zheng, Nai-Ying Yewdell, Jonathan W. Ahmed, Rafi Wilson, Patrick C. Subbarao, Kanta TI Antibody Pressure by a Human Monoclonal Antibody Targeting the 2009 Pandemic H1N1 Virus Hemagglutinin Drives the Emergence of a Virus with Increased Virulence in Mice SO MBIO LA English DT Article ID INFLUENZA-A H5N1; LOWER RESPIRATORY-TRACT; RECEPTOR-BINDING; SEVERE DISEASE; GLOBULAR HEAD; A(H1N1) VIRUS; INFECTION; D222G; ANTIGENICITY; SUBSTITUTION AB In 2009, a novel H1N1 influenza A virus (2009 pH1N1) emerged and caused a pandemic. A human monoclonal antibody (hMAb; EM4C04), highly specific for the 2009 pH1N1 virus hemagglutinin (HA), was isolated from a severely ill 2009 pH1N1 virus-infected patient. We postulated that under immune pressure with EM4C04, the 2009 pH1N1 virus would undergo antigenic drift and mutate at sites that would identify the antibody binding site. To do so, we infected MDCK cells in the presence of EM4C04 and generated 11 escape mutants, displaying 7 distinct amino acid substitutions in the HA. Six substitutions greatly reduced MAb binding (K123N, D131E, K133T, G134S, K157N, and G158E). Residues 131, 133, and 134 are contiguous with residues 157 and 158 in the globular domain structure and contribute to a novel pH1N1 antibody epitope. One mutation near the receptor binding site, S186P, increased the binding affinity of the HA to the receptor. 186P and 131E are present in the highly virulent 1918 virus HA and were recently identified as virulence determinants in a mouse-passaged pH1N1 virus. We found that pH1N1 escape variants expressing these substitutions enhanced replication and lethality in mice compared to wild-type 2009 pH1N1 virus. The increased virulence of these viruses was associated with an increased affinity for alpha 2,3 sialic acid receptors. Our study demonstrates that antibody pressure by an hMAb targeting a novel epitope in the Sa region of 2009 pH1N1 HA is able to inadvertently drive the development of a more virulent virus with altered receptor binding properties. This broadens our understanding of antigenic drift. IMPORTANCE Influenza viruses accumulate amino acid substitutions to evade the antibody response in a process known as antigenic drift, making it necessary to vaccinate against influenza annually. Mapping human monoclonal antibody (hMAb) epitopes is a necessary step towards understanding antigenic drift in humans. We defined the specificity of an hMAb that specifically targeted the 2009 pH1N1 virus and describe a novel epitope. In addition, we identified a previously unappreciated potential for antibody escape to enhance the pathogenicity of a virus. The escape mutation that we identified with in vitro immune pressure was independently reported by other investigators using in vivo selection in nonimmune mice. Although in vitro generation of escape mutants is unlikely to recapitulate antigenic drift in its entirety, the data demonstrate that pressure by a human monoclonal antibody targeting a novel epitope in the hemagglutinin of the 2009 pandemic H1N1 virus can inadvertently drive the development of escape mutants, of which a subset have increased virulence and altered receptor binding properties. C1 [O'Donnell, Christopher D.; Vogel, Leatrice; Wright, Amber; Subbarao, Kanta] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Das, Suman R.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Wrammert, Jens; Li, Gui-Mei; McCausland, Megan; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA USA. [Wrammert, Jens; Li, Gui-Mei; McCausland, Megan; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Zheng, Nai-Ying; Wilson, Patrick C.] Univ Chicago, Dept Med, Rheumatol Sect, Chicago, IL 60637 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov RI Das, Suman/C-8760-2009 FU Intramural Research Program of the NIH, NIAID FX This work was conducted in part under a CRADA between MedImmune and NIAID/NIH. This research was supported in part by the Intramural Research Program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 14 Z9 15 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAY-JUN PY 2012 VL 3 IS 3 AR e00120-12 DI 10.1128/mBio.00120-12 PG 10 WC Microbiology SC Microbiology GA 003DE UT WOS:000308587600015 ER PT J AU Guo, H Qiao, GL Ying, HY Li, ZP Zhao, YX Liang, YR Yang, LF Lipkowitz, S Penninger, JM Langdon, WY Zhang, J AF Guo, Hui Qiao, Guilin Ying, Haiyan Li, Zhenping Zhao, Yixia Liang, Yanran Yang, Lifen Lipkowitz, Stanley Penninger, Josef M. Langdon, Wallace Y. Zhang, Jian TI E3 Ubiquitin Ligase Cbl-b Regulates Pten via Nedd4 in T Cells Independently of Its Ubiquitin Ligase Activity SO CELL REPORTS LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE; TUMOR SUPPRESSION; CUTTING EDGE; NEGATIVE REGULATION; CD28 COSTIMULATION; ACTIVATION; RECEPTOR; MICE; AUTOIMMUNITY; DEGRADATION AB E3 ubiquitin ligase Cbl-b plays a crucial role in T cell activation and tolerance induction. However, the molecular mechanism by which Cbl-b inhibits T cell activation remains unclear. Here, we report that Cbl-b does not inhibit PI3K but rather suppresses TCR/CD28-induced inactivation of Pten. The elevated Akt activity in Cbl-b(-/-) T cells is therefore due to heightened Pten inactivation. Suppression of Pten inactivation in T cells by Cbl-b is achieved by impeding the association of Pten with Nedd4, which targets Pten K13 for K63-linked polyubiquitination. Consistent with this finding, introducing Nedd4 deficiency into Cbl-b(-/-) mice abrogates hyper-T cell responses caused by the loss of Cbl-b. Hence, our data demonstrate that Cbl-b inhibits T cell activation by suppressing Pten inactivation independently of its ubiquitin ligase activity. C1 [Guo, Hui; Qiao, Guilin; Ying, Haiyan; Li, Zhenping; Zhao, Yixia; Liang, Yanran; Yang, Lifen; Zhang, Jian] Univ Chicago, Dept Med, Sect Nephrol, Chicago, IL 60637 USA. [Qiao, Guilin; Ying, Haiyan; Zhao, Yixia; Liang, Yanran; Yang, Lifen; Zhang, Jian] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA. [Zhang, Jian] Univ Chicago, Comm Mol Med, Chicago, IL 60637 USA. [Lipkowitz, Stanley] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Penninger, Josef M.] Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria. [Langdon, Wallace Y.] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA 6009, Australia. RP Zhang, J (reprint author), Univ Chicago, Dept Med, Sect Nephrol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM jzhang@medicine.bsd.uchicago.edu RI Penninger, Josef/I-6860-2013; Zhang, Jian/A-2564-2008 OI Penninger, Josef/0000-0002-8194-3777; FU National Institutes of Health (NIH) [R01AR049775, AI090901]; American Heart Association [09GRNT2010084] FX We thank Drs. D. Bohmann, A. M. Weissman, R. Wange, K-L. Guan, X. Jiang, S. Srivastava, Xiangdong Zhu, and N. Leslie for providing His-tagged ubiquitin, Nedd4, HA-tagged Nedd4, Flag-tagged Pten, HA-tagged Pten K13R and K289R mutants, Myr-tagged Pten, Myr-(iSH2-p85)-p110 alpha-Myc, and GST-Nedd4 constructs, which made this study possible. We also thank Dr. Demin Wang for help with the generation of fetal liver chimeric mice. The project described was supported by grants R01AR049775 and AI090901 to J.Z. from the National Institutes of Health (NIH), and by a grant-in-aid (09GRNT2010084) from the American Heart Association. J.Z. was an American Lung Association Career Investigator. NR 46 TC 27 Z9 28 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REPORTS JI Cell Reports PD MAY PY 2012 VL 1 IS 5 BP 472 EP 482 DI 10.1016/j.celrep.2012.04.008 PG 11 WC Cell Biology SC Cell Biology GA 019BT UT WOS:000309712600009 PM 22763434 ER PT J AU Zhang, Q Pan, J North, PE Yang, S Lubet, RA Wang, Y You, M AF Zhang, Qi Pan, Jing North, Paula E. Yang, Shoua Lubet, Ronald A. Wang, Yian You, Ming TI Aerosolized 3-Bromopyruvate Inhibits Lung Tumorigenesis without Causing Liver Toxicity SO CANCER PREVENTION RESEARCH LA English DT Article ID HEXOKINASE-II; CANCER-CELLS; CHEMOPREVENTION; GLYCOLYSIS; METABOLISM; CASPASES; EFFICACY; MODELS; DEATH; MICE AB 3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a) pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer. Cancer Prev Res; 5(5); 717-25. (c) 2012 AACR. C1 [Zhang, Qi; Pan, Jing; Wang, Yian; You, Ming] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [North, Paula E.; Yang, Shoua] NCI, Dept Pathol & Lab Med, Bethesda, MD 20892 USA. [Lubet, Ronald A.] NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Med Coll Wisconsin, Ctr Canc, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM myou@mcw.edu NR 28 TC 18 Z9 18 U1 1 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 MAY PY 2012 VL 5 IS 5 BP 717 EP 725 DI 10.1158/1940-6207.CAPR-11-0338 PG 9 WC Oncology SC Oncology GA 998FH UT WOS:000308222300003 PM 22401980 ER PT J AU Yuan, HY Upadhyay, G Lu, J Kopelovich, L Glazer, RI AF Yuan, Hongyan Upadhyay, Geeta Lu, Jin Kopelovich, Levy Glazer, Robert I. TI The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature SO CANCER PREVENTION RESEARCH LA English DT Article ID PROGESTERONE-RECEPTOR MODULATORS; HUMAN-BREAST-CANCER; ANTITUMOR-ACTIVITY; MEDROXYPROGESTERONE ACETATE; CLINICAL-APPLICATIONS; REPLACEMENT THERAPY; GLAND DEVELOPMENT; EARLY-PREGNANCY; NUDE-MICE; ANTIPROGESTINS AB Progesterone receptor (PR) antagonists are potent antitumor agents in carcinogen and progestin-dependent mammary tumorigenesis models through both PR-and non-PR-mediated mechanisms. The PR antagonist mifepristone/RU486 has been used primarily as an abortifacient possessing high affinity for both the PR and glucocorticoid receptors (GR). To determine whether mifepristone would be effective as a chemopreventive agent, we assessed its effect on progestin/7,12-dimethylbenz(a) anthracene (DMBA)induced mammary carcinogenesis in wild-type (WT) and estrogen receptor-alpha-positive (ER+) transgenic mice expressing the dominant-negative Pax8PPAR gamma (Pax8) fusion protein. Mifepristone administered at a dose of 2.5 mg significantly delayed mammary tumorigenesis in WT, but not in Pax8 mice, whereas, a threefold higher dose almost completely blocked tumorigenesis in both WT and Pax8 mice. The sensitivity of WT mice to 2.5 mg mifepristone correlated with an expression profile of 79 genes in tumors, 52 of which exhibited the opposite response in Pax8 mice, and corresponded primarily to the downregulation of genes associated with metabolism, inflammation, and invasion. These results suggest that the chemopreventive activity of mifepristone in WT mice correlates with a specific gene expression signature that is associated with multiple nuclear receptor signaling pathways. Cancer Prev Res; 5(5); 754-64. (C) 2012 AACR. C1 [Yuan, Hongyan; Upadhyay, Geeta; Lu, Jin; Glazer, Robert I.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Yuan, Hongyan; Upadhyay, Geeta; Lu, Jin; Glazer, Robert I.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Kopelovich, Levy] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Glazer, RI (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. EM glazerr@georgetown.edu FU NIH [1NO1 CN43302 WA19]; National Cancer Institute, NIH [P30CA051008] FX The study was supported by NIH grant 1NO1 CN43302 WA19, and award P30CA051008 from the National Cancer Institute, NIH, to the Lombardi Comprehensive Cancer Center. NR 57 TC 2 Z9 2 U1 0 U2 0 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 MAY PY 2012 VL 5 IS 5 BP 754 EP 764 DI 10.1158/1940-6207.CAPR-11-0526 PG 11 WC Oncology SC Oncology GA 998FH UT WOS:000308222300007 PM 22427346 ER PT J AU Eriksson, PR Ganguli, D Nagarajavel, V Clark, DJ AF Eriksson, Peter R. Ganguli, Dwaipayan Nagarajavel, V. Clark, David J. TI Regulation of Histone Gene Expression in Budding Yeast SO GENETICS LA English DT Review ID CELL-CYCLE REGULATION; UPSTREAM ACTIVATING SEQUENCE; SACCHAROMYCES-CEREVISIAE; CHROMATIN-STRUCTURE; S-PHASE; TRANSCRIPTION FACTOR; MESSENGER-RNA; GENOME STABILITY; DNA-REPLICATION; HIR COMPLEX AB We discuss the regulation of the histone genes of the budding yeast Saccharomyces cerevisiae. These include genes encoding the major core histones (H3, H4, H2A, and H2B), histone H1 (HHO1), H2AZ (HTZ1), and centromeric H3 (CSE4). Histone production is regulated during the cell cycle because the cell must replicate both its DNA during S phase and its chromatin. Consequently, the histone genes are activated in late G1 to provide sufficient core histones to assemble the replicated genome into chromatin. The major core histone genes are subject to both positive and negative regulation. The primary control system is positive, mediated by the histone gene-specific transcription activator, Spt10, through the histone upstream activating sequences (UAS) elements, with help from the major G1/S-phase activators, SBF (Swi4 cell cycle box binding factor) and perhaps MBF (MIul cell cycle box binding factor). Spt10 binds specifically to the histone UAS elements and contains a putative histone acetyltransferase domain. The negative system involves negative regulatory elements in the histone promoters, the RSC chromatin-remodeling complex, various histone chaperones [the histone regulatory (HIR) complex, Asf1, and Rtt106], and putative sequence-specific factors. The SWI/SNF chromatin-remodeling complex links the positive and negative systems. We propose that the negative system is a damping system that modulates the amount of transcription activated by Spt10 and SBF. We hypothesize that the negative system mediates negative feedback on the histone genes by histone proteins through the level of saturation of histone chaperones with histone. Thus, the negative system could communicate the degree of nucleosome assembly during DNA replication and the need to shut down the activating system under replication-stress conditions. We also discuss post-transcriptional regulation and dosage compensation of the histone genes. C1 [Eriksson, Peter R.; Ganguli, Dwaipayan; Nagarajavel, V.; Clark, David J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Clark, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bldg 6A,Rm 2A14,6 Ctr Dr, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (National Institute of Child Health and Human Development) FX We thank Rohinton Kamakaka for helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health (National Institute of Child Health and Human Development). NR 114 TC 24 Z9 25 U1 1 U2 14 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 2012 VL 191 IS 1 BP 7 EP 20 DI 10.1534/genetics.112.140145 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 009AT UT WOS:000308998400002 PM 22555441 ER PT J AU Debbache, J Zaidi, MR Davis, S Guo, T Bismuth, K Wang, X Skuntz, S Maric, D Pickel, J Meltzer, P Merlino, G Arnheiter, H AF Debbache, Julien Zaidi, M. Raza Davis, Sean Guo, Theresa Bismuth, Keren Wang, Xin Skuntz, Susan Maric, Dragan Pickel, James Meltzer, Paul Merlino, Glenn Arnheiter, Heinz TI In Vivo Role of Alternative Splicing and Serine Phosphorylation of the Microphthalmia-Associated Transcription Factor SO GENETICS LA English DT Article ID FACTOR MITF; GENE; KIT; MUTATIONS; EXPRESSION; MELANOMA; PROTEIN; LOCUS; CELLS; MELANOCYTES AB The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper protein that plays major roles in the development and physiology of vertebrate melanocytes and melanoma cells. It is regulated by post-translational modifications, including phosphorylation at serine 73, which based on in vitro experiments imparts on MITF an increased transcriptional activity paired with a decreased stability. Serine 73 is encoded by the alternatively spliced exon 2B, which is preferentially skipped in mice carrying a targeted serine-73-to-alanine mutation. Here, we measured the relative abundance of exon 2B(+) and exon 2B(-) RNAs in freshly isolated and FACS-sorted wild-type melanoblasts and melanocytes and generated a series of knock-in mice allowing forced incorporation of either alanine, aspartate, or wild-type serine at position 73. None of these knock-in alleles, however, creates a striking pigmentation phenotype on its own, but differences between them can be revealed either by a general reduction of Mitf transcript levels or in heteroallelic combinations with extant Mitf mutations. In fact, compared with straight serine-73 knock-in mice with their relative reduction of 2B(+) Mitf, forced incorporation of alanine 73 leads to greater increases in MITF protein levels, melanoblast and melanocyte numbers, and extent of pigmentation in particular allelic combinations. These results underscore, in vivo, the importance of the link between alternative splicing and post-translational modifications and may bear on the recent observation that exon 2B skipping can be found in metastatic melanoma. C1 [Arnheiter, Heinz] NINDS, NIH, Mammalian Dev Sect, Bethesda, MD 20892 USA. [Zaidi, M. Raza; Guo, Theresa; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Davis, Sean; Meltzer, Paul] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. RP Arnheiter, H (reprint author), NINDS, NIH, Mammalian Dev Sect, 35 Convent Dr,Bldg 35,Room 2A-201,MSC 3706, Bethesda, MD 20892 USA. EM ha3p@nih.gov RI Zaidi, M. Raza/H-1386-2016; OI Zaidi, M. Raza/0000-0003-0480-3188; Davis, Sean/0000-0002-8991-6458 FU National Institutes of Health; National Cancer Institute, NINDS; National Institute of Mental Health FX We thank Colin Goding for microphthalmia-associated transcription factor-estrogen receptor constructs, and L. Baweke, the National Institute of Neurological Disorders and Stroke (NINDS) Animal Health and Care Section, and the NINDS sequencing facility for excellent support. This work was supported by the intramural research program of the National Institutes of Health, NINDS, the National Cancer Institute, and the National Institute of Mental Health. NR 29 TC 3 Z9 4 U1 1 U2 3 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 2012 VL 191 IS 1 BP 133 EP + DI 10.1534/genetics.111.135996 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 009AT UT WOS:000308998400010 PM 22367038 ER PT J AU Yu, CH Bonaduce, MJ Klar, AJS AF Yu, Chuanhe Bonaduce, Michael J. Klar, Amar J. S. TI Remarkably High Rate of DNA Amplification Promoted by the Mating-Type Switching Mechanism in Schizosaccharomyces pombe SO GENETICS LA English DT Article ID STRAND-BREAK REPAIR; FISSION YEAST; S-POMBE; GENE AMPLIFICATION; REPLICATION; RECOMBINATION; CELLS; CASSETTES; INTERCONVERSION; REARRANGEMENTS AB A novel mating-type switching-defective mutant showed a highly unstable rearrangement at the mating-type locus (mat1) in fission yeast. The mutation resulted from local amplification of a 134-bp DNA fragment by the mat1-switching phenomenon. We speculate that the rolling-circle-like replication and homologous recombination might be the general mechanisms for local genome region expansion. C1 [Yu, Chuanhe; Bonaduce, Michael J.; Klar, Amar J. S.] NCI, Dev Genet Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Dev Genet Sect, Gene Regulat & Chromosome Biol Lab, NIH, POB B, Frederick, MD 21702 USA. EM klara@mail.nih.gov FU Intramural Research Program of the National Cancer Institute of the National Institutes of Health FX We thank members of the Amar Klar, Jeff Strathern, and Thomas Peterson laboratories for discussions and advice. The Intramural Research Program of the National Cancer Institute of the National Institutes of Health supported this work. NR 32 TC 1 Z9 1 U1 0 U2 1 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD MAY PY 2012 VL 191 IS 1 BP 285 EP + DI 10.1534/genetics.112.138727 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 009AT UT WOS:000308998400021 PM 22377633 ER PT J AU Cizza, G Brown, RJ Rother, KI AF Cizza, G. Brown, R. J. Rother, K. I. TI Rising incidence and challenges of childhood diabetes. A mini review SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Review DE Autoimmunity; chronic stress; genetic; leptin; obesity; prevention; sleep deprivation; socioeconomic status; Vitamin D ID BETA-CELL FUNCTION; INSULIN-RESISTANCE; ACCELERATOR HYPOTHESIS; BARIATRIC SURGERY; OBESE CHILDREN; BODY-MASS; VITAMIN-D; TYPE-1; MELLITUS; YOUTH AB Approximately 215,000 people younger than 20 yr of age, or 1 in 500 children and adolescents, had diabetes in the United States in 2010 - and the incidence is rising. We still have insufficient knowledge about the precise mechanisms leading to the autoimmune mediated beta-cell destruction in Type 1 diabetes, and the beta-cell failure associated with insulin resistance in Type 2 diabetes. Long-term complications are similar: micro-and macrovascular disease occurs prematurely and presents an enormous burden on affected individuals, often as early as in middle age. In Type 1 diabetes, technological advances have clearly improved blood glucose management, but chronic peripheral over-insulinization remains a problem even with the most advanced systems. Thus, in Type 1 diabetes our research must focus on 1) finding the stimulus that ignites the immune response and 2) developing treatments that avoid hyperinsulinemia. In Type 2 diabetes in youth, the challenges start much earlier: most young patients do not even benefit from existing therapies due to non-compliance. Therefore, prevention of Type 2 diabetes and improvement of compliance, especially with non-pharmacological interventions, are the greatest challenges. (J. Endocrinol. Invest. 35: 541-546, 2012) (C) 2012, Editrice Kurtis C1 [Cizza, G.] NIDDKD, Sect Neuroendocrinol Obes, NIH, Bethesda, MD 20892 USA. [Brown, R. J.; Rother, K. I.] NIDDKD, Sect Pediat Diabet & Metab, Diabet Endocrinol & Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Rother, KI (reprint author), Bldg 10,Room 8C432A, Bethesda, MD 20892 USA. EM Kr58q@nih.gov FU NIDDK, NIH FX This research was supported by the Intramural Research Program of NIDDK, NIH. NR 63 TC 12 Z9 12 U1 4 U2 19 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD MAY PY 2012 VL 35 IS 5 BP 541 EP 546 DI 10.3275/8411 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 009QW UT WOS:000309041300016 PM 22572768 ER PT J AU Newburger, JW Sleeper, LA Bellinger, DC Goldberg, CS Tabbutt, S Lu, MM Mussatto, KA Williams, IA Gustafson, KE Mital, S Pike, N Sood, E Mahle, WT Cooper, DS Dunbar-Masterson, C Krawczeski, CD Lewis, A Menon, SC Pemberton, VL Ravishankar, C Atz, TW Ohye, RG Gaynor, JW AF Newburger, Jane W. Sleeper, Lynn A. Bellinger, David C. Goldberg, Caren S. Tabbutt, Sarah Lu, Minmin Mussatto, Kathleen A. Williams, Ismee A. Gustafson, Kathryn E. Mital, Seema Pike, Nancy Sood, Erica Mahle, William T. Cooper, David S. Dunbar-Masterson, Carolyn Krawczeski, Catherine Dent Lewis, Alan Menon, Shaji C. Pemberton, Victoria L. Ravishankar, Chitra Atz, Teresa W. Ohye, Richard G. Gaynor, J. William CA Pediat Heart Network Investigators TI Early Developmental Outcome in Children With Hypoplastic Left Heart Syndrome and Related Anomalies The Single Ventricle Reconstruction Trial SO CIRCULATION LA English DT Article DE cardiac surgery; congenital cardiac defects; congenital heart disease; heart defects, congenital; hypoplastic left heart syndrome ID HYPOTHERMIC CIRCULATORY ARREST; PH-STAT STRATEGIES; AGE 8 YEARS; CARDIOPULMONARY BYPASS; DEVELOPING BRAIN; NEURODEVELOPMENTAL OUTCOMES; NORWOOD PROCEDURE; RANDOMIZED-TRIAL; GREAT-ARTERIES; ALPHA-STAT AB Background-Survivors of the Norwood procedure may experience neurodevelopmental impairment. Clinical trials to improve outcomes have focused primarily on methods of vital organ support during cardiopulmonary bypass. Methods and Results-In the Single Ventricle Reconstruction trial of the Norwood procedure with modified Blalock-Taussig shunt versus right-ventricle-to-pulmonary-artery shunt, 14-month neurodevelopmental outcome was assessed by use of the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. We used multivariable regression to identify risk factors for adverse outcome. Among 373 transplant-free survivors, 321 (86%) returned at age 14.3 +/- 1.1 (mean +/- SD) months. Mean PDI (74 +/- 19) and MDI (89 +/- 18) scores were lower than normative means (each P < 0.001). Neither PDI nor MDI score was associated with type of Norwood shunt. Independent predictors of lower PDI score (R-2 = 26%) were clinical center (P = 0.003), birth weight <2.5 kg (P = 0.023), longer Norwood hospitalization (P < 0.001), and more complications between Norwood procedure discharge and age 12 months (P < 0.001). Independent risk factors for lower MDI score (R-2 = 34%) included center (P < 0.001), birth weight <2.5 kg (P = 0.04), genetic syndrome/anomalies (P = 0.04), lower maternal education (P = 0.04), longer mechanical ventilation after the Norwood procedure (P < 0.001), and more complications after Norwood discharge to age 12 months (P < 0.001). We found no significant relationship of PDI or MDI score to perfusion type, other aspects of vital organ support (eg, hematocrit, pH strategy), or cardiac anatomy. Conclusions-Neurodevelopmental impairment in Norwood survivors is more highly associated with innate patient factors and overall morbidity in the first year than with intraoperative management strategies. Improved outcomes are likely to require interventions that occur outside the operating room. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934. (Circulation. 2012;125:2081-2091.) C1 [Newburger, Jane W.] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Newburger, Jane W.; Bellinger, David C.] Harvard Univ, Sch Med, Boston, MA USA. [Sleeper, Lynn A.; Lu, Minmin] New England Res Inst, Watertown, MA 02172 USA. [Goldberg, Caren S.; Ohye, Richard G.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Tabbutt, Sarah; Ravishankar, Chitra; Gaynor, J. William] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Tabbutt, Sarah; Ravishankar, Chitra; Gaynor, J. William] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Mussatto, Kathleen A.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Mussatto, Kathleen A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Williams, Ismee A.] Morgan Stanley Childrens Hosp New York Presbyteri, New York, NY USA. [Gustafson, Kathryn E.] E Carolina Univ, Greenville, NC USA. Duke Univ, N Carolina Consortium, Durham, NC 27706 USA. [Gustafson, Kathryn E.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Mital, Seema] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Pike, Nancy; Lewis, Alan] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Sood, Erica] Nemours Cardiac Ctr, Wilmington, DE USA. [Mahle, William T.] Emory Univ, Atlanta, GA 30322 USA. [Cooper, David S.] Congenital Heart Inst Florida, St Petersburg, FL USA. [Krawczeski, Catherine Dent] Cincinnati Childrens Med Ctr, Cincinnati, OH USA. [Menon, Shaji C.] Primary Childrens Med Ctr, Salt Lake City, UT 84103 USA. [Menon, Shaji C.] Univ Utah, Salt Lake City, UT USA. [Pemberton, Victoria L.] NHLBI, Bethesda, MD 20892 USA. [Atz, Teresa W.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Newburger, JW (reprint author), Childrens Hosp, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA. EM jane.newburger@cardio.chboston.org RI gaynor, James william/E-5194-2013 OI gaynor, James william/0000-0001-7955-5604 FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, HL085057]; Harvard Catalyst/The Harvard Clinical and Translational Science Center (NIH) [UL1 RR 025758]; Harvard University FX This work was supported by grants HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, and HL085057 from the National Heart, Lung, and Blood Institute. This work is solely the responsibility of the authors and does not necessarily represent the official views of NHLBI or NIH. This work was conducted with support from Harvard Catalyst/The Harvard Clinical and Translational Science Center (NIH Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health. NR 43 TC 89 Z9 91 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 1 PY 2012 VL 125 IS 17 BP 2081 EP + DI 10.1161/CIRCULATIONAHA.111.064113 PG 20 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981IC UT WOS:000306959200017 PM 22456475 ER PT J AU Robbins, IM Moore, TM Blaisdell, CJ Abman, SH AF Robbins, Ivan M. Moore, Timothy M. Blaisdell, Carol J. Abman, Steven H. TI National Heart, Lung, and Blood Institute Workshop Improving Outcomes for Pulmonary Vascular Disease SO CIRCULATION LA English DT Article DE clinical trials; pediatrics; pulmonary hypertension; pulmonary vascular changes ID ARTERIAL-HYPERTENSION; SURVIVAL; CHILDREN; FRANCE C1 [Moore, Timothy M.] NHLBI, Div Lung Dis, NIH, Rockledge Ctr 2, Bethesda, MD 20892 USA. [Robbins, Ivan M.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Abman, Steven H.] Childrens Hosp, Denver, CO 80218 USA. [Abman, Steven H.] Univ Colorado, Sch Med, Dept Pediat, Denver, CO USA. RP Moore, TM (reprint author), NHLBI, Div Lung Dis, NIH, Rockledge Ctr 2, Suite 10042,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM tim.moore@nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health; Actelion Pharmaceuticals; Gilead; United Therapeutics FX This Workshop was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health.; Dr Robbins serves or has served as a paid consultant for Actelion Pharmaceuticals, Gilead, United Therapeutics, Bayer, Lung Rx, Pfizer, and Ikaria. Dr Robbins' Institution has received grant fund from Actelion Pharmaceuticals, Gilead, and United Therapeutics. Dr Robbins has received compensation for development of a Continuing Medical Education lecture for "Simply Speaking." Drs Moore and Blaisdell are employees of National Institutes of Health. NR 11 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 1 PY 2012 VL 125 IS 17 BP 2165 EP 2170 DI 10.1161/CIRCULATIONAHA.112.092924 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981IC UT WOS:000306959200026 PM 22388326 ER PT J AU Crim, MT Yoon, SS Ortiz, E Wall, HK Schober, S Gillespie, C Sorlie, P Keenan, N Labarthe, D Hong, YL AF Crim, Matthew T. Yoon, Sung Sug (Sarah) Ortiz, Eduardo Wall, Hilary K. Schober, Susan Gillespie, Cathleen Sorlie, Paul Keenan, Nora Labarthe, Darwin Hong, Yuling TI National Surveillance Definitions for Hypertension Prevalence and Control Among Adults SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE hypertension; epidemiology; surveillance; health policy; prevention ID NUTRITION EXAMINATION SURVEY; BLOOD-PRESSURE CONTROL; UNITED-STATES ADULTS; CHRONIC KIDNEY-DISEASE; US ADULTS; RISK-FACTORS; HEALTH; AWARENESS; TRENDS; SUBCOMMITTEE AB Background-Clear and consistent definitions of hypertension and hypertension control are crucial to guide diagnosis, treatment, and surveillance. A variety of surveillance definitions are in frequent use, resulting in variation of reported hypertension prevalence and control, even when based on the same data set. Methods and Results-To assess the variety of published surveillance definitions and rates, we performed a literature search for studies and reports that used National Health and Nutrition Examination Surveys (NHANES) data from at least as recent as the 2003 to 2004 survey cycle. We identified 19 studies that used various criteria for defining hypertension and hypertension control, as well as different parameters for age adjustment and inclusion of subpopulations. This resulted in variation of reported age-standardized hypertension prevalence from 28.9% to 32.1% and hypertension control from 35.1% to 64%. We then assessed the effects of varying the definitions of hypertension and hypertension control, parameters for age adjustment, and inclusion of subpopulations on NHANES data from both 2007 to 2008 (n=5645) and 2005 to 2008 (n=10 365). We propose standard surveillance definitions and age-adjustment parameters for hypertension and hypertension control. By using our recommended approach with NHANES 2007 to 2008 data, the age-standardized prevalence of hypertension in the United States was 29.8% (SE, 0.62%) and the rate of hypertension control was 45.8% (SE, 4.03%). Conclusions-Surveillance definitions of hypertension and hypertension control vary in the literature. We present standard definitions of hypertension prevalence and control among adults and standard parameters for age-adjustment and population composition that will enable meaningful population comparisons and monitoring of trends. (Circ Cardiovasc Qual Outcomes. 2012; 5:343-351.) C1 [Crim, Matthew T.; Wall, Hilary K.; Gillespie, Cathleen; Keenan, Nora; Labarthe, Darwin; Hong, Yuling] Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Chamblee, GA 30341 USA. [Yoon, Sung Sug (Sarah); Schober, Susan] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Ortiz, Eduardo; Sorlie, Paul] NHLBI, NIH, Bethesda, MD 20892 USA. RP Hong, YL (reprint author), Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Hwy NE,MS F-72, Chamblee, GA 30341 USA. EM ico2@cdc.gov FU Intramural NIH HHS [Z99 HL999999] NR 42 TC 20 Z9 22 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD MAY PY 2012 VL 5 IS 3 BP 343 EP 351 DI 10.1161/CIRCOUTCOMES.111.963439 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 002NO UT WOS:000308539100018 PM 22550130 ER PT J AU Kawel, N Nacif, M Zavodni, A Jones, J Liu, ST Sibley, CT Bluemke, DA AF Kawel, Nadine Nacif, Marcelo Zavodni, Anna Jones, Jacquin Liu, Songtao Sibley, Christopher T. Bluemke, David A. TI T1 mapping of the myocardium: Intra-individual assessment of the effect of field strength, cardiac cycle and variation by myocardial region SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T1 mapping; Modified Look-Locker inversion recovery; Extracellular volume fraction; ECV; Field strength ID CARDIOVASCULAR MAGNETIC-RESONANCE; PARTITION-COEFFICIENT; CONTRAST-MEDIA; BLOOD-VOLUME; IN-VIVO; FIBROSIS; HEART; ENHANCEMENT; TISSUE; T-1 AB Background: Myocardial T1 relaxation time (T1 time) and extracellular volume fraction (ECV) are altered in the presence of myocardial fibrosis. The purpose of this study was to evaluate acquisition factors that may result in variation of measured T1 time and ECV including magnetic field strength, cardiac phase and myocardial region. Methods: 31 study subjects were enrolled and underwent one cardiovascular MR exam at 1.5 T and two exams at 3 T, each on separate days. A Modified Look-Locker Inversion Recovery (MOLLI) sequence was acquired before and 5, 10, 12, 20, 25 and 30 min after administration of 0.15 mmol/kg gadopentetate dimeglumine (Gd-DTPA; Magnevist) at 1.5 T (exam 1). For exam 2, MOLLI sequences were acquired at 3 T both during diastole and systole, before and after administration of Gd-DTPA (0.15 mmol/kg Magnevist). Exam 3 was identical to exam 2 except gadobenate dimeglumine was administered (Gd-BOPTA; 0.1 mmol/kg Multihance). T1 times were measured in myocardium and blood. ECV was calculated by (Delta R1(myocardium)/Delta R1(blood))*(1-hematocrit). Results: Before gadolinium, T1 times of myocardium and blood were significantly greater at 3 T versus 1.5 T (28% and 31% greater, respectively, p < 0.001); after gadolinium, 3 T values remained greater than those at 1.5 T (14% and 12% greater for myocardium and blood at 3 T with Gd-DTPA, respectively, p < 0.0001 and 18% and 15% greater at 3 T with Gd-BOPTA, respectively, p < 0.0001). However, ECV did not vary significantly with field strength when using the same contrast agent at equimolar dose (p = 0.2). Myocardial T1 time was 1% shorter at systole compared to diastole pre-contrast and 2% shorter at diastole compared to systole post-contrast (p < 0.01). ECV values were greater during diastole compared to systole on average by 0.01 (p < 0.01 to p < 0.0001). ECV was significantly higher for the septum compared to the non-septal myocardium for all three exams (p < 0.0001-0.01) with mean absolute differences of 0.01, 0.004, and 0.07, respectively, for exams 1, 2 and 3. Conclusion: ECV is similar at field strengths of 1.5 T and 3 T. Due to minor variations in T1 time and ECV during the cardiac cycle and in different myocardial regions, T1 measurements should be obtained at the same cardiac phase and myocardial region in order to obtain consistent results. C1 [Kawel, Nadine; Nacif, Marcelo; Zavodni, Anna; Jones, Jacquin; Liu, Songtao; Sibley, Christopher T.; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Radiol & Imaging Sci & Mol Biomed Imaging Lab, Bethesda, MD USA. [Liu, Songtao; Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), Natl Inst Biomed Imaging & Bioengn, Radiol & Imaging Sci & Mol Biomed Imaging Lab, Bethesda, MD USA. EM bluemked@cc.nih.gov RI Sibley, Christopher/C-9900-2013; OI Bluemke, David/0000-0002-8323-8086 FU NIH intramural research program FX This study was supported by the NIH intramural research program. NR 30 TC 68 Z9 70 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD MAY 1 PY 2012 VL 14 AR 27 DI 10.1186/1532-429X-14-27 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 993RZ UT WOS:000307878600001 PM 22548832 ER PT J AU Vanbellingen, T Lungu, C Lopez, G Baronti, F Muri, R Hallett, M Bohlhalter, S AF Vanbellingen, T. Lungu, C. Lopez, G. Baronti, F. Mueri, R. Hallett, M. Bohlhalter, S. TI Short and valid assessment of apraxia in Parkinson's disease SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Apraxia; Validity; AST; Parkinson's disease ID LIMB-KINETIC APRAXIA; IDEOMOTOR APRAXIA; DEXTERITY; STROKE; TULIA AB Background: Valid assessment of apraxia in usually non-apraxic Parkinson's disease helps to delineate atypical parkinsonism frequently associated with apraxia. Furthermore, in a subgroup of late Parkinson's disease apraxia, typically the ideomotor subtype, may gradually superimpose onto parkinsonian motor symptoms contributing to defective manual skill. Here we evaluate the utility of a brief, standardized test, the apraxia screen of TULIA (AST). Methods: Seventy five Parkinson's disease patients were tested with the AST. Parkinsonian motor deficits were measured using Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III and difficulties in activities of daily living (ADL) by modified MDS-UPDRS part II (eating, dressing, personal hygiene, and writing). Results: No association was found between the AST and MDS-UPDRS part III, indicating that AST discriminates well (discriminative validity) between apraxia and parkinsonism. Furthermore, AST was associated with ADL and Hoehn & Yahr stage (convergent validity). Conclusions: AST is a short and valid test to rule out or detect apraxia in Parkinson's disease. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Bohlhalter, S.] Luzerner Kantonsspital, Div Restorat & Behav Neurol, Dept Internal Med, St Gallen, Switzerland. [Vanbellingen, T.; Mueri, R.] Univ Hosp Bern, Inselspital, Dept Neurol, Percept & Eye Movement Lab, Bern, Switzerland. [Vanbellingen, T.; Mueri, R.; Bohlhalter, S.] Univ Hosp Bern, Inselspital, Dept Clin Res, Percept & Eye Movement Lab, Bern, Switzerland. [Lungu, C.; Lopez, G.; Hallett, M.] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Baronti, F.] Klin Bethesda, Neurorehabil Ctr, Tschugg, Switzerland. RP Bohlhalter, S (reprint author), Luzerner Kantonsspital, Div Restorat & Behav Neurol, Dept Internal Med, St Gallen, Switzerland. EM stephan.bohlhalter@luks.ch OI Muri, Rene/0000-0001-6990-4188 FU Intramural NIH HHS [Z01 NS002667-23] NR 22 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD MAY PY 2012 VL 18 IS 4 BP 348 EP 350 DI 10.1016/j.parkreldis.2011.11.023 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 991CK UT WOS:000307678900008 PM 22177625 ER PT J AU Assumpcao, TCF Ribeiro, JMC Francischetti, IMB AF Assumpcao, Teresa C. F. Ribeiro, Jose M. C. Francischetti, Ivo M. B. TI Disintegrins from Hematophagous Sources SO TOXINS LA English DT Review DE disintegrins; bloodsucking; sialome; sialogenins; platelet aggregation; angiogenesis; snake venom; hematophagy; thrombus; transcriptome; proteome; salivary ID GLYCOPROTEIN-IIB-IIIA; PLATELET-AGGREGATION INHIBITORS; SNAKE-VENOM DISINTEGRINS; SOFT TICK; SALIVARY TRANSCRIPTOME; ORNITHODOROS-MOUBATA; FIBRINOGEN RECEPTOR; NEUTROPHIL FUNCTION; TRIATOMA-INFESTANS; MACROBDELLA-DECORA AB Bloodsucking arthropods are a rich source of salivary molecules (sialogenins) which inhibit platelet aggregation, neutrophil function and angiogenesis. Here we review the literature on salivary disintegrins and their targets. Disintegrins were first discovered in snake venoms, and were instrumental in our understanding of integrin function and also for the development of anti-thrombotic drugs. In hematophagous animals, most disintegrins described so far have been discovered in the salivary gland of ticks and leeches. A limited number have also been found in hookworms and horseflies, and none identified in mosquitoes or sand flies. The vast majority of salivary disintegrins reported display a RGD motif and were described as platelet aggregation inhibitors, and few others as negative modulator of neutrophil or endothelial cell functions. This notably low number of reported disintegrins is certainly an underestimation of the actual complexity of this family of proteins in hematophagous secretions. Therefore an algorithm was created in order to identify the tripeptide motifs RGD, KGD, VGD, MLD, KTS, RTS, WGD, or RED (flanked by cysteines) in sialogenins deposited in GenBank database. The search included sequences from various blood-sucking animals such as ticks (e.g., Ixodes sp., Argas sp., Rhipicephalus sp., Amblyomma sp.), tabanids (e.g., Tabanus sp.), bugs (e.g., Triatoma sp., Rhodnius prolixus), mosquitoes (e.g., Anopheles sp., Aedes sp., Culex sp.), sand flies (e.g., Lutzomyia sp., Phlebotomus sp.), leeches (e.g., Macrobdella sp., Placobdella sp.) and worms (e.g., Ancylostoma sp.). This approach allowed the identification of a remarkably high number of novel putative sialogenins with tripeptide motifs typical of disintegrins (>450 sequences) whose biological activity remains to be verified. This database is accessible online as a hyperlinked worksheet and displays biochemical, taxonomic, and gene ontology aspects for each putative disintegrin. It is also freely available for download (right click with the mouse) at links http://exon.niaid.nih.gov/transcriptome/RGD/RGD-Peps-WEB.xlsx (web version) and http://exon.niaid.nih.gov/transcriptome/RGD/RGD-sialogenins.zip (stand alone version). C1 [Assumpcao, Teresa C. F.; Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAID, NIH, Vector Biol Sect, Lab Malaria Vector Res, Rockville, MD 20852 USA. RP Assumpcao, TCF (reprint author), NIAID, NIH, Vector Biol Sect, Lab Malaria Vector Res, Rockville, MD 20852 USA. EM assumpcaot@niaid.nih.gov; jribeiro@niaid.nih.gov; ifrancischetti@niaid.nih.gov RI Ribeiro, Jose/J-7011-2015; OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank NIAID intramural editor Brenda Rae Marshall for assistance. NR 76 TC 9 Z9 9 U1 2 U2 15 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD MAY PY 2012 VL 4 IS 5 BP 296 EP 322 DI 10.3390/toxins4050296 PG 27 WC Toxicology SC Toxicology GA 995BW UT WOS:000307982700001 PM 22778902 ER PT J AU Xue, X Taylor, M Anderson, E Hao, C Qu, AJ Greenson, JK Zimmermann, EM Gonzalez, FJ Shah, YM AF Xue, Xiang Taylor, Matthew Anderson, Erik Hao, Cathy Qu, Aijuan Greenson, Joel K. Zimmermann, Ellen M. Gonzalez, Frank J. Shah, Yatrik M. TI Hypoxia-Inducible Factor-2 alpha Activation Promotes Colorectal Cancer Progression by Dysregulating Iron Homeostasis SO CANCER RESEARCH LA English DT Article ID LINDAU TUMOR-SUPPRESSOR; METAL-ION TRANSPORTER; CELL-CYCLE ARREST; DIETARY IRON; FACTOR-I; HIF-ALPHA; DEPENDENT MECHANISM; FACTOR 1-ALPHA; COLON-CANCER; MICE AB Hypoxia-inducible factor (HIF), a key modulator of the transcriptional response to hypoxia, is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. In this study, we found that intestinal epithelium-specific disruption of the von Hippel-Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apc(min/+) intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and HIF-2 alpha. Activation of HIF signaling resulted in increased cell survival in normal colon tissue; however, tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apc(min/+) mice in which HIF-2 alpha was activated in the intestine. Consistent with this result, bromodeoxyuridine incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis showed that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2 alpha-mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings show that a chronic increase in HIF-2 alpha in the colon initiates protumorigenic signaling, which may have important implications in developing preventive and therapeutic strategies for colon cancer. Cancer Res; 72(9); 2285-93. (C) 2012 AACR. C1 [Shah, Yatrik M.] Univ Michigan, Dept Internal Med, Dept Mol & Integrat Physiol, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Greenson, Joel K.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Qu, Aijuan; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Shah, YM (reprint author), Univ Michigan, Dept Internal Med, Dept Mol & Integrat Physiol, Div Gastroenterol, Ann Arbor, MI 48109 USA. EM shahy@umich.edu RI Xue, Xiang/P-9071-2014 OI Xue, Xiang/0000-0003-4704-1814 FU NIH [CA148828]; University of Michigan Gastrointestinal Peptide Center; Jeffrey A. Colby Colon Cancer Research; University of Michigan Comprehensive Cancer Center; Intramural Research Program of the National Cancer Institute FX This study was supported by grants to Y.M. Shah from the NIH (CA148828), The University of Michigan Gastrointestinal Peptide Center, and Jeffrey A. Colby Colon Cancer Research and the Tom Liu Memorial Funds of the University of Michigan Comprehensive Cancer Center. F.J. Gonzalez was supported by the Intramural Research Program of the National Cancer Institute. NR 54 TC 44 Z9 45 U1 0 U2 15 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 MAY 1 PY 2012 VL 72 IS 9 BP 2285 EP 2293 DI 10.1158/0008-5472.CAN-11-3836 PG 9 WC Oncology SC Oncology GA 986MI UT WOS:000307345300015 PM 22419665 ER PT J AU Imayama, I Ulrich, CM Alfano, CM Wang, CC Xiao, LR Wener, MH Campbell, KL Duggan, C Foster-Schubert, KE Kong, A Mason, CE Wang, CY Blackburn, GL Bain, CE Thompson, HJ McTiernan, A AF Imayama, Ikuyo Ulrich, Cornelia M. Alfano, Catherine M. Wang, Chiachi Xiao, Liren Wener, Mark H. Campbell, Kristin L. Duggan, Catherine Foster-Schubert, Karen E. Kong, Angela Mason, Caitlin E. Wang, Ching-Yun Blackburn, George L. Bain, Carolyn E. Thompson, Henry J. McTiernan, Anne TI Effects of a Caloric Restriction Weight Loss Diet and Exercise on Inflammatory Biomarkers in Overweight/Obese Postmenopausal Women: A Randomized Controlled Trial SO CANCER RESEARCH LA English DT Article ID C-REACTIVE PROTEIN; NUTRITION EXAMINATION SURVEY; ENDOMETRIAL CANCER-RISK; LIFE-STYLE INTERVENTION; PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; NATIONAL-HEALTH; CLINICAL-TRIAL; METAANALYSIS; MARKERS AB Obese and sedentary persons have increased risk for cancer; inflammation is a hypothesized mechanism. We examined the effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in 439 women. Overweight and obese postmenopausal women were randomized to 1-year: caloric restriction diet (goal of 10% weight loss, N = 118), aerobic exercise (225 min/wk of moderate-to-vigorous activity, N 117), combined diet + exercise (N = 117), or control (N = 87). Baseline and 1-year high-sensitivity C-reactive protein (hs-CRP), serum amyloid A(SAA), interleukin-6 (IL-6), leukocyte, and neutrophil levels were measured by investigators blind to group. Inflammatory biomarker changes were compared using generalized estimating equations. Models were adjusted for baseline body mass index (BMI), race/ethnicity, and age. Four hundred and thirty-eight (N = 1 in diet + exercise group was excluded) were analyzed. Relative to controls, hs-CRP decreased by geometric mean (95% confidence interval, P value): 0.92 mg/L (0.53-1.31, P<0.001) in the diet and 0.87 mg/L (0.51-1.23, P<0.0001) in the diet + exercise groups. IL-6 decreased by 0.34 pg/mL (0.13-0.55, P = 0.001) in the diet and 0.32 pg/mL (0.15-0.49, P < 0.001) in the diet + exercise groups. Neutrophil counts decreased by 0.31 x 10(9)/L (0.09-0.54, P = 0.006) in the diet and 0.30 x 10(9)/L (0.09-0.50, P = 0.005) in the diet + exercise groups. Diet and diet + exercise participants with 5% or more weight loss reduced inflammatory biomarkers (hs-CRP, SAA, and IL-6) compared with controls. The diet and diet + exercise groups reduced hs-CRP in all subgroups of baseline BMI, waist circumference, CRP level, and fasting glucose. Our findings indicate that a caloric restriction weight loss diet with or without exercise reduces biomarkers of inflammation in postmenopausal women, with potential clinical significance for cancer risk reduction. Cancer Res; 72(9); 2314-26. (C) 2012 AACR. C1 [Imayama, Ikuyo; Wang, Chiachi; Xiao, Liren; Duggan, Catherine; Mason, Caitlin E.; Bain, Carolyn E.; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98109 USA. [Ulrich, Cornelia M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. [Wang, Ching-Yun] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Wener, Mark H.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Foster-Schubert, Karen E.; McTiernan, Anne] Univ Washington, Sch Med, Seattle, WA USA. [Wang, Ching-Yun; McTiernan, Anne] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Ulrich, Cornelia M.] German Canc Res Ctr, Div Prevent Oncol, D-6900 Heidelberg, Germany. [Alfano, Catherine M.] NCI, Off Canc Survivorship, NIH, Bethesda, MD 20892 USA. [Campbell, Kristin L.] Univ British Columbia, Fac Med, Vancouver, BC, Canada. [Kong, Angela] Univ Illinois, Canc Educ & Career Dev Program, Chicago, IL USA. [Blackburn, George L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg, Boston, MA 02215 USA. [Thompson, Henry J.] Colorado State Univ, Canc Prevent Lab, Ft Collins, CO 80523 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, Program Epidemiol, 1100 Fairview Ave N,M4-B874, Seattle, WA 98109 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute (NCI) [R01 CA105204-01A1, U54-CA116847, R25CA094880, 2R25CA057699]; National Center for Research Resources, a component of the NIH [5KL2RR025015-03]; NIH Roadmap for Medical Research; Canadian Institutes of Health Research; National Institute of Diabetes and Digestive and Kidney Disease [61-7015] FX This study was supported by R01 CA105204-01A1 and U54-CA116847 from National Cancer Institute (NCI). A. Kong was supported by NCI R25CA094880 at the time of this study and is currently supported by NCI 2R25CA057699. While working on the trial, C. M. Alfano was employed at the Ohio State University and located to NCI following completion of her effort on the NEW trial. K. E. Foster-Schubert was supported by 5KL2RR025015-03 from National Center for Research Resources, a component of the NIH and NIH Roadmap for Medical Research. C. E. Mason is supported by a fellowship from the Canadian Institutes of Health Research. Part of this study was conducted at the University of Washington, Clinical Nutrition Research Unit supported by National Institute of Diabetes and Digestive and Kidney Disease 61-7015. NR 50 TC 71 Z9 73 U1 3 U2 20 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 MAY 1 PY 2012 VL 72 IS 9 BP 2314 EP 2326 DI 10.1158/0008-5472.CAN-11-3092 PG 13 WC Oncology SC Oncology GA 986MI UT WOS:000307345300018 PM 22549948 ER PT J AU Rottenberg, S Vollebergh, MA de Hoon, B de Ronde, J Schouten, PC Kersbergen, A Zander, SAL Pajic, M Jaspers, JE Jonkers, M Loden, M Sol, W van der Burg, E Wesseling, J Gillet, JP Gottesman, MM Gribnau, J Wessels, L Linn, SC Jonkers, J Borst, P AF Rottenberg, Sven Vollebergh, Marieke A. de Hoon, Bas de Ronde, Jorma Schouten, Philip C. Kersbergen, Ariena Zander, Serge A. L. Pajic, Marina Jaspers, Janneke E. Jonkers, Martijn Loden, Martin Sol, Wendy van der Burg, Eline Wesseling, Jelle Gillet, Jean-Pierre Gottesman, Michael M. Gribnau, Joost Wessels, Lodewyk Linn, Sabine C. Jonkers, Jos Borst, Piet TI Impact of Intertumoral Heterogeneity on Predicting Chemotherapy Response of BRCA1-Deficient Mammary Tumors SO CANCER RESEARCH LA English DT Article ID HIGH-DOSE CHEMOTHERAPY; HEREDITARY BREAST-CANCER; INACTIVE X-CHROMOSOME; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; MOUSE MODEL; CELL-LINES; XIST RNA; IN-VIVO; BRCA1 AB The lack of markers to predict chemotherapy responses in patients poses a major handicap in cancer treatment. We searched for gene expression patterns that correlate with docetaxel or cisplatin response in a mouse model for breast cancer associated with BRCA1 deficiency. Array-based expression profiling did not identify a single marker gene predicting docetaxel response, despite an increase in Abcb1 (P-glycoprotein) expression that was sufficient to explain resistance in several poor responders. Intertumoral heterogeneity explained the inability to identify a predictive gene expression signature for docetaxel. To address this problem, we used a novel algorithm designed to detect differential gene expression in a subgroup of the poor responders that could identify tumors with increased Abcb1 transcript levels. In contrast, standard analytical tools, such as significance analysis of microarrays, detected a marker only if it correlated with response in a substantial fraction of tumors. For example, low expression of the Xist gene correlated with cisplatin hypersensitivity in most tumors, and it also predicted long recurrence-free survival of HER2-negative, stage III breast cancer patients treated with intensive platinum-based chemotherapy. Our findings may prove useful for selecting patients with high-risk breast cancer who could benefit from platinum-based therapy. Cancer Res; 72(9); 2350-61. (C) 2012 AACR. C1 [Rottenberg, Sven; Vollebergh, Marieke A.; de Ronde, Jorma; Schouten, Philip C.; Kersbergen, Ariena; Zander, Serge A. L.; Pajic, Marina; Jaspers, Janneke E.; Jonkers, Martijn; Sol, Wendy; van der Burg, Eline; Wesseling, Jelle; Wessels, Lodewyk; Linn, Sabine C.; Jonkers, Jos; Borst, Piet] Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands. [Jonkers, Martijn; Loden, Martin] MRC Holland BV, Amsterdam, Netherlands. [de Hoon, Bas; Gribnau, Joost] Erasmus MC, Dept Reprod & Dev, Rotterdam, Netherlands. [Gillet, Jean-Pierre; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rottenberg, S (reprint author), Netherlands Canc Inst, Div Mol Biol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM s.rottenberg@nki.nl; p.borst@nki.nl RI gillet, jean-pierre/A-3714-2012 FU Dutch Cancer Society [2006-3566, 2006-3706, 2009-4303]; Netherlands Organization for Scientific Research [NWO-VIDI-91711302]; European Union [037665-CHEMORES]; CTMM Breast Care FX This work was supported by grants from the Dutch Cancer Society 2006-3566 (P. Borst/S. Rottenberg/J. Jonkers), 2006-3706 (M. A. Vollebergh/S.C. Linn), 2009-4303 (S. Rottenberg/J. Jonkers/P. Borst), the Netherlands Organization for Scientific Research (NWO-VIDI-91711302 to S. Rottenberg), the European Union FP6 Integrated Project 037665-CHEMORES (P. Borst/S. Rottenberg) and CTMM Breast Care (J. Jonkers/S. Rottenberg). NR 48 TC 24 Z9 24 U1 1 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 MAY 1 PY 2012 VL 72 IS 9 BP 2350 EP 2361 DI 10.1158/0008-5472.CAN-11-4201 PG 12 WC Oncology SC Oncology GA 986MI UT WOS:000307345300021 PM 22396490 ER PT J AU Hayman, TJ Williams, ES Jamal, M Shankavaram, UT Camphausen, K Tofilon, PJ AF Hayman, Thomas J. Williams, Eli S. Jamal, Muhammad Shankavaram, Uma T. Camphausen, Kevin Tofilon, Philip J. TI Translation Initiation Factor eIF4E Is a Target for Tumor Cell Radiosensitization SO CANCER RESEARCH LA English DT Article ID FACTOR 4E; GENE-EXPRESSION; DNA-DAMAGE; CANCER; RIBAVIRIN; PHOSPHORYLATION; TRANSFORMATION; PROGRESSION; ACTIVATION; REPAIR AB A core component in the cellular response to radiation occurs at the level of translational control of gene expression. Because a critical element in translation control is the availability of the initiation factor eIF4E, which selectively enhances the cap-dependent translation of mRNAs, we investigated a regulatory role for eIF4E in cellular radiosensitivity. eIF4E silencing enhanced the radiosensitivity of tumor cell lines but not normal cells. Similarly, pharmacologic inhibition of eIF4E with ribavirin also enhanced tumor cell radiosensitivity. eIF4E attenuation did not affect cell-cycle phase distribution or radiation-induced apoptosis, but it delayed the dispersion of radiation-induced gamma H2AX foci and increased the frequency of radiation-induced mitotic catastrophe. Radiation did not affect 4E-BP1 phosphorylation or cap-complex formation but it increased eIF4E binding to more than 1,000 unique transcripts including many implicated in DNA replication, recombination, and repair. Taken together, our findings suggest that eIF4E represents a logical therapeutic target to increase tumor cell radiosensitivity. Cancer Res; 72(9); 2362-72. (C) 2012 AACR. C1 [Hayman, Thomas J.; Jamal, Muhammad; Shankavaram, Uma T.; Camphausen, Kevin; Tofilon, Philip J.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Hayman, Thomas J.] Univ S Florida, Morsani Coll Med, Tampa, FL USA. [Williams, Eli S.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. RP Tofilon, PJ (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr,MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. EM tofionp@mail.nih.gov NR 38 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 MAY 1 PY 2012 VL 72 IS 9 BP 2362 EP 2372 DI 10.1158/0008-5472.CAN-12-0329 PG 11 WC Oncology SC Oncology GA 986MI UT WOS:000307345300022 PM 22397984 ER PT J AU Switzer, CH Cheng, RYS Ridnour, LA Murray, MC Tazzari, V Sparatore, A Del Soldato, P Hines, HB Glynn, SA Ambs, S Wink, DA AF Switzer, Christopher H. Cheng, Robert Y. -S. Ridnour, Lisa A. Murray, Margaret C. Tazzari, Valerio Sparatore, Anna Del Soldato, Piero Hines, Harry B. Glynn, Sharon A. Ambs, Stefan Wink, David A. TI Dithiolethiones Inhibit NF-kappa B Activity via Covalent Modification in Human Estrogen Receptor-Negative Breast Cancer SO CANCER RESEARCH LA English DT Article ID THERAPEUTIC TARGET; HYDROGEN-SULFIDE; POOR SURVIVAL; ACTIVATION; CELLS; CHEMOPREVENTION; PROGRESSION; MODULATION; EXPRESSION; OLTIPRAZ AB The NF-kappa B transcription factor family influences breast cancer outcomes by regulating genes involved in tumor progression, angiogenesis, and metastasis. Dithiolethiones, a class of naturally occurring compounds with cancer chemoprevention effects that have become clinically available, have been found to inhibit NF-kappa B activity. However, the mechanism of this inhibition has not been identified, and the influence of dithiolethines on NF-kappa B pathway in breast cancer cells has not been examined. Here, we investigated the chemical and biochemical effects of dithiolethione on NF-kappa B and downstream effector molecules in estrogen receptor-negative breast cancer cells and murine tumor xenografts. The dithiolethiones ACS-1 and ACS-2 inhibited NF-kappa B transcriptional activity. Interestingly, this inhibition was not due to H2S release or protein phosphatase 2A activation, which are key properties of dithiolethiones, but occurred via a covalent reaction with the NF-kappa B p50 and p65 subunits to inhibit DNA binding. Dithiolethione-mediated inhibition of NF-kappa B-regulated genes resulted in the inhibition of interleukin (IL)-6, IL-8, urokinase-type plasminogen activator, and VEGF production. ACS-1 also inhibited matrix metalloproteinase-9 activity, cellular migration, and invasion, and ACS-2 reduced tumor burden and resulted in increased tumor host interactions. Together, our findings suggest that dithiolethiones show potential clinical use for estrogen negative breast cancer as a chemotherapeutic or adjuvant therapy. Cancer Res; 72(9); 2394-404. (C) 2012 AACR. C1 [Switzer, Christopher H.; Cheng, Robert Y. -S.; Ridnour, Lisa A.; Murray, Margaret C.; Glynn, Sharon A.; Wink, David A.] NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. [Glynn, Sharon A.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Tazzari, Valerio; Sparatore, Anna] Univ Milan, Dipartimento Sci Farmaceut Pietro Pratesi, Milan, Italy. [Del Soldato, Piero] Sulfidris, Milan, Italy. [Hines, Harry B.] USA, Med Res Inst Infect Dis, Integrated Toxicol Div, Frederick, MD USA. RP Wink, DA (reprint author), Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov RI Glynn, Sharon/D-7136-2013; Switzer, Christopher/D-9203-2013; Sparatore, Anna/J-8634-2015 OI Glynn, Sharon/0000-0003-1459-2580; Sparatore, Anna/0000-0003-2135-2649 FU NIH, National Cancer Institute [1ZIASC007281-16, 1ZIABC010899-02] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute (1ZIASC007281-16 and 1ZIABC010899-02). NR 32 TC 16 Z9 16 U1 1 U2 8 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 MAY 1 PY 2012 VL 72 IS 9 BP 2394 EP 2404 DI 10.1158/0008-5472.CAN-11-3115 PG 11 WC Oncology SC Oncology GA 986MI UT WOS:000307345300025 PM 22436383 ER PT J AU Giulianelli, S Vaque, JP Soldati, R Wargon, V Vanzulli, SI Martins, R Zeitlin, E Molinolo, AA Helguero, LA Lamb, CA Gutkind, JS Lanari, C AF Giulianelli, Sebastian Vaque, Jose P. Soldati, Rocio Wargon, Victoria Vanzulli, Silvia I. Martins, Ruben Zeitlin, Eduardo Molinolo, Alfredo A. Helguero, Luisa A. Lamb, Caroline A. Gutkind, J. Silvio Lanari, Claudia TI Estrogen Receptor Alpha Mediates Progestin-Induced Mammary Tumor Growth by Interacting with Progesterone Receptors at the Cyclin D1/MYC Promoters SO CANCER RESEARCH LA English DT Article ID HUMAN-BREAST-CANCER; CELL-CYCLE PROGRESSION; C-MYC GENE; CROSS-TALK; PROTEIN-KINASES; EXPRESSION; ACTIVATION; CARCINOMAS; DOMAINS; LINES AB Synthetic progesterone used in contraception drugs (progestins) can promote breast cancer growth, but the mechanisms involved are unknown. Moreover, it remains unclear whether cytoplasmic interactions between the progesterone receptor (PR) and estrogen receptor alpha (ER alpha) are required for PR activation. In this study, we used a murine progestin-dependent tumor to investigate the role of ER alpha in progestin-induced tumor cell proliferation. We found that treatment with the progestin medroxyprogesterone acetate (MPA) induced the expression and activation of ER alpha, as well as rapid nuclear colocalization of activated ER alpha with PR. Treatment with the pure antiestrogen fulvestrant to block ER alpha disrupted the interaction of ER alpha and PR in vitro and induced the regression of MPA-dependent tumor growth in vivo. ER alpha blockade also prevented an MPA-induced increase in CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies showed that MPA triggered binding of ER alpha and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAi-mediated silencing of ER alpha inhibited ER alpha, but not PR binding to both regulatory sequences, indicating that an interaction between ER alpha and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER alpha-PR association on target gene promoters is essential for progestin-induced cell proliferation. Cancer Res; 72(9); 2416-27. (C) 2012 AACR. C1 [Giulianelli, Sebastian; Soldati, Rocio; Wargon, Victoria; Helguero, Luisa A.; Lamb, Caroline A.; Lanari, Claudia] IBYME CONICET, Inst Expt Biol & Med, Buenos Aires, DF, Argentina. [Vanzulli, Silvia I.] Natl Acad Med Buenos Aires, Buenos Aires, DF, Argentina. [Martins, Ruben; Zeitlin, Eduardo] Policlin Bancaria, Buenos Aires, DF, Argentina. [Vaque, Jose P.; Molinolo, Alfredo A.; Gutkind, J. Silvio] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Lanari, C (reprint author), IBYME CONICET, Inst Expt Biol & Med, Obligado 2490 C1428ADN, Buenos Aires, DF, Argentina. EM lanari.claudia@gmail.com RI Helguero, Luisa/B-1221-2013; Vaque, Jose/H-8413-2015 OI Helguero, Luisa/0000-0001-8237-2390; Vaque, Jose/0000-0002-3913-2495 FU SECYT [PICT2007/932]; Carrillo-Onativia Fellowships [03/04]; CONICET; Fundacion Sales; Intramural Research Program (NIDCR-NIH); Avon Foundation; ICRETT fellowship (UICC) FX This work was supported by SECYT (PICT2007/932), Carrillo-Onativia Fellowships 03/04, CONICET and Fundacion Sales. J.S. Gutkind, A. A. Molinolo, and J.P. Vaque are supported by the Intramural Research Program (NIDCR-NIH). S. Giulianelli and V. Wargon are fellows of CONICET. C. A. Lamb and C. Lanari are members of the Research Career, CONICET. S. Giulianelli received awards from Avon Foundation to present data at the AACR Meetings 2009-2011, and he received an ICRETT fellowship (UICC) to carry out ChIP studies in Dr. Gutkind's Laboratory. NR 49 TC 31 Z9 31 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 MAY 1 PY 2012 VL 72 IS 9 BP 2416 EP 2427 DI 10.1158/0008-5472.CAN-11-3290 PG 12 WC Oncology SC Oncology GA 986MI UT WOS:000307345300027 PM 22396492 ER PT J AU Kobrinsky, E Lee, JH Soldatov, NM AF Kobrinsky, Evgeny Lee, Jung-Ha Soldatov, Nikolai M. TI Selective fluorophore-assisted light inactivation of voltage-gated calcium channels SO CHANNELS LA English DT Article DE calcium channel; Ca(v)1.2; Ca(v)3.1; in situ photoinactivation; fluorophore-assisted light inactivation; FRET ID TAILS AB Fluorophore-assisted light inactivation (FALI) is an investigative tool to inactivate fluorescently labeled proteins by a mechanism of in situ photodestruction. We found that Ca(v)1.2 (L-type) and Ca(v)3.1 (T-type) calcium channels, labeled by genetic fusion with GFP derivatives, show differential sensitivity to FALI. Specifically, FALI silences Ca(v)1.2 calcium channels containing EYFP-labeled alpha(1C) subunits but does not affect the EYFP-alpha(1G) Ca(v)3.1 calcium channels or Ca(v)1.2 channels containing EYFP-labeled beta subunits. Our findings limit the applicability of acceptor photobleaching for the measurements of FRET but open an opportunity to combine the fluroscent imaging of the live cell expressing labeled calcium channels with selective functional inactivation of their specifics subsets. C1 [Kobrinsky, Evgeny; Soldatov, Nikolai M.] NIA, NIH, Baltimore, MD 21224 USA. [Lee, Jung-Ha] Sogang Univ, Dept Life Sci, Seoul, South Korea. RP Soldatov, NM (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM soldatovn.humgenex@verizon.net FU National Institute on Aging Intramural Research Program [Z01 AG000294-07]; NRF of Korea [0093822] FX This work was supported by the National Institute on Aging Intramural Research Program Z01 AG000294-07 (to N.M.S.) and the Priority Research Centers Program 0093822 through NRF of Korea (to J.H.L.). NR 9 TC 0 Z9 0 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6950 J9 CHANNELS JI Channels PD MAY-JUN PY 2012 VL 6 IS 3 BP 154 EP 156 DI 10.4161/chan.20867 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 983LI UT WOS:000307120400003 PM 22909954 ER PT J AU Schmidt, C Smith, C Barin, B Bakhtyari, A Bart, PA Bekker, LG Chomba, E Clumeck, N Ho, D Hoosen, A Jaoko, W Kaleebu, P Karita, E Keefer, MC van Lunzen, J McMichael, A Mehendale, S Peters, B Ramanathan, VD Robinson, A Rockstroh, J Vardas, E Vets, E Weber, J Graham, BS Than, S Excler, JL Kochhar, S Ho, M Heald, A Fast, PE AF Schmidt, Claudia Smith, Carol Barin, Burc Bakhtyari, Arash Bart, Pierre-Alexandre Bekker, Linda-Gail Chomba, Elwyn Clumeck, Nathan Ho, David Hoosen, Anwar Jaoko, Walter Kaleebu, Pontiano Karita, Etienne Keefer, Michael C. van Lunzen, Jan McMichael, Andrew Mehendale, Sanjay Peters, Barry Ramanathan, Vadakkuppatu D. Robinson, Andrew Rockstroh, Juergen Vardas, Eftyhia Vets, Eva Weber, Jonathan Graham, Barney S. Than, Soe Excler, Jean-Louis Kochhar, Sonali Ho, Martin Heald, Alison Fast, Patricia E. TI Background morbidity in HIV vaccine trial participants from various geographic regions as assessed by unsolicited adverse events SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE adverse events; HIV vaccine trials; geographic regions; background morbidity; developing countries ID VIRUS ANKARA MVA; I CLINICAL-TRIAL; IMMUNOGENICITY EVALUATION; ADENOASSOCIATED VIRUS; CANDIDATE VACCINE; PHASE-1 SAFETY; DNA; EVALUATE; VOLUNTEERS; AFRICA AB Background: Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 uninfected volunteers. Objective: To assess background morbidity as reflected by unsolicited adverse events (AEs), unrelated to study vaccine, reported in clinical trials from four continents. Methods: All but three clinical trials were double-blind, randomized and placebo-controlled. Study procedures and data collection methods were standardized. The frequency and severity of AEs reported during the first year of the trials were analyzed. To avoid confounding by vaccine-related events, solicited reactogenicity and other AEs occurring within 28 d after any vaccination were excluded. Results: In total, 2134 AEs were reported by 76% of all participants; 73% of all events were mild. The rate of AEs did not differ between placebo and vaccine recipients. Overall, the percentage of participants with any AE was higher in Africa (83%) compared with Europe (71%), US (74%) and India (65%), while the percentage of participants with AEs of moderate or greater severity was similar in all regions except India. In all regions, the most frequently reported AEs were infectious diseases, followed by gastrointestinal disorders. Conclusions: Despite some regional differences, in these healthy participants selected for low risk of HIV infection, background morbidity posed no obstacle to clinical trial conduct and interpretation. Data from controlled clinical trials of preventive interventions can offer valuable insights into the health of the eligible population. C1 [Schmidt, Claudia; Than, Soe; Excler, Jean-Louis; Fast, Patricia E.] Int AIDS Vaccine Initiat, New York, NY USA. [Smith, Carol; Barin, Burc; Ho, Martin] EMMES Corp, Rockville, MD USA. [Bakhtyari, Arash] SIMBEC Res Ltd, Merthyr Tydfil, M Glam, Wales. [Bart, Pierre-Alexandre] Vaudois CHUV, Le Ctr Hosp Univ, Lausanne, Switzerland. [Bekker, Linda-Gail] DTHC, Cape Town, South Africa. [Chomba, Elwyn] ZEHRP, Lusaka, Zambia. [Clumeck, Nathan] Div Infect Dis, Clin Res Unit, Brussels, Belgium. [Ho, David] Aaron Diamond Res Ctr ADARC, New York, NY USA. [Hoosen, Anwar] MEDUNSA, Dept Med Microbiol, Ga Rankuwa, Pretorial, South Africa. [Jaoko, Walter] KNH, KAVI, Nairobi, Kenya. [Kaleebu, Pontiano] UVRI, Int AIDS Vaccine Initiat HIV Vaccine Program, Entebbe, Uganda. [Karita, Etienne] PSF, Kigali, Rwanda. [Keefer, Michael C.] Univ Rochester, Rochester, NY USA. [van Lunzen, Jan] Univ Klinikum Eppendorf, Zentrum Innere Med, Hamburg, Germany. [McMichael, Andrew] Univ Oxford, Weatherall Inst Mol Med, Human Immunol Unit, Oxford, England. [Mehendale, Sanjay] NARI, Div Epidemiol, Pune, Maharashtra, India. [Peters, Barry] Kings Coll London, Guys & St Thomas Hosp, London WC2R 2LS, England. [Ramanathan, Vadakkuppatu D.] TRC, Madras, Tamil Nadu, India. [Robinson, Andrew] MRC, Durban, South Africa. [Rockstroh, Juergen] Med Klin & Poliklin, Bonn, Germany. [Vardas, Eftyhia] Chris Hani Baragwanath Hosp, Perinatal HIV Res Unit, Soweto, South Africa. [Vets, Eva] SGS Biopharma SA, Antwerp, Belgium. [Weber, Jonathan] St Marys Hosp, Sch Med, London, England. [Graham, Barney S.] NIAID, VRC, NIH, Bethesda, MD 20892 USA. [Kochhar, Sonali] Int AIDS Vaccine Initiat, New Delhi, India. [Heald, Alison] Targeted Genet Corp, Seattle, WA USA. RP Fast, PE (reprint author), Int AIDS Vaccine Initiat, New York, NY USA. EM pfast@iavi.org OI Vardas, Eftyhia/0000-0002-7804-878X FU International AIDS Vaccine Initiative; US Agency for International Development (USAID) [GPO-A-00-06-00006-00]; Government of Canada; Government of Denmark; Government of Ireland; Government of Netherlands; Government of Norway; Government of Sweden; Government of UK; Basque Autonomous Government; European Union; Bill and Melinda Gates Foundation FX All studies were sponsored by the International AIDS Vaccine Initiative and funded by its donors, including the US Agency for International Development (USAID Cooperative Agreement Number GPO-A-00-06-00006-00), the Governments of Canada, Denmark, Ireland, The Netherlands, Norway, Sweden, the UK, the Basque Autonomous Government, the European Union and the Bill and Melinda Gates Foundation. NR 16 TC 2 Z9 2 U1 1 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD MAY PY 2012 VL 8 IS 5 BP 630 EP 638 DI 10.4161/hv.19454 PG 9 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 983FD UT WOS:000307103200022 PM 22634443 ER PT J AU Nguyen, TL Cera, MR Pinto, A Lo Presti, L Hamel, E Conti, P Gussio, R De Wulf, P AF Nguyen, Tam Luong Cera, Maria Rosaria Pinto, Andrea Lo Presti, Leonardo Hamel, Ernest Conti, Paola Gussio, Rick De Wulf, Peter TI Evading Pgp Activity in Drug-Resistant Cancer Cells: A Structural and Functional Study of Antitubulin Furan Metotica Compounds SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID CHIRAL STATIONARY PHASES; COLCHICINE; TUBULIN; AGENTS; SCREEN; LINES; FIELD AB Tumor resistance to antitubulin drugs resulting from P-glycoprotein (Pgp) drug-efflux activity, increased expression of the beta III tubulin isotype, and alterations in the drug-binding sites are major obstacles in cancer therapy. Consequently, novel antitubulin drugs that overcome these challenges are of substantial interest. Here, we study a novel chemotype named furan metotica that localizes to the colchicine-binding site in beta-tubulin, inhibits tubulin polymerization, and is not antagonized by Pgp. To elucidate the structure-activity properties of this chiral chemotype, the enantiomers of its most potent member were separated and their absolute configurations determined by X-ray crystallography. Both isomers were active and inhibited all 60 primary cancer cell lines tested at the U.S. National Cancer Institute. They also efficiently killed drug-resistant cancer cells that overexpressed the Pgp drug-efflux pump 10(6)-fold. In vitro, the R-isomer inhibited tubulin polymerization at least 4-fold more potently than the S-isomer, whereas in human cells the difference was 30-fold. Molecular modeling showed that the two isomers bind to beta-tubulin in distinct manners: the R-isomer binds in a colchicine-like mode and the S-isomer in a podophyllotoxin-like fashion. In addition, the dynamic binding trajectory and occupancy state of the R-isomer were energetically more favorable then those of the S-isomer, explaining the observed differences in biologic activities. The ability of a racemic drug to assume the binding modes of two prototypical colchicine-site binders represents a novel mechanistic basis for antitubulin activity and paves the way toward a comprehensive design of novel anticancer agents. Mol Cancer Ther; 11(5); 1103-11. (c) 2012 AACR. C1 [Cera, Maria Rosaria; De Wulf, Peter] European Inst Oncol, Dept Expt Oncol, I-20139 Milan, MI, Italy. [Nguyen, Tam Luong] NCI, Target Struct Based Drug Discovery Grp, SAIC Frederick Inc, NIH, Frederick, MD 21701 USA. [Hamel, Ernest] NCI, Screening Technol Branch, NIH, Frederick, MD 21701 USA. [Gussio, Rick] NCI, Informat Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21701 USA. [Pinto, Andrea; Conti, Paola] Univ Milan, Dipartimento Sci Farmaceut Pietro Prate, Milan, Italy. [Lo Presti, Leonardo] Univ Milan, Dipartimento Chim Fis & Elettrochim, Milan, Italy. RP De Wulf, P (reprint author), European Inst Oncol, Dept Expt Oncol, Via Adamello 16, I-20139 Milan, MI, Italy. EM peter.dewulf@ifom-ieo-campus.it RI Conti, Paola/D-1266-2011; pinto, andrea/C-8384-2011; Lo Presti, Leonardo/K-4281-2012; OI pinto, andrea/0000-0002-2501-3348; Lo Presti, Leonardo/0000-0001-6361-477X; De Wulf, Peter/0000-0001-9772-5881; Conti, Paola/0000-0003-2140-0567 FU federal funds from the National Cancer Institute, NIH [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute; Association of International Cancer Research [08-0465]; U.S. Army Medical Research and Material Command Research Plan [02-4-3U-057]; IAA [Y3-CM-100505] FX This project has been funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute.; This research was supported in part by grant 08-0465 from the Association of International Cancer Research to P. De Wulf. The research was also sponsored in part by the U.S. Army Medical Research and Material Command Research Plan #02-4-3U-057 and IAA #Y3-CM-100505 (MRMC and NCI). NR 21 TC 5 Z9 5 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAY PY 2012 VL 11 IS 5 BP 1103 EP 1111 DI 10.1158/1535-7163.MCT-11-1018 PG 9 WC Oncology SC Oncology GA 995CN UT WOS:000307984800006 PM 22442310 ER PT J AU Hassan, M Chernomordik, V Zielinski, R Ardeshirpour, Y Capala, J Gandjbakhche, A AF Hassan, Moinuddin Chernomordik, Victor Zielinski, Rafal Ardeshirpour, Yasaman Capala, Jacek Gandjbakhche, Amir TI In Vivo Method to Monitor Changes in HER2 Expression Using Near-Infrared Fluorescence Imaging SO MOLECULAR IMAGING LA English DT Article ID DOMAIN OPTICAL MAMMOGRAPHY; BREAST-TUMORS; AFFIBODY MOLECULES; THERAPY; CANCER; ANGIOGENESIS; TOMOGRAPHY AB Human epidermal growth factor receptor type 2 (HER2) is a well-known biomarker that is overexpressed in many breast carcinomas. HER2 expression level is an important factor to optimize the therapeutic strategy and monitor the treatment. We used albumin binding domain-fused HER2-specific Affibody molecules, labeled with Alexa Fluor750 dye, to characterize HER2 expression in vivo. Near-infrared optical imaging studies were carried out using mice with subcutaneous HER2-positive tumors. Animals were divided into groups of five: no treatment and 12 hours and 1 week after treatment of the tumors with the Hsp90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). The compartmental ligands-receptor model, describing binding kinetics, was used to evaluate HER2 expression from the time sequence of the fluorescence images after the intravenous probe injection. The normalized rate of accumulation of the specific fluorescent biomarkers, estimated from this time sequence, linearly correlates with the conventional ex vivo enzyme-linked immunosorbent assay (ELISA) readings for the same tumor. Such correspondence makes properly arranged fluorescence imaging an excellent candidate for estimating HER2 overexpression in tumors, complementing ELISA and other ex vivo assays. Application of this method to the fluorescence data from HER2-positive xenografts reveals that the 17-DMAG treatment results in downregulation of HER2. Application of the AngioSense 750 probe confirmed the antiangiogenic effect of 17-DMAG found with Affibody-Alexa Fluor 750 conjugate. C1 [Gandjbakhche, Amir] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Analyt & Funct Biophoton, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD USA. NCI, Mol Targeting Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. John Paul II Catholic Univ Lublin, Dept Mol Biol, Lublin, Poland. RP Gandjbakhche, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Analyt & Funct Biophoton, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD USA. EM amir@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute, National Institutes of Health. NR 27 TC 7 Z9 7 U1 0 U2 14 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 J9 MOL IMAGING JI Mol. Imaging PD MAY-JUN PY 2012 VL 11 IS 3 BP 177 EP 186 DI 10.2310/7290.2011.00038 PG 10 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA 990QP UT WOS:000307646000001 PM 22554482 ER PT J AU Xu, QH Kopp, JB AF Xu, Qihe Kopp, Jeffrey B. TI Retinoid and TGF-beta Families: Crosstalk in Development, Neoplasia, Immunity, and Tissue Repair SO SEMINARS IN NEPHROLOGY LA English DT Review DE Retinol; retinoic acid; retinoic acid receptors; kidneys; immunology ID GROWTH-FACTOR-BETA; REGULATORY T-CELLS; ACID RECEPTOR-ALPHA; VITAMIN-A; DENDRITIC CELLS; TRANSCRIPTIONAL REGULATION; TGF-BETA-2 EXPRESSION; MESANGIAL CELLS; OUTFLOW TRACT; KNOCKOUT MICE AB Transforming growth factor-beta (TGF-beta) isoforms are profibrotic cytokines, par excellence, and have complex multifunctional effects on many systems, depending on the biologic setting. Retinoids are vitamin A derivatives that also have diverse effects in development, physiology, and disease. The interactions between these classes of molecules are, not surprisingly, highly complex and are dependent on the tissue, cellular, and molecular settings. Semin Nephrol 32:287-294 (C) 2012 Elsevier Inc. All rights reserved. C1 [Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Xu, Qihe] Kings Coll London, Dept Renal Med, London WC2R 2LS, England. RP Kopp, JB (reprint author), NIDDKD, Kidney Dis Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov FU National Institute for Diabetes and Digestive and Kidney Disease Intramural Research Program; Kidney Research UK Innovation Grant FX Supported by the National Institute for Diabetes and Digestive and Kidney Disease Intramural Research Program and a Kidney Research UK Innovation Grant. NR 97 TC 12 Z9 12 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAY PY 2012 VL 32 IS 3 BP 287 EP 294 DI 10.1016/j.semnephrol.2012.04.008 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 986DS UT WOS:000307321800009 PM 22835460 ER PT J AU Muhammed, M Feldmesser, M Shubitz, LF Lionakis, MS Sil, A Wang, Y Glavis-Bloom, J Lewis, RE Galgiani, JN Casadevall, A Kontoyiannis, DP Mylonakis, E AF Muhammed, Maged Feldmesser, Marta Shubitz, Lisa F. Lionakis, Michail S. Sil, Anita Wang, Yan Glavis-Bloom, Justin Lewis, Russell E. Galgiani, John N. Casadevall, Arturo Kontoyiannis, Dimitrios P. Mylonakis, Eleftherios TI Mouse models for the study of fungal pneumonia A collection of detailed experimental protocols for the study of Coccidioides, Cryptococcus, Fusarium, Histoplasma and combined infection due to Aspergillus-Rhizopus SO VIRULENCE LA English DT Article DE animal models; Aspergillus; Coccidioides; Cryptococcus; fungal infection; Fusarium; Histoplasma; pulmonary infection; Rhizopus ID IMMUNODEFICIENCY-VIRUS-INFECTION; MURINE PULMONARY INFECTION; HEMATOLOGIC MALIGNANCIES; IMMITIS INFECTION; IMMUNE-RESPONSES; QUANTITATIVE PCR; MICE; NEOFORMANS; CAPSULATUM; FUMIGATUS C1 [Muhammed, Maged; Wang, Yan; Glavis-Bloom, Justin; Mylonakis, Eleftherios] Harvard Univ, Sch Med, Div Infect Dis, Boston, MA 02115 USA. [Muhammed, Maged; Wang, Yan; Glavis-Bloom, Justin; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Feldmesser, Marta; Casadevall, Arturo] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Feldmesser, Marta; Casadevall, Arturo] Albert Einstein Coll Med, Div Infect Dis, Bronx, NY 10467 USA. [Shubitz, Lisa F.; Galgiani, John N.] Univ Arizona, Valley Fever Ctr Excellence, Tucson, AZ USA. [Shubitz, Lisa F.; Galgiani, John N.] Univ Arizona, Dept Vet Sci & Microbiol, Tucson, AZ USA. [Lionakis, Michail S.] NIAID, Clin Mycol Unit, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Sil, Anita] Univ Calif San Francisco, Dept Microbiol & Immunol, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Wang, Yan] Second Mil Med Univ, Sch Pharm, Shanghai, Peoples R China. [Lewis, Russell E.; Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lewis, Russell E.; Kontoyiannis, Dimitrios P.] Univ Houston, Coll Pharm, Houston, TX 77030 USA. RP Mylonakis, E (reprint author), Harvard Univ, Sch Med, Div Infect Dis, Boston, MA 02115 USA. EM emylonakis@partners.org OI Glavis-Bloom, Justin/0000-0002-4879-1572; Lewis, Russell/0000-0002-2002-4339 FU National Institute of Allergy and Infectious Diseases [U54AI065359] FX J.N.G. was supported in part by Award Number U54AI065359 from the National Institute of Allergy and Infectious Diseases. NR 47 TC 8 Z9 8 U1 0 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2150-5594 EI 2150-5608 J9 VIRULENCE JI Virulence PD MAY-JUN PY 2012 VL 3 IS 3 BP 329 EP 338 DI 10.4161/viru.20142 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 995JI UT WOS:000308003900015 PM 22546902 ER PT J AU Yong, RL Lonser, RR AF Yong, Raymund L. Lonser, Russell R. TI Immunotherapy Trials for Glioblastoma Multiforme: Promise and Pitfalls SO WORLD NEUROSURGERY LA English DT Editorial Material DE Dendritic cells; Glioblastoma multiforme; Immunotherapy; Overall survival; Progression-free survival; Vaccine ID DENDRITIC CELL VACCINATION; CENTRAL-NERVOUS-SYSTEM; MALIGNANT GLIOMA; T-CELLS; CEREBROSPINAL-FLUID; IMMUNE-RESPONSES; GROWTH; TEMOZOLOMIDE; EXPRESSION; THERAPY C1 [Yong, Raymund L.; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov NR 26 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 1878-8750 J9 WORLD NEUROSURG JI World Neurosurg. PD MAY-JUN PY 2012 VL 77 IS 5-6 BP 636 EP 638 DI 10.1016/j.wneu.2011.10.010 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 988XC UT WOS:000307523800019 PM 22120230 ER PT J AU Uchime, O Herrera, R Reiter, K Kotova, S Shimp, RL Miura, K Jones, D Lebowitz, J Ambroggio, X Hurt, DE Jin, AJ Long, C Miller, LH Narum, DL AF Uchime, Onyinyechukwu Herrera, Raul Reiter, Karine Kotova, Svetlana Shimp, Richard L., Jr. Miura, Kazutoyo Jones, Dominique Lebowitz, Jacob Ambroggio, Xavier Hurt, Darrell E. Jin, Albert J. Long, Carole Miller, Louis H. Narum, David L. TI Analysis of the Conformation and Function of the Plasmodium falciparum Merozoite Proteins MTRAP and PTRAMP SO EUKARYOTIC CELL LA English DT Article ID MALARIA CIRCUMSPOROZOITE PROTEIN; APICOMPLEXAN PARASITES; TOXOPLASMA-GONDII; GLIDING MOTILITY; CELL INVASION; HOST-CELLS; MYOSIN-A; MEMBRANE; SURFACE; SPOROZOITES AB Thrombospondin repeat (TSR)-like domains are structures involved with cell adhesion. Plasmodium falciparum proteins containing TSR domains play crucial roles in parasite development. In particular, the preerythrocytic P. falciparum circumsporozoite protein is involved in hepatocyte invasion. The importance of these domains in two other malaria proteins, the merozoite-specific thrombospondin-related anonymous protein (MTRAP) and the thrombospondin-related apical membrane protein (PTRAMP), were assessed using near-full-length recombinant proteins composed of the extracellular domains produced in Escherichia coli. MTRAP is thought to be released from invasive organelles identified as micronemes during merozoite invasion to mediate motility and host cell invasion through an interaction with aldolase, an actin binding protein involved in the moving junction. PTRAMP function remains unknown. In this study, the conformation of recombinant MTRAP (rMTRAP) appeared to be a highly extended protein (2 nm by 33 nm, width by length, respectively), whereas rPTRAMP had a less extended structure. Using an erythrocyte binding assay, rMTRAP but not rPTRAMP bound human erythrocytes; rMTRAP binding was mediated through the TSR domain. MTRAP-and in general PTRAMP-specific antibodies failed to inhibit P. falciparum development in vitro. Altogether, MTRAP is a highly extended bifunctional protein that binds to an erythrocyte receptor and the merozoite motor. C1 [Uchime, Onyinyechukwu; Herrera, Raul; Reiter, Karine; Shimp, Richard L., Jr.; Jones, Dominique; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Kotova, Svetlana; Lebowitz, Jacob; Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. [Miura, Kazutoyo; Long, Carole; Miller, Louis H.] NIH, Lab Malaria & Vector Res, Rockville, MD USA. [Ambroggio, Xavier; Hurt, Darrell E.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Narum, DL (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. EM dnarum@niaid.nih.gov RI Hurt, Darrell/B-5076-2013; OI Hurt, Darrell/0000-0002-9829-8567; Jin, Albert/0000-0003-3826-1081 FU Intramural Research Program of the NIH; NIAID; NIBIB; PATH Malaria Vaccine Initiative FX This research was supported by the Intramural Research Program of the NIH, including NIAID and NIBIB, and the GIA Reference Center is supported by the PATH Malaria Vaccine Initiative. NR 43 TC 18 Z9 18 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD MAY PY 2012 VL 11 IS 5 BP 615 EP 625 DI 10.1128/EC.00039-12 PG 11 WC Microbiology; Mycology SC Microbiology; Mycology GA 984KZ UT WOS:000307189900005 PM 22467743 ER PT J AU Kabakchiev, B Silverberg, MS AF Kabakchiev, Boyko Silverberg, Mark S. TI EQTL Analysis Identifies Novel Associations Between Genotype and Gene Expression in the Human Intestine SO GASTROENTEROLOGY LA English DT Meeting Abstract CT Digestive Disease Week (DDW) CY MAY 19-22, 2012 CL San Diego, CA C1 [Kabakchiev, Boyko] NIDDK, IBD Genet Consortium, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2012 VL 142 IS 5 SU 1 BP S875 EP S875 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 981TT UT WOS:000306994305003 ER PT J AU Quick, K Zhao, J Eijkelkamp, N Linley, JE Rugiero, F Cox, JJ Raouf, R Gringhuis, M Sexton, JE Abramowitz, J Taylor, R Forge, A Ashmore, J Kirkwood, N Kros, CJ Richardson, GP Freichel, M Flockerzi, V Birnbaumer, L Wood, JN AF Quick, Kathryn Zhao, Jing Eijkelkamp, Niels Linley, John E. Rugiero, Francois Cox, James J. Raouf, Ramin Gringhuis, Martine Sexton, Jane E. Abramowitz, Joel Taylor, Ruth Forge, Andy Ashmore, Jonathan Kirkwood, Nerissa Kros, Corne J. Richardson, Guy P. Freichel, Marc Flockerzi, Veit Birnbaumer, Lutz Wood, John N. TI TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells SO OPEN BIOLOGY LA English DT Article DE mechanosensation; touch; hearing ID MECHANOSENSITIVE ION CHANNELS; MOUSE INNER-EAR; MECHANOELECTRICAL TRANSDUCTION; HEARING IMPAIRMENT; PERMEANT BLOCKER; MOLECULAR-BASIS; GUINEA-PIG; MICE; EXPRESSION; CURRENTS AB Transient receptor potential (TRP) channels TRPC3 and TRPC6 are expressed in both sensory neurons and cochlear hair cells. Deletion of TRPC3 or TRPC6 in mice caused no behavioural phenotype, although loss of TRPC3 caused a shift of rapidly adapting (RA) mechanosensitive currents to intermediate-adapting currents in dorsal root ganglion sensory neurons. Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents. Double TRPC3/TRPC6 knock-out mice also showed hearing impairment, vestibular deficits and defective auditory brain stem responses to high-frequency sounds. Basal, but not apical, cochlear outer hair cells lost more than 75 per cent of their responses to mechanical stimulation. FM1-43-sensitive mechanically gated currents were induced when TRPC3 and TRPC6 were co-expressed in sensory neuron cell lines. TRPC3 and TRPC6 are thus required for the normal function of cells involved in touch and hearing, and are potential components of mechanotransducing complexes. C1 [Quick, Kathryn; Zhao, Jing; Eijkelkamp, Niels; Linley, John E.; Rugiero, Francois; Cox, James J.; Raouf, Ramin; Gringhuis, Martine; Sexton, Jane E.; Wood, John N.] UCL, Wolfson Inst Biomed Res, Mol Nocicept Grp, London WC1E 6BT, England. [Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Taylor, Ruth; Forge, Andy; Ashmore, Jonathan] UCL Ear Inst, London WC1X 8EE, England. [Kirkwood, Nerissa; Kros, Corne J.; Richardson, Guy P.] Univ Sussex, Sch Life Sci, Brighton BN1 9QG, E Sussex, England. [Freichel, Marc; Flockerzi, Veit] Univ Saarland, Fac Med, Dept Expt & Clin Pharmacol & Toxicol, D-6650 Homburg, Germany. [Wood, John N.] Seoul Natl Univ, Dept Mol Med, WCU Programme, Seoul 151742, South Korea. RP Wood, JN (reprint author), UCL, Wolfson Inst Biomed Res, Mol Nocicept Grp, Mortimer St, London WC1E 6BT, England. EM j.wood@ucl.ac.uk RI Abramowitz, Joel/A-2620-2015; Cox, James/R-1910-2016; OI Eijkelkamp, Niels/0000-0003-0039-7063; Ashmore, Jonathan/0000-0001-6522-3692 FU BBSRC; MRC; WCU at SNU [R31-2008-000-10103-0]; Netherlands Organisation for Scientific Research; IMI Europain consortium FX We thank the BBSRC for a LOLA award, the MRC for a programme grant, and the Wellcome Trust and the Intramural Research Program of the NIH for generous support. J.N.W. was also supported by WCU grant R31-2008-000-10103-0 at SNU. We thank Alan Palmer (MRC Institute for hearing research) for the gift of a click box. We are grateful to our UCL colleagues for helpful comments. N.E. is supported by a Rubicon fellowship of The Netherlands Organisation for Scientific Research. M. G. was supported by the IMI Europain consortium. NR 71 TC 51 Z9 52 U1 0 U2 15 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 2046-2441 J9 OPEN BIOL JI Open Biol PD MAY PY 2012 VL 2 AR 120068 DI 10.1098/rsob.120068 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 983IL UT WOS:000307112900003 PM 22724068 ER PT J AU Patterson, LJ Kuate, S Daltabuit-Test, M Li, QS Xiao, P McKinnon, K DiPasquale, J Cristillo, A Venzon, D Haase, A Robert-Guroff, M AF Patterson, L. Jean Kuate, Seraphin Daltabuit-Test, Mara Li, Qingsheng Xiao, Peng McKinnon, Katherine DiPasquale, Janet Cristillo, Anthony Venzon, David Haase, Ashley Robert-Guroff, Marjorie TI Replicating Adenovirus-Simian Immunodeficiency Virus (SIV) Vectors Efficiently Prime SIV-Specific Systemic and Mucosal Immune Responses by Targeting Myeloid Dendritic Cells and Persisting in Rectal Macrophages, Regardless of Immunization Route SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID DEPENDENT CELLULAR CYTOTOXICITY; BOOST VACCINE REGIMEN; CD4(+) T-CELLS; RHESUS MACAQUES; SUBLINGUAL IMMUNIZATION; NEUTRALIZING ANTIBODIES; SIVMAC251 CHALLENGE; PROTECTIVE EFFICACY; HIV-1 VACCINE; CHIMPANZEES AB Although priming with replicating adenovirus type 5 host range mutant (Ad5hr)-human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) recombinants, followed by HIV/SIV envelope boosting, has proven highly immunogenic, resulting in protection from SIV/simian-human immunodeficiency virus (SHIV) challenges, Ad5hr recombinant distribution, replication, and persistence have not been examined comprehensively in nonhuman primates. We utilized Ad5hr-green fluorescent protein and Ad5hr-SIV recombinants to track biodistribution and immunogenicity following mucosal priming of rhesus macaques by the intranasal/intratracheal, sublingual, vaginal, or rectal route. Ad recombinants administered by all routes initially targeted macrophages in bronchoalveolar lavage (BAL) fluid and rectal tissue, later extending to myeloid dendritic cells in BAL fluid with persistent expression in rectal mucosa 25 weeks after the last Ad immunization. Comparable SIV-specific immunity, including cellular responses, serum binding antibody, and mucosal secretory IgA, was elicited among all groups. The ability of the vector to replicate in multiple mucosal sites irrespective of delivery route, together with the targeting of macrophages and professional antigen-presenting cells, which provide potent immunogenicity at localized sites of virus entry, warrants continued use of replicating Ad vectors. C1 [Patterson, L. Jean; Kuate, Seraphin; Daltabuit-Test, Mara; Xiao, Peng; McKinnon, Katherine; DiPasquale, Janet; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Li, Qingsheng; Haase, Ashley] Univ Minnesota, Sch Publ Hlth, Dept Microbiol, Minneapolis, MN USA. [Cristillo, Anthony] Adv BioSci Labs, Gaithersburg, MD USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: SIVmac239 Gag peptides, complete set. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 42 TC 24 Z9 25 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAY PY 2012 VL 19 IS 5 BP 629 EP 637 DI 10.1128/CVI.00010-12 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 983GU UT WOS:000307108600001 PM 22441384 ER PT J AU Sviridov, D Hoang, A Drew, BG Low, H Remaley, AT Nestel, P Kingwell, BA AF Sviridov, Dmitri Hoang, Anh Drew, Brian G. Low, Hann Remaley, Alan T. Nestel, Paul Kingwell, Bronwyn A. TI Mechanism of systemic cholesterol efflux in humans after infusion of reconstituted high density lipoprotein SO VASCULAR PHARMACOLOGY LA English DT Meeting Abstract CT 6th European Meeting on Vascular Biology and Medicine (EMVBM) CY SEP 21-24, 2011 CL Krakow, POLAND C1 [Sviridov, Dmitri; Hoang, Anh; Drew, Brian G.; Low, Hann; Nestel, Paul; Kingwell, Bronwyn A.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20892 USA. EM dmitri.sviridov@bakeridi.edu.au 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 1537-1891 J9 VASC PHARMACOL JI Vasc. Pharmacol. PD MAY-JUN PY 2012 VL 56 IS 5-6 SI SI BP 384 EP 385 DI 10.1016/j.vph.2011.08.214 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 980JM UT WOS:000306889400226 ER PT J AU Lee, JY Clarke, ML Tokumasu, F Lesoine, JF Allen, DW Chang, R Litorja, M Hwang, J AF Lee, Ji Youn Clarke, Matthew L. Tokumasu, Fuyuki Lesoine, John F. Allen, David W. Chang, Robert Litorja, Maritoni Hwang, Jeeseong TI Absorption-Based Hyperspectral Imaging and Analysis of Single Erythrocytes SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Absorption spectra of hemoglobin; endmember analysis; erythrocyte (red blood cell); hyperspectral imaging; label-free molecular imaging; scattering signature; sequential maximum angle convex cone (SMACC) algorithm; spectral light engine ID PLASMODIUM-FALCIPARUM; MALARIA PIGMENT; HEMOZOIN; SYSTEM AB We report an absorption-based hyperspectral imaging and analysis technique to resolve unique physicochemical characteristics of subcellular substances in single erythrocytes. We constructed a microscope system installed with a spectral light engine capable of controlling the spectral shape of the illumination light by a digital micromirror device. The hyperspectral imaging system and the sequential maximum angle convex cone algorithm allow us to extract unique spectral signatures (i.e., endmembers) for different types of hemoglobin, such as oxyhemoglobin, methemoglobin, and hemozoin, and scatter from cell membrane in single erythrocytes. Further statistical endmember analysis, conducted on the hyperspectral image data, provides the abundances of specific endmembers, which can be used to build intracellular maps of the distribution of substances of interest. In addition, we perform modeling based on Mie theory to explain the scattering signatures as a function of scattering angle. The developed imaging and analysis technique enables label-free molecular imaging of endogenous biomarkers in single erythrocytes in order to build oxymetric standards on a cellular level and ultimately for in vivo as well. C1 [Lee, Ji Youn; Clarke, Matthew L.; Lesoine, John F.; Allen, David W.; Chang, Robert; Litorja, Maritoni; Hwang, Jeeseong] NIST, Opt Technol Div, Gaithersburg, MD 20899 USA. [Tokumasu, Fuyuki] NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. RP Lee, JY (reprint author), NIST, Opt Technol Div, Gaithersburg, MD 20899 USA. EM jiyoun.lee@nist.gov; matthew.clarke@nist.gov; ftokumasu@niaid.nih.gov; john.lesoine@nist.gov; david.allen@nist.gov; robert.chang@nist.gov; maritoni.litorja@nist.gov; jch@nist.gov OI Tokumasu, Fuyuki/0000-0003-2790-1071 FU NIST Innovations in Measurement Science Program on Optical Medical Imaging; Intramural Research Program of the NIAID, NIH; National Research Council Research Associateship Award at NIH (NIBIB)/NIST; National Research Council Research Associateship Award at NIST FX This work was supported by the NIST Innovations in Measurement Science Program on Optical Medical Imaging and by the Intramural Research Program of the NIAID, NIH. J. Y. Lee and M. L. Clarke contributed equally to this work.; The authors would like to thank Dr. D. Samarov, Dr. A. Possolo, Dr. E. Shirley, Dr. Y. J. Lee, and Dr. K. Briggman for useful discussions and valuable comments on this manuscript. This research was performed while J. Y. Lee held a National Research Council Research Associateship Award at NIH (NIBIB)/NIST, and J. F. Lesoine and R. Chang held a National Research Council Research Associateship Award at NIST. NR 30 TC 8 Z9 8 U1 1 U2 16 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X EI 1558-4542 J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD MAY-JUN PY 2012 VL 18 IS 3 BP 1130 EP 1139 DI 10.1109/JSTQE.2011.2164239 PG 10 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA 975PW UT WOS:000306524300011 ER PT J AU Choyke, PL Kobayashi, H AF Choyke, Peter L. Kobayashi, Hisataka TI Medical Uses of Fluorescence Imaging: Bringing Disease to Light SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Fluorescence; medical imaging; optical imaging ID LABELED MONOCLONAL-ANTIBODIES; CANCER-CELLS; QUANTUM-DOT; REAL-TIME; OVARIAN-CANCER; PHOTODYNAMIC THERAPY; INDOCYANINE GREEN; MULTICOLOR; PROBES; METASTASES AB Fluorescence imaging is becoming an important diagnostic method in medicine. Advances in the quantum yields and properties of fluorophores combined with better biologic targeting make fluorescence imaging attractive. The lack of ionizing radiation, the lower costs, and the portability of optical imaging are additional advantages. Traditional fluorescence imaging probes are "always on" and require rapid biologic clearance of the unbound probe to achieve adequate target-to-background ratios. More advanced fluorescence imaging probes are "activatable," meaning that they become fluorescent only under particular circumstances, such as after binding to the cell. This creates opportunities for very high target-to-background ratios, thus dramatically increasing sensitivity. When fluorescent probes also cause phototoxicity, they become both therapeutic and diagnostic (theranostic) agents and enable a "see and treat" paradigms. Here, we discuss the evolution of novel diagnostic probes in our laboratory ending with the development of targeted theranostic probes. C1 [Choyke, Peter L.; Kobayashi, Hisataka] NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. EM pchoyke@nih.gov; kobayash@mail.nih.gov NR 54 TC 6 Z9 6 U1 1 U2 13 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD MAY-JUN PY 2012 VL 18 IS 3 BP 1140 EP 1146 DI 10.1109/JSTQE.2011.2164900 PG 7 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA 975PW UT WOS:000306524300012 ER PT J AU Kastenmayer, RJ Moore, RM Bright, AL Torres-Cruz, R Elkins, WR AF Kastenmayer, Robin J. Moore, Rashida M. Bright, Allison L. Torres-Cruz, Rafael Elkins, William R. TI Select Agent and Toxin Regulations: Beyond the Eighth Edition of the Guide for the Care and Use of Laboratory Animals SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Review ID BIOTERRORISM AB In the interval between the publication of the seventh and eighth editions of the Guide for the Care and Use of Laboratory Animals (Guide), much has changed with regard to the regulation and funding of highly pathogenic biologic agents and toxins (Select Agents). Funding of research involving highly pathogenic agents has increased dramatically during this time, thus increasing the demand for facilities capable of supporting this work. The eighth edition of the Guide briefly mentions Select Agents and provides a limited set of references. Here we provide some background information regarding the relevant laws and regulations, as well as an overview of the programmatic requirements pertaining to the use of Select Agents, with a focus on use in animals. C1 [Kastenmayer, Robin J.; Moore, Rashida M.; Bright, Allison L.; Elkins, William R.] NIAID, Comparat Med Branch, Bethesda, MD 20892 USA. [Torres-Cruz, Rafael] NIH, Div Occupat Hlth & Safety, Bethesda, MD 20892 USA. RP Kastenmayer, RJ (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM rkastenmayer@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX This publication was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 15 TC 2 Z9 2 U1 1 U2 5 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAY PY 2012 VL 51 IS 3 BP 333 EP 338 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 978UX UT WOS:000306772400009 PM 22776191 ER PT J AU Cotroneo, TM Hugunin, KMS Shuster, KA Hwang, HJ Kakaraparthi, BN Nemzek-Hamlin, JA AF Cotroneo, Tara M. Hugunin, Kelly M. S. Shuster, Katherine A. Hwang, Hae J. Kakaraparthi, Bala N. Nemzek-Hamlin, Jean A. TI Effects of Buprenorphine on a Cecal Ligation and Puncture Model in C57BL/6 Mice SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID IMMUNE-RESPONSES; SEX-DIFFERENCES; SEPSIS; MORPHINE; GENDER; MOUSE; GUIDELINES; MORTALITY; INFECTION; SURVIVAL AB Sepsis research relies heavily on animal models. One of the most frequently used models, cecal ligation and puncture (CLP), involves surgery, and animal use committees may require the use of analgesics after CLP. However, some analgesics are immunomodulatory and may affect research outcomes. In addition, both septic inflammation and responses to opioids may vary with the sex of the subject. Therefore, we investigated the effects of buprenorphine in inbred mice of both sexes undergoing CLP. We hypothesized that buprenorphine would not significantly change the outcome or patterns of inflammation in C57BL/6 mice after CLP. Male and female C57BL/6 mice underwent CLP surgery and were randomized into 2 groups to receive either buprenorphine or saline. Three-week survival studies were performed (n = 20 per group). Survival did not differ between groups of female mice, but male mice that received buprenorphine had decreased survival compared with that of controls. Reducing the dose of buprenorphine in male mice ameliorated the difference in survival. To examine inflammation, mice (n = 10 per group) were euthanized at 12, 24, or 48 h after CLP. Cell counts and cytokines were measured in the blood and peritoneal lavage fluid. In female and male C57BL/6 mice, buprenorphine treatment resulted in few differences in inflammatory parameters, although peripheral neutrophil counts were decreased transiently in male mice. The findings suggest that the effects of buprenorphine on sepsis models in C57BL/6 mice may be sex-specific. Consequently the use of analgesics must be assessed on a study-by-study basis, and investigators should define analgesic regimens when publishing sepsis studies. C1 [Cotroneo, Tara M.; Shuster, Katherine A.; Hwang, Hae J.; Kakaraparthi, Bala N.; Nemzek-Hamlin, Jean A.] Univ Michigan, Unit Lab Anim Med, Ann Arbor, MI 48109 USA. [Nemzek-Hamlin, Jean A.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Hugunin, Kelly M. S.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. RP Cotroneo, TM (reprint author), Univ Michigan, Unit Lab Anim Med, Ann Arbor, MI 48109 USA. EM tara.cotroneo@wayne.edu FU American College of Laboratory Animal Medicine FX The authors thank the American College of Laboratory Animal Medicine for supporting this project. NR 37 TC 12 Z9 12 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAY PY 2012 VL 51 IS 3 BP 357 EP 365 PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 978UX UT WOS:000306772400013 PM 22776195 ER PT J AU Fernandes, R Tsuda, C Perumalsamy, AL Naranian, T Chong, J Acton, BM Tong, ZB Nelson, LM Jurisicova, A AF Fernandes, Roxanne Tsuda, Chiharu Perumalsamy, Alagammal L. Naranian, Taline Chong, Jasmine Acton, Beth M. Tong, Zhi-Bin Nelson, Lawrence M. Jurisicova, Andrea TI NLRP5 Mediates Mitochondrial Function in Mouse Oocytes and Embryos SO BIOLOGY OF REPRODUCTION LA English DT Article DE Bax; cell death; embryo; mitochondria; Nlrp5; two-cell arrest ID MATERNAL-EFFECT GENE; DNA COPY NUMBER; ARREST IN-VITRO; PREIMPLANTATION EMBRYO; OXIDATIVE STRESS; GENOME ACTIVATION; EXPRESSION; APOPTOSIS; PROTEIN; EMBRYOGENESIS AB Unraveling molecular pathways responsible for regulation of early embryonic development is crucial for our understanding of female infertility. Maternal determinants that control the transition from oocyte to embryo are crucial molecules that govern developmental competence of the newly conceived zygote. We describe a series of defects that are triggered by a disruption of maternal lethal effect gene, Nlrp5. Previous studies have shown that Nlrp5 hypomorph embryos fail to develop beyond the two-cell stage. Despite its importance in preimplantation development, the mechanism by which the embryo arrest occurs remains unclear. We confirmed that Nlrp5 mutant and wild-type females possess comparable ovarian germ pool and follicular recruitment rates. However, ovulated oocytes lacking Nlrp5 have abnormal mitochondrial localization and increased activity in order to sustain physiological ATP content. This results in an accumulation of reactive oxygen species and increased cellular stress causing mitochondrial depletion. Compromised cellular state is also accompanied by increased expression of cell death inducer Bax and depletion of cytochrome c. However, neither genetic deletion (Bax/Nlrp5 double knockout) nor mimetic interference (BH4 domain or Bax inhibitory peptide) were sufficient to alleviate embryo demise caused by depletion of Nlrp5. We therefore conclude that lack of Nlrp5 in oocytes triggers premature activation of the mitochondrial pool, causing mitochondrial damage that cannot be rescued by inactivation of Bax. C1 [Fernandes, Roxanne; Tsuda, Chiharu; Perumalsamy, Alagammal L.; Naranian, Taline; Chong, Jasmine; Acton, Beth M.; Jurisicova, Andrea] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Fernandes, Roxanne; Naranian, Taline; Acton, Beth M.; Jurisicova, Andrea] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Tong, Zhi-Bin; Nelson, Lawrence M.] NICHHD, Integrat Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Jurisicova, Andrea] Univ Toronto, Dept Obstet & Gynecol, Toronto, ON, Canada. RP Jurisicova, A (reprint author), 25 Orde St,Room 6-1016-1, Toronto, ON M5T 3H7, Canada. EM jurisicova@lunenfeld.ca RI Jurisicova, Andrea/E-4580-2013 FU Canadian Institutes of Health Research [CIHR MOP 14058, 84328]; Canadian Fund for Innovation (CFI) [203771]; Canada Research Chairs Program; Intramural Research Program on Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health FX Supported by the Grants from Canadian Institutes of Health Research (CIHR MOP 14058, 84328), Canadian Fund for Innovation (CFI#203771), and Canada Research Chairs Program. This work was also supported in part by the Intramural Research Program on Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health. NR 67 TC 12 Z9 13 U1 0 U2 7 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD MAY PY 2012 VL 86 IS 5 AR 138 DI 10.1095/biolreprod.111.093583 PG 10 WC Reproductive Biology SC Reproductive Biology GA 975YM UT WOS:000306547700005 PM 22357545 ER PT J AU Matzinger, P AF Matzinger, Polly TI The evolution of the danger theory SO EXPERT REVIEW OF CLINICAL IMMUNOLOGY LA English DT Editorial Material DE autoimmunity; danger theory; hemophilia; immunity; tolerance ID EPITHELIUM C1 NIAID, Ghost Lab, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20894 USA. RP Matzinger, P (reprint author), NIAID, Ghost Lab, Lab Cellular & Mol Immunol, NIH, Bldg 4,Room 211, Bethesda, MD 20894 USA. EM pcm@helix.nih.gov FU Intramural NIH HHS [ZIA AI000581-25, ZIA AI000868-05] NR 6 TC 24 Z9 24 U1 1 U2 38 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1744-666X J9 EXPERT REV CLIN IMMU JI Expert Rev. Clin. Immunol. PD MAY PY 2012 VL 8 IS 4 BP 311 EP 317 DI 10.1586/ECI.12.21 PG 7 WC Immunology SC Immunology GA 970UW UT WOS:000306158800009 PM 22607177 ER PT J AU Vivanco, I Robins, HI Rohle, D Campos, C Grommes, C Nghiemphu, PL Kubek, S Oldrini, B Chheda, MG Yannuzzi, N Tao, H Zhu, SJ Iwanami, A Kuga, D Dang, JL Pedraza, A Brennan, CW Heguy, A Liau, LM Lieberman, F Yung, WKA Gilbert, MR Reardon, DA Drappatz, J Wen, PY Lamborn, KR Chang, SM Prados, MD Fine, HA Horvath, S Wu, N Lassman, AB DeAngelis, LM Yong, WH Kuhn, JG Mischel, PS Mehta, MP Cloughesy, TF Mellinghoff, IK AF Vivanco, Igor Robins, H. Ian Rohle, Daniel Campos, Carl Grommes, Christian Nghiemphu, Phioanh Leia Kubek, Sara Oldrini, Barbara Chheda, Milan G. Yannuzzi, Nicolas Tao, Hui Zhu, Shaojun Iwanami, Akio Kuga, Daisuke Dang, Julie Pedraza, Alicia Brennan, Cameron W. Heguy, Adriana Liau, Linda M. Lieberman, Frank Yung, W. K. Alfred Gilbert, Mark R. Reardon, David A. Drappatz, Jan Wen, Patrick Y. Lamborn, Kathleen R. Chang, Susan M. Prados, Michael D. Fine, Howard A. Horvath, Steve Wu, Nian Lassman, Andrew B. DeAngelis, Lisa M. Yong, William H. Kuhn, John G. Mischel, Paul S. Mehta, Minesh P. Cloughesy, Timothy F. Mellinghoff, Ingo K. TI Differential Sensitivity of Glioma-versus Lung Cancer-Specific EGFR Mutations to EGFR Kinase Inhibitors SO CANCER DISCOVERY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; FACTOR RECEPTOR INHIBITORS; TYROSINE KINASE; MALIGNANT GLIOMAS; TUMOR-CELLS; 3T3 CELLS; THERAPY; GLIOBLASTOMA; GEFITINIB; LAPATINIB AB Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types. SIGNIFICANCE: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain. Cancer Discov; 2(5); 458-71. (c) 2012 AACR. C1 [Mehta, Minesh P.] Northwestern Univ, Chicago, IL 60611 USA. [Fine, Howard A.] NCI, NeuroOncol Branch, Bethesda, MD 20892 USA. [Lamborn, Kathleen R.; Chang, Susan M.; Prados, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Reardon, David A.; Drappatz, Jan; Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Reardon, David A.; Kuhn, John G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Yung, W. K. Alfred; Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lieberman, Frank] Univ Pittsburgh, Pittsburgh, PA USA. [Robins, H. Ian] Univ Wisconsin, Madison, WI USA. [Nghiemphu, Phioanh Leia; Cloughesy, Timothy F.] David Geffen UCLA Sch Med, Dept Neurol, Los Angeles, CA USA. [Liau, Linda M.] David Geffen UCLA Sch Med, Dept Neurosurg, Los Angeles, CA USA. [Zhu, Shaojun; Iwanami, Akio; Kuga, Daisuke; Dang, Julie; Yong, William H.; Mischel, Paul S.] David Geffen UCLA Sch Med, Dept Pathol & Lab Med, Los Angeles, CA USA. [Horvath, Steve] David Geffen UCLA Sch Med, Dept Human Genet & Biostat, Los Angeles, CA USA. [Mischel, Paul S.] David Geffen UCLA Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA USA. [Rohle, Daniel; Kubek, Sara; Mellinghoff, Ingo K.] Weill Cornell Med Coll, Dept Pharmacol, New York, NY USA. [Vivanco, Igor; Campos, Carl; Oldrini, Barbara; Chheda, Milan G.; Yannuzzi, Nicolas; Brennan, Cameron W.; Heguy, Adriana; Mellinghoff, Ingo K.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Grommes, Christian; Lassman, Andrew B.; DeAngelis, Lisa M.; Mellinghoff, Ingo K.] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Tao, Hui; Wu, Nian] Mem Sloan Kettering Canc Ctr, Analyt Pharmacol Core, New York, NY 10021 USA. [Pedraza, Alicia; Brennan, Cameron W.] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10021 USA. RP Cloughesy, TF (reprint author), Geffen UCLA Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. EM tcloughesy@mednet.ucla.edu; mellingi@mskcc.org RI Gilbert, Mark/J-7494-2016; OI Gilbert, Mark/0000-0003-2556-9722; Vivanco, Igor/0000-0001-6347-9416; Brennan, Cameron/0000-0003-4064-8891; Campos, Carl/0000-0002-7616-8518; mehta, minesh/0000-0002-4812-5713 FU National Cancer Institute [U54CA143798, U01 CA141502]; Leon Levy foundation; Sontag Foundation; Doris Duke Charitable Foundation; Advanced Clinical Research Award from the American Society of Clinical Oncology; American Brain Tumor Association Basic Research Fellowship Award; American Italian Cancer Foundation [NIH5K08NS062907]; Memorial Sloan-Kettering Cancer Center (MSKCC) Brain Tumor Center grant; American Brain Tumor Association Medical Student Summer Fellowship; NABTC [CA62399, CA62422]; GCRC grant [M01-RR00079, CA62426, CA62412, CA16672, U01CA62407-08, U01CA62421-08, M01-RR03186, U01CA62405, M01-RR00056, U01CA62399, M01-RR0865]; MSKCC Experimental Therapeutics Center; [5-U01CA62399-09] FX This work was supported through U54CA143798 (I.K. Mellinghoff) and U01 CA141502 from the National Cancer Institute. Further funding support was provided by the Leon Levy foundation, the Sontag Foundation, the Doris Duke Charitable Foundation, and an Advanced Clinical Research Award from the American Society of Clinical Oncology (I.K. Mellinghoff). C. Grommes was supported through an American Brain Tumor Association Basic Research Fellowship Award, M.G. Chheda was supported through NIH5K08NS062907, B. Oldrini was supported through grants from the American Italian Cancer Foundation and a Memorial Sloan-Kettering Cancer Center (MSKCC) Brain Tumor Center grant, and N. Yannuzzi was the recipient of an American Brain Tumor Association Medical Student Summer Fellowship. Investigators of the NABTC-04-01 Clinical Trial were supported through the following funding sources: 5-U01CA62399-09 (A.B. Lassman and L.M. DeAngelis); NABTC number CA62399 and member number CA62422, GCRC grant number M01-RR00079 (S.M. Chang, K.R. Lamborn, and M.D. Prados); CA62426 (J.G. Kuhn); CA62412, GCRC grant number CA16672 (W.K.A. Yung and M. R. Gilbert); U01CA62407-08 (P.Y. Wen); U01CA62421-08, GCRC grant number M01-RR03186 (M.P. Mehta and H.I. Robins); U01CA62405, GCRC grant number M01-RR00056 (F. Lieberman); and U01CA62399, GCRC grant number M01-RR0865 (T.F. Cloughesy). This work was supported in part by the MSKCC Experimental Therapeutics Center. NR 50 TC 98 Z9 99 U1 0 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD MAY PY 2012 VL 2 IS 5 BP 458 EP 471 DI 10.1158/2159-8290.CD-11-0284 PG 14 WC Oncology SC Oncology GA 973BZ UT WOS:000306328600039 PM 22588883 ER PT J AU Ren, DB Nelson, KL Uchakin, PN Smith, AL Gu, XX Daines, DA AF Ren, Dabin Nelson, Kevin L. Uchakin, Peter N. Smith, Arnold L. Gu, Xin-Xing Daines, Dayle A. TI Characterization of extended co-culture of non-typeable Haemophilus influenzae with primary human respiratory tissues SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE NTHi; NHBE; co-culture; persistence ID OUTER-MEMBRANE VESICLES; BRONCHIAL EPITHELIAL-CELLS; ACUTE OTITIS-MEDIA; CYTOKINE GENES; EXPRESSION; DIFFERENTIATION; BACTERIA; TRACT; INFLAMMATION; ACTIVATION AB Non-typeable Haemophilus influenzae (NTHi) are human-adapted Gram-negative bacteria that comprise part of the normal flora of the human upper airway, but are also responsible for a number of mucosal infections such as otitis media and bronchitis. These infections often recur and can become chronic. To characterize the effect of long-term co-culture of NTHi with human tissues, we infected primary respiratory epithelial cells grown at the air liquid interface with three NTHi strains over a range of 1-10 days. Scanning and transmission electron microscopy of tissues confirmed that intact NTHi were persisting paracellularly, while organisms observed in intracellular vacuoles appeared degraded. Furthermore, the apical surface and tight junctions of the infected tissues were undisturbed, with high transepithelial electrical resistances, while the basal cell layer displayed more junctional disorganization and wider intercellular spaces than the uninfected control tissues. Although the tissues elaborated the cytokine profile reported for NTHi-caused otitis media in vivo, there was little change in the dynamics of cytokine secretion over the time points tested. Finally, we report that NTHi strains released outer membrane vesicles (OMVs) during extended co-culture with the tissues, and show that these OMVs directly interact with host cell membranes. C1 [Ren, Dabin; Uchakin, Peter N.; Daines, Dayle A.] Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. [Nelson, Kevin L.; Smith, Arnold L.] Seattle Childrens Res Inst, Seattle, WA 98101 USA. [Gu, Xin-Xing] Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. RP Daines, DA (reprint author), Mercer Univ, Sch Med, Div Basic Med Sci, 1550 Coll St, Macon, GA 31207 USA. EM daines_da@mercer.edu RI Ren, Dabin/H-6263-2013 FU Public Health Service from the National Institute of Allergy and Infectious Diseases [AI044002]; National Institute on Deafness and Other Communication Disorders [DC010187] FX We thank Dr Robert S Munson Jr for strain 86-028NP, Dr Robert J McKallip for critical reading of the manuscript, and Robert M Smith and Libby Perry of the Georgia Health Sciences University Electron Microscopy Core for their excellent technical skills. This study was funded by Public Health Service grants AI044002 from the National Institute of Allergy and Infectious Diseases to ALS and DC010187 from the National Institute on Deafness and Other Communication Disorders to DAD. NR 32 TC 14 Z9 14 U1 1 U2 8 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD MAY PY 2012 VL 237 IS 5 BP 540 EP 547 DI 10.1258/ebm.2012.011377 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 971JN UT WOS:000306200300010 PM 22569032 ER PT J AU Qi, CF Kim, YS Xiang, S Abdullaev, Z Torrey, TA Janz, S Kovalchuk, AL Sun, JF Chen, DL Cho, WC Gu, W Morse, HC AF Qi, Chen-Feng Kim, Yong-Soo Xiang, Shao Abdullaev, Ziedulla Torrey, Ted A. Janz, Siegfried Kovalchuk, Alexander L. Sun, Jiafang Chen, Delin Cho, William C. Gu, Wei Morse, Herbert C., III TI Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE ARF-BP1; B-cell lymphoma; p53; MYC; CTCF; ARF ID E3 UBIQUITIN LIGASE; C-MYC; TRANSCRIPTION FACTOR; BURKITTS-LYMPHOMA; TUMOR-SUPPRESSOR; TRANSGENIC MICE; PROTEIN; DEGRADATION; PHOSPHORYLATION; FBW7 AB Transcriptional activation of MYC is a hallmark of many B cell lineage neoplasms. MYC provides a constitutive proliferative signal but can also initiate ARF-dependent activation of p53 and apoptosis. The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both the MYC and the ARF-p53 signaling pathways, prompting us to determine if it is involved in the pathogenesis of MYC-driven B cell lymphomas. ARF-BP1 was expressed at high levels in cell lines from lymphomas with either wild type or mutated p53 but not in ARF-deficient cells. Downregulation of ARF-BP1 resulted in elevated steady state levels of p53, growth arrest and apoptosis. Co-immunoprecipitation studies identified a multiprotein complex comprised of ARF-BP1, ARF, p53, MYC and the multifunctional DNA-binding factor, CTCF, which is involved in the transcriptional regulation of MYC, p53 and ARF. ARF-BP1 bound and ubiquitylated CTCF leading to its proteasomal degradation. ARF-BP1 and CTCF thus appear to be key cofactors linking the MYC proliferative and p53-ARF apoptotic pathways. In addition, ARF-BP1 could be a therapeutic target for MYC-driven B lineage neoplasms, even if p53 is inactive, with inhibition reducing the transcriptional activity of MYC for its target genes and stabilizing the apoptosis-promoting activities of p53. C1 [Qi, Chen-Feng; Kim, Yong-Soo; Xiang, Shao; Abdullaev, Ziedulla; Kovalchuk, Alexander L.; Sun, Jiafang; Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Xiang, Shao] Cleveland Clin Fdn, Taussig Canc Inst, Cleveland, OH 44195 USA. [Torrey, Ted A.] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. [Janz, Siegfried] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA. [Chen, Delin; Gu, Wei] Columbia Univ Coll Phys & Surg, Inst Canc Genet, New York, NY 10032 USA. [Chen, Delin; Gu, Wei] Columbia Univ Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Cho, William C.] Queen Elizabeth Hosp, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. RP Qi, CF (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM cqi@niaid.nih.gov; kimyongs@mail.nih.gov; xiangshao@gmail.com; zabdul@mail.nih.gov; ttorrey@niaid.nih.gov; siegfried-janz@uiowa.edu; kovalcha@niaid.nih.gov; sunj7@mail.nih.gov; dc723@columbia.edu; chocs@ha.org.hk; wg8@columbia.edu; hmorse@niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705 FU NIH, National Institute of Allergy and Infectious Diseases [R01 CA151354]; MMRF; IWMF; Leukemia and Lymphoma Society FX This work was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases; R01 CA151354 (S.J.); research grants from the MMRF and IWMF to S.J.; and an award from the Leukemia and Lymphoma Society to W.G. NR 50 TC 8 Z9 8 U1 1 U2 10 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD MAY PY 2012 VL 13 IS 5 BP 6204 EP 6219 DI 10.3390/ijms13056204 PG 16 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA 971EJ UT WOS:000306186200063 PM 22754359 ER PT J AU Sergeyeva, O Gorodetskaya, I Ramos, R Schiller, BM Larive, B Raimann, JG Ting, GO Eggers, PW Chertow, GM Levin, NW AF Sergeyeva, Olga Gorodetskaya, Irina Ramos, Rosio Schiller, Brigitte M. Larive, Brett Raimann, Jochen G. Ting, George O. Eggers, Paul W. Chertow, Glenn M. Levin, Nathan W. CA Frequent Hemodialysis Network TI Challenges to enrollment and randomization of the frequent hemodialysis network (FHN) daily trial SO JOURNAL OF NEPHROLOGY LA English DT Article DE Daily hemodialysis; Enrollment; Randomized clinical trial; Randomization; Recruitment ID RECRUITMENT; DIALYSIS AB Background: The US National Institutes of Health (NIH) and Centers for Medicare and Medicaid Services (CMS) sponsored a randomized clinical trial comparing six versus three times per week in-center hemodialysis (the Frequent Hemodialysis Network [FHN] Daily Trial), to test the effects of frequent hemodialysis on an array of intermediate outcomes. Herein we report challenges to enrollment and randomization into the trial. Methods: Screening and enrollment was tracked at all participating dialysis clinics and specific reasons for dropout after baseline assessment were recorded for all enrolled subjects. Reasons for consent refusal were recorded in a subset of (10 out of 65) sites. Results: The trial screened 6276 hemodialysis patients on three times weekly hemodialysis in 65 hemodialysis clinics, 3481 (55%) were considered eligible for enrollment, and 3124 (90%) were approached for consent; 378 (12%) consented and 245 were randomized (65% of those enrolled). Prospective subjects chose not to participate primarily because of the anticipated time required for three extra treatments per week and the difficulties in following the protocol. Conclusions: Recruitment into the FHN Daily Trial proved challenging but the goal of 250 randomized subjects was almost met. C1 [Sergeyeva, Olga; Ramos, Rosio; Raimann, Jochen G.; Levin, Nathan W.] Renal Res Inst, New York, NY 10128 USA. [Gorodetskaya, Irina; Chertow, Glenn M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Gorodetskaya, Irina; Schiller, Brigitte M.; Ting, George O.; Chertow, Glenn M.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. [Schiller, Brigitte M.] Satellite Healthcare, San Jose, CA USA. [Larive, Brett] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Ting, George O.] El Camino Hosp, Mountain View, CA USA. [Eggers, Paul W.] NIDDK, Div Kidney Urol & Hematol, Bethesda, MD USA. RP Raimann, JG (reprint author), Renal Res Inst, 207 E 94th St,Suite 303, New York, NY 10128 USA. EM j.raimann@gmx.net OI Raimann, Jochen/0000-0002-8954-2783 FU National Institutes of Health (NIH), National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK); Center for Medicare and Medical Services; NIH Research Foundation; NIDDK [U01DK066597, 2U01DK066579, 3U01DK066481]; Amgen, Inc. FX Supported by the National Institutes of Health (NIH), National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), the Center for Medicare and Medical Services, and the NIH Research Foundation. Contributors to the NIH Foundation in support of the FHN trials included Amgen, Baxter, and Dialysis Clinics. Additional support was provided by DaVita, Dialysis Clinics, Fresenius Medical Care, Renal Advantage, Renal Research Institute, and Satellite Healthcare.; The FHN Daily Trial was supported by NIDDK grants: U01DK066597 (DCC), 2U01DK066579 (Levin, N.W.), 3U01DK066481 (Chertow, G. M.); Dr. Olga Sergeyeva is an employee of Fresenius Medical Care North America. Dr. Brigitte M. Schiller is Chief Medical Officer of Satellite Healthcare, Inc; and a member of the Scientific Advisory Board of NxStage Medical, Inc. Dr. Glenn M. Chertow is a member of the Board of Directors of Satellite Healthcare, Inc; member of the Scientific Advisory Board of DaVita Research, and has received research support from Amgen, Inc. Dr. Nathan W. Levin holds stock in Fresenius Medical Care North America. All other authors have no relevant financial disclosures. NR 12 TC 12 Z9 12 U1 0 U2 2 PU WICHTIG EDITORE PI MILAN PA 72/74 VIA FRIULI, 20135 MILAN, ITALY SN 1121-8428 J9 J NEPHROL JI J. Nephrol. PD MAY-JUN PY 2012 VL 25 IS 3 BP 302 EP 309 DI 10.5301/jn.5000160 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 969YZ UT WOS:000306096600005 PM 22505248 ER PT J AU Frascella, J AF Frascella, Joseph TI Addiction: A developmental disorder SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Neurobehavioral-Teratology-Society (NBTS)/52nd Annual Meeting of the Teratology-Society/25th Annual Meeting of the Organization-of-Teratology-Information-Specialists CY JUN 23-27, 2012 CL Baltimore, MD SP Neurobehav Teratol Soc (NBTS), Teratol Soc, Org Teratol Informat Specialists C1 [Frascella, Joseph] Natl Inst Drug Abuse, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2012 VL 34 IS 3 BP 375 EP 375 DI 10.1016/j.ntt.2012.05.024 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 970QE UT WOS:000306146600032 ER PT J AU Smith, L LaGasse, L Derauf, C Newman, E Shah, R Arria, A Huestis, M Haning, W Strauss, A DellaGrotta, S Dansereau, L Neal, C Lester, B AF Smith, Lynne LaGasse, L. Derauf, C. Newman, E. Shah, R. Arria, A. Huestis, M. Haning, W. Strauss, A. DellaGrotta, S. Dansereau, L. Neal, C. Lester, B. TI Growth and neurodevelopmental outcomes in children prenatally exposed to methamphetamine SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Neurobehavioral-Teratology-Society (NBTS)/52nd Annual Meeting of the Teratology-Society/25th Annual Meeting of the Organization-of-Teratology-Information-Specialists CY JUN 23-27, 2012 CL Baltimore, MD SP Neurobehav Teratol Soc (NBTS), Teratol Soc, Org Teratol Informat Specialists C1 [Smith, Lynne] Harbor UCLA Med, Los Angeles, CA USA. [LaGasse, L.; DellaGrotta, S.; Dansereau, L.; Lester, B.] Brown Univ, Providence, RI 02912 USA. [Derauf, C.; Haning, W.; Neal, C.] Univ Hawaii, Honolulu, HI 96822 USA. [Newman, E.] Univ Tulsa, Tulsa, OK 74104 USA. [Shah, R.] Blank Hosp Reg Child Protect Ctr, Des Moines, IA USA. [Huestis, M.] Natl Inst Drug Abuse, Baltimore, MD USA. [Strauss, A.] Miller Childrens Hosp, Long Beach, CA USA. [Arria, A.] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2012 VL 34 IS 3 BP 375 EP 376 DI 10.1016/j.ntt.2012.05.025 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 970QE UT WOS:000306146600033 ER PT J AU Burgess, HA Fero, K AF Burgess, Harold A. Fero, Kandice TI Dopaminergic modulation of phototaxis in zebrafish larvae SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Neurobehavioral-Teratology-Society (NBTS)/52nd Annual Meeting of the Teratology-Society/25th Annual Meeting of the Organization-of-Teratology-Information-Specialists CY JUN 23-27, 2012 CL Baltimore, MD SP Neurobehav Teratol Soc (NBTS), Teratol Soc, Org Teratol Informat Specialists C1 [Burgess, Harold A.; Fero, Kandice] NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2012 VL 34 IS 3 BP 377 EP 378 DI 10.1016/j.ntt.2012.05.031 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 970QE UT WOS:000306146600039 ER PT J AU Szabo, D Shah, R Sumner, S Birnbaum, L AF Szabo, David Shah, Ruchir Sumner, Susan Birnbaum, Linda TI Systems biology approach for better understanding of mechanisms of neurodevelopment toxicity: A case study using the major flame retardant HBCD SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Neurobehavioral-Teratology-Society (NBTS)/52nd Annual Meeting of the Teratology-Society/25th Annual Meeting of the Organization-of-Teratology-Information-Specialists CY JUN 23-27, 2012 CL Baltimore, MD SP Neurobehav Teratol Soc (NBTS), Teratol Soc, Org Teratol Informat Specialists C1 [Szabo, David] US EPA, ORISE, NCEA, Washington, DC 20460 USA. [Shah, Ruchir] RTP, SRA, Res Triangle Pk, NC USA. [Sumner, Susan] RTP, RTI, Res Triangle Pk, NC USA. [Birnbaum, Linda] NIEHS, NCI, RTP, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2012 VL 34 IS 3 BP 379 EP 379 DI 10.1016/j.ntt.2012.05.036 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 970QE UT WOS:000306146600044 ER PT J AU Dorea, JG Fenton, SE LaKind, JS Berlin, CM AF Dorea, Jose G. Fenton, Suzanne E. LaKind, Judy S. Berlin, Cheston M., Jr. TI Researching chemicals in human milk can be conducted without discouraging breastfeeding SO BOSNIAN JOURNAL OF BASIC MEDICAL SCIENCES LA English DT Letter DE metals; pollutants; breastfeeding; human milk; biomonitoring ID ENVIRONMENTAL CHEMICALS; SAFER C1 [Dorea, Jose G.] Univ Brasilia, Fac Hlth Sci, BR-70919970 Brasilia, DF, Brazil. [Fenton, Suzanne E.] NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [LaKind, Judy S.] LaKind Associates LLC, Catonsville, MD USA. [LaKind, Judy S.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [LaKind, Judy S.; Berlin, Cheston M., Jr.] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pediat, Hershey, PA 17033 USA. RP Dorea, JG (reprint author), Univ Brasilia, Fac Hlth Sci, CP 04322, BR-70919970 Brasilia, DF, Brazil. EM dorea@rudah.com.br FU Intramural NIH HHS [ZIA ES102785-02] NR 5 TC 6 Z9 6 U1 0 U2 1 PU ASSOC BASIC MEDICAL SCI FEDERATION BOSNIA & HERZEGOVINA SARAJEVO PI CEKALUSA PA UNIV SARAJEVO, MEDICAL FAC, CEKALUSA, SARAJEVO 90, BOSNIA & HERCEG SN 1512-8601 J9 BOSNIAN J BASIC MED JI Bosnian J. Basic Med. Sci. PD MAY PY 2012 VL 12 IS 2 BP 137 EP 138 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 965QA UT WOS:000305781100014 PM 22642600 ER PT J AU Mussap, M Noto, A Cibecchini, F Fanos, V AF Mussap, M. Noto, A. Cibecchini, F. Fanos, V. TI EMERGING BIOMARKERS IN NEONATAL SEPSIS SO DRUGS OF THE FUTURE LA English DT Article DE Neonatal sepsis; EOS; LOS; SAA; sCD14-ST; LBP; ANG-1; ANG-2; Metabotomics ID LIPOPOLYSACCHARIDE-BINDING PROTEIN; C-REACTIVE PROTEIN; AMYLOID-A SAA; SEPTIC SHOCK; SOLUBLE CD14; NECROTIZING ENTEROCOLITIS; ENDOTHELIAL-CELLS; NEWBORN-INFANTS; PRETERM INFANTS; EARLY-DIAGNOSIS AB Approximately 30-40% of neonatal deaths are associated with bacterial infections, which often progress rapidly and result in high mortality Because each year almost one million newborns die from infections, mostly in low-income countries, there is a need for a very early, accurate diagnosis of systemic inflammation and sepsis. On the other hand, in the era of multidrug resistance, it is mandatory to avoid unnecessary use of antibiotics to treat noninfected babies and to start the appropriate therapy in those with sepsis. Thus, rapid diagnostic test(s) that differentiate infected from noninfected newborns and surrogate biomarkers predicting outcome have the potential to significantly improve neonatal care. Various emerging biomarkers for neonatal sepsis have been recently proposed. Among these, the most promising biomarkers potentially measurable in clinical practice seem to be lipopolysaccharide-binding protein (LBP), soluble CD14 subtype presepsin (sCD14-ST) and angiopoietin-1 and -2 (ANG-1 and ANG-2, respectively). In the near future, metabolomics could offer a powerful tool to distinguish not only septic from nonseptic newborns, but also to identify without any overlap several clinical conditions associated with infections and inflammation, such as systemic inflammation, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and septic shock. C1 [Mussap, M.; Cibecchini, F.] Univ Hosp, Dept Lab Med, IRCCS San Martino IST, Natl Canc Inst, Genoa, Italy. [Noto, A.; Fanos, V.] Azienda Mista, Dept Pediat & Clin Med, Sect Neonatal Intens Care Unit, Inst Puericulture, Cagliari, Italy. [Noto, A.; Fanos, V.] Azienda Mista, Neonatal Sect, Cagliari, Italy. RP Fanos, V (reprint author), Univ Cagliari, Neonatal Intens Care Unit, Puericultura Inst, I-09124 Cagliari, Italy. EM vafanos@tiscal.it OI Fanos, Vassilios/0000-0003-2617-2890; Noto, Antonio/0000-0003-3538-0050 NR 65 TC 2 Z9 2 U1 0 U2 9 PU PROUS SCIENCE, SAU-THOMSON REUTERS PI BARCELONA PA 398 PROVENCA, 08025 BARCELONA, SPAIN SN 0377-8282 EI 2013-0368 J9 DRUG FUTURE JI Drug Future PD MAY PY 2012 VL 37 IS 5 BP 353 EP 359 DI 10.1358/dof.2012.37.5.1783796 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 966XR UT WOS:000305871200006 ER PT J AU Joshi, R Reveille, JD Brown, MA Weisman, MH Ward, MM Gensler, LS Wordsworth, BP Evans, DM Assassi, S AF Joshi, Reeti Reveille, John D. Brown, Matthew A. Weisman, Michael H. Ward, Michael M. Gensler, Lianne S. Wordsworth, B. Paul Evans, David M. Assassi, Shervin TI Is There a Higher Genetic Load of Susceptibility Loci in Familial Ankylosing Spondylitis? SO ARTHRITIS CARE & RESEARCH LA English DT Article ID HLA-B27; ASSOCIATION; DISEASES AB Objective. Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome-wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants. Methods. Overall, 502 AS patients were examined, consisting of 312 patients who had first-degree relatives (FDRs) with AS (familial) and 190 patients who had no FDRs with AS or spondylarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York criteria for AS. The patients were recruited from 2 US cohorts (the North American Spondylitis Consortium and the Prospective Study of Outcomes in Ankylosing Spondylitis) and from the UK-Oxford cohort. The frequencies of AS susceptibility loci in IL-23R, IL1R2, ANTXR2, ERAP-1, 2 intergenic regions on chromosomes 2p15 and 21q22, and HLA-B27 status as determined by the tag single-nucleotide polymorphism (SNP) rs4349859 were compared between familial and sporadic cases of AS. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size. Results. HLA-B27 was significantly more prevalent in familial than sporadic cases of AS (odds ratio 4.44 [95% confidence interval 2.06, 9.55], P = 0.0001). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend toward higher frequency in the multiplex cases (P = 0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined. Conclusion. HLA-B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA-B27 positivity. The frequency of the recently described non-major histocompatibility complex susceptibility loci is not markedly different between the sporadic and familial cases of AS. C1 [Assassi, Shervin] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Joshi, Reeti] Washington Univ, St Louis, MO USA. [Brown, Matthew A.] Univ Queensland, Woolloongabba, Qld, Australia. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Ward, Michael M.] NIAMSD, Bethesda, MD 20892 USA. [Gensler, Lianne S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wordsworth, B. Paul] NIHR, Oxford, England. [Evans, David M.] Univ Bristol, Bristol, Avon, England. RP Assassi, S (reprint author), Univ Texas Hlth Sci Ctr Houston, 6431 Fannin St,MSB 5-266, Houston, TX 77030 USA. EM shervin.assassi@uth.tmc.edu RI Evans, David/H-6325-2013; OI Brown, Matthew A/0000-0003-0538-8211; Evans, David/0000-0003-0663-4621 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [1P01-052915-01, AR01-AR-46208, AR-48465, NIH-KL2RR024149-04]; National Center for Research Resources Clinical and Translational Sciences [1U54-RR-23417-01, M01-RR-000425]; Health and Medical Research Council (Australia); Medical Research Council [G0800582]; Abbott; Pfizer FX Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant 1P01-052915-01) and by the National Center for Research Resources Clinical and Translational Sciences Awards to Cedars-Sinai Medical Center (1U54-RR-23417-01 and M01-RR-000425). Dr. Reveille's work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant AR01-AR-46208). Dr. Brown's work was supported by the Health and Medical Research Council (Australia) Principal Research Fellowship. Dr. Weisman's work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant AR-48465). Dr. Ward's work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Evans's work was supported by a Medical Research Council New Investigator Award (G0800582). Dr. Assassi's work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant NIH-KL2RR024149-04).; Dr. Wordsworth has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from Abbott and Pfizer. NR 13 TC 9 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD MAY PY 2012 VL 64 IS 5 BP 780 EP 784 DI 10.1002/acr.21601 PG 5 WC Rheumatology SC Rheumatology GA 965TP UT WOS:000305790500018 PM 22231927 ER PT J AU Konig, G Brooks, BR AF Koenig, Gerhard Brooks, Bernard R. TI Predicting binding affinities of host-guest systems in the SAMPL3 blind challenge: the performance of relative free energy calculations SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE Binding free energy calculations; Bennett's acceptance ratio; Thermodynamic integration; Protonation state; Buffer concentration ID HYDRATION FREE-ENERGIES; SOLVATION FREE-ENERGIES; THERMODYNAMIC INTEGRATION; LIGAND-BINDING; DYNAMICS; SIMULATIONS; CHARMM; PROGRAM AB Relative free energy calculations based on molecular dynamics simulations are combined with available experimental binding free energies to predict unknown binding affinities of acyclic Cucurbituril complexes in the blind SAMPL3 competition. The predictions yield root mean square errors between 2.6 and 3.2 kcal/mol for seven host-guest systems. Those deviations are comparable to results for solvation free energies of small organic molecules. However, the standard deviations found in our simulations range from 0.4 to 2.4 kcal/mol, which indicates the need for better sampling. Three different approaches are compared. Bennett's Acceptance Ratio Method and thermodynamic integration based on the trapezoidal rule with 12 lambda-points exhibit a root mean square error of 2.6 kcal/mol, while thermodynamic integration with Simpson's rule and 11 lambda-points leads to a root mean square error of 3.2 kcal/mol. In terms of absolute median errors, Bennett's Acceptance Ratio Method performs better than thermodynamic integration with the trapezoidal rule (1.7 vs. 2.9 kcal/mol). Simulations of the deprotonated forms of the guest molecules exhibit a poorer correspondence to experimental results with a root mean square error of 5.2 kcal/mol. In addition, a decrease of the buffer concentration by approximately 20 mM in the simulations raises the root mean square error to 3.8 kcal/mol. C1 [Koenig, Gerhard; Brooks, Bernard R.] NHLBI, NIH, Lab Computat Biol, Rockville, MD 20852 USA. RP Konig, G (reprint author), NHLBI, NIH, Lab Computat Biol, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. EM gerhard.koenig@nih.gov FU Intramural NIH HHS [ZIA HL001051-15] NR 29 TC 15 Z9 15 U1 1 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD MAY PY 2012 VL 26 IS 5 SI SI BP 543 EP 550 DI 10.1007/s10822-011-9525-y PG 8 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA 964HO UT WOS:000305684900008 PM 22198474 ER PT J AU Fox, JT Myung, K AF Fox, Jennifer T. Myung, Kyungjae TI Cell-based high-throughput screens for the discovery of chemotherapeutic agents SO ONCOTARGET LA English DT Article DE ATAD5-luciferase; genotoxins; DNA repair mutants; cancer; drug discovery ID DNA-DAMAGE RESPONSE; ACUTE MYELOID-LEUKEMIA; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; GENOTOXICITY ASSAY; TRANSPORTERS; CANCER; INHIBITORS; LINE; CHEMORESISTANCE AB With modern advances in robotics and data processing, high-throughput screening (HTS) is playing an increasingly growing role in the drug discovery process. The ultimate success of HTS depends upon the development of assays that are robust and reproducible in miniaturized formats, have low false-positive rates, and can identify drugs that offer improvements over those currently on the market. One example of such an assay is the ATAD5-luciferase HTS assay, which identified three antioxidants that could kill cancer cells without inducing mutagenesis. Here we discuss the ATAD5-luciferase assay and expand upon the value of HTS in identifying other potential cancer drugs, focusing on cell-based assays that involve DNA damage or repair pathways. C1 [Fox, Jennifer T.; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Myung, K (reprint author), NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM kmyung@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health; [R03 MH092164-01] FX This research was supported by the National Human Genome Research Institute, National Institutes of Health, and by R03 MH092164-01 to K.M. K.M. especially thanks to E. Cho. NR 48 TC 3 Z9 3 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY PY 2012 VL 3 IS 5 BP 581 EP 585 PG 5 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 966BM UT WOS:000305811700010 PM 22653910 ER PT J AU Moss, B AF Moss, Bernard TI Poxvirus Cell Entry: How Many Proteins Does it Take? SO VIRUSES-BASEL LA English DT Review DE vaccinia virus entry; viral membrane fusion; endocytosis; macropinocytosis; transmembrane proteins ID VACCINIA-VIRUS ENTRY; ACTIN-CONTAINING MICROVILLI; INTRACELLULAR MATURE VIRIONS; DISULFIDE BOND FORMATION; RESPIRATORY SYNCYTIAL VIRUS; SERINE-PROTEASE INHIBITOR; SURFACE HEPARAN-SULFATE; OUTER ENVELOPE PROTEIN; OPEN READING FRAME; A-TYPE INCLUSIONS AB For many viruses, one or two proteins enable cell binding, membrane fusion and entry. The large number of proteins employed by poxviruses is unprecedented and may be related to their ability to infect a wide range of cells. There are two main infectious forms of vaccinia virus, the prototype poxvirus: the mature virion (MV), which has a single membrane, and the extracellular enveloped virion (EV), which has an additional outer membrane that is disrupted prior to fusion. Four viral proteins associated with the MV membrane facilitate attachment by binding to glycosaminoglycans or laminin on the cell surface, whereas EV attachment proteins have not yet been identified. Entry can occur at the plasma membrane or in acidified endosomes following macropinocytosis and involves actin dynamics and cell signaling. Regardless of the pathway or whether the MV or EV mediates infection, fusion is dependent on 11 to 12 non-glycosylated, transmembrane proteins ranging in size from 4- to 43-kDa that are associated in a complex. These proteins are conserved in poxviruses making it likely that a common entry mechanism exists. Biochemical studies support a two-step process in which lipid mixing of viral and cellular membranes is followed by pore expansion and core penetration. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID FX I gratefully acknowledge past and present members of our laboratory that contributed to research on poxvirus entry over the past seven years. Tatiana Senkevich (Koonin) and Alan Townsley made early contributions followed by Suany Ojeda, Erica Brown, Tim Wagenaar, Himani Bisht, Gretchen Nelson, Jason Laliberte, Zain Bengali, P. S. Satheskumar and Cindy Wolfe. J.L. and P. S. S. kindly made comments on the manuscript. The work was supported by the Division of Intramural Research, NIAID. NR 137 TC 35 Z9 37 U1 1 U2 13 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAY PY 2012 VL 4 IS 5 BP 688 EP 707 DI 10.3390/v4050688 PG 20 WC Virology SC Virology GA 965XT UT WOS:000305801700003 PM 22754644 ER PT J AU Jordan, I Munster, VJ Sandig, V AF Jordan, Ingo Munster, Vincent J. Sandig, Volker TI Authentication of the R06E Fruit Bat Cell Line SO VIRUSES-BASEL LA English DT Article DE fruit bat cell line; R06E; R05T; Rousettus aegyptiacus ID NF-KAPPA-B; CROSS-CONTAMINATION; TUMORIGENIC PHENOTYPE; VIRUS-REPLICATION; MEASLES-VIRUS; FLYING-FOXES; NIPAH VIRUS; VERO CELLS; INFECTION; CULTURE AB Fruit bats and insectivorous bats are believed to provide a natural reservoir for a wide variety of infectious diseases. Several lines of evidence, including the successful isolation of infectious viruses, indicate that Marburg virus and Ravn virus have found a major reservoir in colonies of the Egyptian rousette (Rousettus aegyptiacus). To facilitate molecular studies on virus-reservoir host interactions and isolation of viruses from environmental samples, we established cell lines from primary cells of this animal. The cell lines were given to several laboratories until we realized that a contamination with Vero cells in one of the cultures had occurred. Here we describe a general diagnostic procedure for identification of cross-species contamination with the focus on Vero and Rousettus cell lines, and summarize newly discovered properties of the cell lines that may pertain to pathogen discovery. C1 [Jordan, Ingo; Sandig, Volker] ProBioGen AG, D-13086 Berlin, Germany. [Munster, Vincent J.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Jordan, I (reprint author), ProBioGen AG, Goethestr 54, D-13086 Berlin, Germany. EM ingo.jordan@probiogen.de; vincent.munster@nih.gov; volker.sandig@probiogen.de OI Jordan, Ingo/0000-0003-2711-7252; Munster, Vincent/0000-0002-2288-3196 FU EUROTRANSBIO-1 (ETB) [0313976]; Division of Intramural Research of the NIAID/NIH FX We gratefully acknowledge Verena Krahling for critical reading of the manuscript. We also thank Deborah Horn and Kristin Howing for excellent technical assistance. IJ is supported by grant #0313976 from EUROTRANSBIO-1 (ETB). VJM is supported by the Division of Intramural Research of the NIAID/NIH. NR 47 TC 8 Z9 9 U1 0 U2 21 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAY PY 2012 VL 4 IS 5 BP 889 EP 900 DI 10.3390/v4050889 PG 12 WC Virology SC Virology GA 965XT UT WOS:000305801700013 PM 22754654 ER PT J AU Spatafora, JW Owensby, CA Douhan, GW Boehm, EWA Schoch, CL AF Spatafora, Joseph W. Owensby, C. Alisha Douhan, Greg W. Boehm, Eric W. A. Schoch, Conrad L. TI Phylogenetic placement of the ectomycorrhizal genus Cenococcum in Gloniaceae (Dothideomycetes) SO MYCOLOGIA LA English DT Article DE Cenococcum; Dothideomycetes; ectomycorrhizae; fungi; Gloniaceae; phylogenetics; systematics ID MOLECULAR SYSTEMATICS; GEOPHILUM POPULATIONS; SEQUENCE DATA; EVOLUTION; FUNGI; PLEOSPOROMYCETIDAE; MYTILINIDIACEAE; CLASSIFICATION; RECOMBINATION; HYSTERIACEAE AB Cenococcum is a genus of ectomycorrhizal Ascomycota that has a broad host range and geographic distribution. It is not known to produce either meiotic or mitotic spores and is known to exist only in the form of hyphae, sclerotia and host-colonized ectomycorrhizal root tips. Due to its lack of sexual and asexual spores and reproductive structures, it has proven difficult to incorporate into traditional classification within Ascomycota. Molecular phylogenetic studies of ribosomal RNA placed Cenococcum in Dothideomycetes, but the definitive identification of closely related taxa remained elusive. Here we report a phylogenetic analysis of five nuclear loci (SSU, LSU, TEF1, RPM, RPB2) of Dothideomycetes that placed Cenococcum as a close relative of the genus Glonium of Gloniaceae (Pleosporomycetidae incertae sedis) with strong statistical support. Glonium is a genus of saprobic Dothideomycetes that produces darkly pigmented, carbonaceous, hysteriate apothecia and is not known to be biotrophic. Evolution of ectomycorhizae, Cenococcum and Dothideomycetes is discussed. C1 [Spatafora, Joseph W.; Owensby, C. Alisha] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97330 USA. [Douhan, Greg W.] Univ Calif Riverside, Dept Plant Pathol & Microbiol, Riverside, CA 92521 USA. [Boehm, Eric W. A.] Kean Univ, Dept Biol Sci, Union, NJ 07083 USA. [Schoch, Conrad L.] NIH, NCBI, Natl Lib Med, Bethesda, MD 20892 USA. RP Spatafora, JW (reprint author), Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97330 USA. EM spatafoj@science.oregonstate.edu RI Schoch, Conrad/J-4825-2012 FU Agricultural Experiment Station, University of California at Riverside; National Science Foundation [DEB-0717476] FX The authors thank Francis Martin, Renaud Maire and Martina Peter for providing DNA for specimen 1.58. CLS acknowledges the Intramural Research Program of the NIH, National Library of Medicine. GWD acknowledges financial support of the Agricultural Experiment Station, University of California at Riverside. Research was financially supported by a grant from the National Science Foundation (DEB-0717476 to JWS). Any opinions, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. NR 37 TC 6 Z9 7 U1 0 U2 20 PU ALLEN PRESS INC PI LAWRENCE PA 810 E 10TH ST, LAWRENCE, KS 66044 USA SN 0027-5514 J9 MYCOLOGIA JI Mycologia PD MAY-JUN PY 2012 VL 104 IS 3 BP 758 EP 765 DI 10.3852/11-233 PG 8 WC Mycology SC Mycology GA 961VO UT WOS:000305497800014 PM 22453119 ER PT J AU Edvardson, S Cinnamon, Y Ta-Shma, A Shaag, A Yim, YI Zenvirt, S Jalas, C Lesage, S Brice, A Taraboulos, A Kaestner, KH Greene, LE Elpeleg, O AF Edvardson, Simon Cinnamon, Yuval Ta-Shma, Asaf Shaag, Avraham Yim, Yang-In Zenvirt, Shamir Jalas, Chaim Lesage, Suzanne Brice, Alexis Taraboulos, Albert Kaestner, Klaus H. Greene, Lois E. Elpeleg, Orly TI A Deleterious Mutation in DNAJC6 Encoding the Neuronal-Specific Clathrin-Uncoating Co-Chaperone Auxilin, Is Associated with Juvenile Parkinsonism SO PLOS ONE LA English DT Article ID COATED VESICLES; MEDIATED ENDOCYTOSIS; DISEASE; PROTEIN; RECEPTORS; COMPLEX; ATPASE; VPS35; GENE; PITS AB Parkinson disease is caused by neuronal loss in the substantia nigra which manifests by abnormality of movement, muscle tone, and postural stability. Several genes have been implicated in the pathogenesis of Parkinson disease, but the underlying molecular basis is still unknown for similar to 70% of the patients. Using homozygosity mapping and whole exome sequencing we identified a deleterious mutation in DNAJC6 in two patients with juvenile Parkinsonism. The mutation was associated with abnormal transcripts and marked reduced DNAJC6 mRNA level. DNAJC6 encodes the HSP40 Auxilin, a protein which is selectively expressed in neurons and confers specificity to the ATPase activity of its partner Hcs70 in clathrin uncoating. In Auxilin null mice it was previously shown that the abnormally increased retention of assembled clathrin on vesicles and in empty cages leads to impaired synaptic vesicle recycling and perturbed clathrin mediated endocytosis. Endocytosis function, studied by transferring uptake, was normal in fibroblasts from our patients, likely because of the presence of another J-domain containing partner which co-chaperones Hsc70-mediated uncoating activity in non-neuronal cells. The present report underscores the importance of the endocytic/lysosomal pathway in the pathogenesis of Parkinson disease and other forms of Parkinsonism. C1 [Edvardson, Simon; Cinnamon, Yuval; Ta-Shma, Asaf; Shaag, Avraham; Zenvirt, Shamir; Elpeleg, Orly] Hebrew Univ Jerusalem, Med Ctr, Monique & Jacques Roboh Dept Genet Res, Jerusalem, Israel. [Yim, Yang-In; Greene, Lois E.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Jalas, Chaim] Ctr Rare Jewish Genet Disorders, Brooklyn, NY USA. [Lesage, Suzanne; Brice, Alexis] Univ Paris 06, Hosp Pitie Salpetriere, CNRS UMR 7225, CRICM,INSERM,UMR S975, Paris, France. [Taraboulos, Albert] Hebrew Univ Jerusalem, Hadassah Med Sch, IMRIC, IL-91010 Jerusalem, Israel. [Kaestner, Klaus H.] Univ Penn, Sch Med, Dept Genet, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. RP Edvardson, S (reprint author), Hebrew Univ Jerusalem, Med Ctr, Monique & Jacques Roboh Dept Genet Res, Jerusalem, Israel. EM Elpeleg@hadassah.org.il OI Jalas, Chaim/0000-0002-3788-0924; Edvardson, Simon/0000-0003-2878-1278 FU Hadassah Hospital FX Internal funds of Hadassah Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 65 Z9 67 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 1 PY 2012 VL 7 IS 5 AR e36458 DI 10.1371/journal.pone.0036458 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UN UT WOS:000305340700050 PM 22563501 ER PT J AU Thompson, DA Khan, NW Othman, MI Chang, B Jia, L Grahek, G Wu, ZJ Hiriyanna, S Nellissery, J Li, TS Khanna, H Colosi, P Swaroop, A Heckenlively, JR AF Thompson, Debra A. Khan, Naheed W. Othman, Mohammad I. Chang, Bo Jia, Lin Grahek, Garrett Wu, Zhijian Hiriyanna, Suja Nellissery, Jacob Li, Tiansen Khanna, Hemant Colosi, Peter Swaroop, Anand Heckenlively, John R. TI Rd9 Is a Naturally Occurring Mouse Model of a Common Form of Retinitis Pigmentosa Caused by Mutations in RPGR-ORF15 SO PLOS ONE LA English DT Article ID RPGR EXON ORF15; ONSET RETINAL DEGENERATION; CONE OPSIN MISLOCALIZATION; GTPASE REGULATOR RPGR; PHOTORECEPTOR DEGENERATION; DISEASE EXPRESSION; NEGATIVE RESPONSE; B-WAVE; A-WAVE; GENE AB Animal models of human disease are an invaluable component of studies aimed at understanding disease pathogenesis and therapeutic possibilities. Mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR) are the most common cause of X-linked retinitis pigmentosa (XLRP) and are estimated to cause 20% of all retinal dystrophy cases. A majority of RPGR mutations are present in ORF15, the purine-rich terminal exon of the predominant splice-variant expressed in retina. Here we describe the genetic and phenotypic characterization of the retinal degeneration 9 (Rd9) strain of mice, a naturally occurring animal model of XLRP. Rd9 mice were found to carry a 32-base-pair duplication within ORF15 that causes a shift in the reading frame that introduces a premature-stop codon. Rpgr ORF15 transcripts, but not protein, were detected in retinas from Rd9/Y male mice that exhibited retinal pathology, including pigment loss and slowly progressing decrease in outer nuclear layer thickness. The levels of rhodopsin and transducin in rod outer segments were also decreased, and M-cone opsin appeared mislocalized within cone photoreceptors. In addition, electroretinogram (ERG) a-and b-wave amplitudes of both Rd9/Y male and Rd9/Rd9 female mice showed moderate gradual reduction that continued to 24 months of age. The presence of multiple retinal features that correlate with findings in individuals with XLRP identifies Rd9 as a valuable model for use in gaining insight into ORF15-associated disease progression and pathogenesis, as well as accelerating the development and testing of therapeutic strategies for this common form of retinal dystrophy. C1 [Thompson, Debra A.; Khan, Naheed W.; Othman, Mohammad I.; Jia, Lin; Grahek, Garrett; Heckenlively, John R.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Thompson, Debra A.] Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Chang, Bo] Jackson Lab, Bar Harbor, ME 04609 USA. [Wu, Zhijian; Hiriyanna, Suja; Nellissery, Jacob; Li, Tiansen; Colosi, Peter; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Khanna, Hemant] Univ Massachusetts, Sch Med, Dept Ophthalmol, Worcester, MA USA. RP Thompson, DA (reprint author), Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. EM swaroopa@nei.nih.gov; jrheck@umich.edu OI Swaroop, Anand/0000-0002-1975-1141 FU National Institutes of Health [RO1-EY007758, RO1-EY007961, RO1-EY019943, P30-EY07003, P60-DK-20572, UL1RR024986]; Foundation Fighting Blindness; Research to Prevent Blindness; intramural program of the National Eye Institute; Senior Scientific Investigator Awards; Clinician-Scientist Award from Research to Prevent Blindness FX This research was supported by grants from National Institutes of Health (RO1-EY007758, RO1-EY007961, RO1-EY019943, P30-EY07003, P60-DK-20572, UL1RR024986), The Foundation Fighting Blindness, Research to Prevent Blindness, and the intramural program of the National Eye Institute. DAT, JRH, and AS are recipients of Senior Scientific Investigator Awards, and JRH received the Clinician-Scientist Award from Research to Prevent Blindness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 31 Z9 32 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 1 PY 2012 VL 7 IS 5 AR e35865 DI 10.1371/journal.pone.0035865 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 959UN UT WOS:000305340700021 PM 22563472 ER PT J AU Kovalchik, SA Cumberland, WG AF Kovalchik, Stephanie A. Cumberland, William G. TI Using aggregate data to estimate the standard error of a treatment-covariate interaction in an individual patient data meta-analysis SO BIOMETRICAL JOURNAL LA English DT Article DE Effect modification; Individual patient data; Meta-analysis; Meta-regression; Subgroup analysis; Treatment-covariate interaction ID LINEAR MIXED MODELS; CLINICAL-TRIALS; META-REGRESSION; SUBGROUP ANALYSES; LEVEL; HETEROGENEITY; BIAS; MEDICINE; NEED AB Subgroup analyses are important to medical research because they shed light on the heterogeneity of treatment effectts. A treatmentcovariate interaction in an individual patient data (IPD) meta-analysis is the most reliable means to estimate how a subgroup factor modifies a treatment's effectiveness. However, owing to the challenges in collecting participant data, an approach based on aggregate data might be the only option. In these circumstances, it would be useful to assess the relative efficiency and power loss of a subgroup analysis without patient-level data. We present methods that use aggregate data to estimate the standard error of an IPD meta-analysis treatmentcovariate interaction for regression models of a continuous or dichotomous patient outcome. Numerical studies indicate that the estimators have good accuracy. An application to a previously published meta-regression illustrates the practical utility of the methodology. C1 [Kovalchik, Stephanie A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Cumberland, William G.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. RP Kovalchik, SA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8047, Rockville, MD 20852 USA. EM kovalchiksa@mail.nih.gov FU NIH/NIAID [T32-AI007370] FX This work was supported by NIH/NIAID training grant T32-AI007370. We thank the anonymous reviewer and Associate Editor for helpful comments on this manuscript. NR 32 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 J9 BIOMETRICAL J JI Biom. J. PD MAY PY 2012 VL 54 IS 3 BP 370 EP 384 DI 10.1002/bimj.201100167 PG 15 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 956FN UT WOS:000305075600005 PM 22685003 ER PT J AU Kshatriya, PP Karuri, SW Chiang, CY Karuri, NW AF Kshatriya, Pradnya P. Karuri, Stella W. Chiang, Chunyi Karuri, Nancy W. TI A combinatorial approach for directing the amount of fibronectin fibrils assembled by cells that uses surfaces derivatized with mixtures of fibronectin and cell binding domains SO BIOTECHNOLOGY PROGRESS LA English DT Article DE fibronectin; cell binding domain; fibronectin binding domain; fibronectin fibril; extracellular matrix ID PERICELLULAR MATRIX; CYTOPLASMIC DOMAIN; COVERAGE DESIGNS; CONFORMATION; ASSOCIATION; DYNAMICS; MOLECULE; GROWTH; SITE AB Fibrillar fibronectin (FN) has the crucial role of attracting and attaching cells as well as molecules that mediate tissue repair during wound healing. A previous study demonstrated higher extracellular staining of FN fibrils in cells cultured on surfaces tethered with an equimolar mixture of a FN binding domain and FN's cell binding domain, III1-2 and III9-10 respectively, than on surfaces with III9-10 alone. The effect of varying surface amounts of III1-2 and III9-10 on the quantity of FN fibrils formed by NIH-3T3 fibroblasts was examined. GST tagged III1-2 and III9-10 were conjugated to polyurethane surfaces and ELISAs were used to identify the experimental design space or the range of concentrations of GST-III1-2 and GST-III9-10 that demarcated the limits of protein loading on the surface. When GST-III1-2 was fixed and GST-III9-10 varied within the design space, the amount of FN fibrils measured by immunoblotting detergent insoluble cell lysates was dependent on the ratio of III9-10 to III1-2. When the total protein concentration was fixed and the mixture composition of GST-III1-2 and GST-III9-10 varied such that it optimally covered the design space, a parabolic relationship between FN fibril amount and the ratio of III9-10 to III1-2 was obtained. This relationship had a maximum value when the surface was bonded to equal amounts of III1-2 and III9-10 (P < 0.05). Thus the ratio of III9-10 to III1-2 can be utilized to direct the quantity of FN fibrils formed on surfaces. (C) 2012 American Institute of Chemical Engineers Biotechnol. Prog., 2012 C1 [Kshatriya, Pradnya P.; Chiang, Chunyi; Karuri, Nancy W.] IIT, Dept Chem & Biol Engn, Chicago, IL 60616 USA. [Karuri, Stella W.] Natl Canc Inst, Biometr Res Branch, Bethesda, MD 20952 USA. RP Karuri, NW (reprint author), IIT, Dept Chem & Biol Engn, Chicago, IL 60616 USA. EM nkaruri1@iit.edu NR 31 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8756-7938 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD MAY-JUN PY 2012 VL 28 IS 3 BP 862 EP 871 DI 10.1002/btpr.1537 PG 10 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 955AP UT WOS:000304989800027 PM 22467639 ER PT J AU Merrick, BA Auerbach, SS Stockton, PS Foley, JF Malarkey, DE Sills, RC Irwin, RD Ticet, RR AF Merrick, B. Alex Auerbach, Scott S. Stockton, Patricia S. Foley, Julie F. Malarkey, David E. Sills, Robert. C. Irwin, Richard D. Ticet, Raymond R. TI Testing an Aflatoxin B1 Gene Signature in Rat Archival Tissues SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID CELL LUNG-CANCER; HUMAN HEPATOCELLULAR-CARCINOMA; PARAFFIN-EMBEDDED SAMPLES; BREAST-CANCER; TUMOR-CELLS; EXPRESSION SIGNATURE; NEGATIVE REGULATOR; QUANTITATIVE PCR; B-MYB; FORMALIN AB Archival tissues from laboratory studies represent a unique opportunity to explore the relationship between genomic changes and agent-induced disease. In this study, we evaluated the applicability of qPCR for detecting genomic changes in formalin-fixed, paraffin-embedded (FFPE) tissues by determining if a subset of 14 genes from a 90-gene signature derived from microarray data and associated with eventual tumor development could be detected in archival liver, kidney, and lung of rats exposed to aflatoxin B1 (AFB1) for 90 days in feed at 1 ppm. These tissues originated from the same rats used in the microarray study. The 14 genes evaluated were Adam8, Cdh13, Ddit4l, Mybl2, Akr7a3, Akr7a2, Fhit, Wwox, Abcblb, Abcc3, Cxcll, Gsta5, Grin2c, and the C8orf46 homologue. The qPCR FFPE liver results were compared to the original liver microarray data and to qPCR results using RNA from fresh frozen liver. Archival liver paraffin blocks yielded 30 to 50 mu g of degraded RNA that ranged in size from 0.1 to 4 kB. qPCR results from FFPE and fresh frozen liver samples were positively correlated (p <= 0.05) by regression analysis and showed good agreement in direction and proportion of change with microarray data for 11 of 14 genes. All 14 transcripts could be amplified from FFPE kidney RNA except the glutamate receptor gene Grin2c; however, only Abcblb was significantly upregulated from control. Abundant constitutive transcripts, S18 and beta-actin, could be amplified from lung FFPE samples, but the narrow RNA size range (25-500 bp length) prevented consistent detection of target transcripts. Overall, a discrete gene signature derived from prior transcript profiling and representing cell cycle progression, DNA damage response, and xenosensor and detoxication pathways was successfully applied to archival liver and kidney by qPCR and indicated that gene expression changes in response to subchronic AFB1 exposure occurred predominantly in the liver, the primary target for AFB 1-induced tumors. We conclude that an evaluation of gene signatures in archival tissues can be an important toxicological tool for evaluating critical molecular events associated with chemical exposures. C1 [Merrick, B. Alex; Auerbach, Scott S.; Stockton, Patricia S.; Ticet, Raymond R.] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Foley, Julie F.; Malarkey, David E.; Sills, Robert. C.] NIEHS, Comparat Med & Pathol Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Irwin, Richard D.] NIEHS, Toxicol Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Merrick, BA (reprint author), NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM merrick@niehs.nih.gov FU National Toxicology Program Division; Intramural Research at the National Institute of Environmental Health Sciences of the NIH FX This research was supported by the Intramural Research Programs of the National Toxicology Program Division and Division of Intramural Research at the National Institute of Environmental Health Sciences of the NIH. NR 61 TC 10 Z9 10 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAY PY 2012 VL 25 IS 5 BP 1132 EP 1144 DI 10.1021/tx3000945 PG 13 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 944WR UT WOS:000304235000016 PM 22545673 ER PT J AU Moriyama, B Henning, SA Penzak, SR Walsh, TJ AF Moriyama, Brad Henning, Stacey A. Penzak, Scott R. Walsh, Thomas J. TI The postantifungal and paradoxical effects of echinocandins against Candida spp. SO FUTURE MICROBIOLOGY LA English DT Article DE Candida spp; echinocandin; paradoxical effect; postantifungal effect ID HIGH DRUG CONCENTRATIONS; ANTIFUNGAL AGENTS; TIME-KILL; IN-VITRO; AMPHOTERICIN-B; CASPOFUNGIN; ALBICANS; PARAPSILOSIS; GLABRATA; BIOFILMS AB Evaluation of: Shields RK, Nguyen MH, Press EG, Clancy CJ. Five-minute exposure to caspofungin results in prolonged postantifungal effects and eliminates the paradoxical growth of Candida albicans. Antimicrob. Agents Chemother. 55(7), 3598-3602 (2011). Echinocandins induce a postantifungal effect and a paradoxical effect. The postantifungal effect Is a concentration-dependent process that allows for sustained kill of Candida spp. after relatively brief exposures to a compound. The paradoxical effect is growth that occurs at high echinocandin concentrations above the MIC. Paradoxical growth varies in terms of media, species, strain and type of echinocandin. The study by Shields et al. evaluated the impact of a brief exposure of caspofungin on paradoxical growth and postantifungal effects in Candida albicans isolates. In the postantifungal effect experiments, prolonged concentration-dependent killing occurred. Maximum postantifungal effects occurred with caspofungin exposures of 5 or 15 min. A brief exposure of caspofungin eliminated the paradoxical growth that was observed in the time-kill experiments. The report by Shields et al, illustrates that short exposures to an echinocandin may lead to prolonged postantifungal effects and furthers our understanding of the paradoxical effect in C. albicans. C1 [Moriyama, Brad; Henning, Stacey A.; Penzak, Scott R.; Walsh, Thomas J.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), Cornell Univ, Transplantat Oncol Infect Dis Program, Weill Cornell Med Ctr, 1300 York Ave,A-421, New York, NY 10065 USA. EM thw2003@med.cornell.edu FU NIH; Novartis; Astellas FX This work was supported in part by the intramural research program of the NIH. B Moriyama has stock in Merck. TJ Walsh has recieved research grants from Novartis and Astellas, and consultancies from Vestagen, iCo Therapeutics, Inc., Trius, Sigma Tau, Astellas and Drais Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 25 TC 5 Z9 5 U1 0 U2 7 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 J9 FUTURE MICROBIOL JI Future Microbiol. PD MAY PY 2012 VL 7 IS 5 BP 565 EP 569 DI 10.2217/FMB.12.31 PG 5 WC Microbiology SC Microbiology GA 951UH UT WOS:000304745000007 PM 22568712 ER PT J AU Mattapallil, MJ Wawrousek, EF Chan, CC Zhao, H Roychoudhury, J Ferguson, TA Caspi, RR AF Mattapallil, Mary J. Wawrousek, Eric F. Chan, Chi-Chao Zhao, Hui Roychoudhury, Jayeeta Ferguson, Thomas A. Caspi, Rachel R. TI The Rd8 Mutation of the Crb1 Gene Is Present in Vendor Lines of C57BL/6N Mice and Embryonic Stem Cells, and Confounds Ocular Induced Mutant Phenotypes SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID DEGENERATION AB PURPOSE. We noted an unexpected inheritance pattern of lesions in several strains of gene-manipulated mice with ocular phenotypes. The lesions, which appeared at various stages of backcross to C57BL/6, bore resemblance to the rd8 retinal degeneration phenotype. We set out to examine the prevalence of this mutation in induced mutant mouse lines, vendor C57BL/6 mice and in widely used embryonic stem cells. METHODS. Ocular lesions were evaluated by fundus examination and histopathology. Detection of the rd8 mutation at the genetic level was performed by PCR with appropriate primers. Data were confirmed by DNA sequencing in selected cases. RESULTS. Analysis of several induced mutant mouse lines with ocular disease phenotypes revealed that the disease was associated 100% with the presence of the rd8 mutation in the Crb1 gene rather than with the gene of interest. DNA analysis of C57BL/6 mice from common commercial vendors demonstrated the presence of the rd8 mutation in homozygous form in all C57BL/6N substrains, but not in the C57BL/6J substrain. A series of commercially available embryonic stem cells of C57BL/6N origin and C57BL/6N mouse lines used to generate ES cells also contained the rd8 mutation. Affected mice displayed ocular lesions typical of rd8, which were detectable by funduscopy and histopathology as early as 6 weeks of age. CONCLUSIONS. These findings identify the presence of the rd8 mutation in the C57BL/6N mouse substrain used widely to produce transgenic and knockout mice. The results have grave implications for the vision research community who develop mouse lines to study eye disease, as presence of rd8 can produce significant disease phenotypes unrelated to the gene or genes of interest. It is suggested that researchers screen for rd8 if their mouse lines were generated on the C57BL/6N background, bear resemblance to the rd8 phenotype, or are of indeterminate origin. (Invest Ophthalmol Vis Sci. 2012; 53: 2921-2927) DOI: 10.1167/iovs.12-9662 C1 [Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20814 USA. [Wawrousek, Eric F.] NEI, Genet Engn Core, Bethesda, MD 20814 USA. [Zhao, Hui; Roychoudhury, Jayeeta; Ferguson, Thomas A.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, Bethesda, MD 20814 USA. EM ferguson@vision.wustl.edu; rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU NIH/NEI [ZIA EY000184-29, ZIA EY000418-08]; NIH [EY06765, EY015570]; Department of Ophthalmology and Visual Sciences [EY02687]; American Health Assistance Foundation (Clarksburg, Maryland); Research to Prevent Blindness (New York, New York) FX Supported by NIH/NEI Intramural funding Grant ZIA EY000184-29 (RRC), NIH/NEI Intramural funding Grant ZIA EY000418-08 (CCC), and NIH extramural Grants EY06765 (TAF) and EY015570 (TAF), the Department of Ophthalmology and Visual Sciences core Grant EY02687 (TAF), The American Health Assistance Foundation (Clarksburg, Maryland, TAF), and Research to Prevent Blindness (New York, New York, TAF). Also supported in part by the NIH Bench-to-Bedside award (RRC and MJM). NR 10 TC 212 Z9 214 U1 2 U2 13 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2012 VL 53 IS 6 BP 2921 EP 2927 DI 10.1167/iovs.12-9662 PG 7 WC Ophthalmology SC Ophthalmology GA 953JY UT WOS:000304864600048 PM 22447858 ER PT J AU Hochberg, C Maul, E Chan, ES Van Landingham, S Ferrucci, L Friedman, DS Ramulu, PY AF Hochberg, Chad Maul, Eugenio Chan, Emilie S. Van Landingham, Suzanne Ferrucci, Luigi Friedman, David S. Ramulu, Pradeep Y. TI Association of Vision Loss in Glaucoma and Age-Related Macular Degeneration with IADL Disability SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID SALISBURY EYE EVALUATION; QUALITY-OF-LIFE; VISUAL FUNCTION; OLDER-ADULTS; MOBILITY PERFORMANCE; EVALUATION PROJECT; READING SPEED; UNITED-STATES; SEE PROJECT; POPULATION AB PURPOSE. To determine if glaucoma and/or age-related macular degeneration (AMD) are associated with disability in instrumental activities of daily living (IADLs). METHODS. Glaucoma subjects (n = 84) with bilateral visual field (VF) loss and AMD subjects (n = 47) with bilateral or severe unilateral visual acuity (VA) loss were compared with 60 subjects with normal vision (controls). Subjects completed a standard IADL disability questionnaire, with disability defined as an inability to perform one or more IADLs unassisted. RESULTS. Disability in one or more IADLs was present in 18.3% of controls as compared with 25.0% of glaucoma subjects (P = 0.34) and 44.7% of AMD subjects (P = 0.003). The specific IADL disabilities occurring more frequently in both AMD and glaucoma subjects were preparing meals, grocery shopping, and out-of-home travelling (P < 0.05 for both). In multivariate logistic regression models run adjusting for age, sex, mental status, comorbidity, and years of education, AMD (odds ratio [OR] = 3.4, P = 0.02) but not glaucoma (OR = 1.4, P = 0.45) was associated with IADL disability. However, among glaucoma and control patients, the odds of IADL disability increased 1.6-fold with every 5 dB of VF loss in the better-seeing eye (P = 0.001). Additionally, severe glaucoma subjects (better-eye MD worse than -13.5 dB) had higher odds of IADL disability (OR = 4.2, P = 0.02). Among AMD and control subjects, every Early Treatment of Diabetic Retinopathy Study line of worse acuity was associated with a greater likelihood of IADL disability (OR = 1.3). CONCLUSIONS. VA loss in AMD and severe VF loss in glaucoma are associated with self-reported difficulties with IADLs. These limitations become more likely with increasing magnitude of VA or VF loss. (Invest Ophthalmol Vis Sci. 2012;53:3201-3206) DOI:10.1167/iovs.12-9469 C1 [Hochberg, Chad; Maul, Eugenio; Chan, Emilie S.; Van Landingham, Suzanne; Friedman, David S.; Ramulu, Pradeep Y.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. RP Ramulu, PY (reprint author), 600 N Wolfe St,Maumenee B110, Baltimore, MD 21287 USA. EM pramulu1@jhmi.edu FU Dennis W. Jahnigen Memorial Award; National Institutes of Health [EY018595]; Research to Prevent Blindness; National Institutes of Health, National Institute of Aging FX Supported by Dennis W. Jahnigen Memorial Award, National Institutes of Health Grant EY018595, the Research to Prevent Blindness Robert and Helen Schaub Special Scholar Award, and the Intramural Research Program of the National Institutes of Health, National Institute of Aging. All funding organizations had no role in the design or conduct of this research. NR 40 TC 28 Z9 28 U1 2 U2 11 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2012 VL 53 IS 6 BP 3201 EP 3206 DI 10.1167/iovs.12-9469 PG 6 WC Ophthalmology SC Ophthalmology GA 953JY UT WOS:000304864600078 PM 22491415 ER PT J AU Sakamuru, S Li, X Attene-Ramos, MS Huang, RL Lu, JM Shou, L Shen, M Tice, RR Austin, CP Xia, MH AF Sakamuru, Srilatha Li, Xiao Attene-Ramos, Matias S. Huang, Ruili Lu, Jianming Shou, Louie Shen, Min Tice, Raymond R. Austin, Christopher P. Xia, Menghang TI Application of a homogenous membrane potential assay to assess mitochondrial function SO PHYSIOLOGICAL GENOMICS LA English DT Article DE Mito-MPS; mitochondrial membrane potential assay; quantitative high-throughput screening; 1,536-well plate ID CYCLIN-DEPENDENT KINASES; PERMEABILITY TRANSITION; OXIDATIVE-PHOSPHORYLATION; CANCER-CELLS; APOPTOSIS; INHIBITORS; MECHANISM; TYRPHOSTINS; INDUCTION; DISCOVERY AB Decreases in mitochondrial membrane potential (MMP) have been associated with mitochondrial dysfunction that could lead to cell death. The MMP is generated by an electrochemical gradient via the mitochondrial electron transport chain coupled to a series of redox reactions. Measuring the MMP in living cells is commonly used to assess the effect of chemicals on mitochondrial function; decreases in MMP can be detected using lipophilic cationic fluorescent dyes. To identify an optimal dye for use in a high-throughput screening (HTS) format, we compared the ability of mitochondrial membrane potential sensor (Mito-MPS), 5,5', 6,6'- tetrachloro-1,1', 3,3' tetraethylbenzimidazolyl-carbocyanine iodide, rhodamine 123, and tetramethylrhodamine to quantify a decrease in MMP in chemically exposed HepG2 cells cultured in 1,536-well plates. Under the conditions used, the optimal dye for this purpose is Mito-MPS. Next, we developed and optimized a homogenous cell-based Mito-MPS assay for use in 1,536-well plate format and demonstrated the utility of this assay by screening 1,280 compounds in the library of pharmacologically active compounds in HepG2 cells using a quantitative high-throughput screening platform. From the screening, we identified 14 compounds that disrupted the MMP, with half-maximal potencies ranging from 0.15 to 18 mu M; among these, compound clusters that contained tyrphostin and 3'-substituted indolone analogs exhibited a structure-activity relationship. Our results demonstrate that this homogenous cell-based Mito-MPS assay can be used to evaluate the ability of large numbers of chemicals to decrease mitochondrial function. C1 [Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. [Li, Xiao] BD Diagnost Diagnost Syst, Sparks, MD USA. [Lu, Jianming] Codex Biosolut, Montgomery Village, MD USA. [Tice, Raymond R.] Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Res Triangle Pk, NC USA. RP Xia, MH (reprint author), NIH, Natl Ctr Adv Translat Sci, NIH Chem Genom Ctr, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. FU Division of the National Toxicology Program, National Institute of Environmental Health Sciences [Y3-ES-7020-01]; National Human Genome Research Institute, National Institutes of Health FX This research was supported by the Intramural Research Program (interagency agreement #Y3-ES-7020-01) of the Division of the National Toxicology Program, National Institute of Environmental Health Sciences, and the National Human Genome Research Institute, National Institutes of Health. NR 38 TC 13 Z9 13 U1 1 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD MAY PY 2012 VL 44 IS 9 BP 495 EP 503 DI 10.1152/physiolgenomics.00161.2011 PG 9 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 958WI UT WOS:000305271300003 PM 22433785 ER PT J AU Fox, CS White, CC Lohman, K Heard-Costa, N Cohen, P Zhang, YY Johnson, AD Emilsson, V Liu, CT Chen, YDI Taylor, KD Allison, M Budoff, M Rotter, JI Carr, JJ Hoffmann, U Ding, JZ Cupples, LA Liu, YM AF Fox, Caroline S. White, Charles C. Lohman, Kurt Heard-Costa, Nancy Cohen, Paul Zhang, Yingying Johnson, Andrew D. Emilsson, Valur Liu, Ching-Ti Chen, Y. -D. Ida Taylor, Kent D. Allison, Matthew Budoff, Matthew Rotter, Jerome I. Carr, J. Jeffrey Hoffmann, Udo Ding, Jingzhong Cupples, L. Adrienne Liu, Yongmei CA CARDIoGRAM Consortium TI Genome-Wide Association of Pericardial Fat Identifies a Unique Locus for Ectopic Fat SO PLOS GENETICS LA English DT Article ID PERIVASCULAR ADIPOSE-TISSUE; VISCERAL ABDOMINAL FAT; BODY-MASS INDEX; GENE-EXPRESSION; ATHEROSCLEROSIS MESA; INTRATHORACIC FAT; RISK-FACTORS; HIP RATIO; HEART; DISEASE AB Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to similar to 2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7 x 10(-08)). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution. C1 [Fox, Caroline S.; Johnson, Andrew D.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [White, Charles C.; Liu, Ching-Ti; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lohman, Kurt; Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Heard-Costa, Nancy] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Cohen, Paul] Brigham & Womens Hosp, Dept Canc Biol, Boston, MA 02115 USA. [Cohen, Paul] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Zhang, Yingying] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Emilsson, Valur] Iceland Heart Assoc, Hjartavernd, Iceland. [Chen, Y. -D. Ida; Taylor, Kent D.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Allison, Matthew] Univ Calif San Diego, Dept Prevent Med, La Jolla, CA 92093 USA. [Budoff, Matthew] Los Angeles Biomed Res Inst, Torrance, CA USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol Sci, Winston Salem, NC USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. [Hoffmann, Udo] Massachusetts Gen Hosp, CT Program, PET, Cardiac MR, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ding, Jingzhong] Wake Forest Sch Med, Dept Internal Med Geriatr, Winston Salem, NC USA. RP Fox, CS (reprint author), NHLBI, Ctr Populat Studies, Framingham, MA USA. EM foxca@nhlbi.nih.gov; yoliu@wfubmc.edu RI Johnson, Andrew/G-6520-2013; Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; Heard-Costa, Nancy/0000-0001-9730-0306; Cupples, L. Adrienne/0000-0003-0273-7965; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-25195, N02-HL-6-4278]; Affymetrix for genotyping services [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; [R01-HL-085323]; [R01-HL-071205]; [N01 HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [RR-024156] FX Framingham Heart Study: This research was conducted in part using data and resources 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. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. MESA Study: MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants R01-HL-085323 and R01-HL-071205 and by contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, and RR-024156. MESA SNP Health Association Resource (SHARe): Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 24 Z9 24 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2012 VL 8 IS 5 AR e1002705 DI 10.1371/journal.pgen.1002705 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 953JT UT WOS:000304864000032 PM 22589742 ER PT J AU Fox, CS Liu, YM White, CC Feitosa, M Smith, AV Heard-Costa, N Lohman, K Johnson, AD Foster, MC Greenawalt, DM Griffin, P Ding, JH Newman, AB Tylavsky, F Miljkovic, I Kritchevsky, SB Launer, L Garcia, M Eiriksdottir, G Carr, JJ Gudnason, V Harris, TB Cupples, LA Borecki, IB AF Fox, Caroline S. Liu, Yongmei White, Charles C. Feitosa, Mary Smith, Albert V. Heard-Costa, Nancy Lohman, Kurt Johnson, Andrew D. Foster, Meredith C. Greenawalt, Danielle M. Griffin, Paula Ding, Jinghong Newman, Anne B. Tylavsky, Fran Miljkovic, Iva Kritchevsky, Stephen B. Launer, Lenore Garcia, Melissa Eiriksdottir, Gudny Carr, J. Jeffrey Gudnason, Vilmunder Harris, Tamara B. Cupples, L. Adrienne Borecki, Ingrid B. CA GIANT Consortium MAGIC Consortium GLGC Consortium TI Genome-Wide Association for Abdominal Subcutaneous and Visceral Adipose Reveals a Novel Locus for Visceral Fat in Women SO PLOS GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; GENE-EXPRESSION; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; ATHEROSCLEROSIS MESA; TISSUE DISTRIBUTION; PERICARDIAL FAT; RISK-FACTORS; HIP RATIO; OBESITY AB Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to similar to 2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 x 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 x 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 x 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits. C1 [Fox, Caroline S.; White, Charles C.; Heard-Costa, Nancy; Johnson, Andrew D.; Foster, Meredith C.; Griffin, Paula; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [Fox, Caroline S.; Johnson, Andrew D.; Foster, Meredith C.] NHLBI, Ctr Populat Studies, NIH, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Liu, Yongmei; Lohman, Kurt] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [White, Charles C.; Heard-Costa, Nancy; Griffin, Paula; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Feitosa, Mary; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmunder] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmunder] Univ Iceland, Reykjavik, Iceland. [Greenawalt, Danielle M.] Merck Res Labs, Boston, MA USA. [Ding, Jinghong; Kritchevsky, Stephen B.] Wake Forest Sch Med, Dept Internal Med Geriatr, Winston Salem, NC USA. [Tylavsky, Fran] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Miljkovic, Iva] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Launer, Lenore; Garcia, Melissa; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol Sci, Winston Salem, NC USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. EM foxca@nhlbi.nih.gov; yoliu@wfubmc.edu; harris99@nih.nih.gov; adrienne@bu.edu; ingrid@dsgmail.wustl.edu RI Johnson, Andrew/G-6520-2013; Rudan, Igor/I-1467-2012; Colaus, PsyColaus/K-6607-2013; Singleton, Andrew/C-3010-2009; Newman, Anne/C-6408-2013; Palmer, Lyle/K-3196-2014; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Polasek, Ozren/B-6002-2011; Prokopenko, Inga/H-3241-2014; Carr, John/A-1938-2012; Smith, Albert/K-5150-2015; Kyvik, Kirsten /K-5680-2016; Visvikis-Siest, Sophie/H-2324-2014; Schwarz, Peter/B-5127-2013; Naitza, Silvia/D-5620-2017; Feitosa, Mary/K-8044-2012; OI Rudan, Igor/0000-0001-6993-6884; Newman, Anne/0000-0002-0106-1150; Palmer, Lyle/0000-0002-1628-3055; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Polasek, Ozren/0000-0002-5765-1862; Prokopenko, Inga/0000-0003-1624-7457; Carr, John/0000-0002-4398-8237; Smith, Albert/0000-0003-1942-5845; Kyvik, Kirsten /0000-0003-2981-0245; Visvikis-Siest, Sophie/0000-0001-8104-8425; Schwarz, Peter/0000-0001-6317-7880; Feitosa, Mary/0000-0002-0933-2410; Seedorf, Udo/0000-0003-4652-5358; Zeggini, Eleftheria/0000-0003-4238-659X; Willems van Dijk, Ko/0000-0002-2172-7394; Pichler, Irene/0000-0001-8251-0757; Heard-Costa, Nancy/0000-0001-9730-0306; Magi, Reedik/0000-0002-2964-6011; Miljkovic, Iva/0000-0002-3155-9777; Kivimaki, Mika/0000-0002-4699-5627; Cupples, L. Adrienne/0000-0003-0273-7965; Kritchevsky, Stephen/0000-0003-3336-6781; Franks, Paul/0000-0002-0520-7604; Kumari, Meena/0000-0001-9716-1035; Melzer, David/0000-0002-0170-3838; Forouhi, Nita/0000-0002-5041-248X; Jorgensen, Torben/0000-0001-9453-2830; Marmot, Michael/0000-0002-2431-6419; Kaprio, Jaakko/0000-0002-3716-2455; Lawlor, Debbie A/0000-0002-6793-2262; de Geus, Eco/0000-0001-6022-2666 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; NIDDK [5R01DK075681]; NHLBI [5R01HL08770']; NIA [N01AG62101, N01AG62103, N01AG62106, R01 AG028288, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, N01-AG-1-2100]; NIH, National Institute on Aging; NIA (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX Framingham Heart Study: This research was conducted in part using data and resources 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. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Family Heart Study: This research was conducted using data and resources from the NHLBI Family Heart Study and Washington University School of Medicine. This work was partially supported by the NIDDK (5R01DK075681, Borecki, PI) and NHLBI (5R01HL08770', Province, PI). Health ABC Study: This research was supported by NIA contracts N01AG62101, N01AG62103, N01AG62106, and R01 AG028288. The Genome-Wide Association Study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Age, Gene/Environment Susceptibility-Reykjavik Study: This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 88 Z9 90 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2012 VL 8 IS 5 AR e1002695 DI 10.1371/journal.pgen.1002695 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 953JT UT WOS:000304864000025 PM 22589738 ER PT J AU Perry, JRB Voight, BF Yengo, L Amin, N Dupuis, J Ganser, M Grallert, H Navarro, P Li, M Qi, L Steinthorsdottir, V Scott, RA Almgren, P Arking, DE Aulchenko, Y Balkau, B Benediktsson, R Bergman, RN Boerwinkle, E Bonnycastle, L Burtt, NP Campbell, H Charpentier, G Collins, FS Gieger, C Green, T Hadjadj, S Hattersley, AT Herder, C Hofman, A Johnson, AD Kottgen, A Kraft, P Labrune, Y Langenberg, C Manning, AK Mohlke, KL Morris, AP Oostra, B Pankow, J Petersen, AK Pramstaller, PP Prokopenko, I Rathmann, W Rayner, W Roden, M Rudan, I Rybin, D Scott, LJ Sigurdsson, G Sladek, R Thorleifsson, G Thorsteinsdottir, U Tuomilehto, J Uitterlinden, AG Vivequin, S Weedon, MN Wright, AF Hu, FB Illig, T Kao, L Meigs, JB Wilson, JF Stefansson, K van Duijn, C Altschuler, D Morris, AD Boehnke, M McCarthy, MI Froguel, P Palmer, CNA Wareham, NJ Groop, L Frayling, TM Cauchi, S AF Perry, John R. B. Voight, Benjamin F. Yengo, Loic Amin, Najaf Dupuis, Josee Ganser, Martha Grallert, Harald Navarro, Pau Li, Man Qi, Lu Steinthorsdottir, Valgerdur Scott, Robert A. Almgren, Peter Arking, Dan E. Aulchenko, Yurii Balkau, Beverley Benediktsson, Rafn Bergman, Richard N. Boerwinkle, Eric Bonnycastle, Lori Burtt, Noel P. Campbell, Harry Charpentier, Guillaume Collins, Francis S. Gieger, Christian Green, Todd Hadjadj, Samy Hattersley, Andrew T. Herder, Christian Hofman, Albert Johnson, Andrew D. Kottgen, Anna Kraft, Peter Labrune, Yann Langenberg, Claudia Manning, Alisa K. Mohlke, Karen L. Morris, Andrew P. Oostra, Ben Pankow, James Petersen, Ann-Kristin Pramstaller, Peter P. Prokopenko, Inga Rathmann, Wolfgang Rayner, William Roden, Michael Rudan, Igor Rybin, Denis Scott, Laura J. Sigurdsson, Gunnar Sladek, Rob Thorleifsson, Gudmar Thorsteinsdottir, Unnur Tuomilehto, Jaakko Uitterlinden, Andre G. Vivequin, Sidonie Weedon, Michael N. Wright, Alan F. Hu, Frank B. Illig, Thomas Kao, Linda Meigs, James B. Wilson, James F. Stefansson, Kari van Duijn, Cornelia Altschuler, David Morris, Andrew D. Boehnke, Michael McCarthy, Mark I. Froguel, Philippe Palmer, Colin N. A. Wareham, Nicholas J. Groop, Leif Frayling, Timothy M. Cauchi, Stephane CA MAGIC DIAGRAM Consortium GIANT Consortium TI Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; EXPRESSION; CELLS; DIFFERENTIATION; INSULIN; DISEASE; GLUCOSE; MOUSE; PROTEIN AB Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes. C1 [Perry, John R. B.; Hattersley, Andrew T.; Weedon, Michael N.; Frayling, Timothy M.] Univ Exeter, Peninsula Med Sch, Exeter, Devon, England. [Perry, John R. B.; Morris, Andrew P.; Prokopenko, Inga; Rayner, William; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Perry, John R. B.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Voight, Benjamin F.; Burtt, Noel P.; Green, Todd; Altschuler, David] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Yengo, Loic; Labrune, Yann; Vivequin, Sidonie; Froguel, Philippe; Cauchi, Stephane] CNRS UMR 8199, Lille, France. [Amin, Najaf; Aulchenko, Yurii; Hofman, Albert; van Duijn, Cornelia] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Johnson, Andrew D.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ganser, Martha; Scott, Laura J.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Ganser, Martha; Scott, Laura J.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Grallert, Harald; Illig, Thomas] Helmholtz Zentrum Muenchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Navarro, Pau; Wright, Alan F.] Univ Edinburgh, Inst Genet & Mol Med, MRC, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Li, Man; Kottgen, Anna; Kao, Linda] Johns Hopkins Bloomberg Sch Publ Hlth & Epidemiol, Baltimore, MD USA. [Qi, Lu; Kraft, Peter; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Qi, Lu; Kraft, Peter; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] DeCODE Genet, Reykjavik, Iceland. [Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.] MRC, MRC Epidemiol Unit, Cambridge, England. [Almgren, Peter; Groop, Leif] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Res Unit, Malmo, Sweden. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Balkau, Beverley] INSERM CESP U1018, Villejuif, France. [Benediktsson, Rafn; Sigurdsson, Gunnar] Landspitali Univ Hosp, Reykjavik, Iceland. [Benediktsson, Rafn; Sigurdsson, Gunnar] Iceland Heart Assoc, Kopavogur, Iceland. [Bergman, Richard N.] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Bonnycastle, Lori; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Campbell, Harry; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Charpentier, Guillaume] Corbeil Essonnes Hosp, Dept Endocrinol Diabetol, Corbeil Essonnes, France. [Gieger, Christian; Petersen, Ann-Kristin] Helmholtz Zentrum Muenchen, Inst Genet Epidemiol, Neuherberg, Germany. [Hadjadj, Samy] Univ Med & Pharmaceut Sci, INSERM U927, CIC INSERM 0801, CHU Poitiers,Dept Endocrinol Diabetol, Poitiers, France. [Herder, Christian; Roden, Michael] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany. [Kottgen, Anna] Freiburg Univ Clin, Div Renal, Freiburg, Germany. [Manning, Alisa K.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Oostra, Ben] Erasmus Univ, Sch Med, Rotterdam, Netherlands. [Pankow, James] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN USA. [Pramstaller, Peter P.] European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy. [Pramstaller, Peter P.] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Prokopenko, Inga; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Rathmann, Wolfgang] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, D-40225 Dusseldorf, Germany. [Roden, Michael] Univ Hosp Dusseldorf, Dept Metab Dis, Dusseldorf, Germany. [Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Rybin, Denis] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Sladek, Rob] McGill Univ, Fac Med, Dept Human Genet, Montreal, PQ, Canada. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Tuomilehto, Jaakko] Hosp Univ La Paz, Red RECAVA Grp RD06 0014 0015, Madrid, Spain. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-3000 Hannover, Germany. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Inst, Dundee DD1 9SY, Scotland. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Genom Common Dis, London, England. RP Perry, JRB (reprint author), Univ Exeter, Peninsula Med Sch, Exeter, Devon, England. EM tim.frayling@pms.ac.uk; Stephane.Cauchi@good.ibl.fr RI Palmer, Colin/C-7053-2008; Rudan, Igor/I-1467-2012; Grallert, Harald/B-3424-2013; Johnson, Andrew/G-6520-2013; Aulchenko, Yurii/M-8270-2013; Pramstaller, Peter/C-2357-2008; Wilson, James F/A-5704-2009; Prokopenko, Inga/H-3241-2014; Study, GoDARTS/K-9448-2016; Yengo, Loic/D-2692-2017 OI Rybin, Denis/0000-0002-3657-4829; Dupuis, Josee/0000-0003-2871-3603; Gieger, Christian/0000-0001-6986-9554; Pankow, James/0000-0001-7076-483X; Sladek, Robert/0000-0002-2730-1204; Navarro, Pau/0000-0001-5576-8584; Palmer, Colin/0000-0002-6415-6560; Rudan, Igor/0000-0001-6993-6884; Aulchenko, Yurii/0000-0002-7899-1575; Wilson, James F/0000-0001-5751-9178; Prokopenko, Inga/0000-0003-1624-7457; Yengo, Loic/0000-0002-4272-9305 FU Wellcome Trust [092447/Z/10/Z, 083270/Z/07/Z]; MRC [G0601261]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, DK062370, DK072193, UL1RR025005, NIDCR: U01DE018993, U01DE018903, NIAAA: U10AA008401, NIDA: P01CA089392, R01DA013423, NCI: CA63464, CA54281, CA136792, Z01CP010200]; NIH Roadmap for Medical Research; Swedish Research Council; NHS Research and Development; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616, K24 DK080140]; European Community [HEALTH-F4-2007-201413]; French Government (Agence Nationale de la Recherche); French Region of Nord Pas De Calais (Contrat de Projets Etat-Region); French Ministry of Health; Association Francaise des Diabetiques; Programme National de Recherche sur le Diabete; Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques; Association Diabete Risque Vasculaire (Paris, France); Groupe d'Etude des Maladies Metaboliques et Systemiques; European Union of European Community [LSHM-CT-2006-518153]; Caisse Nationale d'Assurance Maladie des Travailleurs Salaries; Lilly; Novartis Pharma; Sanofi-Aventis; Institut National de la Sante et de la Recherche Medicale (INSERM) (Reseaux en Sante Publique, Interactions entre les determinants de la sante, Cohortes Sante TGIR); Association Diabete Risque Vasculaire; Federation Francaise de Cardiologie; Fondation de France; Office National Interprofessionnel des Vins; Ardix Medical; Bayer Diagnostics; Becton Dickinson; Cardionics; Merck Sante; Novo Nordisk; Pierre Fabre; Roche and Topcon; NIH Genes, Environment and Health Initiative (GEI) [U01HG004402, U01HG004399, U01HG004738, U01HG004422, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033]; European Union [LSHG-CT-2006-018947]; NWO; Erasmus MC; Centre for Medical Systems Biology (CMSB); Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; South Tyrolean Sparkasse Foundation; Ministry of Science, Education and Sport of the Republic of Croatia [108-1080315-0302]; Medical Research Council UK; German Center for Diabetes Research (DZD); Helmholtz Zentrum Munchen, Neuherberg, Germany; German Federal Ministry of Education and Research the Federal Ministry of Health; Ministry of Innovation, Science, Research, and Technology of the state North Rhine-Westphalia; German National Genome Research Network (NGFN); Munich Center of Health Sciences (MC Health) as part of LMUinnovativ FX JRB Perry is supported by the Wellcome Trust as a Sir Henry Wellcome Postdoctoral Research Fellow (092447/Z/10/Z). This work was partially funded by grants from the Wellcome Trust 083270/Z/07/Z and MRC G0601261. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; National Institutes of Health contract HHSN268200625226C; and grants DK062370 and DK072193. ARIC: Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Work at Lund University diabetes centre was funded by several grants from the Swedish Research Council (LG prject grant, Linne, Exodiab). Norfolk Diabetes Case-Control and ADDITION-Ely Studies: The work on Ely, ADDITION, and EPIC-Norfolk studies was funded by support from the Wellcome Trust and MRC. The Norfolk Diabetes study is funded by the MRC with support from NHS Research and Development and the Wellcome Trust. This research was conducted in part using data and resources 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. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II), funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to JB Meigs and J Dupuis, and NIDDK K24 DK080140 to JB Meigs. The research performed at deCODE Genetics was part funded through the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413. The DGDG study was supported by the French Government (Agence Nationale de la Recherche), the French Region of Nord Pas De Calais (Contrat de Projets Etat-Region), Programme Hospitalier de Recherche Clinique (French Ministry of Health), and the following charities: Association Francaise des Diabetiques, Programme National de Recherche sur le Diabete, Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques, Association Diabete Risque Vasculaire (Paris, France), and Groupe d'Etude des Maladies Metaboliques et Systemiques. This study was also supported in part by a grant from the European Union (Integrated Project EuroDia LSHM-CT-2006-518153 in the Framework Programme 6 [FP6] of the European Community). The D. E. S. I. R.; study was supported by the Caisse Nationale d'Assurance Maladie des Travailleurs Salaries, Lilly, Novartis Pharma and Sanofi-Aventis, Institut National de la Sante et de la Recherche Medicale (INSERM) (Reseaux en Sante Publique, Interactions entre les determinants de la sante, Cohortes Sante TGIR 2008), Association Diabete Risque Vasculaire, Federation Francaise de Cardiologie, Fondation de France, Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques, Office National Interprofessionnel des Vins, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Sante, Novo Nordisk, Pierre Fabre, Roche and Topcon. The D. E. S. I. R. Study Group: INSERM 1018: B Balkau, P Ducimetiere, E Eschwege; INSERM U367: F Alhenc-Gelas; Centre Hospitalier Universitaire D'Angers: Y Gallois, A Girault; Bichat Hospital: F Fumeron, M Marre, R Roussel; CHU de Rennes: F Bonnet; CNRS UMR8199, Lille: P Froguel; Medical Examination Services: Alencon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, Le Mans, Orleans and Tours; Research Institute for General Medicine: J Cogneau; General practitioners of the region; Cross-Regional Institute for Health: C Born, E Caces, M Cailleau, JG Moreau, F Rakotozafy, J Tichet, S. Vol. We are grateful to all patients for participation in the genetic study. We also thank Marianne Deweirder, Frederic Allegaert (UMR CNRS 8199, Genomic and Metabolic Disease, Lille, France) for their technical assistance and their precious management of DNA samples. This work was partially funded by grants from the Wellcome Trust 083270/Z/07/Z and MRC G0601261. This work was presented as a poster at the American Diabetes Association's scientific sessions June 2011. The NHS/HPFS T2D GWA study (U01HG004399) is a component of a collaborative project that includes 13 other GWA studies funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI) (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033) with additional support from individual NIH (NIDCR: U01DE018993, U01DE018903; NIAAA: U10AA008401, NIDA: P01CA089392, R01DA013423; NCI: CA63464, CA54281, CA136792, Z01CP010200). EUROSPAN cohorts were supported by the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). The ERF study was supported by grants from the NWO, Erasmus MC and the Centre for Medical Systems Biology (CMSB). We are grateful to all patients and their relatives, general practitioners and neurologists for their contributions and to P Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and P Snijders for his help in data collection. MICROS: The MICROS study is part of the genomic health care program 'GenNova' and was carried out in three villages of the Val Venosta on the populations of Stelvio, Vallelunga and Martello. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation. The VIS study in the Croatian island of Vis was supported through the grants from the Medical Research Council UK and Ministry of Science, Education and Sport of the Republic of Croatia (number 108-1080315-0302).; The research within the KORA study was partially funded by the German Center for Diabetes Research (DZD), the Helmholtz Zentrum Munchen, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research the Federal Ministry of Health, the Ministry of Innovation, Science, Research, and Technology of the state North Rhine-Westphalia, the German National Genome Research Network (NGFN), and the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The research of I Prokopenko is funded in part through the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 75 Z9 77 U1 0 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2012 VL 8 IS 5 AR e1002741 DI 10.1371/journal.pgen.1002741 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 953JT UT WOS:000304864000058 PM 22693455 ER PT J AU Winter, SF Lukes, L Walker, RC Welch, DR Hunter, KW AF Winter, Scott F. Lukes, Luanne Walker, Renard C. Welch, Danny R. Hunter, Kent W. TI Allelic Variation and Differential Expression of the mSIN3A Histone Deacetylase Complex Gene Arid4b Promote Mammary Tumor Growth and Metastasis SO PLOS GENETICS LA English DT Article ID BREAST-CANCER; COREPRESSOR COMPLEX; TRANSCRIPTIONAL COREPRESSOR; IDENTIFICATION; PROTEINS; PROGRESSION; FAMILY; SUSCEPTIBILITY; RECOGNITION; CANDIDATE AB Accumulating evidence suggests that breast cancer metastatic progression is modified by germline polymorphism, although specific modifier genes have remained largely undefined. In the current study, we employ the MMTV-PyMT transgenic mouse model and the AKXD panel of recombinant inbred mice to identify AT-rich interactive domain 4B (Arid4b; NM_194262) as a breast cancer progression modifier gene. Ectopic expression of Arid4b promoted primary tumor growth in vivo as well as increased migration and invasion in vitro, and the phenotype was associated with polymorphisms identified between the AKR/J and DBA/2J alleles as predicted by our genetic analyses. Stable shRNA-mediated knockdown of Arid4b caused a significant reduction in pulmonary metastases, validating a role for Arid4b as a metastasis modifier gene. ARID4B physically interacts with the breast cancer metastasis suppressor BRMS1, and we detected differential binding of the Arid4b alleles to histone deacetylase complex members mSIN3A and mSDS3, suggesting that the mechanism of Arid4b action likely involves interactions with chromatin modifying complexes. Downregulation of the conserved Tpx2 gene network, which is comprised of many factors regulating cell cycle and mitotic spindle biology, was observed concomitant with loss of metastatic efficiency in Arid4b knockdown cells. Consistent with our genetic analysis and in vivo experiments in our mouse model system, ARID4B expression was also an independent predictor of distant metastasis-free survival in breast cancer patients with ER+ tumors. These studies support a causative role of ARID4B in metastatic progression of breast cancer. C1 [Winter, Scott F.; Lukes, Luanne; Walker, Renard C.; Hunter, Kent W.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Welch, Danny R.] Univ Kansas, Med Ctr, Dept Canc Biol, Kansas City, KS 66103 USA. RP Winter, SF (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov OI Welch, Danny/0000-0002-1951-4947 FU NIH, National Cancer Institute, Center for Cancer Research; NIH [CA134981]; National Foundation for Cancer Research; Susan G. Komen for the Cure [SAC110037] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. DRW is funded by NIH grant CA134981, the National Foundation for Cancer Research, and Susan G. Komen for the Cure SAC110037. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 14 Z9 15 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2012 VL 8 IS 5 AR e1002735 DI 10.1371/journal.pgen.1002735 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 953JT UT WOS:000304864000055 PM 22693453 ER PT J AU Bar, KJ Tsao, CY Iyer, SS Decker, JM Yang, YP Bonsignori, M Chen, X Hwang, KK Montefiori, DC Liao, HX Hraber, P Fischer, W Li, H Wang, SY Sterrett, S Keele, BF Ganusov, VV Perelson, AS Korber, BT Georgiev, I McLellan, JS Pavlicek, JW Gao, F Haynes, BF Hahn, BH Kwong, PD Shaw, GM AF Bar, Katharine J. Tsao, Chun-yen Iyer, Shilpa S. Decker, Julie M. Yang, Yongping Bonsignori, Mattia Chen, Xi Hwang, Kwan-Ki Montefiori, David C. Liao, Hua-Xin Hraber, Peter Fischer, William Li, Hui Wang, Shuyi Sterrett, Sarah Keele, Brandon F. Ganusov, Vitaly V. Perelson, Alan S. Korber, Bette T. Georgiev, Ivelin McLellan, Jason S. Pavlicek, Jeffrey W. Gao, Feng Haynes, Barton F. Hahn, Beatrice H. Kwong, Peter D. Shaw, George M. TI Early Low-Titer Neutralizing Antibodies Impede HIV-1 Replication and Select for Virus Escape SO PLOS PATHOGENS LA English DT Article ID SUBTYPE-C INFECTION; TYPE-1 INFECTION; RHESUS MACAQUES; VIRAL DYNAMICS; CELL RESPONSE; T-LYMPHOCYTES; CTL ESCAPE; IN-VIVO; GP120; ENVELOPE AB Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1:20 to 1:50 (IC50) selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env) in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1-V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical infection is typically one. C1 [Bar, Katharine J.; Iyer, Shilpa S.; Li, Hui; Wang, Shuyi; Hahn, Beatrice H.; Shaw, George M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Tsao, Chun-yen; Bonsignori, Mattia; Chen, Xi; Hwang, Kwan-Ki; Montefiori, David C.; Liao, Hua-Xin; Pavlicek, Jeffrey W.; Gao, Feng; Haynes, Barton F.] Duke Univ, Sch Med, Durham, NC USA. [Decker, Julie M.; Sterrett, Sarah] Univ Alabama Birmingham, Birmingham, AL USA. [Yang, Yongping; Georgiev, Ivelin; McLellan, Jason S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hraber, Peter; Fischer, William; Perelson, Alan S.; Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM USA. [Keele, Brandon F.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Ganusov, Vitaly V.] Univ Tennessee, Knoxville, TN USA. RP Bar, KJ (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM shawg@upenn.edu OI Ganusov, Vitaly/0000-0001-6572-1691; Fischer, Will/0000-0003-4579-4062; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU NIH Center for HIV/AIDS Vaccine Immunology; NIH Vaccine Research Center; NIH [AI67854, AI61734, AI27767, AI50410, AI64518, AI41530, AI028433, RR006555]; DOE [DE-AC52-06NA25396]; Bill & Melinda Gates Foundation [37874] FX This work was supported by the NIH Center for HIV/AIDS Vaccine Immunology; the Intramural Program of the NIH Vaccine Research Center; NIH grants AI67854, AI61734, AI27767, AI50410, AI64518, AI41530, AI028433 and RR006555; DOE contract DE-AC52-06NA25396; and the Bill & Melinda Gates Foundation Grand Challenges Program (#37874). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 69 Z9 69 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAY PY 2012 VL 8 IS 5 AR e1002721 DI 10.1371/journal.ppat.1002721 PG 20 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 959OS UT WOS:000305322900054 PM 22693447 ER PT J AU Campbell, ANC Miele, GM Nunes, EV McCrimmon, S Ghitza, UE AF Campbell, Aimee N. C. Miele, Gloria M. Nunes, Edward V. McCrimmon, Scott Ghitza, Udi E. TI Web-Based, Psychosocial Treatment for Substance Use Disorders in Community Treatment Settings SO PSYCHOLOGICAL SERVICES LA English DT Article DE web delivery; computer-assisted technology; community reinforcement approach; motivational incentives; substance use disorders AB The purpose of this multisite clinical trial was to evaluate the effectiveness of a web-based version of the Community Reinforcement Approach, plus motivational incentives, within community-based, outpatient substance abuse treatment. This ongoing study is being conducted within the National Drug Abuse Treatment Clinical Trials Network, funded by the National Institute on Drug Abuse. Midway through the enrollment of 500 participants, the study is being implemented in 10 treatment programs across the United States. Information is provided on design, sample, intervention and technology, and preliminary lessons learned. C1 [Campbell, Aimee N. C.; Nunes, Edward V.] New York State Psychiat Inst & Hosp, Subst Abuse Div, New York, NY 10032 USA. [Campbell, Aimee N. C.; Miele, Gloria M.; Nunes, Edward V.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY USA. [McCrimmon, Scott] EMMES Corp, Rockville, MD USA. [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. RP Campbell, ANC (reprint author), New York State Psychiat Inst & Hosp, Subst Abuse Div, 1051 Riverside Dr,Unit 120,Room 3732, New York, NY 10032 USA. EM anc2002@columbia.edu FU NIDA NIH HHS [K24 DA022412, U10 DA013035, U10 DA13035] NR 4 TC 0 Z9 0 U1 2 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1541-1559 J9 PSYCHOL SERV JI Psychol. Serv. PD MAY PY 2012 VL 9 IS 2 SI SI BP 212 EP 214 DI 10.1037/a0025968 PG 3 WC Psychology, Clinical SC Psychology GA 957WO UT WOS:000305198000012 PM 22662738 ER PT J AU Lesoine, JF Lee, JY Krogmeier, JR Kang, H Clarke, ML Chang, R Sackett, DL Nossal, R Hwang, J AF Lesoine, John F. Lee, Ji Youn Krogmeier, Jeffrey R. Kang, Hyeonggon Clarke, Matthew L. Chang, Robert Sackett, Dan L. Nossal, Ralph Hwang, Jeeseong TI Quantitative scheme for full-field polarization rotating fluorescence microscopy using a liquid crystal variable retarder SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID SINGLE-MOLECULE ORIENTATIONS; MEMBRANE; SPECTROSCOPY; MICRODOMAINS AB We present a quantitative scheme for full-field polarization rotating fluorescence microscopy. A quarter-wave plate, in combination with a liquid crystal variable retarder, provides a tunable method to rotate polarization states of light prior to its being coupled into a fluorescence microscope. A calibration of the polarization properties of the incident light is performed in order to correct for elliptical polarization states. This calibration allows the response of the sample to linear polarization states of light to be recovered. Three known polarization states of light can be used to determine the average fluorescent dipole orientations in the presence of a spatially varying dc offset or background polarization-invariant fluorescence signal. To demonstrate the capabilities of this device, we measured a series of full-field fluorescence polarization images from fluorescent analogs incorporated in the lipid membrane of Burkitts lymphoma CA46 cells. The fluorescent lipid-like analogs used in this study are molecules that are labeled by either a DiI (1,1'-Dioctadecyl 3,3,3',3'-Tetramethylindocarbocyanine) fluorophore in its head group or a Bodipy (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) molecule in its acyl chain. A spatially varying contrast in the normalized amplitude was observed on the cell surface, where the orientation of the DiI molecules is tangential to the cell membrane. The internally labeled cellular structures showed zero response to changes in linear polarization, and the net linear polarization amplitude for these regions was zero. This instrument provides a low cost calibrated method that may be coupled to existing fluorescence microscopes to perform investigations of cellular processes that involve a change in molecular orientations. [http://dx.doi.org/10.1063/1.4717682] C1 [Lesoine, John F.; Lee, Ji Youn; Krogmeier, Jeffrey R.; Kang, Hyeonggon; Clarke, Matthew L.; Chang, Robert; Hwang, Jeeseong] NIST, Radiat & Biomol Phys Div, Gaithersburg, MD 20899 USA. [Lee, Ji Youn; Sackett, Dan L.; Nossal, Ralph] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Hwang, J (reprint author), NIST, Radiat & Biomol Phys Div, 100 Bur Dr, Gaithersburg, MD 20899 USA. EM jch@nist.gov FU NIST; NIH (NIBIB)/NIST; National Institute for Biomedical Imaging and Bioengineering of the NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX The authors thank Dr. Maritoni Litorja, Dr. David Allen, Dr. Eric Shirley, and Dr. Kimberly Briggman at National Institute of Standards and Technology (NIST) and Fuyuki Tokumasu at National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) for helpful discussions and suggestions. This research was supported by NIST Innovative Measurement Science program on optical medical imaging. This research was performed while J.L. and J.R.K. held National Research Council Research Associateships supported by NIH (NIBIB)/NIST. Funding for these awards was provided by the intramural program of the National Institute for Biomedical Imaging and Bioengineering of the NIH. J.F.L. held a National Research Council Research Associateship supported by NIST. D. S. and R.N. were supported by intramural funds of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Certain commercial equipment, instruments, or materials are identified in this paper. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials and instruments are necessarily the best available for the purpose. NR 26 TC 4 Z9 4 U1 1 U2 13 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0034-6748 EI 1089-7623 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD MAY PY 2012 VL 83 IS 5 AR 053705 DI 10.1063/1.4717682 PG 9 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 952VM UT WOS:000304821500029 PM 22667623 ER PT J AU Frascella, J AF Frascella, J. TI Addiction: A Developmental Disorder SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Frascella, J.] NIDA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 294 EP 294 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800007 ER PT J AU Mackem, S Huang, BL Zhu, J AF Mackem, S. Huang, B-L Zhu, J. TI Regulatory Network Controlling Limb Anterior-Posterior Patterning and Digit Identity: Bridging Steps from Early Patterned Gene Expression to Final Morphogenesis SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Mackem, S.; Huang, B-L; Zhu, J.] NCI, NIH, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 301 EP 301 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800018 ER PT J AU Smith, LM Lagasse, LL Derauf, C Newman, C Shah, R Arria, A Huestis, MA Haning, W Strauss, A Dellagrotta, S Dansereau, LM Neal, C Lester, BM AF Smith, L. M. Lagasse, L. L. Derauf, C. Newman, C. Shah, R. Arria, A. Huestis, M. A. Haning, W. Strauss, A. Dellagrotta, S. Dansereau, L. M. Neal, C. Lester, B. M. TI Growth and Neurodevelopmental Outcomes in Children Prenatally Exposed to Methamphetamine SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Smith, L. M.] Harbor UCLA Med, Los Angeles, CA USA. [Lagasse, L. L.; Dellagrotta, S.; Dansereau, L. M.; Lester, B. M.] Brown Univ, Providence, RI 02912 USA. [Derauf, C.; Haning, W.; Neal, C.] Univ Hawaii, Honolulu, HI 96822 USA. [Newman, C.] Univ Tulsa, Tulsa, OK 74104 USA. [Shah, R.] Blank Hosp Reg Child Protect Ctr, Des Moines, IA USA. [Huestis, M. A.] NIDA, NIH, Baltimore, MD USA. [Strauss, A.] Miller Childrens Hosp Long Beach, Long Beach, CA USA. [Arria, A.] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 303 EP 303 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800022 ER PT J AU Fenton, SE AF Fenton, S. E. TI Early Life Environmental Exposures: Lifelong Impact on Mammary Gland Development and Function SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Fenton, S. E.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 306 EP 306 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800029 ER PT J AU Pollack, AZ Louis, GMB AF Pollack, A. Z. Louis, Buck G. M. TI Early Life Environmental Exposures and Female Reproductive Disease SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Pollack, A. Z.; Louis, Buck G. M.] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 306 EP 306 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800028 ER PT J AU Inselman, AL Nakamura, N White, G Harrouk, W Mcintyre, B Foster, P Hansen, DK AF Inselman, A. L. Nakamura, N. White, G. Harrouk, W. Mcintyre, B. Foster, P. Hansen, D. K. TI Potential Reproductive and Developmental Toxicity of Oxybenzone: A Dose-Finding Study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Inselman, A. L.; Nakamura, N.; White, G.; Hansen, D. K.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Harrouk, W.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Mcintyre, B.; Foster, P.] Natl Inst Environm Hlth, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 349 EP 349 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800110 ER PT J AU Caldwell, KL Mortensen, ME Pan, Y Merrill, LS Moye, JH AF Caldwell, K. L. Mortensen, M. E. Pan, Y. Merrill, L. S. Moye, J. H. TI Urine Iodine in Pregnant Women Enrolled in the National Children's Study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Caldwell, K. L.; Mortensen, M. E.; Pan, Y.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA USA. [Merrill, L. S.] Westat Corp, Rockville, MD USA. [Moye, J. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NCS Program Off, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 385 EP 385 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800173 ER PT J AU Mortensen, ME Calafat, AM Wong, LY Ye, X Pirkle, JL Merrill, LS Moye, JH AF Mortensen, M. E. Calafat, A. M. Wong, L. Y. Ye, X. Pirkle, J. L. Merrill, L. S. Moye, J. H. TI Exposure to Environmental Phenols in Pregnant Women Enrolled in the National Children's Study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Mortensen, M. E.; Calafat, A. M.; Wong, L. Y.; Ye, X.; Pirkle, J. L.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA USA. [Merrill, L. S.] Westat Corp, Rockville, MD USA. [Moye, J. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NCS Program Off, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 385 EP 385 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800174 ER PT J AU Dellarco, M Kasten, C AF Dellarco, M. Kasten, C. TI Evaluation of Environmental Study Visit Measures in the Initial National Children's Vanguard Study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Dellarco, M.; Kasten, C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2012 VL 94 IS 5 SI SI BP 387 EP 387 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 956FF UT WOS:000305074800176 ER PT J AU Barnes, AM Bale, SJ Duncan, G Paton, W Cabral, WA Marini, JC AF Barnes, A. M. Bale, S. J. Duncan, G. Paton, W. Cabral, W. A. Marini, J. C. TI Kuskokwim Disease extends recessive osteogenesis imperfecta type XI phenotypes caused by mutations in FKBP10 SO BONE LA English DT Meeting Abstract CT 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS) CY MAY 19-23, 2012 CL Stockholm, SWEDEN SP European Calcified Tissue Soc (ECTS), Amgen/GSK, Lilly, MSD, Takeda Pharmaceut Int GmbH, Alliance Better Bone Hlth (Warner Chilcott & Sanofi), Act Life Sci Inc, Alex Pharmaceut Inc, Arrow Lakemedel AB, b-cube AG, Biomedica, Ferrosan A/S - Pfizer Inc, Holog Inc, Int Bone & Mineral Soc (IBMS), Immunodiagnost Syst (IDS) Ltd, John Wiley & Sons, Medivir, OsteoMetr Inc, Pharma-Vinci A/S, Quidel Corp & TECO Med Corp, RISyst AG, Scanco Med AG, Sectra, SkyScan NV, Stratec Medizintechnik, Xradia Inc C1 [Barnes, A. M.; Cabral, W. A.; Marini, J. C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD USA. [Bale, S. J.] Gene Dx, Gaithersburg, MD USA. [Duncan, G.] Christchurch Hosp, Christchurch, New Zealand. [Paton, W.] Alaska Native Med Ctr, Anchorage, AK 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 8756-3282 J9 BONE JI Bone PD MAY PY 2012 VL 50 SU 1 BP S60 EP S60 DI 10.1016/j.bone.2012.02.165 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 948LA UT WOS:000304503500140 ER PT J AU Cabral, WA Barnes, AM Makareeva, E Weis, M Chang, W Leikin, S Eyre, DR Marini, JC AF Cabral, W. A. Barnes, A. M. Makareeva, E. Weis, M. Chang, W. Leikin, S. Eyre, D. R. Marini, J. C. TI Abnormal type I collagen folding and matrix deposition in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta SO BONE LA English DT Meeting Abstract CT 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS) CY MAY 19-23, 2012 CL Stockholm, SWEDEN SP European Calcified Tissue Soc (ECTS), Amgen/GSK, Lilly, MSD, Takeda Pharmaceut Int GmbH, Alliance Better Bone Hlth (Warner Chilcott & Sanofi), Act Life Sci Inc, Alex Pharmaceut Inc, Arrow Lakemedel AB, b-cube AG, Biomedica, Ferrosan A/S - Pfizer Inc, Holog Inc, Int Bone & Mineral Soc (IBMS), Immunodiagnost Syst (IDS) Ltd, John Wiley & Sons, Medivir, OsteoMetr Inc, Pharma-Vinci A/S, Quidel Corp & TECO Med Corp, RISyst AG, Scanco Med AG, Sectra, SkyScan NV, Stratec Medizintechnik, Xradia Inc C1 [Makareeva, E.; Leikin, S.] NICHD, Sect Phys Biochem, NIH, Bethesda, MD USA. [Weis, M.; Eyre, D. R.] Univ Washington, Orthopaed Res Labs, Seattle, WA 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 8756-3282 J9 BONE JI Bone PD MAY PY 2012 VL 50 SU 1 BP S38 EP S38 DI 10.1016/j.bone.2012.02.098 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 948LA UT WOS:000304503500074 ER PT J AU Reich, A Cabral, WA Marini, JC AF Reich, A. Cabral, W. A. Marini, J. C. TI Homogeneous mutant collagen in homozygous Brtl or Brtl/mov compound mice leads to improved bone phenotype through altered osteoblast differentiation SO BONE LA English DT Meeting Abstract CT 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS) CY MAY 19-23, 2012 CL Stockholm, SWEDEN SP European Calcified Tissue Soc (ECTS), Amgen/GSK, Lilly, MSD, Takeda Pharmaceut Int GmbH, Alliance Better Bone Hlth (Warner Chilcott & Sanofi), Act Life Sci Inc, Alex Pharmaceut Inc, Arrow Lakemedel AB, b-cube AG, Biomedica, Ferrosan A/S - Pfizer Inc, Holog Inc, Int Bone & Mineral Soc (IBMS), Immunodiagnost Syst (IDS) Ltd, John Wiley & Sons, Medivir, OsteoMetr Inc, Pharma-Vinci A/S, Quidel Corp & TECO Med Corp, RISyst AG, Scanco Med AG, Sectra, SkyScan NV, Stratec Medizintechnik, Xradia Inc C1 [Reich, A.; Cabral, W. A.; Marini, J. C.] NICHD, 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 8756-3282 J9 BONE JI Bone PD MAY PY 2012 VL 50 SU 1 BP S166 EP S166 DI 10.1016/j.bone.2012.02.520 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 948LA UT WOS:000304503500491 ER PT J AU Schetter, AJ Okayama, H Harris, CC AF Schetter, Aaron J. Okayama, Hirokazu Harris, Curtis C. TI The Role of MicroRNAs in Colorectal Cancer SO CANCER JOURNAL LA English DT Review DE microRNAs; colorectal cancer ID TUMOR-SUPPRESSOR MIR-145; II COLON-CANCER; STAGE-II; POOR-PROGNOSIS; 3'-UNTRANSLATED REGION; CELL-PROLIFERATION; DOWN-REGULATION; LUNG-CANCER; IN-VIVO; C-MYC AB During the last decade, it has become clear that aberrant microRNA expression has a functional role in the initiation and progression of colorectal cancer (CRC). Specific microRNAs can act as either tumor suppressors or oncogenes depending on the cellular environment in which they are expressed. The expression of microRNAs is reproducibly altered in CRC, and their expression patterns are associated with diagnosis, prognosis, and therapeutic outcome in CRC. Studies have begun to examine the association of microRNA-related polymorphisms and their association with CRC incidence and prognosis as well as the possibility of using circulating microRNAs or fecal microRNA expression as noninvasive early detection biomarkers. These data suggest that microRNAs may be potential molecular classifiers, early detection biomarkers, and therapeutic targets for CRC. Here, we will review the evidence demonstrating a role of microRNAs in CRC. C1 [Schetter, Aaron J.; Okayama, Hirokazu; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 3068A,MSC 4258, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov FU National Cancer Institute, National Institutes of Health FX All authors receive funding from the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 113 TC 75 Z9 82 U1 3 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD MAY-JUN PY 2012 VL 18 IS 3 BP 244 EP 252 DI 10.1097/PPO.0b013e318258b78f PG 9 WC Oncology SC Oncology GA 952BK UT WOS:000304764500006 PM 22647361 ER PT J AU Mitchell, DC Niu, SL Litman, BJ AF Mitchell, Drake C. Niu, Shui-Lin Litman, Burton J. TI Quantifying the differential effects of DHA and DPA on the early events in visual signal transduction SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Article DE Docosahexaenoic acid; Docosapentaenoic acid; Rhodopsin; GPCR; Visual signal transduction ID ROD OUTER SEGMENT; CHAIN PHOSPHATIDYLCHOLINE VESICLES; PROTEIN-COUPLED RECEPTORS; FATTY-ACID COMPOSITION; HIGHER-ORDER ANALYSIS; METARHODOPSIN-II; DOCOSAHEXAENOIC ACID; BOVINE RHODOPSIN; DISK MEMBRANES; PHOTORECEPTOR-MEMBRANES AB A range of evidence from animal, clinical and epidemiological studies indicates that highly polyunsaturated acyl chains play important roles in development, cognition, vision and other aspects of neurological function. In a number of these studies n3 polyunsaturated fatty acids (PUFAs) appear to be more efficacious than n6 PUFAs. In a previous study of retinal rod outer segments obtained from rats raised on either an n3 adequate or deficient diet, we demonstrated that the replacement of 22:6n3 by 22:5n6 in the n3 deficient rats led to functional deficits in each step in the visual signaling process (Niu et al., 2004). In this study, we examined rhodopsin and phosphodiesterase function and acyl chain packing properties in membranes consisting of phosphatidylcholines with sn-1 = 18:0, and sn-2 = 22:6n3. 22:5n6, or 22:5n3 in order to determine if differences in function are due to the loss of one double bond or due to differences in double bond location. At 37 degrees C the n6 lipid shifted the equilibrium between the active metarhodopsin II (MII) state and inactive metarhodopsin I (MI) state towards MI. In addition, 22:5n6 reduced the rates of MII formation and MII-transducin complex formation by 2- and 6-fold, respectively. At a physiologically relevant level of rhodopsin light stimulation, the activity of phosphodiesterase was reduced by 50% in the 22:5n6 membrane, relative to either of the n3 membranes. Activity levels in the two n3 membranes were essentially identical. Ensemble acyl chain order was assessed with time-resolved fluorescence measurements of the membrane probe diphenylhexatriene (DPH). Analysis in terms of the orientational distribution of DPH showed that acyl chain packing in the two n3 membranes is quite similar, while in the 22:5n6 membrane there was considerably less packing disorder in the bilayer midplane. These results demonstrate that the n3 bond configuration uniquely optimizes the early steps in signaling via a mechanism which may involve acyl chain packing deep in the bilayer. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Mitchell, Drake C.] Portland State Univ, Dept Phys, Portland, OR 97201 USA. [Niu, Shui-Lin] USA, Congress Directed Med Res Programs, Med Res & Mat Command, Dept Def, Frederick, MD 21702 USA. [Litman, Burton J.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. RP Mitchell, DC (reprint author), Portland State Univ, Dept Phys, POB 751, Portland, OR 97201 USA. EM drakem@pdx.edu; shui-lin.niu@amedd.army.mil; blitman@bendbroadband.com NR 54 TC 12 Z9 12 U1 1 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD MAY PY 2012 VL 165 IS 4 SI SI BP 393 EP 400 DI 10.1016/j.chemphyslip.2012.02.008 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 952LL UT WOS:000304793900006 PM 22405878 ER PT J AU Panyutin, IG Onyshchenko, MI Englund, EA Appella, DH Neumann, RD AF Panyutin, Igor G. Onyshchenko, Mykola I. Englund, Ethan A. Appella, Daniel H. Neumann, Ronald D. TI Targeting DNA G-Quadruplex Structures with Peptide Nucleic Acids SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review DE Peptide Nucleic Acids; G-quadruplex; gene expression regulation ID I-MOTIF STRUCTURES; BCL2 PROMOTER REGION; C-MYC; GENE-EXPRESSION; BACKBONE MODIFICATION; LOCALIZATION SIGNAL; PROXIMAL PROMOTER; STRAND INVASION; KRAS PROMOTER; HUMAN-DISEASE AB Regulation of genetic functions based on targeting DNA or RNA sequences with complementary oligonucleotides is especially attractive in the post-genome era. Oligonucleotides can be rationally designed to bind their targets based on simple nucleic acid base pairing rules. However, the use of natural DNA and RNA oligonucleotides as targeting probes can cause numerous off-target effects. In addition, natural nucleic acids are prone to degradation in vivo by various nucleases. To address these problems, nucleic acid mimics such as peptide nucleic acids (PNA) have been developed. They are more stable, show less off-target effects, and, in general, have better binding affinity to their targets. However, their high affinity to DNA can reduce their sequence-specificity. The formation of alternative DNA secondary structures, such as the G-quadruplex, provides an extra level of specificity as targets for PNA oligomers. PNA probes can target the loops of G-quadruplex, invade the core by forming PNA-DNA guanine-tetrads, or bind to the open bases on the complementary cytosine-rich strand. Not only could the development of such G-quadruplex-specific probes allow regulation of gene expression, but it will also provide a means to clarify the biological roles G-quadruplex structures may possess. C1 [Panyutin, Igor G.; Onyshchenko, Mykola I.; Neumann, Ronald D.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Englund, Ethan A.; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Onyshchenko, Mykola I.] NCI, Ctr Clin, Imaging Sci Training Program, Bethesda, MD 20892 USA. [Onyshchenko, Mykola I.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10,Rm 1C401, Bethesda, MD 20892 USA. EM igorp@helix.nih.gov OI Onyshchenko, Mykola/0000-0003-4663-0991 FU Imaging Sciences Training Program; Radiology and Imaging Sciences Department, Clinical Center; National Institute of Biomedical Imaging and Bioengineering; Clinical Center; National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX The study was partially sponsored by the Imaging Sciences Training Program supported in part by the Radiology and Imaging Sciences Department, Clinical Center and Intramural Research Program at the National Institute of Biomedical Imaging and Bioengineering, and supported by Intramural Research Programs of Clinical Center and National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 89 TC 11 Z9 11 U1 1 U2 50 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAY PY 2012 VL 18 IS 14 BP 1984 EP 1991 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 952VZ UT WOS:000304823300010 PM 22376112 ER PT J AU Wilson, WH Jung, SH Porcu, P Hurd, D Johnson, J Martin, SE Czuczman, M Lai, R Said, J Chadburn, A Jones, D Dunleavy, K Canellos, G Zelenetz, AD Cheson, BD Hsi, ED AF Wilson, Wyndham H. Jung, Sin-Ho Porcu, Pierluigi Hurd, David Johnson, Jeffrey Martin, S. Eric Czuczman, Myron Lai, Raymond Said, Jonathan Chadburn, Amy Jones, Dan Dunleavy, Kieron Canellos, George Zelenetz, Andrew D. Cheson, Bruce D. Hsi, Eric D. CA Canc Leukemia Grp B TI A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE diffuse large B-cell lymphoma; DA-EPOCH-rituximab; untreated; outome; molecular ID NON-HODGKINS-LYMPHOMAS; DOSE-ADJUSTED EPOCH; CHEMOTHERAPY PLUS RITUXIMAB; RANDOMIZED CONTROLLED-TRIAL; 3-WEEKLY CHOP CHEMOTHERAPY; GERMINAL-CENTER; ELDERLY-PATIENTS; AGGRESSIVE LYMPHOMAS; TISSUE MICROARRAY; DRUG-RESISTANCE AB Background A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting. Design and Methods The study included 69 patients with untreated diffuse large B-cell lymphoma at least 18 years of age and at least stage II. Radiaton therapy was not permitted on study. Median age was 58 years (range 23-83) and 40% had high-intermediate or high International Prognostic Index risk. Immunohistochemical biomarkers for cell of origin and proliferation were performed. Results With a median follow up of 62 months, time to progression and overall survival were 81% and 84%, respectively, and time to progression was 87%, 92% and 54% for low/low-intermediate, high-intermediate and high International Prognostic Index risk groups, respectively, at 5-years and beyond. The time to progression and event-free survival of germinal center B-cell lymphoma were 100% and 94%, respectively, and non-germinal center B-cell GCB diffuse large B-cell lymphoma were 67% and 58%, respectively, at 62 months (germinal center vs. non-germinal center B cell P=0.008). DA-EPOCH-R was tolerated without significant grade 4 non-hematologic toxicities. Conclusions These results provide the first confirmation by a multi-institutional group that DA-EPOCH-R provides high durable remissions in diffuse large B-cell lymphoma and is effective in both germinal center and non-germinal center B-cell subtypes. C1 [Wilson, Wyndham H.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Jung, Sin-Ho; Johnson, Jeffrey] Duke Univ, Med Ctr, CALGB Stat Ctr, Durham, NC USA. [Porcu, Pierluigi] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Hurd, David] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Martin, S. Eric] Helen F Graham Canc Ctr, Newark, DE USA. [Czuczman, Myron] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Said, Jonathan] Univ Calif Los Angeles, Los Angeles, CA USA. [Said, Jonathan] Univ Alberta, Edmonton, AB, Canada. [Chadburn, Amy] Northwestern Univ, Chicago, IL 60611 USA. [Jones, Dan] Quest Diagnost Nichols Inst, Chantilly, VA USA. [Canellos, George] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Cheson, Bruce D.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Hsi, Eric D.] Cleveland Clin, Cleveland, OH 44106 USA. RP Wilson, WH (reprint author), NCI, Metab Branch, Bldg 10,Room 4N-115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov RI Jones, Daniel/I-7399-2015; OI Zelenetz, Andrew/0000-0003-1403-6883 NR 50 TC 70 Z9 75 U1 0 U2 5 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 EI 1592-8721 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD MAY PY 2012 VL 97 IS 5 BP 758 EP 765 DI 10.3324/haematol.2011.056531 PG 8 WC Hematology SC Hematology GA 950SK UT WOS:000304669000023 PM 22133772 ER PT J AU Biberacher, V Decker, T Oelsner, M Wagner, M Bogner, C Schmidt, B Kreitman, RJ Peschel, C Pastan, I zum Buschenfelde, CM Ringshausen, I AF Biberacher, Viola Decker, Thomas Oelsner, Madlen Wagner, Michaela Bogner, Christian Schmidt, Burkhard Kreitman, Robert J. Peschel, Christian Pastan, Ira zum Bueschenfelde, Christian Meyer Ringshausen, Ingo TI The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC-beta II depletion SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE CLL; bryostatin 1; CD22; immunotoxin; B-cell lymphoma ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; PHASE-I; RFB4(DSFV)-PE38 BL22; TRIAL; APOPTOSIS; IMMUNOTHERAPY; DEGRADATION; FLUDARABINE; RITUXIMAB AB Background In spite of potent first-line therapies for chronic lymphocytic leukemia, treatment remains palliative and all patients frequently relapse. Treatment options for these patients are more limited. BL22 is a recombinant protein composed of the variable region of a monoclonal antibody that binds to CD22 and of PE38, a truncated Pseudomonas exotoxin. BL22 is a very potent drug already used in patients with hairy cell leukemia, whereas in chronic lymphocytic leukemia its cytotoxicity is limited by a lower expression of CD22. Here we demonstrate that this limitation can be overcome by pre-activation of chronic lymphocytic leukemia cells with bryostatin 1. Design and Methods Primary malignant B cells from chronic lymphocytic leukemia and mantle cell lymphoma patients were used in vitro to assess the therapeutic impact of drug combinations using BL22 and bryostatin 1. Results We demonstrate that bryostatin 1 sensitizes chronic lymphocytic leukemia cells for the cytotoxic effects of BL22 through activation of protein kinase C and subsequently increased CD22 surface expression. Dose and time response analysis reveals that activation of protein kinase C further activates an autocrine feedback loop degrading protein kinase C-beta II protein. Depletion of protein kinase C-beta II and upregulation of CD22 persist for several days following pre-stimulation with bryostatin 1. Therefore, our data provide a rationale for the sequential administration of BL22 following bryostatin 1 treatment. In addition to primary chronic lymphocytic leukemia cells, bryostatin 1 also sensitizes diffuse large B-cell lymphoma and mantle cell lymphoma cells to BL22 induced apoptosis. Conclusions Our data suggest that the combination of bryostatin 1 with antibodies directed against CD22 is a potent drug combination for the treatment of low-and high-grade B-cell lymphoma. C1 [Biberacher, Viola; Decker, Thomas; Oelsner, Madlen; Wagner, Michaela; Bogner, Christian; Peschel, Christian; zum Bueschenfelde, Christian Meyer; Ringshausen, Ingo] Tech Univ Munich, Dept Med Hematol & Oncol 3, Munich, Germany. [Schmidt, Burkhard] Onkol Onkol Pasing, Munich, Germany. [Kreitman, Robert J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ringshausen, I (reprint author), Tech Univ Munich, Dept Med Hematol & Oncol 3, Munich, Germany. EM i.ringshausen@lrz.tum.de FU NIH, National Cancer Institute, Center for Cancer Research, USA; Deutsche Forschungsgemeinschaft, Germany (DFG) [SFB TRR54 TPC3] FX this research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA to RJK and IP. This work was also supported by a grant from the Deutsche Forschungsgemeinschaft, Germany (DFG-SFB TRR54 TPC3) to IR. NR 41 TC 9 Z9 9 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD MAY PY 2012 VL 97 IS 5 BP 771 EP 779 DI 10.3324/haematol.2011.049155 PG 9 WC Hematology SC Hematology GA 950SK UT WOS:000304669000025 PM 22180432 ER PT J AU Tumminia, SJ AF Tumminia, Santa J. TI Harnessing Academia, Government, and Industry SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article C1 NEI, Off Director, NIH, Bethesda, MD 20892 USA. RP Tumminia, SJ (reprint author), NEI, Off Director, NIH, 31 Ctr Dr,MSC 2510,Bldg 6,Room 6A03, Bethesda, MD 20892 USA. EM tumminias@nei.nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2012 VL 53 IS 5 SI SI BP 2515 EP 2521 DI 10.1167/iovs.12-9483q PG 7 WC Ophthalmology SC Ophthalmology GA 952YE UT WOS:000304831400018 PM 22562854 ER PT J AU Toth, DJ Toth, JT Gulyas, G Balla, A Balla, T Hunyady, L Varnai, P AF Toth, Daniel J. Toth, Jozsef T. Gulyas, Gergoe Balla, Andras Balla, Tamas Hunyady, Laszlo Varnai, Peter TI Acute depletion of plasma membrane phosphatidylinositol 4,5-bisphosphate impairs specific steps in endocytosis of the G-protein-coupled receptor SO JOURNAL OF CELL SCIENCE LA English DT Article DE Bioluminescence resonance energy transfer; Endocytosis; G-protein-coupled receptors; Phosphoinositides ID CLATHRIN-COATED PITS; AT(1) ANGIOTENSIN RECEPTOR; PLECKSTRIN HOMOLOGY DOMAIN; MEDIATED ENDOCYTOSIS; FLUORESCENT PROTEIN; LIVE CELLS; BINDING; DYNAMIN; VISUALIZATION; TRANSFERRIN AB Receptor endocytosis plays an important role in regulating the responsiveness of cells to specific ligands. Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P-2] has been shown to be crucial for endocytosis of some cell surface receptors, such as EGF and transferrin receptors, but its role in G-protein-coupled receptor internalization has not been investigated. By using luciferase-labeled type 1 angiotensin II (AT1R), type 2C serotonin (5HT2CR) or beta(2) adrenergic (beta 2AR) receptors and fluorescently tagged proteins (beta-arrestin-2, plasma-membrane-targeted Venus, Rab5) we were able to follow the sequence of molecular interactions along the endocytic route of the receptors in HEK293 cells using the highly sensitive method of bioluminescence resonance energy transfer and confocal microscopy. To study the role of plasma membrane PtdIns(4,5)P-2 in receptor endocytosis, we used our previously developed rapamycin-inducible heterodimerization system, in which the recruitment of a 5-phosphatase domain to the plasma membrane degrades PtdIns(4,5)P-2. Here we show that ligand-induced interaction of AT1, 5HT2C and beta(2)A receptors with beta-arrestin-2 was unaffected by PtdIns(4,5)P-2 depletion. However, trafficking of the receptors to Rab5-positive early endosomes was completely abolished in the absence of PtdIns(4,5)P-2. Remarkably, removal of the receptors from the plasma membrane was reduced but not eliminated after PtdIns(4,5)P-2 depletion. Under these conditions, stimulated AT1 receptors clustered along the plasma membrane, but did not enter the cells. Our data suggest that in the absence of PtdIns(4,5)P-2, these receptors move into clathrin-coated membrane structures, but these are not cleaved efficiently and hence cannot reach the early endosomal compartment. C1 [Toth, Daniel J.; Toth, Jozsef T.; Gulyas, Gergoe; Balla, Andras; Hunyady, Laszlo; Varnai, Peter] Semmelweis Univ, Dept Physiol, Fac Med, H-1444 Budapest, Hungary. [Balla, Tamas] NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Varnai, P (reprint author), Semmelweis Univ, Dept Physiol, Fac Med, Ulloi Ut 26, H-1444 Budapest, Hungary. EM peter.varnai@eok.sote.hu OI Gulyas, Gergo/0000-0002-5491-8699; Balla, Tamas/0000-0002-9077-3335; Balla, Andras/0000-0002-6450-2793; Toth, Daniel/0000-0001-6670-3348 FU Hungarian Scientific Research Fund [OTKA NF-68563]; Medical Research Council [ETT 494/2009]; Hungarian Academy of Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX P.V. was supported by the Hungarian Scientific Research Fund [grant number OTKA NF-68563]; and the Medical Research Council [grant number ETT 494/2009]. A. B. was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. T. B. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Deposited in PMC for release after 12 months. NR 62 TC 22 Z9 23 U1 0 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAY 1 PY 2012 VL 125 IS 9 BP 2185 EP 2197 DI 10.1242/jcs.097279 PG 13 WC Cell Biology SC Cell Biology GA 955IP UT WOS:000305011400011 PM 22357943 ER PT J AU Doyle, AD Kutys, ML Conti, MA Matsumoto, K Adelstein, RS Yamada, KM AF Doyle, Andrew D. Kutys, Matthew L. Conti, Mary Anne Matsumoto, Kazue Adelstein, Robert S. Yamada, Kenneth M. TI Micro-environmental control of cell migration - myosin IIA is required for efficient migration in fibrillar environments through control of cell adhesion dynamics SO JOURNAL OF CELL SCIENCE LA English DT Article DE Adhesions; Contractility; Fibrillar; Migration ID FOCAL ADHESIONS; ACTIN; ACTOMYOSIN; MOTILITY; TENSION; PROGRESSION AB Recent evidence suggests that organization of the extracellular matrix (ECM) into aligned fibrils or fibril-like ECM topographies promotes rapid migration in fibroblasts. However, the mechanisms of cell migration that are altered by these changes in micro-environmental topography remain unknown. Here, using 1D fibrillar migration as a model system for oriented fibrillar 3D matrices, we find that fibroblast leading-edge dynamics are enhanced by 1D fibrillar micropatterns and demonstrate a dependence on the spatial positioning of cell adhesions. Although 1D, 2D and 3D matrix adhesions have similar assembly kinetics, both 1D and 3D adhesions are stabilized for prolonged periods, whereas both paxillin and vinculin show slower turnover rates in 1D adhesions. Moreover, actin in 1D adhesions undergoes slower retrograde flow than the actin that is present in 2D lamellipodia. These data suggest an increase in mechanical coupling between adhesions and protrusive machinery. Experimental reduction of contractility resulted in the loss of 1D adhesion structure and stability, with scattered small and unstable adhesions, and an uncoupling of adhesion protein-integrin stability. Genetic ablation of myosin IIA (MIIA) or myosin IIB (MIIB) isoforms revealed that MIIA is required for efficient migration in restricted environments as well as adhesion maturation, whereas MIIB helps to stabilize adhesions beneath the cell body. These data suggest that restricted cell environments, such as 1D patterns, require cellular contraction through MIIA to enhance adhesion stability and coupling to integrins behind the leading edge. This increase in mechanical coupling allows for greater leading-edge protrusion and rapid cell migration. C1 [Doyle, Andrew D.; Kutys, Matthew L.; Matsumoto, Kazue; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Cell Biol Sect, Bethesda, MD 20892 USA. [Conti, Mary Anne; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Doyle, AD (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Cell Biol Sect, Bethesda, MD 20892 USA. EM adoyle@mail.nih.gov; kyamada@dir.nidcr.nih.gov OI Kutys, Matthew /0000-0002-0752-649X; Yamada, Kenneth/0000-0003-1512-6805; Adelstein, Robert/0000-0002-8683-2144 FU National Institute of Dental and Craniofacial Research, National Institutes of Health [DE000524, DE000718] FX Supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health [project numbers DE000524 and DE000718]. Deposited in PMC for release after 12 months. NR 35 TC 40 Z9 40 U1 3 U2 27 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAY 1 PY 2012 VL 125 IS 9 BP 2244 EP 2256 DI 10.1242/jcs.098806 PG 13 WC Cell Biology SC Cell Biology GA 955IP UT WOS:000305011400016 PM 22328520 ER PT J AU Zhang, YS Yuan, J Fang, ZZ Tu, YY Hu, CM Li, G Wang, L Deng, JP Yao, JJ Li, HR AF Zhang, Yong-Sheng Yuan, Jun Fang, Zhong-Ze Tu, Yan-Yang Hu, Cui-Min Li, Gan Wang, Liang Deng, Jian-Ping Yao, Jia-Jiu Li, Hai-Rong TI Gossypol Exhibits a Strong Influence Towards UDP-Glucuronosyltransferase (UGT) 1A1, 1A9 and 2B7-Mediated Metabolism of Xenobiotics and Endogenous Substances SO MOLECULES LA English DT Article DE gossypol; UDP-glucuronosyltransferase (UGT); enzyme inhibition ID BREAST-CANCER CELLS; PROSTATE-CANCER; HEPATOTOXICITY; INHIBITION; CARCINOMA; APOPTOSIS; ANTITUMOR; TOXICITY; ENZYMES; RATS AB Gossypol, the polyphenolic constituent isolated from cottonseeds, has been used as a male antifertility drug for a long time, and has been demonstrated to exhibit excellent anti-tumor activity towards multiple cancer types. The toxic effects of gossypol limit its clinical utilization, and enzyme inhibition is an important facet of this. In the present study, in vitro human liver microsomal incubation system supplemented with UDPGA was used to investigate the inhibition of gossypol towards UGT1A1, 1A9 and 2B7-mediated metabolism of xenobiotics and endogenous substances. Estradiol, the probe substrate of UGT1A1, was selected as representative endogenous substance. Propofol (a probe substrate of UGT1A9) and 3'-azido-3'-deoxythimidine (AZT, a probe substrate of UGT2B7) were employed as representative xenobiotics. The results showed that gossypol noncompetitively inhibits UGT-mediated estradiol-3-glucuronidation and propofol O-glucuronidation, and the inhibition kinetic parameters (K-i) were calculated to be 34.2 and 16.4 mu M, respectively. Gossypol was demonstrated to exhibit competitive inhibition towards UGT-mediated AZT glucuronidation, and the inhibition kinetic parameter (K-i) was determined to be 14.0 mu M. All these results indicated that gossypol might induce metabolic disorders of endogenous substances and alteration of metabolic behaviour of co-administered xenobiotics through inhibition of UGTs' activity. C1 [Zhang, Yong-Sheng; Yuan, Jun; Tu, Yan-Yang; Li, Gan; Wang, Liang; Deng, Jian-Ping; Yao, Jia-Jiu; Li, Hai-Rong] Fourth Mil Med Univ, Tangdu Hosp, Xian 710038, Peoples R China. [Fang, Zhong-Ze] Natl Canc Inst, Ctr Canc Res, Lab Metab, Bethesda, MD 20892 USA. RP Zhang, YS (reprint author), Fourth Mil Med Univ, Tangdu Hosp, Xian 710038, Peoples R China. EM zhangyongsheng979@gmail.com NR 25 TC 15 Z9 15 U1 2 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD MAY PY 2012 VL 17 IS 5 BP 4896 EP 4903 DI 10.3390/molecules17054896 PG 8 WC Chemistry, Organic SC Chemistry GA 949PH UT WOS:000304587600010 PM 22543504 ER PT J AU Shomstein, S Kravitz, DJ Behrmann, M AF Shomstein, Sarah Kravitz, Dwight J. Behrmann, Marlene TI Attentional control: Temporal relationships within the fronto-parietal network SO NEUROPSYCHOLOGIA LA English DT Article DE Spatial attention; Fronto-parietal network; ERP; Control of attention ID LATERAL INTRAPARIETAL AREA; HUMAN PARIETAL CORTEX; FRONTAL EYE FIELD; SPATIAL ATTENTION; TOP-DOWN; VISUAL-ATTENTION; BOTTOM-UP; VISUOSPATIAL ATTENTION; SELECTIVE ATTENTION; CORTICAL MECHANISMS AB Selective attention to particular aspects of incoming sensory information is enabled by a network of neural areas that includes frontal cortex, posterior parietal cortex, and, in the visual domain, visual sensory regions. Although progress has been made in understanding the relative contribution of these different regions to the process of visual attentional selection, primarily through studies using neuroimaging, rather little is known about the temporal relationships between these disparate regions. To examine this, participants viewed two rapid serial visual presentation (RSVP) streams of letters positioned to the left and right of fixation point. Before each run, attention was directed to either the left or the right stream. Occasionally, a digit appeared within the attended stream indicating whether attention was to be maintained within the same stream ('hold' condition) or to be shifted to the previously ignored stream ('shift' condition). By titrating the temporal parameters of the time taken to shift attention for each participant using a fine-grained psychophysics paradigm, we measured event-related potentials time-locked to the initiation of spatial shifts of attention. The results revealed that shifts of attention were evident earlier in the response recorded over frontal than over parietal electrodes and, importantly, that the early activity over frontal electrodes was associated with a successful shift of attention. We conclude that frontal areas are engaged early for the purpose of executing an attentional shift, likely triggering a cascade through the fronto-parietal network ultimately, resulting in the attentional modulation of sensory events in posterior cortices. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Shomstein, Sarah] George Washington Univ, Dept Psychol, Washington, DC 20015 USA. [Kravitz, Dwight J.] NIH, Unit Learning & Plast, Bethesda, MD 20892 USA. [Behrmann, Marlene] Carnegie Mellon Univ, Dept Psychol, Pittsburgh, PA 15213 USA. RP Shomstein, S (reprint author), George Washington Univ, Dept Psychol, Washington, DC 20015 USA. EM shom@gwu.edu RI Shomstein, Sarah/F-2371-2011; OI Behrmann, Marlene/0000-0002-3814-1015 FU National Eye Institute [EY021644]; National Institute of Mental Disorders [MH54246]; National Institute of Mental Health FX This research was partially supported by a grant from the National Eye Institute (EY021644) to S.S., by a grant from the National Institute of Mental Disorders (MH54246) to M.B., and by support from the National Institute of Mental Health Intramural Research Program to D.J.K. NR 63 TC 14 Z9 14 U1 1 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD MAY PY 2012 VL 50 IS 6 SI SI BP 1202 EP 1210 DI 10.1016/j.neuropsychologia.2012.02.009 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 951MK UT WOS:000304724500020 PM 22386880 ER PT J AU Altman, DG McShane, LM Sauerbrei, W Taube, SE AF Altman, Douglas G. McShane, Lisa M. Sauerbrei, Willi Taube, Sheila E. TI Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and Elaboration SO PLOS MEDICINE LA English DT Review ID BREAST-CANCER PATIENTS; CELL LUNG-CANCER; GROUP RANDOMIZED-TRIALS; MULTIVARIATE DATA-ANALYSIS; EPITHELIAL OVARIAN-CANCER; ENDOTHELIAL GROWTH-FACTOR; HAZARDS REGRESSION-MODEL; DISEASE-FREE SURVIVAL; TIME-DEPENDENT BIAS; LEUKEMIA GROUP-B C1 [Altman, Douglas G.] Univ Oxford, Ctr Stat Med, Oxford, England. [McShane, Lisa M.] US Natl Canc Inst, Bethesda, MD USA. [Sauerbrei, Willi] Univ Freiburg Klinikum, Inst Med Biometrie & Med Informat, Freiburg, Germany. [Taube, Sheila E.] ST Consulting, Bethesda, MD USA. RP Altman, DG (reprint author), Univ Oxford, Ctr Stat Med, Oxford, England. EM doug.altman@csm.ox.ac.uk FU Cancer Research UK [C5529] FX No direct funding was received for this study. DGA is supported by a grant from Cancer Research UK (C5529). The other authors were personally salaried by their institutions during the period of writing (though no specific salary was set aside or given for the writing of this paper). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 214 TC 196 Z9 198 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD MAY PY 2012 VL 9 IS 5 AR e1001216 DI 10.1371/journal.pmed.1001216 PG 32 WC Medicine, General & Internal SC General & Internal Medicine GA 951YS UT WOS:000304757300006 PM 22675273 ER PT J AU Coyle, CM Mahanty, S Zunt, JR Wallin, MT Cantey, PT White, AC O'Neal, SE Serpa, JA Southern, PM Wilkins, P McCarthy, AE Higgs, ES Nash, TE AF Coyle, Christina M. Mahanty, Siddhartha Zunt, Joseph R. Wallin, Mitchell T. Cantey, Paul T. White, A. Clinton, Jr. O'Neal, Seth E. Serpa, Jose A. Southern, Paul M. Wilkins, Patricia McCarthy, Anne E. Higgs, Elizabeth S. Nash, Theodore E. TI Neurocysticercosis: Neglected but Not Forgotten SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID HUMAN CYSTICERCOSIS; DISEASE BURDEN; EPILEPSY; AFRICA; SEROPREVALENCE; EPIDEMIOLOGY; PREVALENCE; DIAGNOSIS; SEROLOGY; CAMEROON C1 [Coyle, Christina M.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Mahanty, Siddhartha] NIAID, NIH, Helminth Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Zunt, Joseph R.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Zunt, Joseph R.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Wallin, Mitchell T.] Georgetown Univ, Dept Neurol, Washington, DC USA. [Wallin, Mitchell T.] Univ Maryland, Baltimore, MD 21201 USA. [Cantey, Paul T.; Wilkins, Patricia] Ctr Dis Control, Div Parasit Dis, Atlanta, GA 30333 USA. [White, A. Clinton, Jr.] Univ Texas Galveston, Dept Internal Med, Div Infect Dis, Galveston, TX USA. [O'Neal, Seth E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Serpa, Jose A.] Baylor Coll Med, Dept Med, Infect Dis Sect, Houston, TX 77030 USA. [Southern, Paul M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [McCarthy, Anne E.] Ottawa Gen Hosp, Dept Med, Ottawa, ON K1H 8L6, Canada. [Higgs, Elizabeth S.] NIAID, NIH, Collaborat Clin Res Branch, Div Clin Res, Bethesda, MD 20892 USA. [Nash, Theodore E.] NIAID, NIH, Gastrointestinal Parasites Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Coyle, CM (reprint author), Albert Einstein Coll Med, Bronx, NY 10467 USA. EM christina.coyle@einstein.yu.edu; tnash@niaid.nih.gov OI White, A Clinton/0000-0002-9668-4632; McCarthy, Anne/0000-0001-7195-6366; Mahanty, Siddhartha/0000-0003-1068-0524 FU Division of Intramural Research, National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health; Office of Rare Diseases, National Center for Advancing Translational Sciences, NIH FX Funding for this work was provided in part by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health and by and the Office of Rare Diseases, National Center for Advancing Translational Sciences, NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders financially supported the formation of the consortium (e. g., paid for initial meeting), and communication between the members. NR 31 TC 41 Z9 41 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAY PY 2012 VL 6 IS 5 AR e1500 DI 10.1371/journal.pntd.0001500 PG 3 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 951ZG UT WOS:000304758900002 PM 22666505 ER PT J AU Rohousova, I Subrahmanyam, S Volfova, V Mu, JB Volf, P Valenzuela, JG Jochim, RC AF Rohousova, Iva Subrahmanyam, Sreenath Volfova, Vera Mu, Jianbing Volf, Petr Valenzuela, Jesus G. Jochim, Ryan C. TI Salivary Gland Transcriptomes and Proteomes of Phlebotomus tobbi and Phlebotomus sergenti, Vectors of Leishmaniasis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID FLY LUTZOMYIA-LONGIPALPIS; ROYAL JELLY PROTEINS; SAND FLIES; VISCERAL LEISHMANIASIS; CUTANEOUS LEISHMANIASIS; ANTIBODY-RESPONSE; IMMUNE-RESPONSE; HYALURONIDASE ACTIVITY; MOLECULAR-MECHANISM; ENDEMIC AREAS AB Background: Phlebotomus tobbi is a vector of Leishmania infantum, and P. sergenti is a vector of Leishmania tropica. Le. infantum and Le. tropica typically cause visceral or cutaneous leishmaniasis, respectively, but Le. infantum strains transmitted by P. tobbi can cause cutaneous disease. To better understand the components and possible implications of sand fly saliva in leishmaniasis, the transcriptomes of the salivary glands (SGs) of these two sand fly species were sequenced, characterized and compared. Methodology/Principal Findings: cDNA libraries of P. tobbi and P. sergenti female SGs were constructed, sequenced, and analyzed. Clones (1,152) were randomly picked from each library, producing 1,142 high-quality sequences from P. tobbi and 1,090 from P. sergenti. The most abundant, secreted putative proteins were categorized as antigen 5-related proteins, apyrases, hyaluronidases, D7-related and PpSP15-like proteins, ParSP25-like proteins, PpSP32-like proteins, yellow-related proteins, the 33-kDa salivary proteins, and the 41.9-kDa superfamily of proteins. Phylogenetic analyses and multiple sequence alignments of putative proteins were used to elucidate molecular evolution and describe conserved domains, active sites, and catalytic residues. Proteomic analyses of P. tobbi and P. sergenti SGs were used to confirm the identification of 35 full-length sequences (18 in P. tobbi and 17 in P. sergenti). To bridge transcriptomics with biology P. tobbi antigens, glycoproteins, and hyaluronidase activity was characterized. Conclusions: This analysis of P. sergenti is the first description of the subgenus Paraphlebotomus salivary components. The investigation of the subgenus Larroussius sand fly P. tobbi expands the repertoire of salivary proteins in vectors of Le. infantum. Although P. tobbi transmits a cutaneous form of leishmaniasis, its salivary proteins are most similar to other Larroussius subgenus species transmitting visceral leishmaniasis. These transcriptomic and proteomic analyses provide a better understanding of sand fly salivary proteins across species and subgenera that will be vital in vector-pathogen and vector-host research. C1 [Rohousova, Iva; Volfova, Vera; Volf, Petr] Charles Univ Prague, Dept Parasitol, Fac Sci, Prague, Czech Republic. [Subrahmanyam, Sreenath; Valenzuela, Jesus G.; Jochim, Ryan C.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Mu, Jianbing] NIAID, Malaria Genom Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Rohousova, I (reprint author), Charles Univ Prague, Dept Parasitol, Fac Sci, Prague, Czech Republic. EM jvalenzuela@niaid.nih.gov; rjochim@niaid.nih.gov RI Rohousova, Iva/B-4852-2011; Volf, Petr/C-4300-2012; Jochim, Ryan/C-6756-2013 OI Rohousova, Iva/0000-0003-1830-0813; Volf, Petr/0000-0003-1790-1123; FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; Ministry of Education of the Czech Republic [MSM0021620828, LC06009]; Czech Science Foundation [206/09/0777] FX The study was supported by the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, by the Ministry of Education of the Czech Republic (www.msmt.cz, project nos. MSM0021620828 and LC06009), and by the Czech Science Foundation (www.gacr.cz, project no. 206/09/0777). Participation of Iva Rohousova was supported by the Fulbright Scholar Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 93 TC 22 Z9 22 U1 1 U2 24 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAY PY 2012 VL 6 IS 5 AR e1660 DI 10.1371/journal.pntd.0001660 PG 27 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 951ZG UT WOS:000304758900038 PM 22629480 ER PT J AU Wong, J Morrison, AC Stoddard, ST Astete, H Chu, YY Baseer, I Scott, TW AF Wong, Jacklyn Morrison, Amy C. Stoddard, Steven T. Astete, Helvio Chu, Yui Yin Baseer, Imaan Scott, Thomas W. TI Linking Oviposition Site Choice to Offspring Fitness in Aedes aegypti: Consequences for Targeted Larval Control of Dengue Vectors SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID HABITAT SELECTION; CULISETA-LONGIAREOLATA; BODY-SIZE; PHYTOPHAGOUS INSECTS; WYEOMYIA-SMITHII; MATING SUCCESS; WING-LENGTH; PUERTO-RICO; CULICIDAE; DIPTERA AB Background: Current Aedes aegypti larval control methods are often insufficient for preventing dengue epidemics. To improve control efficiency and cost-effectiveness, some advocate eliminating or treating only highly productive containers. The population-level outcome of this strategy, however, will depend on details of Ae. aegypti oviposition behavior. Methodology/Principal Findings: We simultaneously monitored female oviposition and juvenile development in 80 experimental containers located across 20 houses in Iquitos, Peru, to test the hypothesis that Ae. aegypti oviposit preferentially in sites with the greatest potential for maximizing offspring fitness. Females consistently laid more eggs in large vs. small containers (beta = 9.18, p < 0.001), and in unmanaged vs. manually filled containers (beta = 5.33, p < 0.001). Using microsatellites to track the development of immature Ae. aegypti, we found a negative correlation between oviposition preference and pupation probability (beta = -3.37, p < 0.001). Body size of emerging adults was also negatively associated with the preferred oviposition site characteristics of large size (females: beta = -0.19, p < 0.001; males: beta = -0.11, p = 0.002) and nonmanagement (females: beta = -0.17, p < 0.001; males: beta = -0.11, p < 0.001). Inside a semi-field enclosure, we simulated a container elimination campaign targeting the most productive oviposition sites. Compared to the two post-intervention trials, egg batches were more clumped during the first pre-intervention trial (beta = -0.17, p < 0.001), but not the second (beta = 0.01, p = 0.900). Overall, when preferred containers were unavailable, the probability that any given container received eggs increased (beta = 1.36, p < 0.001). Conclusions/Significance: Ae. aegypti oviposition site choice can contribute to population regulation by limiting the production and size of adults. Targeted larval control strategies may unintentionally lead to dispersion of eggs among suitable, but previously unoccupied or under-utilized containers. We recommend integrating targeted larval control measures with other strategies that leverage selective oviposition behavior, such as luring ovipositing females to gravid traps or egg sinks. C1 [Wong, Jacklyn; Morrison, Amy C.; Stoddard, Steven T.; Chu, Yui Yin; Baseer, Imaan; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Morrison, Amy C.; Astete, Helvio] US Naval Med Res Ctr Unit 6, Lima, Peru. [Stoddard, Steven T.; Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Wong, J (reprint author), Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. EM jacklyn.wong@gmail.com FU UC Davis; Hazeltine; McBeth award; Innovative Vector Control Consortium; Regents of the University of California from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative; National Institutes of Health [R01 AI069341] FX This research was supported by the UC Davis Jastro-Shields, Hazeltine, and McBeth awards; the Innovative Vector Control Consortium; Regents of the University of California from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative; and National Institutes of Health grant R01 AI069341. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 16 Z9 16 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAY PY 2012 VL 6 IS 5 AR e1632 DI 10.1371/journal.pntd.0001632 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 951ZG UT WOS:000304758900015 PM 22563512 ER PT J AU Song, SM Kole, S Bernier, M AF Song, Shaoming Kole, Sutapa Bernier, Michel TI A chemical cross-linking method for the analysis of binding partners of heat shock protein-90 in intact cells SO BIOTECHNIQUES LA English DT Article DE chaperone; heat shock protein; protein cross-linking; small interfering RNA ID ESCHERICHIA-COLI HSP90; CHAPERONE MACHINERY; ATPASE CYCLE; RECEPTOR; CANCER; HEAT-SHOCK-PROTEIN-90; IMMUNOPHILIN; HSP90-ALPHA; EXPRESSION; COMPLEXES AB Members of the heat shock protein-90 (Hsp90) family are key regulators of biological processes through dynamic interaction with a multitude of protein partners. However, the transient nature of these interactions hinders the identification of Hsp90 interactors. Here we show that chemical cross-linking with ethylene glycolbis (succinimidylsuccinate), but not shorter cross-linkers, generated an abundant 240-kDa heteroconjugate of the molecular chaperone Hsp90 in different cell types. The combined use of pharmacological and genetic approaches allowed the characterization of the subunit composition and subcellular compartmentalization of the multimeric protein complex, termed p240. The in situ formation of p240 did not require the N-terminal domain or the ATPase activity of Hsp90. Utilizing subcellular fractionation techniques and a cell-impermeant cross-linker, subpopulations of p240 were found to be present in both the plasma membrane and the mitochondria. The Hsp90-interacting proteins, including Hsp70, p60Hop and the scaffolding protein filamin A, had no role in governing the formation of p240. Therefore, chemical cross-linking combined with proteomic methods has the potential to unravel the protein components of this p240 complex and, more importantly, may provide an approach to expand the range of tools available to the study of the Hsp90 interactome. C1 [Song, Shaoming; Bernier, Michel] Natl Inst Aging, Biomed Res Ctr, Clin Invest Lab, Natl Inst Hlth, Baltimore, MD USA. [Kole, Sutapa] Kelly Govt Solut, Rockville, MD USA. RP Bernier, M (reprint author), Natl Inst Aging, Biomed Res Ctr, Clin Invest Lab, Natl Inst Hlth, 251 Bayview Blvd,Suite 100, Baltimore, MD USA. EM Bernierm@mail.nih.gov OI Bernier, Michel/0000-0002-5948-368X FU NIH, NIA FX We thank the National Institute on Aging (NIA), National Institutes of Health (NIH) Apheresis Unit, and the clinical core laboratory for providing human blood from normal donors. This research was supported entirely by the Intramural Research Program of the NIH, NIA. This paper is subject to the NIH Public Access Policy. NR 36 TC 1 Z9 1 U1 0 U2 2 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD MAY PY 2012 VL 52 IS 5 BP 335 EP 341 DI 10.2144/000113856 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 949LF UT WOS:000304577000010 ER PT J AU Park, HS Kim, J Damiano, DL AF Park, Hyung-Soon Kim, Jonghyun Damiano, Diane L. TI Development of a Haptic Elbow Spasticity Simulator (HESS) for Improving Accuracy and Reliability of Clinical Assessment of Spasticity SO IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING LA English DT Article DE Elbow spasticity; haptic simulation; inter-rater reliability; modified Ashworth scale; spasticity assessment ID MODIFIED ASHWORTH SCALE; MODIFIED TARDIEU SCALE; SEVERE BRAIN-INJURY; CEREBRAL-PALSY; INTERRATER RELIABILITY; CHILDREN; VELOCITY; PATHOPHYSIOLOGY; MODEL; FLEXORS AB This paper presents the framework for developing a robotic system to improve accuracy and reliability of clinical assessment. Clinical assessment of spasticity tends to have poor reliability because of the nature of the in-person assessment. To improve accuracy and reliability of spasticity assessment, a haptic device, named the HESS (Haptic Elbow Spasticity Simulator) has been designed and constructed to recreate the clinical "feel" of elbow spasticity based on quantitative measurements. A mathematical model representing the spastic elbow joint was proposed based on clinical assessment using the Modified Ashworth Scale (MAS) and quantitative data (position, velocity, and torque) collected on subjects with elbow spasticity. Four haptic models (HMs) were created to represent the haptic feel of MAS 1, 1+, 2, and 3. The four HMs were assessed by experienced clinicians; three clinicians performed both in-person and haptic assessments, and had 100% agreement in MAS scores; and eight clinicians who were experienced with MAS assessed the four HMs without receiving any training prior to the test. Inter-rater reliability among the eight clinicians had substantial agreement (kappa = 0.626). The eight clinicians also rated the level of realism (7.63 +/- 0.92 out of 10) as compared to their experience with real patients. C1 [Park, Hyung-Soon; Kim, Jonghyun; Damiano, Diane L.] NIH, Ctr Clin, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Park, HS (reprint author), NIH, Ctr Clin, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. EM parkhs@cc.nih.gov RI Park, Hyung-Soon/B-3334-2010; Damiano, Diane/B-3338-2010 OI Park, Hyung-Soon/0000-0003-4274-7420; Damiano, Diane/0000-0002-2770-5356 FU National Institutes of Health [90-CC-0168]; Center for Neuroscience and Regenerative Medicine [G192HF] FX Manuscript received September 13, 2011; revised February 06, 2012; accepted March 28, 2012. Date of publication May 02, 2012; date of current version May 18, 2012. This work was supported in part by the intramural research program of the National Institutes of Health (protocol number 90-CC-0168) and in part by the Center for Neuroscience and Regenerative Medicine (G192HF). H.-S. Park and J. Kim contributed equally to this work. NR 42 TC 7 Z9 7 U1 2 U2 10 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1534-4320 J9 IEEE T NEUR SYS REH JI IEEE Trans. Neural Syst. Rehabil. Eng. PD MAY PY 2012 VL 20 IS 3 BP 361 EP 370 DI 10.1109/TNSRE.2012.2195330 PG 10 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA 949BO UT WOS:000304550600015 PM 22562769 ER PT J AU Mou, YH Yang, JY Cui, N Wang, JM Hou, Y Song, S Wu, CF AF Mou, Yan Hua Yang, Jing Yu Cui, Nan Wang, Ji Ming Hou, Yue Song, Shuang Wu, Chun Fu TI Effects of cobalt chloride on nitric oxide and cytokines/chemokines production in microglia SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE Cobalt chloride (CoCl2); Microglia; Cytokines/chemokines; ROS; NF-kappa B; p38 MAPK ID HUMAN ENDOTHELIAL-CELLS; TNF-ALPHA PRODUCTION; FACTOR-KAPPA-B; ACTIVATED MICROGLIA; IN-VITRO; PROINFLAMMATORY CYTOKINES; METAL; EXPRESSION; RELEASE; HIP AB The involvement of microglial activation in metal neurotoxicity is becoming increasingly recognized. Some metal ions, such as zinc (II) and manganese (II), have been recently reported as microglial activators to induce the release of inflammatory mediators including cytokines, chemokines and nitric oxide (NO) which are involved in the pathogenesis of neurological diseases. Cobalt is essential for human life. However, excessive cobalt is cytotoxic and neurotoxic. In the present study, we determined cobalt-induced production of NO and cytokines/chemokines in N9 cells, a murine microglial cell line. High levels of cobalt significantly up-regulated iNOS mRNA and protein expression, which resulted in the release of NO. Cobalt induced the production of tumor necrosis factor a (TNF-alpha) and interleukin-6 (IL-6) in a concentration- and time-dependent manner in both N9 cells and primary mouse microglia and increased lipopolysaccharides (LPS)induced cytokine production. Further study showed that cobalt induced cytokine production by a mechanism involving both nuclear factor kappa B (NF-kappa B) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. The involvement of reactive oxygen species (ROS) in microglial activation was also confirmed. These findings suggested that cobalt neurotoxicity should be attributed not only directly to neuronal damage but also indirectly to microglial activation which might potentiate neuronal injury via elevation of proinflammatory mediator levels. (C) 2012 Elsevier B.V. All rights reserved. C1 [Mou, Yan Hua; Yang, Jing Yu; Cui, Nan; Hou, Yue; Song, Shuang; Wu, Chun Fu] Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Wu, CF (reprint author), Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China. EM chunfuw@gmail.com FU Liaoning province; National Key Scientific Project for New Drug Discovery and Development, P. R. China [2009ZX09301-012]; Technology Equipment Sharing Service Platform of Shenyang, China [F10-228-4-00] FX This work was supported by grants from Liaoning province to the Key Laboratory for New Drug Screening and Liaoning province to the Key Laboratory for the Evaluation of Efficacy of New Drugs, by the National Key Scientific Project for New Drug Discovery and Development (2009ZX09301-012), 2009-2010, P. R. China, and by grants (F10-228-4-00) from the Technology Equipment Sharing Service Platform of Shenyang, China. NR 35 TC 9 Z9 9 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD MAY PY 2012 VL 13 IS 1 BP 120 EP 125 DI 10.1016/j.intimp.2012.03.017 PG 6 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 949ML UT WOS:000304580200018 PM 22472292 ER PT J AU Patlolla, AK Berry, A May, L Tchounwou, PB AF Patlolla, Anita K. Berry, Ashley May, LaBethani Tchounwou, Paul B. TI Genotoxicity of Silver Nanoparticles in Vicia faba: A Pilot Study on the Environmental Monitoring of Nanoparticles SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article; Proceedings Paper CT 8th International Symposium on Recent Advances in Environmental Health Research CY SEP 18-21, 2011 CL Jackson, MS SP Jackson State Univ (JSU), Natl Inst Hlth, RCMI-Ctr Environm Hlth, U S Dept Educ, Title III Grad Educ Program, U S Environm Protect Agcy, JSU Off Acad Affairs, JSU Off Res & Fed Relat DE silver nanoparticles; chromosomal aberrations; mitotic index; Vicia faba; genotoxicity; micronucleus ID IN-VITRO CYTOTOXICITY; INDUCE OXIDATIVE STRESS; CARBON NANOTUBES; MITOTIC CYCLE; TOXICITY; CELLS; NANO-TIO2; SPINACH; ALLIUM; CLASTOGENICITY AB The use of silver nanoparticles (AgNPs) in commercial products has increased significantly in recent years. Although there have been some attempts to determine the toxic effects of AgNPs in mammalian and human cell-lines, there is little information on plants which play a vital role in ecosystems. The study reports the use of Vicia faba root-tip meristem to investigate the genotoxicity of AgNPs under modified GENE-TOX test conditions. The root tip cells of V. faba were treated with four different concentrations of engineered AgNPs dispersion to study toxicological endpoints such as mitotic index (MI), chromosomal aberrations (CA) and micronucleus induction (MN). For each concentration, five sets of microscopy observations were carried out. The results demonstrated that AgNPs exposure significantly increased (p < 0.05) the number of chromosomal aberrations, micronuclei, and decreased the MI in exposed groups compared to control. From this study we infer that AgNPs might have penetrated the plant system and may have impaired mitosis causing CA and MN. The results of this study demonstrate that AgNPs are genotoxic to plant cells. Since plant assays have been integrated as a genotoxicity component in risk assessment for detection of environmental mutagens, they should be given full consideration when evaluating the overall toxicological impact of the nanoparticles in the environment. C1 [Patlolla, Anita K.; Berry, Ashley; May, LaBethani; Tchounwou, Paul B.] Jackson State Univ, Mol Toxicol Res Lab, NIH, RCMI Ctr Environm Hlth,Coll Sci Engn & Technol, Jackson, MS 39217 USA. [Berry, Ashley; May, LaBethani] Jackson State Univ, Dept Biol, Jackson, MS 39217 USA. [May, LaBethani] Jackson State Univ, Murray High Sch Student, SEPA Program, Jackson, MS 39217 USA. RP Patlolla, AK (reprint author), Jackson State Univ, Mol Toxicol Res Lab, NIH, RCMI Ctr Environm Hlth,Coll Sci Engn & Technol, Jackson, MS 39217 USA. EM anita.k.patlolla@jsums.edu; ashleyberry@gmail.com; labeth@yahoo.com; paul.b.tchounwou@jsums.edu FU NCRR NIH HHS [R25 RR020405, G12 RR013459, G12RR013459-14, RR020405-02] NR 44 TC 32 Z9 34 U1 3 U2 47 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD MAY PY 2012 VL 9 IS 5 BP 1649 EP 1662 DI 10.3390/ijerph9051649 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 948ZJ UT WOS:000304543200009 PM 22754463 ER PT J AU Radovic, V Vitale, K Tchounwou, PB AF Radovic, Vesela Vitale, Ksenija Tchounwou, Paul B. TI Health Facilities Safety in Natural Disasters: Experiences and Challenges from South East Europe SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article; Proceedings Paper CT 8th International Symposium on Recent Advances in Environmental Health Research CY SEP 18-21, 2011 CL Jackson, MS SP Jackson State Univ (JSU), Natl Inst Hlth, RCMI-Ctr Environm Hlth, U S Dept Educ, Title III Grad Educ Program, U S Environm Protect Agcy, JSU Off Acad Affairs, JSU Off Res & Fed Relat DE environmental security; natural disasters; safety; hospitals planning; critical infrastructure AB The United Nations named 2010 as a year of natural disasters, and launched a worldwide campaign to improve the safety of schools and hospitals from natural disasters. In the region of South East Europe, Croatia and Serbia have suffered the greatest impacts of natural disasters on their communities and health facilities. In this paper the disaster management approaches of the two countries are compared, with a special emphasis on the existing technological and legislative systems for safety and protection of health facilities and people. Strategic measures that should be taken in future to provide better safety for health facilities and populations, based on the best practices and positive experiences in other countries are recommended. Due to the expected consequences of global climate change in the region and the increased different environmental risks both countries need to refine their disaster preparedness strategies. Also, in the South East Europe, the effects of a natural disaster are amplified in the health sector due to its critical medical infrastructure. Therefore, the principles of environmental security should be implemented in public health policies in the described region, along with principles of disaster management through regional collaborations. C1 [Vitale, Ksenija] Univ Zagreb, Sch Med, Sch Publ Hlth, Zagreb 10000, Croatia. [Radovic, Vesela] Univ EDUCONS, Fac Environm Protect, Sremska Kamenica 21208, Ap Vojvodina, Serbia. [Tchounwou, Paul B.] Jackson State Univ, Mol Toxicol Res Lab, NIH, Ctr Environm Hlth,Coll Sci Engn & Technol, Jackson, MS 39217 USA. RP Vitale, K (reprint author), Univ Zagreb, Sch Med, Sch Publ Hlth, 4 Rockefeller St, Zagreb 10000, Croatia. EM veselaradovic@yahoo.com; kvitale@snz.hr; paul.b.tchounwou@jsums.edu NR 16 TC 7 Z9 7 U1 5 U2 16 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD MAY PY 2012 VL 9 IS 5 BP 1677 EP 1686 DI 10.3390/ijerph9051677 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 948ZJ UT WOS:000304543200011 PM 22754465 ER PT J AU Agochukwu, NB Solomon, BD Doherty, ES Muenke, M AF Agochukwu, Nneamaka Barbara Solomon, Benjamin D. Doherty, Emily S. Muenke, Maximilian TI Palatal and Oral Manifestations of Muenke Syndrome (FGFR3-Related Craniosynostosis) SO JOURNAL OF CRANIOFACIAL SURGERY LA English DT Article; Proceedings Paper CT 14th International Congress of the International Society of Craniofacial Surgery (ISCFS) CY SEP 01-01, 2011 CL Zambia, SOUTH AFRICA DE FGFR craniosynostosis palate; palate Muenke syndrome; cleft lip and palate craniosynostosis; FGFR3 craniosynostosis; Muenke syndrome ID GROWTH-FACTOR RECEPTOR-3; CLEFT-PALATE; OROFACIAL CLEFTS; PRO250ARG MUTATION; FACIAL MESENCHYME; APERT SYNDROME; CHICK-EMBRYO; FGF FAMILY; EXPRESSION; GENE AB Although Muenke syndrome is the most common syndromic form of craniosynostosis, the frequency of oral and palatal anomalies including high-arched palate, cleft lip with or without cleft palate has not been documented in a patient series of Muenke syndrome to date. Further, to our knowledge, cleft lip and palate has not been reported yet in a patient withMuenke syndrome (a previous patient with isolated cleft palate has been reported). This study sought to evaluate the frequency of palatal anomalies in patients with Muenke syndrome through both a retrospective investigation and literature review. A total of 21 patients who met criteria for this study were included in the retrospective review. Fifteen patients (71%) had a structural anomaly of the palate. Cleft lip and palate was present in 1 patient (5%). Other palatal findings included high-arched hard palate in 14 patients (67%). Individuals with Muenke syndrome have the lowest incidence of cleft palate among the most common craniosynostosis syndromes. However, high-arched palate in Muenke syndrome is common and may warrant clinical attention, as these individuals are more susceptible to recurrent chronic otitis media with effusion, dental malocclusion, and hearing loss. C1 [Agochukwu, Nneamaka Barbara; Muenke, Maximilian] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Agochukwu, Nneamaka Barbara; Solomon, Benjamin D.; Muenke, Maximilian] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Doherty, Emily S.] Caril Pediat Clin, Roanoke, VA USA. RP Muenke, M (reprint author), NIH, Clin Res Training Program, MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health) FX This research was supported by the Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health). NR 56 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1049-2275 EI 1536-3732 J9 J CRANIOFAC SURG JI J. Craniofac. Surg. 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PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701193 ER PT J AU Bodogai, M Chang, CL Wejksza, K Malchinkhuu, E Chan, A Biragyn, A AF Bodogai, Monica Chang, Catalina Lee Wejksza, Katarzyna Malchinkhuu, Enkhzol Chan, Andrew Biragyn, Arya TI Failure of Rituximab in solid tumors is due to its inability to eliminate tumor evoked B regulatory cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Bodogai, Monica; Chang, Catalina Lee; Wejksza, Katarzyna; Malchinkhuu, Enkhzol; Biragyn, Arya] NIA, LMBI, NIH, Baltimore, MD 21224 USA. [Chan, Andrew] Genentech Inc, Res Dept, San Francisco, CA 94080 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701610 ER PT J AU Borrego, F Andersen, J Calvo, E Choi, SC Coligan, J Simhadri, V AF Borrego, Francisco Andersen, John Calvo, Eric Choi, Seung-Chul Coligan, John Simhadri, Venkateswara TI CD300a binds to phosphatidylethanolamine and phosphatidylserine and modulates the uptake of dead cells. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Borrego, Francisco; Simhadri, Venkateswara] US FDA, Div Monoclonal Antibodies, Bethesda, MD 20014 USA. [Andersen, John; Calvo, Eric] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Choi, Seung-Chul; Coligan, John] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701650 ER PT J AU Chen, J Feigenbaum, L Awasthi, P Butcher, D Anver, M Bamford, R Thomas, C Waldmann, T AF Chen, Jing Feigenbaum, Lionel Awasthi, Parirokh Butcher, Donna Anver, Miriam Bamford, Richard Thomas, Craig Waldmann, Thomas TI Co-expression of IL-15 and IL-15R alpha on pancreatic beta islet cells induced insulin dependent diabetes mellitus in mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Chen, Jing; Waldmann, Thomas] NCI, Metab Branch, Bethesda, MD 20892 USA. [Feigenbaum, Lionel; Awasthi, Parirokh; Butcher, Donna; Anver, Miriam] SAIC Frederick Inc, Lab Anim Sci Program, Frederick, MD USA. [Bamford, Richard] Transponics, Dept Mol Biol, Jacobus, PA USA. [Thomas, Craig] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701496 ER PT J AU Chen, X Wu, XQ Howard, OMZ Oppenheim, J AF Chen, Xin Wu, Xueqiang Howard, O. M. Zack Oppenheim, Joost TI Interaction of TNF and TNFR2 stabilizes the phenotype and function of CD4+FoxP3+regulatory T cells in the inflammatory environment SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Chen, Xin] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Wu, Xueqiang; Howard, O. M. Zack; Oppenheim, Joost] NCI, LMI CIP CCR, Frederick, MD 21701 USA. RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702285 ER PT J AU Cheng, NL Chen, XC Nguyen, C Weng, NP AF Cheng, Nai-Lin Chen, Xiaochun Cuong Nguyen Weng, Nan-ping TI MicroRNAs modulate chemokine expression in naive CD8 T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Cheng, Nai-Lin; Chen, Xiaochun; Weng, Nan-ping] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Cuong Nguyen] NIA, Flow Cytometry Unit, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700114 ER PT J AU Choi, SC Wang, HS Tian, LJ Murakami, Y Shin, DM Borrego, F Morse, H Coligan, J AF Choi, Seung-Chul Wang, Hongsheng Tian, Linjie Murakami, Yousuke Shin, Dong-Mi Borrego, Francisco Morse, Herbert Coligan, John TI The IgM Fc receptor, FCMR, promotes B cell development and modulates antigen-driven immune responses SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Choi, Seung-Chul; Wang, Hongsheng; Tian, Linjie; Murakami, Yousuke; Shin, Dong-Mi; Morse, Herbert; Coligan, John] NIAID, LIG, NIH, Rockville, MD USA. [Borrego, Francisco] US FDA, DMA CDER, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702230 ER PT J AU Choi, SM McAleer, J Deleo, F Hooper, L Qin, SL Reinhart, T Ouyang, WJ Kolls, J AF Choi, Sun-Mi McAleer, Jeremy Deleo, Frank Hooper, Lora Qin, Shulin Reinhart, Todd Ouyang, Wenjun Kolls, Jay TI Epithelial STAT3-induced antimicrobial protein, Reg3 gamma is required for host defense against MRSA pneumonia in mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Choi, Sun-Mi; Kolls, Jay] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Choi, Sun-Mi; McAleer, Jeremy; Kolls, Jay] Childrens Hosp Pittsburgh, Richard King Mellon Fdn Inst, Pittsburgh, PA 15213 USA. [Deleo, Frank] NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. [Hooper, Lora] UT SW, Dallas, TX USA. [Qin, Shulin; Reinhart, Todd] Univ Pittsburgh, Pittsburgh, PA USA. [Ouyang, Wenjun] Genentech Inc, San Francisco, CA 94080 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700372 ER PT J AU Chong, WP Horai, R Silver, P Mattapallil, M Chen, J Caspi, R AF Chong, Wai Po Horai, Reiko Silver, Phyllis Mattapallil, Mary Chen, Jun Caspi, Rachel TI IL27p28 inhibits induction and expression of experimental autoimmune uveitis by concurrently antagonizing autoaggressive Th1 and Th17 responses. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Chong, Wai Po; Horai, Reiko; Silver, Phyllis; Mattapallil, Mary; Chen, Jun; Caspi, Rachel] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701306 ER PT J AU Cook, D Burgents, J Nakano, H AF Cook, Donald Burgents, Joseph Nakano, Hideki TI Migratory properties of pulmonary dendritic cells are developmentally programmed SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Cook, Donald; Burgents, Joseph; Nakano, Hideki] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700459 ER PT J AU Cruse, G Beaven, M Bradding, P Gilfillan, A Metcalfe, D AF Cruse, Glenn Beaven, Michael Bradding, Peter Gilfillan, Alasdair Metcalfe, Dean TI The nascent truncation of Fc epsilon RI beta confers calmodulin binding which is essential for microtubule formation and degranulation in human mast cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Cruse, Glenn; Gilfillan, Alasdair; Metcalfe, Dean] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Bradding, Peter] Univ Leicester, Leicester, Leics, England. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702239 ER PT J AU Cui, Y Kibe, R Zhang, SZ Guo, D Marrero, L Tsien, F Rodriguez, P Zieske, A Huang, JQ Li, WQ Durum, S Iwakuma, T AF Cui, Yan Kibe, Ryoko Zhang, Shuzhong Guo, Darcy Marrero, Luis Tsien, Fern Rodriguez, Paulo Zieske, Arthur Huang, Jiaqiang Li, Wenqing Durum, Scott Iwakuma, Tomoo TI IL-7R alpha deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Cui, Yan; Kibe, Ryoko; Zhang, Shuzhong; Guo, Darcy; Marrero, Luis; Tsien, Fern; Rodriguez, Paulo; Zieske, Arthur; Iwakuma, Tomoo] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Huang, Jiaqiang; Li, Wenqing; Durum, Scott] NCI, Sect Cytokines & Immun, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701492 ER PT J AU Dervovic, D Liang, H Cannons, J Elford, A Ohashi, P Schwartzberg, P Pflucker, JCZ AF Dervovic, Dzana Liang, Haydn Cannons, Jennifer Elford, Alisha Ohashi, Pamela Schwartzberg, Pamela Pflucker, Juan Carlos Zuniga TI Cellular and molecular profiling of CD8 T cell differentiation with respect to positive and negative selection in vitro reveals a role for Notch signaling SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Dervovic, Dzana; Liang, Haydn; Pflucker, Juan Carlos Zuniga] Sunnybrook Res Inst, N York, ON, Canada. 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PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701013 ER PT J AU Ding, YN Hsu, HC Druey, K Wu, Q Li, J Yang, PA Zajac, A Mountz, J AF Ding, Yanna Hsu, Hui-Chen Druey, Kirk Wu, Qi Li, Jun Yang, PingAr Zajac, Allan Mountz, John TI IL-17-induced Rgs16 expression is essential for follicular T helper cell localization in the germinal centers of autoimmune BXD2 mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Ding, Yanna; Hsu, Hui-Chen; Wu, Qi; Li, Jun; Yang, PingAr; Zajac, Allan; Mountz, John] Univ Alabama Birmingham, Birmingham, AL USA. [Druey, Kirk] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. [Mountz, John] Birmingham VA Med Ctr, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. 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PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702286 ER PT J AU Fan, Y Nayak, D McGavern, D AF Fan, Ying Nayak, Debasis McGavern, Dorian TI In vivo analysis of antigen presentation during acute CNS viral infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Fan, Ying; Nayak, Debasis; McGavern, Dorian] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. 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[Yang, De] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Yang, De] NCI, Basic Sci Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. RI Xiao, Weihua/N-2775-2013 OI Xiao, Weihua/0000-0001-9102-6326 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701649 ER PT J AU Feng, DC Kong, XN Weng, HL Park, O Wang, H Dooley, S Gershwin, E Gao, B AF Feng, Dechun Kong, Xiaoni Weng, Honglei Park, Ogyi Wang, Hua Dooley, Steve Gershwin, Eric Gao, Bin TI Interleukin-22 promotes liver progenitor cell proliferation in mice and patients with in viral hepatitis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Feng, Dechun; Kong, Xiaoni; Park, Ogyi; Wang, Hua; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Rockville, MD 20852 USA. [Weng, Honglei; Dooley, Steve] Univ Heidelberg, Med Clin, Fac Med Mannheim, D-6800 Mannheim, Germany. [Gershwin, Eric] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Sch Med, Davis, CA 95616 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700116 ER PT J AU Furuta, K Ishido, S Roche, P AF Furuta, Kazuyuki Ishido, Satoshi Roche, Paul TI Encounter with antigen-specific CD4 T cells promotes down-regulation of MHC-II in Dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Furuta, Kazuyuki; Roche, Paul] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Ishido, Satoshi] RIKEN, Lab Infect Immun, Yokohama, Kanagawa, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700618 ER PT J AU Gilchuk, P Spencer, C Conant, S Niu, XN Erickson, J McAfee, K Oseroff, C Hadrup, S Bennink, J Hildebrand, W Edwards, K Crowe, J Williams, J Buus, S Sette, A Schumacher, T Link, A Joyce, S AF Gilchuk, Pavlo Spencer, Charles Conant, Stephanie Niu, Xinnan Erickson, John McAfee, Kristi Oseroff, Carla Hadrup, Sine Bennink, Jack Hildebrand, William Edwards, Kathryn Crowe, James, Jr. Williams, John Buus, Soren Sette, Alessandro Schumacher, Ton Link, Andrew Joyce, Sebastian TI Naturally processed HLA class I-restricted epitopes inform targets of protective CD8+T cell-mediated immunity SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Gilchuk, Pavlo; Spencer, Charles; Conant, Stephanie; Niu, Xinnan; Erickson, John; McAfee, Kristi; Crowe, James, Jr.; Williams, John; Link, Andrew; Joyce, Sebastian] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37212 USA. [Edwards, Kathryn; Crowe, James, Jr.; Williams, John] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Link, Andrew] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37212 USA. [Oseroff, Carla; Sette, Alessandro] La Jolla Inst Allergy & Immunol, Ctr Infect Dis Allergy & Asthma, La Jolla, CA USA. [Hadrup, Sine] Herlev Hosp, Dept Hematol, Ctr Canc Immunotherapy, DK-2730 Herlev, Denmark. [Bennink, Jack] NIAID, Cellular Biol & Viral Immunol Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Hildebrand, William] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. [Buus, Soren] Univ Copenhagen, Sch Med, Expt Immunol Lab, Copenhagen, Denmark. [Schumacher, Ton] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. RI Spencer, Charles/J-6489-2012 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701113 ER PT J AU Gruver-Yates, A Cidlowski, J AF Gruver-Yates, Amanda Cidlowski, John TI Characterization of glucocorticoid receptor in B lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Gruver-Yates, Amanda; Cidlowski, John] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701010 ER PT J AU Ha, HL Wang, HS Siebenlis, U AF Ha, Hye-Lin Wang, Hongshan Siebenlis, Ulrich TI The adaptor protein CIKS/Act1 is essential for imiquimod-induced psoriasis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Ha, Hye-Lin; Wang, Hongshan; Siebenlis, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702063 ER PT J AU Herz, J McGavern, D AF Herz, Jasmin McGavern, Dorian TI Memory T cells convert tissue resident myeloid cells into APCs during clearance of a persistent viral infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Herz, Jasmin; McGavern, Dorian] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701625 ER PT J AU Hirahara, K Ghoreschi, K Yang, XP Takahashi, H Laurence, A Vahedi, G Sciume, G Hall, A Dupont, C Francisco, L Chen, Q Tanaka, M Kanno, Y Sun, HW Sharpe, A Hunter, C O'Shea, J AF Hirahara, Kiyoshi Ghoreschi, Kamran Yang, Xiang-Ping Takahashi, Hayato Laurence, Arian Vahedi, Golnaz Sciume, Giuseppe Hall, Aisling Dupont, Christopher Francisco, Loise Chen, Qian Tanaka, Masao Kanno, Yuka Sun, Hong-Wei Sharpe, Arlene Hunter, Christopher O'Shea, John TI IL-27 priming of T cells controls IL-17-production in trans via induction of PD-L1 SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Hirahara, Kiyoshi; Ghoreschi, Kamran; Yang, Xiang-Ping; Takahashi, Hayato; Laurence, Arian; Vahedi, Golnaz; Sciume, Giuseppe; Kanno, Yuka; O'Shea, John] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Hall, Aisling; Dupont, Christopher; Hunter, Christopher] Univ Penn, Sch Vet Med, Dept Pathol, Philadelphia, PA 19104 USA. [Francisco, Loise] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA USA. [Chen, Qian] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Tanaka, Masao] NIAMSD, Translat Immunol Sect, Bethesda, MD 20892 USA. [Sun, Hong-Wei] NIAMSD, Biodata Min & Discovery Sect, Bethesda, MD 20892 USA. RI Laurence, Arian/A-8770-2009; Kanno, Yuka/B-5802-2013; Hirahara, Kiyoshi/E-2460-2017 OI Laurence, Arian/0000-0003-0942-8292; Hirahara, Kiyoshi/0000-0002-9128-9449 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700440 ER PT J AU Hodge, D Berthet, C Coppola, V Shirota, H Reynolds, D Klinman, D Young, H AF Hodge, Deborah Berthet, Cyril Coppola, Vincenzo Shirota, Hidekazu Reynolds, Della Klinman, Dennis Young, Howard TI Loss of IFN-gamma 3 ' untranslated region AU-rich element affects B220+B cell and plasmacytoid dendritic cell populations in novel murine lupus model SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Hodge, Deborah; Shirota, Hidekazu; Reynolds, Della; Klinman, Dennis; Young, Howard] NCI, CCR LEI, Frederick, MD 21701 USA. [Berthet, Cyril] Oncodesign, Discovery Program, Dijon, France. [Coppola, Vincenzo] Ohio State Univ, Columbus, OH 43210 USA. RI Coppola, Vincenzo/E-2917-2011 OI Coppola, Vincenzo/0000-0001-6163-1779 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701495 ER PT J AU Holt, M Punkosdy, G Blain, M Glass, D Lozano, M Dudley, J Shevach, E AF Holt, Michael Punkosdy, George Blain, Melissa Glass, Deborah Lozano, Mary Dudley, Jaquelin Shevach, Ethan TI Endogenous mouse mammary tumor viruses influence the development of thymic alpha beta NKT cells and innate CD8+T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Holt, Michael; Punkosdy, George; Blain, Melissa; Glass, Deborah; Shevach, Ethan] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Lozano, Mary; Dudley, Jaquelin] Univ Texas Austin, Sect Mol Genet & Microbiol, Austin, TX 78712 USA. [Lozano, Mary; Dudley, Jaquelin] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701032 ER PT J AU Horton, C Pan, ZJ Lawrence, C Bolland, S Farris, D AF Horton, Christopher Pan, Zijian Lawrence, Christina Bolland, Silvia Farris, Darise TI Altered CD4(+) T cell differentiation with preferential expansion of Th1 cells in TLR7-driven autoimmunity SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Horton, Christopher; Pan, Zijian; Lawrence, Christina; Farris, Darise] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Horton, Christopher; Farris, Darise] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702043 ER PT J AU Hou, WQ Gibbs, J Lu, XJ Brooke, C Roy, D Modlin, R Bennink, J Yewdell, J AF Hou, Wanqiu Gibbs, James Lu, Xiuju Brooke, Christopher Roy, Devika Modlin, Robert Bennink, Jack Yewdell, Jonathan TI Viral Infection Triggers Rapid Differentiation of Human Blood Monocytes into Dendritic Cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Hou, Wanqiu; Roy, Devika; Modlin, Robert] Univ Calif Los Angeles, David Geffen Sch Med, Div Dermatol, Dept Med, Los Angeles, CA 90095 USA. [Hou, Wanqiu; Gibbs, James; Lu, Xiuju; Brooke, Christopher; Bennink, Jack; Yewdell, Jonathan] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Modlin, Robert] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700142 ER PT J AU Iida, N Stewart, C Goldszmid, R Dzutsev, A Trinchieri, G AF Iida, Noriho Stewart, Charles Goldszmid, Romina Dzutsev, Amiran Trinchieri, Giorgio TI Gut commensal bacteria promote anti-tumor innate immune responses in distant tumors after immunotherapy and chemotherapy SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Iida, Noriho; Stewart, Charles; Goldszmid, Romina; Dzutsev, Amiran; Trinchieri, Giorgio] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701509 ER PT J AU Jain, A Ma, C Zhao, YG Temmerman, S AF Jain, Ashish Ma, Chi Zhao, Yongge Temmerman, Stephane TI Defective nuclear IKK alpha function in patients with ectodermal dysplasia with immune deficiency SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Jain, Ashish; Ma, Chi; Zhao, Yongge; Temmerman, Stephane] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702308 ER PT J AU Jain, N Miu, B Jiang, JK Prince, A Greiner, D Thomas, C Sanderson, M Berg, L Kang, J AF Jain, Nitya Miu, Bing Jiang, Jian-kang Prince, Amanda Greiner, Dale Thomas, Craig Sanderson, Michael Berg, Leslie Kang, Joonsoo TI CD28-ITK signals regulate autoreactive T cell trafficking into tissues SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Jain, Nitya; Miu, Bing; Prince, Amanda; Greiner, Dale; Sanderson, Michael; Berg, Leslie; Kang, Joonsoo] Univ Massachussetts, Sch Med, Worcester, MA USA. [Jiang, Jian-kang; Thomas, Craig] NIH, Chem Genom Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701308 ER PT J AU Jin, TC Perry, A Jiang, JS Smith, P Curry, J Unterholzner, L Jiang, ZZ Horvath, G Rathinam, V Hornung, V Johnstone, R Latz, E Bowie, A Fitzgerald, K Xiao, T AF Jin, Tengchuan Perry, Andrew Jiang, Jiansheng Smith, Patrick Curry, James Unterholzner, Leonie Jiang, Zhaozhao Horvath, Gabor Rathinam, Vijay Hornung, Veit Johnstone, Ricky Latz, Eicke Bowie, Andrew Fitzgerald, Katherine Xiao, T. TI Molecular mechanisms of Innate DNA recognition by the AIM2 and IFI16 inflammasomes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Jin, Tengchuan; Perry, Andrew; Jiang, Jiansheng; Smith, Patrick; Curry, James; Xiao, T.] NIAID, Struct Immunobiol Unit, Immunol Lab, Bethesda, MD 20892 USA. [Unterholzner, Leonie; Bowie, Andrew] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin, Ireland. [Jiang, Zhaozhao; Rathinam, Vijay; Latz, Eicke; Fitzgerald, Katherine] Massachusetts Med Sch, Div Infect Dis & Immunol, Worcester, MA USA. [Horvath, Gabor; Latz, Eicke] Univ Bonn, Univ Hosp, Inst Innate Immun, Bonn, Germany. [Hornung, Veit] Univ Bonn, Univ Hosp, Inst Clin Chem & Pharmacol, Unit Clin Biochem, Bonn, Germany. [Johnstone, Ricky] Peter MacCallum Canc Inst, Canc Therapeut Program, Gene Regulat Lab, Melbourne, Vic, Australia. [Johnstone, Ricky] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. RI Xiao, Tsan/A-8590-2010; Horvath, Gabor/J-3917-2014; Latz, Eicke/H-3951-2014 OI Horvath, Gabor/0000-0003-0309-595X; Latz, Eicke/0000-0003-1488-5666 NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700516 ER PT J AU Jung, MY Smrz, D Desai, A Bandara, G Ito, T Kang, JH Beaven, M Metcalfe, D Gilfillan, A AF Jung, Mi-Yeon Smrz, Daniel Desai, Avanti Bandara, Geethani Ito, Tomonobu Kang, Jeong-Han Beaven, Michael Metcalfe, Dean Gilfillan, Alasdair TI Chronic IL-33 exposure induces a hypo-responsive mast cell phenotype SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Jung, Mi-Yeon; Smrz, Daniel; Desai, Avanti; Bandara, Geethani; Ito, Tomonobu; Metcalfe, Dean; Gilfillan, Alasdair] NIAID, NIH, Bethesda, MD 20892 USA. [Kang, Jeong-Han] NCI, NIH, Bethesda, MD 20892 USA. [Beaven, Michael] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702243 ER PT J AU Kasagi, S Maruyama, T Li, J Chen, WJ AF Kasagi, Shimpei Maruyama, Takashi Li, Jun Chen, Wanjun TI Deficiency of Id3 (inhibitor of DNA binding 3) results in Inflammation in salivary glands and gamma-delta (gd) T cell lymphoma SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Kasagi, Shimpei; Maruyama, Takashi; Li, Jun; Chen, Wanjun] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700554 ER PT J AU Kashyap, M Yrina, R Spolski, R Samsel, L Leonard, W AF Kashyap, Mohit Yrina, Rochman Spolski, Rosanne Samsel, Leigh Leonard, Warren TI Thymic stromal lymphopoietin is produced by dendritic cells. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Kashyap, Mohit; Yrina, Rochman; Spolski, Rosanne; Leonard, Warren] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Samsel, Leigh] NHLBI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700396 ER PT J AU Kerkar, S Restifo, N AF Kerkar, Sid Restifo, Nicholas TI IL-12 induced Fas expression in myeloid-derived cells within tumors delivers a co-stimulatory signal for adoptively transferred CD8+T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Kerkar, Sid; Restifo, Nicholas] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Kerkar, Sid] NHLBI, Dept Hematol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700579 ER PT J AU Khandelwal, S Roche, P AF Khandelwal, Sanjay Roche, Paul TI Transmembrane domain sequences regulate the association of MHC- class II with lipid raft microdomains SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Khandelwal, Sanjay; Roche, Paul] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700619 ER PT J AU Lee-Chang, C Wejksza, K Bodogai, M Malchinkhuu, E Ghosh, P Sanchez, AMM de Cabo, R Biragyn, A AF Lee-Chang, Catalina Wejksza, Katarzyna Bodogai, Monica Malchinkhuu, Enkhol Ghosh, Paritosh Sanchez, Alejandro Martin-Montalvo de Cabo, Rafael Biragyn, Arya TI Resveratrol abrogates tumor-evoked Bregs conversion by targeting PPAR-alpha pathway SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Lee-Chang, Catalina; Wejksza, Katarzyna; Bodogai, Monica; Malchinkhuu, Enkhol; Ghosh, Paritosh; Biragyn, Arya] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Sanchez, Alejandro Martin-Montalvo; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RI Lee-Chang, Catalina/A-5580-2015 OI Lee-Chang, Catalina/0000-0002-7675-2124 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701412 ER PT J AU Li, S Yu, YS Fan, R Liao, HY Wang, ZX Yue, YS Huang, L Guo, S Hearth-Holmes, M Cannella, A Chatham, WW Kimberly, R Klassen, L O'Dell, J Carter, R Su, KH Zhang, ZX AF Li, Song Yu, Yangsheng Fan, Run Liao, Hongyan Wang, Zhixin Yue, Yinshi Huang, Lin Guo, Sara Hearth-Holmes, Michelene Cannella, Amy Chatham, W. Winn Kimberly, Robert Klassen, Lynell O'Dell, James Carter, Robert Su, Kaihong Zhang, Zhixin TI The accumulated VH replacement products contribute to the generation of auto/polyreactive antibodies in systemic lupus erythematosus SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Su, Kaihong; Zhang, Zhixin] Univ Nebraska, Med Ctr, Eppley Canc Inst, Omaha, NE USA. [Fan, Run; Chatham, W. Winn; Kimberly, Robert] Univ Alabama Birmingham, Birmingham, AL USA. [Carter, Robert] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701450 ER PT J AU Lin, FC Macfarlane, M Saleh, B Hodge, D Young, H AF Lin, Fanching Macfarlane, Michael Saleh, Bahara Hodge, Deborah Young, Howard TI IFN-gamma is the primary cause of aplastic anemia not autoreactive T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Lin, Fanching; Macfarlane, Michael; Saleh, Bahara; Hodge, Deborah; Young, Howard] NCI, Lab Expt Immunol Canc, Frederick, MD 21701 USA. [Lin, Fanching; Macfarlane, Michael; Saleh, Bahara; Hodge, Deborah; Young, Howard] NCI, Inflammat Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701011 ER PT J AU Longo, D Conroy, A Louie, B Wang, E Pos, Z Marincola, F Hawtin, R Cesano, A AF Longo, Diane Conroy, Andy Louie, Brent Wang, Ena Pos, Zoltan Marincola, Francesco Hawtin, Rachael Cesano, Alessandra TI Single cell network profiling (SCNP) assay allows for the identification of heterogeneity in the activation of multiple signaling pathways in distinct human B cell subsets SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Longo, Diane; Conroy, Andy; Louie, Brent; Hawtin, Rachael; Cesano, Alessandra] Nodality, San Francisco, CA USA. [Wang, Ena; Marincola, Francesco] NIH, Dept Transfus Med, Infect Dis & Immunogenet Sect, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Pos, Zoltan] Semmelweis Univ, Dept Genet Cell & Immunobiol, H-1089 Budapest, Hungary. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702180 ER PT J AU Lucas, C Cordero-Nieves, H Campbell, K Bhatia, S Hodes, R Sanders, V AF Lucas, Christopher Cordero-Nieves, Hector Campbell, Kerry Bhatia, Sumeena Hodes, Richard Sanders, Virginia TI Prohibitins and the cytoplasmic domain of CD86 cooperate to mediate CD86 signaling in B lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Lucas, Christopher; Cordero-Nieves, Hector] Ohio State Univ, Integrated Biomed Sci Grad Program, Columbus, OH 43210 USA. [Campbell, Kerry] Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. [Bhatia, Sumeena; Hodes, Richard] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700056 ER PT J AU Mitre, E Shi, YH Torrero, M Mueller, E Larson, D Soloviova, K Stocker, J Davies, S Tarbell, K Hubner, M AF Mitre, Edward Shi, Yinghui Torrero, Marina Mueller, Ellen Larson, David Soloviova, Katerina Stocker, J. Davies, Stephen Tarbell, Kristin Hubner, Marc TI Immune regulatory mechanisms, not alteration in Th1/Th2 skewing, are responsible for helminth-mediated protection against type 1 diabetes in NOD mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Mitre, Edward; Shi, Yinghui; Torrero, Marina; Mueller, Ellen; Larson, David; Soloviova, Katerina; Stocker, J.; Davies, Stephen; Hubner, Marc] Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. [Tarbell, Kristin] NIDDK, Immune Tolerance Sect, Diabet Branch, NIH, Bethesda, MD USA. [Hubner, Marc] Inst Med Microbiol Immunol & Parasitol, Bonn, Germany. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701149 ER PT J AU Mountz, J Wang, J New, J Yang, P Wu, Q Druey, K Hsu, HC AF Mountz, John Wang, John New, James Yang, PingAr Wu, Qi Druey, Kirk Hsu, Hui-Chen TI IL-17-induced Regulator of G-protein Signaling orchestrates germinal center kinetics in the onset of autoimmunity in BXD2 mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Mountz, John; Wang, John; New, James; Yang, PingAr; Wu, Qi; Hsu, Hui-Chen] Univ Alabama Birmingham, Birmingham, AL USA. [Mountz, John] Birmingham VA Med Ctr, Birmingham, AL USA. [Druey, Kirk] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701457 ER PT J AU Nakatsukasa, H Maruyama, T Chen, WJ AF Nakatsukasa, Hiroko Maruyama, Takashi Chen, Wanjun TI Transcriptional factor E2A regulates the differentiation of Th17 cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Nakatsukasa, Hiroko; Maruyama, Takashi; Chen, Wanjun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700542 ER PT J AU Nasholm, N Duncan, B Capitini, C Fry, T AF Nasholm, Nicole Duncan, Brynn Capitini, Christian Fry, Terry TI Graft versus host disease impairs vaccine responses via decreased CD4+and CD8+T cell proliferation and increased CD8+T cell apoptosis through the perforin pathway SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Nasholm, Nicole; Duncan, Brynn; Capitini, Christian; Fry, Terry] NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Capitini, Christian] Univ Wisconsin Madison, Madison, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701385 ER PT J AU Nayak, D Johnson, K Heydari, S Roth, T Zynselmeyer, B McGavern, D AF Nayak, Debasis Johnson, Kory Heydari, Sara Roth, Theodore Zynselmeyer, Bernd McGavern, Dorian TI Type I Interferon Regulates the Dynamics of Innate Myeloid Sentinel Cells During Persistent Viral Infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Nayak, Debasis; Johnson, Kory; Heydari, Sara; Zynselmeyer, Bernd; McGavern, Dorian] NINDS, NIH, Bethesda, MD 20892 USA. [Roth, Theodore] Stanford Univ, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702005 ER PT J AU Okiyama, N Furumoto, Y Villarroel, V Gutermuth, J Ghoreschi, K Gadina, M Katz, S AF Okiyama, Naoko Furumoto, Yasuko Villarroel, Vadim Gutermuth, Jan Ghoreschi, Kamran Gadina, Massimo Katz, Stephen TI Effective prevention and treatment of CD8 T cell-mediated graft-versus-host-like disease (GvHD) using a JAK inhibitor SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Okiyama, Naoko; Villarroel, Vadim; Gutermuth, Jan; Katz, Stephen] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Furumoto, Yasuko; Ghoreschi, Kamran; Gadina, Massimo] NIAMS, Translat Immunol Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700273 ER PT J AU Park, O Feng, DC Radaeva, S Wang, H Yin, S Kong, XN Zheng, MQ Zakhari, S Kolls, J Gao, B AF Park, Ogyi Feng, Dechun Radaeva, Svetlana Wang, Hua Yin, Shi Kong, Xiaoni Zheng, Mingquan Zakhari, Sam Kolls, Jay Gao, Bin TI Interleukin-22 Ameliorates Cerulein-Induced Pancreatitis in Mice by In-hibiting the Autophagic Pathway SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Park, Ogyi; Feng, Dechun; Wang, Hua; Yin, Shi; Kong, Xiaoni; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 90034 USA. [Radaeva, Svetlana; Zakhari, Sam] NIAAA, Div Metab & Hlth Effects, NIH, Bethesda, MD USA. [Zheng, Mingquan; Kolls, Jay] Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700117 ER PT J AU Parra, G Bok, K Taylor, R Haynes, J Sosnovtsev, S Richardson, C Green, K AF Parra, Gabriel Bok, Karin Taylor, Ross Haynes, Joel Sosnovtsev, Stanislav Richardson, Charles Green, Kim TI Immunogenicity and specificity of Norovirus Consensus GII.4 virus-like particles in monovalent and bivalent vaccine formulations SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Parra, Gabriel; Bok, Karin; Sosnovtsev, Stanislav; Green, Kim] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Taylor, Ross; Haynes, Joel; Richardson, Charles] LigoCyte Pharmaceut Inc, Res & Dev, Bozeman, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701098 ER PT J AU Peruzzi, G Femnou, L Borrego, F Krzewski, K Coligan, J AF Peruzzi, Giovanna Femnou, Laurette Borrego, Francisco Krzewski, Konrad Coligan, John TI Identification of matrix metalloproteinases involved in the activation induced CD16 down-modulation by primary NK cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Peruzzi, Giovanna; Femnou, Laurette; Krzewski, Konrad; Coligan, John] NIAID, RCBS, NIH, Rockville, MD USA. [Borrego, Francisco] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702124 ER PT J AU Peterson, K Woods, T Mukherjee, P AF Peterson, Karin Woods, Tyson Mukherjee, Piyali TI Innate immune response contributes to virus-mediated neuronal death through activation of SARM SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Peterson, Karin; Woods, Tyson; Mukherjee, Piyali] NIAID, LPVD, NIH, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702041 ER PT J AU Petrovas, C Yamamoto, T Gerner, M Boswell, K Roederer, M Seder, R Germain, R Haddas, E Koup, R AF Petrovas, Constantinos Yamamoto, Takuya Gerner, Michael Boswell, Kristin Roederer, Mario Seder, Robert Germain, Ronald Haddas, Elias Koup, Richard TI Increased immune activation during chronic SIV infection drives the T-FH dynamics SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Petrovas, Constantinos; Yamamoto, Takuya; Boswell, Kristin; Roederer, Mario; Seder, Robert; Koup, Richard] NIAID, VRC, NIH, Bethesda, MD 20892 USA. [Gerner, Michael; Germain, Ronald] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Haddas, Elias] VGTI, Port St Lucie, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700038 ER PT J AU Pichugin, A Ehrler, L Sehrawat, S Funk, T Speake, C Duffy, P Ploegh, H Krzych, U AF Pichugin, Alexander Ehrler, Lindsey Sehrawat, Sharvan Funk, Theresa Speake, Cate Duffy, Patrick Ploegh, Hidde Krzych, Urszula TI Identification of Plasmodium berghei novel liver stage CD8 T cell epitopes by caged MHC class I tetramer technology SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Pichugin, Alexander; Ehrler, Lindsey; Funk, Theresa; Krzych, Urszula] Walter Reed Army Inst Res, MMRP, Malaria Vaccine Branch, Silver Spring, MD USA. [Sehrawat, Sharvan; Ploegh, Hidde] Whitehead Inst Biomed Res, Ploegh Lab, Cambridge, MA 02142 USA. [Speake, Cate; Duffy, Patrick] Seattle BioMed, Malaria, Seattle, WA USA. [Duffy, Patrick] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700092 ER PT J AU Price, J Kemmer, D Balboni, I Haddon, D Mandelbaum, G Delepine, G Sokolove, J Shum, A Browne, S Utz, P AF Price, Jordan Kemmer, Dodge Balboni, Imelda Haddon, David Mandelbaum, Gil Delepine, Guillaume Sokolove, Jeremy Shum, Anthony Browne, Sarah Utz, Paul TI Protein microarray analysis of serum factor-reactive autoantibodies reveals BAFF-binding autoantibodies in systemic lupus erythematosus SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Shum, Anthony] UCSF, Div Pulm & Crit Care Med, San Francisco, CA USA. [Browne, Sarah] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700406 ER PT J AU Ramaswamy, M Do, T Barden, M Cruz, A Siegel, R AF Ramaswamy, Madhu Thao Do Barden, Mary Cruz, Anthony Siegel, Richard TI A proteomic study of early signaling events regulating the Fas-FasL Death Inducing Signaling Complex SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Ramaswamy, Madhu; Thao Do; Barden, Mary; Cruz, Anthony; Siegel, Richard] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701565 ER PT J AU Revilleza, MJ Mans, J Natarajan, K Mage, M Carey, R Boyd, L Margulies, D AF Revilleza, Maria Jamela Mans, Janet Natarajan, Kannan Mage, Michael Carey, Rosalene Boyd, Lisa Margulies, David TI Mouse CMV m153 glycoprotein binds a ligand on dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Revilleza, Maria Jamela; Mans, Janet; Natarajan, Kannan; Mage, Michael; Carey, Rosalene; Boyd, Lisa; Margulies, David] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701662 ER PT J AU Revilleza, MJ Levin, D Mage, M Candon, S Natarajan, K Rui, W Teyton, L Robinson, H Shevach, E Margulies, D AF Revilleza, Maria Jamela Levin, Ditza Mage, Michael Candon, Sophie Natarajan, Kannan Rui, Wang Teyton, Luc Robinson, Howard Shevach, Ethan Margulies, David TI Functional and structural basis of T cell recognition in autoimmune gastritis: mapping of autoantigenic peptides of the alpha-chain of the H/K ATPase and X-ray structure of the I-Ad/peptide complexes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Revilleza, Maria Jamela; Mage, Michael; Natarajan, Kannan; Rui, Wang; Shevach, Ethan; Margulies, David] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Levin, Ditza] Ort Braude Engn Coll, Biotechnol Engn Dept, Karmiel, Israel. [Candon, Sophie] Univ Paris 05, Hop Necker Enfants Malad, Sorbonne Paris Cite, Fac Med, Paris, France. [Teyton, Luc] Scripps Res Inst, Dept Immunol, San Diego, CA USA. [Robinson, Howard] Brookhaven Natl Lab, Upton, NY 11973 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700625 ER PT J AU Ribeiro-Gomes, F Peters, N Sacks, D AF Ribeiro-Gomes, Flavia Peters, Nathan Sacks, David TI Efficient capture of infected neutrophils by dendritic cells in the skin inhibits the early anti-leishmanial response SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Ribeiro-Gomes, Flavia; Peters, Nathan; Sacks, David] NIH, Bethesda, MD 20892 USA. RI Ribeiro-Gomes, Flavia/F-7609-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700507 ER PT J AU Robertson, S Lubick, K Freedman, B Best, S AF Robertson, Shelly Lubick, Kirk Freedman, Brett Best, Sonja TI Tick-borne flaviviruses impair IRF-1 and type I IFN signaling to inhibit IL-12 production by dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Robertson, Shelly; Lubick, Kirk; Freedman, Brett; Best, Sonja] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702037 ER PT J AU Rodriguez-Pena, AB Balagopalan, L Gomez-Rodriguez, J Kortum, RL Feigenbaum, L Sommers, CL Samelson, LE AF Rodriguez-Pena, Ana B. Balagopalan, Lakshmi Gomez-Rodriguez, Julio Kortum, Robert L. Feigenbaum, Lionel Sommers, Connie L. Samelson, Lawrence E. TI Enhanced T cell activation in lymphocytes from transgenic mice expressing LAT molecules resistant to ubiquitination SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Rodriguez-Pena, Ana B.; Balagopalan, Lakshmi; Kortum, Robert L.; Sommers, Connie L.; Samelson, Lawrence E.] NCI, Cellular & Mol Biol 1Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gomez-Rodriguez, Julio] Natl Human Genome Res Inst, NIH, Bethesda, MD USA. [Feigenbaum, Lionel] NCI, Anim Sci 3Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700534 ER PT J AU Savan, R Legiewicz, M McFarland, A Schwerk, J Bindewald, E Lin, FC Orr, S Yoshikawa, N Hegamyer, G Yalamanchili, R Ramakrishnan, K Kronfli, A Saleh, B McVicar, D Carrington, M Colburn, N Anderson, S Shapiro, B Le Grice, S Young, H AF Savan, Ram Legiewicz, Michal McFarland, Adelle Schwerk, Johannes Bindewald, Eckart Lin, Fan-ching Orr, Selinda Yoshikawa, Noriko Hegamyer, Glenn Yalamanchili, Rajesh Ramakrishnan, Karthika Kronfli, Anthony Saleh, Bahara McVicar, Daniel Carrington, Mary Colburn, Nancy Anderson, Stephen Shapiro, Bruce Le Grice, Stuart Young, Howard TI MicroRNA-29 Stabilizes IFN-gamma mRNA by inhibiting GW182 SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Savan, Ram; McFarland, Adelle] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Legiewicz, Michal; Schwerk, Johannes; Bindewald, Eckart; Lin, Fan-ching; Orr, Selinda; Yoshikawa, Noriko; Hegamyer, Glenn; Yalamanchili, Rajesh; Ramakrishnan, Karthika; Kronfli, Anthony; Saleh, Bahara; McVicar, Daniel; Carrington, Mary; Colburn, Nancy; Anderson, Stephen; Shapiro, Bruce; Le Grice, Stuart; Young, Howard] NCI, Ctr Canc Res, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702187 ER PT J AU Schneider, E Gao, JL Holmes, G Fowler, S Peiper, S Murphy, P AF Schneider, Erich Gao, Ji-Liang Holmes, Gibran Fowler, Stephen Peiper, Stephen Murphy, Philip TI Behavior-modulating function of the Duffy Antigen Receptor for Chemokines (DARC) in mice under homeostatic conditions SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Schneider, Erich; Gao, Ji-Liang; Holmes, Gibran; Murphy, Philip] NIAID, Lab Mol Immunol, Mol Signaling Sect, NIH, Bethesda, MD 20892 USA. [Fowler, Stephen] Univ Kansas, Dept Pharmacol & Toxicol, Kansas City, KS USA. [Peiper, Stephen] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. RI Abu Laban , Dr. Nidal /E-5809-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700109 ER PT J AU Scholz, J Hao, Y Russell, L Maul, R Paley, M Wherry, E Gearhart, P Cancro, M AF Scholz, Jean Hao, Yi Russell, Lisa Maul, Robert Paley, Michael Wherry, E. Gearhart, Patricia Cancro, Michael TI Molecular analysis of age-associated B cells (ABCs) SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Paley, Michael; Wherry, E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Russell, Lisa; Maul, Robert; Gearhart, Patricia] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Hao, Yi] INSERM, Fac Med Necker Enfants Malad, Paris, France. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700532 ER PT J AU Shanker, A Malhotra, A Dikov, M Biktasova, A Sayers, T Carbone, D AF Shanker, Anil Malhotra, Anshu Dikov, Mikhail Biktasova, Asel Sayers, Thomas Carbone, David TI Enhancing cancer immunotherapy by combining Notch 1 and death receptor activation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Shanker, Anil; Malhotra, Anshu] Meharry Med Coll, Sch Med, Nashville, TN 37208 USA. [Shanker, Anil; Dikov, Mikhail; Biktasova, Asel; Carbone, David] Vanderbilt Ingram Canc Ctr, Dept Canc Biol, Nashville, TN USA. [Shanker, Anil; Sayers, Thomas] NCI Frederick SAIC Frederick, Canc & Inflammat Program, Frederick, MD USA. RI Sayers, Thomas/G-4859-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700163 ER PT J AU Sharma, A Chen, QH Nguyen, T Yu, Q Sen, J AF Sharma, Archna Chen, Qinghua Trang Nguyen Yu, Qing Sen, Jyoti TI T Cell Factor-1 and beta-catenin regulate the development of memory-like CD8 thymocytes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Sharma, Archna; Chen, Qinghua; Trang Nguyen; Sen, Jyoti] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Yu, Qing] Forsyth Inst, Dept Immunol, Cambridge, MA USA. RI Sharma, Archna/R-9377-2016 OI Sharma, Archna/0000-0003-4745-0220 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700679 ER PT J AU Shen, W Li, WQ Feigenbaum, L Hixon, J Durum, S AF Shen, Wei Li, Wenqing Feigenbaum, Lionel Hixon, Julie Durum, Scott TI Visualization of IL-22 in mouse intestinal inflammation with an IL-22 tdTomato reporter mouse SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Shen, Wei; Li, Wenqing; Hixon, Julie; Durum, Scott] NCI, Lab Mol Immunoregulat, Frederick, MD 21701 USA. [Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700099 ER PT J AU Smr, D Beaven, M Metcalfe, D Gilfillan, A AF Smr, Daniel Beaven, Michael Metcalfe, Dean Gilfillan, Alasdair TI Lantrunculin B-induced filamentous actin disassembly enables human mast cell degranulation by SCF alone SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Smr, Daniel; Metcalfe, Dean; Gilfillan, Alasdair] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702253 ER PT J AU Snow, A Xiao, WM Chaigne-Delalande, B Pittaluga, S Stinson, J Matthews, H Lu, W Schmitz, R Jhavar, S Jing, H Su, HL Staudt, L Lenardo, M AF Snow, Andrew Xiao, Wenming Chaigne-Delalande, Benjamin Pittaluga, Stefania Stinson, Jeffrey Matthews, Helen Lu, Wei Schmitz, Roland Jhavar, Sameer Jing, Huie Su, Helen Staudt, Louis Lenardo, Michael TI Congenital B cell lymphocytosis linked to a novel germline CARD11 mutation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Snow, Andrew; Stinson, Jeffrey] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Snow, Andrew; Chaigne-Delalande, Benjamin; Matthews, Helen; Lu, Wei; Lenardo, Michael] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Xiao, Wenming] NIH, Bioinformat & Mol Anal Sect, CIT, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Schmitz, Roland; Jhavar, Sameer; Staudt, Louis] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Matthews, Helen; Jing, Huie; Su, Helen] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700671 ER PT J AU Spolski, R Wang, L Wang, CK Bonville, C Domachowske, J Kim, HP Yu, ZX Leonard, W AF Spolski, Rosanne Wang, Lu Wang, Chi-Keung Bonville, Cynthia Domachowske, Joseph Kim, Hyoung-Pyo Yu, Zuxi Leonard, Warren TI IL-21 promotes the pathologic immune response to Pneumovirus infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Spolski, Rosanne; Wang, Lu; Wang, Chi-Keung; Kim, Hyoung-Pyo; Leonard, Warren] NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. [Bonville, Cynthia; Domachowske, Joseph] SUNY Upstate Med Univ, Syracuse, NY USA. [Yu, Zuxi] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700102 ER PT J AU Su, P Burk, C Fix, W Qin, HY Fry, T AF Su, Paul Burk, Chad Fix, William Qin, Hai-Ying Fry, Terry TI Progression of acute lymphoblastic leukemia (ALL) results in compartment-restricted T cell expression of PD-1 and T cell dysfunction SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Su, Paul; Burk, Chad; Fix, William; Qin, Hai-Ying; Fry, Terry] NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Su, Paul; Burk, Chad] Howard Hughes Med Inst, HHMI NIH Res Scholars Program, Bethesda, MD 20817 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700183 ER PT J AU Takai, S Schlom, J Greiner, J AF Takai, Shinji Schlom, Jeffrey Greiner, John TI TGF-beta inhibits central memory cell differentiation in CD8 T-cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Takai, Shinji; Schlom, Jeffrey; Greiner, John] NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700293 ER PT J AU Tassi, I Claudio, E Wang, HS Siebenist, U AF Tassi, Ilaria Claudio, Estefania Wang, Hongshan Siebenist, Ulrich TI Bcl-3 is a regulator of dendritic cell functions SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Tassi, Ilaria; Claudio, Estefania; Wang, Hongshan; Siebenist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702117 ER PT J AU Tegla, C Cudrici, C Nguyen, V Khan, A Vlaicu, S Rus, V Badea, T Rus, H AF Tegla, Cosmin Cudrici, Cornelia Vinh Nguyen Khan, Ali Vlaicu, Sonia Rus, Violeta Badea, Tudor Rus, Horea TI Enhanced cell cycle activation in response to stimulation in RGC-32(-/-) T lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Tegla, Cosmin; Cudrici, Cornelia; Vinh Nguyen; Khan, Ali; Vlaicu, Sonia; Rus, Violeta; Rus, Horea] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Tegla, Cosmin; Rus, Horea] VA Maryland Hlth Care Syst, Res Serv, Baltimore, MD USA. [Badea, Tudor] NEI, Retinal Circuit Dev & Genet Unit, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701131 ER PT J AU Tewary, P de la Rosa, G Sharma, N Rodriguez, L Shirota, H Steinhagen, F Klinman, D Yang, D Oppenheim, J AF Tewary, Poonam de la Rosa, Gonzalo Sharma, Neeraj Rodriguez, Luis Shirota, Hidekatzu Steinhagen, Folkert Klinman, Dennis Yang, De Oppenheim, Joost TI Effect of antimicrobial proteins/alarmins on DNA mediated activation of pDC and inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Tewary, Poonam; de la Rosa, Gonzalo; Yang, De; Oppenheim, Joost] NCI, LMI, CIP, NIH Frederick, Frederick, MD 21701 USA. [Sharma, Neeraj; Shirota, Hidekatzu; Steinhagen, Folkert; Klinman, Dennis] NCI, LEI, CIP, NIH Frederick, Frederick, MD 21701 USA. [Rodriguez, Luis] NCI, Opit Microscopy & Anal Lab, SAIC Frederick, Frederick, MD 21701 USA. [Yang, De] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700143 ER PT J AU von Moltke, J Moayeri, M Trinidad, N Kintzer, A Wang, S van Rooijen, N Krantz, B Leppla, S Gronert, K Vance, R AF von Moltke, Jakob Moayeri, Mahtab Trinidad, Norver Kintzer, Alexander Wang, Samantha van Rooijen, Nico Krantz, Bryan Leppla, Stephen Gronert, Karsten Vance, Russell TI Rapid induction of lipid mediators is a novel effector function of the inflammasome in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [von Moltke, Jakob; Trinidad, Norver; Vance, Russell] Univ Calif Berkeley, Div Immunol & Pathogenesis, Berkeley, CA USA. [Kintzer, Alexander; Krantz, Bryan] Univ Calif Berkeley, Dept Chem, Berkeley, CA USA. [Wang, Samantha; Gronert, Karsten] Univ Calif Berkeley, Sch Optometry, Vis Sci Program, Berkeley, CA USA. [Moayeri, Mahtab; Leppla, Stephen] NIAID, Parasit Dis Lab, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. [van Rooijen, Nico] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701168 ER PT J AU Voynova, E Bolland, S AF Voynova, Elisaveta Bolland, Silvia TI An IL15-dependent novel immune cell subset with multiple functionalities affecting the onset and severity of autoimmune disease SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Voynova, Elisaveta; Bolland, Silvia] NIAID, Immunogenet Lab, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702052 ER PT J AU Wang, HS Shin, DM Abbasi, S Kovalchuk, A Jain, S Morse, H AF Wang, Hongsheng Shin, Dong-Mi Abbasi, Sadia Kovalchuk, Alexander Jain, Shweta Morse, Herbert TI Identification of novel subsets of CD5+B-1a cells reveals layered populations with distinct innate-like functions SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Wang, Hongsheng; Shin, Dong-Mi; Abbasi, Sadia; Kovalchuk, Alexander; Jain, Shweta; Morse, Herbert] NIAID, Immunogenet Lab, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700504 ER PT J AU Wang, JM Liu, Y Chen, KQ Liu, MY Gong, WH Yoshimura, T Ford, J McVicar, D AF Wang, Ji Ming Liu, Ying Chen, Keqiang Liu, Mingyong Gong, Wanghua Yoshimura, Teizo Ford, Jill McVicar, Daniel TI The G protein-coupled receptor mFPR2 promotes anti-tumor host defense SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Wang, Ji Ming; Liu, Ying; Chen, Keqiang; Yoshimura, Teizo] NCI, Mol Immunoregulat Lab, Frederick, MD 21701 USA. [Gong, Wanghua] SAIC Frederick, Basic Sci Program, Frederick, MD USA. [Ford, Jill; McVicar, Daniel] NCI, Expt Immunol Lab, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701491 ER PT J AU Watanabe, M Hodes, R AF Watanabe, Masashi Hodes, Richard TI Cell type specific role of B7 for T-dependnet antibody response in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Watanabe, Masashi; Hodes, Richard] NCI, EIB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702215 ER PT J AU Webb, T Dorsey, T Goloubeva, O Klyushnenkova, E Alexander, R Ambs, S Mann, D Strome, S Moudgil, K Sun, WJ AF Webb, Tonya Dorsey, Tiffany Goloubeva, Olga Klyushnenkova, Elena Alexander, Richard Ambs, Stefan Mann, Dean Strome, Scott Moudgil, Kamal Sun, Wenji TI A Polymorphism in CD1e is associated with enhanced immune responses in African American Prostate Cancer Patients SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Webb, Tonya; Goloubeva, Olga; Klyushnenkova, Elena; Alexander, Richard; Mann, Dean; Strome, Scott; Moudgil, Kamal; Sun, Wenji] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Dorsey, Tiffany; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700165 ER PT J AU Yoon, JH Feng, JX Morse, H AF Yoon, Jeong Heon Feng, Jianxun Morse, Herbert, III TI IRF8 Interacts with the BCL6 Co-repressor, BCOR SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Yoon, Jeong Heon; Feng, Jianxun; Morse, Herbert, III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700665 ER PT J AU Zanvit, P Chen, WJ AF Zanvit, Peter Chen, Wanjun TI Role of Regulatory T cells and TGF-beta in an Experimental Model of Psoriasis in mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Zanvit, Peter; Chen, Wanjun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659700544 ER PT J AU Zarling, S Spring, M Ehrler, L Chalom, I Funk, T Cowman, A Ockenhouse, C Speake, C Heppner, D Duffy, P Kappe, S Krzych, U AF Zarling, Stasya Spring, Michele Ehrler, Lindsey Chalom, Isaac Funk, Theresa Cowman, Alan Ockenhouse, Christian Speake, Cate Heppner, D. Duffy, Patrick Kappe, Stefan Krzych, Urszula TI Ag-specific recall of cytokine producing CD4 and CD8 T cells in humans immunized with genetically attenuated Plasmodium falciparum sporozoite SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Zarling, Stasya; Spring, Michele; Ehrler, Lindsey; Chalom, Isaac; Funk, Theresa; Ockenhouse, Christian; Heppner, D.; Krzych, Urszula] Walter Reed Army Inst Res, Malaria Vaccine Branch, Silver Spring, MD USA. [Zarling, Stasya] CNR, Res Associateship Program, Washington, DC 20418 USA. [Cowman, Alan] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. [Speake, Cate; Duffy, Patrick; Kappe, Stefan] Seattle Biomed, Malaria, Seattle, WA USA. [Duffy, Patrick] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. RI Cowman, Alan/C-7642-2013 OI Cowman, Alan/0000-0001-5145-9004 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701640 ER PT J AU Zhang, H Mackall, C AF Zhang, Hua Mackall, Crystal TI Identifying an IDO-expressing "fibrocyte" subset of myeloid suppressor cells in pediatric cancer patients. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Zhang, Hua; Mackall, Crystal] NCI, POB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659701425 ER PT J AU Zinselmeyer, B Heydari, S Nayak, D McGavern, D AF Zinselmeyer, Bernd Heydari, Sara Nayak, Debasis McGavern, Dorian TI 2P Imaging Reveals that PD-1 Induces Functional Exhaustion by Stabilizing Synapse Formation during Viral Persistence SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 99th Annual Meeting of the American-Association-of-Immunologists CY MAY 04-08, 2012 CL Boston, MA SP Amer Assoc Immunol C1 [Zinselmeyer, Bernd; Heydari, Sara; Nayak, Debasis; McGavern, Dorian] NINDS, Viral Immunobiol & Intravital Imaging Unit, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2012 VL 188 PG 1 WC Immunology SC Immunology GA 950OX UT WOS:000304659702266 ER PT J AU Li, SZ Zhang, Y Araneta, MF Xiang, Y Johnson, C Innis, RB Shen, J AF Li, Shizhe Zhang, Yan Araneta, Maria Ferraris Xiang, Yun Johnson, Christopher Innis, Robert B. Shen, Jun TI In vivo detection of C-13 isotopomer turnover in the human brain by sequential infusion of C-13 labeled substrates SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE In vivo C-13 MRS; Carboxylic/amide spectral region; Sequential infusion ID MAGNETIC-RESONANCE-SPECTROSCOPY; CEREBRAL METABOLISM; ENERGY-METABOLISM; GLIAL METABOLISM; NMR-SPECTROSCOPY; GLUTAMATE; MRS; CYCLE; POWER AB This study demonstrates the feasibility of simultaneously detecting human brain metabolites labeled by two substrates infused in a sequential order. In vivo C-13 spectra of carboxylic/amide carbons were acquired only during the infusion of the second substrate. This approach allowed dynamic detection of C-13 labeling from two substrates with considerably different labeling patterns. [2-C-13]glucose and [U-C-13(6)]glucose were used to generate singlet and doublet signals of the same carboxylic/amide carbon atom, respectively. Because of the large one-bond C-13-C-13 homonuclear integral coupling between a carboxylic/ amide carbon and an aliphatic carbon (similar to 50 Hz), the singlet and doublet signals of the same carboxylic/amide carbon were well distinguished. The results demonstrated that different C-13 isotopomer patterns could be simultaneously and distinctly measured in vivo in a clinical setting at 3 T. Published by Elsevier Inc. C1 [Araneta, Maria Ferraris; Xiang, Yun; Johnson, Christopher; Innis, Robert B.; Shen, Jun] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Li, Shizhe; Zhang, Yan; Shen, Jun] NIMH, Magnet Resonance Spect Core Facil, NIH, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@mail.nih.gov FU National Institutes of Health, National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health. The authors thank Ms. loline Henter for editing the article. NR 23 TC 4 Z9 4 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD MAY PY 2012 VL 218 BP 16 EP 21 DI 10.1016/j.jmr.2012.03.012 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 948GK UT WOS:000304491400004 PM 22578550 ER PT J AU Subramanian, S Devasahayam, N Matsumoto, S Saito, K Mitchell, JB Krishna, MC AF Subramanian, Sankaran Devasahayam, Nallathamby Matsumoto, Shingo Saito, Keita Mitchell, James B. Krishna, Murali C. TI Echo-based Single Point Imaging (ESPI): A novel pulsed EPR imaging modality for high spatial resolution and quantitative oximetry SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE EPR imaging; Single Point Imaging; Spin-Echo imaging; Spectral-spatial; T2; T-2(+); Oximetry; FT-EPR; Filtered back-projection ID ELECTRON-PARAMAGNETIC-RESONANCE; MAGNETIC-RESONANCE; TUMOR OXYGENATION; RECONSTRUCTION; MICROSCOPY; MRI; HETEROGENEITY; SPECTROMETER; OPTIMIZATION; SPECTROSCOPY AB A novel time-domain spectroscopic EPR imaging approach, that is a unique combination of already known techniques, is described. The first one is multi-gradient Single Point Imaging involving pure phase-encoding where the oximetry is based on T. Line width derived from T-2(+); is subject to susceptibility effects and therefore needs system-dependent line width calibrations. The second approach utilizes the conventional 90 degrees-tau-180 degrees Spin-Echo pulse sequence where the images are obtained by the filtered backprojection after FT of the echoes collected under frequency-encoding gradients. The spatially resolved oximetry information is derived from a set of T-2-weighted images. The back-projection images suffer susceptibility artifacts with resolution determined by T, but the oximetry based on T-2 is quite reliable. The current approach combines Single Point Imaging and the Spin-Echo procedure to take advantage the enhanced spatial resolution associated with the former and the T-2 dependent contrast of the latter. Pairs of images are derived choosing two time points located at identical time intervals on either side of the 180 pulse. The refocusing pulse being exactly in the middle of the two points ensures that artifacts associated with susceptibility and field inhomogeneities are eliminated. In addition, the net phase accumulated by the two time points being identical results in identical field of views, thus avoiding the zoomin effect as a function delay in regular SPI and the associated interpolation requirements employed in T-weighted oximetry. The end result is superior image resolution and reliable oximetry. In spite of the fact that projection-reconstruction methods require less number of measurements compared to SPI, the enormous advantage in SNR of the SPI procedure makes the echo-based SPI equally efficient in terms of measurement time. The Fourier reconstruction, line width independent resolution and the true T-2-weighting make this novel procedure very attractive for in vivo EPR imaging of tissue oxygen quantitatively. C1 [Subramanian, Sankaran; Devasahayam, Nallathamby; Matsumoto, Shingo; Saito, Keita; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM murali@helix.nih.gov NR 39 TC 7 Z9 7 U1 2 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD MAY PY 2012 VL 218 BP 105 EP 114 DI 10.1016/j.jmr.2012.03.022 PG 10 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 948GK UT WOS:000304491400015 PM 22578561 ER PT J AU Hu, KN Qiang, W Bermejo, GA Schwieters, CD Tycko, R AF Hu, Kan-Nian Qiang, Wei Bermejo, Guillermo A. Schwieters, Charles D. Tycko, Robert TI Restraints on backbone conformations in solid state NMR studies of uniformly labeled proteins from quantitative amide N-15-N-15 and carbonyl C-13-C-13 dipolar recoupling data SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Magic-angle spinning; Protein structure; Pulse sequences ID NUCLEAR-MAGNETIC-RESONANCE; CHEMICAL-SHIFT TENSORS; IMMUNOGLOBULIN BINDING DOMAIN; RANGE STRUCTURAL RESTRAINTS; 3D STRUCTURE DETERMINATION; TILTED ROTATING-FRAME; ANGLE-SPINNING NMR; AMYLOID FIBRILS; DISTANCE MEASUREMENTS; SECONDARY-STRUCTURE AB Recent structural studies of uniformly N-15, C-13-labeled proteins by solid state nuclear magnetic resonance (NMR) rely principally on two sources of structural restraints: (i) restraints on backbone conformation from isotropic N-15 and C-13 chemical shifts, based on empirical correlations between chemical shifts and backbone torsion angles: (ii) restraints on inter-residue proximities from qualitative measurements of internuclear dipole-dipole couplings, detected as the presence or absence of inter-residue crosspeaks in multidimensional spectra. We show that site-specific dipole-dipole couplings among N-15-labeled backbone amide sites and among C-13-labeled backbone carbonyl sites can be measured quantitatively in uniformly-labeled proteins, using dipolar recoupling techniques that we call N-15-BARE and C-13-BARE (BAckbone REcoupling), and that the resulting data represent a new source of restraints on backbone conformation. N-15-BARE and C-13-BARE data can be incorporated into structural modeling calculations as potential energy surfaces, which are derived from comparisons between experimental N-15 and C-13 signal decay curves, extracted from crosspeak intensities in series of two-dimensional spectra, with numerical simulations of the N-15-BARE and C-13-BARE measurements. We demonstrate this approach through experiments on microcrystalline, uniformly N-15, C-13-labeled protein GBI. Results for GBI show that N-15-BARE and C-13-BARE restraints are complementary to restraints from chemical shifts and inter-residue crosspeaks, improving both the precision and the accuracy of calculated structures. C1 [Hu, Kan-Nian; Qiang, Wei; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Bermejo, Guillermo A.; Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM rtycko@comcast.net RI Qiang, Wei/I-1053-2012 FU Intramural NIH HHS [ZIA DK029029-15] NR 54 TC 14 Z9 14 U1 0 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD MAY PY 2012 VL 218 BP 115 EP 127 DI 10.1016/j.jmr.2012.03.001 PG 13 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 948GK UT WOS:000304491400016 PM 22449573 ER PT J AU Keffer, JL Hammill, JT Lloyd, JR Plaza, A Wipf, P Bewley, CA AF Keffer, Jessica L. Hammill, Jared T. Lloyd, John R. Plaza, Alberto Wipf, Peter Bewley, Carole A. TI Geographic Variability and Anti-Staphylococcal Activity of the Chrysophaentins and Their Synthetic Fragments SO MARINE DRUGS LA English DT Article DE chrysophaentins; Staphylococcus aureus; antibacterial ID RESISTANT STAPHYLOCOCCUS-AUREUS; UNITED-STATES; CYCLIC BIS(BIBENZYLS); COMMUNITY; INFECTIONS; VIRULENCE; CLONE; MRSA; SUSCEPTIBILITY; BISBIBENZYLS AB Drug-resistant Staphylococcus aureus is a continuing public health concern, both in the hospital and community settings. Antibacterial compounds that possess novel structural scaffolds and are effective against multiple S. aureus strains, including current drug-resistant ones, are needed. Previously, we have described the chrysophaentins, a family of bisdiarylbutene macrocycles from the chrysophyte alga Chrysophaeum taylori that inhibit the growth of S. aureus and methicillin-resistant S. aureus (MRSA). In this study we have analyzed the geographic variability of chrysophaentin production in C. taylori located at different sites on the island of St. John, U.S. Virgin Islands, and identified two new linear chrysophaentin analogs, E2 and E3. In addition, we have expanded the structure activity relationship through synthesis of fragments comprising conserved portions of the chrysophaentins, and determined the antimicrobial activity of natural chrysophaentins and their synthetic analogs against five diverse S. aureus strains. We find that the chrysophaentins show similar activity against all S. aureus strains, regardless of their drug sensitivity profiles. The synthetic chrysophaentin fragments indeed mimic the natural compounds in their spectrum of antibacterial activity, and therefore represent logical starting points for future medicinal chemistry studies of the natural products and their analogs. C1 [Keffer, Jessica L.; Lloyd, John R.; Plaza, Alberto; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Hammill, Jared T.; Wipf, Peter] Univ Pittsburgh, Ctr Chem Methodol & Lib Dev, Pittsburgh, PA 15260 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kefferj@mail.nih.gov; jth25@pitt.edu; lloydj@niddk.nih.gov; a.plaza@mx.uni-saarland.de; pwipf@pitt.edu; caroleb@mail.nih.gov OI Keffer, Jessica/0000-0002-0302-3588 FU Boehringer Ingelheim Pharmaceuticals Inc.; National Institutes of Health (NIDDK); Office of the Director, NIH FX We thank the United States National Park Service for research collecting permits for the U. S. Virgin Islands, P. Dunman for clinical S. aureus strains, and M. Bewley for assistance with collections. We also thank Boehringer Ingelheim Pharmaceuticals Inc. for financial support (P. W.). This work was supported in part by the National Institutes of Health Intramural Research Program (NIDDK), and the Intramural AIDS Targeted Antiviral Program, Office of the Director, NIH (C. A. B.). J.L.K. is a recipient of a predoctoral Intramural AIDS Research Fellowship, Office of the Director, NIH. NR 50 TC 5 Z9 5 U1 2 U2 13 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-3397 J9 MAR DRUGS JI Mar. Drugs PD MAY PY 2012 VL 10 IS 5 BP 1103 EP 1125 DI 10.3390/md10051103 PG 23 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 947UZ UT WOS:000304459100011 PM 22822360 ER PT J AU Tian, E Hoffman, MP Ten Hagen, KG AF Tian, E. Hoffman, Matthew P. Ten Hagen, Kelly G. TI O-glycosylation modulates integrin and FGF signalling by influencing the secretion of basement membrane components SO NATURE COMMUNICATIONS LA English DT Article ID POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; GLAND BRANCHING MORPHOGENESIS; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; QUALITY-CONTROL; EPITHELIAL MORPHOGENESIS; DROSOPHILA-MELANOGASTER; EXTRACELLULAR-MATRIX; TUMORAL CALCINOSIS; CELL-ADHESION AB Extracellular microenvironments have crucial roles in modulating cell interactions during development. Here we discover that a conserved protein modification (O-glycosylation) influences extracellular matrix composition during mammalian organogenesis, affecting integrin signalling and fibroblast growth factor-mediated cell proliferation. Specifically, mice deficient for an enzyme (Galnt1) that adds sugars to proteins during early stages of organogenesis resulted in intracellular accumulation of major basement membrane proteins and endoplasmic reticulum stress, with resultant effects on fibroblast growth factor signalling, epithelial cell proliferation and organ growth. Exogenous addition of basement membrane components rescued fibroblast growth factor signalling and the growth defects in a beta 1-integrin-dependent manner. Our work demonstrates for the first time that O-glycosylation influences the composition of the extracellular matrix during mammalian organ development, influencing specific aspects of the endoplasmic reticulum stress response, cell signalling, cell proliferation and organ growth. Our work provides insight into the role of this conserved protein modification in both development and disease. C1 [Tian, E.; Ten Hagen, Kelly G.] Natl Inst Dent & Craniofacial Res, Dev Glycobiol Unit, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Ten Hagen, KG (reprint author), Natl Inst Dent & Craniofacial Res, Dev Glycobiol Unit, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM Kelly.Tenhagen@nih.gov FU NIDCR at the National Institutes of Health FX We thank our colleagues for many helpful discussions. We thank Drs. Vaishali Patel and Ivan Rebustini for their assistance, and Drs. Lawrence Tabak, Jamey Marth and Yu Guan for providing Galnt1-deficient mice. We also thank Shelagh Johnson for editorial assistance. This research was supported by the Intramural Research Program of the NIDCR at the National Institutes of Health. NR 52 TC 15 Z9 15 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2012 VL 3 AR 869 DI 10.1038/ncomms1874 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 949XP UT WOS:000304611400064 PM 22643896 ER PT J AU Armagan, G Bojnik, E Turunc, E Kanit, L Cinar, OG Benyhe, S Borsodi, A Yalcin, A AF Armagan, Guliz Bojnik, Engin Turunc, Ezgi Kanit, Lutfiye Cinar, Oezge Guenduez Benyhe, Sandor Borsodi, Anna Yalcin, Ayfer TI Kainic acid-induced changes in the opioid/nociceptin system and the stress/toxicity pathways in the rat hippocampus SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE Kainic acid; Opioid/nociceptin system; G-protein activation; Gene expression; PCR array; Hippocampus ID CENTRAL-NERVOUS-SYSTEM; AMYOTROPHIC-LATERAL-SCLEROSIS; CEREBELLAR GRANULE CELLS; D-ASPARTATE RECEPTORS; EARLY GENE-EXPRESSION; HEAT-SHOCK-PROTEIN; INDUCED SEIZURES; MESSENGER-RNA; NOCICEPTIN/ORPHANIN FQ; STATUS EPILEPTICUS AB Excitotoxicity is a contributing factor to the pathogenesis of acute or chronic neurodegenerative disease states. Kainic acid (KA) is an excitotoxic substance and the administration of it to rodents induces seizure activity (status epilepticus, SE) and leads to neurodegeneration. In this study the effect of KA-induced excitotoxicity on the G-protein activations and the gene expression levels of the opioid/nociceptin system receptors as MOPr, KOPr, DOPr, ORL-1, and PNOC (N/OFQ) were investigated, and the regulator effect of naloxone (Nal) on the gene expressions of the opioid system receptors against KA-induced seizures in the rat hippocampus was tested. In addition, the expression levels of stress-toxicity genes were assessed in the hippocampus following KA-induced excitotoxicity in order to determine the potential genetic targets which can be helpful for neuroprotective interventions. Our results indicate that the KA-induced excitotoxicity increased the mRNA levels of MOPr, DOPr, KOPr, PNOC, and ORL-1. However, G-protein activations of MOPr, DOPr, and KOPr remained relatively unchanged while both the potency and efficacy of N/OFQ were significantly increased. The PCR array data showed that KA-induced excitotoxicity altered the expression levels of genes in the cellular stress or toxicity pathways. Our data suggests that the induction of the opioid/nociceptin system may be involved in the cellular stress response following a neurodegenerative insult and that the genes modulated by the KA-treatment in the stress-toxicity pathways may be evaluated as targets of potential neuroprotective interventions. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Armagan, Guliz; Turunc, Ezgi; Yalcin, Ayfer] Ege Univ, Dept Biochem, Fac Pharm, TR-35100 Izmir, Turkey. [Bojnik, Engin; Cinar, Oezge Guenduez; Benyhe, Sandor; Borsodi, Anna] Hungarian Acad Sci, Biol Res Inst, Inst Biochem, H-6726 Szeged, Hungary. [Kanit, Lutfiye] Ege Univ, Fac Med, Dept Physiol, TR-35100 Izmir, Turkey. [Kanit, Lutfiye] Ege Univ, Ctr Brain Res, TR-35100 Izmir, Turkey. [Cinar, Oezge Guenduez] NIAAA, NIH, Rockville, MD 20852 USA. [Kanit, Lutfiye; Yalcin, Ayfer] Ege Univ, Inst Hlth Sci, Dept Neurosci, TR-35100 Izmir, Turkey. RP Yalcin, A (reprint author), Ege Univ, Dept Biochem, Fac Pharm, TR-35100 Izmir, Turkey. EM ayferyalcin@yahoo.com RI Gunduz Cinar, Ozge/E-5756-2010 OI Gunduz Cinar, Ozge/0000-0002-3826-8905 FU Technological and Scientific Council of Turkey (TUBITAK) [SBAG-104S280, MACAR-5-SBAG-106S249]; National Office for Research and Technology, NKTH, Budapest, Hungary [TUR-11/2006]; National Scientific Research Fund [OTKA-CK-78566]; Health Scientific Council [ETT-398-03/2009]; TUBITAK FX This study was co-supported by the Technological and Scientific Council of Turkey (TUBITAK) (SBAG-104S280 and MACAR-5-SBAG-106S249 to A.Y.) and by a Turkish-Hungarian Intergovernmental Bilateral Research Mobility Grant (TUR-11/2006 to A.B.) provided by the National Office for Research and Technology, NKTH, Budapest, Hungary. Further supports were provided by the National Scientific Research Fund (OTKA-CK-78566 Grant to S.B.) and by the Health Scientific Council (ETT-398-03/2009 to A.B.). G.A. and E.T. were also supported by doctoral Grants from TUBITAK. We also like to thank to Dr. Luisa Rocha for her critical reading. NR 92 TC 2 Z9 4 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD MAY PY 2012 VL 60 IS 6 BP 555 EP 564 DI 10.1016/j.neuint.2012.02.015 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 950YB UT WOS:000304686700002 PM 22382076 ER PT J AU Wu, YL Brosh, RM AF Wu, Yuliang Brosh, Robert M., Jr. TI DNA helicase and helicase-nuclease enzymes with a conserved iron-sulfur cluster SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SISTER-CHROMATID COHESION; BASE-EXCISION-REPAIR; SINGLE-STRANDED-DNA; REPLICATION PROTEIN-A; ANEMIA GROUP J; FANCONI-ANEMIA; BREAST-CANCER; CAENORHABDITIS-ELEGANS; GENOMIC STABILITY; ESCHERICHIA-COLI AB Conserved Iron-Sulfur (Fe-S) clusters are found in a growing family of metalloproteins that are implicated in prokaryotic and eukaryotic DNA replication and repair. Among these are DNA helicase and helicase-nuclease enzymes that preserve chromosomal stability and are genetically linked to diseases characterized by DNA repair defects and/or a poor response to replication stress. Insight to the structural and functional importance of the conserved Fe-S domain in DNA helicases has been gleaned from structural studies of the purified proteins and characterization of Fe-S cluster site-directed mutants. In this review, we will provide a current perspective of what is known about the Fe-S cluster helicases, with an emphasis on how the conserved redox active domain may facilitate mechanistic aspects of helicase function. We will discuss testable models for how the conserved Fe-S cluster might operate in helicase and helicase-nuclease enzymes to conduct their specialized functions that help to preserve the integrity of the genome. C1 [Wu, Yuliang] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 5E5, Canada. [Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Wu, YL (reprint author), Univ Saskatchewan, Dept Biochem, Hlth Sci Bldg, Saskatoon, SK S7N 5E5, Canada. EM yuliang.wu@usask.ca; broshr@mail.nih.gov FU National Institutes of Health, National Institute on Aging; Fanconi Anemia Research Fund; Saskatchewan Health Research Foundation (SHRF); University of Saskatchewan FX Intramural Research program of the National Institutes of Health, National Institute on Aging and Fanconi Anemia Research Fund (to R.M.B.); Saskatchewan Health Research Foundation (SHRF); University of Saskatchewan (to Y.W.). Funding for open access charge: Intramural Research program of the National Institutes of Health, National Institute on Aging. NR 121 TC 53 Z9 54 U1 2 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY PY 2012 VL 40 IS 10 BP 4247 EP 4260 DI 10.1093/nar/gks039 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 948XA UT WOS:000304535500010 PM 22287629 ER PT J AU Zhu, BM Kang, K Yu, JH Chen, WP Smith, HE Lee, D Sun, HW Wei, L Hennighausen, L AF Zhu, Bing-Mei Kang, Keunsoo Yu, Ji Hoon Chen, Weiping Smith, Harold E. Lee, Daeyoup Sun, Hong-Wei Wei, Lai Hennighausen, Lothar TI Genome-wide analyses reveal the extent of opportunistic STAT5 binding that does not yield transcriptional activation of neighboring genes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MAMMARY-GLAND; DIFFERENTIATION; MOTIF; PROLIFERATION; EXPRESSION; LEUKEMIA AB Signal Transducers and Activators of Transcription (STAT) 5A/B regulate cytokine-inducible genes upon binding to GAS motifs. It is not known what percentage of genes with GAS motifs bind to and are regulated by STAT5. Moreover, it is not clear whether genome-wide STAT5 binding is modulated by its concentration. To clarify these issues we established genome-wide STAT5 binding upon growth hormone (GH) stimulation of wild-type (WT) mouse embryonic fibroblasts (MEFs) and MEFs overexpressing STAT5A more than 20-fold. Upon GH stimulation, 23 827 and 111 939 STAT5A binding sites were detected in WT and STAT5A overexpressing MEFs, respectively. 13 278 and 71 561 peaks contained at least one GAS motif. 1586 and 8613 binding sites were located within 2.5 kb of promoter sequences, respectively. Stringent filtering revealed 78 genes in which the promoter/upstream region (-10 kb to +0.5 kb) was recognized by STAT5 both in WT and STAT5 overexpressing MEFs and 347 genes that bound STAT5 only in overexpressing cells. Genome-wide expression analyses identified that the majority of STAT5-bound genes was not under GH control. Up to 40% of STAT5-bound genes were not expressed. For the first time we demonstrate the magnitude of opportunistic genomic STAT5 binding that does not translate into transcriptional activation of neighboring genes. C1 [Zhu, Bing-Mei; Kang, Keunsoo; Yu, Ji Hoon; Hennighausen, Lothar] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Zhu, Bing-Mei] Nanjing Univ Chinese Med, Key Lab Acupuncture & Med Res, Minist Educ, Nanjing 210029, Peoples R China. [Kang, Keunsoo; Lee, Daeyoup] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. [Chen, Weiping; Smith, Harold E.] NIDDKD, Microarray Core Facil, Genom Core Lab, Bethesda, MD 20892 USA. [Sun, Hong-Wei] NIAMSD, Biodata Min & Discovery Sect, Bethesda, MD 20892 USA. [Wei, Lai] NEI, NIH, Bethesda, MD 20892 USA. [Hennighausen, Lothar] Dankook Univ, Natl Dept Nanobiomed Sci, Cheonan 330714, Chungnam, South Korea. [Hennighausen, Lothar] Dankook Univ, WCU Res Ctr Nanobiomed Sci, Cheonan 330714, Chungnam, South Korea. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM lotharh@mail.nih.gov RI Lee, Daeyoup/C-1653-2011; Wei, Lai/D-1088-2014; OI Lee, Daeyoup/0000-0003-2006-1823 FU NIDDK; NIAMS; NEI at the National Institutes of Health (NIH), USA; Epigenomic Research Program for Human Stem Cells [2007-2004134]; World Class University, Ministry of Education, Science and Technology, through the National Research Foundation of Korea, South Korea [R31-10069]; National Basic Research Program of China (973 Program) [2012CB518501]; Department of Education, Jiangsu, China [11KJA360003]; WCU Research Center, Dankook University National Institutes of Health FX The Intramural Research Programs (IRP) of NIDDK, NIAMS and NEI at the National Institutes of Health (NIH), USA; Epigenomic Research Program for Human Stem Cells (grant no. 2007-2004134); the World Class University Program, Ministry of Education, Science and Technology, through the National Research Foundation of Korea, South Korea (R31-10069); the National Basic Research Program of China (973 Program, grant no. 2012CB518501); Natural Science Fund for Colleges and Universities, Department of Education, Jiangsu, China (grant no. 11KJA360003); L. H. is an adjunct member of the Department of Nanobiomedical Science and WCU Research Center for Nanobiomedical Science, Dankook University, Chungnam, Korea. Funding for the open access charge: WCU Research Center, Dankook University National Institutes of Health. NR 33 TC 24 Z9 25 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY PY 2012 VL 40 IS 10 BP 4461 EP 4472 DI 10.1093/nar/gks056 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 948XA UT WOS:000304535500027 PM 22319210 ER PT J AU DiCarlo, AL Jackson, IL Shah, JR Czarniecki, CW Maidment, BW Williams, JP AF DiCarlo, Andrea L. Jackson, Isabel L. Shah, Jui R. Czarniecki, Christine W. Maidment, Bert W. Williams, Jacqueline P. TI Development and Licensure of Medical Countermeasures to Treat Lung Damage Resulting from a Radiological or Nuclear Incident SO RADIATION RESEARCH LA English DT Editorial Material ID RADIATION PNEUMONITIS; MOUSE LUNG; RAT LUNG; IRRADIATION; FIBROSIS; INJURY; EXPOSURE; THERAPY; MODELS AB Due to the ever-present threat of a radiological or nuclear accident or attack, the National Institute of Allergy and Infectious Diseases, Radiation Medical Countermeasures Program was initiated in 2004. Since that time, the Program has funded research to establish small and large animal models for radiation damage, as well as the development of approaches to mitigate/treat normal tissue damage following radiation exposure. Because some of these exposures may be high-dose, and yet heterogeneous, the expectation is that some victims will survive initial acute radiation syndromes (e.g. hematopoietic and gastrointestinal), but then suffer from potentially lethal lung complications. For this reason, efforts have concentrated on the development of animal models of lung irradiation damage that mimic expected exposure scenarios, as well as drugs to treat radiation-induced late lung sequelae including pneumonitis and fibrosis. Approaches targeting several pathways are under study, with the eventual goal of licensure by the United States Food and Drug Administration for government stockpiling. This Commentary outlines the status of countermeasure development in this area and provides information on the specifics of licensure requirements, as well as guidance and a discussion of challenges involved in developing and licensing drugs and treatments specific to a radiation lung damage indication. (C) 2012 by Radiation Research Society C1 [DiCarlo, Andrea L.; Shah, Jui R.; Czarniecki, Christine W.; Maidment, Bert W.] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Jackson, Isabel L.] Duke Univ, Med Ctr, Durham, NC USA. [Williams, Jacqueline P.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RP DiCarlo, AL (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr,Room 5301, Bethesda, MD 20892 USA. EM cohena@niaid.nih.gov NR 31 TC 13 Z9 13 U1 0 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD MAY PY 2012 VL 177 IS 5 BP 717 EP 721 DI 10.1667/RR2881.1 PG 5 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 948JD UT WOS:000304498600018 PM 22468704 ER PT J AU Isasi, R Knoppers, BM Andrews, PW Bredenoord, A Colman, A Hin, LE Hull, S Kim, OJ Lomax, G Morris, C Sipp, D Stacey, G Wahlstrom, J Zeng, FY AF Isasi, Rosario Knoppers, Bartha M. Andrews, Peter W. Bredenoord, Annelien Colman, Alan Hin, Lee Eng Hull, Sara Kim, Ock-Joo Lomax, Geoffrey Morris, Clive Sipp, Douglas Stacey, Glyn Wahlstrom, Jan Zeng, Fanyi CA Int Stem Cell Forum Ethics Working TI Disclosure and management of research findings in stem cell research and banking: policy statement SO REGENERATIVE MEDICINE LA English DT Article DE best practice; biorepository; embryonic stem cell; ethics; induced pluripotent stem cell; policy; return of research results ID GENETIC RESEARCH; RESEARCH PARTICIPANTS; INCIDENTAL FINDINGS; ETHICAL FRAMEWORK; WORKING GROUP; RETURN; PERSPECTIVES; INFORMATION; DUTY; RECOMMENDATIONS AB Prompted by an increased interest of both research participants and the patient advocacy community in obtaining information about research outcomes and on the use of their biological samples; the international community has begun to debate the emergence of an ethical 'duty' to return research results to participants. Furthermore, the use of new technologies (e.g., whole-genome and -exome sequencing) has revealed both genetic data and incidental findings with possible clinical significance. These technologies together with the proliferation of biorepositories, provide a compelling rationale for governments and scientific institutions to adopt prospective policies. Given the scarcity of policies in the context of stem cell research, a discussion on the scientific, ethical and legal implications of disclosing research results for research participants is needed. We present the International Stem Forum Ethics Working Party's Policy Statement and trust that it will stimulate debate and meet the concerns of researchers and research participants alike. C1 [Isasi, Rosario; Knoppers, Bartha M.] McGill Univ, Fac Med, Dept Human Genet, Ctr Genom & Policy, Montreal, PQ, Canada. [Andrews, Peter W.] Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England. [Bredenoord, Annelien] Univ Med Ctr Utrecht, Dept Med Eth, Julius Ctr, Utrecht, Netherlands. [Colman, Alan] Singapore Stem Cell Consortium, Inst Med Biol, Singapore, Singapore. [Hin, Lee Eng] Natl Univ Singapore, Fac Med, Div Grad Med Studies, Singapore 117548, Singapore. [Hull, Sara] NHGRI Bioeth Core, NIH, Bethesda, MD USA. [Kim, Ock-Joo] Seoul Natl Univ, Coll Med, Dept Med Hist & Med Humanities, Seoul, South Korea. [Lomax, Geoffrey] Calif Inst Regenerat Med, San Francisco, CA USA. [Morris, Clive] Natl Hlth & Med Res Council, Canberra, ACT, Australia. [Sipp, Douglas] RIKEN, Ctr Dev Biol, Res Unit Sci Policy & Eth Studies, Kobe, Hyogo, Japan. [Stacey, Glyn] Natl Inst Biol Stand & Controls, UK Stem Cell Bank, Div Cell Biol & Imaging, Potters Bar, Herts, England. [Wahlstrom, Jan] Univ Gothenburg, Dept Med Genet, Gothenburg, Sweden. [Zeng, Fanyi] Shanghai Stem Cell Inst, Shanghai Inst Med Genet, Shanghai, Peoples R China. [Int Stem Cell Forum Ethics Working] Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada. RP Isasi, R (reprint author), McGill Univ, Fac Med, Dept Human Genet, Ctr Genom & Policy, Montreal, PQ, Canada. EM rosario.isasi@mcgill.ca RI Sipp, Douglas/C-9218-2017; OI Sipp, Douglas/0000-0002-5979-0938; Morris, Clive/0000-0003-1392-7959 FU International Stem Cell Forum (Ethics Working Policy); Stem Cell Network of Canada (R Isasi and BM Knoppers) FX This project was supported, in part, by the International Stem Cell Forum (Ethics Working Policy) and the Stem Cell Network of Canada (R Isasi and BM Knoppers). The authors' funding sources have played no role in the design, interpretation or writing of the present study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 70 TC 15 Z9 15 U1 4 U2 14 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0751 J9 REGEN MED JI Regen. Med. PD MAY PY 2012 VL 7 IS 3 BP 439 EP 448 DI 10.2217/RME.12.23 PG 10 WC Cell & Tissue Engineering; Engineering, Biomedical SC Cell Biology; Engineering GA 949HV UT WOS:000304568200023 PM 22594334 ER PT J AU Stachowska-Pietka, J Waniewski, J Flessner, MF Lindholm, B AF Stachowska-Pietka, Joanna Waniewski, Jacek Flessner, Michael F. Lindholm, Bengt TI Computer simulations of osmotic ultrafiltration and small-solute transport in peritoneal dialysis: a spatially distributed approach SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE peritoneal transport; distributed model; diffusion and convection; capillary transport; peritoneal tissue ID SKELETAL-MUSCLE CAPILLARIES; PLASMA TRANSPORT; FLUID TRANSPORT; SURFACE-AREA; INTRAPERITONEAL THERAPY; ABDOMINAL-WALL; 3-PORE MODEL; EXCHANGE; MEMBRANE; WATER AB Stachowska-Pietka J, Waniewski J, Flessner MF, Lindholm B. Computer simulations of osmotic ultrafiltration and small-solute transport in peritoneal dialysis: a spatially distributed approach. Am J Physiol Renal Physiol 302: F1331-F1341, 2012. First published February 1, 2012; doi:10.1152/ajprenal.00301.2011.-The aim of this study was to simulate clinically observed intraperitoneal kinetics of dialysis fluid volume and solute concentrations during peritoneal dialysis. We were also interested in analyzing relationships between processes in the peritoneal cavity and processes occurring in the peritoneal tissue and microcirculation. A spatially distributed model was formulated for the combined description of volume and solute mass balances in the peritoneal cavity and flows across the interstitium and the capillary wall. Tissue local parameters were assumed dependent on the interstitial hydration and vasodilatation induced by glucose. The model was fitted to the average volume and solute concentration profiles from dwell studies in 40 clinically stable patients on chronic ambulatory peritoneal dialysis using a 3.86% glucose dialysis solution. The model was able to describe the clinical data with high accuracy. An increase in the local interstitial pressure and tissue hydration within the distance of 2.5 mm from the peritoneal surface of the tissue was observed. The penetration of glucose into the tissue and removal of urea, creatinine, and sodium from the tissue were restricted to a layer located within 2 mm from the peritoneal surface. The initial decline of sodium concentration (sodium dip) was observed not only in intraperitoneal fluid but also in the tissue. The distributed model can provide a precise description of the relationship between changes in the peritoneal tissue and intraperitoneal dialysate volume and solute concentration kinetics. Computer simulations suggest that only a thin layer of the tissue within 2-3 mm from the peritoneal surface participates in the exchange of fluid and small solutes between the intraperitoneal dialysate and blood. C1 [Stachowska-Pietka, Joanna; Waniewski, Jacek] Poland Acad Sci, Inst Biocybernet & Biomed Engn, Warsaw, Poland. [Flessner, Michael F.] NIDDK, Hematol Branch, NIH, Bethesda, MD USA. [Lindholm, Bengt] Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Baxter Novum, Stockholm, Sweden. [Lindholm, Bengt] Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med, Stockholm, Sweden. RP Stachowska-Pietka, J (reprint author), Polish Acad Sci, Inst Biocybernet & Biomed Engn, Ul Trojdena 4, PL-02109 Warsaw, Poland. EM jstachowska@ibib.waw.pl FU Polish Ministry of Science and Higher Education [N N518 417736]; Baxter Healthcare Corporation FX J. Stachowska-Pietka was supported by a grant N N518 417736 from the Polish Ministry of Science and Higher Education. Baxter Novum is the result of a grant from Baxter Healthcare Corporation to the Karolinska Institute. NR 63 TC 10 Z9 10 U1 1 U2 9 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 MAY PY 2012 VL 302 IS 10 BP F1331 EP F1341 DI 10.1152/ajprenal.00301.2011 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 946MQ UT WOS:000304356400014 PM 22301624 ER PT J AU Molinolo, AA Marsh, C El Dinali, M Gangane, N Jennison, K Hewitt, S Patel, V Seiwert, TY Gutkind, JS AF Molinolo, Alfredo A. Marsh, Christina El Dinali, Mohamed Gangane, Nitin Jennison, Kaitlin Hewitt, Stephen Patel, Vyomesh Seiwert, Tanguy Y. Gutkind, J. Silvio TI mTOR as a Molecular Target in HPV-Associated Oral and Cervical Squamous Carcinomas SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN-PAPILLOMAVIRUS; CELL CARCINOMA; NECK-CANCER; OROPHARYNGEAL CANCER; MAMMALIAN TARGET; HEAD; RAPAMYCIN; EXPRESSION; E6; P16(INK4A) AB Purpose: The incidence of head and neck squamous cell carcinomas (HNSCC) associated with human papillomavirus (HPV) infection has increased over the past decades in the United States. We aimed at examining the global impact of HPV-associated HNSCC and whether the established key role of mTOR activation in HNSCC is also observed in HPV+ HNSCC lesions, thereby providing novel treatment options for HPV-associated HNSCC patients. Experimental Design: An international HNSCC tissue microarray (TMA) was used to analyze the expression of p16(INK4A), a surrogate for HPV infection, and Akt-mTOR pathway activation. Results were confirmed in a large collection of HPV- and HPV+ HNSCC cases and in a cervical cancer (CCSCC) TMA. Observations were validated in HNSCC and CCSCC-derived cell lines, which were xenografted into immunodeficient mice for tumorigenesis assays. Results: Approximately 20% of all HNSCC lesions could be classified as HPV+, irrespective of their country of origin. mTOR pathway activation was observed in most HPV+ HNSCC and CCSCC lesions and cell lines. The preclinical efficacy of mTOR inhibition by rapamycin and RAD001 was explored in HPV+ HNSCC and CCSCC tumor xenografts. Both mTOR inhibitors effectively decreased mTOR activity in vivo and caused a remarkable decrease in tumor burden. These results emphasize the emerging global impact of HPV-related HNSCCs and indicate that the activation of the mTOR pathway is a widespread event in both HPV- and HPV-associated HNSCC and CCSCC lesions. Conclusions: The emerging results may provide a rationale for the clinical evaluation of mTOR inhibitors as a molecular targeted approach for the treatment of HPV-associated malignancies. Clin Cancer Res; 18(9); 2558-68. (C) 2012 AACR. C1 [Molinolo, Alfredo A.; Marsh, Christina; Jennison, Kaitlin; Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Hewitt, Stephen] NCI, Adv Technol Ctr, NIH, Bethesda, MD 20892 USA. [Gangane, Nitin] Mahatma Gandhi Inst Med Sci, Dept Pathol, Wardha, Maharashtra, India. [El Dinali, Mohamed; Seiwert, Tanguy Y.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU NIH, National Institute of Dental and Craniofacial Research [Z01DE00558]; Flight Attendant Medical Research Institute (FAMRI); Union for International Cancer Control FX This work was supported by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research, project Z01DE00558. T. Seiwert was supported by a Flight Attendant Medical Research Institute Young Clinical Scientist Award (FAMRI YCSA). N. Gangane was supported by a Yamagiwa-Yoshida fellowship from the Union for International Cancer Control, International cancer technology transfer fellowships (ICRETT). NR 49 TC 64 Z9 67 U1 3 U2 9 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 MAY 1 PY 2012 VL 18 IS 9 BP 2558 EP 2568 DI 10.1158/1078-0432.CCR-11-2824 PG 11 WC Oncology SC Oncology GA 945CA UT WOS:000304249200016 PM 22409888 ER PT J AU Naing, A LoRusso, P Fu, SQ Hong, DS Anderson, P Benjamin, RS Ludwig, J Chen, HLX Doyle, LA Kurzrock, R AF Naing, Aung LoRusso, Patricia Fu, Siqing Hong, David S. Anderson, Pete Benjamin, Robert S. Ludwig, Joseph Chen, Helen X. Doyle, Laurence A. Kurzrock, Razelle TI Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing's Sarcoma Family Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID SOLID TUMORS; PHASE-I; CANCER; AKT; KINASE; TARGET; CELLS AB Purpose: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R). Experimental Design: Patients received cixutumumab, 6 mg/kg i.v. weekly, and temsirolimus, 25 to 37.5 mg i.v. weekly (4-week cycles), with restaging after 8 weeks. Median follow-up was 8.9 months. Results: Twenty patients [17 with Ewing's sarcoma (EWS), 3 with desmoplastic small-round cell tumor (DSRCT)] were enrolled. Twelve patients (60%) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%; mostly grade I-II). Seven of 20 patients (35%) achieved stable disease (SD) for more than 5 months or complete/partial (CR/PR) responses. Tumor regression of more than 20% (23%, 23%, 27%, 100%, 100%) occurred in five of 17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six patients with EWS who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade III mucositis, myelosuppression, or hyperglycemia, which were controlled while maintaining drug dose. Conclusion: Cixutumumab combined with temsirolimus was well-tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated EWS family tumors. Clin Cancer Res; 18(9); 2625-31. (C) 2012 AACR. C1 [Naing, Aung; Fu, Siqing; Hong, David S.; Kurzrock, Razelle] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Clin Trials Program 1, Houston, TX 77030 USA. [Anderson, Pete] Univ Texas MD Anderson Canc Ctr, Dept Pediat, Houston, TX 77030 USA. [Benjamin, Robert S.; Ludwig, Joseph] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. [LoRusso, Patricia] Wayne State Univ, Barbara Ann Karmanos Canc Inst, Detroit, MI USA. [Chen, Helen X.; Doyle, Laurence A.] NCI, Canc Therapy Evaluat Program, NIH, Rockville, MD USA. RP Naing, A (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Clin Trials Program 1, 1515 Holcombe Blvd,Box 455, Houston, TX 77030 USA. EM anaing@mdanderson.org FU [R21CA13763301A1]; [U01CA62461]; [U01CA62487] FX This study was supported by R21CA13763301A1 (A. Naing), U01CA62461 (R. Kurzrock), and U01CA62487 (P. LoRusso). NR 23 TC 85 Z9 88 U1 0 U2 8 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 MAY 1 PY 2012 VL 18 IS 9 BP 2625 EP 2631 DI 10.1158/1078-0432.CCR-12-0061 PG 7 WC Oncology SC Oncology GA 945CA UT WOS:000304249200022 PM 22465830 ER PT J AU Jaeger, LB Nath, A AF Jaeger, Laura B. Nath, Avindra TI Modeling HIV-associated neurocognitive disorders in mice: new approaches in the changing face of HIV neuropathogenesis SO DISEASE MODELS & MECHANISMS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; COAT PROTEIN GP120; HUMANIZED MOUSE MODELS; TRANSGENIC MICE; TAT PROTEIN; STEM-CELLS; T-CELLS; NEUROPROTECTIVE ACTIVITIES AB It is well established that infection with the human immunodeficiency virus (HIV) leads to immune suppression. Less well known is the fact that long-term, progressive HIV disease is associated with the development of cognitive deficits. Since the introduction of combined antiretroviral therapy (cART), the clinical presentation of HIV infection has evolved into a chronic illness with very low levels of viral replication and chronic immune activation, with compliant affected individuals surviving for decades with a high quality of life. Despite these advances, many HIV-infected individuals develop some degree of neurodegeneration and cognitive impairment. The underlying pathophysiological mechanisms are not well understood, and there are no effective treatments. Thus, there is an unmet need for animal models that enable the study of HIV-associated neurocognitive disorders (HAND) and the testing of new therapeutic approaches to combat them. Here, we review the pros and cons of existing mouse models of HIV infection for addressing these aims and propose a detailed strategy for developing a new mouse model of HIV infection. C1 [Jaeger, Laura B.; Nath, Avindra] Natl Inst Neurol Disorders & Stroke, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Nath, A (reprint author), Natl Inst Neurol Disorders & Stroke, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. EM avindra.nath@nih.gov FU National Institute of Neurological Diseases and Stroke, National Institutes of Health, USA FX This research was supported by intramural research funds from the National Institute of Neurological Diseases and Stroke, National Institutes of Health, USA. NR 91 TC 15 Z9 16 U1 0 U2 7 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 J9 DIS MODEL MECH JI Dis. Model. Mech. PD MAY PY 2012 VL 5 IS 3 BP 313 EP 322 DI 10.1242/dmm.008763 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 945PC UT WOS:000304287500005 PM 22563057 ER PT J AU Ahluwalia, D Bienstock, RJ Schaaper, RM AF Ahluwalia, Deepti Bienstock, Rachelle J. Schaaper, Roe M. TI Novel mutator mutants of E-coli nrdAB ribonucleotide reductase: Insight into allosteric regulation and control of mutation rates SO DNA REPAIR LA English DT Article DE Ribonucleotide reductase; dNTP pools; DNA replication fidelity; Allosteric regulation ID DEOXYRIBONUCLEOTIDE POOL IMBALANCE; MITOCHONDRIAL-DNA DEPLETION; PROTEIN DOCKING PREDICTIONS; POLYMERASE III HOLOENZYME; SUBSTRATE-SPECIFICITY; REPLICATION FIDELITY; EFFECTOR-BINDING; LAGGING-STRAND; MUTAGENESIS; OLIGOMERIZATION AB Ribonucleotide reductase (RNR) is the enzyme critically responsible for the production of the 5'-deoxynucleoside-triphosphates (dNTPs), the direct precursors for DNA synthesis. The dNTP levels are tightly controlled to permit high efficiency and fidelity of DNA synthesis. Much of this control occurs at the level of the RNR by feedback processes, but a detailed understanding of these mechanisms is still lacking. Using a genetic approach in the bacterium Escherichia coli, a paradigm for the class Ia RNRs, we isolated 23 novel RNR mutants displaying elevated mutation rates along with altered dNTP levels. The responsible amino-acid substitutions in RNR reside in three different regions: (i) the (d)ATP-binding activity domain, (ii) a novel region in the small subunit adjacent to the activity domain, and (iii) the dNTP-binding specificity site, several of which are associated with different dNTP pool alterations and different mutational outcomes. These mutants provide new insight into the precise mechanisms by which RNR is regulated and how dNTP pool disturbances resulting from defects in RNR can lead to increased mutation. Published by Elsevier B.V. C1 [Ahluwalia, Deepti; Schaaper, Roe M.] Natl Inst Environm & Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Bienstock, Rachelle J.] Natl Inst Environm & Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Schaaper, RM (reprint author), Natl Inst Environm & Hlth Sci, Mol Genet Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov OI Bienstock, Rachelle/0000-0001-5228-3610 FU National Institute of Environmental Health Sciences (NIEHS) [Z01 ES065086] FX We thank Drs. W. Copeland, M. Resnick, and S. Wilson of the NIEHS for their helpful comments on the manuscript for this paper and Dr. J. Stubbe and her laboratory for the coordinates of the Uhlin and Eklund model. This work was supported by project Z01 ES065086 of the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS). NR 52 TC 12 Z9 12 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD MAY 1 PY 2012 VL 11 IS 5 BP 480 EP 487 DI 10.1016/j.dnarep.2012.02.001 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 948HP UT WOS:000304494500004 PM 22417940 ER PT J AU Esmail, H Barry, CE Wilkinson, RJ AF Esmail, Hanif Barry, Clifton E., III Wilkinson, Robert J. TI Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies SO DRUG DISCOVERY TODAY LA English DT Review ID RESUSCITATION-PROMOTING FACTORS; T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; HYPOXIC RESPONSE; HIV-INFECTION; DOUBLE-BLIND; ANTIGENS; VACCINE; MEMORY; ADULTS AB Treatment of latent tuberculosis (LTBI) is a vital component of tuberculosis (TB) elimination but is not efficiently implemented with currently available diagnostics and therapeutics. The tuberculin skin test and interferon-gamma release assays can inform that infection has occurred, but do not prove that it persists. Treatment of LTBI with isoniazid targets actively replicating bacilli but not non-replicating populations, prolonging treatment duration. Developing more predictive diagnostic tests and treatments of shorter duration requires a greater understanding of the biology of LTBI, from both host and bacillary perspectives. In this article, we discuss the basis of current diagnosis and treatment of LTBI and review recent developments in understanding the biology of latency that might enable future improved diagnostic and treatment strategies. C1 [Esmail, Hanif; Wilkinson, Robert J.] Univ Cape Town, Clin Infect Dis Res Initiat, Inst Infect Dis & Mol Med, ZA-7925 Observatory, South Africa. [Esmail, Hanif; Wilkinson, Robert J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London W2 1PG, England. [Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Wilkinson, Robert J.] Natl Inst Med Res, MRC, London NW7 1AA, England. RP Esmail, H (reprint author), Univ Cape Town, Clin Infect Dis Res Initiat, Inst Infect Dis & Mol Med, ZA-7925 Observatory, South Africa. EM h.esmail@imperial.ac.uk RI Barry, III, Clifton/H-3839-2012; OI Wilkinson, Robert/0000-0002-2753-1800; Esmail, Hanif/0000-0002-4278-9316 FU Bill and Melinda Gates Foundation/Wellcome Trust [37822]; Wellcome Trust [084323, 088316, 090170]; National Institute of Allergy and Infectious Disease, National Institutes of Health; NIH [RO1 HL075845]; European Union [SANTE/2005/105-061-102]; EDCTP [IP.07.32080.002]; MRC (UK) FX This work was funded by the Bill and Melinda Gates Foundation/Wellcome Trust Grand challenges in Global Health (37822), the Wellcome Trust (084323, 088316, 090170) and (in part) by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health and by NIH RO1 HL075845. RJW also receives support from the European Union (SANTE/2005/105-061-102), EDCTP (IP.07.32080.002) and MRC (UK). NR 65 TC 40 Z9 41 U1 2 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD MAY PY 2012 VL 17 IS 9-10 BP 514 EP 521 DI 10.1016/j.drudis.2011.12.013 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 945SU UT WOS:000304297100015 PM 22198298 ER PT J AU Tooze, JA Krebs-Smith, SM Troiano, RP Subar, AF AF Tooze, J. A. Krebs-Smith, S. M. Troiano, R. P. Subar, A. F. TI The accuracy of the Goldberg method for classifying misreporters of energy intake on a food frequency questionnaire and 24-h recalls: comparison with doubly labeled water SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE diet; diet surveys; energy intake; statistical bias; questionnaires/standards; research design ID MULTIPLE-PASS METHOD; SOCIAL DESIRABILITY SCALE; BASAL METABOLIC-RATE; FUNDAMENTAL PRINCIPLES; CUTOFF; ADULTS; SPECIFICITY; SENSITIVITY; VALIDATION; PHYSIOLOGY AB Background/Objectives: Adults often misreport dietary intake; the magnitude varies by the methods used to assess diet and classify participants. The objective was to quantify the accuracy of the Goldberg method for categorizing misreporters on a food frequency questionnaire (FFQ) and two 24-h recalls (24HRs). Subjects/Methods: We compared the Goldberg method, which uses an equation to predict total energy expenditure (TEE), with a criterion method that uses doubly labeled water (DLW), in a study of 451 men and women. Underreporting was classified using recommended cut points and calculated values. Sensitivity and specificity, positive predictive value (PPV) and negative predictive value and the area under the receiver operating characteristic curve (AUC) were calculated. Predictive models of underreporting were contrasted for the Goldberg and DLW methods. Results: AUCs were 0.974 and 0.972 on the FFQ, and 0.961 and 0.938 on the 24HR for men and women, respectively. The sensitivity of the Goldberg method was higher for the FFQ (92%) than the 24HR (50%); specificity was higher for the 24HR (99%) than the FFQ (88%); PPV was high for the 24HR (92%) and FFQ (88%). Simulation studies indicate attenuation in odds ratio estimates and reduction of power in predictive models. Conclusions: Although use of the Goldberg method may lead to bias and reduction in power in predictive models of underreporting, the method has high predictive value for both the FFQ and the 24HR. Thus, in the absence of objective measures of TEE or physical activity, the Goldberg method is a reasonable approach to characterize underreporting. European Journal of Clinical Nutrition (2012) 66, 569-576; doi: 10.1038/ejcn.2011.198; published online 30 November 2011 C1 [Tooze, J. A.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Krebs-Smith, S. M.; Troiano, R. P.; Subar, A. F.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Tooze, JA (reprint author), Wake Forest Sch Med, Dept Biostat Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jtooze@wakehealth.edu OI Troiano, Richard/0000-0002-6807-989X FU National Cancer Institute [263-MQ-612378] FX This work was supported by a contract from the National Cancer Institute (263-MQ-612378). We thank Kristen Beavers, Sharon Kirkpatrick and Anne Rodgers for helpful suggestions on the manuscript. We would also like to acknowledge the contribution of Arthur Schatzkin to the conception and conduct of the OPEN Study, and his contributions to this manuscript. NR 29 TC 24 Z9 24 U1 1 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD MAY PY 2012 VL 66 IS 5 BP 569 EP 576 DI 10.1038/ejcn.2011.198 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 936NI UT WOS:000303596700005 PM 22127332 ER PT J AU Jackson, PL Hanson, CD Farrell, AK Butcher, RJ Stables, JP Eddington, ND Scott, KR AF Jackson, Patrice L. Hanson, Clive D. Farrell, Alanna K. Butcher, Raymond J. Stables, James P. Eddington, Natalie D. Scott, K. R. TI Enaminones 12. An explanation of anticonvulsant activity and toxicity per Linus Pauling's clathrate hypothesis SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Isoxazole enaminones; Clathrate; MES; scPTZ; GABA ID SUBSTITUTED VINYLIC BENZAMIDES; ANTIEPILEPTIC DRUGS; GENERAL-ANESTHESIA; GABA(A) RECEPTOR; RATS; THIP; DERIVATIVES; METABOLISM; EPILEPSY; AGONISTS AB The x-ray crystal structure of 3-((5-methylisoxazol-3-yl)amino)-5-methylcyclohex-2-enone (12b) and 3((5-methylisoxazolyl-3-yl)amino)-5,5-dimethylcyclohex-2-enone (12c) were determined and correlated to their anticonvulsant activity in mice and rats. A hypothesis for the toxicity of the analogs are advanced. In addition, a series of 5-methyl-N-(3-oxocyclohex-1-enyl)-isoxazole-3-carboxamides were synthesized and evaluated for anticonvulsant activity. These compounds were compared to the activity of the corresponding amino and aminomethyl enaminones. Additional investigation involved the synthesis and evaluation of a trifluoromethyl analog of the active isoxazole tert-butyl 4-(5-methisoxazol-3-yl-amino)-6-methyl-2-oxo-cyclohex-3-ene carboxylate (4f). Published by Elsevier Masson SAS. C1 [Hanson, Clive D.; Farrell, Alanna K.; Scott, K. R.] Howard Univ, Dept Pharmaceut Sci, Coll Pharm, Washington, DC 20059 USA. [Jackson, Patrice L.] Univ Maryland Eastern Shore, Dept Pharmaceut Sci, Sch Pharm, Princess Anne, MD 21853 USA. [Butcher, Raymond J.] Howard Univ, Dept Chem, Grad Sch, Washington, DC 20059 USA. [Stables, James P.] Natl Inst Neurol Disorders & Stroke, Neurosci Ctr, NIH, Bethesda, MD 20892 USA. [Eddington, Natalie D.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP Scott, KR (reprint author), Howard Univ, Dept Pharmaceut Sci, Coll Pharm, 2300 4th St NW, Washington, DC 20059 USA. EM pljackson@umes.edu; hansonclive@hotmail.com; alanna_farrell@hotmail.com; rbutcher99@yahoo.com; StablesJ@ninds.nih.gov; neddingt@rx.umaryland.edu; kscott@howard.edu FU National Institutes of Health [1 R21 GM634940-02]; RCMI, Division of Research Infrastructure, National Center for Research Resources, NIH [2 G12 RR003048] FX This research was supported by a grant from the National Institutes of Health (1 R21 GM634940-02) for which K.R.S. is the principal investigator and also grant 2 G12 RR003048 from the RCMI Program, Division of Research Infrastructure, National Center for Research Resources, NIH. Log P experiments were carried out by Midwest Research Institute, Kansas City, MO 64110-2299 by Dr. Linda Seimann and Mr. Matthew Armstrong. NR 50 TC 8 Z9 8 U1 0 U2 3 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 MAY PY 2012 VL 51 BP 42 EP 51 DI 10.1016/j.ejmech.2012.02.003 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 945QU UT WOS:000304291900004 PM 22417639 ER PT J AU Thoma, G Antani, S Gill, M Pearson, G Neve, L AF Thoma, George Antani, Sameer Gill, Michael Pearson, Glenn Neve, Leif TI People Locator: A System for Family Reunification SO IT PROFESSIONAL LA English DT Article AB After a large-scale disaster, many people go missing. Survivors often turn up in refugee camps or hospitals, where information is gathered and stored in a database. The People Locator technology processes this information for family reunification. C1 [Thoma, George] NIH, Commun Engn Branch, Lister Hill Natl Ctr Biomed Commun, US Natl Lib Med, Bethesda, MD 20892 USA. RP Thoma, G (reprint author), NIH, Commun Engn Branch, Lister Hill Natl Ctr Biomed Commun, US Natl Lib Med, Bethesda, MD 20892 USA. EM thoma@nlm.nih.gov; santani@mail.nih.gov; mgill@mail.nih.gov; glenn_pearson@nlm.nih.gov; lneve@mail.nih.gov OI Antani, Sameer/0000-0002-0040-1387 FU National Institutes of Health; National Library of Medicine; Lister Hill National Center for Biomedical Communications FX The Intramural Research Program of the National Institutes of Health, the National Library of Medicine, and the Lister Hill National Center for Biomedical Communications supported this work. People Locator, ReUnite, and the Lost Person Finder Design are trademarks of the US Department of Health & Human Services. We thank Greg Miernicki, Merwan Rodriguez, and Michael Chung for their significant contributions to People Locator's design, development, and deployment. We also thank Eugene Borovikov and Girish Lingappa for their contributions to ongoing research in face matching, and Bathiya Senevirathna and Krittach Phichaphop for helping us develop ReUnite. We also acknowledge the collaboration of the Sahana Software Foundation (www.sahanasoftwarefoundation.org) and institutions in the Bethesda Hospitals Emergency Preparedness Partnership (www.bhepp.org). NR 11 TC 2 Z9 2 U1 1 U2 5 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1520-9202 EI 1941-045X J9 IT PROF JI IT Prof. PD MAY-JUN PY 2012 VL 14 IS 3 BP 13 EP 21 PG 9 WC Computer Science, Information Systems; Computer Science, Software Engineering; Telecommunications SC Computer Science; Telecommunications GA 946IQ UT WOS:000304345500004 ER PT J AU Burgess, S Dennis, S Lanka, S Miller, N Potvin, J AF Burgess, Sarena Dennis, Stephanie Lanka, Soma Miller, Naomi Potvin, Joseph TI MedlinePlus Connect: Linking Health IT Systems to Consumer Health Information SO IT PROFESSIONAL LA English DT Article AB The National Library of Medicine's MedlinePlus Connect service extends the reach of the consumer health website MedlinePlus.gov to deliver relevant information to patients and providers via health IT systems, electronic health records, and patient portals. C1 [Burgess, Sarena; Dennis, Stephanie] US Natl Lib Med, Hlth Informat Prod Unit, Bethesda, MD USA. [Lanka, Soma] US Natl Lib Med, Off Comp & Commun Serv, Medline Plus Connect Team, Bethesda, MD USA. RP Burgess, S (reprint author), US Natl Lib Med, Hlth Informat Prod Unit, Bethesda, MD USA. EM sarena.burgess@nih.gov; stephanie.dennis@nih.gov; soma.lanka@nih.hhs.gov; millern@mail.nlm.nih.gov; joseph.potvin@nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 8 TC 1 Z9 1 U1 0 U2 2 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1520-9202 J9 IT PROF JI IT Prof. PD MAY-JUN PY 2012 VL 14 IS 3 BP 22 EP 28 PG 7 WC Computer Science, Information Systems; Computer Science, Software Engineering; Telecommunications SC Computer Science; Telecommunications GA 946IQ UT WOS:000304345500005 PM 23066351 ER PT J AU Lu, CJ McCreedy, L Tormey, D Browne, AC AF Lu, Chris J. McCreedy, Lynn Tormey, Destinee Browne, Allen C. TI A Systematic Approach for Medical Language Processing: Generating Derivational Variants SO IT PROFESSIONAL LA English DT Article AB Medical language processing seeks to analyze linguistic patterns in electronic medical records, which requires managing lexical variations. A systematic approach to generating derivational variants, including prefixes, suffixes, and zero derivations, has improved precision and recall rates. C1 [Lu, Chris J.] US Natl Lib Med, LSG, Bethesda, MD USA. [Browne, Allen C.] US Natl Lib Med, Lister Hill Ctr, Bethesda, MD USA. RP Lu, CJ (reprint author), US Natl Lib Med, LSG, Bethesda, MD USA. EM lu@nlm.nih.gov; mccreedy@nlm.nih.gov; dln4@georgetown.edu; browne@nlm.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 1 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1520-9202 J9 IT PROF JI IT Prof. PD MAY-JUN PY 2012 VL 14 IS 3 BP 36 EP 42 PG 7 WC Computer Science, Information Systems; Computer Science, Software Engineering; Telecommunications SC Computer Science; Telecommunications GA 946IQ UT WOS:000304345500007 ER PT J AU Frant, L Goldstein, B Ma, Y Sun, D Burgess, S AF Frant, Loren Goldstein, Brian Ma, Yue Sun, Dianne Burgess, Sarena TI MedlinePlus Mobile: Consumer Health Information On-the-Go SO IT PROFESSIONAL LA English DT Article AB MedlinePlus Mobile provides a core set of the authoritative health information found on MedlinePlus.gov, optimized for mobile devices. The authors detail the technical approach taken to create this website, from the system architecture through development and testing. C1 [Frant, Loren; Burgess, Sarena] US Natl Lib Med, Hlth Informat Prod Unit, Medline Plus Team, Bethesda, MD USA. RP Frant, L (reprint author), US Natl Lib Med, Hlth Informat Prod Unit, Medline Plus Team, Bethesda, MD USA. EM loren.frant@nih.gov; brnsgoldstein@gmail.com; yue.ma@lmco.com; dianne.sun@nih.gov; sarena.burgess@nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 1 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1520-9202 J9 IT PROF JI IT Prof. PD MAY-JUN PY 2012 VL 14 IS 3 BP 44 EP 49 PG 6 WC Computer Science, Information Systems; Computer Science, Software Engineering; Telecommunications SC Computer Science; Telecommunications GA 946IQ UT WOS:000304345500008 PM 23397361 ER PT J AU Ribeiro, JMC Assumpcao, TCF Pham, VM Francischetti, IMB Reisenman, CE AF Ribeiro, Jose M. C. Assumpcao, Teresa C. F. Pham, Van M. Francischetti, Ivo M. B. Reisenman, Carolina E. TI An Insight Into the Sialotranscriptome of Triatoma rubida (Hemiptera: Heteroptera) SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Chagas disease; vector biology; salivary gland; sialome; transcriptome ID BUG RHODNIUS-PROLIXUS; DISEASE AMERICAN TRYPANOSOMIASIS; MULTIPLE SEQUENCE ALIGNMENT; POLYMERASE-CHAIN-REACTION; RICH SECRETORY PROTEINS; CANINE CHAGAS-DISEASE; BLOODSUCKING BUG; SALIVARY-GLANDS; UNITED-STATES; PLATELET-AGGREGATION AB The kissing bug Triatoma rubida (Uhler, 1894) is found in southwestern United States and parts of Mexico where it is found infected with Trypanosoma cruzi, invades human dwellings and causes allergies from their bites. Although the protein salivary composition of several triatomine species is known, not a single salivary protein sequence is known from T. rubida. Furthermore, the salivary diversity of related hematophagous arthropods is very large probably because of the immune pressure from their hosts. Here we report the sialotranscriptome analysis of T. rubida based on the assembly of 1,820 high-quality expressed sequence tags, 51% of which code for putative secreted peptides, including lipocalins, members of the antigen five family, apyrase, hemolysin, and trialysin families. Interestingly, T. rubida lipocalins are at best 40% identical in primary sequence to those of T. protracta, a kissing bug that overlaps its range with T. rubida, indicating the diversity of the salivary lipocalins among species of the same hematophagous genus. We additionally found several expressed sequence tags coding for proteins of clear Trypanosoma spp. origin. This work contributes to the future development of markers of human and pet exposure to T. rubida and to the possible development of desensitization therapies. Supp. Data 1 and 2(online only) of the transcriptome and deducted protein sequences can be obtained from http://exon.niaid.nih.gov/transcriptome/Trubida/Triru-S1-web.xlsx and http://exon.niaid.nih.gov/transcriptome/Trubida/Triru-S2-web.xlsx. C1 [Ribeiro, Jose M. C.; Assumpcao, Teresa C. F.; Pham, Van M.; Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Reisenman, Carolina E.] Univ Arizona, Coll Sci, Dept Neurosci, Tucson, AZ 85721 USA. RP Ribeiro, JMC (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy,Room 2E32D, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov RI Ribeiro, Jose/J-7011-2015; OI Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank B. Savary for kindly providing specimens of T. rubida. This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 112 TC 10 Z9 11 U1 1 U2 10 PU ENTOMOLOGICAL SOC AMER PI LANHAM PA 10001 DEREKWOOD LANE, STE 100, LANHAM, MD 20706-4876 USA SN 0022-2585 J9 J MED ENTOMOL JI J. Med. Entomol. PD MAY PY 2012 VL 49 IS 3 BP 563 EP 572 DI 10.1603/ME11243 PG 10 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 941TU UT WOS:000303989900016 PM 22679863 ER PT J AU Chung, JY Frank, L Subramanian, A Galen, S Leonhard, S Green, BL AF Chung, Joyce Y. Frank, Lori Subramanian, Asha Galen, Steve Leonhard, Sarah Green, Bonnie L. TI A Qualitative Evaluation of Barriers to Care for Trauma-Related Mental Health Problems Among Low-Income Minorities in Primary Care SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Trauma; primary care; barriers to care; mental health interventions; low-income minorities ID POSTTRAUMATIC-STRESS-DISORDER; ONE-YEAR OUTCOMES; CHILDHOOD ABUSE; TREATING DEPRESSION; WOMEN; PTSD; TRIAL; PREFERENCES; COMORBIDITY; HISTORIES AB This study aimed to identify barriers and facilitators of mental health care for patients with trauma histories via qualitative methods with clinicians and administrators from primary care clinics for the underserved. Individual interviews were conducted, followed by a combined focus group with administrators from three jurisdictions; there were three focus groups with clinicians from each clinic system. Common themes were identified, and responses from groups were compared. Administrators and clinicians report extensive trauma histories among patients. Clinician barriers include lack of time, patient resistance, and inadequate referral options; administrators cite reimbursement issues, staff training, and lack of clarity about the term trauma. A key facilitator is doctor-patient relationship There were differences in perceived barriers and facilitators at the institutional and clinical levels for mental health care for patients with trauma. Importantly, there is agreement about better access to and development of trauma-specific interventions. Findings will aid the development and implementation of trauma-focused interventions embedded in primary care. C1 [Chung, Joyce Y.] NIMH, Intramural Res Program, NIH, DHHS, Bethesda, MD 20892 USA. [Frank, Lori] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Subramanian, Asha] Georgetown Univ, Sch Med, Dept Family Med, Washington, DC USA. [Galen, Steve] Primary Care Coalit, Silver Spring, MD USA. [Leonhard, Sarah] Greater Baden Med Serv, Brandywine, MD USA. [Green, Bonnie L.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. RP Chung, JY (reprint author), NIMH, Intramural Res Program, NIH, DHHS, 10 Ctr Dr,6-5340 MSC 1276, Bethesda, MD 20892 USA. EM chungj@mail.nih.gov FU National Institute Mental Health [P20 MH 068450] FX This work was funded by a grant from the National Institute Mental Health (P20 MH 068450) to Bonnie L. Green. NR 31 TC 0 Z9 1 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD MAY PY 2012 VL 200 IS 5 BP 438 EP 443 DI 10.1097/NMD.0b013e31825322b3 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 946ET UT WOS:000304335000011 PM 22551798 ER PT J AU Abrams, A Enose-Akahata, Y McCormick, M Johnson, K Maloney, E Jacobson, S AF Abrams, Anna Enose-Akahata, Yoshimi McCormick, Matthew Johnson, Kory Maloney, Elizabeth Jacobson, Steven TI HTLV-I/II seroindeterminate western blot patterns and correlated serological antibody responses SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Abrams, Anna; Enose-Akahata, Yoshimi; McCormick, Matthew; Jacobson, Steven] Natl Inst Neurol Disorders & Stroke, Viral Immunol Sect, Neuroimmunol Branch, Bethesda, MD 20824 USA. [Johnson, Kory] Natl Inst Neurol Disorders & Stroke, Informat Technol & Bioinformat Program, Div Intramural Res, Bethesda, MD USA. [Maloney, Elizabeth] US FDA, Div Epidemiol 2, Off Surveillance & Epidemiol, Rockville, MD 20857 USA. EM ahabrams@gmail.com 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P1 BP 1 EP 1 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800002 ER PT J AU Akahata, Y Abrams, A Massoud, R Bialuk, I Maloney, E Jacobson, S AF Akahata, Yoshimi Abrams, Anna Massoud, Raya Bialuk, Izabela Maloney, Elizabeth Jacobson, Steven TI Humoral immune response against HTLV-I HBZ in HTLV-I-infected individuals SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Akahata, Yoshimi; Abrams, Anna; Massoud, Raya; Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD USA. [Bialuk, Izabela] Med Univ Bialystok, Dept Gen & Expt Pathol, Bialystok, Poland. [Maloney, Elizabeth] US FDA, Div Epidemiol 2, Off Surveillance & Epidemiol, Rockville, MD 20857 USA. EM akahatay@ninds.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P8 BP 5 EP 5 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800009 ER PT J AU Anderson, M Akahata, Y Massoud, R Oh, U McCormick, M Maric, D Jacobson, S AF Anderson, Monique Akahata, Yoshimi Massoud, Raya Oh, Unsong McCormick, Matt Maric, Dragan Jacobson, Steven TI Characterization and behavior of T regulatory cells in HTLV-1 associated myelopathy/tropical spastic paraparesis SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Anderson, Monique; Akahata, Yoshimi; Massoud, Raya; McCormick, Matt; Jacobson, Steven] NINDS, NIH, Neuroimmunol Branch, Viral Immunol Sect, Bethesda, MD 20892 USA. [Oh, Unsong] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA 23284 USA. [Maric, Dragan] NINDS, NIH, Flow Cytometry Core Facil, Bethesda, MD USA. EM andersonmr2@mail.nih.gov 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P12 BP 7 EP 7 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800013 ER PT J AU Ferenczy, M Steinberg, S Marshall, L Jensen, P Major, E AF Ferenczy, Michael Steinberg, Shannon Marshall, Leslie Jensen, Peter Major, Eugene TI Clonal immortalized human glial cell lines support varying levels of JCV infection SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Ferenczy, Michael; Marshall, Leslie; Jensen, Peter; Major, Eugene] Natl Inst Neurol Disorders & Stroke, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Steinberg, Shannon] Dartmouth Coll, Mol & Cellular Biol Program, Dept Arts & Sci, Hanover, NH 03755 USA. EM michael.ferenczy@nih.gov 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P75 BP 36 EP 37 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800076 ER PT J AU Ferenczy, M Johnson, K Marshall, L Major, E AF Ferenczy, Michael Johnson, Kory Marshall, Leslie Major, Eugene TI Quiescent JCV in human neural progenitor cells is activated during lineage differentiation to astrocytes SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Ferenczy, Michael; Marshall, Leslie; Major, Eugene] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Johnson, Kory] NINDS, Bioinformat Sect, NIH, Bethesda, MD 20892 USA. EM michael.ferenczy@nih.gov 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P74 BP 36 EP 36 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800075 ER PT J AU Gerena, Y Perez, S Ramirez, G Hilera, C Sierra, J Velez, J Nath, A Wojna, V AF Gerena, Yamil Perez, Sebastian Ramirez, Giovanna Hilera, Claudia Sierra, Javier Velez, Joyce Nath, Avindra Wojna, Valerie TI Secretion of soluble insulin receptor from human neuronal cells exposed to the cerebrospinal fluid from HIV-seropositive women correlates with cognitive performance SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Gerena, Yamil; Perez, Sebastian; Ramirez, Giovanna; Hilera, Claudia; Sierra, Javier; Velez, Joyce; Wojna, Valerie] Univ Puerto Rico, San Juan, PR 00936 USA. [Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. EM yamil.gerena@upr.edu NR 0 TC 0 Z9 0 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P83 BP 40 EP 40 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800084 ER PT J AU Johnson, T Patel, K Calabresi, P Nath, A AF Johnson, Tory Patel, Karan Calabresi, Peter Nath, Avindra TI CNS-IRIS is mediated by HIV-Tat activated T cells via a novel antigen independent mechanism involving histone acetylation SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Johnson, Tory; Patel, Karan; Nath, Avindra] NINDS, NIH, Bethesda, MD USA. [Calabresi, Peter] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. EM tory.johnson@nih.gov 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P106 BP 51 EP 52 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800107 ER PT J AU Lee, MH Pant, HC Amin, N Wang, TG Nath, A AF Lee, Myoung Hwa Pant, Harish C. Amin, Niranjana Wang, Tong-guang Nath, Avindra TI Aberrant neurite outgrowth by HIV-gp120 is mediated via activation of Cdk5 SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Lee, Myoung Hwa; Pant, Harish C.; Amin, Niranjana; Wang, Tong-guang; Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. EM myounghwa.lee@nih.gov 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P122 BP 59 EP 60 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800123 ER PT J AU Leibovitch, E Maggi, P Brunetto, G Motanic, K Wohler, J Macri, S Westmoreland, S Silva, A Reich, D Jacobson, S AF Leibovitch, Emily Maggi, Pietro Brunetto, Giovanna Motanic, Kelsey Wohler, Jillian Macri, Sheila Westmoreland, Susan Silva, Afonso Reich, Daniel Jacobson, Steven TI HHV-6A infection enhances EAE severity in the common marmoset SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Leibovitch, Emily; Maggi, Pietro; Motanic, Kelsey; Wohler, Jillian; Silva, Afonso; Reich, Daniel; Jacobson, Steven] NIH, Bethesda, MD 20892 USA. [Brunetto, Giovanna] Colgate Univ, Hamilton, NY 13346 USA. [Macri, Sheila; Westmoreland, Susan] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. EM emily.leibovitch@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P123 BP 60 EP 60 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800124 ER PT J AU Li, WX Li, GH Douville, R Tyagi, R Nath, A AF Li, Wenxue Li, Guanhan Douville, Renee Tyagi, Richa Nath, Avindra TI Activation of HERV-K expression by HIV-1 infection SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Li, Wenxue; Li, Guanhan; Douville, Renee; Tyagi, Richa; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD USA. EM liw8@mail.nih.gov RI Li, Guanhan/E-3497-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P126 BP 61 EP 62 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800127 ER PT J AU Li, GH Do, T Monaco, M Major, E Subramaniam, S Nath, A AF Li, Guanhan Do, Thao Monaco, Mariachiara Major, Eugene Subramaniam, Sriram Nath, Avindra TI Virological synapses and bridges mediate lymphocyte-to-astrocyte transmission of HIV SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Li, Guanhan; Monaco, Mariachiara; Major, Eugene; Nath, Avindra] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Do, Thao; Subramaniam, Sriram] NCI, NIH, Bethesda, MD 20892 USA. EM guanhan.li@nih.gov RI Li, Guanhan/E-3497-2012 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P128 BP 62 EP 63 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800129 ER PT J AU Li, GH Lifson, J Ibe, C Major, E Subramaniam, S Nath, A AF Li, Guanhan Lifson, Jeffrey Ibe, Carol Major, Eugene Subramaniam, Sriram Nath, Avindra TI Persistent HIV replication in human astrocytes following lysosomal escape SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Li, Guanhan; Ibe, Carol; Major, Eugene; Nath, Avindra] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Lifson, Jeffrey; Subramaniam, Sriram] NCI, NIH, Bethesda, MD 20892 USA. EM guanhan.li@nih.gov RI Li, Guanhan/E-3497-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P127 BP 62 EP 62 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800128 ER PT J AU Manuel, S Makedonas, G Betts, M Gardner, J Goedert, J Khan, Z Jain, P AF Manuel, Sharron Makedonas, George Betts, Michael Gardner, Jay Goedert, James Khan, Zafar Jain, Pooja TI Mechanistic aspects of DC:T cell interaction during HTLV-1 associated oncogenesis and neuroinflammation SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Manuel, Sharron; Khan, Zafar; Jain, Pooja] Drexel Univ, Coll Med, Philadelphia, PA USA. [Makedonas, George; Betts, Michael] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Gardner, Jay; Goedert, James] NCI, Bethesda, MD 20892 USA. EM pjain@drexelmed.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P137 BP 67 EP 68 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800138 ER PT J AU Marshall, L Daley, E Ryschkewitsch, C Major, E AF Marshall, Leslie Daley, Elizabeth Ryschkewitsch, Caroline Major, Eugene TI Novel Spi-B binding sites in PML-associated JC virus sequence: Insights into molecular regulation of viral gene expression SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Marshall, Leslie; Daley, Elizabeth; Ryschkewitsch, Caroline; Major, Eugene] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. EM marshalllj@ninds.nih.gov 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P140 BP 69 EP 69 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800141 ER PT J AU Massoud, R Jacobson, S Enose-Akahata, Y Tagaya, Y Azimi, N Oh, U AF Massoud, Raya Jacobson, Steven Enose-Akahata, Yoshimi Tagaya, Yutaka Azimi, Nazli Oh, Unsong TI BNZ-gamma peptide, a potential therapeutic agent in HTLV-1 associated myelopathy SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Massoud, Raya; Jacobson, Steven; Enose-Akahata, Yoshimi] Natl Inst Neurol Disorders & Stroke, Viral Immunol Sect, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Tagaya, Yutaka] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. EM raya.massoud@nih.gov 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 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P144 BP 70 EP 71 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800145 ER PT J AU Monaco, MC Ryschkewitsch, C Jensen, PN Johnson, K Major, EO AF Monaco, Maria Chiara Ryschkewitsch, Caroline Jensen, Peter N. Johnson, Kory Major, Eugene O. TI CD34+hematopoietic progenitor cells are a reservoir for JC Virus in natalizumab-treated MS patients SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Monaco, Maria Chiara; Ryschkewitsch, Caroline; Jensen, Peter N.; Johnson, Kory; Major, Eugene O.] NIH, Bethesda, MD USA. EM monaco@ninds.nih.gov 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P148 BP 73 EP 73 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800149 ER PT J AU Narasipura, S Min, S Henderson, L Sharma, A Major, E Al-Harthi, L AF Narasipura, Srinivas Min, Stephanie Henderson, Lisa Sharma, Amit Major, Eugene Al-Harthi, Lena TI Beta-catenin, a suppressor of HIV replication, positively regulates glutamate transporter-1 expression in astrocytes SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Narasipura, Srinivas; Min, Stephanie; Henderson, Lisa; Sharma, Amit; Al-Harthi, Lena] Rush Univ, Chicago, IL USA. [Major, Eugene] NINDS, Bethesda, MD USA. EM srinivasa_narasipura@rush.edu 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P158 BP 77 EP 78 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800159 ER PT J AU Richards, M Poluektova, L Major, E Al-Harthi, L AF Richards, Maureen Poluektova, Larisa Major, Eugene Al-Harthi, Lena TI Identification and Survival of HIV Infected CD4+expressing CD8+T cells in the Brain SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Richards, Maureen; Al-Harthi, Lena] Rush Univ, Med Ctr, Chicago, IL USA. [Poluektova, Larisa] Univ Nebraska Med Ctr, Omaha, NE USA. [Major, Eugene] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20824 USA. EM maureen_richards@rush.edu 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P185 BP 91 EP 91 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800186 ER PT J AU Steiner, J Wang, TG Choi, E Nath, A AF Steiner, Joseph Wang, Tongguang Choi, Elliot Nath, Avindra TI Challenges to Neurotherapeutics Development for HIV-associated neurocognitive disorders (HAND) SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Steiner, Joseph; Wang, Tongguang; Choi, Elliot; Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. EM joe.steiner@nih.gov 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 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P217 BP 106 EP 106 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800218 ER PT J AU Velez, JM Bandaru, VVR Hechavarria-Gomez, RM Menendex-Delmestre, R Haughey, N Nath, A Wojna, V AF Velez, Joyce M. Bandaru, Veera V. R. Hechavarria-Gomez, Rosa M. Menendex-Delmestre, Raissa Haughey, Norman Nath, Avindra Wojna, Valerie TI Cocaine and Marijuana alter lipidomics in HAND SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Velez, Joyce M.; Hechavarria-Gomez, Rosa M.; Menendex-Delmestre, Raissa; Wojna, Valerie] Univ Puerto Rico, NeuroAIDS Res Program, San Juan, PR 00936 USA. [Wojna, Valerie] Univ Puerto Rico, Dept Internal Med, Neurol Sect, San Juan, PR 00936 USA. [Bandaru, Veera V. R.; Haughey, Norman] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. EM joyce.velez@upr.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P236 BP 115 EP 116 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800237 ER PT J AU Virtanen, JO Wohler, J Fenton, K Reich, DS Jacobson, S AF Virtanen, Jussi O. Wohler, Jillian Fenton, Kaylan Reich, Daniel S. Jacobson, Steven TI Evidence for humoral regulation of HHV-6 reactivation in multiple sclerosis and association with MRI activity SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract C1 [Virtanen, Jussi O.; Wohler, Jillian; Fenton, Kaylan; Reich, Daniel S.; Jacobson, Steven] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD USA. EM virtanenjo@ninds.nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD MAY PY 2012 VL 18 SU 1 MA P238 BP 116 EP 117 PG 2 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 948FA UT WOS:000304487800239 ER PT J AU Madden, JL Schober, ME Meyers, RL Bratton, SL Holland, SM Hill, HR Rollins, MD AF Madden, Jesse L. Schober, Michelle E. Meyers, Rebecka L. Bratton, Susan L. Holland, Steven M. Hill, Harry R. Rollins, Michael D. TI Successful use of extracorporeal membrane oxygenation for acute respiratory failure in a patient with chronic granulomatous disease SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE Extracorporeal membrane oxygenation; Immunocompromised; Pediatric; Nocardia; Chronic granulomatous disease; Respiratory failure ID FULMINANT MULCH PNEUMONITIS; EMERGENCY; CHILDREN AB A 9-year-old boy presented with pneumonia, bilateral pulmonary lesions, and fulminant respiratory failure requiring support with extracorporeal membrane oxygenation (ECMO). Open lung biopsy and subsequent bronchoscopy identified Nocardia cyriacigeorgica and Burkholderia cepacia pneumonia. Chronic granulomatous disease (CGD) was diagnosed by an abnormal neutrophil oxidative burst assay. An aggressive diagnostic and therapeutic strategy, which included ECMO, allowed for patient survival and return to baseline function. No ECMO survivors with CGD have previously been reported. It is now recognized that several forms of CGD exist, and some forms may be compatible with long-term survival. Therefore, the diagnosis of CGD should not necessarily be considered a contraindication to ECMO. This is the first known survivor of CGD-related acute respiratory failure supported by ECMO. (c) 2012 Elsevier Inc. All rights reserved. C1 [Madden, Jesse L.] Univ Utah, Primary Childrens Med Ctr, Dept Surg, Salt Lake City, UT 84112 USA. [Schober, Michelle E.; Bratton, Susan L.] Primary Childrens Med Ctr, Dept Pediat, Div Crit Care, Salt Lake City, UT 84103 USA. [Meyers, Rebecka L.; Rollins, Michael D.] Primary Childrens Med Ctr, Div Pediat Surg, Salt Lake City, UT 84103 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Hill, Harry R.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Hill, Harry R.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Hill, Harry R.] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. [Hill, Harry R.] ARUP Inst Clin & Expt Pathol, Salt Lake City, UT USA. RP Madden, JL (reprint author), Univ Utah, Primary Childrens Med Ctr, Dept Surg, Salt Lake City, UT 84112 USA. EM jesse.madden@hsc.utah.edu; michelle.schober@hsc.utah.edu; Rebecka.Meyers@hsc.utah.edu; Susan.Bratton@hsc.utah.edu; smh@nih.gov; harry.hill@path.utah.edu; Michael.Rollins@imail.org FU Intramural NIH HHS [Z01 AI000646-16] NR 10 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD MAY PY 2012 VL 47 IS 5 BP E21 EP E23 DI 10.1016/j.jpedsurg.2011.12.029 PG 3 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 943FU UT WOS:000304106700006 PM 22595605 ER PT J AU Introini, A Lisco, A Vanpouille, C Grivel, JC Margolis, L AF Introini, A. Lisco, A. Vanpouille, C. Grivel, J. C. Margolis, L. TI IL-7 promotes HIV-1 transmission to cervico-vaginal tissue ex vivo SO JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Meeting Abstract CT Joint International Congress of the American-Society-for-Reproductive-Immunology (ASRI) and the European-Society-for-Reproductive-Immunology (ESRI) CY MAY 30-JUN 02, 2012 CL Hamburg, GERMANY SP Amer Soc Reproduct Immunol (ASRI), European Soc Reproduct Immunol (ESRI) C1 [Introini, A.; Lisco, A.; Vanpouille, C.; Grivel, J. C.; Margolis, L.] NICHHD, NIH, Sect Intercellular Interact, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-0378 J9 J REPROD IMMUNOL JI J. Reprod. Immunol. PD MAY PY 2012 VL 94 IS 1 BP 17 EP 17 DI 10.1016/j.jri.2012.03.267 PG 1 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 949MD UT WOS:000304579400023 ER PT J AU Edmonds, TG Ochsenbauer, C Ding, H Grivel, JC Shen, R Smith, PD Margolis, L Kappes, JC AF Edmonds, T. G. Ochsenbauer, C. Ding, H. Grivel, J. -C. Shen, R. Smith, P. D. Margolis, L. Kappes, J. C. TI Transmitted/founder virus infectivity in cells derived from blood and female reproductive tract tissue SO JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Meeting Abstract CT Joint International Congress of the American-Society-for-Reproductive-Immunology (ASRI) and the European-Society-for-Reproductive-Immunology (ESRI) CY MAY 30-JUN 02, 2012 CL Hamburg, GERMANY SP Amer Soc Reproduct Immunol (ASRI), European Soc Reproduct Immunol (ESRI) C1 [Edmonds, T. G.; Ochsenbauer, C.; Ding, H.; Shen, R.; Smith, P. D.; Kappes, J. C.] Univ Alabama Birmingham, Birmingham, AL USA. [Grivel, J. -C.; Margolis, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-0378 J9 J REPROD IMMUNOL JI J. Reprod. Immunol. PD MAY PY 2012 VL 94 IS 1 BP 128 EP 128 DI 10.1016/j.jri.2012.03.483 PG 1 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 949MD UT WOS:000304579400237 ER PT J AU Narayan, K Prosa, TJ Fu, J Kelly, TF Subramaniam, S AF Narayan, Kedar Prosa, Ty J. Fu, Jing Kelly, Thomas F. Subramaniam, Sriram TI Chemical mapping of mammalian cells by atom probe tomography SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Atom probe tomography; Focused Ion Beam Scanning Electron Microscopy (FIB-SEM); Chemical imaging ID FIELD-ION MICROSCOPY; SPECIMEN PREPARATION; III-V; NANOWIRES; SURFACE AB In atom probe tomography (APT), a technique that has been used to determine 3D maps of ion compositions of metals and semiconductors at sub-nanometer resolutions, controlled emissions of ions can be induced from needle-shaped specimens in the vicinity of a strong electric field. Detection of these ions in the plane of a position sensitive detector provides two-dimensional compositional information while the sequence of ion arrival at the detector provides information in the third dimension. Here we explore the use of APT technology for imaging biological specimens. We demonstrate that it is possible to obtain 3D spatial distributions of cellular ions and metabolites from unstained, freeze-dried mammalian cells. Multiple peaks were reliably obtained in the mass spectrum from tips with diameters of similar to 50 nm and heights of similar to 200 nm, with mass-to-charge ratios (m/z) ranging from 1 to 80. Peaks at m/z 12, 23, 28 and 39, corresponding to carbon, sodium, carbonyl and potassium ions respectively, showed distinct patterns of spatial distribution within the cell. Our studies establish that APT could become a powerful tool for mapping the sub-cellular distribution of atomic species, such as labeled metabolites, at 3D spatial resolutions as high as similar to 1 nm. Published by Elsevier Inc. C1 [Narayan, Kedar; Fu, Jing; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Prosa, Ty J.; Kelly, Thomas F.] Cameca Instruments Inc, Madison, WI 53726 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov OI Fu, Jing/0000-0002-7752-5417 FU Intramural NIH HHS [Z01 BC010278-11, ZIA BC010826-04] NR 39 TC 10 Z9 10 U1 2 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAY PY 2012 VL 178 IS 2 SI SI BP 98 EP 107 DI 10.1016/j.jsb.2011.12.016 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 945PB UT WOS:000304287400005 PM 22245777 ER PT J AU Frank, GA Bartesaghi, A Kuybeda, O Borgnia, MJ White, TA Sapiro, G Subramaniam, S AF Frank, Gabriel A. Bartesaghi, Alberto Kuybeda, Oleg Borgnia, Mario J. White, Tommi A. Sapiro, Guillermo Subramaniam, Sriram TI Computational separation of conformational heterogeneity using cryo-electron tomography and 3D sub-volume averaging SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Sub-volume averaging; Membrane proteins; Viral glycoproteins; Dynamic molecular complexes ID ELECTRON CRYOMICROSCOPY; ATOMIC MODEL; CLASSIFICATION; VIRUS; CRYSTALLOGRAPHY; ORGANIZATION; ARCHITECTURE; RIBOSOME; GENOME AB We have previously used cryo-electron tomography combined with sub-volume averaging and classification to obtain 3D structures of macromolecular assemblies in cases where a single dominant species was present, and applied these methods to the analysis of a variety of trimeric HIV-1 and Sly envelope glycoproteins (Env). Here, we extend these studies by demonstrating automated, iterative, missing wedge-corrected 3D image alignment and classification methods to distinguish multiple conformations that are present simultaneously. We present a method for measuring the spatial distribution of the vector elements representing distinct conformational states of Env. We identify data processing strategies that allow clear separation of the previously characterized closed and open conformations, as well as unliganded and antibody-liganded states of Env when they are present in mixtures. We show that identifying and removing spikes with the lowest signal-to-noise ratios improves the overall accuracy of alignment between individual Env sub-volumes, and that alignment accuracy, in turn, determines the success of image classification in assessing conformational heterogeneity in heterogeneous mixtures. We validate these procedures for computational separation by successfully separating and reconstructing distinct 3D structures for unliganded and antibody-liganded as well as open and closed conformations of Env present simultaneously in mixtures. Published by Elsevier Inc. C1 [Frank, Gabriel A.; Bartesaghi, Alberto; Borgnia, Mario J.; White, Tommi A.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kuybeda, Oleg; Sapiro, Guillermo] Univ Minnesota, Dept Elect & Comp Engn, Minneapolis, MN 55455 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov FU Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD; Department of Defense; intramural AIDS Research Fellowship FX This work was supported by funds from the Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD (to S.S.), the Department of Defense (to G.S.) and an intramural AIDS Research Fellowship (to G.A.F.). We thank Steve Fellini, Susan Chacko and their colleagues for continued support with use of the Biowulf cluster for computing at NIH. NR 33 TC 15 Z9 15 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAY PY 2012 VL 178 IS 2 SI SI BP 165 EP 176 DI 10.1016/j.jsb.2012.01.004 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 945PB UT WOS:000304287400011 PM 22248450 ER PT J AU Ishijima, M Suzuki, N Hozumi, K Matsunobu, T Kosaki, K Kaneko, H Hassell, JR Arikawa-Hirasawa, E Yamada, Y AF Ishijima, Muneaki Suzuki, Nobuharu Hozumi, Kentaro Matsunobu, Tomoya Kosaki, Keisuke Kaneko, Haruka Hassell, John R. Arikawa-Hirasawa, Eri Yamada, Yoshihiko TI Perlecan modulates VEGF signaling and is essential for vascularization in endochondral bone formation SO MATRIX BIOLOGY LA English DT Article DE Perlecan; Endochondral bone formation; Growth plate; Vascular invasion; VEGF signaling ID ENDOTHELIAL GROWTH-FACTOR; SCHWARTZ-JAMPEL-SYNDROME; SILVERMAN-HANDMAKER TYPE; HEPARAN-SULFATE; FACTOR-RECEPTOR; BRANCHING MORPHOGENESIS; ALPHA-2-BETA-1 INTEGRIN; DYSSEGMENTAL DYSPLASIA; IMPAIRED ANGIOGENESIS; CARTILAGE DEVELOPMENT AB Perlecan (Hspg2) is a heparan sulfate proteoglycan expressed in basement membranes and cartilage. Perlecan deficiency (Hspg2(-/-)) in mice and humans causes lethal chondrodysplasia, which indicates that perlecan is essential for cartilage development. However, the function of perlecan in endochondral ossification is not clear. Here, we report the critical role of perlecan in VEGF signaling and angiogenesis in growth plate formation. The Hspg2(-/-) growth plate was significantly wider but shorter due to severely impaired endochondral bone formation. Hypertrophic chondrocytes were differentiated in Hspg2(-/-) growth plates; however, removal of the hypertrophic matrix and calcified cartilage was inhibited. Although the expression of MMP-13, CTGF, and VEGFA was significantly upregulated in Hspg2(-/-) growth plates, vascular invasion into the hypertrophic zone was impaired, which resulted in an almost complete lack of bone marrow and trabecular bone. We demonstrated that cartilage perlecan promoted activation of VEGF/VEGFR by binding to the VEGFR of endothelial cells. Expression of the perlecan transgene specific to the cartilage of Hspg2(-/-) mice rescued their perinatal lethality and growth plate abnormalities, and vascularization into the growth plate was restored, indicating that perlecan in the growth plate, not in endothelial cells, is critical in this process. These results suggest that perlecan in cartilage is required for activating VEGFR signaling of endothelial cells for vascular invasion and for osteoblast migration into the growth plate. Thus, perlecan in cartilage plays a critical role in endochondral bone formation by promoting angiogenesis essential for cartilage matrix remodeling and subsequent endochondral bone formation. Published by Elsevier B.V. C1 [Ishijima, Muneaki; Suzuki, Nobuharu; Hozumi, Kentaro; Matsunobu, Tomoya; Kosaki, Keisuke; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Ishijima, Muneaki; Kaneko, Haruka] Juntendo Univ, Grad Sch Med, Dept Med Motor Organs, Tokyo 1138421, Japan. [Hassell, John R.] Univ S Florida, Coll Med, Dept Mol Med, Tampa, FL 33612 USA. [Arikawa-Hirasawa, Eri] Juntendo Univ, Grad Sch Med, Res Inst Dis Old Age, Tokyo 1138421, Japan. RP Yamada, Y (reprint author), NIDCR, Lab Cell & Dev Biol, NIH, Bldg 30,Rm 407,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM yoshi.yamada@nih.gov FU NIDCR, NIH; Ministry of Education, Science, and Culture of Japan [19791047, 21791418, 22300223]; Japan Society for the Promotion of Science FX This work was supported by the Intramural Program of the NIDCR, NIH (Y.Y.), and grant-in-aid (to 19791047 and 21791418 for M.I and 22300223 for E.A-E) from the Ministry of Education, Science, and Culture of Japan. M.I., N.S., K.H., and T.M. were supported in part by a fellowship from the Japan Society for the Promotion of Science. NR 63 TC 29 Z9 31 U1 3 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD MAY PY 2012 VL 31 IS 4 BP 234 EP 245 DI 10.1016/j.matbio.2012.02.006 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 948RH UT WOS:000304519800002 PM 22421594 ER PT J AU Ding, KY Shameer, K Jouni, H Masys, DR Jarvik, GP Kho, AN Ritchie, MD McCarty, CA Chute, CG Manolio, TA Kullo, IJ AF Ding, Keyue Shameer, Khader Jouni, Hayan Masys, Daniel R. Jarvik, Gail P. Kho, Abel N. Ritchie, Marylyn D. McCarty, Catherine A. Chute, Christopher G. Manolio, Teri A. Kullo, Iftikhar J. TI Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits SO MAYO CLINIC PROCEEDINGS LA English DT Article ID GENOME-WIDE ASSOCIATION; HORMONE RECEPTOR-BETA; TRANSCRIPTION FACTOR; ERYTHROPOIESIS; IDENTIFICATION; CONSORTIUM; EXPRESSION; BINDING; PROTEIN; REPLICATION AB Objective: To identify common genetic variants influencing red blood cell (RBC) traits. Patients and Methods: We performed a genomewide association study from June 2008 through July 2011 of hemoglobin, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration in 12,486 patients of European ancestry from the electronic MEdical Records and Genomics (eMERGE) network. We developed an electronic medical record-based algorithm that included individuals who had RBC measurements obtained for clinical care and excluded values measured in the setting of hematopoietic disorders, comorbid conditions, or medications known to affect RBC production or a recent history of blood loss. Results: We identified 4 new genetic loci and replicated 11 loci previously reported to be associated with one or more RBC traits in individuals of European ancestry. Notably, genes present in 3 of the 4 newly identified loci (THRB, PTPLAD1, CDT1) and in 6 of the 11 replicated loci (KLF1, ALDH8A1, CCND3, SPTA1, FBXO7, TFR2/EPO) are implicated in erythroid differentiation and regulation of cell cycle in hematopoietic stem cells. Conclusion: Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits. (C) 2012 Mayo Foundation for Medical Education and Research square Mayo Clin Proc. 2012:87(5):461-474 C1 [Ding, Keyue; Shameer, Khader; Jouni, Hayan; Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Chute, Christopher G.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Masys, Daniel R.] Univ Washington, Div Biomed & Hlth Informat, Dept Med Educ & Biomed Informat, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Kho, Abel N.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. RP Kullo, IJ (reprint author), Mayo Clin, Div Cardiovasc Dis, 200 1st St SW, Rochester, MN 55905 USA. EM Kullo.iftikhar@mayo.edu RI Ritchie, Marylyn/C-1114-2012; Jarvik, Gail/N-6476-2014; Khader, Shameer/J-2564-2016; OI Jarvik, Gail/0000-0002-6710-8708; Khader, Shameer/0000-0002-9982-1911 FU National Human Genome Research Institute; National Institute of General Medical Sciences [U01-HG-04599, U01-HG-004610 (GHC), U01-HG-004608 (MC), U01HG004609 (NU), U01-HG-04603] FX The eMERGE network was initiated and funded by the National Human Genome Research Institute, with additional funding from National Institute of General Medical Sciences through the following grants: U01-HG-04599 (Mayo Clinic), U01-HG-004610 (GHC), U01-HG-004608 (MC), U01HG004609 (NU), and U01-HG-04603 (VUMC, also serving as the administrative coordinating center). NR 52 TC 16 Z9 18 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD MAY PY 2012 VL 87 IS 5 BP 461 EP 474 DI 10.1016/j.mayocp.2012.01.016 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 944IX UT WOS:000304194300011 PM 22560525 ER PT J AU Estrada, K Styrkarsdottir, U Evangelou, E Hsu, YH Duncan, EL Ntzani, EE Oei, L Albagha, OME Amin, N Kemp, JP Koller, DL Li, G Liu, CT Minster, RL Moayyeri, A Vandenput, L Willner, D Xiao, SM Yerges-Armstrong, LM Zheng, HF Alonso, N Eriksson, J Kammerer, CM Kaptoge, SK Leo, PJ Thorleifsson, G Wilson, SG Wilson, JF Aalto, V Alen, M Aragaki, AK Aspelund, T Center, JR Dailiana, Z Duggan, DJ Garcia, M Garcia-Giralt, N Giroux, S Hallmans, G Hocking, LJ Husted, LB Jameson, KA Khusainova, R Kim, GS Kooperberg, C Koromila, T Kruk, M Laaksonen, M Lacroix, AZ Lee, SH Leung, PC Lewis, JR Masi, L Mencej-Bedrac, S Nguyen, TV Nogues, X Patel, MS Prezelj, J Rose, LM Scollen, S Siggeirsdottir, K Smith, AV Svensson, O Trompet, S Trummer, O van Schoor, NM Woo, J Zhu, K Balcells, S Brandi, ML Buckley, BM Cheng, SL Christiansen, C Cooper, C Dedoussis, G Ford, I Frost, M Goltzman, D Gonzalez-Macias, J Kahonen, M Karlsson, M Khusnutdinova, E Koh, JM Kollia, P Langdahl, BL Leslie, WD Lips, P Ljunggren, O Lorenc, RS Marc, J Mellstrom, D Obermayer-Pietsch, B Olmos, JM Pettersson-Kymmer, U Reid, DM Riancho, JA Ridker, PM Rousseau, F Slagboom, PE Tang, NLS Urreizti, R Van Hul, W Viikari, J Zarrabeitia, MT Aulchenko, YS Castano-Betancourt, M Grundberg, E Herrera, L Ingvarsson, T Johannsdottir, H Kwan, T Li, R Luben, R Medina-Gomez, C Palsson, ST Reppe, S Rotter, JI Sigurdsson, G van Meurs, JBJ Verlaan, D Williams, FMK Wood, AR Zhou, YH Gautvik, KM Pastinen, T Raychaudhuri, S Cauley, JA Chasman, DI Clark, GR Cummings, SR Danoy, P Dennison, EM Eastell, R Eisman, JA Gudnason, V Hofman, A Jackson, RD Jones, G Jukema, JW Khaw, KT Lehtimaki, T Liu, YM Lorentzon, M McCloskey, E Mitchell, BD Nandakumar, K Nicholson, GC Oostra, BA Peacock, M Pols, HAP Prince, RL Raitakari, O Reid, IR Robbins, J Sambrook, PN Sham, PC Shuldiner, AR Tylavsky, FA van Duijn, CM Wareham, NJ Cupples, LA Econs, MJ Evans, DM Harris, TB Kung, AWC Psaty, BM Reeve, J Spector, TD Streeten, EA Zillikens, MC Thorsteinsdottir, U Ohlsson, C Karasik, D Richards, JB Brown, MA Stefansson, K Uitterlinden, AG Ralston, SH Ioannidis, JPA Kiel, DP Rivadeneira, F AF Estrada, Karol Styrkarsdottir, Unnur Evangelou, Evangelos Hsu, Yi-Hsiang Duncan, Emma L. Ntzani, Evangelia E. Oei, Ling Albagha, Omar M. E. Amin, Najaf Kemp, John P. Koller, Daniel L. Li, Guo Liu, Ching-Ti Minster, Ryan L. Moayyeri, Alireza Vandenput, Liesbeth Willner, Dana Xiao, Su-Mei Yerges-Armstrong, Laura M. Zheng, Hou-Feng Alonso, Nerea Eriksson, Joel Kammerer, Candace M. Kaptoge, Stephen K. Leo, Paul J. Thorleifsson, Gudmar Wilson, Scott G. Wilson, James F. Aalto, Ville Alen, Markku Aragaki, Aaron K. Aspelund, Thor Center, Jacqueline R. Dailiana, Zoe Duggan, David J. Garcia, Melissa Garcia-Giralt, Natalia Giroux, Sylvie Hallmans, Goran Hocking, Lynne J. Husted, Lise Bjerre Jameson, Karen A. Khusainova, Rita Kim, Ghi Su Kooperberg, Charles Koromila, Theodora Kruk, Marcin Laaksonen, Marika Lacroix, Andrea Z. Lee, Seung Hun Leung, Ping C. Lewis, Joshua R. Masi, Laura Mencej-Bedrac, Simona Nguyen, Tuan V. Nogues, Xavier Patel, Millan S. Prezelj, Janez Rose, Lynda M. Scollen, Serena Siggeirsdottir, Kristin Smith, Albert V. Svensson, Olle Trompet, Stella Trummer, Olivia van Schoor, Natasja M. Woo, Jean Zhu, Kun Balcells, Susana Brandi, Maria Luisa Buckley, Brendan M. Cheng, Sulin Christiansen, Claus Cooper, Cyrus Dedoussis, George Ford, Ian Frost, Morten Goltzman, David Gonzalez-Macias, Jesus Kahonen, Mika Karlsson, Magnus Khusnutdinova, Elza Koh, Jung-Min Kollia, Panagoula Langdahl, Bente Lomholt Leslie, William D. Lips, Paul Ljunggren, Osten Lorenc, Roman S. Marc, Janja Mellstrom, Dan Obermayer-Pietsch, Barbara Olmos, Jose M. Pettersson-Kymmer, Ulrika Reid, David M. Riancho, Jose A. Ridker, Paul M. Rousseau, Francois Slagboom, P. Eline Tang, Nelson L. S. Urreizti, Roser Van Hul, Wim Viikari, Jorma Zarrabeitia, Maria T. Aulchenko, Yurii S. Castano-Betancourt, Martha Grundberg, Elin Herrera, Lizbeth Ingvarsson, Thorvaldur Johannsdottir, Hrefna Kwan, Tony Li, Rui Luben, Robert Medina-Gomez, Carolina Palsson, Stefan Th Reppe, Sjur Rotter, Jerome I. Sigurdsson, Gunnar van Meurs, Joyce B. J. Verlaan, Dominique Williams, Frances M. K. Wood, Andrew R. Zhou, Yanhua Gautvik, Kaare M. Pastinen, Tomi Raychaudhuri, Soumya Cauley, Jane A. Chasman, Daniel I. Clark, Graeme R. Cummings, Steven R. Danoy, Patrick Dennison, Elaine M. Eastell, Richard Eisman, John A. Gudnason, Vilmundur Hofman, Albert Jackson, Rebecca D. Jones, Graeme Jukema, J. Wouter Khaw, Kay-Tee Lehtimaki, Terho Liu, Yongmei Lorentzon, Mattias McCloskey, Eugene Mitchell, Braxton D. Nandakumar, Kannabiran Nicholson, Geoffrey C. Oostra, Ben A. Peacock, Munro Pols, Huibert A. P. Prince, Richard L. Raitakari, Olli Reid, Ian R. Robbins, John Sambrook, Philip N. Sham, Pak Chung Shuldiner, Alan R. Tylavsky, Frances A. van Duijn, Cornelia M. Wareham, Nick J. Cupples, L. Adrienne Econs, Michael J. Evans, David M. Harris, Tamara B. Kung, Annie Wai Chee Psaty, Bruce M. Reeve, Jonathan Spector, Timothy D. Streeten, Elizabeth A. Zillikens, M. Carola Thorsteinsdottir, Unnur Ohlsson, Claes Karasik, David Richards, J. Brent Brown, Matthew A. Stefansson, Kari Uitterlinden, Andre G. Ralston, Stuart H. Ioannidis, John P. A. Kiel, Douglas P. Rivadeneira, Fernando TI Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture SO NATURE GENETICS LA English DT Article ID OSTEOPOROTIC FRACTURES; GENE-EXPRESSION; IMPUTED DATA; VARIANTS; DISEASE; WOMEN; LRP5; POPULATION; IMPUTATION; PATTERNS AB Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 x 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 x 10(-4), Bonferroni corrected), of which six reached P < 5 x 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. C1 [Estrada, Karol; Oei, Ling; Castano-Betancourt, Martha; Herrera, Lizbeth; Medina-Gomez, Carolina; van Meurs, Joyce B. J.; Pols, Huibert A. P.; Zillikens, M. Carola; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Estrada, Karol; Oei, Ling; Amin, Najaf; Aulchenko, Yurii S.; Castano-Betancourt, Martha; Medina-Gomez, Carolina; van Meurs, Joyce B. J.; Hofman, Albert; Pols, Huibert A. P.; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Estrada, Karol; Oei, Ling; Slagboom, P. Eline; Castano-Betancourt, Martha; van Meurs, Joyce B. J.; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando] Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands. [Styrkarsdottir, Unnur; Thorleifsson, Gudmar; Johannsdottir, Hrefna; Palsson, Stefan Th; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Evangelou, Evangelos; Ntzani, Evangelia E.; Ioannidis, John P. A.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Hsu, Yi-Hsiang; Nandakumar, Kannabiran; Karasik, David; Kiel, Douglas P.] Hebrew SeniorLife, Inst Aging Res, Boston, MA USA. [Hsu, Yi-Hsiang; Nandakumar, Kannabiran; Karasik, David; Kiel, Douglas P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Duncan, Emma L.; Willner, Dana; Leo, Paul J.; Clark, Graeme R.; Danoy, Patrick; Brown, Matthew A.] Univ Queensland, Diamantina Inst, Human Genet Grp, Brisbane, Qld, Australia. [Duncan, Emma L.] Royal Brisbane & Womens Hosp, Dept Endocrinol, Brisbane, Qld, Australia. [Albagha, Omar M. E.; Alonso, Nerea; Ralston, Stuart H.] Univ Edinburgh, Rheumat Dis Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Kemp, John P.; Evans, David M.] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England. [Koller, Daniel L.; Econs, Michael J.] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Li, Guo] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Liu, Ching-Ti; Zhou, Yanhua; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Minster, Ryan L.; Kammerer, Candace M.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Moayyeri, Alireza; Kaptoge, Stephen K.; Luben, Robert; Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Moayyeri, Alireza; Wilson, Scott G.; Williams, Frances M. K.; Spector, Timothy D.; Richards, J. Brent] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Vandenput, Liesbeth; Eriksson, Joel; Mellstrom, Dan; Lorentzon, Mattias; Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden. [Willner, Dana] Univ Queensland, Australian Ctr Ecogenom, Brisbane, Qld, Australia. [Xiao, Su-Mei; Kung, Annie Wai Chee] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Xiao, Su-Mei; Kung, Annie Wai Chee] Univ Hong Kong, Res Ctr Heart Brain Hormone & Hlth Aging, Hong Kong, Hong Kong, Peoples R China. [Yerges-Armstrong, Laura M.; Mitchell, Braxton D.; Shuldiner, Alan R.; Streeten, Elizabeth A.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Zheng, Hou-Feng; Richards, J. Brent] McGill Univ, Dept Human Genet, Lady Davis Inst, Montreal, PQ, Canada. [Wilson, Scott G.; Lewis, Joshua R.; Zhu, Kun; Prince, Richard L.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Wilson, Scott G.; Lewis, Joshua R.; Zhu, Kun; Prince, Richard L.] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Perth, WA, Australia. [Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Wilson, James F.] Univ Edinburgh, MRC Human Genet Unit, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Aalto, Ville; Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Aalto, Ville; Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Alen, Markku] Oulu Univ Hosp, Dept Med Rehabil, Oulu, Finland. [Alen, Markku] Inst Hlth Sci, Oulu, Finland. [Aragaki, Aaron K.; Kooperberg, Charles; Lacroix, Andrea Z.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Aspelund, Thor; Siggeirsdottir, Kristin; Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Smith, Albert V.; Ingvarsson, Thorvaldur; Sigurdsson, Gunnar; Gudnason, Vilmundur; Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Center, Jacqueline R.; Nguyen, Tuan V.; Eisman, John A.] Garvan Inst Med Res, Osteoporosis & Bone Biol Program, Sydney, NSW, Australia. [Nguyen, Tuan V.; Eisman, John A.] Univ New S Wales, Dept Med, Sydney, NSW, Australia. [Center, Jacqueline R.; Eisman, John A.] St Vincents Hosp, Dept Endocrinol, Sydney, NSW 2010, Australia. [Dailiana, Zoe] Univ Thessalia, Sch Med, Dept Orthopaed Surg, Larisa, Greece. [Duggan, David J.] Translat Genom Res Inst, Phoenix, AZ USA. [Garcia, Melissa; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Garcia-Giralt, Natalia; Nogues, Xavier] Univ Autonoma Barcelona, Red Lemat Invest Cooperat Envejecimiento & Fragil, Dept Internal Med, Hosp Mar,IMIM, E-08193 Barcelona, Spain. [Giroux, Sylvie; Rousseau, Francois] CHUQ HSFA, Unite Rech Genet Humaine & Mol, Ctr Rech, Quebec City, PQ, Canada. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Hocking, Lynne J.; Reid, David M.] Univ Aberdeen, Musculoskeletal Res Programme, Div Appl Med, Aberdeen, Scotland. [Husted, Lise Bjerre; Langdahl, Bente Lomholt] Aarhus Univ Hosp, Dept Endocrinol & Internal Med, Aarhus C, Denmark. [Jameson, Karen A.; Cooper, Cyrus; Dennison, Elaine M.] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Khusainova, Rita; Khusnutdinova, Elza] Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa 450001, Russia. [Khusainova, Rita; Khusnutdinova, Elza] Bashkir State Univ, Dept Biol, Ufa 450074, Russia. [Kim, Ghi Su; Lee, Seung Hun; Koh, Jung-Min] Univ Ulsan, Coll Med, Asan Med Ctr, Div Endocrinol & Metab, Seoul, South Korea. [Koromila, Theodora; Kollia, Panagoula] Univ Athens, Fac Biol, Dept Genet & Biotechnol, Athens, Greece. [Kruk, Marcin; Lorenc, Roman S.] Childrens Mem Hlth Inst, Dept Biochem & Expt Med, Warsaw, Poland. [Laaksonen, Marika] Univ Helsinki, Dept Food & Environm Sci, Helsinki, Finland. [Leung, Ping C.] Chinese Univ Hong Kong, Jockey Club Ctr Osteoporosis Care & Control, Hong Kong, Hong Kong, Peoples R China. [Masi, Laura; Brandi, Maria Luisa] Univ Florence, Dept Internal Med, Florence, Italy. [Mencej-Bedrac, Simona; Marc, Janja] Univ Ljubljana, Dept Clin Biochem, Ljubljana, Slovenia. [Patel, Millan S.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Prezelj, Janez] Univ Med Ctr, Dept Endocrinol, Ljubljana, Slovenia. [Rose, Lynda M.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Scollen, Serena] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England. [Svensson, Olle] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Trummer, Olivia; Obermayer-Pietsch, Barbara] Med Univ Graz, Dept Internal Med, Div Endocrinol & Metab, Graz, Austria. [van Schoor, Natasja M.] Vrije Univ, Univ Med Ctr, Dept Epidemiol & Biostat, Extramuraal Geneeskundig Onderzoek EMGO Inst Hlth, Amsterdam, Netherlands. [Woo, Jean] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Balcells, Susana; Urreizti, Roser] Univ Barcelona, Dept Genet, Inst Biomed, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain. [Buckley, Brendan M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Cheng, Sulin] Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland. [Cheng, Sulin] Kuopio Univ Hosp, Dept Orthopaed & Traumatol, SF-70210 Kuopio, Finland. [Christiansen, Claus] Ctr Clin & Basic Res CCBR Synarc, Ballerup, Denmark. [Dedoussis, George] Harokopio Univ, Dept Nutr & Dietet, Athens, Greece. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Frost, Morten] Odense Univ Hosp, Dept Endocrinol, DK-5000 Odense, Denmark. [Frost, Morten] Univ So Denmark, Clin Inst, Odense, Denmark. [Goltzman, David] McGill Univ, Dept Med, Montreal, PQ, Canada. [Gonzalez-Macias, Jesus; Olmos, Jose M.; Riancho, Jose A.] Univ Cantabria, Dept Med, E-39005 Santander, Spain. [Gonzalez-Macias, Jesus; Olmos, Jose M.; Riancho, Jose A.] Hosp Univ Marques de Valdecilla, Dept Internal Med, Santander, Spain. [Gonzalez-Macias, Jesus; Olmos, Jose M.; Riancho, Jose A.] Inst Formac & Invest Marques de Valdecilla IFIMAV, Santander, Spain. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Karlsson, Magnus] Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden. [Karlsson, Magnus] Lund Univ, Dept Orthopaed, Malmo, Sweden. [Leslie, William D.] Univ Manitoba, Dept Internal Med, Winnipeg, MB, Canada. [Lips, Paul] Vrije Univ Amsterdam, Med Ctr, Dept Endocrinol, Amsterdam, Netherlands. [Lips, Paul] Vrije Univ Amsterdam, Med Ctr, Extramuraal Geneeskundig Onderzoek EMGO Inst Hlth, Amsterdam, Netherlands. [Ljunggren, Osten] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Pettersson-Kymmer, Ulrika] Umea Univ, Dept Pharmacol & Neurosci, Umea, Sweden. [Rousseau, Francois] Univ Laval, Dept Mol Biol Med Biochem & Pathol, Quebec City, PQ, Canada. [Rousseau, Francois] Univ Laval, APOGFF Net CanGeneTest Network Genet Hlth Serv &, Quebec City, PQ, Canada. [Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [Tang, Nelson L. S.] Chinese Univ Hong Kong, Dept Chem Pathol, Hong Kong, Hong Kong, Peoples R China. [Tang, Nelson L. S.] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China. [Van Hul, Wim] Univ Antwerp, Dept Med Genet, B-2020 Antwerp, Belgium. [Viikari, Jorma] Turku Univ Hosp, Dept Med, FIN-20520 Turku, Finland. [Zarrabeitia, Maria T.] Univ Cantabria, Dept Legal Med, E-39005 Santander, Spain. [Grundberg, Elin; Kwan, Tony; Verlaan, Dominique; Pastinen, Tomi] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Grundberg, Elin; Kwan, Tony; Verlaan, Dominique; Pastinen, Tomi] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Grundberg, Elin] Wellcome Trust Sanger Inst, Cambridge, England. [Ingvarsson, Thorvaldur] Akureyri Hosp, Dept Orthoped Surg, Akureyri, Iceland. [Ingvarsson, Thorvaldur] Univ Akureyri, Inst Hlth Sci, Akureyri, Iceland. [Li, Rui; Richards, J. Brent] McGill Univ, Dept Epidemiol & Biostat, Lady Davis Inst, Montreal, PQ, Canada. [Reppe, Sjur; Gautvik, Kaare M.] Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA. [Sigurdsson, Gunnar] Univ Hosp, Dept Endocrinol & Metab, Reykjavik, Iceland. [Wood, Andrew R.] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Gautvik, Kaare M.] Lovisenberg Deacon Hosp, Dept Clin Biochem, Oslo, Norway. [Gautvik, Kaare M.] Univ Oslo, Inst Basic Med Sci, Oslo, Norway. [Pastinen, Tomi] McGill Univ, Ctr Hlth, Dept Med Genet, Montreal, PQ, Canada. [Raychaudhuri, Soumya] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet & Rheumatol, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Cauley, Jane A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Cummings, Steven R.] Calif Pacific Med Ctr, San Francisco, CA USA. [Eastell, Richard; McCloskey, Eugene] Univ Sheffield, NIHR, Musculoskeletal Biomed Res Unit, Sheffield, S Yorkshire, England. [Jackson, Rebecca D.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Jackson, Rebecca D.] Ohio State Univ, Ctr Clin & Translat Sci, Columbus, OH 43210 USA. [Jones, Graeme] Univ Tasmania, Menzies Res Inst, Hobart, Tas, Australia. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Lehtimaki, Terho] Tampere Univ Hosp, Dept Clin Chem, FIN-33521 Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland. [Lehtimaki, Terho] Fimlab, Tampere, Finland. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. [McCloskey, Eugene] Univ Sheffield, Acad Unit Bone Metab, Metab Bone Ctr, Sheffield, S Yorkshire, England. [Nicholson, Geoffrey C.] Univ Queensland, Rural Clin Sch, Toowoomba, Qld, Australia. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Peacock, Munro; Econs, Michael J.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN USA. [Reid, Ian R.] Univ Auckland, Dept Med, Auckland, New Zealand. [Robbins, John] Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA. [Sambrook, Philip N.] Univ Sydney, Kolling Inst, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Sham, Pak Chung] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China. [Sham, Pak Chung] Univ Hong Kong, Ctr Reprod Dev & Growth, Hong Kong, Hong Kong, Peoples R China. [Shuldiner, Alan R.; Streeten, Elizabeth A.] Vet Adm Med Ctr, GRECC, Baltimore, MD 21218 USA. [Tylavsky, Frances A.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Wareham, Nick J.] MRC, MRC Epidemiol Unit Box 285, Cambridge, England. [Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Richards, J. Brent] McGill Univ, Dept Med, Lady Davis Inst, Montreal, PQ, Canada. [Ioannidis, John P. A.] Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. RP Rivadeneira, F (reprint author), Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. EM f.rivadeneira@erasmusmc.nl RI Zheng, Houfeng/K-4424-2012; Evangelou, Evangelos/C-3033-2013; Li, Guo/E-5613-2012; Oei, Ling/E-8163-2013; Aspelund, Thor/C-5983-2008; Evans, David/H-6325-2013; Reeve, Jonathan/C-7551-2012; Dzhemileva, Lilya/K-8636-2013; Duncan, Emma/L-1224-2013; Zhu, Kun/L-2208-2013; Lewis, Joshua/D-5077-2013; Nicholson, Geoffrey/F-1901-2010; Khusnutdinova, Elza/A-4810-2013; Slagboom, P. Eline/R-4790-2016; Balcells, Susana/C-5222-2017; Aulchenko, Yurii/M-8270-2013; Eisman, John/C-2886-2014; Leo, Paul/B-3470-2011; Urreizti, Roser/M-6402-2014; Moayyeri, Alireza/N-3332-2014; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Woo, Jean/K-2625-2014; Rivadeneira, Fernando/O-5385-2015; Frost, Morten/G-9410-2011; Smith, Albert/K-5150-2015 OI Zheng, Houfeng/0000-0002-5684-8313; Oei, Ling/0000-0003-3523-458X; Aspelund, Thor/0000-0002-7998-5433; Reeve, Jonathan/0000-0002-4364-2682; Dzhemileva, Lilya/0000-0003-3315-4746; Duncan, Emma/0000-0002-8143-4403; Zhu, Kun/0000-0002-8723-7574; Lewis, Joshua/0000-0003-1003-8443; Nicholson, Geoffrey/0000-0002-0152-1153; Medina-Gomez, Carolina/0000-0001-7999-5538; Center, Jacqueline/0000-0002-5278-4527; Kemp, John/0000-0002-9105-2249; Evans, David/0000-0003-0663-4621; Mitchell, Braxton/0000-0003-4920-4744; Evangelou, Evangelos/0000-0002-5488-2999; Cauley, Jane A/0000-0003-0752-4408; Pettersson Kymmer, Ulrika/0000-0002-0557-9803; marc, janja/0000-0001-6013-9758; Nguyen, Tuan V./0000-0002-3246-6281; Leslie, William/0000-0002-1056-1691; Hocking, Lynne J/0000-0002-2414-2826; Tang, Nelson/0000-0002-3607-5819; Brown, Matthew A/0000-0003-0538-8211; Luben, Robert/0000-0002-5088-6343; Kiel, Douglas/0000-0001-8474-0310; Karasik, David/0000-0002-8826-0530; Vandenput, Liesbeth/0000-0002-1712-6131; Slagboom, P. Eline/0000-0002-2875-4723; Balcells, Susana/0000-0003-1211-1907; Cupples, L. Adrienne/0000-0003-0273-7965; Williams, Frances/0000-0002-2998-2744; Scollen, Serena/0000-0002-9311-1337; Aulchenko, Yurii/0000-0002-7899-1575; Leo, Paul/0000-0001-8325-4134; Urreizti, Roser/0000-0003-3617-7134; Moayyeri, Alireza/0000-0002-9143-2161; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Woo, Jean/0000-0001-7593-3081; Rivadeneira, Fernando/0000-0001-9435-9441; Frost, Morten/0000-0002-5608-1589; Smith, Albert/0000-0003-1942-5845 FU European Commission [HEALTH-F2-2008-201865-GEFOS, QLRT-2001-02629]; US National Institutes of Health (NIH) [R01 AG18728, R01 HL088119, R01AR046838, U01 HL084756, P30 DK072488, T32 AG000262, F32 AR059469, P01 AG-18397, R01 AG041517, M01 RR-00750, N01-AG-12100]; NIA [AG-023629, AG-15928, AG-20098, AG-027058]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Australian National Health and Medical Research Council [511132, 569807]; Australian Cancer Research Foundation; Rebecca Cooper Foundation; MRC [MRC G0800582, 254627, 303169, 572604]; Health Research Council of New Zealand; Sanofi-Aventis; Eli Lilly; Pfizer; Proctor & Gamble Pharmaceuticals; Roche; Living Well Foundation; Ernst Heine Family Foundation; Arthritis Research UK [17539, 15389]; Victorian Health Promotion Foundation; Geelong Region Medical Research Foundation, Australia [628582]; Action Research UK; UK Food Standards Agency; BioPersMed [825329]; Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT); Austrian Federal Ministry of Economics and Labour (BMWA); Austrian Federal Ministry of Economy, Family and Youth (BMWFJ); Styrian Business Promotion Agency (SFG); Red de Envejecimiento y Fragilidad (RETICEF); Instituto Carlos III; Spanish Ministry of Education and Science [SAF2010-15707]; Government of Catalonia [2009SGR971, 2009SGR818]; Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias [PI 06/0034, PI08/0183]; Healthway Health Promotion Foundation of Western Australia; Australasian Menopause Society; Australian National Health; Merck Frosst Canada; Eli Lilly Canada; Novartis Pharmaceuticals; Procter & Gamble Pharmaceuticals Canada; Servier Canada; Amgen Canada; Dairy Farmers of Canada; Arthritis Society; US National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HL075366, HL087652, HL105756 NINDS, HL 043851, HL69757, CA 047988]; Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc, for genotyping services [N02-HL-6-4278]; Eli Lilly International; Amgen; GE-Lunar; Merck Australia; Sanofi-Aventis Australia; Servier; US National Center for Research Resources [M01-RR00425]; US National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; deCODE Genetics; UK National Institute for Medical Research (NIMR) Biomedical Research Centre; Cancer Research Campaign; Stroke Association; British Heart Foundation; UK Department of Health; Europe Against Cancer Programme Commission of the European Union; Ministry of Agriculture, Fisheries and Food, EU Biomed 1 [BMHICT920182, CIPDCT925012, ERBC1PDCT 940229, ERBC1PDCT930105]; UK MRC [G9321536, G9800062]; Wellcome Trust Collaborative Research Initiative; MAFF [AN0523]; EU [QLK6-CT-2002-02629, LSHG-CT-2006-018947, HEALTH-F2-2009-223004 PHASE]; Food Standards Agency [N05046]; Netherlands Organization for Scientific Research (NWO); Erasmus University Medical Center; Centre for Medical Systems Biology of the Netherlands Genomics Initiative (NGI) [CMSB1, CMSB2]; F.I.R.M.O. Fondazione Raffaella Becagli; National Institute on Aging [R01 AR/AG 41398, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098, R01 AR 050066]; Canadian Institutes for Health Research [86748]; Ministry of Education and Science of the Russian Federation Scientific and Pedagogical Staff of Innovative Russia [P-601]; Federal Program Research and Development of Prior Directions of Scientific-Technological Complex of Russia [16.512.11.2032]; Swedish Research Council [K2010-54X-09894-19-3, 2006-3832, K2010-52X-20229-05-3, K20006-72X-20155013]; Swedish Foundation for Strategic Research; ALF/LUA; Lundberg Foundation; Torsten and Ragnar Sderberg's Foundation; Vastra Gotaland Foundation; Goteborg Medical Society; Novo Nordisk foundation, University of Athens, Greece; UK NIHR Musculoskeletal BRU Oxford; UK NIHR Nutrition BRU Southampton; Center for Inherited Disease Research (CIDR); National Institutes of Health [HHSN268200782096C]; Hong Kong Research Grant Council [HKU 768610M]; HKU Foundation; KC Wong Education Foundation [201007176237]; Committee of Research and Conference Grants (CRCG); Osteoporosis and Endocrine Research Fund; Genomics Strategic Research Theme of The University of Hong Kong; Chinese University of Hong Kong; Korea Health 21 Research & Development Project; Korean Ministry of Health & Welfare, Republic of Korea [A010252]; Korea Healthcare Technology Research & Development Project; Ministry for Health, Welfare and Family Affairs [A110536]; Netherlands Ministry of Health, Welfare and Sports Directorate of Long-Term Care; World Anti-Doping Agency; Danish Ministry of Culture; Institute of Clinical Research of the University of Southern Denmark; Chief Scientists Office of the Scottish Government [CZB/4/276]; Royal Society; Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [RIDE2; 014-93-015]; Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging [01 IG 07015 G]; NIHR Biomedical Research Centre; Chronic Disease Research Foundation; Canadian Institutes of Health Research; Canadian Foundation for Innovation; Fonds de la Recherche en Sante Quebec; Lady Davis Institute; Jewish General Hospital; Ministere du Developpement Economique; Swedish Sports Research Council [87/06]; Swedish Society of Medicine; Kempe Foundation [JCK-1021]; Medical Faculty of Umea University [ALFVLL:968:22-2005, ALFVL:-937-2006, ALFVLL:223:11-2007, ALFVLL:78151-2009]; County Council of Vasterbotten (Spjutspetsanslag) [VLL:159:33-2007]; Donald W. Reynolds Foundation; Fondation Leducq; Academy of Finland [126925, 121584, 124282, 129378, 117787, 41071]; Social Insurance Institution of Finland; Tampere and Turku University; Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation [K08AR055688] FX We thank all study participants for making this work possible. This research and the Genetic Factors for Osteoporosis (GEFOS) consortium have been funded by the European Commission (HEALTH-F2-2008-201865-GEFOS). We acknowledge funding from the following organizations: the US National Institutes of Health (NIH; R01 AG18728, R01 HL088119, R01AR046838, U01 HL084756, P30 DK072488, T32 AG000262, F32 AR059469, P01 AG-18397, R01 AG041517, M01 RR-00750 and N01-AG-12100), the NIA Intramural Research Program (AG-023629, AG-15928, AG-20098 and AG-027058), Hjartavernd (the Icelandic Heart Association), the Althingi (the Icelandic Parliament), the Australian National Health and Medical Research Council (511132), the Australian Cancer Research Foundation and the Rebecca Cooper Foundation, the Australian National Health and Medical Research Council Career Development Award (569807 to E. L. D.), an MRC New Investigator Award (MRC G0800582 to D. M. E.), the Health Research Council of New Zealand, Sanofi-Aventis, Eli Lilly, Pfizer, Proctor & Gamble Pharmaceuticals, Roche, the Medical Benefits Fund (MBF) Living Well Foundation, the Ernst Heine Family Foundation, Arthritis Research UK (17539 and 15389), The Victorian Health Promotion Foundation, Geelong Region Medical Research Foundation, Australia (628582), Action Research UK, the European Commission (QLRT-2001-02629), the UK Food Standards Agency, BioPersMed (COMET K-project 825329), the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Economics and Labour (BMWA), the Austrian Federal Ministry of Economy, Family and Youth (BMWFJ), the Styrian Business Promotion Agency (SFG), the Red de Envejecimiento y Fragilidad (RETICEF), Instituto Carlos III, the Spanish Ministry of Education and Science (SAF2010-15707), the Government of Catalonia (2009SGR971 and 2009SGR818), Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias (PI 06/0034 and PI08/0183), Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and MRC Project (254627, 303169 and 572604), the Finnish Ministry of Education, Merck Frosst Canada, Eli Lilly Canada, Novartis Pharmaceuticals, Procter & Gamble Pharmaceuticals Canada, Servier Canada, Amgen Canada, The Dairy Farmers of Canada, The Arthritis Society, the US National Heart, Lung, and Blood Institute (NHLBI; N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HL075366, HL087652, HL105756 NINDS, HL 043851 and HL69757, CA 047988, and the Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (N02-HL-6-4278)). Untied Educational Grants were provided by Amgen, Eli Lilly International, GE-Lunar, Merck Australia, Sanofi-Aventis Australia and Servier.; Additional support was provided by the US National Center for Research Resources (M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping Core), the US National Institute of Diabetes and Digestive and Kidney Diseases (DK063491 to the Southern California Diabetes Endocrinology Research Center), deCODE Genetics, The UK National Institute for Medical Research (NIMR) Biomedical Research Centre, the Cancer Research Campaign, the Stroke Association, the British Heart Foundation, the UK Department of Health, the Europe Against Cancer Programme Commission of the European Union, the Ministry of Agriculture, Fisheries and Food, EU Biomed 1 (BMHICT920182, CIPDCT925012, ERBC1PDCT 940229 and ERBC1PDCT930105), the UK MRC (G9321536 and G9800062), the Wellcome Trust Collaborative Research Initiative 1995, MAFF AN0523, EU Framework Programme 5 (FP5; QLK6-CT-2002-02629), the Food Standards Agency (N05046), the Netherlands Organization for Scientific Research (NWO), Erasmus University Medical Center, the Centre for Medical Systems Biology (CMSB1 and CMSB2) of the Netherlands Genomics Initiative (NGI), the F.I.R.M.O. Fondazione Raffaella Becagli, the National Institute for Arthritis, Musculoskeletal and Skin Diseases, the National Institute on Aging (R01 AR/AG 41398, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098 and R01 AR 050066), the Canadian Institutes for Health Research (86748), Federal Program of the Ministry of Education and Science of the Russian Federation Scientific and Pedagogical Staff of Innovative Russia in 2009-2013 (P-601), the Federal Program Research and Development of Prior Directions of Scientific-Technological Complex of Russia in 2007-2012 (16.512.11.2032), the Swedish Research Council (K2010-54X-09894-19-3, 2006-3832, K2010-52X-20229-05-3 and K20006-72X-20155013) the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Sderberg's Foundation, the Vastra Gotaland Foundation, the Goteborg Medical Society, the Novo Nordisk foundation, University of Athens, Greece (Kapodistrias 2009), the UK NIHR Musculoskeletal BRU Oxford, the UK NIHR Nutrition BRU Southampton, The Center for Inherited Disease Research (CIDR), National Institutes of Health (HHSN268200782096C), the Hong Kong Research Grant Council (HKU 768610M), The Bone Health Fund of the HKU Foundation, The KC Wong Education Foundation, Small Project Funding (201007176237), Matching Grant, Committee of Research and Conference Grants (CRCG) Grant, the Osteoporosis and Endocrine Research Fund, the Genomics Strategic Research Theme of The University of Hong Kong, Chinese University of Hong Kong, the Korea Health 21 Research & Development Project, the Korean Ministry of Health & Welfare, Republic of Korea (A010252), the Korea Healthcare Technology Research & Development Project, the Ministry for Health, Welfare and Family Affairs (A110536), The Netherlands Ministry of Health, Welfare and Sports Directorate of Long-Term Care, the World Anti-Doping Agency, the Danish Ministry of Culture, the Institute of Clinical Research of the University of Southern Denmark, the Chief Scientists Office of the Scottish Government (CZB/4/276), a Royal Society University Research Fellowship (to J.F.W.), the European Union Framework Program 6 EUROSPAN project (LSHG-CT-2006-018947), the European Union's Seventh Framework Programme (FP7/2007-2013; HEALTH-F2-2009-223004 PHASE), the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.; 011 and 911-03-012), the Research Institute for Diseases in the Elderly (RIDE2; 014-93-015), the Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810), the German Bundesministerium fuer Forschung und Technology (01 AK 803 A-H and 01 IG 07015 G), the NIHR Biomedical Research Centre (grant to Guys' and St. Thomas' Hospitals and King's College London), the Chronic Disease Research Foundation, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Fonds de la Recherche en Sante Quebec, The Lady Davis Institute, the Jewish General Hospital, the Ministere du Developpement Economique, de l'Innovation et de l'Exportation du Quebec, the Swedish Sports Research Council (87/06), the Swedish Society of Medicine, the Kempe Foundation (JCK-1021), the Medical Faculty of Umea University (ALFVLL:968:22-2005, ALFVL:-937-2006, ALFVLL:223:11-2007 and ALFVLL:78151-2009), the County Council of Vasterbotten (Spjutspetsanslag; VLL:159:33-2007), the US National Cancer Institute, the Donald W. Reynolds Foundation, the Fondation Leducq, the Academy of Finland (126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi)), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (9M048 for TeLeht), the Juho Vainio Foundation, the Paavo Nurmi Foundation, the Finnish Foundation of Cardiovascular Research, the Finnish Cultural Foundation, the Tampere Tuberculosis Foundation and the Emil Aaltonen Foundation (K08AR055688 to T. L.). A detailed list of acknowledgments by study is given in the Supplementary Note. The members of the GEFOS Consortium mourn the passing of co-author Philip Neil Sambrook, a good friend, respected colleague and outstanding research scientist in the prevention, treatment, epidemiology and genetics of osteoporosis.; This work was done under the auspices of the European Commission-sponsored Genetic Factors for Osteoporosis (GEFOS) consortium. NR 55 TC 370 Z9 383 U1 8 U2 103 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2012 VL 44 IS 5 BP 491 EP + DI 10.1038/ng.2249 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 934BW UT WOS:000303416300007 PM 22504420 ER PT J AU Taal, HR St Pourcain, B Thiering, E Das, S Mook-Kanamori, DO Warrington, NM Kaakinen, M Kreiner-Moller, E Bradfield, JP Freathy, RM Geller, F Guxens, M Cousminer, DL Kerkhof, M Timpson, NJ Ikram, MA Beilin, LJ Bonnelykke, K Buxton, JL Charoen, P Chawes, BLK Eriksson, J Evans, DM Hofman, A Kemp, JP Kim, CE Klopp, N Lahti, J Lye, SJ McMahon, G Mentch, FD Muller-Nurasyid, M O'Reilly, PF Prokopenko, I Rivadeneira, F Steegers, EAP Sunyer, J Tiesler, C Yaghootkar, H Breteler, MMB Debette, S Fornage, M Gudnason, V Launer, LJ van der Lugt, A Mosley, TH Seshadri, S Smith, AV Vernooij, MW Blakemore, AIF Chiavacci, RM Feenstra, B Fernandez-Banet, J Grant, SFA Hartikainen, AL van der Heijden, AJ Iniguez, C Lathrop, M McArdle, WL Molgaard, A Newnham, JP Palmer, LJ Palotie, A Pouta, A Ring, SM Sovio, U Standl, M Uitterlinden, AG Wichmann, HE Vissing, NH DeCarli, C van Duijn, CM McCarthy, MI Koppelman, GH Estivill, X Hattersley, AT Melbye, M Bisgaard, H Pennell, CE Widen, E Hakonarson, H Smith, GD Heinrich, J Jarvelin, MR Jaddoe, VWV Adair, LS Ang, W Atalay, M van Beijsterveldt, T Bergen, N Benke, K Berry, D Bradfield, JP Charoen, P Coin, L Cousminer, DL Das, S Davis, OSP Elliott, P Evans, DM Feenstra, B Flexeder, C Frayling, T Freathy, RM Gaillard, R Geller, F Groen-Blokhuis, M Goh, LK Guxens, M Haworth, CMA Hadley, D Hedebrand, J Hinney, A Hirschhorn, JN Holloway, JW Holst, C Hottenga, JJ Horikoshi, M Huikari, V Hypponen, E Iniguez, C Kaakinen, M Kilpelainen, TO Kirin, M Kowgier, M Lakka, HM Lange, LA Lawlor, DA Lehtimaki, T Lewin, A Lindgren, C Lindi, V Maggi, R Marsh, J Middeldorp, C Millwood, I Mook-Kanamori, DO Murray, JC Nivard, M Nohr, EA Ntalla, I Oken, E O'Reilly, PF Palmer, LJ Panoutsopoulou, K Pararajasingham, J Prokopenko, I Rodriguez, A Salem, RM Sebert, S Siitonen, N Sovio, U St Pourcain, B Strachan, DP Sunyer, J Taal, HR Teo, YY Thiering, E Tiesler, C Uitterlinden, AG Valcarcel, B Warrington, NM White, S Willemsen, G Yaghootkar, H Zeggini, E Boomsma, DI Cooper, C Estivill, X Gillman, M Grant, SFA Hakonarson, H Hattersley, AT Heinrich, J Hocher, B Jaddoe, VWV Jarvelin, MR Lakka, TA McCarthy, MI Melbye, M Mohlke, KL Dedoussis, GV Ong, KK Pearson, ER Pennell, CE Price, TS Power, C Raitakari, OT Saw, SM Scherag, A Simell, O Sorensen, TIA Timpson, NJ Widen, E Wilson, JF Ang, W van Beijsterveldt, T Bergen, N Benke, K Berry, D Bradfield, JP Charoen, P Coin, L Cousminer, DL Das, S Elliott, P Evans, DM Frayling, T Freathy, RM Gaillard, R Groen-Blokhuis, M Guxens, M Hadley, D Hottenga, JJ Huikari, V Hypponen, E Kaakinen, M Kowgier, M Lawlor, DA Lewin, A Lindgren, C Marsh, J Middeldorp, C Millwood, I Mook-Kanamori, DO Nivard, M O'Reilly, PF Palmer, LJ Prokopenko, I Rodriguez, A Sebert, S Sovio, U St Pourcain, B Standl, M Strachan, DP Sunyer, J Taal, HR Thiering, E Tiesler, C Uitterlinden, AG Valcarcel, B Warrington, NM White, S Willemsen, G Yaghootkar, H Boomsma, DI Estivill, X Grant, SFA Hakonarson, H Hattersley, AT Heinrich, J Jaddoe, VWV Jarvelin, MR McCarthy, MI Pennell, CE Power, C Timpson, NJ Widen, E Ikram, MA Fornage, M Smith, AV Seshadri, S Schmidt, R Debette, S Vrooman, HA Sigurdsson, S Ropele, S Coker, LH Longstreth, WT Niessen, WJ DeStefano, AL Beiser, A Zijdenbos, AP Struchalin, M Jack, CR Nalls, MA Au, R Hofman, A Gudnason, H van der Lugt, A Harris, TB Meeks, WM Vernooij, MW van Buchem, MA Catellier, D Gudnason, V Windham, BG Wolf, PA van Duijn, CM Mosley, TH Schmidt, H Launer, LJ Breteler, MMB DeCarli, C AF Taal, H. Rob St Pourcain, Beate Thiering, Elisabeth Das, Shikta Mook-Kanamori, Dennis O. Warrington, Nicole M. Kaakinen, Marika Kreiner-Moller, Eskil Bradfield, Jonathan P. Freathy, Rachel M. Geller, Frank Guxens, Monica Cousminer, Diana L. Kerkhof, Marjan Timpson, Nicholas J. Ikram, M. Arfan Beilin, Lawrence J. Bonnelykke, Klaus Buxton, Jessica L. Charoen, Pimphen Chawes, Bo Lund Krogsgaard Eriksson, Johan Evans, David M. Hofman, Albert Kemp, John P. Kim, Cecilia E. Klopp, Norman Lahti, Jari Lye, Stephen J. McMahon, George Mentch, Frank D. Mueller-Nurasyid, Martina O'Reilly, Paul F. Prokopenko, Inga Rivadeneira, Fernando Steegers, Eric A. P. Sunyer, Jordi Tiesler, Carla Yaghootkar, Hanieh Breteler, Monique M. B. Debette, Stephanie Fornage, Myriam Gudnason, Vilmundur Launer, Lenore J. van der Lugt, Aad Mosley, Thomas H., Jr. Seshadri, Sudha Smith, Albert V. Vernooij, Meike W. Blakemore, Alexandra I. F. Chiavacci, Rosetta M. Feenstra, Bjarke Fernandez-Banet, Julio Grant, Struan F. A. Hartikainen, Anna-Liisa van der Heijden, Albert J. Iniguez, Carmen Lathrop, Mark McArdle, Wendy L. Molgaard, Anne Newnham, John P. Palmer, Lyle J. Palotie, Aarno Pouta, Annneli Ring, Susan M. Sovio, Ulla Standl, Marie Uitterlinden, Andre G. Wichmann, H-Erich Vissing, Nadja Hawwa DeCarli, Charles van Duijn, Cornelia M. McCarthy, Mark I. Koppelman, Gerard H. Estivill, Xavier Hattersley, Andrew T. Melbye, Mads Bisgaard, Hans Pennell, Craig E. Widen, Elisabeth Hakonarson, Hakon Smith, George Davey Heinrich, Joachim Jarvelin, Marjo-Riitta Jaddoe, Vincent W. V. Adair, Linda S. Ang, Wei Atalay, Mustafa van Beijsterveldt, Toos Bergen, Nienke Benke, Kelly Berry, Diane Bradfield, Jonathan P. Charoen, Pimphen Coin, Lachlan Cousminer, Diana L. Das, Shikta Davis, Oliver S. P. Elliott, Paul Evans, David M. Feenstra, Bjarke Flexeder, Claudia Frayling, Tim Freathy, Rachel M. Gaillard, Romy Geller, Frank Groen-Blokhuis, Maria Goh, Liang-Kee Guxens, Monica Haworth, Claire M. A. Hadley, Dexter Hedebrand, Johannes Hinney, Anke Hirschhorn, Joel N. Holloway, John W. Holst, Claus Hottenga, Jouke Jan Horikoshi, Momoko Huikari, Ville Hypponen, Elina Iniguez, Carmen Kaakinen, Marika Kilpelainen, Tuomas O. Kirin, Mirna Kowgier, Matthew Lakka, Hanna-Maaria Lange, Leslie A. Lawlor, Debbie A. Lehtimaki, Terho Lewin, Alex Lindgren, Cecilia Lindi, Virpi Maggi, Reedik Marsh, Julie Middeldorp, Christel Millwood, Iona Mook-Kanamori, Dennis O. Murray, Jeffrey C. Nivard, Michel Nohr, Ellen Aagaard Ntalla, Ioanna Oken, Emily O'Reilly, Paul F. Palmer, Lyle J. Panoutsopoulou, Kalliope Pararajasingham, Jennifer Prokopenko, Inga Rodriguez, Alina Salem, Rany M. Sebert, Sylvain Siitonen, Niina Sovio, Ulla St Pourcain, Beate Strachan, David P. Sunyer, Jordi Taal, H. Rob Teo, Yik-Ying Thiering, Elisabeth Tiesler, Carla Uitterlinden, Andre G. Valcarcel, Beatriz Warrington, Nicole M. White, Scott Willemsen, Gonneke Yaghootkar, Hanieh Zeggini, Eleftheria Boomsma, Dorret I. Cooper, Cyrus Estivill, Xavier Gillman, Matthew Grant, Struan F. A. Hakonarson, Hakon Hattersley, Andrew T. Heinrich, Joachim Hocher, Berthold Jaddoe, Vincent W. V. Jarvelin, Marjo-Riitta Lakka, Timo A. McCarthy, Mark I. Melbye, Mads Mohlke, Karen L. Dedoussis, George V. Ong, Ken K. Pearson, Ewan R. Pennell, Craig E. Price, Thomas S. Power, Chris Raitakari, Olli T. Saw, Seang-Mei Scherag, Andre Simell, Olli Sorensen, Thorkild I. A. Timpson, Nicholas J. Widen, Elisabeth Wilson, James F. Ang, Wei van Beijsterveldt, Toos Bergen, Nienke Benke, Kelly Berry, Diane Bradfield, Jonathan P. Charoen, Pimphen Coin, Lachlan Cousminer, Diana L. Das, Shikta Elliott, Paul Evans, David M. Frayling, Tim Freathy, Rachel M. Gaillard, Romy Groen-Blokhuis, Maria Guxens, Monica Hadley, Dexter Hottenga, Jouke Jan Huikari, Ville Hypponen, Elina Kaakinen, Marika Kowgier, Matthew Lawlor, Debbie A. Lewin, Alex Lindgren, Cecilia Marsh, Julie Middeldorp, Christel Millwood, Iona Mook-Kanamori, Dennis O. Nivard, Michel O'Reilly, Paul F. Palmer, Lyle J. Prokopenko, Inga Rodriguez, Alina Sebert, Sylvain Sovio, Ulla St Pourcain, Beate Standl, Marie Strachan, David P. Sunyer, Jordi Taal, H. Rob Thiering, Elisabeth Tiesler, Carla Uitterlinden, Andre G. Valcarcel, Beatriz Warrington, Nicole M. White, Scott Willemsen, Gonneke Yaghootkar, Hanieh Boomsma, Dorret I. Estivill, Xavier Grant, Struan F. A. Hakonarson, Hakon Hattersley, Andrew T. Heinrich, Joachim Jaddoe, Vincent W. V. Jarvelin, Marjo-Riitta McCarthy, Mark I. Pennell, Craig E. Power, Chris Timpson, Nicholas J. Widen, Elisabeth Ikram, M. Arfan Fornage, Myriam Smith, Albert V. Seshadri, Sudha Schmidt, Reinhold Debette, Stephanie Vrooman, Henri A. Sigurdsson, Sigurdur Ropele, Stefan Coker, Laura H. Longstreth, W. T., Jr. Niessen, Wiro J. DeStefano, Anita L. Beiser, Alexa Zijdenbos, Alex P. Struchalin, Maksim Jack, Clifford R., Jr. Nalls, Mike A. Au, Rhoda Hofman, Albert Gudnason, Haukur van der Lugt, Aad Harris, Tamara B. Meeks, William M. Vernooij, Meike W. van Buchem, Mark A. Catellier, Diane Gudnason, Vilmundur Windham, B. Gwen Wolf, Philip A. van Duijn, Cornelia M. Mosley, Thomas H., Jr. Schmidt, Helena Launer, Lenore J. Breteler, Monique M. B. DeCarli, Charles CA Cohorts Heart Aging Res Genetic Ep Early Genetics Lifecourse Epidemio Early Growth Genetics EGG Consorti TI Common variants at 12q15 and 12q24 are associated with infant head circumference SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PARKINSONS-DISEASE; BRAIN-DEVELOPMENT; FETAL-GROWTH; IDENTIFICATION; INTELLIGENCE; DISORDERS; MUTATIONS; PROTEIN; GENE AB To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life. C1 [Timpson, Nicholas J.; Evans, David M.; Kemp, John P.; McMahon, George; Lawlor, Debbie A.; St Pourcain, Beate] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Sch Social & Community Med, Bristol, Avon, England. [Taal, H. Rob; Ikram, M. Arfan; Hofman, Albert; Rivadeneira, Fernando; Breteler, Monique M. B.; Vernooij, Meike W.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Jaddoe, Vincent W. V.; Bergen, Nienke; Gaillard, Romy; Mook-Kanamori, Dennis O.; Taal, H. Rob; Jaddoe, Vincent W. V.; Struchalin, Maksim; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Taal, H. Rob; Mook-Kanamori, Dennis O.; van der Heijden, Albert J.; Jaddoe, Vincent W. V.; Jaddoe, Vincent W. V.] Erasmus MC, Dept Pediat, Rotterdam, Netherlands. [Taal, H. Rob; Mook-Kanamori, Dennis O.] Erasmus MC, Generat Study Grp R, Rotterdam, Netherlands. [Thiering, Elisabeth; Tiesler, Carla; Standl, Marie; Wichmann, H-Erich; Heinrich, Joachim; Flexeder, Claudia; Thiering, Elisabeth; Heinrich, Joachim] German Res Ctr Environm Hlth, Inst Epidemiol 1, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Das, Shikta; Charoen, Pimphen; O'Reilly, Paul F.; Sovio, Ulla; Coin, Lachlan; Lewin, Alex; Millwood, Iona; Rodriguez, Alina; Sebert, Sylvain; Valcarcel, Beatriz] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. Weill Cornell Med Coll Qatar, Dept Physiol & Biophys, Doha, Qatar. [Pennell, Craig E.; Ang, Wei; Benke, Kelly; Kowgier, Matthew; Marsh, Julie; Warrington, Nicole M.; White, Scott] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia. [Warrington, Nicole M.; Lye, Stephen J.; Palmer, Lyle J.] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Kaakinen, Marika; Jarvelin, Marjo-Riitta; Huikari, Ville] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Kaakinen, Marika; Pouta, Annneli; Jarvelin, Marjo-Riitta; Huikari, Ville] Univ Oulu, Bioctr Oulu, Oulu, Finland. 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Turku Univ Hosp, FIN-20520 Turku, Finland. Singapore Eye Res Inst, Singapore, Singapore. [Scherag, Andre] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Simell, Olli] Univ Turku, Dept Pediat, Turku, Finland. [Wilson, James F.] Univ Edinburgh, Western Gen Hosp, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Schmidt, Reinhold; Ropele, Stefan; Au, Rhoda] Med Univ Graz, Dept Neurol, Graz, Austria. [Vrooman, Henri A.; Niessen, Wiro J.] Univ Med Ctr, Erasmus Med Ctr, Dept Med Informat, Rotterdam, Netherlands. [Coker, Laura H.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Niessen, Wiro J.] Delft Univ Technol, Fac Sci Appl, Delft, Netherlands. [Zijdenbos, Alex P.] Biospective Inc, Montreal, PQ, Canada. [Jack, Clifford R., Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Catellier, Diane] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. RP Smith, GD (reprint author), Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Sch Social & Community Med, Bristol, Avon, England. EM Julia.Mackay@bristol.ac.uk; heinrich@helmholtz-muenchen.de; m.jarvelin@imperial.ac.uk; v.jaddoe@erasmusmc.nl; heinrich@helmholtz-muenchen.de; v.jaddoe@erasmusmc.nl; m.jarvelin@imperial.ac.uk; heinrich@helmholtz-muenchen.de; v.jaddoe@erasmusmc.nl; m.jarvelin@imperial.ac.uk RI Warrington, Nicole/P-4868-2014; Breteler, Monique /J-5058-2014; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Vernooij, Meike/E-4061-2016; Smith, Albert/K-5150-2015; Fox, Laura /C-6249-2016; Bisgaard, Hans/N-4761-2016; Davey Smith, George/A-7407-2013; Sunyer, J/G-6909-2014; Kronow, Joern/B-1054-2011; Lye, Stephen/E-7269-2013; Evans, David/H-6325-2013; Hypponen, Elina/B-2596-2014; Price, Thomas/B-7372-2008; Buxton, Jessica/I-4033-2014; Palmer, Lyle/K-3196-2014; Estivill, Xavier/A-3125-2013; Haworth, Claire/C-7073-2009; Holloway, John/B-5424-2009; Thiering, Elisabeth/B-3342-2013; Jack, Clifford/F-2508-2010; Davis, Oliver/B-9653-2008; OI Lawlor, Debbie A/0000-0002-6793-2262; Lahti, Jari/0000-0002-4310-5297; Warrington, Nicole/0000-0003-4195-775X; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Smith, Albert/0000-0003-1942-5845; Bisgaard, Hans/0000-0003-4131-7592; Davey Smith, George/0000-0002-1407-8314; Sunyer, J/0000-0002-2602-4110; Thiering, Elisabeth/0000-0002-5429-9584; Hypponen, Elina/0000-0003-3670-9399; Price, Thomas/0000-0001-7356-2109; Buxton, Jessica/0000-0002-0918-9335; Palmer, Lyle/0000-0002-1628-3055; Estivill, Xavier/0000-0002-0723-2256; Haworth, Claire/0000-0002-8608-289X; Holloway, John/0000-0001-9998-0464; Jack, Clifford/0000-0001-7916-622X; Davis, Oliver/0000-0002-6448-3684; Eriksson, Johan/0000-0002-2516-2060; Kemp, John/0000-0002-9105-2249; Evans, David/0000-0003-0663-4621; Nivard, Michel/0000-0003-2015-1888; Newnham, John/0000-0001-9983-7457; Beiser, Alexa/0000-0001-8551-7778; Timpson, Nicholas/0000-0002-7141-9189; Zeggini, Eleftheria/0000-0003-4238-659X; Lakka, Timo/0000-0002-9199-2871; Marsh, Julie/0000-0001-8984-6907; Scherag, Andre/0000-0002-9406-4704; Fernandez Banet, Julio/0000-0003-0901-1286; Kreiner, Eskil/0000-0003-1204-2438; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Coin, Lachlan/0000-0002-4300-455X; St Pourcain, Beate/0000-0002-4680-3517; Seshadri, Sudha/0000-0001-6135-2622; Kaakinen, Marika/0000-0002-9228-0462; Monsalve, Beatriz Elena/0000-0002-5994-866X; Ikram, Mohammad Arfan/0000-0003-0372-8585; Rodriguez, Alina/0000-0003-1209-8802; Freathy, Rachel/0000-0003-4152-2238 FU Academy of Finland [104781, 120315, 129269, 1114194, 134839, 129287]; Biocentrum Helsinki; Biocenter, University of Oulu, Finland; British Heart Foundation; Canadian Institutes of Health Research [MOP 82893]; The Children's Hospital of Philadelphia; Cotswold Foundation; Darlington Trust; Dutch Asthma Foundation; Dutch Ministry of the Environment; Erasmus Medical Center Rotterdam; Erasmus University Rotterdam; European Community [HEALTH-F4-2007-201413]; Exeter National Health Service (NHS) Research and Development; Fundacio La Marato de TV3 (Televisio de Catalunya); Helmholtz Zentrum Muenchen; German Research Center for Environment and Health; Institute of Epidemiology I; Neuherberg; Instituto de Salud Carlos III [FIS PI081151, PS09/00432]; Institut fur Umweltmedizinische Forschung (IUF) Dusseldorf; Marien-Hospital Wesel; UK MRC [G0500539, G0600331, G0600705]; Municipal Health Service Rotterdam; National Health and Medical Research Council of Australia [403981, 003209]; National Public Health Institute, Helsinki, Finland; Netherlands Organisation for Scientific Research (NWO); Netherlands Organisation for Health Research and Development (ZonMw) [SPI 56-464-14192, 904-61-090, 904-61-193, 912-03-031, 480-04-004, 400-05-717]; US NHLBI [5R01HL087679-02, 1RL1MH083268-01]; US NIH [1R01HD056465-01A1]; Peninsula NIHR Clinical Research Facility; RAINE Medical Research Foundation; Rotterdam Homecare Foundation; South West NHS Research and Development; Stichting Astmabestrijding; Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR) Rotterdam; Technical University Munich; Telethon Institute for Child Health Research; UFZ-Centre for Environmental Research Leipzig-Halle; University Hospital Oulu, Finland; University of Bristol; University of Leipzig; Wellcome Trust [GR069224, 085541/Z/08/Z, WT083431MA, WT088431MA]; Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource; ZonMW [21000074]; Dutch Kidney Foundation [C08.2251]; MRC UK [G0500539, PS0476]; MRC [MRC G0800582]; Netherlands Organisation for Health Research (ZonMw) [90700303, 916.10159] FX We thank A. Sayers for helpful discussions with respect to the conducted mediation analysis. Major funding for the research in this paper is from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 134839, 129287 and Center of Excellence in Complex Disease Genetics); Biocentrum Helsinki; Biocenter, University of Oulu, Finland; the British Heart Foundation; the Canadian Institutes of Health Research (grant MOP 82893); The Children's Hospital of Philadelphia (Institute Development Award); the Cotswold Foundation (Research Development Award); the Darlington Trust; the Dutch Asthma Foundation; the Dutch Ministry of the Environment; Erasmus Medical Center Rotterdam; Erasmus University Rotterdam; The European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project and grant agreement HEALTH-F4-2007-201413; Exeter National Health Service (NHS) Research and Development; Fundacio La Marato de TV3 (Televisio de Catalunya); Helmholtz Zentrum Muenchen, the German Research Center for Environment and Health, Institute of Epidemiology I, Neuherberg; Instituto de Salud Carlos III (FIS PI081151 and PS09/00432); Institut fur Umweltmedizinische Forschung (IUF) Dusseldorf; Marien-Hospital Wesel; the UK MRC (G0500539, G0600331, PrevMetSyn/Salve/MRC and G0600705); the Municipal Health Service Rotterdam; the National Health and Medical Research Council of Australia (403981 and 003209); the National Public Health Institute, Helsinki, Finland; the Netherlands Organisation for Scientific Research (NWO) and the Netherlands Organisation for Health Research and Development (ZonMw) (grants SPI 56-464-14192, 904-61-090, 904-61-193, 912-03-031, 480-04-004 and 400-05-717); the US NHLBI (grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01)); the US NIH (grant 1R01HD056465-01A1); the Peninsula NIHR Clinical Research Facility; the RAINE Medical Research Foundation; the Rotterdam Homecare Foundation; South West NHS Research and Development; Stichting Astmabestrijding; Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR) Rotterdam; Technical University Munich; the Telethon Institute for Child Health Research; UFZ-Centre for Environmental Research Leipzig-Halle; University Hospital Oulu, Finland; University of Bristol; University of Leipzig; the Wellcome Trust (project grant GR069224); the Western Australian DNA Bank; the Western Australian Genetic Epidemiology Resource and ZonMW (grant 21000074). Data exchange and deposition has been facilitated by the SIMBioMS platform. Personal funding was provided by the Dutch Kidney Foundation (C08.2251 to H. R. T.), the MRC UK (G0500539, PrevMetSyn and PS0476 to S. Das), a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant 085541/Z/08/Z to R. M. F.), a MRC New Investigator Award (MRC G0800582 to D. M. E.) and Wellcome Trust 4-year PhD studentships (WT083431MA to J.P.K. and WT088431MA to J.L.B.). I. P. and J.F.-B. are in part supported by the European Community's ENGAGE grant HEALTH-F4-2007-201413, A. T. H. is employed as a core member of the Peninsula NIHR Clinical Research Facility and V.W.V.J. is funded by the Netherlands Organisation for Health Research (ZonMw 90700303 and 916.10159). Detailed acknowledgments by study are given in the Supplementary Note. NR 43 TC 54 Z9 54 U1 7 U2 34 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2012 VL 44 IS 5 BP 532 EP + DI 10.1038/ng.2238 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 934BW UT WOS:000303416300013 PM 22504419 ER PT J AU Ikram, MA Fornage, M Smith, AV Seshadri, S Schmidt, R Debette, S Vrooman, HA Sigurdsson, S Ropele, S Taal, HR Mook-Kanamori, DO Coker, LH Longstreth, WT Niessen, WJ DeStefano, AL Beiser, A Zijdenbos, AP Struchalin, M Jack, CR Rivadeneira, F Uitterlinden, AG Knopman, DS Hartikainen, AL Pennell, CE Thiering, E Steegers, EAP Hakonarson, H Heinrich, J Palmer, LJ Jarvelin, MR McCarthy, MI Grant, SFA St Pourcain, B Timpson, NJ Smith, GD Sovio, U Nalls, MA Au, R Hofman, A Gudnason, H van der Lugt, A Harris, TB Meeks, WM Vernooij, MW van Buchem, MA Catellier, D Jaddoe, VWV Gudnason, V Windham, BG Wolf, PA van Duijn, CM Mosley, TH Schmidt, H Launer, LJ Breteler, MMB DeCarli, C Adair, LS Ang, W Atalay, M vanBeijsterveldt, T Bergen, N Benke, K Berry, D Coin, L Davis, OSP Elliott, P Flexeder, C Frayling, T Gaillard, R Groen-Blokhuis, M Goh, LK Haworth, CMA Hadley, D Hedebrand, J Hinney, A Hirschhorn, JN Holloway, JW Holst, C Hottenga, JJ Horikoshi, M Huikari, V Hypponen, E Kilpelainen, TO Kirin, M Kowgier, M Lakka, HM Lange, LA Lawlor, DA Lehtimaki, T Lewin, A Lindgren, C Lindi, V Maggi, R Marsh, J Middeldorp, C Millwood, I Murray, JC Nivard, M Nohr, EA Ntalla, I Oken, E Panoutsopoulou, K Pararajasingham, J Rodriguez, A Salem, RM Sebert, S Siitonen, N Strachan, DP Teo, YY Valcarcel, B Willemsen, G Zeggini, E Boomsma, DI Cooper, C Gillman, M Hocher, B Lakka, TA Mohlke, KL Dedoussis, GV Ong, KK Pearson, ER Price, TS Power, C Raitakari, OT Saw, SM Scherag, A Simell, O Sorensen, TIA Wilson, JF AF Ikram, M. Arfan Fornage, Myriam Smith, Albert V. Seshadri, Sudha Schmidt, Reinhold Debette, Stephanie Vrooman, Henri A. Sigurdsson, Sigurdur Ropele, Stefan Taal, H. Rob Mook-Kanamori, Dennis O. Coker, Laura H. Longstreth, W. T., Jr. Niessen, Wiro J. DeStefano, Anita L. Beiser, Alexa Zijdenbos, Alex P. Struchalin, Maksim Jack, Clifford R., Jr. Rivadeneira, Fernando Uitterlinden, Andre G. Knopman, David S. Hartikainen, Anna-Liisa Pennell, Craig E. Thiering, Elisabeth Steegers, Eric A. P. Hakonarson, Hakon Heinrich, Joachim Palmer, Lyle J. Jarvelin, Marjo-Riitta McCarthy, Mark I. Grant, Struan F. A. St Pourcain, Beate Timpson, Nicholas J. Smith, George Davey Sovio, Ulla Nalls, Mike A. Au, Rhoda Hofman, Albert Gudnason, Haukur van der Lugt, Aad Harris, Tamara B. Meeks, William M. Vernooij, Meike W. van Buchem, Mark A. Catellier, Diane Jaddoe, Vincent W. V. Gudnason, Vilmundur Windham, B. Gwen Wolf, Philip A. van Duijn, Cornelia M. Mosley, Thomas H., Jr. Schmidt, Helena Launer, Lenore J. Breteler, Monique M. B. DeCarli, Charles Adair, Linda S. Ang, Wei Atalay, Mustafa vanBeijsterveldt, Toos Bergen, Nienke Benke, Kelly Berry, Diane Coin, Lachlan Davis, Oliver S. P. Elliott, Paul Flexeder, Claudia Frayling, Tim Gaillard, Romy Groen-Blokhuis, Maria Goh, Liang-Kee Haworth, Claire M. A. Hadley, Dexter Hedebrand, Johannes Hinney, Anke Hirschhorn, Joel N. Holloway, John W. Holst, Claus Hottenga, Jouke Jan Horikoshi, Momoko Huikari, Ville Hypponen, Elina Kilpelainen, Tuomas O. Kirin, Mirna Kowgier, Matthew Lakka, Hanna-Maaria Lange, Leslie A. Lawlor, Debbie A. Lehtimaki, Terho Lewin, Alex Lindgren, Cecilia Lindi, Virpi Maggi, Reedik Marsh, Julie Middeldorp, Christel Millwood, Iona Murray, Jeffrey C. Nivard, Michel Nohr, Ellen Aagaard Ntalla, Ioanna Oken, Emily Panoutsopoulou, Kalliope Pararajasingham, Jennifer Rodriguez, Alina Salem, Rany M. Sebert, Sylvain Siitonen, Niina Strachan, David P. Teo, Yik-Ying Valcarcel, Beatriz Willemsen, Gonneke Zeggini, Eleftheria Boomsma, Dorret I. Cooper, Cyrus Gillman, Matthew Hocher, Berthold Lakka, Timo A. Mohlke, Karen L. Dedoussis, George V. Ong, Ken K. Pearson, Ewan R. Price, Thomas S. Power, Chris Raitakari, Olli T. Saw, Seang-Mei Scherag, Andre Simell, Olli Sorensen, Thorkild I. A. Wilson, James F. CA Early Growth Genetics EGG Consorti Cohorts Heart Aging Res Genomic Ep TI Common variants at 6q22 and 17q21 are associated with intracranial volume SO NATURE GENETICS LA English DT Article ID MATTER HYPERINTENSITY VOLUME; GENOME-WIDE ASSOCIATION; MICRODELETION SYNDROME; ALZHEIMERS-DISEASE; BRAIN; INVERSION; INTELLIGENCE; EVOLUTION; HAPLOTYPE; DEMENTIA AB During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size. C1 [Ikram, M. Arfan; Taal, H. Rob; Mook-Kanamori, Dennis O.; Struchalin, Maksim; Vernooij, Meike W.; Jaddoe, Vincent W. 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[Sovio, Ulla] London Sch Hyg & Trop Med, Dept Med Stat, London WC1, England. [Nalls, Mike A.] NIA, Neurogenet Lab, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Harris, Tamara B.; Launer, Lenore J.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Meeks, William M.; Windham, B. Gwen; Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Dept Med Geriatr, Jackson, MS 39216 USA. [Meeks, William M.; Windham, B. Gwen; Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Dept Neurol, Jackson, MS 39216 USA. [van Buchem, Mark A.] Leiden Univ, Dept Radiol, Med Ctr, Leiden, Netherlands. [Catellier, Diane] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. [Breteler, Monique M. B.] German Ctr Neurol Dis DZNE, Bonn, Germany. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Atalay, Mustafa; Lindi, Virpi; Lakka, Timo A.] Univ Eastern Finland, Dept Physiol, Inst Biomed, Kuopio, Finland. [vanBeijsterveldt, Toos; Groen-Blokhuis, Maria; Hottenga, Jouke Jan; Middeldorp, Christel; Nivard, Michel; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Berry, Diane; Hypponen, Elina; Power, Chris] UCL, Ctr Paediat Epidemiol & Biostat, MRC Ctr Epidemiol Child Hlth, Inst Child Hlth, London, England. [Davis, Oliver S. P.; Haworth, Claire M. A.; Pararajasingham, Jennifer; Rodriguez, Alina; Price, Thomas S.] Kings Coll London, Inst Psychiat, MRC Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Frayling, Tim] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Goh, Liang-Kee; Saw, Seang-Mei] Duke Natl Univ Singapore NUS, Grad Sch Med, Singapore, Singapore. [Goh, Liang-Kee; Teo, Yik-Ying; Saw, Seang-Mei] NUS, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hedebrand, Johannes; Hinney, Anke] Univ Duisburg Essen, Dept Child & Adolescent Psychiat, Essen, Germany. [Hirschhorn, Joel N.; Oken, Emily; Salem, Rany M.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.; Oken, Emily; Salem, Rany M.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.; Oken, Emily; Salem, Rany M.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Hirschhorn, Joel N.; Oken, Emily; Salem, Rany M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Hirschhorn, Joel N.; Oken, Emily; Salem, Rany M.] Broad Inst, Metab Initiat, Cambridge, MA USA. [Hirschhorn, Joel N.; Oken, Emily; Salem, Rany M.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Holloway, John W.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Holst, Claus; Sorensen, Thorkild I. A.] Copenhagen Univ Hosp, Inst Prevent Med, Copenhagen, Denmark. [Hypponen, Elina] Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, Sch Publ Hlth, London, England. [Kilpelainen, Tuomas O.] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth Sci, Copenhagen, Denmark. [Kirin, Mirna; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Lakka, Hanna-Maaria] Univ Eastern Finland, Dept Publ Hlth, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Lange, Leslie A.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Lehtimaki, Terho] Tampere Univ Hosp, Dept Clin Chem, FIN-33521 Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, Sch Med, FIN-33101 Tampere, Finland. [Maggi, Reedik] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Millwood, Iona] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Millwood, Iona] Univ Oxford, Epidemiol Studies Unit CTSU, Oxford, England. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Ntalla, Ioanna; Dedoussis, George V.] Harokopio Univ Athens, Dept Dietet Nutr, Athens, Greece. [Panoutsopoulou, Kalliope; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Cambridge, England. [Rodriguez, Alina] Mid Sweden Univ, Dept Psychol, Ostersund, Sweden. [Siitonen, Niina; Raitakari, Olli T.; Simell, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Strachan, David P.] Univ London, Div Populat Hlth Sci & Educ, London, England. [Cooper, Cyrus] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Gillman, Matthew] Harvard Univ, Sch Med, Dept Populat Med, Obes Prevent Program, Boston, MA USA. [Gillman, Matthew] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Hocher, Berthold] Univ Potsdam, Inst Nutr Sci, Potsdam, Germany. [Hocher, Berthold] Charite, Cardiovasc Res Ctr, Inst Pharmacol, Berlin, Germany. [Ong, Ken K.] Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Pearson, Ewan R.] Univ Dundee, Biomed Res Inst, Dundee, Scotland. [Raitakari, Olli T.] Univ Turku, Dept Clin Physiol, Turku, Finland. [Raitakari, Olli T.] Turku Univ Hosp, FIN-20520 Turku, Finland. [Saw, Seang-Mei] Singapore Eye Res Inst, Singapore, Singapore. [Scherag, Andre] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Simell, Olli] Univ Turku, Dept Pediat, Turku, Finland. [Sorensen, Thorkild I. A.] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark. [Wilson, James F.] Univ Edinburgh, Western Gen Hosp, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. RP Ikram, MA (reprint author), Univ Med Ctr, Erasmus Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. EM m.a.ikram@erasmusmc.nl; cdecarli@ucdavis.edu RI Price, Thomas/B-7372-2008; Coin, Lachlan/A-9001-2014; Fox, Laura /C-6249-2016; Davey Smith, George/A-7407-2013; Breteler, Monique /J-5058-2014; Study, Raine/G-9547-2015; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Vernooij, Meike/E-4061-2016; Smith, Albert/K-5150-2015; Haworth, Claire/C-7073-2009; Holloway, John/B-5424-2009; Thiering, Elisabeth/B-3342-2013; Jack, Clifford/F-2508-2010; Davis, Oliver/B-9653-2008; Hypponen, Elina/B-2596-2014; Palmer, Lyle/K-3196-2014; OI Price, Thomas/0000-0001-7356-2109; Coin, Lachlan/0000-0002-4300-455X; Davey Smith, George/0000-0002-1407-8314; Rodriguez, Alina/0000-0003-1209-8802; Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Thiering, Elisabeth/0000-0002-5429-9584; Monsalve, Beatriz Elena/0000-0002-5994-866X; Ikram, Mohammad Arfan/0000-0003-0372-8585; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Haworth, Claire/0000-0002-8608-289X; Holloway, John/0000-0001-9998-0464; Jack, Clifford/0000-0001-7916-622X; Davis, Oliver/0000-0002-6448-3684; Hypponen, Elina/0000-0003-3670-9399; Palmer, Lyle/0000-0002-1628-3055; Nivard, Michel/0000-0003-2015-1888; Beiser, Alexa/0000-0001-8551-7778; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262; Zeggini, Eleftheria/0000-0003-4238-659X; Lakka, Timo/0000-0002-9199-2871; Marsh, Julie/0000-0001-8984-6907; Scherag, Andre/0000-0002-9406-4704; St Pourcain, Beate/0000-0002-4680-3517; Jarvelin, Marjo-Riitta/0000-0002-2149-0630 FU US National Institute on Aging (NIA) [N01-AG-12100]; US NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL087641, R01-HL093029]; National Human Genome Research Institute [U01-HG004402]; NIH [HHSN268200625226C]; NIH Roadmap for Medical Research [UL1RR025005]; Austrian Science Fond (FWF) [P20545-P05, P13180]; Framingham Heart Study of the NHLBI [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Institute of Neurological Disorders and Stroke [NS17950]; NHLBI [HL093029, 5R01HL087679-02, 1RL1MH083268-01]; NIA [AG08122, AG16495, AG033193, AG033040, AG031287, P30AG013846]; Netherlands Organisation of Scientific Research (NWO) [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)- NWO [050-060-810]; Erasmus Medical Center; Erasmus University 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; NWO [918-46-615, 904-61-096, 904-61-133, 948-00-010]; Nederlandse Hartstichting [2009B102]; Internationaal Parkinson Fonds; Academy of Finland [104781, 120315, 1114194]; University Hospital Oulu, Biocenter, University of Oulu; ENGAGE; UK MRC [G0500539, 74882]; Wellcome Trust [GR069224, 076467]; Biocentrum Helsinki; Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw) [21000074, 90700303, 916.10159]; Dutch Kidney Foundation [C08.2251]; Children's Hospital of Philadelphia; Cotswold Foundation; US NIH [1R01HD056465-01A1]; Healthway Western Australia; National Health and Medical Research Council of Australia [572613]; Canadian Institutes of Health Research [MOP 82893]; University of Bristol; [HEALTH-F4-2007-201413] FX Aging Gene-Environment Susceptibility-Reykjavik Study (AGES-RS): Research was funded by the US National Institute on Aging (NIA) (N01-AG-12100), with contributions from the US National Eye Institute (NEI), National Institute on Deafness and Other Communication Disorders (NIDCD) and the NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).; Atherosclerosis Risk in Communities Study (ARIC): The authors thank the staff and participants of the ARIC study for their important contributions. Research is carried out as a collaborative study supported by the US NHLBI (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL087641 and R01-HL093029), the National Human Genome Research Institute (U01-HG004402) and the NIH (HHSN268200625226C). Infrastructure was partly supported by a component of the NIH and NIH Roadmap for Medical Research (UL1RR025005).; Austrian Stroke Prevention Study (ASPS): The authors thank the staff and participants of the ASPS for their valuable contributions. We thank B. Reinhart for her long-term administrative commitment and I.J. Semmler for technical assistance in creating the DNA bank. The research reported here was funded by the Austrian Science Fond (FWF) (P20545-P05 and P13180). The Medical University of Graz supports the databank of the ASPS.; Framingham Heart Study (FHS): This study is carried out by the US NHLBI of the NIH and Boston University School of Medicine. This work was supported by the Framingham Heart Study of the NHLBI (N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950), the NHLBI (HL093029) and the NIA (AG08122, AG16495, AG033193, AG033040, AG031287 and P30AG013846).; Rotterdam Study (RS): The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The authors thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera and M. Peters for their help in creating the GWAS database and K. Estrada and M. V. Struchalin for their support in creation and analysis of imputed data. The generation and management of GWAS genotype data for the Rotterdam Study were supported by the Netherlands Organisation of Scientific Research (NWO) Investments (nr. 175.010.2005.011 and 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)- NWO project (nr. 050-060-810). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University 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. The Rotterdam Scan Study is supported by the NWO (nrs. 918-46-615, 904-61-096, 904-61-133 and 948-00-010), the Nederlandse Hartstichting (2009B102) and the Internationaal Parkinson Fonds.; EGG Consortium: We gratefully acknowledge the contribution of general practitioners, hospitals, midwives and pharmacies in Rotterdam. Financial support was received from the Academy of Finland (104781, 120315, 1114194 and Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, the US NHLBI (5R01HL087679-02, through the STAMPEED program 1RL1MH083268-01), the ENGAGE project and grant agreement HEALTH-F4-2007-201413, the UK MRC (G0500539 and PrevMetSyn/Salve/MRC) and the Wellcome Trust (GR069224). DNA extraction, sample quality control, biobank upkeep and aliquotting were performed at the National Public Health Institute, Biomedicum Helsinki (Helsinki, Finland) and supported financially by the Academy of Finland and Biocentrum Helsinki. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR). The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw 90700303 and 916.10159). Additional support was provided by a grant from the Dutch Kidney Foundation (C08.2251).; The authors would like to thank all participating subjects and families from the Children's Hospital in Philadelphia. The research was financially supported by an Institute Development Award from the Children's Hospital of Philadelphia, a Research Development Award from the Cotswold Foundation and by the US NIH (1R01HD056465-01A1). The authors are grateful to the Raine Foundation, the RAINE Study families and the RAINE Study research staff. We gratefully acknowledge the assistance of the Western Australian Genetic Epidemiology Resource and the Western Australian DNA Bank (both National Health and Medical Research Council of Australia National Enabling Facilities). The authors also acknowledge the support of Healthway Western Australia, the National Health and Medical Research Council of Australia (572613) and the Canadian Institutes of Health Research (MOP 82893). We gratefully acknowledge the assistance of the Wind Over Water Foundation, the Telethon Institute for Child Health Research and the RAINE Medical Research Foundation of the University of Western Australia. The authors wish to acknowledge the following: Helmholtz Zentrum Muenchen-German Research Center for Environment and Health, Institute of Epidemiology; the Department of Pediatrics, University of Leipzig; Department of Pediatrics, Marien-Hospital; Bad Honnef; the Department of Human Exposure Research and Epidemiology, UFZ-Centre for Environmental Research Leipzig-Halle; the Department of Environmental Immunology, Zentrum fur Umweltforschung (UFZ)-Centre for Environmental Research Leipzig-Halle; the Institut fur Umweltmedizinische Forschung (IUF) and the Department of Pediatrics, Technical University. The UK MRC (74882), the Wellcome Trust (076467) and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children (ALSPAC). We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. NR 27 TC 58 Z9 59 U1 3 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2012 VL 44 IS 5 BP 539 EP + DI 10.1038/ng.2245 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 934BW UT WOS:000303416300014 PM 22504418 ER PT J AU Bis, JC DeCarli, C Smith, AV van der Lijn, F Crivello, F Fornage, M Debette, S Shulman, JM Schmidt, H Srikanth, V Schuur, M Yu, L Choi, SH Sigurdsson, S Verhaaren, BFJ DeStefano, AL Lambert, JC Jack, CR Struchalin, M Stankovich, J Ibrahim-Verbaas, CA Fleischman, D Zijdenbos, A den Heijer, T Mazoyer, B Coker, LH Enzinger, C Danoy, P Amin, N Arfanakis, K van Buchem, MA de Bruijn, RFAG Beiser, A Dufouil, C Huang, JB Cavalieri, M Thomson, R Niessen, WJ Chibnik, LB Gislason, GK Hofman, A Pikula, A Amouyel, P Freeman, KB Phan, TG Oostra, BA Stein, JL Medland, SE Vasquez, AA Hibar, DP Wright, MJ Franke, B Martin, NG Thompson, PM Nalls, MA Uitterlinden, AG Au, R Elbaz, A Beare, RJ van Swieten, JC Lopez, OL Harris, TB Chouraki, V Breteler, MMB De Jager, PL Becker, JT Vernooij, MW Knopman, D Fazekas, F Wolf, PA van der Lugt, A Gudnason, V Longstreth, WT Brown, MA Bennett, DA van Duijn, CM Mosley, TH Schmidt, R Tzourio, C Launer, LJ Ikram, MA Seshadri, S AF Bis, Joshua C. DeCarli, Charles Smith, Albert Vernon van der Lijn, Fedde Crivello, Fabrice Fornage, Myriam Debette, Stephanie Shulman, Joshua M. Schmidt, Helena Srikanth, Velandai Schuur, Maaike Yu, Lei Choi, Seung-Hoan Sigurdsson, Sigurdur Verhaaren, Benjamin F. J. DeStefano, Anita L. Lambert, Jean-Charles Jack, Clifford R., Jr. Struchalin, Maksim Stankovich, Jim Ibrahim-Verbaas, Carla A. Fleischman, Debra Zijdenbos, Alex den Heijer, Tom Mazoyer, Bernard Coker, Laura H. Enzinger, Christian Danoy, Patrick Amin, Najaf Arfanakis, Konstantinos van Buchem, Mark A. de Bruijn, Renee F. A. G. Beiser, Alexa Dufouil, Carole Huang, Juebin Cavalieri, Margherita Thomson, Russell Niessen, Wiro J. Chibnik, Lori B. Gislason, Gauti K. Hofman, Albert Pikula, Aleksandra Amouyel, Philippe Freeman, Kevin B. Phan, Thanh G. Oostra, Ben A. Stein, Jason L. Medland, Sarah E. Vasquez, Alejandro Arias Hibar, Derrek P. Wright, Margaret J. Franke, Barbara Martin, Nicholas G. Thompson, Paul M. Nalls, Michael A. Uitterlinden, Andre G. Au, Rhoda Elbaz, Alexis Beare, Richard J. van Swieten, John C. Lopez, Oscar L. Harris, Tamara B. Chouraki, Vincent Breteler, Monique M. B. De Jager, Philip L. Becker, James T. Vernooij, Meike W. Knopman, David Fazekas, Franz Wolf, Philip A. van der Lugt, Aad Gudnason, Vilmundur Longstreth, W. T., Jr. Brown, Matthew A. Bennett, David A. van Duijn, Cornelia M. Mosley, Thomas H. Schmidt, Reinhold Tzourio, Christophe Launer, Lenore J. Ikram, M. Arfan Seshadri, Sudha CA Enhancing Neuro Imaging Genetics M Cohorts Heart Aging Res Genomic Ep TI Common variants at 12q14 and 12q24 are associated with hippocampal volume SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GUIDED NEURONAL MIGRATION; GLUCAGON-LIKE PEPTIDE-1; ALZHEIMERS-DISEASE; IDENTIFIES VARIANTS; TOTAL HOMOCYSTEINE; GENE-EXPRESSION; CELL-DEATH; BRAIN; ATROPHY AB Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of < 4.0 x 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 x 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 x 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 x 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 x 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. C1 [Debette, Stephanie; DeStefano, Anita L.; Beiser, Alexa; Pikula, Aleksandra; Au, Rhoda; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Smith, Albert Vernon; Sigurdsson, Sigurdur; Gislason, Gauti K.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [van der Lijn, Fedde; Niessen, Wiro J.] Univ Med Ctr, Erasmus Med Ctr, Dept Med Informat, Rotterdam, Netherlands. [van der Lijn, Fedde; Verhaaren, Benjamin F. J.; Niessen, Wiro J.; Vernooij, Meike W.; van der Lugt, Aad; Ikram, M. Arfan] Univ Med Ctr, Erasmus Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Crivello, Fabrice; Mazoyer, Bernard] Univ Bordeaux, Neurofunct Imaging Grp, UMR 5296, Bordeaux, France. [Crivello, Fabrice; Mazoyer, Bernard] Univ Bordeaux, Neurofunct Imaging Grp, CNRS, UMR 5296, Bordeaux, France. [Crivello, Fabrice; Mazoyer, Bernard] CEA, Neurofunct Imaging Grp, UMR 5296, Bordeaux, France. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA. [Debette, Stephanie; Dufouil, Carole; Elbaz, Alexis] INSERM, U708, Paris, France. [Debette, Stephanie] Univ Versailles St Quentin En Yvelines, Dept Epidemiol, Paris, France. [Shulman, Joshua M.; Chibnik, Lori B.; De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Inst Neurosci, Dept Neurol, Boston, MA 02115 USA. [Shulman, Joshua M.; Chibnik, Lori B.; De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. [Srikanth, Velandai; Phan, Thanh G.; Beare, Richard J.] Monash Univ, Dept Med, Stroke & Ageing Res Ctr, So Clin Sch, Melbourne, Vic 3004, Australia. [Srikanth, Velandai; Stankovich, Jim; Thomson, Russell] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia. [Schuur, Maaike; Struchalin, Maksim; Ibrahim-Verbaas, Carla A.; Amin, Najaf; Oostra, Ben A.; van Duijn, Cornelia M.] Univ Med Ctr, Erasmus Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Schuur, Maaike; Ibrahim-Verbaas, Carla A.; den Heijer, Tom; de Bruijn, Renee F. A. 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[Jack, Clifford R., Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Fleischman, Debra] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Fleischman, Debra] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Zijdenbos, Alex] Biospective Inc, Montreal, PQ, Canada. [den Heijer, Tom] St Franciscus Gasthuis, Dept Neurol, Rotterdam, Netherlands. [Coker, Laura H.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Enzinger, Christian; Cavalieri, Margherita; Fazekas, Franz; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Danoy, Patrick] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia. [Arfanakis, Konstantinos] Illinois Inst Technol, Dept Biomed Engn, Chicago, IL USA. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Huang, Juebin; Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Neurol, Jackson, MS 39216 USA. [Niessen, Wiro J.] Delft Univ Technol, Fac Sci Appl, Delft, Netherlands. [Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Ikram, M. Arfan] Netherlands Consortium Hlth Ageing, Leiden, Netherlands. [Amouyel, Philippe] Ctr Hosp Reg Univ Lille, Lille, France. [Freeman, Kevin B.] Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA. [Oostra, Ben A.] Univ Med Ctr, Erasmus Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Stein, Jason L.; Hibar, Derrek P.; Thompson, Paul M.] Univ Calif Los Angeles, David Geffen Sch Med, Lab Neuro Imaging, Los Angeles, CA 90095 USA. [Medland, Sarah E.; Wright, Margaret J.; Martin, Nicholas G.] Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4006, Australia. [Medland, Sarah E.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Vasquez, Alejandro Arias; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Vasquez, Alejandro Arias; Franke, Barbara; Launer, Lenore J.] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Uitterlinden, Andre G.] Univ Med Ctr, Erasmus Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Elbaz, Alexis] Univ Paris 06, UMR S708, Paris, France. [Beare, Richard J.] Royal Childrens Hosp, Dev Imaging Grp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Lopez, Oscar L.; Becker, James T.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Lopez, Oscar L.; Becker, James T.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Lopez, Oscar L.; Becker, James T.] Univ Pittsburgh, Sch Med, Dept Psychol, Pittsburgh, PA USA. [Harris, Tamara B.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Breteler, Monique M. B.] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany. [Breteler, Monique M. B.] Univ Bonn, Bonn, Germany. [Breteler, Monique M. B.] Harvard Univ, Dept Epidemiol, Harvard Sch Publ Hlth, Boston, MA 02115 USA. [De Jager, Philip L.] Harvard Univ, Sch Med, Boston, MA USA. [Knopman, David] Mayo Clin, Dept Neurol, Rochester, MN USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Brown, Matthew A.] Univ Queensland, Human Genet Grp, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld, Australia. [van Duijn, Cornelia M.] Leiden Univ, Med Ctr, Ctr Med Syst Biol, Netherlands Genom Initiat, Leiden, Netherlands. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med Geriatr, Jackson, MS 39216 USA. [Tzourio, Christophe] Univ Bordeaux, U708, Bordeaux, France. [Tzourio, Christophe] INSERM, Neuroepidemiol U708, Bordeaux, France. RP Seshadri, S (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. EM suseshad@bu.edu RI Trabzuni, Daniah/C-4034-2012; Gudnason, Vilmundur/K-6885-2015; Veltman, Joris/F-5128-2010; Cavalleri, Gianpiero/A-6632-2010; Savitz, Jonathan/C-3088-2009; Mattheisen, Manuel/B-4949-2012; Wright, Margaret/A-4560-2016; Arias Vasquez, Alejandro/E-4762-2012; Vernooij, Meike/E-4061-2016; Lambert, jean-charles/A-9553-2014; Smith, Albert/K-5150-2015; Matarin, Mar/F-1771-2016; Melle, Ingrid /B-4858-2011; Hansell, Narelle/A-4553-2016; Cichon, Sven/B-9618-2014; Hulshoff Pol, Hilleke/B-4795-2014; Pike, Bruce/K-5562-2014; Laje, Gonzalo/L-2654-2014; Tzourio, christophe/B-4015-2009; Fox, Peter/B-4725-2010; Lourdusamy, Anbarasu/P-6606-2014; Mazoyer, Bernard/B-6303-2012; lambert, jean-charles/F-8787-2013; LICEND, CEMND/F-1296-2015; Hoogman, Martine/G-8958-2015; Rijpkema, Mark/D-1974-2010; Cavalieri, Margherita/G-8053-2012; Ramasamy, Adaikalavan/G-2632-2010; Thomson, Russell/H-5653-2012; Weale, Michael/F-2587-2010; Dufouil, Carole/J-4968-2012; Jack, Clifford/F-2508-2010; Hagoort, Peter/B-7417-2012; Medland, Sarah/C-7630-2013; Deary, Ian/C-6297-2009; Franke, Barbara/D-4836-2009; Lourdusamy, Anbarasu/G-3387-2011; Saykin, Andrew/A-1318-2007; Cichon, Sven/H-8803-2013 OI Andreassen, Ole A./0000-0002-4461-3568; Beiser, Alexa/0000-0001-8551-7778; Martin, Nicholas/0000-0003-4069-8020; Brown, Matthew A/0000-0003-0538-8211; van den Heuvel, Martijn/0000-0003-1570-1195; Becker, James/0000-0003-4425-4726; Trabzuni, Daniah/0000-0003-4826-9570; Stein, Jason/0000-0003-4829-0513; Arfanakis, Konstantinos/0000-0001-9705-597X; Agartz, Ingrid/0000-0002-9839-5391; Nothen, Markus/0000-0002-8770-2464; Donohoe, Gary/0000-0003-3037-7426; Pikula, Aleksandra/0000-0002-8378-5522; McMahon, Francis/0000-0002-9469-305X; Seshadri, Sudha/0000-0001-6135-2622; Crivello, Fabrice/0000-0001-6950-984X; Au, Rhoda/0000-0001-7742-4491; Ibrahim-verbaas, Carla/0000-0002-4325-0857; Chouraki, Vincent/0000-0002-4698-1794; Romanczuk-Seiferth, Nina/0000-0002-6931-269X; Ikram, Mohammad Arfan/0000-0003-0372-8585; Gudnason, Vilmundur/0000-0001-5696-0084; Veltman, Joris/0000-0002-3218-8250; Savitz, Jonathan/0000-0001-8143-182X; Mattheisen, Manuel/0000-0002-8442-493X; Wright, Margaret/0000-0001-7133-4970; Arias Vasquez, Alejandro/0000-0002-4786-0169; Lambert, jean-charles/0000-0003-0829-7817; Smith, Albert/0000-0003-1942-5845; Matarin, Mar/0000-0002-4717-5735; Melle, Ingrid /0000-0002-9783-548X; Hansell, Narelle/0000-0002-8229-9741; Cichon, Sven/0000-0002-9475-086X; Hulshoff Pol, Hilleke/0000-0002-2038-5281; Pike, Bruce/0000-0001-8924-683X; Laje, Gonzalo/0000-0003-2763-3329; Tzourio, christophe/0000-0002-6517-2984; Fox, Peter/0000-0002-0465-2028; Mazoyer, Bernard/0000-0003-0970-2837; Hoogman, Martine/0000-0002-1261-7628; Rijpkema, Mark/0000-0002-8495-4703; Ramasamy, Adaikalavan/0000-0002-7598-2892; Thomson, Russell/0000-0003-4949-4120; Weale, Michael/0000-0003-4593-1186; Jack, Clifford/0000-0001-7916-622X; Medland, Sarah/0000-0003-1382-380X; Franke, Barbara/0000-0003-4375-6572; Saykin, Andrew/0000-0002-1376-8532; Cichon, Sven/0000-0002-9475-086X FU US National Institute on Aging (NIA) [N01-AG-12100]; US NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HL087641, HL59367, HL086694, HL7825, HL087652, HL105756]; National Human Genome Research Institute [U01HG004402]; NIH [HHSN268200625226C]; NIH Roadmap for Medical Research [UL1RR025005]; NHLBI [HL093029]; NIA [AG20098, AG05133, AG08122, AG16495, AG033193, AG013846, AG031287]; Austrian Science Fond (FWF) [P20545-P05, P13180]; Netherlands Organisation for Scientific Research (NWO); Internationale Stichting Alzheimer Onderzoek (ISAO); Hersenstichting Nederland (HSN); Centre for Medical Systems Biology [CMSB1, CMSB2]; US NIA [P30AG10161, AG17917, AG15819]; Illinois Department of Public Health; Rush Clinical Translational Science Consortium; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at the Boston University School of Medicine and Boston Medical Center; NINDS [NS17950]; NWO [175.010.2005.011, 911-03-012, 918-46-615, 904-61-096, 904-61-133, 948-00-010]; Research Institute for Diseases in the Elderly (RIDE) [014-93-015]; NGI-NWO [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organisation for Health Research and Development (ZonMw); RIDE2; Dutch Ministry of Education, Culture and Science; Dutch Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Nederlandse Hartstichting [2009B102]; Internationaal Parkinson Fonds; National Health and Medical Research Council of Australia (NHMRC) [403000, 491109, 606543, APP1024879]; Wicking Dementia Education and Research Centre, Hobart; NHMRC-National Heart Foundation [606544]; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; Mutuelle Generale de l'Education Nationale (MGEN); Institut de la Longevite; Conseils Regionaux de Aquitaine et Bourgogne; Fondation de France; French Ministry of Research-INSERM; National Foundation for Alzheimer's Disease and Related Disorders; Institut Pasteur de Lille; Centre National de Genotypage FX Aging Gene-Environment Susceptibility-Reykjavik Study (AGES): Research was funded by the US National Institute on Aging (NIA; N01-AG-12100), with contributions from the National Eye Institute (NEI), the National Institute on Deafness and Other Communication Disorders (NIDCD), the US National Heart, Lung, and Blood Institute (NHLBI), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).; The Atherosclerosis Risk in Communities Study (ARIC): The authors thank the staff and participants of the ARIC study for their important contributions. Research was carried out as a collaborative study supported by the US NHLBI (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HL087641, HL59367, HL086694 and HL7825); the National Human Genome Research Institute (U01HG004402) and the NIH (HHSN268200625226C). Infrastructure was partly supported by a component of the NIH and the NIH Roadmap for Medical Research (UL1RR025005). This project was also supported by NHLBI grant HL093029.; The Cardiovascular Health Study (CHS): Coauthors were supported in part by US NHLBI grants (HL087652 and HL105756), as well as by NIA grants (AG20098 and AG05133).; The Austrian Stroke Prevention Study (ASPS): The authors thank the staff and the participants of ASPS for their valuable contributions. We thank B. Reinhart for her long-term administrative commitment and I.J. Semmler for technical assistance in creating the DNA bank. The research reported here was funded by the Austrian Science Fond (FWF; P20545-P05 and P13180). The Medical University of Graz supports the databank of ASPS.; Erasmus Rucphen Family Study (ERF): We thank the participants from the Genetic Research in Isolated Populations in the Erasmus Rucphen Family Study who made this work possible. This study is financially supported by the Netherlands Organisation for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB1 and CMSB2) in the framework of the Netherlands Genomics Initiative (NGI).; Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (contract N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at the Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the NINDS (NS17950) and the NIA (AG08122, AG16495, AG033193, AG013846 and AG031287).; The Religious Order Study and the Rush Memory and Aging Project: ROS and R-MAP data used in this study were obtained with support from the US NIA (grants P30AG10161, AG17917 and AG15819), the Illinois Department of Public Health and the Rush Clinical Translational Science Consortium and a gift from M. Dowd.; The Rotterdam Study (RS): The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners andpharmacists. The authors also thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera and M. Peters for their help in creating the GWAS database and K. Estrada and M. V. Struchalin for their support in the creation and analysis of imputed data. The generation and management of GWAS genotype data for the Rotterdam Study are supported by NWO Investments (nr. 175.010.2005.011 and 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (RIDE2; 014-93-015) and the NGI-NWO project (nr. 050-060-810). The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organisation for Health Research and Development (ZonMw), RIDE2, the Dutch Ministry of Education, Culture and Science, the Dutch Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The Rotterdam Scan Study is supported by the NWO (project nrs. 918-46-615, 904-61-096, 904-61-133 and 948-00-010), Nederlandse Hartstichting (2009B102) and Internationaal Parkinson Fonds.; The Tasmanian Study of Gait and Cognition (TASCOG): This study is supported by project grants from the National Health and Medical Research Council of Australia (NHMRC; 403000, 491109 and 606543) and a grant from the Wicking Dementia Education and Research Centre, Hobart. V. S. is supported by an NHMRC-National Heart Foundation Career Development Fellowship (606544). M. A. B. is supported by an NHMRC Senior Principal Research Fellowship (APP1024879).; Three City Study (3C): We thank the staff and participants of the 3C Study for their important contributions. We also thank A. Boland for her technical help in preparing the DNA samples for analyses. The 3C Study is conducted under a partnership agreement between INSERM, Victor Segalen-Bordeaux II University and Sanofi-Aventis. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale (MGEN), Institut de la Longevite, Conseils Regionaux de Aquitaine et Bourgogne, Fondation de France and the French Ministry of Research-INSERM Programme Cohortes et Collections de Donnees Biologiques. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Genotypage. NR 51 TC 95 Z9 97 U1 5 U2 39 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2012 VL 44 IS 5 BP 545 EP + DI 10.1038/ng.2237 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 934BW UT WOS:000303416300015 PM 22504421 ER PT J AU Stein, JL Medland, SE Vasquez, AA Hibar, DP Senstad, RE Winkler, AM Toro, R Appel, K Bartecek, R Bergmann, O Bernard, M Brown, AA Cannon, DM Chakravarty, MM Christoforou, A Domin, M Grimm, O Hollinshead, M Holmes, AJ Homuth, G Hottenga, JJ Langan, C Lopez, LM Hansell, NK Hwang, KS Kim, S Laje, G Lee, PH Liu, XM Loth, E Lourdusamy, A Mattingsdal, M Mohnke, S Maniega, SM Nho, K Nugent, AC O'Brien, C Papmeyer, M Putz, B Ramasamy, A Rasmussen, J Rijpkema, M Risacher, SL Roddey, JC Rose, EJ Ryten, M Shen, L Sprooten, E Strengman, E Teumer, A Trabzuni, D Turner, J van Eijk, K van Erp, TGM van Tol, MJ Wittfeld, K Wolf, C Woudstra, S Aleman, A Alhusaini, S Almasy, L Binder, EB Brohawn, DG Cantor, RM Carless, MA Corvin, A Czisch, M Curran, JE Davies, G de Almeida, MAA Delanty, N Depondt, C Duggirala, R Dyer, TD Erk, S Fagerness, J Fox, PT Freimer, NB Gill, M Goring, HHH Hagler, DJ Hoehn, D Holsboer, F Hoogman, M Hosten, N Jahanshad, N Johnson, MP Kasperaviciute, D Kent, JW Kochunov, P Lancaster, JL Lawrie, SM Liewald, DC Mandl, R Matarin, M Mattheisen, M Meisenzahl, E Melle, I Moses, EK Muhleisen, TW Nauck, M Nothen, MM Olvera, RL Pandolfo, M Pike, GB Puls, R Reinvang, I Renteria, ME Rietschel, M Roffman, JL Royle, NA Rujescu, D Savitz, J Schnack, HG Schnell, K Seiferth, N Smith, C Steen, VM Hernandez, MCV Van den Heuvel, M van der Wee, NJ Van Haren, NEM Veltman, JA Volzke, H Walker, R Westlye, LT Whelan, CD Agartz, I Boomsma, DI Cavalleri, GL Dale, AM Djurovic, S Drevets, WC Hagoort, P Hall, J Heinz, A Jack, CR Foroud, TM Le Hellard, S Macciardi, F Montgomery, GW Poline, JB Porteous, DJ Sisodiya, SM Starr, JM Sussmann, J Toga, AW Veltman, DJ Walter, H Weiner, MW Bis, JC Ikram, MA Smith, AV Gudnason, V Tzourio, C Vernooij, MW Launer, LJ DeCarli, C Seshadri, S Andreassen, OA Apostolova, LG Bastin, ME Blangero, J Brunner, HG Buckner, RL Cichon, S Coppola, G de Zubicaray, GI Deary, IJ Donohoe, G de Geus, EJC Espeseth, T Fernandez, G Glahn, DC Grabe, HJ Hardy, J Pol, HEH Jenkinson, M Kahn, RS McDonald, C McIntosh, AM McMahon, FJ McMahon, KL Meyer-Lindenberg, A Morris, DW Muller-Myhsok, B Nichols, TE Ophoff, RA Paus, T Pausova, Z Penninx, BW Potkin, SG Samann, PG Saykin, AJ Schumann, G Smoller, JW Wardlaw, JM Weale, ME Martin, NG Franke, B Wright, MJ Thompson, PM AF Stein, Jason L. Medland, Sarah E. Vasquez, Alejandro Arias Hibar, Derrek P. Senstad, Rudy E. Winkler, Anderson M. Toro, Roberto Appel, Katja Bartecek, Richard Bergmann, Orjan Bernard, Manon Brown, Andrew A. Cannon, Dara M. Chakravarty, M. Mallar Christoforou, Andrea Domin, Martin Grimm, Oliver Hollinshead, Marisa Holmes, Avram J. Homuth, Georg Hottenga, Jouke-Jan Langan, Camilla Lopez, Lorna M. Hansell, Narelle K. Hwang, Kristy S. Kim, Sungeun Laje, Gonzalo Lee, Phil H. Liu, Xinmin Loth, Eva Lourdusamy, Anbarasu Mattingsdal, Morten Mohnke, Sebastian Maniega, Susana Munoz Nho, Kwangsik Nugent, Allison C. O'Brien, Carol Papmeyer, Martina Putz, Benno Ramasamy, Adaikalavan Rasmussen, Jerod Rijpkema, Mark Risacher, Shannon L. Roddey, J. Cooper Rose, Emma J. Ryten, Mina Shen, Li Sprooten, Emma Strengman, Eric Teumer, Alexander Trabzuni, Daniah Turner, Jessica van Eijk, Kristel van Erp, Theo G. M. van Tol, Marie-Jose Wittfeld, Katharina Wolf, Christiane Woudstra, Saskia Aleman, Andre Alhusaini, Saud Almasy, Laura Binder, Elisabeth B. Brohawn, David G. Cantor, Rita M. Carless, Melanie A. Corvin, Aiden Czisch, Michael Curran, Joanne E. Davies, Gail de Almeida, Marcio A. A. Delanty, Norman Depondt, Chantal Duggirala, Ravi Dyer, Thomas D. Erk, Susanne Fagerness, Jesen Fox, Peter T. Freimer, Nelson B. Gill, Michael Goering, Harald H. H. Hagler, Donald J. Hoehn, David Holsboer, Florian Hoogman, Martine Hosten, Norbert Jahanshad, Neda Johnson, Matthew P. Kasperaviciute, Dalia Kent, Jack W., Jr. Kochunov, Peter Lancaster, Jack L. Lawrie, Stephen M. Liewald, David C. Mandl, Rene Matarin, Mar Mattheisen, Manuel Meisenzahl, Eva Melle, Ingrid Moses, Eric K. Muehleisen, Thomas W. Nauck, Matthias Noethen, Markus M. Olvera, Rene L. Pandolfo, Massimo Pike, G. Bruce Puls, Ralf Reinvang, Ivar Renteria, Miguel E. Rietschel, Marcella Roffman, Joshua L. Royle, Natalie A. Rujescu, Dan Savitz, Jonathan Schnack, Hugo G. Schnell, Knut Seiferth, Nina Smith, Colin Steen, Vidar M. Hernandez, Maria C. Valdes Van den Heuvel, Martijn van der Wee, Nic J. Van Haren, Neeltje E. M. Veltman, Joris A. Voelzke, Henry Walker, Robert Westlye, Lars T. Whelan, Christopher D. Agartz, Ingrid Boomsma, Dorret I. Cavalleri, Gianpiero L. Dale, Anders M. Djurovic, Srdjan Drevets, Wayne C. Hagoort, Peter Hall, Jeremy Heinz, Andreas Jack, Clifford R., Jr. Foroud, Tatiana M. Le Hellard, Stephanie Macciardi, Fabio Montgomery, Grant W. Poline, Jean Baptiste Porteous, David J. Sisodiya, Sanjay M. Starr, John M. Sussmann, Jessika Toga, Arthur W. Veltman, Dick J. Walter, Henrik Weiner, Michael W. Bis, Joshua C. Ikram, M. Arfan Smith, Albert V. Gudnason, Vilmundur Tzourio, Christophe Vernooij, Meike W. Launer, Lenore J. DeCarli, Charles Seshadri, Sudha Andreassen, Ole A. Apostolova, Liana G. Bastin, Mark E. Blangero, John Brunner, Han G. Buckner, Randy L. Cichon, Sven Coppola, Giovanni de Zubicaray, Greig I. Deary, Ian J. Donohoe, Gary de Geus, Eco J. C. Espeseth, Thomas Fernandez, Guillen Glahn, David C. Grabe, Hans J. Hardy, John Pol, Hilleke E. Hulshoff Jenkinson, Mark Kahn, Rene S. McDonald, Colm McIntosh, Andrew M. McMahon, Francis J. McMahon, Katie L. Meyer-Lindenberg, Andreas Morris, Derek W. Mueller-Myhsok, Bertram Nichols, Thomas E. Ophoff, Roel A. Paus, Tomas Pausova, Zdenka Penninx, Brenda W. Potkin, Steven G. Saemann, Philipp G. Saykin, Andrew J. Schumann, Gunter Smoller, Jordan W. Wardlaw, Joanna M. Weale, Michael E. Martin, Nicholas G. Franke, Barbara Wright, Margaret J. Thompson, Paul M. CA ADNI EPIGEN Consortium IMAGEN Consortium Saguenay Youth Study Grp SYS Cohorts Heart Aging Res Genomic Ep Enhancing Neuro Imaging Genetics M TI Identification of common variants associated with human hippocampal and intracranial volumes SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; TEMPORAL-LOBE EPILEPSY; AUTOMATED SEGMENTATION; GENOTYPE IMPUTATION; ALZHEIMERS-DISEASE; BRAIN VOLUME; HUMAN HEIGHT; FUNCTIONAL IMPLICATIONS; NA+/H+ EXCHANGER; UNIFIED APPROACH AB Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease(1,2) and is reduced in schizophrenia(3), major depression(4) and mesial temporal lobe epilepsy(5). Whereas many brain imaging phenotypes are highly heritable(6,7), identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 x 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 x 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 x 10(-7)). C1 [Stein, Jason L.; Hibar, Derrek P.; Senstad, Rudy E.; Hwang, Kristy S.; Jahanshad, Neda; Toga, Arthur W.; Apostolova, Liana G.; Thompson, Paul M.] Univ Calif Los Angeles, David Geffen Sch Med, Lab Neuro Imaging, Los Angeles, CA 90095 USA. [Medland, Sarah E.; Hansell, Narelle K.; Renteria, Miguel E.; Montgomery, Grant W.; Martin, Nicholas G.; Wright, Margaret J.] Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4006, Australia. [Medland, Sarah E.] Queensland Inst Med Res, Quantitat Genet Lab, Brisbane, Qld 4006, Australia. [Medland, Sarah E.] Broad Inst Harvard Univ & MIT, Cambridge, MA USA. [Vasquez, Alejandro Arias; Hoogman, Martine; Veltman, Joris A.; Brunner, Han G.; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Vasquez, Alejandro Arias; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Vasquez, Alejandro Arias; Rijpkema, Mark; Hoogman, Martine; Hagoort, Peter; Fernandez, Guillen; Franke, Barbara] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands. [Winkler, Anderson M.; Glahn, David C.] Hartford Hosp, Olin Neuropsychiat Res Ctr, Inst Living, Hartford, CT 06115 USA. [Winkler, Anderson M.; Glahn, David C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Toro, Roberto] Inst Pasteur, Lab Human Genet & Cognit Funct, Paris, France. [Toro, Roberto] Inst Pasteur, CNRS, URA Genes Synapses & Cognit 2182, Paris, France. [Toro, Roberto] Univ Paris Diderot, Dept Neurosci, Paris, France. [Appel, Katja; Wittfeld, Katharina; Grabe, Hans J.] Ernst Moritz Arndt Univ Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany. [Appel, Katja] Univ Heidelberg, Inst Psychol, Dept Clin Psychol & Psychotherapy, Heidelberg, Germany. [Bartecek, Richard; Mandl, Rene; Schnack, Hugo G.; Van den Heuvel, Martijn; Van Haren, Neeltje E. M.; Pol, Hilleke E. Hulshoff; Kahn, Rene S.; Ophoff, Roel A.] Univ Med Ctr Utrecht, Dept Psychiat, Rudolf Magnus Inst, Utrecht, Netherlands. [Bergmann, Orjan; Brown, Andrew A.; Mattingsdal, Morten; Melle, Ingrid; Agartz, Ingrid; Djurovic, Srdjan; Andreassen, Ole A.] Univ Oslo, Inst Clin Med, Oslo, Norway. [Bernard, Manon; Pausova, Zdenka] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Brown, Andrew A.] Univ Oslo, Inst Basic Med Sci, Dept Biostat, Oslo, Norway. [Cannon, Dara M.] Natl Univ Ireland Galway, Clin Neuroimaging Lab, Dept Anat, Galway, Ireland. [Langan, Camilla; McDonald, Colm] Natl Univ Ireland Galway, Clin Neuroimaging Lab, Dept Psychiat, Galway, Ireland. [Chakravarty, M. Mallar; Paus, Tomas] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Christoforou, Andrea; Steen, Vidar M.; Le Hellard, Stephanie] Univ Bergen, Dr Einar Martens Res Grp Biol Psychiat, Dept Clin Med, Bergen, Norway. [Christoforou, Andrea; Steen, Vidar M.; Le Hellard, Stephanie] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Domin, Martin; Hosten, Norbert; Puls, Ralf] Ernst Moritz Arndt Univ Greifswald, Dept Diagnost Radiol & Neuroradiol, Greifswald, Germany. [Grimm, Oliver; Rietschel, Marcella; Meyer-Lindenberg, Andreas] Univ Heidelberg, Cent Inst Mental Hlth, Med Fac Mannheim, D-6800 Mannheim, Germany. [Hollinshead, Marisa; Holmes, Avram J.; Buckner, Randy L.] Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA. [Hollinshead, Marisa; Buckner, Randy L.] Howard Hughes Med Inst, Cambridge, MA USA. [Homuth, Georg; Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Hottenga, Jouke-Jan; Boomsma, Dorret I.; de Geus, Eco J. C.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Lopez, Lorna M.; Maniega, Susana Munoz; Liewald, David C.; Royle, Natalie A.; Hernandez, Maria C. Valdes; Porteous, David J.; Starr, John M.; Bastin, Mark E.; Deary, Ian J.; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Lopez, Lorna M.; Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Hwang, Kristy S.; Apostolova, Liana G.; Coppola, Giovanni] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Shen, Li; Saykin, Andrew J.] Indiana Univ Sch Med, Ctr Neuroimaging, Dept Radiol & Imaging Sci, Indianapolis, IN USA. [Kim, Sungeun; Shen, Li; Foroud, Tatiana M.; Saykin, Andrew J.] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA. [Laje, Gonzalo; Liu, Xinmin; McMahon, Francis J.] NIMH, Mood & Anxiety Disorders Sect, Human Genet Branch,US Dept HHS, Intramural Res Program,US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Lee, Phil H.; Brohawn, David G.; Fagerness, Jesen; Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Lee, Phil H.; Roffman, Joshua L.; Buckner, Randy L.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Liu, Xinmin] Columbia Univ, Med Ctr, Taub Inst Res Alzheimer Dis & Aging Brain, New York, NY USA. [Loth, Eva; Lourdusamy, Anbarasu; Schumann, Gunter] Kings Coll London, MRC, Social Genet & Dev Psychiat SGDP Ctr, Inst Psychiat, London WC2R 2LS, England. [Mattingsdal, Morten] Sorlandet Hosp, Res Unit, Kristiansand, Norway. [Mohnke, Sebastian; Erk, Susanne; Seiferth, Nina; Heinz, Andreas; Walter, Henrik] Charite, Dept Psychiat & Psychotherapy, D-13353 Berlin, Germany. [Maniega, Susana Munoz; Royle, Natalie A.; Hernandez, Maria C. Valdes; Bastin, Mark E.; Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland. [Nho, Kwangsik] Regenstrief Inst Hlth Care, Div Med Informat, Indianapolis, IN USA. [Nugent, Allison C.; Savitz, Jonathan; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. [O'Brien, Carol; Rose, Emma J.; Corvin, Aiden; Gill, Michael; Donohoe, Gary; Morris, Derek W.] Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Dept Psychiat, Inst Mol Med, Dublin, Ireland. [O'Brien, Carol; Rose, Emma J.; Corvin, Aiden; Gill, Michael; Donohoe, Gary; Morris, Derek W.] Trinity Coll Dublin, Inst Neurosci, Dublin, Ireland. [Papmeyer, Martina; Sprooten, Emma; Lawrie, Stephen M.; Hall, Jeremy; Sussmann, Jessika; McIntosh, Andrew M.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Putz, Benno; Wolf, Christiane; Binder, Elisabeth B.; Czisch, Michael; Hoehn, David; Holsboer, Florian; Mueller-Myhsok, Bertram; Saemann, Philipp G.] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Ramasamy, Adaikalavan; Weale, Michael E.] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England. [Rasmussen, Jerod; van Erp, Theo G. M.; Macciardi, Fabio; Potkin, Steven G.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Rijpkema, Mark; Hagoort, Peter; Fernandez, Guillen] Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, NL-6525 ED Nijmegen, Netherlands. [Roddey, J. Cooper; Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Ryten, Mina; Trabzuni, Daniah; Hardy, John] UCL, Dept Mol Neurosci, London, England. [Ryten, Mina; Trabzuni, Daniah; Hardy, John] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Strengman, Eric; van Eijk, Kristel] Univ Med Ctr Utrecht, Rudolf Magnus Inst, Utrecht, Netherlands. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Turner, Jessica] Mind Res Network, Albuquerque, NM USA. [van Tol, Marie-Jose; van der Wee, Nic J.; Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [van Tol, Marie-Jose; van der Wee, Nic J.; Penninx, Brenda W.] Leiden Univ, Leiden Inst Brain & Cognit, Leiden, Netherlands. [van Tol, Marie-Jose; Aleman, Andre] Univ Groningen, Univ Med Ctr Groningen, Behav & Cognit Neurosci Neuroimaging Ctr, NL-9713 AV Groningen, Netherlands. [Woudstra, Saskia; Veltman, Dick J.; Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Alhusaini, Saud; Delanty, Norman; Whelan, Christopher D.; Cavalleri, Gianpiero L.] Royal Coll Surgeons Ireland, Dept Mol & Cellular Therapeut, Dublin 2, Ireland. [Almasy, Laura; Carless, Melanie A.; Curran, Joanne E.; de Almeida, Marcio A. A.; Duggirala, Ravi; Dyer, Thomas D.; Johnson, Matthew P.; Kent, Jack W., Jr.; Moses, Eric K.; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Cantor, Rita M.; Freimer, Nelson B.; Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. [Delanty, Norman] Beaumont Hosp, Div Neurol, Dublin 9, Ireland. [Depondt, Chantal; Pandolfo, Massimo] Univ Libre Brussels, Dept Neurol, Hop Erasme, Brussels, Belgium. [Buckner, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Fox, Peter T.; Kochunov, Peter; Lancaster, Jack L.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Hagler, Donald J.; Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Hoogman, Martine; Fernandez, Guillen] Radboud Univ Nijmegen, Dept Cognit Neurosci, Med Ctr, Nijmegen, Netherlands. [Hoogman, Martine; Hagoort, Peter] Max Planck Inst Psycholinguist, Nijmegen, Netherlands. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] UCL, Dept Clin & Expt Epilepsy, Inst Neurol, London, England. [Kochunov, Peter] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Mattheisen, Manuel; Muehleisen, Thomas W.; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Mattheisen, Manuel; Muehleisen, Thomas W.; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Inst Human Genet, Bonn, Germany. [Mattheisen, Manuel] Univ Bonn, Inst Genom Math, Bonn, Germany. [Meisenzahl, Eva; Rujescu, Dan] Univ Munich, Dept Psychiat, D-80804 Munich, Germany. [Melle, Ingrid; Andreassen, Ole A.] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Noethen, Markus M.] German Ctr Neurodegenerat Disorders DZNE, Bonn, Germany. [Olvera, Rene L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Pike, G. Bruce] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. [Reinvang, Ivar; Westlye, Lars T.; Espeseth, Thomas] Univ Oslo, Dept Psychol, Ctr Study Human Cognit, Oslo, Norway. [Reinvang, Ivar; Espeseth, Thomas] Ctr Adv Study, Oslo, Norway. [Renteria, Miguel E.; de Zubicaray, Greig I.] Univ Queensland, Sch Psychol, Brisbane, Qld, Australia. [Savitz, Jonathan; Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. [Schnell, Knut] Univ Heidelberg, Univ Heidelberg Hosp, Dept Gen Psychiat, Heidelberg, Germany. [Schnell, Knut; Walter, Henrik] Univ Bonn, Dept Psychiat, Div Med Psychol, Bonn, Germany. [Smith, Colin; Walker, Robert] Univ Edinburgh, Dept Pathol, MRC Sudden Death Tissue Bank Edinburgh, Edinburgh, Midlothian, Scotland. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Agartz, Ingrid] Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Jack, Clifford R., Jr.] Mayo Clin & Mayo Fdn, Aging & Dementia Imaging Res Lab, Dept Radiol, Rochester, MN USA. [Foroud, Tatiana M.; Saykin, Andrew J.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA. [Poline, Jean Baptiste] Commissariat Energie Atom, Inst Imagerie Biomed I2BM, Gif Sur Yvette, France. [Porteous, David J.] Univ Edinburgh, Western Gen Hosp, Med Genet Sect, Mol Med Ctr,Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Starr, John M.] Univ Edinburgh, Royal Victoria Hosp, Geriatr Med Unit, Edinburgh, Midlothian, Scotland. [Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Weiner, Michael W.] Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Ikram, M. Arfan; Vernooij, Meike W.] Univ Med Ctr, Erasmus Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Arfan; Vernooij, Meike W.] Univ Med Ctr, Erasmus Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Ikram, M. Arfan; Vernooij, Meike W.] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Tzourio, Christophe] Univ Bordeaux, U708, Bordeaux, France. [Tzourio, Christophe] INSERM, U708, Bordeaux, France. [Launer, Lenore J.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Seshadri, Sudha] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Bastin, Mark E.] Univ Edinburgh, Div Hlth Sci Med Phys, Edinburgh, Midlothian, Scotland. [Cichon, Sven] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. [Coppola, Giovanni] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Espeseth, Thomas] Univ Bergen, Dept Biol & Med Psychol, Fac Psychol, Bergen, Norway. [Grabe, Hans J.] German Ctr Neurodegenerat Dis DZNE, Greifswald, Germany. [Jenkinson, Mark; Nichols, Thomas E.] Univ Oxford, FMRIB, Oxford, England. [McMahon, Katie L.] Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 AV Groningen, Netherlands. RP Thompson, PM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Lab Neuro Imaging, Los Angeles, CA 90095 USA. EM thompson@loni.ucla.edu RI Meyer-Lindenberg, Andreas/H-1076-2011; Poustka, Luise/D-9299-2017; Moreno, Margarita/K-9869-2014; Trabzuni, Daniah/C-4034-2012; Wright, Margaret/A-4560-2016; Vollstadt-Klein, Sabine/C-6744-2012; Arias Vasquez, Alejandro/E-4762-2012; McMahon, Katie/C-6440-2009; Vernooij, Meike/E-4061-2016; Macciardi, Fabio/N-3768-2014; Smith, Albert/K-5150-2015; Matarin, Mar/F-1771-2016; Melle, Ingrid /B-4858-2011; Finsterbusch, Jurgen/M-2969-2016; Putz, Benno/P-2630-2016; Winkler, Anderson/P-7773-2016; Lourdusamy, Anbarasu/P-6606-2014; lambert, jean-charles/F-8787-2013; LICEND, CEMND/F-1296-2015; de Zubicaray, Greig/B-1763-2008; Hoogman, Martine/G-8958-2015; Breteler, Monique /J-5058-2014; Turner, Jessica/H-7282-2015; Gudnason, Vilmundur/K-6885-2015; Veltman, Joris/F-5128-2010; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Mattheisen, Manuel/B-4949-2012; Hansell, Narelle/A-4553-2016; Saykin, Andrew/A-1318-2007; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Fernandez, Guillen/B-3771-2009; Desrivieres, Sylvane/B-7399-2011; Hulshoff Pol, Hilleke/B-4795-2014; Munoz Maniega, Susana/I-8730-2014; Pike, Bruce/K-5562-2014; Binder, Elisabeth/K-8905-2014; Laje, Gonzalo/L-2654-2014; McDonald, Colm/C-1430-2009; Tzourio, christophe/B-4015-2009; Hagoort, Peter/B-7417-2012; Porteous, David/C-7289-2013; Medland, Sarah/C-7630-2013; Deary, Ian/C-6297-2009; Brunner, Han/C-9928-2013; Franke, Barbara/D-4836-2009; Lourdusamy, Anbarasu/G-3387-2011; Savitz, Jonathan/C-3088-2009; Fox, Peter/B-4725-2010; Preda, Adrian /K-8889-2013; Cannon, Dara/C-1323-2009; Walter, Henrik/O-2612-2013; Ramasamy, Adaikalavan/G-2632-2010; Lopez, Lorna/F-7265-2010; Cavalleri, Gianpiero/A-6632-2010; Weale, Michael/F-2587-2010; McIntosh, Andrew/B-9379-2008; Potkin, Steven/A-2021-2013; Muller-Myhsok, Bertram/A-3289-2013; Jack, Clifford/F-2508-2010; Hardy, John/C-2451-2009; Rijpkema, Mark/D-1974-2010; Kowall, Neil/G-6364-2012; Rose, Emma/A-9960-2010; Cavalieri, Margherita/G-8053-2012; OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Moreno, Margarita/0000-0001-7336-6167; Stein, Jason/0000-0003-4829-0513; Nichols, Thomas/0000-0002-4516-5103; Lemaitre, Herve/0000-0002-5952-076X; Trabzuni, Daniah/0000-0003-4826-9570; Walker, Robert/0000-0001-7383-7846; Toro, Roberto/0000-0002-6671-858X; Whelan, Christopher/0000-0003-0308-5583; Wright, Margaret/0000-0001-7133-4970; Vollstadt-Klein, Sabine/0000-0002-6210-672X; Arias Vasquez, Alejandro/0000-0002-4786-0169; McMahon, Katie/0000-0002-6357-615X; Macciardi, Fabio/0000-0003-0537-4266; Smith, Albert/0000-0003-1942-5845; Matarin, Mar/0000-0002-4717-5735; Melle, Ingrid /0000-0002-9783-548X; Putz, Benno/0000-0002-2208-209X; Winkler, Anderson/0000-0002-4169-9781; de Zubicaray, Greig/0000-0003-4506-0579; Hoogman, Martine/0000-0002-1261-7628; Turner, Jessica/0000-0003-0076-8434; Gudnason, Vilmundur/0000-0001-5696-0084; Veltman, Joris/0000-0002-3218-8250; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Mattheisen, Manuel/0000-0002-8442-493X; Hansell, Narelle/0000-0002-8229-9741; Saykin, Andrew/0000-0002-1376-8532; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Fernandez, Guillen/0000-0002-5522-0604; Desrivieres, Sylvane/0000-0002-9120-7060; Hulshoff Pol, Hilleke/0000-0002-2038-5281; Munoz Maniega, Susana/0000-0001-5185-6384; Pike, Bruce/0000-0001-8924-683X; Laje, Gonzalo/0000-0003-2763-3329; Tzourio, christophe/0000-0002-6517-2984; Porteous, David/0000-0003-1249-6106; Medland, Sarah/0000-0003-1382-380X; Franke, Barbara/0000-0003-4375-6572; Savitz, Jonathan/0000-0001-8143-182X; Fox, Peter/0000-0002-0465-2028; Preda, Adrian /0000-0003-3373-2438; Cannon, Dara/0000-0001-7378-3411; Ramasamy, Adaikalavan/0000-0002-7598-2892; Weale, Michael/0000-0003-4593-1186; McIntosh, Andrew/0000-0002-0198-4588; Jack, Clifford/0000-0001-7916-622X; Rijpkema, Mark/0000-0002-8495-4703; Kowall, Neil/0000-0002-6624-0213; Rose, Emma/0000-0001-5365-4794; Westlye, Lars T./0000-0001-8644-956X; Martin, Nicholas/0000-0003-4069-8020; Andreassen, Ole A./0000-0002-4461-3568; Flor, Herta/0000-0003-4809-5398; Shen, Li/0000-0002-5443-0503; Beiser, Alexa/0000-0001-8551-7778; Nugent, Allison/0000-0003-2569-2480; Becker, James/0000-0003-4425-4726; Cavalleri, Gianpiero/0000-0002-9802-0506; Agartz, Ingrid/0000-0002-9839-5391; Nothen, Markus/0000-0002-8770-2464; Donohoe, Gary/0000-0003-3037-7426; Morris, Derek/0000-0002-3413-570X; Delaney, Norman/0000-0002-3953-9842; Romanczuk-Seiferth, Nina/0000-0002-6931-269X; Gill, Michael/0000-0003-0206-5337; Ikram, Mohammad Arfan/0000-0003-0372-8585; van den Heuvel, Martijn/0000-0003-1570-1195; Smolka, Michael/0000-0001-5398-5569; Jenkinson, Mark/0000-0001-6043-0166; Seshadri, Sudha/0000-0001-6135-2622; McMahon, Francis/0000-0002-9469-305X; Corvin, Aiden/0000-0001-6717-4089; Kent, Jack/0000-0002-0758-7639; Lourdusamy, Anbarasu/0000-0002-1978-6301 FU Eli Lilly Company; Wyeth; Bristol-Myers Squibb; AstraZeneca; GlaxoSmithKline; German Research Foundation; Federal Ministry of Education and Research Germany; Janssen-Cilag; Novartis; Lundbeck; SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health; Federal Ministry of Education and Research, Germany; BioRad Laboratories; Siemens AG; Zeitschrift fur Laboratoriumsmedizin; Bruker Daltronics; Abbott; Jurilab Kuopio; Roche Diagnostics; Instand; Becton Dickinson; Hofmann La Roche; Humboldt Foundation; Araclon; Medivation/Pfizer; Ipsen; TauRx Therapeutics; Bayer Healthcare; Biogen Idec; Exonhit Therapeutics; SA; Servier; Synarc; Pfizer; Janssen; Merck; Avid; DoD; VA; Alzheimer's Disease Neuroimaging Initiative; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Anonymous Foundation; BioClinica (ADNI 2); Cure Alzheimer's Fund; Eisai; Elan; Gene Network Sciences; Genentech; GE Healthcare; Innogenetics; Johnson Johnson; Medpace; Roche; Schering Plough; US NIH [U01 AG024904, U24 RR21992, MH0708143, MH083824, MH078111, MH59490, C06 RR13556, C06 RR017515, R01D0042157-01A, MH079799]; Foundation for the NIH; NIH [U01 AG024904, RC2 AG036535-01, P30 AG010129, K01 AG030514, EB006395, AG040060, EB008432, P41 RR013642, HD050735, AG036535, AG020098, EB008281]; NIA [R01 AG019771-09]; NCRAD [U24AG021886]; ADNI (NIH) [U01 AG024904]; NIA; National Institute of Biomedical Imaging and Bioengineering (NIBIB); Dana Foundation; Biobanking and Biomolecular Resources Research Infrastructure Netherlands (BBMRI-NL); Netherlands Organisation for Scientific Research (NWO) [93511010]; National Alliance for Research on Schizophrenia and Depression (NARSAD); Health Foundation; Italian Ministry of University and Research [RBIN04SWHR]; European Commission [PL037286]; UK Department of Health National Institute of Health Research (NIHR)-Biomedical Research Centre; MRC [93558]; NIA at the University of California, Los Angeles [AG16570]; Age UK's Disconnected Mind programme; Research Into Ageing [251, 285]; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F019394/1]; UK MRC [G1001401, 8200, G0901254]; Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); Scottish Funding Council through the SINAPSE Collaboration; AXA; German Federal Ministry of Education and Research (BMBF); Exzellenz-Stiftung of the Max Planck Society; BMBF in the framework of the National Genome Research Network (NGFN) [FKZ 01GS0481]; Research Council of Norway [154313/ V50, 177458/V50, 167153/V50, 163070/V50, 183782/V50]; Bergen Research Foundation; University of Bergen; Research Council of Norway (FUGE; Psykisk Helse), Helse Vest Regionalt Helseforetak (RHF); Dr Einar Martens Fund; NWO (MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, SPI 56-464-14192, 10-000-1002]; Center for Medical Systems Biology (CMSB; NWO Genomics); Biobanking and Biomolecular Resources Research Infrastructure; VU University; EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam; European Science Foundation [EU/QLRT-2001-01254]; European Community [HEALTH-F4-2007-201413]; European Science Council (ERC) Genetics of Mental Illness [230374]; Rutgers University Cell; DNA Repository (NIMH) [U24 MH068457-06]; Genetic Association Information Network (a public-private partnership between the NIH and Pfizer, Affymetrix and Abbott Laboratories); National Institute of Mental Health (NIMH) from NIH; US Department of Health and Human Services [K99 MH085098, 1ZIA MH002810, 1ZIA MH002790]; US National Institute of Child Health and Human Development [R01 HD050735]; Australian National Health and Medical Research Council (NHMRC) [496682]; NHMRC [389891, 613667]; Australian Research Council (ARC) [FT0991634, FT110100548]; Achievement Rewards for College Scientists foundation; US NIMH [F31 MH087061, MH078075]; National Science Foundation (NSF) [DGE-0707424]; Canadian Institutes of Health Research; Heart and Stroke Foundation of Quebec; Canadian Foundation for Innovation; German Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; German Research Foundation (DFG) [GR 1912/5-1]; Federal Ministry of Education and Research [03ZIK012, 03IS2061A]; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; German Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Simons Foundation; Howard Hughes Medical Institute; Oslo University Hospital-Ulleval; Eastern Norway Health Authority [2004-123]; Wellcome Trust [072894/z/03/z-Gill, 084730]; Science Foundation Ireland [08/IN.1/B1916_Corvin, 08/RFP/GEN1538]; University College London (UCL)/University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) [114]; European Union Marie Curie Reintegration; UK NIHR [08-08-SCC]; Comprehensive Local Research Network (CLRN) [CEL1300]; The Big Lottery Fund; Wolfson Trust; Epilepsy Society; UK Department of Health's NIHR Biomedical Research Centres; Brainwave-the Irish Epilepsy Association; Fonds National de la Recherche Scientifique [FC 63574 / 3.4.620.06 F]; Fonds Erasme pour la Recherche Medicale at the Universite Libre de Bruxelles; MRC Sudden Death Brain and Tissue Bank; Sun Health Research Institute Brain Bank; Netherlands Organization for Health Research and Development ZonMw [917.46.370]; [NBIC/BioAssist/RK/2008.024] FX Some authors received commercial funding unrelated to the topic of this paper. N.J.v.d. W. received speaking fees from Eli Lilly & Company and Wyeth and served on advisory panels of Eli Lilly & Company, Pfizer, Wyeth and Servier. A. A. received an investigator-initiated unrestricted research grant from Bristol-Myers Squibb and speaker's fees from AstraZeneca, Bristol-Myers Squibb and GlaxoSmithKline. H.J.G. received external research support from the German Research Foundation, the Federal Ministry of Education and Research Germany, speaker's honoraria from Bristol-Myers Squibb, Eli Lilly & Company, Novartis, Eisai, Boehringer Ingelheim and Servier and travel funds from Janssen-Cilag, Eli Lilly & Company, Novartis, AstraZeneca, Lundbeck and the SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. M.N. received research grants from the Federal Ministry of Education and Research, Germany, the German Research Foundation, BioRad Laboratories, Siemens AG, Zeitschrift fur Laboratoriumsmedizin, Bruker Daltronics, Abbott, Jurilab Kuopio, Roche Diagnostics, Instand and Becton Dickinson. H. V. received external research support via research grants from Hofmann La Roche, the Humboldt Foundation, the Federal Ministry of Education and Research (Germany) and the German Research Foundation. M. W. is on the following scientific advisory boards: Lilly, Araclon and Institut Catala de Neurociencies Aplicades, the Gulf War Veterans Illnesses Advisory Committee, VACO, Biogen Idec and Pfizer. M. W. received funding for consulting from Astra Zeneca, Araclon, Medivation/Pfizer, Ipsen, TauRx Therapeutics, Bayer Healthcare, Biogen Idec, Exonhit Therapeutics, SA, Servier, Synarc, Pfizer and Janssen; for travel from NeuroVigil, CHRU-Hopital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Lilly, the University of California, San Diego-ADNI, Paris University, Institut Catala de Neurociencies Aplicades, the University of New Mexico School of Medicine, Ipsen, Clinical Trials on Alzheimer's Disease (CTAD), Pfizer, AD PD Meeting, Paul Sabatier University, Novartis and Tohoku University; and research support from: Merck, Avid, DoD, VA. M. W. received honoraria from PMDA/the Japanese Ministry of Health, Labour, and Welfare, Tohoku University, Neuro Vigil, Insitut Catala de Neurociencies Aplicades. M. W. owns stock options for Synarc, Elan. Organizations contributing to the Foundation for the US NIH and thus to the National Institute on Aging (NIA)-funded Alzheimer's Disease Neuroimaging Initiative included Abbott, the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, Anonymous Foundation, AstraZeneca, Bayer Healthcare, BioClinica (ADNI 2), Bristol-Myers Squibb, the Cure Alzheimer's Fund, Eisai, Elan, Gene Network Sciences, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly & Company, Medpace, Merck, Novartis, Pfizer, Roche, Schering Plough, Synarc and Wyeth.; ADNI: The ADNI study was supported by the US NIH (U01 AG024904) and the Foundation for the NIH for genotype and phenotype data collection, the NIH (RC2 AG036535-01) for data analysis, the NIA (R01 AG019771-09) for additional data analysis and NCRAD (U24AG021886) for DNA used in part for the GWAS. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (see URLs). As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. The ADNI sample wishes to acknowledge the investigators who contributed to the design and implementation of ADNI (see URLs). Data collection and sharing for this project were funded by ADNI (NIH grant U01 AG024904). ADNI is funded by the NIA, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and through generous contributions from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly & Company, Medpace, Merck and Cocpany, Novartis AG, Pfizer, F. Hoffman-La Roche, Schering-Plough and Synarc, as well as from nonprofit partners at the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration (FDA). Private sector contributions to ADNI are facilitated by the Foundation for the NIH (see URLs). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants (P30 AG010129 and K01 AG030514) and by the Dana Foundation. ADNI was launched in 2003 by the NIA, the NIBIB, the FDA, private pharmaceutical companies and nonprofit organizations as a 5-year public-private partnership. The primary goal of ADNI has been to test whether serial MRI), positron emission tomography (PET), other biological markers and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease. Determination of sensitive and specific markers of very early Alzheimer's disease progression is intended to aid researchers and clinicians in developing new treatments and monitoring their effectiveness, as well as lessening the time and cost of clinical trials. The Principal Investigator of this initiative is M. W. Weiner. ADNI is the result of efforts of many coinvestigators from a broad range of academic institutions and private corporations, and subjects have been recruited from over 50 sites across the United States and Canada. The initial goal of ADNI was to recruit 800 adults ages 55 to 90 to participate in the research-approximately 200 cognitively normal older individuals to be followed for 3 years, 400 people with MCI to be followed for 3 years and 200 people with early Alzheimer's disease to be followed for 2 years. For up-to-date information, please visit the ADNI website (see URLs).; BIG: The BIG study wishes to acknowledge S. Kooijman for coordination of sample collection and A. Heister, M. Naber, R. Makkinje, M. Hakobjan and M. Steehouwer for genotyping. The BIG study was supported by a Biobanking and Biomolecular Resources Research Infrastructure Netherlands (BBMRI-NL) complementation grant for brain segmentation and the Netherlands Organisation for Scientific Research (NWO) Horizon Breakthrough grant (grant number 93511010 (to A. A. V.).; Bipolar Family Study: The Bipolar Family Study wishes to thank the Scottish Mental Health Research Network for research assistant support, the Brain Research Imaging Centre Edinburgh (see URLs), a center in the Scottish Funding Council Scottish Imaging Network-A Platform for Scientific Excellence (SINAPSE) Collaboration (see URLs), for image acquisition and the Wellcome Trust Clinical Research Facility for genotyping. Genotyping was supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award (to A. M. M.), and data collection was supported by the Health Foundation Clinician Scientist Fellowship.; fBIRN: fBIRN wishes to acknowledge D. B. Keator for leading fBIRN neuroinformatics development, B. A. Mueller for image calibration and quality assurance and A. Belger, V. D. Calhoun, G. G. Brown, J. M. Ford, G. H. Glover, R. Kikinis, K. Lim, J. Laurriello, J. Bustillo, G. McCarthy, D. S. O'Leary, B. Rosen, A. W. T. and J. T. Voyvodic for their leadership contributions to fBIRN scanner and sequence calibration, tool development and data collection efforts. The fBIRN study was supported by the US NIH (U24 RR21992) for phenotypic data collection. Genotyping was performed with the support of the grant RBIN04SWHR to F. M. from the Italian Ministry of University and Research.; GOBS: The GOBS study was supported by the US NIH (MH0708143 and MH083824 to D. C. G., MH078111 and MH59490 to J. B., C06 RR13556 and C06 RR017515). P. K. was also supported by an NIH grant (EB006395).; IMAGEN: IMAGEN is funded by the European Commission Framework Programme 6 (FP-6) Integrated Project IMAGEN (PL037286), the European Commission Framework Programme 7 (FP-7) Project Alzheimer's Disease, Alcoholism, Memory, Schizophrenia (ADAMS), the FP-7 Innovative Medicine Initiative Project European Autism Interventions (AIMS), the UK Department of Health National Institute of Health Research (NIHR)-Biomedical Research Centre Mental Health program and the MRC programme grant Developmental Pathways into Adolescent Substance Abuse (93558).; ImaGene: ImaGene wishes to acknowledge J. Lee and J. Lane for processing the blood samples, The Easton Consortium for Alzheimer's Disease Drug Discovery and Biomarker Development and the Alzheimer's Disease Research Center (ADRC) funded by the NIA at the University of California, Los Angeles (AG16570).; LBC1936: We thank the participants in LBC1936. We thank C. Murray, A. J. Gow, S. E. Harris, M. Luciano, P. Redmond, E. Sandeman, I. Gerrish, J. Boyd-Ellison, N. Leslie, A. Howden and C. Scott for data collection and preparation. This project is funded by the Age UK's Disconnected Mind programme and also by Research Into Ageing (251 and 285). The entire genome association part of the study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F019394/1). Analysis of brain images was funded by UK MRC grants (G1001401 and 8200). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/ 84698). Imaging was performed at the Brain Research Imaging Centre, Edinburgh, a center in the SINAPSE Collaboration. Funding from BBSRC, the Engineering and Physical Sciences Research Council (EPSRC), the Economic and Social Research Council (ESRC) and the MRC and Scottish Funding Council through the SINAPSE Collaboration is gratefully acknowledged. L. M. L. is the beneficiary of a postdoctoral grant from the AXA Research Fund.; MooDS: This work was funded by the German Federal Ministry of Education and Research (BMBF) in the National Genome Research Network (NGFN-plus) through the MooDs grant Molecular Causes of Major Mood Disorders and Schizophrenia (coordinator M. M. N.). Additional funding for genotyping was provided by a NARSAD Distinguished Investigator award to A. M.-L.; MPIP: The MPIP Munich Morphometry Sample comprises images acquired as part of the Munich Antidepressant Response Signature Study and the Recurrent Unipolar Depression (RUD) Case-Control Study performed at the MPIP and control subjects acquired at the Department of Psychiatry at the Ludwig-Maximilians-University. We wish to acknowledge A. Olynyik and radiographers R. Schirmer, E. Schreiter and R. Borschke for image acquisition and data preparation. We thank D. P. Auer for local study management in the initial phase of the RUD study. We are grateful to GlaxoSmithKline for providing the genotypes of the RUD Case-Control Sample. We thank the staff of the Center of Applied Genotyping (CAGT) for generating the genotypes of the MARS cohort. The study is supported by a grant from the Exzellenz-Stiftung of the Max Planck Society. This work has also been funded by the BMBF in the framework of the National Genome Research Network (NGFN) (FKZ 01GS0481).; NCNG: We would like to thank the personnel involved in recruitment and data collection and, in particular, P. Due-Tonnessen for clinical assessment of the MRI images. The NCNG study was supported by Research Council of Norway grants (154313/ V50 and 177458/V50). The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE; Psykisk Helse), Helse Vest Regionalt Helseforetak (RHF) and the Dr Einar Martens Fund.; NESDA-NTR: Funding was obtained from the NWO (MagW/ZonMW 904-61-090; 985-10-002; 904-61-193; 480-04-004; 400-05-717, Addiction-31160008; 911-09-032; SPI 56-464-14192 and Geestkracht Program, 10-000-1002), the Center for Medical Systems Biology (CMSB; NWO Genomics), NBIC/BioAssist/RK/2008.024, BBMRI-NL, Biobanking and Biomolecular Resources Research Infrastructure, the VU University, the EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, the European Science Foundation (EU/QLRT-2001-01254), the European Community's FP7 (HEALTH-F4-2007-201413), the European Science Council (ERC) Genetics of Mental Illness (230374), Rutgers University Cell and DNA Repository (cooperative agreement NIMH U24 MH068457-06), the US NIH (R01D0042157-01A) and the Genetic Association Information Network (a public-private partnership between the NIH and Pfizer, Affymetrix and Abbott Laboratories).; NIMH-IRP: This study was supported by funding from the Intramural Research Program of the National Institute of Mental Health (NIMH) from the NIH and the US Department of Health and Human Services (K99 MH085098 to G. L., 1ZIA MH002810 to F. J. M. and 1ZIA MH002790 to W. C. D.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.; QTIM: We are extremely grateful to the twins for their participation, the radiographers at the Centre for Advanced Imaging at the University of Queensland for image acquisition and the many research assistants and support staff at the Queensland Institute of Medical Research for twin recruitment and daily management, and we especially thank K. Johnson for MRI scanning and processing, A. Henders for DNA processing and preparation and S. Gordon for quality control and management of the genotypes. Phenotyping was funded by the US National Institute of Child Health and Human Development (R01 HD050735) and the Australian National Health and Medical Research Council (NHMRC) (project grant 496682). Genotyping was funded by the NHMRC (Medical Bioinformatics Genomics Proteomics Program, 389891). G. M. was supported by an NHMRC Fellowship (613667), and G.Z. was supported by Australian Research Council (ARC) Future Fellowship (FT0991634). S. E. M. is funded by an ARC Future Fellowship (FT110100548). J.L.S. was supported by the Achievement Rewards for College Scientists foundation and the US NIMH (F31 MH087061). D. P. H. is partially supported by a National Science Foundation (NSF) Graduate Research Fellowhip Program (GRFP) grant (DGE-0707424). P. T. was also supported by the NIH (grants U01 AG024904, AG040060, EB008432, P41 RR013642, HD050735, AG036535, AG020098 and EB008281).; SYS: The Saguenay Youth Study Group wishes to thank the following individuals for their contribution in acquiring and analyzing the data: N. Arbour, M.-E. Bouchard, A. Houde, A. Gauthier and H. Simard for the recruitment and assessment of participating families, M. Berube, S. Masson, S. Castonguay and M.-J. Morin for MRI acquisition and E. Ding and N. Qiu for MR data management. We thank J. Mathieu for the medical follow up of participants in whom we detected any medically relevant abnormalities. We are grateful to all families for participating in the study. The Saguenay Youth Study Group is supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Quebec and the Canadian Foundation for Innovation. For more information, please see the study website (see URLs).; SHIP: The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403) and the German Research Foundation (DFG; GR 1912/5-1). Genome-wide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. We thank all staff members and participants of the SHIP study, as well as all of the genotyping staff for generating the SHIP SNP data set. The genetic data analysis workflow was created using the Software InforSense. Genetic data were stored using the database Cache (InterSystems).; SHIP-TREND: The authors from SHIP are grateful to M. Stanke for the opportunity to use his Server Cluster for SNP Imputation. This cohort is part of the Community Medicine Research net (CMR) of the University of Greifswald, which is funded by the German Federal Ministry of Education and Research and the German Ministry of Cultural Affairs, as well as by the Social Ministry of the Federal State of Mecklenburg-West Pomerania. CMR encompasses several research projects that share data from the population-based Study of Health in Pomerania (SHIP; see URLs). The work is also supported by the German Research Foundation (DFG; GR 1912/5-1) and the Greifswald Approach to Individualized Medicine (GANI_MED) network funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG.; Superstruct: We thank the investigators and participants who contributed to the brain genomics data collection for Superstruct at Massachusetts General Hospital and Harvard University, with funding from the Simons Foundation, the Howard Hughes Medical Institute and the US NIH (grant MH079799).; TOP: We thank the study participants of TOP and the personnel involved in data collection and logistics, especially T. D. Bjella. This work was supported by the Oslo University Hospital-Ulleval, the Eastern Norway Health Authority (2004-123), the Research Council of Norway (167153/V50, 163070/V50 and 183782/V50), and by Eli Lilly & Company (who covered part of the genotyping costs).; TCD: We wish to express our sincere thanks to all participants and to clinical staff who facilitated patients' involvement. In particular, we acknowledge colleagues from the Trinity College Institute of Neuroscience A. Bodke, J. McGrath, F. Newell, H. Garavan, and J. O'Doherty for their support in sample collection. Collection and analysis of these samples were funded by the Wellcome Trust (072894/z/03/z-Gill) and the Science Foundation Ireland (08/IN.1/B1916_Corvin).; EPIGEN: Work from the London Cohort was supported by research grants from the Wellcome Trust (grant 084730 to S. M. S.), University College London (UCL)/University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) (grant 114 to S. M. S.), the European Union Marie Curie Reintegration (to M. Matarin and S. M. S.), the UK NIHR (08-08-SCC), the Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) (grant CEL1300 to S. M. S.), The Big Lottery Fund, the Wolfson Trust and the Epilepsy Society. This work was undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health's NIHR Biomedical Research Centres funding scheme. Work from the Royal College of Surgeons in Ireland was supported by research grants from the Science Foundation Ireland (Research Frontiers Programme award 08/RFP/GEN1538) and Brainwave-the Irish Epilepsy Association. The collection of Belgian subjects was supported by the Fonds National de la Recherche Scientifique (grant FC 63574 / 3.4.620.06 F) and the Fonds Erasme pour la Recherche Medicale at the Universite Libre de Bruxelles.; UCL Institute of Neurology Control Brain Tissue Collection: Funding was provided by the UK MRC (grant G0901254), the MRC Sudden Death Brain and Tissue Bank and the Sun Health Research Institute Brain Bank.; UMCU: The UMCU study was supported by the Netherlands Organization for Health Research and Development ZonMw (917.46.370 to H. E. H.) and the US NIMH (MH078075 to R.A.O.). NR 68 TC 247 Z9 250 U1 11 U2 123 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2012 VL 44 IS 5 BP 552 EP + DI 10.1038/ng.2250 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 934BW UT WOS:000303416300016 PM 22504417 ER PT J AU Truitt, M Biesecker, B Capone, G Bailey, T Erby, L AF Truitt, Megan Biesecker, Barbara Capone, George Bailey, Thomas Erby, Lori TI The role of hope in adaptation to uncertainty: The experience of caregivers of children with Down syndrome SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Uncertainty; Hope; Adaptation; Down syndrome; Caregiver; Parent ID PARENTS; ILLNESS; RESILIENCE AB Objective: The goal of this study was to investigate the relationships between perceived uncertainty, hope, and adaptation in caregivers of children with Down syndrome (DS). Methods: A total of 546 caregivers were recruited from local and national DS groups and from a DS clinic list. A cross-sectional survey examined caregivers' levels of perceived uncertainty, hope, and adaptation. The hope that caregivers had for their child was also measured. Results: Uncertainty, hope and adaptation were all significantly correlated, with uncertainty and hope independently predicting caregiver adaptation. Caregivers' motivation to reach goals for their child was higher than their ability to think of ways to meet those goals, and their lessened ability to think of ways to reach goals was significantly related to decreased adaptation levels. Conclusion: Findings from this study suggest that having hope in the face of uncertainty is important in adaptation but that caregivers struggle with having hope related to thinking of ways to reach goals for their child. Practice implications: The results of this study indicate that perceived uncertainty and hope may be important targets for improving psychological well-being. Interventions that assist caregivers in setting and attaining appropriate goals may be of particular interest. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Truitt, Megan] Columbia NY Presbyterian Med Ctr, Dept Clin Genet, New York, NY 10032 USA. [Biesecker, Barbara] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Capone, George] Kennedy Krieger Inst, Baltimore, MD USA. [Bailey, Thomas] Univ Maryland, Univ Coll, Adelphi, MD USA. [Erby, Lori] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. RP Truitt, M (reprint author), Columbia NY Presbyterian Med Ctr, Dept Clin Genet, 3959 Broadway,BHN-601A, New York, NY 10032 USA. EM met9024@nyp.org FU National Human Genome Research Institute, National Institutes of Health FX This study was funded by the Intramural Research Training Program of the National Human Genome Research Institute, National Institutes of Health. The authors have no conflict of interest related to this work. We would like to thank the many caregivers who donated their time and shared their hopes with us; in particular, the support group leaders and Kennedy Krieger clinic staff who helped spread the word about this study. NR 27 TC 13 Z9 14 U1 4 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD MAY PY 2012 VL 87 IS 2 BP 233 EP 238 DI 10.1016/j.pec.2011.08.015 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 946UY UT WOS:000304384200017 PM 21937189 ER PT J AU Liu, F Park, JE Qian, WJ Lim, D Scharow, A Berg, T Yaffe, MB Lee, KS Burke, TR AF Liu, Fa Park, Jung-Eun Qian, Wen-Jian Lim, Dan Scharow, Andrej Berg, Thorsten Yaffe, Michael B. Lee, Kyung S. Burke, Terrence R., Jr. TI Identification of High Affinity Polo-like Kinase 1 (Plk1) Polo-box Domain Binding Peptides Using Oxime-Based Diversification SO ACS CHEMICAL BIOLOGY LA English DT Article ID FLUORESCENCE POLARIZATION; INHIBITORS; POLO-LIKE-KINASE-1; LOCALIZATION; RECOGNITION; DISCOVERY AB In an effort to develop improved binding antagonists of the polo-like kinase 1 (Plk1) polo-box domain (PBD), we optimized interactions of the known high affinity 5-mer peptide PLHSpT using oxime,based post solid-phase peptide diversification of the N-terminal Pro residue. This allowed us to achieve up to two orders of magnitude potency enhancement. An X-ray crystal structure of the highest affinity analogue in complex with Plk1 PBD revealed new binding interactions in a hydrophobic channel that had been occluded in X-ray structures of the unliganded protein. This study represents an important example where amino acid modification by post solid-phase oxime ligation can facilitate the development of protein-protein interaction inhibitors by identifying new binding pockets that would not otherwise be accessible to coded amino acid residues. C1 [Park, Jung-Eun; Lee, Kyung S.] NCI, Natl Canc Inst, Ctr Canc Res, Lab Metab, Bethesda, MD 20892 USA. [Liu, Fa; Qian, Wen-Jian; Burke, Terrence R., Jr.] Natl Canc Inst Frederick, Ctr Canc Res, Mol Discovery Program, Chem Biol Lab, Frederick, MD 21702 USA. [Lim, Dan; Yaffe, Michael B.] MIT, Ctr Canc Res, Dept Biol & Biol Engn, Cambridge, MA 02139 USA. [Scharow, Andrej; Berg, Thorsten] Univ Leipzig, Inst Organ Chem, Leipzig, Germany. RP Lee, KS (reprint author), NCI, Natl Canc Inst, Ctr Canc Res, Lab Metab, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov; tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU NIH, Center for Cancer Research, NCI-Frederick; National Cancer Institute, National Institutes of Health; National Institutes of Health [R01 GM60594, ES015339]; Deutsche Forschungsgemeinschaft [BE 4572/1-1] FX This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick, and the National Cancer Institute, National Institutes of Health (F.L., J.-E.P., W.-J.Q., K.S.L., and T.R.B.), National Institutes of Health grant R01 GM60594 and ES015339 (M.B.Y.), and the Deutsche Forschungsgemeinschaft grant BE 4572/1-1 (T.B). 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 19 TC 39 Z9 41 U1 4 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD MAY PY 2012 VL 7 IS 5 BP 805 EP 810 DI 10.1021/cb200469a PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 943NA UT WOS:000304129200004 PM 22292814 ER PT J AU Wood, S Ferre-D'Amare, AR Rueda, D AF Wood, Sharla Ferre-D'Amare, Adrian R. Rueda, David TI Allosteric Tertiary Interactions Preorganize the c-di-GMP Riboswitch and Accelerate Ligand Binding SO ACS CHEMICAL BIOLOGY LA English DT Article ID X-RAY-SCATTERING; SINGLE-MOLECULE; GENE-EXPRESSION; RNA STRUCTURE; BACTERIAL 2ND-MESSENGER; ADENINE RIBOSWITCH; CYCLIC DIGUANYLATE; STRUCTURAL BASIS; TPP RIBOSWITCH; RIBOZYME AB Cyclic diguanylate (c-di-GMP) is a bacterial second messenger important for physiologic adaptation and virulence. Class-I c-di-GMP riboswitches are phylogenetically widespread and thought to mediate pleiotropic genetic responses to the second messenger. Previous studies suggest that the RNA aptamer domain switches from an extended free state to a compact, c-di-GMP-bound conformation in which two helical stacks dock side-by-side. Single molecule fluorescence resonance energy transfer (smFRET) experiments now reveal that the free RNA exists in four distinct populations that differ in dynamics in the extended and docked conformations. In the presence of c-di-GMP and Mg2+, a stably docked population (>30 min) becomes predominant. smFRET mutant analysis demonstrates that tertiary interactions distal to the c-di-GMP binding site strongly modulate the RNA population structure, even in the absence of c-di-GMP. These allosteric interactions accelerate ligand recognition by preorganizing the RNA, favoring rapid c-di-GMP binding. C1 [Ferre-D'Amare, Adrian R.] NHLBI, Bethesda, MD 20892 USA. [Wood, Sharla; Rueda, David] Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov; david.rueda@wayne.edu FU National Institutes of Health [R01 GM085116]; NSF [MCB-0747285]; National Heart, Lung and Blood Institute, NIH FX We thank N. Kulshina for initial characterization of point mutants and N. Baird for calorimetry help. This work was supported in part by the National Institutes of Health (R01 GM085116) and an NSF CAREER award (MCB-0747285) to D.R. and in part by the intramural program of the National Heart, Lung and Blood Institute, NIH (A.R.F.) NR 52 TC 33 Z9 33 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD MAY PY 2012 VL 7 IS 5 BP 920 EP 927 DI 10.1021/cb300014u PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 943NA UT WOS:000304129200019 PM 22380737 ER PT J AU Kumar, S Reddy, LCS Kumar, Y Kumar, A Singh, BK Kumar, V Malhotra, S Pandey, MK Jain, R Thimmulappa, R Sharma, SK Prasad, AK Biswal, S Van der Eycken, E DePass, AL Malhotra, SV Ghosh, B Parmar, VS AF Kumar, Sarvesh Reddy, Chandra Shekhar L. Kumar, Yogesh Kumar, Amit Singh, Brajendra K. Kumar, Vineet Malhotra, Shashwat Pandey, Mukesh K. Jain, Rajni Thimmulappa, Rajesh Sharma, Sunil K. Prasad, Ashok K. Biswal, Shyam Van der Eycken, Erik DePass, Anthony L. Malhotra, Sanjay V. Ghosh, Balaram Parmar, Virinder S. TI Arylalkyl Ketones, Benzophenones, Desoxybenzoins and Chalcones Inhibit TNF-a Induced Expression of ICAM-1: Structure-Activity Analysis SO ARCHIV DER PHARMAZIE LA English DT Article DE Arylalkyl ketones; Benzophenones; Chalcones; Desoxybenzoins; Endothelial cells; ICAM-1 ID CELL-ADHESION MOLECULES; VEIN ENDOTHELIAL-CELLS; CARBOXYLIC-ACIDS; NICKEL BORIDE; KAPPA-B; DERIVATIVES; ALPHA; CATALYST; SOLVENT; CONDENSATION AB The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in the pathogenesis of various inflammatory and autoimmune diseases. Small molecules that block these interactions have been targeted as potential therapeutic agents against acute and chronic inflammatory diseases. In an effort to identify potent intercellular cell adhesion molecule-1 (ICAM-1) inhibitors, a large number of arylalkyl ketones, benzophenones, desoxybenzoins and chalcones and their analogs (54 in total) have been synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity relationship studies of these compounds identified three potent chalcone derivatives and also demonstrated the possible mechanism for their ICAM-1 inhibitory activities. The most active compound was found to be 79. C1 [Kumar, Sarvesh; Ghosh, Balaram] Univ Delhi, CSIR, Inst Genom & Integrat Biol, Immunogenet Lab, Delhi 110007, India. [Kumar, Sarvesh; Thimmulappa, Rajesh; Biswal, Shyam] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Reddy, Chandra Shekhar L.; Kumar, Yogesh; Kumar, Amit; Singh, Brajendra K.; Kumar, Vineet; Malhotra, Shashwat; Pandey, Mukesh K.; Jain, Rajni; Sharma, Sunil K.; Prasad, Ashok K.; Parmar, Virinder S.] Univ Delhi, Dept Chem, Bioorgan Lab, Delhi 110007, India. [Singh, Brajendra K.; Van der Eycken, Erik] Katholieke Univ Leuven, LOMAC, Louvain, Belgium. [Kumar, Amit; Malhotra, Sanjay V.] NCI, Lab Synthet Chem, Dev Therapeut Program Support, SAIC Frederick, Frederick, MD 21701 USA. [Jain, Rajni] Bharat Inst Technol, Dept Chem, Meerut, Uttar Pradesh, India. [DePass, Anthony L.] Long Isl Univ, Dept Biol, Brooklyn, NY USA. RP Ghosh, B (reprint author), Univ Delhi, CSIR, Inst Genom & Integrat Biol, Immunogenet Lab, Mall Rd, Delhi 110007, India. EM bghosh@igib.res.in RI Ganju, Shahji/F-3409-2012; Ghosh, Balaram/G-1248-2010 FU Council of Scientific and Industrial Research, India [NWP0033]; NIH [HL081205, HL095420 (SCCOR), NIEHS-P50ES01590, GM079239, P50ES015903, P01 ES018176, ES03819]; University of Leuven [IDO06/006]; F.W.O. (Fund for Scientific Research-Flanders, Belgium); University of Delhi; Department of Scientific & Industrial Research (DSIR, New Delhi) FX Authors acknowledge the help of St. Stephen's Hospital, Delhi for providing the umbilical cord. This work was partly funded by the Council of Scientific and Industrial Research, India grant NWP0033 (to BG); the NIH grants HL081205, HL095420 (SCCOR), NIEHS-P50ES01590, GM079239, P50ES015903, P01 ES018176 and ES03819 (to SB); the University of Leuven (IDO06/006) & the F.W.O. (Fund for Scientific Research-Flanders, Belgium) grant (to EVDE); the University of Delhi grant under the Strengthening R&D Doctoral Research Programme and the Department of Scientific & Industrial Research (DSIR, New Delhi) to VSP, SKS and AKP. NR 64 TC 3 Z9 3 U1 0 U2 10 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0365-6233 J9 ARCH PHARM JI Arch. Pharm. PD MAY PY 2012 VL 345 IS 5 BP 368 EP 377 DI 10.1002/ardp.201100279 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 942YR UT WOS:000304088100005 PM 22190402 ER PT J AU van Himbergen, TM Beiser, AS Ai, M Seshadri, S Otokozawa, S Au, R Thongtang, N Wolf, PA Schaefer, EJ AF van Himbergen, Thomas M. Beiser, Alexa S. Ai, Masumi Seshadri, Sudha Otokozawa, Seiko Au, Rhoda Thongtang, Nuntakorn Wolf, Philip A. Schaefer, Ernst J. TI Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease Results From the Framingham Heart Study SO ARCHIVES OF NEUROLOGY LA English DT Article ID C-REACTIVE PROTEIN; MILD COGNITIVE IMPAIRMENT; ADIPONECTIN RECEPTORS; DIABETES-MELLITUS; APOLIPOPROTEIN-E; RANCHO-BERNARDO; CAUSE MORTALITY; OLDER PERSONS; PLASMA; ASSOCIATION AB Objective: To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2) levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia. Design: Prospective cohort study. Setting: Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia. Participants: Eight hundred forty (541 women, median age of 76 years) subjects participated in the study. Main Outcome Measures: We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE epsilon 4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD. Results: Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P = .054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P = .050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P = .04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P = .01) as compared with those with values less than the median. Conclusion: In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD. C1 [van Himbergen, Thomas M.; Ai, Masumi; Otokozawa, Seiko; Thongtang, Nuntakorn; Schaefer, Ernst J.] Tufts Univ, Lipid Metab Lab, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Beiser, Alexa S.; Seshadri, Sudha; Au, Rhoda; Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Beiser, Alexa S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Beiser, Alexa S.; Seshadri, Sudha; Au, Rhoda; Wolf, Philip A.] NHLBI, Framingham Heart Study, Boston, MA USA. RP Schaefer, EJ (reprint author), Tufts Univ, Lipid Metab Lab, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM ernst.schaefer@tufts.edu OI Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Beiser, Alexa/0000-0001-8551-7778 FU Unilever Food and Health Research Institute, Unilever R&D, Vlaardingen, the Netherlands; Denka Seiken Co, Tokyo, Japan; Kyowa Medex Co, Tokyo; Siriraj Hospital, Mahidol University, Bangkok, Thailand; National Institutes of Health [R01 HL-60935, HL 74753, PO50HL083813]; US Department of Agriculture Agriculture Research Service [53-3K-06]; Framingham Heart Study's National Heart, Lung, and Blood Institute [N01-HC-25195]; National Institute of Neurological Disorders and Stroke [R01 NS17950]; National Institute on Aging [R01 AG16495, AG08122, AG033040, AG033193, AG031287, P30AG013846] FX Dr Van Himbergen was supported by a research grant from Unilever Food and Health Research Institute, Unilever R&D, Vlaardingen, the Netherlands. Dr Ai and Ms Otokozawa were supported by research fellowships from Denka Seiken Co, Tokyo, Japan, and Kyowa Medex Co, Tokyo.; Dr Thongtang was supported by a research fellowship from Siriraj Hospital, Mahidol University, Bangkok, Thailand. Dr Schaefer was supported by grants R01 HL-60935, HL 74753, and PO50HL083813 from the National Institutes of Health and contract 53-3K-06 from the US Department of Agriculture Agriculture Research Service. This work was also supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute contract N01-HC-25195 and by National Institute of Neurological Disorders and Stroke grant R01 NS17950 and National Institute on Aging grants R01 AG16495, AG08122, AG033040, AG033193 and AG031287, and P30AG013846. NR 46 TC 45 Z9 45 U1 1 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAY PY 2012 VL 69 IS 5 BP 594 EP 600 DI 10.1001/archneurol.2011.670 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 941ZO UT WOS:000304009100005 PM 22213409 ER PT J AU Buist, DSM Walker, R Bowles, EJA Carney, PA Taplin, SH Onega, T Kerlikowske, K Clinton, W Miglioretti, DL AF Buist, Diana S. M. Walker, Rod Bowles, Erin J. Aiello Carney, Patricia A. Taplin, Stephen H. Onega, Tracy Kerlikowske, Karla Clinton, Walter Miglioretti, Diana L. TI Screening Mammography Use among Current, Former, and Never Hormone Therapy Users May Not Explain Recent Declines in Breast Cancer Incidence SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; UNITED-STATES; HYSTERECTOMY; POPULATION; DECREASE; RATES AB Background: Screening mammography and invasive breast cancer and ductal carcinoma in situ (DCIS) rates recently declined in the United States; screening mammography declines among former hormone therapy (HT) users may be an important contributor. We longitudinally examined women and compared mammography use and cancer rates by HT use [current, former, and never users of estrogen + progestin (EPT) and estrogen only (ET)]. Methods: We studied 163,490 unique women aged 50-79 years enrolled in Group Health (Washington State) between 1994-2009. Electronic data identified HT dispensing, mammography use and incident breast cancer diagnosis. We calculated age-adjusted screening compliance as a time-varying variable (screened-within-the-past-26 months, yes/no). Results: Before 2002, screening compliance differed significantly by HT with current EPT users having the highest rates (83%) followed by former EPT (77%), current ET (77%), former ET (72%), and never users (56%). After 2002, screening was high (similar to 81%) among current and former EPT and ET users and significantly increased among never users (similar to 62%). Invasive breast cancer rates significantly decreased over the whole study period (P-trend <= 0.05) for all HT users, except EPT current users (P-trend = 0.68); DCIS rates did not change in any group. Conclusions: Differential screening mammography rates by HT use do not explain invasive breast cancer incidence declines. Our data suggest discontinuing HT has an immediate effect on breast cancer rates, lending support to the mechanism that cessation leads to tumor regression. Impact: Studies examining the influence of a changing exposure in relation to outcomes should account for varying exposures, individuals' characteristics, as well as screening methods and frequency. Cancer Epidemiol Biomarkers Prey; 21(5); 720-7. (C)2012 AACR. C1 [Buist, Diana S. M.; Walker, Rod; Bowles, Erin J. Aiello; Miglioretti, Diana L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Clinton, Walter] Univ Washington, Vet Adm, Seattle, WA 98195 USA. [Miglioretti, Diana L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Family Med & Publ Hlth, Portland, OR 97201 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Prevent Med, Portland, OR 97201 USA. [Taplin, Stephen H.] Natl Canc Inst, Div Canc Control & Populat Sci, Proc Care Res Branch Behav Res Program, Bethesda, MD USA. [Onega, Tracy] Norris Cotton Canc Ctr, Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Onega, Tracy] Norris Cotton Canc Ctr, Dartmouth Med Sch, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Biostat & Epidemiol, San Francisco, CA 94143 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Vet Affairs, Gen Internal Med Sect, San Francisco, CA 94143 USA. RP Buist, DSM (reprint author), Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. EM buist.d@ghc.org FU National Cancer Institute, Breast Cancer Surveillance Consortium [CA63731]; National Cancer Institute [U01CA63731, U01CA63740, U01CA86076, U01CA86082]; SEER of the National Cancer Institute [N01-CN-67009, N01-PC-35142]; Fred Hutchinson Cancer Research Center; State of Washington FX The data collection was supported by a grant from the National Cancer Institute (CA63731) as part of the Breast Cancer Surveillance Consortium. Investigators time was covered by grant funding from the National Cancer Institute (U01CA63731, U01CA63740, U01CA86076, and U01CA86082). The collection of cancer incidence data used in this study was supported by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by contract no. N01-CN-67009 and N01-PC-35142 from the SEER Program of the National Cancer Institute with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington. A list of the BCSC investigators and procedures for requesting BCSC data for research purposes are available at: http://breastscreening.cancer.gov/. NR 38 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2012 VL 21 IS 5 BP 720 EP 727 DI 10.1158/1055-9965.EPI-11-1115 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 940QN UT WOS:000303908200005 PM 22301831 ER PT J AU Cote, ML Colt, JS Schwartz, KL Wacholder, S Ruterbusch, JJ Davis, F Purdue, M Graubard, BI Chow, WH AF Cote, Michele L. Colt, Joanne S. Schwartz, Kendra L. Wacholder, Sholom Ruterbusch, Julie J. Davis, Faith Purdue, Mark Graubard, Barry I. Chow, Wong-Ho TI Cigarette Smoking and Renal Cell Carcinoma Risk among Black and White Americans: Effect Modification by Hypertension and Obesity SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SERUM COTININE LEVELS; UNITED-STATES; TOBACCO USE; CANCER; POPULATION; PREVALENCE; ADULTS; CESSATION; SMOKERS; COHORT AB Background: Incidence of kidney cancer has been increasing over the past three decades, with more rapid increases and higher incidence rates among blacks than whites in the United States. An association between cigarette smoking and renal cell carcinoma (RCC), the most common form of kidney cancer, has been reported for whites, but the association in blacks is less clear. Methods: The association between smoking and RCC was examined in 1,217 incident cases and 1,235 population controls frequency-matched on age, race, gender, and study site in the Kidney Cancer Study in Detroit, MI, and Chicago, IL. Results: In white individuals, increasing duration and number of pack-years of both were associated with increased risk of RCCs after adjusting for age, gender, education, study site, body mass index (BMI) and history of hypertension (P-trend=0.0002 and P-trend=0.002, respectively). Among black individuals, RCC risk increased with duration of smoking (P-trend=0.02) but not other measures. Compared with current smokers, RCC risk decreased with increasing years of smoking cessation among both whites and blacks (P-trend=0.01 and 0.02, respectively). When examining risk according to hypertension history, associations between smoking and RCC risk were observed only among individuals who reported never having been diagnosed with hypertension. Similarly, cigarette smoking was associated with increased risk of RCCs among nonobese individuals but not among those with BMI >= 30 kg/m(2). Conclusion: Our observation that smoking is associated with RCC only in nonobese individuals and those with no history of hypertension are novel findings. Impact: The complex relationships between RCCs, smoking, hypertension, and obesity require additional confirmation. Cancer Epidemiol Biomarkers Prey; 21(5); 770-9. 2012 (C)AACR. C1 [Cote, Michele L.; Schwartz, Kendra L.; Ruterbusch, Julie J.] Wayne State Univ, Sch Med, Detroit, MI 48201 USA. [Cote, Michele L.; Schwartz, Kendra L.] Karmanos Canc Inst, Populat Studies & Dispar Res Program, Detroit, MI USA. [Colt, Joanne S.; Wacholder, Sholom; Purdue, Mark; Graubard, Barry I.; Chow, Wong-Ho] Natl Canc Inst, NIH, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Baltimore, MD USA. [Davis, Faith] Univ Illinois, Div Epidemiol & Biostat, Chicago, IL USA. RP Cote, ML (reprint author), Wayne State Univ, Sch Med, 4100 John R,Mailstop MMO4EP, Detroit, MI 48201 USA. EM cotem@karmanos.org FU National Cancer Institute [NIH N02-CP-11004] FX This research was supported by a grant from the National Cancer Institute, NIH N02-CP-11004. NR 37 TC 5 Z9 5 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2012 VL 21 IS 5 BP 770 EP 779 DI 10.1158/1055-9965.EPI-11-1109 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 940QN UT WOS:000303908200011 PM 22426145 ER PT J AU Nemesure, B Wu, SY Hennis, A Leskel, MC AF Nemesure, Barbara Wu, Suh-Yuh Hennis, Anselm Leskel, M. Cristina CA PCBP Study Grp TI Central Adiposity and Prostate Cancer in a Black Population SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID AFRICAN-ORIGIN POPULATION; BODY-SIZE; PROSPECTIVE COHORT; METABOLIC SYNDROME; PHYSICAL-ACTIVITY; 9-YEAR INCIDENCE; OBESITY; RISK; INSULIN; EPIDEMIOLOGY AB Background: The relationship between central adiposity and prostate cancer remains unclear. Methods: This report includes 963 newly diagnosed cases of histologically confirmed prostate cancer and 941 randomly selected age-matched controls ascertained from the population-based Prostate Cancer in a Black Population study conducted between July 2002 and January. 2011 in Barbados, West Indies. Trained nurse interviewers obtained data on height, weight, waist and hip circumferences, family and medical history, and lifestyle factors. ORs and 95% confidence intervals (Cl) were used to assess associations between anthropometric measures and prostate cancer. Results: A two-fold increased risk of prostate cancer was found among men in the highest quartile of waist hip ratio compared with those in the lowest quartile (OR = 2.11, 95% Cl, 1.54-2.88). Similarly, men with the largest waist circumferences had an OR of 1.84(95% Cl, 1.19-2.85) compared with those with the smallest waist sizes. Conclusions: These results suggest that measures of central rather than global adiposity may be more predictive of prostate cancer, especially in westernized African populations, where patterns of visceral fat distribution are different than other groups. Impact: The findings highlight the need to further elucidate the mechanisms underlying the relationship between central adiposity and prostate cancer in populations of predominantly African descent. Cancer Epidemiol Biomarkers Prev; 21(5); 851-8. (C)2012 AACR. C1 [Nemesure, Barbara; Wu, Suh-Yuh; Hennis, Anselm; Leskel, M. Cristina] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Hennis, Anselm] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. Univ W Indies, Dept Chem & Biol Sci, Bridgetown, Barbados. Translat Genom Res Inst, Phoenix, AZ USA. NHGRI, Bethesda, MD 20892 USA. [PCBP Study Grp] Univ Alberta, Dept Med, Edmonton, AB, Canada. RP Nemesure, B (reprint author), SUNY Stony Brook, Dept Prevent Med, L3 HSC Room 086, Stony Brook, NY 11794 USA. EM Barbara.Nemesure@stonybrook.edu FU NIH, National Human Genome Research Institute [N01HG25487]; National Cancer Institute [R01CA114379] FX This project was supported by the Intramural Research Program of the NIH, National Human Genome Research Institute (contract N01HG25487), and the National Cancer Institute (grant R01CA114379). NR 28 TC 9 Z9 10 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2012 VL 21 IS 5 BP 851 EP 858 DI 10.1158/1055-9965.EPI-12-0071 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 940QN UT WOS:000303908200020 PM 22402288 ER PT J AU Kim, C Zheng, TZ Lan, Q Chen, YT Foss, F Chen, XZ Holford, T Leaderer, B Boyle, P Chanock, SJ Rothman, N Zhang, YW AF Kim, Christopher Zheng, Tongzhang Lan, Qing Chen, Yingtai Foss, Francine Chen, Xuezhong Holford, Theodore Leaderer, Brian Boyle, Peter Chanock, Stephen J. Rothman, Nathaniel Zhang, Yawei TI Genetic Polymorphisms in Oxidative Stress Pathway Genes and Modification of BMI and Risk of Non-Hodgkin Lymphoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID OBESITY; CONNECTICUT; MECHANISMS AB Background: Being overweight and obese increases oxidative stress in the body. To test the hypothesis that genetic variations in oxidative stress pathway genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL), we conducted a population-based case-control study in Connecticut women. Methods: Individuals who were overweight/obese (BMI >= 25) were compared with normal and underweight individuals (BMI < 25), and their risk of NHL stratified assuming a dominant allele model for each oxidative stress pathway single-nucleotide polymorphism. Results: Polymorphisms in AKR1A1, AKR1C1, AKR1C3, CYBA, GPX1, MPO, NCF2, NCF4, NOS1, NOS2A NOS3, OGG1, ATG9B, SOD1, SOD2, SOD3, RAC1, and RAC2 genes after false discovery rate adjustment did not modify the association between BMI and risk of NHL overall and histologic subtypes. Conclusions: The results suggest that common genetic variations in oxidative stress genes do not modify the relationship between BMI and risk of NHL. Impact: Studies of BMI and oxidative stress independently may elevate NHL risk, but this study suggests no interaction of the two risk factors. Future studies with larger study populations may reveal interactions. Cancer Epidemiol Biomarkers Prey; 2.1(5); 866-8. (C)2012 AACR. C1 [Kim, Christopher; Zheng, Tongzhang; Chen, Yingtai; Holford, Theodore; Leaderer, Brian; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Foss, Francine] Yale Univ, Sch Med, New Haven, CT USA. [Chanock, Stephen J.; Rothman, Nathaniel] Natl Canc Inst, NIH, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Rockville, MD USA. [Chen, Yingtai] Lanzhou Univ, Hosp 2, Lanzhou 730000, Peoples R China. [Chen, Xuezhong] Gansu Prov Tumor Hosp, Gansu Prov Acad Med Sci, Lanzhou, Peoples R China. [Boyle, Peter] Int Prevent Res Inst, Lyon, France. [Chanock, Stephen J.] Natl Canc Inst, NIH, DHHS, Adv Technol Ctr,Core Genotyping Facil, Gaithersburg, MD USA. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, 60 Coll St LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Boyle, Peter/A-4380-2014 OI Boyle, Peter/0000-0001-6251-0610 FU NIH [CA62006, CA105666, 1D43TW008323-01, 1D43TW007864-01, HD70324-01]; NIH, National Cancer Institute FX This research was supported by the NIH grant CA62006, the Intramural Research Program of the NIH, National Cancer Institute, and the NIH training grants CA105666, 1D43TW008323-01, 1D43TW007864-01, and HD70324-01. NR 8 TC 3 Z9 3 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 MAY PY 2012 VL 21 IS 5 BP 866 EP 868 DI 10.1158/1055-9965.EPI-12-0010 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 940QN UT WOS:000303908200022 PM 22374993 ER PT J AU Reale, M Kamal, MA Velluto, L Gambi, D Di Nicola, M Greig, NH AF Reale, M. Kamal, M. A. Velluto, L. Gambi, D. Di Nicola, M. Greig, N. H. TI Relationship between Inflammatory Mediators, A beta Levels and ApoE Genotype in Alzheimer Disease SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE IL-18; IL-18BP; ICAM-1; RANTES; MCP-1; THP-1; amyloid-beta peptide; Alzheimer's disease; neuroinflammation ID MILD COGNITIVE IMPAIRMENT; BLOOD-MONONUCLEAR-CELLS; AMYLOID-BETA; ADHESION MOLECULE-1; BRAIN-BARRIER; ACETYLCHOLINESTERASE INHIBITOR; IFN-GAMMA; INTERLEUKIN-18; EXPRESSION; PLASMA AB Activation of inflammatory processes is observed within the brain as well as periphery of subjects with Alzheimer's disease (AD). Whether or not inflammation represents a possible cause of AD or occurs as a consequence of the disease process, or, alternatively, whether the inflammatory response might be beneficial to slow the disease progression remains to be elucidated. The cytokine IL-18 shares with IL-1 the same pro-inflammatory features. Consequent to these similarities, IL-18 and its endogenous inhibitor, IL-18BP, were investigated in the plasma of AD patients versus healthy controls (HC). An imbalance of IL-18 and IL-18BP was observed in AD, with an elevated IL-18/IL-18BP ratio that might be involved in disease pathogenesis. As part of the inflammatory response, altered levels of RANTES, MCP-1 and ICAM-1, molecules involved in cell recruitment to inflammatory sites, were observed in AD. Hence, correlations between IL-18 and other inflammatory plasma markers were analyzed. A negative correlation was observed between IL-18 and IL-18BP in both AD and HC groups. A positive correlation was observed between IL-18 and ICAM-1 in AD patients, whereas a negative correlation was evident in the HC group. IL-18 positively correlated with A beta in both groups, and no significant correlations were observed between IL-18, RANTES and MCP-1. An important piece of evidence supporting a pathophysiologic role for inflammation in AD is the number of inflammatory mediators that have been found to be differentially regulated in AD patients, and specific ones may provide utility as part of a biomarker panel to not only aid early AD diagnosis, but follow its progression. C1 [Reale, M.; Gambi, D.] Univ G DAnnunzio, Dept Oncol & Expt Med, Unit Immunodiagnost, NPD, I-66123 Chieti, Italy. [Kamal, M. A.] King Abdulaziz Univ, King Fahd Med Res Ctr, Jeddah 21589, Saudi Arabia. [Velluto, L.] Villa Serena Hosp, Citta St Agelo Pescara, Italy. [Di Nicola, M.] Univ G DAnnunzio, Dept Biomed Sci, Biostat Unit, I-66123 Chieti, Italy. [Greig, N. H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,Natl Inst Hlth, Baltimore, MD 21224 USA. RP Reale, M (reprint author), Univ G DAnnunzio, Dept Oncol & Expt Med, Unit Immunodiagnost, NPD, Ed C,3 Lev,Via Vestini 31, I-66123 Chieti, Italy. EM mreale@unich.it RI Kamal, Mohammad/H-9643-2012; Kamal, Mohammad/J-4622-2013; OI Kamal, Mohammad/0000-0003-1862-173X; DI NICOLA, MARTA/0000-0003-1748-1931; Kamal, Mohammad Amjad/0000-0003-0088-0565 FU Italian MIUR; National Institute on Aging, NIH; King Fahd Medical Research Center, King Abdulaziz University FX This research was supported by the grants from the Italian MIUR (60%, 2009). NG and KM are supported by the Intramural Research Program of the National Institute on Aging, NIH and King Fahd Medical Research Center, King Abdulaziz University, respectively. Authors are grateful to R. Barbacane for his generosity in providing time for observations on this manuscript to improve its scientific quality. Moreover, authors are grateful to Dr. C. Iarlori for providing motivation and inspiration to initiate this research. NR 65 TC 16 Z9 17 U1 1 U2 9 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 MAY PY 2012 VL 9 IS 4 BP 447 EP 457 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 944HF UT WOS:000304189200006 PM 22272623 ER PT J AU Ozaki, T Matsubara, T Seo, D Okamoto, M Nagashima, K Sasaki, Y Hayase, S Murata, T Liao, XH Hanson, J Rodriguez-Canales, J Thorgeirsson, SS Kakudo, K Refetoff, S Kimura, S AF Ozaki, Takashi Matsubara, Tsutomu Seo, Daekwan Okamoto, Minoru Nagashima, Kunio Sasaki, Yoshihito Hayase, Suguru Murata, Tsubasa Liao, Xiao-Hui Hanson, Jeffrey Rodriguez-Canales, Jaime Thorgeirsson, Snorri S. Kakudo, Kennichi Refetoff, Samuel Kimura, Shioko TI Thyroid Regeneration: Characterization of Clear Cells After Partial Thyroidectomy SO ENDOCRINOLOGY LA English DT Article ID GENE-EXPRESSION PROFILES; C-CELLS; STEM-CELLS; DEFINITIVE ENDODERM; LIVER-REGENERATION; FOLLICULAR CELLS; E-CADHERIN; MOUSE; CANCER; GLAND AB Although having the capacity to grow in response to a stimulus that perturbs the pituitary-thyroid axis, the thyroid gland is considered not a regenerative organ. In this study, partial thyroidectomy (PTx) was used to produce a condition for thyroid regeneration. In the intact thyroid gland, the central areas of both lobes served as the proliferative centers where microfollicles, and bromodeoxyuridine (BrdU)-positive and/or C cells, were localized. Two weeks after PTx, the number of BrdU-positive cells and cells with clear or faintly eosinophilic cytoplasm were markedly increased in the central area and continuous to the cut edge. Clear cells were scant in the cytoplasm, as determined by electron microscopy; some retained the characteristics of calcitonin-producing C cells by having neuroendocrine granules, whereas others retained follicular cell-specific features, such as the juxtaposition to a lumen with microvilli. Some cells were BrdU-positive and expressed Foxa2, the definitive endoderm lineage marker. Serum TSH levels drastically changed due to the thyroidectomy-induced acute reduction in T-4-generating tissue, resulting in a goitrogenesis setting. Microarray followed by pathway analysis revealed that the expression of genes involved in embryonic development and cancer was affected by PTx. The results suggest that both C cells and follicular cells may be altered by PTx to become immature cells or immature cells that might be derived from stem/progenitor cells on their way to differentiation into C cells or follicular cells. These immature clear cells may participate in the repair and/or regeneration of the thyroid gland. (Endocrinology 153: 2514-2525, 2012) C1 [Ozaki, Takashi; Matsubara, Tsutomu; Okamoto, Minoru; Sasaki, Yoshihito; Hayase, Suguru; Murata, Tsubasa; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Seo, Daekwan; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Hanson, Jeffrey; Rodriguez-Canales, Jaime] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Nagashima, Kunio] Natl Canc Inst Frederick, Elect Microscopy Lab, Adv Technol Program, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. [Liao, Xiao-Hui; Refetoff, Samuel] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Liao, Xiao-Hui; Refetoff, Samuel] Univ Chicago, Genet Program, Chicago, IL 60637 USA. [Ozaki, Takashi; Kakudo, Kennichi] Wakayama Med Univ, Dept Pathol, Wakayama 6418509, Japan. [Kakudo, Kennichi] Kobe Tokiwa Univ, Sch Med Technol, Kobe, Hyogo 6530838, Japan. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377 FU National Cancer Institute, Center for Cancer Research [1Z01BC005522]; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; National Institutes of Health [DK 15070] FX This was supported in whole or in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research Grant 1Z01BC005522, with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E, and by the extramural National Institutes of Health Grant DK 15070. NR 51 TC 11 Z9 11 U1 1 U2 4 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 MAY PY 2012 VL 153 IS 5 BP 2514 EP 2525 DI 10.1210/en.2011-1365 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 939ZV UT WOS:000303860700048 PM 22454152 ER PT J AU Ugander, M Oki, AJ Hsu, LY Kellman, P Greiser, A Aletras, AH Sibley, CT Chen, MY Bandettini, WP Arai, AE AF Ugander, Martin Oki, Abiola J. Hsu, Li-Yueh Kellman, Peter Greiser, Andreas Aletras, Anthony H. Sibley, Christopher T. Chen, Marcus Y. Bandettini, W. Patricia Arai, Andrew E. TI Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology SO EUROPEAN HEART JOURNAL LA English DT Article DE Magnetic resonance imaging; Myocardial infarction; Fibrosis; Aging; Gadolinium ID HEART-FAILURE; INVERSION-RECOVERY; BLOOD-FLOW; INFARCTION; FIBROSIS; COLLAGEN; HUMANS; CARDIOMYOPATHY; HYPERTENSION; ENHANCEMENT AB Conventional late gadolinium enhancement (LGE) cardiac magnetic resonance can detect myocardial infarction and some forms of non-ischaemic myocardial fibrosis. However, quantitative imaging of extracellular volume fraction (ECV) may be able to detect subtle abnormalities such as diffuse fibrosis or post-infarct remodelling of remote myocardium. The aims were (1) to measure ECV in myocardial infarction and non-ischaemic myocardial fibrosis, (2) to determine whether ECV varies with age, and (3) to detect sub-clinical abnormalities in onormal appearing' myocardium remote from regions of infarction. Cardiac magnetic resonance ECV imaging was performed in 126 patients with T1 mapping before and after injection of gadolinium contrast. Conventional LGE images were acquired for the left ventricle. In patients with a prior myocardial infarction, the infarct region had an ECV of 51 8 which did not overlap with the remote onormal appearing' myocardium that had an ECV of 27 3 (P 0.001, n 36). In patients with non-ischaemic cardiomyopathy, the ECV of atypical LGE was 37 6, whereas the onormal appearing' myocardium had an ECV of 26 3 (P 0.001, n 30). The ECV of onormal appearing' myocardium increased with age (r 0.28, P 0.01, n 60). The ECV of onormal appearing' myocardium remote from myocardial infarctions increased as left ventricular ejection fraction decreased (r 0.50, P 0.02). Extracellular volume fraction imaging can quantitatively characterize myocardial infarction, atypical diffuse fibrosis, and subtle myocardial abnormalities not clinically apparent on LGE images. Taken within the context of prior literature, these subtle ECV abnormalities are consistent with diffuse fibrosis related to age and changes remote from infarction. C1 [Ugander, Martin; Oki, Abiola J.; Hsu, Li-Yueh; Kellman, Peter; Aletras, Anthony H.; Chen, Marcus Y.; Bandettini, W. Patricia; Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Greiser, Andreas] Siemens AG, Healthcare Sect, Erlangen, Germany. [Sibley, Christopher T.] NIH, Dept Radiol, Ctr Clin, US Dept HHS, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, US Dept HHS, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM araia@nih.gov RI Sibley, Christopher/C-9900-2013; OI Aletras, Anthony/0000-0002-3786-3817; Ugander, Martin/0000-0003-3665-2038 FU National Heart, Lung, and Blood Institute, National Institutes of Health, USA [1 Z01 HL004607-08 CE] FX This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health, USA [1 Z01 HL004607-08 CE]. NR 36 TC 189 Z9 196 U1 0 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD MAY PY 2012 VL 33 IS 10 BP 1268 EP 1278 DI 10.1093/eurheartj/ehr481 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 944IY UT WOS:000304194400023 PM 22279111 ER PT J AU Bakshi, NK Fahle, GA Sereti, I Wiley, H Nussenblatt, RB Sen, HN AF Bakshi, N. K. Fahle, G. A. Sereti, I. Wiley, H. Nussenblatt, R. B. Sen, H. N. TI Cytomegalovirus retinitis successfully treated with ganciclovir implant in a patient with blood ganciclovir resistance and ocular ganciclovir sensitivity SO EYE LA English DT Letter ID MUTATIONS; AIDS C1 [Bakshi, N. K.; Wiley, H.; Nussenblatt, R. B.; Sen, H. N.] NEI, NIH, Bethesda, MD 20892 USA. [Fahle, G. A.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Sereti, I.] NIAID, NIH, Bethesda, MD 20892 USA. RP Bakshi, NK (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM senh@nei.nih.gov NR 8 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X J9 EYE JI Eye PD MAY PY 2012 VL 26 IS 5 BP 759 EP 760 DI 10.1038/eye.2012.17 PG 2 WC Ophthalmology SC Ophthalmology GA 941BP UT WOS:000303937400030 PM 22322999 ER PT J AU Bentley, AR Kritchevsky, SB Harris, TB Newman, AB Bauer, DC Meibohm, B Clark, AG Cassano, PA AF Bentley, Amy R. Kritchevsky, Stephen B. Harris, Tamara B. Newman, Anne B. Bauer, Douglas C. Meibohm, Bernd Clark, Andrew G. Cassano, Patricia A. CA Body Composition Study TI Genetic variation in antioxidant enzymes and lung function SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Antioxidant enzymes; Lung function; Free radicals ID PULMONARY-FUNCTION; OXIDATIVE STRESS; EPITHELIAL-CELLS; DISEASE; EXPRESSION; SMOKING AB Not all cigarette smokers develop chronic obstructive pulmonary disease, and discovering susceptibility factors is an important research priority. The oxidative burden of smoking may overwhelm antioxidant defenses, and vulnerabilities may exist as a result of sequence variants in genes encoding antioxidant enzymes. This study explored the association between genetic variation in a network of antioxidant enzymes and lung phenotypes. Linear models evaluated single-locus marker associations in 2387 European American and African American participants in the Health, Aging, and Body Composition Study. After corrections were made for multiple comparisons, 15 statistically significant associations were identified, all of which were for SNP by smoking interactions. The most statistically significant findings were for genes encoding members of the isocitrate dehydrogenase gene family (IDH3A, IDH3B, IDH2). For rs6107100 (IDH3B) the variant genotype was associated with a difference of 6% in the FEV1/FVC ratio in African American current smokers, but the SNP had little or no association with FEV1/FVC in former and never smokers (nominal P-interaction = 5 x 10(-6)). A variant of the peroxiredoxin gene (rs9787810, PRDX5) was associated with lower percentage predicted FEV1 and a lower ratio in European American current smokers, with little or no association in other smoking groups (nominal P-interaction = 0.0001 and 0.0003, respectively). The studied genes have not been reported in previous candidate gene association studies, and thus the findings suggest novel mechanisms and targets for future research and provide evidence for a contribution of sequence variation in genes encoding antioxidant enzymes to susceptibility in smokers. (c) 2012 Elsevier Inc. All rights reserved. C1 [Bentley, Amy R.; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci & Genet, Ithaca, NY 14853 USA. [Bentley, Amy R.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27106 USA. [Harris, Tamara B.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Ctr Aging & Populat Hlth, Pittsburgh, PA 15260 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Meibohm, Bernd] Univ Tennessee, Memphis, TN 38103 USA. [Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci & Genet, Ithaca, NY 14853 USA. EM pac6@cornell.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU NIH Training [T32 DK007158-31, R01HL74104, R01HL071022]; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459] FX The authors acknowledge the consulting provided by Ms. Francoise Vermeylen, Cornell Statistical Consulting Unit, Cornell University. This project was funded in part by NIH Training Grant T32 DK007158-31 (A.R.B.) and Grants R01HL74104 (S.B.K.) and R01HL071022 (P.A.C.). Genotyping services were provided (to P.A.C.) by the Johns Hopkins University under Federal Contract N01-HV-48195 from the National Heart, Lung, and Blood Institute, NIH. The Health ABC Study is supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-2103, and N01-AG-6-2106; NIA Grant R01-AG028050; and NINR Grant R01-NR012459. This research was supported in part by the Intramural Research Program of the National Institute on Aging, NIH. NR 30 TC 4 Z9 4 U1 3 U2 8 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 MAY 1 PY 2012 VL 52 IS 9 BP 1577 EP 1583 DI 10.1016/j.freeradbiomed.2012.02.025 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 944DB UT WOS:000304177500009 PM 22387199 ER PT J AU Chatterjee, S Rana, R Corbett, J Kadiiska, MB Goldstein, J Mason, RP AF Chatterjee, Saurabh Rana, Ritu Corbett, Jean Kadiiska, Maria B. Goldstein, Joyce Mason, Ronald P. TI P2X7 receptor-NADPH oxidase axis mediates protein radical formation and Kupffer cell activation in carbon tetrachloride-mediated steatohepatitis in obese mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Damage Associated Molecular Pattern; Kupffer cell; Protein radical; Antigen presentation; NADPH oxidase steatohepatitis ID FATTY LIVER-DISEASE; NITRIC-OXIDE; EXTRACELLULAR ATP; OXIDATIVE STRESS; CYTOCHROME-P450 2E1; HEPATIC-FIBROSIS; RAT HEPATOCYTES; REACTIVE OXYGEN; BETA-OXIDATION; IMMUNE-SYSTEM AB While some studies show that carbon tetrachloride-mediated metabolic oxidative stress exacerbates steatohepatitic-like lesions in obese mice, the redox mechanisms that trigger the innate immune system and accentuate the inflammatory cascade remain unclear. Here we have explored the role of the purinergic receptor P2X7-NADPH oxidase axis as a primary event in recognizing the heightened release of extracellular ATP from CCI4-treated hepatocytes and generating redox-mediated Kupffer cell activation in obese mice. We found that an underlying condition of obesity led to the formation of protein radicals and posttranslational nitration, primarily in Kupffer cells, at 24 h post-CCI4 administration. The free radical-mediated oxidation of cellular macromolecules, which was NADPH oxidase and P2X7 receptor-dependent, correlated well with the release of TNF-alpha and MCP-2 from Kupffer cells. The Kupffer cells in CCI4-treated mice exhibited increased expression of MHC Class II proteins and showed an activated phenotype. Increased expression of MHC Class II was inhibited by the NADPH oxidase inhibitor apocynin, P2X7 receptor antagonist A438709 hydrochloride, and genetic deletions of the NADPH oxidase p47 phox subunit or the P2X7 receptor. The P2X7 receptor acted upstream of NADPH oxidase activation by up-regulating the expression of the p47 phox subunit and p47 phox binding to the membrane subunit, gp91 phox. We conclude that the P2X7 receptor is a primary mediator of oxidative stress-induced exacerbation of inflammatory liver injury in obese mice via NADPH oxidase-dependent mechanisms. Published by Elsevier Inc. C1 [Chatterjee, Saurabh; Corbett, Jean; Kadiiska, Maria B.; Mason, Ronald P.] NIEHS, Free Rad Metab Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Rana, Ritu; Goldstein, Joyce] NIEHS, Human Metab Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Chatterjee, S (reprint author), NIEHS, Free Rad Metab Grp, Lab Toxicol & Pharmacol, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM chatterjees2@niehs.nih.gov FU NIH [K99-R00, ES01-19875A]; National Institute of Environmental Health Sciences [Z01 ES05013913, Z01 ES02124] FX The authors gratefully acknowledge James Clark, Tiwanda Marsh, Jeoffrey Hurlburt, Jeff Tucker, and Ralph Wilson for excellent technical assistance. We thank Dr. Carl Bortner for help in analyzing flow cytometry data. We also sincerely thank Dr. Ann Motten and Mary Mason for help in the careful editing of this manuscript. This work has been supported by a K99-R00, NIH Pathway to Independence Award (ES01-19875A to Saurabh Chatterjee) and the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences (Z01 ES05013913 to Ronald P. Mason, Z01 ES02124 to Joyce A. Goldstein). NR 54 TC 22 Z9 22 U1 0 U2 3 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 MAY 1 PY 2012 VL 52 IS 9 BP 1666 EP 1679 DI 10.1016/j.freeradbiomed.2012.02.010 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 944DB UT WOS:000304177500017 PM 22343416 ER PT J AU Sia, KC Huynh, H Chinnasamy, N Hui, KM Lam, PYP AF Sia, K. C. Huynh, H. Chinnasamy, N. Hui, K. M. Lam, P. Y. P. TI Suicidal gene therapy in the effective control of primary human hepatocellular carcinoma as monitored by noninvasive bioimaging SO GENE THERAPY LA English DT Article DE hepatocellular carcinoma; FMDV 2A peptide; herpes simplex virus type 1 amplicon viral vector; noninvasive imaging; yeast cytosine deaminase suicide gene ID MESENCHYMAL STEM-CELLS; CYTOSINE DEAMINASE; TRANSGENE EXPRESSION; BRAIN-TUMORS; IN-VIVO; AMPLICON VECTORS; FUSION GENE; 5-FLUOROURACIL; MECHANISM; CANCER AB Hepatocellular carcinoma (HCC) is usually refractory to the available treatments. For cancer gene therapy purposes, real-time imaging of therapeutic gene expression is of great importance because there are multiple factors that modulate the therapeutic gene expression in a complex tumor microenvironment. As a consequence, multiple doses of therapeutic viral vectors may be required for improved efficacy. In the present study, the luciferase reporter gene and the yeast cytosine deaminase (yCD) genes were bicistronically expressed using the foot-and-mouth disease virus 2A peptide under the regulation of the cytomegalovirus (CMV) promoter. The effectiveness of the yCD/5-FC (5-fluorocytosine) killing efficacy mediated by the herpes simplex virus type 1 (HSV-1) amplicon viral vector was shown using HCC and non-HCC cell lines in vitro. In addition, in vivo experiment also showed tumor regression of a primary HCC 26-1004 tumor xenograft in tumor expressing high levels of the yCD gene (as determined by noninvasive imaging) after intratumoral injection of 1.5x10(6) TU HGCX-L2C HSV-1 amplicon viral vector and 5-FC administration. The HSV-1 amplicon viral vector coupled with the yCD/5-FC prodrug activated suicide gene could potentially be of use in clinical gene therapy for HCC. Gene Therapy (2012) 19, 532-542; doi:10.1038/gt.2011.131; published online 15 September 2011 C1 [Sia, K. C.; Lam, P. Y. P.] Natl Canc Ctr, Lab Canc Gene Therapy, Cellular & Mol Res Div, Humphrey Oei Inst Canc Res, Singapore 169610, Singapore. [Huynh, H.] Natl Canc Ctr, Lab Mol Endocrinol, Cellular & Mol Res Div, Humphrey Oei Inst Canc Res, Singapore 169610, Singapore. [Chinnasamy, N.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Hui, K. M.] Natl Canc Ctr, Bek Chai Heah Lab Canc Genom, Cellular & Mol Res Div, Humphrey Oei Inst Canc Res, Singapore 169610, Singapore. [Lam, P. Y. P.] Natl Univ Singapore, Dept Physiol, Yong Loo Lin Sch Med, Singapore 117548, Singapore. [Lam, P. Y. P.] Duke NUS Grad Med Sch, Canc & Stem Cells Biol Program, Singapore, Singapore. RP Lam, PYP (reprint author), Natl Canc Ctr, Lab Canc Gene Therapy, Cellular & Mol Res Div, Humphrey Oei Inst Canc Res, 11 Hosp Dr, Singapore 169610, Singapore. EM cmrlyp@nccs.com.sg FU National Medical Research Council (NMRC) FX We thank Dr Ivy Ho and Mr Berwini Endaya for useful discussions. This work was supported by grant from the National Medical Research Council (NMRC). NR 67 TC 7 Z9 7 U1 3 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD MAY PY 2012 VL 19 IS 5 BP 532 EP 542 DI 10.1038/gt.2011.131 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 940XV UT WOS:000303927300008 PM 21918545 ER PT J AU Di Pasquale, G Ostedgaard, L Vermeer, D Swaim, WD Karp, P Chiorini, JA AF Di Pasquale, G. Ostedgaard, L. Vermeer, D. Swaim, W. D. Karp, P. Chiorini, J. A. TI Bovine AAV transcytosis inhibition by tannic acid results in functional expression of CFTR in vitro and altered biodistribution in vivo SO GENE THERAPY LA English DT Article DE bovine adeno-associated virus; transcytosis; CFTR; tannic acid; BAAV ID POLARIZED MDCK CELLS; AIRWAY EPITHELIA; APICAL SURFACE; GENE-TRANSFER AB Bovine adeno-associated virus (BAAV) can enter a cell either through a transcytosis or transduction pathway. We previously demonstrated that particles entering via the transcytosis pathway can be redirected to transduce the cell by blocking particle exocytosis with tannic acid (TA). To investigate whether this approach is useful in lung gene therapy applications, we tested the effect of TA on BAAV transduction in cystic fibrosis airway epithelia in vitro, and in mouse lung in vivo. Our findings suggest that BAAV transcytosis can occur in vivo and that treatment with TA reduces transcytosis and increases lung transduction. TA treatment did not impair the sorting and the activity of the BAAV expressed cystic fibrosis transmembrane regulator membrane protein. Gene Therapy (2012) 19, 576-581; doi:10.1038/gt.2011.138; published online 20 October 2011 C1 [Di Pasquale, G.; Swaim, W. D.; Chiorini, J. A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Ostedgaard, L.; Vermeer, D.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Karp, P.] Univ Iowa, Howard Hughes Med Inst, Iowa City, IA 52242 USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, 10-1A31,10 Ctr Dr,MSC1190, Bethesda, MD 20892 USA. EM jchiorini@dir.nidcr.nih.gov FU NIH/NIDCR FX We thank Michael Welsh for his helpful suggestions. This study was supported by an NIH/NIDCR intramural grant to JAC. NR 12 TC 2 Z9 2 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD MAY PY 2012 VL 19 IS 5 BP 576 EP 581 DI 10.1038/gt.2011.138 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 940XV UT WOS:000303927300013 PM 22011646 ER PT J AU Carey, JC Allanson, JE Hennekam, RCM Biesecker, LG AF Carey, John C. Allanson, Judith E. Hennekam, Raoul C. M. Biesecker, Leslie G. TI Standard Terminology for Phenotypic Variations: The Elements of Morphology Project, Its Current Progress, and Future Directions SO HUMAN MUTATION LA English DT Article DE phenotype; definitions; terminology; dysmorphology; nomenclature; minor anomalies ID EYEBROW; REGION; EAR AB In 2005, the authors of this article formed an international working group to develop standardized definitions and terms to describe the physical variations used in human phenotypic analyses. This project, which came to be known as the Elements of Morphology, resulted in six articles proposing consensus definitions for almost 400 phenotypic variations of the head and face; periorbital region; ear, nose, and philtrum; mouth and lips; and hands and feet. Every variation was accompanied by a representative figure depicting the feature. The articles were published in the January 2009 issue of the American Journal of Medical Genetics Part A and are available for free access on both the Journal's Web page and a National Institutes of Health-based site. The publication of the Elements' definitions has spawned an ongoing dialogue about the proposed terms to describe the phenotype. The working group considered the six articles as only the first step in the process, and four more articles on proposed terminology for the trunk, genital region, skin, and remainder of the limb terms are in preparation. The secondary outcome of the Elements project is the provision of a working methodology for the establishment of standardized terminology and definitions for phenotype analysis in general. Hum Mutat 33: 781-786, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Carey, John C.] Univ Utah, Dept Pediat, Div Med Genet, Salt Lake City, UT USA. [Allanson, Judith E.] Childrens Hosp E Ontario, Dept Genet, Ottawa, ON, Canada. [Hennekam, Raoul C. M.] UVA, Acad Mental Ctr, Dept Pediat, Amsterdam, Netherlands. [Biesecker, Leslie G.] NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. RP Carey, JC (reprint author), Amer Journal Med Genet, 419 Wakara Way,Suite 213, Salt Lake City, UT 84108 USA. EM john.carey@hsc.utah.edu NR 16 TC 15 Z9 15 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2012 VL 33 IS 5 SI SI BP 781 EP 786 DI 10.1002/humu.22053 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 941ZK UT WOS:000304008400002 PM 22331827 ER PT J AU Pan, HQ Tryka, KA Vreeman, DJ Huggins, W Phillips, MJ Mehta, JP Phillips, JH McDonald, CJ Junkins, HA Ramos, EM Hamilton, CM AF Pan, Huaqin Tryka, Kimberly A. Vreeman, Daniel J. Huggins, Wayne Phillips, Michael J. Mehta, Jayashri P. Phillips, Jacqueline H. McDonald, Clement J. Junkins, Heather A. Ramos, Erin M. Hamilton, Carol M. TI Using PhenX Measures to Identify Opportunities for Cross-Study Analysis SO HUMAN MUTATION LA English DT Article DE phenotype; environmental exposure; epidemiologic methods; GWAS ID GENOME-WIDE ASSOCIATION; HUMAN-DISEASES; CONSORTIUM; RECORDS; GENE AB The PhenX Toolkit provides researchers with recommended, well-established, low-burden measures suitable for human subject research. The database of Genotypes and Phenotypes (dbGaP) is the data repository for a variety of studies funded by the National Institutes of Health, including genome-wide association studies. The dbGaP requires that investigators provide a data dictionary of study variables as part of the data submission process. Thus, dbGaP is a unique resource that can help investigators identify studies that share the same or similar variables. As a proof of concept, variables from 16 studies deposited in dbGaP were mapped to PhenX measures. Soon, investigators will be able to search dbGaP using PhenX variable identifiers and find comparable and related variables in these 16 studies. To enhance effective data exchange, PhenX measures, protocols, and variables were modeled in Logical Observation Identifiers Names and Codes (LOINC (R)). PhenX domains and measures are also represented in the Cancer Data Standards Registry and Repository (caDSR). Associating PhenX measures with existing standards (LOINC (R) and caDSR) and mapping to dbGaP study variables extends the utility of these measures by revealing new opportunities for cross-study analysis. Hum Mutat 33: 849-857, 2012. Published 2012 Wiley Periodicals, Inc.* C1 [Pan, Huaqin; Huggins, Wayne; Phillips, Michael J.; Hamilton, Carol M.] RTI Int, Res Triangle Pk, NC 27709 USA. [Tryka, Kimberly A.; Mehta, Jayashri P.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Vreeman, Daniel J.; Phillips, Jacqueline H.] Regenstrief Inst Inc, Indianapolis, IN USA. [Vreeman, Daniel J.] Indiana Univ Sch Med, Indianapolis, IN USA. [McDonald, Clement J.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20892 USA. [Junkins, Heather A.; Ramos, Erin M.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Pan, HQ (reprint author), RTI Int, 3040 Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. EM hpan@rti.org OI Tryka, Kimberly/0000-0002-5399-4235 FU National Human Genome Research Institute; American Recovery and Reinvestment Act through NHGRI [U01 HG004597-01]; National Library of Medicine [HHSN2762008000006C]; National Center for Research Resources [3UL1RR025761-02S6]; National Institutes of Health FX Contract grant sponsor: This work was supported by the National Human Genome Research Institute and the American Recovery and Reinvestment Act through NHGRI U01 HG004597-01 to RTI International; by the National Library of Medicine through HHSN2762008000006C and National Center for Research Resources 3UL1RR025761-02S6 to Regenstrief Institute; and by the Intramural Research Program of the National Institutes of Health. NR 24 TC 11 Z9 11 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2012 VL 33 IS 5 SI SI BP 849 EP 857 DI 10.1002/humu.22074 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 941ZK UT WOS:000304008400011 PM 22415805 ER PT J AU Hennekam, RCM Biesecker, LG AF Hennekam, Raoul C. M. Biesecker, Leslie G. TI Next-Generation Sequencing Demands Next-Generation Phenotyping SO HUMAN MUTATION LA English DT Article DE NGS; whole-exome sequencing; whole-genome sequencing; phenotype; dysmorphology; Mendelian; monogenic AB Next-generation sequencing (NGS) is the most powerful diagnostic tool since the roentgenogram. NGS will facilitate diagnosis on a massive scale, allowing interrogation of all genes in a single assay. It has been suggested that NGS will decrease the need for phenotyping in general and medical geneticists in particular. We argue that NGS will shift focus and approach of phenotyping. We predict that NGS performed for diagnostic purposes will yield variants in several genes, and consequences of these variants will need to be analyzed and integrated with clinical findings to make a diagnosis. Diagnostic skills of medical specialists will shift from a pre-NGS-test differential diagnostic mode to a post-NGS-test diagnostic assessment mode. In research phenotyping and medical genetic assessments will remain essential as well. NGS can identify primary causative variants in phenotypes inherited in a Mendelian pattern, but biology is much more complex. Phenotypes are caused by the actions of several genes and epigenetic and environmental influences. Dissecting all influences necessitates ongoing and detailed phenotyping, refinement of clinical diagnostic assignments, and iterative analyses of NGS data. We conclude that there will be a critical need for phenotyping and clinical analysis, and that medical geneticists are uniquely positioned to address this need. Hum Mutat 33: 884-886, 2012. Published 2012 Wiley Periodicals, Inc.* C1 [Hennekam, Raoul C. M.] Univ Amsterdam, Acad Med Ctr, Dept Pediat & Translat Genet, NL-1105 AZ Amsterdam, Netherlands. [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Hennekam, RCM (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Paediat, Floor H7-236,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM r.c.hennekam@amc.uva.nl FU National Human Genome Research Institute of the National Institutes of Health FX Contract grant sponsor: Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health (to L.G.B.). NR 4 TC 57 Z9 58 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2012 VL 33 IS 5 SI SI BP 884 EP 886 DI 10.1002/humu.22048 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 941ZK UT WOS:000304008400015 PM 22457028 ER PT J AU Kanaan, Z Rai, SN Eichenberger, MR Barnes, C Dworkin, AM Weller, C Cohen, E Roberts, H Keskey, B Petras, RE Crawford, NPS Galandiuk, S AF Kanaan, Ziad Rai, Shesh N. Eichenberger, M. Robert Barnes, Christopher Dworkin, Amy M. Weller, Clayton Cohen, Eric Roberts, Henry Keskey, Bobby Petras, Robert E. Crawford, Nigel P. S. Galandiuk, Susan TI Differential MicroRNA Expression Tracks Neoplastic Progression in Inflammatory Bowel Disease-Associated Colorectal Cancer (vol 33, pg 551, 2012) SO HUMAN MUTATION LA English DT Correction C1 [Kanaan, Ziad; Eichenberger, M. Robert; Weller, Clayton; Cohen, Eric; Roberts, Henry; Keskey, Bobby; Galandiuk, Susan] Univ Louisville, Sch Med, Price Inst Surg Res, Dept Surg, Louisville, KY 40292 USA. [Kanaan, Ziad; Eichenberger, M. Robert; Weller, Clayton; Cohen, Eric; Roberts, Henry; Keskey, Bobby; Galandiuk, Susan] Univ Louisville, Sch Med, Sect Colorectal Surg, Louisville, KY 40292 USA. [Rai, Shesh N.; Barnes, Christopher] Univ Louisville, Sch Publ Hlth & Informat Sci, Dept Bioinformat & Biostat, Louisville, KY 40292 USA. [Dworkin, Amy M.; Crawford, Nigel P. S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Petras, Robert E.] Ameripath, Oakwood Village, OH USA. RP Kanaan, Z (reprint author), Univ Louisville, Sch Med, Price Inst Surg Res, Dept Surg, Louisville, KY 40292 USA. OI Kanaan, Ziad/0000-0001-5376-562X NR 1 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2012 VL 33 IS 5 SI SI BP 899 EP 899 DI 10.1002/humu.22063 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 941ZK UT WOS:000304008400018 ER PT J AU Drescher, CW Urban, N Hartge, P Berg, CD AF Drescher, C. W. Urban, N. Hartge, P. Berg, C. D. TI Potential role of HE4 in multimodal screening for epithelial ovarian cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Meeting Abstract C1 [Drescher, C. W.; Urban, N.] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Hartge, P.; Berg, C. D.] Natl Canc Inst, Bethesda, MD USA. RI Berg , Christine/K-1047-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD MAY PY 2012 VL 22 SU 1 BP S44 EP S44 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 942VN UT WOS:000304078200023 ER PT J AU Srivastava, S Patriotis, C AF Srivastava, Sudhir Patriotis, Christos TI Systematic, Evidence-Based Discovery of Biomarkers at the National Cancer Institute SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Editorial Material C1 [Srivastava, Sudhir] NCI, Canc Prevent Div, Canc Biornarkers Res Grp, Bethesda, MD 20892 USA. RP Srivastava, S (reprint author), NCI, Canc Prevent Div, Canc Biornarkers Res Grp, 6130 Execut Blvd,Suite 3142,MSC 7362, Bethesda, MD 20892 USA. EM srivasts@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD MAY PY 2012 VL 22 SU 1 BP S41 EP S41 DI 10.1097/IGC.0b013e318251ccf6 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 942VN UT WOS:000304078200013 PM 22543920 ER PT J AU Munafo, MR Timofeeva, MN Morris, RW Prieto-Merino, D Sattar, N Brennan, P Johnstone, EC Relton, C Johnson, PCD Walther, D Whincup, PH Casas, JP Uhl, GR Vineis, P Padmanabhan, S Jefferis, BJ Amuzu, A Riboli, E Upton, MN Aveyard, P Ebrahim, S Hingorani, AD Watt, G Palmer, TM Timpson, NJ Smith, GD AF Munafo, Marcus R. Timofeeva, Maria N. Morris, Richard W. Prieto-Merino, David Sattar, Naveed Brennan, Paul Johnstone, Elaine C. Relton, Caroline Johnson, Paul C. D. Walther, Donna Whincup, Peter H. Casas, Juan P. Uhl, George R. Vineis, Paolo Padmanabhan, Sandosh Jefferis, Barbara J. Amuzu, Antoinette Riboli, Elio Upton, Mark N. Aveyard, Paul Ebrahim, Shah Hingorani, Aroon D. Watt, Graham Palmer, Tom M. Timpson, Nicholas J. Smith, George Davey CA EPIC Study Grp TI Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID LUNG-CANCER RISK; PERIPHERAL ARTERIAL-DISEASE; RANDOMIZED CONTROLLED-TRIAL; GENOME-WIDE ASSOCIATION; SERUM COTININE LEVEL; NICOTINE DEPENDENCE; SMOKING-BEHAVIOR; SUSCEPTIBILITY LOCUS; HEAVY SMOKING; CLUSTER AB Background Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. Methods We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. Results Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 x 10(-6)) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 x 10(-11)). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). Conclusions Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure. C1 [Munafo, Marcus R.] Univ Bristol, Sch Expt Psychol, Bristol BS8 1TU, Avon, England. [Timofeeva, Maria N.; Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, F-69372 Lyon 08, France. [Morris, Richard W.; Casas, Juan P.; Jefferis, Barbara J.; Ebrahim, Shah] UCL, Div Populat Hlth, London, England. [Prieto-Merino, David; Casas, Juan P.; Amuzu, Antoinette] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1, England. [Sattar, Naveed; Padmanabhan, Sandosh] Univ Glasgow, British Heart Fdn Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Johnstone, Elaine C.] Univ Oxford, Dept Oncol, Oxford, England. [Relton, Caroline] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Johnson, Paul C. D.] Univ Glasgow, Coll Med Vet & Life Sci, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Walther, Donna; Uhl, George R.] NIDA, Mol Neurobiol Branch, NIH IRP, Baltimore, MD USA. [Whincup, Peter H.] St Georges Univ London, Div Populat Hlth Sci & Educ, London, England. [Vineis, Paolo; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Vineis, Paolo] HuGeF Fdn, Turin, Italy. [Upton, Mark N.] Woodlands Family Med Ctr, Stockton On Tees, England. [Aveyard, Paul] Univ Birmingham, Birmingham, W Midlands, England. [Watt, Graham] Univ Glasgow, Div Community Based Sci, Glasgow, Lanark, Scotland. [Palmer, Tom M.; Timpson, Nicholas J.; Smith, George Davey] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol CAiTE, Bristol BS8 1TU, Avon, England. RP Munafo, MR (reprint author), Univ Bristol, Sch Expt Psychol, 12A Priory Rd, Bristol BS8 1TU, Avon, England. EM marcus.munafo@bristol.ac.uk RI Johnson, Paul/O-9695-2014; Jefferis, Barbara/C-1786-2008; Fox, Laura /C-6249-2016; Padmanabhan, Sandosh/S-3963-2016; Davey Smith, George/A-7407-2013; OI Prieto-Merino, David/0000-0001-5001-0061; Morris, Richard/0000-0001-7240-4563; Relton, Caroline/0000-0003-2052-4840; Palmer, Tom/0000-0003-4655-4511; Munafo, Marcus/0000-0002-4049-993X; Timpson, Nicholas/0000-0002-7141-9189; Johnson, Paul/0000-0001-6663-7520; Jefferis, Barbara/0000-0002-0850-3177; Davey Smith, George/0000-0002-1407-8314; Upton, Mark/0000-0003-0839-1141; Whincup, Peter/0000-0002-5589-4107; Padmanabhan, Sandosh/0000-0003-3869-5808; Aveyard, Paul/0000-0002-1802-4217 FU Economic and Social Research Council; British Heart Foundation; Cancer Research UK; Department of Health; Medical Research Council under UK Clinical Research Collaboration; European Commission (SANCO); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research; Deutsches Krebsforschungszentrum; German Federal Ministry of Education and Research; Danish Cancer Society; Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra; ISCIII Network RCESP, Spain; Medical Research Council, UK; Hellenic Health Foundation; Stavros Niarchos Foundation; Greek Ministry of Health; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Compagnia di San Paolo; Ministero della Salute-Regione Toscana-Programma Integrato Oncologia; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Vasterbotten, Sweden; Norwegian Cancer Society; Research Council of Norway; French League against Cancer (LNCC); National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; General Councils of France; Wellcome Trust; National Health Service FX MRM is a member of the UK Centre for Tobacco Control Studies, a UK Clinical Research Collaboration Public Health Research Centre of Excellence. Funding from the Economic and Social Research Council, the British Heart Foundation, Cancer Research UK, the Department of Health and the Medical Research Council, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged.; The British Regional Heart Study (BRHS) is supported by the British Heart Foundation. The British Women's Heart and Health Study (BWHHS) is commissioned by the Department of Health Policy Research Programme and the British Heart Foundation. The European Prospective Investigation into Cancer and Nutrition (EPIC) study has been supported by the Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra; the ISCIII Network RCESP, Spain; Cancer Research UK; Medical Research Council, UK; Hellenic Health Foundation; Stavros Niarchos Foundation; Greek Ministry of Health; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Compagnia di San Paolo; Ministero della Salute-Regione Toscana-Programma Integrato Oncologia; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Vasterbotten, Sweden; Norwegian Cancer Society; Research Council of Norway; French League against Cancer (LNCC); National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; and General Councils of France. The Midspan study is supported by the Wellcome Trust and the National Health Service Cardiovascular Research and Development Programme. The Patch II and Patch in Practice studies were supported by a Cancer Research UK programme grant. NR 56 TC 77 Z9 77 U1 1 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAY PY 2012 VL 104 IS 10 BP 740 EP 748 DI 10.1093/jnci/djs191 PG 9 WC Oncology SC Oncology GA 944KH UT WOS:000304199600008 PM 22534784 ER PT J AU Smith, L Brinton, LA Spitz, MR Lam, TK Park, Y Hollenbeck, AR Freedman, ND Gierach, GL AF Smith, Llewellyn Brinton, Louise A. Spitz, Margaret R. Lam, Tram Kim Park, Yikyung Hollenbeck, Albert R. Freedman, Neal D. Gierach, Gretchen L. TI Body Mass Index and Risk of Lung Cancer Among Never, Former, and Current Smokers SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HORMONE REPLACEMENT THERAPY; POSTMENOPAUSAL WOMEN; REPRODUCTIVE FACTORS; EPIDEMIOLOGIC EVIDENCE; NURSES HEALTH; SEX-HORMONES; DNA-ADDUCTS; COHORT; MORTALITY; OBESITY AB Background Although obesity has been directly linked to the development of many cancers, many epidemiological studies have found that body mass index (BMI)-a surrogate marker of obesity-is inversely associated with the risk of lung cancer. These studies are difficult to interpret because of potential confounding by cigarette smoking, a major risk factor for lung cancer that is associated with lower BMI. Methods We prospectively examined the association between BMI and the risk of lung cancer among 448 732 men and women aged 50-71 years who were recruited during 1995-1996 for the National Institutes of Health-AARP Diet and Health Study. BMI was calculated based on the participant's self-reported height and weight on the baseline questionnaire. We identified 9437 incident lung carcinomas (including 415 in never smokers) during a mean follow-up of 9.7 years through 2006. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for lung cancer risk factors, including smoking status. To address potential bias due to preexisting undiagnosed disease, we excluded potentially unhealthy participants in sensitivity analyses. All statistical tests were two-sided. Results The crude incidence rate of lung cancer over the study follow-up period was 233 per 100 000 person-years among men and 192 per 100 000 person-years among women. BMI was inversely associated with the risk of lung cancer among both men and women (BMI >= 35 vs 22.5-24.99 kg/m(2): HR = 0.81, 95% CI = 0.70 to 0.94 and HR = 0.73, 95% CI = 0.61 to 0.87, respectively). The inverse association was restricted to current and former smokers and was stronger after adjustment for smoking. Among smokers, the inverse association persisted even after finely stratifying on smoking status, time since quitting smoking, and number of cigarettes smoked per day. Sensitivity analyses did not support the possibility that the inverse association was due to prevalent undiagnosed disease. Conclusions Our results suggest that a higher BMI is associated with a reduced risk of lung cancer in current and former smokers. Our inability to attribute the inverse association between BMI and the risk of lung cancer to residual confounding by smoking or to bias suggests the need for considering other explanations. C1 [Smith, Llewellyn; Brinton, Louise A.; Gierach, Gretchen L.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Lam, Tram Kim] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Park, Yikyung; Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Hollenbeck, Albert R.] AARP, Org & Tracking Res Dept, Washington, DC USA. RP Gierach, GL (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Ste 550,Rm 5016, Rockville, MD 20852 USA. EM gierachg@mail.nih.gov RI Brinton, Louise/G-7486-2015; Freedman, Neal/B-9741-2015; Gierach, Gretchen/E-1817-2016; OI Brinton, Louise/0000-0003-3853-8562; Freedman, Neal/0000-0003-0074-1098; Gierach, Gretchen/0000-0002-0165-5522; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute at the National Institutes of Health; Florida Department of Health (FDOH) FX This research was supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. The authors have no financial disclosures.; The authors are indebted to the participants in the NIH-AARP Diet and Health Study for their cooperation. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. NR 46 TC 38 Z9 38 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD MAY PY 2012 VL 104 IS 10 BP 778 EP 789 DI 10.1093/jnci/djs179 PG 12 WC Oncology SC Oncology GA 944KH UT WOS:000304199600011 PM 22457475 ER PT J AU Cole, VT Apud, JA Weinberger, DR Dickinson, D AF Cole, Veronica T. Apud, Jose A. Weinberger, Daniel R. Dickinson, Dwight TI Using Latent Class Growth Analysis to Form Trajectories of Premorbid Adjustment in Schizophrenia SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE developmental trajectories; schizophrenia; latent class growth analysis ID 1ST-EPISODE PSYCHOSIS; COGNITIVE DEFICITS; UNTREATED PSYCHOSIS; 1ST EPISODE; CHILDHOOD; PATTERNS; MIXTURE; MODEL; PREDICTORS; DISORDERS AB Premorbid adjustment varies widely among individuals with schizophrenia and has been shown to bear significantly on prodrome and onset characteristics, and on cognition, symptoms, and functioning after onset. The current analysis focused on the Premorbid Adjustment Scale, a retrospective measure assessing social and academic function at several time points from early childhood to illness onset. In an effort to explore discrete developmental subtypes, we applied latent class growth analysis to data from the Premorbid Adjustment Scale in our sample of individuals with schizophrenia (N = 208), finding three latent trajectory classes. The first of these classes showed consistently adequate-to-good social and academic functioning before onset; the second showed initially good function and deterioration with time until onset; the third showed poor functioning in childhood that deteriorated further during the years up to diagnosis. The classes differed significantly in terms of age of onset, processing speed, and functioning after onset. There were no significant differences in symptomatology. Our findings illustrate a potentially powerful methodological approach to the problem of heterogeneity in schizophrenia research, and add weight to the notion that aspects of premorbid history may be useful for subtyping schizophrenia patients. The potential implications of this subtyping strategy, including those pertaining to potential genetics studies, are discussed. C1 [Cole, Veronica T.; Apud, Jose A.; Weinberger, Daniel R.; Dickinson, Dwight] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Dickinson, D (reprint author), NIMH, Clin Brain Disorders Branch, 10 Ctr Dr,7SE 5350, Bethesda, MD 20892 USA. EM dwight.dickinson@nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 59 TC 9 Z9 9 U1 0 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD MAY PY 2012 VL 121 IS 2 BP 388 EP 395 DI 10.1037/a0026922 PG 8 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA 943NQ UT WOS:000304131400009 PM 22250661 ER PT J AU Lodish, M Dunn, SV Sinaii, N Keil, MF Stratakis, CA AF Lodish, Maya Dunn, Somya Verma Sinaii, Ninet Keil, Margaret F. Stratakis, Constantine A. TI Recovery of the Hypothalamic-Pituitary-Adrenal Axis in Children and Adolescents after Surgical Cure of Cushing's Disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ADRENOCORTICAL FUNCTION; TRANSSPHENOIDAL SURGERY; ACTH-TEST; INSUFFICIENCY; CORTICOTROPIN; SUPPRESSION; THERAPY; TERM; ADENOMECTOMY AB Context: Recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after transsphenoidal surgery (TSS) for Cushing's disease (CD) in children has not been adequately studied. Objective: Our objective was to assess time to recovery of the HPAA after TSS in children with CD. Design and Setting: This was a case series at the National Institutes of Health Clinical Center. Patients: Fifty-seven patients with CD (6-18 yr, mean 13.0 +/- 3.1 yr) given a standard regimen of glucocorticoid tapering after TSS were studied out of a total of 73 recruited. Interventions: ACTH (250 mu g) stimulation tests were administered at approximately 6-month intervals for up to 36 months. Age, sex, pubertal status, body mass index, length of disease, midnight cortisol, and urinary free cortisol at diagnosis were analyzed for effects on recovery. Main Outcome Measure: The main outcome measure was complete recovery of the HPAA as defined by a cortisol level of at least 18 mu g/dl in response to 250 mu g ACTH. Results: Full recovery was reached by 43 (75.4%) of 57 patients, with 29 of the 43 (67.4%) and 41 of the 43 (95.3%) recovering by 12 and 18 months, respectively. The overall mean time to recovery was 12.6 +/- 3.3 months. Kaplan-Meier survivor function estimated a 50% chance of recovering by 12 months after TSS and 75% chance of recovering within 14 months. By receiver operating characteristic curve assessment, the cutoff of at least 10-11 mu g/dl of cortisol as the peak of ACTH stimulation testing at 6 months after TSS yielded the highest sensitivity (70-80%) and specificity (64-73%) to predict full recovery of the HPAA at 12 months. Two of the four patients that recovered fully within 6 months had recurrent CD. Conclusions: Although this is not a randomized study, we present our standardized tapering regimen for glucocorticoid replacement after TSS that led to recovery of the HPAA in most patients within the first postoperative year. Multiple factors may affect this process, but an early recovery may indicate disease recurrence. (J Clin Endocrinol Metab 97: 1483-1491, 2012) C1 [Lodish, Maya; Dunn, Somya Verma; Keil, Margaret F.; Stratakis, Constantine A.] NIH, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Lodish, Maya; Dunn, Somya Verma; Keil, Margaret F.; Stratakis, Constantine A.] NIH, Sect Endocrinol & Genet, Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. [Sinaii, Ninet] NIH, Warren Grant Magnuson Clin Res Ctr, Bethesda, MD 20892 USA. RP Lodish, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, CRC, Bldg 10,Room I-3330 E Labs, 10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 25 TC 18 Z9 18 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2012 VL 97 IS 5 BP 1483 EP 1491 DI 10.1210/jc.2011-2325 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 940TL UT WOS:000303915900038 PM 22399509 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI "Patients Can Have as Many Gene Variants as They Damn Well Please": Why Contemporary Genetics Presents Us Daily with a Version of Hickam's Dictum SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID FAMILIAL GLUCOCORTICOID DEFICIENCY; PRIMARY ADRENAL INSUFFICIENCY; ADDISONS-DISEASE; SKIN PIGMENTATION; PROOPIOMELANOCORTIN; MUTATIONS; RECEPTOR; HYPERPIGMENTATION; POPULATION C1 [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, CRC,NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, CRC,NIH, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD000642, Z01-HD-000642-04] NR 36 TC 1 Z9 1 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2012 VL 97 IS 5 BP E802 EP E804 DI 10.1210/jc.2012-1650 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 940TL UT WOS:000303915900016 PM 22563116 ER PT J AU Uldrick, TS Wyvill, KM Kumar, P O'Mahony, D Bernstein, W Aleman, K Polizzotto, MN Steinberg, SM Pittaluga, S Marshall, V Whitby, D Little, RF Yarchoan, R AF Uldrick, Thomas S. Wyvill, Kathleen M. Kumar, Pallavi O'Mahony, Deirdre Bernstein, Wendy Aleman, Karen Polizzotto, Mark N. Steinberg, Seth M. Pittaluga, Stefania Marshall, Vickie Whitby, Denise Little, Richard F. Yarchoan, Robert TI Phase II Study of Bevacizumab in Patients With HIV-Associated Kaposi's Sarcoma Receiving Antiretroviral Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PEGYLATED-LIPOSOMAL DOXORUBICIN; VASCULAR-PERMEABILITY FACTOR; AIDS MALIGNANCY CONSORTIUM; METALLOPROTEINASE INHIBITOR COL-3; HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEIN-COUPLED RECEPTOR; EFFUSION LYMPHOMA-CELLS; ASCITES TUMOR-GROWTH; CLINICAL-TRIAL AB Purpose Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti-VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS. Patients and Methods Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately. Results Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T-1), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/mu L. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2). Conclusion Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients. C1 [Uldrick, Thomas S.; Wyvill, Kathleen M.; Kumar, Pallavi; O'Mahony, Deirdre; Bernstein, Wendy; Aleman, Karen; Polizzotto, Mark N.; Steinberg, Seth M.; Pittaluga, Stefania; Little, Richard F.; Yarchoan, Robert] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Marshall, Vickie; Whitby, Denise] NCI, SAIC Frederick, Frederick, MD 21701 USA. RP Yarchoan, R (reprint author), 10 Ctr Dr,Room 6N106,MSC 1868, Bethesda, MD 20892 USA. EM Robert.Yarchoan@nih.gov FU National Cancer Institute (NCI), National Institutes of Health (NIH) [HHSN261200800001E]; Genentech FX Supported in part by the Intramural Research Program, National Cancer Institute (NCI), National Institutes of Health (NIH). Additional funding provided by the NCI, NIH, under Contract No. HHSN261200800001E.; Robert Yarchoan, bevacizumab provided to National Cancer Institute by Genentech under a Cooperative Research and Development Agreement NR 61 TC 29 Z9 29 U1 0 U2 1 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 MAY 1 PY 2012 VL 30 IS 13 BP 1476 EP 1483 DI 10.1200/JCO.2011.39.6853 PG 8 WC Oncology SC Oncology GA 939ZJ UT WOS:000303859400017 PM 22430271 ER PT J AU Hollevoet, K Reitsma, JB Creaney, J Grigoriu, BD Robinson, BW Scherpereel, A Cristaudo, A Pass, HI Nackaerts, K Portal, JAR Schneider, J Muley, T Di Serio, F Baas, P Tomasetti, M Rai, AJ van Meerbeeck, JP AF Hollevoet, Kevin Reitsma, Johannes B. Creaney, Jenette Grigoriu, Bogdan D. Robinson, Bruce W. Scherpereel, Arnaud Cristaudo, Alfonso Pass, Harvey I. Nackaerts, Kristiaan Rodriguez Portal, Jose A. Schneider, Joachim Muley, Thomas Di Serio, Francesca Baas, Paul Tomasetti, Marco Rai, Alex J. van Meerbeeck, Jan P. TI Serum Mesothelin for Diagnosing Malignant Pleural Mesothelioma: An Individual Patient Data Meta-Analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID MEGAKARYOCYTE POTENTIATING FACTOR; SOLUBLE MESOTHELIN; LUNG-CANCER; NONINVASIVE DIAGNOSIS; FAMILY PROTEINS; TUMOR-MARKER; PHASE-III; OSTEOPONTIN; PEPTIDES; ASBESTOS AB Purpose Mesothelin is currently considered the best available serum biomarker of malignant pleural mesothelioma. To examine the diagnostic accuracy and use of serum mesothelin in early diagnosis, we performed an individual patient data (IPD) meta-analysis. Methods The literature search identified 16 diagnostic studies of serum mesothelin, measured with the Mesomark enzyme-linked immunosorbent assay. IPD of 4,491 individuals were collected, including several control groups and 1,026 patients with malignant pleural mesothelioma. Mesothelin levels were standardized for between-study differences and age, after which the diagnostic accuracy and the factors affecting it were examined with receiver operating characteristic (ROC) regression analysis. Results At a common diagnostic threshold of 2.00 nmol/L, the sensitivities and specificities of mesothelin in the different studies ranged widely from 19% to 68% and 88% to 100%, respectively. This heterogeneity can be explained by differences in study population, because type of control group, mesothelioma stage, and histologic subtype significantly affected the diagnostic accuracy. The use of mesothelin in early diagnosis was evaluated by differentiating 217 patients with stage I or II epithelioid and biphasic mesothelioma from 1,612 symptomatic or high-risk controls. The resulting area under the ROC curve was 0.77 (95% CI, 0.73 to 0.81). At 95% specificity, mesothelin displayed a sensitivity of 32% (95% CI, 26% to 40%). Conclusion In patients suspected of having mesothelioma, a positive blood test for mesothelin at a high-specificity threshold is a strong incentive to urge further diagnostic steps. However, the poor sensitivity of mesothelin clearly limits its added value to early diagnosis and emphasizes the need for further biomarker research. J Clin Oncol 30: 1541-1549. (C) 2012 by American Society of Clinical Oncology C1 [Hollevoet, Kevin] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hollevoet, Kevin; van Meerbeeck, Jan P.] Ghent Univ Hosp, Ghent, Belgium. [Nackaerts, Kristiaan] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Reitsma, Johannes B.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Baas, Paul] Netherlands Canc Inst, Amsterdam, Netherlands. [Creaney, Jenette; Robinson, Bruce W.] Univ Western Australia, Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia. [Grigoriu, Bogdan D.] Univ Med, Iasi, Romania. [Scherpereel, Arnaud] Ctr Hosp Reg & Univ Lille 2, Univ Hosp, Lille, France. [Cristaudo, Alfonso] Univ Pisa, Pisa, Italy. [Di Serio, Francesca] Univ Hosp, Bari, Italy. [Tomasetti, Marco] Polytech Univ Marche, Ancona, Italy. [Rodriguez Portal, Jose A.] Virgen del Rocio Univ Hosp, Seville, Spain. [Schneider, Joachim] Univ Giessen, Giessen, Germany. [Muley, Thomas] Univ Klinikum Heidelberg, Thoraxklin, Heidelberg, Germany. [Pass, Harvey I.] NYU, Langone Med Ctr, New York, NY 10003 USA. [Pass, Harvey I.] NYU, Ctr Canc, New York, NY 10003 USA. [Rai, Alex J.] Columbia Univ, Med Ctr, New York, NY USA. RP Hollevoet, K (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5110, Bethesda, MD 20892 USA. EM kevin.hollevoet@nih.gov RI Robinson, Bruce/N-1900-2014; IBIS, ENF. RESPIRATO/P-3887-2015; IBIS, RESPIRATORIAS/P-3982-2015 FU Foundation Against Cancer, a Belgian foundation of public interest; Flemish League Against Cancer; National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; Early Detection Research Network of the National Cancer Institute, NIH; National Health and Medical Research Council of Australia; Western Australian Insurance Commission; CIS Bio International; Fujirebio Diagnostics FX K.H. is supported in part by the Foundation Against Cancer, a Belgian foundation of public interest; by the research grant Emmanuel Van der Schueren of the Flemish League Against Cancer, and by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. H.I.P. received research support from the Early Detection Research Network of the National Cancer Institute, NIH. B.W.R. and J.C. are supported by the National Health and Medical Research Council of Australia and the Western Australian Insurance Commission.; Employment or Leadership Position: None Consultant or Advisory Role: Harvey I. Pass, Fujirebio Diagnostics (C) Stock Ownership: None Honoraria: Harvey I. Pass, Fujirebio Diagnostics Research Funding: Jan P. van Meerbeeck, CIS Bio International; Harvey I. Pass, Fujirebio Diagnostics; Arnaud Scherpereel, CIS Bio International Expert Testimony: None Other Remuneration: None NR 49 TC 75 Z9 76 U1 1 U2 19 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 MAY 1 PY 2012 VL 30 IS 13 BP 1541 EP 1549 DI 10.1200/JCO.2011.39.6671 PG 9 WC Oncology SC Oncology GA 939ZJ UT WOS:000303859400026 PM 22412141 ER PT J AU Lewis, SS Loram, LC Hutchinson, MR Li, CM Zhang, YN Maier, SF Huang, Y Rice, KC Watkins, LR AF Lewis, Susannah S. Loram, Lisa C. Hutchinson, Mark R. Li, Chien-Ming Zhang, Yingning Maier, Steven F. Huang, Yong Rice, Kenner C. Watkins, Linda R. TI (+)-Naloxone, an Opioid-Inactive Toll-Like Receptor 4 Signaling Inhibitor, Reverses Multiple Models of Chronic Neuropathic Pain in Rats SO JOURNAL OF PAIN LA English DT Article DE TLR4; neuropathic pain; chronic constriction injury; spinal nerve ligation; HEK293-TLR4 ID NALOXONE; LIPOPOLYSACCHARIDE; RECOGNITION; ACTIVATION; NALTREXONE; BACTERIA; INJURY; MD-2 AB Previous work demonstrated that both the opioid antagonist (-)-naloxone and the non-opioid (+)-naloxone inhibit toll-like receptor 4 (TLR4) signaling and reverse neuropathic pain expressed shortly after chronic constriction injury. The present studies reveal that the TLR4 contributes to neuropathic pain in another major model (spinal nerve ligation) and to long established (2-4 months) neuropathic pain, not just to pain shortly after nerve damage. Additionally, analyses of plasma levels of (+)-naloxone after subcutaneous administration indicate that (+)-naloxone has comparable pharmacokinetics to (-)-naloxone with a relatively short half-life. This finding accounts for the rapid onset and short duration of allodynia reversal produced by subcutaneous (+)-naloxone. Given that toll-like receptor 2 (TLR2) has also recently been implicated in neuropathic pain, cell lines transfected with either TLR4 or TLR2, necessary co-signaling molecules, and a reporter gene were used to define whether (+)-naloxone effects could be accounted for by actions at TLR2 in addition to TLR4. (+)-Naloxone inhibited signaling by TLR4 but not TLR2. These studies provide evidence for broad involvement of TLR4 in neuropathic pain, both early after nerve damage and months later. Additional, they provide further support for the TLR4 inhibitor (+)-naloxone as a novel candidate for the treatment of neuropathic pain. Perspective: These studies demonstrated that (+)-naloxone, a systemically available, blood-brain barrier permeable, small molecule TLR4 inhibitor can reverse neuropathic pain in rats, even months after nerve injury. These findings suggest that (+)-naloxone, or similar compounds, be considered as a candidate novel, first-in-class treatment for neuropathic pain. (C) 2012 by the American Pain Society. Published by Elsevier Inc. All rights reserved C1 [Lewis, Susannah S.; Loram, Lisa C.; Zhang, Yingning; Maier, Steven F.; Watkins, Linda R.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Hutchinson, Mark R.] Univ Adelaide, Sch Med Sci, Discipline Physiol, Adelaide, SA, Australia. [Li, Chien-Ming; Huang, Yong] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, Drug Studies Unit, San Francisco, CA 94143 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, Kenner C.] NIAAA, NIH, Rockville, MD 20852 USA. RP Lewis, SS (reprint author), Univ Colorado, Dept Psychol & Neurosci, Campus Box 345, Boulder, CO 80309 USA. EM susannah.lewis@colorado.edu RI Hutchinson, Mark/G-4147-2014 OI Hutchinson, Mark/0000-0003-2154-5950 FU NIH [DA024044, DE017782, DA023132]; NIDA [N01DA-9-8883]; NIH of NIDA; NIAAA FX This work was funded in part by NIH Grants DA024044, DE017782, DA023132 and NIDA contract N01DA-9-8883. This work was also supported in part by the NIH Intramural Research Programs of NIDA and NIAAA. Mark R. Hutchinson is a NHMRC CJ Martin Fellow (ID 465423; 2007-2010) and an Australian Research Council Research Fellow (DP110100297). HEK-TLR4 cells were gifted from Avigen. NR 29 TC 32 Z9 32 U1 0 U2 11 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD MAY PY 2012 VL 13 IS 5 BP 498 EP 506 DI 10.1016/j.jpain.2012.02.005 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 944UG UT WOS:000304228700009 PM 22520687 ER PT J AU Kirkpatrick, SI AF Kirkpatrick, Sharon I. TI Understanding and Addressing Barriers to Healthy Eating among Low-Income Americans SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Editorial Material DE Food security; Poverty; Supplemental Nutrition Assistance Program; Food environment; Food deserts ID ADULTS C1 NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Kirkpatrick, SI (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4005, Bethesda, MD 20892 USA. EM kirkpatricksi@mail.nih.gov OI Kirkpatrick, Sharon/0000-0001-9896-5975 NR 20 TC 3 Z9 3 U1 2 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD MAY PY 2012 VL 112 IS 5 BP 617 EP 620 DI 10.1016/j.jand.2012.02.009 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 943NO UT WOS:000304131200006 PM 22709765 ER PT J AU Kirkpatrick, SI Dodd, KW Reedy, J Krebs-Smith, SM AF Kirkpatrick, Sharon I. Dodd, Kevin W. Reedy, Jill Krebs-Smith, Susan M. TI Income and Race/Ethnicity Are Associated with Adherence to Food-Based Dietary Guidance among US Adults and Children SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Dietary guidance; Disparities; Usual dietary intakes; 24-hour recall; NHANES ID SOCIOECONOMIC-STATUS; UNITED-STATES; DISPARITIES; HEALTH; TRENDS; RECOMMENDATIONS; PREVALENCE; BIOMARKERS; PATTERNS; QUALITY AB Background Income and race/ethnicity are associated with differences in dietary intakes that may contribute to health disparities among members of the US population. Objective To examine alignment of intakes of food groups and energy from solid fats, added sugars, and alcohol with the 2005 Dietary Guidelines for Americans and MyPyramid, by family income and race/ethnicity. Design Data from the National Health and Nutrition Examination Survey, a cross-sectional, nationally representative survey, for 2001-2004. Participants/setting Persons aged >= 2 years for whom reliable dietary intake data were available (n=16,338) were categorized by income (lowest, middle, and highest) and race/ethnicity (non-Hispanic. white, non-Hispanic black, and Mexican American). Statistical analyses performed The National Cancer Institute method was used to estimate the proportions of adults and children in each income and race/ethnic group whose usual intakes met the recommendations. Results Higher income was associated with greater adherence to recommendations for most food groups; the proportions meeting minimum recommendations among adults in the highest income group were double that observed for the lowest income group for total vegetables, milk, and oils. Fewer differences by income were apparent among children. Among the race/ethnic groups, the proportions meeting recommendations were generally lowest among non-Hispanic blacks. Marked differences were observed for milk-15% of non-Hispanic black children met the minimum recommendations compared with 42% of non-Hispanic white children and 35% of Mexican-American children; a similar pattern was evident for adults. One in five Mexican-American adults met the dry beans and peas recommendations compared with approximately 2% of non-Hispanic whites and non-Hispanic blacks. Most adults and children consumed excess energy from solid fats and added sugars irrespective of income and race/ethnicity. Conclusions The diets of some subpopulations, particularly individuals in lower-income households and non-Hispanic blacks, are especially poor in relation to dietary recommendations, supporting the need for comprehensive strategies to enable healthier dietary intake patterns. J Acad Nutr Diet. 2012;112:624-635. C1 [Kirkpatrick, Sharon I.; Reedy, Jill; Krebs-Smith, Susan M.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dodd, Kevin W.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kirkpatrick, SI (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4005, Bethesda, MD 20892 USA. EM kirkpatricksi@mail.nih.gov OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 98 Z9 98 U1 5 U2 33 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD MAY PY 2012 VL 112 IS 5 BP 624 EP 635 DI 10.1016/j.jand.2011.11.012 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 943NO UT WOS:000304131200008 PM 22709767 ER PT J AU Bailey, RL Fulgoni, VL Keast, DR Dwyer, JT AF Bailey, Regan Lucas Fulgoni, Victor L., III Keast, Debra R. Dwyer, Johanna T. TI Examination of Vitamin Intakes among US Adults by Dietary Supplement Use SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Dietary supplements; NHANES; Vitamins; Users and non-users of supplements ID NUTRIENT INTAKE; MULTIVITAMIN/MINERAL SUPPLEMENTS; MULTIETHNIC COHORT; NUTRITION; MINERALS; ENERGY; FOODS; ACID AB Background More than half of US adults use dietary supplements. Some reports suggest that supplement users have higher vitamin intakes from foods than nonusers, but this observation has not been examined using nationally representative survey data. Objective The purpose of this analysis was to examine vitamin intakes from foods by supplement use and how dietary supplements contribute to meeting or exceeding the Dietary Reference Intakes for selected vitamins using data from the National Health and Nutrition Examination Survey among adults (aged >= 19 years) in 2003-2006 (n=8,860). Results Among male users, mean intakes of folate and vitamins A, E, and K from food sources were significantly higher than among nonusers. Among women, mean intakes of folate and vitamins A, C, D, and E from foods were higher among users than nonusers. Total intakes (food and supplements) were higher for every vitamin we examined among users than the dietary vitamin intakes of nonusers. Supplement use helped lower the prevalence of intakes below the Estimated Average Requirement for every vitamin we examined, but for folic acid and vitamins A, B-6, and C, supplement use increased the likelihood of intakes above the Tolerable Upper Intake Level. Conclusions Supplement use was associated with higher mean intakes of some vitamins from foods among users than nonusers, but it was not associated with the prevalence of intakes less than the Estimated Average Requirement from foods. Those who do not use vitamin supplements had significantly higher prevalence of inadequate vitamin intakes; however, the use of supplements can contribute to excess intake for some vitamins. J Acad Nutr Diet. 2012;112:657-663. C1 [Bailey, Regan Lucas; Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Fulgoni, Victor L., III] Nutr Impact LLC, Battle Creek, MI USA. [Keast, Debra R.] Food & Nutr Database Res Inc, Okemos, MI USA. [Dwyer, Johanna T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Bailey, RL (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU Fortification Committee of the International Life Sciences Institute, North American Branch; US Department of Agriculture Research Service [58-1950-7-707]; Office of Dietary Supplements at the National Institutes of Health FX The original statistical analysis to separate fortified and enriched foods from other foods and dietary supplements used in this article was funded by the Fortification Committee of the International Life Sciences Institute, North American Branch. The International Life Sciences Institute was not involved in the interpretation or presentation of data for this work. This work was supported in part by resources from the US Department of Agriculture Research Service under agreement no. 58-1950-7-707 and the Office of Dietary Supplements at the National Institutes of Health. NR 28 TC 43 Z9 43 U1 0 U2 29 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD MAY PY 2012 VL 112 IS 5 BP 657 EP 663 DI 10.1016/j.jand.2012.01.026 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 943NO UT WOS:000304131200012 PM 22709770 ER PT J AU Nicklett, EJ Semba, RD Xue, QL Tian, J Sun, K Cappola, AR Simonsick, EM Ferrucci, L Fried, LP AF Nicklett, Emily J. Semba, Richard D. Xue, Qian-Li Tian, Jing Sun, Kai Cappola, Anne R. Simonsick, Eleanor M. Ferrucci, Luigi Fried, Linda P. TI Fruit and Vegetable Intake, Physical Activity, and Mortality in Older Community-Dwelling Women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE diet; carotenoids; physical activity; mortality; women ID SERUM CAROTENOIDS; LEISURE-TIME; ACTIVITY QUESTIONNAIRE; OXIDATIVE STRESS; FRAILTY SYNDROME; MUSCLE STRENGTH; HEALTH; ADULTS; ASSOCIATION; DISABILITY AB OBJECTIVES To examine the relationship between fruit and vegetable intake, physical activity, and all-cause mortality in older women. DESIGN Six Cox proportional hazards models examined independent and additive relationships between physical activity, carotenoids, and all-cause mortality. Additional models tested whether physical activity and carotenoids were conjointly related to mortality. Models were adjusted for age, education, and race and ethnicity. SETTING Baltimore, Maryland. PARTICIPANTS Seven hundred thirteen women aged 70 to 79 participating in the Women's Health and Aging Studies. MEASUREMENTS Total serum carotenoids, a marker of fruit and vegetable intake, and physical activity were measured at baseline. Physical activity was measured according to kilocalorie expenditure. RESULTS During 5 years of follow-up, 82 (11.5%) participants died. Measured continuously, physical activity improved survival (HR = 0.52, 95% CI = 0.410.66, P < .001). The most active women were more likely to survive than the least physically active women (HR = 0.28, 95% CI = 0.130.59, P < .001). Continuous measures of carotenoids improved survival (HR = 0.67, 95% CI = 0.510.89, P = .01). Women in the highest tertile of total carotenoids were more likely to survive those in the lowest (HR = 0.50, 95% CI = 0.270.91, P = .03). When examined in the same model, continuous measures of physical activity (HR = 0.54, 95% CI = 0.420.68, P < .001) and carotenoids (HR = 0.76, 95% CI = 0.590.98, P = .04) predicted survival during follow-up. CONCLUSION The combination of low total serum carotenoids and low physical activity, both modifiable risk factors, strongly predicted earlier mortality. These findings provide preliminary support that higher fruit and vegetable intake and exercise improve survival. C1 [Nicklett, Emily J.] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Semba, Richard D.; Xue, Qian-Li; Sun, Kai] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Xue, Qian-Li; Simonsick, Eleanor M.; Ferrucci, Luigi] Univ Penn, Div Geriatr Med & Gerontol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Tian, Jing] Univ Penn, Dept Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Cappola, Anne R.] Univ Penn, Div Endocrinol Diabet & Metab, Perelman Sch Med, Philadelphia, PA 19104 USA. NIA, Longitudinal Studies Sect, Bethesda, MD 20892 USA. [Fried, Linda P.] Columbia Univ, Coll Phys & Surg, Mailman Sch Publ Hlth, New York, NY USA. [Fried, Linda P.] Columbia Univ, Coll Phys & Surg, Dept Med, Div Epidemiol, New York, NY USA. RP Nicklett, EJ (reprint author), Univ Michigan, Sch Social Work, 1080 S Univ Ave,Rm 2773, Ann Arbor, MI 48109 USA. EM enicklet@umich.edu FU National Institute on Aging FX Funding was provided by the National Institute on Aging. NR 47 TC 18 Z9 20 U1 3 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2012 VL 60 IS 5 BP 862 EP 868 DI 10.1111/j.1532-5415.2012.03924.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 942HE UT WOS:000304033900007 PM 22587851 ER PT J AU Kelly, B Rid, A Wendler, D AF Kelly, Brenna Rid, Annette Wendler, David TI Systematic Review: Individuals' Goals for Surrogate Decision-Making SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE surrogate; end of life; decision-making; incapacity; goals; preferences; values ID OF-LIFE CARE; ADVANCE DIRECTIVES; HEALTH-CARE; TREATMENT PREFERENCES; CLINICAL-PRACTICE; ELDERLY PATIENTS; DURABLE POWER; ILL PATIENTS; FAMILY; PHYSICIANS AB OBJECTIVES To determine to what extent current practice promotes the goals of individuals who did not designate a surrogate while competent with respect to decision-making during periods of decisional incapacity. DESIGN Systematic literature search for studies published in English and listed in PubMed, Scopus, Embase, CINAHL, or PsycINFO. Studies were eligible if they provided quantitative or qualitative empirical data on how adults want treatment decisions to be made for them during periods of incapacity. SETTING Primarily United States, with six other countries. PARTICIPANTS Fourteen qualitative articles, representing 11 distinct data sets, and 26 quantitative articles, representing 25 distinct data sets, providing data on the views of 22,828 individuals, met the inclusion criteria. Most of the respondents were elderly or seriously ill. MEASUREMENTS Quantitative surveys and qualitative interview studies assessing individuals' goals. RESULTS The majority wanted close family members to act as their surrogate. The most common reason for preferring family members was the belief that they know which treatments the patient would want. Individuals also wanted to reduce the burden on their families. There was significant variation in the extent to which respondents wanted their surrogates to have leeway when making treatment decisions. CONCLUSION Individuals have three primary goals with respect to making treatment decisions for them during periods of incapacity: involve their family, treat them consistently with their own treatment preferences, and reduce the burden on their family. Unfortunately, prior systematic reviews have found that family members often are not able to determine which treatment patients want, and family members frequently experience substantial distress when acting as surrogates. These findings suggest that current practice frequently fails to promote individuals' primary goals for treatment decision-making. Future research should evaluate ways to better promote individuals' goals. In the meantime, clinicians should be aware of these findings and should encourage patients to document their own goals, including their treatment preferences and their preferences regarding how they want decisions to be made for them during periods of decisional incapacity. J Am Geriatr Soc 60:884-895, 2012. C1 [Rid, Annette; Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Kelly, Brenna] Univ Michigan, Sch Law, Ann Arbor, MI 48109 USA. [Rid, Annette] Univ Zurich, Inst Biomed Eth, Zurich, Switzerland. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU Department of Bioethics; NIH Clinical Center FX The present project was funded by the Department of Bioethics, NIH Clinical Center. However, the NIH had no role in the design, methods, subject recruitment, data collections, analysis or preparation of the paper. NR 57 TC 23 Z9 23 U1 6 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2012 VL 60 IS 5 BP 884 EP 895 DI 10.1111/j.1532-5415.2012.03937.x PG 12 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 942HE UT WOS:000304033900010 PM 22469395 ER PT J AU Abrass, CK Appelbaum, JS Boyd, CM Braithwaite, RS Broudy, VC Covinsky, K Crothers, KA Harrington, R Drootin, M Gebo, K Goodkin, K Havlik, RJ Hazzard, W High, K Hsue, P John, MD Justice, A Karpiak, S McCormick, WC McNicholl, IR Newman, A Simone-Skidmore, MJ South, K Spach, D Valcour, V AF Abrass, Christine K. Appelbaum, Jonathan S. Boyd, Cynthia M. Braithwaite, R. Scott Broudy, Virginia C. Covinsky, Kenneth Crothers, Kristina Anne Harrington, Robert Drootin, Marianna Gebo, Kelly Goodkin, Karl Havlik, Richard J. Hazzard, William High, Kevin Hsue, Priscilla John, Malcolm D. Justice, Amy Karpiak, Stephen McCormick, Wayne C. McNicholl, Ian R. Newman, Anne Simone-Skidmore, Mark J. South, Ken Spach, David Valcour, Victor CA Work Grp HIV Aging Consensus Proje TI Summary Report from the Human Immunodeficiency Virus and Aging Consensus Project: Treatment Strategies for Clinicians Managing Older Individuals with the Human Immunodeficiency Virus SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE geriatrics; HIV; AIDS; multimorbidity AB By 2015, most of the people living with the human immunodeficiency virus (HIV) in the United States will be aged 50 and older. Many will have known their HIV status for at least a decade, and most will have received antiretroviral therapy for some, if not all, of the time since testing positive. As these individuals advance in years, they frequently acquire diseases more commonly associated with aging than with HIV. This represents a unique challenge for today's medical providers. Although these individuals may appear considerably older than their chronological age, they are typically too young to see a geriatrician. An HIV specialist, although knowledgeable in the nuances of antiretroviral therapy, may be less comfortable managing multiple age-related illnesses. Similarly, a geriatrician experienced in managing multiple, age-related conditions may be less familiar with adjusting HIV-related therapies. In this era of caring for older adults with HIV, these two medical disciplines are finding they have much to learn from each other. J Am Geriatr Soc 60:974-979, 2012. C1 [McCormick, Wayne C.] Univ Washington, Harborview Med Ctr, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98104 USA. [Abrass, Christine K.; Hazzard, William] Univ Washington, Sch Med, Div Gerontol & Geriatr Med, Seattle, WA 98104 USA. [Appelbaum, Jonathan S.] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Boyd, Cynthia M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. [Braithwaite, R. Scott] NYU, Sch Med, New York, NY USA. [Covinsky, Kenneth] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Drootin, Marianna] Amer Geriatr Soc, New York, NY USA. [Drootin, Marianna] ADGAP & Geriatr Specialists Initiat, New York, NY USA. [Goodkin, Karl] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [Havlik, Richard J.] NIA, New York, NY USA. [High, Kevin] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Hsue, Priscilla] Univ Calif San Francisco, San Francisco Gen Hosp, San Francisco, CA USA. [John, Malcolm D.] UCSF Med Ctr, Posit Care Ctr, San Francisco, CA USA. [Justice, Amy] Yale Univ, Sch Med, VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. [Karpiak, Stephen] NYU, Coll Nursing, New York, NY USA. [Havlik, Richard J.; Karpiak, Stephen] AIDS Community Res Initiat Amer, New York, NY USA. [McNicholl, Ian R.] AAHIVE UCSF Posit Hlth Program, San Francisco, CA USA. [Newman, Anne] Ctr Aging & Populat Hlth, Pittsburgh, PA USA. [Simone-Skidmore, Mark J.] Harvard Univ, Brigham & Womens Hosp, Boston, MA 02115 USA. [South, Ken] Amer Acad HIV Med, HIV & Aging Consensus Project, Washington, DC USA. [Spach, David] Univ Washington, Sch Med, NW AIDS Educ & Training Ctr, Seattle, WA 98104 USA. [Valcour, Victor] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP McCormick, WC (reprint author), Univ Washington, Harborview Med Ctr, Dept Med, Div Gerontol & Geriatr Med, 325 9th Ave 359755, Seattle, WA 98104 USA. EM mccorm@uw.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU Janssen Pharmaceuticals Inc.; Campbell Foundation; Strativa Pharmaceuticals, Ltd.; Tibotec; Johnson Johnson; Pfizer; Merck; American Psychiatric Association; Chimerix; Optimer; Cubist; Gilead FX We thank Elizabeth C. White and Brendan O'Connell for editorial assistance. The American Geriatrics Society (AGS) participated as supporting organization of the HIV & Aging Consensus Project. In keeping with the AGS Guidelines policies and the Council of Medical Specialty Societies Code for Interactions with Companies, AGS did not accept company support for guideline developmental activities. This effort is a partnership between the American Academy of HIV Medicine, the AGS, and the AIDS Community Research Initiative of America and was made possible through unrestricted grants from Janssen Pharmaceuticals Inc., The Campbell Foundation, and Strativa Pharmaceuticals, Ltd.; Abrass, Applebaum, Boyd, Justice, McCormick, Spach, Simone, and Valcour report no financial relationships with relevant commercial entities. Dr. Gebo serves on the scientific advisory board for Tibotec. She also has grants or has received grants from Tibotec. Her spouse/partner also has grants or has received grants from Johnson & Johnson. Dr. Goodkin is a paid consultant or served as a paid consultant within the past 12 months for Universidad Central del Caribe, Universidad Estadual, and the University of South Florida. He has grants or received grants in the past 12 months from Pfizer. He is a member or has been a member of the speaker's bureau within the past 12 months for Merck and the American Psychiatric Association and has other financial relationships or had in the past 12 months with the American Psychiatric Publishing, Inc. and the American Society for Microbiology. Dr. High is a paid consultant or served as a paid consultant within the past 12 months for Optimer Pharmaceuticals, Inc. and Glaxo SmithKline. He has grants or received grants in the past 12 months from Chimerix, Optimer, Pfizer, Merck, and Cubist. Dr. Newman served as a paid consultant within the past 12 months for the 23andMe Company. Dr. McNicholl is a member or has been a member of the speaker's bureau within the past 12 months for Bristol Myers Squibb, Tibotec and ViiV Healthcare. His spouse/partner works for Genentech. Dr. Malcolm has grants or has received grants from Gilead. He is a member or has been a member of the speaker's bureau within the past 12 months for Gilead. All participants, including the author, were blinded to the sources of support for the Project. All participants received modest honoraria to cover expenses. NR 2 TC 24 Z9 24 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2012 VL 60 IS 5 BP 974 EP 979 DI 10.1111/j.1532-5415.2012.03948.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 942HE UT WOS:000304033900024 ER EF